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【结 构 式】

【分子编号】10101

【品名】Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene

【CA登记号】501-53-1

【 分 子 式 】C8H7ClO2

【 分 子 量 】170.59508

【元素组成】C 56.33% H 4.14% Cl 20.78% O 18.76%
与该中间体有关的原料药合成路线共 63 条
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合成路线1

该中间体在本合成路线中的序号：(III)

A new procedure for the synthesis of acivicin has been reported: The photochlorination of L-glutamic acid (I) gives 3-chloroglutamic acid (II); the corresponding diastereomers were separed by ion-exchange chromatography over Dowex-50 (H+). The reaction of (II) with benzyl chloroformate (III) affords N-carbobenzoxy-3-chloroglutamic acid (IV), which is anhydrized with dicyclohexylcarbodiimide to the corresponding protected anhydride (V). The reaction of (V) with lithium N-hydroxyphthalimide (VI) yields the phthalimidoxy derivative (VII), which is converted to the protected hydroxamic acid (VIII) by a treatment with hydroxylamine. The cyclization of (VIII) with triethylamine affords N-carbobenzoxytricholomic acid (IX), which is esterified with diphenyldiazomethane (X) giving the corresponding protected benzhydryl ester (Xl). The reaction of (XI) with dichloro-trisdimethylaminophosphorane (XII) yields the deprotected final compound (XIII), which is finally treated with trifluoroacetic acid and thioanisole (A).

参考文献 中间体
合成目标
【1】 Holladay, M.W.; Silverman, R.B.; Stereospecific total synthesis of the natural antitumor agent, (alphaS,5S)-alpha-maino-3-chloro-4,5-dihydro-5-isooxazoleacetic acid and its unnatural C-5 epimer. J Am Chem Soc 1981, 103, 24, 7357-58.
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) 19272 methyl phenyl sulfide; 1-(methylsulfanyl)benzene 100-68-5 C7H8S 详情 详情
(I) 28752 DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid 617-65-2 C5H9NO4 详情 详情
(II) 35997 3-chloroglutamic acid C5H8ClNO4 详情 详情
(III) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(IV) 35998 N-[(benzyloxy)carbonyl]-3-chloroglutamic acid C13H14ClNO6 详情 详情
(V) 35999 benzyl 4-chloro-2,6-dioxotetrahydro-2H-pyran-3-ylcarbamate C13H12ClNO5 详情 详情
(VI) 36000 lithium 1,3-dioxo-1,3-dihydro-2H-isoindol-2-olate C8H4LiNO3 详情 详情
(VII) 36001 lithium 2-[[(benzyloxy)carbonyl]amino]-3-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]-5-oxopentanoate C21H16ClLiN2O8 详情 详情
(VIII) 36002 N(2)-[(benzyloxy)carbonyl]-3-chloro-N(5)-hydroxyglutamine C13H15ClN2O6 详情 详情
(IX) 36003 2-[[(benzyloxy)carbonyl]amino]-2-(3-oxo-5-isoxazolidinyl)acetic acid C13H14N2O6 详情 详情
(XI) 36004 benzhydryl 2-[[(benzyloxy)carbonyl]amino]-2-(3-oxo-5-isoxazolidinyl)acetate C26H24N2O6 详情 详情
(XII) 36005 N-[dichloro[bis(dimethylamino)]phosphoranyl]-N,N-dimethylamine; N-[dichloro[bis(dimethylamino)]phosphoranyl]-N-methylmethanamine C6H18Cl2N3P 详情 详情
(XIII) 36006 benzhydryl 2-[[(benzyloxy)carbonyl]amino]-2-(3-chloro-4,5-dihydro-5-isoxazolyl)acetate C26H23ClN2O5 详情 详情

合成路线2

该中间体在本合成路线中的序号：

The acylation of 3',4'-dideoxykanamycin B (dibekacin) (I) with benzyloxycarbonyl chloride in water gives 6'-N-benzyloxycarbonyldibekacin (V), which is then acylated with (IV) as before and deprotected by hydrogenolysis with H2 over Pd/C in water - acetic acid.

参考文献 中间体
合成目标
【1】 Umezawa, H.; Umezawa, S.; Maeda, K.; Tsuchiya, O.; Kondo, S.; Fukatsu, S. (Microbial Chemistry Research Foundation); 1-N-[(S)-alpha-hydroxy-omega-aminoacyl]. DE 2530169; FR 2201875; GB 1426908; JP 7462442; JP 7480039; JP 7494648; JP 7733629; JP 8003357; US 4001208; US 4107424 .
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Habekacin. Drugs Fut 1983, 8, 5, 410.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 30662 Dibekacin; 3',4'-Dideoxykanamycin B; (2R,3R,4S,5S,6R)-4-amino-2-[((1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol C18H37N5O8 详情 详情
(IV) 30665 1-[[(2S)-4-amino-2-hydroxybutanoyl]oxy]-2,5-pyrrolidinedione C8H12N2O5 详情 详情
(V) 30666 6'-N-benzyloxycarbonyldibekacin; benzyl [(2S,5R,6R)-5-amino-6-[((1R,2S,3S,4R,6S)-4,6-diamino-3-[[(2R,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]tetrahydro-2H-pyran-2-yl]methylcarbamate C26H43N5O10 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The reaction of 3-aminotetrahydrofuran-2-one (I) with benzyloxycarbonyl chloride (II) and TEA in chloroform gives the carbamate (III), which is reduced to the lactol (IV) by means of DIBAL in toluene. It has been observed that lactol (IV) is in equilibrium with its tautomeric open chain aldehydic form.(V). The reaction of (IV)??(V) with phosphonium bromide (VI) by means of Bu-Li in THF yields 3-amino-4-penten-1-ol (VII), which is reprotected with benzyloxycarbonyl chloride (II) and TEA to afford the carbamate (VIII). The reaction of (VIII) with CBr4 and PPh3 in dichloromethane provides the pentenyl bromide (IX), which is treated with LiCN in THF to give 4-(benzyloxycarbonylamino)-5-hexenenitrile (X). Finally this compound is hydrolyzed with conc. HCl to yield the target 4-amino-5-hexenoic acid.

参考文献 中间体
合成目标
【1】 Zhang, Z.; Ding, Y.S.; Studenov, A.R.; Gerasimov, M.R.; Ferrieri, R.A.; Novel synthesis of [1-11C]gamma-vinyl-gamma-aminobutyric acid ([1-11C]GVG) for pharmacokinetic studies of addiction treatment. J Label Compd Radiopharm 2002, 45, 3, 199.
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) 59984 3-aminodihydro-2(3H)-furanone C4H7NO2 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 59985 benzyl 2-oxotetrahydro-3-furanylcarbamate C12H13NO4 详情 详情
(IV) 59986 benzyl 2-hydroxytetrahydro-3-furanylcarbamate C12H15NO4 详情 详情
(V) 59987 benzyl 1-formyl-3-hydroxypropylcarbamate C12H15NO4 详情 详情
(VI) 59988 methyl(triphenyl)phosphonium C19H18P 详情 详情
(VII) 59989 3-amino-4-penten-1-ol C5H11NO 详情 详情
(VIII) 59990 benzyl 1-(2-hydroxyethyl)-2-propenylcarbamate C13H17NO3 详情 详情
(IX) 59991 benzyl 1-(2-bromoethyl)-2-propenylcarbamate C13H16BrNO2 详情 详情
(X) 59992 benzyl 1-(2-cyanoethyl)-2-propenylcarbamate C14H16N2O2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

The reaction of 3-aminotetrahydrofuran-2-one (I) with benzyloxycarbonyl chloride (II) and TEA in chloroform gives the carbamate (III), which is reduced to the lactol (IV) by means of DIBAL in toluene. It has been observed that lactol (IV) is in equilibrium with its tautomeric open chain aldehydic form (V). The reaction of (IV)??(V) with phosphonium bromide (VI) by means of Bu-Li in THF yields 3-amino-4-penten-1-ol (VII), which is reprotected with benzyloxycarbonyl chloride (II) and TEA to afford the carbamate (VIII). The reaction of (VIII) with CBr4 and PPh3 in dichloromethane provides the pentenyl bromide (IX), which is treated with 11C labeled LiCN in THF to give 4-(benzyloxycarbonylamino)-5-hexenenitrile (X). Finally this compound is hydrolyzed with conc. HCl to yield the target 11C labeled 4-amino-5-hexenoic acid.

参考文献 中间体
合成目标
【1】 Zhang, Z.; Ding, Y.S.; Studenov, A.R.; Gerasimov, M.R.; Ferrieri, R.A.; Novel synthesis of [1-11C]gamma-vinyl-gamma-aminobutyric acid ([1-11C]GVG) for pharmacokinetic studies of addiction treatment. J Label Compd Radiopharm 2002, 45, 3, 199.
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) 59984 3-aminodihydro-2(3H)-furanone C4H7NO2 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 59985 benzyl 2-oxotetrahydro-3-furanylcarbamate C12H13NO4 详情 详情
(IV) 59986 benzyl 2-hydroxytetrahydro-3-furanylcarbamate C12H15NO4 详情 详情
(V) 59987 benzyl 1-formyl-3-hydroxypropylcarbamate C12H15NO4 详情 详情
(VI) 59988 methyl(triphenyl)phosphonium C19H18P 详情 详情
(VII) 59989 3-amino-4-penten-1-ol C5H11NO 详情 详情
(VIII) 59990 benzyl 1-(2-hydroxyethyl)-2-propenylcarbamate C13H17NO3 详情 详情
(IX) 59991 benzyl 1-(2-bromoethyl)-2-propenylcarbamate C13H16BrNO2 详情 详情
(X) 59992 benzyl 1-(2-cyanoethyl)-2-propenylcarbamate C14H16N2O2 详情 详情
(X) 59993 benzyl 1-(2-cyanoethyl)-2-propenylcarbamate C14H16N2O2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(II)

A new enantioselective synthesis for denopamine has been reported: The acylation of 1-(4-benzyloxyphenyl)-2-[2-(3,4-dimethoxyphenyl)ethylamino]ethanone (I) with benzyloxycarbonyl chloride (II) by means of NaHCO3 in dichloromethane gives the protected aminoketone (III), which is submitted to an asymmetric reduction with (R)-(+)-2-amino-3-methyl-1,1-diphenyl-1-butanol-borane complex in THF yielding the (R)-(-)-protected alcohol (V). Finally, the debenzylation of (V) by hydrogenolysis with H2 over Pd/C in methanol affords denopamine with 96% optical purity.

参考文献 中间体
合成目标
【1】 Takeda, M.; Saito, K.; Kawaguchi, T.; Matsuki, K.; Iwakuma, T.; Asymmetric reduction of aromatic ketones. I. Enantioselective synthesis of denopamine. Chem Pharm Bull 1993, 41, 4, 639.
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) 10100 1-[4-(Benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanone; N-(3,4-Dimethoxyphenylethyl)-4-benzyloxyphenacylamine C25H27NO4 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 10102 Benzyl 2-[4-(benzyloxy)phenyl]-2-oxoethyl(3,4-dimethoxyphenethyl)carbamate; Benzyl (4-benzyloxy)phenacyl-(3,4-dimethoxyphenethyl)carbamate C33H33NO6 详情 详情
(IV) 10103 (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol 56755-20-5 (hydrochloride) C17H21NO 详情 详情
(V) 10104 benzyl (2R)-2-[4-(benzyloxy)phenyl]-2-hydroxyethyl(3,4-dimethoxyphenethyl)carbamate C33H35NO6 详情 详情

合成路线6

该中间体在本合成路线中的序号：(B)

The cyclization of 2,2'-di(benzyloxycarbonylamino)pimelic acid (I) with PCl5 in methylene chloride gives the bis-N-carboxy anhydride (II), which by reaction with tert-butyl carbazate (A) is converted into the bis(tert-butyloxycarbonylhydrazide) compound (III). The enzymatic hydrolysis of (III) with an aminopeptidase from Streptomyces sapporonensis affords the mono-tert-butoxycarbonylhydrazide (IV), which by selective protection of the amino group with benzyloxycarbonyl chloride (B) under copper chelate conditions yields the selectively protected hydrazide (V). Full protection of (V) with tert-butoxycarbonyl anhydride (C) affords the fully protected monohydrazide (VI), which is condensed with benzyl glycinate (VII) to give the protected dipeptide (VIII). Hydrogenolysis of (VIII) with H2 over Pd/C in methanol-acetic acid yields the di-tert-butoxycarbonyldipeptide (IX), which is condensed with 2-acetoxypropanoylalanylglutamic acid monobenzyl ester (X) by means of isobutoxycarbonyl chloride (D) yielding the protected FK-156 (XI).

参考文献 中间体
合成目标
【1】 Hemmi, K.; Nakaguchi, O.; Hashimoto, M.; Taleno, H.; Kitaura, Y.; Okada, S.; An efficient method for selective amino acid protection of meso-2,2'-diaminocarboxylic acid: An improved synthesis of FK-156. Tetrahedron Lett 1982, 23, 6, 693-696.
【2】 Okada, S.; Hemmi, K.; Takano, H.; Hashimoto, M.; Nakaguchi, O.; Kitaura, Y.; Aratani, M.; Miyazaki, Y.; Studies of a new immunoactive peptide, FK-156. IV. Synthesis od FK-156 and its geometric isomer. J Antibiot 1982, 35, 10, 1300-11.
【3】 Okahara, M.; Nakahara, K.; Gotoh, T.; Hashimoto, M..; Kino, T.; Aoki, H.; Imanaka, H.; Kohsaka, M.; Nishiura, T.; Kuroda, Y.; Studies on a new immunoactive peptide, FK-156. II. Fermentation, extraction and chemical and biological charaterization. J Antibiot 1982, 35, 10, 1286-92.
【4】 Gotoh, T.; Imoraka, H.; Nakahara, K.; Tanaka, H.; Uchida, I.; Kawai, Y.; Studies on a new immunoactive peptide, FK-156. III. Structure elucidation. J Antibiot 1982, 35, 10, 1293-99.
【5】 Imanaka, H.; Nakahaa, K.; Gotoh, T.; Aoki, H.; Iwami, M.; Studies on a new immunoactive peptide, FK-156. I. Taxonomy of the producing strains. J Antibiot 1982, 35, 10, 1280-85.
【6】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K.; Aratani, M.; Takeno, H.; Okada, S.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New peptides, processes for their preparation and pharmaceutical compsns. containing them. EP 0027260 .
【7】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K. (Fujisawa Pharmaceutical Co., Ltd.); New lactyl tetrapeptide, processes for preparation thereof and pharmaceutical compsns. containing it. EP 0011283 .
【8】 Arya, V.P.; Blancafort, P.; Castaner, J.; Serradell, M.N.; FK-156. Drugs Fut 1983, 8, 8, 667.
【9】 Hemmi, K.; Takeno, H.; Okada, S.; Nakaguchi, O.; Kitaura, Y.; Hashimoto, M.; Total synthesis of FK-156 isolated from a Streptomyces as an immunostimulating peptide: Application of a novel copper chelate amino protection. J Am Chem Soc 1981, 103, 7026.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(A) 10893 tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate 870-46-2 C5H12N2O2 详情 详情
(D) 36103 2-[(Chlorocarbonyl)oxy]-2-methylpropane; tert-Butoxycarbonyl chloride C5H9ClO2 详情 详情
(I) 10130 (2R,6S)-2,6-Bis[[(benzyloxy)carbonyl]amino]heptanedioic acid C23H26N2O8 详情 详情
(II) 10892 (4R)-4-[3-[(4S)-2,5-Dioxo-1,3-oxazolan-4-yl]propyl]-1,3-oxazolane-2,5-dione C9H10N2O6 详情 详情
(III) 10894 tert-butyl 2-[(2R,6S)-2,6-diamino-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoyl]-1-hydrazinecarboxylate C17H34N6O6 详情 详情
(IV) 10895 (2S,6R)-2,6-Diamino-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoic acid C12H24N4O5 详情 详情
(V) 10896 (2S,6R)-6-Amino-2-[[(benzyloxy)carbonyl]amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoic acid C20H30N4O7 详情 详情
(VI) 10897 (2S,6R)-2-[[(Benzyloxy)carbonyl]amino]-6-[(tert-butoxycarbonyl)amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoic acid C25H38N4O9 详情 详情
(VII) 13601 benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride 1738-68-7 C9H11NO2 详情 详情
(VIII) 36100 tert-butyl 2-[(2R,6S)-6-[[(benzyloxy)carbonyl]amino]-7-[[2-(benzyloxy)-2-oxoethyl]amino]-2-[(tert-butoxycarbonyl)amino]-7-oxoheptanoyl]-1-hydrazinecarboxylate C34H47N5O10 详情 详情
(IX) 36101 2-([(2S,6R)-2-amino-6-[(tert-butoxycarbonyl)amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoyl]amino)acetic acid C19H35N5O8 详情 详情
(X) 36102 (4R)-4-[((2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoyl)amino]-5-(benzyloxy)-5-oxopentanoic acid C20H26N2O8 详情 详情
(XI) 36104 (4R,7S,10R,15S)-10-[(benzyloxy)carbonyl]-15-[(4R)-4-[(tert-butoxycarbonyl)amino]-5-[2-(tert-butoxycarbonyl)hydrazino]-5-oxopentyl]-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid C39H59N7O15 详情 详情
(C) 13214 Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate 24424-99-5 C10H18O5 详情 详情

合成路线7

该中间体在本合成路线中的序号：(B)

The reaction of the dianhydride (II) with benzyl carbazate (E) gives the bis(benzyloxycarbonylhydrazide) compound (XXI), which by an enzymatic treatment with an aminopeptidase from Streptomyces sapporonensis yields the monohydrazide (XXII). The protection of (XXII) with benzyloxycarbonyl chloride (B) affords the protected monohydrazide (XXIII), which is cyclized by treatment with SOCl2 giving the monocarboxy anhydride (XXIV). Hydrolysis of (XXIV) with HCl yields amino acid (XXV), which is condensed with glycine (XXVI) to afford the dipeptide (XXVII). The condensation of (XXVII) with (X) gives the protected FK-156 (XXVIII), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol-acetic acid affording FK-156 still protected with an acetoxy and a hydrazine group (XXIX).

