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【结 构 式】 
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【分子编号】20137 【品名】3-(5-amino-2-methoxybenzyl)-6-hydroxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one 【CA登记号】 |
【 分 子 式 】C19H21NO4 【 分 子 量 】327.38008 【元素组成】C 69.71% H 6.47% N 4.28% O 19.55% |
合成路线1
该中间体在本合成路线中的序号：(V)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).
| 【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：(V)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)-5,6-difluorobenzothiazole (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).
| 【1】 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. |
| 【2】 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. |
| 【3】 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. |
| 【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) | 20150 | 2-(chloromethyl)-5,6-difluoro-1,3-benzothiazole | C8H4ClF2NS | 详情 | 详情 | |
| (VII) | 20151 | 3-(5-amino-2-methoxybenzyl)-6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one | C27H24F2N2O4S | 详情 | 详情 | |
| (VIII) | 20152 | N-[3-([6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | C29H22F8N2O8S3 | 详情 | 详情 | |
| (IX) | 20153 | N-[3-([6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide | C28H23F5N2O6S2 | 详情 | 详情 | |
| (X) | 20154 | N-[3-([6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide | C28H25F5N2O6S2 | 详情 | 详情 | |
| (XI) | 23214 | N-[3-([(3S,4R)-6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide | C28H25F5N2O6S2 | 详情 | 详情 | |
| (XII) | 20156 | (3S,4R)-6-[(5,6-difluoro-1,3-benzothiazol-2-yl)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 | C44H43F5N4O9S2 | 详情 | 详情 |