Synthesis method of brexpiprazole

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of brexpiprazole. The preparation method comprises the following steps: taking a compound 7-hydroxyquinoline-2 (1H)-ketone as a starting material, carrying out Mitsunobu reaction on the starting material and a compound 4-bromobutane-1-alcohol to prepare an intermediate 7-(4-bromobutoxy) quinoline-2 (1H)-ketone, and then carrying out substitution reaction on the intermediate 7-(4-bromobutoxy) quinoline-2 (1H)-ketone and 1-(benzo [b] thiophene-4-yl) piperazine hydrochloride to prepare the target product burepidazole. According to the process, the use of a noble metal catalyst and the generation of related dimer and ectopic substitution impurities can be effectively avoided, and the product obtained by the process has higher yield and 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 synthetic 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 on 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 agonist effect and 5-HT 2A partial receptor antagonism, which is a new drug developed 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, which has better efficacy and tolerability, and 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 in the following formula:

[0007]

[0008] Chinese patent application CN105461704A uses 2-chloro-6-fluorobenzaldehyde as the starting material, which reacts with N-Boc-piperazine and then with mercaptoacetic acid to construct a benzo[b]thiophene ring, and finally high-temperature deprotection and decarboxylation to obtain the key intermediate 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride. 7-Hydroxy-1H-quinolin-2-one is used as another starting material, which undergoes substitution reaction with 1-bromo-4-chlorobutane to obtain another key intermediate 7-(4-chlorobutoxy)-1H-quinolin-2-one, and finally the two intermediates undergo substitution reaction to obtain the target product. This 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 in the following formula:

[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 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 to obtain the target product. The synthetic route is shown in the following formula:

[0011]

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

[0013] WO2017078621A1 (family US20170145001A1, TW201718562A) also uses 7-hydroxyquinolin-(1H)-2-one as the starting material, first substituted 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, and then remove the acetal protecting group under acidic conditions to obtain 4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butanal. Finally, 1-(benzo[b]thiophen-4-yl)piperazine is reduced and aminated to obtain the target product. However, this process also has the possibility of producing double substitution and hetero-substitution impurities. The synthesis route and related impurity structures are shown in the following formula:

[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 in a toluene system to obtain 4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butanal; then, 1-(benzo[b]thiophen-4-yl)piperazine is reduced and aminated to obtain 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 starting material 7-(4-hydroxybutoxy)-3,4-dihydro-1H-quinolin-2-one can also be acylated and activated with methanesulfonyl chloride to obtain 4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butyl methanesulfonate; then, after reamination with 1-(benzo[b]thiophen-4-yl)piperazine, the above strategy is used for oxidative dehydrogenation to obtain brexpiprazole. The above two routes are too expensive in raw materials and have high production costs, so they are not suitable for industrial production. The synthesis route is shown in the following formula:

[0018]

[0019] Similarly, Chinese patent application CN104447723A is to take 7-hydroxy-3,4-dihydro-2(1H)-quinolinone as 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 synthetic route is shown in the following formula:

[0020]

[0021] Similarly, Chinese patent application CN104829602A is to take 7-(4-chlorobutoxy)-3,4-dihydro-1H-quinolin-2-one as 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 synthetic route is shown in the following formula:

[0022]

[0023] Although taking 7-hydroxy-3,4-dihydro-2(1H)-quinolinone as starting material can effectively avoid the generation of "double substitution" and "hetero-substitution" impurities, and using alkyl halide to react with 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 not friendly to the environment, the 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 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 synthetic route and related impurity structures are shown in the following formula:

[0025]

[0026] In view of the many technical problems existing in the above processes in the preparation of brexpiprazole, therefore, it is still one of the problems to be solved at present to research and 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 problems in the prior art in the preparation of brexpiprazole, the present application provides a new method for preparing brexpiprazole. The method has mild reaction conditions, safe and simple operation process, and the prepared target product 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 the conditions of room temperature and light shielding, an oxidizing azo reagent is added into anhydrous solvent of compound SM-1, compound SM-2 and a reducing phosphine reagent, and after the dropwise addition is completed, the temperature T1 is controlled until the reaction is completed, and then the intermediate compound I-1 is prepared by post-treatment.

