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【结 构 式】

【分子编号】12912

【品名】1-(Bromomethyl)benzene; Alpha-bromotoluene

【CA登记号】100-39-0

【 分 子 式 】C7H7Br

【 分 子 量 】171.03658

【元素组成】C 49.16% H 4.13% Br 46.72%
与该中间体有关的原料药合成路线共 73 条
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合成路线1

该中间体在本合成路线中的序号：(A)

The dipeptide intermediate (XI) has been obtained as follows: The coupling of the two synthons (I) and (II) by means of K2CO3 and 18-C-6 in DMSO gives the diphenyl ether (III), which is reduced at its nitro group with H2 over Pd/C yielding the amine (IV). The treatment of (IV) with tert-butyl nitrite, HBF4 and Cu2O affords the phenol (V), which is methylated with MeI and K2CO3 to provide the corresponding methyl ether (VI). The protection of the primary alcohol of (VI) with benzyl bromide (A) and K2CO3 gives the benzyl ether (VII), which is deprotected at the Mem and trifluoroacetamido groups yielding the aminoethanol derivative (VIII). The condensation of (VIII) with the protected phenylalanine derivative (IX) by means of EDC and HOBT affords the corresponding amide (X), which is finally oxidized with Dess Martin periodinane (DMP) and NaClO2 to afford the desired dipeptide intermediate (XI).

参考文献 中间体
合成目标
【1】 Boger, D.L.; et al.; First and second generation total synthesis of the teicoplanin aglycon. J Am Chem Soc 2001, 123, 9, 1862.
【2】 Boger, D.L.; et al.; Total synthesis of the teicoplanin aglycon. J Am Chem Soc 2000, 122, 30, 7416.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 40551 2,2,2-trifluoro-N-[(1S)-1-(3-hydroxy-5-methoxyphenyl)-2-[(2-methoxyethoxy)methoxy]ethyl]acetamide C15H20F3NO6 详情 详情
(II) 40552 tert-butyl (1R)-1-(3-fluoro-4-nitrophenyl)-2-hydroxyethylcarbamate C13H17FN2O5 详情 详情
(III) 40553 tert-butyl (1R)-2-hydroxy-1-[3-(3-methoxy-5-[(1S)-2-[(2-methoxyethoxy)methoxy]-1-[(2,2,2-trifluoroacetyl)amino]ethyl]phenoxy)-4-nitrophenyl]ethylcarbamate C28H36F3N3O11 详情 详情
(IV) 40554 tert-butyl (1R)-1-[4-amino-3-(3-methoxy-5-[(1S)-2-[(2-methoxyethoxy)methoxy]-1-[(2,2,2-trifluoroacetyl)amino]ethyl]phenoxy)phenyl]-2-hydroxyethylcarbamate C28H38F3N3O9 详情 详情
(V) 40555 tert-butyl (1R)-2-hydroxy-1-[4-hydroxy-3-(3-methoxy-5-[(1S)-2-[(2-methoxyethoxy)methoxy]-1-[(2,2,2-trifluoroacetyl)amino]ethyl]phenoxy)phenyl]ethylcarbamate C28H37F3N2O10 详情 详情
(VI) 40556 tert-butyl (1R)-2-hydroxy-1-[4-methoxy-3-(3-methoxy-5-[(1S)-2-[(2-methoxyethoxy)methoxy]-1-[(2,2,2-trifluoroacetyl)amino]ethyl]phenoxy)phenyl]ethylcarbamate C29H39F3N2O10 详情 详情
(VII) 40557 tert-butyl (1R)-2-(benzyloxy)-1-[4-methoxy-3-(3-methoxy-5-[(1S)-2-[(2-methoxyethoxy)methoxy]-1-[(2,2,2-trifluoroacetyl)amino]ethyl]phenoxy)phenyl]ethylcarbamate C36H45F3N2O10 详情 详情
(VIII) 40558 tert-butyl (1R)-1-(3-[3-[(1S)-1-amino-2-hydroxyethyl]-5-methoxyphenoxy]-4-methoxyphenyl)-2-(benzyloxy)ethylcarbamate C30H38N2O7 详情 详情
(IX) 40559 (2R)-3-(4-fluoro-3-nitrophenyl)-2-(propionylamino)propionic acid C12H13FN2O5 详情 详情
(X) 40560 tert-butyl (1R)-2-(benzyloxy)-1-[3-[3-((1S)-1-[[(2R)-3-(4-fluoro-3-nitrophenyl)-2-(propionylamino)propanoyl]amino]-2-hydroxyethyl)-5-methoxyphenoxy]-4-methoxyphenyl]ethylcarbamate C42H49FN4O11 详情 详情
(XI) 40561 (2S)-2-[3-(5-[(1R)-2-(benzyloxy)-1-[(tert-butoxycarbonyl)amino]ethyl]-2-methoxyphenoxy)-5-methoxyphenyl]-2-[[(2R)-3-(4-fluoro-3-nitrophenyl)-2-(propionylamino)propanoyl]amino]ethanoic acid C42H47FN4O12 详情 详情

合成路线2

该中间体在本合成路线中的序号：(F)

The lactyl dipeptide (X) is obtained as follows: The condensation of tert-butoxycarbonylalanine (XV) with glutamic acid (XVI) gives tert-butoxycarbonylalanylglutamic acid (XVII), which is esterified partially with benzyl bromide (F) yielding the mono ester (XVIII). Elimination of the tert-butoxycarbonyl group of (XVIII) with trifluoroacetic acid affords alanylglutamic acid monobenzyl ester (XIX), which is finally condensed with 2-acetoxypropionyl chloride (XX) to afford (X).

参考文献 中间体
合成目标
【1】 Hemmi, K.; Nakaguchi, O.; Hashimoto, M.; Taleno, H.; Kitaura, Y.; Okada, S.; An efficient method for selective amino acid protection of meso-2,2'-diaminocarboxylic acid: An improved synthesis of FK-156. Tetrahedron Lett 1982, 23, 6, 693-696.
【2】 Imanaka, H.; Nakahaa, K.; Gotoh, T.; Aoki, H.; Iwami, M.; Studies on a new immunoactive peptide, FK-156. I. Taxonomy of the producing strains. J Antibiot 1982, 35, 10, 1280-85.
【3】 Gotoh, T.; Imoraka, H.; Nakahara, K.; Tanaka, H.; Uchida, I.; Kawai, Y.; Studies on a new immunoactive peptide, FK-156. III. Structure elucidation. J Antibiot 1982, 35, 10, 1293-99.
【4】 Okada, S.; Hemmi, K.; Takano, H.; Hashimoto, M.; Nakaguchi, O.; Kitaura, Y.; Aratani, M.; Miyazaki, Y.; Studies of a new immunoactive peptide, FK-156. IV. Synthesis od FK-156 and its geometric isomer. J Antibiot 1982, 35, 10, 1300-11.
【5】 Okahara, M.; Nakahara, K.; Gotoh, T.; Hashimoto, M..; Kino, T.; Aoki, H.; Imanaka, H.; Kohsaka, M.; Nishiura, T.; Kuroda, Y.; Studies on a new immunoactive peptide, FK-156. II. Fermentation, extraction and chemical and biological charaterization. J Antibiot 1982, 35, 10, 1286-92.
【6】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K.; Aratani, M.; Takeno, H.; Okada, S.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New peptides, processes for their preparation and pharmaceutical compsns. containing them. EP 0027260 .
【7】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K. (Fujisawa Pharmaceutical Co., Ltd.); New lactyl tetrapeptide, processes for preparation thereof and pharmaceutical compsns. containing it. EP 0011283 .
【8】 Arya, V.P.; Blancafort, P.; Castaner, J.; Serradell, M.N.; FK-156. Drugs Fut 1983, 8, 8, 667.
【9】 Hemmi, K.; Takeno, H.; Okada, S.; Nakaguchi, O.; Kitaura, Y.; Hashimoto, M.; Total synthesis of FK-156 isolated from a Streptomyces as an immunostimulating peptide: Application of a novel copper chelate amino protection. J Am Chem Soc 1981, 103, 7026.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(F) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(X) 36102 (4R)-4-[((2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoyl)amino]-5-(benzyloxy)-5-oxopentanoic acid C20H26N2O8 详情 详情
(XV) 15859 Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid 7764-95-6 C8H15NO4 详情 详情
(XVI) 12005 L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid 56-86-0 C5H9NO4 详情 详情
(XVII) 36118 (2R)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)pentanedioic acid C13H22N2O7 详情 详情
(XVIII) 36119 (4R)-5-(benzyloxy)-4-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-5-oxopentanoic acid C20H28N2O7 详情 详情
(XIX) 36120 (4R)-4-[[(2S)-2-aminopropanoyl]amino]-5-(benzyloxy)-5-oxopentanoic acid C15H20N2O5 详情 详情
(XX) 36121 2-chloro-1-methyl-2-oxoethyl acetate 36394-75-9 C5H7ClO3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(X)

Two different routes have been described for the preparation of Et-18-OCH3: 1) The methylation of 1,3-benzylideneglycerol (I) with methyl iodide and KOH gives 1,3-benzytidene-2-O-methylglycerol (II), which is hydrolyzed with HCl to 2-O-methylglycerol (III). The condensation of (III) with octadecyl bromide (IV) and KOH in DMSO/THF yields 1-O-octadecyl-2-O-methyl-(rac)-glycerol (V), which by reaction with phosphorodichloric acid 2-bromoethyl ester (VI) and pyridine is converted to 3-octadecyloxy-2-methoxypropyl bromoethyl phosphate (VII). Finally, this compound is converted to Et-18-OCH3 with trimethylamine (VIII) in toluene and treated with silver carbonate to remove traces of bromide. 2) The reaction of 1,2-isopropylidene-sn-glycerol (IX) with benzyl bromide (X) and NaNH2 in benzene gives 1,2-isopropylidene-3-O-benzyl-sn-glycerol (XI), which is hydrolyzed with acetic acid to 3-O-benzyl-sn-glycerol (XII). The etherification of (XII) with (IV) as before or with NaNH2 gives 1-O-octadecyl-3-O-benzyl-sn-glycerol (XIII), which is methylated with methyl iodide and NaNH2 in dioxane to give 1-O-octadecyl-2-O-methyl-3-O-benzyl-sn-glycerol (XIV). Finally, this compound is debenzytaled by hydrogenolysis with H2 over Pd/C in petroleum ether to form (V), an intermediate previously described above.

参考文献 中间体
合成目标
【1】 Tsutsumi, H.; Kamata, T.; Nakajima, K.; Katagi, M.; Tsuchihashi, H.; Nishioka, H.; Nishikawa, M.; Miki, A.; Tatsuno, M.; Chem Phys Lipids 1982, 30, 9, 389-392.
【2】 Fast, L.D.; et al.; Chem Pharm Bull 1982, 30, 9, 3260-3270.
【3】 Castaner, R.M.; Castaner, J.; Serradell, M.N.; ET-18-OCH3. Drugs Fut 1987, 12, 4, 341.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 28795 2-phenyl-1,3-dioxan-5-ol 1708-40-3 C10H12O3 详情 详情
(II) 28796 5-methoxy-2-phenyl-1,3-dioxane C11H14O3 详情 详情
(III) 13579 2-Methoxy-1,3-propanediol C4H10O3 详情 详情
(IV) 28797 1-bromooctadecane 112-89-0 C18H37Br 详情 详情
(V) 28798 2-methoxy-3-(octadecyloxy)-1-propanol C22H46O3 详情 详情
(VI) 13033 Dichlorophosphoric acid 2-bromoethyl ester C2H4BrCl2O2P 详情 详情
(VII) 28799 2-bromoethyl 2-methoxy-3-(octadecyloxy)propyl hydrogen phosphate C24H50BrO6P 详情 详情
(IX) 16476 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane; (2,2-dimethyl-1,3-dioxolan-4-yl)methanol; 2,3-o-Isopropylideneglycerol 100-79-8 C6H12O3 详情 详情
(X) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XI) 28800 benzyl 2,2-dimethyl-1,3-dioxolan-4-yl ether C12H16O3 详情 详情
(XII) 28801 1-(benzyloxy)-1,2-ethanediol C9H12O3 详情 详情
(XIII) 28802 1-(benzyloxy)-2-(octadecyloxy)-1-ethanol C27H48O3 详情 详情
(XIV) 28803 1-[[1-methoxy-2-(octadecyloxy)ethoxy]methyl]benzene C28H50O3 详情 详情

合成路线4

该中间体在本合成路线中的序号：

The condensation of (3-methoxyphenyl)acetonitrile (VIII) with 3-bromopropyltetrahydropyranyl ether (IX) by means of lithium diisopropylamide in THF gives 2-(3-methoxyphenyl)-5-tetrahydropyranyloxypentanonitrile (X), which is oxidized with chromic anhydride-H2SO4 yielding 4-cyano-3-(3-methoxyphenyl)butyric acid (XI). The hydrolysis of (XI) with KOH in ethanol-water affords 2-(3-methoxyphenyl)glutaric acid (XII), which is anhydrized with refluxing acetic anhydride giving 2-(3-methoxyphenyl)glutaric anhydride (XIII). The reaction of (XIII) with propylamine (C) in refluxing benzene yields 2-(3-methoxyphenyl)-N-propylglutarimide (XIV), which is demethylated with BBr3 in methylene chloride to 2-(3-hydroxyphenyl)-N-propylglutarimide (XV). The benzylation of (XV) with benzyl bromide and K2CO3 in DMF affords 2-(3-benzyloxyphenyl)-N-propylglutarimide (XVI), which is reduced with LiAlH4 in THF giving 3-(3-benzyloxyphenyl)-N-propylpiperidine (XVII). Finally, this compound is debenzylated by hydrogenolysis with H2 over Pd/C in AcOH.

参考文献 中间体
合成目标
【1】 Brands, F.T.L.; Loozen, H.J.J.; An efficient synthesis of 3-arylpiperidines. J R Neth Chem Soc 1981, 100, 9, 333-336.
【2】 Serradell, M.N.; Nohria, V.; Castaner, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(VIII) 24061 3-methoxyphenylacetonitrile; 2-(3-methoxyphenyl)acetonitrile 19924-43-7 C9H9NO 详情 详情
(IX) 29460 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether C9H17BrO2 详情 详情
(X) 35989 2-(3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile C18H25NO3 详情 详情
(XI) 35990 4-cyano-4-(3-methoxyphenyl)butyric acid C12H13NO3 详情 详情
(XII) 35991 2-(3-methoxyphenyl)pentanedioic acid C12H14O5 详情 详情
(XIII) 35992 3-(3-methoxyphenyl)dihydro-2H-pyran-2,6(3H)-dione C12H12O4 详情 详情
(XIV) 35993 3-(3-methoxyphenyl)-1-propyl-2,6-piperidinedione C15H19NO3 详情 详情
(XV) 35994 3-(3-hydroxyphenyl)-1-propyl-2,6-piperidinedione C14H17NO3 详情 详情
(XVI) 35995 3-[3-(benzyloxy)phenyl]-1-propyl-2,6-piperidinedione C21H23NO3 详情 详情
(XVII) 35996 benzyl 3-(1-propyl-3-piperidinyl)phenyl ether; 3-[3-(benzyloxy)phenyl]-1-propylpiperidine C21H27NO 详情 详情
(C) 23923 1-propanamine 107-10-8 C3H9N 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

The optical resolution of the racemic 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (I) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (S)-isomer (II), which is N-demethylated by means of CN-Br to yield 7,8-dimethoxy-1(S)-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with MsOH and methionine. An earlier alternative route to demethylation of (III) involves its conversion to the N-benzyl derivative (V) with benzyl bromide (IV), followed by demethylation with BBr3, yielding (VI), and final debenzylation with H2 over Pd/C.

参考文献 中间体
合成目标
【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645.
【2】 Bass, L.S.; Dandridge, P.A.; Setler, P.E.; Sarau, H.M.; Garvey, E.; Clardy, J.; Hanhn, R.A.; Kaiser, C.; Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine. J Med Chem 1982, 25, 6, 697-703.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 44063 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C19H23NO2 详情 详情
(II) 44064 (1S)-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether; (1S)-7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine C19H23NO2 详情 详情
(III) 44065 (1S)-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (1S)-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C18H21NO2 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 44066 (1S)-3-benzyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether; (1S)-3-benzyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine C25H27NO2 详情 详情
(VI) 44067 (1S)-3-benzyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol C23H23NO2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(IV)

The optical resolution of the racemic 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (I) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (R)-isomer (II), which is N-demethylated by means of CN-Br to yield 7,8-dimethoxy-1(R)-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with Ms-OH and methionine. An earlier alternative route to demethylation of (III) involves its conversion to the N-benzyl derivative (V) with benzyl bromide (IV), followed by demethylation with BBr3, yielding (VI), and final debenzylation with H2 over Pd/C.

参考文献 中间体
合成目标
【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645.
【2】 Bass, L.S.; Dandridge, P.A.; Setler, P.E.; Sarau, H.M.; Garvey, E.; Clardy, J.; Hanhn, R.A.; Kaiser, C.; Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine. J Med Chem 1982, 25, 6, 697-703.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 44063 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C19H23NO2 详情 详情
(II) 44068 (1R)-7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (1R)-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C19H23NO2 详情 详情
(III) 44069 (1R)-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (1R)-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C18H21NO2 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 44070 (1R)-3-benzyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (1R)-3-benzyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C25H27NO2 详情 详情
(VI) 44071 (1R)-3-benzyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol C23H23NO2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(A)

2) The epoxidation of nerol (XII) with tert-butyl peroxide and titanium isopropoxide gives the epoxide (XIII), which is benzylated with benzyl bromide to the protected epoxide (XIV). A stereo- and regioselective cleavage of the epoxide (XIV) with methanol yields the methoxy hydroxy derivative (XV), which is ozonolyzed in methanol dichloromethane to the aldehyde (XVI). The Wittig condensation of (XVI) with triphenylmethylphosphonium bromide and potassium tert-butoxide affords the methylene alcohol (XVII), which is protected with tert-butyldimethylsilyl chloride as before to give silyl derivative (XVIII). The hydrogenation of (XVIII) with H2 over Pd in ethyl acetate yields the saturated alcohol (XIX), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XX).The reaction of (XX) with tetrabromomethane and triphenylphosphine affords the dibromovinyl compound (XXI), which by reaction with butyllithium in THF is converted into the acetylene (XXII). Finally, this compound is treated with tributylstannyl hydride and azobisisobutyronitrile to give the stannyl derivative (II).

参考文献 中间体
合成目标
【1】 Kolb, M.; Van Hijfte, L.; Ireland, R.E.; A highly convergent synthesis of mexiprostil: 16(R) 16-methoxy 16-methyl PGE1 methyl ester. Tetrahedron Lett 1988, 29, 51, 6769.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(A) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(II) 21528 (1R,2R,3E)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(tributylstannyl)-3-butenyl methyl ether C28H60O2SiSn 详情 详情
(XII) 21538 (2Z)-3,7-dimethyl-2,6-octadien-1-ol 106-25-2 C10H18O 详情 详情
(XIII) 21539 [(2R,3S)-3-methyl-3-(4-methyl-3-pentenyl)oxiranyl]methanol C10H18O2 详情 详情
(XIV) 21540 (2S,3R)-3-[(benzyloxy)methyl]-2-methyl-2-(4-methyl-3-pentenyl)oxirane C17H24O2 详情 详情
(XV) 21541 (2R,3R)-1-(benzyloxy)-3-methoxy-3,7-dimethyl-6-octen-2-ol C18H28O3 详情 详情
(XVI) 21542 (4R,5R)-6-(benzyloxy)-5-hydroxy-4-methoxy-4-methylhexanal C15H22O4 详情 详情
(XVII) 21543 (2R,3R)-1-(benzyloxy)-3-methoxy-3-methyl-6-hepten-2-ol C16H24O3 详情 详情
(XVIII) 21544 ([(1R,2R)-1-[(benzyloxy)methyl]-2-methoxy-2-methyl-5-hexenyl]oxy)(tert-butyl)dimethylsilane C22H38O3Si 详情 详情
(XIX) 21545 (2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methoxy-3-methyl-1-heptanol C15H34O3Si 详情 详情
(XX) 21546 (3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyloctanal C16H34O3Si 详情 详情
(XXI) 21547 tert-butyl(dimethyl)silyl (1R)-3,3-dibromo-1-[(1R)-1-methoxy-1-methylpentyl]-2-propenyl ether C16H32Br2O2Si 详情 详情
(XXII) 21548 (1R,2R)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-3-butynyl methyl ether C16H32O2Si 详情 详情

合成路线8

该中间体在本合成路线中的序号：(A)

The reaction of 3-hydroxypyridine (I) first with formaldehyde and NaOH in water, and then with benzyl bromide (A) in ethanol gives 3-benzyloxy-2,6-bis(hydroxymethyl)pyridine hydrochloride (II), which is oxidized with MnO2 in refluxing benzene yielding 2-hydroxmethyl-3-benzyloxy-6-pyridincarboxaldehyde (III). The condensation of (III) with tertbutylisonitrile (B) and acetic acid in refluxing CHCl3 affords N-tertbutyl-2-(5-benzyloxy-6-hydroxymethyl-2-pyridil)-2-acetoxyacetamide (IV), which is hydrolyzed with 12N HCl yielding N-tertbutyl-2-(5-benzyloxy-6-hydroxymethyl-2-pyridil)-2-hydroxyacetamide (V). The reduction of the amide group of (V) with diborane in THF gives 2-hydroxymethyl-3-benzyloxy-6-(1-hydroxy-2-tertbutylaminoethyl)pyridine (VI), which is finally debenzylated with H2 over Pd/C in methanol.

