CN113214150A

CN113214150A - Synthesis of high-purity aripiprazole and preparation method of hydrate particles thereof

Info

Publication number: CN113214150A
Application number: CN202110421501.7A
Authority: CN
Inventors: 丁坚英; 韩斌; 吴恩龙
Original assignee: Beijing Yi Cheng Medical Science And Technology Co ltd
Current assignee: Beijing Yi Cheng Medical Science And Technology Co ltd
Priority date: 2021-04-20
Filing date: 2021-04-20
Publication date: 2021-08-06

Abstract

The invention discloses a method for synthesizing high-purity aripiprazole and preparing hydrate particles thereof, which comprises the following steps: step (1), 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone and 1, 4-dibromobutane are subjected to Williamson etherification under the action of potassium carbonate to obtain 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone; step (2), synthesizing 2, 3-dichlorophenyl piperazine hydrochloride from 2, 3-dichloroaniline and bis (2-chloroethyl) amine hydrochloride; step (3), carrying out nitrogen alkylation coupling reaction on 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone and 1- (2, 3-dichlorophenyl) piperazine hydrochloride to prepare aripiprazole; step (4), refining, namely recrystallizing the aripiprazole with ethyl acetate to obtain high-purity anhydrous aripiprazole; step (5), preparation of aripiprazole hydrate particles: the anhydrous aripiprazole is refluxed and dissolved in an ethanol water system, and aripiprazole hydrate particles are obtained by controlling the stirring rate and the cooling rate.

Description

Synthesis of high-purity aripiprazole and preparation method of hydrate particles thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to synthesis of aripiprazole and a preparation method of hydrate particles of the aripiprazole.

Background

Aripiprazole (Aripiprazole), chemical name: 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] -3, 4-dihydro-2 (1H) -quinolinone, abbreviated herein as HARA, and having the following structural formula:

aripiprazole quinolinone derivatives, the first third-generation atypical antipsychotic drug, were invented in 1988 by Otsuka (Otsuka) and developed in combination with American Bethes-Baishi (Bristo-Myeres Squibb) in 2002, were approved by the American FDA in 11/15 days and are on the market, and are currently clinically used for the treatment of schizophrenia, and the chemical structures thereof are shown in FIG. 1. Research shows that compared with typical and atypical antipsychotics, the medicine has better curative effect on negative symptoms of psychosis, and has small probability of generating adverse reactions such as extrapyramidal reaction, weight gain and the like, thereby having wide market prospect.

Aripiprazole is currently marketed in the general dosage forms: tablets, orally disintegrating tablets, oral liquid and the like, so that the aripiprazole can be used as a first-line medicament in the field of mental disease treatment and can meet the clinical requirements. However, the common dosage forms of aripiprazole need to be taken daily, which makes drug compliance an important factor in the success of treatment. The current preferred mode of treatment for schizophrenia is the chronic use of antipsychotics, and to address such problems, aripiprazole long acting sustained release formulations are now approved by the FDA. The particle technology is the top technology in the novel pharmaceutical preparation, has the characteristics of improving the stability of the medicament, enabling the medicament to be released slowly or in a controlled manner and the like, and is mainly used for a long-acting injection administration system. The aripiprazole hydrate particles have the advantages of good dispersion, no agglomeration, good affinity with water, slow dissolution and release, good processability and the like which are not possessed by anhydrous aripiprazole, and are particularly suitable for being used as raw material medicaments of sustained-release liquid. Meanwhile, the anhydrous aripiprazole with good crystal form and difficult moisture absorption can still be widely applied to the dosage forms such as tablets and the like. In the prior art, many researches on aripiprazole synthetic methods are carried out, and people like Chengliong [ aripiprazole synthetic route scheme, China journal of pharmaceutical industry 2007, 38(12), 895-896] summarize aripiprazole synthetic methods, and from the article and can know that many methods for synthesizing aripiprazole exist, but the aripiprazole total yield is low, side reactions are easy to occur in the synthetic process, and from other patents and documents, the method mainly comprises the following steps of preparing quinolinone derivatives:

wherein X is halogen element bromine or chlorine, active ester, etc

The first step is as follows: reacting 7-hydroxy-3, 4-dihydro-2 (1H) quinolinone in an organic solvent or water in the presence of an inorganic basic compound to prepare a quinolinone compound represented by the formula HARA2,

the second step is that: a quinolinone compound represented by the formula HARA2 is reacted with HARA1 piperazine compound or a salt thereof in an organic solvent or water in the presence of an inorganic basic compound or an organic amine to prepare aripiprazole. The synthetic route is basically the same route, but the selection of reaction conditions is very different, the main difference is in the synthesis of an intermediate HARA2, and the step is also the key to influence the quality and yield of the aripiprazole. The advantages and disadvantages of each reaction scheme and conditions are compared as follows, using several of these patents as examples:

for example, in patent CN201410720807, it is mentioned that the process of synthesizing HARA2 using dihaloalkane is prone to generate dimer (HARA dimer, structure as shown in the above figure, content about 10%), the impurity is not easy to remove by recrystallization, only can be purified by column chromatography, and is difficult to industrialize, so they have adopted the following route to synthesize aripiprazole.

The patent has low yield, and the final step adopts column chromatography purification. Even if the price of byproducts and materials is high, the used azo reagent, phosphine reagent, methanesulfonic acid reagent and organic amine reagent are all high-toxicity reagents, and some reagents can be genetic toxicity impurity risk structures. Therefore, the route is difficult to use in the real drug substance synthesis.

