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【结 构 式】

【药物名称】XU-065

【化学名称】3-[3-(4-Amidinobenzyloxy)isoxazol-5-ylcarboxamido]-2(R)-(butoxycarbonylamino)propionic acid methyl ester trifluoroacetate

【CA登记号】

【 分 子 式 】C23H28F3N5O9

【 分 子 量 】575.50291

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists

合成路线1

The esterification of (S)-3-amino-2-(benzyloxycarbonylamino)propionic acid (I) with methanol/HCl gives the expected methyl ester (II), which is protected with di-tert-butyl dicarbonate and triethylamine in chloroform to the fully protected compound (III). The debenzylation of (III) by treatment with formic acid over Pd/C in methanol yields the 2-amino compound (IV), which is acylated with butyl chloroformate and NaHCO3 in THF affording 2(S)-(n-butoxycarbonylamino)-3-(tert-butoxycarbonylamino)propionic acid methyl ester (V).The selctive deacylation of (V) with trifluoroacetic acid in dichloromethane affords the 3-amino-2(S)-(n-butoxycarbonylamino)propionic ester (VI), which is acylated with 3-(4-cyanobenzyloxy)isoxazole-5-carboxylic acid (VII) by means of BOP or TBTU and triethylamine or DIEA in DMF giving the cyanobenzyl derivative (VIII). Finally, this compound treated first with HCl in methanol, and then with NH3 in the same solvent to provide the target compound.

1 Xue, C.-B.; Roderick, J.; Mousa, S.; Olson, R.E.; DeGrado, W.F.; Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists. Bioorg Med Chem Lett 1998, 8, 24, 3499.
2 Degrado, W.F.; Xue, C.-B. (DuPont Pharmaceuticals Co.); Cpds. containing basic and acidic termini useful as fibrinogen receptor antagonists. US 5563158; WO 9518111 .
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) 18008 (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid 35761-26-3 C11H14N2O4 详情 详情
(II) 25093 methyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate C12H16N2O4 详情 详情
(III) 25094 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate C17H24N2O6 详情 详情
(IV) 25095 methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate C9H18N2O4 详情 详情
(V) 25096 methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[(butoxycarbonyl)amino]propanoate C14H26N2O6 详情 详情
(VI) 25097 methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate C9H18N2O4 详情 详情
(VII) 25098 3-[(4-cyanobenzyl)oxy]-5-isoxazolecarboxylic acid C12H8N2O4 详情 详情
(VIII) 25099 methyl (2S)-2-[(butoxycarbonyl)amino]-3-[([3-[(4-cyanobenzyl)oxy]-5-isoxazolyl]carbonyl)amino]propanoate C21H24N4O7 详情 详情
(X) 25100 methyl (2S)-3-([[3-([4-[amino(imino)methyl]benzyl]oxy)-5-isoxazolyl]carbonyl]amino)-2-[(butoxycarbonyl)amino]propanoate C21H27N5O7 详情 详情

合成路线2

The intermediate 3-(4-cyanobenzyloxy)isoxazole-5-carboxylic acid (VII) has been obtained by condensation of 4-(bromomethyl)benzonitrile (IX) with 3-hydroxyisoxazole-5-carboxylic acid methyl ester (X) by means of K2CO3 in hot DMF to yield the benzyloxy derivative (XI), which is finally hydrolyzed with LiOH in THF to provide the target intermediate (VII).

1 Xue, C.-B.; Roderick, J.; Mousa, S.; Olson, R.E.; DeGrado, W.F.; Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists. Bioorg Med Chem Lett 1998, 8, 24, 3499.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 25098 3-[(4-cyanobenzyl)oxy]-5-isoxazolecarboxylic acid C12H8N2O4 详情 详情
(IX) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(X) 25101 methyl 3-hydroxy-5-isoxazolecarboxylate 10068-07-2 C5H5NO4 详情 详情
(XI) 25103 N-omega'-nitro-D-arginine C6H13N5O4 详情 详情
Extended Information