A preparation method of 1-(2,3-dichlorophenyl)piperazine

Abstract

The invention provides a preparation method of 1-(2,3-dichlorophenyl)piperazine in the field of pharmaceutical production technology, wherein diethanolamine and hydrogen bromide are reacted at high temperature, and then 2,3-dichloroaniline is added dropwise to continue the reaction; after the reaction is completed, sodium hydroxide is added to hydrolyze the residual bis(2-bromoethyl)amine at high temperature, and then a solvent is added, and the mixture is allowed to stand for stratification; the organic layer is subjected to vacuum distillation to obtain the compound 1-(2,3-dichlorophenyl)piperazine. The preparation method has the advantages of low raw material cost, short reaction time, high product purity and yield, and solves the harm of bis(2-haloethyl)amine to humans and the environment, and meets the requirements of green chemical processes.

Description

Technical Field

[0001] The invention relates to a preparation method of 1-(2,3-dichlorophenyl)piperazine, belonging to the technical field of pharmaceutical production. Background Art

[0002] The English name of 1-(2,3-dichlorophenyl)piperazine (CPQ) is: 1-(2, 3-dichlorophenyl)piperazine; CAS#: 41202-77-1; the product appearance is off-white to light yellow solid, melting point; 62-66°C; bp: 179°C / 15 Torr or 128–130°C / 0.5 Torr.

[0003] The structural formula is as follows:

[0004]

[0005] 1-(2,3-Dichlorophenyl)piperazine is a key intermediate in the synthesis of cariprazine and aripiprazole.

[0006]

[0007] Aripiprazole is a quinolone derivative, jointly developed by Otswka and Bristol-Myers Squibb for the treatment of schizophrenia, bipolar disorder and mental disorders associated with Alzheimer's dementia. It was approved by the U.S. FDA for the treatment of schizophrenia in November 2002.

[0008] On September 17, 2015, Actavis and Gedeon Richter announced that the U.S. FDA approved Actavis' resubmitted new drug application for the atypical antipsychotic cariprazine, which is a dopamine D3 / D2 receptor partial agonist. Cariprazine is an experimental atypical antipsychotic used for patients with schizophrenia and manic or mixed episodes associated with bipolar I disorder.

[0009] At present, the synthesis routes of 1-(2,3-dichlorophenyl)piperazine mainly include the following:

[0010] 1. It is prepared by cyclization reaction of 2,3-dichloroaniline and bis-(2-chloroethyl)amine hydrochloride in different solvents.

[0011] The reaction is as follows:

[0012]

[0013] This route is currently a commonly used process route at home and abroad. Although the literature has been diligently optimizing its process conditions, bis(2-chloroethyl)amine hydrochloride is toxic when inhaled, ingested or absorbed through the skin, and has a mutagenic effect on humans. Therefore, when using bis(2-chloroethyl)amine hydrochloride solid, there is harm to the human body and the environment, especially the large amount of waste liquid generated in the post-reaction treatment, which is very polluting.

[0014] 2. It is prepared by direct condensation reaction of 2,3-dichlorobromobenzene with piperazine.

[0015] The reaction is as follows:

[0016]

[0017] The starting material of this route, 2,3-dichlorobromobenzene, is expensive; at the same time, the reaction requires the use of precious metal catalysts to obtain the target product, resulting in low yield and high cost.

[0018] 3. A method in which 2,3-dichloroaniline reacts with diethanolamine and concentrated hydrochloric acid at high temperature to produce the product.

[0019] The reaction is as follows:

[0020]

[0021] This route requires a reaction at about 220°C, which places very high demands on equipment. Concentrated hydrochloric acid easily evaporates and escapes at high temperatures, polluting the environment and making it unsuitable for production.

[0022] The shortcomings of the prior art are: bis(2-haloethyl)amine hydrochloride is toxic when inhaled, ingested or absorbed through the skin, and has a mutagenic effect on humans; when preparing or using bis(2-haloethyl)amine hydrochloride, it is very harmful to the human body and the environment, especially the post-reaction treatment produces a large amount of waste liquid, which is very polluting. For example, the molar ratio of bis(2-chloroethyl)amine hydrochloride to 2,3-dichloroaniline is 1.3, and the post-treatment is a crystallization and filtration operation, and the mother liquor contains a large amount of unreacted bis(2-chloroethyl)amine hydrochloride. The method of preparing the product by cyclization reaction of 2,3-dichloroaniline with diethanolamine and concentrated hydrochloric acid at a high temperature of 220°C in water has very harsh reaction conditions because the chlorination ability of hydrochloric acid is too weak and the activity of chlorine atoms being replaced by nucleophilic is too low.

[0023] In summary, finding a synthetic route for 1-(2,3-dichlorophenyl)piperazine with the advantages of "low raw material cost, high product purity and yield, and less three wastes" has become a technical problem that needs to be solved urgently. Summary of the invention

[0024] The purpose of the present invention is to provide a method for preparing 1-(2,3-dichlorophenyl)piperazine, which aims to solve the shortcomings of the existing process, has the advantages of low raw material cost, short reaction time, high product purity and yield, and meets the requirements of green chemical process.

