Revaprazan hydrochloride, SB-641257, YH-1885, -Drug Synthesis Database

【结构式】

【药物名称】Revaprazan hydrochloride, SB-641257, YH-1885

【化学名称】N-(4-Fluorophenyl)-4,5-dimethyl-6-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidin-2-amine hydrochloride
　　　　　　N-[4,5-Dimethyl-6-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidin-2-yl]-N-(4-fluorophenyl)amine hydrochloride

【CA登记号】178307-42-1

【分子式】C₂₂H₂₄ClFN₄

【分子量】398.91478

【开发单位】Yuhan (Originator), GlaxoSmithKline (Licensee)

【药理作用】Antiulcer Drugs, Esophageal Diseases, Treatment of, Gastroesophageal Reflux Disease, Agents for, GASTROINTESTINAL DRUGS, H+/K+-ATPase Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The intermediate tetrahydroisoquinoline (IV) has been prepared by two synthetic strategies. Condensation of alpha-methyl benzylamine (I) with alpha-chloro-alpha-(methylsulfanyl)acetyl chloride (II) in the presence of SnCl2 furnished the tetrahydroisoquinolinone (III). Reductive cleavage of the methylsulfanyl group of (III) employing Raney-Ni, followed by lactam reduction, provided intermediate (IV).

参考文献中间体

【1】 Lee, J.W.; Chae, J.S.; Kim, C.S.; Kim, J.K.; Lim, D.S.; Lee, J.W.; Shon, M.K.; Jo, D.W. (Yuhan Corp.); Quinazoline derivs.. EP 0677049; WO 9414795 .

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)	15148	1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine	618-36-0	C₈H₁₁N	详情	详情
(II)	54969	2-chloro-2-(methylsulfanyl)acetyl chloride		C₃H₄Cl₂OS	详情	详情
(III)	54970	1-methyl-4-(methylsulfanyl)-1,4-dihydro-3(2H)-isoquinolinone		C₁₁H₁₃NOS	详情	详情
(IV)	54971	1-methyl-1,2,3,4-tetrahydroisoquinoline		C₁₀H₁₃N	详情	详情

合成路线2

In a different method, amine (I) was alkylated with 2-bromoethanol (V) to give the N-(hydroxyethyl) amine (VI), which was further converted to bromo amine (VII) by treatment with concentrated HBr. Friedel-Crafts cyclization of (VII) upon heating in the presence of AlCl3 furnished tetrahydroisoquinoline (IV).

参考文献中间体

【1】 Lee, Y.N.; Hong, Y.W.; Kim, H.B. (Yuhan Corp.); Process for preparation of pyrmidine derivs.. US 5990311; WO 9742186 .

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)	15148	1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine	618-36-0	C₈H₁₁N	详情	详情
(IV)	54971	1-methyl-1,2,3,4-tetrahydroisoquinoline		C₁₀H₁₃N	详情	详情
(V)	10059	Ethylene bromohydrin; 2-Bromo-1-ethanol	540-51-2	C₂H₅BrO	详情	详情
(VI)	54972	2-[(1-phenylethyl)amino]-1-ethanol		C₁₀H₁₅NO	详情	详情
(VII)	54973	N-(2-bromoethyl)-1-phenyl-1-ethanamine; N-(2-bromoethyl)-N-(1-phenylethyl)amine		C₁₀H₁₄BrN	详情	详情

合成路线3

Chlorination of 5,6-dimethyl-2,4-dihydroxypyrimidine (VIII) using phosphorus oxychloride in the presence of N,N-dimethylaniline provided dichloropyrimidine (IX). The 4-chloro group of (IX) was then selectively displaced with tetrahydroisoquinoline (IV) to afford adduct (X). The title compound was then obtained by condensation of the 2-chloropyrimidine (X) with 4-fluoroaniline (XI), followed by conversion to the corresponding hydrochloride salt

参考文献中间体

【1】 Lee, J.W.; Chae, J.S.; Kim, C.S.; Kim, J.K.; Lim, D.S.; Shon, M.K.; Choi, Y.S.; Lee, S.H. (Yuhan Corp.); Novel pyrimidine derivs. and processes for the preparation thereof. EP 0775120; JP 1997509188; US 5750531; WO 9605177 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	54971	1-methyl-1,2,3,4-tetrahydroisoquinoline		C₁₀H₁₃N	详情	详情
(VIII)	54974	2,4-Dihydroxy-5,6-dimethylpyrimidine; 5,6-Dimethyl-2,4-pyrimidinediol; 5,6-Dimethyluracil	26305-13-5	C₆H₈N₂O₂	详情	详情
(IX)	54975	2,4-dichloro-5,6-dimethylpyrimidine		C₆H₆Cl₂N₂	详情	详情
(X)	54976	2-(2-chloro-5,6-dimethyl-4-pyrimidinyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline		C₁₆H₁₈ClN₃	详情	详情
(XI)	37690	4-fluorophenylamine; 4-fluoroaniline	371-40-4	C₆H₆FN	详情	详情

合成路线4

In an alternative procedure, 4-fluoroaniline (XI) was condensed with cyanamide under acidic conditions to afford the fluorophenyl guanidine (XII). Cyclization of guanidine (XII) with ethyl 2-methylacetoacetate (XIII) in hot DMF produced pyrimidine (XIV). After chlorination of (XIV) with POCl3, the resultant chloropyrimidine (XV) was condensed with tetrahydroisoquinoline (IV) in the presence of either KOAc or Et3N to furnish the title diaminopyrimidine.

参考文献中间体

【1】 Lee, Y.N.; Hong, Y.W.; Kim, H.B. (Yuhan Corp.); Process for preparation of pyrmidine derivs.. US 5990311; WO 9742186 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	54971	1-methyl-1,2,3,4-tetrahydroisoquinoline		C₁₀H₁₃N	详情	详情
(XI)	37690	4-fluorophenylamine; 4-fluoroaniline	371-40-4	C₆H₆FN	详情	详情
(XII)	54977	N-(4-fluorophenyl)guanidine		C₇H₈FN₃	详情	详情
(XIII)	10362	ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate	609-14-3	C₇H₁₂O₃	详情	详情
(XIV)	54978	2-(4-fluoroanilino)-5,6-dimethyl-4-pyrimidinol		C₁₂H₁₂FN₃O	详情	详情
(XV)	54979	N-(4-chloro-5,6-dimethyl-2-pyrimidinyl)-N-(4-fluorophenyl)amine; 4-chloro-N-(4-fluorophenyl)-5,6-dimethyl-2-pyrimidinamine		C₁₂H₁₁ClFN₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)