Synthesis and preparation method of ebastine impurity

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a synthesis and preparation method of an ebastine impurity. The preparation method comprises the following steps: step one, adding 20g of p-tert-butyl-4-chlorobutanone, adding 15g of sodium hydroxide and 100g of methylbenzene, stirring and heating until a reflux reaction is performed for 10-12 hours; 2, cooling the product obtained in the step 1 to below 50 DEG C, adding 60g of water, stirring for 15 minutes, standing to remove a water layer, adding a regulator to a toluene layer to regulate the pH value, and removing the water layer; step 3, washing the toluene layer with 50g of water, and removing a water layer; step 4, concentrating the methylbenzene layer under reduced pressure until no liquid drop exists to obtain 15.7 g of oily liquid, adding 20g of petroleum ether and 5g of ethyl acetate, stirring, cooling to 0-10 DEG C, and crystallizing for 1-2 hours; 5, the product in the step 4 is subjected to suction filtration, and a proper amount of detergent is added before suction filtration. The method has the advantages of being easy to operate, short in preparation period, high in yield, high in purity and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly to a method for synthesizing and preparing impurities of ebastine. Background Art

[0002] Ebastine is a commonly used non-sedating H1-receptor antihistamine drug, belonging to anti-allergic drugs. Its characteristics are that it has no or very little sedative effect on the central nervous system, has a stronger antihistamine effect, can significantly inhibit the flushing and wheals caused by histamine, and does not affect the release of histamine from mast cells.

[0003] Impurities are very important for the quality control of drugs. The presence of impurities may directly affect the quality and safety of drugs. By consulting the main literature on the synthesis of ebastine, it is found that both CN114671802A and CN109593058 use the same raw material, p-tert-butyl-4-chlorobenzoylacetone, to react under alkaline conditions to obtain ebastine. It is difficult to avoid the reaction of p-tert-butyl-4-chlorobenzoylacetone to generate the impurity p-tert-butylphenylcyclopropylmethanone under alkaline conditions. Therefore, the synthesis of the impurity p-tert-butylphenylcyclopropylmethanone and its research and control as a process impurity of ebastine raw material are of great significance for improving the yield of ebastine and controlling the quality of ebastine. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for synthesizing and preparing impurities of ebastine to solve the problems raised in the above background art.

[0005] To achieve the above purpose, the present invention provides the following technical solution: A method for synthesizing and preparing impurities of ebastine, comprising the following steps; Step 1: Put 20 g of p-tert-butyl-4-chlorobenzoylacetone, add 15 g of sodium hydroxide and 100 g of toluene, start stirring and heat up to reflux for reaction for 10 - 12 hours; Step 2: Cool the product of Step 1 to below 50 °C, then add 60 g of water, stir for 15 minutes, let it stand and separate the water layer, add a regulator to adjust the pH value in the toluene layer, and separate the water layer; Step 3: Wash the toluene layer with 50 g of water again, and separate the water layer; Step 4: Concentrate the toluene layer under reduced pressure until there are no more droplets to obtain 15.7 g of an oily liquid, then add 20 g of petroleum ether and 5 g of ethyl acetate, stir and cool down to 0 - 10 °C, and crystallize for 1 - 2 hours; Step 5: Filter the product in Step 4 by suction, and add an appropriate amount of detergent before suction filtration; Step 6: Dry the product of Step 5 at 50 °C to obtain 9 g of a white solid crystalline impurity - p-tert-butylphenylcyclopropylmethanone; Step 7: Take a sample for analysis.

[0006] Preferably, the regulator in the second step is 3 mol / L hydrochloric acid, and the pH is adjusted to 6-7.

[0007] Preferably, the detergent is petroleum ether.

[0008] Preferably, the GC purity of the sample analysis is 99.67%.

[0009] Compared with the prior art, the beneficial effects of the present invention are as follows: First, the present invention has the advantages of simple operation, short preparation period, high yield, high purity, etc.

[0010] Second, the impurities of the prepared tert-butyl phenyl cyclopropyl ketone can effectively make up for the gap in the control of pharmacopoeia impurities. Using it as an impurity reference substance for the process of ebastine raw material medicine is of great significance for improving the quality control and drug safety of ebastine.

[0011] Third, it has guiding significance for the control of synthetic process parameters, and effectively improves the yield and quality of ebastine. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 It is the synthesis process of tert-butyl-4-chlorobenzene butanone under alkaline conditions.

[0013] Figure 2 It is the GC spectrum of p-tert-butyl phenyl cyclopropyl ketone.

[0014] Figure 3 It is the 1H NMR spectrum of p-tert-butyl phenyl cyclopropyl ketone.

[0015] Figure 4 It is the 13C NMR spectrum of p-tert-butyl phenyl cyclopropyl ketone.

[0016] Figure 5 It is the high-resolution mass spectrum of p-tert-butyl phenyl cyclopropyl ketone.

