2-chloro-4-nitrobenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】41126

【品名】2-chloro-4-nitrobenzoic acid

【CA登记号】99-60-5

【分子式】C₇H₄ClNO₄

【分子量】201.5658

【元素组成】C 41.71% H 2% Cl 17.59% N 6.95% O 31.75%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

Condensation of 2-chloro-4-nitrobenzoic acid (I) with dimethyl malonate produced the arylmalonate (II). This was subjected to hydrolysis and subsequent decarboxylation to afford diacid (III). Conversion of (III) to the cyclic anhydride (IV) upon refluxing with Ac2O, and then reduction with borane in THF gave rise to diol (V). Optionally, diol (V) was obtained by direct reduction of diacid (III) with borane. Nitro diol (V) was reduced to amine (VI) by hydrogenation over Pt/C. This was condensed with acid chloride (VIII) (prepared from carboxylic acid (VII) and SOCl2) to afford amide (IX). After conversion to dimesylate (X), cyclization with N-acetyl ethylenediamine (XI) furnished the tetrahydroisoquinoline (XII). Acidic hydrolysis of the acetamido group of (XIV) gave primary amine (XIII) which was finally treated with methyl chloroformate to furnish the title carbamate.

参考文献中间体

合成目标

【1】 Chang, G.; Quallich, G.J. (Pfizer Inc.); Apo B-secretion/MTP inhibitory amides. EP 0944602; JP 2000505810; WO 9823593 .

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)	41126	2-chloro-4-nitrobenzoic acid	99-60-5	C₇H₄ClNO₄	详情	详情
(II)	41127	2-[2-methoxy-1-(methoxycarbonyl)-2-oxoethyl]-4-nitrobenzoic acid		C₁₂H₁₁NO₈	详情	详情
(III)	41128	2-(carboxymethyl)-4-nitrobenzoic acid		C₉H₇NO₆	详情	详情
(IV)	41129	6-nitro-1H-isochromene-1,3(4H)-dione		C₉H₅NO₅	详情	详情
(V)	41130	2-[2-(hydroxymethyl)-5-nitrophenyl]-1-ethanol		C₉H₁₁NO₄	详情	详情
(VI)	41131	2-[5-amino-2-(hydroxymethyl)phenyl]-1-ethanol		C₉H₁₃NO₂	详情	详情
(VII)	41132	4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid		C₁₄H₉F₃O₂	详情	详情
(VIII)	41133	4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride		C₁₄H₈ClF₃O	详情	详情
(IX)	41134	N-[3-(2-hydroxyethyl)-4-(hydroxymethyl)phenyl]-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide		C₂₃H₂₀F₃NO₃	详情	详情
(X)	41135	2-[[(methylsulfonyl)oxy]methyl]-5-([[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino)phenethyl methanesulfonate		C₂₅H₂₄F₃NO₇S₂	详情	详情
(XI)	41136	N-(2-aminoethyl)acetamide	1001-53-2	C₄H₁₀N₂O	详情	详情
(XII)	41137	N-[2-[2-(acetamido)ethyl]-1,2,3,4-tetrahydro-6-isoquinolinyl]-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide		C₂₇H₂₆F₃N₃O₂	详情	详情
(XIII)	41138	N-[2-(2-aminoethyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide		C₂₅H₂₄F₃N₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

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

合成目标

【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

Extended Information