参考文献 中间体
合成目标
【1】 Hemmi, K.; Nakaguchi, O.; Hashimoto, M.; Taleno, H.; Kitaura, Y.; Okada, S.; An efficient method for selective amino acid protection of meso-2,2'-diaminocarboxylic acid: An improved synthesis of FK-156. Tetrahedron Lett 1982, 23, 6, 693-696.
【2】 Imanaka, H.; Nakahaa, K.; Gotoh, T.; Aoki, H.; Iwami, M.; Studies on a new immunoactive peptide, FK-156. I. Taxonomy of the producing strains. J Antibiot 1982, 35, 10, 1280-85.
【3】 Okada, S.; Hemmi, K.; Takano, H.; Hashimoto, M.; Nakaguchi, O.; Kitaura, Y.; Aratani, M.; Miyazaki, Y.; Studies of a new immunoactive peptide, FK-156. IV. Synthesis od FK-156 and its geometric isomer. J Antibiot 1982, 35, 10, 1300-11.
【4】 Gotoh, T.; Imoraka, H.; Nakahara, K.; Tanaka, H.; Uchida, I.; Kawai, Y.; Studies on a new immunoactive peptide, FK-156. III. Structure elucidation. J Antibiot 1982, 35, 10, 1293-99.
【5】 Okahara, M.; Nakahara, K.; Gotoh, T.; Hashimoto, M..; Kino, T.; Aoki, H.; Imanaka, H.; Kohsaka, M.; Nishiura, T.; Kuroda, Y.; Studies on a new immunoactive peptide, FK-156. II. Fermentation, extraction and chemical and biological charaterization. J Antibiot 1982, 35, 10, 1286-92.
【6】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K.; Aratani, M.; Takeno, H.; Okada, S.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New peptides, processes for their preparation and pharmaceutical compsns. containing them. EP 0027260 .
【7】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K. (Fujisawa Pharmaceutical Co., Ltd.); New lactyl tetrapeptide, processes for preparation thereof and pharmaceutical compsns. containing it. EP 0011283 .
【8】 Arya, V.P.; Blancafort, P.; Castaner, J.; Serradell, M.N.; FK-156. Drugs Fut 1983, 8, 8, 667.
【9】 Hemmi, K.; Takeno, H.; Okada, S.; Nakaguchi, O.; Kitaura, Y.; Hashimoto, M.; Total synthesis of FK-156 isolated from a Streptomyces as an immunostimulating peptide: Application of a novel copper chelate amino protection. J Am Chem Soc 1981, 103, 7026.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(E) 36108 benzyl 1-hydrazinecarboxylate 5331-43-1 C8H10N2O2 详情 详情
(II) 10892 (4R)-4-[3-[(4S)-2,5-Dioxo-1,3-oxazolan-4-yl]propyl]-1,3-oxazolane-2,5-dione C9H10N2O6 详情 详情
(X) 36102 (4R)-4-[((2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoyl)amino]-5-(benzyloxy)-5-oxopentanoic acid C20H26N2O8 详情 详情
(XXI) 36109 benzyl 2-((2R,6S)-2,6-diamino-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoyl)-1-hydrazinecarboxylate C23H30N6O6 详情 详情
(XXII) 36110 (2S,6R)-2,6-diamino-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoic acid C15H22N4O5 详情 详情
(XXIII) 36111 (2S,6R)-2,6-bis[[(benzyloxy)carbonyl]amino]-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoic acid C31H34N4O9 详情 详情
(XXIV) 36112 benzyl 2-[(2R)-2-[[(benzyloxy)carbonyl]amino]-5-[(4S)-2,5-dioxo-1,3-oxazolidin-4-yl]pentanoyl]-1-hydrazinecarboxylate C24H26N4O8 详情 详情
(XXV) 36113 (2S,6R)-2-amino-6-[[(benzyloxy)carbonyl]amino]-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoic acid C23H28N4O7 详情 详情
(XXVI) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(XXVII) 36114 2-[((2S,6R)-2-amino-6-[[(benzyloxy)carbonyl]amino]-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoyl)amino]acetic acid C25H31N5O8 详情 详情
(XXVIII) 36115 (4R,7S,10R,15S)-10-[(benzyloxy)carbonyl]-15-((4R)-4-[[(benzyloxy)carbonyl]amino]-5-[2-[(benzyloxy)carbonyl]hydrazino]-5-oxopentyl)-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid C45H55N7O15 详情 详情
(XXIX) 36116 (4R,7S,10R,15S)-15-[(4R)-4-amino-5-hydrazino-5-oxopentyl]-10-carboxy-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid C22H37N7O11 详情 详情

合成路线8

该中间体在本合成路线中的序号：

Antineopleston A10 (A10) can be obtained by two different ways: 1) A10 has been synthesized in two steps: Condensation of phenylacetic acid (I) with L-glutamine (V) to give phenylacetyl-L-glutamine (VI), followed by intramolecular cyclization of the latter. In the first step (I) is activated by reacting with various reagents such as HOSu (N-hydroxysuccinimide) (II) in the presence of DCC, DCC (N,N-dicyclohexylcarbodiimide) or 2-mercaptothiazoline (III) in the presence of DCC to afford the intermediates (IVa), (IVb) and (IVc), respectively. Without isolation, the intermediate (IVa), (IVb) or (IVc) is treated with a solution of L-glutamine in CH3CN:H2O (2:1) containing NaHCO3 to give (VI) in 60, 87 and 82% yields, respectively. In the second step (VI) is converted to the activated intermediate (IXa) or (IXb) by treatment with CDI (1,1'-carbonydiimidazole) (VII) or HOSu (VIII) in the presence of DCC. Finally, intramolecular cyclization of (IXa) or (IXb) is effected by treating the latter at 80 C to yield A10 in 85 or 82% yield, respectively. 2) Reaction of phenylacetyl chloride with L-glutamine in aqueous solution containing NaHCO3 affords phenylacetyl-L-glutamine (VI), which is heated at 160 C to give A10.

参考文献 中间体
合成目标
【1】 Verhoef, J.; Schmitz, F.-J.; Fluit, A.C.; Milatovic, D.; 13th Intl Cong Chemother (Aug. 28-Sept. 2, Vienna) 1983, 50, 2, PS 12.4-11-4.
【2】 Burzynski, S.R. (Burzynski Research Institute); Purified antineoplaston factions and methods of treating neoplastic disease. EP 0069232; JP 5032548; JP 5058886; JP 58010521; US 4470970 .
【3】 Burzynski, S.R.; Hai, T.T.; Antineoplaston A10. Drugs Fut 1985, 10, 2, 103.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(IVa) 24947 1-[(2-phenylacetyl)oxy]-2,5-pyrrolidinedione C12H11NO4 详情 详情
(IVb) 28896 phenylacetic anhydride C16H14O3 详情 详情
(IVc) 28897 2-phenyl-1-(2-thioxo-1,3-thiazolidin-3-yl)-1-ethanone C11H11NOS2 详情 详情
(IXa) 28899 (3S)-4-(1H-imidazol-1-yl)-4-oxo-3-[(2-phenylacetyl)amino]butanamide C15H16N4O3 详情 详情
(IXb) 28900 (3S)-4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-4-oxo-3-[(2-phenylacetyl)amino]butanamide C16H17N3O6 详情 详情
(I) 16148 Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid 103-82-2 C8H8O2 详情 详情
(II) 10264 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione 6066-82-6 C4H5NO3 详情 详情
(III) 28895 4,5-dihydro-1,3-thiazol-2-ylhydrosulfide 96-53-7 C3H5NS2 详情 详情
(V) 24948 L-glutamine 56-85-9 C5H10N2O3 详情 详情
(VI) 28898 (2S)-4-amino-4-oxo-2-[(2-phenylacetyl)amino]butyric acid C12H14N2O4 详情 详情
(VII) 11353 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) 530-62-1 C7H6N4O 详情 详情
(VIII) 10264 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione 6066-82-6 C4H5NO3 详情 详情

合成路线9

该中间体在本合成路线中的序号：(V)

Two related syntheses of a known intermediate of carumonam are presented: 1) The reaction of calcium L-threonate (I) with HBr in acetic acid - acetic anhydride and then with refluxing methanol gives methyl (2S,3S)-2,4-dibromo-3-hydroxybutanoate (II), which by reaction with concentrated NH4OH is converted into (2S, 3R)-3-(bromomethyl)oxiranecarboxamide (III). The reaction of (III) with KI and potassium acetate in hot DMF affords (2R, 3S)-3-(acetoxymethyl)oxiranecarboxamide (IV), which is treated with concentrated NH4OH at 60 C and then with benzyl chloroformate (V) to give (2S, 3R)-2-(benzyloxycarbonylamino)-3,4-dihydroxybutanamide (VIII), an intermediate compound previously obtained in the synthesis described in Drugs Fut 1985, 10: 967. 2) The treatment of dibromide (II) with KI and potassium acetate in hot DMF gives methyl (2S,3S)-4-acetoxy-2,3-epoxybutanoate (VI), which is treated first with NaOH in methanol and then with hot NH4OH to yield (2S, 3R)-2-amino-3,4-dihydroxybutanamide (VII). Finally, this compound is treated with benzyl chloroformate (V) as before to give the intermediate (VIII) previously mentioned.

参考文献 中间体
合成目标
【1】 Manchand, P.S.; Luk, K.-C.; Belica, P.S.; Choudhry, S.C.; Wei, C.C.; Soukup, M.; A novel synthesis of the monobactam antibiotic carumonam. J Org Chem 1988, 53, 23, 5507.
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) 21521 calcium di[(2R,3S)-2,3,4-trihydroxybutanoate] C8H14CaO10 详情 详情
(II) 21522 methyl (2S,3S)-2,4-dibromo-3-hydroxybutanoate C5H8Br2O3 详情 详情
(III) 21523 (2R,3R)-3-(bromomethyl)-2-oxiranecarboxamide C4H6BrNO2 详情 详情
(IV) 21524 [(2S,3R)-3-(aminocarbonyl)oxiranyl]methyl acetate C6H9NO4 详情 详情
(V) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VI) 21525 methyl (2R,3S)-3-[(acetoxy)methyl]-2-oxiranecarboxylate C7H10O5 详情 详情
(VII) 21526 (2S,3R)-2-amino-3,4-dihydroxybutanamide C4H10N2O3 详情 详情
(VIII) 28759 benzyl (1S,2R)-1-(aminocarbonyl)-2,3-dihydroxypropylcarbamate C12H16N2O5 详情 详情

合成路线10

该中间体在本合成路线中的序号：(II)

The tetahydroimidazopyridine (I) is prepared by condensation of histamine with propionaldehyde in the presence of NaOH. The alkylation in position 1 or 3 is performed with ethyl bromide in a catalytic two-phase system, after protection of the amine group in position 5 as benzyloxycarbonyl derivative, and followed by removal of the protecting group by catalytic hydrogenation. The resulting amines (IVa-b) are then made to react with isopropyl isothiocyanate and the two regioisomers obtained are separated by crystallization.

参考文献 中间体
合成目标
【1】 Acari, G.; Bernardi, L.; Falconi, G.; Scarponi, U. (Pharmacia Corp.); 4,5,6,7-Tetrahydroimidazo[4,5-c]pyridine derivatives. BE 0871985; DE 2849572; FR 2433022; GB 2028798; JP 55024158; US 4223146 .
【2】 Riva, F.; 386/1634. Drugs Fut 1985, 10, 2, 101.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IVa) 28915 benzyl 1,4-diethyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate C18H23N3O2 详情 详情
(IVb) 28916 benzyl 3,4-diethyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate C18H23N3O2 详情 详情
(Va) 28917 1,4-diethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine C10H17N3 详情 详情
(Vb) 28918 3,4-diethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine C10H17N3 详情 详情
(VIIa) 28920 1,4-diethyl-N-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carbothioamide C14H24N4S 详情 详情
(VIIb) 28921 3,4-diethyl-N-isopropyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carbothioamide C14H24N4S 详情 详情
(I) 28913 4-ethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine C8H13N3 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 28914 benzyl 4-ethyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate C16H19N3O2 详情 详情
(VI) 28919 2-isothiocyanatopropane 2253-73-8 C4H7NS 详情 详情

合成路线11

该中间体在本合成路线中的序号：

The reaction of N-tert-butoxycarbonylthreonin (I) with O-benzylhydroxylamine (II) by means of N-hydroxybenzotriazole acid dicyclohexylcarbodiimide in THF gives N-tert-butoxycarbonyl-N-benzyloxythreoninamide (III), which is cyclized by means of triphenylphosphine and diethyl azodicarboxylate in THF yielding N-benzyloxy-3-(tert-butoxycarbonylamino)-4-methylazetidin-2-one (IV). The hydrogenolysis of (IV) with H2 over Pd/C in ethanol affords 3-(tert-butoxycarbonylamino)-4-methyl-N-hydroxyazetidin-2-one (V), which is reduced with TiCl3 in ethanol - aqueous ammnonium acetate giving 3-(tert-butoxycarbonylamino)-4-methylazetidin-2-one (VI). The hydrolysis of (VI) with trifluoroacetic acid in CH2Cl2 anisole, followed by reaction with benzyl chloroformate in acetone yields 3-(benzyloxycarbonylamino)-4-methylazetidin-2-one (VII). The sulfonation of (VII) with SO3 in DMF, and treatment of the resulting product with tetrabutylammonium sulfate in CH2Cl2 affords 3-(benzyloxycarbonylamino)-4-methyl-2-oxoazetidin-1-sulfonic acid tetrabutylammonium salt (VIII), which is debenzylated by hydrogenolysis with H2 over Pd/C in DMF giving 3-amino-4-methyl-2-oxoazetidin-1-sulfonic acid tetrabutylammonium salt (IX). The condensation of (IX) with alpha-[[(1-diphenylmethoxycarbonyl)-1-methylethoxy]imino]-(2-amino-4-thiazolyl)acetic acid (X), by means of N-hydroxybenzotriazole or N-hydroxysuccinimide and dicyclohexylcarbodiimide in acetone yields 3-[[(2-amino-4-thiazolyl)[[1-(diphenylmethoxycarbonyl]-1-methylethoxy]imino]acetyl]amino]-4-methyl-2-oxoazetidine-1-sulfonic acid (XI), which is finally hydrolyzed with trifluoroacetic acid.

参考文献 中间体
合成目标
【1】 Fox, R.; Denzel, T.W.; Singh, J.; et al.; Regioselective activation of aminothiazole(iminoxyacetic acid)acetic acid: An efficient synthesis of the monobactam aztreonam. Org Process Res Dev 2002, 6, 6, 863.
【2】 Sykes, R.B.; Parker, W.L.; Cimarusti, C.M.; Koster, W.H.; Slusarchyk, W.A.; Fritz, A.W.; Floyd, D.M. (Bristol-Myers Squibb Co.); beta-Lactam antibiotics containing sulphonic groups. BE 0887428; DE 3104145; GB 2071650; JP 56125362 .
【3】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Aztreonam. Drugs Fut 1983, 8, 4, 295.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 30642 (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutyric acid 2592-18-9 C9H17NO5 详情 详情
(II) 14640 O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene 622-33-3 C7H9NO 详情 详情
(III) 30643 tert-butyl (1S,2S)-1-[[(benzyloxy)amino]carbonyl]-2-hydroxypropylcarbamate C16H24N2O5 详情 详情
(IV) 30644 tert-butyl (2S,3S)-1-(benzyloxy)-2-methyl-4-oxoazetidinylcarbamate C16H22N2O4 详情 详情
(V) 30645 tert-butyl (2S,3S)-1-hydroxy-2-methyl-4-oxoazetidinylcarbamate C9H16N2O4 详情 详情
(VI) 30646 tert-butyl (2S,3S)-2-methyl-4-oxoazetidinylcarbamate C9H16N2O3 详情 详情
(VII) 30647 benzyl (2S,3S)-2-methyl-4-oxoazetidinylcarbamate C12H14N2O3 详情 详情
(VIII) 30648 N,N,N-tributyl-1-butanaminium (2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-methyl-4-oxo-1-azetidinesulfonate C28H49N3O6S 详情 详情
(IX) 30649 N,N,N-tributyl-1-butanaminium (2S,3S)-3-amino-2-methyl-4-oxo-1-azetidinesulfonate C20H43N3O4S 详情 详情
(X) 30650 2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(benzhydryloxy)-1,1-dimethyl-2-oxoethoxy]imino]acetic acid C22H21N3O5S 详情 详情
(XI) 30651 (2S,3S)-3-[(2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(benzhydryloxy)-1,1-dimethyl-2-oxoethoxy]imino]acetyl)amino]-2-methyl-4-oxo-1-azetidinesulfonic acid C26H27N5O8S2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VII)

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13

该中间体在本合成路线中的序号：(IV)

The hydrolysis of 1-benzyl-4-(methylamino)piperidine-4-carboxamide (I) with refluxing concentrated aqueous HCl gives the corresponding free acid (II), which is debenzylated with H2 over Pd/C in basic medium yielding 4-(methylamino)piperidine-4-carboxylic acid sodium salt (III). The protection of (III) with benzyl chloroformate (IV) in basic THF - water affords 1-(benzyloxycarbonyl)-4-(methylamino)piperidine 4 carboxylic acid (V), which by cyclization with phosgene in dioxane is converted to benzyl 1-methyl-2,4-dioxo 3-oxa-1,8-diazaspiro[4.5]decane-8 carboxylate (VI). The reaction of (VI) with 2,6-dimethylaniline (II) by heating at 160 C gives benzyl 4-(2,6-dimethylphenylaminocarbonyl)-4-(methylamino)piperidine-1-carboxylate (VIII), which is methylated with refluxing methyl iodide to the corresponding dimethylamino compound (IX). The deprotection of (IX) with H2 over Pd/C in methanol yields 4-(dimethylamino)-N-(2,6-dimethylphenyl)piperidine-4-carboxamide (X), which is finally condensed with 1,2-epoxycyclohexane (XI) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 De Bruyn, M.F.L.; Van Daele, G.H.P.; Verdonck, M.G.C. (Janssen Pharmaceutica NV); N-Aryl-alpha-aminocarboxamide derivs.. EP 0121972; ES 8506615 .
【2】 Castaner, J.; Prous, J.; Transcainidine. Drugs Fut 1988, 13, 3, 239.
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) 22019 1-benzyl-4-(methylamino)-4-piperidinecarboxamide 1024-11-9 C14H21N3O 详情 详情
(II) 22020 1-benzyl-4-(methylamino)-4-piperidinecarboxylic acid C14H20N2O2 详情 详情
(III) 22021 sodium 4-(methylamino)-4-piperidinecarboxylate C7H13N2NaO2 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 22023 1-[(benzyloxy)carbonyl]-4-(methylamino)-4-piperidinecarboxylic acid C15H20N2O4 详情 详情
(VI) 22024 benzyl 1-methyl-2,4-dioxo-3-oxa-1,8-diazaspiro[4.5]decane-8-carboxylate C16H18N2O5 详情 详情
(VII) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(VIII) 22026 benzyl 4-[(2,6-dimethylanilino)carbonyl]-4-(methylamino)-1-piperidinecarboxylate C23H29N3O3 详情 详情
(IX) 22027 benzyl 4-(dimethylamino)-4-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate C24H31N3O3 详情 详情
(X) 22028 4-(dimethylamino)-N-(2,6-dimethylphenyl)-4-piperidinecarboxamide C16H25N3O 详情 详情
(XI) 17986 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide 286-20-4 C6H10O 详情 详情

合成路线14

该中间体在本合成路线中的序号：

The reduction of L-pyroglutamic acid (I) with NaBH4 gives 5(S)-(hydroxymethyl)pyrrolidin-2-one (II), which is cyclized with benzaldehyde (III) by means of p-toluenesulfonic acid yielding the perhydropyrrolooxazolone (IV). The alkylation of (IV) with 2-cyclohexenyl bromide (V) and LDA in THF affords the corresponding cyclohexenyl derivative (VI), which is reduced with LiAlH4 in THF to give 1-benzyl-3(S)-(2-cyclohexenyl)-5(S)-(hydroxymethyl)pyrrolidine (VII). Elimination of the benzyl protecting group of (VII) with H2 over Pd/C yields the pyrrolidine (VIII), which is reprotected with benzyl chloroformate and K2CO3 to afford the carbamate (IX). The oxidation of the carbinol group of (IX) with Jones reagent or oxygen and platinum black gives the protected proline (X), which is finally deprotected with H2 over Pd/C providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).

参考文献 中间体
合成目标
【1】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140.
【2】 Thottathil, J.K. (Bristol-Myers Squibb Co.); Process and intermediates for preparing trans-4-substd.-S-prolines. EP 0183390; US 4588819 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 32046 (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one C29H40O7 详情 详情
(II) 38560 (5S)-5-(hydroxymethyl)-2-pyrrolidinone 17342-08-4 C5H9NO2 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IV) 38561 (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one 103201-79-2 C12H13NO2 详情 详情
(V) 30800 3-bromo-1-cyclohexene 1521-51-3 C6H9Br 详情 详情
(VI) 38562 (3R,6S,7aS)-6-[(1S)-2-cyclohexen-1-yl]-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C18H21NO2 详情 详情
(VII) 38563 [(2S,4S)-1-benzyl-4-[(1S)-2-cyclohexen-1-yl]pyrrolidinyl]methanol C18H25NO 详情 详情
(VIII) 38564 [(2S,4S)-4-cyclohexylpyrrolidinyl]methanol; trans-4-cyhexyl-L-Proline 90657-55-9 C11H21NO 详情 详情
(IX) 38565 benzyl (2S,4S)-4-cyclohexyl-2-(hydroxymethyl)-1-pyrrolidinecarboxylate C19H27NO3 详情 详情
(X) 38566 (2S,4S)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinecarboxylic acid C19H25NO4 详情 详情
(XI) 38567 (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid C11H19NO2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The reaction of cysteine (I) with benzyl chloroformate (II) in the usual way gives the corresponding di(benzyloxycarbonyl) derivative (III), which is treated with PCl5 or SOCl2 in CHCl3 to afford the bisacyl chloride (IV). Finally, this compound is condensed with 4,6-dibromo-2-(cyclohexylmethylaminomethyl) aniline (V) in ethyl acetate.

