CN114181202A

CN114181202A - Preparation method of brexpiprazole

Info

Publication number: CN114181202A
Application number: CN202111554063.8A
Authority: CN
Inventors: 刘进兵; 彭泽根; 杨贞皓
Original assignee: Hunan Province Xiangzhong Pharmaceutical Co ltd
Current assignee: Hunan Province Xiangzhong Pharmaceutical Co ltd
Priority date: 2021-12-17
Filing date: 2021-12-17
Publication date: 2022-03-15

Abstract

The invention relates to a preparation method of brexpiprazole; the preparation method comprises the following steps: synthesizing a compound 1 by using 4-substituted butyronitrile and 7-hydroxyquinoline-2- (1H) ketone as starting materials, reducing the compound 1 to obtain a compound 2, closing a ring of the compound 2 and BOC-dichloroethyl imine to obtain a compound 3, deprotecting the compound 3 to obtain a compound 4, and reacting the compound 4 with 4-bromobenzothiophene to obtain a target product, namely the ipiprazole; the method has the advantages of simple operation, easy control of reaction, easy obtainment of raw materials, easy separation of products, environmental protection and suitability for industrial production.

Description

Preparation method of brexpiprazole

Technical Field

The invention belongs to the technical field of medicine production, relates to preparation of a medicine for treating schizophrenia, and particularly relates to a preparation method of brexpiprazole.

Background

Ipiprazole was co-developed by tsukamur japan and north danazol, and approved by the FDA in the united states for marketing at 7/10 days 2015. Eperisone tablet batches (accession number: JXHL1000032) were obtained by beijing conriston pharmaceutical technology development ltd in 2016 (11 months). Wherein the chemical name: 7- [4- (4- (benzo [ b ] thiophen-4-yl) -piperazin-1-yl) butoxy ] -1H-quinolin-2-one, English name: 7- [4- (4- (benzob ] thien-4-yl) -piperazin-1-yl) butoxy ] -1H-quin-olin-2-one. Belongs to 5-HT/DA receptor modulators, is used for treating adult schizophrenia, and can also be combined with antidepressants to treat adult major depression. Epipconazole is the first dopamine, partial 5-HT1A receptor agonist and 5-HT2A receptor antagonist class of compounds. Compared with aripiprazole, the ipipiprazole has better curative effect and tolerance, and can reduce the incidence rate of adverse reactions of patients such as akathisia, uneasiness, insomnia and the like.

At present, the synthesis methods of the ipiprazole are more, and the preparation methods reported in the literature mainly comprise the following methods:

(1) the patent publication WO2018172463A1 discloses the preparation of ipiprazole as follows:

and reacting the Boc-protected piperazine with 1, 4-disubstituted butane to substitute for one substituent in the 1, 4-disubstituted butane to obtain a butane derivative containing the Boc-protected piperazine, reacting the derivative with 7-hydroxyquinolinone to obtain Boc-protected 7- (4- (piperazin-1-yl) butoxy) quinolin-2- (1H) one, deprotecting to obtain 7- (4- (piperazin-1-yl) butoxy) quinolin-2- (1H) one, and reacting with 4-bromobenzothiophene to obtain the ipiprazole. The yield of the first step reaction of the method is not high, and both ends of the 1, 4-disubstituted butane can be simultaneously substituted by piperazine.

(2) The patent document with publication number WO201725987 improves the above synthetic route:

the method has the problems of high raw material price, complex production process, long production period, high toxicity of used reagents and the like, and particularly, the methanesulfonyl chloride has high corrosion to equipment and is not environment-friendly and is not suitable for industrial production.

(3) The publication number is WO201887775, CN105440026A and CN106496206A adopt a similar method to synthesize the ipiprazole through 7- (4- (piperazine-1-yl) butoxy) quinoline-2- (1H) ketone. The preparation method comprises the following steps of taking 7-hydroxyquinoline-2- (1H) ketone as a starting material, firstly reacting with bromochlorobutane to obtain 4-chlorochlorochlorochlorochlorochloroquinolinone, then reacting with piperazine hydrochloride or Boc protected piperazine to obtain 7- (4- (piperazine-1-yl) butoxy) quinoline-2- (1H) ketone, and then reacting with 4-bromobenzothiophene to obtain the ipiprazole. The method has the disadvantage that the one-step post-treatment of piperazine is inconvenient for industrialization.

