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【结 构 式】

【分子编号】12893

【品名】Ethanethioic S-acid

【CA登记号】

【 分 子 式 】C2H4OS

【 分 子 量 】76.11916

【元素组成】C 31.56% H 5.3% O 21.02% S 42.13%
与该中间体有关的原料药合成路线共 15 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

该中间体在本合成路线中的序号：(IX)

It is prepared by hydrolysis with ammonia in methanol of N-(3-acetylthio-2-methylpropanoyl)-L-proline (I). Compound (I) can be obtained in three different ways: 1) The reaction of L-proline tert-butyl ester (II) with 3-acetylthio-2-methyl-propanoic acid (III) by means of dicyclohexylcarbodiimide in CH2Cl2 gives N-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester (IV), which is hydrolyzed with trifluoroacetic acid in anisole. 2) By condensation of L-proline (V) with 3-acetylthio-2-methylpropanoyl chloride (VI) (prepared from the corresponding acid (III) with SOCl2) by means of NaOH in water. 3) The condensation of L-proline (V) with methacryloyl chloride (VII) by means of NaHCO3 in water yields N-methacryloyl-L-proline (VIII), which is then treated with thiolacetic acid (A) and azobisisobutyronitrile. The acid (III) is obtained by addition of thiolacetic acid (IX) to methacrylic acid (X) at 100 C.

参考文献 中间体
合成目标
【1】 Cushman, D.W.; Ondetti, M.A.; Azetidine-2-carboxylic acid derivatives. BE 0851361; DD 283999; JP 58189113; JP 58189158; US 4046889; US 4154840 .
【2】 Roberts, P.J.; Castaner, J.; Captopril. Drugs Fut 1978, 3, 11, 795.
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) 33555 Thiolacetic acid; Thioacetic acid; ethanethioic O-acid; Ethanethioic acid 507-09-5 C2H4OS 详情 详情
(I) 33552 (2S)-1-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid 65167-28-4 C11H17NO4S 详情 详情
(II) 19832 tert-butyl (2S)-2-pyrrolidinecarboxylate C9H17NO2 详情 详情
(III) 33556 3-(acetylsulfanyl)-2-methylpropionic acid C6H10O3S 详情 详情
(IV) 33551 tert-butyl (2S)-1-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]-2-pyrrolidinecarboxylate C15H25NO4S 详情 详情
(V) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(VI) 33557 S-(3-chloro-2-methyl-3-oxopropyl) ethanethioate C6H9ClO2S 详情 详情
(VII) 33553 2-methylacryloyl chloride 920-46-7 C4H5ClO 详情 详情
(VIII) 33554 (2S)-1-methacryloyl-2-pyrrolidinecarboxylic acid C9H13NO3 详情 详情
(IX) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(X) 33550 2-methylacrylic acid 79-41-4 C4H6O2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(C)

Condensation of 3,4,5-trichloro nitrobenzene (I) with 4-chlorobenzeneacetonitrile (II) by means of NaOH and N,N,N-triethylbenzylammonium chloride in THF yields substituted nitrobenzeneacetonitrile (III), which is subjected to hydrogenation over Pt/C in MeOH in the presence of thiophene to provide aniline (IV). Treatment of (IV) with HCl, HOAc and NaNO2, followed by reaction with ethyl N-(2-cyanoacetyl) carbamate (V) in AcOEt, furnishes ethyl carbamate derivative (VI), which is then subjected to cyclization by means of KOAc in refluxing HOAc to yield perhydro-3,5-dioxo-1,2,4-triazine derivative (VII). Hydrolysis of the nitrile moiety of (VII) by treatment with HCl in refluxing HOAc gives carboxylic acid (VIII), which is finally decarboxylated by heating in 2-mercaptoacetic acid to provide the desired product.