[0033] The synthetic route is as follows:

[0034]

[0035] Preferably, the oxidizing azo reagent in step 1 is selected from one or a combination of diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DBAD), di-p-chlorobenzyl azodicarboxylate (DCAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP), N,N,N',N'-tetraisopropylazodicarboxamide (TIPA), N,N,N',N'-tetramethylazodicarboxamide (TMAD), 4,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,4,7-tetraazocine-3,8-dione (DHTD), and particularly preferably diisopropyl azodicarboxylate (DIAD).

[0036] Preferably, the reducing phosphine reagent in step 1 is selected from one or a combination of trimethyl phosphine (TMP), tri-n-butyl phosphine (TBP), triphenyl phosphine (TPP), 1,2-bis(diphenylphosphino)ethane (DPPE), diphenyl-(2-pyridyl)phosphine, 4-(dimethylamino)triphenylphosphine, and tris[4-(dimethylamino)phenyl]phosphine, and particularly preferably triphenyl phosphine.

[0037] Preferably, the anhydrous solvent in step 1 is selected from one or a combination of dichloromethane, chloroform, toluene, tetrahydrofuran, methyl tert-butyl ether, N,N-dimethylformamide, and acetonitrile, and particularly preferably tetrahydrofuran.

[0038] Preferably, the molar ratio of the compound SM-1 to the compound SM-2, the reducing phosphine reagent, and the oxidizing azo reagent in step 1 is 1:1.05-1.8:1.8-2.5:1.8-2.5, and particularly preferably 1:1.2:2.1:2.1.

[0039] Preferably, the temperature for dropping the oxidizing azo reagent in step 1 is -10-10°C, and particularly preferably 0-5°C; and the reaction temperature is 10-40°C, and particularly preferably 25-30°C.

[0040] Preferably, the post-treatment step in step 1 is as follows: the reaction solution is added to purified water, extracted with dichloromethane, the organic phases are combined, washed with saturated brine, and then concentrated to dryness under reduced pressure, and then recrystallized from an N,N-dimethylformamide-water system to obtain the intermediate compound I-1.

[0041] Step 2: Preparation of the compound I

[0042] Under inert gas protection, the compound I-1, the compound SM-3, and a base are added to a reaction solvent, and reacted at a temperature T2, and then the reaction solution is cooled to room temperature and stirred to precipitate crystals, filtered, and then the obtained solid is dried under reduced pressure to obtain the target product brexpiprazole I.

[0043]

[0044] Preferably, the base in step 2 is selected from one or a combination of sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, and N,N-diisopropylethylamine, and particularly preferably potassium carbonate.

[0045] Preferably, the reaction solvent in step 2 is selected from one or a combination of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, and isopropanol, and particularly preferably ethanol.

[0046] Preferably, the molar ratio of the compound I-1 to the compound SM-3 and the base in step 2 is 1:1.05-1.5:1.3-2.5, and particularly preferably 1:1.1:2.1.

[0047] Preferably, the reaction temperature T2 in step 2 is 40-110°C, and particularly preferably 70-75°C.

[0048] Preferably, the inert gas in step 2 is one or a combination of nitrogen and argon, and particularly preferably nitrogen.

[0049] Advantages of the present application:

[0050] 1.The present application provides a new preparation method of brexpiprazole, which takes compound SM-1 as a starting material, and then, after Mitsunobu reaction with compound SM-2, an intermediate I-1 is prepared, and then, after substitution reaction with SM-3, the target product brexpiprazole I is prepared.

[0051] 2.The process can effectively avoid the use of noble metal catalysts and the generation of related "dimer" and "allochthonous substitution" impurities, and the product obtained by the process has high yield and purity, and is suitable for industrial production. DETAILED DESCRIPTION

[0052] The present application will be further described by the following examples, and it should be understood that: the examples of the present application are only used to illustrate the present application, and are not a limitation of the present application, so, simple improvements of the present application under the premise of the method of the present application all belong to the scope of protection of the present application.

