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【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

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.

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 CAS号 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.

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