【结 构 式】 |
【分子编号】33753 【品名】3-butenoic acid 【CA登记号】625-38-7 |
【 分 子 式 】C4H6O2 【 分 子 量 】86.09044 【元素组成】C 55.81% H 7.02% O 37.17% |
合成路线1
该中间体在本合成路线中的序号:(IX)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.
【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:(III)4-Formylbenzonitrile (I) was converted to oxime (II) by treatment with hydroxylamine hydrochloride in pyridine-ethanol. Chlorination of the oxime with NaOCl, followed by dehydrohalogenation of the intermediate imidoyl chloride and dipolar cycloaddition to vinylacetic acid (III) produced the racemic isoxazoline (IV). The cyano group of (IV) was then converted to amidine (V) by formation of the corresponding imidate and subsequent treatment with methanolic ammonia. After protection of the amidine function of (V) as the Boc-derivative, ester hydrolysis employing LiOH yielded carboxylic acid (VI). Methyl 2-piperidine acetate (VIII) was obtained by catalytic hydrogenation of 2-pyridylacetic acid (VII) in the presence of MeOH and HCl. Coupling of acid (VI) with the racemic methyl 2-piperidineacetate (VIII) in the presence of O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoborate (TBTU) furnished a diastereomeric mixture of amides (IX). Cleavage of the Boc group of (IX) by means of either trifluoroacetic acid or methanolic HCl provided amidine (X). Finally, basic hydolysis of the methyl ester of (X) gave rise to the title compound.
【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 . |
【2】 Olson, R.E.; Wityak, J.; Wexler, R.R.; Sielecki, T.M.; Mous, S.A.; Liu, J.; Thoolen, M.; Ring constrained analogues of beta-alanine-containing GPIIb/IIIa receptor antagonists. Bioorg Med Chem Lett 2000, 10, 5, 449. |
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) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
(II) | 17553 | 4-[(hydroxyimino)methyl]benzonitrile | C8H6N2O | 详情 | 详情 | |
(III) | 33753 | 3-butenoic acid | 625-38-7 | C4H6O2 | 详情 | 详情 |
(IV) | 40752 | 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C12H10N2O3 | 详情 | 详情 | |
(V) | 28137 | methyl 2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate | C13H15N3O3 | 详情 | 详情 | |
(VI) | 28139 | 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C17H21N3O5 | 详情 | 详情 | |
(VII) | 35366 | 2-(2-pyridinyl)acetic acid | 16179-97-8 | C7H7NO2 | 详情 | 详情 |
(VIII) | 40753 | methyl 2-(2-piperidinyl)acetate | C8H15NO2 | 详情 | 详情 | |
(IX) | 40750 | methyl 2-(1-[2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetyl]-2-piperidinyl)acetate | C25H34N4O6 | 详情 | 详情 | |
(X) | 40751 | methyl 2-[1-[2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]-2-piperidinyl]acetate | C20H26N4O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(III)4-Formylbenzonitrile (I) was converted to oxime (II) by treatment with hydroxylamine hydrochloride in pyridine-ethanol. Chlorination of the oxime with NaOCl, followed by dehydrohalogenation of the intermediate imidoyl chloride and dipolar cycloaddition to vinylacetic acid (III) produced the racemic isoxazoline (IV). The cyano group of (IV) was then converted to amidine (V) by formation of the corresponding imidate and subsequent treatment with methanolic ammonia. After protection of the amidine function of (V) as the Boc-derivative, ester hydrolysis employing LiOH yielded carboxylic acid (VI) (1). Coupling of acid (VI) with the racemic ethyl 2-piperidineacetate (VII) in the presence of O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoborate (TBTU) furnished a diastereomeric mixture of amides (VIII). The Boc group of (VIII) was finally cleaved by means of trifluoroacetic acid.
【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 . |
【2】 Olson, R.E.; Wityak, J.; Wexler, R.R.; Sielecki, T.M.; Mous, S.A.; Liu, J.; Thoolen, M.; Ring constrained analogues of beta-alanine-containing GPIIb/IIIa receptor antagonists. Bioorg Med Chem Lett 2000, 10, 5, 449. |
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) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
(II) | 17553 | 4-[(hydroxyimino)methyl]benzonitrile | C8H6N2O | 详情 | 详情 | |
(III) | 33753 | 3-butenoic acid | 625-38-7 | C4H6O2 | 详情 | 详情 |
(IV) | 40752 | 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C12H10N2O3 | 详情 | 详情 | |
(V) | 28137 | methyl 2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate | C13H15N3O3 | 详情 | 详情 | |
(VI) | 28139 | 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C17H21N3O5 | 详情 | 详情 | |
(VII) | 40754 | ethyl 2-(2-piperidinyl)acetate | C9H17NO2 | 详情 | 详情 | |
(VIII) | 40755 | ethyl 2-(1-[2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetyl]-2-piperidinyl)acetate | C26H36N4O6 | 详情 | 详情 |