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【结 构 式】 
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【分子编号】17553 【品名】4-[(hydroxyimino)methyl]benzonitrile 【CA登记号】 |
【 分 子 式 】C8H6N2O 【 分 子 量 】146.14852 【元素组成】C 65.75% H 4.14% N 19.17% O 10.95% |
合成路线1
该中间体在本合成路线中的序号：(II)Reaction of 4-cyanobenzaldehyde (I) with hydroxylamine sulfate in methanol gives 4-cyanobenzaldoxime (II). A 1,3-dipolar cycloaddition of (II) with isobutyl vinylacetate using N-chlorosuccinimide provides the racemic isoxazoline derivative (III). Treatment of (III) with lipase PS30 selectively converts the (R)-isomer to an optically pure acid (IV). Coupling of (IV) with methyl N2-(n-butyloxycarbonyl)-L-2,3-diaminopropionate (VI), which is derived from its corresponding commerically available acid (V), gives the intermediate (VII). Treatment of (VII) with HCl in methanol and ethyl acetate followed by ammonium acetate affords DMP 754 as a crystalline product. Saponification of DMP 754 using LiOH provides the corresponding acid (VIII).
| 【1】 Anzalone, L.; Storace, L. Ward, R.; Kauffman, G.S.; Zhang, L.-H.; Ma, P.; The chiral specific synthesis of DMP 754, a platelet GPIIb/IIIa antagonist. Tetrahedron Lett 1996, 37, 26, 4455-8. |
| 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) | 17554 | isobutyl 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C16H18N2O3 | 详情 | 详情 | |
| (IV) | 17555 | 2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C12H10N2O3 | 详情 | 详情 | |
| (V) | 17556 | (2S)-3-amino-2-[(butoxycarbonyl)amino]propionic acid | C8H16N2O4 | 详情 | 详情 | |
| (VI) | 17557 | methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate hydrochloride | C9H19ClN2O4 | 详情 | 详情 | |
| (VII) | 17558 | methyl (2S)-2-[(butoxycarbonyl)amino]-3-([2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino)propanoate | C21H26N4O6 | 详情 | 详情 | |
| (VIII) | 17559 | (2S)-3-[[2-((5R)-3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[(butoxycarbonyl)amino]propionic acid | C20H27N5O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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3
该中间体在本合成路线中的序号：(VI)Oxime (VI) was prepared from 4-cyanobenzaldehyde (V) upon treatment with hydroxylamine-HCl and pyridine. The nitrile oxide generated from oxime (VI) and NaOCl underwent a dipolar cycloaddition to methyl butenoate (VII) to produce the racemic isoxazoline (VIII). After conversion of the nitrile group of (VIII) to imidate (IX), reaction with methanolic ammonia yielded amidine (X), which was protected with Boc2O to give (XI). Hydrolysis of the methyl ester of (XI) with LiOH provided carboxylic acid (XII), which was coupled to amine (IV) using TBTU to afford amide (XIII) as a diasteromeric mixture. After Boc group removal by acidic treatment yielding (XIV), its methyl ester group was hydrolyzed with LiOH to afford the corresponding acid. The diastereomeric mixture of carboxylic acids was finally separated by preparative chiral HPLC.
| 【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 |
|---|---|---|---|---|---|---|
| (IV) | 28133 | methyl (2S)-3-amino-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C11H16N2O4S | 详情 | 详情 | |
| (V) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
| (VI) | 17553 | 4-[(hydroxyimino)methyl]benzonitrile | C8H6N2O | 详情 | 详情 | |
| (VII) | 28134 | methyl 3-butenoate | C5H8O2 | 详情 | 详情 | |
| (VIII) | 28135 | methyl 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C13H12N2O3 | 详情 | 详情 | |
| (IX) | 28136 | methyl 2-(3-[4-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate | C14H16N2O4 | 详情 | 详情 | |
| (X) | 28137 | methyl 2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate | C13H15N3O3 | 详情 | 详情 | |
| (XI) | 28138 | methyl 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetate | C18H23N3O5 | 详情 | 详情 | |
| (XII) | 28139 | 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C17H21N3O5 | 详情 | 详情 | |
| (XIII) | 28140 | methyl (2S)-3-[[2-(3-[4-[[(tert-butoxycarbonyl)amino](imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C28H35N5O8S | 详情 | 详情 | |
| (XIV) | 28141 | methyl (2S)-3-[[2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C23H27N5O6S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)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5
该中间体在本合成路线中的序号：(II)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 |