N(4)-Acetylcytosine -Drug Synthesis Database

【结构式】

【分子编号】55073

【品名】N(4)-Acetylcytosine

【CA登记号】14631-20-0

【分子式】C₆H₇N₃O₂

【分子量】153.1406

【元素组成】C 47.06% H 4.61% N 27.44% O 20.9%

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：(VII)

The title compound was prepared starting from the known menthyl 5(S)-acetoxy-1,3-oxathiolan-2(R)-carboxylate (I). Transposition of the 5-acetoxy group of (I) to the target 4-acetoxy derivative (VI) was achieved by the following sequence. The acetoxy group of (I) was first removed by reduction with triethylsilaneto give (II), followed by ester reduction with NaBH4, to give the hydroxymethyl oxathiolane (III). The primary alcohol of (III) was then protected by silylation with tert-butyldiphenylsilyl chloride. The resultant silylated oxathiolane (IV) was oxidized to a diastereomeric mixture of sulfoxides (V) using m-CPBA. Pummerer rearrangement of sulfoxides (V) in the presence of Ac2O and Bu4NOAc furnished the desired 4-acetoxy thiolane (VI). Glycosylation of (VI) with N-acetylcytosine (VII) in the presence of trimethylsilyl triflate provided a mixture of cis- and trans-coupled products, which were separated by preparative TLC. The required cis-isomer (VIII) was desilylated with tetrabutylammonium fluoride, followed by acetamide hydrolysis with K2CO3 in MeOH, to provide the title compound.

参考文献中间体

合成目标

【1】 Mansour, T.S.; et al.; Structure-activity relationships among a new class of antiviral heterosubstituted 2',3'-dideoxynucleoside analogs. Nucleosides Nucleotides 1995, 14, 3-5, 627.
【2】 Wang, W.; et al.; Synthesis of optically active 2',3'-dideoxy-3'-oxa-4'-thio-ribonucleoside analogs by transposition of a leaving group on chiral oxathiolanes via a reductive-oxidative process. Tetrahedron Lett 1994, 35, 27, 4739.
【3】 Mansour, T.S.; et al.; Anti-human immunodeficiency virus and anti-hepatitis-B virus activities and toxicities of the enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine and their 5-fluoro analogues in vitro. J Med Chem 1995, 38, 1, 1.
【4】 Mansour, T.S.; Jin, H. (Shire BioChem Inc.); Substd. 1,3-oxathiolanes with antiviral properties. EP 0756595; EP 1153924; JP 1997512526; WO 9529176 .

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)	55067	(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5R)-5-(acetyloxy)-1,3-oxathiolane-2-carboxylate		C₁₆H₂₆O₅S	详情	详情
(II)	55068	(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R)-1,3-oxathiolane-2-carboxylate		C₁₄H₂₄O₃S	详情	详情
(III)	55069	(2R)-1,3-oxathiolan-2-ylmethanol		C₄H₈O₂S	详情	详情
(IV)	55070	tert-butyl[(2R)-1,3-oxathiolan-2-ylmethoxy]diphenylsilane; tert-butyl(diphenyl)silyl (2R)-1,3-oxathiolan-2-ylmethyl ether		C₂₀H₂₆O₂SSi	详情	详情
(V)	55071	(2R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3lambda~4~-oxathiolan-3-one		C₂₀H₂₆O₃SSi	详情	详情
(VI)	55072	(2R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3-oxathiolan-4-yl acetate		C₂₂H₂₈O₄SSi	详情	详情
(VII)	55073	N(4)-Acetylcytosine	14631-20-0	C₆H₇N₃O₂	详情	详情
(VIII)	55074	N-{1-[(2R,4R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3-oxathiolan-4-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl}acetamide		C₂₆H₃₁N₃O₄SSi	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

A new asymmetric synthesis has been reported. Oxidative cleavage of mono-benzoyl glycerol (IX) by means of NaIO4 provided aldehyde (X). Condensation of (X) with mercaptoethanol (XI) in the presence of ploystyryl diphenylphosphane-iodine complex gave rise to the oxathiolane (XII). Sharpless asymmetric oxidation of (XII) using tert-butyl hydroperoxide and L-diethyl tartrate led to an 82:18 mixture of (E)- and (Z)-sulfoxides (XIII) and (XIV). The desired (E)-isomer (XIII) was then isolated by column chromatography, displaying an enantiomeric excess of 60%. Coupling of (XIII) with N-acetylcytosine (VII) under Pummerer rearrangement conditions led to an equimolecular mixture of (Z)- and (E)-adducts (XV) and (XVI). After chromatographic separation of the desired (Z)-isomer (XV), the acetyl and benzoyl protecting groups were removed by treatment with sodium methoxide.

参考文献中间体

合成目标

【1】 Caputo, R.; et al.; A new strategy for the asymmetric synthesis of 1,3-oxathiolane-based nucleoside analogues. Eur J Org Chem 1999, 6, 1455.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	55073	N(4)-Acetylcytosine	14631-20-0	C₆H₇N₃O₂	详情	详情
(IX)	55075	2,3-dihydroxypropyl benzoate		C₁₀H₁₂O₄	详情	详情
(X)	15605	2-oxoethyl benzoate		C₉H₈O₃	详情	详情
(XII)	55076	1,3-oxathiolan-2-ylmethyl benzoate		C₁₁H₁₂O₃S	详情	详情
(XIII)	55077	[(2R)-3-oxo-1,3lambda~4~-oxathiolan-2-yl]methyl benzoate		C₁₁H₁₂O₄S	详情	详情
(XIV)	55080	[(2S)-3-oxo-1,3lambda~4~-oxathiolan-2-yl]methyl benzoate		C₁₁H₁₂O₄S	详情	详情
(XV)	55078	{(2R,4R)-4-[4-(acetylamino)-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl}methyl benzoate		C₁₇H₁₇N₃O₅S	详情	详情
(XVI)	55079	{(2R,4S)-4-[4-(acetylamino)-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl}methyl benzoate		C₁₇H₁₇N₃O₅S	详情	详情
(XXI)	36375	2-Sulfanyl-1-ethanol; 2-Mercaptoethanol	60-24-2	C₂H₆OS	详情	详情

Extended Information