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【结 构 式】 
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【药物名称】VML-530, ABT-080 【化学名称】4,4-Bis[4-(quinolin-2-ylmethoxy)phenyl]pentanoic acid sodium salt 【CA登记号】 【 分 子 式 】C37H31N2NaO4 【 分 子 量 】590.66042 |
【开发单位】Abbott (Originator), Vernalis (Licensee) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Leukotriene Synthesis Inhibitors |
合成路线1
Esterification of 4,4-bis(4-hydroxyphenyl)pentanoic acid (I) was performed in a refluxing methanolic solution, using sulfuric acid as the catalyst. The resulting methyl ester (II) was alkylated on both phenolic groups with 2-(chloromethyl)quinoline hydrochloride (III) in the presence of potassium carbonate to afford IV. Hydrolysis of this ester (IV) with NaOH in a refluxing mixture of dioxane-methanol yielded acid (V), which was then converted into the sodium salt on treatment with one equivalent of NaOH in dioxane-methanol.
| 【1】 Brooks, C.D.W.; Bhatia, P.; Kolasa, T.; Stewart, A.O.; Gunn, D.E.; Craig, R.A. (Abbott Laboratories Inc.); Symmetrical bis-heteroarylmethoxyphenylalkyl carboxylates as inhibitors of leukotriene biosynthesis. EP 0862557; US 5795900; WO 9712867 . |
| 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) | 22391 | 4,4-bis(4-hydroxyphenyl)pentanoic acid | 126-00-1 | C17H18O4 | 详情 | 详情 |
| (II) | 22392 | methyl 4,4-bis(4-hydroxyphenyl)pentanoate | C18H20O4 | 详情 | 详情 | |
| (III) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (IV) | 22394 | methyl 4,4-bis[4-(2-quinolinylmethoxy)phenyl]pentanoate | C38H34N2O4 | 详情 | 详情 | |
| (V) | 22395 | 4,4-bis[4-(2-quinolinylmethoxy)phenyl]pentanoic acid | C37H32N2O4 | 详情 | 详情 |
合成路线2
The reaction of phenol (I) with 4-oxopentanoic acid (II) by means of H2SO4 gives 4,4-bis(4-hydroxyphenyl)pentanoic acid (III), which is esterified with MeOH and H2SO4 to yield the methyl pentanoate (IV). The condensation of (IV) with 2-(chloromethyl)quinoline (V) by means of K2CO3 in DMF affords the adduct (VI), which is finally hydrolyzed with NaOH in methanol/dioxane to provide the target sodium salt. Alternatively, the intermediate methyl pentanoate (IV) can also be obtained by direct condensation of phenol (I) with methyl 4-oxopentanoate (VII) by means of H2SO4 as before.
| 【1】 Gunn, D.E.; Bhatia, P.; Kolasa, T.; et al.; Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis. J Med Chem 2000, 43, 17, 3322. |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 36170 | 4-oxopentanoic acid | 123-76-2 | C5H8O3 | 详情 | 详情 |
| (III) | 22391 | 4,4-bis(4-hydroxyphenyl)pentanoic acid | 126-00-1 | C17H18O4 | 详情 | 详情 |
| (IV) | 22392 | methyl 4,4-bis(4-hydroxyphenyl)pentanoate | C18H20O4 | 详情 | 详情 | |
| (V) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (VI) | 22394 | methyl 4,4-bis[4-(2-quinolinylmethoxy)phenyl]pentanoate | C38H34N2O4 | 详情 | 详情 | |
| (VII) | 50960 | Methyl levulinate | C6H10O3 | 详情 | 详情 |