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Preparation method of loratadine

A technology of loratadine and m-chlorobenzyl chloride, which is applied in the field of drug synthesis, can solve the problems of low yield, difficult separation and purification of products, and high temperature, and achieve the advantages of being beneficial to industrial production, easy to industrial production, and simplifying post-processing steps Effect

Pending Publication Date: 2021-02-09
CHENGDU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the above-mentioned synthetic route, there are following problems to be solved: the one-step reaction of the cyclization reaction uses a strong acid with higher cost such as trifluoromethanesulfonic acid and hydrofluoric acid to catalyze the reaction, and the temperature is higher, and the yield is low. The processing technology is not simple enough and other problems; the starting materials of route 2 and route 4 are expensive and costly, and they are usually not directly used as starting materials in actual industrial production, and the last step of route 4 is catalyzed by high-valent titanium. The product is difficult to separate and purify, and silica gel column chromatography is required to purify the final product; Route 3 requires the use of highly toxic organophosphides, which is highly polluting to the environment, and the yield of the cyclization reaction is low
The above reasons all limit the industrialized production of loratadine to a large extent

Method used

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  • Preparation method of loratadine

Examples

Experimental program
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Effect test

Embodiment 1

[0044] The preparation method of compound III

[0045] Add tert-butanol (100ml) to the reaction flask, compound II (50.0g, 423.2mmol) is heated to 70°C, after compound II is completely dissolved, slowly add concentrated sulfuric acid (50ml), and the system is heated to 75°C after the dropwise addition After 0.5 h of reaction, TLC detected that the reaction was complete (V ethyl acetate: V petroleum ether = 1:5). Cool to 50-55°C, add water (50ml) and concentrated ammonia water (about 150ml) to adjust the pH to about 9-10, a white solid precipitates, and cool to room temperature. Suction filtration and drying in a blast oven at 25°C for 12 hours gave white crystalline particles (compound III, 70.3 g, 86.5%).

Embodiment 2

[0047] The preparation method of compound IV

[0048]Put compound III (30.0g, 156mmol) in a 1L dry three-neck flask, add freshly distilled tetrahydrofuran (about 450ml) at -10°C under nitrogen protection, cool to -30°C, stir for 10min and then drop slowly Add 2.5mol / L n-butyl lithium (131ml, 327mmol), control the dropping speed, and continue stirring for 10min after the dropping is completed. Then m-chlorobenzyl chloride (22ml, 174mmol) was dissolved in anhydrous tetrahydrofuran (120ml) and added dropwise to the reaction solution. After the dropwise addition, the temperature was kept at -10°C and stirred for 1h. After the reaction was completed, add water (about 100ml) dropwise to quench the reaction. At this time, the red color of the system faded, extracted with EA (150ml×3), anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain a brown-red oily liquid (compound IV, 43.0 g, 87.1%).

Embodiment 3

[0050] The preparation method of compound V

[0051] Phosphorus oxychloride (about 200ml) was added to compound IV (50.0g, 158mmol), and the temperature was raised to 110°C for 4h under reflux. TLC point plate detection reaction is complete (V 乙酸乙酯 :V 石油醚 =1:5), most of the phosphorus oxychloride was distilled off under reduced pressure. After cooling to room temperature, the remaining liquid was poured into ice water (200ml), and 50% sodium hydroxide solution was slowly added under stirring to adjust the pH to 9-10. After the brown solid was precipitated, the stirring was continued for 1 h, and a dark brown solid (34.63 g), stand at room temperature for 2 days. Isopropanol was recrystallized at 55°C (30ml), filtered with suction, and the filter cake was air-dried at 50°C for 12 hours to obtain a light gray solid (Compound V, 21.6g, 50.14%).

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Abstract

The invention provides a preparation method of loratadine. The method comprises the following steps: taking 2-cyano-3-methylpyridine as a raw material, and carrying out Ritter reaction, m-chlorobenzylchloride condensation, POCl3 deprotection group, Grignard reaction, cyclization and ethyl chloroformate substitution to obtain 4(8-chlorine-5, 6-dihydro-11H-benzo-[5, 6]cycloheptano[1, 2-b]pyridine-11-subunit)-1-piperidine carboxylic acid ethyl ester. According to the invention, a post-treatment process is innovated, and a new cyclization system is adopted to catalyze the reaction, so that the use of high-cost and high-toxicity strong acid is avoided, and a milder and more economical synthesis method is provided for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of loratadine. Background technique [0002] Allergic reaction refers to the allergic reaction induced by the human body's immune system caused by allergens, and the H1 receptor of histamine plays a very important role in this process. Antiallergic drugs compete with histamine for histamine receptors and block the allergic reaction induced by the immune system, thus playing an antiallergic effect. [0003] Loratadine (Loratadine), chemical name: 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridyl-11 alkylene Base) ethyl piperidine-1-carboxylate, its molecular formula is: C 22 h 23 ClN 2 o 2 , the structural formula is: It can be used as an anti-allergic drug. [0004] At present, the second-generation tricyclic antiallergic drug loratadine, because of its high selectivity to peripheral H1 receptors, has no side effect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 曹胜华姚忠全宋明伟杜伟宏董宏波唐克慧王宇驰王瑛瑛张静霞
Owner CHENGDU UNIV
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