参考文献 中间体
合成目标
【1】 Giannini, E.H.; Farm Sci Ed 1985, 40, 2, 108-119.
【2】 Nardi, D.; Tajana, A.; Motta, G.; Cazzulani, P.; Graziani, G. (Recordati Industria Chimica e Farmaceutica SpA); Therapeutically effective derivatives of cystine. DE 3225274; EP 0069527; FR 2509298; GB 2102792; JP 58032860; US 4438133 .
【3】 Castaner, J.; Serradell, M.N.; Cistinexine. Drugs Fut 1986, 11, 3, 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
(I) 28171 (2S)-2-amino-3-[[(2R)-2-amino-2-carboxyethyl]disulfanyl]propionic acid 56-89-3 C6H12N2O4S2 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 28172 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[((2R)-2-[[(benzyloxy)carbonyl]amino]-2-carboxyethyl)disulfanyl]propionic acid 6968-11-2 C22H24N2O8S2 详情 详情
(IV) 27173 (1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate C10H17BrO2 详情 详情
(V) 28174 2,4-dibromo-6-[[cyclohexyl(methyl)amino]methyl]aniline C14H20Br2N2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VII)

L-Picolinic acid (II) is protected with benzyl chloroformiate (VII) to afford compound (VIII), which is condensed with 2-methylaniline (IX) by means SOCl2/DMAP to yield amide (X). This compound (X) is methylated by treatment with palladium acetate (Pd(Oac)2) to obtain compound (XI), which is deprotected by means HBr to yield compound (V). Finally, this compound (V) is alkylated with 1-iodopropane by means potassium carbonate (K2CO3) to yield Ropivacaine.

参考文献 中间体
合成目标
【1】 Sandeberg, R.V. (AstraZeneca plc); S-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, process for its preparation and pharmaceutical preparation containing it. EP 0239710; US 4870086 .
【2】 T. af Ekenstam, B.; Bovin, C. (Alpharma Inc.); L-N-n-Propylpipecolic acid-2,6-xylidide and method for preparing the same. JP 1985502054; WO 8500599 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
28758 1-iodopropane 107-08-4 C3H7I 详情 详情
(II) 17380 (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid 3105-95-1 C6H11NO2 详情 详情
(V) 17531 (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide C14H20N2O 详情 详情
(VII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VIII) 19504 (2S)-1-[(benzyloxy)carbonyl]-2-piperidinecarboxylic acid C14H17NO4 详情 详情
(IX) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(X) 19506 benzyl (2S)-2-(2-toluidinocarbonyl)-1-piperidinecarboxylate C21H24N2O3 详情 详情
(XI) 19507 benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate C22H26N2O3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VII)

Compound (XII) is protected with benzyl chloroformiate (VII) to afford compound (XIII), which is condensed with 2,5-dimethylaniline (XIV) by means SOCl2/DMAP to yield amide (XIV). This compound (XIV) is deprotected by means trimethylsillyl chloride to yield compound (XV), which is hydrogenated by means Rh/Al2O3. Finally, this compound (V) is alkylated with 1-iodopropane by means potassium carbonate (K2CO3) to yield Ropivacaine.

参考文献 中间体
合成目标
【1】 T. af Ekenstam, B.; Bovin, C. (Alpharma Inc.); L-N-n-Propylpipecolic acid-2,6-xylidide and method for preparing the same. JP 1985502054; WO 8500599 .
【2】 Sandeberg, R.V. (AstraZeneca plc); S-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, process for its preparation and pharmaceutical preparation containing it. EP 0239710; US 4870086 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
28758 1-iodopropane 107-08-4 C3H7I 详情 详情
(IV) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(V) 17531 (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide C14H20N2O 详情 详情
(VII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(XII) 19508 (2S)-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid C6H9NO2 详情 详情
(XIII) 19509 (2S)-1-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid C14H15NO4 详情 详情
(XIV) 19510 benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-3,4-dihydro-1(2H)-pyridinecarboxylate C22H24N2O3 详情 详情
(XV) 19511 (2S)-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-2-pyridinecarboxamide C14H18N2O 详情 详情

合成路线18

该中间体在本合成路线中的序号：(VII)

2) The protection of L-pipecolic acid (II) with benzyl chloroformate (VII) gives the benzyloxycarbonyl compound (VIII), which is condensed with o-toluidine (IX) by means of SOCl2 and dimethylaminopyridine (DMAP) yielding the amide (X). The methylation of (X) with methyl iodide and palladium diacetate in acetic acid affords the 2,6-xylidide (XI), which is deprotected with HBr in acetic acid to give L-pipecolic acid 2,6-xylidide (V). Finally, this compound is alkylated with propyl iodide and K2CO3 in acetonitrile.

参考文献 中间体
合成目标
【1】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767.
【2】 Sahlberg, C.; Synthesis of carbon-14 labelled ropivacaine, a local anaesthetic agent. J Label Compd Radiopharm 1987, 24, 5, 529.
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) 17380 (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid 3105-95-1 C6H11NO2 详情 详情
(V) 17531 (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide C14H20N2O 详情 详情
(VI) 19502 Propyl bromide; 1-Bromopropane 106-94-5 C3H7Br 详情 详情
(VII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VIII) 19504 (2S)-1-[(benzyloxy)carbonyl]-2-piperidinecarboxylic acid C14H17NO4 详情 详情
(IX) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(X) 19506 benzyl (2S)-2-(2-toluidinocarbonyl)-1-piperidinecarboxylate C21H24N2O3 详情 详情
(XI) 19507 benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate C22H26N2O3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(VII)

3) The protection of 1,2,3,6-tetrahydropyridine-2(S)-carboxylic acid (XII) with benzyl chloroformate (VII) gives the benzyloxycarbonyl derivative (XIII), which is condensed with 2,6-xylidine (IV) with SOCl2 and DMAP as before yielding the amide (XIV). Deprotection of (XIV) with iodotrimethylsilane in dichloromethane affords N-(2,6-dimethylphenyl)-1,2,3,6-tetrahydropyridine-2(S)-carboxamide (XV), which is reduced with H2 over Rh/Al2O3 in DMF giving the saturated amide (V). Finally, this compound is alkylated with propyl iodide and K2CO3 as before.

参考文献 中间体
合成目标
【1】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767.
【2】 Gawell, L.; Synthesis of tritium labelled ropivacaine - A new potential local anaesthetic. J Label Compd Radiopharm 1987, 24, 5, 521.
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) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(V) 17531 (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide C14H20N2O 详情 详情
(VI) 19502 Propyl bromide; 1-Bromopropane 106-94-5 C3H7Br 详情 详情
(VII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(XII) 19508 (2S)-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid C6H9NO2 详情 详情
(XIII) 19509 (2S)-1-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid C14H15NO4 详情 详情
(XIV) 19510 benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-3,4-dihydro-1(2H)-pyridinecarboxylate C22H24N2O3 详情 详情
(XV) 19511 (2S)-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-2-pyridinecarboxamide C14H18N2O 详情 详情

合成路线20

该中间体在本合成路线中的序号：

Trovafloxacin can be obtained by two related ways: 1) The cyclization of ethyl diazoacetate (I) with N-benzylmaleimide (II) in ethyl ether gives 5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester (III), which by thermolysis at 185 C is converted into (1alpha,5alpha,6alpha)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (IV). The reduction of (IV) with LiAlH4 in refluxing THF affords (1alpha,5alpha,6alpha)-3-benzyl-6-(hydroxymethyl)-3-azabicyclo[3.1.0] hexane (V), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol to the free azabicyclo compound (VI) (1, 2). The reaction of (VI) with benzyl chloroformate and NaHCO3 in doxane/water yields the corresponding N-benzyloxycarbonyl compound (VII), which is oxidized with the Jones reagent to (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (VIII). The reaction of (VIII) with diphenylphosphoryl azide (DPA) and triethylamine in refluxing tert-butanol gives (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexane (IX), which is submitted to hydrogenolysis with ammonium formate over Pd/C to afford (1alpha,5alpha,6alpha)-6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0] hexane (X). The condensation of (X) with 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (XI) by means of triethylamine in hot acetonitrile gives (1alpha,5alpha,6alpha)-7-[6-(tert-butoxycarbonylamino)-3-azabicyclo [3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (XII) (1-3), which is finally deprotected with refluxing 6N HCl (1) or methanesulfonic acid in dioxane/water. The cyclization of 1-(benzyloxycarbonyl)-2,5-dihydro-1H-pyrrole (XIII) with ethyl diazoacetate (I) gives 5-(benzyloxycarbonyl)-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester (XIV), which by thermolysis is converted into (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-2,4-dioxo-3-azabicyclo [3.1.0]hexane-6-carboxylic acid ethyl ester (XV). Finally, this compound is hydrolyzed to the desired carboxylic acid (VIII). 2) The carboxylic acid (VIII) can also be obtained as follows:

参考文献 中间体
合成目标
【1】 Fromtling, R.A.; Castaner, J.; Trovafloxacin Mesylate. Drugs Fut 1996, 21, 5, 496.
【2】 Brighty, K.E. (Pfizer Inc.); Azabicyclo quinolone carboxylic acids. AU 9161042; EP 0413455; JP 1991086875; US 5164402; WO 9102526 .
【3】 Gootz, T.D.; Brighty, K.E.; Anderson, M.R.; Haskell, S.L.; Sutcliffe, J.A.; Castaldi, M.J.; Miller, S.A.; In vitro activity and synthesis of CP-99,219, a novel 7-(3-azabicyclo[3.1.0]hexyl)naphthyridone. 32nd Intersci Conf Antimicrob Agents Chemother (Oct 11-14, Anaheim) 1992, Abst 751.
【4】 Brighty, K.E.; Gootz, T.D.; Girard, A.; et al.; 7-(3-Azabicyclo[3.1.0]hexyl)quinolone antibacterial agents: Synthesis and biological evaluation resulting in identification of CP-99,219. 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 1509.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 15911 Ethyldiazoacetate; ethyl 2-diazoacetate 623-73-4 C4H6N2O2 详情 详情
(II) 15912 N-Benzylmaleimide; 1-benzyl-1H-pyrrole-2,5-dione 1631-26-1 C11H9NO2 详情 详情
(III) 15913 ethyl 5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylate C15H15N3O4 详情 详情
(IV) 15914 ethyl 2-[(1R,5S)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]acetate C16H17NO4 详情 详情
(V) 15915 [(1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl]methanol C13H17NO 详情 详情
(VI) 15916 (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylmethanol C6H11NO 详情 详情
(VII) 15917 benzyl (1R,5S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate C14H17NO3 详情 详情
(VIII) 15918 (1R,5S)-3-[(benzyloxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid C14H15NO4 详情 详情
(IX) 15919 benzyl (1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate C18H24N2O4 详情 详情
(X) 15920 tert-butyl (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylcarbamate C10H18N2O2 详情 详情
(XI) 15230 ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate C17H10ClF3N2O3 详情 详情
(XII) 15922 ethyl 7-[(1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate C27H27F3N4O5 详情 详情
(XIII) 15923 1-Benzyloxycarbonyl-3-pyrroline;3-Pyrroline-1-carboxylicacid, benzyl ester ;N-(Benzyloxycarbonyl)-3-pyrroline;Benzyl 3-pyrroline-1-carboxylate;2H,5H-Pyrrole-1-carboxylicacid benzyl ester;2,5-Dihydropyrrole-1-carboxylic acid benzyl ester;benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate 31970-04-4 C12H13NO2 详情 详情
(XIV) 15924 5-benzyl 3-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-c]pyrazole-3,5(1H)-dicarboxylate C16H19N3O4 详情 详情
(XV) 15925 3-benzyl 6-ethyl (1R,5S)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate C16H19NO4 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

The acylation of 4-hydroxypiperidine (I) with benzyl chloroformate (II) by means of triethylamine in dichloromethane gives 4-hydroxypiperidine-1-carboxylic acid benzyl ester (III), which is condensed with tert-butyl bromoacetate (IV) by means of tetrabutylammonium hydrogensulfate and NaOH in toluene/water, affording 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (V). The deprotection of (V) by hydrogenation with H2 over Pd/C in ethanol gives the piperidine (VI), which is condensed with N-(benzyloxycarbonyl)-4-O-tert-butyl-L-tyrosine (VII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) in dichloromethane, yielding the expected condensation product (VIII). The deprotection of the amino group of (VIII) by hydrogenation as before affords (IX), which is N-acylated with 4-amidinobenzoyl chloride (X), prepared by reaction of 4-amidinobenzoic acid (XI) with SOCl2, giving the bis-tert-butylated product (XII). Finally, this compound is deprotected by means of trifluoroacetic acid in dichloromethane.

参考文献 中间体
合成目标
【1】 Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393.
【2】 Castaner, J.; Merlos, M.; Cases, A.; Rabasseda, X.; Lamifiban. Drugs Fut 1999, 24, 3, 261.
【3】 Alig, L.; Hadvary, P.; Huzeler, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); N-acyl-alpha-aminoacids derivs.. EP 0505868; JP 1993148204; US 5378712; US 5545658; US 5658928; US 5670515; US 5747522 .
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) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 19284 benzyl 4-hydroxy-1-piperidinecarboxylate C13H17NO3 详情 详情
(IV) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(V) 19286 benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate C19H27NO5 详情 详情
(VI) 19287 tert-butyl 2-(4-piperidinyloxy)acetate C11H21NO3 详情 详情
(VII) 22478 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propionic acid C21H25NO5 详情 详情
(VIII) 22479 tert-butyl 2-[(1-[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate C32H44N2O7 详情 详情
(IX) 22480 tert-butyl 2-[(1-[(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate C24H38N2O5 详情 详情
(X) 22481 4-[amino(imino)methyl]benzoyl chloride C8H7ClN2O 详情 详情
(XI) 22482 4-Amidinobenzic acid; 4-[amino(imino)methyl]benzoic acid 15535-95-2 C8H8N2O2 详情 详情
(XII) 22483 tert-butyl 2-[(1-[(2S)-2-([4-[amino(imino)methyl]benzoyl]amino)-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate C32H44N4O6 详情 详情

合成路线22

该中间体在本合成路线中的序号：(II)

The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III), which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V). The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI), which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII). The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX), which by treatment with HCl in methanol and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X). Finally, this compound is hydrolyzed with NaOH in methanol to afford the target acetic acid derivative.

参考文献 中间体
合成目标
【1】 Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Müller, T.; Weisenberger, J.; Linz, G.; Krüger, G. (Dr. Karl Thomae GmbH); Cyclic imino derivs., process for their preparation and drugs containing them. DE 4035961; EP 0483667; JP 1992264068; US 5591769 .
【2】 Himmelsbach, F.; Austel, V.; Pieper, H.; Linz, G.; Wisenberger, J.; Muller, T. (Dr. Karl Thomae GmbH); Cyclic imino derivs., medicaments containing these cpds. and processes for the production thereof. DE 4213919; EP 0567966; JP 1994073001 .
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) 48730 (S)-(+)-5-(Trityloxymethyl)-2-pyrrolidinone C24H23NO2 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 48731 benzyl (5S)-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate C32H29NO4 详情 详情
(IV) 40664 tert-butyl 2-chloroacetate 107-59-5 C6H11ClO2 详情 详情
(V) 48732 benzyl (3S,5S)-3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate C38H39NO6 详情 详情
(VI) 48733 tert-butyl 2-[(3S,5S)-5-(hydroxymethyl)-2-oxopyrrolidinyl]acetate C11H19NO4 详情 详情
(VII) 48734 tert-butyl 2-((3S,5S)-5-[[(methylsulfonyl)oxy]methyl]-2-oxopyrrolidinyl)acetate C12H21NO6S 详情 详情
(VIII) 48735 4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile 19812-93-2 C13H9NO 详情 详情
(IX) 48736 tert-butyl 2-((3S,5S)-5-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-2-oxopyrrolidinyl)acetate C24H26N2O4 详情 详情
(X) 48737 methyl 2-[(3S,5S)-5-[([4'-[amino(imino)methyl][1,1'-biphenyl]-4-yl]oxy)methyl]-2-oxopyrrolidinyl]acetate C21H23N3O4 详情 详情

合成路线23

该中间体在本合成路线中的序号：

The methylation of N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (I) with methyl iodide and KOH gives the protected 4-O-methyl-L-tyrosine methyl ester (II), which is deprotected with TFA yielding (III). The Grundke oxidation of (III) affords the N-hydroxy derivative (IV), which is cyclocondensed with cyclohexane-1,4-dione monoethylene ketal (V) and ethyl acrylate (VI) in refluxing toluene to afford the spiroisoxazolidinone (VII). The reductive rearrangement of (VII) with H2 over Pd/C in acetic acid provides the spiropyrrolidinone (VIII), which is treated successively with tosyl chloride and with sodium azide to obtain the azido derivative (IX). The reduction of (IX) with H2 over Pd/C, protection of the resulting amine with Boc2O, and methylation of the resulting carbamate with NaH and methyl iodide affords the N-methylcarbamate (X). The reduction of the methoxycarbonyl group of (X) with LiBH4 in THF gives the carbinol (XI), which is oxidized with Dess-Martin periodinane to the aldehyde (XII). The rearrangement of (XII) by means of potassium tert-butoxide, followed by deprotection of the carbamate group yields the 7,10a-methanopyrrolo[1,2-a]azocin-8-one derivative (XIII), which is reduced at the carbonyl group with LiAlH4 in THF affords the 8(R)-hydroxy derivative (XIV). The protection of the amino group of (XIV) with benzyloxycarbonyl chloride and triethylamine yields the carbamate (XV).

参考文献 中间体
合成目标
【1】 Snider, B.B.; et al.; Total synthesis of (-)-FR901483. J Am Chem Soc 1999, 121, 34, 7778.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 19875 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate 4326-36-7 C15H21NO5 详情 详情
(II) 32453 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate C16H23NO5 详情 详情
(III) 32454 methyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate C11H15NO3 详情 详情
(IV) 32455 methyl (2S)-2-(hydroxyamino)-3-(4-methoxyphenyl)propanoate C11H15NO4 详情 详情
(V) 11377 1,4-Dioxaspiro[4.5]decan-8-one 4746-97-8 C8H12O3 详情 详情
(VI) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(VII) 32456 ethyl (3R)-1-[(1S)-2-methoxy-1-(4-methoxybenzyl)-2-oxoethyl]-2,9,12-trioxa-1-azadispiro[4.2.4.2]tetradecane-3-carboxylate C24H33NO8 详情 详情
(VIII) 32457 methyl (2S)-2-[(11R)-11-hydroxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate C22H29NO7 详情 详情
(IX) 32458 methyl (2S)-2-[(11S)-11-azido-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate C22H28N4O6 详情 详情
(X) 32459 methyl (2S)-2-[(11S)-11-[(tert-butoxycarbonyl)(methyl)amino]-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate C28H40N2O8 详情 详情
(XI) 32460 tert-butyl (3S)-1-[(1S)-2-hydroxy-1-(4-methoxybenzyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate C25H36N2O6 详情 详情
(XII) 32461 tert-butyl (3S)-1-[(1S)-1-formyl-2-(4-methoxyphenyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate C25H34N2O6 详情 详情
(XIII) 32462 (1S,3S,6S,7S,8S)-7-hydroxy-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecan-9-one C20H28N2O3 详情 详情
(XIV) 32463 (1S,3S,6S,7S,8R,9R)-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecane-7,9-diol C20H30N2O3 详情 详情
(XV) 32464 benzyl (1S,3S,6S,7S,8R,9R)-7,9-dihydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate C28H36N2O5 详情 详情

合成路线24

该中间体在本合成路线中的序号：(II)

The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III), which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V). The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI), which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII). The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX), which by treatment with HCl in methanol, and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X). Finally, this compound is condensed with methyl chloroformate (XI) by means of NaOH in dichloromethane to afford the target compound.