参考文献 中间体
合成目标
【1】 Barth, W.; 2-Hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines. DE 2204195; FR 2125309; GB 1367668; GB 1367669; US 3700681; US 3763173 .
【2】 Castaner, J.; Thorpe, P.; Pirbuterol. Drugs Fut 1977, 2, 1, 60.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(B) 33871 pivalonitrile 630-18-2 C5H9N 详情 详情
(I) 12911 3-Hydroxypyridine; 3-Pyridinol 109-00-2 C5H5NO 详情 详情
(II) 33869 [3-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]methanol C14H15NO3 详情 详情
(III) 33870 5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinecarbaldehyde C14H13NO3 详情 详情
(IV) 33872 1-[5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]-2-(tert-butylamino)-2-oxoethyl acetate C21H26N2O5 详情 详情
(V) 33873 2-[5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]-N-(tert-butyl)-2-hydroxyacetamide C19H24N2O4 详情 详情
(VI) 33874 1-[5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]-2-(tert-butylamino)-1-ethanol C19H26N2O3 详情 详情

合成路线9

该中间体在本合成路线中的序号：

RU-16117 is synthesized from D9(11)-estradiol (I). After protecting the hydroxyl groups by the formation of a benzyl ether (II), the double bond is hydrated by hydroboration, followed by oxidation with hydrogen peroxide in alkali. The alcohol thus formed (III) is treated with sodium hydride and then methyliodide (IV). After deprotection of the 3 and 17 hydroxyl groups (V), the C-17 hydroxyl is oxidized to a ketone by chromic oxidation (VI) and the 17-alpha-ethynyl group is introduced directly with potassium acetylide.

参考文献 中间体
合成目标
【1】 Bouton, M.M.; Raynaud, J.P.; Azadian-Boulanger, G.; Bucourt, .; Pierdet, A.; Torelli, V.; Nédélec, L.; Dérivés 11-alpha-méthoxylés de l'estradiol: Activité anti-estrogène du 11-alpha-méthoxy éthynyl estradiol: RU-16117. Eur J Med Chem 1978, 13, 4, 313-319.
【2】 Précigous, G.; Analyse Radiocristallographique de Molécules Oestrogènes et Androgènes et Etude de leur Affinité et de leur Spécificité. Ph. D. Thesis, Univ. Bordeaux I 1978.
【3】 Azadian-Boulanger, G.; Raynaud, J.P.; RU-16117. Drugs Fut 1985, 10, 5, 926.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
23634 acetylene 74-86-2 C2H2 详情 详情
(I) 29791 (8S,13S,14S)-13-methyl-7,8,12,13,14,15,16,17-octahydro-6H-cyclopenta[a]phenanthrene-3,17-diol C18H22O2 详情 详情
(II) 29792 (8S,13S,14S)-3,17-bis(benzyloxy)-13-methyl-7,8,12,13,14,15,16,17-octahydro-6H-cyclopenta[a]phenanthrene; benzyl (8S,13S,14S)-17-(benzyloxy)-13-methyl-7,8,12,13,14,15,16,17-octahydro-6H-cyclopenta[a]phenanthren-3-yl ether C32H34O2 详情 详情
(III) 29793 (8S,9S,11R,13S,14S)-3,17-bis(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-ol C32H36O3 详情 详情
(IV) 29794 (8S,9S,11R,13S,14S)-3,17-bis(benzyloxy)-11-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene; benzyl (8S,9S,11R,13S,14S)-17-(benzyloxy)-11-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl ether C33H38O3 详情 详情
(V) 29795 (8S,9S,11R,13S,14S)-11-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol C19H26O3 详情 详情
(VI) 29796 (8S,9S,11R,13S,14S)-3-hydroxy-11-methoxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one C19H24O3 详情 详情

合成路线10

该中间体在本合成路线中的序号：

The benzoylation of 2'-deoxy-5-(trifluoromethyl)uridine (VI) with benzoyl chloride by means of triethylamine in dimethylacetamide gives 3-benzoyl-2'-deoxy-5-(trifluoromethyl)uridine (VII), which is benzylated with benzyl bromide and silver oxide in refluxing 2-butanone to afford 3-benzoyl-3'-O-benzyl-2'-deoxy-5-(trifluoromethyl)uridine (VIII). Finally, this compound is debenzoylated with 30% aqueous ammonia at room temperature. The deprotection of 2'-deoxy-3'-O-(thiobenzoyl)-5-(trifluoromethyl)-5'-O-trityluridine (XIII) with 0.1N HCl gives 2'-deoxy-3'-O-(thiobenzoyl)-5-(trifluoromethyl)uridine (XIV), which is submitted to desulfurization with Raney-Ni in THF.

参考文献 中间体
合成目标
【1】 Noguchi, K.; Yasumoto, M.; Kobayashi, K. (Taiho Pharmaceutical Co., Ltd.); Method for the preparation of 5-trifluromethyl-2'-deoxy-beta-uridines. JP 1988145296 .
【2】 Yamashita, J.-I.; Matsumoto, H.; Kobayashi, K.; Noguchi, K.; Yasumoto, M.; Ueda, T.; Studies on antitumor agents. IX. Synthesis of 3'-O-benzyl-2'-deoxy-5-trifluromethyluridine. Chem Pharm Bull 1989, 37, 9, 2287-92.
【3】 Hoshi, A.; Prous, J.; Castaner, J.; FTC-092. Drugs Fut 1990, 15, 8, 790.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(VI) 31162 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione 70-00-8 C10H11F3N2O5 详情 详情
(VII) 31163 3-benzoyl-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione C17H15F3N2O6 详情 详情
(VIII) 31164 3-benzoyl-1-[(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione C24H21F3N2O6 详情 详情
(XIII) 31165 O-[(2R,3S,5R)-5-[2,4-dioxo-5-(trifluoromethyl)-3,4-dihydro-1(2H)-pyrimidinyl]-2-[(trityloxy)methyl]tetrahydro-3-furanyl] benzenecarbothioate C36H29F3N2O5S 详情 详情
(XIV) 31166 O-[(2R,3S,5R)-5-[2,4-dioxo-5-(trifluoromethyl)-3,4-dihydro-1(2H)-pyrimidinyl]-2-(hydroxymethyl)tetrahydro-3-furanyl] benzenecarbothioate C17H15F3N2O5S 详情 详情

合成路线11

该中间体在本合成路线中的序号：

The protection of the NH group of trans-4-hydroxy-L-proline (XII) with tert-butoxycarbonyl anhydride and NaOH in tert-butanol/water gives the N-protected proline (XIII), which is esterified with benzyl alcohol and triethylamine to the benzyl ester (XIV). The tosylation of (XIV) with tosyl chloride and pyridine affords the tosylate (XV), which is debenzylated with H2 over Pd/C yielding the tosylated proline (XVI). The arylation of (XVI) with phenyllithium (XVII) and CuBr in ether/THF affords 1-(tert-butoxycarbonyl)-4(S)-phenyl)-L-proline (XVIII), which is deprotected with TFA in chloroform giving 4(S)-phenyl-L-proline (XIX). Finally, this compound is reduced with H2 over PtO2 in ethanol providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).

参考文献 中间体
合成目标
【1】 Moniot, J.L.; Thottathil, J.K.; Littium diphenylcuprate reactions with 4-tosyloxy-L-prolines; An interesting stereochemical outcome. A synthesis of trans-4-phenyl-L-proline. Tetrahedron Lett 1986, 27, 2, 151.
【2】 Floyd, D.; Thottathil, J.K.; Brandt, S.; Moniot, J.L. (Bristol-Myers Squibb Co.); Method for making substd. prolines. DE 3434121; US 4501901 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XI) 38567 (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid C11H19NO2 详情 详情
(XII) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(XIII) 16094 (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid 16094 C10H17NO5 详情 详情
(XIV) 38568 2-benzyl 1-(tert-butyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate C17H23NO5 详情 详情
(XV) 38569 2-benzyl 1-(tert-butyl) (2S,4R)-4-[[(4-methylphenyl)sulfonyl]oxy]-1,2-pyrrolidinedicarboxylate C24H29NO7S 详情 详情
(XVI) 38570 (2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-methylphenyl)sulfonyl]oxy]-2-pyrrolidinecarboxylic acid C17H23NO7S 详情 详情
(XVII) 24014 Phenyllithium 591-51-5 C6H5Li 详情 详情
(XVIII) 38571 (2S,4S)-1-(tert-butoxycarbonyl)-4-phenyl-2-pyrrolidinecarboxylic acid C16H21NO4 详情 详情
(XIX) 38572 (2S,4S)-4-phenyl-2-pyrrolidinecarboxylic acid C11H13NO2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(A)

The reaction of 4-benzoyloxycyclohexanone (I) with pyrrolidine (II) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane yielding the mixture of hexahydroquinolones (V) and (VI). Benzylation of this mixture with benzylbromide (A) and NaH in THF affords the mixture of N-benzylquinolones (VII) and (VIII), which is reduced with LiAlH4 to the mixture of N-benzylhexahydroquinolines (IX) and (X). The reduction of this mixture with sodium cyanoborohydride in THF affords trans-1-benzyl-6-hydroxydecahydro quinoline (XI), which by reaction with BN in CH2Cl2 is converted to trans-1-cyano-6-hydroxydecahydro quinoline (XII). Oxidation of (XII) with CrO3/pyridine in CH2Cl2 gives the corresponding quinolone (XIII), which by reaction with dimethylformamide dimethyl acetal (XIV) in refluxing benzene is converted to 1-cyano-6-oxo-7-(dimethylaminomethylene)decahydroquinoline (XV). The cyclization of (XV) with hydrazine in refluxing methanol affords 5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVI), which by a reductive cleavage with Zn and acetic acid gives 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVII). Finally, this compound is alkylated with propionaldehyde (B) and sodium cyanoborohydride in methanol.

参考文献 中间体
合成目标
【1】 Bach, N.; Kornfeld, E.C. (Eli Lilly and Company); Prolactin inhibiting octahydropyrazolo[3,4-g]quinolines. DD 148517; EP 0013787; ES 482087; FR 2446820; FR 2446821; FR 2446822; GB 2040915; GB 2092579; US 4198415 .
【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Mannhold, R.; Quinpirole Hydrochloride. Drugs Fut 1987, 12, 6, 558.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(B) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(I) 16967 N-(tert-butyl)-5-propyl-2-thiophenecarboxamide C12H19NOS 详情 详情
(II) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(III) 28829 4-(1-pyrrolidinyl)-3-cyclohexen-1-yl benzoate C17H21NO2 详情 详情
(IV) 10851 Acrylamide 79-06-1 C3H5NO 详情 详情
(V) 28830 2-oxo-1,2,3,4,5,6,7,8-octahydro-6-quinolinyl benzoate C16H17NO3 详情 详情
(VI) 28831 2-oxo-1,2,3,4,4a,5,6,7-octahydro-6-quinolinyl benzoate C16H17NO3 详情 详情
(VII) 28832 1-benzyl-2-oxo-1,2,3,4,5,6,7,8-octahydro-6-quinolinyl benzoate C23H23NO3 详情 详情
(VIII) 28833 1-benzyl-2-oxo-1,2,3,4,4a,5,6,7-octahydro-6-quinolinyl benzoate C23H23NO3 详情 详情
(IX) 28834 1-benzyl-6-hydroxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone C16H19NO2 详情 详情
(X) 28835 1-benzyl-6-hydroxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone C16H19NO2 详情 详情
(XI) 28836 (4aR,8aR)-1-benzyldecahydro-6-quinolinol C16H23NO 详情 详情
(XII) 28837 (4aR,8aR)-1-cyanodecahydro-6-quinolinol C10H16N2O 详情 详情
(XIII) 28838 (4aR,8aR)-1-cyanooctahydro-6(2H)-quinolinone C10H14N2O 详情 详情
(XIV) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(XV) 28839 (4aR,8aR)-1-cyano-7-[(Z)-(dimethylamino)methylidene]octahydro-6-quinolinone C13H19N3O 详情 详情
(XVI) 28840 (4aR,8aR)-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline C11H14N4 详情 详情
(XVII) 28841 (4aR,8aR)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline C10H15N3 详情 详情

合成路线13

该中间体在本合成路线中的序号：

1,4-Dichloro-5-hydroxy-9,10-anthracenedione (I) is alkylated with powdered potassium carbonate and benzyl bromide to give the ether (II). The ether is condensed with threee equivalents of 2-[(2-hydrazinoethyl)amino]ethanol in anhydrous dimethylsulfoxide to give regioisomers (III) and (IV), which are separated by flash silica gel chromatography. The isomer (III) is reacted with an excess of 2-[(2-aminoethyl)amino]ethanol in refluxing pyridine to give the intermediate (V). The intermediate is converted to the 10-hydroxy isomer by hydrogenolysis of the benzyl protecting group with Pearlman's catalyst in glacial acetic acid, followed by dihydrochloride salt formation.

参考文献 中间体
合成目标
【1】 Showalter, H.D.H.; Werbel, L.M.; Johnson, J.L.; Elslager, E.F. (Warner-Lambert Co.); Substituted anthra[1,9-cd]pyrazol-6(2H)-ones. EP 0103381 .
【2】 Eastland, G. Jr.; BIANTRAZOLE. Drugs Fut 1989, 14, 8, 742.
【3】 Showalter, H.D.H.; Johnson, J.L.; Werbel, L.M.; Leopold, W.R.; Jackson, R.C.; Elslager, E.F.; 5-[(Aminoalkyl)amino]-substituted anthra[1, 9-cd]pyrazol-6(2H)-ones as novel anticancer agents. Synthesis and biological evaluation. J Med Chem 1984, 27, 3, 253-5.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
27775 2-[(2-hydrazinoethyl)amino]-1-ethanol C4H13N3O 详情 详情
32676 2-[(2-aminoethyl)amino]-1-ethanol 111-41-1 C4H12N2O 详情 详情
(I) 21210 1,4-dichloro-5-hydroxyanthra-9,10-quinone C14H6Cl2O3 详情 详情
(II) 21211 5-(benzyloxy)-1,4-dichloroanthra-9,10-quinone C21H12Cl2O3 详情 详情
(III) 21212 7-(benzyloxy)-5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]dibenzo[cd,g]indazol-6(2H)-one C25H22ClN3O3 详情 详情
(IV) 21213 10-(benzyloxy)-5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]dibenzo[cd,g]indazol-6(2H)-one C25H22ClN3O3 详情 详情
(V) 21214 7-(benzyloxy)-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-([2-[(2-hydroxyethyl)amino]ethyl]amino)dibenzo[cd,g]indazol-6(2H)-one C29H33N5O4 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

AHR-53338 is synthesized in an overall yield of 62% from ethyl isonipecotate (I): Ethyl isonipecotate (I) is protected with benzyl bromide (II) to give (III), which is then treated with 2.5 moles of 4-fluorophenylmagnesium bromide to give the tertiary alcohol (IV). The benzyl group is removed by catalytic hydrogenolysis to give the secondary piperidine (V). The reaction of 1-bromo-3-chloropropane (VI) with acetovanillone (VII) gives 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (VIII) in excellent yield. A mixture of (V) and (VIII) in 1-butanol and triethylamine heated at reflux yields AHR-53338 isolated as the mandelic acid salt.

参考文献 中间体
合成目标
【1】 Yanni, J.M.; Walsh, D.A.; Franzyshen, S.K.; The synthesis and antiallergy activity of 1-[4-[3-. 193rd ACS Natl Meet 1987, Abst MEDI 85.
【2】 Yanni, J.M.; Walsh, D.A.; AHR-5333B. Drugs Fut 1988, 13, 7, 605.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 13643 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide 352-13-6 C6H4BrFMg 详情 详情
(B) 28161 2-hydroxy-2-phenylacetic acid 611-72-3 C8H8O3 详情 详情
(I) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 22600 ethyl 1-benzyl-4-piperidinecarboxylate; N-Benzyl-4-carbethoxy piperidine 24228-40-8 C15H21NO2 详情 详情
(IV) 22601 (1-benzyl-4-piperidinyl)[bis(4-fluorophenyl)]methanol C25H25F2NO 详情 详情
(V) 22602 bis(4-fluorophenyl)(4-piperidinyl)methanol 60284-98-2 C18H19F2NO 详情 详情
(VI) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VII) 22604 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone 498-02-2 C9H10O3 详情 详情
(VIII) 22605 4-(3-Chloropropoxy)-3-Methoxyacetophenone;3-(4-Acetyl-2-methoxyphenoxy)propyl chloride;1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone;1-[4-(3-chloropropoxy)-3-methoxyphenyl]-1-ethanone 58113-30-7 C12H15ClO3 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The synthesis of baogongteng A has been published: The alkylation of 3-hydroxypyridine (I) with benzylbromide (II) gives 1-benzyl-3-hydropyridinium bromide (III), which is condensed with acrylonitrile (IV) by means of triethylamine at reflux temperature, yielding the bicyclic nitrile (V). The reduction of (V) with LiAlH4 gives the bicyclic hydroxy nitrile (VII), also obtained by stepwise reduction of (V) with H2 over Pd/C to (VI) and posterior reduction to (VII) with NaBH4. The protection of (VII) with trimethylsilyl chloride and triethylamine affords the silyloxy derivative (VIII), which is treated with methylmagnesium iodide to yield the acetyl derivative (IX). Oxidation of (IX) with m-chloroperbenzoic acid (MCPBA) in CHCl3 affords the acetoxy compound (X), which is finally debenzylated by hydrogenation with H2 and Pd/C in ethanol to give the free base (XI). This is then treated with benzoic acid.

参考文献 中间体
合成目标
【1】 Zeng, L.M.; Jung, M.E.; Peng, T.S.; Zeng, H.Y.; Le, Y.; Su, J.Y.; Total synthesis of Bao Gong Teng-A, a natural antiglaucoma compound. J Org Chem 1992, 57, 13, 3528.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12911 3-Hydroxypyridine; 3-Pyridinol 109-00-2 C5H5NO 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 12913 1-Benzyl-3-hydroxypyridinium bromide C12H12BrNO 详情 详情
(IV) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(V) 12915 8-Benzyl-2-oxo-8-azabicyclo[3.2.1]oct-3-ene-6-carbonitrile C15H14N2O 详情 详情
(VI) 12916 8-Benzyl-2-oxo-8-azabicyclo[3.2.1]octane-6-carbonitrile C15H16N2O 详情 详情
(VII) 12917 8-Benzyl-2-hydroxy-8-azabicyclo[3.2.1]octane-6-carbonitrile C15H18N2O 详情 详情
(VIII) 12918 8-Benzyl-2-[(trimethylsilyl)oxy]-8-azabicyclo[3.2.1]octane-6-carbonitrile C18H26N2OSi 详情 详情
(IX) 12919 1-(8-Benzyl-2-hydroxy-8-azabicyclo[3.2.1]oct-6-yl)-1-ethanone C16H21NO2 详情 详情
(X) 12920 8-benzyl-2-hydroxy-8-azabicyclo[3.2.1]oct-6-yl acetate C16H21NO3 详情 详情
(XI) 12921 2-hydroxy-8-azabicyclo[3.2.1]oct-6-yl acetate C9H15NO3 详情 详情
(XII) 10202 Benzoic acid 65-85-0 C7H6O2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(F)

The reaction of D-glucopyranose (A) with allyl alcohol (B) by means of HCl gives glucoside (C), which is treated with acetaldehyde diethylacetal (D) and TsOH in dichloromethane to yield the 4,6-O-ethylideneglucoside (E). Reaction of (E) with benzyl bromide (F), by means of NaH in DMF, affords the 2,3-di-O-benzyl-4,6-O-ethylideneglucoside (G), which is treated with potassium tert-butoxide and with HgO, HgCl2 to give the fully protected sugar (III).

参考文献 中间体
合成目标
【1】 Vemishetti, P.; Sleezer, P.D.; Dillon, J.L.; Discordia, R.P.; Hartung, K.B.; Silverberg, L.J.; Efficient synthesis of the anticancer drug etoposide 4'-phosphate: Use of benzylic ether-protecting groups on the carbohydrate segment. Org Process Res Dev 2000, 4, 1, 34.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 12234 2-Propen-1-ol; Allyl alcohol 107-18-6 C3H6O 详情 详情
(F) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(A) 23276 5-(hydroxymethyl)-1,2,3,4-cyclohexanetetrol C6H12O6 详情 详情
(E) 40484 (2R,4aR,7R,8R,8aS)-6-(allyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol C11H18O6 详情 详情
(G) 40485 (2R,4aR,7R,8R,8aS)-6-(allyloxy)-7,8-bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxine; (2R,4aR,7R,8R,8aS)-6-(allyloxy)-7-(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-8-yl benzyl ether C25H30O6 详情 详情
(D) 40486 1-ethoxyethyl ethyl ether; 1,1-diethoxyethane 105-57-7 C6H14O2 详情 详情
(III) 13055 (2R,4aR,6S,7R,8R,8aS)-7,8-Bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-ol C22H26O6 详情 详情
(C) 40483 (3R,4S,5S,6R)-2-(allyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol C9H16O6 详情 详情

合成路线17

该中间体在本合成路线中的序号：

An alternative procedure for the preparation of the intermediate urea (IX) has been reported. Alkylation of L-phenylalanine (XIV) with benzyl bromide provided the N,N-dibenzyl amine (XV), which was reduced to amino alcohol (XVI) using DIBAL in cold toluene. In an improved large-scale process, amino alcohol (XVI) was prepared by benzylation of L-phenylalaninol (XVII). Swern oxidation of the alcohol function of (XVI) afforded aldehyde (XVIII). Subsequent reaction of (XVIII) with chloromethyllithium at low temperature furnished the desired epoxide (XX) along with minor amounts of its diastereoisomer (XIX). Opening of this mixture with isobutyl amine (V) gave diamino alcohol (XXIa-b). After coupling of (XXIa-b) with tert-butyl isocyanate (VII) to produce the corresponding ureas (XXIIa-b) [the required isomer (XXIIb) was isolated by recrystallization]. Removal of the benzyl protecting groups of (XXIIb) then yielded the target intermediate (IX).