参考文献 中间体
合成目标
【1】 Boeckx, G.M.; Sipido, V.; Raeymaekers, A.H.M. (Janssen Pharmaceutica NV); alpha-Aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitriles. AU 8545664; EP 0170316; ES 8609284; ES 8705403; JP 1986043176; JP 1993017454; US 4631278 .
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) 13297 Thiophene 110-02-1 C4H4S 详情 详情
(A) 48246 N-benzyl-N,N-dipropyl-1-propanaminium chloride C16H28ClN 详情 详情
(I) 48245 1,2,3-trichloro-5-nitrobenzene 20098-48-0 C6H2Cl3NO2 详情 详情
(II) 22871 2-(4-chlorophenyl)acetonitrile 140-53-4 C8H6ClN 详情 详情
(III) 48247 2-(4-chlorophenyl)-2-(2,6-dichloro-4-nitrophenyl)acetonitrile C14H7Cl3N2O2 详情 详情
(IV) 48248 2-(4-amino-2,6-dichlorophenyl)-2-(4-chlorophenyl)acetonitrile C14H9Cl3N2 详情 详情
(V) 48249 ethyl 2-cyanoacetylcarbamate C6H8N2O3 详情 详情
(VI) 48250 ethyl 2-cyano-2-((Z)-2-[3,5-dichloro-4-[(4-chlorophenyl)(cyano)methyl]phenyl]hydrazono)acetylcarbamate C20H14Cl3N5O3 详情 详情
(VII) 48251 2-[3,5-dichloro-4-[(4-chlorophenyl)(cyano)methyl]phenyl]-3,5-dioxo-1,2,4-triazinane-6-carbonitrile C18H10Cl3N5O2 详情 详情
(VIII) 48252 2-[3,5-dichloro-4-[(4-chlorophenyl)(cyano)methyl]phenyl]-3,5-dioxo-1,2,4-triazinane-6-carboxylic acid C18H11Cl3N4O4 详情 详情
(C) 12893 Ethanethioic S-acid C2H4OS 详情 详情

合成路线3

该中间体在本合成路线中的序号：

The mercaptopyrrolidine (XIII) is prepared as follows: trans-4-hydroxy-L-proline (XV) is protected with 4-nitrobenzyl chloride (XVI) giving trans 4-hydroxy-N-(4-nitrobenzyloxycarbonyl)-L-proline (XVII), which is esterified with 4-methoxy benzyl chloride (XVIII) to the corresponding ester (XIX). The reaction of (XIX) with thioacetic acid by means of diethyl azodicarboxylate arid triphenyl-phosphine in THF affords the 4-acetylthio derivative (XX), which is partially hydrolyzed with trifluoroacetic acid and anisole to 4beta-(acetylthio)-N-(4-nitrobenzyloxycarbonyl)pyrrolidine-2beta-carboxylic acid (XXI). The condensation of (XXI) with dimethylamine by means of dicyclohexylcarbodiimide (DCC) gives the fully protected dimethylamide (XXII), which is deacetylated with NaOH in water to atford the desired product (XIII).

参考文献 中间体
合成目标
【1】 Fukasawa, M.; Inoue, T.; Kato, M.; Matsumura, H.; Sunagawa, M. (Sumitomo Pharmaceuticals Co., Ltd.); Thiopyrrolidinyl-beta-lactam derivs.. EP 0126587; ES 8600305; JP 1985001186; JP 1985019787; JP 1991041066; US 4933333; US 4943569; US 5122604 .
【2】 Prous, J.; Castaner, J.; SM-7338. Drugs Fut 1988, 13, 6, 534.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12893 Ethanethioic S-acid C2H4OS 详情 详情
(XIII) 22578 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate C15H19N3O5S 详情 详情
(XV) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(XVI) 22580 1-(chloromethyl)-4-nitrobenzene 100-14-1 C7H6ClNO2 详情 详情
(XVII) 22581 (2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid C13H14N2O7 详情 详情
(XVIII) 11910 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether 824-94-2 C8H9ClO 详情 详情
(XIX) 22583 2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate C21H22N2O8 详情 详情
(XX) 22584 2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4S)-4-(acetylsulfanyl)-1,2-pyrrolidinedicarboxylate C23H24N2O8S 详情 详情
(XXI) 18241 (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid C15H16N2O7S 详情 详情
(XXII) 22586 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(dimethylamino)carbonyl]-1-pyrrolidinecarboxylate C17H21N3O6S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(IV)

The Friedel-Crafts condensation of toluene (I) with itaconic anhydride (2-methylenesuccinic anhydride) (II) by means of AlCl3 in methylene chloride or 1,2-dichloroethane gives 3-(4-methylbenzoyl)-2-methylenepropionic acid (III), which is then treated with thioacetic acid (IV) and K2CO3 in DMF/water.