[0053] The purity of brexpiprazole is determined by HPLC, and the chromatographic conditions are as follows:

[0054] Chromatographic column: YMC-Pack ODS-AQ-C (4.6mm×250mm, 5.0μm) or a chromatographic column with equivalent performance; 18

[0055] Mobile phase: mobile phase A: 0.02mol / L potassium dihydrogen phosphate solution (pH value is adjusted to 2.3 by phosphoric acid); mobile phase B: acetonitrile;

[0056] Column temperature: 40℃;

[0057] Detection wavelength: 215nm;

[0058] Flow rate: 1.5mL / min;

[0059] Injection volume: 10μL;

[0060] Among them, the retention time of brexpiprazole is about 30min or so.

[0061] Table 1 elution gradient table

[0062]

[0063] In the following examples, various processes and methods that are not described in detail are conventional methods known in the art.

[0064] Example 1

[0065] ​Intermediate 7-hydroxy-lH-quinolin-2-one (compound SM-1, 16.12 g, 0.10 mol), 4-bromo-l-butanol (compound SM-2, 18.36 g, 0.12 mol), triphenylphosphine (55.08 g, 0.21 mol) were added into tetrahydrofuran (200 mL) at room temperature under light protection. After the material was completely dissolved, diisopropyl azodicarboxylate (DIAD, 42.46 g, 0.21 mol) was added dropwise at 0-5 °C. After the dropwise addition was completed, the reaction was carried out at 25-30 °C. After the reaction was detected to be completed, the reaction liquid was added into purified water (2 L). The organic phase was extracted with dichloromethane (700 ml x 3), washed with saturated brine (600 ml x 2), and concentrated to dryness under reduced pressure. After recrystallization from N,N-dimethylformamide-water system, the intermediate compound I-1 was obtained in a yield of 98.6% and a purity of 99.92%.

[0066] Example 2

[0067] Intermediate 7-hydroxy-lH-quinolin-2-one (compound SM-1, 16.12 g, 0.10 mol), 4-bromo-l-butanol (compound SM-2, 16.07 g, 0.105 mol), trimethylphosphine (1 mol / L in THF, 210 mL, 0.21 mol) were added into tetrahydrofuran (200 mL) at room temperature under light protection. After the material was completely dissolved, diethyl azodicarboxylate (DEAD, 46.57 g, 0.21 mol) was added dropwise at 0-5 °C. After the dropwise addition was completed, the reaction was carried out at 25-30 °C. After the reaction was detected to be completed, the reaction liquid was added into purified water (2 L). The organic phase was extracted with dichloromethane (700 ml x 3), washed with saturated brine (600 ml x 2), and concentrated to dryness under reduced pressure. After recrystallization from N,N-dimethylformamide-water system, the intermediate compound I-1 was obtained in a yield of 94.1% and a purity of 99.71%.

[0068] Example 3

[0069] The intermediate 7-hydroxy-1H-quinolin-2-one (compound SM-1, 16.12 g, 0.10 mol), 4-bromo-1-butanol (compound SM-2, 27.54 g, 0.18 mol), tri-n-butyl phosphine (42.49 g, 0.21 mol) were added into toluene (250 mL) under room temperature and light shielding condition, after the material was completely dissolved, di-tert-butyl azodicarboxylate (DBAD, 48.35 g, 0.21 mol) was added dropwise at 0-5 ℃, after the dropwise addition was completed, the reaction was carried out at 25-30 ℃, after the reaction was completed by detection, the reaction liquid was added into purified water (2 L), the organic phase was separated, the aqueous phase was extracted with dichloromethane (700 ml x 2), the combined organic phase was washed with saturated brine (500 ml x 2), after the organic phase was concentrated to dryness under reduced pressure, the intermediate compound I-1 was obtained by recrystallization from N,N-dimethylformamide-water system, the yield was 95.2%, and the purity was 99.62%.

[0070] Example 4

[0071] The intermediate 7-hydroxy-1H-quinolin-2-one (compound SM-1, 16.12 g, 0.10 mol), 4-bromo-1-butanol (compound SM-2, 27.54 g, 0.18 mol), tri-n-butyl phosphine (42.49 g, 0.21 mol) were added into toluene (250 mL) under room temperature and light shielding condition, after the material was completely dissolved, di-tert-butyl azodicarboxylate (DBAD, 48.35 g, 0.21 mol) was added dropwise at 0-5 ℃, after the dropwise addition was completed, the reaction was carried out at 25-30 ℃, after the reaction was completed by detection, the reaction liquid was added into purified water (2 L), the organic phase was separated, the aqueous phase was extracted with dichloromethane (700 ml x 2), the combined organic phase was washed with saturated brine (500 ml x 2), after the organic phase was concentrated to dryness under reduced pressure, the intermediate compound I-1 was obtained by recrystallization from N,N-dimethylformamide-water system, the yield was 95.2%, and the purity was 99.62%.

[0072] Example 5

[0073] The intermediate 7-hydroxy-lH-quinolin-2-one (compound SM-1, 16.12 g, 0.10 mol), 4-bromo-l-butanol (compound SM-2, 18.36 g, 0.12 mol), and triphenylphosphine (65.57 g, 0.25 mol) were added to N,N-dimethylformamide (200 mL) under room temperature and light shielding condition. After the material was completely dissolved, 1,1'-(azodicarbonyl)dipiperidine (ADDP, 52.99 g, 0.21 mol) was added dropwise at 0-5 °C. After the dropwise addition was completed, the reaction was carried out at 25-30 °C. After the reaction was completed, the reaction liquid was added to purified water (2 L), extracted with dichloromethane (700 ml x 3), and the organic phases were combined and washed with saturated brine (600 ml x 2). After the organic phase was concentrated to dryness under reduced pressure, the intermediate compound I-1 was obtained by recrystallization from an N,N-dimethylformamide-water system, with a yield of 95.3% and a purity of 99.66%.

[0074] Example 6

[0075] The intermediate 7-hydroxy-lH-quinolin-2-one (compound SM-1, 16.12 g, 0.10 mol), 4-bromo-l-butanol (compound SM-2, 18.36 g, 0.12 mol), and 1,2-bisdiphenylphosphinoethane (83.67 g, 0.21 mol) were added to acetonitrile (200 mL) under room temperature and light shielding condition. After the material was completely dissolved, N,N,N',N'-tetraisopropylazodicarbonamide (TIPA, 51.19 g, 0.18 mol) was added dropwise at -10- -5 °C. After the dropwise addition was completed, the reaction was carried out at 10-15 °C. After the reaction was completed, the reaction liquid was added to purified water (2 L), extracted with dichloromethane (700 ml x 3), and the organic phases were combined and washed with saturated brine (600 ml x 2). After the organic phase was concentrated to dryness under reduced pressure, the intermediate compound I-1 was obtained by recrystallization from an N,N-dimethylformamide-water system, with a yield of 97.0% and a purity of 99.71%.

[0076] Example 7

[0077] The intermediate 7-hydroxy-1H-quinolin-2-one (compound SM-1, 16.12 g, 0.10 mol), 4-bromo-1-butanol (compound SM-2, 18.36 g, 0.12 mol), diphenyl-(2-pyridyl)phosphine (55.29 g, 0.21 mol) were added into acetonitrile (200 mL) at room temperature under light protection, after the material was completely dissolved, N,N,N',N'-tetramethylazodicarbonamide (TMAD, 43.05 g, 0.25 mol) was added dropwise at 5-10 °C, after the dropwise addition was completed, the reaction was carried out at 35-40 °C, after the reaction was detected to be completed, the reaction liquid was added into purified water (2 L), dichloromethane (700 ml x 3) was used for extraction, the combined organic phase was washed with saturated brine (600 ml x 2), the organic phase was concentrated to dryness under reduced pressure, and then recrystallized from an N,N-dimethylformamide-water system to obtain the intermediate compound I-1, with a yield of 96.1% and a purity of 99.64%.

