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

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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References

[1]	. Guangzhou Chem Ind（广州化工），2015，43（10）：107-108.
[2]	Huang Q，Zhao SY. Synthesis of 1-（3-ethoxy-4-methoxyphenyl）-2-（methylsulfonyl）ethenamine［J］. Biol Chem Eng（生物化工），2016，2（2）：4-7.
[3]	Lan XB，Zhu CS. Study on the synthesis of related substance of apremilast［J］. Guangdong Chem Ind（广东化工），2016，43（9）：105-106.
[4]	Liu FM. Improvement of synthesis processes of ramelteon，apremilast and chalcone（雷美替胺、阿普斯特及查耳酮合成工艺的改良）［D］. Wuxi：Jiangnan University，2015.
[5]	SchaferP，MullerG，ManHW，et al. Preparing methods of（+）-2-［ 1-（3-ethoxy-4-methoxyphenyl）-2-methylsulfonylethyl］- 4 acetylaminoisoindoline 1， 3-dione and its compound（（+）-2-［ 1-（3-乙氧基-4-甲氧基苯基）-2-甲磺酰基乙基］- 4-乙酰氨基异吲哚啉-1，3-二酮、其合成方法及其组合物）： CN1965823 B［P］. 2010-05-12.
[6]	Ruchelman AL，Connolly TJ. Enantioselective synthesis of the apremilast aminosulfone using catalytic asymmetric hydrogenation［J］. Tetrahedron Asymmetry，2015，26（10/11）：553-559.
[7]	Man HW，Schafer P，Wong LM，et al. Discovery of（S）-N-［2-［1-（3-ethoxy-4-methoxyphenyl）-2-methanesulfonylethyl］-1，3-dioxo-2，3-dihydro-1H-isoindol-4-yl］acetamide（apremilast），a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor［J］. J Med Chem，2009，52（6）：1522-1524.
[8]	Connolly TJ，Ruchelman AL，Yong KHY，et al. Processes for the preparation of isoindole compounds and isotopologues thereof： US8981117［P］. 2015-03-17.
[9]	Strong M. FDA policy and regulation of stereoisomers：paradigm shift and the future of safer，more effective drugs［J］. Food Drug Law J，1999，54（3）：463-487.
[10]	Odingo JO. Inhibitors of PDE4：a review of recent patent literature［J］. Expert Opin Ther Patents，2005，15（7）：773-787.
[11]	Banner KH，Trevethick MA. PDE4 inhibition：a novel approach for the treatment of inflammatory bowel disease［J］. Trends Pharmacol Sci，2004，25（8）：430-436.
[12]	Jennifer RS，Duarte FJ，Stephanie AD. Oligomer-containing apremilast moiety compounds： WO2012083153［P］. 2012-06-21.
[13]	Man HW，Schafer P，Wong LM，et al. Discovery of（S）-N-｛2-［1-（3-ethoxy-4-methoxyphenyl）-2-methanesulfonylethyl］-1，3-dioxo-2，3-dihydro-1H-isoindol-4-yl｝acetamide（apremilast），a potent and orally active phosphodiesterase 4 and tumor necrosis factor-α inhibitor［J］. J Med Chem，2009，52（6）：1522-1524.
[14]	Zhou JC. Applications of ammonium formate and other derivatives of formic acid in the drug synthesis［J］. J China Pharm Univ（中国药科大学学报），1989，20（5）：313-320.
[15]	Pharmaceuticals and Medical Devices Agency. Phosphodiesterase-4 inhibitors apremilast tablets（Otezla^? tablets 10 mg 20 mg 30 mg）［EB/OL］. https：//www.info.pmda.go.jp/go/interview/2/112922_3999042F1025_2_001_1F.pdf.

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