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王栋, 钟健, 王玲, 周志慧, 蒋海婷, 罗鹏, 王西芝, 王崇益. 阿普斯特的合成工艺改进[J]. 中国药科大学学报, 2021, 52(5): 536-540. DOI: 10.11665/j.issn.1000-5048.20210504
引用本文: 王栋, 钟健, 王玲, 周志慧, 蒋海婷, 罗鹏, 王西芝, 王崇益. 阿普斯特的合成工艺改进[J]. 中国药科大学学报, 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
Citation: 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

阿普斯特的合成工艺改进

Improved synthetic process of apremilast

  • 摘要: 改进阿普斯特(APST)合成中的氢化还原反应工艺。以3-硝基邻苯二甲酸酐(4)和(S)-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲磺酰基)乙胺]-N-乙酰基-L-亮氨酸盐(7)为起始原料,经过胺化反应得到(S)-2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲磺酰基乙基]-4-硝基异吲哚啉-1,3-二酮(8),再以甲酸铵作为氢源,氢氧化钯碳为催化剂,将化合物8还原成(S)-2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲磺酰基乙基]-4-氨基异吲哚啉-1,3-二酮(9),最后与醋酐完成乙酰化反应得到APST。目标产物结构经比旋度、1H NMR、13C NMR、MS和元素分析等确证,胺化、还原和乙酰化3步反应总收率提高至67.0%。改进后的还原工艺,避开了氢化加压特种反应,降低了安全风险和生产成本,适合工业化生产,具有较高的商业价值。

     

    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.

     

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