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【结 构 式】 
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【分子编号】14433 【品名】3,3,5,5-tetramethylcyclohexanone 【CA登记号】14376-79-5 |
【 分 子 式 】C10H18O 【 分 子 量 】154.25232 【元素组成】C 77.87% H 11.76% O 10.37% |
合成路线1
该中间体在本合成路线中的序号：(I)The 2-chloro-4,4,6,6-tetramethylcyclohexene aldehyde (II), prepared by a Vilsmeier reaction on commercially available 3,3,5,5-tetramethylcyclohexanone (I), underwent a copper catalyzed 1,4 addition of the Grignard reagent derived from 5-bromo-2-fluorotoluene(III) to yield the 2-aryl substituted 4,4,6,6-tetramethylcyclohexene aldehyde (IV). Treatment of the aldehyde (IV) with the anion of ethylidenecyclohexylamine (V), followed by hydrolysis of the intermediate beta-hydroxyimine by silica gel chromatography, gave the extended aldehyde (VI). Addition of the dianion of methyl acetoacetate (VII) to aldehyde (VI) and stereospecific reduction of the resulting delta-hydroxy-beta-ketoester (VIII) with triethylborane and sodium borohydride yielded the erythro 3,5-dihydroxy methyl ester (IX). Hydrolysis of the methyl ester, followed by lactonization with triethylamine and methyl chloroformate produced dalvastatin).
| 【1】 Neuenschwander, K.W.; Regan, J.R.; Kosmider, B.J.; Scotese, A.C. (Aventis Pharma SA); Novel HMG-CoA reductase inhibitors. EP 0403487; JP 1991503280; US 4863957; WO 8905639 . |
| 【2】 Amin, D.; Neuenschwander, K.; Dalvastatin. Drugs Fut 1992, 17, 5, 377. |
| 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) | 14433 | 3,3,5,5-tetramethylcyclohexanone | 14376-79-5 | C10H18O | 详情 | 详情 |
| (II) | 14434 | 2-chloro-4,4,6,6-tetramethyl-1-cyclohexene-1-carbaldehyde | C11H17ClO | 详情 | 详情 | |
| (III) | 63828 | bromo(4-fluoro-3-methylphenyl)magnesium | 82297-89-0 | C7H6BrFMg | 详情 | 详情 |
| (IV) | 14435 | 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexene-1-carbaldehyde | C18H23FO | 详情 | 详情 | |
| (V) | 63829 | N-[(E)ethylidene]cyclohexanamine; N-cyclohexyl-N-[(E)ethylidene]amine | C8H15N | 详情 | 详情 | |
| (VI) | 14436 | (E)-3-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]-2-propenal | C20H25FO | 详情 | 详情 | |
| (VII) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VIII) | 14437 | methyl (E)-7-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]-5-hydroxy-3-oxo-6-heptenoate | C25H33FO4 | 详情 | 详情 | |
| (IX) | 14438 | methyl (3R,5S,6E)-7-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]-3,5-dihydroxy-6-heptenoate | C25H35FO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Addition of methylmagnesium iodide to 3,3,5,5-tetramethylcyclohexanone (I) produced the tertiary alcohol (II). Subsequent treatment of alcohol (II) with hydrazoic acid in the presence of TiCl4 gave azide (III). This was then reduced with LiAlH4 to the corresponding amine, which was isolated as the hydrochloride salt.
| 【1】 Jirgensons, A.; et al.; Synthesis and structure-affinity relationships of 1,3,5-alkylsubstituted cyclohexylamines binding at NMDA receptor PCP site. Eur J Med Chem 2000, 35, 6, 555. |
| 【2】 Kalvinsh, I.; Gold, M.; Parsons, C.G.R.; Jirgensons, A.; Klauss, V. (Merz Pharmaceuticals GmbH); 1-Amino-alkylcyclohexane NMDA receptor antagonists. JP 2002511873; WO 9901416 . |