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【结 构 式】

【分子编号】10463

【品名】Benzoyl chloride

【CA登记号】98-88-4

【 分 子 式 】C7H5ClO

【 分 子 量 】140.5688

【元素组成】C 59.81% H 3.59% Cl 25.22% O 11.38%
与该中间体有关的原料药合成路线共 67 条
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合成路线1

该中间体在本合成路线中的序号：(II)

The phenylhydrazone of benzaldehyde (I) is obtained in the usual way, phenylhydrazine (A) with benzaldehyde (B), which by reaction with benzoyl chloride (II) gives (C) and further treatment with HCl in an organic solvent results in the substituted hydrazine hydrochloride (III). Finally, this compound is condensed with levulinic acid (IV) at high temperature.

参考文献 中间体
合成目标
【1】 Francia, E.; Marin, A. (Uriach & Cia S.A.); Procedimiento de obtencion del acido 1-benzoil-2-metilindol-3-acetico. ES 471436 .
【2】 Francia, E.; Garcia Rafanell, J.; Delmetacin. Drugs Fut 1983, 8, 9, 764.
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(A) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(I) 36167 benzaldehyde N-phenylhydrazone 588-64-7 C13H12N2 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 36169 N-phenylbenzohydrazide C13H12N2O 详情 详情
(IV) 36170 4-oxopentanoic acid 123-76-2 C5H8O3 详情 详情
(C) 36168 N-phenyl-N'-[(E)-benzylidene]benzohydrazide C20H16N2O 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The benzoylation of tyrosine (I) with benzoyl chloride (II) in aqueous NaOH gives O,N-(di-benzoyl)-D,L-tyrosine (III), which by reaction with di-n-propylamine (A) by means of ethyl chlorocarbonate and triethylamine in acetone is converted into O,N-(di-benzoyl)-D,L-tyrosyl-di-n-propylamide (IV). Selective hydrolysis of (IV) with NaOH in methanol - water affords N-benzoyl-D,L-tyrosyl-di-n-propylamide (V), which is finally condensed with 2-(diethylamino)ethyl chloride (VI) by means of sodium methoxide in refluxing toluene.

参考文献 中间体
合成目标
【1】 Senin; et al.; Activity of derivatives of tyrosine on gastrointestinal motility. Gastrointestinal Motility in Health and Disease. Duthie, H.L. (Ed.); MTP Press Limited, Lancaster 1978, 417-427.
【2】 Makovec, F.; Rovati, L.; Senini, P. (Rotta Research Laboratorium SpA); O-Tertiary amino-alkyl-N-benzoyl tyrosil amides. DE 2503992; FR 2259592; GB 1467927; JP 50116442; NL 167683C; US 4004008 .
【3】 Serradell, M.N.; de Angelis, L.; Blancafort, P.; Castaner, J.; Tiropramide. Drugs Fut 1982, 7, 6, 413.
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) 21856 N,N-dipropylamine; N-propyl-1-propanamine 142-84-7 C6H15N 详情 详情
(I) 31970 4-Hydroxy-17O-phenylalanine; Hydroxy Phenyl Alanine; DL-tyrosine; 2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)alanine; beta-(p-Hydroxyphenyl)alanine; tyrosine 556-03-6 C9H11NO3 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 31971 N-benzoyl-4-(benzoyloxy)phenylalanine C23H19NO5 详情 详情
(IV) 31972 4-[2-(benzoylamino)-3-(dipropylamino)-3-oxopropyl]phenyl benzoate C29H32N2O4 详情 详情
(V) 31973 N-[2-(dipropylamino)-1-(4-hydroxybenzyl)-2-oxoethyl]benzamide C22H28N2O3 详情 详情
(VI) 16194 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine 100-35-6 C6H14ClN 详情 详情

合成路线3

该中间体在本合成路线中的序号：(D)

N-bromoacetyl compound (IV) can also be obtained by bromoacetylation of (XV) with bromoacetyl bromide (B) in refluxing benzene affording 4-chloro-N-bromoacetyl-N-(2,2,2-trifluoroethyl)aniline (XVI), followed by a Friedel-Crafts reaction with benzoyl chloride by means of AlCl3.

参考文献 中间体
合成目标
【1】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .
【2】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(B) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(IV) 33849 N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-(2,2,2-trifluoroethyl)acetamide C17H12BrClF3NO2 详情 详情
(XV) 33475 N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline C8H7ClF3N 详情 详情
(XVI) 33852 2-bromo-N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)acetamide C10H8BrClF3NO 详情 详情

合成路线4

该中间体在本合成路线中的序号：(D)

The starting benzophenone (I) can also be obtained in several different ways: a) By a Friedel-Crafts reaction of p-chloroaniline (X) and benzoyl chloride (D). b) By reaction of 5-chloroanthranilic acid (XI) with acetic anhydride to the bicyclic compound (XII), which is then submitted to a Grignard reaction with phenylmagnesium bromide (E). c) By oxidation of 2,3-diphenyl-5-chloroindole (XIII) with CrO3 to the N-benzoylbenzophenone (XIV), followed by debenzoylation with NaOH.

参考文献 中间体
合成目标
【1】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .
【2】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(E) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(I) 10279 (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone 719-59-5 C13H10ClNO 详情 详情
(X) 12034 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline 106-47-8 C6H6ClN 详情 详情
(XI) 10285 2-Amino-5-chlorobenzoic acid 635-21-2 C7H6ClNO2 详情 详情
(XII) 33853 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one C9H6ClNO2 详情 详情
(XIII) 33854 5-chloro-2,3-diphenyl-1H-indole C20H14ClN 详情 详情
(XIV) 33855 N-(2-benzoyl-4-chlorophenyl)benzamide C20H14ClNO2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(D)

The reaction of 4-chloro-N-(2,2,2-trifluoroethyl)aniline (V) with ethyleneimine (C) by means of AlCl3 in benzene affords the N-(2-aminoethyl) compound (VI), which is benzoylated with benzoyl chloride (D) as usual yielding the benzamide (VII). Compound (VII) is cyclized with P2O5 in POCl3 giving 7-chloro-1,2-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-3H-1,4-benzodiazepine (VIII), which is finally oxidized with RuO4.

参考文献 中间体
合成目标
【1】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(V) 33475 N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline C8H7ClF3N 详情 详情
(VI) 33476 N(1)-(4-chlorophenyl)-N(1)-(2,2,2-trifluoroethyl)-1,2-ethanediamine; N-(2-aminoethyl)-N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine C10H12ClF3N2 详情 详情
(VII) 33850 N-[2-[4-chloro(2,2,2-trifluoroethyl)anilino]ethyl]benzamide C17H16ClF3N2O 详情 详情
(VIII) 33851 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine C17H14ClF3N2 详情 详情
(C) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线6

该中间体在本合成路线中的序号：

The reaction of 3,4-dihydro-1H-2-benzopyran (VII) with benzoyl chloride and ZnCl2 gives benzoic acid 2-[2-(chloromethyl)phenyl]ethyl ester (XIII), which is condensed with hexamethylenetetramine (XIV) yielding the amminium salt (XV). The hydrolysis of (XV) affords 2-(2-benzoyloxyethyl) benzaldehyde (XVI), which is condensed with nitromethane as before to give the nitrostyrene (XVII). The cyclization of (XVII) with FeCl3 and acetyl chloride as before yields 4-(2-benzoyloxyethyl)-3-chloroindolin-2-one (XVIII), which is dechlorinated with hydrazine and Pd/C to the indolinone (XIX). The hydrolysis of (XIX) with NaOH affords 4-(2-hydroxyethyl)indolin-2-one (XX), which is acylated with TsCl giving the tosylate (XXI). Finally, this compound is condensed with dipropylamine (II).

参考文献 中间体
合成目标
【1】 Hayler, J.D.; et al.; Development of large-scale syntheses or ropinirole in the pursuit of a manufacturing process. Org Process Res Dev 1998, 2, 1, 3.
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
19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
39563 nitromethane 75-52-5 CH3NO2 详情 详情
(II) 21856 N,N-dipropylamine; N-propyl-1-propanamine 142-84-7 C6H15N 详情 详情
(VII) 34866 3,4-dihydro-1H-isochromene 493-05-0 C9H10O 详情 详情
(XIII) 34872 2-(chloromethyl)phenethyl benzoate C16H15ClO2 详情 详情
(XIV) 34873 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane 100-97-0 C6H12N4 详情 详情
(XV) 34874 1-[2-[2-(benzoyloxy)ethyl]benzyl]-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane chloride C22H27ClN4O2 详情 详情
(XVI) 34875 2-formylphenethyl benzoate C16H14O3 详情 详情
(XVII) 34876 2-[(E)-2-nitroethenyl]phenethyl benzoate C17H15NO4 详情 详情
(XVIII) 34877 2-(3-chloro-2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate C17H14ClNO3 详情 详情
(XIX) 34878 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate C17H15NO3 详情 详情
(XX) 34879 4-(2-Hydroxyethyl)indolin-2-one 139122-19-3 C10H11NO2 详情 详情
(XXI) 34880 4-heptanol 589-55-9 C7H16O 详情 详情

合成路线7

该中间体在本合成路线中的序号：

A process for the preparation of taxol has been described: The acylation of baccatin III (I) with 2,2,2-trichloroethyl chloroformate in pyridine yields the chloroformate (II), which is acylated with cinnamic acid (III) by means of oxalyl chloride of dicyclohexylcarbodiimide to the cinnamate (IV). The oxidative addition of tert-butyl N-chlorocarbamate (V) to (IV) by means of OsO4 in water affords the protected amino hydroxyester (VI), which is deprotected with iodotrimethylsilane in acetonitrile to give the free aminoester (VII). The benzoylation of (VII) with benzoyl chloride in pyridine affords the protected N-benzoyl derivative (VIII), which is finally deprotected by treatment with Zn and acetic acid to eliminate the trichloroethoxycarbonyl group.

参考文献 中间体
合成目标
【1】 Colin, M.; Guenard, D.; Gueritte-Voegelein, F.; Potier, P. (Aventis SA); Process for the preparation of taxol and 10-deacetyltaxol. US 4857653 .
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
(I) 10447 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C31H38O11 详情 详情
(II) 10448 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C34H39Cl3O13 详情 详情
(III) 10449 (Z)-3-Phenyl-2-propenoic acid 621-82-9 C9H8O2 详情 详情
(IV) 10450 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-15-[[(Z)-3-phenyl-2-propenoyl]oxy]-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H45Cl3O14 详情 详情
(VI) 10451 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C48H56Cl3NO17 详情 详情
(VII) 10452 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[(3-amino-2-hydroxy-3-phenylpropanoyl)oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H48Cl3NO15 详情 详情
(VIII) 10453 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C50H52Cl3NO16 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IX)

A new partial synthesis for taxol has been reported: The cyclization of N-(4-methoxyphenyl)benzylideneimine (I) with acetoxyacetyl chloride (II) by means of triethylamine in dichloromethane gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (III), which is treated with ceric ammonium nitrate in acetonitrile to afford cis-3-acetoxy-4-phenylazetidin-2-one (IV). Hydrolysis of (IV) with KOH in THF-water yields cis-3-hydroxy-4-phenylazetidin-2-one (V), which is submitted to optical resolution giving the (3R,4S)-isomer (VI). The reaction of (VI) with ethyl vinyl ether (VII) by means of methanesulfonic acid in THF affords (3R,4S)-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (VIII), which is benzoylated with benzoyl chloride (IX) and butyllithium in hexane to give (X). Opening of the azetidine ring of (X) with KOH in THF-water gives (2R,3S)-3-(benzamido)-2-(1-ethoxyethoxy)propanoic acid (XI), which is cyclized with potassium tert-butoxide and methanesulfonyl chloride to (4S,5R)-5-(1-ethoxyethoxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-6-one (XII). Finally, this compound is condensed with 7-O-(triethylsilyl)baccatin III (XIV) [prepared from 10-deacetylbaccatin III (XIII) by successive reaction with triethylsilyl chloride and acetyl chloride] by means of dimethylaminopyridine (DMAP) in pyridine.

参考文献 中间体
合成目标
【1】 Holton, R.A. (University of Florida); Method for preparation of taxol using an oxazinone. US 5015744 .
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) 10455 N-(4-Methoxyphenyl)-N-[(Z)-benzylidene]amine; 4-Methoxy-N-[(Z)-benzylidene]aniline 783-08-4 C14H13NO 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(III) 10457 (3R,4S)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetanyl acetate C18H17NO4 详情 详情
(IV) 10458 (3R,4S)-2-oxo-4-phenylazetanyl acetate C11H11NO3 详情 详情
(V) 63030 cis-3-Hydroxy-4-phenyl-2-azetanone; (3R*,4S*)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(VI) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(VII) 18762 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene 109-92-2 C4H8O 详情 详情
(VIII) 10462 (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone C13H17NO3 详情 详情
(IX) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(X) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 详情 详情
(XI) 10465 (2R,3S)-3-(Benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropionic acid C20H23NO5 详情 详情
(XII) 10466 (4S,5R)-5-(1-Ethoxyethoxy)-2,4-diphenyl-4,5-dihydro-6H-1,3-oxazin-6-one C20H21NO4 详情 详情
(XIII) 10467 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12,15-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate 32981-86-5 C29H36O10 详情 详情
(XIV) 10468 (1S,2S,3R,4S,7R,9R,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XIV)

The synthesis of tritium-labeled taxol [3''-3H]-taxol has been described: The reaction of baccatin III (I) with chlorotriethylsilane in pyridine gives the protected compound (II), which is condensed with cis-1-benzoyl-4-(3-bromophenyl)-3-(triethylsilyloxy)azetidin-2-one (III) by means of butyllithium in THF, yielding 3''-bromo-2',7-bis-O-(triethylsilyl)taxol (IV). The deprotection of (IV) with pyridine and 48% HF in THF affords 3''-bromotaxol (V), which is finally debrominated with tritium by means of Pd/C and triethylamine in THF. The starting azetidinone (III) is obtained as follows: The condensation of 3-bromobenzaldehyde (VI) with 4-methoxyaniline (VII) in refluxing benzene gives the enamine (VIII), which is cyclized with acetoxyacetyl chloride (IX) by means of triethylamine in dichloromethane, yielding cis-3-acetoxy-4-(3-bromophenyl)-1-(4-methoxyphenyl)azetidin-2-one (X). The reaction of (X) with ceric ammonium nitrate (CAN) in acetonitrile affords cis-3-acetoxy-4-(3-bromophenyl)azetidin-2-one (XI), which is deacetylated with KOH in THF-water giving cis-4-(3-bromophenyl)-3-hydroxyazetidin-2-one (XII). The silylation of (XII) with chlorotriethylsilane in pyridine yields cis-4-(3-bromophenyl)-3-(triethylsilyloxy)azetidin-2-one (XIII), which is finally benzoylated with benzoyl chloride (XIV) and butyllithium in THF to afford the desired azetidinone (III).

参考文献 中间体
合成目标
【1】 Taylor, G.F.; Thornton, S.S.; Tallent, C.R.; Kepler, J.A.; Synthesis of [3''-3H]taxol and [13-3H]taxol. J Label Compd Radiopharm 1993, 33, 6, 501.
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) 10447 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C31H38O11 详情 详情
(II) 10473 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(III) 10474 (3R,4S)-1-Benzoyl-4-(3-bromophenyl)-3-[(triethylsilyl)oxy]-2-azetidinone C22H26BrNO3Si 详情 详情
(IV) 10475 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-(3-bromophenyl)-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C59H78BrNO14Si2 详情 详情
(V) 10476 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-3-(3-bromophenyl)-2-hydroxypropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C47H50BrNO14 详情 详情
(VI) 10477 3-Bromobenzaldehyde; m-Bromobenzaldehyde 3132-99-8 C7H5BrO 详情 详情
(VII) 10478 p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine 104-94-9 C7H9NO 详情 详情
(VIII) 10479 N-[(Z)-(3-Bromophenyl)methylidene]-N-(4-methoxyphenyl)amine; N-[(Z)-(3-Bromophenyl)methylidene]-4-methoxyaniline C14H12BrNO 详情 详情
(IX) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(X) 10481 (2S,3R)-2-(3-bromophenyl)-1-(4-methoxyphenyl)-4-oxoazetanyl acetate C18H16BrNO4 详情 详情
(XI) 10482 (2S,3R)-2-(3-bromophenyl)-4-oxoazetanyl acetate C11H10BrNO3 详情 详情
(XII) 10483 (3R,4S)-4-(3-Bromophenyl)-3-hydroxy-2-azetanone C9H8BrNO2 详情 详情
(XIII) 10484 (3R,4S)-4-(3-Bromophenyl)-3-[(triethylsilyl)oxy]-2-azetanone C15H22BrNO2Si 详情 详情
(XIV) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XI)

A new partial synthesis of taxol has been described: The esterification of (1S,2R)-2-phenylcyclohexanol (I) with benzyloxyacetyl chloride (II) gives the corresponding chiral ester (III), which is deprotected by hydrogenolysis to the hydroxy ester (IV). Silylation of (IV) with triisopropylsilyl chloride affords the silylated ester (V), which is cyclized with trimethylsilylbenzaldimine (VI) [obtained from benzaldehyde (VII) and hexamethyldisilazane (HMSA)] by means of butyllithium in THF giving (3R,4S)-3-(triisopropylsilyloxy)-4-phenylazetidin-2-one (VIII). The deprotection of (VIII) with tetrabutylammonium fluoride affords (3R,4S)-3-hydroxy-4-phenylazetidin-2-one (IX), which is treated with ethyl vinyl ether to give the 1-ethoxyethyl ether (X). The benzoylation of (X) with benzoyl chloride (XI) by means of dimethylaminopyridine and triethylamine yields (3R,4S)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (XII), which is condensed with 7-O-(triethylsilyl)baccatin III (XIII) by means of NaH in THF, affording 2'-O-(1-ethoxyethyl)-7-O-(triethylsilyl)taxol (XIV). Finally, this compound is deprotected with HCl in ethanol.

