methyl 2-(3-hydroxy-2-propylphenoxy)benzoate -Drug Synthesis Database

【结构式】

【分子编号】16217

【品名】methyl 2-(3-hydroxy-2-propylphenoxy)benzoate

【CA登记号】

【分子式】C₁₇H₁₈O₄

【分子量】286.32752

【元素组成】C 71.31% H 6.34% O 22.35%

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：(X)

The key diaryl ethyl fragment of LY293111 begins with the deprotonation and alkylation of 1,3-dimethoxybenzene (VII) to provide compound (VIII). Two routes may be used to construct the diaryl ether phenol (X). The first route, utilizing an Ullmann ether synthesis, begins with the demethylation of (VIII) with molten pyridinium hydrochloride to give diol (IX). Subsequent coupling of (IX) with methyl 2-iodobenzoate in the presence of copper and potassium carbonate in refluxing pyridine provides the target phenol (X). In the alternative route, compound (VIII) is mono-demethylated with sodium ethanethiolate in hot N,N-dimethylformamide to provide phenol (XI). The addition of 2-fluorobenzonitrile to (XI), mediated by potassium fluoride-alumina and 18-crown-6 in refluxing acetonitrile, provides nitrile (XII). Boron tribromide-assisted demethylation of (XII), followed by hydrolysis and esterification, completes the alternate synthesis of intermediate (X).

参考文献中间体

合成目标

【1】 Schmittling, E.A.; Sawyer, J.S.; Synthesis of diaryl ethers, diaryl thioethers, and diaryl amines mediated by potassium fluoride-alumina and 18-crown-6. J Org Chem 1993, 58, 3229-30.
【2】 Sawyer, J.S.; Bach, N.J.; Baker, S.R.; et al.; Synthetic and structure/activity studies on acid-substituted 2-arylphenols: The discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist. J Med Chem 1995, 38, 22, 4411-32.
【3】 Sawyer, J.S.; Baldwin, R.F.; Sofia, M.J.; et al.; Biphenylyl-substituted xanthones: Highly potent leukotriene B4 receptor antagonists. J Med Chem 1993, 36, 24, 3982-4.
【4】 Sawyer, J.S.; LY-293111 Sodium. Drugs Fut 1996, 21, 6, 610.
【5】 Sawyer, J.S.; Baldwin, R.F.; Saussy, D.L. Jr.; Froelich, L.L.; Jackson, W.T.; Diaryl ether/carboxylic acid derivatives of LY255283: Receptor antagonists of leukotriene B4. Bioorg Med Chem Lett 1993, 3, 10, 1985-90.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	41199	2-fluorobenzonitrile	394-47-8	C₇H₄FN	详情	详情
	64701	methyl 2-iodobenzoate		C₈H₇IO₂	详情	详情
(VII)	11934	m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether	151-10-0	C₈H₁₀O₂	详情	详情
(VIII)	16215	3-methoxy-2-propylphenyl methyl ether; 1,3-dimethoxy-2-propylbenzene		C₁₁H₁₆O₂	详情	详情
(IX)	16216	2-propyl-1,3-benzenediol		C₉H₁₂O₂	详情	详情
(X)	16217	methyl 2-(3-hydroxy-2-propylphenoxy)benzoate		C₁₇H₁₈O₄	详情	详情
(XI)	16218	3-methoxy-2-propylphenol		C₁₀H₁₄O₂	详情	详情
(XII)	16219	2-(3-methoxy-2-propylphenoxy)benzonitrile		C₁₇H₁₇NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The final coupling of fragments (VI) and (X) to give (XIII) is shown in Scheme 19757001c, and is accomplished in the presence of potassium carbonate in N,N-dimethylformamide. The final deprotection sequence is effected by hydrogenolysis of the benzyl ether followed by hydrolysis of the resulting ester to provide LY293111 as the sodium salt.

参考文献中间体

合成目标

【1】 Schmittling, E.A.; Sawyer, J.S.; Synthesis of diaryl ethers, diaryl thioethers, and diaryl amines mediated by potassium fluoride-alumina and 18-crown-6. J Org Chem 1993, 58, 3229-30.
【2】 Sawyer, J.S.; LY-293111 Sodium. Drugs Fut 1996, 21, 6, 610.
【3】 Sawyer, J.S.; Bach, N.J.; Baker, S.R.; et al.; Synthetic and structure/activity studies on acid-substituted 2-arylphenols: The discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist. J Med Chem 1995, 38, 22, 4411-32.
【4】 Sawyer, J.S.; Baldwin, R.F.; Sofia, M.J.; et al.; Biphenylyl-substituted xanthones: Highly potent leukotriene B4 receptor antagonists. J Med Chem 1993, 36, 24, 3982-4.
【5】 Sawyer, J.S.; Baldwin, R.F.; Saussy, D.L. Jr.; Froelich, L.L.; Jackson, W.T.; Diaryl ether/carboxylic acid derivatives of LY255283: Receptor antagonists of leukotriene B4. Bioorg Med Chem Lett 1993, 3, 10, 1985-90.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	16213	benzyl 5-ethyl-4'-fluoro-4-(3-iodopropoxy)[1,1'-biphenyl]-2-yl ether; 2-(benzyloxy)-5-ethyl-4'-fluoro-4-(3-iodopropoxy)-1,1'-biphenyl	C₂₄H₂₄FIO₂	详情	详情
(X)	16217	methyl 2-(3-hydroxy-2-propylphenoxy)benzoate	C₁₇H₁₈O₄	详情	详情
(XIII)	16220	methyl 2-[3-(3-[[6-(benzyloxy)-3-ethyl-4'-fluoro[1,1'-biphenyl]-4-yl]oxy]propoxy)-2-propylphenoxy]benzoate	C₄₁H₄₁FO₆	详情	详情

Extended Information