-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-[3(R)-Carboxy-2,2,3-trimethylcyclopent-1(S)-ylcarbonyl]-4-(2,4,6-trichlorobenzamido)-L-phenylalanine

【CA登记号】219494-80-1

【分子式】C₂₆H₂₇Cl₃N₂O₆

【分子量】569.87389

【开发单位】Pfizer (Originator), Tanabe Seiyaku (Originator)

【药理作用】Antiarthritic Drugs, Asthma Therapy, RESPIRATORY DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Cell Adhesion Inhibitors, Integrin alpha4beta1 (VLA-4) Antagonists

合成路线1 合成路线2

合成路线1

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).

参考文献中间体

【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

合成路线2

Coupling of aniline (X) with 2,4,6-trichlorobenzoyl chloride (XI) generated amide (XII). Subsequent 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.

参考文献中间体

【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
(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
(XI)	25718	2,4,6-trichlorobenzoyl chloride	4136-95-2	C₇H₂Cl₄O	详情	详情
(XII)	32584	tert-butyl (1R,3S)-3-[[((1S)-2-methoxy-2-oxo-1-[4-[(2,4,6-trichlorobenzoyl)amino]benzyl]ethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylate		C₃₁H₃₇Cl₃N₂O₆	详情	详情
(XIII)	32585	(1R,3S)-3-[[((1S)-2-methoxy-2-oxo-1-[4-[(2,4,6-trichlorobenzoyl)amino]benzyl]ethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylic acid		C₂₇H₂₉Cl₃N₂O₆	详情	详情

Extended Information