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【结 构 式】 
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【药物名称】SR-265579, WIN-65579 【化学名称】1-Cyclopentyl-6-(3-ethoxy-4-pyridinyl)-3-ethyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one 【CA登记号】158020-82-7 【 分 子 式 】C19H23N5O2 【 分 子 量 】353.42746 |
【开发单位】Sanofi-synthélabo (Originator) 【药理作用】Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, Phosphodiesterase V (PDE5A) Inhibitors |
合成路线1
Reaction of triethyl orthopropionate (I) with malononitrile (II) at reflux temperature provided (1-ethoxypropylidene)malononitrile (III). Cyclopentanone (IV) was condensed with tert-butyl carbazate (V) to afford the corresponding hydrazone (VI). Subsequent reduction with sodium cyanoborohydride, followed by acid deprotection furnished cyclopentylhydrazine (VII). Then, condensation of (VII) with malononitrile derivative (III) produced pyrazole (VIII). Partial hydrolysis of the cyano group of (VIII) using concentrated sulfuric acid gave carboxamide (IX).
| 【1】 Bacon, E.R.; Singh, B.; Lesher, G.Y.; Lesher, L.E. (Sanofi-Synthelabo); 6-Heterocyclyl pyrazolo[3,4-d]pyrimidin-4-ones and compsns. and method of use. US 5294612 . |
| 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) | 10395 | 1,1,1-Triethoxypropane; 1,1-Diethoxypropyl ethyl ether; Triethyl orthopropionate | 115-80-0 | C9H20O3 | 详情 | 详情 |
| (II) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (III) | 26907 | 2-(1-ethoxypropylidene)malononitrile | C8H10N2O | 详情 | 详情 | |
| (IV) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (V) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (VI) | 26908 | tert-butyl 2-cyclopentylidene-1-hydrazinecarboxylate | C10H18N2O2 | 详情 | 详情 | |
| (VII) | 26909 | 1-cyclopentylhydrazine | C5H12N2 | 详情 | 详情 | |
| (VIII) | 26910 | 5-amino-1-cyclopentyl-3-ethyl-1H-pyrazole-4-carbonitrile | C11H16N4 | 详情 | 详情 | |
| (IX) | 26911 | 5-amino-1-cyclopentyl-3-ethyl-1H-pyrazole-4-carboxamide | C11H18N4O | 详情 | 详情 |
合成路线2
Treatment of 4-cyanopyridine N-oxide (X) with phosphorus oxychloride and phosphorus pentachloride under reflux produced a mixture of 2-chloro (XI) and 3-chloropyridines (XII), which were separated by column chromatography. The 3-chloro isomer (XII) was further treated with sodium ethoxide in DMF to produce the ethoxypyridine (XIII). The pyrazolopyrimidine nucleus (XIV) was then obtained by condensation of cyanopyridine (XIII) with aminopyrazole (IX) in the presence of NaH. Finally, diazotization of (XIV) in 50% sulfuric acid converted the aminopyrimidine group into the required pyrimidinone.
| 【1】 Bacon, E.R.; Singh, B.; Lesher, G.Y.; Lesher, L.E. (Sanofi-Synthelabo); 6-Heterocyclyl pyrazolo[3,4-d]pyrimidin-4-ones and compsns. and method of use. US 5294612 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 26911 | 5-amino-1-cyclopentyl-3-ethyl-1H-pyrazole-4-carboxamide | C11H18N4O | 详情 | 详情 | |
| (X) | 26912 | 4-cyano-1-pyridiniumolate | 14906-59-3 | C6H4N2O | 详情 | 详情 |
| (XI) | 23940 | 2-Chloro-4-pyridinecarbonitrile; 2-chloroisonicotinonitrile | 33252-30-1 | C6H3ClN2 | 详情 | 详情 |
| (XII) | 26913 | 3-chloroisonicotinonitrile | C6H3ClN2 | 详情 | 详情 | |
| (XIII) | 26914 | 3-ethoxyisonicotinonitrile | C8H8N2O | 详情 | 详情 | |
| (XIV) | 26915 | 1-cyclopentyl-6-(3-ethoxy-4-pyridinyl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine | C19H24N6O | 详情 | 详情 |