An improved process for the preparation of an aripiprazole intermediate

Abstract

The present application relates to aripiprazole synthesis technical field, specifically to a kind of preparation of 1-(2,3-dichlorophenyl) piperazine hydrochloride substantially without following dimer impurity compound (I), the structure of the impurity is determined to clarify the generation mechanism of the impurity, provide the train of thought for better control of the impurity and make corresponding judgment to the impurity derived subsequently, provide help to the quality research of subsequent intermediates and finished products;The present application replaces the existing multiple recrystallization process by means of filtration and salting-out, which can effectively simplify the operation and greatly reduce the use of organic solvents.

Description

Technical Field

[0001] This invention relates to the field of aripiprazole synthesis technology, and more specifically to an improved method for preparing aripiprazole intermediates. Background Technology

[0002] Aripiprazole is a novel dimeric atypical antipsychotic drug with the following structure:

[0003]

[0004] In the synthesis of aripiprazole, the intermediate 1-(2,3-dichlorophenyl)piperazine hydrochloride needs to be synthesized first, and the reaction equation is as follows:

[0005]

[0006] Impurities are introduced during the synthesis of the intermediate 1-(2,3-dichlorophenyl)piperazine hydrochloride, which can affect the quality of the product. In order to more accurately control the quality of 1-(2,3-dichlorophenyl)piperazine hydrochloride and ensure the quality of the final drug aripiprazole prepared from it as a starting material or intermediate, it is necessary to study the impurities in the synthesis process of 1-(2,3-dichlorophenyl)piperazine hydrochloride. Summary of the Invention

[0007] The problem addressed by this invention is to provide an improved method for preparing aripiprazole intermediates, which enables the preparation of 1-(2,3-dichlorophenyl)piperazine hydrochloride with low levels of dimer impurities.

[0008] Specifically, in a first aspect, the present invention provides a method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride substantially free of the following dimer impurity compound (I), the method comprising the steps of:

[0009]

[0010] 1) Preparation of crude product:

[0011] Add 2,3-dichloroaniline, NMP, and bis-(2-chloroethyl)amine hydrochloride to a flask, stir, heat and react. After the reaction is complete, cool once, add anhydrous ethanol, cool a second time, stir for 2 hours, filter, and wash with anhydrous ethanol to obtain filter cake.

[0012] 2) Water-soluble filtration:

[0013] Take the 1-(2,3-dichlorophenyl)piperazine hydrochloride containing the dimer impurity compound (I) obtained in step 1), dissolve it in water, and then filter to obtain the filtrate;

[0014] 3) Salting out with sodium chloride:

[0015] Sodium chloride was added to the filtrate obtained in step 2) to salt out crystals, and then filtered to obtain 1-(2,3-dichlorophenyl)piperazine hydrochloride, which is substantially free of dimer impurity compound (I).

[0016] Further, in step 1), the weight ratio of 2,3-dichloroaniline:NMP:bis-(2-chloroethyl)amine hydrochloride is 90:450:144.

[0017] Further, in step 1), the weight-to-volume ratio of 2,3-dichloroaniline to anhydrous ethanol is 3:10 (g / ml).

[0018] Furthermore, the heating reaction temperature in step 1) is 135°C, and the heating reaction time is 29 hours.

[0019] Furthermore, the temperature of the first cooling step in step 1) is 75–80°C.

[0020] Furthermore, the temperature of the secondary cooling in step 1) is 0-5°C.

[0021] Further, in step 2), the volume (ml) of water used is 1-4 times, preferably 3 times, the weight (g) of 1-(2,3-dichlorophenyl)piperazine hydrochloride containing the dimer impurity compound (I).

[0022] Furthermore, the dissolution temperature in step 2) is either room temperature or heated to 50°C.

[0023] Further, in step 3), the mass concentration of sodium chloride in the salting-out process is >5%, preferably 5%-10%, and the salting-out temperature in step 3) is 0-10℃.

[0024] Furthermore, the crystallization time in step 3) is 2-3 hours.

[0025] On the other hand, the present invention provides a compound of formula (I) as a new chemical entity.

[0026] On the other hand, the present invention provides the use of isolated formula (I) dimer impurities as “reference markers” and / or “reference standards” in methods for determining the identity and / or amount of said impurities in a sample of aripiprazole or its precursor.

[0027] The beneficial effects of this invention are:

[0028] 1) Determining the structure of this impurity clarifies the impurity's generation mechanism, provides insights for better control of the impurity, and allows for the identification of subsequent impurities derived from it, thus aiding in the research on the quality of intermediates and finished products.

[0029] 2) Replacing the existing multiple recrystallization process with filtration and salting out can effectively simplify the operation.

[0030] 3) This method for removing impurities is simple and convenient, greatly reducing the use of organic solvents. This method is also a good reference for the removal of impurities in other products.

[0031] 4) The identification and removal of relevant impurities provide a strong guarantee for controlling the quality of the final drug, such as aripiprazole, prepared from its starting materials or intermediates. Attached Figure Description

[0032] Figure 1 This is the mass spectrum of the dimer impurity compound (I) in Example 1. Detailed Implementation

[0033] The present invention will be further described in detail through the following embodiments, but these descriptions should not be used to limit the scope of protection of the present invention.

[0034] The reagents used in this invention are all commercially available products and can be purchased on the market.

[0035] Example 1

[0036] 100g of 1-(2,3-dichlorophenyl)piperazine hydrochloride of the dimer impurity compound (I) from the large-scale production process was taken, then added to 400ml of water, dissolved at 25℃, filtered, and dried to obtain the dimer impurity compound (I). Liquid chromatography analysis showed its purity to be 96.6%. Figure 1 This is the mass spectrum of the dimer impurity compound (I).

