XU-065, -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

【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).

参考文献中间体

【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

Drug NewChemical Entity Original Patent(1)