| 1,4-Dihydropyridine (DHP) calcium channel blockers (DHP-type CCBs)are clinically effective antihypertensives which is similar toβ-receptor antagonist, angiotensin-converting enzyme (ACE) inhibitor and thiazide diuretic. Since nifedipine was found to possess coronary vasodilating activity in 1969 and to be a so-called calcium antagonist in 1973, DHP-type CCBs have been a hot spot of research for all the pharmaceutical companies all over the world. More and more DHP-type CCBs have been discovered, such as nifedipine, nitrendipine, nisoldipine, nimodipine, nicardipine, amlodipine and furaldipine and so on. Although they were proven to be very effective in lowering blood pressure in hypertensive patients, their use was limited because of several side effects: most of them induced reflex tachycardia, facial flush and headache, and some of them had to be administered twice daily to achieve a 24-hr control of blood pressure. Azelnidipine is a new 1,4-dihydropyridine calcium channel blocker that was lanunched in 2003 in Japan by Sankyo Company for the treatment of hypertension. Comparing with other DHP-type CCBs, Azelnidipine is more effective and safe. The cardiac slowing action of Azelnidipine can not be attributed to a blockade of T-type calcium channels since the drug blocks only L-type calcium channels at pharmacologically relevant concentrations. The reflex increase in heart rate was minimal probably because of a gradual fall in blood pressure. Heart rate and plasma renin activity even decreased or tended to decrease on long-term administration.Stereoisomers of chirl 1,4-DHPs usually have different biological activities. sometimes the undesired enantiomer caused serious side effects, while in other cases enantiomers were reported to even have the opposite action profile. Azelnidipine has two enantiomers due to an asymmetric carbon at 4-position of the dihydropyridine ring. So it is important to synthesize and resolve enantiomers of Azelnidipine.Objective:The project aims to study and improve synthesis of Azelnidipine [(±)-3-(1-benzhydryl-3-azetidinyl) 5-isopropyl 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate] and to make initial research on chiral separation, HPLC chiral resolution and quality analysis.Methods:The key intermediate isopropyl 2-(3-nitrobenzylidene) acetoacetate was synthesized in improved method. It was prepared successfully from m-nitrobenzaldehyde and acetoacetatisoproyl ester using sulfuric acid catalyst in the yield of 89.5%.The intermediate (1-benzhydryl-3-azetidinyl)- 3,3-diaminoacrylate acetate was prepared from benzhydrylamine and epichlorohydrin by nuclephilic substitution, esterification and aminolysis. The yield of the compound was 49.4%. We also made some reasonable improvement to simplify the working steps, to save the cost and to reduce pollution.A simple and rapid high-performance liquid chromatographic method has been developed for the direct resolution of Azelnidipine by using Chiralpak AD-H as chiral stationary phase. The effects of different contents of n-hexane and isopropanol on the chiral separation were discussed. Method (To (±)-Azelnidipine): Using Chiralpak AD-H (250mm×4.6mm, 5μm)column, using the optimized mobile phase composed of n-hexane-isopropanol (90:10) at 25℃and 0.8 ml·min-1. The wavelength of the detector is 254 nm.Results: The synthesis was accomplished and the synthetic conditions were optimized. The total yield of title compound was 38.8% and the purity was more than 98%. mp119.1-120.5℃1H-NMR(CDCl3)δ(ppm):1.08,1.26 (3H×2 ,d×2,CH(CH3)2),2.33(3H,s,C6-CH3),2.61,3.04,3.50,3.62 (1H×4,t×4,CH2),4.24 (1H,s,NCH(Ph)2),4.92-5.02(3H,m,CH(CH3)2,COOCH,C4-H),6.02(1H,brs,NH),6.10(2H,brs,NH2),7.15-8.16(14H,m,Ar-H); According to the data above, the product is confirmed to be azelnidipine. We also made some reasonable improvement to simplify the working steps, to save the cost and to reduce pollution. The retention times for the two enantiomers of azelnidipine by HPLC are 10.9 min and 13.4 min, with a resolution factor of 3.3 Conclusion:1 1,4-Dihydropyridine calcium channel blockers Azelnidipine was synthesized. The synthesis can be run smoothly and efficiently on a large scale. The starting materials were cheap and available.2 The isopropyl 2-(3-nitrobenzylidene) acetoacetate was prepared in improved method to increase the yield from 63.5% to 89.5%, and it was prepared successfully in the presence of a catalytic amount of sulfuric acid rather than piperidinium acetate. We also made sure the best ratio between sulfuric acid and other materials.3 In the preparation of compound (1-benzhydryl-3-azetidinyl)-3,3-diaminoacrylate acetate, we chose a convenient synthrtic route. The optinium reaction time was 48h and temperature was at -5℃. The process for preparing (1-benzhydryl-3-azetidinyl)-3,3-diaminoacrylate acetate was optimized by using sodium hydroxide instead of ammonia. Minmizing the number of reaction steps results in minimisation of waste and a good overall yields.4 The HPLC determination and resolution of Azelnidipine was researched, and this work is great significance for the futrue research of Azelnidipine.
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