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【结 构 式】 
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【药物名称】L-054264 【化学名称】N-(Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl)-Dtryptophan 3(S)-(aminomethyl)-1?-cyclohexylmethylamide 【CA登记号】 【 分 子 式 】C33H41N5O2 【 分 子 量 】539.72702 |
【开发单位】Merck & Co 【药理作用】TREATMENT OF GROWTH HORMONE SECRETION DISORDERS |
合成路线1
The chiral intermediate (X) was synthesized from 3-cyanobenzoic acid (I) through the following sequence. Hydrogenation of the cyano group over Raney-nickel provided 3-(aminomethyl)benzoic acid (II), which was protected as the tert-buyl carbamate (III) with Boc2O. Subsequent hydrogenation of the benzene ring of (III) over PtO2 yielded the racemic amino acid (IV), predominantly as the cis isomer. The chiral resolution of (IV) with (S)-a-methylbenzyl amine (V) in EtOAc provided the optically pure 1(R),3(S) compound (VI), which was then reduced with borane in THF. The resulting aminoalcohol (VII), after conversion to mesylate (VIII) with methanesulfonyl chloride, was treated with NaN3 to give azide (IX), and this was then reduced to amine (X) with H2 over Pd/C.
| 【1】 Yang, L.; et al.; Spiro[1H-indene-1,4'-piperidine] derivatives as potent and selective non-peptide human somatostatin receptor subtype 2 (sst2) agonists. J Med Chem 1998, 41, 13, 2175. |
| 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) | 20406 | 3-cyanobenzoic acid | 1877-72-1 | C8H5NO2 | 详情 | 详情 |
| (II) | 20407 | 3-(aminomethyl)benzoic acid | C8H9NO2 | 详情 | 详情 | |
| (III) | 20408 | 3-[[(tert-butoxycarbonyl)amino]methyl]benzoic acid | C13H17NO4 | 详情 | 详情 | |
| (IV) | 20409 | 3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexanecarboxylic acid | C13H23NO4 | 详情 | 详情 | |
| (V) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VI) | 20411 | (1R,3S)-3-(Tert-butoxycarbonylamino)cyclohexanecarboxylic acid (S)-1-phenylethylamine salt | C21H34N2O4 | 详情 | 详情 | |
| (VII) | 20412 | tert-butyl [(1S,3R)-3-(hydroxymethyl)cyclohexyl]methylcarbamate | C13H25NO3 | 详情 | 详情 | |
| (VIII) | 20413 | ((1R,3S)-3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexyl)methyl methanesulfonate | C14H27NO5S | 详情 | 详情 | |
| (IX) | 20414 | tert-butyl [(1S,3R)-3-(azidomethyl)cyclohexyl]methylcarbamate | C13H24N4O2 | 详情 | 详情 | |
| (X) | 20415 | tert-butyl [(1S,3R)-3-(aminomethyl)cyclohexyl]methylcarbamate | C13H26N2O2 | 详情 | 详情 |
合成路线2
Treatment of D-tryptophan methyl ester (XI) with N,N'-disuccinimidyl carbonate (XII) gave the intermediate succinimidyl carbamate (XIII), which was subsequently converted to urea (XV) upon reaction with spiro(indene-1,4'-piperidine) (XIV). Saponification of the ester function of (XV) with LiOH afforded the carboxylic acid (XVI), and this was then coupled with the Boc-protected chiral diamine (X) using EDC and HOBt. The resulting precursor (XVII) was finally deprotected with HCl in EtOAc to provide the title compound.
| 【1】 Yang, L.; et al.; Spiro[1H-indene-1,4'-piperidine] derivatives as potent and selective non-peptide human somatostatin receptor subtype 2 (sst2) agonists. J Med Chem 1998, 41, 13, 2175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 20415 | tert-butyl [(1S,3R)-3-(aminomethyl)cyclohexyl]methylcarbamate | C13H26N2O2 | 详情 | 详情 | |
| (XI) | 20416 | methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate | C12H14N2O2 | 详情 | 详情 | |
| (XII) | 20417 | 1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione | 74124-79-1 | C9H8N2O7 | 详情 | 详情 |
| (XIII) | 20418 | methyl (2R)-2-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]amino)-3-(1H-indol-3-yl)propanoate | C17H17N3O6 | 详情 | 详情 | |
| (XIV) | 20419 | Spiro[indene-1,4'-piperidine] | C13H15N | 详情 | 详情 | |
| (XV) | 20420 | N-[Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl]-D-tryptophan methyl ester | C26H27N3O3 | 详情 | 详情 | |
| (XVI) | 20421 | N-[Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl]-D-tryptophan | C25H25N3O3 | 详情 | 详情 | |
| (XVII) | 20422 | N-[3(R)-[N-alpha-[Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl]-D-tryptophanamidomethyl]cyclohex-1(S)-ylmethyl]carbamic acid tert-butyl ester | C38H49N5O4 | 详情 | 详情 |