3-(Dihydroxyboryl)benzaldehyde; 3-Boronobenzaldehyde; 3-Formylbenzeneboronic acid; 3-Formylphenylboronic acid; Benzaldehyde-3-boronic acid -Drug Synthesis Database

【结构式】

【分子编号】57061

【品名】3-(Dihydroxyboryl)benzaldehyde; 3-Boronobenzaldehyde; 3-Formylbenzeneboronic acid; 3-Formylphenylboronic acid; Benzaldehyde-3-boronic acid

【CA登记号】87199-16-4

【分子式】C₇H₇BO₃

【分子量】149.94178

【元素组成】C 56.07% H 4.71% B 7.21% O 32.01%

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)

2-Bromo-4-methylaniline (I) is converted to quinoline (II) upon condensation with glycerol under Skraup synthesis conditions. Radical bromination of (II) with N-bromosuccinimide affords the benzylic bromide (III), which is subsequently displaced with sodium methanesulfinate to yield sulfone (IV). Alkylation of sulfone (IV) with iodomethane in the presence of potassium tert-butoxide affords the dimethylated sulfone (V). This is then subjected to Suzuki coupling with the boronic acid (VI) to produce the 8-aryl quinoline (VII). Condensation of aldehyde (VII) with 4-(methylthio)aniline (VIII) generates imine (IX), to which methyllithium is added to furnish the alpha methylated amine (X). Acylation of amine (X) by 4-fluorobenzoyl chloride (XI) gives amide (XII). The methylsulfanyl group of (XII) is finally oxidized with oxone to the target bis-sulfone derivative.

参考文献中间体

合成目标

【1】 Lacombe, P.; Dubé, D.; Deschenes, D.; et al.; Heteroatom-bridged substituted 8-arylquinolines as potent PDE IV inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 328.

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)	57056	2-Bromo-4-methylaniline; 2-Bromo-p-toluidine; 3-Bromo-4-aminotoluene; 4-Amino-3-bromotoluene	583-68-6	C₇H₈BrN	详情	详情
(II)	57057	8-bromo-6-methylquinoline		C₁₀H₈BrN	详情	详情
(III)	57058	8-bromo-6-(bromomethyl)quinoline		C₁₀H₇Br₂N	详情	详情
(IV)	57059	8-bromo-6-[(methylsulfonyl)methyl]quinoline; (8-bromo-6-quinolinyl)methyl methyl sulfone		C₁₁H₁₀BrNO₂S	详情	详情
(V)	57060	1-(8-bromo-6-quinolinyl)-1-methylethyl methyl sulfone; 8-bromo-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline		C₁₃H₁₄BrNO₂S	详情	详情
(VI)	57061	3-(Dihydroxyboryl)benzaldehyde; 3-Boronobenzaldehyde; 3-Formylbenzeneboronic acid; 3-Formylphenylboronic acid; Benzaldehyde-3-boronic acid	87199-16-4	C₇H₇BO₃	详情	详情
(VII)	57062	3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}benzaldehyde		C₂₀H₁₉NO₃S	详情	详情
(VIII)	57066	4-(Methylmercapto)aniline; 4-(Meylthio)aniline; 4-(Meylthio)benzenamine; 4-Aminothioanisole; p-(Methylmercapto)aniline; p-(Meylthio)aniline; p-(Meylthio)benzenamine; p-Aminothioanisole	104-96-1	C₇H₉NS	详情	详情
(IX)	57063	N-[(E)-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)methylidene]-N-[4-(methylsulfanyl)phenyl]amine; N-[(E)-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)methylidene]-4-(methylsulfanyl)aniline		C₂₇H₂₆N₂O₂S₂	详情	详情
(X)	57064	N-[1-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)ethyl]-4-(methylsulfanyl)aniline; N-[1-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)ethyl]-N-[4-(methylsulfanyl)phenyl]amine		C₂₈H₃₀N₂O₂S₂	详情	详情
(XI)	17263	4-fluorobenzoyl chloride	403-43-0	C₇H₄ClFO	详情	详情
(XII)	57065	4-fluoro-N-[1-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)ethyl]-N-[4-(methylsulfanyl)phenyl]benzamide		C₃₅H₃₃FN₂O₃S₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Suzuki coupling of 4-bromo-3,5-dimethylphenol (I) with 3-formylphenylboronic acid (II) in the presence of Pd(PPh)3 and Na2CO3 in EtOH/toluene at 80 °C affords 4’-hydroxy-2’,6’-dimethylbiphenyl-3-carbaldehyde (III), which is then condensed with 3-(methylsulfonyl)propyl tosylate (IV) by means of K2CO3 at 90 °C in DMF to give 2’,6’-dimethyl-4’-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (V). Reduction of aldehyde (V) with NaBH4 in MeOH/THF at 0 °C produces the corresponding alcohol (VI), which upon Mitsunobu condensation with methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate (VII) in the presence of Bu3P and ADDP in toluene yields the corresponding ether (VIII). Finally, ester (VIII) is hydrolyzed with NaOH in MeOH/THF/H2O at 50 °C .
3-(Methylsulfonyl)propyl tosylate (IV) is prepared by sulfonylation of 3-(methylsulfanyl)-1-propanol (IX) using TsCl in the presence of TMHDA and Et3N in toluene to produce the corresponding tosylate (X), which is finally oxidized with oxone in MeOH/H2O .