In patent CN201510504434, it is mentioned that in patent WO2008146156, 4-dibromobutane is used for synthesizing 4-bromobutoxyquinolinone, even if 1, 4-dibromobutane is 10 times in excess, the dimer impurity still is 5% -10%, and large amount of toluene and silica gel is used for removing the dimer, and the yield is only 39%. They therefore used the following route to synthesize aripiprazole:

the utilization rate of 7-hydroxy-3, 4-dihydro-2 (1H) quinolinone in the route is high, but the previous application of p-tert-butylbenzene sulfonyl chloride can introduce genotoxic impurities, aluminum trichloride is difficult to process and high in pollution, more impurities can be generated, and the advantage of the route is not obvious.

In patent CN03132278.6, the one-pot method is directly adopted, the operation seems very simple, but the yield is very low, the impurities are theoretically very many, and it is difficult to ensure the quality of the final raw material drug.

The synthesis of aripiprazole and the preparation of each crystal form are very numerous, most of the patents are independent in each step and need to be purified separately, and especially the synthesis and purification of the first step, namely 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone, are very complicated, so the price of the aripiprazole on the market is almost close to that of the aripiprazole.

Therefore, a new preparation method is required to solve the problems in the prior art.

Disclosure of Invention

The invention discloses a preparation method of high-purity aripiprazole and hydrate particles thereof, which comprises the following steps:

step (1), 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone and 1, 4-dibromobutane are subjected to Williamson etherification under the action of potassium carbonate to obtain 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone;

step (2), synthesizing 2, 3-dichlorophenyl piperazine hydrochloride from 2, 3-dichloroaniline and bis (2-chloroethyl) amine hydrochloride;

step (3), carrying out nitrogen alkylation coupling reaction on 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone and 1- (2, 3-dichlorophenyl) piperazine hydrochloride to prepare aripiprazole;

step (4), refining, namely recrystallizing the aripiprazole with ethyl acetate to obtain high-purity anhydrous aripiprazole;

step (5), preparation of aripiprazole hydrate particles: the anhydrous aripiprazole is refluxed and dissolved in an ethanol water system, and aripiprazole hydrate particles are obtained by controlling the stirring rate and the cooling rate.

Wherein, in the step (1), 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone and 1, 4-dibromobutane are subjected to Williamson etherification under the action of potassium carbonate to obtain 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone, and the solvent can be acetone or DMF (N, N-dimethylformamide). The reaction formula is as follows:

in the step (1), the molar ratio of the 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone to the 1, 4-dibromobutane is 1 (1-4), preferably 1 (1.5-2);

in the step (1), the reaction solvent is acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, acetone and DMF, preferably acetone and then DMF;

the alkali in the step (1) is potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate, preferably potassium carbonate; the molar ratio is 1 (1-5), preferably 1: 1.2;

wherein, in the step (2), 2, 3-dichloroaniline reacts with bis (2-chloroethyl) amine hydrochloride at 160 ℃ to synthesize 2, 3-dichlorophenyl piperazine hydrochloride, and the reaction formula is as follows:

and (3) the molar ratio of the 2, 3-dichloroaniline to the bis (2-chloroethyl) amine hydrochloride in the step (2) is 1 to 1.

The reaction temperature in the step (2) is 100-.

In the step (3), 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone and 1- (2, 3-dichlorophenyl) piperazine hydrochloride are subjected to coupling alkylation reaction to prepare aripiprazole, wherein the reaction formula is as follows:

in the step (3), the molar ratio of the 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone to the 1- (2, 3-dichlorophenyl) piperazine hydrochloride is 1 (0.8-3), and preferably 1: 1.05;

in the step (3), the reaction solvent is N, N-dimethylformamide, acetonitrile, tetrahydrofuran and acetone, preferably acetonitrile;

in the step (3), the alkali is triethylamine, sodium hydroxide, potassium carbonate and sodium carbonate, the 4-dimethylaminopyridine is preferably potassium carbonate, and the molar ratio of the alkali to the potassium carbonate is 1 (2-5), preferably 1: 2.5;

the ratio of the catalyst sodium iodide to the 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone in the step (3) is 0.1-2.0: 1, preferably 0.5: 1.

wherein, the step (4) -refining, the aripiprazole is dissolved by ethyl acetate at high temperature and is filtered by heating, and the high-purity anhydrous aripiprazole (mainly referring to D-type crystal) is obtained by cooling, crystallizing and filtering, and the process is as follows:

in the step (4), the refining solvent is ethanol or ethyl acetate, preferably ethyl acetate.

In the step (4), the ratio of the refining solvent to aripiprazole is 12 ml for each 1g aripiprazole added solvent. The hot filtration temperature was 60 ℃. The filtering temperature is 15-25 ℃;

wherein, the step (5) of preparing the aripiprazole hydrate particles comprises the following steps: the anhydrous aripiprazole is refluxed and dissolved in ethanol and a water system, and aripiprazole hydrate particles are obtained by controlling the stirring rate and the cooling rate, and the process is as follows:

in the step (5), the solvent is ethanol and water.

In the step (5), the amount of ethanol and water is 16 ml of ethanol and 4 ml of water per 1g of aripiprazole.

In the step (5), the temperature reduction rate is 15-25 ℃ per minute, and the stirring rate is 150-200 revolutions per minute. The filtration temperature is 15-25 ℃.

