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【结 构 式】 
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【分子编号】43082 【品名】benzyl 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate 【CA登记号】 |
【 分 子 式 】C21H20F2N2O3 【 分 子 量 】386.3982864 【元素组成】C 65.28% H 5.22% F 9.83% N 7.25% O 12.42% |
合成路线1
该中间体在本合成路线中的序号：(IX)The Knoevenagel condensation between benzyl propionylacetate (V) and 2,4-difluorobenzaldehyde (VI) afforded the benzylidene derivative (VII), which was cyclized with O-methylisourea hemisulfate (VIII), yielding the dihydropyrimidine (IX). This compound, upon reaction with 4-nitrophenyl chloroformate, regioselectively produced the carbamate ester (X). Resolution of the enantiomers of (X) was achieved by condensation with the chiral auxiliary (S)-(-)-alpha-methylbenzylamine (XI) to obtain a mixture of diastereomeric amides, which were separated by flash chromatography. The alpha-methylbenzylaminocarbonyl moiety was then removed from the desired diastereomer (+)-(XII) by treatment with DBU, and the resulting chiral dihydropyridine was again condensed with 4-nitrophenyl chloroformate to give (+)-(X). Coupling of the chiral carbamate (+)-(X) with amine (IV) provided adduct (XIII), which on treatment with aqueous HCl gave the dihydropyrimidinone (XIV). After catalytic hydrogenolysis of the benzyl ester of (XIV), the resulting acid was converted to the title amide by reaction with ammonia in the presence of EDC and DMAP.
| 【1】 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. |
| 【2】 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. |
| 【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 |
|---|---|---|---|---|---|---|
| (IV) | 43079 | 1-(3-aminopropyl)-4-phenyl-4-piperidinecarbonitrile | C15H21N3 | 详情 | 详情 | |
| (V) | 43080 | benzyl 3-oxopentanoate | 4949-45-5 | C12H14O3 | 详情 | 详情 |
| (VI) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (VII) | 43081 | benzyl (Z)-3-(2,4-difluorophenyl)-2-propionyl-2-propenoate | C19H16F2O3 | 详情 | 详情 | |
| (VIII) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (IX) | 43082 | benzyl 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate | C21H20F2N2O3 | 详情 | 详情 | |
| (X) | 43084 | 5-benzyl 1-(4-nitrophenyl) 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,5(6H)-pyrimidinedicarboxylate | C28H23F2N3O7 | 详情 | 详情 | |
| (XI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XII) | 43083 | benzyl 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1-([[(1R)-1-phenylethyl]amino]carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate | C30H29F2N3O4 | 详情 | 详情 | |
| (XIII) | 43085 | benzyl 1-([[3-(4-cyano-4-phenyl-1-piperidinyl)propyl]amino]carbonyl)-6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate | C37H39F2N5O4 | 详情 | 详情 | |
| (XIV) | 43086 | benzyl 3-([[3-(4-cyano-4-phenyl-1-piperidinyl)propyl]amino]carbonyl)-4-(2,4-difluorophenyl)-6-ethyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C36H37F2N5O4 | 详情 | 详情 |