参考文献 中间体
合成目标
【1】 Onodera, A.; Tomisawa, K.; Noguchi, T.; Yokomori, S.; A practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, an antirheumatic agent (Part 1). Chem Pharm Bull 2002, 50, 10, 1407.
【2】 Mealy, N.; Castaner, J.; KE-298. Drugs Fut 1996, 21, 7, 691.
【3】 Tomisawa, K.; Kameo, K.; Matsunaga, T.; Saito, S.; Sota, K. (Taisho Pharmaceutical Co., Ltd.); Benzoylpropionic acid derivs., their use and pharmaceutical compsns. EP 0164101; ES 8603818; JP 1985258160 .
【4】 Tomisawa, K.; Kameo, K.; Matsunaga, Y.; Saito, H.; Sodu, H. (Taisho Pharmaceutical Co., Ltd.); 2-Acylthiomethyl-3-benzoylpropionic acid derivs. JP 1987132825 .
【5】 Kameo, K.; Ogawa, K.; Takeshita, K.; Nakaike, S.; Tomisawa, K.; Sota, K.; Studies on antirheumatic agents: 3-Benzoylpropionic acid derivatives. Chem Pharm Bull 1988, 36, 6, 2050-60.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12890 Toluene 108-88-3 C7H8 详情 详情
(II) 12891 3-Methylenedihydro-2,5-furandione; Itaconic anhydride 2170-03-8 C5H4O3 详情 详情
(III) 12892 2-[2-(4-Methylphenyl)-2-oxoethyl]acrylic acid C12H12O3 详情 详情
(IV) 12893 Ethanethioic S-acid C2H4OS 详情 详情

合成路线5

该中间体在本合成路线中的序号：(V)

The reaction of 2-benzylacrylic acid (I) with SOCl2 in hot toluene gives the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) by means of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 C to afford the target acylthio compound.

参考文献 中间体
合成目标
【1】 Schwartz, J.-C.; Lecomte, J.-M.; Duhamel, P.; Duhamel, L.; Danvy, D.; Plaquevent, J.-C.; Monteil, T.; Piettre, S. (Societe Civile Bioprojet); Process for synthesizing N-(mercaptoacyl)amino acid derivs. from alpha-substd. acrylic acids. FR 2816309; US 2002055645 .
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) 37279 2-benzylacrylic acid C10H10O2 详情 详情
(II) 55227 2-benzylacryloyl chloride C10H9ClO 详情 详情
(III) 55228 N-p-Tosylglycine benzyl ester C16H17NO4S 详情 详情
(IV) 55229 benzyl 2-[(2-benzylacryloyl)amino]acetate C19H19NO3 详情 详情
(V) 12893 Ethanethioic S-acid C2H4OS 详情 详情

合成路线6

该中间体在本合成路线中的序号：(V)

Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.

参考文献 中间体
合成目标
【1】 Roques, B.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs. and their therapeutic application. EP 0038758 .
【2】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 .
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) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(VI) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(VII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VIII) 49460 Dimethyl benzylidenemalonate C12H12O4 详情 详情
(IX) 49461 dimethyl 2-benzylmalonate C12H14O4 详情 详情
(X) 37280 2-benzylmalonic acid 616-75-1 C10H10O4 详情 详情
(XI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XII) 37482 diethyl 2-benzylidenemalonate 5292-53-5 C14H16O4 详情 详情
(XIII) 20208 diethyl 2-benzylmalonate 607-81-8 C14H18O4 详情 详情
(XIV) 37279 2-benzylacrylic acid C10H10O2 详情 详情
(XV) 55230 3-(acetylsulfanyl)-2-benzylpropanoic acid C12H14O3S 详情 详情
(XVI) 55228 N-p-Tosylglycine benzyl ester C16H17NO4S 详情 详情

