1-[5-(benzyloxy)-2-hydroxyphenyl]-1-ethanone -Drug Synthesis Database

【结构式】

【分子编号】20133

【品名】1-[5-(benzyloxy)-2-hydroxyphenyl]-1-ethanone

【CA登记号】

【分子式】C₁₅H₁₄O₃

【分子量】242.27436

【元素组成】C 74.36% H 5.82% O 19.81%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

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：(I)

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).

参考文献中间体

合成目标

【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

合成路线3

该中间体在本合成路线中的序号：(XII)

Selective O-protection of 2,5-dihydroxyacetophenone (XI) with benzyl bromide by means of K2Co3 in acetone or methylisobutylketone yields 2’-hydroxy-5’-benzyloxyacetophenone (XII) , which is then nitrated with fuming Hno3 in AcoH to give the 3’-nitroacetophenone derivative (XIII) . Reduction of the nitro group in compound (XIII) by catalytic hydrogenation over Rh/C in MeoH or Pto2 in 2-MeTHF (4, 5) provides the corresponding aniline (XIV) , which finally undergoes cyclization with chloroacetyl chloride (XV) in the presence of K2Co3 in refluxing acetonitrile or 2-MeTHF .

参考文献中间体

合成目标

【1】 Bouyssou, T., Hoenke, C., Rudolf, K. et al. Discovery of olodaterol, a novel inhaled b2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bioorg Med Chem Lett 2010, 20(4): 1410-4.
【2】 Konetzki, I., Lustenberger, P., Sieger, P. (Boehringer Ingelheim Pharma GmbH & Co. KG). Novel enantiomerically pure beta-agonists, method for the production and the use thereof in the form of a drug. EP 1789405, JP 2007537196, US 2005267106, US 2007027148, US 7220742, US 7491719, US 2009137578, US 8034809, Wo 2005111005.
【3】 Krueger, T., Ries, U., Schnaubelt, J., Rall, W., Leuter, Z.A., Duran, A., Soyka, R. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 1917253, JP 2009504708, US 201114859, Wo 2007020227.
【4】 Rodriguez Dehli, J.M., Hagenkoetter, R., Schul, M., Stange, C. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 2125759, JP 2010516739, US 2010022770, Wo 2008090193.

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)	68012	8-acetyl-6-benzyloxy-1,4-benzoxazin-3-one		C₁₇H₁₅NO₄	详情	详情
(XI)	38479	1-(2,5-dihydroxyphenyl)-1-ethanone	490-78-8	C₈H₈O₃	详情	详情
(XII)	20133	1-[5-(benzyloxy)-2-hydroxyphenyl]-1-ethanone		C₁₅H₁₄O₃	详情	详情
(XIII)	68024	1-(5-(benzyloxy)-2-hydroxy-3-nitrophenyl)ethanone		C₁₅H₁₃NO₅	详情	详情
(XIV)	68025	1-(3-amino-5-(benzyloxy)-2-hydroxyphenyl)ethanone		C₁₅H₁₅NO₃	详情	详情
(XV)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情

Extended Information