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【结 构 式】 
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【分子编号】22645 【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; Lovastatin 【CA登记号】75330-75-5 |
【 分 子 式 】C24H36O5 【 分 子 量 】404.54684 【元素组成】C 71.26% H 8.97% O 19.77% |
合成路线1
该中间体在本合成路线中的序号：(I)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.
| 【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
该中间体在本合成路线中的序号：(VII)The condensation of 3-(4-morpholinylmethyl)-2H-1-benzopyran-8-ol (VI) with 2(R)-(p-toluenesulfonyloxymethyl)-4-(triphenylmethyl)morpholine (XVI) by means of K2CO3 in DMF gives the protected target compound (XVII), which is finally deprotected with acetic acid and salified with methanesulfonic acid. The intermediates benzopyran (VI) and morpholine (XVI) have been obtained as follows: Benzopyran (VI): The reaction of 8-methoxy-4H-1-benzopyran-3-carboxylic acid (I) with SOCl2 in refluxing toluene gives the acyl chloride (II), which is condensed with morpholine (III) in dioxane yielding the methanone (IV). The reaction of (IV) with BBr3 in dichloromethane affords the 1-(8-hydroxy-2H-1-benzopyran-3-yl)-1-(4-morpholinyl)methanone (V), which is reduced with LiAlH4 in THF giving the desired intermediate benzopyran (VI). Morpholine (XVI): The reaction of benzyl (S)-glycicyl ether (VII) with benzylamine (VIII) gives 1-(benzylamino)-3-(benzyloxy)-2(R)-propanol (IX), which is cyclized with chloroacetyl chloride (X) and triethylamine in dichloromethane yielding the morpholinone (XI). The reduction of (XI) with LiAlH4 in ethyl ether affords the fully protected morpholine (XII), which is debenzylated with H2 over Pd/C in ethanol giving 2(R)-(hydroxyethyl)morpholine (XIII). The reaction of (XIII) with trityl chloride (XIV) and TEA in dichloromethane yields the N-tritylmorpholine (XV), which is finally tosylated with tosyl chloridde and pyridine affording the desired intermediate morpholine (XVI).
| 【1】 Berg, S.; et al.; (R)-(+)-2[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl]morpholine methanesulfonate: A new selective rat 5-hydroxytryptamine1B receptor antagonist. J Med Chem 1998, 41, 11, 1934. |
| 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) | 28621 | 8-methoxy-2H-chromene-3-carboxylic acid | 57543-59-6 | C11H10O4 | 详情 | 详情 |
| (II) | 28622 | 8-methoxy-2H-chromene-3-carbonyl chloride | C11H9ClO3 | 详情 | 详情 | |
| (III) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (IV) | 28623 | (8-methoxy-2H-chromen-3-yl)(4-morpholinyl)methanone | C15H17NO4 | 详情 | 详情 | |
| (V) | 28624 | (8-hydroxy-2H-chromen-3-yl)(4-morpholinyl)methanone | C14H15NO4 | 详情 | 详情 | |
| (VI) | 28625 | 3-(4-morpholinylmethyl)-2H-chromen-8-ol | C14H17NO3 | 详情 | 详情 | |
| (VII) | 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 |
| (VIII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IX) | 28626 | (2S)-1-(benzylamino)-3-(benzyloxy)-2-propanol | C17H21NO2 | 详情 | 详情 | |
| (X) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XI) | 28627 | (6R)-4-benzyl-6-[(benzyloxy)methyl]-3-morpholinone | C19H21NO3 | 详情 | 详情 | |
| (XII) | 28628 | benzyl [(2R)-4-benzylmorpholinyl]methyl ether | C19H23NO2 | 详情 | 详情 | |
| (XIII) | 12353 | (2R)-1,4-Oxazinan-2-ylmethanol | C5H11NO2 | 详情 | 详情 | |
| (XIV) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (XV) | 28629 | [(2R)-4-tritylmorpholinyl]methanol | C24H25NO2 | 详情 | 详情 | |
| (XVI) | 28631 | [(2R)-4-tritylmorpholinyl]methyl 4-methylbenzenesulfonate | C31H31NO4S | 详情 | 详情 | |
| (XVII) | 28632 | (2R)-2-([[3-(4-morpholinylmethyl)-2H-chromen-8-yl]oxy]methyl)-4-tritylmorpholine | C38H40N2O4 | 详情 | 详情 |