参考文献 中间体
合成目标
【1】 Habus, I.; Zhao, M.; Brigaud, T.; Zucco, M.; Ojima, I.; Sun, C.M.; Park, Y.H.; New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of beta-lactam synthon method. Tetrahedron 1992, 48, 34, 6985.
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) 10492 (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol 2362-61-0 C12H16O 详情 详情
(II) 10493 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride 19810-31-2 C9H9ClO2 详情 详情
(III) 10494 (1S,2R)-2-phenylcyclohexyl 2-(benzyloxy)acetate C21H24O3 详情 详情
(IV) 10495 (1S,2R)-2-phenylcyclohexyl 2-hydroxyacetate C14H18O3 详情 详情
(V) 10496 (1S,2R)-2-phenylcyclohexyl 2-(triisopropylsilyl)acetate C23H38O2Si 详情 详情
(VI) 10507 Trimethyl-N-[(E)-benzylidene]silanamine; N-[(E)-Benzylidene]-N-(trimethylsilyl)amine 17599-61-0 C10H15NSi 详情 详情
(VII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VIII) 10499 (3R,4S)-4-Phenyl-3-[(triisopropylsilyl)oxy]-2-azetanone C18H29NO2Si 详情 详情
(IX) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(X) 10462 (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone C13H17NO3 详情 详情
(XI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XII) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 详情 详情
(XIII) 10473 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(XIV) 10505 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C57H73NO15Si 详情 详情

合成路线11

该中间体在本合成路线中的序号：

A new synthesis of paclitaxel has been reported: The cyclization of the 4-methoxyphenylimine of benzaldehyde (I) with acetoxyacetyl chloride (II) by means of triethylamine gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (III), which is treated with ceric ammonium nitrate to afford cis-3-acetoxy-4-phenylazetidin-2-one (IV). The hydrolysis of (IV) with KOH in THF/water affords the corresponding hydroxy compound (V), which is submitted to optical resolution by crystallization of the 2-methoxy-2-[2-(trifluoromethyl)phenyl]acetic esters. The (3R,4S)-regioisomer (VI) is protected with ethyl vinyl ether, giving the 1-ethoxyethyl derivative (VII), which is benzoylated with benzoyl chloride and butyllithium to afford (3R,4S)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (VIII). The condensation of (VIII) with baccatin III (IX) by means of dimethylaminopyridine (DMAP) in pyridine yields the protected paclitaxel derivative (X), which is finally deprotected with HCl in ethanol/water.

参考文献 中间体
合成目标
【1】 Holton, R.A. (University of Florida); Method for preparation of taxol. EP 0400971; US 5336785 .
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
(I) 10455 N-(4-Methoxyphenyl)-N-[(Z)-benzylidene]amine; 4-Methoxy-N-[(Z)-benzylidene]aniline 783-08-4 C14H13NO 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(III) 10457 (3R,4S)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetanyl acetate C18H17NO4 详情 详情
(IV) 10458 (3R,4S)-2-oxo-4-phenylazetanyl acetate C11H11NO3 详情 详情
(V) 63030 cis-3-Hydroxy-4-phenyl-2-azetanone; (3R*,4S*)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(VI) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(VII) 10462 (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone C13H17NO3 详情 详情
(VIII) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 详情 详情
(IX) 10473 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(X) 10505 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C57H73NO15Si 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XIII)

A new synthesis of [14C]-labeled paclitaxel has been published: The protection of L-threonine methyl ester (I) with tert-butoxydiphenylchlorosilane (BPS-Cl) gives the compound (II), which is condensed with [14C]-labeled benzaldehyde (III), yielding the imine (IV). The cyclization of (IV) with acetoxyacetyl chloride (V) by means of triethylamine affords the azetidinone (VI), which is deprotected with tetrabutylammonium fluoride to the hydroxy ester (VII). The dehydration of (VII) with p-toluenesulfonyl chloride and triethylamine affords the unsaturated ester (VIII), which by ozonolysis is converted to the oxalimide (IX). Elimination of the oxalyl group with hydrazine gives the labeled azetidinone (X), which is deacetylated to the hydroxyazetidinone (XI) and protected with triethylchlorosilane (TES-Cl) to (XII). The benzoylation of (XII) with benzoyl chloride (XIII) and dimethylaminopyridine (DMAP) yields the corresponding benzoylated compound (XIV), which is then condensed with triethylsilyl-baccatin III (XV) by means of butyllithium to afford silylated labeled paclitaxel (XVI). Finally, this compound is deprotected with HCl. The intermediate silylated baccatin III (XV) is obtained from paclitaxel (XVII) by hydrogenolysis with NaBH4 to baccatin III (XVIII) and silylation with triethylsilyl chloride to (XV).

参考文献 中间体
合成目标
【1】 Walker, D.G.; Swigor, J.E.; Standridge, R.T.; Synthesis of paclitaxel-C3'-C-14. J Label Compd Radiopharm 1995, 36, 5, 479.
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) 10674 (2S,3R)-3-Hydroxy-1-methoxy-1-oxo-2-butanaminium chloride C5H12ClNO3 详情 详情
(II) 10675 methyl (2S,3R)-2-amino-3-methoxybutanoate C21H29NO4Si 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 44663 benzaldehyde C7H6O 详情 详情
(IV) 10677 methyl (2S,3R)-3-methoxy-2-[[(E)-benzylidene]amino]butanoate C28H33NO4Si 详情 详情
(IV) 44664 methyl (2S,3R)-3-methoxy-2-[[(E)-benzylidene]amino]butanoate C13H17NO3 详情 详情
(V) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(VI) 10679 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-methoxybutanoate C32H37NO7Si 详情 详情
(VI) 44665 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-methoxybutanoate C17H21NO6 详情 详情
(VII) 10680 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-hydroxybutanoate C16H19NO6 详情 详情
(VII) 44666 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-hydroxybutanoate C16H19NO6 详情 详情
(VIII) 10681 methyl (Z)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-butenoate C16H17NO5 详情 详情
(VIII) 44667 methyl (Z)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-butenoate C16H17NO5 详情 详情
(IX) 10682 methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate C14H13NO6 详情 详情
(IX) 44668 methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate C14H13NO6 详情 详情
(X) 10683 methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate C14H13NO6 详情 详情
(X) 44669 (3R,4S)-2-oxo-4-phenylazetidinyl acetate C11H11NO3 详情 详情
(XI) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(XI) 44670 (3R,4S)-3-hydroxy-4-phenyl-2-azetidinone C9H9NO2 详情 详情
(XII) 10685 (3R,4S)-4-Phenyl-3-[(triethylsilyl)oxy]-2-azetidinone C15H23NO2Si 详情 详情
(XII) 44673 (3R,4S)-3-hydroxy-4-phenyl-2-azetidinone C9H9NO2 详情 详情
(XIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XIV) 10687 (3R,4S)-1-Benzoyl-3-hydroxy-4-phenyl-2-azetidinone C16H13NO3 详情 详情
(XIV) 44671 (3R,4S)-1-benzoyl-3-hydroxy-4-phenyl-2-azetidinone C16H13NO3 详情 详情
(XV) 10473 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(XVI) 10689 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate n/a AB 详情 详情
(XVI) 44672 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C47H51NO14 详情 详情
(XVII) 10595 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate 33069-62-4 C47H51NO14 详情 详情
(XVIII) 10447 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C31H38O11 详情 详情

合成路线13

该中间体在本合成路线中的序号：

A new method for the synthesis of paclitaxel side chain has been developed: The esterification of (S)-phenylglycine (I) with SOCl2 and methanol gives the corresponding methyl ester (II), which is acylated with benzoyl chloride and pyridine to the benzoyl derivative (III). The reduction of (III) with dibutylaluminum hydride (DIBAL) in toluene yields the corresponding aldehyde (IV), which is condensed with 2-(trimethylsilyl)thiazole (V) by means of tetrabutylammonium fluoride (TBAF) to afford the (1R,2S)-N-[2-hydroxy-1-phenyl-2-(2-thiazolyl)ethyl]benzamide (VI) with a 95% enantiomeric purity. The cyclization of (VI) with 2,2-dimethoxypropane (VII) catalyzed by camphosulfonic acid (CSA) gives (4S,5R)-3-benzoyl-2,2-dimethyl-4-phenyl-5-(2-thiazolyl)oxazolidine (VIII), which is treated with methyl trifluoromethanesulfonate to afford (4S,5R)-3-benzoyl-2,2-dimethyl-4-phenyloxazolidine-5-carbaldehyde (IX). Finally, this compound is oxidized with KMnO4 in tert-butanol/aqueous potassium phosphate buffer to yield (4S,5R)-3-benzoyl-2,2-dimethyl-4-phenyloxazolidine-5-carboxylic acid (X), the side chain of paclitaxel suitably protected.

参考文献 中间体
合成目标
【1】 Semola, T.; Dondoni, A.; Perrone, D.; Synthesis of Taxol and Taxotere side chains by 2-(trimethylsilyl)thiazole based homologation of L-phenylglycine. Synthesis 1995, 2, 2, 181.
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
(I) 10716 (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine 2935-35-5 C8H9NO2 详情 详情
(II) 10717 methyl (2S)-2-amino-2-phenylethanoate C9H11NO2 详情 详情
(III) 10718 methyl (2S)-2-(benzoylamino)-2-phenylethanoate C16H15NO3 详情 详情
(IV) 10719 N-[(1S)-2-Oxo-1-phenylethyl]benzamide C15H13NO2 详情 详情
(V) 10720 2-(Trimethylsilyl)-1,3-thiazole 79265-30-8 C6H11NSSi 详情 详情
(VI) 10721 N-[(1S,2R)-2-Hydroxy-1-phenyl-2-(1,3-thiazol-2-yl)ethyl]benzamide C18H16N2O2S 详情 详情
(VII) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(VIII) 10723 [(4S,5R)-2,2-Dimethyl-4-phenyl-5-(1,3-thiazol-2-yl)-1,3-oxazolidin-3-yl](phenyl)methanone C21H20N2O2S 详情 详情
(IX) 10724 (4S,5R)-3-Benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-5-carbaldehyde C19H19NO3 详情 详情
(X) 10725 (4S,5R)-3-Benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-5-carboxylic acid C19H19NO4 详情 详情

合成路线14

该中间体在本合成路线中的序号：(V)

Three partial syntheses of Taxol are described starting from Taxol analogues such as Taxol C or Taxol B (cephalomannine): 1) The reaction of Taxol C (I) with triethylsilyl chloride (TES-Cl) in pyridine gives the bis(triethylsilyl) derivative (II), which by reduction with zirconocene chloride hydride [bis(cyclopentadienyl)zirconium chloride hydride] in dry THF yields compound (III). The hydrolytic cleavage of (III) with simultaneous desilylation by means of HCl in ethanol affords [2aR-[2aalpha,4beta,4abeta,6beta,9alpha(2R,3S),11beta,12alpha,12aalpha,12balpha]]-6,12b-diacetoxy-9-(3-amino-2-hydroxy-3-phenylpropionyloxy)-1 2-benzoyloxy-4,11-dihydroxy-4a,8,13,13-tetramethyl-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxet-5-one (IV) with a free amino group, which is benzoylated with benzoyl chloride (V) and pyridine to Taxol.

参考文献 中间体
合成目标
【1】 Young, T.H. (Hauser, Inc.); Preparation of Taxol and docetaxel through primary amines. EP 0852581; WO 9623780 .
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) 10726 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(hexanoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C46H57NO14 详情 详情
(II) 10727 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(hexanoylamino)-2-methoxy-3-phenylpropanoyl]oxy]-1-hydroxy-9-methoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C48H61NO14 详情 详情
(III) 10728 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(E)hexylideneamino]-2-methoxy-3-phenylpropanoyl]oxy)-1-hydroxy-9-methoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C48H61NO13 详情 详情
(IV) 10729 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C40H47NO13 详情 详情
(V) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线15

该中间体在本合成路线中的序号：(V)

The benzoylation of (IV) with benzoyl chloride (V) and triethylamine in ethyl acetate affords the fully protected Taxol derivative (VI), which is desillylated with HF in acetonitrile giving the partially protected Taxol derivative (VII). Finally, this compound is fully deprotected by hydrogenation with H2 over Pd/C in isopropanal at 40 atm to give taxol.

参考文献 中间体
合成目标
【1】 Sisti, N.J.; Swindell, C.S.; Chander, M.C. (NaPro BioTherapeutics, Inc.); Paclitaxel synthesis from precursor compounds and methods of producing the same. US 5675025 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 10729 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C40H47NO13 详情 详情
(V) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(VI) 10746 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-2-[(benzyloxy)methoxy]-3-phenylpropanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C61H73NO15Si 详情 详情
(VII) 10747 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-2-[(benzyloxy)methoxy]-3-phenylpropanoyl]oxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C55H59NO15 详情 详情

合成路线16

该中间体在本合成路线中的序号：(IX)

A new synthesis of paclitaxel has been reported: The esterification of (2R,3S)-2,3-epoxy-3-phenylpropionic acid (I) with 2-(trimethylsilyl)ethanol (II) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene gives the expected ester (III), which is treated with LiBr in acetic acid to yield the (2R,3R)-3-bromo-2-hydroxy ester (IV). The reaction of (IV) with sodium azide in hot DMF affords the corresponding azido derivative (V), which is reduced with ammonium formate or H2 over Pd/C giving the (2R,3S)-3-amino-2-hydroxy ester (VI). The amidation of (VI) with benzyl chloroformate (VII) yields the corresponding benzyloxycarbonylamino compound (VIII), which is esterified with benzoyl chloride (IX) and triethylamine affording (2R,3S)-2-(benzoyloxy)-3-(benzyloxycarbonylamino)-3-phenylpropionic acid 2-(trimethylsilyl)ethyl ester (X). The condensation of the ester (X) with 7-O-(triethylsilyl)baccatin (XI) by means of 4-(1-pyrrolidinyl)-piperidine (4-PP) and dicyclohexylcarbodiimide (DCC) in hot toluene gives the mixed ester (XII). Finally, this compound is hydrogenated with ammonium formate and Pd/C to obtain a free amino group to which the benzoyl group of the a-position is transferred by a treatment with formic acid yielding pure paclitaxel.

参考文献 中间体
合成目标
【1】 Gao, Y.; Zepp, C.M. (Sepracor Inc.); Taxol process and cpds.. US 5760251 .
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) 20322 (2R,3S)-3-phenyl-2-oxiranecarboxylic acid C9H8O3 详情 详情
(II) 20323 2-(trimethylsilyl)-1-ethanol 2916-68-9 C5H14OSi 详情 详情
(III) 20324 2-(trimethylsilyl)ethyl (2R,3S)-3-phenyl-2-oxiranecarboxylate C14H20O3Si 详情 详情
(IV) 20325 2-(trimethylsilyl)ethyl (2S,3S)-3-bromo-2-hydroxy-3-phenylpropanoate C14H21BrO3Si 详情 详情
(V) 20326 2-(trimethylsilyl)ethyl (2R,3S)-3-azido-2-hydroxy-3-phenylpropanoate C14H21N3O3Si 详情 详情
(VI) 20327 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoate C14H23NO3Si 详情 详情
(VII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VIII) 20329 2-(trimethylsilyl)ethyl (2R,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-3-phenylpropanoate C22H29NO5Si 详情 详情
(IX) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(X) 20331 (1R,2S)-2-[[(benzyloxy)carbonyl]amino]-2-phenyl-1-[[2-(trimethylsilyl)ethoxy]carbonyl]ethyl benzoate C29H33NO6Si 详情 详情
(XI) 20332 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(XII) 20333 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[((2R,3S)-2-(benzoyloxy)-3-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C61H71NO16Si 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VII)

The reaction of baccatine III (I) with trichloroacetyl chloride in pyridine gives 7-O-(trichloroacetyl)baccatine III (II), which is condensed with 2,3-epoxy-3-phenylpropionic acid (III) by means of DCC and DMAP in toluene to yield the ester (IV). Opening of the epoxide ring of (IV) by means of sodium azide and methyl formate in methanol affords the expected hydroxy azide (V), which is reduced with PPh3 in dichloromethane/water to provide the corresponding amino derivative (VI). Finally, the amino group of (VI) is benzoylated with benzoyl chloride (VII) and NaHCO3 in ethyl acetate/water to furnish the target paclitaxel.

参考文献 中间体
合成目标
【1】 Bombardelli, E.; Pontiroli, A.; Battaglia, A.; Dambruoso, P.; Guerrini, A. (Indena SpA); A process for the preparation of paclitaxel. WO 0246177 .
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) 10447 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C31H38O11 详情 详情
(II) 38901 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(2,2,2-trichloroacetyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C33H37Cl3O12 详情 详情
(III) 23891 (2R,3R)-3-phenyl-2-oxiranecarboxylic acid C9H8O3 详情 详情
(IV) 54903 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(2,2,2-trichloroacetyl)oxy]-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl (2R,3R)-3-phenyl-2-oxiranecarboxylate C42H43Cl3O14 详情 详情
(V) 54904 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-{[(2R,3S)-3-azido-2-hydroxy-3-phenylpropanoyl]oxy}-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate C40H45N3O13 详情 详情
(VI) 10729 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C40H47NO13 详情 详情
(VII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线18

该中间体在本合成路线中的序号：(V)

The Grignard reaction of phenylmagnesium bromide (I) with 11C labeled CO2 (II) in THF gives the radiolabeled benzoic acid (III), which is treated with phthaloyl dichloride (IV) in the same solvent to yield radiolabeled benzoyl chloride (V). Finally, this compound is treated with N-debenzoylated paclitaxel (VI) in acetonitrile to afford the target radiolabeled paclitaxel.

参考文献 中间体
合成目标
【1】 Ravert, H.T.; et al.; Radiosynthesis of [11C]paclitaxel. J Label Compd Radiopharm 2002, 45, 6, 471.
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) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(III) 10202 Benzoic acid 65-85-0 C7H6O2 详情 详情
(III) 55347 benzoic acid C7H6O2 详情 详情
(IV) 23811 phthaloyl dichloride;1,2-Benzenedicarbonyl dichloride;o-Phthaloyl chloride 88-95-9 C8H4Cl2O2 详情 详情
(V) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(V) 55348 benzoyl chloride C7H5ClO 详情 详情
(VI) 10729 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C40H47NO13 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XI)

The reaction of (2R,3S)-phenylisoserine (I) with 2-propynyl chloroformate (II) in aq. NaHCO3 gives the N-acylated compound (III), which is treated with diazomethane in ethyl ether (CDI and methanol) to yield the corresponding methyl ester (IV). The reaction of (IV) with 2-methoxypropene (V) and pyridinium p-toluenesulfonate in toluene affords the oxazolidine (VI), which is treated with LiOH in water to provide the oxazolidine-5-carboxylic acid (VII). The esterification of 7-O-(trichloroethoxycarbonyl)baccatin (VIII) with acid (VII) by means of DCC in toluene gives the corresponding ester (IX), which is treated with ammonium tetrathiomolybdate to cleave the oxazolidine ring and yield the 3-amino-2-hydroxypropionyl ester (X). The reaction of (X) with benzoyl chloride (XI) and NaHCO3 in ethyl acetate affords the expected benzamido derivative (XII), which is finally deprotected by means of Zn and AcOH to afford the target paclitaxel.

