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【结 构 式】

【分子编号】50136

【品名】4-Cyanopyridine; Pyridine-4-carbonitrile; Isonicotinic acid nitrile; Isonicotinonitrile; iso-Nicotinonitrile

【CA登记号】100-48-1

【 分 子 式 】C6H4N2

【 分 子 量 】104.11124

【元素组成】C 69.22% H 3.87% N 26.91%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(I)

Reaction of 4-cyano-pyridine (I) with Na in methanol followed by treatment with ammonium chloride provides 4-amidino-pyridine hydrochloride (II), which is then converted into 5-(2-methoxyphenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (IV) by condensation with diethyl malonate derivative (III) by means of Na in MeOH. By heating compound (IV) with phosphorus oxychloride (POCl3), 4,6-dichloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl)pyrimidine (V) is obtained, which in turn is oxidized with peracetic acid in refluxing acetonitrile to afford N-oxide derivative (VI). Condensation of (VI) with 5-isopropylpyridine-2-sulfonamide potassium (VII) furnishes 5-isopropylpyridine-2-sulfonic acid 6-chloro-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide (VIII), which is then dissolved in dimethoxyethane and subjected to reaction with Na in hot ethylene glycol (IX) to provide N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-5-isopropylpyridine-2-sulfonamide (X). Refluxing of (X) with trimethylsilylcyanide and Et3N in acetonitrile yields cyano derivative (XI), which is then converted into the tetrazole derivative (XII) by reaction with sodium azide and NH4Cl in DMF at 70 C. Finally, the disodium salt of tezosentan is obtained by treatment of (XII) with Na/MeOH in THF.

1 Chilman-Blair, K.; Castaner, J.; Leeson, P.A.; Bayes, M.; Tezosentan Disodium. Drugs Fut 2003, 28, 8, 754.
2 Breu, V.; Burri, K.; Cassal, J.-M.; Clozel, M.; Hirth, G.; Loffler, B.-M.; Muller, M.; Neidhart, W.; Ramuz, H. (F. Hoffmann-La Roche AG); Novel sulfonamides. EP 0799209; JP 1998509182; WO 9619459 .
3 Spurr, P. (F. Hoffmann-La Roche AG); Process for the preparation of 2,5-disubstd. pyridines. EP 0897914 .
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) 50136 4-Cyanopyridine; Pyridine-4-carbonitrile; Isonicotinic acid nitrile; Isonicotinonitrile; iso-Nicotinonitrile 100-48-1 C6H4N2 详情 详情
(II) 50137 4-pyridinecarboximidamide C6H7N3 详情 详情
(III) 50138 diethyl 2-(2-methoxyphenoxy)malonate C14H18O6 详情 详情
(IV) 50139 5-(2-methoxyphenoxy)-2-(4-pyridinyl)-4,6-pyrimidinediol C16H13N3O4 详情 详情
(V) 50140 4,6-dichloro-2-(4-pyridinyl)-5-pyrimidinyl 2-methoxyphenyl ether; 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridinyl)pyrimidine C16H11Cl2N3O2 详情 详情
(VI) 50141 4-[4,6-dichloro-5-(2-methoxyphenoxy)-2-pyrimidinyl]-1-pyridiniumolate C16H11Cl2N3O3 详情 详情
(VII) 50142   C8H11KN2O2S 详情 详情
(VIII) 50143 4-[4-chloro-6-[[(5-isopropyl-2-pyridinyl)sulfonyl]amino]-5-(2-methoxyphenoxy)-2-pyrimidinyl]-1-pyridiniumolate C24H22ClN5O5S 详情 详情
(IX) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(X) 50144 4-[4-(2-hydroxyethoxy)-6-[[(5-isopropyl-2-pyridinyl)sulfonyl]amino]-5-(2-methoxyphenoxy)-2-pyrimidinyl]-1-pyridiniumolate C26H27N5O7S 详情 详情
(XI) 50145 N-[2-(2-cyano-4-pyridinyl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-5-isopropyl-2-pyridinesulfonamide C27H26N6O6S 详情 详情
(XII) 50146 N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-1,2,3,4-tetraazol-5-yl)-4-pyridinyl]-4-pyrimidinyl]-5-isopropyl-2-pyridinesulfonamide C27H27N9O6S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

 

1 杨园园,周国权,陈新志.2004.4-氨基吡啶合成方法改进. 应用化学,21(5):530~531.
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) 50136 4-Cyanopyridine; Pyridine-4-carbonitrile; Isonicotinic acid nitrile; Isonicotinonitrile; iso-Nicotinonitrile 100-48-1 C6H4N2 详情 详情
Extended Information