Preparation method of chlorpheniramine maleate impurity

A kind of chlorpheniramine acid, impurity technology, is applied in the preparation field of chlorpheniramine maleate impurity, can solve the problems such as shortage of reference substance, few by-products, etc., achieves convenient operation, few by-products, and high yield. Effect

Pending Publication Date: 2022-01-21
艾希尔(深圳)药物研发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] An object of the present invention is to provide a kind of preparation method with the chlorpheniramine maleate impurity that is simple to operate, short preparation cycle, few by-products, easy to purify, high yield, solves the problem of this reference substance shortage, simultaneously to Provide standard reference substances for quality control of chlorpheniramine maleate raw materials and finished preparations

Method used

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  • Preparation method of chlorpheniramine maleate impurity
  • Preparation method of chlorpheniramine maleate impurity
  • Preparation method of chlorpheniramine maleate impurity

Examples

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Effect test

Embodiment 1

[0035] Embodiment 1: the preparation of intermediate formula 3 compound

[0036] Put a 250mL three-necked bottle with a thermometer and a constant pressure funnel, seal it and replace it with N 2 , then add 30mL of anhydrous tetrahydrofuran and ethyl p-chlorophenylacetate (Compound 1) (6.00 g, 30.20 mmol, 1.0 eq), after cooling to -20°C, slowly add 1.0M bistrimethylsilylamine under stirring Lithium tetrahydrofuran solution (33.20ml, 33.20 mmol, 1.1 eq), after the addition was completed, the stirring was continued at -20°C for 30 minutes, and finally 6-fluoro-2-chloropyridine (compound 2) (11.92 g, 90.6mmol, 3.0 eq), after the addition was complete, return to room temperature and react for 4h, LC-Ms showed that the raw material was completely consumed. Slowly add 20mL of water in ice bath to quench the excess lithium bistrimethylsilylamide, remove tetrahydrofuran by rotary evaporation, then extract with 40mL ethyl acetate for 3 times, combine the organic layers, spin dry, and ...

Embodiment 2

[0037] Embodiment 2: the preparation of intermediate formula 4 compound

[0038] Intermediate 3 (5.50 g, 17.80 mmol, 1.0 eq), LiOH (4.35 g, 178.00 mmol, 10.0 eq), 30 mL of methanol and 30 mL of water were successively added into a 100 mL flask, and the temperature was raised to 100 °C under stirring, and reacted for 12 h. After LC-Ms showed that the reaction was complete, 20 mL of water was added to the system, methanol was removed by rotary evaporation, and then the organic layers were combined after extraction with 50 mL of ethyl acetate for 3 times and washed with anhydrous Na 2 SO 4 After drying, suction filtration, the filtrate was spin-dried to obtain intermediate 4 (3.99 g, 95% yield), light yellow liquid, R f =0.3(DCM:PE=1:2).

Embodiment 3

[0039] Embodiment 3: the preparation of chlorpheniramine maleate impurity

[0040] Put a 100mL three-necked bottle with a thermometer and a constant pressure funnel, seal it, and replace it with N 2 , then add 30mL of anhydrous tetrahydrofuran and intermediate 4 (2.98 g, 12.57 mmol, 1.0 eq), place in an ice bath and stir to dissolve, then slowly add 1.0M bistrimethylsilylamide lithium tetrahydrofuran solution, the addition is complete Continue to stir under ice bath for 30 minutes; then add N,N-dimethylaminobromoethane (2.19 g, 14.38 mmol, 1.1 eq), and continue to react under ice bath for 2 hours after the addition, LC- Ms shows complete consumption of starting material. Slowly add 10 mL of water in an ice bath to quench the excess lithium bistrimethylsilylamide ， THF was removed by rotary evaporation, and then the organic layers were combined after being extracted 3 times with 50 mL ethyl acetate, and after being spin-dried, column chromatography (DCM:PE=1:1→DCM:MeOH=10:1 g...

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Abstract

The invention provides a preparation method of a chlorpheniramine maleate impurity, and belongs to the technical field of preparation of drug impurity standard substances. The method comprises the following steps: dissolving a compound shown in a formula 1 in a first solvent, conducting reacting with a first alkali for 30 minutes at a first temperature, and then conducting reacting with a compound shown in a formula 2 to obtain a compound shown in a formula 3; 2, reacting the compound shown in the formula 3 with second alkali in a second solvent at a second temperature to obtain a compound shown in a formula 4; and 3, reacting the compound shown in the formula 4 with a third alkali in a third solvent at a third temperature for 30 minutes, and conducting reacting with a compound shown in a formula 5 to obtain the chlorpheniramine maleate impurity. The method for preparing the chlorpheniramine maleate impurity has the advantages of simplicity in operation, short preparation period, few byproducts, easiness in purification and high yield, solves the problem of shortage of reference substances, and provides standard reference substances for quality control of chlorpheniramine maleate raw material medicines and finished preparation products.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical impurity standard products, and in particular relates to a preparation method of chlorpheniramine maleate impurity. Background technique [0002] Chlorpheniramine maleate, the chemical name is N, N-dimethyl-γ-(4-chlorophenyl)-2-pyridine propylamine maleate, also known as chlorpheniramine, its chemical structure is shown in Formula Ⅰ, is the first generation H 1 Receptor antagonists, which can selectively block histamine receptors, play an antihistamine effect, and can also resist telangiectasia caused by allergic reactions (histamine), reduce capillary permeability, relieve Wheezing due to contraction of bronchial smooth muscle. It is clinically used to relieve the early clinical symptoms of common cold and influenza and the treatment of allergic diseases. [0003] Impurities are very important to the quality control of drugs, and the existence of related substances may di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/61
CPCC07D213/61
Inventor 何冬梅李方林彭锦安
Owner 艾希尔(深圳)药物研发有限公司
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