Synthesis Of Efonidipine Hydrochloride Ethanolate And Research Of Crystal Forms

Efonidipine is the third generation calcium channel blockers, with activity of blocking both L- and T-type calcium channel. The trade name is “Landel” in Japan and South Korea, and it is commonly used in treating essential hypertension, renal hypertension, severe hypertension, type 2 diabetes associated with hypertension and heartfailture associated with tachycardia of treatment. It shows significant performance in clinical effect. This drug shows a longer half-life and is more efficient in treatment of hypertension and angina than the prior calcium channel blockers. Particularly, this drug could provide protection for heart and kidney. Synthesis of efonidipine efficiently and environment friendly could break the technology blockade of foreign, but can also bring considerable economic and social benefits.This article includes two parts:Part 1: Efonidipine was synthesized by Hantzsch pyridine cyclization method, and two intermediates, phosphonates-fragment and amino-fragment, were used as raw material. Effects of solvent materials, temperature, reaction time and the ratio of two intermediates, to drug yield were investigated. Optimum process condition was obtained: Chose isopropyl alcohol as reaction solvent, reflux for 3 h at 83 ℃,and the ratio of phosphonates-fragment to amino-fragment was 1.2:1(mol: mol). In order to avoid oil substances’ occurrence when immediately cooling down, gradient cooling method was used for crystallization. After the reaction finished, temperature of the system was subsequently maintained at 50, 40 and 30 ℃, each for 1 h, respectively. Then, the system was cooling down to room temperature and stirred for 12 h. Yield of efonidipine was raised from 63.6 to 85.8 %. Research of crystal forms was helpful to technology improvement of salt formation and to evaluate the active of efonidipine, then research the crystal forms character of efonidipine. We found that efonidipine could form acetone solvate, toluene solvate, and conglomerate of efnonidipine in ethanol solvent. Structures of the crystal forms were identified by SXRD, PXRD, TG-DSC, IR, and SEM.Part 2: the medical of efonidipine is its hydrochloride ethanolate, salt formation of efonidipine in all reported references was stirred for 8 h in 20% hydrochlorine-ethanol solution, after recrystallization with ethanol. Repeating this process found that: Single impurity was higher than the pharmacopeia criteria, and recrystallized the product didn’t reduce the impurity. Using efonidipine, recrystallized with acetone, as raw materials, then mix with ethanol and salt formation by blowing dry hydrochloride, in this way we could obtain the target product comply with pharmacopeia criteria. Yield of target product was 95.4%, 2% higher than reported in references. The better technological process was: raw efonidipine recrystallized with acetone, then ground and passed 100 mesh sieve. Mixed ratio of efonidipine and ethanol was 1:12(m: v). Flow rate of dry hydrochloride was 60 bubble/min and the mass percent was 5.05%. 3/4 of hydrochloride was saved than prior method and reaction time reduced 3 h.In this study, synthesis of efonidipine hydrochloride ethanolate was evaluated and optimized, with phosphonates-fragment and amino-fragment used as raw materials. This optimized technological process had significant advantages with high atom economy, stable and repeatable, the product up to pharmacopeia criteria and kg level.