An improved kilogram-scale process of synthesis of nalbuphine was developed by investigating the critical parameters. Ten process-related impurities were identified, of which the source and control strategy was elucidated. Moreover, tetramethylammonium triacetoxyborohydride (Me₄NBH(OAc)₃) was developed to reduce the imine and ketone in one pot. As a result, 6-β-epimer was significantly controlled to only 0.08% in the crude nalbuphine. The improved process was robust at kilogram scale in 60.4% overall yield with 99.95% high-performance liquid chromatography (HPLC) purity.

中文翻译：

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一锅法合成盐酸纳布啡的工艺及杂质控制策略

通过研究关键参数，开发了一种改进的公斤级合成纳布啡的方法。确定了十种与过程相关的杂质，其中阐明了来源和控制策略。此外，开发了四乙酰基三乙酰氧基硼氢化铵（Me ₄ NBH（OAc）₃）以在一锅中还原亚胺和酮。结果，在粗制纳布啡中6-β-顶基被显着地控制为仅0.08％。改进后的方法在千克规模上非常可靠，总收率为60.4％，高效液相色谱（HPLC）纯度为99.95％。