The advantages of the invention are explained in detail below by comparing with the technical solutions of WO2008059518a2 and CN200910264361 and the like:

the synthetic route adopted by patent WO2008059518A2 is as follows:

the synthetic route of the invention is as follows:

it can be seen that the present invention does not require strict control of the dimer produced during the reaction of step 1, but reduces the content of the dimer by a simple purification operation to a level that does not affect the quality of the final aripiprazole at all. The aripiprazole raw material medicine with the purity of 99.98 percent can be easily obtained by the invention, and the anhydrous aripiprazole crystal form B, the aripiprazole crystal form D, the conventional aripiprazole hydrate and the aripiprazole hydrate A can be obtained. According to the equipment condition of self three-waste treatment, proper solvent and experimental conditions are selected, and the invention can almost realize pollution-free production.

Comparing the two routes, the steps are five steps, but the intermediate 1(HARA1) of the invention is synthesized by itself, and quality control is carried out by one step, so that the risk of influencing the quality of the final product aripiprazole due to the quality of the intermediate 1 is reduced.

Patent WO2008059518a2 is more than two steps of salifying with hydrogen chloride and then dissociating in order to purify aripiprazole, using strong acids and bases to increase the risk of hydrolytic ring opening of quinolinone and to increase acidic and alkaline waste water. In the invention, not only organic impurities but also some ionic inorganic salts (potassium chloride, potassium carbonate and the like) remained in the crude product can be removed by adding ethyl acetate for hot filtration, and the dimer is difficult to be reduced to below 0.1 percent even if the dimer is recrystallized for more than 10 times by using an alcohol solvent for recrystallization according to the operation in the patent WO2008059518A 2. The advantages of the five-step operation of the invention with respect to patent WO2008059518a2 are compared in steps below.

Step one reaction type

The operation in patent WO2008059518a2 is as follows: adding 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone, 1, 4-dibromobutane (4 equivalents) and potassium carbonate (1.5 equivalents) into acetone, refluxing for 16 hours, cooling to 15-20 ℃ after the reaction is finished, filtering, leaching a filter cake with acetone, concentrating the filtrate, recovering acetone at 60 ℃ and 1, 4-dibromobutane at 120 ℃, and dissolving the residue with dichloromethane, washing with an alkali solution and washing with water. Separating organic phase, adsorbing with active carbon, filtering, distilling off dichloromethane, pulping the residue with ethyl acetate and cyclohexane, filtering, eluting with cyclohexane, and drying the product by blowing at 55-60 ℃.

The operation of the invention is as follows: adding 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone, 1, 4-dibromobutane (1.7 equivalent) and potassium carbonate (1.2 equivalent) into acetone, refluxing, stirring, reacting for 20H, cooling, filtering to room temperature, recovering acetone from the reaction solution filtrate under reduced pressure, adding water into the residue, filtering, pulping the filter cake with n-hexane, filtering, and drying the filter cake at 60 ℃ for 2H by air blast to obtain 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (intermediate 2). And extracting the water phase by using n-hexane for pulping, and recovering the n-hexane and the 1, 4-dibromobutane.

In the first step, acetone is also used as a solvent, but the using amount of 1, 4-dibromobutane is reduced, salt is directly filtered out after the reaction is finished, the acetone is distilled and recovered, the remainder is added into water for crystallization, liquid separation steps such as extraction and water washing are omitted, crude n-hexane obtained by filtration is pulped and filtered, the n-hexane and 1, 4-dibromobutane are recovered from the filtrate at low temperature, and the high-temperature quinolinone is prevented from hydrolysis and ring opening. The method does not produce waste water containing organic matters, has low reaction temperature and few byproducts, and most of the only dimer which is difficult to remove can be filtered out together with salt. Concentrating the filtrate, adding the filtrate into water for crystallization, filtering and pulping to obtain a crude product which directly meets the requirements of subsequent reaction without further purification, if DMF (N, N-dimethylformamide) is adopted as a solvent, the reaction can be carried out at room temperature, but waste water containing DMF can be generated, so acetone is preferentially selected as the solvent in the process, and the qualified intermediate can be obtained by only adding ethyl acetate for pulping after the reaction of the crude product, wherein the optimal liquid phase ratio of the dimer is less than 5% according to the current experimental data, and if the liquid phase ratio of the dimer is more than 5%, the final product can be crystallized once to obtain high purity. Compared with other patents, the invention considers the removal of the main impurity dimer from the first step, and saves a great deal of manpower and materials for the subsequent purification.

Step two reaction formula

The invention refers to patent CN201210286068.1, wherein, the reaction is faster and more thorough without solvent in the second step, the invention has the advantages that the optimized starting material is fed in a ratio of one to one, the utilization rate of the material is high, the reaction is directly crystallized and purified, the intermediate with the quality meeting the requirement of the subsequent reaction can be obtained only by twice crystallization, the purification for many times is not needed, the loss in the recrystallization process is reduced, and the yield (more than 10 percent) higher than that of the literature is obtained.

Reaction formula of step three

The operation in patent WO2008059518a2 is as follows: and refluxing the intermediate 2 and the intermediate 1(1.67 equivalent) in methanol for 6-8 hours, cooling to 25-30 ℃ after the reaction is finished, filtering, leaching with methanol, leaching with water, pulping a filter cake with hot water, filtering, leaching with water until the pH value is 6.5-7.5, and drying.