[0078] Example 8

[0079] The intermediate 7-hydroxy-1H-quinolin-2-one (compound SM-1, 16.12 g, 0.10 mol), 4-bromo-1-butanol (compound SM-2, 18.36 g, 0.12 mol), diphenyl-(2-pyridyl)phosphine (55.29 g, 0.21 mol) were added into acetonitrile (200 mL) at room temperature under light protection, after the material was completely dissolved, N,N,N',N'-tetramethylazodicarbonamide (TMAD, 43.05 g, 0.25 mol) was added dropwise at 5-10 °C, after the dropwise addition was completed, the reaction was carried out at 35-40 °C, after the reaction was detected to be completed, the reaction liquid was added into purified water (2 L), dichloromethane (700 ml x 3) was used for extraction, the combined organic phase was washed with saturated brine (600 ml x 2), the organic phase was concentrated to dryness under reduced pressure, and then recrystallized from an N,N-dimethylformamide-water system to obtain the intermediate compound I-1, with a yield of 96.1% and a purity of 99.64%.

[0080] Example 9

[0081] Intermediate 7-hydroxy-1H-quinolin-2-one (compound SM-1, 16.12 g, 0.10 mol), 4-bromo-1-butanol (compound SM-2, 30.60 g, 0.2 mol), tris[4- (dimethylamino)phenyl]phosphine (109.62 g, 0.28 mol) were added into tetrahydrofuran (300 mL), after the material was completely dissolved, diisopropyl azodicarboxylate (DIAD, 56.59 g, 0.28 mol) was added dropwise at 10-15 °C, after the dropwise addition was completed, the reaction was carried out at 40-45 °C, after the reaction was completed by detection, the reaction liquid was added into purified water (2 L), dichloromethane (700 ml x 3) was used for extraction, the combined organic phase was washed with saturated brine (600 ml x 2), the organic phase was concentrated to dryness under reduced pressure, and then recrystallized from N,N-dimethylformamide-water system to obtain the intermediate compound I-1, the yield was 88.3%, and the purity was 97.85%.

[0082] Preparation of brexpiprazole

[0083] Example 10

[0084] Intermediate I-1 (SM-2, 14.81 g, 0.05 mol), compound 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride (SM-1, 14.01 g, 0.055 mol), potassium carbonate (14.51 g, 0.105 mol) were added into ethanol (200 mL), and the reaction was carried out at 70-75 °C, after the reaction was completed by detection, the reaction liquid was cooled to room temperature, and stirred for crystallization for 2 h, then filtered, the filter cake was washed with purified water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the target product brexpiprazole I, the yield was 98.6%, and the purity was 99.95%.

[0085] Example 11

[0086] Intermediate compound I-1 (14.81 g, 0.05 mol), compound 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride (SM-3, 13.50 g, 0.053 mol), sodium bicarbonate (8.82 g, 0.105 mol) were added into N-methylpyrrolidone (200 mL), and the reaction was carried out at 70-75 °C, after the reaction was completed by detection, the reaction liquid was cooled to room temperature, and stirred for crystallization for 2 h, then filtered, the filter cake was washed with purified water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the target product brexpiprazole I, the yield was 97.5%, and the purity was 99.92%.

[0087] Example 12

[0088] Under nitrogen protection, intermediate compound I-1 (14.81 g, 0.05 mol), compound 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride (SM-3, 19.11 g, 0.075 mol), cesium carbonate (34.21 g, 0.105 mol) were added into N,N-dimethylformamide (400 mL), and the reaction was carried out at 70-75°C. After the reaction was completed, the reaction solution was cooled to room temperature, stirred for 2 h, and then filtered. The filter cake was washed with water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the target product brexpiprazole I, with a yield of 96.5% and a purity of 99.65%.

[0089] Example 13

[0090] Under nitrogen protection, intermediate I-1 (14.81 g, 0.05 mol), compound 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride (SM-3, 14.01 g, 0.055 mol), potassium carbonate (8.98 g, 0.065 mol) were added into acetonitrile (200 mL), and the reaction was carried out at 40-45°C. After the reaction was completed, the reaction solution was cooled to room temperature, stirred for 2 h, and then filtered. The filter cake was washed with water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the target product brexpiprazole I, with a yield of 94.6% and a purity of 99.71%.

[0091] Example 14

[0092] Under nitrogen protection, intermediate I-1 (14.81 g, 0.05 mol), compound 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride (SM-3, 14.01 g, 0.055 mol), potassium carbonate (17.28 g, 0.125 mol) were added into dimethyl sulfoxide (300 mL), and the reaction was carried out at 105-110°C. After the reaction was completed, the reaction solution was cooled to room temperature, stirred for 2 h, and then filtered. The filter cake was washed with water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the target product brexpiprazole I, with a yield of 95.3% and a purity of 99.60%.

