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【结 构 式】 
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【药物名称】Ruprintrivir, AG-7088 【化学名称】4(S)-[2(R)-(4-Fluorobenzyl)-6-methyl-5(S)-(5-methylisoxazol-3-ylcarboxamido)-4-oxoheptanamido]-5-[2-oxo-3(S)-pyrrolidinyl]-2(E)-pentenoic acid ethyl ester 【CA登记号】223537-30-2 【 分 子 式 】C31H39FN4O7 【 分 子 量 】598.67748 |
【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
Tetrahydrofuranone (XIII): The Grignard condensation of isobutyraldehyde (I) with vinylmagnesium bromide (II) in THF gives the magnesium alcoholate (III), which is condensed with ethyl malonyl chloride (IV) in the same solvent, yielding the mixed ester (V). Treatment of (V) with Ti(OEt)4 at 190 C affords 6-methyl-4(E)-heptenoic acid methyl ester (VI), which by reaction with (R,R)-(-)-pseudoephedrine (VII), oxalyl chloride and DMF in benzene gives the amide (VIII). The regiocontrolled addition of 4-fluorobenzyl chloride (IX) to the chiral amide (VIII) by means of BuLi and LiCl in THF yields the 2(S)-(4-fluorobenzyl)heptanamide (X), which by reaction with NBS in THF/water/acetic acid at 0 C, followed by reflux for 45 min, affords 5(S)-[1(R)-bromo-2-methylpropyl]-3(R)-(4-fluorobenzyl)tetrahydrofuran-2-one (XI). The reaction of (XI) with NaN3 in DMF gives the corresponding azide (XII), which is reduced with H2 over Pd/C, and the resulting amine is protected with tert-butoxycarbonyl anhydride to obtain the desired tetrahydrofuranone (XIII).
| 【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203. |
| 【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9. |
| 【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 . |
| 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) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (II) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (III) | 32096 | 4-Methyl-1-penten-3-ol bromomagnesium salt | C6H11BrMgO | 详情 | 详情 | |
| (IV) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| (V) | 32097 | 1-ethyl 3-(1-isopropyl-2-propenyl) malonate | C11H18O4 | 详情 | 详情 | |
| (VI) | 32098 | methyl (E)-6-methyl-4-heptenoate | C9H16O2 | 详情 | 详情 | |
| (VII) | 32104 | (1R,2R)-2-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (VIII) | 32099 | (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-6-methyl-4-heptenamide | C17H25NO2 | 详情 | 详情 | |
| (IX) | 24611 | 1-(bromomethyl)-4-fluorobenzene | 459-46-1 | C7H6BrF | 详情 | 详情 |
| (X) | 32100 | (2S,4E)-2-(4-fluorobenzyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-6-methyl-4-heptenamide | C24H30FNO2 | 详情 | 详情 | |
| (XI) | 32101 | (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18BrFO2 | 详情 | 详情 | |
| (XII) | 32102 | (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18FN3O2 | 详情 | 详情 | |
| (XIII) | 32103 | tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate | C20H28FNO4 | 详情 | 详情 |
合成路线2
Pyrrolidinone (XXVI): The selective hydrolysis of the known methyl ester (XIV) with NaOH in methanol/water gives the corresponding carboxylic acid (XV), which is coupled with the chiral oxazolidinone (XVI) by means of pivaloyl chloride and Et3N in THF to yield the amide (XVII). The regiocontrolled alkylation of (XVII) with allyl iodide and NaN(SiMe3)2 in THF affords the allyl derivative (XVIII), which is submitted to ozonolysis in dichloromethane to provide the aldehyde (XIX). The condensation of (XIX) with 2,4-dimethoxybenzylamine (XX) yields imine (XXI), which by a reductive cyclization with NaBH3CN in THF/EtOH affords pyrrolidinone (XXII). Cleavage of the oxazolidine ring of (XXII) with TsOH in hot methanol gives the amino alcohol (XXIII), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XXIV). Finally, this compound is condensed with triethyl phosphonoacetate (XXV) by means of NaN(SiMe3)2 in THF to provide the desired pyrrolidinone (XXVI).
