(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 -Drug Synthesis Database

【结构式】

【分子编号】64415

【品名】(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

【CA登记号】

【分子式】C₂₄H₃₆O₅

【分子量】404.54684

【元素组成】C 71.26% H 8.97% O 19.77%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(I)

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：(I)

Two new related proceases to synthesize simvastatin have been described: 1) The reduction of the lactone function of lovastatin (I) with diisobutylaluminum hydride (DIBAL) in THF/dichoromethane gives the hemiacetal (II), which by reaction with acetyl chloride in methanol yields the acetal (III). The methylation of (III) with methyl iodide by means of BuLi and pyrrolidine in THF affords the 2,2-dimethylbutyric acid ester (IV), which is treated with HCl in THF to give the hemiacetal (V). Finally, this compound is oxidized with Ag2CO3 in refluxing toluene. 2) The direct methylation of hemiacetal (II) with methyl iodide by means of BuLi and pyrrolidine in THF directly yields the methylated herniacetal (V) although with a little bit less purity.

参考文献中间体

合成目标

【1】 Doucette, G.; Tam, T.F.; Tao, Y.; Karimian, K.; Li, Y. (Apotex Inc.); Process to manufacture simvastatin and intermediates. WO 9965892 .

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)	37617	(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate	C₂₄H₃₈O₅	详情	详情
(III)	37618	(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate	C₂₅H₄₀O₅	详情	详情
(IV)	37619	(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate	C₂₆H₄₂O₅	详情	详情
(V)	37620	(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate	C₂₅H₄₀O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

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

合成路线4

该中间体在本合成路线中的序号：(I)

The reaction of lovastatin (I) with benzoyl chloride (II) and pyridine gives the expected benzoate (III), which is treated with ethyleneglycol (IV), triethyl orthoformate and H2SO4 to yield the cyclic orthoformate (V). The methylation of (V) by means of MeI and BuLi in pyrrolidine affords the 2,2-dimethylbutyrate ester (VI), which is finally deprotected with HCl in THF to provide the target simvastatin.

参考文献中间体

合成目标

【1】 Dabak, K.; Adiyaman, M.; A new method for the synthesis of antihypercholesterolemic agent simvastatin. Helv Chim Acta 2003, 86, 3, 673.

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)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(III)	64416	(2R,4R)-2-[2-((1S,2S,6R,8S,8aR)-2,6-dimethyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8a-hexahydro-1-naphthalenyl)ethyl]-6-oxotetrahydro-2H-pyran-4-yl benzoate		C₃₁H₄₀O₆	详情	详情
(IV)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(V)	64417	(7R,9R)-7-[2-((1S,2S,6R,8S,8aR)-2,6-dimethyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8a-hexahydro-1-naphthalenyl)ethyl]-1,4,6-trioxaspiro[4.5]dec-9-yl benzoate		C₃₃H₄₄O₇	详情	详情
(VI)	64418	(1S,3R,7S,8S,8aR)-8-{2-[(7R,9R)-9-hydroxy-1,4,6-trioxaspiro[4.5]dec-7-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate		C₂₇H₄₂O₆	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

Dehydration of mevinolin (I) by means of acetic anhydride in the presence of DMAP gives rise to the conjugated lactone (II). Subsequent reaction of (II) with 4-(tert-butyldimethylsilyloxy)-3-methoxybenzylamine (III) in MeOH leads to the amino hydroxy ester (IV). This is then treated with carbonyldiimidazole in DMF to produce the cyclic carbamate (V). Finally, ester group aminolysis with simultaneous desilylation with ethanolamine in boiling MeOH furnishes the title compound.

参考文献中间体

合成目标

【1】 Hommel, U.; Bauer, W.; Meingassner, J.G.; Weitz-Schmidt, G.; Ehrhardt, C.; Kallen, J.; Banteli, R.; Cottens, S.; Nuninger, F. (Novartis AG; Novartis-Erfindungen VmbH); Mevinolin derivs.. EP 1154988; WO 0048989 .

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)	65024	3,7-dimethyl-8-[2-(6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2-methylbutanoate	C₂₄H₃₄O₄	详情	详情
(III)	65025	[4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-(methyloxy)phenyl]methanamine; [4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-(methyloxy)phenyl]methylamine	C₁₄H₂₅NO₂Si	详情	详情
(IV)	65026	methyl 3-({[4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-(methyloxy)phenyl]methyl}amino)-7-{2,6-dimethyl-8-[(2-methylbutanoyl)oxy]-1,2,6,7,8,8a-hexahydro-1-naphthalenyl}-5-hydroxyheptanoate	C₃₉H₆₃NO₇Si	详情	详情
(V)	65027	8-(2-{3-{[4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-(methyloxy)phenyl]methyl}-4-[2-(methyloxy)-2-oxoethyl]-2-oxo-1,3-oxazinan-6-yl}ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2-methylbutanoate	C₄₀H₆₁NO₈Si	详情	详情

Extended Information