7-chloro-2-(chloromethyl)quinoline -Drug Synthesis Database

【结构式】

【分子编号】20138

【品名】7-chloro-2-(chloromethyl)quinoline

【CA登记号】

【分子式】C₁₀H₇Cl₂N

【分子量】212.07772

【元素组成】C 56.63% H 3.33% Cl 33.43% N 6.6%

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：(VI)

Condensation of 5-(benzyloxy)-2-hydroxyacetophenone (I) with acetone in the presence of pyrrolidine in toluene with azeotropical removal of water yielded chromanone (II). Subsequent aldol condensation of (II) with 2-methoxy-5-nitrobenzaldehyde (III), promoted by tetramethyl orthosilicate and KF, produced the benzylidenechromanone (IV). Palladium-catalysed hydrogenation of the benzylidene double bond of (IV), with concomitant benzyl ether cleavage and nitro group reduction, gave benzylchromanone (V). Then, the phenolic hydroxyl group of (V) was alkylated with 2-(chloromethyl)-7-chloroquinoline (VI) in the presence of NaH in DMF to afford ether (VII). Treatment of (VII) with trifluoromethanesulfonic anhydride and Et3N produced the bis(sulfonamide) (VIII), which after basic hydrolysis yielded the mono-trifluoromethylsulfonamide (IX). Subsequent reduction of (IX) with Super Hydride(R) afforded the racemic cis alcohol (X).

参考文献中间体

合成目标

【1】 Chambers, R.J.; et al.; Development of 2,2-dimethylchromanol antagonists of leukotriene D4. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 036.
【2】 Marfat, A.; Chambers, R.J.; Aldol condensation of 6-alkoxy-2,2-dimethylchroman-4-ones with substituted benzaldehydes using tetramethylorthosilicate and potassium fluoride. J Heterocycl Chem 1995, 32, 4, 1401.
【3】 Chambers, R.J.; Antognoli, G.W.; Cheng, J.B.; Kuperman, A.V.; Liston, T.C.; Marfat, A.; Owens, B.S.; Pillar, J.S.; Shirley, J.T.; Watson, J.W.; Development of 2,2-dimethylchromanol cysteinyl LT1 receptor antagonists. Bioorg Med Chem Lett 1998, 8, 24, 3577.
【4】 Marfat, A. (Pfizer Inc.); Sulfonamide derivs. of benzenefused hydroxy substd. cycloalkyl and heterocyclic ring cpds.. EP 0665842; JP 1995508534; US 5641789; WO 9408996 .

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)	20133	1-[5-(benzyloxy)-2-hydroxyphenyl]-1-ethanone		C₁₅H₁₄O₃	详情	详情
(II)	20134	6-(benzyloxy)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one		C₁₈H₁₈O₃	详情	详情
(II)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情
(III)	20135	2-methoxy-5-nitrobenzaldehyde		C₈H₇NO₄	详情	详情
(IV)	20136	6-(benzyloxy)-3-[(E)-(2-methoxy-5-nitrophenyl)methylidene]-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one		C₂₆H₂₃NO₆	详情	详情
(V)	20137	3-(5-amino-2-methoxybenzyl)-6-hydroxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one		C₁₉H₂₁NO₄	详情	详情
(VI)	20138	7-chloro-2-(chloromethyl)quinoline		C₁₀H₇Cl₂N	详情	详情
(VII)	20139	3-(5-amino-2-methoxybenzyl)-6-[(7-chloro-2-quinolinyl)methoxy]-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one		C₂₉H₂₇ClN₂O₄	详情	详情
(VIII)	20140	N-[3-([6-[(7-chloro-2-quinolinyl)methoxy]-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide		C₃₁H₂₅ClF₆N₂O₈S₂	详情	详情
(IX)	20141	N-[3-([6-[(7-chloro-2-quinolinyl)methoxy]-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide		C₃₀H₂₆ClF₃N₂O₆S	详情	详情
(X)	20142	N-[3-([6-[(7-chloro-2-quinolinyl)methoxy]-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide		C₃₀H₂₈ClF₃N₂O₆S	详情	详情
(XI)	23208	N-[3-([(3S,4R)-6-[(7-chloro-2-quinolinyl)methoxy]-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide		C₃₀H₂₈ClF₃N₂O₆S	详情	详情
(XII)	20144	(3S,4R)-6-[(7-chloro-2-quinolinyl)methoxy]-3-(2-methoxy-5-[[(trifluoromethyl)sulfonyl]amino]benzyl)-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate		C₄₆H₄₆ClF₃N₄O₉S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The demethylation of 6-methoxy-3,4-dihydro-2H-1-benzopyran-4-one (I) with 48% HBr in refluxing acetic acid gives the corresponding hydroxy compound (II), which is protected with benzyl bromide and K2CO3 in acetone yielding the benzyl ether (III). The condensation of (III) with 3-formyl-4-methoxybenzoic acid methyl ester (IV) by means of pyrrolidine in methanol affords the benzylidene derivative (V), which is reduced to the corresponding benzyl analogue (VI) with H2 over Pd/C in ethyl acetate. The reduction of the ketone group of (VI) with NaBH4 in MeOH/THF in the presence of CeCl3 gives the expected cis alcohol as a racemic mixture, which is submitted to optical resolution by esterification with Boc-D-tryptophan, chromatographic separation of the diastereomeric mixture, and basic hydrolysis of the ester groups yielding the (3S,4R)-alcohol (VII). The Curtius rearrangement of (VII) by reaction with diphenylphosphoryl azide (DPPA), benzyl alcohol and triethylamine affords carbamate (VIII), which is treated with H2 over Pd(OH)2 in dioxane to give the amine (IX). The condensation of (IX) with 7-chloro-2-(chloromethyl)quinoline (X) by means of NaH in DMF yields the corresponding ether (XI), which is finally treated with trifluoromethanesulfonic anhydride and triethylamine in dichloromethane to afford the target sulfonamide.