参考文献 中间体
合成目标
【1】 Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Müller, T.; Weisenberger, J.; Linz, G.; Krüger, G. (Dr. Karl Thomae GmbH); Cyclic imino derivs., process for their preparation and drugs containing them. DE 4035961; EP 0483667; JP 1992264068; US 5591769 .
【2】 Himmelsbach, F.; Austel, V.; Pieper, H.; Linz, G.; Wisenberger, J.; Muller, T. (Dr. Karl Thomae GmbH); Cyclic imino derivs., medicaments containing these cpds. and processes for the production thereof. DE 4213919; EP 0567966; JP 1994073001 .
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) 48730 (S)-(+)-5-(Trityloxymethyl)-2-pyrrolidinone C24H23NO2 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 48731 benzyl (5S)-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate C32H29NO4 详情 详情
(IV) 40664 tert-butyl 2-chloroacetate 107-59-5 C6H11ClO2 详情 详情
(V) 48732 benzyl (3S,5S)-3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate C38H39NO6 详情 详情
(VI) 48733 tert-butyl 2-[(3S,5S)-5-(hydroxymethyl)-2-oxopyrrolidinyl]acetate C11H19NO4 详情 详情
(VII) 48734 tert-butyl 2-((3S,5S)-5-[[(methylsulfonyl)oxy]methyl]-2-oxopyrrolidinyl)acetate C12H21NO6S 详情 详情
(VIII) 48735 4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile 19812-93-2 C13H9NO 详情 详情
(IX) 48736 tert-butyl 2-((3S,5S)-5-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-2-oxopyrrolidinyl)acetate C24H26N2O4 详情 详情
(X) 48737 methyl 2-[(3S,5S)-5-[([4'-[amino(imino)methyl][1,1'-biphenyl]-4-yl]oxy)methyl]-2-oxopyrrolidinyl]acetate C21H23N3O4 详情 详情
(XI) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情

合成路线25

该中间体在本合成路线中的序号：(IV)

The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is protected with benzyl chloroformate (IV) and TEA, yielding the dicarbamate (V). Selective deprotection of (V) with dry HCl in ethyl acetate affords the primary amine (VI), which is treated with 3(S)-tetrahydrofuryl N-succinimidinyl carbonate (VII) (prepared by condensation of tetrahydrofuran-3(S)-ol (VIII) with phosgene and N-hydroxysuccinimide (IX)) and DIEA in acetonitrile to provide the corresponding carbamate (X). The deprotection of (X) by hydrogenation with H2 over Pd/C in ethanol gives the secondary amine (XI), which is condensed with 4-nitrophenylsulfonyl chloride (XII) by means of NaHCO3 in dichloromethane/water to yield the sulfonamide (XIII). Finally, the nitro group of (XIII) is reduced with H2 over Pd/C in ethyl acetate to afford the target compound.

参考文献 中间体
合成目标
【1】 Tung, R.D.; Murcko, M.A.; Bhisetti, G.R. (Vertex Pharmaceuticals Inc.); Sulfonamide inhibitors of HIV-aspartyl protease. EP 0659181; EP 0885887; JP 1996501299; US 5585397; WO 9405639 .
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) 19730 tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate 98737-29-2 C15H21NO3 详情 详情
(II) 13306 2-Methyl-1-propanamine; Isobutylamine 78-81-9 C4H11N 详情 详情
(III) 44417 tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate 160232-08-6 C19H32N2O3 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 44418 benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(isobutyl)carbamate C27H38N2O5 详情 详情
(VI) 44419 benzyl (2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(isobutyl)carbamate C22H30N2O3 详情 详情
(VII) 39664 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione C9H11NO6 详情 详情
(VIII) 44420 (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran 86087-23-2 C4H8O2 详情 详情
(IX) 10264 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione 6066-82-6 C4H5NO3 详情 详情
(X) 44421 benzyl (2R,3S)-2-hydroxy-4-phenyl-3-([[(3S)tetrahydro-3-furanyloxy]carbonyl]amino)butyl(isobutyl)carbamate C27H36N2O6 详情 详情
(XI) 44422 (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate C19H30N2O4 详情 详情
(XII) 15809 4-nitrobenzenesulfonyl chloride 98-74-8 C6H4ClNO4S 详情 详情
(XIII) 44423 (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate C25H33N3O8S 详情 详情

合成路线26

该中间体在本合成路线中的序号：

The known antibiotic staurosporine (I) was protected as the N-benzyloxycarbonyl derivative (II) by treatment with benzyl chloroformate in the presence of NaHCO3. Subsequent alkylation of (II) at the 2-N atom by treatment with iodomethane and NaH in DMF provided the N-methyl derivative (III). Finally, deprotection of the benzyloxycarbonyl group of (III) by hydrogenation over Pd/C furnished the title compound.

参考文献 中间体
合成目标
【1】 Murakata, C.; Sato, A.; Kasai, M.; Morimoto, M.; Akinaga, S. (Kyowa Hakko Kogyo Co., Ltd.); Staurosporin derivatives. EP 0383919; JP 2766360B2; WO 8907105 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 36327 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 62996-74-1 C28H26N4O3 详情 详情
(II) 36328 benzyl 3-methoxy-2-methyl-16-oxo-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-4-yl(methyl)carbamate C36H32N4O5 详情 详情
(III) 36329 benzyl 3-methoxy-2,17-dimethyl-16-oxo-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-4-yl(methyl)carbamate C37H34N4O5 详情 详情

合成路线27

该中间体在本合成路线中的序号：

The reaction of isovanillin with hydroxylamine sulfate and NaOH in refluxing ethanol/water gives the corresponding oxime (II), which is reduced with Raney-Ni and NaOH in the same solvent yielding the benzylamine (III). The protection of the amino group of (III) with benzyloxycarbonyl chloride affords the carbamate (IV), which is condensed with ethyl bromoacetate (IV) by means of K2CO3 in refluxing 2-butanone to give the ester (VI). The hydrolysis of (VI) with NaOH in hot methanol/water yields the corresponding acid (VII), which is condensed with 1-benzylpiperazine (VIII) by means of ethyl chloroformate in THF to afford the piperazide (IX). The deprotection of the amino group of (IX) with H2 over Pd/C in hot ethanol gives the benzylamine (X), which is finally condensed with 4,5-dichloropyridazin-3(2H)-one (XI) by means of triethylamine in refluxing ethanol/water.

参考文献 中间体
合成目标
【1】 Tanikawa, K.; Saito, A.; Hirotsuka, M.; Shikada, K. (Nissan Chemical Industry, Ltd.); Pyridazinone derivs. with pharmaceutical activity. EP 0706517; JP 1996041033; US 5728702; US 5929074; WO 9501343 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 18455 3-hydroxy-4-methoxybenzaldehyde; Isovanillin 621-59-0 C8H8O3 详情 详情
(II) 30957 2-methoxy-5-[(methylimino)methyl]phenol C9H11NO2 详情 详情
(III) 30958 5-(aminomethyl)-2-methoxyphenol C8H11NO2 详情 详情
(IV) 30959 benzyl 3-hydroxy-4-methoxybenzylcarbamate C16H17NO4 详情 详情
(V) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VI) 30960 ethyl 2-[5-([[(benzyloxy)carbonyl]amino]methyl)-2-methoxyphenoxy]acetate C20H23NO6 详情 详情
(VII) 30961 2-[5-([[(benzyloxy)carbonyl]amino]methyl)-2-methoxyphenoxy]acetic acid C18H19NO6 详情 详情
(VIII) 28542 N-Benzylpiperazine; 1-Benzylpiperazine 2759-28-6 C11H16N2 详情 详情
(IX) 30962 benzyl 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethoxy]-4-methoxybenzylcarbamate C29H33N3O5 详情 详情
(X) 30963 2-[5-(aminomethyl)-2-methoxyphenoxy]-1-(4-benzyl-1-piperazinyl)-1-ethanone C21H27N3O3 详情 详情
(XI) 24750 Bis(isopropylamine)dichloro platinum complex C6H18Cl2N2Pt 详情 详情

合成路线28

该中间体在本合成路线中的序号：(VIII)

2) The reaction of 4-hydroxypiperidine (VII) with benzyl chloroformate (VIII) by means of triethylamine in dichloromethane gives the expected benzyloxycarbonyl derivative (IX), which is condensed with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium bisulfate and NaOH, yielding 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (XI). The deprotection of (XI) as ususal affords 2-(4-piperidinyloxy)acetic acid tert-butyl ester (XII), which is condensed with N-(benzyloxycarbonyl)-L-alanine (XIII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl-morpholine (NMM) in dichloromethane to yield the acylated piperidine (XIV). The deprotection of (XIV) as usual affords compound (XV), which is acylated at the free amino group with 4-cyanobenzoyl chloride (V) and tetrabutylammonium bisulfate to give 2-[1-[N-(4-cyanobenzoyl)-L-alanyl]piperidin-4-yloxy]acetic acid tert-butyl ester (XVI). The reaction of the cyano group of (XVI) with hydroxylamine affords compound (XVII) with a hydroxyamidino substituent. Finally, the tert-butyl ester group of (XVII) is converted in ethyl ester by hydrolysis with hot fomic acid to the corresponding acetic acid (XVIII) and subsequent esterification with ethanol/H2SO4.

参考文献 中间体
合成目标
【1】 Alig, L.; Beresini, M.; Weller, T.; et al.; Orally active fibrinogen receptor antagonists. 2. Amidoximes as prodrugs of amidines. J Med Chem 1996, 39, 16, 3139.
【2】 Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393.
【3】 Castañer, J.; Graul, A.; Merlos, M.; Sibrafiban . Drugs Fut 1998, 23, 12, 1297.
【4】 Alig, L.; Hadvary, P.; Hurzeler Muller, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); Acetic acid derivs. as medicaments. EP 0656348; JP 1995196592; US 5726185 .
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) 19280 4-cyanobenzoyl chloride 6068-72-0 C8H4ClNO 详情 详情
(VII) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(VIII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(IX) 19284 benzyl 4-hydroxy-1-piperidinecarboxylate C13H17NO3 详情 详情
(X) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 19286 benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate C19H27NO5 详情 详情
(XII) 19287 tert-butyl 2-(4-piperidinyloxy)acetate C11H21NO3 详情 详情
(XIII) 61209 CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine C11H13NO4 详情 详情
(XIV) 19289 tert-butyl 2-[[1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-4-piperidinyl]oxy]acetate C22H32N2O6 详情 详情
(XV) 19290 tert-butyl 2-([1-[(2S)-2-aminopropanoyl]-4-piperidinyl]oxy)acetate C14H26N2O4 详情 详情
(XVI) 19291 tert-butyl 2-[(1-[(2S)-2-[(4-cyanobenzoyl)amino]propanoyl]-4-piperidinyl)oxy]acetate C22H29N3O5 详情 详情
(XVII) 19292 tert-butyl 2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetate C22H32N4O6 详情 详情
(XVIII) 19293 2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetic acid C18H24N4O6 详情 详情

合成路线29

该中间体在本合成路线中的序号：(X)

The condensation of 2,3-dimethoxybenzaldehyde (VI) with pyruvic acid (VII) by means of KOH in ethanol/water gives 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid (VIII), which is reductocondensed with methylamine (IV) by means of H2 over Pd/C in ethanol/ acetic acid to yield 4-(2,3-dimethoxyphenyl)-2-methylamino)butyric acid (IX). Reaction of acid (IX) with benzyl chloroformate (X) and NaOH in water affords the carbamate (XI), which is treated with refluxing SOCl2 to provide 4-[2-(2,3-dimethoxyphenyl)ethyl]-3-methyloxazolidine-2,5-dione (XII). Reaction of oxazolidinone (XII) with AlCl3 in dichloromethane provides 5,6-dimethoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIII), which is reduced with H2 over Pd/C in ethanol containing some methanolic HCl in an autoclave at 80 C to yield N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylamine (V). Finally, this compound is demethylated by treatment with AlCl3 in hot toluene. Alternatively, 5,6-dimethoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIII) can first be demethylated with 48% HBr to give 5,6-dihydroxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIV), which is then reduced by means of H2 over Pd/C in an autoclave at 80 C.

参考文献 中间体
合成目标
【1】 Castaner, J.; Mealy, N.E.; Bayes, M.; Leeson, P.A.; Nolomirole Hydrochloride. Drugs Fut 2001, 26, 11, 1046.
【2】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 .
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) 49435 6-(methylamino)-5,6,7,8-tetrahydro-1,2-naphthalenediol C11H15NO2 详情 详情
(IV) 11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
(V) 37381 N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine C13H19NO2 详情 详情
(VI) 17615 2,3-Dimethoxybenzaldehyde 86-51-1 C9H10O3 详情 详情
(VII) 24066 2-oxopropionic acid 127-17-3 C3H4O3 详情 详情
(VIII) 37376 (E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid C12H12O5 详情 详情
(IX) 37377 4-(2,3-dimethoxyphenyl)-2-(methylamino)butyric acid C13H19NO4 详情 详情
(X) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(XI) 37378 2-[[(benzyloxy)carbonyl](methyl)amino]-4-(2,3-dimethoxyphenyl)butyric acid C21H25NO6 详情 详情
(XII) 37379 4-(2,3-dimethoxyphenethyl)-3-methyl-1,3-oxazolidine-2,5-dione C14H17NO5 详情 详情
(XIII) 37380 5,6-dimethoxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone C13H17NO3 详情 详情
(XIV) 37387 5,6-dihydroxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone C11H13NO3 详情 详情

合成路线30

该中间体在本合成路线中的序号：

Pinner reaction of ethyl 5-cyano-2-benzofurancarboxylate (VI) gave imidate (VII) and subsequent treatment with ethanolic ammonia afforded amidine (VIII). After basic hydrolysis of the ester group of (VIII), protection with benzyl chloroformate provided the benzyloxycarbonyl derivative (IX). Coupling of (IX) with aminoester (V) in the presence of EDC and HOBt yielded amide (X). Sequential cleavage of benzyloxycarbonyl and tert-butyl groups orf (X) provided amidino acid (XI), which was finally esterified with EtOH and methanesulfonic acid.

参考文献 中间体
合成目标
【1】 Ono, S.; Yoshida, T.; Ashimori, A.; Kosaka, K.; Okada, T.; Maeda, K.; Eda, M.; Mori, F.; Inoue, Y.; Ebisu, H.; Imada, T.; Ikegawa, R.; Wang, F.; Nakamura, N. (Welfide Corporation); Novel fused-ring carboxylic acid cpds. or salt thereof,and medicinal use thereof. EP 0712844; JP 1996053398; JP 1996231548; US 5635527; US 5753670; WO 9533720 .
【2】 Nakamura, N.; Imada, T.; Inoue, Y.; Kosaka, K.; Yoshida, T.; Ono, S.; Fukaya, C.; Maeda, K.; Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 2. Condensed heterocyclic derivatives. Chem Pharm Bull 1999, 47, 12, 1694.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 37352 tert-butyl 2-[(4-aminocyclohexyl)oxy]acetate C12H23NO3 详情 详情
(VI) 37353 ethyl 5-cyano-1-benzofuran-2-carboxylate C12H9NO3 详情 详情
(VII) 37354 ethyl 5-[ethoxy(imino)methyl]-1-benzofuran-2-carboxylate C14H15NO4 详情 详情
(VIII) 37355 ethyl 5-[amino(imino)methyl]-1-benzofuran-2-carboxylate C12H12N2O3 详情 详情
(IX) 37356 5-[[[(benzyloxy)carbonyl]amino](imino)methyl]-1-benzofuran-2-carboxylic acid C18H14N2O5 详情 详情
(X) 37357 ethyl 2-([4-[([5-[[[(benzyloxy)carbonyl]amino](imino)methyl]-1-benzofuran-2-yl]carbonyl)amino]cyclohexyl]oxy)acetate C28H31N3O7 详情 详情
(XI) 37358 2-([4-[([5-[amino(imino)methyl]-1-benzofuran-2-yl]carbonyl)amino]cyclohexyl]oxy)acetic acid C18H21N3O5 详情 详情

合成路线31

该中间体在本合成路线中的序号：

A new efficient process for the diastereoselective synthesis of the key intermediate (XXIV) has been reported. Cyclization of L-alpha-aminoadipic acid (XIV) in either refluxing AcOH or in DMSO at 130 C provided (S)-6-oxopipecolic acid (XV), which was converted to the benzhydryl ester (XVI) upon treatment with diphenyldiazomethane. Subsequent protection with benzyl chloroformate produced the N-benzyloxycarbonyl derivative (XVII). Methylation of (XVII) using iodomethane and lithium hexamethyldisilazide at -78 C furnished a 4:1 mixture of the desired trans compound (XIX) and the cis isomer (XVIII). The diastereomer specific reduction of the mixture (XVIII)/(XIX) with LiAlH(O-t-Bu)3 yielded the trans cyclic aminal (XX) along with the unreacted cis isomer (XVIII). Further condensation of aminal (XX) with methyl L-cysteinate.HCl (VIII) produced the required thiazolidine (XXI) as a diastereomeric mixture while leaving the unchanged lactam (XVIIIa-b). Then, acid cleavage of the benzhydryl esters allowed the separation of the HCl-soluble thiazolidine acid (XXIIa-b) from the ether-soluble cis lactam (XVIII).

参考文献 中间体
合成目标
【1】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor. I. Diastereoselective alkylation of protected 6-oxopipecolic acid esters. Chem Pharm Bull 1999, 47, 11, 1525.
【2】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor.II. Stereoselective synthesis of peptidomimetic [5.7]-bycyclic compounds. Chem Pharm Bull 1999, 47, 11, 1532.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(XXIa) 35115 methyl (2S,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate C32H36N2O6S 详情 详情
(XXIb) 35116 methyl (2R,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate C32H36N2O6S 详情 详情
(XXIIa) 35117 (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2R,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid C19H26N2O6S 详情 详情
(XXIIb) 35118 (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2S,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid C19H26N2O6S 详情 详情
(VIII) 27413 methyl (2R)-2-amino-3-sulfanylpropanoate C4H9NO2S 详情 详情
(XIV) 35109 (2S)-2-aminohexanedioic acid 1118-90-7 C6H11NO4 详情 详情
(XV) 22661 (2S)-6-oxo-2-piperidinecarboxylic acid C6H9NO3 详情 详情
(XVI) 35110 benzhydryl (2S)-6-oxo-2-piperidinecarboxylate C19H19NO3 详情 详情
(XVII) 35111 2-benzhydryl 1-benzyl (2S)-6-oxo-1,2-piperidinedicarboxylate C27H25NO5 详情 详情
(XVIII) 35113 2-benzhydryl 1-benzyl (2S,5S)-5-methyl-6-oxo-1,2-piperidinedicarboxylate C28H27NO5 详情 详情
(XIX) 35112 2-benzhydryl 1-benzyl (2S,5R)-5-methyl-6-oxo-1,2-piperidinedicarboxylate C28H27NO5 详情 详情
(XX) 35114 2-benzhydryl 1-benzyl (2S,5R)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate C28H29NO5 详情 详情

合成路线32

该中间体在本合成路线中的序号：

The reaction between 1,2,3-triazole (I) and 3,4-difluoronitrobenzene (II) afforded a mixture of two regioisomeric substituted triazoles (III) and (IV), from which the required 1-substituted isomer (III) was isolated by column chromatography. Reduction of the nitro group of (III) by hydrogenation over Raney-Ni gave aniline (V), which was converted to carbamate (VI) upon treatment with benzyl chloroformate. Subsequent condensation of (VI) with (R)-(-)-glycidyl butyrate (VII) in the presence of lithium bis(trimethylsilyl)amide produced the chiral oxazolidinone (VIII). Mesylation of the alcohol group of (VIII), followed by displacement with NaN3 yielded azide (IX). This was reduced by hydrogenation over Raney-Ni to give amine (X), which was finally acetylated using Ac2O and pyridine.

参考文献 中间体
合成目标
【1】 Emmert, D.E.; Reischer, R.J.; Ford, C.W.; Garmon, S.A.; Zurenko, G.E.; Barbachyn, M.R.; Hutchinson, D.K.; Stelzer, L.S.; Hester, J.B.; Synthesis and antibacterial activity of azolylphenyloxazolidinones having nitrogen-bound five-membered heterocyclic rings. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-137.
【2】 Hutchinson, D.K. (Pharmacia & Upjohn AB); Hetero-aromatic ring substd. phenyloxazolidinone antimicrobials. EP 0807112; JP 1998513446; US 5910504; WO 9623788 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 29404 1H-1,2,3-triazole 288-36-8 C2H3N3 详情 详情
(II) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(III) 29405 1-(2-fluoro-4-nitrophenyl)-1H-1,2,3-triazole C8H5FN4O2 详情 详情
(IV) 29406 2-(2-fluoro-4-nitrophenyl)-2H-1,2,3-triazole C8H5FN4O2 详情 详情
(V) 29407 3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenylamine3-fluoro-4-(1H-1,2,3-triazol-1-yl)aniline C8H7FN4 详情 详情
(VI) 29408 benzyl 3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenylcarbamate C16H13FN4O2 详情 详情
(VII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VIII) 29409 (5R)-3-[3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C12H11FN4O3 详情 详情
(IX) 29410 (5R)-5-(azidomethyl)-3-[3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-oxazolidin-2-one C12H10FN7O2 详情 详情
(X) 29411 (5S)-5-(aminomethyl)-3-[3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-oxazolidin-2-one C12H12FN5O2 详情 详情

合成路线33

该中间体在本合成路线中的序号：(VI)

This compound can be obtained by two different ways: 1) The acetylation of 1-nitrosopiperazine (I) with acetyl chloride and pyridine in dioxane gives 1-acetyl-4-nitrosopiperazine (II), which is reduced with Zn and acetic acid/water to 1-acetyl-4-aminopiperazine (III). Finally, this compound is acylated with 4-fluorobenzoyl chloride (IV) by means of triethylamine in dichloromethane. 2) The nitrosation of piperazine (V) with NaNO2/HCl in water, followed by condensation with benzyloxycarbonyl chloride (VI) by means of NaOH yields 1-(benzyloxycarbonyl)-4-nitrosopiperazine (VII), which is reduced with Zn and acetic acid/water as before to the corresponding amino derivative (VIII). The acylation of (VIII) with 4-fluorobenzoyl chloride and triethylamine in dichloromethane affords N-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-fluorobenzamide (IX), which is deprotected with HBr in acetic acid to yield N-(1-piperazinyl)-4-fluorobenzamide (X). Finally, this compound is acetylated with acetic anhydride/NaOH in water.