参考文献 中间体
合成目标
【1】 Sharma, A.P.; Sarkar, S. (Dabur India Ltd.); Method of preparation of paclitaxel (Taxol) using 3-(alk-2-ynyloxy)carbonyl-5-oxazolidine carboxylic acid. WO 0266448 .
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) 54908 (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoic acid 136561-53-0 C9H11NO3 详情 详情
(II) 55690 Propargyl chloroformate C4H3ClO2 详情 详情
(III) 55691 (2R,3S)-2-hydroxy-3-phenyl-3-{[(2-propynyloxy)carbonyl]amino}propanoic acid C13H13NO5 详情 详情
(IV) 55692 methyl (2R,3S)-2-hydroxy-3-phenyl-3-{[(2-propynyloxy)carbonyl]amino}propanoate C14H15NO5 详情 详情
(V) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(VI) 55693 5-methyl 3-(2-propynyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate C17H19NO5 详情 详情
(VII) 55694 (4S,5R)-2,2-dimethyl-4-phenyl-3-[(2-propynyloxy)carbonyl]-1,3-oxazolidine-5-carboxylic acid C16H17NO5 详情 详情
(VIII) 10448 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C34H39Cl3O13 详情 详情
(IX) 55695 5-((1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl) 3-(2-propynyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate C50H54Cl3NO17 详情 详情
(X) 10554 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H48Cl3NO15 详情 详情
(XI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XII) 55696 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetyloxy)-15-{[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-1,4-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate C48H50Cl3NO15 详情 详情

合成路线20

该中间体在本合成路线中的序号：(III)

The hydrogenation of the protected taxol derivative (I) with H2 over Pd/C in aqueous THF in the presence of HCl gives the 3'-amino-taxol derivative (II), which is N-benzoylated by means of benzoyl chloride (III) and TEA to provide the target paclitaxel.

参考文献 中间体
合成目标
【1】 McChesney, J.D.; Zygmunt, J. (NaPro BioTherapeutics, Inc.); Two-step conversion of protected taxane ester to paclitaxel. WO 0285878 .
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) 56876 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-({(2R,3S)-3-{[(benzyloxy)carbonyl]amino}-2-[(benzyloxy)methoxy]-3-phenylpropanoyl}oxy)-9-{[(benzyloxy)carbonyl]oxy}-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate C64H67NO18 详情 详情
(II) 10729 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C40H47NO13 详情 详情
(III) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线21

该中间体在本合成路线中的序号：

The benzoylation of 2'-deoxy-5-iodouridine (I) with benzoyl chloride by means of pyridine in dichloromethane gives 5'-O-benzoyl-2'-deoxy-5-iodouridine (II), which is treated with benzyl trichloroacetimidate (III) and trifluoromethanesulfonic acid in dichloromethane - THF to afford the 3'-O-benzyl derivative (IV). The hydrolysis of (IV) with sodium ethoxide in ethanol yields 3'-O-benzyl-2'-deoxy-5-iodouridine (V), which is finally trifluoromethylated with bromotrifluoromethane and copper in pyridine-DMF by means of dimethylaminopyridine. The tritylation of 2'-deoxyuridine (IX) with trityl chloride in hot pyridine gives 2'-deoxy-5'-O-trityluridine (X), which is benzylated with benzyl chloride and NaH in THF yielding 3'-O-benzyl-2'-deoxy-5'-O-trityluridine (XI). The photochemical trifluoromethylation of (XI) with N-nitroso-N-(trifluoromethyl)trifluoromethanesulfonamide and biacetyl in acetonitrile irradiated with a high-pressure Hg lamp in a glass tube at room temperature affords 3'-O-benzyl-2'-deoxy-5-(trifluoromethyl-5'-O-trityluridine (XII), which is finally deprotected with HCl in methanol.

参考文献 中间体
合成目标
【1】 Fujii, S.; Yamashita, J.; Matsumoto, H.; Takeda, S.; Terada, T.; Yasumoto, M.; Unemi, N. (Taiho Pharmaceutical Co., Ltd.); Novel 2'-deoxy-5-substd. uridine derivs., processes for preparing the same and antitumor agent containing the same. EP 0129984; ES 8606381; ES 8606382; ES 8607982; ES 8706715; JP 1984216899; JP 1985061591 .
【2】 Yasumoto, M.; Matsumoto, H.; Tada, Y.; Kobayashi, K.; Noguchi, K. (Taiho Pharmaceutical Co., Ltd.); Method for the preparation of 3'-O-benzyl-2'-deoxy-beta-uridines. JP 1987187484 .
【3】 Yamashita, J.-I.; Takeda, S.; Matsumoto, H.; Unemi, N.; Yasumoto, M.; Studies on antitumor agents. 8. Antitumor activities of O-alkyl derivatives of 2'-deoxy-5-(trifluoromethyl)uridine and 2'-deoxy-5-fluorouridine. J Med Chem 1989, 32, 1, 136-139.
【4】 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
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 31154 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione 54-42-2 C9H11IN2O5 详情 详情
(II) 31155 [(2R,3S,5R)-3-hydroxy-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate C16H15IN2O6 详情 详情
(III) 31156 benzyl 2,2,2-trichloroethanimidoate 81927-55-1 C9H8Cl3NO 详情 详情
(IV) 31157 [(2R,3S,5R)-3-(benzyloxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate C23H21IN2O6 详情 详情
(V) 31158 1-[(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione C16H17IN2O5 详情 详情
(IX) 11875 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; 2'-Deoxyuridine 951-78-0 C9H12N2O5 详情 详情
(X) 31159 1-[(2R,4S,5R)-4-hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C28H26N2O5 详情 详情
(XI) 31160 1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C35H32N2O5 详情 详情
(XII) 31161 1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione C36H31F3N2O5 详情 详情

合成路线22

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23

该中间体在本合成路线中的序号：

The condensation of 1-benzoyl-1,2,2a,3,4,5-hexahydrobenzo[c,d]indol-4-one (I) with methylamine followed by acylation of the resulting enamine with benzoyl chloride gives 1,N-dibenzoyl-4-(methylamino)-1,2,2a,3-tetrahydrobenzo[c,d]indole (II) which, by irradiation with UV light in acetone, is isomerized to (5aR*,6aS*,12bS*)-4-benzoyl-7-methyl-4,5,5a,6,6a,7,8,12b-octahydroindolo[4,3-ab]phenanthridin-8-one (III). The reduction of (III) with LiAlH4 in ether, followed by hydrolysis with NaOH, and optical resolution with (+)-mandelic acid affords (+)-(5aS,6aR,12bR)-7-methyl-4,5,5a,6,6a,7,8,12b-octahydroindolo[4,3-ab]phenanthridine (IV), which is finally dehydrogenated with MnO2 in methylene chloride.

参考文献 中间体
合成目标
【1】 Hagenbach, A.; Seiler, M.P.; Wuthrich, H.J. (Novartis AG; Novartis Deutschland GmbH); Indolophenanthidines, their preparation and use. DE 3402392; EP 0155903; ES 8606339; JP 1985197687; US 4634708 .
【2】 Prous, J.; Castaner, J.; CY-208-243. Drugs Fut 1990, 15, 4, 344.
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
(I) 11143 1-Benzoyl-1,2,2a,5-tetrahydrobenzo[cd]indol-4(3H)-one C18H15NO2 详情 详情
(II) 11144 N-(1-Benzoyl-1,2,2a,3-tetrahydrobenzo[cd]indol-4-yl)-N-methylbenzamide C26H22N2O2 详情 详情
(III) 11145 (5aR,6aR,12bS)-4-Benzoyl-7-methyl-4,5,5a,6a,7,12b-hexahydroindolo[4,3-ab]phenanthridin-8(6H)-one C26H22N2O2 详情 详情
(IV) 11146 (5aR,6aR,12bR)-7-Methyl-4,5,5a,6,6a,7,8,12b-octahydroindolo[4,3-ab]phenanthridine C19H20N2 详情 详情

合成路线24

该中间体在本合成路线中的序号：(C)

The dehydrogenation of 3beta-hydroxycholest-5-en-24-one with dichlorodicyanobenzoquinone in refluxing dioxane, or of cholest-4-ene-3,24-dione (II) with chloranil in refluxing tert-butyl alcohol gives cholesta-1,4,6-triene-3,24-dione (III), which is epoxidized with 30% H2O2 and NaOH in methanol-dioxane-THF yielding 1 alpha,2alpha-epoxycholesta-4,6-diene-3,24-dione (IV). The reduction of (IV) with Li in liquid NH3 affords 1alpha,3beta,24-trihydroxycholest-5-ene (V), which is benzoylated with benzoyl chloride in pyridine and submitted to column chromatography on silica gel to give 1alpha,3beta,24R-tribenzoyloxycholest-5-ene (VI). The dehydrogenation of (VI) with dibromodimethylhydantoin of N-bromosuccinimide yields lalpha,3beta,24R-trihydroxy-cholesta-5,7-diene (VII), which is finally submitted to irradiation with a medium-pressure Hg lamp in ether.

参考文献 中间体
合成目标
【1】 Ikekawa, N.; Koizumi, N.; Morisaki, M.; Synthesis of active forms of vitamin D. Part IX. S. J Chem Soc - Perkins Trans I 1975, 1421.
【2】 Takeshita, T.; Hashimoto, Y.; Kawashima, H.; Ishimoto, S.; Ikekawa, N.; Morisaki, M. (Teijin Ltd.); 1alpha,24-Dihydroxycholecalciferol derivs. and pro. DE 2526981; US 4022891 .
【3】 Castaner, J.; Prous, J.; TV-02. Drugs Fut 1988, 13, 2, 133.
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) 21890 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile 84-58-2 C8Cl2N2O2 详情 详情
(B) 21891 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil 118-75-2 C6Cl4O2 详情 详情
(I) 21883 6-[(3S,10R,13R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-3-heptanone C27H44O2 详情 详情
(II) 21884 (10R,13R)-17-(1,5-dimethyl-4-oxohexyl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one C27H42O2 详情 详情
(III) 21885 (10S,13R)-17-(1,5-dimethyl-4-oxohexyl)-10,13-dimethyl-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-one C27H38O2 详情 详情
(IV) 21886 (2aR,3aR,3bR,5aR)-6-(1,5-dimethyl-4-oxohexyl)-3b,5a-dimethyl-2a,3a,3b,3c,4,5,5a,6,7,8,8a,8b-dodecahydro-2H-cyclopenta[7,8]phenanthro[3,4-b]oxiren-2-one C27H38O3 详情 详情
(V) 21887 (1S,3R,10R,13R)-17-(4-hydroxy-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol C27H46O3 详情 详情
(VI) 21888 (1S,3R,10R,13R)-1-(benzoyloxy)-17-[(4R)-4-(benzoyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl benzoate C48H58O6 详情 详情
(VII) 21889 (1S,3R,10R,13R)-17-[(4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol C27H44O3 详情 详情
(C) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线25

该中间体在本合成路线中的序号：(A)

The cyclization of 2,4-dichlorophenacyl bromide (I) with glycerol (II) gives cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-hydroxymethyl-1,3-dioxolane (III), which is then benzoylated with benzoyl chloride (A) yielding cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-benzoyloxymethyl-1,3-dioxolane (IV). The condensation of (IV) with 1H-imidazole (V) affords cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-benzoyloxymethyl-1,3-dioxolane (VI), which is then debenzoylated in basic medium giving cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolane (VII). The reaction of (VII) with methanesulfonyl chloride (B) yields cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate (VIII). Finally, this compound is condensed with 1-acetyl-4-(4-hydroxyphenyl)piperazine (IX) by means of NaH in benzene - DMSO. Compound (IX) is obtained by reaction of 4-(1-piperazinyl)phenol dihydrobromide (X) with acetic anhydride by means of K2CO3 in refluxing acetic acid.

参考文献 中间体
合成目标
【1】 Heeres, J.; et al.; DE 2804096 .
【2】 Blancafort, P.; Sweetman, A.J.; Castaner, J.; Serradell, M.N.; Ketoconazole. Drugs Fut 1979, 4, 7, 496.
【3】 Backx, L.J.J.; Mostmans, J.H.; Heeres, J. (Janssen Pharmaceutica NV); 1-(1,3-Dioxolan-2-ylmethyl)-1H-imidazoles. US 4335125 .
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) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(B) 13467 Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride 124-63-0 CH3ClO2S 详情 详情
(I) 36408 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone C8H5BrCl2O 详情 详情
(II) 13289 Glycerine; Glycerin; Glycerol 56-81-5 C3H8O3 详情 详情
(III) 39602 [(2S,4R)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methanol C11H11BrCl2O3 详情 详情
(IV) 30485 [(2S,4S)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate; cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate C18H15BrCl2O4 详情 详情
(V) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情
(VI) 39603 [(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl benzoate C21H18Cl2N2O4 详情 详情
(VII) 39604 [(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methanol 170210-50-1 C14H14Cl2N2O3 详情 详情
(VIII) 39605 [(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate; cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate C15H16Cl2N2O5S 详情 详情
(IX) 29119 1-Acetyl-4-(4-hydoxyphenyl)piperazine; 1-[4-(4-hydroxyphenyl)-1-piperazinyl]-1-ethanone; N-Acetyl-4-(4-hydoxyphenyl)piperazine 67914-60-7 C12H16N2O2 详情 详情
(X) 39606 4-(1-piperazinyl)phenol; 1-(4-Hydroxyphenyl)piperazine 56621-48-8 C10H14N2O 详情 详情

合成路线26

该中间体在本合成路线中的序号：(II)

The reaction of lovastatin (I) with benzoyl chloride (II) and pyridine gives the expected benzoate (III), which is treated with ethyleneglycol (IV), triethyl orthoformate and H2SO4 to yield the cyclic orthoformate (V). The methylation of (V) by means of MeI and BuLi in pyrrolidine affords the 2,2-dimethylbutyrate ester (VI), which is finally deprotected with HCl in THF to provide the target simvastatin.

参考文献 中间体
合成目标
【1】 Dabak, K.; Adiyaman, M.; A new method for the synthesis of antihypercholesterolemic agent simvastatin. Helv Chim Acta 2003, 86, 3, 673.
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) 64415 (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate C24H36O5 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 64416 (2R,4R)-2-[2-((1S,2S,6R,8S,8aR)-2,6-dimethyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8a-hexahydro-1-naphthalenyl)ethyl]-6-oxotetrahydro-2H-pyran-4-yl benzoate C31H40O6 详情 详情
(IV) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(V) 64417 (7R,9R)-7-[2-((1S,2S,6R,8S,8aR)-2,6-dimethyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8a-hexahydro-1-naphthalenyl)ethyl]-1,4,6-trioxaspiro[4.5]dec-9-yl benzoate C33H44O7 详情 详情
(VI) 64418 (1S,3R,7S,8S,8aR)-8-{2-[(7R,9R)-9-hydroxy-1,4,6-trioxaspiro[4.5]dec-7-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate C27H42O6 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 benzoylation of thiazolidine-4(R)-carboxylic acid (I) with benzoyl chloride (II) by means of NaOH in acetone water gives the corresponding N-benzoyl derivative (III), which is then condensed with alpha-(R)-methylbenzylamine (IV) by means of isobutyl chloroformate and triethylamine in dichloromethane.

参考文献 中间体
合成目标
【1】 Matsui, T.; Nagano, M.; KLitamura, K.; Shimizu, F. (Sankyo Co., Ltd.); Amino acid derivatives having anti-tumor activity and compositions containing them.. EP 0173441; ES 8703830; US 4904680 .
【2】 Castaner, J.; Prous, J.; RS-0481. Drugs Fut 1988, 13, 7, 627.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(I) 12899 L-(-)-Thiazolidine-4-carboxylic acid; (4R)-1,3-Thiazolidine-4-carboxylic acid; (R)-(-)-Thiazolidine-4-carboxylic acid 34592-47-7 C4H7NO2S 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 22557 (4R)-3-benzoyl-1,3-thiazolidine-4-carboxylic acid C11H11NO3S 详情 详情
(IV) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情

合成路线28

该中间体在本合成路线中的序号：(VI)

4-Chloro-alpha-methylbenzhydrol (I) is alkylated with N-(2-chloroethyl)hexamethyleneimine (II) in benzene in the presence of sodium amide to give setastine. The starting products are obtained as follows; Caprolactame (III) is O-alkylated with dimethyl sulfate to yield the lactimether (IV), which is reduced with sodium borohydride to hexamethyleneimine (II). Friedel Cratts acylation of chlorobenzene (V) with benzoyl chloride (VI) affords the benzophenone (VII), to which methylmagnesium bromide is added to give the carbinol (I).

参考文献 中间体
合成目标
【1】 Rakoczi, J.; Bolla, K.; Beck, I.; Porszasz, K. (Egis Pharmaceuticals Ltd.); New benzhydryloxy-alkylamine derivs. and process f. DE 2528194; GB 1463038 .
【2】 Nogradi, M.; Setastine hydrochloride. Drugs Fut 1987, 12, 4, 357.
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) 22917 1-(4-chlorophenyl)-1-phenyl-1-ethanol C14H13ClO 详情 详情
(II) 22918 1-(2-chloroethyl)azepane C8H16ClN 详情 详情
(III) 22919 2-azepanone 105-60-2 C6H11NO 详情 详情
(IV) 22920 7-methoxy-3,4,5,6-tetrahydro-2H-azepine; methyl 3,4,5,6-tetrahydro-2H-azepin-7-yl ether 2525-16-8 C7H13NO 详情 详情
(V) 10190 1-Chlorobenzene 108-90-7 C6H5Cl 详情 详情
(VI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(VII) 22923 (4-chlorophenyl)(phenyl)methanone; 4-Chlorobenzophenone 134-85-0 C13H9ClO 详情 详情

合成路线29

该中间体在本合成路线中的序号：(II)

1) The Friedel-Crafts condensation of 4,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester (I) with benzoyl chloride (II) by means of AlCl3 in dichloroethane, followed by hydrolysis with ethanolic NaOH gives 5-benzoyl-4,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (III), which by reaction with hydroxylamine in refluxing pyridine is converted into the corresponding oxime (IV). Finally, this compound is cyclized with NaH in DMF or with KOH in ethanol. 2) The Friedel-Crafts condensation of (V) with (II) as before gives 2-hydroxy-4-methoxybenzophenone (XVI), which by cyclocondensation with hydroxylamine as before is converted into 6-methoxy-3-phenyl-1,2-benzisoxazole (XVII). Demethylation of (XVII) as already indicated yields 6-hydroxy-3-phenyl-1,2-benzisoxazole (XVIII), which is converted into the allyloxy derivative (XIX). The rearrangement of (XIX) with N,N-dimethylamine as before affords the 7-allyl derivative (XX), which is cyclized with m-chloroperbenzoic acid (m-CPBA) to 3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol (XXI). Finally, this compound is chlorinated with SO2Cl2 in CH2Cl2 yielding compound (XV), which is oxidized with CrO3 / H2SO4 or KMnO4 in dichloromethane.

