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【结 构 式】

【分子编号】36968

【品名】(5-oxo-1,3-oxathiolan-2-yl)methyl butyrate

【CA登记号】

【 分 子 式 】C8H12O4S

【 分 子 量 】204.24688

【元素组成】C 47.05% H 5.92% O 31.33% S 15.7%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XXVI)

The acylation of 2-butene-1,4-diol (XXII) with butyryl chloride and DMAP in pyridine gives the dibutyrate (XXIII), which is ozonolyzed with O3 in dichloromethane yielding the aldehyde (XXIV). The cyclization of (XXIV) with mercaptoacetic acid (XXV) in refluxing toluene affords 2-(butyryloxymethyl)-1,3-oxathiolane-5-one (XXVI), which is reduced with lithium tri-tert-butoxyaluminum hydride and acetylated with acetic anhydride in THF to give 5-acetoxy-2-(butyryloxymethyl)-1,3-oxathiolane (XXVII). The condensation of (XXVII) with disilylated 5-fluorocytosine (XV) (obtained from cytosine (XVI) as described) by means of SnCl4 in dichloromethane yields the racemic butyryl nucleoside rac-(cis)-(XXVIII). The biological resolution of this racemic mixture has been performed by digestion with the enzyme pig liver esterase (PLE-A) providing a mixture of unreacted (-)-(cis)-(2R,5S)-(XXVIII) butyrate and hydrolyzed (+)-(cis)-(2S,5R)-(XXIX) that are separated by fractional extraction. The desired (-)-(cis)-(2R,5S)-enantiomer is finally hydrolyzed to the target compound with NaOMe in methanol. The biological resolution of rac-(cis)-(XXVIII) can also be performed with the enzyme Amano PS-800 yielding a mixture of unreacted (+)-(cis)-(2S,5R)-(XXVIII) butyrate and the desired (-)-(cis)-(2R,5S) target nuceloside that are separated by fractional extraction.

1 Liotta, D.C.; Schinazi, R.F.; Choi, W.-B. (Emory University); Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1, 3-oxathiolane. EP 0984013; JP 1994508605; JP 1998147586; WO 9214743 .
2 Hoong, L.K.; et al.; Enzyme-mediated enantioselective preparation of pure enantiomers of the antiviral agent 2', 3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) and related compounds. J Org Chem 1992, 57, 21, 5563.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac)-(XXVIII) 36970 (rac)-[(2R,5S)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl butyrate C12H16FN3O4S 详情 详情
(+)-(XXVIII) 36971 [(2S,5R)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl butyrate C12H16FN3O4S 详情 详情
(-)-cis-(XXVIII) 36972 (-)-cis-[(2R,5S)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl butyrate C12H16FN3O4S 详情 详情
(XV) 36959 5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine C10H20FN3OSi2 详情 详情
(XVI) 16747 4-amino-5-fluoro-2(1H)-pyrimidinone; 5-fluorocytosine 2022-85-7 C4H4FN3O 详情 详情
(XXII) 36965 (Z)-2-butene-1,4-diol 6117-80-2 C4H8O2 详情 详情
(XXIII) 36966 (Z)-4-(butyryloxy)-2-butenyl butyrate C12H20O4 详情 详情
(XXIV) 36967 2-oxoethyl butyrate C6H10O3 详情 详情
(XXV) 18524 2-sulfanylacetic acid 68-11-1 C2H4O2S 详情 详情
(XXVI) 36968 (5-oxo-1,3-oxathiolan-2-yl)methyl butyrate C8H12O4S 详情 详情
(XXVII) 36969 [5-(acetoxy)-1,3-oxathiolan-2-yl]methyl butyrate C10H16O5S 详情 详情
(XXIX) 36963 4-amino-5-fluoro-1-[(2S,5R)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone C8H10FN3O3S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(V)

A new process for the preparation of emtricitabine has been described: The esterification of 2-butene-1,4-diol (I) with butyryl chloride and DMAP in pyridine gives the diester (II), which by ozonolysis with O3 in methanol provides the hemiacetal (III). Cyclization of (III) with 2-mercaptoacetic acid in refluxing toluene affords racemic 2-(butyryloxymethyl)-1,3-oxathiolan-5-one (V), which is submitted to optical resolution to afford the (R)-enantiomer (VI). The reduction of (VI) with Li(t-BuO)3AlH, followed by acetylation with acetic anhydride gives 5-(acetoxy)-2(R)-(butyryloxy)-1,3-oxathiolane (VII), which by treatment with HCl in dichloroethane is converted into 2(R)-(butyryloxy)-5-chloro-1,3-oxathiolane (VIII). Condensation of (VIII) with 5-fluoro-bis(trimethylsilyl)cytosine (IX) ­ obtained by silylation of cytosine (X) with HMDS ­ by means of NaHCO3 in dichloroethane gives a diastereomeric mixture of the butyrate nucleosides (XI), which is hydrolyzed with butylamine in methanol yielding the corresponding diastereomeric mixture of the (2R,5S)-isomer, emtricitabine, and the (2R,5R)-isomer (XII). This mixture is separated by crystallization of the corresponding hydrochlorides obtained by treatment with HCl in methanol/dioxane.

1 Almond, M.; Painter, G.R.; Liotta, D.C.; Cleary, D.; Soria, J. (Emory University; Triangle Pharmaceuticals, Inc.); Method of manufacture of 1,3-oxathiolane nucleosides. WO 0009494 .
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) 36965 (Z)-2-butene-1,4-diol 6117-80-2 C4H8O2 详情 详情
(II) 36966 (Z)-4-(butyryloxy)-2-butenyl butyrate C12H20O4 详情 详情
(III) 39681 2-hydroxy-2-methoxyethyl butyrate C7H14O4 详情 详情
(IV) 18524 2-sulfanylacetic acid 68-11-1 C2H4O2S 详情 详情
(V) 36968 (5-oxo-1,3-oxathiolan-2-yl)methyl butyrate C8H12O4S 详情 详情
(VI) 39682 [(2R)-5-oxo-1,3-oxathiolan-2-yl]methyl butyrate C8H12O4S 详情 详情
(VII) 39683 [(2R)-5-(acetoxy)-1,3-oxathiolan-2-yl]methyl butyrate C10H16O5S 详情 详情
(VIII) 39685 [(2R)-5-chloro-1,3-oxathiolan-2-yl]methyl butyrate C8H13ClO3S 详情 详情
(IX) 36959 5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine C10H20FN3OSi2 详情 详情
(X) 16747 4-amino-5-fluoro-2(1H)-pyrimidinone; 5-fluorocytosine 2022-85-7 C4H4FN3O 详情 详情
(XI) 36970 (rac)-[(2R,5S)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl butyrate C12H16FN3O4S 详情 详情
(XII) 36984 benzyl 6-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate C18H17NO3 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

 

1 Painter GR,Lrotta DC,et且1. 2000.Method ofmanufacture of l,3-oxathiolane nucleosides. wo 2000009494
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) 36968 (5-oxo-1,3-oxathiolan-2-yl)methyl butyrate C8H12O4S 详情 详情
(II) 66310 (5-acetoxy-1,3-oxathiolan-2-yl)methyl butyrate   C10H16O5S 详情 详情
(III) 66311 (5-chloro-1,3-oxathiolan-2-yl)methyl butyrate   C8H13ClO3S 详情 详情
(IV) 66312 (5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolan-2-yl)methyl butyrate   C12H16FN3O4S 详情 详情
(V) 36970 (rac)-[(2R,5S)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl butyrate C12H16FN3O4S 详情 详情
Extended Information