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【结 构 式】 
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【分子编号】25081 【品名】(1S,5R,13R,14R,17S)-4-(cyclopropylmethyl)-14-(methylamino)-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-triene-10,17-diol 【CA登记号】 |
【 分 子 式 】C21H28N2O3 【 分 子 量 】356.465 【元素组成】C 70.76% H 7.92% N 7.86% O 13.47% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reductocondensation of naltrexone (I) with N-methylbenzylamine (II) by means of sodium cyanoborohydride in THF gives the N-benzyl-N-methylaminomorphinan derivative (III), which is debenzylated by hydrogenation with H2 over Pd/C in methanol yielding the methylaminomorphinan (IV). Finally, this compound is acylated with 3(E)-(3-furyl)acryloyl chloride and NaOH, Na2CO3 or triethylamine in methanol, THF or chloroform. Alternatively, methylaminomorphinan (IV) can also be obtained by direct reductocondensation of naltrexone (I) with methylamine by means of H2 over PtO2 in methanol.
| 【1】 Leeson, P.A.; Sorbera, L.A.; Castañer, J.; Nalfurafine Hydrochloride. Drugs Fut 2003, 28, 3, 237. |
| 【2】 Nagase, H.; et al.; Discovery of a structurally novel opioid kappa-agonist derived from 4,5-epoxymorphinan. Chem Pharm Bull 1998, 46, 2, 366. |
| 【3】 Nagase, H.; Hayakawa, J.; Kawamura, H.; Kawai, K.; Endoh, T. (Toray Industries, Inc.); Morphinan derivative and medicinal use. AU 686203; AU 7237394; EP 0663401 . |
| 【4】 Nagase, H.; Kawai, K.; Endo, T.; Ueno, S.; Negishi, Y. (Toray Industries, Inc.); Antitussive. EP 0657163; JP 1995503397; US 5739145; WO 9501178 . |
| 【5】 Nagase, H.; Kawai, K.; Kawamura, K.; Hayakawa, J.; Endo, T. (Toray Industries, Inc.); Morphinan deriv. and medicinal use. EP 0577847; EP 0846694; JP 1994509616; US 6277859; US 6323212; WO 9315081 . |
| 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 | |
| (I) | 25079 | (1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one; Naltrexone | 16590-41-3 | C20H23NO4 | 详情 | 详情 |
| (II) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (III) | 25080 | (1S,5R,13R,14R,17S)-14-[benzyl(methyl)amino]-4-(cyclopropylmethyl)-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-triene-10,17-diol | C28H34N2O3 | 详情 | 详情 | |
| (IV) | 25081 | (1S,5R,13R,14R,17S)-4-(cyclopropylmethyl)-14-(methylamino)-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-triene-10,17-diol | C21H28N2O3 | 详情 | 详情 | |
| (V) | 25082 | (E)-3-(3-furyl)-2-propenoyl chloride | C7H5ClO2 | 详情 | 详情 |