参考文献 中间体
合成目标
【1】 Sato, H.; Koga, H.; Dan, T.; Onuma, E. (Chugai Pharmaceutical Co. Ltd.); Furobenzisoxazole derivs. EP 0205872; US 4791209 .
【2】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the preparation of furobenzisoxazole derivs. JP 1989131180 .
【3】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the synthesis of furobenzisoxazole derivs. JP 1989143876 .
【4】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Industrial process for the preparation of furobenzisoxazole derivs. JP 1989143875 .
【5】 Prous, J.; Castaner, J.; AA-193. Drugs Fut 1991, 16, 11, 985.
【6】 Onuma, E.; Dan, T.; Koga, H.; Sato, H.; Aoki, B.; Tanaka, H.; Studies on uricosuric diuretics. II. Substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids. Chem Pharm Bull 1991, 39, 7, 1760-72.
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) 11930 ethyl 4,7-dichloro-2,3-dihydro-1-benzofuran-2-carboxylate C11H10Cl2O3 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 11932 5-Benzoyl-4,7-dichloro-2,3-dihydro-1-benzofuran-2-carboxylic acid C16H10Cl2O4 详情 详情
(IV) 11933 4,7-Dichloro-5-[(hydroxyimino)(phenyl)methyl]-2,3-dihydro-1-benzofuran-2-carboxylic acid C16H11Cl2NO4 详情 详情
(V) 11934 m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether 151-10-0 C8H10O2 详情 详情
(XV) 11941 (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol C16H12ClNO3 详情 详情
(XVI) 11935 2-Hydroxy-4-methoxybenzophenone; (2-Hydroxy-4-methoxyphenyl)(phenyl)methanone 131-57-7 C14H12O3 详情 详情
(XVII) 11936 Methyl 3-phenyl-1,2-benzisoxazol-6-yl ether; 6-Methoxy-3-phenyl-1,2-benzisoxazole C14H11NO2 详情 详情
(XVIII) 11937 3-Phenyl-1,2-benzisoxazol-6-ol C13H9NO2 详情 详情
(XIX) 11938 6-(Allyloxy)-3-phenyl-1,2-benzisoxazole; Allyl 3-phenyl-1,2-benzisoxazol-6-yl ether C16H13NO2 详情 详情
(XX) 11939 7-Allyl-3-phenyl-1,2-benzisoxazol-6-ol C16H13NO2 详情 详情
(XXI) 11940 (3-Phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol C16H13NO3 详情 详情

合成路线30

该中间体在本合成路线中的序号：(II)

3) The chlorination of 1,3-dimethoxybenzene (V) with SO2Cl2 in CHCl3 gives 1-chloro-2,4-dimethoxybenzene (VI), which is condensed with (II) by means of AlCl3 in dichloroethane yielding 5-chloro-2-hydroxy-4-methoxybenzophenone (VII). The cyclocondensation of (VII) with hydroxylamine - HCl and then with acetic anhydride - sodium acetate in refluxing DMF affords 5-chloro-6-methoxy-3-phenyl-1,2-benzoisoxazole (VIII), which is demethylated with pyridine hydrochloride at 180 C, giving 5-chloro-6-hydroxy-3-phenyl-1,2-benzoisoxazole (IX). The condensation of (IX) with dimethylamine and formaldehyde in water gives 5-chloro-7-(dimethylaminomethyl)-6-hydroxy-3-phenyl-1,2-benzoisoxazole (X), which is cyclized with (ethoxycarbonylmethyl)dimethylsulfonium bromide (XI) by means of K2CO3 in DMF, yielding 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzoisoxazole-7-carboxyli c acid ethyl ester (XII). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol. 4) The condensation of isoxazole (IX) with allyl bromide by means of K2CO3 in DMF gives 6-allyloxy-5-chloro-3-phenyl-1,2-benzoisoxazole (XIII), which is rearranged with refluxing N,N-dimethylaniline yielding 7-allyl-5-chloro-6-hydroxy-3-phenyl-1,2-benzisoxazole (XIV). The cyclization of (XIV) with m-chloroperbenzoic acid (MCPBA) in refluxing CHCl3 or N-bromosuccinimide in DMSO affords 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol (XV), which is finally oxidized with CrO3-H2SO4 in acetone or KMnO4 in dichloroethane. 5) The alkylation of phenol (IX) with ortho-acrylic acid trietyl ester (XXI) by means of pivalic acid in refluxing toluene gives the substituted chromane (XXIII), which is then treated with Br2 in pyridine-CHCl3 to afford ethyl ester (XII), already obtained.

参考文献 中间体
合成目标
【1】 Sato, H.; Koga, H.; Dan, T.; Onuma, E. (Chugai Pharmaceutical Co. Ltd.); Furobenzisoxazole derivs. EP 0205872; US 4791209 .
【2】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Industrial process for the preparation of furobenzisoxazole derivs. JP 1989143875 .
【3】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the synthesis of furobenzisoxazole derivs. JP 1989143876 .
【4】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the preparation of furobenzisoxazole derivs. JP 1989131180 .
【5】 Prous, J.; Castaner, J.; AA-193. Drugs Fut 1991, 16, 11, 985.
【6】 Onuma, E.; Dan, T.; Koga, H.; Sato, H.; Aoki, B.; Tanaka, H.; Studies on uricosuric diuretics. II. Substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids. Chem Pharm Bull 1991, 39, 7, 1760-72.
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) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(V) 11934 m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether 151-10-0 C8H10O2 详情 详情
(VI) 11942 1-Chloro-2,4-dimethoxybenzene; 2-Chloro-5-methoxyphenyl methyl ether 7051-13-0 C8H9ClO2 详情 详情
(VII) 11943 (5-Chloro-2-hydroxy-4-methoxyphenyl)(phenyl)methanone C14H11ClO3 详情 详情
(VIII) 11944 5-Chloro-3-phenyl-1,2-benzisoxazol-6-yl methyl ether; 5-Chloro-6-methoxy-3-phenyl-1,2-benzisoxazole C14H10ClNO2 详情 详情
(IX) 11945 5-Chloro-3-phenyl-1,2-benzisoxazol-6-ol C13H8ClNO2 详情 详情
(X) 11946 5-Chloro-7-[(dimethylamino)methyl]-3-phenyl-1,2-benzisoxazol-6-ol C16H15ClN2O2 详情 详情
(XI) 11947 (2-Ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide 5187-82-6 C6H13BrO2S 详情 详情
(XII) 11948 ethyl 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazole-7-carboxylate C18H14ClNO4 详情 详情
(XIII) 11949 Allyl 5-chloro-3-phenyl-1,2-benzisoxazol-6-yl ether; 6-(Allyloxy)-5-chloro-3-phenyl-1,2-benzisoxazole C16H12ClNO2 详情 详情
(XIV) 11950 7-Allyl-5-chloro-3-phenyl-1,2-benzisoxazol-6-ol C16H12ClNO2 详情 详情
(XV) 11941 (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol C16H12ClNO3 详情 详情
(XXII) 11951 3,3,3-Triethoxy-1-propene; 1,1-Diethoxy-2-propenyl ethyl ether C9H18O3 详情 详情
(XXIII) 11952 5-Chloro-7-ethoxy-3-phenyl-8,9-dihydro-7H-chromeno[6,5-d]isoxazol-7-yl ethyl ether; 5-Chloro-7,7-diethoxy-3-phenyl-8,9-dihydro-7H-chromeno[6,5-d]isoxazole C20H20ClNO4 详情 详情

合成路线31

该中间体在本合成路线中的序号：(II)

Several related syntheses for AA-193 have been reported: 1) The Friedel-Crafts' condensation of 2,5-dichlorophenol (I) with benzoyl chloride (II) by means of AlCl3 gives 2,5-dichloro-4-hydroxybenzophenone (III), which by reaction with hydroxylamine and KOH is converted to 5-chloro-6-hydroxy-3-phenylbenzisoxazole (IV). The condensation of (IV) with allyl bromide (V) by means of K2CO3 affords the 7-allyl derivative (VI), which is cyclized by means of N-bromosuccinimide and NaOH to 5-chloro-7-(hydroxymethyl)-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisox azole (VII). Finally, this compound is oxidized to the final product with KMnO4 in refluxing dichloromethane. 2) The chlorination of 1,3-dimethoxybenzene (VIII) with SO2Cl2 gives 1-chloro-2,4-dimethoxybenzene (IX), which is condensed with benzoyl chloride (II) as before, yielding 5-chloro-2,4-dihydroxybenzophenone (X). Tosylation of (X) with tosyl chloride gives the corresponding ditosyl derivative (XI), which by reaction with hydroxylamine is converted to the oxime (XII). Finally, this compound is treated with KOH in order to cyclize to the benzisoxazole (IV). 3) The reaction of the benzisoxazole (IV) with formaldehyde and dimethylamine gives 5-chloro-7-(dimethylaminomethyl)-6-hydroxy-3-phenylbenzisoxazole (XIII), which is condensed and cyclized with the ylide (XIV) to yield the ethyl ester of the desired product (XV). Finally, this compound is hydrolyzed with NaOH.

参考文献 中间体
合成目标
【1】 Koga, H.; Kuromaru, K.; Ishizawa, T.; Aoki, B.; Sato, H.; Studies on uricosuric diuretics. V. Convenient and efficient synthesis of 2,3-dihydrobenzofuran derivatives. Chem Pharm Bull 1992, 40, 10, 2597.
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) 11953 2,5-Dichlorophenol 583-78-8 C6H4Cl2O 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 11955 (2,5-Dichloro-4-hydroxyphenyl)(phenyl)methanone C13H8Cl2O2 详情 详情
(IV) 11945 5-Chloro-3-phenyl-1,2-benzisoxazol-6-ol C13H8ClNO2 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 11950 7-Allyl-5-chloro-3-phenyl-1,2-benzisoxazol-6-ol C16H12ClNO2 详情 详情
(VII) 11941 (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol C16H12ClNO3 详情 详情
(VIII) 11934 m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether 151-10-0 C8H10O2 详情 详情
(IX) 11942 1-Chloro-2,4-dimethoxybenzene; 2-Chloro-5-methoxyphenyl methyl ether 7051-13-0 C8H9ClO2 详情 详情
(X) 11962 (5-Chloro-2,4-dihydroxyphenyl)(phenyl)methanone C13H9ClO3 详情 详情
(XI) 11963 2-benzoyl-4-chloro-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate C27H21ClO7S2 详情 详情
(XII) 11964 4-chloro-2-[(hydroxyimino)(phenyl)methyl]-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate C27H22ClNO7S2 详情 详情
(XIII) 11946 5-Chloro-7-[(dimethylamino)methyl]-3-phenyl-1,2-benzisoxazol-6-ol C16H15ClN2O2 详情 详情
(XIV) 11966 2-(Dimethylsulfonium)acetic acid ethyl ester inner salt C6H12O2S 详情 详情
(XV) 11948 ethyl 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazole-7-carboxylate C18H14ClNO4 详情 详情

合成路线32

该中间体在本合成路线中的序号：(VI)

By condensation of 3-[3-(chlorocarbonyl)benzoyl]-1-(ethoxymethyl)-5-fluorouracil (I) with 6-benzoyloxy-3-cyano-2-hydroxypyridine (II) by means of triethylamine in refluxing acetonitrile. The starting compounds (I) and (II) are obtained as follows: The reaction of 1-(ethoxymethyl)-5-fluorouracil (III) with isophthaloyl dichloride (IV) by means of triethylamine in refluxing dioxane gives uracil (I). The esterification of 3-cyano-2,6-dihydroxypyridine (V) with benzoyl chloride (VI) by means of triethylamine in dimethylacetamide affords pyridine (II).

参考文献 中间体
合成目标
【1】 Fujii, S. (Otsuka Pharmaceutical Co., Ltd.); 5-Fluorouracil derivs., process for their preparation and their use. DE 3709699; FR 2605006; GB 2192880; JP 1988201127; JP 1988301880 .
【2】 Castaner, J.; Hoshi, A.; Emitefur. Drugs Fut 1993, 18, 5, 418.
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) 12498 3-[[3-(Ethoxymethyl)-5-fluoro-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]carbonyl]benzoyl chloride C15H12ClFN2O5 详情 详情
(II) 12499 5-cyano-6-hydroxy-2-pyridinyl benzoate C13H8N2O3 详情 详情
(III) 12500 1-(Ethoxymethyl)-5-fluoro-2,4(1H,3H)-pyrimidinedione C7H9FN2O3 详情 详情
(IV) 12501 Isophthaloyl dichloride 99-63-8 C8H4Cl2O2 详情 详情
(V) 12502 2,6-Dihydroxynicotinonitrile C6H4N2O2 详情 详情
(VI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线33

该中间体在本合成路线中的序号：(II)

The reaction of [benzene-U-13C]benzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is cyclized with the ethanolamine (III) to yield the oxazoline (IV).The chlorination of (IV) with sec-BuLi and hexachloroethane in toluene affords the 2-chlorophenyl derivative (V), which is methylated with MeI to provide the oxazolinium salt (VI). The reduction of (VI) with NaBH4 in ethanol yields the oxazolidine (VII), which is hydrolyzed with HCl to afford the labeled 2-chlorobenzaldehyde (VIII). The condensation of aldehyde (VIII) with the tetrahydrothienopyridine (IX) by means of acetone cyanohydrine in hot toluene affords the substituted acetonitrile (X), which is hydrolyzed to the substituted acetamide (XI) with HCl in methanol. Finally, this compound is treated with H2SO4 in refluxing methanol to afford the target labeled methyl ester as a racemic mixture.

参考文献 中间体
合成目标
【1】 Kashimura, S.; Kuwata, F.; Ishige, O.; Uyama, H.; Shono, T.; Yamaguchi, Y.; Formation of a novel acyl anion equivalent by the electroreduction of oxazolinium salts. Chem Lett 1987, 1511.
【2】 Burgos, A.; Simpson, I.; Herbert, J.M.; Ortho-metalation/chlorination of benzoic acid derivatives: Preparation of [benzene-U-C-13]-rac-clopidogrel ([benzene-U-C-13]-rac-SR25990C). J Label Compd Radiopharm 2000, 43, 9, 891.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
63476 methyl 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate C16H16ClNO2S 详情 详情
63477 methyl 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate C16H16ClNO2S 详情 详情
(I) 10202 Benzoic acid 65-85-0 C7H6O2 详情 详情
(I) 44623 　 C7H6O2 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(II) 45137 　 C7H5ClO 详情 详情
(III) 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
(IV) 44072 4,4-dimethyl-2-phenyl-4,5-dihydro-1,3-oxazole 19312-06-2 C11H13NO 详情 详情
(IV) 45138 　 C11H13NO 详情 详情
(V) 44073 2-(2-chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole C11H12ClNO 详情 详情
(V) 45139 　 C11H12ClNO 详情 详情
(VI) 44074 2-(2-chlorophenyl)-3,4,4-trimethyl-4,5-dihydro-1,3-oxazol-3-ium iodide C12H15ClINO 详情 详情
(VI) 45140 　 C12H15ClINO 详情 详情
(VII) 44075 2-(2-chlorophenyl)-3,4,4-trimethyl-1,3-oxazolidine C12H16ClNO 详情 详情
(VII) 45141 　 C12H16ClNO 详情 详情
(VIII) 24114 2-chlorobenzaldehyde 89-98-5 C7H5ClO 详情 详情
(VIII) 45142 　 C7H5ClO 详情 详情
(IX) 34011 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 54903-50-3 C7H9NS 详情 详情
(X) 44076 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetonitrile C15H13ClN2S 详情 详情
(X) 45143 　 C15H13ClN2S 详情 详情
(XI) 44077 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetamide C15H15ClN2OS 详情 详情
(XI) 45144 　 C15H15ClN2OS 详情 详情

合成路线34

该中间体在本合成路线中的序号：(VI)

The protected ligand (IV) was also prepared by a related method. The acylation of thioglycolic acid (V) with benzoyl chloride (VI) under Schotten-Baumann conditions afforded S-benzoyl thioglycolic acid (VII). After activation of (VII) as the corresponding succinimidyl ester (VIII) with N-hydroxysuccinimide and DCC, coupling with triglycine (I) furnished compound (IV).

参考文献 中间体
合成目标
【1】 Grummon, G.; et al.; Synthesis, characterization and crystal structures of technetium(V)-oxo complexes useful in nuclear medicine. 1. Complexes of mercaptoacetylglycylglycylglycine (MAG3) and its methyl ester derivative (MAG3OMe). Inorg Chem 1995, 34, 7, 1764.
【2】 Brandau, W.; et al.; Technetium-99m labeled renal function and imaging agents. 3. Synthesis of Tc-99m-MAG3 and biodistribution of by-products. Int J Radiat Appl Instrum Part A - Appl Radiat Isotop 1988, 39, 2, 121.
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) 56518 2-({2-[(2-aminoacetyl)amino]acetyl}amino)acetic acid C6H11N3O4 详情 详情
(IV) 56520 1,4,7,10-tetraoxo-1-phenyl-2-thia-5,8,11-triazatridecan-13-oic acid C15H17N3O6S 详情 详情
(V) 18524 2-sulfanylacetic acid 68-11-1 C2H4O2S 详情 详情
(VI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(VII) 56522 2-(benzoylsulfanyl)acetic acid C9H8O3S 详情 详情
(VIII) 56523 S-{2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl} benzenecarbothioate C13H11NO5S 详情 详情

合成路线35

该中间体在本合成路线中的序号：(II)

The title benzamide was prepared by acylation of the alkaloid staurosporine (I) with benzoyl chloride (II) in the presence of diisopropylethylamine in chloroform.