参考文献 中间体
合成目标
【1】 Graul, A.; Tracy, M.; Castañer, J.; FK-960. Drugs Fut 1997, 22, 8, 830.
【2】 Oku, T.; Todo, E.; Yokota, Y.; Kayakiri, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New aminopiperazine derivs. EP 0436734; JP 1991510050; US 5250528; WO 9101979 .
【3】 Oku, T.; Kayakiri, H.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Novel intermediate for synthetic use and process for producing aminopiperazine derivs. WO 9500502 .
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) 17260 1-nitrosopiperazine C4H9N3O 详情 详情
(II) 17261 1-(4-nitrosopiperazino)-1-ethanone C6H11N3O2 详情 详情
(III) 17262 1-(4-aminopiperazino)-1-ethanone C6H13N3O 详情 详情
(IV) 17263 4-fluorobenzoyl chloride 403-43-0 C7H4ClFO 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VII) 17266 benzyl 4-nitrosotetrahydro-1(2H)-pyrazinecarboxylate C12H15N3O3 详情 详情
(VIII) 17267 benzyl 4-aminotetrahydro-1(2H)-pyrazinecarboxylate C12H17N3O2 详情 详情
(IX) 17268 benzyl 4-[(4-fluorobenzoyl)amino]tetrahydro-1(2H)-pyrazinecarboxylate C19H20FN3O3 详情 详情
(X) 17269 4-fluoro-N-piperazinobenzamide C11H14FN3O 详情 详情

合成路线34

该中间体在本合成路线中的序号：(II)

Condensation of alpha-methyl tryptophan methyl ester (I) with benzylchloroformate (II) in the presence of Et3N in THF yields urethane (III), which is hydrolyzed with LiOH in THF/MeOH/H2O and then activated with DCCI and pentafluorophenol (IV) to furnish ester (V). Treatment of (V) with alpha-methyl-benzylamine (VI) gives derivative (VII), which is then debenzylated by hydrogenation over Pd(OH)2 in EtOH to afford (VIII). Finally, amine (VIII) reacts in DMF with DMAP and carbonate (IX), which has been previously prepared from 2-benzofuranylmethanol (X), 4-nitrophenylchloroformate (XI) and pyridine in CH2Cl2.

参考文献 中间体
合成目标
【1】 Boyle, S.; et al.; Rational design of high affinity tachykinin NK1 receptor antagonists. Bioorg Med Chem 1994, 2, 5, 357.
【2】 Horwell, D.C.; Howson, W.; Rees, D.C.; Roberts, E.; Pritchard, M.C. (Pfizer Inc.); Tachykinin antagonists. EP 0655055; EP 1000930; US 5594022; WO 9404494 .
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) 44166 methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate C13H16N2O2 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 44167 methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C21H22N2O4 详情 详情
(IV) 22662 2,3,4,5,6-pentafluorophenol 771-61-9 C6HF5O 详情 详情
(V) 44168 2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C26H19F5N2O4 详情 详情
(VI) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VII) 44169 benzyl (1R)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[(1S)-1-phenylethyl]amino]ethylcarbamate C28H29N3O3 详情 详情
(VIII) 44170 (2R)-2-amino-3-(1H-indol-3-yl)-2-methyl-N-[(1S)-1-phenylethyl]propanamide C20H23N3O 详情 详情
(IX) 44171 1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate C16H11NO6 详情 详情
(X) 38335 1-benzofuran-2-ylmethanol C9H8O2 详情 详情
(XI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情

合成路线35

该中间体在本合成路线中的序号：(IV)

Treatment of N(alpha)-Cbz-D-tryptophan (I) with diazomethane (CH2N2) in Et2O/CH2Cl2 provides methyl ester derivative (II), which is then cyclized to afford pyrrolo-indole derivative (III) by long treatment with TFA. N-protection of (III) by reaction with benzyl chloroformate (IV) and Na2CO3 in dioxane yields derivative (V), which is then converted into labeled methylated derivative (VI) by first deprotonation with LHDMS followed by treatment with labeled methyl iodide (MeI) in THF. Ring opening of (VI) by means of TFA furnishes protected methyltryptophan (VII), whose Cbz groups are removed by hydrogenolysis over Pd/C in EtOH to yield derivative (VIII). Coupling of (VIII) with carbonate (IX) by means of DMAP in DMF affords derivative (X), which is then subjected to saponification with LiOH in MeOH to provide carboxylic acid derivative (XI). Finally, (XI) is coupled with methylbenzylamine (XII) by means of HOBt, EDC and N-methylmorpholine (NMM).

参考文献 中间体
合成目标
【1】 Ekhato, I.V.; Huang, Y.; Tetrahydro-pyrrolo-[2,3-b]indole-1,2,8-tricarboxylic acid ester in the enantiospecific preparation of alpha-methyltryptophan: Application in the preparation of carbon-14 labeled PD 145942 and PD 154075. J Label Compd Radiopharm 1997, 39, 12, 1019.
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) 44180 (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid C19H18N2O4 详情 详情
(II) 44174 methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propanoate C20H20N2O4 详情 详情
(III) 44175 1-benzyl 2-methyl (2R,3aS,8aS)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate C20H20N2O4 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 44176 1,8-dibenzyl 2-methyl (2R,3aS,8aR)-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate C28H26N2O6 详情 详情
(VI) 44177 1,8-dibenzyl 2-methyl (2R,3aS,8aS)-2-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate C29H28N2O6 详情 详情
(VI) 45341 1,8-dibenzyl 2-methyl (2R,3aS,8aS)-2-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate C29H28N2O6 详情 详情
(VII) 44178 benzyl 3-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxy-2-methyl-3-oxopropyl)-1H-indole-1-carboxylate C29H28N2O6 详情 详情
(VII) 45340 benzyl 3-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxy-2-methyl-3-oxopropyl)-1H-indole-1-carboxylate C29H28N2O6 详情 详情
(VIII) 44166 methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate C13H16N2O2 详情 详情
(VIII) 45342 methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate C13H16N2O2 详情 详情
(IX) 44171 1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate C16H11NO6 详情 详情
(X) 44179 methyl (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C23H22N2O5 详情 详情
(X) 45343 methyl (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C23H22N2O5 详情 详情
(XI) 44173 (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid C22H20N2O5 详情 详情
(XI) 45344 (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid C22H20N2O5 详情 详情
(XII) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情

合成路线36

该中间体在本合成路线中的序号：(IX)

The acetylation of 5-bromopyridine-2-amine (I) with acetic anhydride in AcOH gives the expected amide (II), which is alkylated with ethylene by means of palladium acetate, tri p-tolylphosphine and triethylamine in hot acetonitrile to yield N-(5-vinylpyridin-2-yl)acetamide (III). The regioselective dihydroxylation of the vinyl group of (III) with AD-Mix-B in tert-butanol affords N-[5-(1(R),2-dihydroxyethyl)pyridin-2-yl]acetamide (IV), which is monotosylated with Ts-Cl in cool pyridine to give the tosylate (V). The reaction of (V) with potassium tert.-butoxide in THF yields the epoxide (VI), which is condensed with 2-[4-(2-aminoethoxy)phenyl]-N-methylacetamide (VII) in hot toluene/DMSO to provide the expected addition product (VIII). Finally, this compound is treated with 6N HCl on a steam bath. The intermediate 2-[4-(2-aminoethoxy)phenyl]-N-methylacetamide (VII) has been obtained as follows: The reaction of benzyl chloroformate (IX) with ethanolamine (X) by means of NaHCO3 in water gives the carbamate (XI), which is condensed with 2-(4-hydroxyphenyl)-N-methylacetamide (XII) (obtained by reaction of the corresponding methyl ester (XIII) with methylamine), by means of PPh3 and diisopropyl azodicarboxylate (DIAD) in THF yielding the intermediate (XIV). Finally, this compound is submitted to elimination of the carbamate protecting group by hydrogenation with H2 over Pd/C in methanol to provide the target intermediate (VII).

参考文献 中间体
合成目标
【1】 Dow, R.L. (Pfizer Inc.); beta-Adrenergic agonists to reduce a wasting condition. EP 0887079 .
【2】 Devries, K.M.; Dow, R.L.; Wright, S.W. (Pfizer Inc.); Process for substd. pyridines. EP 0938476; WO 9821184 .
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) 12123 5-Bromo-2-pyridinylamine; 5-Bromo-2-pyridinamine; 2-Amino-5-bromopyridine 1072-97-5 C5H5BrN2 详情 详情
(II) 32490 N-(5-bromo-2-pyridinyl)acetamide C7H7BrN2O 详情 详情
(III) 32491 N-(5-vinyl-2-pyridinyl)acetamide C9H10N2O 详情 详情
(IV) 32492 N-[5-[(1R)-1,2-dihydroxyethyl]-2-pyridinyl]acetamide C9H12N2O3 详情 详情
(V) 32493 (2R)-2-[6-(acetamido)-3-pyridinyl]-2-hydroxyethyl 4-methylbenzenesulfonate C16H18N2O5S 详情 详情
(VI) 32494 N-[5-[(2R)oxiranyl]-2-pyridinyl]acetamide C9H10N2O2 详情 详情
(VII) 32495 2-[4-(2-aminoethoxy)phenyl]-N-methylacetamide C11H16N2O2 详情 详情
(VIII) 32496 2-[4-[2-([(2R)-2-[6-(acetamido)-3-pyridinyl]-2-hydroxyethyl]amino)ethoxy]phenyl]-N-methylacetamide C20H26N4O4 详情 详情
(IX) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(X) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(XI) 32497 benzyl 2-hydroxyethylcarbamate 77987-49-6 C10H13NO3 详情 详情
(XII) 32498 2-(4-hydroxyphenyl)-N-methylacetamide C9H11NO2 详情 详情
(XIII) 15822 Methyl 4-hydroxyphenylacetate; methyl 2-(4-hydroxyphenyl)acetate 14199-15-6 C9H10O3 详情 详情
(XIV) 32499 benzyl 2-[4-[2-(methylamino)-2-oxoethyl]phenoxy]ethylcarbamate C19H22N2O4 详情 详情

合成路线37

该中间体在本合成路线中的序号：(VI)

The condensation of azetidine (I) with B-2-cyclohexenyl(2-methylcyclohexyl)2 by means of Et2Zn gives the adduct (II), which is epoxidated with Mg monoperphthalic acid (MgPOPH) in CH2Cl2 to yield the epoxide (III). Opening of the epoxide (III) with methylamine and LiClO4 in CH3CN affords the methylamino derivative (IV), which is oxidated with oxalyl chloride and Et3N in DMSO/CH2Cl2 to provide the cyclohexanone derivative (V). The protection of the methylamino group of (V) with benzyl chloroformate (VI) and Et3N in CH2Cl2 gives the carbamate (VII), which is condensed with 9-fluorenyl chlorooxalate (VIII) by means of Et3N in toluene to yield the oxalamic ester (IX). The cyclization of (IX) by means of P(OEt)3 in refluxing toluene affords the tricyclic carboxylate (X), which is desilylated with Bu4NBr and KF in HOAc/THF providing the intermediate (XI). The deprotection of the ester and carbamate groups of (XI) with H2 over Pd/C in i-PrOH/H2O furnishes the tricyclic aminoacid (XII), which is finally treated with benzyloxy formimidate (XIII) over amberlyst IRA68 in CH3CN/H2O to afford the target N-methylformamidino compound.

参考文献 中间体
合成目标
【1】 Biondi, S.; et al.; Highly diastereoselective synthesis of 4-N-methylformamidino trinem (GV129606), a potent antibacterial agent. Tetrahedron 2000, 56, 31, 5649.
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) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(II) 15576 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-2-cyclohexen-1-yl]-2-azetanone C17H31NO2Si 详情 详情
(III) 15577 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S,2R,6R)-7-oxabicyclo[4.1.0]hept-2-yl]-2-azetidinone C17H31NO3Si 详情 详情
(IV) 41929 (4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,2S,3S)-2-hydroxy-3-(methylamino)cyclohexyl]-2-azetidinone C18H36N2O3Si 详情 详情
(V) 41923 (4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-(methylamino)-2-oxocyclohexyl]-2-azetidinone C18H34N2O3Si 详情 详情
(VI) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VII) 41930 benzyl (1S,3R)-3-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxocyclohexyl(methyl)carbamate C26H40N2O5Si 详情 详情
(VIII) 41931 2-(9H-fluoren-9-yloxy)-2-oxoacetyl chloride C15H9ClO3 详情 详情
(IX) 41932 9H-fluoren-9-yl 2-((2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R,3S)-3-[(methoxycarbonyl)(methyl)amino]-2-oxocyclohexyl]-4-oxoazetidinyl)-2-oxoacetate C35H44N2O8Si 详情 详情
(X) 41933 9H-fluoren-9-yl (5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-[(methoxycarbonyl)(methyl)amino]-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C35H44N2O6Si 详情 详情
(XI) 41934 9H-fluoren-9-yl (5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-[(methoxycarbonyl)(methyl)amino]-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C29H30N2O6 详情 详情
(XII) 41927 (5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-(methylamino)-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylic acid C14H20N2O4 详情 详情
(XIII) 41928 1-[[amino(imino)methoxy]methyl]benzene C8H10N2O 详情 详情

合成路线38

该中间体在本合成路线中的序号：

The cyclization of L-serine (I) with pivalaldehyde (II) by means of LDA in THF gives the oxazolidine (III), which is acylated with formic and acetic anhydride yielding the N-formyloxazolidine (IV). The reaction of (IV) with LDA affords the chiral enol (V), which is treated with allyl bromide in THF to give the chiral 4-allyloxazolidine (VI). Cleavage of the oxazolidine ring with acetyl chloride and treatment with benzyl chloroformate yields the protected chiral 2-allylserine (VII), which is oxidized with oxalyl chloride to the corresponding aldehyde (VIII). The Wittig condensation of (VIII) with triphenylphosphoranylideneacetic acid methyl ester (IX) affords the intermediate (X), which is submitted to UV irradiation with an Hanovia medium pressure mercury lamp through a Pyrex filter in benzene containing benzophenone. A mixture of isomeric bicyclic compounds from which the desired compound (XI) is isolated by column chromatography. The hydrogenation of (IX) with H2 over Pd/C in methanol provides the bicyclic aminoester (XII), which is finally hydrolyzed with 6N HCl.

参考文献 中间体
合成目标
【1】 von Diester, S.; et al.; Stereoselektive Alkylierung an C(alpha) von Serin, Glycerinsaure, Threonin und Weinsaure uber heterocyclische Enolate mit exocyclischer Doppelbindung. Helv Chim Acta 1987, 70, 1194-1216.
【2】 Kozikowski, A.P.; et al.; Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I, a potent mGluR agonist. J Med Chem 1998, 41, 10, 1641.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(I) 20915 methyl (2S)-2-amino-3-hydroxypropanoate 5680-80-8 C4H9NO3 详情 详情
(II) 19797 Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal 630-19-3 C5H10O 详情 详情
(III) 36839 methyl (4S)-2-(tert-butyl)-1,3-oxazolidine-4-carboxylate C9H17NO3 详情 详情
(IV) 36840 methyl (4S)-2-(tert-butyl)-3-formyl-1,3-oxazolidine-4-carboxylate C10H17NO4 详情 详情
(V) 36841 lithium [(2R)-2-(tert-butyl)-3-formyl-1,3-oxazolidin-4-ylidene](methoxy)methanolate C10H16LiNO4 详情 详情
(VI) 36842 methyl (2R,4S)-4-allyl-2-(tert-butyl)-3-formyl-1,3-oxazolidine-4-carboxylate C13H21NO4 详情 详情
(VII) 36843 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-2-(hydroxymethyl)-4-pentenoate C15H19NO5 详情 详情
(VIII) 36844 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-2-(2-oxoethyl)-4-pentenoate C16H19NO5 详情 详情
(IX) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(X) 36845 dimethyl (E,4S)-4-allyl-4-[[(benzyloxy)carbonyl]amino]-2-pentenedioate C18H21NO6 详情 详情
(XI) 36846 dimethyl (1R,2S,4R,5S)-2-[[(benzyloxy)carbonyl]amino]bicyclo[2.1.1]hexane-2,5-dicarboxylate C18H21NO6 详情 详情
(XII) 36847 dimethyl (1R,2S,4R,5S)-2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylate C10H15NO4 详情 详情

合成路线39

该中间体在本合成路线中的序号：

The cyclization of acetyl cyclopropane (I) with 2-nitroacetamide (II) and formamide dimethylacetal (III) by means of p-tolulenesulfonic acid gives the nitro-pyridinone (IV) (1), which is reduced with H2 over Pd/C affording 3-amino-6-propylpyridin-2(1H)-one (V). The protection of the amino group of (V) with benzyl chloroformate affords the carbamate (VI), which is condensed with tert-butyl bromoacetate (VII) by means of NaH in THF giving substituted acetate ester (VIII). The deprotection of (VIII) by hydrogenolysis with H2 over Pd/C in ethyl acetate yields intermediate (IX) with a free amino group, which is treated with benzylsulfonyl chloride (X) and pyridine to afford the sulfonamide (XI). Hydrolysis of the ester group of (XI) with HCl in ethyl acetate gives the carboxylic acid (XII), which is condensed with the pyridylmethylamine (XIII) by means of EDC and HOBT to afford the carboxamide (XIV). Finally, this compound is deprotected with HCl as usual.

参考文献 中间体
合成目标
【1】 C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption. Bioorg Med Chem Lett 1998, 8, 13, 1719.
【2】 Sanderson, P.E.; Naylor-Olsen, A.M.; Dyer, D.L.; Vacca, J.P.; Isaacs, R.C.A.; Dorsey, B.D.; Fraley, M.E. (Merck & Co., Inc.); Pyridinone-thrombin inhibitors. EP 0835109; JP 1999508558; WO 9701338 .
【3】 Dorsey, B.D.; Isaacs, R.C.A.; Sanderson, P.E.; Dyer, D.L.; Naylor-Olsen, A.M.; Fraley, M.E.; Vacca, J.P. (Merck & Co., Inc.); Pyridinone thrombin inhibitors. US 5668289 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 12435 Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone 765-43-5 C5H8O 详情 详情
(II) 27209 2-nitroacetamide C2H4N2O3 详情 详情
(III) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(IV) 27210 6-cyclopropyl-3-nitro-2(1H)-pyridinone C8H8N2O3 详情 详情
(V) 27211 3-amino-6-propyl-2(1H)-pyridinone C8H12N2O 详情 详情
(VI) 27212 benzyl 2-oxo-6-propyl-1,2-dihydro-3-pyridinylcarbamate C16H18N2O3 详情 详情
(VII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VIII) 27213 tert-butyl 2-[3-[[(benzyloxy)carbonyl]amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetate C22H28N2O5 详情 详情
(IX) 27214 tert-butyl 2-[3-amino-2-oxo-6-propyl-1(2H)-pyridinyl]acetate C14H22N2O3 详情 详情
(X) 27215 phenylmethanesulfenyl chloride C7H7ClS 详情 详情
(XI) 27216 tert-butyl 2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetate C21H28N2O5S 详情 详情
(XII) 27217 2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetic acid C17H20N2O5S 详情 详情
(XIII) 27218 tert-butyl 5-(aminomethyl)-6-methyl-2-pyridinylcarbamate C12H19N3O2 详情 详情
(XIV) 27219 tert-butyl 5-[([2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetyl]amino)methyl]-6-methyl-2-pyridinylcarbamate C29H37N5O6S 详情 详情

合成路线40

该中间体在本合成路线中的序号：(VI)

The selective protection of piperazine-2-carboxylic acid (I) with tert-butoxycarbonyl anhydride gives the carbamate (II), which is sulfonated with 4-methoxybenzenesulfonyl chloride (II) and triethylamine yielding the sulfonamide (IV). The esterification and simultaneous deprotection of (IV) with SOCl2 and methanol affords the methyl ester (V), which is treated with benzyl chloroformate (VI) and triethylamine to afford the benzyloxycarbonyl derivative (VII). Finally, this compound is treated with KOH and hydroxylamine in methanol to provide the target hydroxamic acid.

