ammonium (3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]-3,5-dihydroxyheptanoate -Drug Synthesis Database

【结构式】

【分子编号】37616

【品名】ammonium (3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]-3,5-dihydroxyheptanoate

【CA登记号】

【分子式】C₂₅H₄₃NO₆

【分子量】453.61956

【元素组成】C 66.2% H 9.55% N 3.09% O 21.16%

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：(IV)

A cost-efficient synthesis of simvastatin has been reported: 1) The reaction of lovastatin (mevinolin) (I) with cyclopropylamine (II) gives the corresponding amide (III), which is methylated by means of BuLi, methyl iodide and pyrrolidine in THF yielding the dimethylbutyryl derivative (IV). Hydrolysis of (IV) with NaOH in refluxing methanol, followed by a treatment with NH4OH in methanol affords the ammonium salt (V), which is finally lactonized in acidic medium. 2) The cyclopropylamide (III) can also be obtained by reaction of mevinolinic acid ammonium salt (VI) with cyclopropylamine in hot toluene.

参考文献中间体

合成目标

【1】 Thaper, R.K.; Misra, S.; Kumar, Y.; Kumar, S.M.D.; Khanna, J.M.; A cost-efficient synthesis of simvastatin via high-conversion methylation of an alkoxide ester enolate. Org Process Res Dev 1999, 3, 6, 476.

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)	64415	(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate		C₂₄H₃₆O₅	详情	详情
(II)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(III)	37613	(1S,3R,7S,8S,8aR)-8-[(3R,5R)-7-(cyclopropylamino)-3,5-dihydroxy-7-oxoheptyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate		C₂₇H₄₃NO₅	详情	详情
(IV)	37616	ammonium (3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]-3,5-dihydroxyheptanoate		C₂₅H₄₃NO₆	详情	详情
(V)	37615	(1S,3R,7S,8S,8aR)-8-[(3R,5R)-7-(cyclopropylamino)-3,5-dihydroxy-7-oxoheptyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate		C₂₈H₄₅NO₅	详情	详情
(VI)	37614	ammonium (3R,5R)-7-((1S,2S,6R,8S,8aR)-2,6-dimethyl-8-[[(2S)-2-methylbutanoyl]oxy]-1,2,6,7,8,8a-hexahydro-1-naphthalenyl)-3,5-dihydroxyheptanoate		C₂₄H₄₁NO₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The reaction of Lovastatin (I) with refluxing butylamine gives the N-butylamide (II), which is silylated with TBDMS-Cl and imidazole to yield the bis(silyl) ether (III). The careful methylation of (III) with MeI (only 1.5 mol) and lithium pyrrolidide in THF at -10 C affords a high yield of 2,2-dimethylbutyrate (IV) avoiding the methylation of the amide nitrogen. The desilylation of (IV) with MsOH in methanol gives the dihydroxyamide (V), which is treated successively with NaOH in methanol/water, with HCl, and finally with ammonia in methanol to give the ammonium salt (VI). Finally, this compound is cyclized by heating at 100 C in toluene to afford the target simvastatin.

参考文献中间体

合成目标

【1】 Askin, D.; et al.; Synthesis of synvinolin: Extremely high conversion alkylation of an ester enolate. J Org Chem 1991, 56, 16, 4929.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	64415	(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate	C₂₄H₃₆O₅	详情	详情
(II)	38664	(1S,3R,7S,8S,8aR)-8-[(3R,5R)-7-(butylamino)-3,5-dihydroxy-7-oxoheptyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate	C₂₈H₄₇NO₅	详情	详情
(III)	38665	(1S,3R,7S,8S,8aR)-8-((3R,5R)-7-(butylamino)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-7-oxoheptyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate	C₄₀H₇₅NO₅Si₂	详情	详情
(IV)	38666	(1S,3R,7S,8S,8aR)-8-((3R,5R)-7-(butylamino)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-7-oxoheptyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate	C₄₁H₇₇NO₅Si₂	详情	详情
(V)	38667	(1S,3R,7S,8S,8aR)-8-[(3R,5R)-7-(butylamino)-3,5-dihydroxy-7-oxoheptyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate	C₂₉H₄₉NO₅	详情	详情
(VI)	37616	ammonium (3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]-3,5-dihydroxyheptanoate	C₂₅H₄₃NO₆	详情	详情

Extended Information