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【结 构 式】 
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【分子编号】39303 【品名】methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate 【CA登记号】 |
【 分 子 式 】C14H14F2N2O4 【 分 子 量 】312.2730464 【元素组成】C 53.85% H 4.52% F 12.17% N 8.97% O 20.49% |
合成路线1
该中间体在本合成路线中的序号：(XI)The cyclization between 3,4-difluorobenzaldehyde (VIII), methyl 4-methoxyacetoacetate (IX) and urea (X) in the presence of cuprous oxide and boron trifluoride etherate gave rise to racemic pyrimidinone (XI). Optical resolution of (XI) by means of chiral HPLC furnished the desired (-)-enantiomer (XII), which was then hydrolyzed to carboxylic acid (XIII). Alternatively, kinetic resolution of (XI) by enzymatic hydrolysis using subtilistin furnished the desired (-)-carboxylic acid (XIII), which was then separated from the unreacted (+)-ester. Finally, coupling of carboxylic acid (XIII) with amine (V) using EDC and HOBt yielded the title amide.
| 【1】 Rittle, K.; et al.; Dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 90. |
| 【2】 Selnick, H.G.; Barrow, J.C.; Nanterment, P.G.; et al.; In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists for the treatment of benign prostatic hyperplasia. J Med Chem 2000, 43, 14, 2703. |
| 【3】 Selnick, H.G.; Nantermet, P.G.; Barrow, J.C. (Merck & Co., Inc.); alpha1a Adrenergic receptor antagonists. WO 0006565 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 39302 | 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine | C14H21FN2 | 详情 | 详情 | |
| (VIII) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (IX) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (X) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (XI) | 39303 | methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XII) | 39304 | methyl (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XIII) | 39305 | (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid | C13H12F2N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXX)In a related synthetic method, condensation between 4-methoxyacetoacetate (XIV), 3,4-difluorobenzaldehyde (XVII) and urea (XXIX) in the presence of copper acetate and boron trifluoride etherate furnished the racemic pyrimidinone (XXX). Enzymatic resolution of (XXX) by incubation with subtilisin yielded a separable mixture of the (R)-acid (XXXII) and the unreacted (S)-ester (XXXI). Alternatively, the (S)-enantiomer (XXXI) was isolated by chiral preparative HPLC. Pyrimidinone (XXXI) was activated by conversion to either aryl carbamate (XXXIII) using 4-nitrophenyl chloroformate or to imidazolide (XXXIV) with carbonyl diimidazole. Finally, coupling of the intermediate amine (X) with either the carbamate (XXXIII) or the imidazolide (XXXIV) furnished the title compound.
| 【1】 O'Malley, S.S.; Chen, T.-B.; Chang, R.S.L.; et al.; In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist. Eur J Pharmacol 2000, 409, 3, 301. |
| 【2】 Broten, T.P.; Nichtberger, S.A.; Siegl, P.K.S. (Merck & Co., Inc.); Combination therapy for the treatment of benign prostatic hyperplasia. WO 9948530 . |
| 【3】 Evans, B.; Dunn, M.; Lagu, B.; Kari, H.P.; Nagarathnam, D.; Vyas, K.P.; Cui, D.; Davis, M.R.; Zhang, K. (Merck & Co., Inc.; Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. WO 0037026 . |
| 【4】 Ikemoto, N.; Taylor, C.S.; Sidler, D.R.; Chartrain, M.; Bills, G.F.; Roberge, C.M.; Li, W.; Larsen, R.D. (Merck & Co., Inc.); alpha 1a Adrenergic receptor antagonist. WO 9907695 . |
| 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 | |
| (XIV) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (XVII) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (XXIX) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (XXX) | 39303 | methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XXXI) | 48402 | methyl (4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XXXII) | 39304 | methyl (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XXXIII) | 48400 | 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate | C21H17F2N3O8 | 详情 | 详情 | |
| (XXXIV) | 48401 | methyl (4S)-4-(3,4-difluorophenyl)-3-(1H-imidazol-1-ylcarbonyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C18H16F2N4O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)3,4-Difluorobenzaldehyde (I) is condensed with methyl 4-methoxyacetoacetate (II) and urea in the presence of boron trifluoride etherate and copper (I) oxide to produce the dihydropyrimidinone adduct (III). After isolation of the desired enantiomer by means of chiral HPLC, reaction with p-nitrophenyl chloroformate leads to the nitrophenyl carbamate (IV). Then, condensation of (IV) with 3 bromoproylamine (V) furnishes the N-bromopropyl urea derivative (VI).
| 【1】 Gluchowski, C.; Chiu, G.; Marzabadi, M.R.; Nagarathnam, D.; Lagu, B.; Noble, S.; Wetzel, J.; Deleon, J.E. (Synaptic Pharmaceutical Corp.); Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof. EP 1299362; WO 0206245 . |
| 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) | 39303 | methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (IV) | 48400 | 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate | C21H17F2N3O8 | 详情 | 详情 | |
| (V) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (VI) | 60991 | methyl (4S)-3-{[(3-bromopropyl)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C18H20BrF2N3O5 | 详情 | 详情 |