Old is Gold? Nefopam Hydrochloride, a Non-opioid and Non-steroidal Analgesic Drug and Its Practical One-Pot Synthesis in a Single Solvent for Large-Scale Production,Organic Process Research & Development

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Old is Gold? Nefopam Hydrochloride, a Non-opioid and Non-steroidal Analgesic Drug and Its Practical One-Pot Synthesis in a Single Solvent for Large-Scale Production
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2017-11-01 00:00:00 , DOI: 10.1021/acs.oprd.7b00228
Mohan Reddy Bodireddy ₁ , Kiran Krishnaiah ₁ , Prashanth Kumar Babu ₁ , Chaithanya Bitra ₁ , Madhusudana Rao Gajula ₁ , Pramod Kumar ₁

Affiliation

Nefopam hydrochloride is extensively used in most of the European countries until today as an analgesic because of its non-opiate (non-narcotic) and non-steroidal action with fewer side effects compared with opioid and other analgesics, which cause more troublesome side effects. A multikilogram synthesis of nefopam hydrochloride has been achieved in one pot using a single solvent (toluene). A ≥99.9% purity of the active pharmaceutical ingredient (API) was achieved in excellent overall yield (≥79%). The one-pot, five-step synthetic process involves formation of an acid chloride (3) from benzoylbenzoic acid (2) followed by amidation (4), reduction (5), cyclization (6), and formation of the hydrochloride salt (1). The major advantages include (i) use of a single solvent, (ii) >90% conversion in each step, (iii) a cost-effective and operationally friendly process, (iv) averting the formation of genotoxic impurities, and (v) improved overall yield (≥79%) provided by the one-pot operation. For the first time, we report the characterization data of API 1, intermediates 3, 4, and 5, and also a possible impurity (5a).

中文翻译：

黄金老了吗？盐酸奈非帕姆，一种非阿片类药物和非甾体类止痛药，并且在单一溶剂中大规模生产的实用一罐合成方法

盐酸奈非帕姆因其非阿片类药物（非麻醉药）和非类固醇的作用，与阿片类和其他镇痛药相比副作用少，因此在欧洲大多数国家/地区至今一直被广泛用作镇痛药。使用单一溶剂（甲苯）在一个锅中即可完成多公斤盐酸奈福opa的合成。活性药物成分（API）的纯度达到≥99.9％，具有极好的总收率（≥79％）。一锅五步合成工艺涉及从苯甲酰基苯甲酸（2）形成酰氯（3），然后进行酰胺化（4），还原（5），环化（6）和形成盐酸盐（5）。1）。主要优点包括：（i）使用单一溶剂；（ii）每个步骤中的转化率均> 90％；（iii）具有成本效益且操作简便的工艺；（iv）避免了遗传毒性杂质的形成；以及（v）一锅操作提高了总产量（≥79％）。对于第一次，我们报告API的表征数据1，中间体3，4，和5，以及还可能的杂质（图5a）。

更新日期：2017-11-01

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