合成路线7

该中间体在本合成路线中的序号：

Swern oxidation of protected (hydroxymethyl)pyrrolidine (I), followed by Wittig condensation of the resulting aldehyde (II) with methylene triphenylphosphorane provided vinylpyrrolidine (III). Hydroboration of (III) with 9-borabicyclo[3.3.1]nonane and subsequent oxidative treatment with sodium perborate gave alcohol (IV). Interconversion of the N-benzyl protecting group for an allyloxycarbonyl group was achieved by catalytic hydrogenation and then treatment of the deprotected amine (V) with allyloxycarbonyl chloride (VI). Alcohol (VII) was activated as the corresponding mesylate (VIII), which was condensed with imidazole (IX) in the presence of t-BuOK to afford the N-alkylated imidazole (X). Acid deprotection of the silyl ether of (X) yielded the corresponding secondary alcohol, which was further converted to mesylate (XI). Subsequent displacement in (XI) by potassium thioacetate furnished the thioacetate ester (XII).

参考文献 中间体
合成目标
【1】 Barrett, D.; Azami, H.; Matsuda, K.; et al.; Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems. Part III: Novel 2-alkyl substituents containing cationic heteroaromatics linked via a C-N bond. Bioorg Med Chem 1999, 7, 8, 1665.
【2】 Murata, M.; Tsutsumi, H.; Matsuda, K.; Hattori, K.; Nakajima, T. (Fujisawa Pharmaceutical Co., Ltd.); Substd. 3-pyrrolidinylthio-carbapenems as antimicrobial agents. EP 0636133; JP 1995505650; WO 9321186 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12893 Ethanethioic S-acid C2H4OS 详情 详情
38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情
(I) 32605 ((2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)methanol C18H31NO2Si 详情 详情
(II) 32606 (2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinecarbaldehyde C18H29NO2Si 详情 详情
(III) 32607 (2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]-2-vinylpyrrolidine; (3S,5S)-1-benzyl-5-vinylpyrrolidinyl tert-butyl(dimethyl)silyl ether C19H31NOSi 详情 详情
(IV) 32608 2-((2R,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)-1-ethanol C19H33NO2Si 详情 详情
(V) 32609 2-((2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)-1-ethanol C12H27NO2Si 详情 详情
(VII) 32610 allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate C16H31NO4Si 详情 详情
(VIII) 32611 allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-[(methylsulfonyl)oxy]ethyl]-1-pyrrolidinecarboxylate C17H33NO6SSi 详情 详情
(IX) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情
(X) 32612 allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-(1H-imidazol-1-yl)ethyl]-1-pyrrolidinecarboxylate C19H33N3O3Si 详情 详情
(XI) 32613 allyl (2R,4S)-2-[2-(1H-imidazol-1-yl)ethyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C14H21N3O5S 详情 详情
(XII) 31614 (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid C21H36ClNO5 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

Treatment of D-homo-17-oxaandrosta-1,4,6-triene-3,17a-dione (I) with refluxing thioacetic acid (II) yields either 7-alpha-(acetylthio) derivative (III) or 1alpha,7alpha-bis(acetylthio) derivative (IV). The desired product can then be obtained either by treatment of (III) with NaOH in THF or by reaction of (IV) with sodium methylate in methanol.

