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【结 构 式】

【分子编号】15609

【品名】[5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl benzoate

【CA登记号】

【 分 子 式 】C15H15N3O4S

【 分 子 量 】333.36792

【元素组成】C 54.04% H 4.54% N 12.6% O 19.2% S 9.62%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(V)

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.

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
Extended Information