[0025] To this end, the technical solution provided by the present invention is as follows: a method for preparing 1-(2,3-dichlorophenyl)piperazine, comprising the following steps:

[0026] S1, Preparation of Compound 1:

[0027] Diethanolamine 3 and hydrogen bromide are reacted at a high temperature of 100-200°C, and then 3-dichloroaniline 2 is added dropwise, and the reaction is continued; after the reaction is completed, sodium hydroxide is added, and the residual bis(2-bromoethyl)amine is hydrolyzed at 90-100°C with stirring, and then the temperature is lowered and a solvent is added, and the mixture is allowed to stand for stratification; the organic layer is subjected to high vacuum distillation to obtain compound 1;

[0028] The reaction formula is as follows:

[0029] .

[0030] Step S1 includes the following sub-steps:

[0031] S1-1: react diethanolamine 3 and hydrogen bromide at a high temperature of 100-200°C, then dropwise add 2,3-dichloroaniline 2, and continue the reaction until the molar amount "2 / (2+1) is less than 5%", and the reaction is terminated;

[0032] S1-2: After the reaction is completed, sodium hydroxide is added, and the residual bis(2-bromoethyl)amine is hydrolyzed at 90-100°C with stirring, and then the temperature is lowered and the solvent is added, and the mixture is allowed to stand to separate into layers; the organic layer is subjected to high vacuum distillation to obtain compound 1-(2,3-dichlorophenyl)piperazine 1.

[0033] The hydrogen bromide used in step S1-1 is hydrogen bromide aqueous solution or hydrogen bromide gas. Preferably, hydrogen bromide gas. In step S1-1, the reaction temperature is preferably 130-150°C. The hydrolysis temperature used in step S1-2 is 50-100°C. Preferably, it is 90-100°C.

[0034] The core technology of the present invention is to adopt a one-pot method to feed materials, and the reaction can be decomposed into the following process:

[0035] During the reaction, bis(2-bromoethyl)amine hydrobromide is formed in situ, avoiding the risk of direct contact between personnel and materials during the material transfer process. At the same time, it undergoes a cyclization reaction with 2,3-dichloroaniline to generate 2,3-dichlorophenylpiperazine, making the process operation simple and enhancing production safety. At the end of the reaction, sodium hydroxide is added. The reaction principle is as follows:

[0036]

[0037] This reaction completely hydrolyzes unreacted bis(2-bromoethyl)amine into non-toxic diethanolamine at high temperature, making the entire process green and environmentally friendly.

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows: the new preparation process provided by the present invention avoids the harm of bis-(2-haloethyl)amine to humans and the environment, meets the requirements of safe production and green chemical processes, and also solves the shortcomings of the prior art, and has the advantages of low raw material cost, short reaction time, high product purity and yield, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the HPLC spectrum of the CPQ purity test in Example 1. DETAILED DESCRIPTION

[0040] Example 1

[0041] Synthesis of compound 1

[0042] In a 500mL reaction bottle, add 105.5g of diethanolamine, heat to 120-130℃, and pass 240g of hydrogen bromide gas. The heat release is very obvious, and the passing speed needs to be controlled. The reaction takes about 3 hours; then the temperature is raised to 140-150℃, and 135.5g of 2,3-dichloroaniline is slowly added dropwise for about 6 hours. After the addition is completed, continue the reaction until the molar amount "2 / (2+1) is less than 5%"; after the reaction is completed, slowly add 20% sodium hydroxide dropwise to pH=9-10, and keep at 90-100℃ for 1 hour; then add 300mL of toluene and stir for 1 hour; let it stand for stratification, and discard the water layer; recover the solvent toluene from the organic layer, and perform vacuum distillation on the residue, collect the fraction of 170-175℃ / 10mmHg, and obtain 137.6g of compound 1, with an HPLC purity of 99.79% and a yield of 71.2%.

[0043] The reaction temperature of diethanolamine and hydrogen bromide can be selected within the range of 100-200°C, and the hydrolysis temperature can be selected within the range of 50-100°C, both of which can obtain a yield of more than 50%.

[0044] The HPLC spectrum of the product purity test is attached. Figure 1 .

[0045] The product purity test of the present invention adopts the following HPLC conditions:

[0046] .

[0047] Example 2

[0048] Synthesis of compound 1

[0049] In a 1000mL reaction bottle, add 105.5g diethanolamine and 600g 48% hydrobromic acid solution, heat the reaction mixture to 120-130℃ and react for 3 hours; then heat to 150-160℃, slowly add 135g 2,3-dichloroaniline for about 6 hours. After the addition is completed, continue the reaction until the molar amount "2 / (2+1) is less than 5%"; after the reaction is completed, slowly add 20% sodium hydroxide to pH = 9-10, keep at 90-100℃ for 1.5 hours; then add 300mL toluene and stir for 1 hour; let stand to separate, discard the water layer; recover the solvent toluene from the organic layer under reduced pressure, and distill the residue under reduced pressure, collect the fraction of 170-175℃ / 10mmHg, and obtain 122.3g compound 1, HPLC purity of 99.70%, yield of 63.5%.

