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【结 构 式】 
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【分子编号】17555 【品名】2-[(5R)-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% |
合成路线1
该中间体在本合成路线中的序号：(IV)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：(V)The sulfonation of 2(S)-amino-3-(tert-butoxycarbonylamino)propionic acid methyl ester (I) with 3,5-dimethylisoxazol-4-ylsulfonyl chloride (II) by means of triethylamine in dichloromethane gives the corresponding sulfonamide (III), which is deprotected with trifluoroacetic acid yielding the 3-aminopropionic acid derivative (IV). The condensation of (IV) with [3-(4-cyanophenyl)-4,5-dihydroisoxazol-5(R)-yl]acetic acid (V) by means of TBTU and triethylamine in DMF affords the carboxamide (VI). The cyano group of (VI) is treated first with dry HCl and then with NH3, NH4OAc, or CO3(NH4)2 to obtain the amidino group of (VII). Finally, compound (VII) is hydrolyzed with LiOH, 6N HCl, or rabbit liver esterase.
| 【1】 Sielecki, T.M.; Olson, R.E.; Wityak, J.; et al.; Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action. J Med Chem 1999, 42, 7, 1178. |
| 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) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (II) | 21618 | 3,5-dimethyl-4-isoxazolesulfonyl chloride | 80466-79-1 | C5H6ClNO3S | 详情 | 详情 |
| (III) | 25912 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]propanoate | C14H23N3O7S | 详情 | 详情 | |
| (IV) | 25913 | methyl (2S)-3-amino-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]propanoate | C9H15N3O5S | 详情 | 详情 | |
| (V) | 17555 | 2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C12H10N2O3 | 详情 | 详情 | |
| (VI) | 25910 | methyl (2S)-3-([2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino)-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]propanoate | C21H23N5O7S | 详情 | 详情 | |
| (VII) | 25911 | methyl (2S)-3-[[2-((5R)-3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]propanoate | C21H26N6O7S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(Xb)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4
该中间体在本合成路线中的序号：(V)Condensation of methyl N3-Boc-2,3-diaminopropionate (I) with o-tolylsulfonyl chloride (II) produced sulfonamide (III). Subsequent acid cleavage of the Boc protecting group of (III) gave amine (IV). Coupling of amine (IV) with the previously described (R)-oxazolidineacetic acid (V) using TBTU afforded amide (VI). Pinner reaction of (VI) with methanolic HCl converted nitrile (VI) into imidate (VII), which was further treated with ammonium acetate to furnish amidine (VIII). Finally, selective hydrolysis of the ester function of (VIII) was achieved with either LiOH or with an enzymatic method using rabbit liver esterase.
| 【1】 Sielecki, T.M.; et al.; Synthesis and pharmacology of modified amidine isoxazoline glycoprotein IIb/IIIa receptor antagonists. Bioorg Med Chem Lett 2001, 11, 16, 2201. |
| 【2】 Sielecki, T.M.; Olson, R.E.; Wityak, J.; et al.; Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action. J Med Chem 1999, 42, 7, 1178. |
| 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) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (II) | 49841 | o-Toluenesulfonyl Chloride | 133-59-5 | C7H7ClO2S | 详情 | 详情 |
| (III) | 49842 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C16H24N2O6S | 详情 | 详情 | |
| (IV) | 49843 | methyl (2S)-3-amino-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C11H16N2O4S | 详情 | 详情 | |
| (V) | 17555 | 2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C12H10N2O3 | 详情 | 详情 | |
| (VI) | 49844 | methyl (2S)-3-([2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino)-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C23H24N4O6S | 详情 | 详情 | |
| (VII) | 49845 | methyl (2S)-3-[[2-((5R)-3-[4-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C24H28N4O7S | 详情 | 详情 | |
| (VIII) | 49846 | methyl (2S)-3-[[2-((5R)-3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C23H27N5O6S | 详情 | 详情 |