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Preparation method of loratadine intermediate

A technology of loratadine and an intermediate, which is applied in the field of chemical preparation, can solve the problems that the added amount of extraction and liquid separation is not suitable for stratification, complicated post-processing, a large amount of waste acid, etc., and achieves the effect of avoiding heavy metal pollution

Inactive Publication Date: 2021-04-27
BEIJING VENTUREPHARM BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a large excess of AlCl still needs to be used after the process 3 (3.98 eq) and PC1 5 (1.49 eq), resulting in a large amount of waste acid; and the post-treatment is tedious, due to the 3 Excessive addition will result in a lot of jelly, which will make it difficult to separate layers in the subsequent extraction and separation, which needs to be carried out at high temperature

Method used

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  • Preparation method of loratadine intermediate
  • Preparation method of loratadine intermediate
  • Preparation method of loratadine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (1) Add 5.0g AcOH and 2mLH to a three-necked flask at room temperature 2 O, and 14.0 g concentrated H 2 SO 4 , then add 10.0g of starting material trimethyl-2-cyanopyridine (compound 1, 84.65 mmol), slowly raise the temperature to 60°C and stir the reaction, then slowly add 15.0g of tert-butanol dropwise, and stir at 70-80°C The reaction was followed by TLC at the same time, and the reaction was completed after about 2.5 h.

[0042] After the reaction was completed and returned to room temperature, concentrated ammonia water was slowly added dropwise to the reaction liquid in an ice bath to adjust the pH to 8-9, and at the same time, 25 mL of water was added to dissolve the precipitated salt, and 40 mL of DCM was added for extraction, washed with 20 mL of DCM, and the organic phase, anhydrous NaSO 4 After drying, suction filtration and rotary evaporation of the solvent, the crude product of a transparent oil was obtained, and then recrystallized from petroleum ether ...

Embodiment 2

[0050] (1) Add 7.5g AcOH and 2mLH to a three-necked flask at room temperature 2 O, and 14.0 g concentrated H 2 SO 4 , then add 10.0g of starting material trimethyl-2-cyanopyridine (compound 1, 84.65 mmol), slowly raise the temperature to 60°C and stir the reaction, then slowly add 15.0g of tert-butanol dropwise, and stir at 70-80°C The reaction was followed by TLC at the same time, and the reaction was completed after about 2.5 h.

[0051] After the reaction was completed and returned to room temperature, concentrated ammonia water was slowly added dropwise to the reaction liquid in an ice bath to adjust the pH to 8-9, and at the same time, 25 mL of water was added to dissolve the precipitated salt, and 40 mL of DCM was added for extraction, washed with 20 mL of DCM, and the organic phase, anhydrous NaSO 4 After drying, the solvent was concentrated by suction filtration and rotary evaporation to obtain a crude product of a transparent oil, which was then recrystallized from...

Embodiment 3

[0056] (1) Add 2.5g AcOH and 2mLH to a three-necked flask at room temperature 2 O, and 14.0 g concentrated H 2 SO 4 , then add 10.0g of starting material trimethyl-2-cyanopyridine (compound 1, 84.65 mmol), slowly raise the temperature to 60°C and stir the reaction, then slowly add 15.0g of tert-butanol dropwise, and stir at 70-80°C The reaction was followed by TLC at the same time, and the reaction was completed after about 2.5 h.

[0057] After the reaction was completed and returned to room temperature, concentrated ammonia water was slowly added dropwise to the reaction liquid in an ice bath to adjust the pH to 8-9, and at the same time, 25 mL of water was added to dissolve the precipitated salt, and 40 mL of DCM was added for extraction, washed with 20 mL of DCM, and the organic phase, anhydrous NaSO 4 After drying, suction filtration and rotary evaporation of the solvent, the crude product of a transparent oil was obtained, and then recrystallized from petroleum ether ...

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Abstract

The invention provides a preparation method of a loratadine intermediate, and belongs to the technical field of chemical medicine preparation. The preparation method comprises the following steps: by taking trimethyl-2-cyanopyridine as an initial synthesis raw material, protecting cyano by tert-butyl alcohol to obtain an intermediate 2, performing nucleophilic substitution on the intermediate 2 and benzyl chloride to obtain an intermediate 3, performing deprotection by using phosphorus oxychloride to obtain an intermediate 4, and finally performing addition with a Grignard reagent and obtaining a key intermediate 1 of loratadine under an acidic condition.

Description

technical field [0001] The invention relates to a preparation method of a key intermediate of loratadine, belonging to the technical field of chemical medicine preparation. Background technique [0002] Loratadine (loratadine) was developed by Schering Plow Company in the United States. It is a second-generation H1 receptor antagonist that selectively resists peripheral H1 receptors, does not enter the central nervous system, and has no adverse reactions such as sedation and drowsiness. It is a quick-acting, A strong, long-acting antihistamine. In addition, due to its low cardiotoxicity and good curative effect on allergic reactions such as rhinitis and chronic urticaria, its prescription has occupied a leading position among the second-generation antihistamines. The U.S. FDA approved loratadine to be sold as an OTC drug. In July 2005, China's State Food and Drug Administration approved Schering-Plough's anti-allergic drug Claritan to enter the OTC list. The market prospect...

Claims

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Application Information

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IPC IPC(8): C07D401/06
CPCC07D401/06
Inventor 张慧政郭佳志赵国磊
Owner BEIJING VENTUREPHARM BIOTECH