Synthesis process of loratadine intermediate

Abstract

The synthesis process of loratadine intermediate includes: adding P2O5 in 3-20 wt% into polyphosphoric acid ester through stirring at 175-240 deg.c to obtain homogeneous system; adding 3-[2-(3-chlorophenyl) ethyl]-2-pyridyl formonitrile in 4-16 wt% into the system and reaction at 175-240 deg.c for 5-14 hr to obtain the loratadine intermediate 8-chloro-5, 6-dihydro-11H-benzyo[5, 6]cycloheptyl[1, 2-b] pyridyl-11-tone; and re-crystallizing the intermediate with mixed solvent of ethyl acetate, n-hexane and petroleum in the volume ratio of 1 to 1 to 3. The present invention has mild reaction condition, simple operation, fast reaction speed, reaction conversion rate as high as 83.7-93.1 %, product yield of 62.9-78.2 %, product purity after re-crystallization of 98-99 %, and excellent industrial application foreground.

Description

Technical field [0001] The invention relates to a method for synthesizing loratadine intermediate 8-chloro-5,6-dihydro-11H-benzo[5,6]cycloheptyl[1,2-b]pyridin-11-one . Background technique [0002] Loratadine (loratadine), the chemical name is 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cycloheptyl[1,2-b]pyridine-11ene)- Ethyl 1-piperidine carboxylate is an oral long-acting tricyclic antihistamine. It has a fast onset and strong effect. It is highly selective for peripheral histamine H1 receptors and is a long-acting, non-sedative A new generation of antihistamine drugs with no anticholinergic effect [DuBuske L M., Clin Ther. 1999, 21(2), 281~285]. [0003] Regarding the synthesis of loratadine, the synthetic methods reported in the literature are mainly based on 3-methyl-2-cyanopyridine as the raw material, respectively through (1-methyl-4-piperidinyl) [3-(2-( 3-chlorophenyl)-ethyl-)-2-pyridyl]-methanone intermediate (1) and 8-chloro-5,6-dihydro-11H-benzo[5,6]cycloheptyl[ 1,2-b]Pyridi...

AI Technical Summary

Problems solved by technology

This route avoids the superacid that needs to use specific equipment, thereby can reduce the equipment investment of production, has reduced the pollution to environment, but the big shortcoming of this route is that the yield of reaction is lower than the aforementioned route, For example, using 3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarbonitrile as a raw material, the acid chloride is prepared by hydrolysis and thionyl chloride, and then the yield of the Friedel-Crafts reaction only 50%

The total time of the reaction is also longer, and these three-step reactions need a total of nearly 30 hours. When preparing with oxalyl chloride, although the yield has increased from 50% to 63%, the reaction time is also longer, and a total of 40 hours is needed.

[0006] For above-mentioned two kinds of methods, need to use specific equipment to synthesize loratadine with intermediate (1), and can cause more serious environmental pollution, but the yield of intermediate (2) is relatively low again, and the reaction time And very long, these will increase the production cost