2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid -Drug Synthesis Database

【结构式】

【分子编号】33754

【品名】2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid

【CA登记号】

【分子式】C₁₂H₁₀N₂O₃

【分子量】230.22308

【元素组成】C 62.61% H 4.38% N 12.17% O 20.85%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XI),(Xa)

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

合成目标

【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2

该中间体在本合成路线中的序号：(XI)

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

合成目标

【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3

该中间体在本合成路线中的序号：(XI)

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

合成目标

【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