(1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate -Drug Synthesis Database

【结构式】

【分子编号】45374

【品名】(1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate

【CA登记号】

【分子式】C₉H₁₂O₄

【分子量】184.19188

【元素组成】C 58.69% H 6.57% O 34.75%

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：(I)

The condensation of 6-chloropurine-2-amine (III) with the chiral monoacetate (II) (obtained by enzymatic desymmetrization of diacetate (I)) by means of Pd(PPh3)4 in DMSO gives the cyclopentenol derivative (IV), which is treated with dimethyl dicarbonate and DMAP in dichloromethane to yield the carbonate (V). The condensation of (V) with ethyl 2-nitroacetate (VI) by means of Pd in THF affords the adduct (VII), which is decarboxylated by means of NaCl in DMSO/water at 150 C to provide the nitromethylcyclopentene derivative (VIII). The reaction of (VIII) with tBuOK, O3 and NaBH4 in methanol gives the corresponding hydroxymethyl derivative (IX), which is finally hydrolyzed with NaOH in refluxing water to afford the target guanine as a racemic compound. Alternatively, the nitromethyl-cyclopentene derivative (VIII) can also be obtained by condensation of carbonate (V) with 2-(trimethylsilyl)ethyl 2-nitroacetate (X) by means of Pd in THF to give the adduct (XI), which is decarboxylated by means of CsF in hot acetonitrile, affording (VIII).

参考文献中间体

合成目标

【1】 Peel, M.R.; et al.; A short, enantioselective synthesis of the carbocyclic nucleoside carbovir. J Org Chem 1991, 56, 16, 4990.

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)	45374	(1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate		C₉H₁₂O₄	详情	详情
(II)	33169	(1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate		C₇H₁₀O₃	详情	详情
(III)	11644	6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine	10310-21-1	C₅H₄ClN₅	详情	详情
(IV)	45368	(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-ol		C₁₀H₁₀ClN₅O	详情	详情
(V)	45369	(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl methyl carbonate		C₁₂H₁₂ClN₅O₃	详情	详情
(VI)	15050	ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester	626-35-7	C₄H₇NO₄	详情	详情
(VII)	45370	ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate		C₁₄H₁₅ClN₆O₄	详情	详情
(VIII)	45371	6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-ylamine; 6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-amine		C₁₁H₁₁ClN₆O₂	详情	详情
(IX)	17650	[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol		C₁₁H₁₂ClN₅O	详情	详情
(X)	45372	2-(trimethylsilyl)ethyl 2-nitroacetate		C₇H₁₅NO₄Si	详情	详情
(XI)	45373	2-(trimethylsilyl)ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate		C₁₇H₂₃ClN₆O₄Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The photooxidation of cyclopentadiene (I) gives cis-4-cyclopentene-1,3-diol (II), which is acylated with Ac2O to yield the diacetate (II). Enzymatic selective hydrolysis of (II) using porcine pancreas lipase (PPL) affords the chiral monoacetate (IV), which is protected with dihydropyran (DHP) and Ts-OH to provide the tetrahydropyranyl ether (V). The hydrolysis of the acetate group of (V) with KOH in methanol gives the alcohol (VI), which is silylated with TbdmsCl and imidazole to yield the silyl ether (VII). Elimination of the THP-protecting group of (VII) with Me2AlCl in dichloromethane affords the cyclopentenol (VIII), which is oxidized with PCC to the cyclopentenone (IX). The condensation of (IX) with chloroiodomethane and BuLi in THF gives the chiral chloromethyl derivative (X), which is treated with potassium methoxide in THF to obtain the chiral epoxide (XI). Stereocontrolled opening of the epoxide ring of (XI) by means of DIBAL in hexane provides the cyclopentenyl-methanol derivative (XII), which is desilylated with TBAF in THF to give the chiral diol (XIII). The esterification of the diol (XIII) with methyl chloroformate and pyridine yields the bis-carbonate (XIV), which is condensed with 2-amino-6-chloropurine (XV) by means of Pd(PPh3)4 in DMF to afford the carbocyclic purine derivative (XVI). Finally, this compound is hydrolyzed with NaOH in refluxing water to provide the target carbocyclic guanine.

参考文献中间体

合成目标

【1】 Nokami, J.; et al.; Palladium-catalyzed chemoselective reaction of allylic carbonate with nucleoside bases and its application for the synthesis of carbocyclic nucleosides. (-)-and (+)-carbovirs. Chem Lett 1994, 1071.

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)	11183	1,3-Cyclopentadiene		C₅H₆	详情	详情
(II)	33168	(1R,3S)-4-cyclopentene-1,3-diol		C₅H₈O₂	详情	详情
(III)	45374	(1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate		C₉H₁₂O₄	详情	详情
(IV)	45407	(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol	60410-16-4	C₇H₁₀O₃	详情	详情
(V)	45339			C₈H₁₁N	详情	详情
(VI)	45400	(1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-ol		C₁₁H₁₈O₃	详情	详情
(VII)	45401	tert-butyl(dimethyl)([(1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl]oxy)silane; tert-butyl(dimethyl)silyl (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl ether		C₁₇H₃₂O₃Si	详情	详情
(VIII)	33174	(1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol		C₁₁H₂₂O₂Si	详情	详情
(IX)	13805	(4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one		C₁₁H₂₀O₂Si	详情	详情
(X)	45402	(1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-(chloromethyl)-2-cyclopenten-1-ol		C₁₂H₂₃ClO₂Si	详情	详情
(XI)	45403	tert-butyl(dimethyl)silyl (3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yl ether; tert-butyl(dimethyl)[(3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yloxy]silane		C₁₂H₂₂O₂Si	详情	详情
(XII)	45404	((1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl)methanol		C₁₂H₂₄O₂Si	详情	详情
(XIII)	45405	(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol		C₆H₁₀O₂	详情	详情
(XIV)	45406	[(1S,4R)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl]methyl methyl carbonate		C₁₀H₁₄O₆	详情	详情
(XV)	11644	6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine	10310-21-1	C₅H₄ClN₅	详情	详情
(XVI)	45398	[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate		C₁₃H₁₄ClN₅O₃	详情	详情

Extended Information