参考文献 中间体
合成目标
【1】 Koizumi, N.; Takegawa, S.; Iwashita, S.; Kawachi, T.; Inoue, F.; Honma, S.; Takahashi, H.; Mieda, M.; Ueda, K.; Shibata, K. (Teikoku Hormone Manufacturing Co., Ltd.); Novel 7-substd. oxa- or azasteroid cpd.. EP 0663402; JP 1994508897; US 5539127; WO 9407908 .
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) 46697 (4aS,4bR,10aS,10bS,12aS)-10a,12a-dimethyl-3,4,4a,10a,10b,11,12,12a-octahydro-1H-naphtho[2,1-f]isochromene-1,8(4bH)-dione C19H22O3 详情 详情
(II) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(III) 46698 S-[(4aS,4bR,5R,10aR,10bS,12aS)-10a,12a-dimethyl-1,8-dioxo-3,4,4a,4b,5,6,8,10a,10b,11,12,12a-dodecahydro-1H-naphtho[2,1-f]isochromen-5-yl] ethanethioate C21H26O4S 详情 详情
(IV) 46699 S-[(4aS,4bS,5R,10S,10aR,10bS,12aS)-10-(acetylsulfanyl)-10a,12a-dimethyl-1,8-dioxo-3,4,4a,4b,5,6,8,9,10,10a,10b,11,12,12a-tetradecahydro-1H-naphtho[2,1-f]isochromen-5-yl] ethanethioate C23H30O5S2 详情 详情

合成路线9

该中间体在本合成路线中的序号：

Halogenation of allylamine (I) with either bromine or sulfuryl chloride produced the corresponding (halomethyl)aziridines (II). Subsequent treatment of (II) with n-butyllithium at -78 C yielded 1-azabicyclobutane (III). Opening of the bicyclic system of (III) with formic acid followed by acid hydrolysis provided 3-hydroxyazetidine (IV). This was condensed with 2-(methylsulfanyl)thiazoline (V) to give thiazolinylazetidine (VI). Alternatively, 3-hydroxyazetidine (IV) was condensed with 2-chloroethyl isothiocyanate (VII) to give the intermediate thiourea (VIII), which cyclized to the thiazoline (VI). Conversion of the hydroxyl group of (VI) into the thioacetate (IX) was carried out by either coupling with thioacetic acid under Mitsunobu conditions or by conversion to mesylate (X) followed by displacement with potassium thioacetate. The required thiol (XI) was then obtained from (IX) by basic hydrolysis of the thioacetate ester.

参考文献 中间体
合成目标
【1】 Satoh, C.; Mihira, A.; Yamamoto, S.; Hayashi, K.; Kitamura, M.; Tamai, S.; Abe, T.; Kumagai, T.; Hikida, M.; L-084, a new oral carbapenem: Synthesis and structure-activity relationships of C2-substituted 1beta-methylcarbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-64.
【2】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 .
【3】 Abe, T.; Kumagai, T. (Lederle (Japan), Ltd.); Carbapenem-3-carboxylic acid ester derivs.. EP 0808315; JP 1999504039; US 5886172; WO 9721712 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12893 Ethanethioic S-acid C2H4OS 详情 详情
17190 potassium ethanethioate 10387-40-3 C2H3KOS 详情 详情
(IIa) 31394 2-(chloromethyl)aziridine C3H6ClN 详情 详情
(IIb) 31395 2-(bromomethyl)aziridine C3H6BrN 详情 详情
(I) 13672 Allylamine; 2-Propen-1-amine 107-11-9 C3H7N 详情 详情
(III) 31396 1-azabicyclo[1.1.0]butane C3H5N 详情 详情
(IV) 31397 3-azetidinol C3H7NO 详情 详情
(V) 31398 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole; 4,5-dihydro-1,3-thiazol-2-yl methyl sulfide 19975-56-5 C4H7NS2 详情 详情
(VI) 31399 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinol C6H10N2OS 详情 详情
(VII) 31400 2-chloroethyl isothiocyanate; 1-chloro-2-isothiocyanatoethane 6099-88-3 C3H4ClNS 详情 详情
(VIII) 31401 N-(2-chloroethyl)-3-hydroxy-1-azetidinecarbothioamide C6H11ClN2OS 详情 详情
(IX) 31402 S-[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl] ethanethioate C8H12N2OS2 详情 详情
(X) 31403 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl methanesulfonate C7H12N2O3S2 详情 详情
(XI) 31404 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol 179337-57-6 C6H10N2S2 详情 详情

合成路线10

该中间体在本合成路线中的序号：

1-azabicyclobutane (III) was opened with thioacetic acid with concomitant N-acetylation yielding (XII). Further acid hydrolysis of (XII) gave 3-mercaptoazetidine (XIII). Condensation of (XIII) with either 2-(methylthio)thiazoline (V) or 2-chloroethyl isothiocyanate (VII) then produced thiazolinylazetidine (XI).

