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【结 构 式】 
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【药物名称】 【化学名称】(-)-4(R)-(3,4-Difluorophenyl)-N-[3-[4-(4-fluorophenyl)piperidin-1-yl]propyl]-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 【CA登记号】 【 分 子 式 】C27H31F3N4O3 【 分 子 量 】516.56832 |
【开发单位】Merck & Co. (Originator), Synaptic (Codevelopment) 【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, alpha1A-Adrenoceptor Antagonists |
合成路线1
Catalytic hydrogenation of tetrahydropyridine (I) produced piperidine (II). Alkylation of (II) with N-(3-bromopropyl)phthalimide (III) gave (IV). Subsequent hydrazinolysis of the phthalimido group of (IV) yielded amine (V). In a related procedure, piperidine (II) was alkylated with N-Boc-3-bromopropylamine (VI) to give (VII), which was deprotected with HCl in EtOAc to give the diamino precursor (V).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 23465 | 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine | 1978-59-2 | C11H12FN | 详情 | 详情 |
| (II) | 39299 | 4-(4-fluorophenyl)piperidine | 37656-48-7 | C11H14FN | 详情 | 详情 |
| (III) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (IV) | 39300 | 2-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-1H-isoindole-1,3(2H)-dione | C22H23FN2O2 | 详情 | 详情 | |
| (V) | 39302 | 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine | C14H21FN2 | 详情 | 详情 | |
| (VI) | 37752 | tert-butyl 3-bromopropylcarbamate | C8H16BrNO2 | 详情 | 详情 | |
| (VII) | 39301 | tert-butyl 3-[4-(4-fluorophenyl)-1-piperidinyl]propylcarbamate | C19H29FN2O2 | 详情 | 详情 |
合成路线2
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 |