参考文献 中间体
合成目标
【1】 Pikul, S.; Natchus, M.G.; Cheng, M.; et al.; Design and synthesis of piperazine-based MMP inhibitors. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 044.
【2】 De, B.; Natchus, M.G.; Pikul, S.; Almstead, N.G.; Matthews, R.S.; Taiwo, Y.O.; Cheng, M. (The Procter & Gamble Co.); 1,4-Heterocyclic metalloprotease inhibitors. EP 0923563; EP 0925287; WO 9808825; WO 9808827 .
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) 25933 2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid C5H10N2O2 详情 详情
(II) 25934 4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid C10H18N2O4 详情 详情
(III) 15719 4-methoxybenzenesulfonyl chloride 98-68-0 C7H7ClO3S 详情 详情
(IV) 25935 4-(tert-butoxycarbonyl)-1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylic acid C17H24N2O7S 详情 详情
(V) 25936 methyl 1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylate C13H18N2O5S 详情 详情
(VI) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VII) 25938 1-benzyl 3-methyl 4-[(4-methoxyphenyl)sulfonyl]-1,3-piperazinedicarboxylate C21H24N2O7S 详情 详情

合成路线41

该中间体在本合成路线中的序号：

Alkylation of N-acetyl-D-cysteine (I) with 1-fluoro-5-methyl-2-nitrobenzene (II) gave adduct (III). After hydrolysis of the acetamido group of (III) with aqueous sulfuric acid, the resulting amine (IV) was protected as the benzyl carbamate (V). Reduction of the nitro group of (V) provided amino acid (VI), which was cyclized to the benzothiazepinone (VII) using EDC. Subsequent alkylation of (VII) with ethyl bromoacetate under phase-transfer conditions yielded (VIII) (1). Cleavage of both N-Cbz group and ethyl ester by HBr in AcOH, followed by introduction of the N-Boc group afforded intermediate (X) (2). Optionally, hydrogenolysis of the N-Cbz group of (VIII) provided amino lactam (XI). This was coupled with N-Boc-O-benzylserine (XII) to give amide (XIII). Then, basic hydrolysis of the ethyl ester produced carboxylic acid (XIV).

参考文献 中间体
合成目标
【1】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(I) 39365 (2S)-2-(acetamido)-3-sulfanylpropionic acid 616-91-1 C5H9NO3S 详情 详情
(II) 39366 2-fluoro-4-methyl-1-nitrobenzene 446-34-4 C7H6FNO2 详情 详情
(III) 39367 (2S)-2-(acetamido)-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid C12H14N2O5S 详情 详情
(IV) 39368 (2S)-2-amino-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid C10H12N2O4S 详情 详情
(V) 39369 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid C18H18N2O6S 详情 详情
(VI) 39370 (2S)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid C18H20N2O4S 详情 详情
(VII) 39371 benzyl (3S)-8-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate C18H18N2O3S 详情 详情
(VIII) 39372 ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C22H24N2O5S 详情 详情
(IX) 39376 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C12H14N2O3S 详情 详情
(X) 39377 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C17H22N2O5S 详情 详情
(XI) 39373 ethyl 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C14H18N2O3S 详情 详情
(XII) 16886 (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine 23680-31-1 C15H21NO5 详情 详情
(XIII) 39374 ethyl 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C29H37N3O7S 详情 详情
(XIV) 39375 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C27H33N3O7S 详情 详情

合成路线42

该中间体在本合成路线中的序号：

The reaction between pyrrole (I) and 3,4-difluoronitrobenzene (II) afforded the N-aryl pyrrole (III). Selective reduction of the nitro group of (III) by hydrogenation over sulfided platinum on carbon gave aniline (IV), which was converted to carbamate (V) upon treatment with benzyl chloroformate. Subsequent condensation of (V) with (R)-(-)-glycidyl butyrate (VI) in the presence of lithium bis(trimethylsilyl)amide produced the chiral oxazolidinone (VII). Mesylation of the alcohol group of (VII), followed by displacement with NaN3 yielded azide (VIII). This was reduced by hydrogenation over Pt/C/S to give amine (IX), which was finally acetylated using Ac2O and pyridine.

参考文献 中间体
合成目标
【1】 Emmert, D.E.; Reischer, R.J.; Ford, C.W.; Garmon, S.A.; Zurenko, G.E.; Barbachyn, M.R.; Hutchinson, D.K.; Stelzer, L.S.; Hester, J.B.; Synthesis and antibacterial activity of azolylphenyloxazolidinones having nitrogen-bound five-membered heterocyclic rings. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-137.
【2】 Hutchinson, D.K. (Pharmacia & Upjohn AB); Hetero-aromatic ring substd. phenyloxazolidinone antimicrobials. EP 0807112; JP 1998513446; US 5910504; WO 9623788 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 21674 1H-pyrrole 109-97-7 C4H5N 详情 详情
(II) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(III) 29412 1-(2-fluoro-4-nitrophenyl)-1H-pyrrole C10H7FN2O2 详情 详情
(IV) 29413 3-fluoro-4-(1H-pyrrol-1-yl)phenylamine3-fluoro-4-(1H-pyrrol-1-yl)aniline C10H9FN2 详情 详情
(V) 29414 benzyl 3-fluoro-4-(1H-pyrrol-1-yl)phenylcarbamate C18H15FN2O2 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 29415 (5R)-3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C14H13FN2O3 详情 详情
(VIII) 29416 (5R)-5-(azidomethyl)-3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl]-1,3-oxazolidin-2-one C14H12FN5O2 详情 详情
(IX) 29417 (5S)-5-(aminomethyl)-3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl]-1,3-oxazolidin-2-one C14H14FN3O2 详情 详情

合成路线43

该中间体在本合成路线中的序号：

The hydroboration of allyl bromide (I) with diisopinocampheylborane gives the 3-bromopropylboronic ester (II), which by treatment with acetaldehyde and water yields the boronic acid (III). The reaction of (III) with NaN3 and ethanol affords 3-azidoboronic acid ethyl ester (IV), which is transesterified with optically active pipanediol (V) giving the cyclic ester (VI). The homologation of (VI) with LDA, ZnCl2 and dichloromethane in THF yields the alpha-chlorobutylboronic ester (VII), which is aminated with hexamethyldisylazane (HMDS) and BuLi to provide the silylated alpha-aminoboronic ester (VIII). The desilylation of (VIII) with methanol, and its protection with benzyl chloroformate gives the protected alpha-aminoboronic ester (IX). The hydrogenation of the azido group of (IX) with H2 over PtO2 affords the 4-aminobutylboronic ester (X), which is treated with N,N'-bis(tert-butoxycarbonyl)thiourea (XI), HgCl2 and TEA in DMF to give the guanidine derivative (XII). Finally, this compound is hydrolyzed and deprotected with refluxing 6N HCl.

参考文献 中间体
合成目标
【1】 Lebarbier, C.; Carreaux, F.; Carboni, B.; Boucher, J.L.; Synthesis of boronic acid analogs of L-arginine as alternate substrates or inhibitors of nitric oxide synthase. Bioorg Med Chem Lett 1998, 8, 18, 2573.
【2】 Lebarbier, C.; et al.; Synthesis of a boronic acid analogue of L-ornithine. Synthesis 1996, 1371.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(II) 36654 bis[[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]methyl] 3-bromopropylboronate C25H44BBrO2 详情 详情
(III) 36655 3-bromopropylboronic acid C3H8BBrO2 详情 详情
(IV) 36656 diethyl 3-azidopropylboronate C7H16BN3O2 详情 详情
(V) 32535 (1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol C10H18O2 详情 详情
(VI) 36657 3-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]propyl azide; (1S,2R,6S,8S)-4-(3-azidopropyl)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane C13H22BN3O2 详情 详情
(VII) 36658 (4S)-4-chloro-4-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl azide; (1S,2R,6S,8S)-4-[(1S)-4-azido-1-chlorobutyl]-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane C14H23BClN3O2 详情 详情
(VIII) 36659 N-[(1R)-4-azido-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl](trimethyl)-N-(trimethylsilyl)silanamine; N-[(1R)-4-azido-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl]-N,N-bis(trimethylsilyl)amine C20H41BN4O2Si2 详情 详情
(IX) 36660 benzyl (1R)-4-azido-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylcarbamate C22H31BN4O4 详情 详情
(X) 36661 benzyl (1R)-4-amino-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylcarbamate C22H33BN2O4 详情 详情
(XI) 21843 tert-butyl [(tert-butoxycarbonyl)amino]carbothioylcarbamate 145013-05-4 C11H20N2O4S 详情 详情
(XII) 36662 benzyl (1R)-4-([[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]amino)-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylcarbamate C33H51BN4O8 详情 详情

合成路线44

该中间体在本合成路线中的序号：

The protection of 3-piperidinol (I) with tert-butoxycarbonyl anhydride or benzyloxycarbonyl chloride gives the corresponding protected piperidine (II), which is oxidized with CrO3 and acetic anhydride in pyridine yielding the piperidinone (III). The condensation of (III) with phosphinate (IV) and triethylamine at 100 C affords the alpha-hydroxyphosphinate (V), which is acylated with methoxalyl chloride (VI) and DMAP giving the methoxalyl ester (VII). The reduction of (VII) with tributyl in hydride and AIBN yields the protected phophinate (VIII), which is finally deprotected and hydrolyzed with 6M HCl.

参考文献 中间体
合成目标
【1】 Stensbol, T.B.; Kehler, J.; Krogsgaard-Larsen, P.; Piperidinyl-3-phosphinic acids as novel uptake inhibitors of the neurotransmitter gamma-aminobutyric acid (GABA). Bioorg Med Chem Lett 1999, 9, 6, 811.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(IIa) 26964 benzyl 3-hydroxy-1-piperidinecarboxylate C13H17NO3 详情 详情
(IIb) 26965 tert-butyl 3-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(IIIa) 26966 benzyl 3-oxo-1-piperidinecarboxylate C13H15NO3 详情 详情
(IIIb) 26967 1-N-Boc-3-piperodone; tert-butyl 3-oxo-1-piperidinecarboxylate 98977-36-7 C10H17NO3 详情 详情
(Va) 26969 benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate C20H32NO7P 详情 详情
(Vb) 26970 tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate C17H34NO7P 详情 详情
(VIIa) 26972 benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate C23H34NO10P 详情 详情
(VIIb) 26973 tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate C20H36NO10P 详情 详情
(VIIIa) 26974 benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate C20H32NO6P 详情 详情
(VIIIb) 26975 tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate C17H34NO6P 详情 详情
(I) 24255 3-piperidinol 6859-99-0 C5H11NO 详情 详情
(IV) 26968 ethyl diethoxymethylphosphinate C7H17O4P 详情 详情
(VI) 26971 2-methoxy-2-oxoacetyl chloride 5781-53-3 C3H3ClO3 详情 详情

合成路线45

该中间体在本合成路线中的序号：

The protection of 3-piperidinol (I) with tert-butoxycarbonyl anhydride or benzyloxycarbonyl chloride gives the corresponding protected piperidine (II), which is oxidized with CrO3 and acetic anhydride in pyridine yielding the piperidinone (III). The condensation of (III) with phosphinate (IV) and triethylamine at 100 C affords the alpha-hydroxyphosphinate (V), which is acylated with methoxalyl chloride (VI) and DMAP giving the methoxalyl ester (VII). The reduction of (VII) with tributyl in hydride and AIBN yields the protected phophinate (VIII), which is deprotected with trifluoroacetic acid affording (IX) with its free NH group. The alkylation of (IX) with 4,4-diphenyl-3-butenyl bromide (X) provides the alkylated piperidinephosphinate (XI), which is finally hydrolyzed with refluxing 6M HCl.

参考文献 中间体
合成目标
【1】 Stensbol, T.B.; Kehler, J.; Krogsgaard-Larsen, P.; Piperidinyl-3-phosphinic acids as novel uptake inhibitors of the neurotransmitter gamma-aminobutyric acid (GABA). Bioorg Med Chem Lett 1999, 9, 6, 811.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(IIa) 26964 benzyl 3-hydroxy-1-piperidinecarboxylate C13H17NO3 详情 详情
(IIb) 26965 tert-butyl 3-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(IIIa) 26966 benzyl 3-oxo-1-piperidinecarboxylate C13H15NO3 详情 详情
(IIIb) 26967 1-N-Boc-3-piperodone; tert-butyl 3-oxo-1-piperidinecarboxylate 98977-36-7 C10H17NO3 详情 详情
(Va) 26969 benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate C20H32NO7P 详情 详情
(Vb) 26970 tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate C17H34NO7P 详情 详情
(VIIa) 26972 benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate C23H34NO10P 详情 详情
(VIIb) 26973 tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate C20H36NO10P 详情 详情
(VIIIa) 26974 benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate C20H32NO6P 详情 详情
(VIIIb) 26975 tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate C17H34NO6P 详情 详情
(I) 24255 3-piperidinol 6859-99-0 C5H11NO 详情 详情
(IV) 26968 ethyl diethoxymethylphosphinate C7H17O4P 详情 详情
(VI) 26971 2-methoxy-2-oxoacetyl chloride 5781-53-3 C3H3ClO3 详情 详情
(IX) 27066 1-(4,4-diphenyl-3-butenyl)-3-piperidinylphosphinic acid C21H26NO2P 详情 详情
(X) 24116 1-(4-bromo-1-phenyl-1-butenyl)benzene C16H15Br 详情 详情
(XI) 27067 ethyl 1-(4,4-diphenyl-3-butenyl)-3-piperidinylphosphinate C23H30NO2P 详情 详情

合成路线46

该中间体在本合成路线中的序号：(IV)

The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is protected with benzyl chloroformate (IV) and TEA, yielding dicarbamate (V). Selective deprotection of (V) with dry HCl in ethyl acetate affords the primary amine (VI), which is treated with 3(S)-tetrahydrofuryl N-succinimidinyl carbonate (VII) -- obtained by reaction of tetrahydrofuran-3(S)-ol (VIII) first with phosgene and then with N-hydroxysuccinimide (IX) -- and DIEA in acetonitrile to provide the corresponding carbamate (X). Deprotection of (X) by hydrogenation with H2 over Pd/C in ethanol gives the secondary amine (XI), which is condensed with 4-nitrophenylsulfonyl chloride (XII) by means of NaHCO3 in dichloromethane/water to yield the sulfonamide intermediate (XIII).

参考文献 中间体
合成目标
【1】 Martin, L.; Castaner, R.M.; Sorbera, L.A.; Castaner, J.; Fosamprenavir. Drugs Fut 2001, 26, 3, 224.
【2】 Tung, R.D.; Murcko, M.A.; Bhisetti, G.R. (Vertex Pharmaceuticals Inc.); Sulfonamide inhibitors of HIV-aspartyl protease. EP 0659181; EP 0885887; JP 1996501299; US 5585397; WO 9405639 .
【3】 Tung, R.D. (Vertex Pharmaceuticals Inc.); THF-containing sulfonamide inhibitors of aspartyl protease. EP 0846110; WO 9633184 .
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) 19730 tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate 98737-29-2 C15H21NO3 详情 详情
(II) 13306 2-Methyl-1-propanamine; Isobutylamine 78-81-9 C4H11N 详情 详情
(III) 44417 tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate 160232-08-6 C19H32N2O3 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 44418 benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(isobutyl)carbamate C27H38N2O5 详情 详情
(VI) 44419 benzyl (2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(isobutyl)carbamate C22H30N2O3 详情 详情
(VII) 39664 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione C9H11NO6 详情 详情
(VIII) 44420 (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran 86087-23-2 C4H8O2 详情 详情
(IX) 10264 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione 6066-82-6 C4H5NO3 详情 详情
(X) 44421 benzyl (2R,3S)-2-hydroxy-4-phenyl-3-([[(3S)tetrahydro-3-furanyloxy]carbonyl]amino)butyl(isobutyl)carbamate C27H36N2O6 详情 详情
(XI) 44422 (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate C19H30N2O4 详情 详情
(XII) 15809 4-nitrobenzenesulfonyl chloride 98-74-8 C6H4ClNO4S 详情 详情
(XIII) 44423 (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate C25H33N3O8S 详情 详情

合成路线47

该中间体在本合成路线中的序号：

The condensation of cyclohexanone (I) with ethyl cyanacetate (II) gives the cyclohexylidene derivative (II), which is cyclized with N-benzylglycine (IV) and formal-dehyde by means of TEA in refluxing benzene yielding the spiro derivative (V). The decarboxylative hydrolysis of (V) with refluxing 6N HCl affords 2-benzyl-2-azaspiro [4,5]decane-4-carboxylic acid (VI), which is esterified with methanol/HCl giving the methyl ester (VII). The debenzylation of (VII) with H2 over Pd(OH)2 in methanol yields 2-azaspiro[4.5]decane-4-carboxylic acid methyl ester (VIII), which is reprotected with benzyl chloroformate and pyridine to provide the carbamate (IX). The hydrolysis of the methyl ester group of (IX) with NaOH in dioxane/water afford the protected carboxylic acid (Xa-b) as a racemic mixture that is treated with oxalyl chloride in dichloromethane to give the acyl chloride (XIa-b). The condensation of (XIa-b) with the chiral (R)(+)-1-(2-naphthyl)ethylamine (XII) yields the amide (XIIIa-b) as a diastereomeric mixture that is resolved by flash chromatography providing chiral (XIV) as a single diastereomer. Finally, this compound is hydrolyzed and deprotected with 6N HCl in refluxing THF.

参考文献 中间体
合成目标
【1】 Singh, L.; Bryans, J.S.; Receveur, J.-M.; Horwell, D.C.; Field, M.J.; Synthesis and biological evaluation of conformationally restricted gabapentin analogues. Bioorg Med Chem Lett 1999, 9, 16, 2329.
【2】 Horwell, D.C.; Bryans, J.S.; Receveur, J.-M. (Pfizer Inc.); Conformationally constrained amino acid cpds. having affinity for the alpha2delta subunit of a calcium channel. WO 9961424 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(Xa) 38351 (4S)-2-[(benzyloxy)carbonyl]-2-azaspiro[4.5]decane-4-carboxylic acid C18H23NO4 详情 详情
(Xb) 38352 (4R)-2-[(benzyloxy)carbonyl]-2-azaspiro[4.5]decane-4-carboxylic acid C18H23NO4 详情 详情
(XIa) 38353 benzyl (4S)-4-(chlorocarbonyl)-2-azaspiro[4.5]decane-2-carboxylate C18H22ClNO3 详情 详情
(XIb) 38354 benzyl (4R)-4-(chlorocarbonyl)-2-azaspiro[4.5]decane-2-carboxylate C18H22ClNO3 详情 详情
(XIIIa) 38356 benzyl (4S)-4-([[(1R)-1-(2-naphthyl)ethyl]amino]carbonyl)-2-azaspiro[4.5]decane-2-carboxylate C30H34N2O3 详情 详情
(XIIIb), (XIV) 38357 benzyl (4R)-4-([[(1R)-1-(2-naphthyl)ethyl]amino]carbonyl)-2-azaspiro[4.5]decane-2-carboxylate C30H34N2O3 详情 详情
(I) 11059 Cyclohexanone 108-94-1 C6H10O 详情 详情
(II) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(III) 38345 ethyl 2-cyano-2-cyclohexylideneacetate C11H15NO2 详情 详情
(IV) 27895 N-(benzylamino)acetic acid; N-Benzylglycine; 2-(benzylamino)acetic acid 17136-36-6 C9H11NO2 详情 详情
(V) 38346 ethyl 2-benzyl-4-cyano-2-azaspiro[4.5]decane-4-carboxylate C20H26N2O2 详情 详情
(VI) 38347 2-benzyl-2-azaspiro[4.5]decane-4-carboxylic acid C17H23NO2 详情 详情
(VII) 38348 methyl 2-benzyl-2-azaspiro[4.5]decane-4-carboxylate C18H25NO2 详情 详情
(VIII) 38349 methyl 2-azaspiro[4.5]decane-4-carboxylate C11H19NO2 详情 详情
(IX) 38350 2-benzyl 4-methyl 2-azaspiro[4.5]decane-2,4-dicarboxylate C19H25NO4 详情 详情
(XII) 38355 (1R)-1-(2-naphthyl)-1-ethanamine; (1R)-1-(2-naphthyl)ethylamine C12H13N 详情 详情

合成路线48

该中间体在本合成路线中的序号：

Condensation of 2,3-dimethoxybenzaldehyde (I) with pyruvic acid (II) in the presence of KOH produced oxobutenoic acid (III), which was hydrogenated in the presence of methylamine to give amino acid (IV). Reaction of (IV) with benzyl chloroformate afforded carbamate (V), which was subsequently cyclized to the N-carboxyanhydride (VI) upon treatment with SOCl2. Friedel-Crafts intramolecular acylation using AlCl3 yielded amino tetralone (VII). Reduction of the keto group of (VII) to give amino tetralin (VIII) was effected by catalytic hydrogenation over Pd/C. Finally, dealkylation of the methyl ether groups of (VIII) with AlCl3 in hot toluene afforded the title dihydroxy compound.

参考文献 中间体
合成目标
【1】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 17615 2,3-Dimethoxybenzaldehyde 86-51-1 C9H10O3 详情 详情
(II) 24066 2-oxopropionic acid 127-17-3 C3H4O3 详情 详情
(III) 37376 (E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid C12H12O5 详情 详情
(IV) 37377 4-(2,3-dimethoxyphenyl)-2-(methylamino)butyric acid C13H19NO4 详情 详情
(V) 37378 2-[[(benzyloxy)carbonyl](methyl)amino]-4-(2,3-dimethoxyphenyl)butyric acid C21H25NO6 详情 详情
(VI) 37379 4-(2,3-dimethoxyphenethyl)-3-methyl-1,3-oxazolidine-2,5-dione C14H17NO5 详情 详情
(VII) 37380 5,6-dimethoxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone C13H17NO3 详情 详情
(VIII) 37381 N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine C13H19NO2 详情 详情

合成路线49

该中间体在本合成路线中的序号：

The enantiopure diol (II) was prepared by the Sharpless asymmetric dihydroxylation of ethyl sorbate (I). Catalytic hydrogenation of (II) generated the gamma-lactone (III). After conversion of the hydroxyl group of (III) to the corresponding mesylate, displacement by NaN3 afforded azide (IV). Reduction of (IV) to amine gave rise to the formation of lactam (V). Sequential protection of alcohol and amide functions provided (VI), which was treated with lithium hexamethyldisilazide and Comin's reagent to furnish the aminovinyl triflate (VII). The enantiopure propargyl alcohol (X), prepared by treatment of (S)-glycidol pivalate (VIII) with lithium trimethylsilylacetylide (IX) followed by desilylation with tetrabutylammonium fluoride, was then coupled with triflate (VII) in the presence of Pd(PPh3)4 and CuI to yield adduct (XI), which was reduced to the trisubstituted piperidine (XII) by means of NaBH3CN and trifluoroacetic acid. Hydrogenation of the alkyne function of (XII) with concomitant removal of the benzyloxycarbonyl group gave (XIII). This was further protected as the allyl carbamate (XIV) by treatment with allyl chloroformate. The secondary alcohol of (XIV) was then protected as the tetrahydropyranyl ether (XV), and subsequent reductive cleavage of the pivaloyl ester with DIBAL liberated the primary alcohol (XVI).

参考文献 中间体
合成目标
【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情
(I) 40236 ethyl (2E,4E)-2,4-hexadienoate 2396-84-1 C8H12O2 详情 详情
(II) 40237 ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate C8H14O4 详情 详情
(III) 40238 (5R)-5-[(1R)-1-hydroxyethyl]dihydro-2(3H)-furanone C6H10O3 详情 详情
(IV) 40239 (5R)-5-[(1R)-1-azidoethyl]dihydro-2(3H)-furanone C6H9N3O2 详情 详情
(V) 40240 (5R,6S)-5-hydroxy-6-methyl-2-piperidinone C6H11NO2 详情 详情
(VI) 40241 benzyl (2S,3R)-2-methyl-6-oxo-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C23H37NO4Si 详情 详情
(VII) 40242 benzyl (2S,3R)-2-methyl-6-[[(trifluoromethyl)sulfonyl]oxy]-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate C24H36F3NO6SSi 详情 详情
(VIII) 12235 (2S)oxiranylmethyl pivalate C8H14O3 详情 详情
(IX) 16299 Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium 54655-07-1 C5H9LiSi 详情 详情
(X) 12236 (2S)-2-hydroxy-4-pentynyl pivalate C10H16O3 详情 详情
(XI) 40243 benzyl (2S,3R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate C33H51NO6Si 详情 详情
(XII) 40244 benzyl (2S,3R,6R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C33H53NO6Si 详情 详情
(XIII) 40245 (2R)-2-hydroxy-5-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]pentyl pivalate C25H51NO4Si 详情 详情
(XIV) 40246 allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxypentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C29H55NO6Si 详情 详情
(XV) 40247 allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C34H63NO7Si 详情 详情
(XVI) 40248 allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C29H55NO6Si 详情 详情

合成路线50

该中间体在本合成路线中的序号：

The enantiopure diol (II) was prepared by the Sharpless asymmetric dihydroxylation of ethyl sorbate (I). Catalytic hydrogenation of (II) generated the gamma-lactone (III). After conversion of the hydroxyl group of (III) to the corresponding mesylate, displacement by NaN3 afforded azide (IV). Reduction of (IV) to amine gave rise to the formation of lactam (V). Sequential protection of alcohol and amide functions of (V) provided (VI), which was treated with lithium hexamethyldisilazide and Comin's reagent to furnish the aminovinyl triflate (VII). The enantiopure propargyl alcohol (X), prepared by treatment of (S)-glycidol pivalate (VIII) with lithium trimethylsilylacetylide (IX) followed by desilylation with tetrabutylammonium fluoride, was then coupled with triflate (VII) in the presence of Pd(PPh3)4 and CuI to yield adduct (XI), which was reduced to the trisubstituted piperidine (XII) by means of NaBH3CN and trifluoroacetic acid. Hydrogenation of the alkyne function of (XII) with concomitant removal of the benzyloxycarbonyl group gave (XIII). This was further protected as the allyl carbamate (XIV) by treatment with allyl chloroformate. The secondary alcohol of (XIV) was then protected as the tetrahydropyranyl ether (XV), and subsequent reductive cleavage of the pivaloyl ester with DIBAL liberated the primary alcohol (XVI).

参考文献 中间体
合成目标
【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情
(I) 40236 ethyl (2E,4E)-2,4-hexadienoate 2396-84-1 C8H12O2 详情 详情
(II) 40237 ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate C8H14O4 详情 详情
(III) 40238 (5R)-5-[(1R)-1-hydroxyethyl]dihydro-2(3H)-furanone C6H10O3 详情 详情
(IV) 40239 (5R)-5-[(1R)-1-azidoethyl]dihydro-2(3H)-furanone C6H9N3O2 详情 详情
(V) 40240 (5R,6S)-5-hydroxy-6-methyl-2-piperidinone C6H11NO2 详情 详情
(VI) 40241 benzyl (2S,3R)-2-methyl-6-oxo-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C23H37NO4Si 详情 详情
(VII) 40242 benzyl (2S,3R)-2-methyl-6-[[(trifluoromethyl)sulfonyl]oxy]-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate C24H36F3NO6SSi 详情 详情
(VIII) 12235 (2S)oxiranylmethyl pivalate C8H14O3 详情 详情
(IX) 16299 Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium 54655-07-1 C5H9LiSi 详情 详情
(X) 12236 (2S)-2-hydroxy-4-pentynyl pivalate C10H16O3 详情 详情
(XI) 40243 benzyl (2S,3R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate C33H51NO6Si 详情 详情
(XII) 40244 benzyl (2S,3R,6R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C33H53NO6Si 详情 详情
(XIII) 40245 (2R)-2-hydroxy-5-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]pentyl pivalate C25H51NO4Si 详情 详情
(XIV) 40246 allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxypentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C29H55NO6Si 详情 详情
(XV) 40247 allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C34H63NO7Si 详情 详情
(XVI) 40248 allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C29H55NO6Si 详情 详情

合成路线51

该中间体在本合成路线中的序号：

A new efficient process for the synthesis of the key intermediate (XII) has been reported. Cyclization of L-alpha-aminoadipic acid in either refluxing AcOH or in DMSO at 130 C provided (S)-6-oxopipecolic acid (II), which was converted to the benzhydryl ester (III) upon treatment with diphenyldiazomethane. Further protection of (III) with benzyl chloroformate produced the N-benzyloxycarbonyl derivative (IV). Methylation of (IV) using iodomethane and lithium hexamethyldisilazide at -78 C produced a 4:1 mixture of the desired trans compound (V) and the cis isomer (VI). The diastereomer specific reduction of the mixture (V+VI) with LiAlH(O-t-Bu)3 yielded the trans cyclic aminal (VII) along with the unreacted cis isomer (VI). Subsequent condensation of aminal (VII) with L-cysteine methyl ester - HCl (VIII) produced the required thiazolidine (IX) as a diastereomeric mixture while leaving the unchanged lactam (VI). Then, acid cleavage of the benzhydryl esters of (VI) and (IXa, IXb) allowed the separation of the HCl-soluble thiazolidine acid (Xa, Xb) from the ether-soluble cis lactam.

参考文献 中间体
合成目标
【1】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor.II. Stereoselective synthesis of peptidomimetic [5.7]-bycyclic compounds. Chem Pharm Bull 1999, 47, 11, 1532.
【2】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor. I. Diastereoselective alkylation of protected 6-oxopipecolic acid esters. Chem Pharm Bull 1999, 47, 11, 1525.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
40585 1-[diazo(phenyl)methyl]benzene C13H10N2 详情 详情
(IXa) 35115 methyl (2S,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate C32H36N2O6S 详情 详情
(IXb) 35116 methyl (2R,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate C32H36N2O6S 详情 详情
(Xa) 35117 (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2R,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid C19H26N2O6S 详情 详情
(Xb) 35118 (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2S,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid C19H26N2O6S 详情 详情
(I) 35109 (2S)-2-aminohexanedioic acid 1118-90-7 C6H11NO4 详情 详情
(II) 22661 (2S)-6-oxo-2-piperidinecarboxylic acid C6H9NO3 详情 详情
(III) 35110 benzhydryl (2S)-6-oxo-2-piperidinecarboxylate C19H19NO3 详情 详情
(IV) 35111 2-benzhydryl 1-benzyl (2S)-6-oxo-1,2-piperidinedicarboxylate C27H25NO5 详情 详情
(V) 35112 2-benzhydryl 1-benzyl (2S,5R)-5-methyl-6-oxo-1,2-piperidinedicarboxylate C28H27NO5 详情 详情
(VI) 35113 2-benzhydryl 1-benzyl (2S,5S)-5-methyl-6-oxo-1,2-piperidinedicarboxylate C28H27NO5 详情 详情
(VII) 35114 2-benzhydryl 1-benzyl (2S,5R)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate C28H29NO5 详情 详情
(VIII) 27413 methyl (2R)-2-amino-3-sulfanylpropanoate C4H9NO2S 详情 详情

合成路线52

该中间体在本合成路线中的序号：

D-Serine (I) was protected as the N-benzyloxycarbonyl derivative (II) by means of benzyl chloroformate in the presence of MgO. Methylation of the alcohol hydroxyl of (II) under Williamson conditions using iodomethane and Ag2O also produced esterification of the carboxyl group to give (III), which was further hydrolyzed to carboxylic acid (IV) with K2CO3 in MeOH-H2O. After activation of (IV) as the mixed anhydride with isobutyl chloroformate, coupling with benzyl amine furnished amide (V). This was alternatively obtained through a related procedure involving coupling of N-Cbz-serine (II) with benzylamine, followed by O-methylation of the resulting hydroxy amide (VI) with iodomethane and Ag2O. Finally, the N-carbobenzoxy protecting group of (V) was removed by catalytic hydrogenolysis in the presence of Pd/C.

参考文献 中间体
合成目标
【1】 Andurkar, S.V.; et al.; Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives. Tetrahedron Asymmetry 1998, 9, 21, 3841.
【2】 Kohn, H.; Andurkar, S.V. (Research Corporation Technologies, Inc.); Anticonvulsant enantiomeric amino acid derivs.. US 6048899; WO 0000463 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 15728 (+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine 312-84-5 C3H7NO3 详情 详情
(II) 32794 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropionic acid C11H13NO5 详情 详情
(III) 38794 methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxypropanoate C13H17NO5 详情 详情
(IV) 38795 (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxypropionic acid C12H15NO5 详情 详情
(V) 38796 benzyl (1R)-2-(benzylamino)-1-(methoxymethyl)-2-oxoethylcarbamate C19H22N2O4 详情 详情
(VI) 38797 benzyl (1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxoethylcarbamate C18H20N2O4 详情 详情

合成路线53

该中间体在本合成路线中的序号：

Pinner reaction of ethyl 5-cyano-2-benzofurancarboxylate (I) gave imidate (II) and subsequent treatment with ethanolic ammonia afforded amidine (III). After basic hydrolysis of the ester group of (III), protection with benzyl chloroformate provided the benzyloxycarbonyl derivative (IV). Coupling of (IV) with ethyl trans-3-(4-aminocyclohexyl)propionate (V) in the presence of EDC and HOBt yielded amide (VI). Finally, hydrogenolysis of the benzyloxycarbonyl protecting group of (VI) provided the title amidino ester.

参考文献 中间体
合成目标
【1】 Ono, S.; Yoshida, T.; Ashimori, A.; Kosaka, K.; Okada, T.; Maeda, K.; Eda, M.; Mori, F.; Inoue, Y.; Ebisu, H.; Imada, T.; Ikegawa, R.; Wang, F.; Nakamura, N. (Welfide Corporation); Novel fused-ring carboxylic acid cpds. or salt thereof,and medicinal use thereof. EP 0712844; JP 1996053398; JP 1996231548; US 5635527; US 5753670; WO 9533720 .
【2】 Nakamura, N.; Imada, T.; Inoue, Y.; Kosaka, K.; Yoshida, T.; Ono, S.; Fukaya, C.; Maeda, K.; Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 2. Condensed heterocyclic derivatives. Chem Pharm Bull 1999, 47, 12, 1694.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 37353 ethyl 5-cyano-1-benzofuran-2-carboxylate C12H9NO3 详情 详情
(II) 37354 ethyl 5-[ethoxy(imino)methyl]-1-benzofuran-2-carboxylate C14H15NO4 详情 详情
(III) 37355 ethyl 5-[amino(imino)methyl]-1-benzofuran-2-carboxylate C12H12N2O3 详情 详情
(IV) 37356 5-[[[(benzyloxy)carbonyl]amino](imino)methyl]-1-benzofuran-2-carboxylic acid C18H14N2O5 详情 详情
(V) 37352 tert-butyl 2-[(4-aminocyclohexyl)oxy]acetate C12H23NO3 详情 详情
(VI) 37357 ethyl 2-([4-[([5-[[[(benzyloxy)carbonyl]amino](imino)methyl]-1-benzofuran-2-yl]carbonyl)amino]cyclohexyl]oxy)acetate C28H31N3O7 详情 详情

合成路线54

该中间体在本合成路线中的序号：(XIII)

The reaction of 3-(2,2-dimethoxyethyl)-2-phenyl-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid (IX) with isobutyl chloroformate and hydroxylamine gives the corresponding hydroxamic acid (X), which is acylated with Ac2O in pyridine to yield the acetoxy compound (XI). The degradation of (XI) by reaction with DBU in refluxing THF affords the amine (XII), which is protected with benzyl chloroformate (XIII) and NaHCO3, providing the carbamate (XIV). The hydrolysis of the dimethylacetal group of (XIV) with HCl in hot acetic acid gives the acetaldehyde derivative (XV), which is oxidized with NaClO2 in tert-butanol/water yielding the corresponding acetic acid derivative (XVI). The condensation of (XVI) with the intermediate amine (VIII) by means of ethyl chloroformate and NMM in THF affords the amide (XVII), which is hydrogenolyzed with H2 over Pd/C in order to eliminate its carbamate protecting group and provide the target racemic 285811.

参考文献 中间体
合成目标
【1】 Kojima, T.; Hachiya, K.; Ohmoto, K. (Ono Pharmaceutical Co., Ltd.); 1,3,4-Oxadiazole derivs. and process for producing the same. EP 1162199; WO 0055145 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 47823 2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone C11H19N3O2 详情 详情
(IX) 51960 1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarboxylic acid C15H16N2O5 详情 详情
(X) 51961 1-(2,2-dimethoxyethyl)-N-hydroxy-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarboxamide C15H17N3O5 详情 详情
(XI) 51962 5-[[(acetoxy)amino]carbonyl]-3-(2,2-dimethoxyethyl)-2-phenyl-4(3H)-pyrimidinone C17H19N3O6 详情 详情
(XII) 51963 5-amino-3-(2,2-dimethoxyethyl)-2-phenyl-4(3H)-pyrimidinone C14H17N3O3 详情 详情
(XIII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(XIV) 51964 benzyl 1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate C22H23N3O5 详情 详情
(XV) 51965 benzyl 6-oxo-1-(2-oxoethyl)-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate C20H17N3O4 详情 详情
(XVI) 47808 2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid C20H17N3O5 详情 详情
(XVII) 51966 benzyl 1-[2-[(1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)amino]-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate C31H34N6O6 详情 详情

合成路线55

该中间体在本合成路线中的序号：

Protection of methyl (R)-3-aminobutyrate (VI) with di-tert-butyl dicarbonate provided the Boc derivative (VII), which was alkylated with 3-cyanobenzyl bromide (VIII) in the presence of lithium bis(trimethylsilyl)amide at -78 C to afford adduct (IX). Acid deprotection of the Boc group of (IX) yielded amino ester (X). Alternatively, (X) was obtained by protection of methyl 3-aminobutyrate (VI) with benzyl chloroformate, followed by alkylation with 3-cyanobenzyl bromide to give (XI). The carbobenzoxy group of (XI) was then deprotected by hydrogenation over Pd/C. Coupling of amino ester (X) with acid chloride (V) gave rise to amide (XII). Conversion of (XII) to the required amidine was then achieved by treatment with methanolic HCl, followed by reaction of the resulting imidate with ammonia in boiling MeOH. The title compound was isolated after conversion to the trifluoroacetate salt.

参考文献 中间体
合成目标
【1】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 38455 3',4'-dimethoxy[1,1'-biphenyl]-4-carbonyl chloride C15H13ClO3 详情 详情
(VI) 38456 methyl (3R)-3-aminobutanoate C5H11NO2 详情 详情
(VII) 38457 methyl (3R)-3-[(tert-butoxycarbonyl)amino]butanoate C10H19NO4 详情 详情
(VIII) 13244 alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile 28188-41-2 C8H6BrN 详情 详情
(IX) 38458 methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate C18H24N2O4 详情 详情
(X) 38459 methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate C13H16N2O2 详情 详情
(XI) 38460 methyl (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-(3-cyanobenzyl)butanoate C21H22N2O4 详情 详情
(XII) 38461 methyl (2R,3R)-2-(3-cyanobenzyl)-3-[[(3',4'-dimethoxy[1,1'-biphenyl]-4-yl)carbonyl]amino]butanoate C28H28N2O5 详情 详情

合成路线56

该中间体在本合成路线中的序号：(VI)

Condensation between 2-iodo-5-fluoroaniline (I) and phenylacetylene (II) under catalysis with Pd(PPh3)4, CuI and diethylamine, followed by cyclization catalyzed by CuI and CaCO3 in DMF, affords phenylindole (III), which is then coupled with 4-piperidone (IV) in H3PO4/HOAc to provide tetrahydropyridine derivative (V). Protection of (V) as its benzyloxycarbonyl derivative (VII) by reaction with acid chloride (VI), followed by hydroboration with bis-isopinocampheylborane ((-)-Ipc2BH) and H2O2 in NaOH, provides the secondary alcohol (VIII). Isolation of enantiomer (IX) is then performed by reaction of (VIII) with the acid chloride derived from (1R)-(+)-camphanic acid, separation of diastereoisomers by chromatography and hydrolysis with K2CO3 in MeOH. Treatment of (IX) with diethylaminosulfur trifluoride (DAST) in EtOAc induces a regiospecific and enantioselective rearrangement affording 3-(3-indolyl)-4-fluoropiperidine (X), which is finally converted into the desired compound by deprotection with formic acid and Pd/C.