In order to avoid the above risks, acetonitrile is directly used as the solvent in the invention, but the reaction is slow in the case of not adding sodium iodide, so that the final amount of sodium iodide is optimized to be 0.5 equivalent according to other patents. After the reaction is finished, cooling, stirring and crystallizing, and directly filtering, wherein a filter cake is a product and inorganic salt, and almost all impurities (main impurities in HARA1 and HARA2 and by-product impurities in the reaction) are dissolved in the filtrate. Distilling the filtrate to recover acetonitrile, adding the filter cake into water, and filtering to obtain crude aripiprazole with HPLC purity of about 99%. The equivalent of the intermediate 1 in the patent WO2008059518A2 is 1.67, the large excess of the intermediate 1 is not easy to remove in the subsequent operation, and the equivalent is controlled to be 1 to 1.05 by the invention, so that the utilization rate is 100 percent. According to the invention, organic solvent extraction is not needed in the post-treatment of the three-step synthesis reaction, and products are completely separated by filtration, so that the steps of extraction and liquid separation are omitted, and the pollution and the cost are reduced. All solvents used in crystallization and pulping can be recycled. The operation of other documents in this step is also complicated, and the post-treatment adopts extraction operation, such as the operation of patent CN200910266341 of Otsuka pharmaceutical Co., Ltd, new impurities are introduced into triethylamine used in the reaction, chloroform with relatively high toxicity is used in the post-treatment, synthesis of two intermediates is not studied in the document, and even if high-quality intermediates with high price are used, the purity of the final product is difficult to achieve high purity according to the above operation.

In patent CN03132278.6, the one-pot method is adopted, so that the synthesis yield is low, and the purity is difficult to ensure.

In the fourth step, the invention adopts ethyl acetate for refining, and the product quality can be controlled to reach high-purity quality by combining the operations of the step 1 and the step three. The crude product is dissolved by ethyl acetate and then is filtered by heating, and residual inorganic salt in the crude product can be removed by the hot filtration, so that the quality of the aripiprazole is ensured, and the influence of solid impurities on subsequent crystallization is reduced (the solid impurities belong to heterogeneous nucleation and influence on crystallization speed and grain growth). Compared with the procedure of WO2008059518A2, which is performed as hydrochloride salt and then free, the dimer is difficult to remove in the system, and the procedure is as follows: dissolving, salifying with hydrogen chloride, filtering, drying, dissolving again, dissociating with sodium hydroxide, filtering, and drying. The method is simple to operate and environment-friendly, and the ethyl acetate used for refining has higher impurity dissolving capacity than acetone in the first step and methanol in the second step, so that the impurities which are not removed in the previous two steps can be completely removed in the refining process, the obtained aripiprazole has high purity and very uniform particle size, and residual solvents such as acetonitrile used in the previous step can be dissolved in the ethyl acetate and removed. In the fifth step, the hydrate micronization of the invention adopts crystallization conditions of slower cooling and faster stirring, and the purity of the aripiprazole is higher, and nucleation and grain growth are more stable in the crystallization process, so that the precipitated crystal has more uniform granularity and larger specific surface area, can be uniformly dispersed in water, has better solubility and larger specific gravity of the hydrate crystal, can be sheared into smaller particles by a shearing machine, and is very favorable for the processing of the subsequent preparation process.

The following illustrates the beneficial effects of the present invention by comparing data:

step 1 is compared with the prior art, and the obtained technical parameters are as follows:

step 3 is compared with the prior art, and the obtained technical parameters are as follows:

	embodiment 13(12) of the present invention	Prior Art
			Work-up (isolation of the product)	Filtration	Extracting with chloroform, ethyl acetate, etc., and filtering
Intermediate feeding proportion	1:1.05	1:1.2-2
			Purity of crude product	99.00% (example 12)	90-95％
Yield of crude product	100% (the crude product may contain solid salts)	90-100％

Step 4 is compared with the prior art, and the obtained technical parameters are as follows:

	inventive example 13	Prior Art
			Purification mode	Recrystallization	Salifying and then dissociating, recrystallizing
Number of refinements	1 time of	3-8 times
			Purity of final product	99.98％	95-98％
Yield in combination with step 3	79.47％	About 50 percent

Compared with the prior art, the invention obtains the following technical parameters in the whole process:

the optimization effect of the second and fifth steps is actually the inevitable result of the additional three steps of optimization. The advantages of the single-step operation are not obvious, but the defects of all process routes are perfectly avoided in the whole view, so that the optimization limit of the compound synthesis is reached. The method has the advantages of easy operation (synthesis steps, refining times, extraction filtration and other operations), environmental friendliness (use of toxic solvent auxiliary materials and generation of strong acid, strong base and high-toxicity waste liquid), and better total yield and especially better product quality (HPLC purity, potential genotoxic impurities and the like) than the prior art according to the following indexes.

The method has the advantages that the route used by the method is simple, green and economic, but the difficulty in removing impurities is the greatest defect, tests prove that the method is difficult to obtain a high-purity intermediate by the reaction of the single step, and the process problem is solved if the quality control is carried out on the third step, the first step and the second step as a whole. Therefore, the method takes the step as a key step, and all the steps are integrally considered and matched in front and back in the selection of the solvent and the post-treatment operation, so that the quality is ensured, the yield is considered, the operation is very simple, and the method has absolute advantages compared with other routes.

All the following confirmation of nuclear magnetic hydrogen spectrum and crystal form (except dimer nuclear magnetic hydrogen spectrum) refer to Japanese red-letter drug Co., Ltd, CN 200910266341-low hygroscopic aripiprazole drug and its preparation method. Due to the determination of the reference line and the difference of the grinding particle size, the chemical shift and the peak height of the characteristic peak in different batches of spectra have slight difference. With respect to the HPLC chart, the ratio of mobile phase and pH of the formulation may vary depending on the date of production of the samples of different batches of the same experiment, resulting in deviation of the retention time of the peaks. For brevity, similar spectra and control spectra are not repeated.

