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【结 构 式】 
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【药物名称】 【化学名称】2-[5-[3(R)-(Dimethylamino)pyrrolidin-1-ylsulfonyl]-2-propoxyphenyl]-5-(4-fluorobenzylamino)-4,8-dihydro-3H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-4-one 【CA登记号】 【 分 子 式 】C30H33FN8O4S 【 分 子 量 】620.71111 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】RENAL-UROLOGIC DRUGS, Treatment of Erectile Dysfunction, Treatment of Male Sexual Dysfunction, Phosphodiesterase V (PDE5A) Inhibitors |
合成路线1
3-Amino-4-carbethoxypyrazole (I) was protected with p-methoxybenzyl chloride (II) in the presence of NaH to give two alkylated regioisomers (III) and (IV). This mixture was subjected to condensation with diethyl malonate under basic conditions to furnish the respective pyrazolopyridines (V) and (VI). Only isomer (VI) could be converted to its corresponding dichloro derivative (VII) under reflux in POCl3. Regioselective displacement of one chloride group from (VII) with ethanolic ammonia afforded amine (VIII). The ester group of (VIII) was then hydrolyzed by LiOH to the carboxylic acid (IX), which was converted to amide (X) via activation as the pentafluorophenyl ester.
| 【1】 Bi, Y.; et al.; The discovery of novel, potent and selective PDE5 inhibitors. Bioorg Med Chem Lett 2001, 11, 18, 2461. |
| 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) | 51140 | 3-Amino-4-pyrazolecarboxylic acid ethyl ester; Ethyl 3-aminopyrazole-4-carboxylate; 3-Amino-4-carbethoxypyrazole | 6994-25-8 | C6H9N3O2 | 详情 | 详情 |
| (II) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (III) | 51141 | ethyl 5-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate | C14H17N3O3 | 详情 | 详情 | |
| (IV) | 51142 | ethyl 3-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate | C14H17N3O3 | 详情 | 详情 | |
| (V) | 51143 | ethyl 4,6-dihydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate | C17H17N3O5 | 详情 | 详情 | |
| (VI) | 51144 | ethyl 4,6-dihydroxy-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate | C17H17N3O5 | 详情 | 详情 | |
| (VII) | 51145 | ethyl 4,6-dichloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate | C17H15Cl2N3O3 | 详情 | 详情 | |
| (VIII) | 51146 | ethyl 4-amino-6-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate | C17H17ClN4O3 | 详情 | 详情 | |
| (IX) | 51147 | 4-amino-6-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid | C15H13ClN4O3 | 详情 | 详情 | |
| (X) | 51148 | 4-amino-6-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxamide | C15H14ClN5O2 | 详情 | 详情 |
合成路线2
The pyrazolopyridopyrimidine tricyclic system (XII) was generated by acylation of amine (X) with acid chloride (XI), followed by base-mediated cyclization. Displacement of the remaining chloride of (XII) with p-fluorobenzyl amine (XIII) afforded (XIV). The p-methoxybenzyl group of (XIV) was finally removed by treatment with trifluoroacetic acid yielding the title compound.
| 【1】 Bi, Y.; et al.; The discovery of novel, potent and selective PDE5 inhibitors. Bioorg Med Chem Lett 2001, 11, 18, 2461. |
| 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) | 51148 | 4-amino-6-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxamide | C15H14ClN5O2 | 详情 | 详情 | |
| (XI) | 51149 | 5-[[(3R)-3-(dimethylamino)pyrrolidinyl]sulfonyl]-2-propoxybenzoyl chloride | C16H23ClN2O4S | 详情 | 详情 | |
| (XII) | 51150 | 5-chloro-2-(5-[[(3R)-3-(dimethylamino)pyrrolidinyl]sulfonyl]-2-propoxyphenyl)-8-(4-methoxybenzyl)-3,8-dihydro-4H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-4-one | C31H34ClN7O5S | 详情 | 详情 | |
| (XIII) | 31095 | 4-fluorobenzylamine; (4-fluorophenyl)methanamine | 140-75-0 | C7H8FN | 详情 | 详情 |
| (XIV) | 51151 | 2-(5-[[(3R)-3-(dimethylamino)pyrrolidinyl]sulfonyl]-2-propoxyphenyl)-5-[(4-fluorobenzyl)amino]-8-(4-methoxybenzyl)-3,8-dihydro-4H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-4-one | C38H41FN8O5S | 详情 | 详情 |