(Z)-4-(butyryloxy)-2-butenyl butyrate -Drug Synthesis Database

【结构式】

【分子编号】36966

【品名】(Z)-4-(butyryloxy)-2-butenyl butyrate

【CA登记号】

【分子式】C₁₂H₂₀O₄

【分子量】228.2884

【元素组成】C 63.14% H 8.83% O 28.03%

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：(XXIII)

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.

参考文献中间体

合成目标

【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：(II)

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.

参考文献中间体

合成目标

【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

Extended Information