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【结 构 式】 
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【药物名称】LY-674, LY-518674 【化学名称】2-Methyl-2-[4-[3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl]phenoxy]propionic acid 【CA登记号】425671-29-0 【 分 子 式 】C23H27N3O4 【 分 子 量 】409.48934 |
【开发单位】Lilly (Originator), Ligand (Codevelopment) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Fibrates, PPARalpha Agonists |
合成路线1
Demethylation of methyl 4-(4-methoxyphenyl)butyrate (I) using boron tribromide affords phenol (II). Subsequent alkylation of (II) with t-butyl 2-bromoisobutyrate (III) yields ether (IV). The methyl ester group of (IV) is then selectively displaced with hydrazine hydrate to form hydrazide (V). This is condensed with p-methylbenzaldehyde (VI) to give hydrazone (VII), which is further reduced to (VIII) by catalytic hydrogenation over PtO2. Reaction of acyl hydrazide (VIII) with trimethylsilyl isocyanate leads to the acyl semicarbazide (IX). Finally, simultaneous t-butyl ester cleavage and cyclization to the target triazolone is accomplished by treatment of (IX) with several different sulfonic acids.
| 【1】 Braden, T.; et al.; Novel acid-catalyzed synthesis of triazolones from acyl semicarbazides. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 381. |
| 【2】 Perixosome proliferator activated receptor alpha agonists. WO 0238553 . |
| 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) | 57580 | methyl 4-(4-methoxyphenyl)butanoate | C12H16O3 | 详情 | 详情 | |
| (II) | 57581 | methyl 4-(4-hydroxyphenyl)butanoate | C11H14O3 | 详情 | 详情 | |
| (III) | 34947 | tert-butyl 2-bromo-2-methylpropanoate | 23877-12-5 | C8H15BrO2 | 详情 | 详情 |
| (IV) | 57582 | methyl 4-{4-[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]phenyl}butanoate | C19H28O5 | 详情 | 详情 | |
| (V) | 57583 | tert-butyl 2-[4-(4-hydrazino-4-oxobutyl)phenoxy]-2-methylpropanoate | C18H28N2O4 | 详情 | 详情 | |
| (VI) | 10161 | 4-Methylbenzaldehyde | 104-87-0 | C8H8O | 详情 | 详情 |
| (VII) | 57584 | tert-butyl 2-methyl-2-[4-(4-{2-[(E)-(4-methylphenyl)methylidene]hydrazino}-4-oxobutyl)phenoxy]propanoate | C26H34N2O4 | 详情 | 详情 | |
| (VIII) | 57585 | tert-butyl 2-methyl-2-(4-{4-[2-(4-methylbenzyl)hydrazino]-4-oxobutyl}phenoxy)propanoate | C26H36N2O4 | 详情 | 详情 | |
| (IX) | 57586 | tert-butyl 2-(4-{4-[2-(aminocarbonyl)-2-(4-methylbenzyl)hydrazino]-4-oxobutyl}phenoxy)-2-methylpropanoate | C27H37N3O5 | 详情 | 详情 |
合成路线2
In an alternative method, 4-(4-methoxyphenyl)butyric acid (I) is demethylated to phenol (II) by heating at 190 C with pyridine hydrochloride. Alkylation of phenol (II) with ethyl 2-bromoisobutyrate (III) gives ether (IV). The carboxyl group of (IV) is then activated as the corresponding acid chloride (V) by treatment with oxalyl chloride in the presence of DMF.
| 【1】 Braden, T.; et al.; Novel acid-catalyzed synthesis of triazolones from acyl semicarbazides. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 381. |
| 【2】 Perixosome proliferator activated receptor alpha agonists. WO 0238553 . |
| 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) | 57587 | 4-(4-Methoxyphenyl)butyric acid | C11H14O3 | 详情 | 详情 | |
| (II) | 57588 | 4-(4-hydroxyphenyl)butanoic acid | C10H12O3 | 详情 | 详情 | |
| (III) | 39799 | ethyl 2-bromo-2-methylpropanoate | 600-00-0 | C6H11BrO2 | 详情 | 详情 |
| (IV) | 57589 | 4-[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)phenyl]butanoic acid | C16H22O5 | 详情 | 详情 | |
| (V) | 57590 | ethyl 2-[4-(4-chloro-4-oxobutyl)phenoxy]-2-methylpropanoate | C16H21ClO4 | 详情 | 详情 |
合成路线3
Reductive alkylation of tert-butyl carbazate (VI) with 4-methylbenzaldehyde (VII) under catalytic hydrogenation conditions affords the N-p-methylbenzyl carbazate (VIII). This is then condensed with trimethylsilyl isocyanate to form the semicarbazide derivative (IX). Subsequent acidic Boc group cleavage in (IX) yields (X). Semicarbazide (X) is then acylated with acid chloride (V) producing (XI). Cyclization of the acyl semicarbazide (XI) in the presence of CSA leads to triazolone (XII). Finally, alkaline hydrolysis of the ethyl ester group of (XII) furnishes the title carboxylic acid.
| 【1】 Braden, T.; et al.; Novel acid-catalyzed synthesis of triazolones from acyl semicarbazides. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 381. |
| 【2】 Perixosome proliferator activated receptor alpha agonists. WO 0238553 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 57590 | ethyl 2-[4-(4-chloro-4-oxobutyl)phenoxy]-2-methylpropanoate | C16H21ClO4 | 详情 | 详情 | |
| (VI) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (VII) | 10161 | 4-Methylbenzaldehyde | 104-87-0 | C8H8O | 详情 | 详情 |
| (VIII) | 57591 | tert-butyl 2-(4-methylbenzyl)-1-hydrazinecarboxylate | C13H20N2O2 | 详情 | 详情 | |
| (IX) | 57592 | tert-butyl 2-(aminocarbonyl)-2-(4-methylbenzyl)-1-hydrazinecarboxylate | C14H21N3O3 | 详情 | 详情 | |
| (X) | 57593 | 1-(4-methylbenzyl)-1-hydrazinecarboxamide | C9H13N3O | 详情 | 详情 | |
| (XI) | 57594 | ethyl 2-(4-{4-[2-(aminocarbonyl)-2-(4-methylbenzyl)hydrazino]-4-oxobutyl}phenoxy)-2-methylpropanoate | C25H33N3O5 | 详情 | 详情 | |
| (XII) | 57595 | ethyl 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoate | C25H31N3O4 | 详情 | 详情 |