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【结 构 式】 
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【分子编号】16606 【品名】Isobutyramide; 2-methylpropanamide 【CA登记号】563-83-7 |
【 分 子 式 】C4H9NO 【 分 子 量 】87.1216 【元素组成】C 55.15% H 10.41% N 16.08% O 18.36% |
合成路线1
该中间体在本合成路线中的序号：(XXII)The N-substituted valine (XIII) has been synthesized as follows: The reaction of isobutyramide (XXII) with phosphorus pentasulfide (P4S10) in ethyl ether gives the corresponding thioamide (XXIII), which is cyclized with 1,3-dichloroacetone (XXIV) by means of MgSO4 in refluxing acetone yielding 4-(chloromethyl)-2-isopropylthiazole (XXV). The reaction of (XXV) with methylamine in water affords N-(2-isopropylthiazol-4-ylmethyl)-N-methylamine (XXVI), which is condensed with N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) by means of 4-(dimethylamino)pyridine (DMAP) and triethylamine in refluxing THF to give the thiazol-substituted L-valine ester (XXVIII). Finally, this compound is converted into the corresponding free acid with LiOH in dioxane/water. The N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) has been synthesized by reaction of chloroformate (XXI) with L-valine methyl ester (XXIX) by means of 4-methylmorpholine (MPH) in dichloromethane.
| 【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700. |
| 【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 . |
| 【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 . |
| 【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35. |
| 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) | 16597 | (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutyric acid | C14H23N3O3S | 详情 | 详情 | |
| (XXI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XXII) | 16606 | Isobutyramide; 2-methylpropanamide | 563-83-7 | C4H9NO | 详情 | 详情 |
| (XXIII) | 16607 | 2-methylpropanethioamide | 13515-65-6 | C4H9NS | 详情 | 详情 |
| (XXIV) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (XXV) | 16609 | 4-(chloromethyl)-2-isopropyl-1,3-thiazole | C7H10ClNS | 详情 | 详情 | |
| (XXVI) | 16610 | (2-isopropyl-1,3-thiazol-4-yl)-N-methylmethanamine; N-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-N-methylamine | 154212-60-9 | C8H14N2S | 详情 | 详情 |
| (XXVII) | 16611 | methyl (2S)-3-methyl-2-[[(4-nitrophenoxy)carbonyl]amino]butanoate | C13H16N2O6 | 详情 | 详情 | |
| (XXVIII) | 16612 | methyl (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutanoate | C15H25N3O3S | 详情 | 详情 | |
| (XXIX) | 16613 | methyl (2S)-2-amino-3-methylbutanoate | C6H13NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III), which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V). The optical resolution of dihydropyrimidine (V) can also be performed as follows: Dihydropyrimidine (V) is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP giving the 4-nitrophenyl ester (VII), which is treated with (R)-(+)-alpha-methylbenzylamine [(R)-MBA] yielding amide (VIII) as mixture of diastereomers that is separated by column chromatography. The (+) isomer was then treated with DBU in hot toluene to provide the dihydropyrimidine (+)(IX), already reported. The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.
| 【1】 Nagarathnam, D.; et al.; Design, synthesis and evaluation of dihydropyrimidinones as alpha-1A selective antagonists: 7. Modification of the piperidine moiety into 4-aminocyclohexane; identification and structure-activity relationship of SNAP 6991 analogs. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 110. |
| 【2】 Nagarathnam, D.; Wong, W.C.; Miao, S.W.; Patane, M.A.; Gluchowski, C. (Merck & Co., Inc.; Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 0866708; JP 2000500470; WO 9717969 . |
| 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) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (II) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (III) | 26656 | methyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate | C13H12F2O4 | 详情 | 详情 | |
| (IV) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (V) | 26658 | methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C15H16F2N2O4 | 详情 | 详情 | |
| (VI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VII) | 26659 | 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C22H19F2N3O8 | 详情 | 详情 | |
| (VIII) | 26660 | methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1-[[(1-phenylethyl)amino]carbonyl]-1,6-dihydro-5-pyrimidinecarboxylate | C24H25F2N3O5 | 详情 | 详情 | |
| (IX) | 26658 | methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C15H16F2N2O4 | 详情 | 详情 | |
| (X) | 16606 | Isobutyramide; 2-methylpropanamide | 563-83-7 | C4H9NO | 详情 | 详情 |
| (XI) | 26659 | 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C22H19F2N3O8 | 详情 | 详情 | |
| (XII) | 26661 | 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate | C21H17F2N3O8 | 详情 | 详情 | |
| (XIII) | 26662 | 4-[(2-aminoethyl)amino]-1-phenylcyclohexanecarbonitrile | C15H21N3 | 详情 | 详情 | |
| (XIV) | 26663 | 4-oxo-1-phenylcyclohexanecarbonitrile | 25115-74-6 | C13H13NO | 详情 | 详情 |
| (XV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III), which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V). The optical resolution of (V) by chiral chromatography affords the (+)(IX) isomer, which is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP in dichloromethane giving the active 4-nitrophenyl ester (+)(X). The hydrolysis of the enol methyl ether of (X) with HCl in ether/dichloromethane yields the pyrimidinone (+)(XI), which is finally condensed with 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) in dichloromethane. The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.
| 【1】 Nagarathnam, D.; et al.; Design, synthesis and evaluation of dihydropyrimidinones as alpha-1A selective antagonists: 7. Modification of the piperidine moiety into 4-aminocyclohexane; identification and structure-activity relationship of SNAP 6991 analogs. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 110. |
| 【2】 Nagarathnam, D.; Wong, W.C.; Miao, S.W.; Patane, M.A.; Gluchowski, C. (Merck & Co., Inc.; Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 0866708; JP 2000500470; WO 9717969 . |
| 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) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (II) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (III) | 26656 | methyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate | C13H12F2O4 | 详情 | 详情 | |
| (IV) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (V) | 26658 | methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C15H16F2N2O4 | 详情 | 详情 | |
| (IX) | 26658 | methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C15H16F2N2O4 | 详情 | 详情 | |
| (X) | 16606 | Isobutyramide; 2-methylpropanamide | 563-83-7 | C4H9NO | 详情 | 详情 |
| (XI) | 26659 | 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C22H19F2N3O8 | 详情 | 详情 | |
| (XII) | 26661 | 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate | C21H17F2N3O8 | 详情 | 详情 | |
| (XIII) | 26662 | 4-[(2-aminoethyl)amino]-1-phenylcyclohexanecarbonitrile | C15H21N3 | 详情 | 详情 | |
| (XIV) | 26663 | 4-oxo-1-phenylcyclohexanecarbonitrile | 25115-74-6 | C13H13NO | 详情 | 详情 |
| (XV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |