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【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
Extended Information