【结 构 式】 |
【药物名称】 【化学名称】3-(3,5-Dichlorophenyl)-3-[5-oxo-1-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)phenyl]pyrrolidin-3-ylcarboxamido]propionic acid 【CA登记号】345296-69-7, 345296-70-0 (trifluoroacetate) 【 分 子 式 】C24H25Cl2N5O4 【 分 子 量 】518.40395 |
【开发单位】Amgen (Originator) 【药理作用】Bone Diseases, Treatment of, METABOLIC DRUGS, OCULAR MEDICATIONS, ONCOLYTIC DRUGS, Ophthalmic Drugs, Treatment of Osteoporosis, Integrin alphavbeta3 (Vitronectin) Antagonists, Integrin alphavbeta5 Antagonists |
合成路线1
Cyclization of itaconic acid (I) with 3-nitroaniline (II) at 100 C gives rise to 1-(3-nitrophenyl)-5-oxopyrrolidine-3-carboxylic acid (III). Subsequent condensation of acid (III) with methyl 3-amino-3-(3,5-dichlorophenyl)propanoate (IV) in the presence of EDC and HOAt yields amide (V). Reduction of the nitro group of (V) to the corresponding amine (VI) is effected by means of Zn and HOAc. Amine (VI) is then condensed with the cyclic thiourea (VII) employing HgCl2 to furnish the di-Boc-protected guanidine (VIII). Saponification of the methyl ester function of (VIII) then gives acid (IX). The N-Boc groups of (IX) are finally removed by treatment with trifluoroacetic acid to furnish the title compound.
【1】 Dominguez, C.; Chen, G.; Liu, L.; Liu, Q.; Han, N.; Xi, N.; Xu, S.; Huang, Q.; Siegmund, A.; Handley, M.; Kiselyov, A.S. (Amgen Inc.); 1-(Aminophenyl)-2-pyrrolidones as integrin inhibitors. EP 1240158; US 2002019402; WO 0144230 . |
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) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
(II) | 57781 | 1-Amino-3-Nitrobenzene; 3-Nitroaniline; m-Nitroaniline | 99-09-2 | C6H6N2O2 | 详情 | 详情 |
(III) | 57782 | 1-(3-nitrophenyl)-5-oxo-3-pyrrolidinecarboxylic acid | C11H10N2O5 | 详情 | 详情 | |
(IV) | 57783 | methyl 3-amino-3-(3,5-dichlorophenyl)propanoate | C10H11Cl2NO2 | 详情 | 详情 | |
(V) | 57784 | methyl 3-(3,5-dichlorophenyl)-3-({[1-(3-nitrophenyl)-5-oxo-3-pyrrolidinyl]carbonyl}amino)propanoate | C21H19Cl2N3O6 | 详情 | 详情 | |
(VI) | 57785 | methyl 3-({[1-(3-aminophenyl)-5-oxo-3-pyrrolidinyl]carbonyl}amino)-3-(3,5-dichlorophenyl)propanoate | C21H21Cl2N3O4 | 详情 | 详情 | |
(VII) | 57786 | di(tert-butyl) 2-thioxodihydro-1,3(2H,4H)-pyrimidinedicarboxylate | C14H24N2O4S | 详情 | 详情 | |
(VIII) | 57787 | di(tert-butyl) 2-({3-[4-({[1-(3,5-dichlorophenyl)-3-methoxy-3-oxopropyl]amino}carbonyl)-2-oxo-1-pyrrolidinyl]phenyl}imino)dihydro-1,3(2H,4H)-pyrimidinedicarboxylate | C35H43Cl2N5O8 | 详情 | 详情 | |
(IX) | 57788 | N-{[1-(3-{[1,3-bis(tert-butoxycarbonyl)tetrahydro-2(1H)-pyrimidinylidene]amino}phenyl)-5-oxo-3-pyrrolidinyl]carbonyl}-3-(3,5-dichlorophenyl)-beta-alanine | C34H41Cl2N5O8 | 详情 | 详情 |