参考文献中间体

合成目标

【1】 Negoro, N., Sasaki, S., Mikami, S. et al. Discovery of TAK-875: A potent, selective, and orally bioavailable GPR40 agonist. ACS Med Chem Lett 2010, 1: 290-4.
【2】 Yasuma, T., Negoro, N., Yamashita, M., Itou, M. (Takeda Pharmaeutical Co., Ltd.). Fused cyclic compounds. CA 2656003, EP 2041123, EP 2248812, JP 2009280585, JP 2009542580, US 2010004312, US 7732626, WO 2008001931.

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)	68874	4-bromo-3,5-dimethylphenol；4-Bromo-3,5-xylenol	7463-51-6	C₈H₉BrO	详情	详情
(II)	57061	3-(Dihydroxyboryl)benzaldehyde; 3-Boronobenzaldehyde; 3-Formylbenzeneboronic acid; 3-Formylphenylboronic acid; Benzaldehyde-3-boronic acid	87199-16-4	C₇H₇BO₃	详情	详情
(III)	68875	4'-hydroxy-2',6'-dimethyl-[1,1'-biphenyl]-3-carbaldehyde		C₁₅H₁₄O₂	详情	详情
(IV)	68877	3-(methylsulfonyl)propyl tosylate;3-(methylsulfonyl)propyl 4-methylbenzenesulfonate		C₁₁H₁₆O₅S₂	详情	详情
(V)	68876	2’,6’-dimethyl-4’-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde;2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-carbaldehyde		C₁₉H₂₂O₄S	详情	详情
(VI)	68878	(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methanol		C₁₉H₂₄O₄S	详情	详情
(VII)	68881	methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate;(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate		C₁₁H₁₂O₄	详情	详情
(VIII)	68881	methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate;(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate		C₁₁H₁₂O₄	详情	详情
(IX)	68880	3-Methylthiopropanol;3-(Methylthio)propanol;3-Methylthio-1-propanol；3-(methylthio)propan-1-ol；3-(methylsulfanyl)-1-propanol	505-10-2	C₄H₁₀OS	详情	详情
(X)	68879	Toluene-4-sulfonic acid 3-methylsulfanyl-propyl ester；3-(METHYLTHIO)-1-(TOSYLOXY)PROPANE;3-(methylthio)propyl 4-methylbenzenesulfonate	187722-18-5	C₁₁H₁₆O₃S₂	详情	详情

Extended Information