Drawings

FIG. 1 is an HPLC chromatogram of example 1.

FIG. 2 is an HPLC chromatogram of example 2.

FIG. 3 is an HPLC chromatogram of example 3.

FIG. 4 is an HPLC chromatogram of example 3.

FIG. 5 depicts the HARA dimerization obtained in example 3Of an object¹H-NMR spectrum.

FIG. 6 is an HPLC chromatogram of example 8.

FIG. 7 is an HPLC chromatogram of example 8.

FIG. 8 is an HPLC chromatogram of example 8.

FIG. 9 is an HPLC chromatogram of example 10.

FIG. 10 is an HPLC chromatogram of example 10.

FIG. 11 is an HPLC chromatogram of example 10.

FIG. 12 is an HPLC chromatogram of example 10.

FIG. 13 is an HPLC chromatogram of example 12.

FIG. 14 is an HPLC chromatogram of example 12.

FIG. 15 is an HPLC chromatogram of example 12.

FIG. 16 is an HPLC chromatogram of example 12.

FIG. 17 shows the D-form crystals of anhydrous aripiprazole obtained in example 12¹H-NMR spectrum.

FIG. 18 is an X-ray diffraction pattern of anhydrous aripiprazole D-form crystal obtained in example 12.

FIG. 19 is a graph showing the particle size distribution of anhydrous aripiprazole D-form crystals obtained in example 12.

FIG. 20 is an HPLC chromatogram of example 13.

FIG. 21 is an HPLC chromatogram of example 13.

FIG. 22 is a differential scanning calorimetry trace of aripiprazole hydrate A obtained in example 14

FIG. 23 is an X-ray diffraction pattern of aripiprazole hydrate A obtained in example 14.

FIG. 24 is an X-ray diffraction pattern of the conventional aripiprazole hydrate obtained in example 15.

FIG. 25 is a schematic representation of the conventional aripiprazole hydrate obtained in example 15¹H-NMR spectrum.

FIG. 26 is a graph showing the particle size distribution of the conventional aripiprazole hydrate obtained in example 15.

FIG. 27 is a differential scanning calorimetry trace of the conventional aripiprazole hydrate obtained in example 15.

FIG. 28 is an X-ray diffraction pattern of aripiprazole hydrate A obtained in example 15.

FIG. 29 is an X-ray diffraction pattern of aripiprazole crystalline form B obtained in example 15.

FIG. 30 is a graph of particle size distribution after shearing for conventional hydrates in example 15.

Detailed Description

The present invention will be further described with reference to the following examples; it should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

EXAMPLE 1 Synthesis of 7- (4-Bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (HARA2)

7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone (155.08g, 0.95mol), 1, 4-dibromobutane (821.05g, 3.80mol), anhydrous potassium carbonate (196.97g, 1.43mol) and acetone (700m1) were added to a 2L reaction flask, and the mixture was stirred under reflux for 10 hours, cooled, evaporated under reduced pressure to remove acetone, and water (800ml) was added to the residue, followed by filtration, washing of the cake with water (500ml), beating and filtration of the cake with n-hexane (400m1) twice, and forced air drying at 60 ℃ for 2 hours to obtain intermediate 2(201.60g, 88.00%) in which the dimer was 11.76% (HPLC chart shown in FIG. 1) in a yield of 62.47% based on pure intermediate 2. The product is used for the next step without purification.

EXAMPLE 2 Synthesis of 7- (4-Bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (HARA2)

Adding 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone (8.16g, 0.05mol), 1, 4-dibromobutane (16.19g, 0.075mol), anhydrous potassium carbonate (7.60g, 0.055mol) and acetone (100m1) into a 250ml reaction bottle, carrying out reflux stirring reaction for 20H, cooling, filtering, adding a filter cake into 100ml water, filtering to obtain a solid (dimer accounts for 85%), distilling off the acetone under reduced pressure, adding water (100ml) into the residue, filtering, pulping the filter cake with n-hexane (70m1), and drying the filter cake at 60 ℃ for 2 hours by air blowing to obtain an intermediate 2(9.88g, 94.25%) wherein the dimer accounts for 3.79% (an HPLC chart is shown in the attached figure 2). The yield thereof was found to be 62.44%.

EXAMPLE 3 Synthesis of 7- (4-Bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (HARA2)

7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone (8.16g, 0.05mol), 1, 4-dibromobutane (5.39g, 0.025mol), anhydrous potassium carbonate (7.60g, 0.055mol), DMF (100m1) were added to a 250ml reaction flask, stirred at room temperature for 20H, added to 100ml water, and filtered to give 4.50g of a solid (dimer ratio 77.07%, HPLC chart in FIG. 3)). 4.40 g of solid is beaten with 100ml of ethyl acetate under reflux, cooled and filtered to obtain 3.55 g of solid (dimer proportion 91.67%, HPLC chart is shown in figure 4), nuclear magnetic hydrogen spectrum is shown in figure 5, this example shows that the equivalent of 1, 4-dibromobutane directly affects the proportion of dimer impurities, the solubility of dimer is relatively low, and most of dimer can be removed by beating with ethyl acetate.