[0050] Example 3

[0051] Synthesis of compound 1

[0052] In a 1000mL reaction bottle, 105.5g of diethanolamine and 135.2g of 2,3-dichloroaniline were added, the reaction mixture was heated to 120-130°C, and 230g of hydrogen bromide gas was slowly introduced. The exotherm was very obvious, and the introduction rate needed to be controlled to react for 3 hours; then the temperature was raised to 130-150°C, and the reaction was continued until the molar amount "2 / (2+1) was less than 5%"; after the reaction was completed, 20% sodium hydroxide was slowly added dropwise to pH = 9-12, and maintained at 90-100°C for 1 hour; 300mL of toluene was added and stirred for 1 hour; the mixture was allowed to stand for stratification, and the aqueous layer was discarded; the organic layer was decompressed to recover the solvent toluene, and the residue was subjected to decompression distillation, and the fraction at 170-175°C / 10mmHg was collected to obtain 126.5g of compound 1, with an HPLC purity of 99.56% and a yield of 65.6%.

[0053] Comparative Example 1

[0054] Preparation of compound 1 using concentrated hydrochloric acid

[0055] In a 1000mL reaction bottle, add 105.5g of diethanolamine, 350g of concentrated hydrochloric acid (36%) and 135.5g of 2,3-dichloroaniline, then slowly heat up to 130-150°C, and continue to react until the molar amount "2 / (2+1) is less than 5%"; after the reaction is completed, slowly add 20% sodium hydroxide dropwise to pH = 8-9, and keep at 90-100°C for 1 hour; then add 300mL of toluene, stir for 1 hour; let stand to separate, and discard the aqueous layer; recover the solvent toluene from the organic layer, and distill the residue under reduced pressure, collect the fraction at 170-175°C / 10mmHg, and obtain 88.1g of compound 1 with HPLC purity of 95.80% and yield of 45.6%.

[0056] It can be seen from the above examples 1-3 and comparative example 1 that the final yield of the reaction of diethanolamine with hydrobromic acid solution, hydrogen bromide gas and concentrated hydrochloric acid is the highest in the scheme of hydrogen bromide gas, and the yield of the scheme of concentrated hydrochloric acid is lower. The reaction temperature of diethanolamine 3 and hydrogen bromide can be selected in the range of 100-200°C, and the hydrolysis temperature can be selected in the range of 50-100°C, and a higher yield than that of comparative example 1 can be obtained.

[0057] The present invention is not limited to the above-mentioned embodiments. On the basis of the technical solution disclosed in the present invention, technicians in this field can make some substitutions and deformations to some technical features therein according to the disclosed technical content without creative labor, and these substitutions and deformations are all within the protection scope of the present invention.

Claims

1. A method for preparing 1-(2,3-dichlorophenyl)piperazine, characterized in that The steps include: S1, Preparation of compound 1-(2,3-dichlorophenyl)piperazine 1: Diethanolamine 3 and hydrogen bromide are reacted at a high temperature of 100-200°C, and then 2,3-dichloroaniline 2 is added dropwise and the reaction is continued; after the reaction is completed, sodium hydroxide is added, and the residual bis(2-bromoethyl)amine is hydrolyzed at 90-100°C with stirring, and solvent toluene is added after cooling, and the mixture is allowed to stand for stratification; the organic layer is subjected to high vacuum distillation to obtain compound 1-(2,3-dichlorophenyl)piperazine 1; The reaction formula is as follows: 。 2. The method for preparing 1-(2,3-dichlorophenyl)piperazine according to claim 1, characterized in that: Step S1 includes the following sub-steps: S1-1: react diethanolamine 3 and hydrogen bromide at a high temperature of 100-200°C, then dropwise add 2,3-dichloroaniline 2, and continue the reaction until "the molar amount of compound 2 / (the molar amount of compound 2+the molar amount of compound 1) is less than 5%", and the reaction is terminated; S1-2: After the reaction is completed, sodium hydroxide is added, and the residual bis(2-bromoethyl)amine is hydrolyzed at 90-100°C with stirring, and then the temperature is lowered and the solvent is added, and the mixture is allowed to stand to separate into layers; the organic layer is subjected to high vacuum distillation to obtain compound 1-(2,3-dichlorophenyl)piperazine 1.

3. The method for preparing 1-(2,3-dichlorophenyl)piperazine according to claim 2, characterized in that: The hydrogen bromide used in step S1-1 is hydrogen bromide aqueous solution or hydrogen bromide gas.

4. The method for preparing 1-(2,3-dichlorophenyl)piperazine according to claim 2, characterized in that: In step S1-1, the reaction temperature is 130-150°C.

5. The method for preparing 1-(2,3-dichlorophenyl)piperazine according to claim 2, characterized in that: The hydrolysis temperature used in step S1-2 is 50-100°C.

6. The method for preparing 1-(2,3-dichlorophenyl)piperazine according to claim 5, characterized in that: The hydrolysis temperature of step S1-2 is 90-100°C.

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