参考文献 中间体
合成目标
【1】 Talley, J.J.; Getman, D.P.; DeCrescenzo, G.A.; Lin, K.-O.; Vazquez, M.L.; Mueller, R.A.; Reed, K.L.; Heintz, R.M.; Clare, M.; Freskos, J.N.; Sun, E.T. (Pharmacia Corp.); Urea-containing hydroxyethylamine cpds. as retroviral protease inhibitors. JP 1995508041; WO 9323368 .
【2】 Liu, C.; et al.; Development of large-scale process for an HIV protease inhibitor. Org Process Res Dev 1997, 1, 1, 45.
【3】 Getman, D.P.; et al.; Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. J Med Chem 1993, 36, 2, 288.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XXIa) 37939 (2S,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol C28H36N2O 详情 详情
(XXIb) 37940 (2R,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol C28H36N2O 详情 详情
(XXIIa) 37941 N'-(tert-butyl)-N-[(2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutylurea C33H45N3O2 详情 详情
(XXIIb) 37942 N'-(tert-butyl)-N-[(2R,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutylurea C33H45N3O2 详情 详情
(V) 13306 2-Methyl-1-propanamine; Isobutylamine 78-81-9 C4H11N 详情 详情
(VII) 16976 tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane 1609-86-5 C5H9NO 详情 详情
(IX) 37931 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N'-(tert-butyl)-N-isobutylurea C19H33N3O2 详情 详情
(XIV) 13952 (S)-(-)-Phenylalanine; L-Phenylalanine 63-91-2 C9H11NO2 详情 详情
(XV) 37935 (2S)-2-(dibenzylamino)-3-phenylpropionic acid C23H23NO2 详情 详情
(XVI) 30457 (2S)-2-(dibenzylamino)-3-phenyl-1-propanol 111060-52-7 C23H25NO 详情 详情
(XVII) 28523 (2S)-2-amino-3-phenyl-1-propanol; L-phenylalanilol; (S)-2-amino-3-phenyl-1-propanol 5267-64-1 C9H13NO 详情 详情
(XVIII) 37936 (2S)-2-(dibenzylamino)-3-phenylpropanal C23H23NO 详情 详情
(XIX) 37937 N,N-dibenzyl-N-[(1S)-1-[(2R)oxiranyl]-2-phenylethyl]amine; (1S)-N,N-dibenzyl-1-[(2R)oxiranyl]-2-phenyl-1-ethanamine C24H25NO 详情 详情
(XX) 37938 N,N-dibenzyl-N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]amine; (1S)-N,N-dibenzyl-1-[(2S)oxiranyl]-2-phenyl-1-ethanamine C24H25NO 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XXV)

The condensation of 2(S)-benzylsuccinic acid (XVII) with cis-perhydroisoindole (V) by means of imidazole, SOCl2 and TEA in ethyl acetate gives the succinamic acid (XIII), which is esterified with benzyl bromide (XXV) and K2CO3 in ethyl acetate or with benzyl alcohol (XXVI) and DCC in the same solvent, yielding the succinamic ester (XXIV). Finally, this compound is treated with NaOH or with H2 over Pd/C and reacted with CaCl2, yielding high purity mitiglinide calcium. The one-pot sequential reaction of imidazole with SOCl2, 2(S)-benzylsuccinic acid (XVII) and cis-perhydroisoindole (V), followed by hydrolysis with HCl, gives succinamic acid (XIII), which is finally treated with 2N NaOH and CaCl2.

参考文献 中间体
合成目标
【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034.
【2】 Yamaguchi, T.; Yanagi, T.; Yamamoto, I.; Mukaiyama, Y.; Kamijo, T.; Hokari, H.; Preparation of optically active succinic acid derivatives. III. Regioselective condensation reactions of optically active 2-substituted succinic acids with diimidazolide. Yakugaku Zasshi 1998, 118, 6, 248-255.
【3】 Yamaguchi, T.; et al.; Synthesis of KAD-1229, a succinic acid derivative with optical activity (1). 118th Annu Meet Pharmaceut Soc Jpn (March 31 1998, Kyoto) 1998, Abst 01(XD)13-1.
【4】 Yanagi, T.; Kamijo, T.; Yamaguchi, T. (Kissei Pharmaceutical Co., Ltd.); Process for producing benzylsuccinic acid derivs.. EP 0967204; WO 9832736 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 41059 (3aR,7aS)octahydro-1H-isoindole C8H15N 详情 详情
(XIII) 41064 (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid C19H25NO3 详情 详情
(XVII) 41068 (2S)-2-benzylbutanedioic acid C11H12O4 详情 详情
(XXIV) 41074 benzyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate C26H31NO3 详情 详情
(XXV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XXVI) 18710 Benzyl alcohol; Phenylmethanol 100-51-6 C7H8O 详情 详情

合成路线19

该中间体在本合成路线中的序号：(V)

The Friedel-Crafts condensation of 1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine (I) with 3-(1-acetylpiperidin-4-yl)propionyl chloride (II) by means of AlCl3 in 1,2-dichloroethane gives 3-(1-acetylpiperidin-4-yl)-1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone (III), which is deacetylated in refluxing concentrated aqueous HCl yielding 3-(piperidin-4-yl)-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone (IV). Finally, this compound is benzylated with benzyl bromide (V) and K2CO3 in ethanol affording the final product as free base, which is then treated with fumaric acid in MeOH/CH2Cl2.

参考文献 中间体
合成目标
【1】 Mealy, N.; Rabasseda, X.; Castaner, J.; TAK-147. Drugs Fut 1995, 20, 3, 248.
【2】 Goto, G.; Ishihara, Y.; Miyamoto, M. (Takeda Chemical Industries, Ltd.); Condensed heterocyclic cpds., their production and use. EP 0487071; US 5273974 .
【3】 Ishihara, Y.; Hirai, K.; Miyamoto, M.; Goto, G.; Central cholinergic agents. 6. Synthesis and evaluation of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanones and their analogs as central selective acetylcholinesterase inhibitors. J Med Chem 1994, 37, 15, 2292-9.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15970 1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1-ethanone C12H15NO 详情 详情
(II) 15971 3-(1-acetyl-4-piperidinyl)propanoyl chloride C10H16ClNO2 详情 详情
(III) 15972 3-(1-acetyl-4-piperidinyl)-1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone C22H30N2O3 详情 详情
(IV) 15973 3-(4-piperidinyl)-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone C18H26N2O 详情 详情
(V) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

N-Alkylation of 2-chlorobenzimidazole (I) with benzyl bromide (II) by means of NaH in DMF provides benzylated derivative (III), which is converted into the desired compound by heating with piperazine (IV).

参考文献 中间体
合成目标
【1】 Parihar, H.S.; et al.; 5-HT3R binding of lerisetron: An interdisciplinary approach to drug-receptor interactions. Bioorg Med Chem Lett 2001, 11, 16, 2133.
【2】 Orjales, A.; et al.; New 2-piperazinylbenzimidazole derivatives as 5-HT3 antagonists. Synthesis and pharmacological evaluation. J Med Chem 1997, 40, 4, 586.
【3】 Orjales-Venero, A.; Garcia-Dominguez, N.; Rubio-Royo, V.; Rodes-Solanes, R. (FAES); New 2-piperazinylbenzimidazole derivs.. EP 0512939; JP 1995002795; US 5256665 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 26761 2-chloroimidazo[1,2-a]pyridine; 2-chlorobenzimidazole; 2-Amino-4'-chlorodiphenylether; 2-Aminodiphenylether; 2-chloro-1H-benzimidazole 4857-06-1 C7H5ClN2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 49687 1-Benzyl-2-chloro-1H-benzoimidazole C14H11ClN2 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(XIII)

3) The alkylation of 5(S)-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran-2-one (XII) by means of benzyl bromide (XIII) and lithium diisopropylamide (LDA) gives the corresponding 3(R)-benzyl derivative (XIV), which is deprotected with aqueous HF, yielding the hydroxymethyl compound (XV). The esterification of (XV) with trifluoromethanesulfonic anhydride affords the corresponding triflate (XVI), which is condensed with the chiral piperazine (VII) by means of diisopropylethylamine in isopropanol, giving the substituted furanone (XVII). Ring opening of the furanone (XVII) with LiOH, DME and imidazole yields the substituted hydroxypentanamide (XVIII), which is protected with tert-butyldimethylsilyl chloride to afford the protected amide (XIX). The trans-amidation of (XIX) with 2-hydroxyindan-1-amine (II) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in DMF gives the protected dihydroxy diamide (XX), which is deprotected with trimethylsilyl triflate, affording the dihydroxy diamide (VII), already obtained. This compound is then alkylated with 3-(chloromethyl)pyridine (IX) as before.

参考文献 中间体
合成目标
【1】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600.
【2】 Vacca, J.P.; Holloway, M.K.; Dorsey, B.D.; Hungate, R.W.; Guare, J.P. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0541168; JP 1993279337; WO 9309096 .
【3】 Vacca, J.P.; Guare, J.P.; Dorsey, B.D.; Holloway, M.K.; Hungate, R.W. (Merck & Co., Inc.); HIV protease inhibitors in pharmaceutical combinations for the treatment of AIDS. EP 0617968; JP 1996508496; WO 9422480 .
【4】 Vacca, J.P.; Dorsey, B.D.; Guare, J.P.; Holloway, M.K.; Hungate, R.W.; Levin, R.B. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0696277; JP 1996509980; US 5413999; WO 9426717 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 16239 (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol 126456-43-7 C9H11NO 详情 详情
(VII) 16244 tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate 150323-35-6 C14H27N3O3 详情 详情
(VIII) 16245 (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide C30H42N4O4 详情 详情
(IX) 15793 3-(Chloromethyl)pyridine 3099-31-8 C6H6ClN 详情 详情
(XII) 16249 (5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)dihydro-2(3H)-furanone C11H22O3Si 详情 详情
(XIII) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XIV) 16251 (3R,5S)-3-benzyl-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)dihydro-2(3H)-furanone C18H28O3Si 详情 详情
(XV) 16252 (3R,5S)-3-benzyl-5-(hydroxymethyl)dihydro-2(3H)-furanone C12H14O3 详情 详情
(XVI) 16253 [(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]methyl trifluoromethanesulfonate C13H13F3O5S 详情 详情
(XVII) 16254 tert-butyl (3S)-4-[[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]methyl]-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate C26H39N3O5 详情 详情
(XVIII) 16255 tert-butyl (3S)-4-[(2S,4R)-5-amino-4-benzyl-2-hydroxy-5-oxopentyl]-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate C26H42N4O5 详情 详情
(XIX) 16256 tert-butyl (3S)-4-((2S,4R)-5-amino-4-benzyl-2-[[tert-butyl(dimethyl)silyl]oxy]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate C32H56N4O5Si 详情 详情
(XX) 16257 tert-butyl (3S)-4-((2S,4R)-4-benzyl-2-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate C41H64N4O6Si 详情 详情
(XXI) 16258 tert-butyl (3S)-4-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate C35H50N4O6 详情 详情

合成路线22

该中间体在本合成路线中的序号：

The isoquinoline intermediate (IX) has been synthesized as follows: The reduction of methyl 3,5-dimethoxybenzoate (I) with LiAlH4 gives the benzyl alcohol (II), which is treated with Swern oxidant to yield the benzaldehyde (III). The treatment of (III) with the sequence outlined in the scheme the chiral secondary amine is obtained. The cyclization of (IV) with ammonium formate catalyzed by Pd, followed by a treatment with acetic anhydride and POCl3 afforded the dihydroisoquinoline (V), which is reduced with LiAlH4 to the tetrahydro derivative (VI). Cleavage of the methoxy groups of (VI) with BBr3 affords the dihydroxycompound (VII), which is benzylated with benzyl bromide and Cs2CO3 providing the fully benzylated tetrahydroisoquinoline (VIII). Finally, this compound is iodinated with I2 and Ag2SO4 furnishing the desired isoquinoline intermediate (IX).

参考文献 中间体
合成目标
【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
40727 2-phenyl-2-propanamine; 1-methyl-1-phenylethylamine 585-32-0 C9H13N 详情 详情
(I) 37841 methyl 3,5-dimethoxybenzoate 2150-37-0 C10H12O4 详情 详情
(II) 35424 (3,5-dimethoxyphenyl)methanol 705-76-0 C9H12O3 详情 详情
(III) 21720 3,5-dimethoxybenzaldehyde 7311-34-4 C9H10O3 详情 详情
(IV) 37842 (2R)-1-(3,5-dimethoxyphenyl)-N-(1-methyl-1-phenylethyl)-2-propanamine; N-[(1R)-2-(3,5-dimethoxyphenyl)-1-methylethyl]-N-(1-methyl-1-phenylethyl)amine C20H27NO2 详情 详情
(V) 37843 (3R)-6-methoxy-1,3-dimethyl-3,4-dihydro-8-isoquinolinyl methyl ether; (3R)-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline C13H17NO2 详情 详情
(VI) 37844 (1R,3R)-6-methoxy-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether; (1R,3R)-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C13H19NO2 详情 详情
(VII) 37845 (1R,3R)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol C11H15NO2 详情 详情
(VIII) 37846 benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C32H33NO2 详情 详情
(IX) 37847 benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C32H32INO2 详情 详情

合成路线23

该中间体在本合成路线中的序号：(IV)

The condensation of 4-hydroxy-6-methyl-2H-pyran-2-one (I) with 1-phenyl-1-propanol (II) by means of TsOH in toluene gives 4-hydroxy-6-methyl-3-(1-phenyl-propyl)-2H-pyran-2-one (III), which is alkylated with benzyl bromide and LDA in THF yielding 4-hydroxy-6-(2-phenylethyl)-3-(1-phenylpropyl)-2H-pyran-2-one (V). Finally this compound is submitted to a new alkylation process with ethyl iodide and LDA in THF to afford the target compound.

参考文献 中间体
合成目标
【1】 Romines, K.R.; Thaisrivongs, S.; Analogs of 4-hydroxypyrone: potent, non-peptidic HIV protease inhibitors. Drugs Fut 1995, 20, 4, 377.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 41231 4-hydroxy-6-methyl-2H-pyran-2-one 675-10-5 C6H6O3 详情 详情
(II) 41232 1-phenyl-1-propanol C9H12O 详情 详情
(III) 41233 4-hydroxy-6-methyl-3-(1-phenylpropyl)-2H-pyran-2-one C15H16O3 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 41234 4-hydroxy-6-phenethyl-3-(1-phenylpropyl)-2H-pyran-2-one C22H22O3 详情 详情
(VI) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情

合成路线24

该中间体在本合成路线中的序号：(II)

Synthesis of intermediate (VIII): Condensation of salicyl alcohol (I) with benzyl bromide (II) by means of KOtBu in DMF gives 2-benzyloxybenzyl alcohol (III), which is converted into chloride (IV) by reaction with SOCl2 in THF. Treatment of derivative (IV) with PPh3 in refluxing toluene furnishes triphenylphosphonium chloride (V), which is condensed with aldehyde (VI) by means of DBU in acetonitrile to afford benzyloxystilbene derivative (VII). Finally, intermediate (VIII) is obtained by hydrogenation of (VII) over Pd/C in EtOH.

参考文献 中间体
合成目标
【1】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 42341 2-(hydroxymethyl)phenol 90-01-7 C7H8O2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 42342 [2-(benzyloxy)phenyl]methanol C14H14O2 详情 详情
(IV) 42343 benzyl 2-(chloromethyl)phenyl ether; 1-(benzyloxy)-2-(chloromethyl)benzene C14H13ClO 详情 详情
(V) 42344 [2-(benzyloxy)benzyl](triphenyl)phosphonium chloride C32H28ClOP 详情 详情
(VI) 20589 3-methoxybenzaldehyde; m-Anisaldehyde 591-31-1 C8H8O2 详情 详情
(VII) 42345 1-(benzyloxy)-2-[(E)-2-(3-methoxyphenyl)ethenyl]benzene; benzyl 2-[(E)-2-(3-methoxyphenyl)ethenyl]phenyl ether C22H20O2 详情 详情
(VIII) 13604 2-(3-Methoxyphenethyl)phenol C15H16O2 详情 详情

合成路线25

该中间体在本合成路线中的序号：(VII)

The Friedel Crafts condensation of 6-methoxyindolin-2-one (I) with acetyl chloride and AlCl3 gives the 5-acetyl-6-methoxyindolin-2-one (II), which is treated with hydroxylamine and acetic anhydride to yield the O-acetyloxime (III). The cyclization of (III) affords the 3-methyl-6,7-dihydro-5H-isoxazolo[4,5-f]indol-6-one (IV), which is condensed with 4-(iodomethyl)piperidine-1-carboxylic acid tert-butyl ester (V) to provide the adduct (VI). Finally this compound is deprotected with TFA and benzylated with benzyl bromide (VII) to furnish the target compound.

参考文献 中间体
合成目标
【1】 Maggi, A.; Brufani, M.; Lappa, S.; Filocamo, L.; New acetylcholinesterease inhibitors. Drugs Fut 1997, 22, 4, 397.
【2】 Villalobos, A.; et al.; 5, 7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxaxol-6-one: A potent and centrally-selective inhibitor of acetylcholinesterase with an improved margin of safety. J Med Chem 1995, 38, 15, 2802.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 41235 6-methoxy-1,3-dihydro-2H-indol-2-one C9H9NO2 详情 详情
(II) 41236 5-acetyl-6-hydroxy-1,3-dihydro-2H-indol-2-one C10H9NO3 详情 详情
(III) 41237 5-ethanimidoyl-6-hydroxy-1,3-dihydro-2H-indol-2-one C12H12N2O4 详情 详情
(IV) 41238 3-methyl-5,7-dihydro-6H-isoxazolo[4,5-f]indol-6-one C10H8N2O2 详情 详情
(V) 41239 tert-butyl 4-(iodomethyl)-1-piperidinecarboxylate C11H20INO2 详情 详情
(VI) 41240 tert-butyl 4-[2-(6-oxo-6,7-dihydro-5H-isoxazolo[4,5-f]indol-3-yl)ethyl]-1-piperidinecarboxylate C21H27N3O4 详情 详情
(VII) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情

合成路线26

该中间体在本合成路线中的序号：(IV)

The cyclization of 2,5-dimethoxy-1,3,4-trimethylbenzene (I) with 2-bromo-2-methylpropionyl bromide (II) by means of FeCl3 and NaOH in methanol/water gives 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-one (III), which is treated with benzyl bromide (IV) and K2CO3 to yield the benzyl ether (V). The reaction of (V) with methylmagnesium bromide, followed by dehydration of the intermediate carbinol affords the methylene derivative (VI), which is hydroxylated with borane / dimethylsulfide and NaOH/H2O2 to furnish the hydroxymethyl compound (VII). The reaction of (VII) with MsCl and TEA gives the mesylate (VIII), which is finally condensed with 1-methylpiperazine (IX) by means of K2CO3 and debenzylated by hydrogenation with H2 over Pd/C in ethanol/HOAc to afford the target compound as a racemic mixture.

参考文献 中间体
合成目标
【1】 Petty, M.A.; Marciniak, G.; Design and biological evaluation of new antioxidants for use in cerebrovascular disorders. Drugs Fut 1996, 21, 10, 1037.
【2】 Ayers, T.A.; Schnettler, R.A.; Marciniak, G.; Krysan, D.J. (Hoechst Marion Roussel Inc.); Novel process for preparing derivatives of 2,2,4,6,7-pentaalkyl-2,2-dihydrobenzofuranols. EP 0813530 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 41220 1,4-dimethoxy-2,3,5-trimethylbenzene; 4-methoxy-2,3,5-trimethylphenyl methyl ether C11H16O2 详情 详情
(II) 19367 2-bromo-2-methylpropanoyl bromide 20769-85-1 C4H6Br2O 详情 详情
(III) 41221 5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one C13H16O3 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 41222 5-(benzyloxy)-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one C20H22O3 详情 详情
(VI) 41223 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-methylene-2,3-dihydro-1-benzofuran; benzyl 2,2,4,6,7-pentamethyl-3-methylene-2,3-dihydro-1-benzofuran-5-yl ether C21H24O2 详情 详情
(VII) 30773 [5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol C21H26O3 详情 详情
(VIII) 26455 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2,3-dihydro-1-benzofuran C24H32O3S 详情 详情
(IX) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线27

该中间体在本合成路线中的序号：(II)

The N-benzyl indole derivative (III) was prepared by alkylation of 5-(benzyloxy)indole (I) with benzyl bromide (II) in the presence of KOH. The O-benzyl protecting group of (III) was subsequently removed by transfer hydrogenolysis with ammonium formate and Pd/C to afford the 5-hydroxyindole (IV), which was further condensed with 3-chloro-4-fluorobenzonitrile (V) to produce the diaryl ether (VI). Finally, basic hydrolysis of the cyano group of (VI) gave the corresponding benzoic acid.

参考文献 中间体
合成目标
【1】 Mase, T.; Inami, H.; Hara, H.; Fujii, M; Oritani, H.; Koutoku, H.; Igarashi, S.; A novel class of inhibitors for human steroid 5alpha-reductase: Synthesis and biological evaluation of indole derivatives. II. Chem Pharm Bull 2000, 48, 3, 382.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 30840 5-Benzyloxyindole; benzyl 1H-indol-5-yl ether; 5-(benzyloxy)-1H-indole 1215-59-4 C15H13NO 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 51281 benzyl 1-benzyl-1H-indol-5-yl ether; 1-benzyl-5-(benzyloxy)-1H-indole C22H19NO 详情 详情
(IV) 51282 1-benzyl-1H-indol-5-ol C15H13NO 详情 详情
(V) 51277 3-Chloro-4-fluorobenzonitrile 117482-84-5 C7H3ClFN 详情 详情
(VI) 51283 4-[(1-benzyl-1H-indol-5-yl)oxy]-3-chlorobenzonitrile C22H15ClN2O 详情 详情

合成路线28

该中间体在本合成路线中的序号：

The isoquinoline intermediate (IX) has been synthesized as follows: The reduction of methyl 3,5-dimethoxybenzoate (I) with LiAlH4 gives the benzyl alcohol (II), which is treated with Swern oxidant to yield the benzaldehyde (III). The treatment of (III) with the sequence outlined in the scheme the chiral secondary amine is obtained. The cyclization of (IV) with ammonium formate catalyzed by Pd, followed by a treatment with acetic anhydride and POCl3 afforded the dihydroisoquinoline (V), which is reduced with LiAlH4 to the tetrahydro derivative (VI). Cleavage of the methoxy groups of (VI) with BBr3 affords the dihydroxycompound (VII), which is benzylated with benzyl bromide and Cs2CO3 providing the fully benzylated tetrahydroisoquinoline (VIII). Finally, this compound is iodinated with I2 and Ag2SO4 furnishing the desired isoquinoline intermediate (IX).

