XP-280(as besilate), XV-459, -Drug Synthesis Database

【结构式】

【药物名称】XP-280(as besilate), XV-459

【化学名称】3-[3-(4-Amidinophenyl)-4,5-dihydroisoxazol-5(R)-ylacetamido]-2(S)-(butoxycarbonylamino)propionic acid
　　　　　　3-[2-[3-(4-Amidinophenyl)-4,5-dihydroisoxazol-5(R)-yl]acetamido]-N-(butoxycarbonyl)-L-alanine

【CA登记号】170902-52-0, 185966-11-4 (monotrifluoroacetate)

【分子式】C₂₀H₂₇N₅O₆

【分子量】433.46809

【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3 合成路线4

合成路线1

Esterification of N2-benzyloxycarbonyl-(S)-2,3-diaminopropionic acid (I) by means of methanolic HCl, followed by protection of the resulting aminoester (II) with Boc2O provided methyl N2-Cbz-N3-Boc-L-2,3-diaminopropionate (III). Removal of the benzyloxycarbonyl group of (III) was effected by catalytic transfer hydrogenolysis with formic acid and Pd/C. The deprotected aminoester (IV) was then condensed with n-butyl chloroformate to give carbamate (V). Subsequent cleavage of the Boc protecting group of (V) using trifluoroacetic acid furnished the target intermediate (VI).

参考文献中间体

【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 .

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

合成路线2

Intermediate (XI) has been obtained as follows: Aldehyde (VII) was converted to the corresponding oxime (VIII) by treatment with hydroxylamine hydrochloride in pyridine. Dipolar cycloaddition of 3-butenoic acid (IX) with the nitrile oxide formed in situ by chlorination of oxime (VIII) and further elimination of HCl produced the racemic isoxazoline (X). Isolation of the required (R)-enantiomer (XI) was performed by chiral preparative HPLC on a Chiralpak AD column or, alternatively, through fractional crystallization of the diastereomeric cinchonidine salts.

参考文献中间体

【1】 Wityak, J.; et al.; Discovery of potent isoxazoline glycoprotein IIb/IIIa receptor antagonists. J Med Chem 1997, 40, 1, 50.
【2】 Wityak, J.; Sielecki, T.M.; Xue, C.-B.; et al.; Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists. J Med Chem 1997, 40, 13, 2064-84.
【3】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Xb)	17555	2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid		C₁₂H₁₀N₂O₃	详情	详情
(XI),(Xa)	33754	2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid		C₁₂H₁₀N₂O₃	详情	详情
(VII)	17552	4-formylbenzonitrile; 4-Cyanobenzaldehyde	105-07-7	C₈H₅NO	详情	详情
(VIII)	17553	4-[(hydroxyimino)methyl]benzonitrile		C₈H₆N₂O	详情	详情
(IX)	33753	3-butenoic acid	625-38-7	C₄H₆O₂	详情	详情

合成路线3

In a further procedure, lipase-mediated hydrolysis of the racemic n-butyl ester (XII) provided the required (R)-acid (XI) along with unreacted (S)-ester (XIII), which was recycled through racemization using potassium tert-butoxide.

参考文献中间体

【1】 Wityak, J.; Sielecki, T.M.; Xue, C.-B.; et al.; Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists. J Med Chem 1997, 40, 13, 2064-84.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIIa)	33755	butyl 2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate	C₁₆H₁₈N₂O₃	详情	详情
(XIIb),(XIII)	33756	butyl 2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate	C₁₆H₁₈N₂O₃	详情	详情
(XI)	33754	2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid	C₁₂H₁₀N₂O₃	详情	详情

合成路线4

Coupling of (R)-acid (XI) with (S)-aminoester (VI) employing either BOP or TBTU gave rise to amide (XIV). Conversion of the nitrile group of (XIV) to imidate (XV), followed by reaction with ammonium carbonate in MeOH afforded amidine (XVI). Finally, the methyl ester group of (XVI) was hydrolyzed by means of LiOH in aqueous methanol.

参考文献中间体

【1】 Wityak, J.; Sielecki, T.M.; Xue, C.-B.; et al.; Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists. J Med Chem 1997, 40, 13, 2064-84.
【2】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	25097	methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate	C₉H₁₈N₂O₄	详情	详情
(XI)	33754	2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid	C₁₂H₁₀N₂O₃	详情	详情
(XIV)	33757	methyl (2S)-2-[(butoxycarbonyl)amino]-3-([2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino)propanoate	C₂₁H₂₆N₄O₆	详情	详情
(XV)	33758	methyl (2S)-2-[(butoxycarbonyl)amino]-3-[[2-((5S)-3-[4-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]propanoate	C₂₂H₃₀N₄O₇	详情	详情
(XVI)	33759	methyl (2S)-3-[[2-((5S)-3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[(butoxycarbonyl)amino]propanoate	C₂₁H₂₉N₅O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)