Lamivudine, GG-714, (-)-BCH-189, (-)-SddC, BCH-790(fomer code), GR-109714X, 3TC, Zefix, Heptovir, Heptodin, Epivir-HBV, Zeffix, Epivir, 3TC, -Drug Synthesis Database

【结构式】

【药物名称】Lamivudine, GG-714, (-)-BCH-189, (-)-SddC, BCH-790(fomer code), GR-109714X, 3TC, Zefix, Heptovir, Heptodin, Epivir-HBV, Zeffix, Epivir, 3TC

【化学名称】(-)-1-[(2R,5S)-2-(Hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine
　　　　　　(-)-(2'R,5'S)-1-[2-(Hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine

【CA登记号】134678-17-4, 131086-21-0 (cis-isomer)

【分子式】C₈H₁₁N₃O₃S

【分子量】229.25917

【开发单位】Shire BioChem (Originator), GlaxoSmithKline (Licensee)

【药理作用】Agents for Liver Cirrhosis, AIDS Medicines, Anti-Hepatitis B Virus Drugs, Anti-Hepatitis Virus Drugs, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Antiviral Drugs, GASTROINTESTINAL DRUGS, Liver and Biliary Tract Disorders, Treatment of, Reverse Transcriptase Inhibitors

合成路线1 合成路线2

合成路线1

There are two options for the synthesis of lamivudine: In the first approach the intact nucleoside analogue is prepared in racemic form by resolution to afford the required chiral product. This can be effected by an enzyme-mediated enantiospecific reaction. In the second approach synthesis of a chiral sugar component precedes coupling with the cytosine base under conditions where the chirality of the sugar precursor is maintained. The first approach is outlined in Scheme 18435601a. The oxathiolane (III) is obtained as a 1:1 mixture of anomers from reaction of benzoyloxyacetaldehyde (I) with mercaptoacetaldehyde dimethylacetal (II) in the presence of a Lewis acid. Treatment of (III) with silylated cytosine (IV) in the presence of TMS-triflate affords a 1:1 mixture of beta- and alpha-anomers (V) from which the required beta-anomer may be obtained by crystallization. Various alternative coupling conditions have been reported which yield almost exclusively the beta-anomer, notably as a result of the use of SnCl4. Subsequent deprotection affords the racemic nucleoside (VI) (BCH189). The resolution may be effected by a variety of enzymatic processes. Treatment of the nucleoside with phosphorus oxychloride and trimethylphosphate affords the 5'-monophosphate (VII). The natural enantiomer is selectively recognized by the 5'-nucleotidase from Crotalus atrox venom to afford the (+)-beta-D-nucleoside (VIII) and leave the unatural (-)-beta-L-enantiomer as the monophosphate (IX). Facile separation of these two products and subsequent dephosphorylation of (IX) using bacterial alkaline phosphatase affords lamivudine. Selective enzymatic recognition of the natural enantiomer may also be used to advantage in the resolution using cytidine deaminase derived from E. coli. In this case the enzyme is responsible for enantiospecific hydrolysis of the natural form to afford a readily separable mixture of lamivudine and the uridine derivative (X). Other enzymes including esterases and phosphodiesterases have application in the resolution of derivatives of the racemic nucleoside.

参考文献中间体

【1】 Choi, W.-B.; Yeola, S.; Liotta, D.C.; Wilson, L.S.; Schinazi, R.F.; In situ complexation directs the stereochemistry of N-glycosylation in the synthesis of oxathiolanyl and dioxolanyl nucleoside analogues. J Am Chem Soc 1991, 113, 9377-9.
【2】 Coates, J.A.V.; Mutton, I.M.; Penn, C.R.; Storer, R.; Williamson, C. (BioChem Pharma Inc.); 1,3-Oxathiolane nucleoside analogues. EP 0625150; JP 1993501117; JP 1999080153; JP 2000128787; WO 9117159 .
【3】 Belleau, B.; Nguyen-Ba, N. (BioChem Pharma Inc.); Substd.-1,3-oxathiolanes with antiviral properties. EP 0382526; EP 0711771; JP 1996119967; JP 2000143662; US 5047407 .
【4】 Storer, R.; Belleau, B.; Noble, S.A.; Lamont, B.; Clemens, I.R.; Williamson, C.; The resolution and absolute stereochemistry of the enantiomers of cis-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (BCH189): Equipotent anti-HIV agents. Nucleosides Nucleotides 1993, 12, 2, 225.
【5】 Storer, R.; Wilcox, P.; Daniel, M.; Collis, P.; Cameron, J.M.; Lamivudine. Drugs Fut 1993, 18, 4, 319.

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)	15605	2-oxoethyl benzoate		C₉H₈O₃	详情	详情
(II)	15606	2,2-dimethoxy-1-ethanethiol; 2,2-dimethoxyethylhydrosulfide		C₄H₁₀O₂S	详情	详情
(III)	15607	(5-methoxy-1,3-oxathiolan-2-yl)methyl benzoate		C₁₂H₁₄O₄S	详情	详情
(IV)	12706	Cytosine; 4-Amino-2(1H)-pyrimidinone	71-30-7	C₄H₅N₃O	详情	详情
(V)	15609	[5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl benzoate		C₁₅H₁₅N₃O₄S	详情	详情
(VI)	15610	4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone		C₈H₁₁N₃O₃S	详情	详情
(VII)	15611	[5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl dihydrogen phosphate		C₈H₁₂N₃O₆PS	详情	详情
(VIII)	15612	4-amino-1-[(2S,5R)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone		C₈H₁₁N₃O₃S	详情	详情
(IX)	15613	[(2R,5S)-5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl dihydrogen phosphate		C₈H₁₂N₃O₆PS	详情	详情
(X)	15614	1-[(2S,5R)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2,4(1H,3H)-pyrimidinedione		C₈H₁₀N₂O₄S	详情	详情

合成路线2

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

【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

Drug NewChemical Entity Original Patent(3)