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【结 构 式】 
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【药物名称】PD-123497, RSD-921 【化学名称】(+)-(1R,2R)-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene-4-acetamide 【CA登记号】114419-77-1 【 分 子 式 】C21H28N2OS 【 分 子 量 】356.53411 |
【开发单位】Pfizer (Originator), Cardiome (Licensee), Chemical Company of Malaysia (Licensee) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Anesthetic Drugs, Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, Local Anesthetics, Sodium Channel Blockers |
合成路线1
Ring opening of cyclohexene oxide (I) with aqueous methylamine gave trans 2-(methylamino)cyclohexanol (II), which was further cyclized to the aziridine (III) upon treatment with chlorosulfonic acid and then with NaOH. Subsequent condensation of (III) with pyrrolidine (IV) yielded the racemic trans diamine (V). Resolution was achieved by fractional crystallization of the 2,3-di-p-toluoyl-D-tartaric acid salt in MeOH. The required (-)-(R,R) enantiomer was finally coupled with 4-benzothiopheneacetyl chloride (VI) to provide the corresponding amide.
| 【1】 MacLeod, B.A.; Walker, M.J.A.; Wall, R.A. (University of British Columbia); Aminocyclohexylamides for antiarrhythmic and anaesthetic uses. EP 0632806; JP 1995505151; US 5506257; WO 9319056 . |
| 【2】 Bain, A.I. (Nortran Pharmaceuticals Inc.); Mixtures of enantiomers of aminocyclohexylamides to produce simultaneous analgesia with local anaesthesia or antiarrhythmia. WO 9916431 . |
| 【3】 Halfpenny, P.R.; Schofield, D.; Hughes, J.; Rees, D.C.; Jarvis, T.C.; Hill, R.G.; Horwell, D.C.; Clark, C.R.; Highly selective kappa opioid analgesics. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy]acetamide derivatives. J Med Chem 1988, 31, 4, 831. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| (+)-(V) | 11051 | (1S,2S)-N-Methyl-2-(1-pyrrolidinyl)cyclohexanamine; N-Methyl-N-[(1S,2S)-2-(1-pyrrolidinyl)cyclohexyl]amine | C11H22N2 | 详情 | 详情 | |
| (-)-(V) | 31357 | N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; (1R,2R)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine | C11H22N2 | 详情 | 详情 | |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (II) | 31355 | (1R,2R)-2-(methylamino)cyclohexanol | C7H15NO | 详情 | 详情 | |
| (III) | 31356 | 7-methyl-7-azabicyclo[4.1.0]heptane | C7H13N | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VI) | 11050 | 2-(1-Benzothiophen-4-yl)acetyl chloride | C10H7ClOS | 详情 | 详情 |