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【结 构 式】

【药物名称】TA-0201, T-0201

【化学名称】N-[6-[2-(5-Bromopyridin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl]-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide monosodium salt sesquihydrate

【CA登记号】

【 分 子 式 】C27H29BrN5NaO6S

【 分 子 量 】654.51988

【开发单位】Tanabe Seiyaku (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Endothelin ETA Receptor Antagonists

合成路线1

Ethyl phenylacetate (I) was alkylated with two equivalents of methyl iodide in the presence of potassium tert-butoxide to yield 2-methyl-2-phenylpropionic ester (II), which was reduced to alcohol (III) with LiAlH4. The alcohol function of (III) was esterified with Ac2O in pyridine, and the resulting compound (IV) was converted to sulfonyl chloride (V) by sulfonation with H2SO4, followed by treatment with SOCl2. Further reaction of (V) with ammonium hydroxide yielded sulfonamide (VI). Condensation of this sulfonamide with the dichloropyrimidine (VII) furnished, after saponification with NaOH, the N-pyrimidinylsulfonamide (VIII)). The alcohol function of (VIII) was then protected as the tetrahydropyranyl ether with dihydropyran and camphorsulfonic acid, and further treatment with the sodium salt of ethylene glycol at 100 C yielded the (2-hydroxyethoxy)pyrimidine (IX). Condensation of (IX) with 5-bromo-2-chloropyrimidine (X) in the presence of NaH gave (XI), which was finally converted to the target compound by acid deprotection of the tetrahydropyranyl acetal, followed by formation of the sodium salt with NaOMe in THF-MeOH.

1 Yamada, K.; et al.; Syntheses and structure-activity relationships of sulfonamide derivatives as endothelin antagonists: A potent and selective ET-A antagonist, TA-0201 and related compounds. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 057.
2 Yamada, K.; Yasuda, K.; Kikkawa, K.; Kohno, R. (Tanabe Seiyaku Co., Ltd.); Benzenesulfonamide deriv. and process for preparing thereof. CA 2137953; EP 0658548; JP 1996099961; US 5589478; US 5728706 .
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) 21045 ethyl 2-phenylacetate 101-97-3 C10H12O2 详情 详情
(II) 17609 ethyl 2-methyl-2-phenylpropanoate C12H16O2 详情 详情
(III) 17174 2-methyl-2-phenyl-1-propanol C10H14O 详情 详情
(IV) 17175 2-methyl-2-phenylpropyl acetate 2901-13-5 C12H16O2 详情 详情
(V) 21049 2-[4-(chlorosulfonyl)phenyl]-2-methylpropyl acetate C12H15ClO4S 详情 详情
(VI) 21050 2-[4-(aminosulfonyl)phenyl]-2-methylpropyl acetate C12H17NO4S 详情 详情
(VII) 21051 4,6-dichloro-5-(4-methylphenyl)pyrimidine C11H8Cl2N2 详情 详情
(VIII) 21052 N-[6-chloro-5-(4-methylphenyl)-4-pyrimidinyl]-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide C21H22ClN3O3S 详情 详情
(IX) 21053 4-[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-N-[6-(2-hydroxyethoxy)-5-(4-methylphenyl)-4-pyrimidinyl]benzenesulfonamide C28H35N3O6S 详情 详情
(X) 21054 5-bromo-2-chloropyrimidine C4H2BrClN2 详情 详情
(XI) 21055 N-[6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-5-(4-methylphenyl)-4-pyrimidinyl]-4-[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benzenesulfonamide C32H36BrN5O6S 详情 详情
Extended Information