EXAMPLE 4 Synthesis of 7- (4-Bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (HARA2)

7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone (8.16g, 0.05mol), 1, 4-dibromobutane (12.95g, 0.06mol), anhydrous potassium carbonate (8.29g, 0.06mol), DMF (50m1) were added to a 250ml reaction flask, stirred at room temperature for 20 hours, cooled, added to 200ml water, filtered to obtain 12.31g of a solid (dimer content: 35.35%), 10.43g of the solid was slurried and filtered with n-hexane (100m1), the cake was then slurried and filtered with 80ml ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain intermediate 2(6.15g, 95.12%) in which dimer content: 2.57%. The yield thereof was found to be 46.26%.

EXAMPLE 5 Synthesis of 7- (4-Bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (HARA2)

7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone (16.32g, 0.1mol), 1, 4-dibromobutane (43.18g, 0.2mol), anhydrous potassium carbonate (16.59g, 0.12mol), DMF (50m1) were charged into a 250ml reaction flask, stirred at room temperature for 20 hours, added to 200ml of water, filtered, the cake was slurried in 200ml of petroleum ether, filtered to obtain 27.44g of a solid (dimer content: 19%), 26.14g of the solid was slurried with 200ml of ethyl acetate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2(17.25g, 96.00%) wherein the dimer content: 3.00%. The yield thereof was found to be 58.27%.

EXAMPLE 6 Synthesis of 7- (4-Bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (HARA2)

7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone (16.32g, 0.1mol), 1, 4-dibromobutane (86.36g, 0.4mol), anhydrous potassium carbonate (16.59g, 0.12mol), DMF (50m1) were charged into a 250ml reaction flask, stirred at room temperature for 36 hours, added to 200ml of water, filtered, the cake was slurried in 200ml of petroleum ether, filtered to obtain 22.23g of a solid (dimer content: 10%), 21.03g of the solid was slurried with 200ml of ethyl acetate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2(17.50g, 96.30%) in which the dimer content: 3.30%. The yield thereof was found to be 59.70%. And (4) experimental conclusion: the equivalent of 1, 4-dibromobutane is increased to 4 equivalents, the reaction time is longer, the dimer proportion is reduced, but the yield is not obviously increased, the post-treatment is difficult to cure, the state after curing is not good, and the suction filtration is difficult. The recovery rate of 1, 4-dibromobutane is only about 80%, so that the amount of the dibromobutane is not more than better.

Example 7 Synthesis of 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (HARA2)

Adding 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone (130.54g, 0.8mol), 1, 4-dibromobutane (293.64g, 1.36mol), anhydrous potassium carbonate (132.68g, 0.96mol) and DMF (400m1) into a 1L reaction flask, stirring at room temperature for 20H, adding into 1.8L of water, filtering, adding a filter cake into 1.6L of petroleum ether, pulping, filtering to obtain 240.40g of solid (dimer accounts for 24%), pulping and filtering the 239.40g of solid with 1.7L of ethyl acetate, and concentrating the filtrate under reduced pressure to obtain intermediate 2(159.88g, 95.90%) wherein the dimer accounts for 3.60%. The yield thereof was found to be 64.25%.

EXAMPLE 8 Synthesis of 2, 3-dichlorophenyl piperazine hydrochloride

2, 3-dichloroaniline (81.01g, 0.5mol) was added to a 500ml three-necked flask and warmed to 100 ℃ and bis (2-chloroethyl) amine hydrochloride (89.25g, 0.5mol) was added in portions, warmed to 120 ℃ and reacted for 4 hours, and then reacted for 8 hours at 160 ℃. And after the reaction is finished and the temperature is reduced, 160g of n-butanol is added into the system, the stirring is started after the heating reflux and the complete dissolution, the cooling crystallization and the filtration are carried out to obtain 115.23 g of solid (the content of the main impurity liquid phase is 1.19 percent, and the HPLC (high performance liquid chromatography) graph is shown in the figure 6), 113.23 g of solid is refluxed and dissolved by 300 g of methanol, the cooling crystallization and the filtration are carried out to obtain 74.88 g of solid (the liquid phase purity is 100 percent, the HPLC graph is shown in the figure 7), the mother liquor is concentrated and crystallized to obtain 18.29 g of solid (the content of the main impurity liquid phase is 0.09 percent, the HPLC graph is shown in the figure 8), the qualified intermediate 1 of 93.17 g is obtained, and the yield is 69.64%.

EXAMPLE 9 Synthesis of 2, 3-dichlorophenyl piperazine hydrochloride

2, 3-dichloroaniline (97.21g, 0.6mol) was added to a 1L three-necked flask and heated to 100 ℃ and bis (2-chloroethyl) amine hydrochloride (107.10g, 0.6mol) was added in portions, heated to 120 ℃ and reacted for 2 hours, and then reacted for 7 hours at 160 ℃. After the reaction is finished and the temperature is reduced, 500ml of n-butanol is added into the system, stirring is started after heating reflux and complete dissolution, cooling crystallization and filtration are carried out to obtain 140.08 g of solid (the main impurity liquid phase accounts for 3.4%), 140.08 g of solid is dissolved by 320 g of methanol in a reflux manner, cooling crystallization and filtration are carried out to obtain 95.56 g of solid, mother liquor is concentrated and crystallized to obtain 15.03 g of solid, and 110.59 g of qualified intermediate 1 (the purity is 95.02%, the main impurity is 4.2%) is obtained, and the yield is 65.44%.

