Preparation method of brexpiprazole

Abstract

The invention relates to a brexpiprazole preparation method, and belongs to the technical field of chemical medicine preparation. Comprising the following steps: taking 7-hydroxy-1H-quinolin-2 ketone (formula I) as a raw material, and reacting the 7-hydroxy-1H-quinolin-2 ketone with 4-halogenated butyraldehyde to obtain 7-(1-aldehyde) butoxy-1H-quinolin-2 ketone (formula II); carrying out reductive amination reaction on the 7-(1-dichloro ethyl amino) butoxy-1H-quinolin-2 ketone (shown in the formula II) and dichloro ethyl imine to obtain 7-(1-dichloro ethyl amino) butoxy-1H-quinolin-2 ketone (shown in the formula III); and carrying out substitution reaction on the compound shown in the formula III and 4-amino-benzo [b] thiophene to obtain brexpiprazole (formula IV). The brexpiprazole preparation method has the beneficial effects that the brexpiprazole preparation method is simple in process and mild in condition, use of a double-reaction-site reagent is avoided, use of a coupling reagent is avoided, side reactions are greatly reduced, impurities are reduced, post-treatment is simple, and the purity is higher.

Description

Technical Field

[0001] This invention relates to a method for preparing epipiperidazole, 7-[4-(4-(benzo[b]thiophen-4-yl)-piperazin-1-yl)butoxy]-1Hquinoline-2-one, belonging to the technical field of chemical drug preparation. Background Technology

[0002]

[0003] Epilippazole, jointly developed by Japan's Daiichi Pharmaceutical and Denmark's Lundbeck, was approved for marketing by the US FDA on July 10, 2015. Its scientific name is 7-[4-(4-(benzo[b]thiophene-4-yl)-piperazin-1-yl)butoxy]-1Hquinolin-2-one, belonging to the 5-HT / DA receptor modulator class. It is used to treat schizophrenia in adults and can also be used in combination with antidepressants to treat major depressive disorder in adults. Epilippazole is the first compound to be classified as a dopamine, partial 5-HT1A receptor agonist, and 5-HT2A receptor antagonist, exhibiting good efficacy and tolerability, and reducing the incidence of adverse reactions such as akathisia, restlessness, and insomnia.

[0004] The previously reported synthetic routes for epipiperazole have two significant drawbacks. First, the synthetic routes are lengthy, with most using two reagents, 1-bromo-4-chlorobutane and piperazine. This results in poor reaction selectivity, two reaction sites, and a tendency to generate impurities that are difficult to remove in post-processing, leading to low product purity (e.g., WO2006112464A1, CN101155804A, and CN106496206A). Even using BOC-piperazine increases the need for deprotection reactions, making the process cumbersome and costly (e.g., CN103717587, CN 106496206A). Secondly, most patented routes employ coupling to form CN bonds. For example, the Buchwald reaction involves the use of precious metals such as palladium. Because palladium-catalyzed reactions require harsh reaction conditions (oxygen-free reaction), there are many side reactions, mainly cross-coupled products. In addition, there are some impurities generated by the ligands of the phosphine reagents used, resulting in low yields and complicated post-processing. The palladium-catalyzed method is also more expensive, as seen in CN105440026A, WO2013015456, and WO2006 / 112464A1. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for preparing epipiperidazole.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A method for preparing epipiperidazole includes the following steps:

[0008] S1. Using 7-hydroxy-1H-quinoline-2 one (Formula I) as a raw material, 4-halobutyraldehyde is reacted with 4-halobutyraldehyde under the action of alkali and solvent to undergo a Williamson ether synthesis reaction to obtain 7-(1-aldehyde)butoxy-1H-quinoline-2 one (Formula II).

[0009] S2, 7-(1-aldehyde)butoxy-1H-quinoline-2 one (Formula II) undergoes a reductive amination reaction with dichloroethylimine in the presence of a catalyst and a reducing agent to give 7-(1-dichloroethylamino)butoxy-1H-quinoline-2 one (Formula III);

[0010] S3, 7-(1-dichloroethylamino)butoxy-1H-quinoline-2 one (Formula III) undergoes a substitution reaction with 4-amino-benzo[b]thiophene in the presence of a base and an iodine salt to give epipiperazole (Formula IV).

[0011] The reaction route is shown below:

[0012]

[0013] In a preferred embodiment, in S1, X is one of chlorine, bromine, and iodine, preferably bromine; the base is an alkali metal carbonate, an alkali metal hydroxide, pyridine, piperidine, triethylamine, or N,N-diisopropylethylamine, preferably potassium carbonate; the solvent is dimethyl sulfoxide, acetone, acetonitrile, or N,N-dimethylformamide, preferably dimethyl sulfoxide.

[0014] Further, in S1, the molar ratio of compound I to 4-halobutyraldehyde is 1:1.5 to 2.5; the molar ratio of compound I to the base is 1:1 to 1.3, preferably 1:1.15.

[0015] This invention uses 4-halobutyraldehyde as a raw material instead of 1-bromo-4-chlorobutane. This is because 1-bromo-4-chlorobutane has poor reaction selectivity, has two reaction sites, is prone to generating impurities, and is difficult to remove in post-processing, resulting in low product purity.

[0016] In this invention, S1 uses an aldehyde group. The aldehyde group does not react with the hydroxyl group of compound I, resulting in good reaction selectivity. Furthermore, the aldehyde group in compound II reacts with the halogenated imine in step S2, and is unaffected by the imine's own reaction under acidic conditions. Therefore, steps S1 and S2 have virtually no side reactions. If the aldehyde group in this invention is replaced with other groups, such as a carboxyl group, the hydroxyl group of compound I undergoes an acylation reaction with the carboxyl group, generating an amide via S2. Further reduction is required to obtain compound III, making the technical route more cumbersome. If the aldehyde group in this invention is replaced with a halogen, the side reactions in steps S1 and S2 increase significantly. For example, in step S1, both sites will react with the hydroxyl group, and step S2 requires changing the reaction conditions to allow the halogen (e.g., chlorine) to react with the amine group. In this case, the imine itself will also react.

[0017] Preferably, in S1, the reaction temperature is 50-100℃, more preferably 60-70℃.

[0018] In the preferred embodiment, in S2, the reaction temperature is room temperature (20-25°C). The formation of the Schiff base in the reductive amination reaction is crucial. Some poorly reactive substrates require increased temperature to complete the reaction. Aldehydes, on the other hand, are highly reactive and can react at room temperature. If the temperature is increased, side reactions or degradation reactions may occur, making purification difficult and affecting purity.

[0019] In S2, the catalyst is HCl, TiCl4, HOAc, TEA, DIPEA, Ti(OiPr)4, InCl3, B(OiPr)3, preferably Ti(OiPr)4; the reducing agent is selected from NaCNBH3, NaBH(OAc)3, NaBH4, preferably NaCNBH3; the solvent is selected from one or more of isopropyl acetate, dioxane, THF, DCM, methanol, ethanol, and acetonitrile, preferably methanol.

[0020] In S2, the molar ratio of compound II to dichloroethylimine is 1:1.0 to 1.3, preferably 1:1.1; the molar ratio of compound II to catalyst is 1:1.4 to 1.8; and the molar ratio of compound II to reducing agent is 1:1.0 to 3.0, preferably 1:2.0.

[0021] In S3, an alkali and an iodine salt are added to the reaction. The alkali is an alkali metal carbonate, an alkali metal acid carbonate, triethylamine, or N,N-diisopropylethylamine, preferably potassium carbonate. The iodine salt is KI or NaI, preferably KI. The solvent is dimethyl sulfoxide, acetonitrile, DMF, N-methylpyrrolidone, ethylene glycol monomethyl ether, or n-butanol, preferably DMF.

[0022] In S3, the molar ratio of compound III to 4-amino-benzo[b]thiophene is 1:0.9 to 1.3, preferably 1:1.05. Too much 4-amino-benzo[b]thiophene should not be added, otherwise one molecule of compound III will be attached to two 4-amino-benzo[b]thiophene impurities, making post-processing difficult and resulting in low purity.

[0023] The molar ratio of compound III to KI is 1:1.5 to 2.5, preferably 1:2; the molar ratio of compound III to potassium carbonate is 1:1 to 4, preferably 1:3; the reaction temperature is 65-70℃.

[0024] The advantages of this invention are: the preparation method of epipiperazole of this invention is simple, the conditions are mild, the use of dual-reaction site reagents and coupling reagents is avoided, the occurrence of side reactions is greatly reduced, the generation of impurities is reduced, the post-processing is simple, and the purity is higher. Detailed Implementation

[0025] The following specific embodiments are provided to further illustrate the present invention and should not be construed as limiting the present invention.

[0026] The yields (referring to the actual yields of the target substances) in the following examples and comparative examples are all calculated based on the number of moles of substrate added in each specific step.

[0027]

[0028] Example 1: Preparation of 7-(1-aldehyde)butoxy-1H-quinoline-2 one (Formula II)

[0029] 4-Bromobutyraldehyde (9.06 g, 60 mmol) was added to a 100 mL reaction flask, followed by compound I (4.83 g, 30 mmol), anhydrous potassium carbonate (4.77 g, 34.5 mmol), and 40 mL of dimethyl sulfoxide. The mixture was stirred and heated to 65 °C and maintained at this temperature for 5 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed twice with 20 mL of dimethyl sulfoxide each time. After drying, 6.20 g of a white solid with a purity of 98.51% and a yield of 88.0% was obtained.

[0030] Example 2: Preparation of 7-(1-aldehyde)butoxy-1H-quinoline-2 one (Formula II)

[0031] 4-Bromobutyraldehyde (9.06 g, 60 mmol) was added to a 100 mL reaction flask, followed by compound I (4.83 g, 30 mmol), anhydrous potassium carbonate (4.77 g, 34.5 mmol), and 40 mL of dimethyl sulfoxide. The mixture was stirred and heated to 70 °C and maintained at this temperature for 5 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed twice with 20 mL of dimethyl sulfoxide each time. After drying, 6.30 g of a white solid with a purity of 98.76% and a yield of 89.7% was obtained.

[0032] Example 3: Preparation of 7-(1-dichloroethylamino)butoxy-1H-quinoline-2 one (Formula III)

[0033] Compound II (4.63 g, 20 mmol) was added to a 100 mL reaction flask, followed by dichloroethylimine (3.12 g, 22 mmol) and 50 mL of methanol. The mixture was stirred thoroughly at room temperature, and Ti(OiPr)4 (10.2 g, 36 mmol) was slowly added. The mixture was stirred for 30 min, and then NaCNBH3 (2.51 g, 40 mmol) was added. The reaction was carried out at room temperature for 5 h, cooled in an ice bath, and neutralized to approximately pH 7 with saturated NaHCO3 solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a brown oily substance. The oil was purified with methanol to obtain 6.75 g of a white solid with a purity of 99.3% and a yield of 93.8%.

[0034] Example 4: Preparation of 7-(1-dichloroethylamino)butoxy-1H-quinoline-2 one (Formula III)

[0035] Compound II (4.63 g, 20 mmol) was added to a 100 mL reaction flask, followed by dichloroethylimine (3.12 g, 22 mmol) and 50 mL of methanol. The mixture was stirred thoroughly at room temperature, and Ti(OiPr)4 (9.10 g, 32 mmol) was slowly added. The mixture was stirred for 30 min, and then NaCNBH3 (2.51 g, 40 mmol) was added. The reaction was carried out at room temperature for 6 h, cooled in an ice bath, and neutralized to approximately pH 7 with saturated NaHCO3 solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a brown oily substance. The oil was purified with methanol to obtain 6.73 g of a white solid with a purity of 99.2% and a yield of 93.4%.

[0036] Example 5: Preparation of epipiperidazole (Formula IV)

[0037] 4-Amino-benzo[b]thiophene (2.35 g, 15.75 mmol) was added to a 50 mL reaction flask, followed by 20 mL of DMF, KI (4.98 g, 30 mmol), and potassium carbonate (6.22 g, 45 mmol), and then compound III (4.63 g, 15 mmol). The mixture was stirred and heated to 70 °C under nitrogen protection for 4 h. After cooling to room temperature, the mixture was poured into 60 mL of ice water with stirring. The mixture was filtered, the filter cake was washed with water, and dried to obtain 6.18 g of a white solid, ipiperazole, with a purity of 99.6% and a yield of 94.6%.

[0038] Example 6: Preparation of epipiperidazole (Formula IV)

[0039] 4-Amino-benzo[b]thiophene (2.35 g, 15.75 mmol) was added to a 50 mL reaction flask, followed by 20 mL of DMF, KI (4.98 g, 30 mmol), and potassium carbonate (6.22 g, 45 mmol), and then compound III (4.63 g, 15 mmol). The mixture was stirred, heated to 65 °C under nitrogen protection, and reacted for 4 h. After cooling to room temperature, the mixture was poured into 60 mL of ice water with stirring. The mixture was filtered, the filter cake was washed with water, and dried to obtain 6.25 g of a white solid, ipilipazole, with a purity of 99.5% and a yield of 95.6%.

[0040] Comparative Example 1: Preparation of 7-(4-chlorobutoxy)-1H-quinoline-2-one

[0041] 1-Chloro-4-bromobutane (10.29 g, 60 mmol) was added to a 100 mL reaction flask, followed by compound I (4.83 g, 30 mmol), anhydrous potassium carbonate (4.77 g, 34.5 mmol), and 40 mL of dimethyl sulfoxide. The mixture was stirred and heated to 65 °C and maintained at this temperature for 5 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed twice with 20 mL of dimethyl sulfoxide each time. After drying, 6.48 g of a white solid with a purity of 87.4% and a yield of 75% was obtained.

[0042] Comparative Example 2: Preparation of 7-(1-dichloroethylamino)butoxy-1H-quinoline-2 one (Formula III)

[0043] Compound II (4.63 g, 20 mmol) was added to a 100 mL reaction flask, followed by dichloroethylimine (3.12 g, 22 mmol) and 50 mL of methanol. The mixture was thoroughly mixed, heated to 50 °C, and Ti(OiPr)₄ (9.10 g, 32 mmol) was slowly added. The mixture was stirred for 30 min, followed by the addition of NaCNBH₃ (2.51 g, 40 mmol). The reaction was carried out at room temperature for 6 h, cooled in an ice bath, and neutralized to approximately pH 7 with saturated NaHCO₃ solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a brown oily substance. The oil was purified with methanol to obtain 6.29 g of a white solid with a purity of 95.9% and a yield of 84.4%.

[0044] Comparative Example 3: Preparation of Epilapiazole (Formula IV)

[0045] 4-Amino-benzo[b]thiophene (3.36 g, 22.5 mmol) was added to a 50 mL reaction flask, followed by 20 mL of DMF, KI (4.98 g, 30 mmol), and potassium carbonate (6.22 g, 45 mmol), and then compound III (4.63 g, 15 mmol). The mixture was stirred and heated to 70 °C under nitrogen protection for 4 h. After cooling to room temperature, the mixture was poured into 60 mL of ice water with stirring. The mixture was filtered, the filter cake was washed with water, and dried to obtain 5.69 g of white solid epipiperazole with a purity of 87.7% and a yield of 76.7%.

[0046] The above embodiments are only used to illustrate the technical solutions of the present invention. Those skilled in the art should understand that the above embodiments do not limit the present invention in any way. All technical solutions obtained by equivalent substitution or equivalent transformation fall within the protection scope of the present invention.

Claims

1. A method for preparing epipiperazole, characterized in that, Includes the following steps: S1. Using 7-hydroxy-1H-quinoline-2 one (Formula I) as a raw material, 4-halobutyraldehyde is reacted with 4-halobutyraldehyde under the action of alkali and solvent to undergo a Williamson ether synthesis reaction to obtain 7-(1-aldehyde)butoxy-1H-quinoline-2 one (Formula II). S2, 7-(1-aldehyde)butoxy-1H-quinoline-2 one (Formula II) undergoes a reductive amination reaction with dichloroethylimine in the presence of a catalyst and a reducing agent to give 7-(1-dichloroethylamino)butoxy-1H-quinoline-2 one (Formula III); S3, 7-(1-dichloroethylamino)butoxy-1H-quinoline-2 one (Formula III) undergoes a substitution reaction with 4-amino-benzo[b]thiophene in the presence of a base and an iodine salt to give epipiperazole (Formula IV).

2. The method for preparing epipiperidazole according to claim 1, characterized in that, The reaction route is shown below:

3. The method for preparing epipiperidazole according to claim 2, characterized in that, In S1, X is one of chlorine, bromine, and iodine, preferably bromine; the base is an alkali metal carbonate, alkali metal hydroxide, pyridine, piperidine, triethylamine, or N,N-diisopropylethylamine, preferably potassium carbonate; the solvent is dimethyl sulfoxide, acetone, acetonitrile, or N,N-dimethylformamide, preferably dimethyl sulfoxide.

4. The method for preparing epipiperidazole according to claim 2, characterized in that, In S1, the molar ratio of compound I to 4-halobutyraldehyde is 1:1.5 to 2.5; the molar ratio of compound I to the base is 1:1 to 1.3, preferably 1:1.

15.

5. The method for preparing epipiperidazole according to claim 2, characterized in that, In S1, the reaction temperature is 50-100℃, preferably 60-70℃.

6. The method for preparing epipiperidazole according to claim 1, characterized in that, In S2, the reaction temperature is room temperature, 20-25℃.

7. The method for preparing epipiperidazole according to claim 1, characterized in that, In S2, the catalyst is HCl, TiCl4, HOAc, TEA, DIPEA, Ti(OiPr)4, InCl3, B(OiPr)3, preferably Ti(OiPr)4; the reducing agent is selected from NaCNBH3, NaBH(OAc)3, NaBH4, preferably NaCNBH3; the solvent is selected from one or more of isopropyl acetate, dioxane, THF, DCM, methanol, ethanol, and acetonitrile, preferably methanol.

8. The method for preparing epipiperidazole according to claim 1, characterized in that, In S2, the molar ratio of compound II to dichloroethylimine is 1:1.0 to 1.3, preferably 1:1.1; the molar ratio of compound II to catalyst is 1:1.4 to 1.8; and the molar ratio of compound II to reducing agent is 1:1.0 to 3.0, preferably 1:2.

0.

9. The method for preparing epipiperidazole according to claim 1, characterized in that, In S3, an alkali and an iodine salt are added to the reaction. The alkali is an alkali metal carbonate, an alkali metal acid carbonate, triethylamine, or N,N-diisopropylethylamine, preferably potassium carbonate. The iodine salt is KI or NaI, preferably KI. The solvent is dimethyl sulfoxide, acetonitrile, DMF, N-methylpyrrolidone, ethylene glycol monomethyl ether, or n-butanol, preferably DMF.

10. The method for preparing epipiperidazole according to claim 1, characterized in that, In S3, the molar ratio of compound III to 4-amino-benzo[b]thiophene is 1:0.9 to 1.3, preferably 1:1.05; the molar ratio of compound III to KI is 1:1.5 to 2.5, preferably 1:2; the molar ratio of compound III to potassium carbonate is 1:1 to 4, preferably 1:3; and the reaction temperature is 65-70℃.

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