参考文献 中间体
合成目标
【1】 Rowley, M.; et al.; 3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT2A receptor antagonists. J Med Chem 2001, 44, 10, 1603.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
50178 7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride C9H11ClO3 详情 详情
(I) 50173 5-fluoro-2-iodoaniline; 5-fluoro-2-iodophenylamine C6H5FIN 详情 详情
(II) 20597 1-ethynylbenzene 536-74-3 C8H6 详情 详情
(III) 50174 6-fluoro-2-phenyl-1H-indole C14H10FN 详情 详情
(IV) 27115 4-piperidinone 40064-34-4 C5H9NO 详情 详情
(V) 50175 6-fluoro-2-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole C19H17FN2 详情 详情
(VI) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VII) 50176 benzyl 4-[2-(1,2,3,5-cyclohexatetraen-1-yl)-6-fluoro-1H-indol-3-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate C27H21FN2O2 详情 详情
(VIII) 50177 benzyl 4-(6-fluoro-2-phenyl-1H-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate C27H25FN2O3 详情 详情
(IX) 50179 benzyl (3S,4S)-4-(6-fluoro-2-phenyl-1H-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate C27H25FN2O3 详情 详情
(X) 50180 benzyl (3R,4R)-4-fluoro-3-(6-fluoro-2-phenyl-1H-indol-3-yl)-1-piperidinecarboxylate C27H24F2N2O2 详情 详情

合成路线57

该中间体在本合成路线中的序号：(IV)

o-Fluoronitrobenzene (I) is converted into (III) by an aromatic nucleophilic substitution with N-Ac-Cysteine (II) in EtOH in the presence of NaHCO3. Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and in the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (Scheme 28946801a).

参考文献 中间体
合成目标
【1】 Slade, J.; Mazzegna, G.C.; Ben-David, D.; Stanton, J.L.; Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives. J Med Chem 1985, 28, 1517-1521.
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) 13463 o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene 1493-27-2 C6H4FNO2 详情 详情
(II) 39365 (2S)-2-(acetamido)-3-sulfanylpropionic acid 616-91-1 C5H9NO3S 详情 详情
(III) 43244 (2S)-2-(acetamido)-3-[(2-nitrophenyl)sulfanyl]propionic acid C11H12N2O5S 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 43245 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-nitrophenyl)sulfanyl]propionic acid C17H16N2O6S 详情 详情
(VI) 43246 (2S)-3-[(2-aminophenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid C17H18N2O4S 详情 详情
(VII) 43247 benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate C17H16N2O3S 详情 详情
(VIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IX) 43248 ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C21H22N2O5S 详情 详情

合成路线58

该中间体在本合成路线中的序号：(IV)

Aromatic nucleophilic substitution of o-fluoronitrobenzene (I) with N-Ac-cysteine (II) in EtOH in the presence of NaHCO3 yields (III). Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (1) (Scheme 28947001a). Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in AcOH, followed by introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH, Boc-Gly-OH, Boc-Hyp-OH, Boc-Pro-OH, Boc Arg(Tos)-OH, Boc-Lys(COOCH2Ph)-OH (x2)) with BOP/DIEA, providing derivative (XIV), which is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole (2,3) (Scheme 28947001[b-d]).

参考文献 中间体
合成目标
【1】 Slade, J.; Mazzegna, G.C.; Ben-David, D.; Stanton, J.L.; Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives. J Med Chem 1985, 28, 1517-1521.
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) 13463 o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene 1493-27-2 C6H4FNO2 详情 详情
(II) 39365 (2S)-2-(acetamido)-3-sulfanylpropionic acid 616-91-1 C5H9NO3S 详情 详情
(III) 43244 (2S)-2-(acetamido)-3-[(2-nitrophenyl)sulfanyl]propionic acid C11H12N2O5S 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 43245 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-nitrophenyl)sulfanyl]propionic acid C17H16N2O6S 详情 详情
(VI) 43246 (2S)-3-[(2-aminophenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid C17H18N2O4S 详情 详情
(VII) 43247 benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate C17H16N2O3S 详情 详情
(VIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IX) 43248 ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C21H22N2O5S 详情 详情

合成路线59

该中间体在本合成路线中的序号：(XVII)

The reaction of D-methionine (XIV) with Boc2O in dioxane gives the N-protected methionine (XV), which is treated with Boc2O, pyridine and ammonium bicarbonate to yield the methioninamide (XVI). The reaction of (XVI) with benzyl chloroformate (XVII) by means of BuLi in DMF/pyridine affords the carbamate (XVIII), which is treated with methyl iodide in acetone to provide the sulfonium salt (XIX). The cyclization of (XIX) by means of Dowex 2XB-400 (OH form) in acetonitrile gives the N-protected pyrrolidinone (XX), which is deprotected with HCl in dioxane to yield the amino compound (XXI). Finally, this compound is acylated with methyl trifluoroacetate (XXII) and NMM in dichloromethane to afford the target pyrrolidinone intermediate (XXIII).

参考文献 中间体
合成目标
【1】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 26695 D-methionine 348-67-4 C5H11NO2S 详情 详情
(XV) 26710 (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid 5241-66-7 C10H19NO4S 详情 详情
(XVI) 26696 tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate C10H20N2O3S 详情 详情
(XVII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(XVIII) 26697 benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate C18H26N2O5S 详情 详情
(XIX) 26698 [(3R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide C19H29IN2O5S 详情 详情
(XX) 26699 benzyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate C17H22N2O5 详情 详情
(XXI) 47798 benzyl (3R)-3-amino-2-oxo-1-pyrrolidinecarboxylate C12H14N2O3 详情 详情
(XXII) 47799 Methyl trifluoroacetate; Trifluoroacetic acid methyl ester; methyl 2,2,2-trifluoroacetate 431-47-0 C3H3F3O2 详情 详情
(XXIII) 26700 benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate C14H13F3N2O4 详情 详情

合成路线60

该中间体在本合成路线中的序号：

The antibacterial activity of RBx-7644 is due to the 5(S)-acetamidomethyl configuration at the oxazolidinone ring, and thus, asymmetric synthesis of only the 5(S)-enantiomer was desirable: 3,4-Difluoronitrobenzene (I) is condensed with piperazine in acetonitrile to give 4-(2-fluoro-4-nitrophenyl)-piperazine (II) as a light yellow compound. Compound (II) is dissolved in dichloromethane and triethylamine, followed by the addition of Boc-anhydride, to provide compound (III). 4-(tert-Butoxycarbonyl)-1-(2-fluoro-4-nitrophenyl)piperazine (III), upon hydrogenation with H2 over Pd/C in methanol at 50 psi, yields 4-(tert-butoxycarbonyl)-1-(2-fluoro-4-aminophenyl)piperazine (IV) as a dark solid. Compound (IV) reacts with benzylchloroformate in dry THF in the presence of solid sodium bicarbonate to afford the desired compound (V). 4-(tert-Butoxycarbonyl)-1-[2-fluoro-4-(benzyloxycarbonylamino)phenyl]piperazine (V), upon treatment with n-BuLi and (R)-glycidyl butyrate at -78 °C, gives the desired (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone (VI). The hydroxymethyl compound (VI) is treated with methanesulfonyl chloride in dichloromethane in the presence of triethylamine to give (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(methylsulfonyloxymethyl)-2-oxazolidinone (VII). The sulfonyl derivative (VII) is treated with sodium azide in dimethylformamide to provide the azide (VIII) as a white solid. (R)-(-)-3-[3-Fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl]-5-(azidomethyl)-2-oxazolidinone (VIII), upon hydrogenation with H2 over Pd/C at 45 psi, gives (S)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)-piperazin-1-yl]phenyl]-5-(aminomethyl)-2-oxazolidinone (IX). The aminomethyl compound (IX), upon treatment with acetic anhydride in dichloromethane in the presence of triethylamine, affords the acetamide derivative (X). The acetamidomethyl-oxazolidinone derivative (X), upon treatment with trifluoroacetic acid, gives (S)-(-)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-5-(acetamidomethyl)-2-oxazolidinone, which, without isolation, is treated with 5-nitro-2-furaldehyde in the presence of sodium triacetoxy borohydride to provide compound (XI). Compound (XI), upon treatment with ethanolic HCl, affords RBx-7644 as a light yellow crystalline solid.

参考文献 中间体
合成目标
【1】 Rattan, A.; RBx-7644. Drugs Fut 2003, 28, 11, 1070.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
51375 5-Nitro-2-furaldehyde; 5-Nitrofurfural 698-63-5 C5H3NO4 详情 详情
(I) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 18382 1-(2-fluoro-4-nitrophenyl)piperazine C10H12FN3O2 详情 详情
(III) 63060 tert-butyl 4-(2-fluoro-4-nitrophenyl)-1-piperazinecarboxylate C15H20FN3O4 详情 详情
(IV) 63061 tert-butyl 4-(4-amino-2-fluorophenyl)-1-piperazinecarboxylate C15H22FN3O2 详情 详情
(V) 63062 tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)-1-piperazinecarboxylate C23H28FN3O4 详情 详情
(VI) 63063 tert-butyl 4-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-piperazinecarboxylate C19H26FN3O5 详情 详情
(VII) 63064 tert-butyl 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-1,3-oxazolidin-3-yl)phenyl]-1-piperazinecarboxylate C20H28FN3O7S 详情 详情
(X) 63067 tert-butyl 4-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl)-1-piperazinecarboxylate C21H29FN4O5 详情 详情
(XI) 63068 N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]-1-piperazinyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C21H24FN5O6 详情 详情

合成路线61

该中间体在本合成路线中的序号：(XIX)

The condensation of 1,3,5-tribromobenzene (VII) with benzaldehyde (VIII) by means of BuLi in ethyl ether gives 3,5-dibromodiphenylmethanol (IX), which is reduced with Tes-H and BF3/Et2O to yield 3,5-dibromodiphenylmethane (X). The carbonylation of (X) with BuLi and DMF in THF affords the benzaldehyde (XI), which is reduced by means of NaBH4 in methanol to provide the benzyl alcohol (XII). The reaction of (XII) with CBr4 and PPh3 in dichloromethane gives the bromomethyl derivative (XIII), which is condensed with 1,3-propanesultam (XIV) by means of K2CO3 in refluxing acetonitrile to yield the adduct (XV). The reaction of (XV) with thalium acetate and palladium acetate in DMF affords the acetyl derivative (XVI), which is brominated with Br2 and AlCl3 in dioxane to provide the bromoacetyl compound (XVII). The condensation of (XVII) with the intermediate amine (VI) by means of TEA in acetonitrile gives the secondary amine (XVIII), which is protected with benzyl chloroformate (XIX) to yield the carbamate (XX). The carboxylation of (XX) by means of CO, EtOH, TEA and PdCl2(PPh3)2 in ethyl acetate affords the pyridine-2-carboxylate derivative (XXI), which is finally cyclized by means of NaOMe in THF to provide the target naphthyridine derivative.

参考文献 中间体
合成目标
【1】 Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J Med Chem 2003, 46, 4, 453.
【2】 Young, S.D.; Guare, J.P.; Wai, J.S.; Payne, L.S.; Fisher, T.E.; Zhuang, L.; Embrey, M. (Merck & Co., Inc.); Aza- and polyaza-naphthalenyl ketones useful as HIV integrase inhibitors. WO 0236734 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 61832 (2-chloro-3-pyridinyl)methanamine; (2-chloro-3-pyridinyl)methylamine C6H7ClN2 详情 详情
(VII) 26991 1,3,5-tribromobenzene 626-39-1 C6H3Br3 详情 详情
(VIII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IX) 61833 (3,5-dibromophenyl)(phenyl)methanol C13H10Br2O 详情 详情
(X) 61834 1-benzyl-3,5-dibromobenzene C13H10Br2 详情 详情
(XI) 61835 3-benzyl-5-bromobenzaldehyde C14H11BrO 详情 详情
(XII) 61836 (3-benzyl-5-bromophenyl)methanol C14H13BrO 详情 详情
(XIII) 61837 1-benzyl-3-bromo-5-(bromomethyl)benzene C14H12Br2 详情 详情
(XIV) 61838 1lambda~6~-isothiazolidine-1,1-dione C3H7NO2S 详情 详情
(XV) 61839 2-(3-benzyl-5-bromobenzyl)-1lambda~6~-isothiazolidine-1,1-dione C17H18BrNO2S 详情 详情
(XVI) 61840 2-(3-acetyl-5-benzylbenzyl)-1lambda~6~-isothiazolidine-1,1-dione C19H21NO3S 详情 详情
(XVII) 61841 2-[3-benzyl-5-(2-bromoacetyl)benzyl]-1lambda~6~-isothiazolidine-1,1-dione C19H20BrNO3S 详情 详情
(XVIII) 61842 2-[3-benzyl-5-(2-{[(2-chloro-3-pyridinyl)methyl]amino}acetyl)benzyl]-1lambda~6~-isothiazolidine-1,1-dione C25H26ClN3O3S 详情 详情
(XIX) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(XX) 61843 benzyl 2-{3-benzyl-5-[(1,1-dioxo-1lambda~6~-isothiazolidin-2-yl)methyl]phenyl}-2-oxoethyl[(2-chloro-3-pyridinyl)methyl]carbamate C33H32ClN3O5S 详情 详情
(XXI) 61844 ethyl 3-({(2-{3-benzyl-5-[(1,1-dioxo-1lambda~6~-isothiazolidin-2-yl)methyl]phenyl}-2-oxoethyl)[(benzyloxy)carbonyl]amino}methyl)-2-pyridinecarboxylate C36H37N3O7S 详情 详情

合成路线62

该中间体在本合成路线中的序号：(IV)

Substitution of 1,2-difluoro-4-nitrobenzene (I) with benzyl alcohol in the presence of KOH in CH2Cl2 gives 1-benzyloxy-2-fluoro-4-nitrobenzene (II), which is reduced to 4-benzyloxy-3-fluoroaniline (III) by means of H2 and Pt/C in EtOAc. Condensation of aniline (III) with benzyl chloroformate (IV) in the presence of NaHCO3 in acetone/H2O affords carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) using BuLi in THF at –60 °C to provide the oxazolidinone derivative (VII) . Debenzylation of compound (VII) with H2 over Pd/C in THF/MeOH produces alcohol (VIII), which is condensed with epoxide (IX) in the presence of Na2CO3 in DMF at 100 °C to obtain the corresponding ether (X). N-Deprotection of intermediate (X) by means of H2 over Pd/C in EtOAc/MeOH gives the piperidine derivative (XI), which is finally condensed with the quinolone boron chelate (XII) —prepared by reaction of the quinolone ester (XIII) with B(OH)3 and AcOH in the presence of ZnCl2 at 110 °C — using DIEA in NMP at 85 °C .

参考文献 中间体
合成目标
【1】 Hermecz, I., Kereszturi, g., Vasvari, L. et al. (Chinoin Zrt). Quinoline carboxylic acid boric acid anhydrides and process for the preparation thereof. CN 88101941, EP 0310647, JP 1989003300, US 4940794, WO 1988007998.
【2】 Hubschwerlen, C., Panchaud, P., Specklin, J.-L. (Actelion Pharmaceuticals, Ltd.). 5-Hydroxymethyl-oxazolidin-2-one derivatives. CN 102014903, EP 2086968, JP 2010509314, JP 2010132677, KR 2010137569, US 2009247578, US 8124623, WO 2008056335.
【3】 Hubschwerlen, C., Locher, H. (Actelion Pharmaceuticals, Ltd.). 5-Hydroxymethyl-oxazolidin-2-one derivatives for treating bacterial intestinal diseases. EP 2296651, JP 2011519914, WO 2009136379.
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) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 67754 1-benzyloxy-2-fluoro-4-nitrobenzene;1-(benzyloxy)-2-fluoro-4-nitrobenzene 　 C13H10FNO3 详情 详情
(III) 67755 4-benzyloxy-3-fluoroaniline 　 C13H12FNO 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 67756 benzyl (4-(benzyloxy)-3-fluorophenyl)carbamate 　 C21H18FNO3 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 67757 (R)-3-(4-(benzyloxy)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one 　 C17H16FNO4 详情 详情
(VIII) 67758 (R)-3-(3-fluoro-4-hydroxyphenyl)-5-(hydroxymethyl)oxazolidin-2-one 　 C10H10FNO4 详情 详情
(IX) 67759 benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate 　 C14H17NO3 详情 详情
(X) 67760 (R)-benzyl 4-((2-fluoro-4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxypiperidine-1-carboxylate 　　 C24H27FN2O7 详情 详情
(XI) 67761 (R)-3-(3-fluoro-4-((4-hydroxypiperidin-4-yl)methoxy)phenyl)-5-(hydroxymethyl)oxazolidin-2-one 　 C16H21FN2O5 详情 详情
(XII) 67762 　 　 C17H14BClFNO7 详情 详情
(XIII) 30340 ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate 86483-54-7 C15H13ClFNO3 详情 详情

合成路线63

该中间体在本合成路线中的序号：(V)

Condensation of 1,2-difluoro-4-nitrobenzene (I) with thiomorpholine (II) using DIEA in refluxing acetonitrile at 85 °C yields 4-(2-fluoro-4-nitrophenyl)thiomorpholine (III) , which is then reduced by means of either Na2S2O4 in THF , Fe in the presence of NH4Cl in refluxing H2O/EtOH/dioxane , or by catalytic hydrogenation over Raney-Ni in THF/H2O (1) or sulfided Pd/C in MeOH , providing 3-fluoro-4-thiomorpholin-4-ylaniline (IV) . Acylation of amine (IV) with benzyl chloroformate (V), optionally in the presence of DMA , in THF affords carbamate (VI) , which then cyclizes with (R)-(–)-glycidyl butyrate (VII) using BuLi in THF at –78 °C to produce the 5-(hydroxymethyl)-2-oxazolidinone derivative (VIII). Reaction of the primary alcohol (VIII) with MsCl using Et3N in CH2Cl2 or with TsCl in pyridine yields the corresponding mesylate (IXa) or tosylate (IXb) , respectively, which by substitution with NaN3 in DMF at 65-85 °C provides azide (X). Staudinger reduction of azide (X) with PPh3 in THF/H2O then yields the corresponding amine (XIa). Finally, amine (XIa) or its hydrochloride (XIb) are acylated with acetic anhydride (XII) in the presence of pyridine in CH2Cl2 or NaOH in H2O/MeOH/CH2Cl2 .

参考文献 中间体
合成目标
【1】 Barbachyn, M.R., Hutchinson, D.K., Brickner, S.J. et al. Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity. J Med Chem 1996, 39(3): 680-5.
【2】 Brickner, S.J., Barbachyn, M.R., Hutchinson, D.K. (Pfizer, Inc.). Substituted oxazine and thiazine oxazolidinone antimicrobials. US 5880118.
【3】 Barbachyn, M.R., Brickner, S.J., Hutchinson, D.K. (Pfizer, Inc.). Substituted oxazine and thiazine oxazolidinone antimicrobials. EP 0717738, JP 1997502436, US 5688792, WO 1995007271.
【4】 Brickner, S.J., Nuermberger, E., Stover, C.K. (Pfizer, Inc.). Combination therapy for tuberculosis. CN 102143748, EP 2340022, JP 20122502017, KR 2011063518, US 2011190199, WO 2010026526.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IXa) 68063 (R)-(3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate 　 C15H19FN2O5S2 详情 详情
(IXb) 68064 (R)-(3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate 　 C21H23FN2O5S2 详情 详情
(XIa) 68066 (R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one 　 C14H18FN3O2S 详情 详情
(XIb) 68067 (R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one hydrochloride 　 C14H18FN3O2S.HCl 详情 详情
(I) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 36317 thiomorpholine 123-90-0 C4H9NS 详情 详情
(III) 68060 4-(2-fluoro-4-nitrophenyl)thiomorpholine 　 C10H11FN2O2S 详情 详情
(IV) 68061 3-fluoro-4-thiomorpholinoaniline 　 C10H13FN2S 详情 详情
(V) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VI) 68062 benzyl (3-fluoro-4-thiomorpholinophenyl)carbamate 　 C18H19FN2O2S 详情 详情
(VII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VIII) 56305 (5R)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C14H17FN2O3S 详情 详情
(X) 68065 (R)-5-(azidomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one 　 C14H16FN5O2S 详情 详情
(XII) 49701 Acetic anhydride; Acetyl oxide 108-24-7 C4H6O3 详情 详情
Extended Information