BAY-27-9955, -Drug Synthesis Database

【结构式】

【药物名称】BAY-27-9955

【化学名称】(+)-1-(4'-Fluoro-3,5-diisopropyl-6-propylbiphenyl-2-yl)ethanol

【CA登记号】202855-56-9

【分子式】C₂₃H₃₁FO

【分子量】342.50132

【开发单位】Bayer (Originator)

【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Glucagon Antagonists

合成路线1 合成路线2

合成路线1

Aldol condensation between dimethyl 1,3-acetonedicarboxylate (I) and 3,5-heptanedione (II) produced dimethyl 4,6-diethyl-2-hydroxy-1,3-benzenedicarboxylate (III). After conversion of phenol (III) to the corresponding aryl triflate (IV), Suzuki coupling with 4-fluorobenzeneboronic acid (V) yielded the biphenyl derivative (VI). The diisopropyl compound (VII) was then obtained by methylation of (VI) at the benzylic position using iodomethane and LDA. Partial reduction of diester (VII) with Red-Al?gave rise to the hydroxy ester (VIII), which was further oxidized to aldehyde (IX) by treatment with pyridinium chlorochromate. Wittig reaction of aldehyde (IX) with ethyl triphenylphosphonium bromide furnished the propenyl compound (X)

参考文献中间体

【2】 Schmidt, G.; Wolanin, D.J.; Bischoff, H.; Schoen, W.R.; Angerbauer, R.; Schmidt, D.; Kramss, R.H.; Wohlfeil, S.; Brandes, A.; Muller-Gliemann, M.; Lease, T.G.; Ladouceur, G.H.; Osterhout, M.H.; Hertzog, D.L.; Cook, J.H. II (Bayer AG; Bayer Corp.); Substd. pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents. WO 9804528 .
【1】 Wolanin, D.J.; Schoen, W.R.; Kramss, R.H.; Lease, T.G.; Ladouceur, G.H.; Osterhout, M.H.; Hertzog, D.L.; Cook, J.H. II (Bayer AG; Bayer Corp.); Substd. biphenyls. US 6218431 .

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)	22692	dimethyl 3-oxopentanedioate	1830-54-2	C₇H₁₀O₅	详情	详情
(II)	39689	3,5-heptanedione	7424-54-6	C₇H₁₂O₂	详情	详情
(III)	60521	dimethyl 4,6-diethyl-2-hydroxyisophthalate		C₁₄H₁₈O₅	详情	详情
(IV)	60522	dimethyl 4,6-diethyl-2-{[(trifluoromethyl)sulfonyl]oxy}isophthalate		C₁₅H₁₇F₃O₇S	详情	详情
(V)	38403	4-fluorophenylboronic acid	1765-93-1	C₆H₆BFO₂	详情	详情
(VI)	60523	dimethyl 3,5-diethyl-4'-fluoro[1,1'-biphenyl]-2,6-dicarboxylate		C₂₀H₂₁FO₄	详情	详情
(VII)	60524	dimethyl 4'-fluoro-3,5-diisopropyl[1,1'-biphenyl]-2,6-dicarboxylate		C₂₂H₂₅FO₄	详情	详情
(VIII)	60525	methyl 4'-fluoro-6-(hydroxymethyl)-3,5-diisopropyl[1,1'-biphenyl]-2-carboxylate		C₂₁H₂₅FO₃	详情	详情
(IX)	60526	methyl 4'-fluoro-6-formyl-3,5-diisopropyl[1,1'-biphenyl]-2-carboxylate		C₂₁H₂₃FO₃	详情	详情
(X)	60527	methyl 4'-fluoro-3,5-diisopropyl-6-[(E)-1-propenyl][1,1'-biphenyl]-2-carboxylate		C₂₃H₂₇FO₂	详情	详情

合成路线2

The ester group of (X) was reduced to alcohol (XI) employing LiAlH4 in boiling THF. Subsequent olefin hydrogenation in the presence of Pd/C produced the propyl compound (XII). After oxidation of the primary alcohol (XII) to aldehyde (XIII) by means of pyridinium chlorochromate, addition of methylmagnesium bromide led to the desired secondary alcohol (1,2).

参考文献中间体

【1】 Schmidt, G.; Wolanin, D.J.; Bischoff, H.; Schoen, W.R.; Angerbauer, R.; Schmidt, D.; Kramss, R.H.; Wohlfeil, S.; Brandes, A.; Muller-Gliemann, M.; Lease, T.G.; Ladouceur, G.H.; Osterhout, M.H.; Hertzog, D.L.; Cook, J.H. II (Bayer AG; Bayer Corp.); Substd. pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents. WO 9804528 .
【2】 Wolanin, D.J.; Schoen, W.R.; Kramss, R.H.; Lease, T.G.; Ladouceur, G.H.; Osterhout, M.H.; Hertzog, D.L.; Cook, J.H. II (Bayer AG; Bayer Corp.); Substd. biphenyls. US 6218431 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	60527	methyl 4'-fluoro-3,5-diisopropyl-6-[(E)-1-propenyl][1,1'-biphenyl]-2-carboxylate	C₂₃H₂₇FO₂	详情	详情
(XI)	60528	{4'-fluoro-3,5-diisopropyl-6-[(E)-1-propenyl][1,1'-biphenyl]-2-yl}methanol	C₂₂H₂₇FO	详情	详情
(XI)	60529	(4'-fluoro-3,5-diisopropyl-6-propyl[1,1'-biphenyl]-2-yl)methanol	C₂₂H₂₉FO	详情	详情
(XIII)	60530	4'-fluoro-3,5-diisopropyl-6-propyl[1,1'-biphenyl]-2-carbaldehyde	C₂₂H₂₇FO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)