参考文献 中间体
合成目标
【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
40727 2-phenyl-2-propanamine; 1-methyl-1-phenylethylamine 585-32-0 C9H13N 详情 详情
(I) 37841 methyl 3,5-dimethoxybenzoate 2150-37-0 C10H12O4 详情 详情
(II) 35424 (3,5-dimethoxyphenyl)methanol 705-76-0 C9H12O3 详情 详情
(III) 21720 3,5-dimethoxybenzaldehyde 7311-34-4 C9H10O3 详情 详情
(IV) 37842 (2R)-1-(3,5-dimethoxyphenyl)-N-(1-methyl-1-phenylethyl)-2-propanamine; N-[(1R)-2-(3,5-dimethoxyphenyl)-1-methylethyl]-N-(1-methyl-1-phenylethyl)amine C20H27NO2 详情 详情
(V) 37843 (3R)-6-methoxy-1,3-dimethyl-3,4-dihydro-8-isoquinolinyl methyl ether; (3R)-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline C13H17NO2 详情 详情
(VI) 37844 (1R,3R)-6-methoxy-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether; (1R,3R)-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C13H19NO2 详情 详情
(VII) 37845 (1R,3R)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol C11H15NO2 详情 详情
(VIII) 37846 benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C32H33NO2 详情 详情
(IX) 37847 benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C32H32INO2 详情 详情

合成路线29

该中间体在本合成路线中的序号：(XI)

2) The reaction of the previously described (R)-2-(2-tetrahydropyranyloxy)-1-propanol (III) with benzyl bromide (XI) by means of NaH in DMF, followed by a treatment with Dowex 50X, gives 1-benzyloxy-2(R)-propanol (XII), which is condensed with tosyloxymethylphosphonic acid diisopropyl ester (IX) by means of NaH in THF, yielding 2-benzyloxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIII). The hydrogenolysis of (XIII) over Pd/C in methanol affords 2-hydroxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIV), which is tosylated with tosyl chloride/dimethyl-aminopyridine in pyridine to give the expected tosylate (XV). The condensation of (XV) with adenine (VI) by means of Cs2CO3 in hot DMF yields 9-[2(R)-(diisopropoxyphosphorylmethoxy)propyl]adenine (X), which is finally hydrolyzed as before.

参考文献 中间体
合成目标
【1】 Masojídková, M.; Holý, A.; Synthesis of enantiomeric N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. I. The stepwise approach. Coll Czech Chem Commun 1995, 60, 7, 1196.
【2】 Sorbera, L.A.; Castañer, J.; (R)-PMPA and Bis(POC)PMPA. Drugs Fut 1998, 23, 12, 1279.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 19228 (2S)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanol 76946-21-9 C8H16O3 详情 详情
(V) 10343 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine 73-24-5 C5H5N5 详情 详情
(IX) 19234 (diisopropoxyphosphoryl)methyl 4-methylbenzenesulfonate C14H23O6PS 详情 详情
(X) 19235 diisopropyl [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate C15H26N5O4P 详情 详情
(XI) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XII) 19237 (2R)-1-(benzyloxy)-2-propanol C10H14O2 详情 详情
(XIII) 19238 diisopropyl [[(1S)-2-(benzyloxy)-1-methylethyl]oxy]methylphosphonate C17H29O5P 详情 详情
(XIV) 19239 diisopropyl [[(1S)-2-hydroxy-1-methylethyl]oxy]methylphosphonate C10H23O5P 详情 详情
(XV) 19240 (2S)-2-[(diisopropoxyphosphoryl)methoxy]propyl 4-methylbenzenesulfonate C17H29O7PS 详情 详情

合成路线30

该中间体在本合成路线中的序号：

The isoquinoline intermediate (IX) has been synthesized as follows: The reduction of methyl 3,5-dimethoxybenzoate (I) with LiAlH4 gives the benzyl alcohol (II), which is treated with Swern oxidant to yield the benzaldehyde (III). The treatment of (III) with the sequence outlined in the scheme the chiral secondary amine is obtained. The cyclization of (IV) with ammonium formate catalyzed by Pd, followed by a treatment with acetic anhydride and POCl3 afforded the dihydroisoquinoline (V), which is reduced with LiAlH4 to the tetrahydro derivative (VI). Cleavage of the methoxy groups of (VI) with BBr3 affords the dihydroxycompound (VII), which is benzylated with benzyl bromide and Cs2CO3 providing the fully benzylated tetrahydroisoquinoline (VIII). Finally, this compound is iodinated with I2 and Ag2SO4 furnishing the desired isoquinoline intermediate (IX).

参考文献 中间体
合成目标
【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
40727 2-phenyl-2-propanamine; 1-methyl-1-phenylethylamine 585-32-0 C9H13N 详情 详情
(I) 37841 methyl 3,5-dimethoxybenzoate 2150-37-0 C10H12O4 详情 详情
(II) 35424 (3,5-dimethoxyphenyl)methanol 705-76-0 C9H12O3 详情 详情
(III) 21720 3,5-dimethoxybenzaldehyde 7311-34-4 C9H10O3 详情 详情
(IV) 37842 (2R)-1-(3,5-dimethoxyphenyl)-N-(1-methyl-1-phenylethyl)-2-propanamine; N-[(1R)-2-(3,5-dimethoxyphenyl)-1-methylethyl]-N-(1-methyl-1-phenylethyl)amine C20H27NO2 详情 详情
(V) 37843 (3R)-6-methoxy-1,3-dimethyl-3,4-dihydro-8-isoquinolinyl methyl ether; (3R)-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline C13H17NO2 详情 详情
(VI) 37844 (1R,3R)-6-methoxy-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether; (1R,3R)-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C13H19NO2 详情 详情
(VII) 37845 (1R,3R)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol C11H15NO2 详情 详情
(VIII) 37846 benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C32H33NO2 详情 详情
(IX) 37847 benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C32H32INO2 详情 详情

合成路线31

该中间体在本合成路线中的序号：

The isoquinoline intermediate (IX) has been synthesized as follows: The reduction of methyl 3,5-dimethoxybenzoate (I) with LiAlH4 gives the benzyl alcohol (II), which is treated with Swern oxidant to yield the benzaldehyde (III). The treatment of (III) with the sequence outlined in the scheme the chiral secondary amine is obtained. The cyclization of (IV) with ammonium formate catalyzed by Pd, followed by a treatment with acetic anhydride and POCl3 afforded the dihydroisoquinoline (V), which is reduced with LiAlH4 to the tetrahydro derivative (VI). Cleavage of the methoxy groups of (VI) with BBr3 affords the dihydroxycompound (VII), which is benzylated with benzyl bromide and Cs2CO3 providing the fully benzylated tetrahydroisoquinoline (VIII). Finally, this compound is iodinated with I2 and Ag2SO4 furnishing the desired isoquinoline intermediate (IX).

参考文献 中间体
合成目标
【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
40727 2-phenyl-2-propanamine; 1-methyl-1-phenylethylamine 585-32-0 C9H13N 详情 详情
(I) 37841 methyl 3,5-dimethoxybenzoate 2150-37-0 C10H12O4 详情 详情
(II) 35424 (3,5-dimethoxyphenyl)methanol 705-76-0 C9H12O3 详情 详情
(III) 21720 3,5-dimethoxybenzaldehyde 7311-34-4 C9H10O3 详情 详情
(IV) 37842 (2R)-1-(3,5-dimethoxyphenyl)-N-(1-methyl-1-phenylethyl)-2-propanamine; N-[(1R)-2-(3,5-dimethoxyphenyl)-1-methylethyl]-N-(1-methyl-1-phenylethyl)amine C20H27NO2 详情 详情
(V) 37843 (3R)-6-methoxy-1,3-dimethyl-3,4-dihydro-8-isoquinolinyl methyl ether; (3R)-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline C13H17NO2 详情 详情
(VI) 37844 (1R,3R)-6-methoxy-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether; (1R,3R)-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C13H19NO2 详情 详情
(VII) 37845 (1R,3R)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol C11H15NO2 详情 详情
(VIII) 37846 benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C32H33NO2 详情 详情
(IX) 37847 benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline C32H32INO2 详情 详情

合成路线32

该中间体在本合成路线中的序号：

(S)-6-Hydroxy-2-phthalimidohexanoic acid (I) was converted to benzyl ester (II) by treatment with benzyl bromide and Cs2CO3. Subsequent Swern oxidation of the alcohol function of (II) followed by reaction of the resulting aldehyde (III) with Me3Al afforded secondary alcohol (IV). A new Swern oxidation of (IV) provided ketone (V). Introduction of a further methyl group to give the tertiary alcohol (VI) was achieved by means of methyltitanium trichloride, generated in situ from MeLi and TiCl4. Azide (VII) was then obtained by treatment of (VI) with Me3SiN3 and BF3-Et2O. Palladium-catalyzed hydrogenation effected both reduction of the azide to amine and hydrogenolysis of the benzyl ester. Then, EDC-mediated cyclization of the intermediate amino acid gave azepinone (VIII).

参考文献 中间体
合成目标
【1】 Robl, J.A.; Sulsky, R.; Sieber-McMaster, E.; Ryono DE; Cimarusti MP; Simpkins LM; Karanewsky, D.S.; Chao, S.; Asaad, M.M.; Seymour, A.A.; Fox, M.E.; Smith, P.L.; Trippodo, N.C.; Vasopeptidase inhibitors: Incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides. J Med Chem 1999, 42, 2, 305.
【2】 Karanewsky, D.S.; Barrish, J.C.; Petrillo, E.W. Jr.; Robl, J.A.; Ryono, D.E. (Bristol-Myers Squibb Co.); Dual action inhibitors. EP 0599444; US 5552397 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 22512 (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid C14H15NO5 详情 详情
(II) 26841 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoate C21H21NO5 详情 详情
(III) 26842 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxohexanoate C21H19NO5 详情 详情
(IV) 26843 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyheptanoate C22H23NO5 详情 详情
(V) 26844 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxoheptanoate C22H21NO5 详情 详情
(VI) 26845 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxy-6-methylheptanoate C23H25NO5 详情 详情
(VII) 26846 benzyl (2S)-6-azido-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-methylheptanoate C23H24N4O4 详情 详情
(VIII) 26847 2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione C16H18N2O3 详情 详情

合成路线33

该中间体在本合成路线中的序号：(A)

Treatment of 3-nitro-7-hydroxyquinoline (I) with NaH and benzyl bromide (A) provides benzyloxyderivative (II), which is reduced with SnCl4 in HCl/EtOH to yield (III). Amine (III) is then converted into (IV) via the diazonium salt by treatment with NaNO2 in HCl followed by reaction with methyl acrylate (B) in presence of CuO. Cyclization of (IV) with thiourea in 2-methoxyethanol in presence of NaOAc affords imino-thiazolidinone (V), which is finally hydrolyzed with HCl and EtOH.

参考文献 中间体
合成目标
【1】 Nomura, Y.; Sakuma, S.; Masui, S. (Nippon Chemiphar Co., Ltd.); Quinoline deriv.. EP 0787725; JP 1997100280; US 5693651; WO 9612719 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
(A) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(B) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(I) 41511 3-nitro-7-quinolinol C9H6N2O3 详情 详情
(II) 41512 7-(benzyloxy)-3-nitroquinoline; benzyl 3-nitro-7-quinolinyl ether C16H12N2O3 详情 详情
(III) 41513 7-(benzyloxy)-3-quinolinamine; 7-(benzyloxy)-3-quinolinylamine C16H14N2O 详情 详情
(IV) 41514 methyl 3-[7-(benzyloxy)-3-quinolinyl]-2-chloropropanoate C20H18ClNO3 详情 详情
(V) 41515 5-[[7-(benzyloxy)-3-quinolinyl]methyl]-2-imino-1,3-thiazolidin-4-one C20H17N3O2S 详情 详情

合成路线34

该中间体在本合成路线中的序号：

The condensation of 2-nitrophenol (I) with 2,2,2-trrifluoroethyl p-toluenesulfonate (II) by means of K2CO3 in DMF gives 2-(2,2,2-trifluoroethoxy) nitrobenzene (III), which isreduced with H2 over PtO2 in ethanol yiedling the aniline (IV). The cyclization of (IV) with bis (2-chloroethyl)amine (V) and K2CO3 affords the piperazine (VI), which is condensed with 1-benzyl-3-(3-chloro-propyl)-5-methylpyrimidine-2,4(1H,3H)-dione (VII) by means of K2CO3 in refluxing acetonitrile to give the benzylated target compound (VIII). Finally, this compound is deprotected by hydrogenation with ammonium formate and Pd/C. The intermediate pyrimidine (VII) has been obtained by benzylation of thymine (IX) with benzyl bromide and K2CO3 to give the 1-benzylthymine (X), which is alkylated with 1-bromo-3-chloropropane and K2CO3 to the target intemediate (VII).

参考文献 中间体
合成目标
【1】 Bantle, G.W.; Elworthy, T.R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F.J.; Morgans, D.J. Jr.; Perez-Medrano, A.; Pfister, J.R.; Sjogren, E.B.; Talamas, F.X. (F. Hoffmann-La Roche AG); Pyrimidinedione, pyrimidinetrione, triazinedione, tetrahydroquinazolinedione derivs. as alpha1-adrenergic receptor antagonists. EP 0748800; JP 1997100269 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 19106 2-nitrophenol 88-75-5 C6H5NO3 详情 详情
(II) 29561 2,2,2-trifluoroethyl 4-methylbenzenesulfonate 433-06-7 C9H9F3O3S 详情 详情
(III) 29562 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene C8H6F3NO3 详情 详情
(IV) 29563 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine C8H8F3NO 详情 详情
(V) 21583 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine 821-48-7 C4H9Cl2N 详情 详情
(VI) 29564 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether C12H15F3N2O 详情 详情
(VII) 29565 1-benzyl-3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione C15H17ClN2O2 详情 详情
(VIII) 29566 1-benzyl-5-methyl-3-(3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl)-2,4(1H,3H)-pyrimidinedione C27H31F3N4O3 详情 详情
(IX) 12204 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine 65-71-4 C5H6N2O2 详情 详情
(X) 29567 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione C12H12N2O2 详情 详情

合成路线35

该中间体在本合成路线中的序号：(XXII)

The intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII) has been obtained as follows: The reaction of 4(S)-isopropyloxazolidin-2-one (XIX) with propionyl chloride (XX) by means of BuLi in THF gives 4(S)-isopropyl-3-propionyloxazolidin-2-one (XXI), which is condensed with benzyl bromide (XXII) by means of LHMDS in THF yielding 4(S)-isopropyl-3-(2(R)-methyl-3-phenylpropionyl)oxazolidin-2-one (XXIII). The oxidative cleavage of (XXIII) with H2O2 in THF/water affords 2(R)-methyl-3-phenylpropionic acid (XXIV), which is hydrogenated with H2 over alumina providing 3-cyclohexyl-2(R)-methylpropionic acid (XXV). Finally, this compound is treated with oxalyl chloride in DMF to afford the desired intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII).

参考文献 中间体
合成目标
【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 27157 (2R)-3-cyclohexyl-2-methylpropanoyl chloride C10H17ClO 详情 详情
(XIX) 12867 (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone 17016-83-0 C6H11NO2 详情 详情
(XX) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(XXI) 11535 (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one 77877-19-1 C9H15NO3 详情 详情
(XXII) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XXIII) 27167 (4S)-4-isopropyl-3-[(2R)-2-methyl-3-phenylpropanoyl]-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(XXIV) 27168 (2R)-2-methyl-3-phenylpropionic acid C10H12O2 详情 详情
(XXV) 27169 (2R)-3-cyclohexyl-2-methylpropionic acid C10H18O2 详情 详情

合成路线36

该中间体在本合成路线中的序号：(XII)

The oxidation of N-(benzyloxycarbonyl)-D-phenylalaninol (I) with NaOCl catalized by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaBr in water gives the corresponding aldehyde (II), which is dimerized by means of the Coulton's reagent (VCl3/Zn/THF) to the pinacol (III)(1). The silylation of (III) with triethylsilyl chloride and imidazole in DMF yields the silylated diol (IV), which is submitted to hydrogenolysis with H2 over Pd/C in toluene to afford the free diamine (V). The cyclization of (V) with carbonyldimidazole (CDI) in toluene followed by desilylation with 1N HCl gives (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxyperhydro-1,3-diazepin-2-one (VI), which is treated with 2,2-dimethoxypropane (VII) and p-toluenesulfonic acid in DMF yielding the corresponding acetonide (VIII). The methylation of (VIII) with methyl triflate in refluxing dichloroethane affords the cyclic isourea (IX), which is alkylated with 3-cyano-4-fluorobenzyl bromide (X)/NaH in DMF giving the N-monobenzyl derivative (XI). A new alkylation of (XI) with benzyl bromide (XII) in refluxing acetonitrile yields the disubstituted cyclic urea (XIII), which is finally treated with hydrazine in refluxing butanol to generate the indazole ring and treated with HCl in methanol to eliminate the acetonide group.

参考文献 中间体
合成目标
【1】 Rodgers, J.D.; Lam, P.Y.S.; Johnson, B.L.; Wang, H.; Li, R.; Ru, Y.; Ko, S.S.; Seitz, S.P.; Trainor, G.L.; Anderson, P.S.; Klabe, R.M.; Bacheler, L.T.; Cordova, B.; Garber, S.; Reid, C.; Wright, M.R.; Chang, C.-H.; Erickson-Viitanen, S.; Design and selection of DMP 850 and DMP 851: The next generation of cyclic urea HIV protease inhibitors. Chem Biol 1998, 5, 10, 597.
【2】 Pierce, M.E.; et al.; Stereoselective synthesis of HIV-1 protease inhibitor, DMP 323. J Org Chem 1996, 61, 2, 444.
【3】 Rodgers, J.D.; Sun, J.-H. (DuPont Pharmaceuticals Co.); Method for preparing N-monosubstd. and N,N'-disubstd. unsymmetrical cyclic ureas. AU 96059868; EP 0837855; EP 1029859; US 5532357; WO 9640652 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 27228 benzyl (1R)-1-benzyl-2-hydroxyethylcarbamate C17H19NO3 详情 详情
(II) 27220 benzyl (1R)-1-benzyl-3-oxopropylcarbamate C18H19NO3 详情 详情
(III) 19618 benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate C34H36N2O6 详情 详情
(IV) 27221 benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylcarbamate C46H64N2O6Si2 详情 详情
(V) 27222 (1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylamine C30H52N2O2Si2 详情 详情
(VI) 27223 (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one C19H22N2O3 详情 详情
(VII) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(VIII) 27049 (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethylhexahydro-6H-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one C22H26N2O3 详情 详情
(IX) 27224 (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethyl-4,5,8,8a-tetrahydro-3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6-yl methyl ether C23H28N2O3 详情 详情
(X) 27225 5-(bromomethyl)-2-fluorobenzonitrile C8H5BrFN 详情 详情
(XI) 27226 5-[[(3aS,4R,8R,8aS)-4,8-dibenzyl-6-methoxy-2,2-dimethyl-3a,4,8,8a-tetrahydro-5H-[1,3]dioxolo[4,5-e][1,3]diazepin-5-yl]methyl]-2-fluorobenzonitrile C31H32FN3O3 详情 详情
(XII) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XIII) 27227 5-[[(3aS,4R,8R,8aS)-4,7,8-tribenzyl-2,2-dimethyl-6-oxohexahydro-5H-[1,3]dioxolo[4,5-e][1,3]diazepin-5-yl]methyl]-2-fluorobenzonitrile C37H36FN3O3 详情 详情

合成路线37

该中间体在本合成路线中的序号：(V)

Hydrogenation of D-4-hydroxyphenyl glycine (I) over Raney-Ni in NaOH affords 4-hydroxycyclohexylglycine (II), which is condensed with sulfonyl chloride (III) in dioxane in the presence of Et3N to yield derivative (IV). Carboxylic acid (IV) is converted into benzyl ester (VI) by treatment with benzyl bromide (V) by means of N,N'-dicyclohexylamine (DCHA) in DMF and (VI) is then oxidized by treatment with NaBr, 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaClO2 in CH2Cl2/H2O to provide ketone (VII). Condensation of (VII) with n-propanol (VIII) by means of PhSiH3 and TFA gives a mixture of compounds from which trans-(IX) is cromatographically separated. Then ketone (IX) reacts with 4-picolyl chloride (X) and K2CO3 in DMF to furnish compound (XI). Hydrogenation of benzyl acetate (XI) over Pd/C in EtOH/HCl affords acetic acid derivative (XII), which is coupled to O-t-butylhydroxylamine hydrochloride by means of HOBt, N-methylmorpholine and N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (EDC·HCl) in CH2Cl2. Finally, removal of the t-Bu group with HCl (gas) in dichloroethane/EtOH yields the desired compound.

参考文献 中间体
合成目标
【1】 Parker, D.T. (Novartis AG); alpha-Substd. arylsulphonamido hydroxamic acids as TNF-alpha and matrix metalloproteinase inhibitors. EP 0873312; JP 2000502088; US 5770624; WO 9722587 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 31690 (2R)-2-amino-2-(4-hydroxyphenyl)ethanoic acid; (2R)-2-(4-hydroxyphenyl)glycine; D-(-)-p-Hydroxyphenylglycine; (R)-2-amino-2-(4-hydroxyphenyl)acetic acid 22818-40-2 C8H9NO3 详情 详情
(II) 45921 (2R)-2-amino-2-(4-hydroxycyclohexyl)ethanoic acid C8H15NO3 详情 详情
(III) 45922 4-ethoxybenzenesulfonyl chloride C8H9ClO3S 详情 详情
(IV) 45923 (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-hydroxycyclohexyl)ethanoic acid C16H23NO6S 详情 详情
(V) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(VI) 45924 benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-hydroxycyclohexyl)ethanoate C23H29NO6S 详情 详情
(VII) 45925 benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-oxocyclohexyl)ethanoate C23H27NO6S 详情 详情
(VIII) 29338 1-propanol 71-23-8 C3H8O 详情 详情
(IX) 45926 benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-propoxycyclohexyl)ethanoate C26H35NO6S 详情 详情
(X) 10844 4-(Chloromethyl)pyridine 10445-91-7 C6H6ClN 详情 详情
(XI) 45927 benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl](4-pyridinylmethyl)amino]-2-(4-propoxycyclohexyl)ethanoate C32H40N2O6S 详情 详情
(XII) 45928 (2R)-2-[[(4-ethoxyphenyl)sulfonyl](4-pyridinylmethyl)amino]-2-(4-propoxycyclohexyl)ethanoic acid C25H34N2O6S 详情 详情

合成路线38

该中间体在本合成路线中的序号：

Wittig reaction of N-(benzyloxycarbonyl)-L-phenylalaninal (I) with methyl (triphenylphosphoranylidene)acetate produced unsaturated ester (II). Double bond reduction in (II) with concomitant cyclization and N-deprotection upon treatment with Mg in MeOH furnished (R)-5-benzyl-2-pyrrolidinone (III), which was further protected as the N-Boc derivative (IV) (1). Alkylation of (IV) with benzyl bromide in the presence of LDA in THF at -78 C provided the trans-3,5-dimethylpyrrolidinone (V) as the predominant diastereoisomer. After Boc group cleavage using trifluoroacetic acid, pyrrolidinone (VI) was coupled with epoxide (VII) yielding adduct (VIII). The acetonide protecting group of (VIII) was finally hydrolyzed with HCl to give the title compound.

