5-(acetoxy)-1,3-oxathiolane-2-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】15619

【品名】5-(acetoxy)-1,3-oxathiolane-2-carboxylic acid

【CA登记号】

【分子式】C₆H₈O₅S

【分子量】192.19252

【元素组成】C 37.5% H 4.2% O 41.62% S 16.68%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

The condensation of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (I) with 4-bromoacetoacetyl bromide (II) by means of trimethylsilylacetamide in ethyl acetate gives benzhydryl 7-(4-bromoaceto-acetamido)-3-vinyl-3-cephem-4-carboxylate (III), which by reaction with NaNO2 - acetic acid in dichloromethane and then with urea is converted to benzhydryl 7-[4-bromo-2-(hydroxyimino)acetoacetamido]-3-vinyl-3-cephem-4 carboxylate (IV). The cyclization of (IV) with thiourea in dimethylacetamide affords benzhydryl 7-[2-(2-aminothiazol-4-yl) (hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (V), which is finally hydrolyzed with trifluoroacetic acid - anisole as usual.

参考文献中间体

合成目标

【1】 Kawabata, K.; Masugi, T.; Takaya, T.; Taksugi, H.; Yamanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Syn-isomer of 7-substd.-3-vinyl-3-cephem cpds., pr. EP 0105459; ES 8600309; ES 8800235; US 4559334 .
【2】 Castaner, J.; Prous, J.; FK-482. Drugs Fut 1988, 13, 3, 224.

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)	22001	benzhydryl (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₂H₂₀N₂O₃S	详情	详情
(II)	15619	5-(acetoxy)-1,3-oxathiolane-2-carboxylic acid		C₆H₈O₅S	详情	详情
(III)	22003	benzhydryl (6R,7R)-7-[(4-bromo-3-oxobutanoyl)amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₆H₂₃BrN₂O₅S	详情	详情
(IV)	22004	benzhydryl (6R,7R)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₆H₂₂BrN₃O₆S	详情	详情
(V)	22005	benzhydryl (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₇H₂₃N₅O₅S₂	详情	详情
(VI)	63021	N-(trimethylsilyl)acetamide	13435-12-6	C₅H₁₃NOSi	详情	详情
(VII)	19310	urea	57-13-6	CH₄N₂O	详情	详情
(VIII)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

The second general approach to synthesis of lamivudine does not involve intermediacy of the racemic nucleoside. A variety of routes are available for preparing chiral oxathiolane intermediates which may be coupled to the cytosine base under appropriate conditions where the chirality of the oxathiolane is maintained. Various natural carbohydrate precursors have utility in the synthesis of lamivudine; for example, a synthesis from L-gulose has recently been reported. (+)-Thiolactic acid (XI) has served as a starting material for chiral oxathiolane (XII), which is coupled to silylated cytosine in the presence of TMS-iodide to afford (XIII). Separation of the pure beta-anomer and deprotection affords lamivudine. Alternatively, racemic acid (XV) may be prepared from glyoxylic acid (XIV) and resolution using a suitable chiral base such as norephedrine would afford the chiral acid (XVI), which may be esterified prior to coupling with cytosine to give (XVII) followed by final reduction to lamivudine.

参考文献中间体

合成目标

【1】 Jones, M.F.; Siddiqui, A.; Payne, J.J.; Tse, H.L.A.; Humber, D.-C.; Ramsey, M.V.J.; Zacharie, B.; Jin, H.; Evans, C.A.; Expeditious preparation of (-)-2'-deoxy-3'-thiacytidine (3TC). Tetrahedron Lett 1992, 33, 32, 4625-8.
【2】 Storer, R.; Wilcox, P.; Daniel, M.; Collis, P.; Cameron, J.M.; Lamivudine. Drugs Fut 1993, 18, 4, 319.
【3】 Kim, H.O.; Chu, C.K.; Beach, J.W.; Schinazi, R.F.; Doong, S.-L.; Alves, A.J.; Pohl, D.; Chang, C.-N.; Jeong, L.S.; Cheng, Y.-C.; Synthesis of enantiomerically pure (2'R'5'S)-(-)-1-[2-(hydroxymethyl)oxathiolan-5yl]cytosine as a potential antiviral agent against hepatitis B virus (HBV) and human immunodeficiency virus (HIV). J Org Chem 1992, 57, 8, 2217-9.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	64669	(2S,5S)-2-[(benzoyloxy)methyl]-1,3-oxathiolane-5-carboxylic acid		C₁₂H₁₂O₅S	详情	详情
	64670	(2R,5S)-2-[(benzoyloxy)methyl]-1,3-oxathiolane-5-carboxylic acid		C₁₂H₁₂O₅S	详情	详情
	64671	methyl (2R,5R)-5-(acetyloxy)-1,3-oxathiolane-2-carboxylate		C₇H₁₀O₅S	详情	详情
(I)	15606	2,2-dimethoxy-1-ethanethiol; 2,2-dimethoxyethylhydrosulfide		C₄H₁₀O₂S	详情	详情
(XI)	15615	(2S)-2-hydroxy-3-sulfanylpropionic acid		C₃H₆O₃S	详情	详情
(XII)	15616	[(2R)-5-(acetoxy)-1,3-oxathiolan-2-yl]methyl benzoate		C₁₃H₁₄O₅S	详情	详情
(XIII)	15617	[(2R)-5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl benzoate		C₁₅H₁₅N₃O₄S	详情	详情
(XIV)	15618	2-Oxoacetic acid; Glyoxylic Acid	298-12-4	C₂H₂O₃	详情	详情
(XV)	15619	5-(acetoxy)-1,3-oxathiolane-2-carboxylic acid		C₆H₈O₅S	详情	详情
(XVI)	15620	(2R,5R)-5-(acetoxy)-1,3-oxathiolane-2-carboxylic acid	147027-05-2	C₆H₈O₅S	详情	详情
(XVII)	15621	methyl (2R,5S)-5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolane-2-carboxylate		C₉H₁₁N₃O₄S	详情	详情

Extended Information