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【结 构 式】 
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【分子编号】32572 【品名】(1S,3R)-3-(tert-butoxycarbonyl)-2,2,3-trimethylcyclopentanecarboxylic acid 【CA登记号】 |
【 分 子 式 】C14H24O4 【 分 子 量 】256.34216 【元素组成】C 65.6% H 9.44% O 24.97% |
合成路线1
该中间体在本合成路线中的序号：(IV)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2
该中间体在本合成路线中的序号：(IV)Fischer esterification of L-4-nitrophenylalanine (V) afforded nitrophenylalanine methyl ester (VI), which was then protected as the tert-butyl carbamate (VII) using (Boc)2O. Reduction of the nitro group of (VII) by catalytic hydrogenation gave aniline (VIII). Subsequent coupling of (VIII) with 2,6-dichlorobenzoyl chloride (IX) generated amide (X). Deprotection of the Boc group of (X) using HCl in dioxan provided aminoester (XI), which was coupled with camphoric acid derivative (IV) in the presence of benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (BOP) to yield amide (XII). Deprotection of the tert-butyl ester group of (XII) by means of trifluoroacetic acid gave acid (XIII). Finally, the methyl ester group of (XIII) was hydrolyzed with LiOH to furnish the title compound.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (IV) | 32572 | (1S,3R)-3-(tert-butoxycarbonyl)-2,2,3-trimethylcyclopentanecarboxylic acid | C14H24O4 | 详情 | 详情 | |
| (V) | 15341 | (2S)-2-amino-3-(4-nitrophenyl)propionic acid; 4-nitro-L-phenylalanine | 949-99-5 | C9H10N2O4 | 详情 | 详情 |
| (VI) | 15342 | methyl (2S)-2-amino-3-(4-nitrophenyl)propanoate | C10H12N2O4 | 详情 | 详情 | |
| (VII) | 32574 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propanoate | C15H20N2O6 | 详情 | 详情 | |
| (VIII) | 32575 | methyl (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate | C15H22N2O4 | 详情 | 详情 | |
| (IX) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (X) | 32576 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[(2,6-dichlorobenzoyl)amino]phenyl]propanoate | C22H24Cl2N2O5 | 详情 | 详情 | |
| (XI) | 32578 | methyl (2S)-2-amino-3-[4-[(2,6-dichlorobenzoyl)amino]phenyl]propanoate | C17H16Cl2N2O3 | 详情 | 详情 | |
| (XII) | 32573 | tert-butyl (1R,3S)-3-[[((1S)-1-[4-[(2,6-dichlorobenzoyl)amino]benzyl]-2-methoxy-2-oxoethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylate | C31H38Cl2N2O6 | 详情 | 详情 | |
| (XIII) | 32577 | (1R,3S)-3-[[((1S)-1-[4-[(2,6-dichlorobenzoyl)amino]benzyl]-2-methoxy-2-oxoethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylic acid | C27H30Cl2N2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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 |