参考文献 中间体
合成目标
【1】 Kazmierski, W.; Andrews, W. III; Baker, C.; et al.; Heterocyclic isosteres of the P1/P2 domain of amprenavir: Discovery of novel, picomolar HIV-1 protease inhibitors. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 126.
【2】 Tung, R.D.; Salituro, F.G.; Deininger, D.D.; Bhisetti, G.R.; Baker, C.T.; Spaltenstein, A.; Kazmierski, W.M.; Andrews, C.W. III (Vertex Pharmaceuticals Inc.); Aspartyl protease inhibitors. JP 2000501111; US 5945413; WO 9727180 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(I) 16586 benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate C17H17NO3 详情 详情
(II) 38970 methyl (E,4S)-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2-pentenoate C20H21NO4 详情 详情
(III) 38971 (5R)-5-benzyl-2-pyrrolidinone C11H13NO 详情 详情
(IV) 38972 tert-butyl (2R)-2-benzyl-5-oxo-1-pyrrolidinecarboxylate C16H21NO3 详情 详情
(V) 38973 tert-butyl (3S,5R)-3,5-dibenzyl-2-oxo-1-pyrrolidinecarboxylate C23H27NO3 详情 详情
(VI) 38974 (3S,5R)-3,5-dibenzyl-2-pyrrolidinone C18H19NO 详情 详情
(VII) 16243 (2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone C24H27NO3 详情 详情
(VIII) 38975 (3S,5R)-1-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3,5-dibenzyl-2-pyrrolidinone C42H46N2O4 详情 详情

合成路线39

该中间体在本合成路线中的序号：

The reaction of (S)-2-amino-6-hydroxyhexanoic acid (I) with N-(ethoxycarbonyl)phthalimide (II) by means of Na2CO3 in water gives 6-hydroxy-2(S)-(phthalimido)hexanoic acid (III), which is esterified with benzyl bromide and Cs2CO3 in DMF yielding the benzyl ester (IV). The oxidation of the terminal OH group of (IV) with (COCl)2 in dichloromethane affords the aldehyde (V), which is methylated with AlMe3 in dichloromethane giving 6-hydroxy-2(S)-(phthalimido)heptanoic acid (VI). The oxidation of (VI) with oxalyl chloride as before yields the ketone (VII), which is methylated with TiCl4 and methylmagnesium chloride to provide the carbinol (VIII). The reaction of (VIII) with trimethylsilyl azide in dichloromethane gives the azido derivative (IX), which is cyclized by reduction with H2 over Pd/C in DMF yielding the perhydroazepinone (X). Elimination of phthalimido protecting group of (X) with hydrazine in methanol/dichloromethane affords 3(S)-amino-7,7-dimethylperhydroazepin-2-one (XI), which is protected with trityl chloride and TEA in dichloromethane to give the tritylamino compound (XII). The condensation of (XII) with ethyl 2-bromoacetate (XIII) by means of LHMDS, followed by deprotection with TFA affords the adduct (XIV) with a free amino group, which is acylated with 2(R)-benzyl-3-(benzyloxyamino)propionic acid (XV) by means of HOBT and EDAD in dichloromethane providing the amide (XVI). The formylation of (XVI) with formic acid and acetic anhydride gives the formamide (XVII), which is deprotected with H2 over Pd/C in ethanol yielding intermediate (XVIII). Finally, this compound is hydrolyzed with NaOH in methanol.

参考文献 中间体
合成目标
【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257.
【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 22502 (2S)-2-amino-6-hydroxyhexanoic acid 6033-32-5 C6H13NO3 详情 详情
(II) 10283 ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide 22509-74-6 C11H9NO4 详情 详情
(III) 22512 (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid C14H15NO5 详情 详情
(IV) 26841 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoate C21H21NO5 详情 详情
(V) 26842 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxohexanoate C21H19NO5 详情 详情
(VI) 26843 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyheptanoate C22H23NO5 详情 详情
(VII) 26844 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxoheptanoate C22H21NO5 详情 详情
(VIII) 26845 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxy-6-methylheptanoate C23H25NO5 详情 详情
(IX) 26846 benzyl (2S)-6-azido-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-methylheptanoate C23H24N4O4 详情 详情
(X) 26847 2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione C16H18N2O3 详情 详情
(XI) 26848 (3S)-3-amino-7,7-dimethyl-2-azepanone C8H16N2O 详情 详情
(XII) 37281 (3S)-7,7-dimethyl-3-(tritylamino)-2-azepanone C27H30N2O 详情 详情
(XIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XIV) 37282 ethyl 2-[(6S)-6-amino-2,2-dimethyl-7-oxoazepanyl]acetate C12H22N2O3 详情 详情
(XV) 37283 (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid C17H19NO3 详情 详情
(XVI) 37284 ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate C29H39N3O5 详情 详情
(XVII) 37285 ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate C30H39N3O6 详情 详情
(XVIII) 37286 ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[formyl(hydroxy)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate C23H33N3O6 详情 详情

合成路线40

该中间体在本合成路线中的序号：

The condensation of N-phthaloyl-L-phenylalanine (I) with 2(S)-amino-6-hydroxyhexanoic acid methyl ester (II) by means of HOBT and EDAC in DMF/dichloromethane gives the dipeptide (III), which is oxidized at the terminal OH with (COCl)2 in dichloromethane yielding the aldehyde (IV). The cyclization of (IV) with TFA in dichloromethane affords the tetrahydropyridine (V), which is cyclized again by means of trifluoromethanesulfonic acid in dichloromethane to provide the tricyclic carboxylic acid (VI). The esterification of (VI) with PhCH2Br and Cs2CO3 in DMF gives the benzyl ester (VII), which is treated with hydrazine to eliminate the phthalimido group and yielding intermediate (VIII). The reaction of the free amino group of (VIII) with 2(R)-benzyl-3-(benzyloxyamino)propionic acid (IX) by means of HOBT and EDAC in dichloromethane affords the amide (X), which is formylated with formic acid and acetic anhydride to provide the formamide (XI). Finally, this compound is debenzylated with H2 over Pd/C in methanol to furnish the target compound.

参考文献 中间体
合成目标
【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257.
【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 37293 (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropionic acid 5123-55-7 C17H13NO4 详情 详情
(II) 22488 methyl (2S)-2-amino-6-hydroxyhexanoate C7H15NO3 详情 详情
(III) 37294 methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-hydroxyhexanoate C24H26N2O6 详情 详情
(IV) 37295 methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-oxohexanoate C24H24N2O6 详情 详情
(V) 37296 methyl (2S)-1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylate C24H22N2O5 详情 详情
(VI) 37297 (4S,7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid C23H18N2O5 详情 详情
(VII) 37298 benzyl (4S,7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate C30H24N2O5 详情 详情
(VIII) 37299 benzyl (4S,7S)-7-amino-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate C22H22N2O3 详情 详情
(IX) 37283 (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid C17H19NO3 详情 详情
(X) 37300 benzyl (4S,7S)-7-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate C39H39N3O5 详情 详情
(XI) 37301 benzyl (4S,7S)-7-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate C40H39N3O6 详情 详情

合成路线41

该中间体在本合成路线中的序号：

The intermediate benzyl 5,7-dimethylindole-2-carboxylate (X) was prepared by several procedures. Diazotization of 2,4-dimethylaniline (I), followed by Japp-Klingemann condensation of the diazonium salt (II) with ethyl 2-methyl-3-oxobutyrate (III) furnished hydrazone (IV). Subsequent Fischer indole synthesis in formic acid at 75 C provided ethyl 5,7-dimethylindole-2-carboxylate (V). An alternative route to indole (V) involved condensation of 3,5-dimethylbenzaldehyde (VI) with ethyl azidoacetate (VII) in ethanolic NaOEt, followed by thermal cyclization of the resulting azidocinnamate ester (VIII). Basic hydrolysis of ethyl ester (V) gave carboxylic acid (IX), which was converted to the benzyl ester (X) upon treatment with benzyl bromide and DBU.

参考文献 中间体
合成目标
【1】 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 32911 2,4-dimethylaniline; 2,4-dimethylphenylamine 95-68-1 C8H11N 详情 详情
(II) 32912 2,4-dimethylbenzenediazonium C8H9N2 详情 详情
(III) 10362 ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate 609-14-3 C7H12O3 详情 详情
(IV) 32913 ethyl 2-[(Z)-2-(2,4-dimethylphenyl)hydrazono]propanoate C13H18N2O2 详情 详情
(V) 32914 ethyl 5,7-dimethyl-1H-indole-2-carboxylate C13H15NO2 详情 详情
(VI) 32915 3,5-dimethylbenzaldehyde 5779-95-3 C9H10O 详情 详情
(VII) 32916 ethyl 2-azidoacetate 637-81-0 C4H7N3O2 详情 详情
(VIII) 32917 ethyl (Z)-2-azido-3-(3,5-dimethylphenyl)-2-propenoate C13H15N3O2 详情 详情
(IX) 32918 5,7-dimethyl-1H-indole-2-carboxylic acid C11H11NO2 详情 详情
(X) 32919 benzyl 5,7-dimethyl-1H-indole-2-carboxylate C18H17NO2 详情 详情

合成路线42

该中间体在本合成路线中的序号：

A further route to benzyl ester (X) is shown in the next scheme: Protection of 2,4,6-trimethylaniline (XI) with Boc2O gave carbamate (XII). Condensation of (XII) with diethyl oxalate in the presence of sec-butyllithium produced the intermediate ketoester (XIII), which was deprotected and cyclized under acidic conditions to yield indole (V). Hydrolysis, followed by alkylation with benzyl bromide as above provided the corresponding benzyl ester (X). An alternative and more direct procedure consisted in the condensation of protected aniline (XII) with dibenzyl oxalate, and then cyclization upon treatment with trifluoroacetic acid. The intermediate indole (X) was N-alkylated with tert-butyl bromoacetate and NaH to give the indole diester (XIV). Subsequent deprotection of the benzyl ester group by hydrogenation over Pd/C gave rise to diacid mono tert-butyl ester (XV). Optionally, the analogous methyl ester (XVII) was prepared by alkylation of indole (X) with methyl bromoacetate, followed by benzyl group hydrogenolysis.

参考文献 中间体
合成目标
【1】 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
40591 benzyl 2-(benzyloxy)-2-oxoacetate C16H14O4 详情 详情
(V) 32914 ethyl 5,7-dimethyl-1H-indole-2-carboxylate C13H15NO2 详情 详情
(X) 32919 benzyl 5,7-dimethyl-1H-indole-2-carboxylate C18H17NO2 详情 详情
(XI) 28804 2,4,6-trimethylaniline 88-05-1 C9H13N 详情 详情
(XII) 32920 tert-butyl mesitylcarbamate C14H21NO2 详情 详情
(XIII) 32921 ethyl 3-[2-[(tert-butoxycarbonyl)amino]-3,5-dimethylphenyl]-2-oxopropanoate C18H25NO5 详情 详情
(XIV) 32922 benzyl 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylate C24H27NO4 详情 详情
(XV) 32923 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylic acid C17H21NO4 详情 详情
(XVI) 32924 benzyl 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylate C21H21NO4 详情 详情
(XVII) 32925 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid C14H15NO4 详情 详情

合成路线43

该中间体在本合成路线中的序号：(II)

The N-alkylation of N-(tert-butoxycarbonyl)glycine (I) with benzyl bromide (II) by means of NaH in THF gives N-benzyl-N-(tert-butoxycarbonyl)glycine (III), which is condensed with 4-aminoacetophenone (IV) by means of isobutyl chloroformate and TEA in dichloromethane yielding the corresponding glycinamide (V). The cyclization of (V) with thiourea (VI) by means of I2 in refluxing isopropanol affords, after work up, the N-benzyl-glycinamide (VII), which is finally acylated with pyridine-4-carbonyl chloride by means of TEA and DMAP in dichloromethane.

参考文献 中间体
合成目标
【1】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 27846 2-[benzyl(tert-butoxycarbonyl)amino]acetic acid C14H19NO4 详情 详情
(IV) 27847 1-(4-aminophenyl)-1-ethanone 99-92-3 C8H9NO 详情 详情
(V) 27848 tert-butyl 2-(4-acetylanilino)-2-oxoethyl(benzyl)carbamate C22H26N2O4 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VII) 27849 N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]-2-(benzylamino)acetamide C18H18N4OS 详情 详情
(VIII) 27850 isonicotinoyl chloride 39178-35-3 C6H4ClNO 详情 详情

合成路线44

该中间体在本合成路线中的序号：

Methyl 4-oxopiperidine-3-carboxylate (IX) was protected as the tert-butyl carbamate (X) with Boc2O. This was alkylated with benzyl bromide in the presence of NaH to provide the racemic benzyl derivative (XI). Subsequent cyclization of (XI) with methylhydrazine produced the pyrazolopyridine (XII), which was deprotected with trifluoroacetic acid. The resulting amine (XIII) was then coupled with dipeptide (VI) using EDC and HOBt to afford the diastereomeric amides (XIV). After chromatographic isolation of the (R,R)-diastereoisomer, acid deprotection of the Boc group furnished the title compound.

参考文献 中间体
合成目标
【1】 Carpino, P.A.; Lefker, B.A.; Toler, S.M.; et al.; Design, synthesis and biological evaluation of a novel series of pyrazolidone-piperidine growth hormone secretagogues. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 276.
【2】 Carpino, P.A.; Jardine, D.P.A.; Lefker, B.A.; Ragan, J.A. (Pfizer Inc.); Growth-hormone secretagogues. EP 0869968; JP 1999501945; WO 9724369 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12091 1-Methylhydrazine; Monomethyl hydrazine 60-34-4 CH6N2 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(VI) 28103 (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid C19H28N2O6 详情 详情
(IX) 28106 methyl 4-oxo-3-piperidinecarboxylate 56026-52-9 C7H11NO3 详情 详情
(X) 28107 1-(tert-butyl) 3-methyl 4-oxo-1,3-piperidinedicarboxylate C12H19NO5 详情 详情
(XI) 28108 1-(tert-butyl) 3-methyl 3-benzyl-4-oxo-1,3-piperidinedicarboxylate C19H25NO5 详情 详情
(XII) 28109 tert-butyl 3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate C19H25N3O3 详情 详情
(XIII) 28110 3a-benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one C14H17N3O 详情 详情
(XIV) 28111 tert-butyl 2-([(1R)-2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-1-[(benzyloxy)methyl]-2-oxoethyl]amino)-1,1-dimethyl-2-oxoethylcarbamate C33H43N5O6 详情 详情

合成路线45

该中间体在本合成路线中的序号：(II)

Intermediate 2-benzylpyridazinone (V) was obtained either by alkylation of dibromopyridazinone (I) with benzyl bromide (II) or by condensation of mucobromic acid (III) with benzylhydrazine (IV). Alkaline hydrolysis of (V) with KOH in HMPA then provided the hydroxy derivative (VI). Further treatment of (VI) with trifluoromethanesulfonic anhydride and Et3N produced sulfonate (VII), which was subsequently coupled with 4-(methylthio)phenylboronic acid (VIII) in the presence of palladium catalyst and Na2CO3. Oxidation of the resulting sulfide (IX) with magnesium monoperphthalate (MMPP) in CH2Cl2 gave the corresponding sulfone (X). Finally, the reaction of (X) with isopropanol in the presence of Cs2CO3 furnished the target isopropyl ether.

参考文献 中间体
合成目标
【1】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 22278 4,5-dibromo-3(2H)-pyridazinone 5788-58-9 C4H2Br2N2O 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 22280 (Z)-2,3-dibromo-4-oxo-2-butenoic acid 21577-50-4 C4H2Br2O3 详情 详情
(IV) 22281 1-benzylhydrazine C7H10N2 详情 详情
(V) 22282 2-benzyl-4,5-dibromo-3(2H)-pyridazinone C11H8Br2N2O 详情 详情
(VI) 22283 2-benzyl-4-bromo-5-hydroxy-3(2H)-pyridazinone C11H9BrN2O2 详情 详情
(VII) 22284 1-benzyl-5-bromo-6-oxo-1,6-dihydro-4-pyridazinyl trifluoromethanesulfonate C12H8BrF3N2O4S 详情 详情
(VIII) 18561 4-(methylsulfanyl)phenylboronic acid 98546-51-1 C7H9BO2S 详情 详情
(IX) 22286 2-benzyl-4-bromo-5-[4-(methylsulfanyl)phenyl]-3(2H)-pyridazinone C18H15BrN2OS 详情 详情
(X) 22287 2-benzyl-4-bromo-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone C18H15BrN2O3S 详情 详情

合成路线46

该中间体在本合成路线中的序号：

Alkylation of methyl 3,5-dihydroxybenzoate (I) with benzyl bromide in the presence of NaH gave dibenzyl ether (II). Subsequent basic hydrolysis of the ester function of (II) provided carboxylic acid (III). This was protected as the oxazoline (VI) via conversion into acid chloride with SOCl2, followed by coupling with 2-amino-2-methyl-1-propanol (IV), and then cyclization of the hydroxy amide (V) with SOCl2. After lithiation of (VI) with n-BuLi at -78 C, the 2-benzyl substituent was introduced by treatment with benzyl bromide to afford (VII). Quaternization of (VII) with boiling CH3I provided iminium salt (VIII), which was reduced with NaBH4 and then hydrolyzed to aldehyde (IX). Hydantoin (X) was then prepared from (IX) under Bucherer-Bergs conditions in the presence of KCN and (NH4)2CO3. Finally, hydrogenolytic cleavage of the O-benzyl groups, of (X) yielded (XI), which by basic hydrolysis of the hydantoin ring provided the title amino acid.

参考文献 中间体
合成目标
【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270.
【2】 Baker, S.R.; Clark, B.P.; Goldsworthy, J.; Harris, J.R. (Eli Lilly and Company); Derivs. of phenylglycine and use thereof as pharmaceuticals. EP 0807621; JP 1998067723; US 5863947 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 25155 methyl 3,5-dihydroxybenzoate 2150-44-9 C8H8O4 详情 详情
(II) 25156 methyl 3,5-bis(benzyloxy)benzoate C22H20O4 详情 详情
(III) 25157 3,5-bis(benzyloxy)benzoic acid 28917-43-3 C21H18O4 详情 详情
(IV) 21513 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol 124-68-5 C4H11NO 详情 详情
(V) 25158 3,5-bis(benzyloxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide C25H27NO4 详情 详情
(VI) 25159 benzyl 3-(benzyloxy)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl ether C25H25NO3 详情 详情
(VII) 25160 2-[2-benzyl-3,5-bis(benzyloxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole C32H31NO3 详情 详情
(VIII) 25161 2-[2-benzyl-3,5-bis(benzyloxy)phenyl]-3,4,4-trimethyl-4,5-dihydro-1,3-oxazol-3-ium iodide C33H34INO3 详情 详情
(IX) 25162 2-benzyl-3,5-bis(benzyloxy)benzaldehyde C28H24O3 详情 详情
(X) 25163 5-[2-benzyl-3,5-bis(benzyloxy)phenyl]-2,4-imidazolidinedione C30H26N2O4 详情 详情
(XI) 25164 5-(2-benzyl-3,5-dihydroxyphenyl)-2,4-imidazolidinedione C16H14N2O4 详情 详情

合成路线47

该中间体在本合成路线中的序号：(II)

The reaction of benzohydroxamic acid (I) with benzyl bromide (II) by means of NaOH on ethanol gives the corresponding benzyl ester (III), which is treated with HCl yielding O-benzylhydroxylamine (IV). The reaction of (IV) with dicyaniamide (V) in ethanol affords the biguanide (VI), which is cyclized with cyclopentanone (VII) and HCl giving 1-benzyloxy-2,2-dimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine (VIII). The debenzylation of (VIII) with H2 over PtO2 in ethanol yields 1-hydroxy-2,2-dimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine (IX), which is finally condensed with 1,6-dibromohexane (X) by means of NaOH in methanol.

参考文献 中间体
合成目标
【1】 Zhang, X.P.; Shen, J.; Xin, Z.M.; Qiu, Q.P.; Zhou, W.C.; Synthesis and antiprotozoal activities of some new triazine derivatives including a new antitrypanosomal agent: SIPI-1029. Acta Pharm Sin 1996, 31, 11, 823.
【2】 Zhou, W.; Zhang, X.; Trybizine Hydrochloride. Drugs Fut 1999, 24, 10, 1084.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 24777 N-hydroxybenzamide 495-18-1 C7H7NO2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 24779 N-(benzyloxy)benzamide C14H13NO2 详情 详情
(IV) 14640 O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene 622-33-3 C7H9NO 详情 详情
(V) 23611 N-cyanoguanidine 461-58-5 C2H4N4 详情 详情
(VI) 24782 1-[([[[[amino(imino)methyl]amino](imino)methyl]amino]oxy)methyl]benzene C9H13N5O 详情 详情
(VII) 15113 cyclopentanone 120-92-3 C5H8O 详情 详情
(VIII) 24784 10-(benzyloxy)-6,8,10-triazaspiro[4.5]deca-6,8-diene-7,9-diamine C14H19N5O 详情 详情
(IX) 24785 7,9-diamino-6,8,10-triazaspiro[4.5]deca-7,9-dien-6-ol C7H13N5O 详情 详情
(X) 24786 1,6-dibromohexane 629-03-8 C6H12Br2 详情 详情

合成路线48

该中间体在本合成路线中的序号：(IX)

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III). Condensation of (III) with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with benzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

参考文献 中间体
合成目标
【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 24605 4-methyl-1-penten-3-ol C6H12O 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 24607 diethyl 2-[(E)-4-methyl-2-pentenyl]malonate C13H22O4 详情 详情
(VI) 24608 (E)-6-methyl-4-heptenoic acid C8H14O2 详情 详情
(VII) 24609 (1R,2R)-2-(methylamino)-1-phenyl-1-propanol C10H15NO 详情 详情
(VIII) 24610 (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C18H27NO2 详情 详情
(IX) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(X) 24634 (2S,4E)-2-benzyl-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C25H33NO2 详情 详情
(XI) 24635 (3R,5S)-3-benzyl-5-[(1R)-1-bromo-2-methylpropyl]dihydro-2(3H)-furanone C15H19BrO2 详情 详情
(XII) 24636 (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-benzyldihydro-2(3H)-furanone C15H19N3O2 详情 详情
(XIII) 24637 tert-butyl (1S)-1-[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate C20H29NO4 详情 详情
(XIV) 24638 (2R,4S,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-6-methylheptanoic acid C20H31NO5 详情 详情
(XV) 24639 (2R,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-6-methyl-4-oxoheptanoic acid C20H29NO5 详情 详情

合成路线49

该中间体在本合成路线中的序号：(VII)

Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) with DMSO and oxalyl chloride afforded the corresponding aldehyde (II). Subsequent pinacol dimerization by treatment with VCl3 and Zn gave diol (III) with a 98% diastereomeric purity. After protection of the hydroxyl groups of (III) as the [2-(trimethylsilyl) ethoxy]methyl (SEM) ethers upon treatment with SEMCl and diisopropyl ethylamine, (IV) was obtained, then the N-benzyloxycarbonyl groups were removed by hydrogenolysis in the presence of Pd/C. The resulting diamine (V) was cyclized with carbonyl diimidazole and pyridine to furnish the cyclic urea (VI). Alkylation with benzyl bromide (VII) and NaH provided the bisbenzylated compound, which was subsequently deprotected by treatment with HCl in MeOH-dioxan to give (VIII) (1). The stereoselective hydroxyl inversion of the diol was then achieved Swern by oxidation to the ketol (IX), followed by reduction with NaBH4 in EtOH, and purification of the major isomer by column chromatography.