(4) The original route of tsukamur medicine synthesis was via the coupling of a 7- (4-chlorobutoxy) -2- (1H) -quinolinone intermediate, or an analog thereof, and a 4- (1-piperazinyl) benzo [ b ] thiophene intermediate to provide ipiprazole. The method is relatively common and suitable for industrialization, and the patent applied in China is CN 200680011923.

The method has the defects that the possibility that hydrogen on piperazine nitrogen is respectively replaced by benzothiophene exists when synthesizing the 4- (1-piperazinyl) benzo [ b ] thiophene intermediate, and the 1-bromo-4-chlorobutane used when synthesizing the 7- (4-chlorobutoxy) -2- (1H) -quinolinone intermediate has no good selectivity.

(5) In the patent publication No. CN105399736B, 7-hydroxy-3, 4-dihydro-2- (1H) -quinolinone as a starting material is reacted with 4-bromobutanol to obtain a 7- (4-hydroxybutoxy) -3, 4-dihydro-2- (1H) -quinolinone intermediate, which is then reacted with methanesulfonyl chloride to produce an intermediate having a readily removable group, which is reacted with a 4- (1-piperazinyl) benzo [ b ] thiophene intermediate followed by dehydrogenation with 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) to obtain ipiprazole.

In the method, methanesulfonyl chloride has strong corrosivity to equipment, DDQ has high toxicity, post-treatment is difficult, and the method is not environment-friendly, so that the industrialization of the method is limited.

Disclosure of Invention

The invention provides a preparation method of brexpiprazole, which has the advantages of easily obtained raw materials, easy operation, environmental protection, convenient industrialization, and higher yield and purity.

The preparation method of brexpiprazole is characterized by comprising the following steps:

the first step is as follows: reacting 4-substituted butyronitrile with 7-hydroxy 2- (1H) -quinolinone to obtain a compound 1, wherein a substituent in the 4-substituted butyronitrile is selected from one of chlorine, bromine, iodine and hydroxy, and preferably 4-chlorobutyronitrile or 4-bromobutyronitrile;

the second step is that: adding a reducing agent or a catalyst, and reducing the cyano group of the compound 1 to obtain a compound 2;

the third step: adding alkali, and reacting the compound 2 with BOC-dichloroethylenimine to obtain a compound 3;

the fourth step: under an acidic solution, deprotecting the compound 3 to obtain a compound 4;

the fifth step: adding a catalyst and a ligand, and reacting the compound 4 with 4-bromobenzothiophene to obtain the ipiprazole.

The specific synthetic route is as follows:

further, an alkali metal carbonate, pyridine, piperidine, tetrahydropyrrole or morpholine, preferably potassium carbonate, is added in the first step.

Further, the reducing agent in the second step is sodium borohydride or sodium cyanoborohydride; or the catalyst is Raney nickel or palladium carbon.

Further, the reaction solvent of the second step is an alcohol containing iodine, ether, tetrahydrofuran or toluene.

Further, the reaction solvent of the third step is dimethyl sulfoxide, acetonitrile, N-dimethylformamide, N-methylpyrrolidone, ethylene glycol monomethyl ether or N-butanol, preferably N, N-dimethylformamide.

Further, the base added in the third step is carbonate, triethylamine, N-diisopropylethylamine, morpholine, piperidine or pyrrolidine, preferably potassium carbonate.

Further, the acidic solution in the fourth step is concentrated hydrochloric acid, concentrated hydrochloric acid acetone solution or alcohol solution of hydrogen chloride, preferably methanol solution of 6N hydrogen chloride or ethanol solution of hydrogen chloride.

Further, the solvent of the fifth step is toluene, xylene, tetrahydrofuran or 1, 4-dioxane; alternatively, the catalyst is palladium acetate or palladium dibenzylidene acetonate; alternatively, the ligand is triphenylphosphine or 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine.