[0017] Figure 6 IR spectrum of p-tert-butyl phenyl cyclopropyl ketone. DETAILED DESCRIPTION OF THE INVENTION

[0018] In order to deepen the understanding and recognition of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described and introduced with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments, and no formal restrictions are imposed on this embodiment. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention. Example 1

[0019] Please refer to Figure 1-6, the present invention provides a technical solution: a method for synthesizing and preparing impurities of ebastine, comprising the following steps; Step 1: Add 20 g of p-tert-butyl-4-chlorobenzoylacetone, 15 g of sodium hydroxide and 100 g of toluene, start stirring and heat up to reflux for 10 - 12 hours; Step 2: Cool the product of Step 1 to below 50 °C, then add 60 g of water, stir for 15 minutes, let it stand and separate the aqueous layer. Add a regulator to the toluene layer to adjust the pH value, and separate the aqueous layer; Step 3: Wash the toluene layer with 50 g of water once again, and separate the aqueous layer; Step 4: Concentrate the toluene layer under reduced pressure until no droplets are left to obtain 15.7 g of an oily liquid. Then add 20 g of petroleum ether and 5 g of ethyl acetate, stir and cool down to 0 - 10 °C, and crystallize for 1 - 2 hours; Step 5: Filter the product in Step 4 by suction, and add an appropriate amount of detergent before suction filtration; Step 6: Dry the product of Step 5 at 50 °C to obtain 9 g of a pale white solid crystalline impurity - p-tert-butylphenylcyclopropylmethanone; Step 7: Take a sample for analysis.

[0020] The regulator in Step 2 uses 3 mol / L hydrochloric acid, and the pH is adjusted to 6.

[0021] The detergent uses petroleum ether.

[0022] The GC purity of the sample analysis is 99.67%. Example 2

[0023] Please refer to Figure 1-6 , the present invention provides a technical solution: a method for synthesizing and preparing impurities of ebastine, comprising the following steps; Step 1: Add 20 g of p-tert-butyl-4-chlorobenzoylacetone, 15 g of sodium hydroxide and 100 g of toluene, start stirring and heat up to reflux for 10 - 12 hours; Step 2: Cool the product of Step 1 to below 50 °C, then add 60 g of water, stir for 15 minutes, let it stand and separate the aqueous layer. Add a regulator to the toluene layer to adjust the pH value, and separate the aqueous layer; Step 3: Wash the toluene layer with 50 g of water once again, and separate the aqueous layer; Step 4: Concentrate the toluene layer under reduced pressure until no droplets are left to obtain 15.7 g of an oily liquid. Then add 20 g of petroleum ether and 5 g of ethyl acetate, stir and cool down to 0 - 10 °C, and crystallize for 1 - 2 hours; Step 5: Filter the product in Step 4 by suction, and add an appropriate amount of detergent before suction filtration; Step 6: Dry the product of Step 5 at 50 °C to obtain 9 g of a pale white solid crystalline impurity - p-tert-butylphenylcyclopropylmethanone; Step 7: Sampling and analysis.

[0024] The regulator in Step 2 is 3 mol / L hydrochloric acid, and the pH is adjusted to 7.

[0025] The detergent is petroleum ether.

[0026] The GC purity of the sampling and analysis is 99.67%.

[0027] Although the embodiments of the present invention have been shown and described, it should be emphasized that the above description is only an introduction and description of the usage mode of the embodiments of the present invention, and does not impose any formal limitation on the present invention. For those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principle and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing and preparing impurities of ebastine, characterized in that: It includes the following steps; Step 1: Charge 20 g of 4-chloro-1-(4-tert-butylphenyl)-1-butanone, add 15 g of sodium hydroxide and 100 g of toluene, start stirring and heat up to reflux for reaction for 10 - 12 hours; Step 2: Cool the product of Step 1 to below 50 °C, then add 60 g of water, stir for 15 minutes, let it stand and separate the aqueous layer. Add a regulator to the toluene layer to adjust the pH value, and separate the aqueous layer; Step 3: Wash the toluene layer once with 50 g of water and separate the aqueous layer; Step 4: Concentrate the toluene layer under reduced pressure until no liquid droplets are obtained to get 15.7 g of an oily liquid. Then add 20 g of petroleum ether and 5 g of ethyl acetate, stir and cool down to 0 - 10 °C, and crystallize for 1 - 2 hours; Step 5: Filter the product in Step 4 by suction, and add an appropriate amount of detergent before suction filtration; Step 6: Dry the product of Step 5 at 50 °C to obtain 9 g of a white solid crystal impurity - 4-tert-butylphenyl cyclopropyl ketone; Step 7: Take a sample for analysis.

2. The synthetic preparation method of an ebastine impurity according to claim 1, wherein: The regulator in Step 2 uses 3 mol / L hydrochloric acid, and the pH is adjusted to 6 - 7.

3. A method for synthesizing and preparing an ebastine impurity according to claim 1, characterized in that: The detergent uses petroleum ether.

4. A method for synthesizing and preparing an ebastine impurity according to claim 1, characterized in that: The GC purity of the sample analysis is 99.67%.

Images