|
【结 构 式】 
|
【药物名称】 【化学名称】4(S)-[3-(3,4-Difluorophenyl)-2(S)-[3-(5-methylisoxazol-3-ylcarboxamido)-2-oxo-1,2-dihydropyridin-1-yl]propionamido]-5-[2-oxopyrrolidin-3(S)-yl]-2(E)-pentenoic acid isopropyl ester 【CA登记号】343566-12-1 【 分 子 式 】C31H33F2N5O7 【 分 子 量 】625.63476 |
【开发单位】Agouron (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Anti-Rhinovirus Drugs, Antiviral Drugs, HRV 3C Protease Inhibitors |
合成路线1
Catalytic hydrogenation of 2-hydroxy-3-nitropyridine (I) in the presence of Pd/C affords 3-amino-2-hydroxypyridine (II). This is then acylated by 5-methylisoxazole-3-carbonyl chloride (III) to furnish the corresponding amide (IV). (1)
| 【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; Johnson, T.O. Jr. (Agouron Pharmaceuticals, Inc.); Antipicornaviral cpds. and compsns., their pharmaceutical uses, and material for their synthesis. JP 2003515591; US 2001047006; US 6514997; WO 0140189 . |
合成路线2
Deprotection of N-Boc-D-3,4-difluorophenylalanine (V) by means of HCl in dioxane yields aminoacid (VI). Subsequent diazotization of (VI) with NaNO2/H2SO4 leads to hydroxyacid (VII). After esterification of (VII) with methanolic HCl, the hydroxyester (VIII) is converted into triflate (IX) upon treatment with trifluoromethanesulfonic anhydride and 2,6-lutidine. Condensation of hydroxypyridine (IV) with triflate (IX) in the presence of NaH gives rise to the N-alkylated pyridone (X). The methyl ester group of (X) is then hydrolyzed to the corresponding carboxylic acid (XI) by means of either NaOH or LiI in pyridine. (1,2)
| 【1】 Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors: 6. Structure-activity studies of orally bioavailable, 2-pyridone-containing peptidomimetics. J Med Chem 2002, 45, 8, 1607. |
| 【2】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; Johnson, T.O. Jr. (Agouron Pharmaceuticals, Inc.); Antipicornaviral cpds. and compsns., their pharmaceutical uses, and material for their synthesis. JP 2003515591; US 2001047006; US 6514997; WO 0140189 . |
| 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) | 63727 | N-(2-hydroxy-3-pyridinyl)-5-methyl-3-isoxazolecarboxamide | C10H9N3O3 | 详情 | 详情 | |
| (V) | 63728 | N-{[(1,1-dimethylethyl)oxy]carbonyl}-3,4-difluorophenylalanine | C14H17F2NO4 | 详情 | 详情 | |
| (VI) | 63729 | 3,4-difluorophenylalanine | C9H9F2NO2 | 详情 | 详情 | |
| (VII) | 63730 | 3-(3,4-difluorophenyl)-2-hydroxypropanoic acid | C9H8F2O3 | 详情 | 详情 | |
| (VIII) | 63731 | methyl 3-(3,4-difluorophenyl)-2-hydroxypropanoate | C10H10F2O3 | 详情 | 详情 | |
| (IX) | 63732 | methyl 3-(3,4-difluorophenyl)-2-{[(trifluoromethyl)sulfonyl]oxy}propanoate | C11H9F5O5S | 详情 | 详情 | |
| (X) | 63733 | methyl 3-(3,4-difluorophenyl)-2-[3-{[(5-methyl-3-isoxazolyl)carbonyl]amino}-2-oxo-1(2H)-pyridinyl]propanoate | C20H17F2N3O5 | 详情 | 详情 | |
| (XI) | 63734 | 3-(3,4-difluorophenyl)-2-[3-{[(5-methyl-3-isoxazolyl)carbonyl]amino}-2-oxo-1(2H)-pyridinyl]propanoic acid | C19H15F2N3O5 | 详情 | 详情 |
合成路线3
Treatment of the Boc-protected aminoalcohol (XII) with trifluoroacetic acid furnishes (XIII). This is then coupled with acid (XI) in the presence of HATU to afford the amide alcohol (XIV). Oxidation of (XIV) with the Dess-Martin periodinane (DMP) reagent gives rise to aldehyde (XV). Finally, Wittig condensation of aldehyde (XV) with isopropoxycarbonylmethylene triphenylphosphorane provides the target unsaturated ester. (1,2)
| 【1】 Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors: 6. Structure-activity studies of orally bioavailable, 2-pyridone-containing peptidomimetics. J Med Chem 2002, 45, 8, 1607. |
| 【2】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; Johnson, T.O. Jr. (Agouron Pharmaceuticals, Inc.); Antipicornaviral cpds. and compsns., their pharmaceutical uses, and material for their synthesis. JP 2003515591; US 2001047006; US 6514997; WO 0140189 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 63734 | 3-(3,4-difluorophenyl)-2-[3-{[(5-methyl-3-isoxazolyl)carbonyl]amino}-2-oxo-1(2H)-pyridinyl]propanoic acid | C19H15F2N3O5 | 详情 | 详情 | |
| (XII) | 55039 | tert-butyl (1S)-2-hydroxy-1-{[(3S)-2-oxopyrrolidinyl]methyl}ethylcarbamate | C12H22N2O4 | 详情 | 详情 | |
| (XIII) | 63735 | 3-(2-amino-3-hydroxypropyl)-2-pyrrolidinone | C7H14N2O2 | 详情 | 详情 | |
| (XIV) | 63736 | N-{1-[1-[(3,4-difluorophenyl)methyl]-2-({2-hydroxy-1-[(2-oxo-3-pyrrolidinyl)methyl]ethyl}amino)-2-oxoethyl]-2-oxo-1,2-dihydro-3-pyridinyl}-5-methyl-3-isoxazolecarboxamide | C26H27F2N5O6 | 详情 | 详情 | |
| (XV) | 63737 | N-[1-(1-[(3,4-difluorophenyl)methyl]-2-{[1-formyl-2-(2-oxo-3-pyrrolidinyl)ethyl]amino}-2-oxoethyl)-2-oxo-1,2-dihydro-3-pyridinyl]-5-methyl-3-isoxazolecarboxamide | C26H25F2N5O6 | 详情 | 详情 |