参考文献 中间体
合成目标
【1】 Lam, P.Y.S.; et al.; Cyclic HIV protease inhibitors. Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas. J Med Chem 1996, 39, 18, 3514.
【2】 Kaltenbach, R.F. III; Nugiel, D.A.; Lam, P.Y.; Klabe, R.M.; Seitz, S.P.; Stereoisomers of cyclic urea HIV-1 protease inhibitors: Synthesis and binding affinities. J Med Chem 1998, 41, 25, 5113.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 16586 benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate C17H17NO3 详情 详情
(II) 19618 benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate C34H36N2O6 详情 详情
(IV) 19920 benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylcarbamate C46H64N2O8Si2 详情 详情
(V) 19921 (1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylamine; (2R,3S,4S,5R)-1,6-diphenyl-3,4-bis[[2-(trimethylsilyl)ethoxy]methoxy]-2,5-hexanediamine C30H52N2O4Si2 详情 详情
(VI) 19922 (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis[[2-(trimethylsilyl)ethoxy]methoxy]-1,3-diazepan-2-one C31H50N2O5Si2 详情 详情
(VII) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(VIII) 19924 (4R,5S,6S,7R)-1,3,4,7-tetrabenzyl-5,6-dihydroxy-1,3-diazepan-2-one C33H34N2O3 详情 详情
(IX) 19925 (4R,6S,7R)-1,3,4,7-tetrabenzyl-6-hydroxy-1,3-diazepane-2,5-dione C33H32N2O3 详情 详情

合成路线50

该中间体在本合成路线中的序号：

The chiral bicyclic alcohol (I) was converted to the benzyl ether (II) using benzyl bromide and NaH. Subsequent reduction of the ester group of (III) with LiBH4 provided primary alcohol (III), and further Swern oxidation yielded aldehyde (IV). Pinacol coupling of (IV) with D-phenylalaninal (V) by means of VCl3 - (THF)3 and Zn furnished diol (VI) with 85% diastereoselectivity. This was protected as the acetonide (VIII) upon treatment with 2,2-dimethoxypropane (VII) and camphorsulfonic acid. Selective removal of the two N-benzyloxycarbonyl groups of (VIII) by hydrogenation in the presence of Pd/C and NH3 gave diamine (IX), which was cyclized to the urea (X) employing carbonyldiimidazole and pyridine.

参考文献 中间体
合成目标
【1】 Han, W.; Pelletier, J.C.; Hodge, C.N.; Tricyclic ureas: A new class of HIV-1 protease inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3615.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 29582 7-benzyl 1-(tert-butyl) (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate C19H25NO5 详情 详情
(II) 29583 7-benzyl 1-(tert-butyl) (1S,3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate C26H31NO5 详情 详情
(III) 29584 benzyl (1S,3R,4R)-3-(benzyloxy)-1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C22H25NO4 详情 详情
(IV) 29585 benzyl (1S,3R,4R)-3-(benzyloxy)-1-formyl-7-azabicyclo[2.2.1]heptane-7-carboxylate C22H23NO4 详情 详情
(V) 27884 benzyl (1R)-1-benzyl-2-oxoethylcarbamate C17H17NO3 详情 详情
(VI) 29586 benzyl (1S,3R,4R)-3-(benzyloxy)-1-((1R,2R,3R)-3-[[(benzyloxy)carbonyl]amino]-1,2-dihydroxy-4-phenylbutyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C39H42N2O7 详情 详情
(VII) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(VIII) 29587 benzyl (1S,3R,4R)-3-(benzyloxy)-1-[(4R,5R)-5-((1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]heptane-7-carboxylate C42H46N2O7 详情 详情
(IX) 29588 (1R)-1-[(4R,5R)-5-[(3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]hept-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylamine; (1R)-1-[(4R,5R)-5-[(3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]hept-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenyl-1-ethanamine C26H34N2O3 详情 详情
(X) 29589 (1S,2R,6R,7R,11R,12R)-7-benzyl-12-(benzyloxy)-4,4-dimethyl-3,5-dioxa-8,10-diazatetracyclo[9.2.2.0(1,10).0(2,6)]pentadecan-9-one C27H32N2O4 详情 详情

合成路线51

该中间体在本合成路线中的序号：

2-Chloro-4-propionylpyridine (I) was protected as the cyclic ketal (II) with 1,3-propanediol and p-toluenesulfonic acid in refluxing toluene with azeotropical removal of water. Subsequent halogen displacement in (II) with sodium methoxide in boiling acetonitrile gave methoxypyridine (III). Lithiation of (III) with mesityllithium, followed by condensation with dimethylformamide provided formylpyridine (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. The hydroxyl group of (V) was protected as the benzyl ether (VI), and the ketal group was then hydrolyzed to ketone (VII) with aqueous trifluoroacetic acid. Reformatskii reaction of (VII) with tert-butyl bromoacetate and zinc afforded the beta-hydroxyester (VIII). Further hydrogenolysis of benzyl ether of (VIII) over Pd/C gave alcohol (IX). Then, treatment of (IX) with trifluoroacetic acid produced lactone (X), and hydrolysis of the methoxy group of (X) with aqueous HCl furnished pyridone (XI). Condensation of 3,4-difluoroacetanilide (XII) with Vilsmeier reagent yielded quinolinecarboxaldehyde (XIII), which was reduced to alcohol (XIV) with NaBH4. This was then coupled with pyridone (XI) under Mitsunobu conditions to give (XV). Finally, Heck reaction of (XV) with palladium acetate and triphenyl phosphine generated the target pentacyclic compound.

参考文献 中间体
合成目标
【1】 Lavergne, O.; Lesuer-Ginot, L.; Pla Rodas, F.; Kasprzyk, P.G.; Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A.M.; Harnett, J.; Pons, D.; Camara, J.; Bigg, D.C.; Homocamptothecins: Synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J Med Chem 1998, 41, 27, 5410.
【2】 Bigg, D.; Lavergne, O.; Pla Rodas, F.; Pommier, J.; Ulibarri, G. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Novel camptothecin analogues, preparation methods therefor, use thereof as drugs, and pharmaceutical compsns. containing said analogues. EP 0835258; JP 1999508249; US 5981542; WO 9700876 .
【3】 Lanco, C.; Rolland, A.; Bigg, D.; Lavergne, O.; Harnett, J.; Liberatore, A.-M. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Pro-drugs and counterparts of camptothecin, their application as medicines . EP 0946566; WO 9828304 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
14685 1,3-propanediol; Trimethylene Glycol 504-63-2 C3H8O2 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 25461 1-(2-chloro-4-pyridinyl)-1-propanone C8H8ClNO 详情 详情
(II) 25462 2-chloro-4-(2-ethyl-1,3-dioxan-2-yl)pyridine C11H14ClNO2 详情 详情
(III) 25463 4-(2-ethyl-1,3-dioxan-2-yl)-2-pyridinyl methyl ether; 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine C12H17NO3 详情 详情
(IV) 25464 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxynicotinaldehyde C13H17NO4 详情 详情
(V) 25465 [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methanol C13H19NO4 详情 详情
(VI) 25466 3-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine; benzyl [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methyl ether C20H25NO4 详情 详情
(VII) 25467 1-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-1-propanone C17H19NO3 详情 详情
(VIII) 25468 tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate C23H31NO5 详情 详情
(IX) 25469 tert-butyl 3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate C16H25NO5 详情 详情
(X) 25470 5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one C12H15NO4 详情 详情
(XI) 25471 5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione C11H13NO4 详情 详情
(XII) 25472 N-(3,4-difluorophenyl)acetamide 458-11-7 C8H7F2NO 详情 详情
(XIII) 25473 2-chloro-6,7-difluoro-3-quinolinecarbaldehyde C10H4ClF2NO 详情 详情
(XIV) 25474 (2-chloro-6,7-difluoro-3-quinolinyl)methanol C10H6ClF2NO 详情 详情
(XV) 25475 8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione C21H17ClF2N2O4 详情 详情

合成路线52

该中间体在本合成路线中的序号：(IX)

Alternatively, the monosulfonate (III) can also be obtained as follows: The benzylation of orcinol (I) with benzyl bromide (IX) and NaH in DMF gives the monoether (X), which is sulfonated with 2-chlorobenzenesulfonyl chloride (II) and DIPEA in CH2Cl2 affording the protected sulfonate (XI). Finally, this compound is deprotected by hydro-genation with H2 over Pd/C in THF to furnish the target monosulfonate (III).

参考文献 中间体
合成目标
【1】 Zetter, B.R.; Smith, R. (Children's Medical Center Corp.); Treatment of human prostate cancer with spermine. WO 9711691 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 27257 5-Methyl-1,3-benzenediol; Orcinol 505-15-4 C7H8O2 详情 详情
(II) 30817 2-chlorobenzenesulfonyl chloride 2905-23-9 C6H4Cl2O2S 详情 详情
(III) 30818 3-hydroxy-5-methylphenyl 2-chlorobenzenesulfonate C13H11ClO4S 详情 详情
(IX) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(X) 40400 3-(benzyloxy)-5-methylphenol C14H14O2 详情 详情
(XI) 40401 3-(benzyloxy)-5-methylphenyl 2-chlorobenzenesulfonate C20H17ClO4S 详情 详情

合成路线53

该中间体在本合成路线中的序号：

The reaction of 6-methoxy-3,4-dihydro-2H-1-benzopyran-4-one (I) with 48% HBr in refluxing acetic acid gives the corresponding hydroxy derivative (II), which is treated with benzyl bromide and K2CO3 in acetone to yield the benzyl ether (III). The condensation of (III) with 3-formyl-4-methoxybenzoic acid methyl ester (IV) by means of pyrrolidine in methanol affords the benzylidene derivative (V), which is reduced with H2 over Pd/C in ethyl acetate to afford the corresponding benzyl compound (VI). The reduction of the carbonyl group of (VI) with NaBH4 and CeCl3 in methanol/THF gives the racemic cis alcohol (±)-(VII), which is submitted to optical resolution by reaction with Boc-D-Trp-OH and DEC, crystallization, and hydrolysis of the resulting diastereomer with NaOH in refluxing methanol affording (3R,4R)-3-(6-benzyloxy-4-hydroxy-3,4-dihydro-2H-1-benzopyran-3-yl)-4-methoxybenzoic acid (+)-(VIII). The degradation of the carboxy group of (+)-(VIII) with diphenylphosphoryl azide (DPPA) and benzyl alcohol in dioxane affords the benzyloxycarbonylamino derivative (IX), which is deprotected with H2 over Pd(OH)2 providing (3R,4R)-3-(5-amino-2-methoxybenzyl)-3,4-dihydro-2H-1-benzopyran-4,6-diol (X). The reaction of (X) with 2-(chloromethyl)-5,6-difluorobenzothiazole (XI) by means of NaH in DMF gives the expected condensation product (XII), which is finally treated with trifluoromethanesulfonic anhydride and triethylamine.

参考文献 中间体
合成目标
【1】 Watson, J.W.; Damon, D.B.; Antognoli, G.W.; Cheng, J.B.; Marfat, A.; Mebus, C.; Kuperman, A.V.; Shirley, J.T.; Pillar, J.S.; Liston, T.C.; Chambers, R.J.; Discovery of CP-199,330 and CP-199,331: Two potent and orally efficacious cysteinyl LT1 receptor antagonists devoid of liver toxicity. Bioorg Med Chem Lett 1999, 9, 18, 2773.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 30183 6-methoxy-2,3-dihydro-4H-chromen-4-one C10H10O3 详情 详情
(II) 30184 6-hydroxy-2,3-dihydro-4H-chromen-4-one C9H8O3 详情 详情
(III) 30185 6-(benzyloxy)-2,3-dihydro-4H-chromen-4-one C16H14O3 详情 详情
(IV) 30186 methyl 3-formyl-4-methoxybenzoate C10H10O4 详情 详情
(V) 31657 methyl 3-[[6-(benzyloxy)-4-oxo-2H-chromen-3(4H)-ylidene]methyl]-4-hydroxybenzoate C25H20O6 详情 详情
(VI) 30188 methyl 3-[[6-(benzyloxy)-4-oxo-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxybenzoate C26H24O6 详情 详情
(VII) 31658 methyl 3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxybenzoate C26H26O6 详情 详情
(VIII) 30189 3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxybenzoic acid C25H24O6 详情 详情
(IX) 30190 benzyl 3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxyphenylcarbamate C32H31NO6 详情 详情
(X) 30191 (3R,4R)-3-(5-amino-2-methoxybenzyl)-3,4-dihydro-2H-chromene-4,6-diol C17H19NO4 详情 详情
(XI) 20150 2-(chloromethyl)-5,6-difluoro-1,3-benzothiazole C8H4ClF2NS 详情 详情
(XII) 31659 (3R,4R)-3-(5-amino-2-methoxybenzyl)-6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-3,4-dihydro-2H-chromen-4-ol C25H22F2N2O4S 详情 详情

合成路线54

该中间体在本合成路线中的序号：

The benzylation of 4-C-(hydroxymethyl)-1,2-isopropylidene-alpha-D-ribofuranose (I) with benzyl bromide and NaH in DMF gives the 3,5-di-O-benzyl derivative (II), which is treated with I2, imidazole and triphenylphosphine in refluxing toluene/acetonitrile yielding the iodomethyl derivative (III). The deiodination of (III) with tributyltin hydride and AIBN in hot toluene affords the 4-C-methyl compound (IV), which is treated with acetic anhydride and H2SO4 in acetic acid to give the 1,2-di-O-acetyl derivative (V). The condensation of (V) with uracil (VI) by means of TMS-OTf yields the uridine derivative (VII), which is deprotected first by deacetylation with ammonia and then by debenzylation with H2 over Pd/C affording the 4'-C-methyl-uridine (VIII). The reaction of (VIII) with acetyl bromide in refluxing acetonitrile gives the acetylated 2'-bromo derivative (IX), which is debrominated with tributyltin hydride and AIBN in hot toluene yielding 3',5'-O-diacetyl-2'-deoxy-4'-C-methyl-uridine (X). The iodination of (X) with I2 and ceric ammonium nitrate (CAN) affords the 5-iodo derivative (XI), which is condensed with methyl acrylate by means of Pd(OAc)2 and triphenylphosphine in dioxane giving the methoxycarbonylvinyl derivative (XII). The hydrolysis of (XII) with NaOH in methanol yields 5-(2(E)-carboxyvinyl)-2'-deoxy-4'-C-methyl-uridine (XIII), which is finally submitted to a decarboxylative bromination with N-bromosuccinimide ans KHCO3 in DMF.

参考文献 中间体
合成目标
【1】 Waga, T.; et al.; Synthesis of 4'-C-methylnucleosides. Biosci Biotech Biochem 1993, 57, 9, 1433-38.
【2】 Waga, T.; et al.; Synthesis and biological evaluation of 4'-C-methylnucleosides. Nucleosides Nucleotides 1996, 15, 1-3, 287-304.
【3】 Machida, H.; Kitano, K.; Miura, S.; Synthesis of novel 4'-C-methyl-pyrimidine nucleosides and their biological activities. Bioorg Med Chem Lett 1999, 9, 6, 827.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(I) 30916 [(3aR,6S,6aR)-6-(benzyloxy)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol C16H22O6 详情 详情
(II) 30917 [(3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol C23H28O6 详情 详情
(III) 30918 (3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-5-(iodomethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole; [(3aR,5S,6S,6aR)-6-(benzyloxy)-5-(iodomethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether C23H27IO5 详情 详情
(IV) 30919 (3aR,5S,6S,6aR)-5-[(benzyloxy)methyl]-2,2,5-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl benzyl ether; (3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2,5-trimethyltetrahydrofuro[2,3-d][1,3]dioxole C23H28O5 详情 详情
(V) 30920 (2S,3R,4S,5S)-2-(acetoxy)-4-(benzyloxy)-5-[(benzyloxy)methyl]-5-methyltetrahydro-3-furanyl acetate C24H28O7 详情 详情
(VI) 30921 2,4(1H,3H)-pyrimidinedione; Uracil 66-22-8 C4H4N2O2 详情 详情
(VII) 30922 (2R,3R,4S,5S)-4-(benzyloxy)-5-[(benzyloxy)methyl]-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-5-methyltetrahydro-3-furanyl acetate C26H28N2O7 详情 详情
(VIII) 30923 1-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)-5-methyltetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C10H14N2O6 详情 详情
(IX) 30924 [(2S,3R,4R,5R)-3-(acetoxy)-4-bromo-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methyltetrahydro-2-furanyl]methyl acetate C14H17BrN2O7 详情 详情
(X) 30925 [(2S,3S,5R)-3-(acetoxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methyltetrahydro-2-furanyl]methyl acetate C14H18N2O7 详情 详情
(XI) 30926 [(2S,3S,5R)-3-(acetoxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methyltetrahydro-2-furanyl]methyl acetate C14H17IN2O7 详情 详情
(XII) 30927 methyl (E)-3-(1-[(2R,4S,5S)-4-(acetoxy)-5-[(acetoxy)methyl]-5-methyltetrahydro-2-furanyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-2-propenoate C18H22N2O9 详情 详情
(XIII) 30928 (E)-3-[1-[(2R,4S,5S)-4-hydroxy-5-(hydroxymethyl)-5-methyltetrahydro-2-furanyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]-2-propenoic acid C13H16N2O7 详情 详情

合成路线55

该中间体在本合成路线中的序号：

6-Methoxytryptamine (I) was condensed with methyl chloroformate to give carbamate (II), and further alkylation with benzyl bromide yielded the N-benzyl indole (III). Oxidation of the indole ring of (III) with DMSO/HCl gave oxindole (IV). Phase-transfer methylation using iodomethane and benzyltrimethylammonium bromide afforded the racemic methyl derivative (Va-b). Subsequent reduction and cyclization of (Va-b) by means of Red-Al furnished the tricyclic compound (VIa-b), which was resolved with dibenzoyl D-tartaric acid to provide the (3aS)-enantiomer (VII). Conversion of (VII) to the N,N'-dibenzyl analogue (XI) was achieved via quaternization to the ammonium salt (VIII) with iodomethane in Et2O. Ring-opening of (VIII) under basic conditions produced the hydroxy tryptamine (IX), which was again quaternized to (X) with iodomethane and then cyclized with benzylamine to provide directly the dibenzyl compound (XI). Ether cleavage of (XI) with boron tribromide gave the phenolic derivative (XII). This was coupled with 4-isopropylphenyl isocyanate in the presence of a catalytic amount of Na to yield carbamate (XIV). Finally, hydrogenolytic cleavage of the benzyl groups of (XIV) over Pd(OH)2 furnished the title compound.

参考文献 中间体
合成目标
【1】 Yu, Q.-S.; et al.; Total syntheses and anticholinesterase activities of (3aS)-N(8)-norphysostigmine, (3aS)-N(8)-norphenserine, their antipodal isomers and other N(8)-substituted analogues. J Med Chem 1997, 40, 18, 2895-2901.
【2】 Yu, Q.-S.; et al.; Syntheses and anticholinesterase activities of (3aS)-N1,N8-bisnorphenserine, (3aS)-N1,N8-bisnorphysostigmine. Their antipodal isomers and other potential metabolites of phenserine. J Med Chem 1998, 41, 13, 2371-79.
【3】 Holloway, H.W.; Yu, Q.-S.; Greig, N.H.; Utsuki, T.; Brossi, A.; Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for Alzheimer's disease. J Med Chem 1999, 42, 10, 1855.
【4】 Soncrant, T.T.; Brossi, A.; Greig, N.H.; Hausman, M.; Yu, Q.-S. (Axonyx Inc.; National Institutes of Health); Highly selective butyrylcholinesterase inhibitors for the treatment and diagnosis of Alzheimer's disease and dementias. CA 2264750; EP 0949920; WO 9902154 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(Va) 36829 methyl 2-[(3S)-1-benzyl-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]ethylcarbamate C21H24N2O4 详情 详情
(VIa),(VII) 36830 (3aS)-8-benzyl-5-methoxy-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole; (3aS)-8-benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether C20H24N2O 详情 详情
(Vb) 36837 methyl 2-[(3R)-1-benzyl-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]ethylcarbamate C21H24N2O4 详情 详情
(VIb) 36838 (3aR)-8-benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aR)-8-benzyl-5-methoxy-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole C20H24N2O 详情 详情
(I) 36825 O-Methylserotonin; 3-(2-Aminoethyl)-5-methoxyindole; 2-(5-Methoxy-1H-indol-3-yl)ethylamine; 2-(5-Methoxy-1H-indol-3-yl)-1-ethanamine; 5-Methoxytryptamine 608-07-1 C11H14N2O 详情 详情
(II) 36826 methyl 2-(5-methoxy-1H-indol-3-yl)ethylcarbamate C13H16N2O3 详情 详情
(III) 36827 methyl 2-(1-benzyl-5-methoxy-1H-indol-3-yl)ethylcarbamate C20H22N2O3 详情 详情
(IV) 36828 methyl 2-(1-benzyl-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)ethylcarbamate C20H22N2O4 详情 详情
(VIII) 36831 (3aS)-8-benzyl-5-methoxy-1,1,3a-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-1-ium iodide C21H27IN2O 详情 详情
(IX) 36832 (3S)-1-benzyl-3-[2-(dimethylamino)ethyl]-5-methoxy-3-methyl-2,3-dihydro-1H-indol-2-ol C21H28N2O2 详情 详情
(X) 36833 2-[(3S)-1-benzyl-2-hydroxy-5-methoxy-3-methyl-2,3-dihydro-1H-indol-3-yl]-N,N,N-trimethyl-1-ethanaminium iodide C22H31IN2O2 详情 详情
(XI) 36834 (3aS,8aR)-1,8-dibenzyl-5-methoxy-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole; (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether C26H28N2O 详情 详情
(XII) 36835 (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol C25H26N2O 详情 详情
(XIII) 34537 4-isopropylphenyl isocyanate; 1-isocyanato-4-isopropylbenzene 31027-31-3 C10H11NO 详情 详情
(XIV) 36836 (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl 4-isopropylphenylcarbamate C35H37N3O2 详情 详情

合成路线56

该中间体在本合成路线中的序号：

Benzothiadiazine dioxide (II) was prepared by cyclization of methyl anthranylate (I) with sulfamoyl chloride, followed by aqueous NaOH. After silylation of (II) by means of hexamethyldisilazane, alkylation with benzyloxymethyl acetate (III) in the presence of boron trifluoride etherate produced the 3-(benzyloxymethyl)benzothiazine (IV). Further alkylation of (IV) with benzyl bromide in aqueous NaHCO3 furnished the title compound.