参考文献 中间体
合成目标
【1】 Caravatti, G.; et al.; Inhibitory activity and selectivity of staurosporine derivatives towards protein kinase C. Bioorg Med Chem Lett 1994, 4, 3, 399.
【2】 Caravatti, G.; Fredenhagen, A. (Novartis AG); Staurosporine derivs. substd. for the nitrogen atom of the methylamino group. EP 0296110; JP 1989034989; US 5093330 .
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) 52822 (2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.1~2,6~.0~7,28~.0~8,13~.0~15,19~.0~20,27~.0~21,26~]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one C28H26N4O3 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线36

该中间体在本合成路线中的序号：

A new practical asymmetric synthesis of lubocavir has been described: The diastereoselective cycloaddition of (-)-dimenthyl fumarate (I) with ketene dimethylacetal (II) by means of diisobutylaluminum chloride (DIBAC) in toluene gives the cyclobutane (III), which is reduced with LiAlH4 yielding the cyclobutyl dicarbinol (IV). The reaction of (IV) with benzoyl chloride affords the dibenzoate (V), which is deprotected in acidic medium to give the cyclobutanone (VI). The stereoselective reduction of (VI) with DIBAC yields the chiral cyclobutanol (VII), which is treated with triflic anhydride to afford the activated triflate (VIII). The regioselective condensation of (VIII) with 2-amino-6-iodopurine benzyltriethylammonium salt (IX) gives the expected addition product (X), which is debenzoylated with NaOMe in methanol yielding the 2-amino-6-methoxypurine (XI). Finally, this compound is converted to lobucavir by refluxing with aqueous hydrochloric acid.

参考文献 中间体
合成目标
【1】 Singh, J.; Bisacchi, G.S.; Ahmad, S.; et al.; A practical asymmetric synthesis of the antiviral agent lobucavir, BMS-180194. Org Process Res Dev 1998, 2, 6, 393.
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
(I) 34029 bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (E)-2-butenedioate C24H40O4 详情 详情
(II) 34030 1-methoxyvinyl methyl ether; 1,1-dimethoxyethylene C4H8O2 详情 详情
(III) 34031 bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1S,2R)-3,3-dimethoxy-1,2-cyclobutanedicarboxylate C28H48O6 详情 详情
(IV) 34032 [(1S,2S)-2-(hydroxymethyl)-3,3-dimethoxycyclobutyl]methanol C8H16O4 详情 详情
(V) 34033 [(1S,2S)-2-[(benzoyloxy)methyl]-3,3-dimethoxycyclobutyl]methyl benzoate C22H24O6 详情 详情
(VI) 14380 [(1S,2S)-2-[(benzoyloxy)methyl]-4-oxocyclobutyl]methyl benzoate C20H18O5 详情 详情
(VII) 14381 [(1S,2S,4S)-2-[(benzoyloxy)methyl]-4-hydroxycyclobutyl]methyl benzoate C20H20O5 详情 详情
(VIII) 14387 ((1S,2S,4S)-2-[(benzoyloxy)methyl]-4-[[(trifluoromethyl)sulfonyl]oxy]cyclobutyl)methyl benzoate C21H19F3O7S 详情 详情
(IX) 34036 2-Amino-6-iodo-6,9-dihydro-1H-purin-9-ide anion C5H5IN5 详情 详情
(X) 34034 [(1R,2R,4S)-2-(2-amino-6-iodo-1,6-dihydro-9H-purin-9-yl)-4-[(benzoyloxy)methyl]cyclobutyl]methyl benzoate C25H24IN5O4 详情 详情
(XI) 34035 [(1S,2R,3R)-3-(2-amino-6-methoxy-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)cyclobutyl]methanol C12H19N5O3 详情 详情

合成路线37

该中间体在本合成路线中的序号：(LXIX)

Tetrahydrofurfurylamine (XLVII) was converted into the corresponding phthalimide (XLVIII) by reaction of phthalic anhydride (V) in boiling chloroform. Subsequent ruthenium-catalyzed oxidation of (XLVIII) produced keto acid (XI), along with a pentanolide by-product, which was removed by column chromatography. Finally, acid hydrolysis of (XI) led to the desired compound. A closely related strategy was based in the ruthenium oxidation of N-benzoyl tetrahydrofurfurylamine (LXX), prepared from amine (XLVII) and benzoyl chloride (XLIX), to afford 5-benzoylaminolevulinic acid (XXXV), which was then hydrolyzed in boiling 6 N HCl .

参考文献 中间体
合成目标
【1】 Kawakami, H.; et al.; A new synthesis of 5-aminolevulinic acid. Agric Biol Chem 1991, 55, 6, 1687.
【2】 Matsumoto, K.; Kawakami, H.; Koseki, K.; Ebata, T.; Matsushita, H. (Japan Tobacco Inc.); Method of preparing an acid additional salt of delta-aminolevulinic acid. US 5284973 .
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) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(XI) 59147 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid C13H11NO5 详情 详情
(XXXV) 59156 5-(benzoylamino)-4-oxopentanoic acid C12H13NO4 详情 详情
(LXVII) 27335 Tetrahydro-2-furanylmethanamine; Tetrahydrofurfurylamine 4795-29-3 C5H11NO 详情 详情
(LXVIII) 59191 2-(tetrahydro-2-furanylmethyl)-1H-isoindole-1,3(2H)-dione C13H13NO3 详情 详情
(LXIX) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(LXX) 59192 N-(tetrahydro-2-furanylmethyl)benzamide C12H15NO2 详情 详情

合成路线38

该中间体在本合成路线中的序号：(II)

Friedel-Crafts acylation of 4-hydroxy-1-phenyl[1,8]naphthyridin-2(1H)-one (I) with benzoyl chloride (II) using AlCl3 in hot nitrobenzene produced the 3-benzoyl naphthyridinone (III). This was cyclized to the title pyrazolonaphthyridinone by treatment with hydrazine in refluxing HOAc.

参考文献 中间体
合成目标
【1】 Suzuki, F.; Kawakita, T.; Kuroda, T.; Ohmori, K.; Nakajima, H.; Kamiya, T.; Tamaoki, T. (Kyowa Hakko Kogyo Co., Ltd.); Condensed naphthyridine derivs.. EP 0526840; JP 1993194515; US 5281610 .
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) 12018 4-Hydroxy-1-phenyl[1,8]naphthyridin-2(1H)-one C14H10N2O2 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 51629 3-benzoyl-4-hydroxy-1-phenyl[1,8]naphthyridin-2(1H)-one C21H14N2O3 详情 详情

合成路线39

该中间体在本合成路线中的序号：(XXIII)

Compound (XIX) is condensed with 2-[1-(acetylsulfanylmethyl)cyclopropyl]acetic acid methyl ester (XX) by means of Cs2CO3 in acetonitrile yielding the expected condensation product (XXI). Finally, this compound is treated successively with pyridine and p-toluenesulfonic acid to eliminate the tetrahydropyranyl protecting group, and with NaOH to hydrolyzed the acetate ester group of (XXI). 4) The 2-[1-(acetylsulfanylmethyl)cyclopropyl]acetic acid methyl ester (XX) has been obtained as follows: The reduction of diethyl cyclopropane-1,1-dicarboxylate (XXII) with LiAlH4 in THF gives 1,1-cyclopropanedimethanol (XI), which is monobenzoylated with benzoyl chloride (XXIII) and pyridine in dichloromethane yielding benzoic acid 1-(hydroxymethyl)cyclopropylmethyl ester (XXIV). The mesylation of (XXIV) as usual affords the mesylate (XXV), which is treated with NaCN in DMSO to give 2-[1-(benzoyloxymethyl)cyclopropyl]acetonitrile (XXVI). The hydrolysis of (XXVI) with KOH in refluxing ethanol, followed by methylation with diazomethane, yields methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate (XXVII), which is mesylated as usual affording the mesylate (XXIII). Finally, this compound is treated with cesium thiocetate in dichloromethane to give (XX).

参考文献 中间体
合成目标
【1】 Graul, A.; Martín, L.; Castañer, J.; Montelukast Sodium. Drugs Fut 1997, 22, 10, 1103.
【2】 Labelle, M.; Belley, M.; Gareau, Y.; et al.; Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enzyme induction. Bioorg Med Chem Lett 1995, 5, 3, 283-8.
【3】 Belley, M.L.; Leger, S.; Roy, P.; Xiang, Y.B.; Labelle, M.; Guay, D. (Merck Frosst Canada Inc.); Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists. EP 0480717; JP 1993105665 .
【4】 Bhupathy, M.; McNamara, J.M.; Sidler, D.R.; Volante, R.P.; Bergan, J.J. (Merck & Co., Inc.); Process for the preparation of leukotriene antagonists. WO 9518107 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 16533 [1-(hydroxymethyl)cyclopropyl]methanol C5H10O2 详情 详情
(XVIII) 16540 (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]-1-propanol C34H36ClNO3 详情 详情
(XIX) 16541 (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]propyl methanesulfonate C35H38ClNO5S 详情 详情
(XX) 16542 methyl 2-[1-[(acetylsulfanyl)methyl]cyclopropyl]acetate C9H14O3S 详情 详情
(XXI) 16543 methyl 2-(1-[[((1R)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]propyl)sulfanyl]methyl]cyclopropyl)acetate C41H46ClNO4S 详情 详情
(XXII) 16544 diethyl 1,1-cyclopropanedicarboxylate 1559-02-0 C9H14O4 详情 详情
(XXIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XXIV) 16546 [1-(hydroxymethyl)cyclopropyl]methyl benzoate C12H14O3 详情 详情
(XXV) 16547 (1-[[(methylsulfonyl)oxy]methyl]cyclopropyl)methyl benzoate C13H16O5S 详情 详情
(XXVI) 16548 [1-(cyanomethyl)cyclopropyl]methyl benzoate C13H13NO2 详情 详情
(XXVII) 16549 methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate C7H12O3 详情 详情

合成路线40

该中间体在本合成路线中的序号：(XXI)

In an alternative route, 2-N-acetyl-4,6-O-isopropylidene-D-glucosamine benzyl pyranoside (XVII) was alkylated with 1-bromo-2-butene (XVIII) in the presence of barium oxide and barium hydroxide to produce the 3-O-crotyl ether (XIX). After acidic hydrolysis of the isopropylidene ketal (XIX), the resultant diol (XX) was selectively mono-acylated at the primary hydroxyl with benzoyl chloride (XXI) to afford the 6-benzoate ester (XXII). Protection of the 3-hydroxyl group of (XXII) by means of dihydropyran (DHP) and p-toluenesulfonic acid gave rise to the tetrahydropyranyl ether (XXIII). After methanolysis of the benzoate ester of (XXIII) in the presence of NaOMe, the resultant primary alcohol (XXIV) was protected as the benzyl ether (XXV). Subsequent hydrolysis of the tetrahydropyranyl group of (XXV) in aqueous HOAc furnished the protected glucosamine intermediate (XXVI).

参考文献 中间体
合成目标
【1】 Kiso, M.; et al.; A general, convenient synthesis of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan by the oxazoline method. Carbohydr Res 1980, 83, 1, C8.
【2】 Kiso, M.; et al.; Synthesis and immunoadjuvant activities of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan and of some carbohydrate analogs. Carbohydr Res 1982, 104, 2, 253.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 56337 N-[(4aR,6S,7R,8R,8aS)-6-(benzyloxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]acetamide C18H25NO6 详情 详情
(XVIII) 35252 (E)-1-bromo-2-butene 29576-14-5 C4H7Br 详情 详情
(XIX) 56338 N-{(4aR,6S,7R,8R,8aS)-6-(benzyloxy)-8-[(E)-2-butenyloxy]-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl}acetamide C22H31NO6 详情 详情
(XX) 56339 N-[(2S,3R,4R,5S,6R)-2-(benzyloxy)-4-[(E)-2-butenyloxy]-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide C19H27NO6 详情 详情
(XXI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XXII) 56340 {(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-4-[(E)-2-butenyloxy]-3-hydroxytetrahydro-2H-pyran-2-yl}methyl benzoate C26H31NO7 详情 详情
(XXIII) 56341 [(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-4-[(E)-2-butenyloxy]-3-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]methyl benzoate C31H39NO8 详情 详情
(XXIV) 56342 N-[(2S,3R,4R,5S,6R)-2-(benzyloxy)-4-[(E)-2-butenyloxy]-6-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-3-yl]acetamide C24H35NO7 详情 详情
(XXV) 56343 N-[(2S,3R,4R,5S,6R)-2-(benzyloxy)-6-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-3-yl]acetamide C31H41NO7 详情 详情
(XXVI) 56344 N-{(2S,3R,4R,5S,6R)-2-(benzyloxy)-6-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]-5-hydroxytetrahydro-2H-pyran-3-yl}acetamide C26H33NO6 详情 详情

合成路线41

该中间体在本合成路线中的序号：(VIII)

Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which then reacts with benzoyl chloride (VIII) in pyridine to furnish (IX). Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (+)-(XV) is obtained by HPLC chromatography of (XIV) on a chiral stationary phase. Treatment of (+)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (+)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.

参考文献 中间体
合成目标
【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 .
【2】 Kise, M.; Amimoto, I.; Kitano, M.; Segawa, J.; Tomii, Y.; Matsuoka, M.; Masui, Y.; Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives. Chem Pharm Bull 1999, 47, 12, 1765.
【3】 Segawa, J.; Kitano, M.; Kazuno, K.; Matsuoka, M.; Shirahase, I.; Ozaki, M.; Matsuda, M.; Tomii, Y.; Kise, M.; Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3, 2-a]quinoline-3-carboxylic acids. J Med Chem 1992, 35, 25, 4727.
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) 13451 3,4-Difluoroaniline; 3,4-Difluorophenylamine 3863-11-4 C6H5F2N 详情 详情
(II) 42953 3,4-difluorophenylcarbamodithioic acid C7H5F2NS2 详情 详情
(III) 13453 1,2-Difluoro-4-isothiocyanatobenzene; 3,4-difluorophenyl isothiocyanate 113028-75-4 C7H3F2NS 详情 详情
(IV) 42954 potassium 1-(3,4-difluoroanilino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propene-1-thiolate C14H14F2KNO4S 详情 详情
(V) 18319 Chloro(methoxy)methane; Chloromethyl methyl ether 107-30-2 C2H5ClO 详情 详情
(VI) 13455 diethyl 2-[(3,4-difluoroanilino)[(methoxymethyl)sulfanyl]methylene]malonate C16H19F2NO5S 详情 详情
(VII) 13456 ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C14H13F2NO4S 详情 详情
(VIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(IX) 42955 ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C21H17F2NO5S 详情 详情
(X) 42956 ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate C19H13F2NO4S 详情 详情
(XI) 28769 1-bromo-2-fluoroethane 762-49-2 C2H4BrF 详情 详情
(XII) 42957 ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(2-fluoroethyl)sulfanyl]-3-quinolinecarboxylate C21H16F3NO4S 详情 详情
(XIII) 42958 ethyl 4-(benzoyloxy)-2-[(1-chloro-2-fluoroethyl)sulfanyl]-6,7-difluoro-3-quinolinecarboxylate C21H15ClF3NO4S 详情 详情
(XIV) 42959 ethyl 6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H10F3NO3S 详情 详情
(XV) 42960 ethyl (1R)-6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H10F3NO3S 详情 详情
(XVI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVII) 42961 ethyl (1R)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C19H21F2N3O3S 详情 详情

合成路线42

该中间体在本合成路线中的序号：(VIII)

Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane, and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which is then converted into (IX) by means of benzoyl chloride (VIII) in pyridine. Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (-)-(XV) is then obtained by HPLC chromatography on a chiral stationary phase. Treatment of (-)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (-)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.

参考文献 中间体
合成目标
【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 .
【2】 Kise, M.; Amimoto, I.; Kitano, M.; Segawa, J.; Tomii, Y.; Matsuoka, M.; Masui, Y.; Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives. Chem Pharm Bull 1999, 47, 12, 1765.
【3】 Segawa, J.; Kitano, M.; Kazuno, K.; Matsuoka, M.; Shirahase, I.; Ozaki, M.; Matsuda, M.; Tomii, Y.; Kise, M.; Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3, 2-a]quinoline-3-carboxylic acids. J Med Chem 1992, 35, 25, 4727.
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) 13451 3,4-Difluoroaniline; 3,4-Difluorophenylamine 3863-11-4 C6H5F2N 详情 详情
(II) 42953 3,4-difluorophenylcarbamodithioic acid C7H5F2NS2 详情 详情
(III) 13453 1,2-Difluoro-4-isothiocyanatobenzene; 3,4-difluorophenyl isothiocyanate 113028-75-4 C7H3F2NS 详情 详情
(IV) 42954 potassium 1-(3,4-difluoroanilino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propene-1-thiolate C14H14F2KNO4S 详情 详情
(V) 18319 Chloro(methoxy)methane; Chloromethyl methyl ether 107-30-2 C2H5ClO 详情 详情
(VI) 13455 diethyl 2-[(3,4-difluoroanilino)[(methoxymethyl)sulfanyl]methylene]malonate C16H19F2NO5S 详情 详情
(VII) 13456 ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C14H13F2NO4S 详情 详情
(VIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(IX) 42955 ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C21H17F2NO5S 详情 详情
(X) 42956 ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate C19H13F2NO4S 详情 详情
(XI) 28769 1-bromo-2-fluoroethane 762-49-2 C2H4BrF 详情 详情
(XII) 42957 ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(2-fluoroethyl)sulfanyl]-3-quinolinecarboxylate C21H16F3NO4S 详情 详情
(XIII) 42958 ethyl 4-(benzoyloxy)-2-[(1-chloro-2-fluoroethyl)sulfanyl]-6,7-difluoro-3-quinolinecarboxylate C21H15ClF3NO4S 详情 详情
(XIV) 42959 ethyl 6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H10F3NO3S 详情 详情
(XV) 42971 octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate C21H25F2NO4S 详情 详情
(XVI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVII) 42975 ethyl (1S)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C19H21F2N3O3S 详情 详情

合成路线43

该中间体在本合成路线中的序号：

Condensation of ethyl 4-piperidinecarboxylate (I) with benzoyl chloride in pyridine afforded the corresponding benzamide (II). After reduction of the ester group of (II) with NaBH4, the resulting alcohol (III) was converted to chloride (IV) by means of SOCl2. Elimination of the chlorine atom of (IV) with potassium tert-butoxide produced N-benzoyl-4-methylenepiperidine (V), which was hydrolyzed with KOH to yield 4-methylenepiperidine (VI). Finally, condensation of (VI) with the known epoxide (VII) in refluxing EtOH furnished the title compound.

