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【结 构 式】 
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【分子编号】27474 【品名】tert-butyl (3R)-3-([[(1S)-3-methoxy-3-oxo-1-(3-pyridinyl)propyl]amino]carbonyl)-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C20H29N3O5 【 分 子 量 】391.46748 【元素组成】C 61.36% H 7.47% N 10.73% O 20.44% |
合成路线1
该中间体在本合成路线中的序号：(X)Knoevenagel condensation of pyridine-3-carboxaldehyde (I) with malonic acid in the presence of ammonium acetate afforded the racemic amino acid (III), which was acylated with phenylacetyl chloride (IV) to give amide (V). Optical resolution of (V) by means of penicillin amidase produced the hydrolysis of the undesired (R)-enantiomer. After isolation of the unreacted (S)-enantiomer (VI), its hydrolysis with aqueous HCl furnished the chiral amino acid (VII), which was converted to methyl ester (VIII) with 2,2-dimethoxypropane in MeOH. Coupling of (VIII) with N-Boc-(R)-nipecotic acid (IX) using 2-benzotriazolyl-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) provided amide (X). Deprotection of the Boc group of (X) was then achieved with HCl in dioxan resulting amine (XI).
| 【1】 Hoekstra, W.J.; Damiano, B.P.; Maryanoff, B.E.; et al.; Potent orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure - Activity studies leading to the discovery of RWJ-53308. J Med Chem 1999, 42, 25, 5254. |
| 【2】 Costanzo, M.J.; Hoekstra, W.J.; Maryanoff, B.E. (Ortho-McNeil Pharmaceutical, Inc.); Carboxamide derivs. of pyrrolidine, piperidine and hexahydroazepine for the treatment of thrombosis disorders. EP 0923555; JP 2000510111; US 6069254; WO 9741102 . |
| 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) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (II) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (III) | 27468 | 3-(3-pyridinyl)-beta-alanine | C8H10N2O2 | 详情 | 详情 | |
| (IV) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (V) | 27469 | N-(2-phenylacetyl)-3-(3-pyridinyl)-beta-alanine | C16H16N2O3 | 详情 | 详情 | |
| (VI) | 27470 | (3S)-3-[(2-phenylacetyl)amino]-3-(3-pyridinyl)propionic acid | C16H16N2O3 | 详情 | 详情 | |
| (VII) | 27471 | (3S)-3-amino-3-(3-pyridinyl)propionic acid | C8H10N2O2 | 详情 | 详情 | |
| (VIII) | 27472 | methyl (3S)-3-amino-3-(3-pyridinyl)propanoate | C9H12N2O2 | 详情 | 详情 | |
| (IX) | 27473 | (3R)-1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (X) | 27474 | tert-butyl (3R)-3-([[(1S)-3-methoxy-3-oxo-1-(3-pyridinyl)propyl]amino]carbonyl)-1-piperidinecarboxylate | C20H29N3O5 | 详情 | 详情 | |
| (XI) | 27475 | methyl (3S)-3-[[(3R)piperidinylcarbonyl]amino]-3-(3-pyridinyl)propanoate | C15H21N3O3 | 详情 | 详情 |