【结 构 式】 |
【药物名称】CP-664511 【化学名称】3-[3-[1(S)-[2-[3-Methoxy-4-[3-(2-methylphenyl)ureido]phenyl]acetamido]-3-methylbutyl]isoxazol-5-yl]propionic acid 【CA登记号】379692-00-9, 253347-08-9 (racemate) 【 分 子 式 】C28H34N4O6 【 分 子 量 】522.60638 |
【开发单位】Pfizer (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Integrin alpha4beta1 (VLA-4) Antagonists |
合成路线1
The isoxazolepropionate intermediate (IV) has been obtained as follows: The cyclization of N-(tert-butoxycarbonyl)-L-leucinal oxime (I) with 4-pentynoic acid methyl ester (II) by means of NaOCl and TEA in dichloromethane gives the protected isoxazole derivative (III), which is then treated with Cl in dioxane to afford the desired isoxazole intermediate (IV).
【1】 Duplantier, A.J.; et al.; Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha4beta1 integrin antagonists. Bioorg Med Chem Lett 2001, 11, 19, 2593. |
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) | 51632 | tert-butyl (1S)-1-[(hydroxyimino)methyl]-3-methylbutylcarbamate | C11H22N2O3 | 详情 | 详情 | |
(II) | 51633 | methyl 4-pentynoate | C6H8O2 | 详情 | 详情 | |
(III) | 51634 | methyl 3-(3-[(1S)-1-[(tert-butoxycarbonyl)amino]-3-methylbutyl]-5-isoxazolyl)propanoate | C17H28N2O5 | 详情 | 详情 | |
(IV) | 51635 | methyl 3-[3-[(1S)-1-amino-3-methylbutyl]-5-isoxazolyl]propanoate | C12H20N2O3 | 详情 | 详情 |
合成路线2
The condensation of 5-chloro-2-nitroanisole (V) with diethyl malonate (VI) by means of NaH in hot DMF gives 2-(3-methoxy-4-nitrophenyl)malonic acid diethyl ester (VII), which is reduced with H2 over Pd/C in ethyl acetate, yielding the corresponding amino derivative (VIII). The condensation of (VIII) with 2-methylphenyl isocyanate (IX) by means of TEA in dichloromethane affords the expected urea (X), which is submitted to a decarboxylative hydrolysis with NaOH in refluxing tert-butanol to provide the phenylacetic acid (XI). The condensation of acetic acid (XI) with the amino group of the isoxazole intermediate (IV) by means of HOBt, DIEA and EDC in DMF gives the amide (XII), which is treated with NaOH in tert-butanol to afford the target propionic acid.
【1】 Duplantier, A.J.; et al.; Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha4beta1 integrin antagonists. Bioorg Med Chem Lett 2001, 11, 19, 2593. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IV) | 51635 | methyl 3-[3-[(1S)-1-amino-3-methylbutyl]-5-isoxazolyl]propanoate | C12H20N2O3 | 详情 | 详情 | |
(V) | 51636 | 4-Chloro-2-methoxy-1-nitrobenzene; 4-Chloro-2-methoxynitrobenzene; 5-Chloro-2-nitroanisole | 6627-53-8 | C7H6ClNO3 | 详情 | 详情 |
(VI) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
(VII) | 51637 | diethyl 2-(3-methoxy-4-nitrophenyl)malonate | C14H17NO7 | 详情 | 详情 | |
(VIII) | 51638 | diethyl 2-(4-amino-3-methoxyphenyl)malonate | C14H19NO5 | 详情 | 详情 | |
(IX) | 27106 | 1-isocyanato-2-methylbenzene | 614-68-6 | C8H7NO | 详情 | 详情 |
(X) | 51639 | diethyl 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]malonate | C22H26N2O6 | 详情 | 详情 | |
(XI) | 39718 | 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid | C17H18N2O4 | 详情 | 详情 | |
(XII) | 51640 | methyl 3-(3-[(1S)-1-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]-3-methylbutyl]-5-isoxazolyl)propanoate | C29H36N4O6 | 详情 | 详情 |