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【结 构 式】 
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【药物名称】VML-295, LY-293111 Sodium, LY-293111Na 【化学名称】2-[3-[3-(5-Ethyl-4'-fluoro-2-hydroxybiphenyl-4-yloxy)propoxy]-2-propylphenoxy]benzoic acid sodium salt 【CA登记号】161172-51-6 (free acid) 【 分 子 式 】C33H32FNaO6 【 分 子 量 】566.60759 |
【开发单位】Lilly (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, RESPIRATORY DRUGS, 5-Lipoxygenase Inhibitors, Leukotriene BLT (LTB4) Antagonists, PPARgamma Agonists |
合成路线1
The biphenyl side chain of LY293111 can be constructed as illustrated in Scheme 19757001a: 4-Benzyloxy-2-hydroxyacetophenone (I) is alkylated with 1-bromo-3-chloropropane to provide compound (II). Reduction of the keto group with triethylsilane in trifluoroacetic acid provides (III), which is then regiospecifically brominated with N-bromosuccinimide to give (IV). A Suzuki biaryl coupling of (IV) with 4-fluorophenylboronic acid is used to prepare chloride (V), which is treated with sodium iodide in refluxing 2-butanone to give intermediate iodide (VI).
| 【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 |
|---|---|---|---|---|---|---|
| 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 | |
| 38403 | 4-fluorophenylboronic acid | 1765-93-1 | C6H6BFO2 | 详情 | 详情 | |
| (I) | 16208 | 4'-Benzyloxy-2'-hydroxyacetophenone; 1-[4-(Benzyloxy)-2-hydroxyphenyl]-1-ethanone | 29682-12-0 | C15H14O3 | 详情 | 详情 |
| (II) | 16209 | 1-[4-(benzyloxy)-2-(3-chloropropoxy)phenyl]-1-ethanone | C18H19ClO3 | 详情 | 详情 | |
| (III) | 16210 | 4-(benzyloxy)-2-(3-chloropropoxy)-1-ethylbenzene; benzyl 3-(3-chloropropoxy)-4-ethylphenyl ether | C18H21ClO2 | 详情 | 详情 | |
| (IV) | 16211 | benzyl 2-bromo-5-(3-chloropropoxy)-4-ethylphenyl ether; 1-(benzyloxy)-2-bromo-5-(3-chloropropoxy)-4-ethylbenzene | C18H20BrClO2 | 详情 | 详情 | |
| (V) | 16212 | benzyl 4-(3-chloropropoxy)-5-ethyl-4'-fluoro[1,1'-biphenyl]-2-yl ether; 2-(benzyloxy)-4-(3-chloropropoxy)-5-ethyl-4'-fluoro-1,1'-biphenyl | C24H24ClFO2 | 详情 | 详情 | |
| (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 |
合成路线2
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).
| 【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3
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.
| 【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 | CAS号 | 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 |