Synvinolin, Simvastatin, MK-733, Pantok, Colemin, Sinvacor, Lipex, Medipo, Zocor, Lipovas, Denan, Lodal鑣, Zocord, -Drug Synthesis Database

【结构式】

【药物名称】Synvinolin, Simvastatin, MK-733, Pantok, Colemin, Sinvacor, Lipex, Medipo, Zocor, Lipovas, Denan, Lodal鑣, Zocord

【化学名称】2,2-Dimethylbutyric acid [1S-[1alpha,3alpha,7beta,8beta(2S*,4S*),8abeta]-3,7-dimethyl-8-[2-(4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-1,2,3,7,8,8a-hexahydro-1-naphthyl ester
　　　　　　2,2-Dimethylbutyric acid,8-ester with (4R,6R)-6-[2-[(1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one

【CA登记号】79902-63-9

【分子式】C₂₅H₃₈O₅

【分子量】418.57861

【开发单位】Merck & Co. (Originator), Merck Sharp & Dohme (Originator), Boehringer Ingelheim (Not Determined), Mediolanum (Not Determined), National Institute on Aging (Not Determined), Neopharmed (Not Determined), Sanofi-Synthélabo (Not Determined), Banyu (Licensee)

【药理作用】Alzheimer's Dementia, Treatment of , CARDIOVASCULAR DRUGS, Cognition Disorders, Treatment of, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, NEUROLOGIC DRUGS, Restenosis Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HDL-Cholesterol Increasing Agents, HMG-CoA Reductase Inhibitors

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6

合成路线1

The deacylation of lovastatin (I) with aqueous LiOH gives the free diol (II), which is partially protected with tert-butyldimethylsilyl chloride as usual, yielding the monosilylated derivative (III). The acylation of (III) with 2,2-dimethylbutyryl chloride (IV) by means of 4-pyrrolidino pyridine (py-py) in pyridine affords the silylated ester (V), which is finally deprotected with tetrabutylammonium fluoride and acetic acid in THF.

参考文献中间体

【1】 Hoffman, W.F.; Alberts, A. W.; Anderson, P.S.; Smith, R.L.; Chen, J.S.; Willard, A.K.; 3-Hydroxy-3-methylglutaryl-coenzyme A reductase in. J Med Chem 1986, 29, 5, 849.
【2】 Hoffman, W.F.; Smith, R.L.; Willard, A.K. (Merck & Co., Inc.); Antihypercholesterolemic cpds.. US 4444784 .
【3】 Askin, D.; et al.; Synthesis of synvinolin: Extremely high conversion alkylation of an ester enolate. J Org Chem 1991, 56, 16, 4929.
【4】 Zlicar, M. (LEK Pharmaceutical and Chemical Co.); Process for the preparation of simvastatin and analogs thereof. WO 0032585 .
【5】 Prous, J.; Castaner, J.; Simvastatin. Drugs Fut 1988, 13, 6, 531.

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)	22645	(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; Lovastatin	75330-75-5	C₂₄H₃₆O₅	详情	详情
(II)	22646	(4R,6R)-6-[2-[(1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]ethyl]-4-hydroxytetrahydro-2H-pyran-2-one		C₁₉H₂₈O₄	详情	详情
(III)	22647	(4R,6R)-6-[2-[(1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]ethyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-one		C₂₅H₄₂O₄Si	详情	详情
(IV)	22648	2,2-dimethylbutanoyl chloride		C₆H₁₁ClO	详情	详情
(V)	22649	(1S,3R,7S,8S,8aR)-8-[2-((2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-oxotetrahydro-2H-pyran-2-yl)ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate		C₃₁H₅₂O₅Si	详情	详情

合成路线2

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

【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3

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

【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4

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

【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5

The esterification of 6(R)-[2-(8(S)-hydroxy-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydro-1(S)-naphthyl)ethyl]-4(R)-(tert-butyldimethylsilyloxy)tetrahydropyran-2-one (I) with 2,2-dimethylbutyric acid (II) by means of PPh3 and hexachloroethane in dichloromethane gives the protected intermediate (III), which is finally desilylated by means of Me-SO3H in water to yield the target simvastatin.

参考文献中间体

【1】 Kim, J.W.; Bae, H.; Lee, K.H.; Choi, K.D. (Cheil Jedang Corp.); A process for producing simvastatin. WO 0172734 .

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)	22647	(4R,6R)-6-[2-[(1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]ethyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-one		C₂₅H₄₂O₄Si	详情	详情
(II)	50845	2,2'-Dimethyl butyric acid; 2,2-Dimethylbutyric acid; Dimethylethylacetic acid	595-37-9	C₆H₁₂O₂	详情	详情
(III)	22649	(1S,3R,7S,8S,8aR)-8-[2-((2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-oxotetrahydro-2H-pyran-2-yl)ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate		C₃₁H₅₂O₅Si	详情	详情

合成路线6

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

【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

Extended Information