【结 构 式】 |
【药物名称】Gantofiban, YM-028, EMD-122-347 【化学名称】2-[4-[3-[4-[N1-(Methoxycarbonyl)amidino]phenyl]-2-oxooxazolidin-5(R)-ylmethyl]piperazin-1-yl]acetic acid ethyl ester 【CA登记号】183547-57-1 【 分 子 式 】C21H29N5O6 【 分 子 量 】447.49518 |
【开发单位】Merck KGaA (Originator), Yamanouchi (Licensee) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists |
合成路线1
The condensation of 4-aminobenzonitrile (I) with the chiral 2,3-epoxypropanol (II) in refluxing methanol gives 4-(2,3-dihydroxypropylamino)benzonitrile (III), which is cyclized with diethyl carbonate (IV) by means of tBu-OK at 100 C to yield the oxazolidinone (V). The reaction of the cyano group of (V) with hydroxylamine in methanol affords the N-hydroxyamidine (VI), which is cyclized with Ac2O at 120 C to provide the 1,2,4-oxadiazole (VII). The hydrolysis of the acetoxy group of (VII) with K2CO3 in refluxing methanol gives the primary alcohol (VIII), which is treated with Ms-Cl and pyridine to yield the corresponding mesylate (IX). The condensation of (IX) with 2-(1-piperazinyl)acetic acid ethyl ester (X) in refluxing acetonitrile affords the adduct (XI), which is hydrogenated with H2 over Pd/C and hydrolyzed with HOAc to obtain the benzamidine derivative (XII). Finally, this compound is acylated with methyl chloroformate (XIII) and NaOH in dichloromethane/water.
【1】 Gante, J.; et al.; New antithrombotic RGD-mimetics with bioavailability. Bioorg Med Chem Lett 1996, 6, 20, 2425. |
【2】 Gante, J.; Juraszyk, H.; Raddatz, P.; Wurziger, H.; Bernotat-Danielowski, S.; Melzer, G. (Merck Patent GmbH); Adhesion receptor antagonists. CA 2175767; DE 19516483; EP 0741133; JP 1996301857; US 6455529 . |
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) | 15361 | 4-Aminobenzonitrile | 873-74-5 | C7H6N2 | 详情 | 详情 |
(II) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
(III) | 54669 | 4-{[(2S)-2,3-dihydroxypropyl]amino}benzonitrile | C10H12N2O2 | 详情 | 详情 | |
(IV) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
(V) | 54670 | 4-[(5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzonitrile | C11H10N2O3 | 详情 | 详情 | |
(VI) | 54671 | N'-hydroxy-4-[(5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzenecarboximidamide | C11H13N3O4 | 详情 | 详情 | |
(VII) | 54672 | {(5S)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl acetate | C15H15N3O5 | 详情 | 详情 | |
(VIII) | 54673 | (5S)-5-(hydroxymethyl)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,3-oxazolidin-2-one | C13H13N3O4 | 详情 | 详情 | |
(IX) | 54674 | {(5S)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate | C14H15N3O6S | 详情 | 详情 | |
(X) | 54675 | 1-(Ethoxycarbonylmethyl)piperazine; N-(Carboethoxymethyl)piperazine; (1-Piperazino)acetic acid ethyl ester | 40004-08-8 | C8H16N2O2 | 详情 | 详情 |
(XI) | 54676 | ethyl 2-[4-({(5R)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-1-piperazinyl]acetate | C21H27N5O5 | 详情 | 详情 | |
(XII) | 54677 | ethyl 2-{4-[((5R)-3-{4-[amino(imino)methyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-1-piperazinyl}acetate | C19H27N5O4 | 详情 | 详情 | |
(XIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester;[(chlorocarbonyl)oxy]methane;methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |