Tezosentan disodium, Ro-61-0612, Veletri, -Drug Synthesis Database

【结构式】

【药物名称】Tezosentan disodium, Ro-61-0612, Veletri

【化学名称】N-[6-(2-Hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-isopropylpyridine-2-sulfonamide disodium salt

【CA登记号】180384-58-1, 180384-57-0 (free acid)

【分子式】C₂₇H₂₅N₉Na₂O₆S

【分子量】649.6006

【开发单位】Roche (Originator), Actelion (Licensee), Genentech (Codevelopment)

【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Renal Failure, Agents for, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, Endothelin ETA Receptor Antagonists, Endothelin ETB Receptor Antagonists

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

Reaction of 2-chloro-5-ispropylpyridine (VII) with thiourea (A) in aqueous HCl gives 5-isopropyl- pyridine-2-thiol (VIII), which is chlorinated with chlorine in acetic acid to yield 5-isopropylpyridine-2-sulfochloride (IX). This compound is converted into 5-isopropylpyridine-2-sulfonamide potassium salt (X).

参考文献中间体

【1】 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 .
【2】 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
(A)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VII)	62973	2-chloro-5-isopropylpyridine		C₈H₁₀ClN	详情	详情
(VIII)	62974	5-isopropyl-2-pyridinethiol; 5-isopropyl-2-pyridinylhydrosulfide		C₈H₁₁NS	详情	详情
(IX)	62975	5-isopropyl-2-pyridinesulfonyl chloride		C₈H₁₀ClNO₂S	详情	详情
(X)	50142			C₈H₁₁KN₂O₂S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)