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【结 构 式】 
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【药物名称】Nateglinide, DJN-608, SDZ-DJN-608, YM-026, AY-4166, A-4166, Trazec, Fastic, Starlix, Starsis 【化学名称】(-)-N-(trans-4-Isopropylcyclohexyl-1-carbonyl)-D-phenylalanine 【CA登记号】105816-04-4 【 分 子 式 】C19H27NO3 【 分 子 量 】317.43194 |
【开发单位】Ajinomoto (Originator), Aventis Pharma (Marketer), Novartis (Licensee), Yamanouchi (Codevelopment) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Secretagogues, K(ATP) Channel Blockers |
合成路线1
| 【1】 Chen SN, Feng QJ, Yu YM, et aL 2007. Preparation of H type nateglinide crystal.发明专利申请公开说明书．CN 1887858 (Hangzhou Pollen Co, Ltd, Peop Rep China) |
| 【2】 Wang D, Liang YH, Gang P,et aL 2002.A new synthesis method of nateglinide as antidiabetic drug. 中国药物化学杂志，12 (2): 94～96 |
| 【3】 Yahalomi R 2004. Process for preparing nateglirude and intermediates thereof. W0 2004005240[本专利为Teva Pharmaceutical Industries Ltd (IL)-所有] |
| 【4】 Zhu XY, Peng K, Wang XQ, et aL 2001. Synthesis of nateglinide.合成化学,9(6): 537～540 |
合成路线2
The hydrogenation of 4-isopropylbenzoic acid (I) with H2 over PtO2 in acetic acid gives 4-isopropylcyclohexanecarboxylic acid as a mixture of cis- and trans-isomers (II). This mixture is esterified with methanol to the corresponding mixture of methyl esters (III), which is isomerized with NaH at 150 C without solvent, affording the trans-methyl ester (IV). Hydrolysis of (IV) with NaOH in methanol - water gives the free acid (V), which is finally condensed with D-phenylalanine (VI) by means of N-hydroxysuccinimide and dicyclohexylcarbodiimide in chloroform.
| 【1】 Toyoshima, S.; Seto, Y.; Shinkai, H.; Toi, K.; Kumashiro, I. (Ajinomoto Co., Inc.); Hypoglycemic agent. EP 0196222; US 4816484 . |
| 【2】 Shinkai, H.; Dan, K.; Toi, K.; Kumashiro, I.; Seto, Y.; Toyoshima, S.; Nishikawa, M.; Fukuma, M.; Sato, Y.; N-(Cyclohexyl)carbonyl-D-phenylalanines and related compounds. A new class of oral hypoglycemic agents. 2. J Med Chem 1989, 32, 7, 1436. |
| 【3】 Prous, J.; Graul, A.; Castaner, J.; AY-4166. Drugs Fut 1993, 18, 6, 503. |
| 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) | 11698 | 4-Isopropylbenzoic acid | 536-66-3 | C10H12O2 | 详情 | 详情 |
| (II) | 11699 | 4-Isopropylcyclohexanecarboxylic acid | C10H18O2 | 详情 | 详情 | |
| (III) | 11700 | methyl 4-isopropylcyclohexanecarboxylate | C11H20O2 | 详情 | 详情 | |
| (IV) | 11701 | methyl 4-isopropylcyclohexanecarboxylate | C11H20O2 | 详情 | 详情 | |
| (V) | 11702 | 4-Isopropylcyclohexanecarboxylic acid | C10H18O2 | 详情 | 详情 | |
| (VI) | 11703 | D-Phenylalanine; (R)-Phenylalanine | 673-06-3 | C9H11NO2 | 详情 | 详情 |