[0093] Example 15

[0094] Under nitrogen protection, intermediate I-1 (14.81 g, 0.05 mol), compound 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride (SM-3, 12.74 g, 0.05 mol), triethylamine (5.57 g, 0.055 mol) were added into isopropanol (200 mL), and the reaction was carried out at 35-40°C. After the reaction was completed, the reaction solution was cooled to room temperature, stirred for 2 h, and then filtered. The filter cake was washed with water (50 mL x 2), and the obtained solid was dried under reduced pressure to obtain the target product brexpiprazole I, with a yield of 84.3% and a purity of 98.89%.

[0095] Example 16

[0096] Under argon protection, intermediate I-1 (14.81 g, 0.05 mol), compound 1- (benzo [b] thiophen-4-yl) piperazine hydrochloride (SM-3, 22.93 g, 0.09 mol), N, N- diisopropyl ethyl amine (18.10 g, 0.14 mol) were added into N, N-dimethyl acetamide (400 mL) and reacted at 110-115 °C. After the reaction was completed, the reaction solution was cooled to room temperature and stirred for 2 h. 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 target product brexpiprazole I with a yield of 86.5% and a purity of 97.65%.

Claims

1. A method for synthesizing birepiperazole, characterized in that, The synthesis method includes the following steps: Step 1: Under room temperature and light-protected conditions, add the oxidizing azo reagent to the anhydrous solvent of compound SM-1, compound SM-2, and reducing phosphine reagent. After the addition is complete, control the temperature T1 until the reaction is finished. After post-treatment, obtain intermediate compound I-1. Step 2: Under inert gas protection, compound I-1, compound SM-3, and base are added to the reaction solvent and the reaction is carried out at temperature T2. After the reaction is detected to be complete, the reaction solution is cooled to room temperature and stirred to precipitate crystals. After filtration, the resulting solid is dried under reduced pressure to obtain the target product buripazil I. The reaction route is as follows:

2. The synthesis method according to claim 1, characterized in that, The oxidizing azo reagent mentioned in step 1 is selected from one of the following: diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, di-p-chlorobenzyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, N,N,N',N'-tetraisopropylazodicarboxamide, N,N,N',N'-tetramethylazodicarboxamide, and 4,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,4,7-tetraazaoctane-3,8-dione.

3. The synthesis method according to claim 1, characterized in that, The reducing phosphine reagent mentioned in step 1 is selected from one of trimethylphosphine, tri-n-butylphosphine, triphenylphosphine, 1,2-bis(diphenylphosphine ethane), diphenyl-(2-pyridyl)phosphine, 4-(dimethylamino)triphenylphosphine, and tris[4-(dimethylamino)phenyl]phosphine.

4. The synthesis method according to claim 1, characterized in that, The anhydrous solvent mentioned in step 1 is selected from one of dichloromethane, chloroform, toluene, tetrahydrofuran, methyl tert-butyl ether, N,N-dimethylformamide, and acetonitrile.

5. The synthesis method according to claim 1, characterized in that, The molar ratio of compound SM-1 to compound SM-2, reducing phosphine reagent, and oxidizing azo reagent in step 1 is 1:1.05-1.8:1.8-2.5:1.8-2.

5.

6. The synthesis method according to claim 1, characterized in that, The temperature at which the oxidizing azo reagent is added dropwise in step 1 is -10 to 10°C; the reaction temperature is 10 to 40°C.

7. The synthesis method according to claim 1, characterized in that, The alkali mentioned in step 2 is selected from sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, and N,N-diisopropylethylamine.

8. The synthesis method according to claim 1, characterized in that, The reaction solvent mentioned in step 2 is selected from one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, and isopropanol.

9. The synthesis method according to claim 1, characterized in that, The molar ratio of compound I-1 to compound SM-3 and alkali in step 2 is 1:1.05-1.5:1.3-2.

5.

10. The synthesis method according to claim 1, characterized in that, The reaction temperature T2 mentioned in step 2 is 40 to 110°C.

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