|
【结 构 式】 
|
【药物名称】Lamifiban, Ro-44-9883/023(mono HCl salt), Ro-44-9883/000, Ro-44-9883, Lamstat 【化学名称】2-[1-[N-(4-Amidinobenzoyl)-L-tyrosyl]piperidin-4-yloxy]acetic acid 【CA登记号】144412-49-7, 243835-65-6 (monoHCl) 【 分 子 式 】C24H28N4O6 【 分 子 量 】468.51396 |
【开发单位】Roche (Originator) 【药理作用】Acute Myocardial Infarction, Treatment of, Angina pectoris, Treatment of, Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists |
合成路线1
The acylation of 4-hydroxypiperidine (I) with benzyl chloroformate (II) by means of triethylamine in dichloromethane gives 4-hydroxypiperidine-1-carboxylic acid benzyl ester (III), which is condensed with tert-butyl bromoacetate (IV) by means of tetrabutylammonium hydrogensulfate and NaOH in toluene/water, affording 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (V). The deprotection of (V) by hydrogenation with H2 over Pd/C in ethanol gives the piperidine (VI), which is condensed with N-(benzyloxycarbonyl)-4-O-tert-butyl-L-tyrosine (VII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) in dichloromethane, yielding the expected condensation product (VIII). The deprotection of the amino group of (VIII) by hydrogenation as before affords (IX), which is N-acylated with 4-amidinobenzoyl chloride (X), prepared by reaction of 4-amidinobenzoic acid (XI) with SOCl2, giving the bis-tert-butylated product (XII). Finally, this compound is deprotected by means of trifluoroacetic acid in dichloromethane.
| 【1】 Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393. |
| 【2】 Castaner, J.; Merlos, M.; Cases, A.; Rabasseda, X.; Lamifiban. Drugs Fut 1999, 24, 3, 261. |
| 【3】 Alig, L.; Hadvary, P.; Huzeler, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); N-acyl-alpha-aminoacids derivs.. EP 0505868; JP 1993148204; US 5378712; US 5545658; US 5658928; US 5670515; US 5747522 . |
| 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) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (II) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (III) | 19284 | benzyl 4-hydroxy-1-piperidinecarboxylate | C13H17NO3 | 详情 | 详情 | |
| (IV) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (V) | 19286 | benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate | C19H27NO5 | 详情 | 详情 | |
| (VI) | 19287 | tert-butyl 2-(4-piperidinyloxy)acetate | C11H21NO3 | 详情 | 详情 | |
| (VII) | 22478 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propionic acid | C21H25NO5 | 详情 | 详情 | |
| (VIII) | 22479 | tert-butyl 2-[(1-[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate | C32H44N2O7 | 详情 | 详情 | |
| (IX) | 22480 | tert-butyl 2-[(1-[(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate | C24H38N2O5 | 详情 | 详情 | |
| (X) | 22481 | 4-[amino(imino)methyl]benzoyl chloride | C8H7ClN2O | 详情 | 详情 | |
| (XI) | 22482 | 4-Amidinobenzic acid; 4-[amino(imino)methyl]benzoic acid | 15535-95-2 | C8H8N2O2 | 详情 | 详情 |
| (XII) | 22483 | tert-butyl 2-[(1-[(2S)-2-([4-[amino(imino)methyl]benzoyl]amino)-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate | C32H44N4O6 | 详情 | 详情 |