Yaozh News Star Club Edu TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【药物名称】CP-319340

【化学名称】N-[2-(1H-Imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-4'-(trifluoromethyl)biphenyl-2-carboxamide hydrochloride

【CA登记号】186390-35-2 (free base)

【 分 子 式 】C27H24ClF3N4O

【 分 子 量 】512.96673

【开发单位】Pfizer (Originator)

【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, ApoB Secretion Inhibitors, Microsomal Triglyceride Transfer Protein (MTTP) Inhibitors
合成路线1合成路线2合成路线3

合成路线1

4-Bromophenethyl amine (I) was refluxed with ethyl formate to afford formamide (II). Cyclization of (II) employing polyphosphoric acid and phosphorus pentoxide at 200 C furnished 7-bromo-3,4-dihydroisoquinoline, which was isolated as the corresponding hydrochloride salt (III). Reduction of (III) with NaBH4 gave the tetrahydroisoquinoline (IV), that was nitrated with KNO3 and H2SO4 to provide (V). After protection of (V) as the N-Boc derivative (VI), reduction of the nitro group with concomitant hydrogenolysis of the bromine by hydrogenation over Pd/CaCO3 yielded aminoisoquinoline (VII). This was coupled with 4’-(trifluoromethyl)biphenyl-2-carboxylic acid (VIII) by means of EDC to produce amide (IX). Cleavage of the Boc group of (IX) with trifluoroacetic acid gave amine (X). Finally, reductive alkylation of (X) with imidazole-2-carbaldehyde (XI) and sodium cyanoborohydride furnished the title compound.

参考文献 中间体
【1】 Quallich, G.J.; Dorff, P.H.; Chang, G. (Pfizer Inc.); Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide derivs., their preparation and their use as inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion. JP 1999514964; US 5919795; WO 9640640 .
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) 41139 4-bromophenethylamine; 2-(4-bromophenyl)-1-ethanamine 73918-56-6 C8H10BrN 详情 详情
(II) 41140 4-bromophenethylformamide C9H10BrNO 详情 详情
(III) 41141 7-bromo-3,4-dihydroisoquinoline C9H8BrN 详情 详情
(IV) 41142 7-bromo-1,2,3,4-tetrahydroisoquinoline C9H10BrN 详情 详情
(V) 41143 7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline C9H9BrN2O2 详情 详情
(VI) 41144 tert-butyl 7-bromo-6-nitro-3,4-dihydro-2(1H)-isoquinolinecarboxylate C14H17BrN2O4 详情 详情
(VII) 41145 tert-butyl 6-amino-3,4-dihydro-2(1H)-isoquinolinecarboxylate C14H20N2O2 详情 详情
(VIII) 41132 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid C14H9F3O2 详情 详情
(IX) 41146 tert-butyl 6-([[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino)-3,4-dihydro-2(1H)-isoquinolinecarboxylate C28H27F3N2O3 详情 详情
(X) 41147 N-(1,2,3,4-tetrahydro-6-isoquinolinyl)-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide C23H19F3N2O 详情 详情
(XI) 41148 1H-imidazole-2-carbaldehyde 10111-08-7 C4H4N2O 详情 详情

合成路线2

Condensation of 2-chloro-4-nitrobenzoic acid (XII) with dimethyl malonate produced the arylmalonate (XIII). Hydrolysis and subsequent decarboxylation of (XIII) afforded diacid (XIV). This was converted into cyclic anhydride (XV) upon refluxing with Ac2O and then reduced to diol (XVI) with borane in THF. Optionally, diol (XVI) was obtained by direct reduction of diacid (XIV) with borane. After conversion of (XVI) to dimesylate (XVII), cyclization with ammonia produced tetrahydroisoquinoline (XVIII). This was protected as the N-Boc derivative (XIX) and the nitro group was reduced to the target amine (VII) by hydrogenation over Pt/C .

参考文献 中间体
【1】 Quallich, G.J.; Dorff, P.H.; Chang, G. (Pfizer Inc.); Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide derivs., their preparation and their use as inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion. JP 1999514964; US 5919795; WO 9640640 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 41145 tert-butyl 6-amino-3,4-dihydro-2(1H)-isoquinolinecarboxylate C14H20N2O2 详情 详情
(XII) 41126 2-chloro-4-nitrobenzoic acid 99-60-5 C7H4ClNO4 详情 详情
(XIII) 41127 2-[2-methoxy-1-(methoxycarbonyl)-2-oxoethyl]-4-nitrobenzoic acid C12H11NO8 详情 详情
(XIV) 41128 2-(carboxymethyl)-4-nitrobenzoic acid C9H7NO6 详情 详情
(XV) 41129 6-nitro-1H-isochromene-1,3(4H)-dione C9H5NO5 详情 详情
(XVI) 41130 2-[2-(hydroxymethyl)-5-nitrophenyl]-1-ethanol C9H11NO4 详情 详情
(XVII) 41149 2-[[(methylsulfonyl)oxy]methyl]-5-nitrophenethyl methanesulfonate C11H15NO8S2 详情 详情
(XVIII) 41150 6-nitro-1,2,3,4-tetrahydroisoquinoline C9H10N2O2 详情 详情
(XIX) 41151 tert-butyl 6-nitro-3,4-dihydro-2(1H)-isoquinolinecarboxylate C14H18N2O4 详情 详情

合成路线3

In a further procedure, nitro diol (XVI) was hydrogenated over Pt/C, and the resulting amine (XX) was condensed with acid chloride (XXI) (prepared from carboxylic acid (VIII) and SOCl2) to afford amide (XXII). After conversion of (XXII) to dimesylate (XXIII), cyclization with ammonia furnished intermediate (X).

参考文献 中间体
【1】 Quallich, G.J.; Dorff, P.H.; Chang, G. (Pfizer Inc.); Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide derivs., their preparation and their use as inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion. JP 1999514964; US 5919795; WO 9640640 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 41132 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid C14H9F3O2 详情 详情
(X) 41147 N-(1,2,3,4-tetrahydro-6-isoquinolinyl)-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide C23H19F3N2O 详情 详情
(XVI) 41130 2-[2-(hydroxymethyl)-5-nitrophenyl]-1-ethanol C9H11NO4 详情 详情
(XX) 41131 2-[5-amino-2-(hydroxymethyl)phenyl]-1-ethanol C9H13NO2 详情 详情
(XXI) 41133 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride C14H8ClF3O 详情 详情
(XXII) 41134 N-[3-(2-hydroxyethyl)-4-(hydroxymethyl)phenyl]-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide C23H20F3NO3 详情 详情
(XXIII) 41135 2-[[(methylsulfonyl)oxy]methyl]-5-([[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino)phenethyl methanesulfonate C25H24F3NO7S2 详情 详情
Extended Information