EXAMPLE 10 Synthesis and refinement of Aripiprazole

900ml of acetonitrile was added to a 2L three-necked flask, and then 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (106.74g,0.358mol, dimer proportion 11.76%) was added with 1- (2, 3-dichlorophenyl) piperazine hydrochloride (127.43g, 0.4762mol), sodium iodide (119.00g, 0.64mol), and triethylamine (64.76g, 0.64mol), heated under reflux for 14 hours, the acetonitrile was distilled off under reduced pressure after the reaction was completed, 500ml of water was added, solid wet product was obtained by filtration, about 600ml of ethanol was used each time, crystallization was repeated 5 times to obtain crude product 74.75 g (95.45%, dimer proportion 4.51%, HPLC diagram is shown in FIG. 9), and solid 61.02 g (98.75%, dimer proportion 1.11%, HPLC diagram is shown in FIG. 10) was obtained by repeated five times with ethanol. The yield thereof was found to be 38.01%.

20.00 g of the obtained solid is taken, added with 150ml of ethyl acetate for reflux dissolution, heated and filtered, cooled and crystallized, and then filtered to obtain 13.27 g of solid (99.53 percent, the dimer is 0.35 percent, the HPLC diagram is shown in figure 11), and then 10g of the solid is taken and crystallized by 120ml of ethanol and 30ml of water to obtain 8.90 g of aripiprazole hydrate (99.83 percent, the dimer is 0 percent, the HPLC diagram is shown in figure 12).

EXAMPLE 11 Synthesis and refinement of Aripiprazole

To a 250ml three-necked flask, 80ml of acetonitrile was charged, and then 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (8.05g,0.027mol, dimer content: 3.79%) and 1- (2, 3-dichlorophenyl) piperazine hydrochloride (10.84g, 0.0405mol, main impurity 0.54%), sodium iodide (8.09g, 0.054mol), triethylamine (5.46g, 0.054mol) were added, the reaction was refluxed for 4 hours, after completion of the reaction, acetonitrile was distilled off under reduced pressure, 100ml of water was added, and crystallization was filtered and dried to obtain 16.48 g of a solid (81.72%, intermediate 1 content: 14.71%, dimer content: 1.74%, intermediate 1 content: 0.27%), 10.05 g of the solid was recrystallized with 150ml of ethanol to obtain 7.20 g of a solid (98.29%, intermediate 1 content: 0.74%, dimer content: 0.59%, intermediate 1 content: 0.22%). The yield was 97.55%, and the solid may contain an inorganic salt.

EXAMPLE 12 Synthesis and refinement of Aripiprazole

Adding 300ml acetonitrile into a 500ml three-neck flask, then adding 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (34.95g,0.1225mol, dimer proportion 3.20%) and 1- (2, 3-dichlorophenyl) piperazine hydrochloride (31.60g, 0.1181mol, main impurity 0.54%), sodium iodide (5.09g, 0.034mol), potassium carbonate (38.88g, 0.2813mol), heating and refluxing for 30 hours, filtering after the reaction, distilling the filtrate to recover acetonitrile, spin-drying to obtain 11.10 g of oily substance (41.44%, intermediate 1 proportion 33.38%, dimer proportion 8.06%, intermediate 1 main impurity proportion 2.12%, HPLC diagram shown in figure 13), adding 300ml water into the filter cake, crystallizing, filtering, air drying to obtain solid 54.80 g (99.00%, intermediate 1 proportion 0.04%, dimer proportion 0.36%, intermediate 1 main impurity proportion 0.12%, HPLC is shown in figure 14), 53.80 g is taken and recrystallized by 650ml ethanol to obtain 48.50 g of solid (99.84%, the intermediate 1 accounts for 0.05%, the dimer accounts for 0.06%, the intermediate 1 accounts for 0%, and the HPLC is shown in figure 15). 47.50 g of aripiprazole D-type crystals are heated, refluxed and dissolved by 600ml of ethyl acetate, heated and filtered at 60 ℃, cooled, crystallized and filtered to obtain 38.35 g of anhydrous aripiprazole D-type crystals (99.97 percent, 0 percent of intermediate 1, 0 percent of dimer and 0 percent of intermediate 1), and the HPLC chromatogram is shown in figure 16). The yield thereof was found to be about 71.64%. The anhydrous aripiprazole nuclear magnetic hydrogen spectrum diagram is shown in figure 17, the XRD diagram is shown in figure 18, and the particle size distribution diagram is shown in figure 19. This example confirms that the reaction impurities are almost completely dissolved in acetonitrile, while the product is almost completely in the precipitated solid.

EXAMPLE 13 Synthesis and refinement of Aripiprazole

1362ml of acetonitrile is added into a 3L three-necked flask, then 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (158.88g,0.51mol, dimer accounts for 3.60%) and 1- (2, 3-dichlorophenyl) piperazine hydrochloride (141.82g, 0.53mol, main impurity 4.20%), sodium iodide (38.23g, 0.255mol) and potassium carbonate (176.91g, 1.28mol) are added, heating reflux reaction is carried out for 10 hours, filtering is completed, the filtrate is distilled to recover acetonitrile, spin-drying is carried out to obtain 55.18 g of oily matter (28.60%, intermediate 1 accounts for 23.98%, dimer accounts for 20.44%, intermediate 1 main impurity accounts for 13.48%, HPLC (HPLC diagram is shown in figure 20), 1300ml of water is added into the filter cake, crystallization filtration and airing are carried out to obtain 249.83 g of solid, heating reflux dissolution is carried out by 2100ml of ethyl acetate, heating filtration is carried out at 60 ℃, cooling is carried out to 25 ℃ for crystallization filtration, and drying is carried out at 105 ℃ by air blast, 181.74 g of refined aripiprazole product (99.98%, intermediate 1 content 0%, dimer content 0%, intermediate 1 main content 0%, HPLC chromatogram shown in figure 21) is obtained. The yield was about 79.47%.

