Improved synthetic process of apremilast
10.11665/j.issn.1000-5048.20210504
- VernacularTitle:阿普斯特的合成工艺改进
- Author:
Dong WANG
1
;
Jian ZHONG
;
Ling WANG
;
Zhihui ZHOU
;
Haiting JIANG
;
Peng LUO
;
Xizhi WANG
;
Chongyi WANG
Author Information
1. 江苏润安制药有限公司
- Publication Type:Journal Article
- Keywords:
apremilast;
phosphodiesterase-4 inhibitors;
ammonium formate;
synthesis;
productive technology improvement
- From:
Journal of China Pharmaceutical University
2021;52(5):536-540
- CountryChina
- Language:Chinese
-
Abstract:
To optimize the process of hydrogenation reduction in the synthesis of apremilast (APST), 3-nitrophthalic anhydride (4) and (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine-(S)-2-acetamido-4-methylpentanoate (7) were used as starting materials to synthesize (S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4-nitroisoindoline-1,3-dione (8) by amination.Then compound 8 was reduced to (S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl) isoindoline-1,3-dione (9) with ammonium formate as hydrogen source and palladium hydroxide as catalyst.Finally, apremilast was obtained by the acetylation reaction with acetic anhydride.The structure of the products were verified by optical rotation, 1H NMR, 13C NMR, MS and elemental analysis.And the total yield of three steps was increased to 67.0%.The improved reduction process can avoid the special reaction of hydrogenation and pressurization, and reduce the safety risk and production costs with high commercial value.