[0037] Example 2

[0038] Take 100 ml of water at 25°C and add 1-(2,3-dichlorophenyl)piperazine hydrochloride while stirring until it cannot be dissolved. The solubility of 1-(2,3-dichlorophenyl)piperazine hydrochloride was measured to be 227 mg / ml. Take 100 ml of water at 25°C and add dimer impurity compound (I) while stirring until it cannot be dissolved. The solubility of dimer impurity compound (I) was measured to be <0.01 mg / ml.

[0039] Example 3

[0040] 18 g of 2,3-dichloroaniline, 90 g of NMP, and 28.8 g of bis-(2-chloroethyl)amine hydrochloride were added to a 500 ml three-necked flask. The mixture was stirred and heated to 135 °C for 29 hours. After the reaction was completed, the mixture was cooled to 75–80 °C, 60 ml of anhydrous ethanol was added, and the mixture was cooled to 0–5 °C and stirred for 2 hours. The mixture was filtered, washed with anhydrous ethanol to obtain a filter cake of 29.7 g, and then dissolved in 160 ml of water at 25 °C. The mixture was filtered, and 55 ml of saturated sodium chloride solution was added to the filtrate. Crystallization was carried out at 0 °C for 3 hours, and the mixture was filtered and dried to obtain 20.8 g of 1-(2,3-dichlorophenyl)piperazine hydrochloride, with a yield of 70%, a purity of 99.6%, and a content of 0.20% of the dimer impurity compound (I).

[0041] Example 4

[0042] Add 18g of 2,3-dichloroaniline, 90g of NMP, and 28.8g of bis-(2-chloroethyl)amine hydrochloride to a 500ml three-necked flask. Start stirring and heat to 135℃, reacting for 29 hours. After the reaction is complete, cool to 75-80℃, add 60ml of anhydrous ethanol, cool to 0-5℃, stir for 2 hours, filter, wash with anhydrous ethanol to obtain a filter cake of 31.4g, then add 160ml of water, dissolve at 25℃, filter, add 60ml of saturated sodium chloride solution to the filtrate, crystallize at 10℃ for 3 hours, filter, and dry to obtain 19.3g of 1-(2,3-dichlorophenyl)piperazine hydrochloride, yield 65%, purity 99.6%, content of dimer impurity compound (I) 0.23%.

[0043] Comparative Example 1

[0044] 18 g of 2,3-dichloroaniline, 90 g of NMP, and 28.8 g of bis-(2-chloroethyl)amine hydrochloride were added to separate 500 ml three-necked flasks. The mixture was stirred and heated to 135 °C for 29 hours. After the reaction was complete, the mixture was cooled to 75–80 °C, and 60 ml of anhydrous ethanol was added. The mixture was then cooled to 0–5 °C and stirred for 2 hours. After filtration, the filter cake was washed with anhydrous ethanol to obtain 27.8 g of filter cake. 200 ml of anhydrous ethanol was added and heated to 75–80 °C to dissolve the cake. The mixture was then cooled to 0 °C and crystallized for 3 hours. After filtration, the filter cake was recrystallized once more with 200 ml of anhydrous ethanol, yielding 17.2 g of 1-(2,3-dichlorophenyl)piperazine hydrochloride, with a yield of 58%, purity of 96.6%, and 3.39% of the dimer impurity compound (I).

Claims

1. A method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride, characterized in that... The method includes the following steps: Formula I 1) Preparation of crude product: Add 2,3-dichloroaniline, NMP, and bis-(2-chloroethyl)amine hydrochloride to a flask, stir, heat and react. After the reaction is complete, cool once, add anhydrous ethanol, cool a second time, stir for 2 hours, filter, and wash with anhydrous ethanol to obtain filter cake. 2) Water-soluble filtration: Take the 1-(2,3-dichlorophenyl)piperazine hydrochloride containing the dimer impurity compound (I) obtained in step 1), dissolve it in water, and then filter to obtain the filtrate; 3) Sodium chloride salting-out: Sodium chloride was added to the filtrate obtained in step 2) to induce salting out and crystallization, and then filtered to obtain 1-(2,3-dichlorophenyl)piperazine hydrochloride with a content of 0.23% or 0.20% of the dimer impurity compound (I).

2. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... In step 1), the weight ratio of 2,3-dichloroaniline:NMP:bis-(2-chloroethyl)amine hydrochloride is 90:450:

144.

3. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... In step 1), the weight-to-volume ratio of 2,3-dichloroaniline to anhydrous ethanol is 3:10 (g / ml).

4. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... In step 1), the heating reaction temperature is 135°C and the heating reaction time is 29 hours.

5. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... The temperature of the first cooling step in step 1) is 75~80℃.

6. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... The temperature of the secondary cooling in step 1) is 0-5℃.

7. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... In step 2), the volume of water used (ml) is 1-4 times the weight (g) of 1-(2,3-dichlorophenyl)piperazine hydrochloride containing the dimer impurity compound (I).

8. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 7, characterized in that... In step 2), the volume of water used (ml) is 3 times the weight (g) of 1-(2,3-dichlorophenyl)piperazine hydrochloride containing the dimer impurity compound (I).

9. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... The dissolution temperature in step 2) is either room temperature or heated to 50°C.

10. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... In step 3), the sodium chloride concentration during salting out is >5%, and the salting-out temperature in step 3) is 0-10℃.

11. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... In step 3), the mass concentration of sodium chloride used for salting out is 5%-10%.

12. The method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride according to claim 1, characterized in that... The crystallization time in step 3) is 2-3 hours.

Images