参考文献 中间体
合成目标
【1】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12893 Ethanethioic S-acid C2H4OS 详情 详情
(III) 31396 1-azabicyclo[1.1.0]butane C3H5N 详情 详情
(V) 31398 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole; 4,5-dihydro-1,3-thiazol-2-yl methyl sulfide 19975-56-5 C4H7NS2 详情 详情
(VII) 31400 2-chloroethyl isothiocyanate; 1-chloro-2-isothiocyanatoethane 6099-88-3 C3H4ClNS 详情 详情
(XI) 31404 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol 179337-57-6 C6H10N2S2 详情 详情
(XII) 31405 S-(1-acetyl-3-azetidinyl) ethanethioate C7H11NO2S 详情 详情
(XIII) 31406 3-azetidinylhydrosulfide; 3-azetidinethiol C3H7NS 详情 详情

合成路线11

该中间体在本合成路线中的序号：

Halogenation of allylamine (I) with either bromine or sulfuryl chloride produced the corresponding (halomethyl)aziridines (II). Subsequent treatment of (II) with n-butyllithium at -78 C yielded 1-azabicyclobutane (III). Opening of the bicyclic system of (III) with formic acid followed by acid hydrolysis provided 3-hydroxyazetidine (IV). This was condensed with 2-(methylsulfanyl)thiazoline (V) to give thiazolinylazetidine (VI). Alternatively, 3-hydroxyazetidine (IV) was condensed with 2-chloroethyl isothiocyanate (VII) to give the intermediate thiourea (VIII), which cyclized to the thiazoline (VI). Conversion of the hydroxyl group of (VI) into the thioacetate (IX) was carried out by either coupling with thioacetic acid under Mitsunobu conditions or by conversion to mesylate (X) followed by displacement with potassium thioacetate. The required thiol (XI) was then obtained from (IX) by basic hydrolysis of the thioacetate ester.

参考文献 中间体
合成目标
【1】 Satoh, C.; Mihira, A.; Yamamoto, S.; Hayashi, K.; Kitamura, M.; Tamai, S.; Abe, T.; Kumagai, T.; Hikida, M.; L-084, a new oral carbapenem: Synthesis and structure-activity relationships of C2-substituted 1beta-methylcarbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-64.
【2】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 .
【3】 Abe, T.; Kumagai, T. (Lederle (Japan), Ltd.); Carbapenem-3-carboxylic acid ester derivs.. EP 0808315; JP 1999504039; US 5886172; WO 9721712 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12893 Ethanethioic S-acid C2H4OS 详情 详情
17190 potassium ethanethioate 10387-40-3 C2H3KOS 详情 详情
(IIa) 31394 2-(chloromethyl)aziridine C3H6ClN 详情 详情
(IIb) 31395 2-(bromomethyl)aziridine C3H6BrN 详情 详情
(I) 13672 Allylamine; 2-Propen-1-amine 107-11-9 C3H7N 详情 详情
(III) 31396 1-azabicyclo[1.1.0]butane C3H5N 详情 详情
(IV) 31397 3-azetidinol C3H7NO 详情 详情
(V) 31398 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole; 4,5-dihydro-1,3-thiazol-2-yl methyl sulfide 19975-56-5 C4H7NS2 详情 详情
(VI) 31399 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinol C6H10N2OS 详情 详情
(VII) 31400 2-chloroethyl isothiocyanate; 1-chloro-2-isothiocyanatoethane 6099-88-3 C3H4ClNS 详情 详情
(VIII) 31401 N-(2-chloroethyl)-3-hydroxy-1-azetidinecarbothioamide C6H11ClN2OS 详情 详情
(IX) 31402 S-[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl] ethanethioate C8H12N2OS2 详情 详情
(X) 31403 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl methanesulfonate C7H12N2O3S2 详情 详情
(XI) 31404 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol 179337-57-6 C6H10N2S2 详情 详情

合成路线12

该中间体在本合成路线中的序号：

1-azabicyclobutane (III) was opened with thioacetic acid with concomitant N-acetylation yielding (XII). Further acid hydrolysis of (XII) gave 3-mercaptoazetidine (XIII). Condensation of (XIII) with either 2-(methylthio)thiazoline (V) or 2-chloroethyl isothiocyanate (VII) then produced thiazolinylazetidine (XI).

