3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxybenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】30189

【品名】3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxybenzoic acid

【CA登记号】

【分子式】C₂₅H₂₄O₆

【分子量】420.46196

【元素组成】C 71.42% H 5.75% O 22.83%

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：(VII)

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

合成路线2

该中间体在本合成路线中的序号：(VIII)

The reaction of 6-methoxy-3,4-dihydro-2H-1-benzopyran-4-one (I) with 48% HBr in refluxing acetic acid gives the corresponding hydroxy derivative (II), which is treated with benzyl bromide and K2CO3 in acetone to yield 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 with H2 over Pd/C in ethyl acetate to afford the corresponding benzyl compound (VI). The reduction of the carbonyl group of (VI) with NaBH4 and CeCl3 in methanol/THF gives the racemic cis alcohol (±)-(VII), which is submitted to optical resolution by reaction with Boc-D-Trp-OH and DEC, crystallization, and hydrolysis of the resulting diastereomer with NaOH in refluxing methanol affording (3R,4R)-3-(6-benzyloxy-4-hydroxy-3,4-dihydro-2H-1-benzopyran-3-yl)-4-methoxybenzoic acid (+)-(VIII). The degradation of the carboxy group of (+)-(VIII) with diphenylphosphoryl azide (DPPA) and benzyl alcohol in dioxane affords the benzyloxycarbonylamino derivative (IX), which is deprotected with H2 over Pd(OH)2 providing (3R,4R)-3-(5-amino-2-methoxybenzyl)-3,4-dihydro-2H-1-benzopyran-4,6-diol (X). The reaction of (X) with 2-(chloromethyl)-5,6-difluorobenzothiazole (XI) by means of NaH in DMF gives the expected condensation product (XII), which is finally treated with trifluoromethanesulfonic anhydride and triethylamine.

参考文献中间体

合成目标

【1】 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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(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)	31657	methyl 3-[[6-(benzyloxy)-4-oxo-2H-chromen-3(4H)-ylidene]methyl]-4-hydroxybenzoate		C₂₅H₂₀O₆	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)	31658	methyl 3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxybenzoate		C₂₆H₂₆O₆	详情	详情
(VIII)	30189	3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxybenzoic acid		C₂₅H₂₄O₆	详情	详情
(IX)	30190	benzyl 3-[[(3R,4R)-6-(benzyloxy)-4-hydroxy-3,4-dihydro-2H-chromen-3-yl]methyl]-4-methoxyphenylcarbamate		C₃₂H₃₁NO₆	详情	详情
(X)	30191	(3R,4R)-3-(5-amino-2-methoxybenzyl)-3,4-dihydro-2H-chromene-4,6-diol		C₁₇H₁₉NO₄	详情	详情
(XI)	20150	2-(chloromethyl)-5,6-difluoro-1,3-benzothiazole		C₈H₄ClF₂NS	详情	详情
(XII)	31659	(3R,4R)-3-(5-amino-2-methoxybenzyl)-6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-3,4-dihydro-2H-chromen-4-ol		C₂₅H₂₂F₂N₂O₄S	详情	详情

Extended Information