TR-9109, -Drug Synthesis Database

【结构式】

【药物名称】TR-9109

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

【CA登记号】

【分子式】C₂₆H₂₈Cl₂N₂O₆

【分子量】535.42886

【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 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).

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.

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

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.

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
(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

Extended Information

Drug NewChemical Entity Original Patent(1)