Improved synthetic process of apremilast

WANG Dong; ZHONG Jian; WANG Ling; ZHOU Zhihui; JIANG Haiting; LUO Peng; WANG Xizhi; WANG Chongyi

doi:10.11665/j.issn.1000-5048.20210504

Journal of China Pharmaceutical University > 2021 > 52(5): 536-540. > DOI: 10.11665/j.issn.1000-5048.20210504

WANG Dong, ZHONG Jian, WANG Ling, ZHOU Zhihui, JIANG Haiting, LUO Peng, WANG Xizhi, WANG Chongyi. Improved synthetic process of apremilast[J]. Journal of China Pharmaceutical University, 2021, 52(5): 536-540. DOI: 10.11665/j.issn.1000-5048.20210504

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Improved synthetic process of apremilast

1.
Jiangsu Runan Pharmaceutical Co., Ltd. Huai'an 223299
2.
Research Institute, Jiangsu Chiatai Qingjiang Pharmaceutical Co., Ltd. Huai'an 223001, China

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Received Date: March 04, 2021
Revised Date: September 06, 2021

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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.
- apremilast,
- phosphodiesterase-4 inhibitors,
- ammonium formate,
- synthesis,
- productive technology improvement

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