The beneficial effect of the invention is that,

(1) the adopted raw materials are common raw materials and do not relate to special reagents, wherein the raw materials used for synthesizing the compound 1 are common chemical raw materials, and the price of the 4-halogenated butyronitrile is low;

(2) the whole process route does not involve special reaction conditions such as high temperature, high pressure, low temperature and the like, the operation is convenient, the industrialization is convenient to realize, and the problem that the operation steps which are inconvenient to industrialize in the prior art are solved, wherein the product in the second step is simple in post-treatment and can be directly used for the next reaction, and the third step does not use the reaction of protecting piperazine with Boc, so that the industrial production is convenient;

(3) the whole process does not involve toxic reagents, does not use methanesulfonyl chloride which is highly corrosive to equipment, does not use dichloro dicyano benzoquinone (DDQ) which has high toxicity, difficult post-treatment and is not friendly to the environment, and the like; the used solvent can be recycled, so that the environmental pollution is avoided, and the green production is realized.

(4) And step four, preferably selecting an alcoholic solution of hydrogen chloride, reducing the solubility of the product and improving the yield of the product.

(5) The invention selects 4-substituted butyronitrile as raw material, changes cyano into amino after reduction, and then reacts with BOC-dichloroethylenimine to obtain the compound 3, the whole reaction condition is mild, the product yield is higher, the purity is higher, the cost can be effectively reduced, and the benefit is improved. The purity of the product obtained by adopting the reaction route of the method can reach 99.3 percent, which is higher than 98 percent of the prior art, and the content of impurities is effectively reduced.

Drawings

FIG. 1 is a synthesis scheme of the present invention.

Detailed Description

Example 1

The first step is as follows: synthesis of Compound 1

Adding 0.013mol (1.924 g) of 4-bromobutyronitrile into a 50mL reaction bottle, adding 0.012mol (1.930 g) of 7-hydroxy 2- (1H) -quinolinone, 0.006mol (0.829 g) of anhydrous potassium carbonate and 20mL of acetone respectively, stirring and heating to reflux, carrying out heat preservation reaction, tracking reaction by TLC (developing agent: dichloromethane/methanol ═ 10/1), cooling to room temperature after the reaction is finished, carrying out suction filtration, washing a filter cake with 10mL of acetone twice each time, combining filtrates, evaporating the solvent under reduced pressure, adding 10mL of petroleum ether into a residue, fully stirring, placing in a refrigerator for overnight, carrying out suction filtration, washing the filter cake with 5mL of petroleum ether twice respectively, and drying to obtain a white solid compound 1, wherein the yield after purification is 78.12% and the purity is 98.16%.

1H NMRδ:11.57(s,1H,-NH),7.77(d,J＝7.8Hz,1H,Ph-H),7.53(d,J＝7.5Hz,1H,Ph-H),6.76-6.75(m,2H,Ph-H),6.27(d,J＝6.3Hz,1H,Ph-H),4.02(t,J＝4.0Hz,2H,-CH2),2.65(t,J＝2.6Hz,2H,-CH2),2.03-2.00(m,2H,-CH2)；MS(ESI):m/z(100％)229(M+H)。

The second step is that: synthesis of Compound 2

1.14 g (5mmol) of compound 1 is added into a 100mL three-mouth reaction flask, 30mL tetrahydrofuran is added, the mixture is cooled to 0 ℃ under stirring, 1 g (27mmol) of sodium borohydride is added, and a solution of 3 g (12mmol) of iodine in 20mL tetrahydrofuran is added dropwise at 0 ℃ under the protection of nitrogen, and the solution is dropped out after 2-3 hours. After the completion of the dropwise addition, the temperature was raised for reflux reaction, the reaction was followed by TLC (developing solvent: dichloromethane/methanol: 5/1), after the completion of the reaction, the reaction was cooled to 0 ℃ and quenched by dropwise addition of 3N hydrochloric acid until no gas was released, the reaction was neutralized with 3N sodium hydroxide solution to produce a precipitate, the precipitate was filtered, the filter cake was washed twice with 10mL of anhydrous ethanol, and the precipitate was dried to obtain a yellow solid with a yield of 96.55% and a purity of 98.25%.

