Efficient synthesis method of brexpiprazole

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to an efficient synthesis method of brexpiprazole. The invention provides a novel preparation method of bupreprazole, which comprises the following steps: by taking 1-(benzo [b] thiophene-4-yl)-4-(4-bromobutyl) piperazine as a starting material, carrying out substitution reaction on the 1-(benzo [b] thiophene-4-yl)-4-(4-bromobutyl) piperazine and 7-hydroxy-2H-benzopyran-2-ketone to prepare an intermediate 7-(4-(4-(benzo [b] thiophene-4-yl) piperazin-1-yl) butoxy)-2H-benzopyran-2-ketone; according to the present invention, with the process, the use of the noble metal catalyst and the generation of the related dimer and the heterotopic substitution impurity can be effectively avoided, and the product obtained through the process has characteristics of high yield and high purity, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a high-efficiency synthesis method of brexpiprazole. BACKGROUND

[0002] The incidence of adult schizophrenia and major depressive disorder (MDD) is increasing year by year worldwide. According to the statistics of the World Health Organization (WHO), about 1 million people die from this every year, and about 1% of people are affected to date. In recent years, psychopharmacology has gradually become one of the disciplines developing most rapidly in the field of clinical medicine, and a large number of new antipsychotic drugs with different structures have been put into the market.

[0003] On July 10, 2015, the U.S. Food and Drug Administration (FDA) approved brexpiprazole (also known as Brexpiprazole) developed by Lundbeck (license) and Otsuka Pharmaceutical Co., Ltd. (original research) for marketing. The drug is an oral tablet, and there are six specifications: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg, and the trade name is: Brexpiprazole is an experimental serotonin-dopamine activity modulator (SDAM), a new type of multi-target mechanism for the treatment of mental disorders. In addition to mainly having dopamine D2 receptor partial agonist effect, it also has D3 receptor partial agonist effect, 5-HT 1A partial receptor agonist effect and 5-HT 2A partial receptor antagonism. It is a new drug for monoamine neurotransmitter multi-targets with anti-schizophrenia and anti-depression effects. Brexpiprazole is considered to be another heavy product after the best-selling drug aripiprazole developed by the company, with better efficacy and tolerability, which can reduce adverse reactions such as akathisia, restlessness and / or insomnia in patients. It is mainly used for the adjuvant treatment of schizophrenia and major depressive disorder in clinical practice.

[0004] Brexpiprazole is chemically named 7-{4-[4-(benzo[b]thiophene)-4-yl-piperazin-1-yl]butoxy}-1H-quinolin-2-one, and the CAS number is 913611-97-9. Its chemical structural formula is as follows:

[0005]

[0006] Currently there are many methods for the synthesis of brexpiprazole, among which, in the original patent WO2006112464A1 (counterpart CN101155804A), 4-bromobenzo[b]thiophene is used as the starting material, which undergoes Buchwald-Hartwig coupling reaction with piperazine under the catalysis of palladium to obtain the key intermediate 1-(benzo[b]thiophen-4-yl)piperazine (I'). 7-Hydroxy-1H-quinolin-2-one reacts with 1-bromo-4-chlorobutane under the alkaline condition of potassium hydroxide to obtain another intermediate 7-(4-chlorobutoxy)-1H-quinolin-2-one. Finally, the two intermediates undergo substitution reaction to obtain the final product brexpiprazole. The route reported in the patent requires column chromatography separation for each step, which is high in cost and low in total yield of 36%. In the synthesis of 1-(benzo[b]thiophen-4-yl)piperazine, aryl halide is reacted with secondary amine, which is poor in activity and needs to use palladium catalysis reaction system, which is high in cost. Due to the high activity of palladium, double substitution of piperazine and thiophene coupling by-products are prone to occur, which causes low reaction yield and difficulty in post-treatment, and is not suitable for industrial production. The synthetic route and the structures of related impurities are shown below:

[0007]

[0008] Chinese patent application CN105461704A uses 2-chloro-6-fluorobenzaldehyde as the starting material, which is reacted with N-Boc-piperazine and then with mercaptoacetic acid to construct a benzo[b]thiophene ring. Finally, the key intermediate 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride is prepared by high-temperature deprotection and decarboxylation. 7-Hydroxy-1H-quinolin-2-one is used as another starting material, which is subjected to substitution reaction with 1-bromo-4-chlorobutane to obtain another key intermediate 7-(4-chlorobutoxy)-1H-quinolin-2-one. Finally, the two intermediates are subjected to substitution reaction to obtain the target product. The process can effectively avoid the use of noble metal catalysts due to the use of alkyl halide and secondary amine reaction. The synthetic route and the structures of related impurities are shown below:

[0009]

[0010] Chinese patent CN103717587A (B) (counterpart WO2013015456A1) and CN105175401A use 7-hydroxy-1H-quinolin-2-one as the starting material, which undergoes substitution reaction with 1-chloro-4-bromobutane to obtain 7-(4-chlorobutoxy)-1H-quinolin-2-one. Under the action of potassium carbonate, substitution reaction and deprotection with N-Boc-piperazine are carried out to obtain 7-(1-piperazine) butoxy-)-quinoline-(1H)-2-one dihydrochloride. Finally, under the action of isopropyl magnesium chloride, substitution reaction with 4-bromobenzo[b]thiophene is carried out to obtain the target product. The synthetic route is shown below:

[0011]

[0012] However, the above two processes are prone to produce double substitution and allochthonous substitution impurities when preparing 7-(4-chlorobutoxy)-1H-quinolin-2-one, which greatly affects the quality of intermediates and target products.

[0013] WO2017078621A1 (congener US20170145001A1, TW201718562A) also takes 7-hydroxyquinolin-(1H)-2-one as the starting material, first reacts with 1,1-dimethoxy-4-chlorobutane in a dimethyl sulfoxide, potassium carbonate / tetrabutylammonium bromide system to obtain 7-(4,4-dimethoxybutoxy)-1H-quinolin-2-one through substitution reaction, removes the acetal protecting group under acidic conditions to obtain 4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butanal, and finally reduces and aminates with 1-(benzo[b]thiophen-4-yl)piperazine to obtain the target product. However, this process also has the possibility of producing double substitution and allochthonous substitution impurities. The synthesis route and related impurity structures are shown below:

[0014]

[0015] In addition, the patent also discloses two other methods for preparing brexpiprazole:

[0016] Method one: 7-(4-hydroxybutoxy)-3,4-dihydro-1H-quinolin-2-one is used as the starting material, 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) is used as the oxidant to prepare 4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butanal in a toluene system; then, 1-(benzo[b]thiophen-4-yl)piperazine is used for reductive amination to prepare 7-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-3,4-dihydro-1H-quinolin-2-one; finally, 2,3-dichloro-5,6-dicyanoquinone (DDQ) is used for oxidative dehydrogenation to obtain brexpiprazole.

[0017] Method two: the hydroxyl group of the raw material 7-(4-hydroxybutoxy)-3,4-dihydro-1H-quinolin-2-one can also be acylated and activated by methanesulfonyl chloride to obtain 4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butyl methanesulfonate; then, after reductive amination with 1-(benzo[b]thiophen-4-yl)piperazine, brexpiprazole is obtained by oxidative dehydrogenation according to the above strategy. The above two routes are too expensive in raw materials and have high production cost, and therefore are not suitable for industrial production. The synthesis route is shown below:

[0018]

[0019] Similarly, Chinese patent application CN104447723A is to take 7-hydroxy-3,4-dihydro-2(1H)-quinolinone as a starting material, first react with 1,4-dibromobutane to obtain 7-(4-bromobutoxy)-3,4-dihydro-1H-quinolin-2-one, then react with 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride, and then dehydrogenate by DDQ to obtain the target product brexpiprazole. The synthesis route is shown below:

[0020]

[0021] Similarly, Chinese patent application CN104829602A is to take 7-(4-chlorobutoxy)-3,4-dihydro-1H-quinolin-2-one as a starting material, first react with 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride, and then dehydrogenate by DDQ to obtain the target product brexpiprazole. The synthesis route is shown below:

[0022]

[0023] Although taking 7-hydroxy-3,4-dihydro-2(1H)-quinolinone as a starting material can effectively avoid the generation of "double substitution" and "hetero-substitution" impurities, and the use of alkyl halide and secondary amine can effectively avoid the use of noble metal catalyst, but the above three processes also use DDQ dehydrogenation, on the one hand, due to its high toxicity, difficult post-treatment, and environmental unfriendliness, industrial application is limited; on the other hand, it will also seriously affect the product quality.