参考文献 中间体
合成目标
【1】 Ogura, H.; et al.; Synthesis and antifungal activities of (2R,3R)-2-aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives as topical antifungal agents. Chem Pharm Bull 1999, 47, 10, 1417.
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
(I) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 31733 ethyl 1-benzoyl-4-piperidinecarboxylate C15H19NO3 详情 详情
(III) 31734 [4-(hydroxymethyl)-1-piperidinyl](phenyl)methanone C13H17NO2 详情 详情
(IV) 31735 [4-(chloromethyl)-1-piperidinyl](phenyl)methanone C13H16ClNO 详情 详情
(V) 31736 (4-methylene-1-piperidinyl)(phenyl)methanone C13H15NO 详情 详情
(VI) 31737 4-methylenepiperidine C6H11N 详情 详情
(VII) 31738 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole C12H11F2N3O 详情 详情

合成路线44

该中间体在本合成路线中的序号：(X)

Treatment of carboxylic acid (I) with refluxing cyclohexanone (II) and H2SO4 affords derivative (III), which is then condensed with propargyl bromide (IV) by means of NaH in DMF to yield propargyl ether (V). Treatment of (V) with Et3N in toluene followed by condensation with 4-cloro-iodobenzene (VI) by means of PdCl2, PPh3 and CuI provides propinyloxy derivative (VII), which is then converted into propenyloxy derivative (VIII) by hydrogenation over Pd/ BaSO4 in pyridine. Opening of the lactone ring of (VIII) by means of NaH in MeOH and THF affords methyl ester (IX), which is then condensed with benzoyl chloride (X) by means of DMAP and Et3N in CH2Cl2 to give benzoate (XI). Treatment of (XI) with Et2Zn and chloroiodomethane in dichloroethane (or alternatively in CH2Cl2 or THF) followed by recrystallization from isopropanol furnishes cyclopropane derivative (XII), which is then hydrolyzed by treatment with NaOH in dioxane to yield alcohol (XIII). Finally, (XIII) is condensed with intermediate (XIV) by means of NaH in DMF and then deprotected by treatment with HCl in dioxane to afford the target compound.

参考文献 中间体
合成目标
【1】 Hemmerle, H.; Schindler, P.; Herling, A. (Aventis SA); Derivs. of substd. cyclohexane, their process of preparation and their application for the treatment of diseases. EP 0587088; JP 1994211736; US 5463062 .
【2】 Hemmerle, H.; Schubert, G.; Burger, H.-J.; Herling, A.; Efendic, S. (Aventis SA); Cyclohexane derivs., processes for their preparation and their use as glucose-6-phosphatase inhibitors. CA 2149007; CA 4416433; EP 0682024; JP 1995330767; US 5739147 .
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) 44864 Quinic acid; 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid C7H12O6 详情 详情
(II) 11059 Cyclohexanone 108-94-1 C6H10O 详情 详情
(III) 44855 　 C13H18O5 详情 详情
(IV) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(V) 44856 　 C16H20O5 详情 详情
(VI) 19395 1-chloro-4-iodobenzene 637-87-6 C6H4ClI 详情 详情
(VII) 44857 　 C22H23ClO5 详情 详情
(VIII) 44858 　 C22H25ClO5 详情 详情
(IX) 44859 　 C23H29ClO6 详情 详情
(X) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XI) 44860 　 C30H33ClO7 详情 详情
(XII) 44861 　 C31H35ClO7 详情 详情
(XIII) 44862 　 C23H29ClO6 详情 详情
(XIV) 44863 　 C17H12N6O 详情 详情

合成路线45

该中间体在本合成路线中的序号：

Wittig reaction of 2,4-O-benzylidene-D-threose (I) with the phosphorane derived from tetradecyl triphenyl phosphonium salt (II) provided the trans olefin (III). After conversion of hydroxyl group of (III) into the corresponding triflate, displacement with NaN3 yielded azide (IV) with inversion of configuration. Acid hydrolysis of the benzylidene acetal of (IV) gave diol (V). Then, selective protection of the primary hydroxyl group with tert-butyldimethylsilyl chloride produced silyl ether (VI). Subsequent benzoylation of the remaining hydroxyl group of (VI) gave benzoate ester (VII). The silyl protecting group of (VII) was then removed using tetra n-butylammonium fluoride in THF to give azido alcohol (VIII). This was coupled with tetraacetyl-D-galactosyl bromide (IX) to give the corresponding galactopyranoside (X) as an epimeric mixture. After chromatographic separation of the major beta-anomer, removal of the acetyl protecting groups with sodium methoxide yielded (XI).

参考文献 中间体
合成目标
【1】 Banville, J.; Martel, A.; Aruffo, A.A. (Bristol-Myers Squibb Co.); Sulfated beta-glycolipid derivs. as cell adhesion inhibitors. EP 0671406; JP 1995285985; US 5565433 .
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
(I) 26505 (2S,4S,5R)-5-hydroxy-2-phenyl-1,3-dioxane-4-carbaldehyde C11H12O4 详情 详情
(II) 26506 triphenyl(tetradecyl)phosphorane C32H45P 详情 详情
(III) 26507 (2S,4R,5R)-4-[(Z)-1-pentadecenyl]-2-phenyl-1,3-dioxan-5-ol C25H40O3 详情 详情
(IV) 26508 (2S,4R,5S)-4-[(Z)-1-pentadecenyl]-2-phenyl-1,3-dioxan-5-yl azide C25H39N3O2 详情 详情
(V) 26509 (2S,3R,4Z)-2-azido-4-octadecene-1,3-diol C18H35N3O2 详情 详情
(VI) 26510 (2S,3R,4Z)-2-azido-1-[[tert-butyl(dimethyl)silyl]oxy]-4-octadecen-3-ol C24H49N3O2Si 详情 详情
(VII) 26511 (1R,2Z)-1-((1S)-1-azido-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-hexadecenyl benzoate C31H53N3O3Si 详情 详情
(VIII) 26512 (1R,2Z)-1-[(1S)-1-azido-2-hydroxyethyl]-2-hexadecenyl benzoate C25H39N3O3 详情 详情
(IX) 26513 (2R,3R,4S,5R,6R)-3,5-bis(acetoxy)-2-[(acetoxy)methyl]-6-bromotetrahydro-2H-pyran-4-yl acetate 3068-32-4 C14H19BrO9 详情 详情
(X) 26514 (1R,2Z)-1-[(1S)-1-azido-2-([(3R,4S,5S,6R)-3,4,5-tris(acetoxy)-6-[(acetoxy)methyl]tetrahydro-2H-pyran-2-yl]oxy)ethyl]-2-hexadecenyl benzoate C39H57N3O12 详情 详情
(XI) 26515 (1R,2Z)-1-((1S)-1-azido-2-[[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]ethyl)-2-hexadecenyl benzoate C31H49N3O8 详情 详情

合成路线46

该中间体在本合成路线中的序号：

Protection of the 4- and 6-hydroxyl groups of (XI) was achieved by conversion into the benzylidene acetal (XII) upon treatment with benzaldehyde and formic acid. The remaining 2- and 3-hydroxyl groups of (XII) were benzoylated with benzoyl chloride to afford the corresponding benzoate ester (XIII). After reduction of the azide group of (XIII) to amine (XIV) with H2S and pyridine, condensation with hexadecanoyl chloride produced the corresponding amide (XV). Deprotection of the acetal group of (XV) with TFA in CH2Cl2 gave diol (XVI), which was finally treated with SO3-Me3N complex, and then with NaHCO3 to form the title disulfate sodium salt.

参考文献 中间体
合成目标
【1】 Banville, J.; Martel, A.; Aruffo, A.A. (Bristol-Myers Squibb Co.); Sulfated beta-glycolipid derivs. as cell adhesion inhibitors. EP 0671406; JP 1995285985; US 5565433 .
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
10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
16480 Palmitoyl Chloride; hexadecanoyl chloride 112-67-4 C16H31ClO 详情 详情
(XI) 26515 (1R,2Z)-1-((1S)-1-azido-2-[[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]ethyl)-2-hexadecenyl benzoate C31H49N3O8 详情 详情
(XII) 26516 (1R,2Z)-1-((1S)-2-[[(2S,4aR,6S,7R,8R,8aR)-7,8-dihydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-azidoethyl)-2-hexadecenyl benzoate C38H53N3O8 详情 详情
(XIII) 26517 (1R,2Z)-1-((1S)-2-[[(2S,4aR,6S,7R,8S,8aS)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-azidoethyl)-2-hexadecenyl benzoate C52H61N3O10 详情 详情
(XIV) 26518 (1R,2Z)-1-((1S)-2-[[(2S,4aR,6S,7R,8S,8aS)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-aminoethyl)-2-hexadecenyl benzoate C52H63NO10 详情 详情
(XV) 26519 (1R,2Z)-1-[(1S)-2-[[(2S,4aR,6S,7R,8S,8aS)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-(palmitoylamino)ethyl]-2-hexadecenyl benzoate C68H93NO11 详情 详情
(XVI) 26520 (1R,2Z)-1-[(1S)-2-[[(2S,3R,4S,5S,6R)-3,4-bis(benzoyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-1-(palmitoylamino)ethyl]-2-hexadecenyl benzoate C61H89NO11 详情 详情

合成路线47

该中间体在本合成路线中的序号：(III)

The reaction of bromobenzene (I) with 14CO2 by means of Mg in ether gives the corresponding benzoic acid (II), which is treated with SOCl2 and DMAP to yield the benzoyl chloride (III). The homologation of (III) with diazomethane in ether affords the phenacyl chloride (IV), which is enantioselectively reduced with borane and a chiral borolidine catalyst in THF to give (R)-2-chloro-1-phenylethanol (V). The cyclization of (V) by means of NaOH in ethyl ether yields the oxirane (VI), which by reaction with ammonia is converted into the (R)-2-amino-1-phenylethanol (VII). The condensation of (VII) with 4'-chlorobiphenyl-4-carboxylic acid (VIII) by means of CDI in DMF provides the amide (IX), which is cyclized to the oxazoline (X) by means of methanesulfonic anhydride and TEA in THF. Finally, this compound is condensed with imidazole (XI) by heating at 125 C.

参考文献 中间体
合成目标
【1】 Moenius, T.; et al.; C-14 labelling of NVPVID400 - a specific vitamin D-3-hydroxylase inhibitor. J Label Compd Radiopharm 1999, 42, 11, 1053.
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) 13365 Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene 108-86-1 C6H5Br 详情 详情
(II) 10202 Benzoic acid 65-85-0 C7H6O2 详情 详情
(III) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(IV) 38669 2-chloro-1-phenyl-1-ethanone 532-27-4 C8H7ClO 详情 详情
(V) 38670 (1R)-2-chloro-1-phenyl-1-ethanol 1674-30-2 C8H9ClO 详情 详情
(VI) 38671 (2R)-2-phenyloxirane C8H8O 详情 详情
(VII) 10173 (1R)-2-Amino-1-phenyl-1-ethanol 2549-14-6 C8H11NO 详情 详情
(VIII) 38672 4'-chloro[1,1'-biphenyl]-4-carboxylic acid C13H9ClO2 详情 详情
(IX) 38673 4'-chloro-N-[(2R)-2-hydroxy-2-phenylethyl][1,1'-biphenyl]-4-carboxamide C21H18ClNO2 详情 详情
(X) 38674 (5S)-2-(4'-chloro[1,1'-biphenyl]-4-yl)-5-phenyl-4,5-dihydro-1,3-oxazole C21H16ClNO 详情 详情
(XI) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情

合成路线48

该中间体在本合成路线中的序号：(X)

The reaction of 2-bromoethanol (I) with dihydropyran by means of a strong acid ion exchange resin gives the tetrahydropyranyl ether (II), which is condensed with 2-(3,4-dichlorophenyl)acetonitrile (III) by means of NaH in THF yielding thebutyronitrile (IV). The reduction of (IV) with H2 over RaNi in ethanol/NH4OH affords the butylamine (V), which is deprotected with HCl in methanol providing racemic 2-(3,4-dichlorophenyl)-4-hydroxybutylamine (VI). The optical resolution of (VI) with D-tartaric acid affords the corresponding (S) isomer (VII), which is treated with ethyl chloroformate and triethylamine in dichloromethane to give the carbamate (VIII). The reduction of (VIII) with LiAlH4 in THF yields N-[2(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylamine (IX), which is acylated with benzoyl chloride (X) and triethylamine in dichloromethane to affords the amide (XI). Oxidation of the hydroxyl group of (XI) with Dess-Martin periodinane yields the corresponding aldehyde (XII), which is reductocondensed with 4-[N-(trifluoroacetyl)-N-[3-(trifluoroacetamido)propyl]amino]piperidine (XIII) by means of NaBH3CN in methanol/acetic acid providing the bis(trifluoroacetylated) intermediate (XIV). The deprotection of (XIV) with KOH in methanol/water gives the diamine intermediate (XV), which is finally cyclized with carbonyldiimidazole (CDI) in chloroform.

参考文献 中间体
合成目标
【1】 Miller, S.C. (AstraZeneca plc); Therapeutic heterocycles which antagonize neurokinin receptors. JP 1997501439; US 5567700; US 5990130; US 6124279; WO 9505377 .
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) 10059 Ethylene bromohydrin; 2-Bromo-1-ethanol 540-51-2 C2H5BrO 详情 详情
(II) 26934 2-bromoethyl tetrahydro-2H-pyran-2-yl ether C7H13BrO2 详情 详情
(III) 26935 2-(3,4-dichlorophenyl)acetonitrile 3218-49-3 C8H5Cl2N 详情 详情
(IV) 26936 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile C15H17Cl2NO2 详情 详情
(V) 26937 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine C15H21Cl2NO2 详情 详情
(VI) 26938 4-amino-3-(3,4-dichlorophenyl)-1-butanol C10H13Cl2NO 详情 详情
(VII) 26939 (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol C10H13Cl2NO 详情 详情
(VIII) 26940 ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate C13H17Cl2NO3 详情 详情
(IX) 26941 (3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol C11H15Cl2NO 详情 详情
(X) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XI) 26942 N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide C18H19Cl2NO2 详情 详情
(XII) 26943 N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide C18H17Cl2NO2 详情 详情
(XIII) 26944 2,2,2-trifluoro-N-(4-piperidinyl)-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]acetamide C12H17F6N3O2 详情 详情
(XIV) 26945 N-[(2S)-2-(3,4-dichlorophenyl)-4-[4-((2,2,2-trifluoroacetyl)[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino)-1-piperidinyl]butyl]-N-methylbenzamide C30H34Cl2F6N4O3 详情 详情
(XV) 26946 N-[(2S)-4-[4-[(3-aminopropyl)amino]-1-piperidinyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide C26H36Cl2N4O 详情 详情

合成路线49

该中间体在本合成路线中的序号：(II)

YM-905 has been obtained by two related ways: 1) The benzoylation of 2-phenylethylamine (I) with benzoyl chloride (II) and triethylamine in chloroform, or with benzoic acid (III), DPPA and triethylamine in DMF, gives the corresponding benzamide (IV), which is cyclized by means of POCl3 and P2O5 in refluxing xylene and reduced with NaBH4 in ethanol, yielding racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V). The reaction of (V) with ethyl chloroformate by means of K2CO3 in chloroform affords racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI), which is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to provide the quinuclidinyl ester (VIII) as a diastereomeric mixture. This mixture is resolved by chiral HPLC, giving the target compound as a pure enantiomer. 2) The racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V) can also be submitted to optical resolution with (+)-tartaric acid to give 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (IX), which is condensed with ethyl chloroformate by means of K2CO3 in chloroform to afford 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI). This compound is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to directly provide the pure enantiomer.

参考文献 中间体
合成目标
【1】 Mealy, N.; Castañer, J.; YM-905. Drugs Fut 1999, 24, 8, 871.
【2】 Takeuchi, M.; Naito, R.; Hayakawa, M.; Okamoto, Y.; Yonetoku, Y.; Ikeda, K.; Isomura, Y. (Yamanouchi Pharmaceutical Co., Ltd.); Novel quinuclidine derivs. and medicinal compsn. thereof. EP 0801067; US 6017927; WO 9620194 .
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) 18333 Phenethylamine; 2-Phenyl-1-ethanamine 64-04-0 C8H11N 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 10202 Benzoic acid 65-85-0 C7H6O2 详情 详情
(IV) 26007 N-phenethylbenzamide C15H15NO 详情 详情
(V) 26008 1-phenyl-1,2,3,4-tetrahydroisoquinoline C15H15N 详情 详情
(VI) 26009 ethyl 1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate C18H19NO2 详情 详情
(VII) 16152 (3R)-1-azabicyclo[2.2.2]octan-3-ol; (R)-(-)-Quinuclidinol 42437-96-7 C7H13NO 详情 详情
(VIII) 26010 (3R)-1-azabicyclo[2.2.2]oct-3-yl 1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate C23H26N2O2 详情 详情
(IX) 26011 (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline C15H15N 详情 详情
(X) 26012 ethyl (1S)-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate C18H19NO2 详情 详情

合成路线50

该中间体在本合成路线中的序号：(XI)

Benzamide (XII) was prepared by acylation of morpholine (X) with benzoyl chloride (XI). The benzoate ester of (XII) was subsequently hydrolyzed under basic conditions to the alcohol (XIII), which was further converted to the mesylate ester (XIV) by means of methanesulfonyl chloride and triethylamine.

参考文献 中间体
合成目标
【1】 Emonds-Alt, X.; Grossriether, I.; Gueule, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthélabo); Substd. heterocyclic cpds., preparation method therefor and pharmaceutical compsns. containing same. EP 1156049; FR 2729952; FR 2729953; FR 2729954; JP 1999507324; JP 2001131171; US 5641777; WO 9623787 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 54989 2-[(2R)-2-(3,4-difluorophenyl)morpholinyl]ethyl benzoate C19H19F2NO3 详情 详情
(XI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XII) 54990 2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl benzoate C26H23F2NO4 详情 详情
(XIII) 54991 [(2R)-2-(3,4-difluorophenyl)-2-(2-hydroxyethyl)morpholinyl](phenyl)methanone C19H19F2NO3 详情 详情
(XIV) 54992 2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl methanesulfonate C20H21F2NO5S 详情 详情

合成路线51

该中间体在本合成路线中的序号：(D)

Ethyl 2,3-dibromopropionate (I) is condensed with N-tosyl-O-benzylhydroxylamine (A) by means of NaOEt in ethanol to give after a treatment with ammonia, propionic acid (II), which is detosylated by treatment with phenol and 36% HBr- yielding D,L-2-amino-3-(benzyloxyamino)propionic acid (III). The benzoylation of (III) with N-benzoyloxysuccinimide (B) by means of Triton B - in methanol affords D,L-2-benzoylamino-3-benzyloxyaminopropionic acid (IV), which is resolved into its optical isomers by treatment with aniline (C) and papain in 0.5M NaOH - 0.5M citric acid and L-cysteine hydrochloride; L-2-benzoylamino-3-benzyloxyaminopropionanilide (L)-(V) was isolated. The benzoylation of (L)-(V) with benzoyl chloride (D) in pyridine affords L-2-benzoylamino-3-(N-benzoyl-N-benzyloxyamino)propionanilide (L)-(VI), which is debenzylated by hydrogenation with H2 over Pd/C in methanol giving L-2-benzoylamino-3-(N-benzoyl-N-hydroxyamino)propionanilide (L)-(VII). The protecting groups of (L)-(VII) are eliminated by treatment with 6M HCl at 90-5 C yielding L-2-amino-3-hydroxyaminopropionic acid (L)-(VIII), which is finally nitrosated with NaNO2 and HCl.

参考文献 中间体
合成目标
【1】 Serradell, M.N.; Castañer, J.; Cabanillas, F.; Blancafort, P.; Alanosine. Drugs Fut 1979, 4, 7, 469.
【2】 Yoshikazu, I.; et al.; Synthesis of alanosine. Bull Chem Soc Jpn 1973, 46, 1847-50.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(A) 39517 N-(benzyloxy)-4-methylbenzenesulfonamide C14H15NO3S 详情 详情
(B) 39520 1-(benzoyloxy)-2,5-pyrrolidinedione C11H9NO4 详情 详情
(L)-(V) 39522 N-((1S)-2-anilino-1-[[(benzyloxy)amino]methyl]-2-oxoethyl)benzamide C23H23N3O3 详情 详情
(L)-(VI) 39523 N-[(2S)-3-anilino-3-oxo-2-(propionylamino)propyl]-N-(benzyloxy)benzamide C26H27N3O4 详情 详情
(L)-(VII) 39524 N-((1S)-2-anilino-1-[[benzoyl(hydroxy)amino]methyl]-2-oxoethyl)benzamide C23H21N3O4 详情 详情
(L)-(VIII) 39525 (2S)-2-amino-3-(hydroxyamino)propionic acid C3H8N2O3 详情 详情
(I) 18341 ethyl 2,3-dibromopropanoate 3674-13-3 C5H8Br2O2 详情 详情
(II) 39518 3-[(benzyloxy)[(4-methylphenyl)sulfonyl]amino]alanine C17H20N2O5S 详情 详情
(III) 39519 3-[(benzyloxy)amino]alanine C10H14N2O3 详情 详情
(IV) 39521 N-benzoyl-3-[(benzyloxy)amino]alanine C17H18N2O4 详情 详情
(C) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情

合成路线52

该中间体在本合成路线中的序号：

The oxidation of 1-O-mehyl 2,3-isopropylidene-D-ribofuranoside (I) gives the corresponding aldehyde (II), which is condensed with methyltriphenylphosphonium bromide by means of butyllithium in THF yielding methyl 5-deoxy-2,3-isopropylidene-5-methylene-D-ribofuranoside (III). Elimination of the isopropylidene protecting group by passing through an Amberlyst resin (acid form) affords the free ribofuranoside (IV), which is benzoylated with benzoyl chloride and triethylamine in dichloromethane to afford the dibenzoyl derivative (V). The methyl ribofuranoside (V) was converted into the 1-O-acetyl derivative (VI) and condensed with 2,6-dichloro-9H-purine (VII) by heating at 150 C to provide the dichloropurine derivative (VIII), which is treated with O-methylhydroxylamine and triethylamine to afford 2',3'-di-O-benzoyl-2-chloro-5'-deoxy-N-methoxy-5'-methyleneadenosine (IX). Finally, this compound is debenzoylated with ammonia in methanol.

参考文献 中间体
合成目标
【1】 Lau, J.; Knutsen, L.J.S. (Novo Nordisk A/S); Chemical cpds., their preparation and use. EP 0719275; JP 1999511436; US 5589467; WO 9507921 .
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
15455 (aminooxy)methane; O-methylhydroxylamine 67-62-9 CH5NO 详情 详情
(I) 10017 [(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol 4099-85-8 C9H16O5 详情 详情
(II) 10018 (3aR,4S,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde C9H14O5 详情 详情
(III) 25257 (3aS,4R,6R,6aR)-4-methoxy-2,2-dimethyl-6-vinyltetrahydrofuro[3,4-d][1,3]dioxole; (3aS,4R,6R,6aR)-2,2-dimethyl-6-vinyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl methyl ether C10H16O4 详情 详情
(IV) 25258 (2R,3S,4S,5R)-2-methoxy-5-vinyltetrahydro-3,4-furandiol C7H12O4 详情 详情
(V) 25259 (2R,3R,4R,5R)-4-(benzoyloxy)-2-methoxy-5-vinyltetrahydro-3-furanyl benzoate C21H20O6 详情 详情
(VI) 25260 (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-vinyltetrahydro-3-furanyl benzoate C22H20O7 详情 详情
(VII) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(VIII) 25261 (2R,3R,4S,5R)-4-(benzoyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-vinyltetrahydro-3-furanyl benzoate C25H18Cl2N4O5 详情 详情
(IX) 25262 (2R,3R,4S,5R)-4-(benzoyloxy)-2-[2-chloro-6-(methoxyamino)-9H-purin-9-yl]-5-vinyltetrahydro-3-furanyl benzoate C26H22ClN5O6 详情 详情

合成路线53

该中间体在本合成路线中的序号：

The cyclization of ribofuranoside (I) with trimethylsilyl acetylene (II) by means of NBS in DMF gives the trimethylsilylisoxazole (III), which is desilylated with NaOH in methanol yielding the isoxazole (IV). Elimination of the isopropylidene protecting group of (IV) by passing through a Dowex 50 H+ column affords the dihydroxy compound (V), which is benzoylated with benzoyl chloridde and DMAP in pyridine giving the dibenzoyl derivative (VI). The condensation of (VI) with 2,6-dichloro-9H-purine (VII) in refluxing hexamethyldisilazane (HMDA) provides the purine derivative (VIII), which is treated with 0-methylhydroxylamine and triethylamine in refluxing dioxane yielding the adenosine derivative (IX). Finally, this compound is debenzoylated with ammonia in methanol.

参考文献 中间体
合成目标
【1】 Knutsen, L.; Olsen, U.B.; Roberts, S.M.; Varley, D.R.; Bowler, A.N. (Novo Nordisk A/S); Novel N-alkoxyadenine derivs. acting as cytokine inhibitors. WO 9801459 .
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
15455 (aminooxy)methane; O-methylhydroxylamine 67-62-9 CH5NO 详情 详情
(I) 25249 (3aR,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde O-methyloxime C10H17NO5 详情 详情
(II) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(III) 25250 3-[(3aR,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-5-(trimethylsilyl)isoxazole; (3aS,4R,6R,6aR)-2,2-dimethyl-6-[5-(trimethylsilyl)-3-isoxazolyl]tetrahydrofuro[3,4-d][1,3]dioxol-4-yl methyl ether C14H23NO5Si 详情 详情
(IV) 25251 3-[(3aR,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]isoxazole; (3aS,4R,6R,6aR)-6-(3-isoxazolyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl methyl ether C11H15NO5 详情 详情
(V) 25252 (2R,3S,4S,5R)-2-(3-isoxazolyl)-5-methoxytetrahydro-3,4-furandiol C8H11NO5 详情 详情
(VI) 25253 (2R,3R,4R,5R)-4-(benzoyloxy)-2-(3-isoxazolyl)-5-methoxytetrahydro-3-furanyl benzoate C22H19NO7 详情 详情
(VII) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(VIII) 25255 (2R,3R,4S,5R)-4-(benzoyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-(3-isoxazolyl)tetrahydro-3-furanyl benzoate C26H17Cl2N5O6 详情 详情
(IX) 25256 (2R,3R,4S,5R)-4-(benzoyloxy)-2-[2-chloro-6-(methoxyamino)-9H-purin-9-yl]-5-(3-isoxazolyl)tetrahydro-3-furanyl benzoate C27H21ClN6O7 详情 详情

合成路线54

该中间体在本合成路线中的序号：(V)

Condensation between 5-bromoindole (I) in ether and oxalyl chloride (II) in dichloromethane followed by treatment with dimethylamine provides N,N-dimethyaminoglyoxyl derivative (III), which is then reduced with LiAlH4 in THF to yield compound (IV). Coupling of (IV) with benzoyl chloride (V) by means of Et3N and DMAP in dichloromethane affords benzoylindole derivative (VI), which is then subjected to reaction with tributylstannyl derivative (VII) in toluene in the presence of Pd(PPh3)4 to furnish compound (VIII). Treatment of (VIII) with NaOH in refluxing MeOH gives indole (IX), which is converted into the final product by reduction with LiAlH4 in refluxing THF) and treatment with HCl for the formation of the corresponding hydrochloride salt. Alternatively, the target compound can be obtained as follows: treatment of (IV) with KH in ether and tert-butyllithium in pentane followed by reaction with N-methylpiperidinone (X) affords hydroxy derivative (XI), which is finally converted into the desired product.

参考文献 中间体
合成目标
【1】 Arora, J.; et al.; 5-Bicyclopiperidinetryptamine derivatives as selective 5-HT1D agonists. Soc Neurosci Abst 2000, 26, Part 1, Abst 145.14.
【2】 Slassi, A.; Edwards, L.; Meng, Q.; Rakhit, S. (NPS Allelix Corp.); 5-Cyclo indole cpds. as 5-HT1D receptor ligands. EP 0944595; JP 2001504501; WO 9823587 .
【3】 Rakhit, S.; Edwards, L.; Slassi, A.; Meng, Q. (NPS Allelix Corp.); 5-Cyclo indole cpds.. US 5998438 .
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) 13309 5-Bromo-1H-indole; 5-Bromoindole 10075-50-0 C8H6BrN 详情 详情
(II) 29841 Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride 79-37-8 C2Cl2O2 详情 详情
(III) 40926 2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide C12H11BrN2O2 详情 详情
(IV) 49717 N-[2-(5-bromo-1H-indol-3-yl)ethyl]-N,N-dimethylamine; 2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-1-ethanamine C12H15BrN2 详情 详情
(V) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(VI) 49718 [5-bromo-3-[2-(dimethylamino)ethyl]-1H-indol-1-yl](phenyl)methanone C19H19BrN2O 详情 详情
(VII) 49719 tert-butyl 4-(tributylstannyl)-3,6-dihydro-1(2H)-pyridinecarboxylate C22H43NO2Sn 详情 详情
(VIII) 49720 tert-butyl 4-[1-benzoyl-3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate C29H35N3O3 详情 详情
(IX) 49721 tert-butyl 4-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate C22H31N3O2 详情 详情
(X) 10919 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one 1445-73-4 C6H11NO 详情 详情
(XI) 49722 4-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-1-methyl-4-piperidinol C18H27N3O 详情 详情

合成路线55

该中间体在本合成路线中的序号：(IX)

Friedel Crafts acylation of methyl 2-methylazulene-1-carboxylate (I) with benzoyl chloride (II) and AlCl3 yielded the benzoylazulene (III). Subsequent saponification of the ester function with NaOH, followed by decarboxylation of the resulting acid (IV) using p-TsOH in boiling benzene provided (V). Mannich reaction of (V) with bis(dimethylamino)methane and paraformaldehyde produced amine (VI), which was quaternized with MeI to furnish the ammonium salt (VII). This was displaced by ethanolic KCN to give nitrile (VIII). Thioamide (IX) was then obtained by reaction of (VIII) with thioacetamide and HCl. Finally, the thiazole ring was constructed by cyclization of (IX) with bromoacetone.

参考文献 中间体
合成目标
【1】 Tomiyama, T.; Kasai, R.; Takeuchi, S.; Onkura, Y.; Benzoylazulene derivatives as selective cyclooxygenase-2 inhibitors. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 170.
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) 22157 methyl 2-methyl-1-azulenecarboxylate C13H12O2 详情 详情
(III) 22159 methyl 3-benzoyl-2-methyl-1-azulenecarboxylate C20H16O3 详情 详情
(IV) 22160 3-benzoyl-2-methyl-1-azulenecarboxylic acid C19H14O3 详情 详情
(V) 22161 (2-methyl-1-azulenyl)(phenyl)methanone C18H14O 详情 详情
(VI) 22162 [3-[(dimethylamino)methyl]-2-methyl-1-azulenyl](phenyl)methanone C21H21NO 详情 详情
(VII) 22163 [2-methyl-3-[(trimethyl-lambda(5)-azanyl)methyl]-1-azulenyl](phenyl)methanone C22H25NO 详情 详情
(VIII) 22164 2-(3-benzoyl-2-methyl-1-azulenyl)acetonitrile C20H15NO 详情 详情
(IX) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(IX) 22165 2-(3-benzoyl-2-methyl-1-azulenyl)ethanethioamide C20H17NOS 详情 详情

合成路线56

该中间体在本合成路线中的序号：

Alkylation of aminotetralin (I) with bromoacetonitrile in boiling acetone gave cyanomethyl compound (II). This was subsequently reduced to diamine (III) using LiAlH4. Condensation of (III) with benzoyl chloride under Schotten-Baumann conditions then yielded the corresponding benzamide.

参考文献 中间体
合成目标
【1】 Homan, E.J.; Copinga, S.; Elfström, L.; van der Veen, T.; Hallema, J.-P.; Mohell, N.; Unelius, L.; Johansson, R.; Wikström, H.V.; Grol, C.J.; 2-Aminotetralin-derived substituted benzamides with mixed dopamine D2, D3, and serotonin 5-HT1A receptor binding properties: A novel class of potential atypical antipsychotic agents. Bioorg Med Chem 1998, 6, 11, 2111.
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
31883 2-bromoacetonitrile 590-17-0 C2H2BrN 详情 详情
(I) 14648 N-(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-propylamine; 5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine C14H21NO 详情 详情
(II) 27938 2-[(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)(propyl)amino]acetonitrile C16H22N2O 详情 详情
(III) 27939 N-(2-aminoethyl)-N-(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-propylamine C16H26N2O 详情 详情

合成路线57

该中间体在本合成路线中的序号：(II)

The acylation of 3-amino-2,2-dimethyl-5-phenylpentanoic acid (I) with benzoyl chloride (II) in pyridine gives the corresponding amide (III), which is finally converted into the target anhydride by reaction with bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) and triethylamine in dichloromethane.

参考文献 中间体
合成目标
【1】 Iijima, K.; Hayashi, Y.; Katada, J.; Symmetrical anhydride-type serine protease inhibitors: Structure-activity relationship studies of human chymase inhibitors. Bioorg Med Chem Lett 1999, 9, 3, 413.
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) 28656 3-amino-2,2-dimethyl-5-phenylpentanoic acid C13H19NO2 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 28657 3-(benzoylamino)-2,2-dimethyl-5-phenylpentanoic acid C20H23NO3 详情 详情

合成路线58

该中间体在本合成路线中的序号：(XI)

The protection of 3-bromo-1-propanol (I) with dihydropyran (DHP) and p-toluenesulfonic acid gives the tetrahydropyranyl ether (II), which is condensed with 3,4-dichlorophenylacetonitrile (III) by means of NaH in THF yielding the pentanenitrile (IV). The condensation of (IV) with ethyl 3-bromopropionate (V) by means of potassium hexamethyldisylazide (KHMDS) in THF affords the heptanoate (VI), which is reductocyclized with H2 over RaNi in ethanol/aq. NH4OH affording the piperidone (VII). The reduction of (VII) by means of LiAlH4 in THF gives the piperidine (VIII), which is deprotected with HCl in ethyl ether yielding the racemic propanol (IX). The optical resolution of (IX) by means of (+)-camphorsulfonic acid in isopropanol affords the desired enantiomer (X), which is acylated with benzoyl chloride (XI) and DIEA in dichloromethane providing the benzoylpiperidine (XII). The reaction of (XII) with methanesulfonyl chloride and triethylamine gives the mesylate (XIII), which is treated with KI in refluxing acetone to yield the 3-iodopropyl derivative (XIV). Finally, (XIV) is condensed with 4-hydroxy-4-phenylpiperidine (XV) by means of KHCO3 in hot acetonitrile. The intermediate 4-hydroxy-4-phenylpiperidine (XV) has been obtained as follows: The reaction of 1-benzyl-4-piperidone (XVI) with phenyllithium in THF gives 1-benzyl-4-hydroxy-4-phenylpiperidine (XVII), which is then debenzy-lated by hydrogenation with H2.

参考文献 中间体
合成目标
【1】 Kuo, B.-S.; Lee, H.T.; Roth, B.D.; Chung, F.-Z.; Atherton, J.; Chen, M.H.; Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists. Acta Pharm Sin 1999, 20, 3, 283.
【2】 Chen, M.H.G.; Lee, H.T.; Chung, F.-Z. (Pfizer Inc.); 3-Alkyl-3-phenyl-piperidines. WO 9811090 .
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) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(II) 29460 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether C9H17BrO2 详情 详情
(III) 26935 2-(3,4-dichlorophenyl)acetonitrile 3218-49-3 C8H5Cl2N 详情 详情
(IV) 29461 2-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile C17H21Cl2NO2 详情 详情
(V) 29132 ethyl 3-bromopropanoate 539-74-2 C5H9BrO2 详情 详情
(VI) 29462 ethyl 4-cyano-4-(3,4-dichlorophenyl)-8-(tetrahydro-2H-pyran-2-yloxy)octanoate C22H29Cl2NO4 详情 详情
(VII) 29463 5-(3,4-dichlorophenyl)-5-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-2-piperidinone C20H27Cl2NO3 详情 详情
(VIII) 29464 3-(3,4-dichlorophenyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]piperidine; 4-[3-(3,4-dichlorophenyl)-3-piperidinyl]butyl tetrahydro-2H-pyran-2-yl ether C20H29Cl2NO2 详情 详情
(IX) 29465 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol C14H19Cl2NO 详情 详情
(X) 29466 3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol C14H19Cl2NO 详情 详情
(XI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XII) 29467 [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone C21H23Cl2NO2 详情 详情
(XIII) 29468 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate C22H25Cl2NO4S 详情 详情
(XIV) 29469 [(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone C21H22Cl2INO 详情 详情
(XV) 28021 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine 40807-61-2 C11H15NO 详情 详情
(XVI) 15720 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one 3612-20-2 C12H15NO 详情 详情
(XVII) 24014 Phenyllithium 591-51-5 C6H5Li 详情 详情
(XVIII) 29470 1-benzyl-4-phenyl-4-piperidinol C18H21NO 详情 详情

合成路线59

该中间体在本合成路线中的序号：(VIII)

The acylation of 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-(R)-amine (I) with propionyl chloride (II) and NaOH in dichloromethane/water gives the corresponding amide (III), which is reduced with LiAlH4 in refluxing THF yielding the corresponding secondary amine (IV). The alkylation of (IV) with bromoacetonitrile (V) by means of K2CO3 in refluxing acetone affords the expected tertiary amine (VI), which is reduced with LiAlH4 in refluxing THF providing the ethylenediamine (VII). Finally, this compound is benzoylated with benzoyl chloride and NaOH in dichloromethane/water.

