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【结 构 式】 
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【分子编号】25450 【品名】methyl 1-(3-aminopropyl)-4-phenyl-4-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C16H24N2O2 【 分 子 量 】276.37884 【元素组成】C 69.53% H 8.75% N 10.14% O 11.58% |
合成路线1
该中间体在本合成路线中的序号：(X)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：(X)Condensation of 4-nitrobenzaldehyde (I) with N-methyl acetoacetamide (II) in the presence of piperidine acetate gave benzylideneacetoacetamide (III). This was further condensed with 2-cyanoethyl 3-amino-2-butenoate (IV) to provide dihydropyridine (V), which was resolved into the enantiomers using chiral HPLC. Then, basic hydrolysis of the cyanoethyl ester from the appropriate enantiomer of (V) yielded carboxylic acid (VI). The aminopropyl piperidine (X) was obtained by esterification of 4-phenyl-4-piperidinecarboxylic acid (VII) with MeOH and H2SO4, followed by alkylation of piperidine (VIII) with 3-bromopropylamine (IX). Finally, amine (X) was coupled to acid (VI) by means of EDC and DMAP to furnish the target compound.
| 【1】 Nagarathnam, D.; Wetzel, J.M.; Miao, S.W.; Marzabadi, M.R.; Chiu, G.; Wong, W.C.; Hong, X.; Fang, J.; Forray, C.; Branchek, T.A.; Heydorn, W.E.; Chang, R.S.; Broten, T.; Schorn, T.W.; Gluchowski, C.; Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia. J Med Chem 1998, 41, 26, 5320. |
| 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) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (II) | 25443 | N-methyl-3-oxobutanamide | 20306-75-6 | C5H9NO2 | 详情 | 详情 |
| (III) | 25444 | (Z)-2-acetyl-N-methyl-3-(4-nitrophenyl)-2-propenamide | C12H12N2O4 | 详情 | 详情 | |
| (IV) | 13987 | 2-cyanoethyl (E)-3-amino-2-butenoate | C7H10N2O2 | 详情 | 详情 | |
| (V) | 25445 | 2-cyanoethyl 2,6-dimethyl-5-[(methylamino)carbonyl]-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate | C19H20N4O5 | 详情 | 详情 | |
| (VI) | 25446 | 2,6-dimethyl-5-[(methylamino)carbonyl]-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H17N3O5 | 详情 | 详情 | |
| (VII) | 25447 | 4-phenyl-4-piperidinecarboxylic acid | 3627-45-0 | C12H15NO2 | 详情 | 详情 |
| (VIII) | 25448 | methyl 4-phenyl-4-piperidinecarboxylate | C13H17NO2 | 详情 | 详情 | |
| (IX) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (X) | 25450 | methyl 1-(3-aminopropyl)-4-phenyl-4-piperidinecarboxylate | C16H24N2O2 | 详情 | 详情 |