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【结 构 式】 
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【分子编号】48396 【品名】5-(2-cyanoethyl) 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate 【CA登记号】 |
【 分 子 式 】C24H20F2N4O8 【 分 子 量 】530.4417664 【元素组成】C 54.34% H 3.8% F 7.16% N 10.56% O 24.13% |
合成路线1
该中间体在本合成路线中的序号：(XXV)Methyl 4-methoxyacetoacetate (XIV) was transesterified with 3-hydroxypropionitrile (XV) at 180 C to yield the 2-cyanoethyl ester (XVI). Subsequent condensation between 3,4-difluorobenzaldehyde (XVII) and ketoester (XVI) in the presence of piperidine acetate furnished the benzylidene derivative (XVIII), which was cyclized with O-methylisourea hemisulfate (XIX) to produce the racemic pyrimidine (XX). Resolution of (XX) was achieved via conversion to the 4-nitrophenyl carbamate (XXI), which was then condensed with (R)-1-phenylethylamine (XXII) to afford a separable mixture of diastereoisomeric amides. The desired isomer (XXIII) was treated with DBU in hot toluene to give the (+)-pyrimidine (XXIV). This was again converted to the corresponding 4-nitrophenyl carbamate (XXV) by reaction with 4-nitrophenyl chloroformate and DMAP.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (XIV) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (XV) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XVI) | 48390 | 2-cyanoethyl 4-methoxy-3-oxobutanoate | C8H11NO4 | 详情 | 详情 | |
| (XVII) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (XVIII) | 48391 | 2-cyanoethyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate | C15H13F2NO4 | 详情 | 详情 | |
| (XIX) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (XX) | 48392 | 2-cyanoethyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C17H17F2N3O4 | 详情 | 详情 | |
| (XXI) | 48393 | 5-(2-cyanoethyl) 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C24H20F2N4O8 | 详情 | 详情 | |
| (XXII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXIII) | 48394 | 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1-([[(1R)-1-phenylethyl]amino]carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate | C26H26F2N4O5 | 详情 | 详情 | |
| (XXIV) | 48395 | 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C17H17F2N3O4 | 详情 | 详情 | |
| (XXV) | 48396 | 5-(2-cyanoethyl) 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C24H20F2N4O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXV)Coupling of (XXV) with the intermediate amine (X) gave urea (XXVI). The methoxydihydropyrimidine ring (XXVI) was hydrolyzed to the tetrahydropyrimidinone (XXVII) by treatment with HCl, and the cyanoethyl ester group was further removed using NaOH in aqueous acetone. The resultant carboxylic acid (XXVIII) was finally esterified with methanol by using EDC and DMAP as the coupling reagents.
| 【1】 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 . |
| 【2】 Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Wong, W.C.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. WO 9851311 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 48387 | 3-[4-(2-pyridinyl)-1-piperidinyl]propylamine; 3-[4-(2-pyridinyl)-1-piperidinyl]-1-propanamine | C13H21N3 | 详情 | 详情 | |
| (XXV) | 48396 | 5-(2-cyanoethyl) 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C24H20F2N4O8 | 详情 | 详情 | |
| (XXVI) | 48397 | 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1-[([3-[4-(2-pyridinyl)-1-piperidinyl]propyl]amino)carbonyl]-1,6-dihydro-5-pyrimidinecarboxylate | C31H36F2N6O5 | 详情 | 详情 | |
| (XXVII) | 48398 | 2-cyanoethyl (4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-3-[([3-[4-(2-pyridinyl)-1-piperidinyl]propyl]amino)carbonyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C30H34F2N6O5 | 详情 | 详情 | |
| (XXVIII) | 48399 | (4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-3-[([3-[4-(2-pyridinyl)-1-piperidinyl]propyl]amino)carbonyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid | C27H31F2N5O5 | 详情 | 详情 |