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【结 构 式】 
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【分子编号】31357 【品名】N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; (1R,2R)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine 【CA登记号】 |
【 分 子 式 】C11H22N2 【 分 子 量 】182.30916 【元素组成】C 72.47% H 12.16% N 15.37% |
合成路线1
该中间体在本合成路线中的序号：(VII)The condensation of cyclohexene-epoxide (I) with pyrrolidine (II) gives trans-2-(1-pyrrolidinyl)cyclohexanol (III), which by reaction with NaH and methanesulfonyl chloride, and then with benzylamine is converted into trans-2-(1-pyrrolidinyl)-N-benzylcyclohexylamine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords trans-2-(1-pyrrolidinyl)cyclohexylamine (V), which is formylated with ethyl formate to the corresponding N-formyl-trans-2-(1-pyrrolidinyl)cyclohexylamine (VI). The reduction of (VI) with LiAlH4 in refluxing ether gives trans-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (VII), which is finally condensed with 3,4-dichlorophenylacetic acid (VIII) by means of carbonyl diimidazole (IX) in THF.
| 【1】 Blancafort, P.; Castaner, J.; Serradell, M.N.; U-50488. Drugs Fut 1982, 7, 6, 416. |
| 【2】 Szmuszkovicz, J.; 2-Aminocycloaliphatic amide compounds. DE 2749950; ES 463876; FR 2370723; GB 1569225; JP 53063351; JP 61233654; US 4145435 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (B) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 14637 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexanol | C10H19NO | 详情 | 详情 | |
| (IV) | 37038 | N-phenyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]aniline | C16H24N2 | 详情 | 详情 | |
| (V) | 37040 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexylamine; (1R,2R)-2-(1-pyrrolidinyl)cyclohexanamine | C10H20N2 | 详情 | 详情 | |
| (VI) | 37011 | 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-one | C15H20N2O | 详情 | 详情 | |
| (VII) | 31357 | N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; (1R,2R)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine | C11H22N2 | 详情 | 详情 | |
| (VIII) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (IX) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (X) | 37039 | 7-azabicyclo[4.1.0]heptane | C6H11N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(-)-(V)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 |