[0024] Chinese patent application CN106916148A is to take 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride as a starting material, first substituted by 1,4-dibromobutane, and then directly reacted with 7-hydroxy-1H-quinolin-2-one by "one-pot method" to obtain brexpiprazole crude product, but this process also cannot avoid the generation of double substitution impurities. The synthesis route and related impurity structures are shown below:

[0025]

[0026] In view of the many technical problems existing in the above processes in the preparation of brexpiprazole, it is still one of the problems to be solved to find a safe, simple, high-yield and high-purity process for producing brexpiprazole to ensure the production, market supply and quality of related products. SUMMARY

[0027] In view of the many problems existing in the preparation of brexpiprazole in the prior art, the present application provides a new method for preparing brexpiprazole. The method has mild reaction conditions, safe and simple operation process, and the target product prepared has high purity and yield.

[0028] The specific technical solutions of the present application are as follows:

[0029]

[0030] A preparation method of brexpiprazole as shown in formula I, comprising the following steps:

[0031] Step 1: preparation of intermediate compound I-1

[0032] Under inert gas protection, compound SM-1, compound SM-2, base are added into reaction solvent A, temperature T1 is controlled for reaction, after detection of reaction completion, the reaction solution is cooled to room temperature for stirring and crystallization, filtration, and the obtained solid is dried under reduced pressure to obtain intermediate compound I-1. The synthetic route is as shown below:

[0033]

[0034] In a preferred embodiment, the base in step 1 is selected from one or a combination of sodium bicarbonate, sodium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine, and particularly preferably sodium carbonate.

[0035] In a preferred embodiment, the reaction solvent A in step 1 is selected from one or a combination of N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 1,4-dioxane, methanol, ethanol, and isopropanol, and particularly preferably isopropanol.

[0036] In a preferred embodiment, the molar ratio of compound SM-1 to compound SM-2 and base in step 1 is 1:1.05-1.4:1.1-2.0, and particularly preferably 1:1.1:1.3.

[0037] In a preferred embodiment, the reaction temperature T1 in step 1 is 40-100°C, and particularly preferably 65-70°C.

[0038] Step 2: preparation of compound I

[0039] Under inert gas protection, compound I-1 and ammonium acetate are added into acetic acid, and reflux reaction is carried out at a controlled temperature, after detection of reaction completion, the pH is adjusted with sodium hydroxide solution, and the obtained solid is dried under reduced pressure after filtration to obtain brexpiprazole I. The synthetic route is as shown below:

[0040]

[0041] In a preferred embodiment, the molar ratio of compound I-1 to ammonium acetate in step 2 is 1:1.5-3.0, and particularly preferably 1:2.0.

[0042] Preferably, the mass-volume ratio of the compound I-1 to acetic acid in step 2 is 1:6-20, wherein 1:10.0 g / mL is particularly preferred.

[0043] Preferably, the pH adjusted in the crystallization in the post-treatment in step 2 is 8-10, wherein 9 is particularly preferred.

[0044] Preferably, the inert gas is one of nitrogen and argon, wherein nitrogen is particularly preferred.

[0045] Advantages of the present application:

[0046] 1. The present application provides a new preparation method of brexpiprazole, in which SM-1 is used as a starting material, an intermediate I-1 is prepared by substitution reaction of SM-1 with SM-2, and then brexpiprazole I is prepared by reaction of the intermediate I-1 with ammonium acetate.

[0047] 2. The process can effectively avoid the use of noble metal catalysts and the generation of related "dimer" and "hetero-substitution" impurities, and the product obtained by the process has high yield and purity, and is suitable for industrial production. DETAILED DESCRIPTION

[0048] The present application will be further described by examples, and it should be understood that the examples of the present application are only used to illustrate the present application, but not to limit the present application, so that simple improvements of the present application under the premise of the method of the present application are within the scope of the present application.

[0049] The purity of brexpiprazole is determined by HPLC, and the chromatographic conditions are as follows:

[0050] Chromatographic column: YMC-Pack ODS-AQ-C (4.6 mm x 250 mm, 5.0 μm) or a chromatographic column with equivalent performance; 18

[0051] Mobile phase: mobile phase A: 0.02 mol / L potassium dihydrogen phosphate solution (pH value is adjusted to 2.3 by phosphoric acid); mobile phase B: acetonitrile;

[0052] Column temperature: 40°C;

[0053] Detection wavelength: 215 nm;

[0054] Flow rate: 1.5 mL / min;

[0055] Injection volume: 10 μL;

[0056] The retention time of brexpiprazole is about 30 min.

[0057] Table 1 elution gradient table ​

[0058]

[0059] In the following examples, various processes and methods not specifically described are conventional methods well known in the art.

[0060] Example 1

[0061] Compound SM-1 (35.33 g, 0.10 mol), 7-hydroxyquinolin-1 (H)-2-one (SM-2, 17.84 g, 0.11 mol), sodium carbonate (13.78 g, 0.13 mol) were added into isopropanol (300 mL) under nitrogen protection, and the reaction was carried out at 65-70 °C. After the reaction was detected to be completed, the reaction liquid was cooled to room temperature, stirred for 2 h for crystallization, filtered, and the filter cake was washed with water (50 mL x 2). The obtained solid was dried under reduced pressure to obtain the intermediate compound I-1, with a yield of 98.3% and a purity of 99.95%.

[0062] Example 2

[0063] Compound SM-1 (35.33 g, 0.10 mol), 7-hydroxyquinolin-1 (H)-2-one (SM-2, 17.84 g, 0.11 mol), sodium carbonate (13.78 g, 0.13 mol) were added into isopropanol (300 mL) under nitrogen protection, and the reaction was carried out at 65-70 °C. After the reaction was detected to be completed, the reaction liquid was cooled to room temperature, stirred for 2 h for crystallization, filtered, and the filter cake was washed with water (50 mL x 2). The obtained solid was dried under reduced pressure to obtain the intermediate compound I-1, with a yield of 98.3% and a purity of 99.95%.

[0064] Example 3

[0065] Compound SM-1 (35.33 g, 0.10 mol), 7-hydroxyquinolin-1 (H)-2-one (SM-2, 17.84 g, 0.11 mol), sodium carbonate (13.78 g, 0.13 mol) were added into isopropanol (300 mL) under nitrogen protection, and the reaction was carried out at 65-70 °C. After the reaction was detected to be completed, the reaction liquid was cooled to room temperature, stirred for 2 h for crystallization, filtered, and the filter cake was washed with water (50 mL x 2). The obtained solid was dried under reduced pressure to obtain the intermediate compound I-1, with a yield of 98.3% and a purity of 99.95%.

[0066] Example 4

[0067] Under nitrogen protection, compound SM-1 (35.33 g, 0.10 mol), 7-hydroxyquinolin- (1H)-2-one (SM-2, 17.84 g, 0.11 mol), sodium carbonate (11.66 g, 0.11 mol) were added into acetonitrile (300 mL), and the reaction was carried out at 40-45 °C. After the reaction was completed, the reaction solution was cooled to room temperature, and stirred for 2.5 h for crystallization. After filtration, the filter cake was washed with water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the intermediate compound I-1, with a yield of 95.1% and a purity of 99.68%.

[0068] Example 5

[0069] Under nitrogen protection, compound SM-1 (35.33 g, 0.10 mol), 7-hydroxyquinolin- (1H)-2-one (SM-2, 17.84 g, 0.11 mol), sodium carbonate (11.66 g, 0.11 mol) were added into acetonitrile (300 mL), and the reaction was carried out at 40-45 °C. After the reaction was completed, the reaction solution was cooled to room temperature, and stirred for 2.5 h for crystallization. After filtration, the filter cake was washed with water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the intermediate compound I-1, with a yield of 95.1% and a purity of 99.68%.

[0070] Example 6

[0071] Under nitrogen protection, compound SM-1 (35.33 g, 0.10 mol), 7-hydroxyquinolin- (1H)-2-one (SM-2, 17.84 g, 0.11 mol), sodium carbonate (11.66 g, 0.11 mol) were added into acetonitrile (300 mL), and the reaction was carried out at 40-45 °C. After the reaction was completed, the reaction solution was cooled to room temperature, and stirred for 2.5 h for crystallization. After filtration, the filter cake was washed with water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the intermediate compound I-1, with a yield of 95.1% and a purity of 99.68%.

[0072] Example 7

[0073] Under nitrogen protection, compound SM-1 (35.33 g, 0.10 mol), 7-hydroxyquinolin- (1H)-2-one (SM-2, 17.84 g, 0.11 mol), sodium carbonate (11.66 g, 0.11 mol) were added into acetonitrile (300 mL), and the reaction was carried out at 40-45 °C. After the reaction was completed, the reaction solution was cooled to room temperature, and stirred for 2.5 h for crystallization. After filtration, the filter cake was washed with water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the intermediate compound I-1, with a yield of 95.1% and a purity of 99.68%.

[0074] Example 8

[0075] Compound I-1 (4.35 g, 0.01 mol), ammonium acetate (1.54 g, 0.02 mol) were added into acetic acid (45 mL) under nitrogen protection, and the reaction was controlled to reflux at a constant temperature. After the reaction was detected to be completed, 3 mol / L sodium hydroxide solution was used to adjust the pH to 9, and the product was obtained by stirring and crystallization, filtering, washing the filter cake with water (20 mL x 2), and drying the obtained solid under reduced pressure. The yield of the target product brexpiprazole I was 98.8%, and the purity was 99.98%.

