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【结 构 式】 
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【分子编号】32569 【品名】(1R,3S)-1,2,2-trimethyl-1,3-cyclopentanedicarboxylic acid; (+)-Camphoric acid 【CA登记号】124-83-4 |
【 分 子 式 】C10H16O4 【 分 子 量 】200.23464 【元素组成】C 59.98% H 8.05% O 31.96% |
合成路线1
该中间体在本合成路线中的序号：(A)The (+) isomer of fenfluramine is obtained in the following way: The action of d-camphoric acid on (rac)-fenfluramine (I) forms the camphorate of (+)-fenfluramine (II). After purification of this salt by crystallization, sodium hydroxide in methylene chloride is added, forming (+)-fenfluramine (III) after removal of camphoric acid. Finally, the action of hydrogen chloride in methyl cyclohexane on (+)-fenfluramine produces the corresponding salt: (+)-fenfluramine hydrochloride.
| 【1】 Nathan, C.; Dexfenfluramine Hydrochloride. Drugs Fut 1987, 12, 9, 845. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 32569 | (1R,3S)-1,2,2-trimethyl-1,3-cyclopentanedicarboxylic acid; (+)-Camphoric acid | 124-83-4 | C10H16O4 | 详情 | 详情 |
| (I) | 28740 | rac-(N-ethyl-1-[3-(trifluoromethyl)phenyl]-2-propanamine) | C12H16F3N | 详情 | 详情 | |
| (II) | 65178 | C22H32F3NO4 | 详情 | 详情 | ||
| (III) | 28742 | (2S)-N-ethyl-1-[3-(trifluoromethyl)phenyl]-2-propanamine | C12H16F3N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Partial esterification of (1R,3S)-camphoric acid (I) with MeOH and HCl produced mono methyl ester (II). Further esterification with isobutylene in the presence of H2SO4 yielded methyl tert-butyl ester (III). The methyl ester group of (III) was then selectively hydrolyzed with LiOH to provide tert-butyl ester (IV).
| 【1】 Teegarden, B.R.; Rishton, G.M.; Yamagishi, M.; et al.; Discovery of TR-9109: A novel small molecule inhibitor of alpha4beta1 integrin mediated cell adhesion. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 58. |
| 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) | 32569 | (1R,3S)-1,2,2-trimethyl-1,3-cyclopentanedicarboxylic acid; (+)-Camphoric acid | 124-83-4 | C10H16O4 | 详情 | 详情 |
| (II) | 32570 | (1R,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid | C11H18O4 | 详情 | 详情 | |
| (III) | 32571 | 1-(tert-butyl) 3-methyl (1R,3S)-1,2,2-trimethyl-1,3-cyclopentanedicarboxylate | C15H26O4 | 详情 | 详情 | |
| (IV) | 32572 | (1S,3R)-3-(tert-butoxycarbonyl)-2,2,3-trimethylcyclopentanecarboxylic acid | C14H24O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Partial esterification of (1R,3S)-camphoric acid (I) with MeOH and HCl produced mono methyl ester (II). Further esterification of (II) with isobutylene in the presence of H2SO4 yielded the corresponding methyl tert-butyl ester, which was selectively hydrolyzed with LiOH to provide camphoric acid mono tert-butyl ester (III). From this, intermediate (X) was synthesized by two related methods. Fischer esterification of L-4-nitrophenylalanine (IV) afforded nitrophenylalanine methyl ester (V), which was then coupled with camphoric acid derivative (IV) in the presence of benzotriazolyloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) to yield amide (VI). Then, reduction of the nitro group of (VI) by catalytic hydrogenation gave aniline (X). In an alternative procedure, N-Boc-4-(carbobenzoxyamino)-L-phenylalanine (VII) was deprotected and esterified with MeOH and HCl to provide 4-(carbobenzoxyamino)phenylalanine methyl ester (VIII). Coupling of (VIII) with camphoric acid derivative (III) as above produced amide (IX). Then, hydrogenolytic removal of the carbobenzoxy group of (IX) yielded aniline (X).
| 【1】 Teegarden, B.R.; Rishton, G.M.; Yamagishi, M.; et al.; Discovery of TR-9109: A novel small molecule inhibitor of alpha4beta1 integrin mediated cell adhesion. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 58. |
| 【2】 Rishton, G.; Chrusciel, R.A.; Yamagishi, M.; Polinsky, A.; Thomas, E.W.; Lobl, T.J.; Tanis, S.P.; Teegarden, B.; Fisher, J.F. (Pharmacia Corp.; Tanabe Seiyaku Co., Ltd.); Inhibitors of alpha4beta1 mediated cell adhesion. EP 0991619; WO 9858902 . |
| 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) | 32569 | (1R,3S)-1,2,2-trimethyl-1,3-cyclopentanedicarboxylic acid; (+)-Camphoric acid | 124-83-4 | C10H16O4 | 详情 | 详情 |
| (II) | 32570 | (1R,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid | C11H18O4 | 详情 | 详情 | |
| (III) | 32572 | (1S,3R)-3-(tert-butoxycarbonyl)-2,2,3-trimethylcyclopentanecarboxylic acid | C14H24O4 | 详情 | 详情 | |
| (IV) | 15341 | (2S)-2-amino-3-(4-nitrophenyl)propionic acid; 4-nitro-L-phenylalanine | 949-99-5 | C9H10N2O4 | 详情 | 详情 |
| (V) | 15342 | methyl (2S)-2-amino-3-(4-nitrophenyl)propanoate | C10H12N2O4 | 详情 | 详情 | |
| (VI) | 32579 | tert-butyl (1R,3S)-3-([[(1S)-2-methoxy-1-(4-nitrobenzyl)-2-oxoethyl]amino]carbonyl)-1,2,2-trimethylcyclopentanecarboxylate | C24H34N2O7 | 详情 | 详情 | |
| (VII) | 32580 | (2S)-3-(4-[[(benzyloxy)carbonyl]amino]phenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid | C22H26N2O6 | 详情 | 详情 | |
| (VIII) | 32581 | methyl (2S)-2-amino-3-(4-[[(benzyloxy)carbonyl]amino]phenyl)propanoate | C18H20N2O4 | 详情 | 详情 | |
| (IX) | 32582 | tert-butyl (1R,3S)-3-([[(1S)-1-(4-[[(benzyloxy)carbonyl]amino]benzyl)-2-methoxy-2-oxoethyl]amino]carbonyl)-1,2,2-trimethylcyclopentanecarboxylate | C32H42N2O7 | 详情 | 详情 | |
| (X) | 32583 | tert-butyl (1R,3S)-3-([[(1S)-1-(4-aminobenzyl)-2-methoxy-2-oxoethyl]amino]carbonyl)-1,2,2-trimethylcyclopentanecarboxylate | C24H36N2O5 | 详情 | 详情 |