1H NMRδ:11.82(s,1H,-NH),7.76(d,J＝7.7Hz,1H,Ph-H),7.50(d,J＝7.5Hz,1H,Ph-H),6.75-6.71(m,2H,Ph-H),6.26(d,J＝6.2Hz,1H,Ph-H),4.51(s,1H,-NH2),3.95(t,J＝4.0Hz,2H,-CH2),2.58-2.54(m,2H,-CH2),1.71-1.69(m,2H,-CH2),1.49-1.46(m,2H,-CH2)；13C NMRδ:162.9,161.3,141.3,140.7,130.2,119.0,114.1,111.4,99.4,68.0,41.2,29.1,26.5；MS(ESI):m/z(100％)233(M+H)。

The third step: synthesis of Compound 3

0.232 g (1mmol) of Compound 2 was charged in a reaction flask, and 0.266 g (1mmol) of BOC-dichloroethylenimine and 5mL of N, N-dimethylformamide were added, respectively, and 0.332 g (2mmol) of potassium iodide and 0.415 g (3mmol) of anhydrous potassium carbonate were added with stirring. The temperature is raised to 70 ℃ under the protection of nitrogen, the reaction is kept warm, and the progress of the reaction is tracked by TLC (developing solvent: ammonia/dichloromethane/methanol-1/6/18). After the reaction is finished, cooling to room temperature, pouring into 15mL of ice water while stirring, carrying out suction filtration, washing a filter cake with water, and drying to obtain a white-like solid with the yield of 80.9% and the purity of 97.89%.

1H NMRδ:12.51(s,1H,-NH),7.75(d,J＝7.8Hz,1H,Ph-H),7.45(d,J＝7.6Hz,1H,Ph-H),6.83-6.79(m,2H,Ph-H),6.56(d,J＝6.6Hz,1H,Ph-H),4.10(t,J＝4.1Hz,2H,-CH2),3.45-3.43(m,2H,-CH2),2.44-2.41(m,2H,-CH2),1.72-1.69(m,2H,-CH2),1.48(s,9H,3-CH3)；MS(ESI):m/z(100％)402(M+H)。

The fourth step: synthesis of Compound 4

Adding 0.402 g (1mmol) of compound 3 into a reaction bottle, adding 10mL of methanol saturated with hydrogen chloride, stirring at room temperature for 2 hours, placing in a refrigerator for freezing, performing suction filtration, washing a filter cake with methanol, and drying to obtain a white solid, wherein the yield is 73.1% and the purity is 98.52%.

1H NMRδ:11.59(s,1H,-NH),7.76(d,J＝7.8Hz,1H,Ph-H),7.49(d,J＝7.5Hz,1H,Ph-H),6.75-6.72(m,2H,Ph-H),6.26(d,J＝6.2Hz,1H,Ph-H),4.20(t,J＝4.2Hz,2H,-CH2),3.98(t,J＝4.0Hz,2H,-CH2),3.53(t,J＝3.5Hz,2H,-CH2),3.19(t,J＝3.2Hz,2H,-CH2),2.68(t,J＝2.7Hz,2H,-CH2),2.55(t,J＝2.6Hz,2H,-CH2),1.84(s,1H,-NH),1.72-1.69(m,2H,-CH2),1.56-1.51(m,2H,-CH2)；MS(ESI):m/z(100％)302(M+H)。

The fifth step: synthesis of brexpiprazole

Adding 0.0135mol (2.88 g) of 4-bromobenzothiophene into a 100mL reaction bottle, respectively adding 0.0135mol (4.07 g) of compound 4, 0.019mol (2.12 g) of potassium tert-butoxide, 0.13 g of 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine, 0.12 g of palladium catalyst and 50mL of tetrahydrofuran, stirring and heating to reflux under the protection of nitrogen, performing TLC tracking reaction (developing agent: dichloromethane/methanol ═ 20/1), cooling to room temperature after the reaction is finished, evaporating the solvent under reduced pressure, adding 30mL of water and 30mL of dichloromethane at room temperature, dropwise adding 2N hydrochloric acid under stirring to adjust the pH value to acidity, continuing stirring for 40 minutes, filtering, layering the filtrate, adding methanol into the organic phase, fully stirring, performing suction filtration, washing the filter cake with dichloromethane, performing vacuum drying to obtain a white-like solid, wherein the yield of the crude product can reach 92.56% and the purity of 92.78%, the yield of the refined target product is 68.49%, the purity is 99.3%, and the content of single impurities is less than 0.1%.