参考文献中间体

合成目标

【1】 Cheng, J.B.; Chambers, R.J.; Antognoli, G.W.; et al.; Discovery of CP-199,330 and CP-199,331, two potent, orally bioavailable and efficacious antagonists of leukotriene D4. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 204.
【2】 Watson, J.W.; Damon, D.B.; Antognoli, G.W.; Cheng, J.B.; Marfat, A.; Mebus, C.; Kuperman, A.V.; Shirley, J.T.; Pillar, J.S.; Liston, T.C.; Chambers, R.J.; Discovery of CP-199,330 and CP-199,331: Two potent and orally efficacious cysteinyl LT1 receptor antagonists devoid of liver toxicity. Bioorg Med Chem Lett 1999, 9, 18, 2773.
【3】 Marfat, A. (Pfizer Inc.); Sulfonamide derivs. of benzenefused hydroxy substd. cycloalkyl and heterocyclic ring cpds.. EP 0665842; JP 1995508534; US 5641789; WO 9408996 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	30183	6-methoxy-2,3-dihydro-4H-chromen-4-one	C₁₀H₁₀O₃	详情	详情
(II)	30184	6-hydroxy-2,3-dihydro-4H-chromen-4-one	C₉H₈O₃	详情	详情
(III)	30185	6-(benzyloxy)-2,3-dihydro-4H-chromen-4-one	C₁₆H₁₄O₃	详情	详情
(IV)	30186	methyl 3-formyl-4-methoxybenzoate	C₁₀H₁₀O₄	详情	详情
(V)	30187	methyl 3-[[6-(benzyloxy)-4-oxo-2H-chromen-3(4H)-ylidene]methyl]-4-methoxybenzoate	C₂₆H₂₂O₆	详情	详情
(VI)	30188	methyl 3-[[6-(benzyloxy)-4-oxo-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxybenzoate	C₂₆H₂₄O₆	详情	详情
(VII)	30189	3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxybenzoic acid	C₂₅H₂₄O₆	详情	详情
(VIII)	30190	benzyl 3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxyphenylcarbamate	C₃₂H₃₁NO₆	详情	详情
(IX)	30191	(3R,4R)-3-(5-amino-2-methoxybenzyl)-3,4-dihydro-2H-chromene-4,6-diol	C₁₇H₁₉NO₄	详情	详情
(X)	20138	7-chloro-2-(chloromethyl)quinoline	C₁₀H₇Cl₂N	详情	详情
(XI)	30192	(3R,4R)-3-(5-amino-2-methoxybenzyl)-6-[(7-chloro-2-quinolinyl)methoxy]-3,4-dihydro-2H-chromen-4-ol	C₂₇H₂₅ClN₂O₄	详情	详情

Extended Information