One-Pot Synthesis of Papaverine Hydrochloride and Identification of Impurities
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ne-Pot Synthesis of Papaverine Hydrochloride and Identification of Impurities Wen-Shuai Yua,b, Ze-Nong Wub,c, Zeng-Feng Qiud, Chun-Jie Zhaoa,*, Fu-Li Zhangb, and Zhe-Zhou Yangb a b
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016 China
Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203 China c d
School of Pharmacy, Fudan University, Shanghai, 201203 China
College of Chemistry and Material Science, Shandong Agricultural University, Taian, 271018 China *e-mail: [email protected] Received February 21, 2020; revised February 28, 2020; accepted May 17, 2020
Abstract—A one-pot synthesis of papaverine hydrochloride with 99.6% purity was performed using xylene as solvent for the entire process. The critical parameters of each step, as well as the impurities generated, were identified. The overall yield was improved to 63%. The proposed synthetic procedure is suitable for industrial production. Keywords: papaverine hydrochloride, one-pot synthesis, impurities, efficiency
DOI: 10.1134/S1070428020070258 INTRODUCTION In 1978, papaverine hydrochloride (1), promoted under the trade name Oxadilene, was marketed in France for the treatment of ischemia, as well as kidney, gallbladder, and gastrointestinal visceral fistulae caused by brain, heart, and peripheral vasospasms [1]. There are many ways to synthesize papaverine hydrochloride [2], and the general route [3–5] used for its synthesis is shown in Scheme 1. First, 3,4-dimethoxyphenylacetic acid (2) was reacted with SOCl2 in toluene to form 3,4-dimethoxyphenylacetyl chloride. The reaction of 3,4-dimethoxyphenylacetyl chloride with 2-(3,4-dimethoxyphenyl)ethanamine (3) in dichloromethane at room temperature for 3 h gave amide 4. The latter was treated with POCl3 in acetonitrile at 80°C to generate dihydroisoquinoline derivative 5, and the latter was dehydrogenated in toluene over Pd/C at 230°C to yield papaverine (6). Finally, papaverine (6) was converted to papaverine hydrochloride (1) by treat ment with a solution of hydrogen chloride in ethanol. The process shown in Scheme 1 would first generate acid waste, which is contrary to the requirements of green environmental protection. In addition, frequent solvent changes makes solvent recycling im-
possible, which results in increased production costs and reduced atom economy. Finally, the use of Pd/C as a dehydrogenation catalyst requires a high temperature. Therefore, development of an economical, efficient, practical, and robust synthetic route for industrial production is highly desired, and such process is described in the present article. RESULTS AND DISCUSSION The proposed synthetic process involves the following four steps. First, 3,4-dimethoxyphenylacetic acid (2) and 2-(3,4-dimethoxyphenyl)ethanamine (3) reacted at high temperature [6]. Amide 4 reacted with POCl3 to yield imine 5 [7]. Imine 5 was dehydrogenated with Raney nickel at high temperature [8] to form papaverine 6, which was treated with hydrochloric acid t
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