1H NMRδ:11.54(s,1H,-NH),7.60(d,J＝7.6Hz,1H,Ph-H),7.64(d,J＝7.6Hz,1H,Ph-H),7.55(d,J＝7.6Hz,1H,Ph-H),7.51(d,J＝7.5Hz,1H,Ph-H),7.35(d,J＝7.3Hz,1H,Ph-H),7.23(t,J＝7.2Hz,1H,Ph-H),6.82(d,J＝6.8Hz,1H,Ph-H),6.76-6.74(m,2H,Ph-H),6.26(d,J＝6.3Hz,1H,Ph-H),4.00(t,J＝4.2Hz,2H,-CH2),3.02-2.98(m,4H,-CH2),2.57-2.54(m,4H,-CH2),2.37(t,J＝2.6Hz,2H,-CH2),1.74-1.71(m,2H,-CH2),1.59-1.57(m,2H,-CH2)；MS(ESI):m/z(100％)434(M+H)。

Example 2

In the first step of synthesis of compound 1, 4-bromobutyronitrile was changed to 4-hydroxybutyronitrile, and the other reaction steps, starting materials and reaction amounts were the same as in example 1, with a crude product yield of 75.36% and a purity of 95.72%.

Example 3

In the first step of the synthesis of compound 1, anhydrous potassium carbonate was replaced by pyrrolidine, and the other reaction steps, starting materials and reaction amounts were the same as in example 1, so that the yield of the crude product was 63.25% and the purity was 97.62%.

Example 4

In the second step of the synthesis of compound 2, the metal hydride reduction method is replaced by a catalytic hydrogenation method, the catalyst is Raney nickel, the other reaction steps, raw materials and reaction amount are the same as those in example 1, the yield of the crude product is 87.59%, and the purity is 96.91%.

Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to intimate that the scope of the disclosure, including the claims, is limited to these examples; within the spirit of the present disclosure, features from the above embodiments or from different embodiments may also be combined, steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments in this application as described above, which are not provided in detail for the sake of brevity.

It is intended that the one or more embodiments of the present application embrace all such alternatives, modifications and variations as fall within the broad scope of the appended claims. Therefore, any omissions, modifications, substitutions, improvements, and the like that may be made without departing from the spirit and principles of one or more embodiments of the present disclosure are intended to be included within the scope of the present disclosure.

Claims

1. The preparation method of brexpiprazole is characterized by comprising the following steps:

the first step is as follows: reacting 4-substituted butyronitrile with 7-hydroxy 2- (1H) -quinolinone to obtain a compound 1, wherein a substituent in the 4-substituted butyronitrile is selected from one of chlorine, bromine, iodine and hydroxy;

the fifth step: adding a catalyst and a ligand, and reacting the compound 4 with 4-bromobenzothiophene to obtain ipiprazole;

the specific synthetic route is as follows:

2. the process for preparing ipiprazole of claim 1, wherein the 4-substituted butyronitrile is 4-chlorobutyronitrile or 4-bromobutyronitrile.

3. The process for preparing ipiprazole of claim 1, wherein one of an alkali metal carbonate, pyridine, piperidine, tetrahydropyrrole and morpholine is added in the first step.

4. The process for preparing ipiprazole of claim 1, wherein the reducing agent of the second step is sodium borohydride or sodium cyanoborohydride; or the catalyst is Raney nickel or palladium carbon.

5. The process for preparing ipiprazole of claim 1 or 4, wherein the reaction solvent of the second step is an iodine-containing alcohol, ether, tetrahydrofuran or toluene.

6. The process for preparing ipiprazole of claim 1, wherein the reaction solvent in the third step is dimethyl sulfoxide, acetonitrile, N-dimethylformamide, N-methylpyrrolidone, ethylene glycol monomethyl ether or N-butanol.

7. The process for preparing ipiprazole of claim 1 or 6, wherein the base added in the third step is carbonate, triethylamine, N-diisopropylethylamine, morpholine, piperidine or tetrahydropyrrole.

8. The process for producing ipiprazole according to claim 1, wherein the acidic solution in the fourth step is concentrated hydrochloric acid, a concentrated hydrochloric acid acetone solution, or an alcohol solution of hydrogen chloride.

9. The process for preparing ipiprazole of claim 8, wherein the alcoholic hydrogen chloride solution is a methanolic hydrogen chloride solution or an ethanolic hydrogen chloride solution.

10. The process for preparing ipiprazole of claim 1, wherein the solvent of the fifth step is toluene, xylene, tetrahydrofuran or 1, 4-dioxahexaalkane; or the catalyst is palladium acetate or palladium dibenzylidene acetone; alternatively, the ligand is triphenylphosphine or 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine.