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【结 构 式】 
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【分子编号】38075 【品名】methyl (Z)-2-acetyl-3-(3,4-difluorophenyl)-2-propenoate 【CA登记号】 |
【 分 子 式 】C12H10F2O3 【 分 子 量 】240.2064064 【元素组成】C 60% H 4.2% F 15.82% O 19.98% |
合成路线1
该中间体在本合成路线中的序号：(III)The reaction of methyl acetoacetate (I) with 3,4-difluorobenzaldehyde (II) in hot benzene gives the corresponding benzylidene derivative (III), which is cyclized with O-methylisourea (IV) by means of NaHCO3 in hot DMF yielding the dihydropyrimidine (V). The condensation of (V) with 4-nitrophenyl chloroformate (VI) by means of DMAP in dichloromethane affords the 4-nitrophenyl ester (VII), which is brominated with Br2 in chloroform to the bromomethyl compound (VIII). The cyclization of (VIII) by heating at 130 C affords the furopyrimidine (X), which is treated with propylamine derivative (X) in THF or dichloromethane to furnish the target amide.
| 【1】 Chiu, G.; Tian, D.; Lagu, B.; et al.; Synthesis and evaluation of furo[3,4-d]pyrimidinones as selective alpha1a-adrenergic receptor antagonists. Bioorg Med Chem Lett 2000, 10, 2, 175. |
| 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) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (II) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (III) | 38075 | methyl (Z)-2-acetyl-3-(3,4-difluorophenyl)-2-propenoate | C12H10F2O3 | 详情 | 详情 | |
| (IV) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (V) | 38076 | methyl 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate | C14H14F2N2O3 | 详情 | 详情 | |
| (VI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VII) | 38077 | 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate | C21H17F2N3O7 | 详情 | 详情 | |
| (VIII) | 38078 | 5-methyl 1-(4-nitrophenyl) 4-(bromomethyl)-6-(3,4-difluorophenyl)-2-methoxy-1,5(6H)-pyrimidinedicarboxylate | C21H16BrF2N3O7 | 详情 | 详情 | |
| (IX) | 38079 | 4-nitrophenyl 4-(3,4-difluorophenyl)-2-methoxy-5-oxo-5,6-dihydrofuro[2,3-d]pyrimidine-3(4H)-carboxylate | C20H13F2N3O7 | 详情 | 详情 | |
| (X) | 25450 | methyl 1-(3-aminopropyl)-4-phenyl-4-piperidinecarboxylate | C16H24N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The Knoevenagel condensation between methyl acetoacetate (I) and 3,4-difluorobenzaldehyde (II) afforded the benzylidene derivative (III), which was cyclized with O-methylisourea hemisulfate (IV), yielding the dihydropyrimidine (V). This compound, upon reaction with 4-nitrophenyl chloroformate, regioselectively produced the carbamate ester (VI) (1,2). Treatment of (VI) with aqueous HCl gave the dihydropyrimidinone (VII), which was subsequently coupled with 3-bromopropylamine·HBr (VIII) to give the bromopropyl amide (IX) (1). The intermediate N-(2-carboxamidophenyl)piperazine (XIII) was obtained by condensation of 2-bromobenzonitrile (X) with piperazine (XI), followed by partial hydrolysis of the nitrile group with H2SO4. The title compound was finally obtained by condensation between piperazine (XIII) and bromide (IX) in the presence of KI and K2CO3 in refluxing acetone.
| 【1】 Lagu, B.; Nagarathnam, D.; Miao, S.W.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones. J Med Chem 1999, 42, 23, 4764. |
| 【2】 Marzabadi, M.R.; Murali Dhar, T.G.; Nagarathnam, D.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety. J Med Chem 1999, 42, 23, 4778. |
| 【3】 Wong, W.C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 1021185; JP 2000506904; WO 9742956 . |
| 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) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (II) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (III) | 38075 | methyl (Z)-2-acetyl-3-(3,4-difluorophenyl)-2-propenoate | C12H10F2O3 | 详情 | 详情 | |
| (IV) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (V) | 38076 | methyl 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate | C14H14F2N2O3 | 详情 | 详情 | |
| (VI) | 43072 | 5-benzyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate | C27H21F2N3O7 | 详情 | 详情 | |
| (VII) | 43073 | 5-benzyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-methyl-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate | C26H19F2N3O7 | 详情 | 详情 | |
| (VIII) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (IX) | 43074 | benzyl 3-[[(3-bromopropyl)amino]carbonyl]-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C23H22BrF2N3O4 | 详情 | 详情 | |
| (X) | 15541 | o-bromobenzonitrile; 2-bromobenzonitrile | 2042-37-7 | C7H4BrN | 详情 | 详情 |
| (XI) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (XII) | 43075 | 2-(1-piperazinyl)benzonitrile | C11H13N3 | 详情 | 详情 | |
| (XIII) | 43076 | 2-(1-piperazinyl)benzamide | C11H15N3O | 详情 | 详情 |