参考文献 中间体
合成目标
【1】 Esteban, A.I.; Martinez, A.; De Clercq, E.; Benzothiadiazine dioxide acyclonucleosides as lead compounds for the development of new agents against human cytomegalovirus and varicella-zoster virus infection. Bioorg Med Chem Lett 1997, 7, 8, 1031.
【2】 Martinez, A.; et al.; Novel potential agents for human cytomegalovirus infection: Synthesis and antiviral activity evaluation of benzothiadiazine dioxide acyclonucleosides. J Med Chem 1999, 42, 7, 1145.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
40598 amidosulfonoyl chloride 7778-42-9 H2ClNO2S 详情 详情
(I) 11161 methyl 2-aminobenzoate; Methyl anthranilate 134-20-3 C8H9NO2 详情 详情
(II) 34452 2lambda(6),1,3-benzothiadiazine-2,2,4(1H,3H)-trione C7H6N2O3S 详情 详情
(III) 34453 (benzyloxy)methyl acetate C10H12O3 详情 详情
(IV) 34454 3-[(benzyloxy)methyl]-2lambda(6),1,3-benzothiadiazine-2,2,4(1H,3H)-trione C15H14N2O4S 详情 详情

合成路线57

该中间体在本合成路线中的序号：

The alkylation of (R)-2-amino-8-methoxy-1,2,3,4-tetrahydronaphthalene (I) with benzyl bromide provided the corresponding dibenzyl amine (II). After conversion of (II) to the hydrochloride salt, methyl ether cleavage by means of BBr3 at low temperature gave rise to naphthol (III). Condensation of (III) with 2-bromoisobutyramide (IV) yielded the naphthyloxybutyramide (V), which was rearranged at 130 C in the presence of NaH to the N-naphthyl-2-hydroxybutyramide (VI). Acid hydrolysis of the amide function of (VI) gave diamine (VII). This was condensed with N-methyl iminodiacetic acid (VIII) using CDI in boiling THF to produce the piperazinedione (IX). After reduction of (IX) to the corresponding piperazine (X) with LiAlH4, the N-benzyl groups were cleaved by hydrogenolysis over Pd/C to afford the primary amine (XI). Finally, coupling of (XI) with 4-mo-pholinobenzoic (XII) acid using CDI provided the title amide.

参考文献 中间体
合成目标
【1】 Berg, S.; Florvall, L.; Ross, S.; Thorberg, S.-O. (AstraZeneca plc); Substd. 1,2,3,4-tetrahydronaphthalene derivs.. EP 0888319; JP 2000506883; US 6124283; WO 9734883 .
【2】 Thorberg, S.-O.; Ross, S.; Berg, S. (AstraZeneca plc); A combination of a selective 5-HT1A antagonist and a selective h5-HT1B antagonist or partial agonist. WO 9913876 .
【3】 Berg, S.; Ross, S.; Thorberg, S.-O. (AstraZeneca AB); A Combination of a 5-HT reuptake inhibitor and a H5-HT1B antagonist or partial agonist. AU 9193098; EP 1014985; WO 9913877 .
【4】 Berg, S.; Ross, S.; Thorberg, S.-O. (AstraZeneca AB); A combination of a monoamine oxidase inhibitor and a H5-HT1B antagonist or partial agonist. AU 9193198; EP 1014986; WO 9913878 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 36251 (2R)-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2R)-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine C11H15NO 详情 详情
(II) 36252 N,N-dibenzyl-N-[(2R)-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]amine; (2R)-N,N-dibenzyl-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine C25H27NO 详情 详情
(III) 36253 (7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenol C24H25NO 详情 详情
(IV) 36254 2-bromo-2-methylpropanamide C4H8BrNO 详情 详情
(V) 36255 2-[[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenyl]oxy]-2-methylpropanamide C28H32N2O2 详情 详情
(VI) 36256 N-[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenyl]-2-hydroxy-2-methylpropanamide C28H32N2O2 详情 详情
(VII) 36257 (7R)-N(7),N(7)-dibenzyl-5,6,7,8-tetrahydro-1,7-naphthalenediamine; N-[(2R)-8-amino-1,2,3,4-tetrahydro-2-naphthalenyl]-N,N-dibenzylamine C24H26N2 详情 详情
(VIII) 36258 2-[(carboxymethyl)(methyl)amino]acetic acid 4408-64-4 C5H9NO4 详情 详情
(IX) 36259 1-[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenyl]-4-methyl-2,6-piperazinedione C29H31N3O2 详情 详情
(X) 36260 (2R)-N,N-dibenzyl-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenamine; N,N-dibenzyl-N-[(2R)-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenyl]amine C29H35N3 详情 详情
(XI) 36261 (2R)-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenamine; (2R)-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenylamine C15H23N3 详情 详情
(XII) 36262 4-(4-morpholinyl)benzoic acid C11H13NO3 详情 详情

合成路线58

该中间体在本合成路线中的序号：

Treatment of hydroxylactone (I) with benzyl bromide and silver oxide gave the corresponding benzyl ether (II). Subsequent reduction of the lactone (II) with LiAlH4 afforded the linear diol (III). Tioether (IV) was prepared by treatment of (III) with diphenyl disulfide and tributylphosphine, and the remaining hydroxyl group of (IV) was then protected as the ketal (VI) using ethyl vinyl ether (V) and pyridinium tosylate. Oxidation of (VI) to sulfone (VII) was accomplished with m-chloroperbenzoic acid. Condensation of (VII) with 2-methyl-delta-valerolactone (VIII), followed by BF3 - Et2O-catalyzed cyclization furnished spiroketal (IX). Finally, the phenylsulfonyl group of (IX) was reductively removed by means of sodium amalgam.

参考文献 中间体
合成目标
【1】 Oikawa, H.; et al.; Highly regio- and stereoselective reductions of spiroketals. Tetrahedron Lett 1993, 34, 33, 5303.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 35134 (4S,5S)-5-(hydroxymethyl)-4-methyldihydro-2(3H)-furanone C6H10O3 详情 详情
(II) 35135 (4S,5S)-5-[(benzyloxy)methyl]-4-methyldihydro-2(3H)-furanone C13H16O3 详情 详情
(III) 35136 (3S,4S)-5-(benzyloxy)-3-methyl-1,4-pentanediol C13H20O3 详情 详情
(IV) 35137 (2S,3S)-1-(benzyloxy)-3-methyl-5-(phenylsulfanyl)-2-pentanol C19H24O2S 详情 详情
(V) 18762 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene 109-92-2 C4H8O 详情 详情
(VI) 35138 benzyl (2S,3S)-2-(1-ethoxyethoxy)-3-methyl-5-(phenylsulfanyl)pentyl ether; 1-([[(2S,3S)-2-(1-ethoxyethoxy)-3-methyl-5-(phenylsulfanyl)pentyl]oxy]methyl)benzene C23H32O3S 详情 详情
(VII) 35139 (3S,4S)-5-(benzyloxy)-4-(1-ethoxyethoxy)-3-methylpentyl phenyl sulfone; [(3S,4S)-5-(benzyloxy)-4-(1-ethoxyethoxy)-3-methylpentyl](dioxo)phenyl-lambda(6)-sulfane C23H32O5S 详情 详情
(VIII) 35140 3-methyltetrahydro-2H-pyran-2-one C6H10O2 详情 详情
(IX) 35141 (2S,3S,5R,6S,11R)-2-[(benzyloxy)methyl]-3,11-dimethyl-1,7-dioxaspiro[5.5]undec-5-yl phenyl sulfone; (2S,3S,5R,6S,11R)-2-[(benzyloxy)methyl]-3,11-dimethyl-5-(phenylsulfonyl)-1,7-dioxaspiro[5.5]undecane C25H32O5S 详情 详情

合成路线59

该中间体在本合成路线中的序号：

Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 .
【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 25390 4-methylpentanoyl chloride 38136-29-7 C6H11ClO 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(III) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(IV) 25392 tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate C22H31NO5 详情 详情
(V) 25393 (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid C12H22O4 详情 详情
(VI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 35082 (2R,3R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(VIII) 35083 (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(IX) 35084 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-isobutylbutanedioate C22H32O4 详情 详情
(X) 35085 4-benzyl 1-(tert-butyl) (2S,3R)-2-(3-hydroxypropyl)-3-isobutylbutanedioate C22H34O5 详情 详情
(XI) 35086 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate C29H37NO9 详情 详情
(XII) 35087 methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate C15H22N2O4 详情 详情
(XIII) 35088 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate C38H54N2O10 详情 详情

合成路线60

该中间体在本合成路线中的序号：

Alkylation of N-Boc-4-(R)-hydroxyproline (I) with 2-(bromomethyl)-naphthalene (II) in the presence of NaH afforded the (naphthylmethyl) ether (III). N-Boc-norvaline (IV) was converted to the benzyl ester (V) by treatment with benzyl bromide and DBU. Subsequent acid cleavage of the Boc group of (V) yielded norvaline benzyl ester (VI). This was coupled with proline derivative (III) using HATU to give the protected dipeptide (VII).

参考文献 中间体
合成目标
【1】 Rancourt, J.; Tsantrizos, Y.; Simoneau, B.; Wernic, D.; Poupart, M.-A.; Llinas-Brunet, M. (Boehringer Ingelheim (Canada) Ltd.); Hepatitis C inhibitor peptides. EP 1003775; WO 9907733 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 16094 (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid 16094 C10H17NO5 详情 详情
(II) 35612 2-(bromomethyl)naphthalene 939-26-4 C11H9Br 详情 详情
(III) 35613 (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-naphthylmethoxy)-2-pyrrolidinecarboxylic acid C21H25NO5 详情 详情
(IV) 35614 (2S)-2-[(tert-butoxycarbonyl)amino]pentanoic acid 53308-95-5 C10H19NO4 详情 详情
(V) 35615 benzyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanoate C17H25NO4 详情 详情
(VI) 35616 benzyl (2S)-2-aminopentanoate C12H17NO2 详情 详情
(VII) 35617 tert-butyl (2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)-1-pyrrolidinecarboxylate C33H40N2O6 详情 详情

合成路线61

该中间体在本合成路线中的序号：

In an alternative synthesis of compound (XXXII), methyl (S)-lactate (XXXIII) was converted to amide (XXXIV) by treatment with pyrrolidine, and then protected as the benzyl ether (XXXV). Reduction of (XXXV) by means of sodium bis(methoxyethoxy)aluminum hydride produced aldehyde (XXXVI). Condensation of (XXXVI) with formic hydrazide produced the formyl hydrazone (XXXVII), to which was added ethylmagnesium bromide affording a mixture of diastereoisomeric hydrazides. Separation by column chromatography provided the required (S,S) isomer (XXXVIII). Cyclization of (XXXVIII) with the phenyl carbamate (XXIII) in the presence of DBU furnished the triazolone (XXXIX). This was deprotected by hydrogenation in the presence of Pd/C and formic acid to produce compound (XXXII)

参考文献 中间体
合成目标
【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
15486 formic hydrazide; Formylhydrazine 624-84-0 CH4N2O 详情 详情
(XXIII) 16349 phenyl 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylcarbamate C37H36F2N6O4 详情 详情
(XXXII) 34850 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C37H42F2N8O4 详情 详情
(XXXIII) 17075 propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate 27871-49-4 C4H8O3 详情 详情
(XXXIV) 17099 (2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone C7H13NO2 详情 详情
(XXXV) 17100 (2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone 122151-32-0 C14H19NO2 详情 详情
(XXXVI) 34851 (2R)-2-(benzyloxy)propanal C10H12O2 详情 详情
(XXXVII) 34852 N'-[(E,2R)-2-(benzyloxy)propylidene]formic hydrazide C11H14N2O2 详情 详情
(XXXVIII) 17106 N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide C13H20N2O2 详情 详情
(XXXIX) 34853 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C44H48F2N8O4 详情 详情

合成路线62

该中间体在本合成路线中的序号：

Sodium 4-hydroxybutyrate (XLII) was diben-zylated to give (XLIII), and then hydrolyzed with NaOH yielding 4-benzyl-oxybutyric acid (XLIV). Coupling of (XLIV) with alcohol (XXXII) then afforded ester (XLV). Deprotection of the benzyl ether of (XLV) by transfer hydrogenation with HCOOH and Pd catalyst produced hydroxy ester (XLVI). The precursor dibenzyl phosphate (XLI) was then obtained by coupling of (XLVI) with N,N-diisopropyl dibenzyl phosphoramidite, followed by oxidation of the intermediate phosphite with tertbutyl hydroperoxide. Finally, the hydrogenolysis of the benzyl groups of (XLI) as above furnished the title compound.

参考文献 中间体
合成目标
【1】 Bennett, F.; Girijavallabhan, V.M.; Patel, N.M.; Ganguly, A.; Saksena, A.K. (Schering Corp.); Tetrahydrofuran phosphate- and hydroxy esters, as prodrugs for the corresponding antifungal agent. EP 1027349; WO 9915522 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
40602 　 C17H22NO3P 详情 详情
(XXXII) 34850 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C37H42F2N8O4 详情 详情
(XLI) 34855 (1S,2S)-2-(4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-methylbutyl 4-[[bis(benzyloxy)phosphoryl]oxy]butanoate C55H61F2N8O9P 详情 详情
(XLII) 34856 sodium 4-hydroxybutanoate 502-85-2 C4H7NaO3 详情 详情
(XLIII) 34857 benzyl 4-(benzyloxy)butanoate C18H20O3 详情 详情
(XLIV) 34858 4-(benzyloxy)butyric acid C11H14O3 详情 详情
(XLV) 34859 (1S,2S)-2-(4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-methylbutyl 4-(benzyloxy)butanoate C48H54F2N8O6 详情 详情
(XLVI) 34860 (1S,2S)-2-(4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-methylbutyl 4-hydroxybutanoate C41H48F2N8O6 详情 详情

合成路线63

该中间体在本合成路线中的序号：(II)

Treatment of salicyl alcohol (I) with benzyl bromide (II) in DMF in the presence of KOtBu affords benzyloxybenzyl alcohol (III), which is converted into its chloride form (IV) by means of SOCl2 in THF. Reaction of (IV) with PPh3 in refluxing toluene gives triphenyl phosphonium chloride derivative (V), which is then subjected to a Wittig reaction with aldehyde (VI) to yield olefine (VII). Catalytic hydrogenolysis of (VII) over Pd/C provides phenol derivative (VIII), which is then alkylated by reaction with tosylate (XVI) and KOtBu in dimethylacetamide to yield (XVII). Finally, ethoxycarbonyl derivative (XVII) is reduced by means of LiAlH4 in THF and converted into its hydrochloride form by treatment with HCl in dioxane. Intermediate (XVI) can be prepared as follows: Protection of 2(S)-pyrrolidinemethanol (IX) by reaction with ethyl chloroformate in the presence of Et3N in dichloromethane affords carbamate (XI), which is tosylated by means of Ts2O and Et3N in dichloromethane to yield (XII). One carbon elongation of (XII) by reaction with NaCN in DMF provides (XIII), which is then converted into ester (XIV) by means of H2SO4 in EtOH. Reduction of ester (XIV) with LiAlH4 in THF gives alcohol (XV), which is finally tosylated by reaction with Ts2O and Et3N in dichloromethane.

参考文献 中间体
合成目标
【1】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 .
【2】 Goto, R.; Hayakawa, M.; Ito, R.; Ogawa, T.; Sugidachi, A.; Tanaka, N.; Asai, F.; Fujimoto, K.; [2-(omega-Phenylalkyl)phenoxy]alkylamines II: Synthesis and selective serotonin-2 receptor binding. Chem Pharm Bull 2000, 48, 2, 245.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 42341 2-(hydroxymethyl)phenol 90-01-7 C7H8O2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 42342 [2-(benzyloxy)phenyl]methanol C14H14O2 详情 详情
(IV) 42343 benzyl 2-(chloromethyl)phenyl ether; 1-(benzyloxy)-2-(chloromethyl)benzene C14H13ClO 详情 详情
(V) 42344 [2-(benzyloxy)benzyl](triphenyl)phosphonium chloride C32H28ClOP 详情 详情
(VI) 20589 3-methoxybenzaldehyde; m-Anisaldehyde 591-31-1 C8H8O2 详情 详情
(VII) 42345 1-(benzyloxy)-2-[(E)-2-(3-methoxyphenyl)ethenyl]benzene; benzyl 2-[(E)-2-(3-methoxyphenyl)ethenyl]phenyl ether C22H20O2 详情 详情
(VIII) 13604 2-(3-Methoxyphenethyl)phenol C15H16O2 详情 详情
(IX) 21347 (2S)pyrrolidinylmethanol 23356-96-9 C5H11NO 详情 详情
(X) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(XI) 42346 ethyl (2S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate C8H15NO3 详情 详情
(XII) 42347 ethyl (2S)-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-pyrrolidinecarboxylate C15H21NO5S 详情 详情
(XIII) 42348 ethyl (2S)-2-(cyanomethyl)-1-pyrrolidinecarboxylate C9H14N2O2 详情 详情
(XIV) 42349 ethyl (2S)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate C11H19NO4 详情 详情
(XV) 42350 ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate C9H17NO3 详情 详情
(XVI) 42351 ethyl (2S)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate C16H23NO5S 详情 详情
(XVII) 42352 ethyl (2S)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate C24H31NO4 详情 详情

合成路线64

该中间体在本合成路线中的序号：

Horner-Emmons condensation of 2,3-isopropylidene-D-glyceraldehyde (I) with phosphonate (II) produced the unsaturated ester (IIIa-b). Ketal deprotection and lactone ring closure of (II) under acidic conditions, followed by O-silylation afforded (IV). The lactone function of (IV) was reduced with DIBAL and then with NaBH4-CeCl3 to produce the corresponding diol. Further silylation of the primary hydroxyl group furnished (V). Condensation of (V) with triethyl orthoacetate followed by Claisen rearrangement gave rise to the gamma,delta-unsaturated ester (VI). This was reduced to alcohol with LiAlH4 and then alkylated with benzyl bromide to yield benzyl ether (VII). Ozonization of (VII) in methanol at -78 C, followed by decomposition of the ozonide with dimethyl sulfide gave aldehyde (VIII). Horner-Emmons condensation of (VIII) with the sodium salt of triethyl phosphonoacetate (IX) produced the alpha,beta-unsaturated ester (X). Double bond hydrogenation in (X) with simultaneous benzyl group cleavage afforded hydroxy ester (XI), which was then converted to mesylate (XII). This was cyclized to the cyclopentane (XIIIa-b) by means of NaH in refluxing THF.

参考文献 中间体
合成目标
【1】 Hong, J.H.; et al.; Enantiomeric synthesis of 3'-fluoro-apionucleosides using claisen rearrangement. Tetrahedron Lett 1998, 39, 21, 3443.
【2】 Gumina, G.; et al.; Stereoselective synthesis of carbocyclic L-4'-fluoro-2',3'-dideoxyadenosine. Org Lett 2000, 2, 9, 1229.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XIIIa) 36757 ethyl (1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate C15H29FO3Si 详情 详情
(XIIIb) 36758 ethyl (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate C15H29FO3Si 详情 详情
(IIIa) 36760 ethyl (E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate C10H15FO4 详情 详情
(IIIb) 36761 ethyl (E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate C10H15FO4 详情 详情
(I) 36759 (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 15186-48-8 C6H10O3 详情 详情
(II) 18192 ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate 2356-16-3 C8H16FO5P 详情 详情
(IV) 36762 (5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2(5H)-furanone C11H19FO3Si 详情 详情
(V) 36750 (6S,7E)-8-fluoro-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disila-7-tridecen-6-ol C17H37FO3Si2 详情 详情
(VI) 36751 ethyl (3S,4E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-4-hexenoate C21H43FO4Si2 详情 详情
(VII) 36752 benzyl (3S,4E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-4-hexenyl ether; (E,8S)-8-[2-(benzyloxy)ethyl]-8-fluoro-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disila-6-tridecene C26H47FO3Si2 详情 详情
(VIII) 36753 (2R)-4-(benzyloxy)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-fluorobutanal C18H29FO3Si 详情 详情
(IX) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(X) 36754 ethyl (E,4S)-6-(benzyloxy)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-2-hexenoate C22H35FO4Si 详情 详情
(XI) 36755 ethyl (4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-6-hydroxyhexanoate C15H31FO4Si 详情 详情
(XII) 36756 ethyl (4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-6-[(methylsulfonyl)oxy]hexanoate C16H33FO6SSi 详情 详情

合成路线65

该中间体在本合成路线中的序号：(XI)

The reaction of 1-benzyl-3-piperidone (I) with trimethylsilylpropargyl alcohol in THF in presence of EtMgBr, followed by deprotection ot the silylated moiety with Bu4NF, yields alcohol (II), which is converted into (III) by treatment with Bu3SnH and Pd(PPh3)4 in toluene, followed by chromatografic separation from its isomer 1-benzyl-3-(3-hydroxy-1-tributylstannyl-1-propen-1-yl)piperidin-3-ol. Cyclization of (III) by means of DEAD and PPh3 in THF affords oxaazaspirodecene (IV), which reacts with (VIII) in presence of LiCl and Pd(PPh3)4 in toluene to provide derivative (IX). Intermediate (VIII) can be obtained as follows: Reduction of 2-bromo-4-nitro-anisole (V) with Fe in H2O/HOAc provides amine (VI) which is then trifluoroacetylated by means of (CF3CO)2O in CH2Cl2 in the presence of Et3N to afford (VII). Finally, treatment of (VII) with PPh3 in CCl4 followed by reaction with NaN3 in DMF affords (VIII). Hydrogenation of (IX) with H2 over Pd/C in HOAc/MeOH (simultaneous reduction of the double bond and loss of the benzylic moiety) yields oxaaxaspirodecane (X), which is finally treated with benzyl bromide and K2CO3 in DMF to obtain the mixture of diastereomers (3R*,5R*) and (3S*,5R*) which are chromatographically separated.