参考文献 中间体
合成目标
【1】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12893 Ethanethioic S-acid C2H4OS 详情 详情
(III) 31396 1-azabicyclo[1.1.0]butane C3H5N 详情 详情
(V) 31398 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole; 4,5-dihydro-1,3-thiazol-2-yl methyl sulfide 19975-56-5 C4H7NS2 详情 详情
(VII) 31400 2-chloroethyl isothiocyanate; 1-chloro-2-isothiocyanatoethane 6099-88-3 C3H4ClNS 详情 详情
(XI) 31404 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol 179337-57-6 C6H10N2S2 详情 详情
(XII) 31405 S-(1-acetyl-3-azetidinyl) ethanethioate C7H11NO2S 详情 详情
(XIII) 31406 3-azetidinylhydrosulfide; 3-azetidinethiol C3H7NS 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

The acylation of 2-pyridylmethanol (I) with thioacetic acid (II) by means of Ph3P and DEAD in THF gives the corresponding thioacetate (III), which is condensed with 4-acetoxyazetidin-2-one (IV) by means of NaOH in methanol yielding 4-(2-pyridylmethylsulfanyl)azetidin-2-one (V). Finally, this compound is condensed with 1(R)-phenylethyl isocyanate (VI) by means of Et3N and DMAP in dichloromethane.

参考文献 中间体
合成目标
【1】 Deziel, R.; Malenfant, E.; Inhibition of human cytomegalovirus protease N(o) with monocyclic beta-lactams. Bioorg Med Chem Lett 1998, 8, 11, 1437.
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) 30208 2-pyridinylmethanol；pyridin-2-ylmethanol；2-pyridylmethanol 586-98-1 C6H7NO 详情 详情
(II) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(III) 30209 S-(2-pyridinylmethyl) ethanethioate C8H9NOS 详情 详情
(IV) 30210 4-oxo-2-azetidinyl acetate C5H7NO3 详情 详情
(V) 30211 4-[(2-pyridinylmethyl)sulfanyl]-2-azetidinone C9H10N2OS 详情 详情
(VI) 30212 1-[(1R)-1-isocyanatoethyl]benzene; (1R)-1-phenylethyl isocyanate 33375-06-3 C9H9NO 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VIII)

The reduction of 1-indanone (I) with NaBH4 in methanol gives 1-indanol (II), which is brominated with Tms-Br in chloroform to yield 1-bromoindane (III) (1). The condensation of (III) with triethyl phosphonoacetate (IV) and NaH in DMF affords 2-(diethoxyphosphoryl)-2-(1-indanyl)acetic acid ethyl ester (V), which is treated with paraformaldehyde and K2CO3 in refluxing THF to provide 2-(1-indanyl)acrylic acid ethyl ester (VI). The hydrolysis of (VI) with NaOH in acetone/water gives the corresponding acrylic acid (VII), which is condensed with thioacetic acid (VIII) in refluxing chloroform to yield 3-(acetylsulfanyl)-2-(1-indanyl)propionic acid ethyl ester (IX) as a mixture of the two (R,R)+(S,S) and (R,S)+(S,R) racemates. These two racemates are easily separated by HPLC affording the desired (R,R)+(S,S)-(X) racemate. The condensation of (X) with L-tryptophan methyl ester (XI) by means of EDC and HOBT in THF/chloroform to provide a diastereomeric mixture (R,R,S)+(S,S,S) of compounds that is separated by HPLC to provide the desired (R,R,S) diastereomer (XII). Finally, this compound is hydrolyzed with NaOH in methanol/water to furnish the target tryptophan derivative.