[0076] Example 9

[0077] Compound I-1 (4.35 g, 0.01 mol), ammonium acetate (1.16 g, 0.015 mol) were added into acetic acid (25 mL) under nitrogen protection, and the reaction was controlled to reflux at a constant temperature. After the reaction was detected to be completed, 3 mol / L sodium hydroxide solution was used to adjust the pH to 8, and the product was obtained by stirring and crystallization, filtering, washing the filter cake with water (20 mL x 2), and drying the obtained solid under reduced pressure. The yield of the target product brexpiprazole I was 94.3%, and the purity was 99.68%.

[0078] Example 10

[0079] Compound I-1 (4.35 g, 0.01 mol), ammonium acetate (2.31 g, 0.03 mol) were added into acetic acid (50 mL) under nitrogen protection, and the reaction was controlled to reflux at a constant temperature. After the reaction was detected to be completed, 3 mol / L sodium hydroxide solution was used to adjust the pH to 10, and the product was obtained by stirring and crystallization, filtering, washing the filter cake with water (20 mL x 2), and drying the obtained solid under reduced pressure. The yield of the target product brexpiprazole I was 95.3%, and the purity was 99.57%.

[0080] Example 11

[0081] Compound I-1 (4.35 g, 0.01 mol), ammonium acetate (1.0 g, 0.013 mol) were added into acetic acid (18 mL) under nitrogen protection, and the reaction was controlled to reflux at a constant temperature. After the reaction was detected to be completed, 3 mol / L sodium hydroxide solution was used to adjust the pH to 8, and the product was obtained by stirring and crystallization, filtering, washing the filter cake with water (20 mL x 2), and drying the obtained solid under reduced pressure. The yield of the target product brexpiprazole I was 87.3%, and the purity was 98.95%.

[0082] Example 12

[0083] Compound I-1 (4.35 g, 0.01 mol), ammonium acetate (2.47 g, 0.032 mol) were added into acetic acid (90 mL) under nitrogen protection, and the reaction was controlled to reflux. After the reaction was detected to be completed, 3 mol / L sodium hydroxide solution was used to adjust the pH to 11. After stirring and crystallization, filtration was performed, the filter cake was washed with water (20 mL x 2), and the obtained solid was dried under reduced pressure to obtain the target product brexpiprazole I, with a yield of 89.1% and a purity of 97.23%.

Claims

1. A process for the efficient synthesis of brexpiprazole, characterized by, The synthetic method comprises the following steps: Step 1: under inert gas protection, compound SM-1, compound SM-2, base are added into reaction solvent A, temperature T1 is controlled for reaction, after detection of reaction completion, the reaction solution is cooled to room temperature for stirring and crystallization, filtration, and the obtained solid is dried under reduced pressure to obtain intermediate compound I-1; Step 2: under inert gas protection, compound I-1, ammonium acetate are added into acetic acid, temperature is controlled for reflux reaction, after detection of reaction completion, pH is adjusted with sodium hydroxide solution, stirring and crystallization are carried out, then filtration is carried out, and the obtained solid is dried under reduced pressure to obtain the target product brexpiprazole I; The reaction route is as follows:

2. The method of synthesis of claim 1, wherein, The base in step 1 is selected from one of sodium bicarbonate, sodium carbonate, cesium carbonate, triethylamine and N,N-diisopropylethylamine.

3. The method of synthesis of claim 1, wherein, The reaction solvent A in step 1 is selected from one or a combination of N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 1,4-dioxane, methanol, ethanol and isopropanol.

4. The method of synthesis of claim 1, wherein, The feeding molar ratio of compound SM-1 to compound SM-2 and base in step 1 is 1:1.05-1.4:1.1-2.

0.

5. The method of synthesis of claim 1, wherein, The reaction temperature T1 in step 1 is 40-100 DEG C.

6. The method of synthesis of claim 1, wherein, The feeding molar ratio of compound I-1 to ammonium acetate in step 2 is 1:1.5-3.

0.

7. The method of synthesis of claim 1, wherein, The feeding mass-volume ratio of compound I-1 to acetic acid in step 2 is 1:6-20.

8. The method of synthesis of claim 1, wherein, The adjusted pH for crystallization in the post-treatment in step 2 is 8-10.

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