参考文献 中间体
合成目标
【1】 Curtis, N.R.; Huscroft, I.T.; Kulagowski, J.J.; Swain, C.J. (Merck Sharp & Dohme Ltd.); Spiro-piperidine derivs. and their use as therapeutic agents. EP 0912579; US 6071928; WO 9801450 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
41652 bromo[3-[(trimethylsilyl)oxy]-1-propynyl]magnesium C6H11BrMgOSi 详情 详情
(I) 41651 1-benzyl-3-piperidinone 40114-49-6 C12H15NO 详情 详情
(II) 41653 1-benzyl-3-(3-hydroxy-1-propynyl)-3-piperidinol C15H19NO2 详情 详情
(III) 41654 1-benzyl-3-[(E)-3-hydroxy-2-(tributylstannyl)-1-propenyl]-3-piperidinol C27H47NO2Sn 详情 详情
(IV) 41655 7-benzyl-3-(tributylstannyl)-1-oxa-7-azaspiro[4.5]dec-3-ene C27H45NOSn 详情 详情
(V) 41656 2-bromo-1-methoxy-4-nitrobenzene; 2-bromo-4-nitrophenyl methyl ether 5197-28-4 C7H6BrNO3 详情 详情
(VI) 41657 3-bromo-4-methoxyphenylamine; 3-bromo-4-methoxyaniline C7H8BrNO 详情 详情
(VII) 41658 N-(3-bromo-4-methoxyphenyl)-2,2,2-trifluoroacetamide C9H7BrF3NO2 详情 详情
(VIII) 41659 1-(3-bromo-4-methoxyphenyl)-5-(trifluoromethyl)-1H-1,2,3,4-tetraazole; 2-bromo-4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl methyl ether C9H6BrF3N4O 详情 详情
(IX) 41660 7-benzyl-3-[2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl]-1-oxa-7-azaspiro[4.5]dec-3-ene; 2-(7-benzyl-1-oxa-7-azaspiro[4.5]dec-3-en-3-yl)-4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl methyl ether C24H24F3N5O2 详情 详情
(X) 41661 3-[2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl]-1-oxa-7-azaspiro[4.5]decane; methyl 2-(1-oxa-7-azaspiro[4.5]dec-3-yl)-4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl ether C17H20F3N5O2 详情 详情
(XI) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情

合成路线66

该中间体在本合成路线中的序号：(III)

N-Protection of L-Dopa (I) by means of Boc2O and Et3N in H2O-dioxane yields Boc derivative (II), which is then benzylated by reaction with benzyl bromide (III) and K2CO3 in refluxing acetone to provide (IV). Benzyl ester moiety of (IV) is saponified by treatment with NaOH in H2O-dioxane to give carboxylic acid (V), and deprotection of the amino group by means of TFA in CH2Cl2 furnishes trifluoroacetate salt (VI). Acylation of the amine group of (VI) with chloroacetyl chloride (VII) in NaOH yields N-chloroacetyl derivative (VIII), which is cyclized by heating in DMF in the presence of Et3N to afford morpholinedione (IX). Hydrogenation of (IX) over Pd/C in HCl/EtOH provides debenzylated derivative (X), which is finally converted into the desired compound by selective acylation with pivaloyl chloride (XI) in TFA.

参考文献 中间体
合成目标
【1】 Gingolani, G.M.; et al.; Synthesis of L-(+)-3-(3-hydroxy-4-pivaloyloxybenzyl)-2,5-diketomorpholine as potential prodrug of L-Dopa. Bioorg Med Chem Lett 2000, 10, 12, 1385.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15272 (2S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid; 3-hydroxy-L-tyrosine; Levodopa 59-92-7 C9H11NO4 详情 详情
(II) 15273 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propionic acid C14H19NO6 详情 详情
(III) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(IV) 46700 phenyl (3S)-4-[3,4-bis(benzyloxy)phenyl]-3-[(tert-butoxycarbonyl)amino]butanoate C35H37NO6 详情 详情
(V) 46701 (2S)-3-[3,4-bis(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid C28H31NO6 详情 详情
(VI) 46702 (2S)-2-amino-3-[3,4-bis(benzyloxy)phenyl]propionic acid C23H23NO4 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 46703 (2S)-3-[3,4-bis(benzyloxy)phenyl]-2-[(2-chloroacetyl)amino]propionic acid C25H24ClNO5 详情 详情
(IX) 46704 (3S)-3-[3,4-bis(benzyloxy)benzyl]-2,5-morpholinedione C25H23NO5 详情 详情
(X) 46705 (3S)-3-(3,4-dihydroxybenzyl)-2,5-morpholinedione C11H11NO5 详情 详情
(XI) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情

合成路线67

该中间体在本合成路线中的序号：(VI)

Treatment of adenosine (I) with H2O2 and HOAc affords N-oxide (II), which is converted into the benzyloxime (IV) via N-benzyloxyadenosine perchlorate (III). Treatment of (IV) with CS2 and NaOH in MeOH followed by separation by filtration and chromatography yields 2-thioadenosine (V), which is then converted into the sodium thiolate salt by treatment with NaOH in MeOH and condensed with benzylbromide (VI) in DMF, providing derivative (VII). Finally, conversion of (VII) into the target compound is achieved by following these steps: (i) treatment of (VII) with thiophosphoryl chloride (PSCl3) in pyridine; (ii) addition of a mixture of Bu3N and (Bu3NH+)2P2O7H2 in DMF; and (iii) treatment with TEAB and chromatographic separation of regioisomers.

参考文献 中间体
合成目标
【1】 Kikugawa, K.; et al.; Platelet aggregation inhibitors. IX. Chemical transformation of adenosine into 2-thioadenosine derivatives. Chem Pharm Bull 1977, 25, 8, 1959.
【2】 Fischer, B.; Chulkin, A.; Boyer, J.L.; Gendron, F.-P.; Chapal, J.; Petit, P.; Hillaire-Buys, D.; Harden, K.T.; Beaudoin, A.R.; 2-Thiother 5'-O-(1-thiotriphosphate)adenosine derivatives as new insulin secretagogues acting through P2Y-receptors. J Med Chem 1999, 42, 18, 3636.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 44895 (2R,3R,4S)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C10H13N5O4 详情 详情
(II) 44891 6-amino-9-[(2R,3R,4S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-1-ium-1-olate C10H13N5O5 详情 详情
(III) 44892 6-amino-1-(benzyloxy)-9-[(2R,3R,4S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-1-ium perchlorate C17H20ClN5O9 详情 详情
(IV) 44893 5-amino-N'-(benzyloxy)-1-[(2R,3R,4S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carboximidamide C16H21N5O5 详情 详情
(V) 44896 (2R,3R,4S)-2-(6-amino-2-sulfanyl-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C10H13N5O4S 详情 详情
(VI) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(VII) 44894 (2R,3R,4S)-2-[6-amino-2-(benzylsulfanyl)-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol C17H19N5O4S 详情 详情

合成路线68

该中间体在本合成路线中的序号：(IV)

Treatment of allomaltol (I) with acetaldehyde (II) and NaOH in H2O affords pyranone derivative (III), which is benzylated by means of benzyl bromide (IV) and NaOH in refluxing H2O/MeOH to provide compound (V). O-Methylation of (V) by reaction with NaH and MeI in DMF furnishes methoxyethyl derivative (VI), which is then heated with methylamine and NaOH in EtOH/H2O to yield pyridinone derivative (VII). Finally, the benzyl group of (VII) is removed by hydrogenation over Pd/C in MeOH to give the desired product.

参考文献 中间体
合成目标
【1】 Tilbrook, G.S.; Hider, R.C.; Liu, Z. (BTG International Ltd.); Novel orally active iron (III) chelators. WO 9854138 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 45934 5-hydroxy-2-methyl-4H-pyran-4-one C6H6O3 详情 详情
(II) 11974 Acetaldehyde 75-07-0 C2H4O 详情 详情
(III) 45935 3-hydroxy-2-(1-hydroxyethyl)-6-methyl-4H-pyran-4-one C8H10O4 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 45936 3-(benzyloxy)-2-(1-hydroxyethyl)-6-methyl-4H-pyran-4-one C15H16O4 详情 详情
(VI) 45937 3-(benzyloxy)-2-(1-methoxyethyl)-6-methyl-4H-pyran-4-one C16H18O4 详情 详情
(VII) 45938 3-(benzyloxy)-2-(1-methoxyethyl)-1,6-dimethyl-4(1H)-pyridinone C17H21NO3 详情 详情

合成路线69

该中间体在本合成路线中的序号：(IV)

Condensation of 4-fluorobenzenesulfonyl chloride (I) with anthranilic acid derivative (II) by means of pyridine yields sulfonamide derivative (III), which is then N-alkylated by reaction with benzyl bromide (IV) by means of NaH in DMF to furnish compound (V). Saponification of the methyl ester group of (V) by treatment with NaOH in refluxing MeOH affords carboxylic acid (VI) (1), which is then converted into compound (X) by condensation with hydroxy derivative (IX) by means of NaH in DMF. (In turn, compound (IX) can be obtained by coupling of 2-benzofurancarboxylic acid (VII) with ethanolamine (VIII) by means of HOBt/EDC and NMM in DMF. Finally, the target product is obtained by derivatization of the carboxylic acid moiety of (X) with hydroxylamine hydrochloride by means of HOBt/EDC and Et3N in DMF.

参考文献 中间体
合成目标
【2】 Gu, Y.; Nelson, F.C.; Zask, A.; Du, M.T.; Levin, J.I.; Venkatesan, M. (American Cyanamid Co.); Preparation and use of orthosulfonamido aryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors. US 5929097 .
【1】 Levin, J.I.; Nilakantan, R.; Mobilio, D.; Chen, J.M.; Nelson, F.C.; Powers, R.; Moy, F.J.; Zask, A.; Structure-based design of a novel, potent, and selective inhibitor for MMP-13 utilizing NMR spectroscopy and computer-aided molecular design. J Am Chem Soc 2000, 122, 40, 9648.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12292 4-Fluorobenzenesulfonyl chloride 349-88-2 C6H4ClFO2S 详情 详情
(II) 47141 methyl 2-amino-3,5-dimethylbenzoate C10H13NO2 详情 详情
(III) 47142 methyl 2-[[(4-fluorophenyl)sulfonyl]amino]-3,5-dimethylbenzoate C16H16FNO4S 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 47143 methyl 2-[benzyl[(4-fluorophenyl)sulfonyl]amino]-3,5-dimethylbenzoate C23H22FNO4S 详情 详情
(VI) 47144 2-[benzyl[(4-fluorophenyl)sulfonyl]amino]-3,5-dimethylbenzoic acid C22H20FNO4S 详情 详情
(VII) 38339 Benzofuran-2-carboxylic acid; 1-benzofuran-2-carboxylic acid 496-41-3 C9H6O3 详情 详情
(VIII) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(IX) 47145 N-(2-hydroxyethyl)-1-benzofuran-2-carboxamide C11H11NO3 详情 详情
(X) 47146 2-[[(4-[2-[(1-benzofuran-2-ylcarbonyl)amino]ethoxy]phenyl)sulfonyl](benzyl)amino]-3,5-dimethylbenzoic acid C33H30N2O7S 详情 详情

合成路线70

该中间体在本合成路线中的序号：(II)

Synthesis of intermediate (VIII): Condensation of salicyl alcohol (I) with benzyl bromide (II) by means of KOtBu in DMF gives 2-benzyloxybenzyl alcohol (III), which is then converted into chloride (IV) by reaction with SOCl2 in THF. Treatment of derivative (IV) with PPh3 in refluxing toluene furnishes triphenylphosphonium chloride (V), which is then condensed with aldehyde (VI) by means of DBU in acetonitrile to afford benzyloxystilbene derivative (VII). Finally, intermediate (VIII) is obtained by hydrogenation of (VII) over Pd/C in EtOH.

参考文献 中间体
合成目标
【1】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 42341 2-(hydroxymethyl)phenol 90-01-7 C7H8O2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 42342 [2-(benzyloxy)phenyl]methanol C14H14O2 详情 详情
(IV) 42343 benzyl 2-(chloromethyl)phenyl ether; 1-(benzyloxy)-2-(chloromethyl)benzene C14H13ClO 详情 详情
(V) 42344 [2-(benzyloxy)benzyl](triphenyl)phosphonium chloride C32H28ClOP 详情 详情
(VI) 20589 3-methoxybenzaldehyde; m-Anisaldehyde 591-31-1 C8H8O2 详情 详情
(VII) 42345 1-(benzyloxy)-2-[(E)-2-(3-methoxyphenyl)ethenyl]benzene; benzyl 2-[(E)-2-(3-methoxyphenyl)ethenyl]phenyl ether C22H20O2 详情 详情
(VIII) 13604 2-(3-Methoxyphenethyl)phenol C15H16O2 详情 详情

合成路线71

该中间体在本合成路线中的序号：(II)

N-Protection of 4-aminophenylacetonitrile (I) with benzyl bromide (II) by means of K2CO3 and KI in DMF affords dibenzylamino derivative (III), which is then methylated by first treatment with lithium bis(trimethylsilyl)amide (LiN(SiMe3)2) followed by MeI in THF to provide propionitrile derivative (IV). Reduction of the cyano moiety of (IV) by means of borane methylsulfide (BH3.DMS) in refluxing THF, followed by treatment with HCl/MeOH in Et2O, yields propylamine hydrochloride (V), which is then allowed to react with isopropylsulfonyl chloride in CH2Cl2 in the presence of either DBU or Et3N to furnish isopropylsulfonamide derivative (VI). Hydrogenation of (VI) over Pd/C in EtOH in the presence of ammonium formate (NH4+COO-) allows benzyl removal to yield compound (VII), which is finally condensed with benzoyl chloride (VIII) by means of Et3N in CH2Cl2 to provide the target product. Alternatively, protection of the sulfonamide group of derivative (VI) can be performed by means of Boc2O and DMAP. Then hydrogenation of (VI) over Pd/C in EtOH in the presence of ammonium formate (NH4+COO-) allows benzyl removal, yielding compound (IX). Finally, condensation of (IX) with benzoyl chloride (VIII) by means of Et3N in CH2Cl2 followed by Boc removal by means of TFA in CH2Cl2 leads to the desired compound.

参考文献 中间体
合成目标
【1】 Zarrinmayed, H.; et al.; [3H]N-2-(4-benzamido)phenyl)propyl-2-propanesulfonamide: A novel AMPA receptor potentiator and radioligand. J Med Chem 2001, 44, 3, 302.
【3】 Ornstein, P.L.; Jones, W.D.; Zarrinmayeh, H.; Zimmerman, D.M.; Arnold, M.B. (Eli Lilly and Company); N-Substd. sulfonamide derivs.. WO 0006537 .
【2】 Arnold, M.B.; Bleakman, D.; Simon, R.L.; Cantrell, B.E.; Ornstein, P.L.; McKennon, T.E.; Tizzano, J.P.; Bleisch, T.J.; Zimmerman, D.M.; Baker, S.R.; Smith, E.; Zarrinmayeh, H.; Matsumoto, K.; Escribano, A.M. (Eli Lilly and Company); Sulphonamide derivs.. EP 0860428; WO 9833496 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 48841 4-Aminobenzyl cyanide; 4-Aminophenylacetonitrile; p-Aminophenylacetonitrile 3544-25-0 C8H8N2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 48842 2-[4-(dibenzylamino)phenyl]acetonitrile C22H20N2 详情 详情
(IV) 48843 2-[4-(dibenzylamino)phenyl]propanenitrile C23H22N2 详情 详情
(V) 48844 4-(2-amino-1-methylethyl)-N,N-dibenzylaniline; N-[4-(2-amino-1-methylethyl)phenyl]-N,N-dibenzylamine C23H26N2 详情 详情
(VI) 48845 N-[2-[4-(dibenzylamino)phenyl]propyl]-2-propanesulfonamide C26H32N2O2S 详情 详情
(VII) 48846 N-[2-(4-aminophenyl)propyl]-2-propanesulfonamide C12H20N2O2S 详情 详情
(VIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(IX) 48847 tert-butyl 2-(4-aminophenyl)propyl(isopropylsulfonyl)carbamate C17H28N2O4S 详情 详情

合成路线72

该中间体在本合成路线中的序号：(IV)

Swern oxidation of derivative (I) by means of oxalyl chloride and DMSO in CH2Cl2 followed by Wittig reaction with MePPh3Br and BuLi in THF yields alkene (II), which is then converted into alcohol (III) by hydroboration with 9-BBN in EtOH and oxidation with NaOH and H2O2 in THF followed by isomer separation. Benzylation of (III) by means of NaH and BnBr (IV) in DMF, followed by hydrolysis with acetyl chloride (V) in CH2Cl2/MeOH, affords derivative (VI), which is further benzylated with BnBr (IV) and NaH in DMF and then hydrolyzed with HCl in MeOH to provide diol (VII). Derivative (VII) is O-stannylated by means of Bu2SnO in refluxing toluene and selectively allylated with allyl bromide and CsF to furnish compound (VIII), which is then benzylated with BnBr (IV) and NaH in DMF to give completely protected derivative (IX). Removal of the allyl group of (IX) is then performed by catalytic treatment with RhCl(PPh3)3 and DABCO in refluxing EtOH, and subsequent hydrolysis with HCl in refluxing acetone yields inositol derivative (X). Conversion of (X) into protected phosphatidylinositol (XII) is then performed by a standard phosphitylation protocol with BnOP(N-i-Pr2)2 and diisopropylamine-tetrazole, followed by treatment with the imidazolyl derivative (XI) in the presence of tetrazole and final adjustment of the oxidation state of the P atom by means of tert-BuOOH. Finally, hydrogenolysis of the benzyl groups of compound (XII) with Pd(OH)2/C in tert-butanol gives the desired phosphate.

参考文献 中间体
合成目标
【1】 Hu, Y.; et al.; 3-(Hydroxymethyl)-bearing phosphatidylinositol ether lipid analogues and carbonate surrogates block PI3-K, Akt, and cancer cell growth. J Med Chem 2000, 43, 16, 3045.
【2】 Meuillet, E.J.; Kozikowski, A.P.; Hu, Y.; Berggren, M.; Powis, G.; 3-Deoxy-3-substituted-D-myo-inositol imidazolyl ether lipid phosphates and carbonate as inhibitors of the phosphatidylinositol 3-kinase pathway and cancer cell growth. Bioorg Med Chem Lett 2001, 11, 2, 173.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(I) 48135 (3aR,4aR,7aR,8aS)-8-(benzyloxy)-2,2,6,6-tetramethylhexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxol-4-ol C19H26O6 详情 详情
(II) 48136 (3aR,4aS,7aR,8aR)-4-(benzyloxy)-2,2,6,6-tetramethyl-8-methylenehexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxole; (3aR,4aS,7aR,8aR)-2,2,6,6-tetramethyl-8-methylenehexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxol-4-yl benzyl ether C20H26O5 详情 详情
(III) 48137 [(3aR,4aR,7aR,8aS)-8-(benzyloxy)-2,2,6,6-tetramethylhexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxol-4-yl]methanol C20H28O6 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
(VI) 48138 (3aS,4R,5S,6R,7S,7aR)-4-(benzyloxy)-7-[(benzyloxy)methyl]-2,2-dimethylhexahydro-1,3-benzodioxole-5,6-diol C24H30O6 详情 详情
(VII) 48139 (1R,2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-1,2-cyclohexanediol C35H38O6 详情 详情
(VIII) 48140 (1R,2R,3S,4S,5R,6R)-2-(allyloxy)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]cyclohexanol C38H42O6 详情 详情
(IX) 48141 1-[([(1S,2R,3R,4R,5R,6S)-2-(allyloxy)-3,5,6-tris(benzyloxy)-4-[(benzyloxy)methyl]cyclohexyl]oxy)methyl]benzene; allyl (1R,2S,3S,4R,5R,6R)-2,3,4,6-tetrakis(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl ether C45H48O6 详情 详情
(X) 48142 (1R,2S,3S,4R,5R,6R)-2,3,4,6-tetrakis(benzyloxy)-5-[(benzyloxy)methyl]cyclohexanol C42H44O6 详情 详情
(XI) 48143 (2R)-2-(1H-imidazol-1-yl)-3-(octadecyloxy)-1-propanol C24H46N2O2 详情 详情
(XII) 48144 benzyl (2S)-2-(1H-imidazol-1-yl)-3-(octadecyloxy)propyl (1R,2R,3S,4R,5S,6R)-2,3,4,6-tetrakis(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl phosphate C73H95N2O10P 详情 详情

合成路线73

该中间体在本合成路线中的序号：(II)

The cyclization of 2-amino-1-(ethoxycarbonylmethyl)pyridinium bromide (I) with benzyl bromide (II) by means of sodium ethoxide in ethanol gives the target imidazopyridinone derivative.

参考文献 中间体
合成目标
【1】 Saitoh, K.; Fukuda, N.; Matsuno, T.; Yamaguchi, Y.; Kawashima, S.; Higashi, M. (Zenyaku Kogyo Co., Ltd.); Azaindolizinone derivs. and cerebral function improvers containing the same as the active ingredient. EP 1219621; WO 0109131 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 55799 2-amino-1-(2-ethoxy-2-oxoethyl)pyridinium bromide C9H13BrN2O2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
Extended Information