参考文献 中间体
合成目标
【1】 Homan, E.J.; Grol, C.J.; Unelius, L.; Wilkstrom, H.V.; Copinga, S.; Jackson, D.M.; Synthesis and pharmacology of the enantiomers of the potential atypical antipsychotic agents 5-OMe-BPAT and 5-OMe-(2,6-di-OMe)-BPAT. Bioorg Med Chem 1999, 7, 7, 1263.
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) 31886 (2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine; (2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine C11H15NO 详情 详情
(II) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(III) 31882 N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide; N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide C14H19NO2 详情 详情
(IV) 14649 (2S)-5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine C14H21NO 详情 详情
(V) 31883 2-bromoacetonitrile 590-17-0 C2H2BrN 详情 详情
(VI) 31884 2-[[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl](propyl)amino]acetonitrile C16H22N2O 详情 详情
(VII) 31885 N(1)-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N(1)-propyl-1,2-ethanediamine; N-(2-aminoethyl)-N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine C16H26N2O 详情 详情
(VIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线60

该中间体在本合成路线中的序号：(VII)

Demethylation of compound (XI) by means of BBr3 in refluxing dichloromethane gives 5-hydroxytetralinyl derivative (XII), which is then condensed with bromoacetic acid ethyl ester (XIII) by means of K2CO3 in DMF or acetonitrile to furnish (ethoxycarbonylmethoxy)tetraline derivative (XIV). Finally, the target product is obtained by saponification of the ethyl ester group of (XIV) by means of NaOH in 1,2-dimethoxyethane.

参考文献 中间体
合成目标
【1】 Wenzel, T.; Nair, V.; Self-complementary oligodeoxyribonucleotides incorporating L-related isodeoxynucleosides: Synthesis, physical characterization, enzymology, and CD studies. Bioconjugate Chem 1998, 9, 6, 683.
【2】 Nair, V.; Taktakishvili, M.; Pommier, Y.; Neamati, N.; Recognition and inhibition of HIV integrase by a novel dinucleotide. Bioorg Med Chem Lett 2000, 10, 3, 249.
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) 46810 (2R,3S,4S)-2-(hydroxymethyl)tetrahydro-3,4-furandiol C5H10O4 详情 详情
(II) 46811 (2R,3S,4S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)tetrahydro-3,4-furandiol C21H28O4Si 详情 详情
(III) 46812 (2R,3R,4S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]tetrahydro-3-furanol C24H34O4SSi 详情 详情
(IV) 46813 tert-butyl(diphenyl)silyl ((2R,3R,4S)-3-[[tert-butyl(diphenyl)silyl]oxy]-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]tetrahydro-2-furanyl)methyl ether; tert-butyl[((2R,3R,4S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]tetrahydro-3-furanyl)oxy]diphenylsilane C40H52O4SSi2 详情 详情
(V) 10343 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine 73-24-5 C5H5N5 详情 详情
(VI) 46814 (2R,3S,4R)-4-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanol C10H13N5O3 详情 详情
(VII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(VIII) 46815 N-[9-[(3R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-3-furanyl]-9H-purin-6-yl]benzamide C17H17N5O4 详情 详情
(IX) 46816 N-[9-((3R,4S,5R)-5-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]-4-hydroxytetrahydro-3-furanyl)-9H-purin-6-yl]benzamide C38H35N5O6 详情 详情
(X) 46817 sodium [((2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydro-3-furanyl)oxy](2-chlorophenoxy)oxophosphoranolate C44H38ClN5NaO9P 详情 详情
(XI) 46818 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-(hydroxymethyl)tetrahydro-3-furanyl acetate C18H19N3O6 详情 详情
(XII) 46819 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[[((2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydro-3-furanyl)oxy](2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate C62H56ClN8O14P 详情 详情
(XIII) 46820 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[[[(2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-(hydroxymethyl)tetrahydro-3-furanyl]oxy](2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate C41H38ClN8O12P 详情 详情
(XIV) 46821 cyanomethyl dihydrogen phosphate C2H4NO4P 详情 详情

合成路线61

该中间体在本合成路线中的序号：(IV)

Protection of 5-methoxyindole (I) with benzenesulfonyl chloride (II) in the presence of NaH affords the N-sulfonyl indole (III). Acylation of the 2-lithio derivative of (III) with benzoyl chloride (IV) gives rise to ketone (V). Finally, removal of the phenylsulfonyl protecting group of (V) is achieved by either basic hydrolysis or by treatment with tetrabutylammonium fluoride.

参考文献 中间体
合成目标
【1】 Hufsky, H.; Pongratz, H.; Mahboobi, S.; et al.; Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents. J Med Chem 2001, 44, 26, 4535.
【2】 Teller, S.; Pongratz, H.; Mahboobi, S.; et al.; Bis(1H-2-indolyl) methanones as a novel class of inhibitors of the platelet-derived growth factor receptor kinase. J Med Chem 2002, 45, 5, 1002.
【3】 Burger, A.; Mahboobi, S.; Pongratz, H.; Hufsky, H.; Böhmer, F.-D.; Beckers, T.; Klenner, T.; Baasner, S.; Frieser, M.; Hockemeyer, J.; Fiebig, H.-H. (Asta Medica AG); 2-Acyl indol derivs. and their use as anti-tumour agents. DE 10020852; WO 0182909 .
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) 25902 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole 1006-94-6 C9H9NO 详情 详情
(II) 14713 benzenesulfonyl chloride 98-09-9 C6H5ClO2S 详情 详情
(III) 57928 5-methoxy-1-(phenylsulfonyl)-1H-indole; methyl 1-(phenylsulfonyl)-1H-indol-5-yl ether C15H13NO3S 详情 详情
(IV) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(V) 57929 [5-methoxy-1-(phenylsulfonyl)-1H-indol-2-yl](phenyl)methanone C22H17NO4S 详情 详情

合成路线62

该中间体在本合成路线中的序号：(B)

Solid phase synthesis: Attachment of 8-Fmoc-3-carboxymethyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (I) to Wang resin by means of 2,6-dichlorobenzoyl chloride (A) in DMF in the presence of pyridine, followed by treatment with benzoyl chloride (B) in dichloromethane in the presence of pyridine, provides resin-anchored derivative (II). Treatment of resin (II) with piperidine in DMF allows Fmoc removal to yield deprotected piperidine derivative (III), which is then converted into the target compound by alkylation with 1-(bromomethyl)naphthalene (IV) by heating in DMSO in the presence of DIEA, followed by cleavage of the molecule from the resin by heating with NaOMe in THF/MeOH. Alternatively, the conversion of (III) into the desired compound can be achieved by reductive amination between resin (III) and aldehyde (V) by means of NaBH3CN in THF in the presence of HOAc to afford anchored derivative (VI), followed by cleavage from the resin by heating with NaOMe in THF/MeOH.

参考文献 中间体
合成目标
【1】 Watson, B.; Thomsen, C.; Hohlweg, R. (Novo Nordisk A/S); Novel 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes. EP 1080091; WO 9959997 .
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) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(A) 25087 2,6-dichlorobenzoyl chloride 4659-45-4 C7H3Cl3O 详情 详情
(I),(II) 47322 2-[8-[(9H-fluoren-9-ylmethoxy)carbonyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid C30H29N3O5 详情 详情
(III) 47323 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl)acetic acid C15H19N3O3 详情 详情
(IV) 47324 1-(bromomethyl)naphthalene 3163-27-7 C11H9Br 详情 详情
(V) 12314 1-Naphthaldehyde 66-77-3 C11H8O 详情 详情
(VI) 47325 2-[8-(1-naphthylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid C26H27N3O3 详情 详情

合成路线63

该中间体在本合成路线中的序号：(VIII)

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64

该中间体在本合成路线中的序号：(XII)

Acylation of phenylalanine (XI) with benzoyl chloride (XII) under Schotten-Baumann conditions produced the corresponding benzamide (XIII). The cyclization of benzoylphenylalanine (XIII) in the presence of acetic anhydride afforded oxazolone (XIV), which was then reacted with trifluoroacetic anhydride producing the trifluoromethyl ketone (XV). After ketone (XV) reduction to carbinol (XVI) with NaBH4, the acidic hydrolysis of the benzamido group of (XVI) yielded the amino alcohol (XVII) (1). Condensation of acid (X) with amine (XVII) using EDC and HOBt gave amide (XVIII). The hydroxyl group of (XVIII) was then oxidized to ketone (XIX) employing a modified Pfitzner-Moffatt oxidation. Finally, hydrogenolysis of the benzyloxycarbonyl group of (XIX) furnished the desired aminopyrimidinone.

参考文献 中间体
合成目标
【1】 Akahoshi, F.; Ashimori, A.; Yoshimura, T.; et al.; Non-peptidic inhibitors of human chymase. Synthesis, structure-activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1,6-dihydropyrimidine-containing trifluoromethyl ketones. Bioorg Med Chem 2001, 9, 2, 301.
【2】 Akahoshi, F.; Yoshimura, T.; Eda, M.; Ashimori, A.; Fukuyama, H.; Nakajima, M.; Imada, T.; Okunishi, H.; Miyazaki, M. (Welfide Corporation); Heterocyclic amide cpds. and medicinal use of the same. EP 0826671; US 5948785; WO 9633974 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 49080 2-[5-[[(benzyloxy)carbonyl]amino]-2-(4-fluorophenyl)-6-oxo-1(6H)-pyrimidinyl]acetic acid C20H16FN3O5 详情 详情
(XI) 26219 Phenylalanine 150-30-1 C9H11NO2 详情 详情
(XII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XIII) 49081 N-Benzoyl-DL-phenylalanine 2901-76-0 C16H15NO3 详情 详情
(XIV) 49082 4-Benzyl-2-phenyl-2-oxazolin-5-one 5874-61-3 C16H13NO2 详情 详情
(XV) 49083 N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)benzamide C17H14F3NO2 详情 详情
(XVI) 49084 N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)benzamide C17H16F3NO2 详情 详情
(XVII) 49085 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol C10H12F3NO 详情 详情
(XVIII) 49086 benzyl 1-[2-[(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)amino]-2-oxoethyl]-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinylcarbamate C30H26F4N4O5 详情 详情
(XIX) 49087 benzyl 1-[2-[(1-benzyl-3,3,3-trifluoro-2-oxopropyl)amino]-2-oxoethyl]-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinylcarbamate C30H24F4N4O5 详情 详情

合成路线65

该中间体在本合成路线中的序号：(A)

Benclonidine has been synthesized by various routes: 1) Condensation of 1-benzoylimidazolidin-2-one (II) [obtained by reaction of imidazolidin-2-one (I) with benzoyl chloride (A)] and 2,6-dichloroaniline (III) in the presence of phosphoroxy chloride at elevated temperature yields title compound. (1) 2) Clonidine (IV) reacts with benzoylimidazole (V) in aprotic solvents to give directly benclonidine. (2) 3) 2,6-Dichlorophenylisocyanide dichloride (VI) and benzoylethylenediamine (VII) are condensed in the presence of an acid acceptor to give benclonidine. (2)

参考文献 中间体
合成目标
【1】 Franzmair, R.; Pittner, H. (Chemie Linz AG); AU 333749 .
【2】 Franzmair, R. (Chemie Linz AG); AU 339897 .
【3】 Koch, H.; Benclonidine. Drugs Fut 1984, 9, 6, 408.
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) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(I) 36228 2-imidazolidinone 120-93-4 C3H6N2O 详情 详情
(II) 60764 1-benzoyl-2-imidazolidinone C10H10N2O2 详情 详情
(III) 60765 2,6-dichloroaniline; 2,6-dichlorophenylamine C6H5Cl2N 详情 详情
(IV) 60767 2,6-dichloro-N-(2-imidazolidinylidene)aniline; N-(2,6-dichlorophenyl)-N-(2-imidazolidinylidene)amine C9H9Cl2N3 详情 详情
(V) 60766 1H-imidazol-1-yl(phenyl)methanone C10H8N2O 详情 详情
(VI) 60768 1,3-dichloro-2-[(dichloromethylene)amino]benzene C7H3Cl4N 详情 详情
(VII) 60769 N-(2-aminoethyl)benzamide C9H12N2O 详情 详情

合成路线66

该中间体在本合成路线中的序号：(I)

Condensation of benzoyl chloride (I) with ammonium thiocyanate in boiling acetone produces benzoyl isothiocyanate (II). This is then coupled with the known 3-amino-5-phenyl-1,2,4-thiadiazole (III) to afford the N-benzoyl thiourea (IV) (1). Finally, hydrolysis of (IV) under alkaline conditions gives rise to the target thiadiazolyl thiourea

参考文献 中间体
合成目标
【1】 Kurzer, F.; 1,2,4-Thiadiazolylureas. A postcript to the oxidative cyclisation of thionoamidines. J Chem Soc - Perkins Trans I 1985, 2, 311.
【2】 Camden, J.B. (The Procter & Gamble Co.); Thiadiazolyl urea or thiourea derivs. for antiviral treatment. JP 2002540156; US 6258831; WO 0057878 .
【3】 Agyin, J.K. (The Procter & Gamble Co.); Process for the preparation of 1,2,4-thiadiazoles. US 6297384 .
【4】 Camden, J.B. (The Procter & Gamble Co.); Viral treatment. JP 2002540150; US 6245788; WO 0057869 .
【5】 Camden, J.B. (The Procter & Gamble Co.); Viral treatment. US 6340696 .
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) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(II) 23530 benzoyl isothiocyanate 532-55-8 C8H5NOS 详情 详情
(III) 62354 　 C18H19N3O4 详情 详情
(IV) 62358 N-benzoyl-N'-(5-phenyl-1,2,4-thiadiazol-3-yl)thiourea C16H12N4OS2 详情 详情

合成路线67

该中间体在本合成路线中的序号：(X)

Intermediate (V) is prepared by treatment of ethyl β-D-thiogalactopyranoside (VII) with Bu2SnO in MeOH, followed by regioselective alkylation with triflate (VIII) in the presence of CsF in DME to afford ether (IX), which by subsequent esterification with benzoyl chloride (X) by means of pyridine and DMAP gives tribenzoate (XI). Coupling of thioglycoside (XI) with the acceptor alcohol (XII) in the presence of DMTST in CH2Cl2 yields adduct (XIII), which is then subjected to reductive acylation with orotic acid chloride (XIV) by means of PPh3 in CH2Cl2 to provide amide (XV). Finally, compound (XV) is debenzylated by hydrogenolysis with H2 over Pd/C in dioxane/H2O, followed by selective didebenzoylation by means of NaOMe in MeOH .

参考文献 中间体
合成目标
【1】 Magnani, J.L., Patton, J.T. Jr., Sarkar, A.K., Svarovsky, S.A., Ernst, B. (GlycoMimetics, Inc.). Heterobifunctional pan-selectin inhibitors. EP 1934236, EP 2264043, JP 2009507031, US 2007054870, US 7728117, WO 2007028050.
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) 68486 (2R)-2-(((2S,3S,4R,5R,6S)-2-(((1S,3R,5S)-5-((2-aminoethyl)carbamoyl)-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-2-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-3-(benzoyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)oxy)-3-cyclohexylpropanoic acid 　 C41H55N3O19 详情 详情
(VII) 68488 Ethyl 1-thio-β-D-galactopyranoside;Ethyl 1-deoxy-1-thio-β-D-galactopyranoside;(2S,3S,4R,5S,6R)-2-(ethylthio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;β-D-thiogalactopyranoside 56245-60-4 C8H16O5S 详情 详情
(VIII) 68489 (R)-benzyl 3-cyclohexyl-2-(((trifluoromethyl)sulfonyl)oxy)propanoate 　 C17H21F3O5S 详情 详情
(IX) 68490 (R)-benzyl 3-cyclohexyl-2-(((2S,3S,4R,5S,6R)-2-(ethylthio)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)oxy)propanoate 　 C24H36O7S 详情 详情
(X) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XI) 68495 (2S,3S,4R,5S,6R)-2-((benzoyloxy)methyl)-4-(((R)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl)oxy)-6-(ethylthio)tetrahydro-2H-pyran-3,5-diyl dibenzoate 　 C45H48O10S 详情 详情
(XII) 68493 (1S,3S,4R,5R)-methyl 3-azido-5-hydroxy-4-(((2S,3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexanecarboxylate 　 C35H41N3O8 详情 详情
(XIII) 68494 (2S,3S,4R,5S,6R)-2-(((2S,5S)-3-azido-5-(methoxycarbonyl)-2-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-6-((benzoyloxy)methyl)-4-(((R)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl)oxy)tetrahydro-2H-pyran-3,5-diyl dibenzoate 　 C78H83N3O18 详情 详情
(XIV) 68491 orotic acid chloride;Orotoylchloride;Orotyl chloride;1,2,3,6-tetrahydro-2,6-dioxo-4-Pyrimidinecarbonylchloride 3346-64-3 C5H3ClN2O3 详情 详情
(XV) 68492 (2S,3S,4R,5S,6R)-2-((benzoyloxy)methyl)-4-(((R)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl)oxy)-6-(((2S,3R,5S)-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-5-(methoxycarbonyl)-2-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)tetrahydro-2H-pyran-3,5-diyl dibenzoate 　 C83H87N3O21 详情 详情
Extended Information