参考文献 中间体
合成目标
【1】 Inguimbert, N.; Roques, B.P.; Meudal, H.; Teffot, F.; Poras, H.; Fournié-Zaluski, M.-C.; Coric, P.; Toward an optimal joint recognition of the S1' subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP). J Med Chem 2002, 45, 7, 1477.
【2】 Roques, B.P.; Renard, P.; Scalbert, E.; Bennejean, C.; Fournie-Lazuski, M.-C.; Inguimbert, N.; Poras, H. (ADIR et Cie.; INSERM (Institut National de la Sante et de la Recherche Medicale)); Amino acid derivs. and use thereof as NEP, ACE and ECE inhibitors. FR 2805259; WO 0160822 .
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) 23857 1-indanone 83-33-0 C9H8O 详情 详情
(II) 53590 1-Hydroxyhydrindene; 1-Hydroxyindan; 1-Indanol 6351-10-6 C9H10O 详情 详情
(III) 53591 1-bromoindane n/a C9H9Br 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 53592 ethyl 2-(diethoxyphosphoryl)-2-(2,3-dihydro-1H-inden-1-yl)acetate n/a C17H25O5P 详情 详情
(VI) 53593 ethyl 2-(2,3-dihydro-1H-inden-1-yl)acrylate n/a C14H16O2 详情 详情
(VII) 53594 2-(2,3-dihydro-1H-inden-1-yl)acrylic acid n/a C12H12O2 详情 详情
(VIII) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(IX) 53595 3-(acetylsulfanyl)-2-(2,3-dihydro-1H-inden-1-yl)propanoic acid n/a C14H16O3S 详情 详情
(X) 53596 (2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoic acid n/a C14H16O3S 详情 详情
(XI) 30387 2-amino-6-isopropyl-4-pyrimidinol C7H11N3O 详情 详情
(XII) 53597 methyl (2S)-2-({(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoyl}amino)-3-(1H-indol-3-yl)propanoate n/a C26H28N2O4S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IX)

The intermediate benzaldehyde (XII) has been obtained as follows: The reduction of 4-nitrobenzaldehyde (I) with NaBH4 and NiCl2 gives 4-aminobenzyl alcohol (II), which is treated with benzyl chloroformate to yield the carbamate (III). The protection of the OH group of (III) with Tbdms-Cl affords the silyl ether (IV). The cyclization of (IV) with glycidyl butyrate (V) by means of BuLi provides the hydroxymethyl oxazolidinone (VI), which is treated with MsCl and TEA to give the mesylate (VII). The reaction of (VII) with NaN3 yields the azidomethyl compound (VIII), which is condensed with thioacetic acid (IX) to afford the acetamide (X). The cleavage of the Tbdms protecting group of (X) by means of TBAF provides the benzyl alcohol (XI), which is oxidized with PDC to furnish the target benzaldehyde intermediate (XII)

参考文献 中间体
合成目标
【1】 Selvakumar, N.; et al.; Synthesis and antibacterial activity of novel chalcone oxazolidinone hybrids. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1323.
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) 18184 4-Nitrobenzaldehyde 555-16-8 C7H5NO3 详情 详情
(II) 34431 diallyl (2S)-2-isocyanatopentanedioate C12H15NO5 详情 详情
(III) 61803 benzyl 4-(hydroxymethyl)phenylcarbamate C15H15NO3 详情 详情
(IV) 61804 benzyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenylcarbamate C21H29NO3Si 详情 详情
(V) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VI) 61805 (5R)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C17H27NO4Si 详情 详情
(VII) 61806 {(5R)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate C18H29NO6SSi 详情 详情
(VIII) 61807 (5R)-5-(azidomethyl)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-1,3-oxazolidin-2-one C17H26N4O3Si 详情 详情
(IX) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(X) 61808 N-({(5S)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide C19H30N2O4Si 详情 详情
(XI) 61809 N-({(5S)-3-[4-(hydroxymethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide C13H16N2O4 详情 详情
(XII) 61812 N-{[(5S)-3-(4-formylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C13H14N2O4 详情 详情
Extended Information