EXAMPLE 14 preparation of Aripiprazole hydrate microparticles

Adding 2.00 g of anhydrous aripiprazole into 20ml of ethanol, heating for dissolving, dropwise adding into 80ml of 80 ℃ stirring hot water, separating out white solid, cooling, and filtering to obtain 1.75 g of aripiprazole hydrate A, wherein a differential scanning calorimetry diagram is shown in figure 22, and an XRD diagram is shown in figure 23.

EXAMPLE 15 preparation of Aripiprazole hydrate microparticles

130.08 g of anhydrous aripiprazole is added into 2080ml of ethanol, 520ml of water is added, heating and refluxing are carried out until the aripiprazole is completely dissolved, the internal temperature is about 80 ℃, natural temperature reduction is carried out, the magnetic stirring speed is set to 180 r/min, the temperature is reduced to 16 ℃ after about 4 hours, suction filtration is carried out, 131.27 g of aripiprazole conventional hydrate is obtained after blowing and drying a filter cake at 50 ℃, the XRD diagram is shown in figure 24, the nuclear magnetic hydrogen spectrum diagram is shown in figure 25, the particle size diagram is shown in figure 26, and the differential scanning calorimetry diagram is shown in figure 27. Take 5g of conventional hydrate and grind carefully with mortar to get hydrate A, XRD pattern is shown in figure 28. The loss on drying of the conventional hydrate is about 3.85 percent at 115 ℃, the obtained aripiprazole absorbs moisture quickly after being taken out, and hardening occurs, so that powder diffraction cannot be carried out. Taking the ground hydrate A, measuring the drying weight loss at 115 ℃ of about 3.96 percent to obtain the anhydrous aripiprazole crystal form B, wherein an XRD (X-ray diffraction) diagram is shown in figure 29, the aripiprazole conventional hydrate is dispersed in water, a shearing machine is used for shearing for 30 minutes, and a particle size diagram is shown in figure 30.

Claims

1. A preparation method of high-purity aripiprazole and hydrate particles thereof is characterized by comprising the following steps:

step 1, 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone and 1, 4-dibromobutane are subjected to Williamson etherification under the action of potassium carbonate to obtain 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone;

step 2, 2, 3-dichloroaniline and bis (2-chloroethyl) amine hydrochloride are synthesized into 2, 3-dichlorophenyl piperazine hydrochloride;

3, carrying out nitrogen alkylation coupling reaction on 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone and 1- (2, 3-dichlorophenyl) piperazine hydrochloride to prepare aripiprazole;

step 4, recrystallizing the aripiprazole with ethyl acetate to obtain high-purity anhydrous aripiprazole;

and 5, refluxing and dissolving the anhydrous aripiprazole in an ethanol water system, and controlling the stirring rate and the cooling rate to obtain aripiprazole hydrate particles.

2. The method according to claim 1, wherein the solvent of step (1) is acetone or DMF; in the step (1), the molar ratio of the 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone to the 1, 4-dibromobutane is 1 (1-4); the reaction solvent in the step (1) is selected from: acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, acetone, DMF; in the step (1), the alkali is selected from: potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate; the molar ratio is 1 (1-5).

3. The preparation process according to claim 1, wherein in step (2), the molar ratio of 2, 3-dichloroaniline to bis (2-chloroethyl) amine hydrochloride is 1 to 1; the reaction temperature in the step (2) is 100-.

4. The preparation method according to claim 1, wherein the molar ratio of 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone to 1- (2, 3-dichlorophenyl) piperazine hydrochloride in the step (3) is 1 (0.8-3); the reaction solvent in the step (3) is selected from: n, N-dimethylformamide, acetonitrile, tetrahydrofuran, acetone; in the step (3), the alkali is selected from: triethylamine, sodium hydroxide, potassium carbonate, sodium carbonate and 4-dimethylamino pyridine, wherein the molar ratio of the triethylamine to the sodium hydroxide to the potassium carbonate to the sodium carbonate to the 4-dimethylamino pyridine is 1 (2-5); the ratio of the catalyst sodium iodide to the 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone in the step (3) is 0.1-2.0: 1.

5. the production method according to claim 1, wherein, in the step (4), the refining solvent is selected from the group consisting of: ethanol, ethyl acetate; in the step (4), the ratio of the refined solvent to the aripiprazole is 12 ml for each 1g aripiprazole added solvent, the hot filtration temperature is 60 ℃, and the filtration temperature is 15-25 ℃.

6. The process according to claim 1, wherein in the step (5), the solvent is ethanol and water in amounts of 16 ml of ethanol and 4 ml of water per 1g of aripiprazole; the cooling rate is 15-25 ℃ per minute, the stirring rate is 150-200 revolutions per minute, and the filtering temperature is 15-25 ℃.

7. The process according to claim 1, wherein the molar ratio of 7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone to 1, 4-dibromobutane in step (1) is 1 (1.5-2); in the step (1), the reaction solvent is acetone or DMF; the alkali in the step (1) is potassium carbonate; the molar ratio is 1: 1.2.

8. The production process according to claim 1, wherein the molar ratio of 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone to 1- (2, 3-dichlorophenyl) piperazine hydrochloride in step (3) is 1: 1.05; in the step (3), the reaction solvent is acetonitrile; in the step (3), the alkali is potassium carbonate, and the molar ratio of the potassium carbonate to the alkali is 1: 2.5; the ratio of the catalyst sodium iodide to the 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone in step (3) was 0.5: 1.