| 【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; et al.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. J Med Chem 1999, 42, 7, 1213. |
| 【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9. |
| 【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 | |
| (XIV) | 32109 | tert-butyl (4S)-4-(3-methoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C14H25NO5 | 详情 | 详情 | |
| (XV) | 32110 | 3-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]propionic acid | C13H23NO5 | 详情 | 详情 | |
| (XVI) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (XVII) | 32111 | tert-butyl (4S)-4-[3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C23H32N2O6 | 详情 | 详情 | |
| (XVIII) | 32113 | tert-butyl (4S)-4-((2S)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-pentenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C26H36N2O6 | 详情 | 详情 | |
| (XIX) | 32114 | tert-butyl (4S)-4-((2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C25H34N2O7 | 详情 | 详情 | |
| (XX) | 32115 | (2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine | 20781-21-9 | C9H13NO2 | 详情 | 详情 |
| (XXI) | 32116 | tert-butyl (4S)-4-[(2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-[(2,4-dimethoxybenzyl)imino]butyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C34H45N3O8 | 详情 | 详情 | |
| (XXII) | 32117 | tert-butyl (4S)-4-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C24H36N2O6 | 详情 | 详情 | |
| (XXIII) | 32118 | tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-(hydroxymethyl)ethylcarbamate | C21H32N2O6 | 详情 | 详情 | |
| (XXIV) | 32119 | tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-formylethylcarbamate | C21H30N2O6 | 详情 | 详情 | |
| (XXV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (XXVI) | 32105 | ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate | C25H36N2O7 | 详情 | 详情 |
合成路线3
Final coupling: Deprotection of (XXVI) with HCl in dioxane followed by condensation with tetrahydrofuranone (XIII) by means of DIEA in DMF gives the amide (XXVII). This compound is also deprotected with HCl as before and condensed with 5-methylisoxazol-3-ylcarbonyl chloride (XVIII) by means of pyridine to afford the protected compound (XXIX), which is finally treated with DDQ, yielding AG-7088.
| 【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; et al.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. J Med Chem 1999, 42, 7, 1213. |
| 【2】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203. |
| 【3】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 32103 | tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate | C20H28FNO4 | 详情 | 详情 | |
| (XXVI) | 32105 | ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate | C25H36N2O7 | 详情 | 详情 | |
| (XXVII) | 32106 | ethyl (E,4S)-4-[[(2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoyl]amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate | C40H54FN3O9 | 详情 | 详情 | |
| (XXVIII) | 32107 | 5-methyl-3-isoxazolecarbonyl chloride | C5H4ClNO2 | 详情 | 详情 | |
| (XXIX) | 32108 | ethyl (E,4S)-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-4-[((2R,5S)-2-(4-fluorobenzyl)-6-methyl-5-[[(5-methyl-3-isoxazolyl)carbonyl]amino]-4-oxoheptanoyl)amino]-2-pentenoate | C40H49FN4O9 | 详情 | 详情 |
合成路线4
The alkylation of dimethyl L-glutamate (I) with 2-bromoacetonitrile (II) by means of LiHMDS in THF gives stereoselectively the cyanomethyl derivative (III), which is reduced with H2 over PtO2 in methanol/CHCl3 to yield the corresponding 2-aminoethyl derivative (IV). The cyclization of (IV) by means of Na2CO3 in the same solvent affords the pyrrolidinone (V), whose ester group is reduced with NaBH4 in methanol/THF to provide the propanol derivative (VI). The oxidation of (VI) with SO3/pyridine and DIEA in DMSO/dichloromethane gives the aldehyde (VII), which is finally condensed with ethyl 2-bromoacetate (VIII) by means of Et3P in dichloromethane to yield the chiral 4-(tert-butoxycarbonyl)-5-(2-oxopyrrolidin-3-yl)-2-pentanoic acid ethyl ester (IX), the desired target key intermediate.
| 【1】 Tian, Q.; et al.; An efficient synthesis of a key intermediate for the preparation of the rhinovirus protease inhibitor AG7088 via asymmetric dianionic cyanomethylation of N-Boc-L-(+)-glutamic acid dimethyl ester. Tetrahedron Lett 2001, 42, 39, 6807. |
| 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) | 55035 | dimethyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate | C12H21NO6 | 详情 | 详情 | |
| (II) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (III) | 55036 | dimethyl (2S,4R)-2-[(tert-butoxycarbonyl)amino]-4-(cyanomethyl)pentanedioate | C14H22N2O6 | 详情 | 详情 | |
| (IV) | 55037 | dimethyl (2S,4S)-2-(2-aminoethyl)-4-[(tert-butoxycarbonyl)amino]pentanedioate | C14H26N2O6 | 详情 | 详情 | |
| (V) | 55038 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidinyl]propanoate | C13H22N2O5 | 详情 | 详情 | |
| (VI) | 55039 | tert-butyl (1S)-2-hydroxy-1-{[(3S)-2-oxopyrrolidinyl]methyl}ethylcarbamate | C12H22N2O4 | 详情 | 详情 | |
| (VII) | 55040 | tert-butyl (1S)-1-formyl-2-[(3S)-2-oxopyrrolidinyl]ethylcarbamate | C12H20N2O4 | 详情 | 详情 | |
| (VIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IX) | 55041 | ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-2-oxopyrrolidinyl]-2-pentenoate | C16H26N2O5 | 详情 | 详情 |