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Novel synthetic method of loratadine

A newly synthesized technology for loratadine, which is applied in the field of preparation of loratadine, can solve the problems of high risk, high impurity content, and many pollutants in the process, and achieve stable process, good repeatability, and low price Effect

Inactive Publication Date: 2009-01-21
ZHEJIANG JINGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the process of preparing the raw material 4-diethyl phosphate-N-ethoxycarbonylpiperidine, the method needs to separate the isomers produced in the reaction process, and then carry out hydrogenation, which is very dangerous in the process and difficult to operate. It is cumbersome and difficult to control; the final product has high impurity content and produces many pollutants

Method used

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  • Novel synthetic method of loratadine
  • Novel synthetic method of loratadine
  • Novel synthetic method of loratadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Dissolve 10 g of tricyclic ketone and 7.4 g of 4-ethoxycarbonylpiperidone in 50 ml of n-hexane solution and set aside.

[0018] Put 6.6g of magnesium powder and 120ml of n-hexane into a 250ml flask; stir and control the temperature to 10°C; add 12ml of titanium tetrachloride dropwise and control the dropwise addition for 30 minutes; keep warm at 10°C for 30 minutes; add n-hexane solution dropwise for 30 minutes Add dropwise; finish, keep warm for 2 hours; keep warm, add 2 drops of concentrated sulfuric acid, heat up and reflux for 3 hours; finish, add 100g of water, stir for 30 minutes; separate liquid, add 40ml of n-hexane to extract the water layer twice; combine the oil layer , washed twice with 50ml of water; after that, 150ml of n-hexane was concentrated, cooled to room temperature and crystallized to obtain the crude product of loratadine. Recrystallized from acetonitrile to obtain 11 g of white solid. The yield is 70%, and the melting point is 132-136°C.

Embodiment 2

[0020] 10 g of tricyclic ketone and 7.4 g of 4-ethoxycarbonylpiperidone were dissolved in 40 ml of toluene solution and set aside.

[0021] Put 7.4g of aluminum powder and 120ml of toluene into a 250ml flask; stir and control the temperature to 20°C; add 12ml of titanium tetrachloride dropwise and control the dropwise addition for 30 minutes; keep warm at 20°C for 30 minutes; add the toluene solution dropwise for 30 minutes OK; Bi, keep warm for 2 hours; keep warm well, add 2 drops of concentrated sulfuric acid, heat up and reflux for 3 hours; finish, add 100g of water, stir for 30 minutes; separate liquid, add 40ml of toluene to extract the water layer twice; combine the oil layers, use 50ml Washed twice with water; after that, toluene was recovered to dryness, and acetonitrile was added to cool down to room temperature for crystallization to obtain crude loratadine. Recrystallized from acetonitrile to obtain 11.2 g of white solid. The yield is 71.3%, and the melting point i...

Embodiment 3

[0023] 10 g of tricyclic ketone and 7.4 g of 4-ethoxycarbonylpiperidone were dissolved in 40 ml of methyl tetrahydrofuran solution and set aside.

[0024] Put 6.6g of magnesium powder and 120ml of methyl tetrahydrofuran into a 250ml flask; stir and control the temperature to 0°C; add 12ml of titanium tetrachloride dropwise, and add dropwise for 30 minutes; keep warm at 0°C for 30 minutes; add methyltetrahydrofuran solution dropwise Add dropwise in 30 minutes; finish, keep warm for 2 hours; keep warm, add 2 drops of concentrated sulfuric acid, heat and reflux for 3 hours; finish, recover methyl tetrahydrofuran to dryness; add water 100g and petroleum ether, stir for 30 minutes; separate liquid, water The layer was extracted twice by adding 40ml of petroleum ether; the combined oil layers were washed twice with 50ml of water; after that, 150ml of petroleum ether was concentrated, cooled to room temperature for crystallization, and crude loratadine was obtained. Recrystallized fr...

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Abstract

The invention discloses a method for preparing a drug of Loratadine. The prior art has stricter requirement on reaction conditions and is difficult to control, with higher price of raw materials and catalysts, high production cost; and high content of impurities in the final products and a great amount of produced pollutants. The invention comprises the following steps that tricyclic ketone and 4-Ethoxycarbon piperidone undergo condensation in an inertia solvent by a low valent titanium, followed by acid hydrolysis to obtain Loratadine. The invention lowers the cost on the basis of the ensured yield rate through using the low valent titanium, and has mild operation condition, easy control, generally no pollution, stable technology, and good repeatability.

Description

technical field [0001] The invention relates to a preparation method of loratadine medicine. Background technique [0002] Loratadine is a long-acting, non-sedating, non-anticholinergic, new-generation antihistamine drug that selectively inhibits peripheral histamine H1 receptors. Within the therapeutic dose range, No drowsiness, suitable for tearing, sneezing, allergic rhinitis, acute or chronic urticaria and other allergic skin diseases, its chemical name is: 4-(8-chloro-5,6-dihydro-11H-benzene Ethyl [5,6]cycloheptyl[1,2-b]pyridine-11ene)-1-piperidinecarboxylate, English name: Loratadine. According to literature reports, the synthesis route of the loratadine medicine using the intermediate tricyclic ketone mainly includes the following two types: one is the Grignard reagent synthesis route, and the other is the phosphate ester synthesis route. [0003] Grignard reagent synthesis route: use tricyclic ketone as raw material, react with Grignard reagent in a solvent, and re...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCY02P20/582
Inventor 王明光盛利飞钱沛良
Owner ZHEJIANG JINGXIN PHARMA
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