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【结 构 式】 
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【分子编号】26190 【品名】(2R)-2-(acetoxy)-2-phenylethanoic acid 【CA登记号】 |
【 分 子 式 】C10H10O4 【 分 子 量 】194.187 【元素组成】C 61.85% H 5.19% O 32.96% |
合成路线1
该中间体在本合成路线中的序号：(VI)Protection of ethyl piperidine-3-carboxylate (I) with di tert-butyl dicarbonate gave carbamate (II), which was alkylated with 4-(bromomethyl)thiazole (III) in the presence of potassium hexamethyldisilazide to afford racemic (IV). Acid deprotection of the Boc group of (IV) yielded amine (V). This was resolved by coupling with (R)-O-acetyl mandelic acid (VI), followed by chromatographic separation of the diastereoisomers. Then, acid hydrolysis of the desired isomer (VII) provided the (S)-piperidine (VIII). Subsequent coupling of (VIII) with N-Boc-D-tryptophan (IX) in the presence of EDC and HOBt gave amide (X). After Boc deprotection of (X), the resulting amine (XI) was coupled with N-Boc-2-aminoisobutyric acid (XII) to produce (XIII). Finally, acid removal of the Boc group of (XIII) furnished the title compound.
| 【1】 Schleim, K.D.; Leung, K.; Cheng, K.; Patchent, A.A.; Morriello, G.; Smith, R.; Jacks, T.; Yang, L.; Thiazole-derived potent, highly bioavailable short duration growth hormone secretagogues. Bioorg Med Chem Lett 1999, 9, 13, 1761. |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 26196 | 4-(bromomethyl)-1,3-thiazole | C4H4BrNS | 详情 | 详情 | |
| (IV) | 26197 | 1-(tert-butyl) 3-ethyl 3-(1,3-thiazol-4-ylmethyl)-1,3-piperidinedicarboxylate | C17H26N2O4S | 详情 | 详情 | |
| (V) | 26198 | ethyl 3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C12H18N2O2S | 详情 | 详情 | |
| (VI) | 26190 | (2R)-2-(acetoxy)-2-phenylethanoic acid | C10H10O4 | 详情 | 详情 | |
| (VII) | 26199 | ethyl (3S)-1-[(2R)-2-(acetoxy)-2-phenylethanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C22H26N2O5S | 详情 | 详情 | |
| (VIII) | 26200 | ethyl (3S)-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C12H18N2O2S | 详情 | 详情 | |
| (IX) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (X) | 26201 | ethyl (3S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C28H36N4O5S | 详情 | 详情 | |
| (XI) | 26202 | ethyl (3S)-1-[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C23H28N4O3S | 详情 | 详情 | |
| (XII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XIII) | 26203 | ethyl (3S)-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C32H43N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Protection of ethyl piperidine-3-carboxylate (I) with di tert-butyl dicarbonate gave carbamate (II), which was alkylated with 2-(chloromethyl)pyridine chloride (III) in the presence of potassium hexamethyldisilazide to afford racemic (IV). Acid deprotection of the Boc group of (IV) yielded amine (V). This was resolved by coupling with (R)-O-acetyl mandelic acid (VI), followed by chromatographic separation of the diastereoisomers. Then, acid hydrolysis of the desired isomer (VII) provided the (S)-piperidine (VIII). Subsequent coupling of (VIII) with N-Boc-D-tryptophan (IX) in the presence of EDC and HOBt gave amide (X). After Boc deprotection of (X), the resulting amine (XI) was coupled with N-Boc-2-aminoisobutyric acid (XII) to produce (XIII). Finally, acid removal of the Boc group of (XIII) furnished the title compound.
| 【1】 Schleim, K.D.; Leung, K.; Cheng, K.; Patchent, A.A.; Morriello, G.; Smith, R.; Jacks, T.; Yang, L.; Thiazole-derived potent, highly bioavailable short duration growth hormone secretagogues. Bioorg Med Chem Lett 1999, 9, 13, 1761. |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 26187 | 2-(Chloromethyl)pyridine | 4377-33-7 | C6H6ClN | 详情 | 详情 |
| (IV) | 26188 | 1-(tert-butyl) 3-ethyl 3-(2-pyridinylmethyl)-1,3-piperidinedicarboxylate | C19H28N2O4 | 详情 | 详情 | |
| (V) | 26189 | ethyl 3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (VI) | 26190 | (2R)-2-(acetoxy)-2-phenylethanoic acid | C10H10O4 | 详情 | 详情 | |
| (VII) | 26191 | ethyl (3S)-1-[(2R)-2-(acetoxy)-2-phenylethanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C24H28N2O5 | 详情 | 详情 | |
| (VIII) | 26192 | ethyl (3S)-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (IX) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (X) | 26193 | ethyl (3S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C30H38N4O5 | 详情 | 详情 | |
| (XI) | 26194 | ethyl (3S)-1-[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C25H30N4O3 | 详情 | 详情 | |
| (XII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XIII) | 26195 | ethyl (3S)-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C34H45N5O6 | 详情 | 详情 |