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【结 构 式】 
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【药物名称】 【化学名称】N-(4-Fluorophenyl)-N-[2-[3-(2-naphthyl)pyrrolidin-1-yl]ethyl]adamantane-1-carboxamide oxalate 【CA登记号】 【 分 子 式 】C35H39FN2O5 【 分 子 量 】586.70988 |
【开发单位】Merck KGaA (Originator) 【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT Reuptake Inhibitors, 5-HT1A Antagonists |
合成路线1
Reduction of 2,2-diphenylpropionitrile (I) with LiAlH4 in Et2O produced aldehyde (II), which was further converted to cyanohydrin (III) upon treatment with KCN and p-toluenesulfonic acid. The required alpha-hydroxy ester (V) was obtained either by sequential hydrolysis of (III) to amide (IV) and then to ester (V) under acidic conditions or by direct conversion of nitrile (III) to ester (V) with boiling hydroalcoholic HCl. Subsequent saponification of the ester group of (V) with LiOH provided hydroxy acid (VI). This was finally condensed with 4,6-dimethyl-2-chloropyrimidine (VII) in the presence of NaH to give the racemic pyrimidinyl ether.
| 【1】 Klinge, D.; Amberg, W.; Baumann, E.; Kling, A.; Riechers, H.; Unger, L.; Raschack, M.; Hergenroder, S.; Schult, S. (BASF AG); Novel alpha-hydroxylic acid derivs., their production and use. DE 19614533; EP 0892787; JP 2000508326; WO 9738981 . |
| 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) | 48521 | 1,1-Diphenylethyl cyanide; alpha,alpha-Diphenylpropionitrile; 2,2-Diphenylpropionitrile | 5558-67-8 | C15H13N | 详情 | 详情 |
| (II) | 48522 | 2,2-diphenylpropanal | C15H14O | 详情 | 详情 | |
| (III) | 48523 | 2-hydroxy-3,3-diphenylbutanenitrile | C16H15NO | 详情 | 详情 | |
| (IV) | 48524 | 2-hydroxy-3,3-diphenylbutanamide | C16H17NO2 | 详情 | 详情 | |
| (V) | 48525 | ethyl 2-hydroxy-3,3-diphenylbutanoate | C18H20O3 | 详情 | 详情 | |
| (VI) | 48526 | 2-hydroxy-3,3-diphenylbutyric acid | C16H16O3 | 详情 | 详情 | |
| (VII) | 48527 | 2-chloro-4,6-dimethylpyrimidine | C6H7ClN2 | 详情 | 详情 |
合成路线2
A pilot plant process was further developed for the (S)-enantiomer. Darzens condensation of benzophenone (VIII) with methyl chloroacetate gave the glycidic ester (X). Epoxide opening in (X) with trimethylaluminum furnished methyl 2-hydroxy-3,3-diphenylbutyrate (XI), which was hydrolyzed to the corresponding acid (VI) by using KOH in isopropanol. Treatment of the racemic acid (VI) with (S)-1-(4-chlorophenyl)ethylamine (XII) provided the desired (S)-acid salt (XIII). This was finally condensed with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (XIV) in the presence of lithium amide to yield the title compound.
| 【1】 Jansen, R.; et al.; Structural similarity and its suprises: Endothelin receptor antagonists - Process research and development report. Org Process Res Dev 2001, 5, 1, 16. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 48526 | 2-hydroxy-3,3-diphenylbutyric acid | C16H16O3 | 详情 | 详情 | |
| (VIII) | 18732 | benzophenone | 119-61-9 | C13H10O | 详情 | 详情 |
| (IX) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (X) | 21148 | methyl 3,3-diphenyl-2-oxiranecarboxylate | C16H14O3 | 详情 | 详情 | |
| (XI) | 48528 | methyl 2-hydroxy-3,3-diphenylbutanoate | C17H18O3 | 详情 | 详情 | |
| (XII) | 48529 | (S)-4-Chloro-alpha-methylbenzylamine; 1-(4-Chlorophenyl)ethylamine | 4187-56-8 | C8H10ClN | 详情 | 详情 |
| (XIII) | 48530 | (1S)-1-(4-chlorophenyl)-1-ethanaminium (2S)-2-hydroxy-3,3-diphenylbutanoate | C24H26ClNO3 | 详情 | 详情 | |
| (XIV) | 38714 | 4,6-dimethyl-2-(methylsulfonyl)pyrimidine; 4,6-dimethyl-2-pyrimidinyl methyl sulfone | C7H10N2O2S | 详情 | 详情 |