Synthesis method of brexpiprazole
Through the synthesis route of nucleophilic substitution and condensation/decarboxylation under alkaline conditions, the use of genotoxic substances and transition metals in the prior art is solved, and the quality control and environmentally friendly epipipizole is achieved. Synthesis process simplifies operation and avoids heavy metal wastewater discharge.
Patent Information
- Application Number
- CN202310803753.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-07-03
- Publication Date
- 2025-01-03
AI Technical Summary
The last step in the existing epipiprazole synthesis process involves the use of genotoxic substances and transition metals, which are difficult to remove and affects product quality and industrialization.
The synthesis route of nucleophilic substitution reaction and condensation/decarboxylation reaction under alkaline conditions was adopted, and the coupling reaction between Ullmann and Buchwald-Hartwig was avoided, using potassium fluoride as the base, N,N-dimethylformamide as the solvent. The reaction temperature was controlled between 100~140℃ and 90~130℃, and no copper powder and palladium catalyst were added.
It overcomes the introduction of genotoxic substances and elemental impurities, simplifies reaction conditions, improves product quality control, avoids the discharge of heavy metal wastewater, and is conducive to environmental protection and industrial production.
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of pharmaceutical chemical industry, and in particular relates to a method for synthesizing an antidepressant drug, epiprazole. Background Art
[0002] Brexpiprazole is a central nervous system drug jointly developed by Lundbeck and Otsuka Pharmaceutical. It was approved by the FDA in July 2015 for the adjuvant treatment of adult schizophrenia and adult major depressive disorder (MDD). Brexpiprazole produces anti-schizophrenia effects through partial agonism of dopamine D2 and 5-hydroxytryptamine 1A (5-HT1A) receptors and antagonism of 5-HT2A receptors and adrenaline α2. It has better efficacy and tolerability, and can reduce adverse reactions such as akathisia, restlessness or insomnia in patients.
[0003] The chemical name of epipiprazole is 7-(4-(4-(benzo[b]thiophen-4-yl-piperazine-1-yl)butoxy)-1H-quinolin-2-one, and the chemical structure is as follows:
[0004] Currently, many documents have disclosed the synthesis methods of epiprazole, mainly including the following syntheses and routes.
[0005] Route 1: In the patent published by Otsuka Pharmaceutical Co., Ltd. (CN2006800011923.0), 7-hydroxyquinoline-2(1 H )-ketone, 4-bromobenzo[b]thiophene, 1-bromo-4-chlorobutane and piperazine are used as starting materials, and 7-(4-chlorobutoxy)quinolin-2(1H)-one and 4-(1-piperazinyl)-benzo[b]thiophene hydrochloride are reacted under alkaline conditions to prepare epiriprazole. The synthetic route is as follows:
[0006] Route 2: Patent CN105440026A also discloses that 7-hydroxyquinoline-2(1H)-one, 4-bromobenzo[b]thiophene, 1-bromo-4-chlorobutane and piperazine are used as starting materials, 7-hydroxyquinoline-2(1H)-one is used as starting material, chlorobutane and piperazine are introduced in sequence through two nucleophilic substitution reactions to obtain 7-(1-piperazinebutyloxy)-1H-quinoline-2-one, and finally benzo[b]thiophene fragment is introduced through Buchwald-Hartwig coupling reaction to prepare epiriprazole. The synthetic route is as follows:
[0007] Route 3: Patent CN201610006862.4 discloses a synthetic route using 4-amino-benzo[b]thiophene as a starting material. 4-amino-benzo[b]thiophene is first reacted with bis(2-chloroethyl)amine hydrochloride to prepare 4-(1-piperazinyl)-benzo[b]thiophene hydrochloride, and then 4-(1-piperazinyl)-benzo[b]thiophene hydrochloride is reacted with 7-(4-methylsulfonyloxybutyloxy)quinoline-2(1 H )-ketone reaction to achieve the synthesis of epiprazole. The synthesis route is as follows:
[0008] Route 4: Patent CN105541819 discloses a method for synthesizing epiriprazole. N,N-bis(2-chloroethyl)benzo[b]thiophene-4-amine is used as an intermediate and reacted with 7-(4-aminobutyloxy)quinoline-2(1H)-one under alkaline conditions to synthesize epiriprazole. The synthetic route is as follows:
[0009] Route 5: Patent CN115521298 discloses a method for synthesizing epiriprazole. 4-(4-(Benzo[b]thiophene-4-yl)piperazine-1-yl)butan-1-ol and 7-bromoquinolin-2(1H)-one are coupled under Ullmann reaction conditions to obtain epiriprazole. The synthetic route is as follows:
[0010] The last step reaction in the disclosed synthesis route of epiriprazole involves the use of potential genotoxic compounds (compounds with halogenated alkanes or sulfonate groups). The closer the use of genotoxic compounds is to the final product, the more difficult it is to remove. The removal of genotoxic or potentially genotoxic compounds is a huge challenge to the industrialization of epiriprazole. Although the preparation method of epiriprazole disclosed in patent CN115521298 avoids the use of potential genotoxic compounds in the last step, copper salt catalyst is used. Epiriprazole is a poorly soluble compound that is easily encapsulated with inorganic salts, and it is difficult to remove transition metal copper salts through crystallization or washing processes, thereby affecting the quality of the product. Therefore, it is of great significance to develop a new synthesis method of epiriprazole. Summary of the invention
[0011] The technical problem to be solved by the present invention is to avoid the use of genotoxic substances and transition metals in the last step of the synthesis process of epiriprazole and provide an epiriprazole synthesis process that is beneficial to quality control.
[0012] To achieve the above invention purpose, the present invention adopts the following technical scheme: a method for synthesizing epiriprazole, characterized by comprising the following steps: step 1, compound 1 undergoes a nucleophilic substitution reaction with compound 2 under the action of an alkaline reagent to obtain compound 3; step 2, compound 3 undergoes a condensation / decarboxylation reaction with compound 4 under alkaline conditions to obtain epiriprazole. The synthetic route is shown in the figure:
[0013] The base in step 1 is one or more of potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, and N,N-diisopropylethylamine; preferably, the base in step 1 is potassium fluoride.
[0014] The reaction solvent in step 1 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone or 1,4-dioxane; preferably, the solvent in step 1 is N,N-dimethylformamide.
[0015] The reaction temperature range of step 1 is 100-140°C.
[0016] The molar ratio of compound 1, compound 2 and base in step 1 is 1:0.8-3:1-10.
[0017] In the steps, the two bases are one or more of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, and N,N-diisopropylethylamine.
[0018] The reaction solvent in step 2 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,4-dioxane, sulfolane or dimethyl sulfoxide; preferably, the solvent in step 1 is N,N-dimethylformamide. And The reaction temperature in step 2 is in the range of 90-130°C.
[0019] In the step 2, the molar ratio of compound 3, compound 4 and base is 1:1-5:1-10.
[0020] The benefits of the present invention are: (1) Compared with the existing similar technology, the present invention overcomes the introduction of genotoxic substances and elemental impurities (transition metal copper or palladium) in the last step of the synthesis process of epiriprazole, and provides an epiriprazole synthesis process that is conducive to quality control.
[0021] (2) Compared with the existing similar technology, the benzene invention avoids the Ullmann and Buchenwald coupling reaction conditions, and the reaction conditions are simple and the operation is simple, which is beneficial to industrial production. (3) Compared with the existing similar technology, in the synthesis route of the present invention, no copper powder and palladium catalyst are added, and no heavy metal-containing wastewater is discharged, which is beneficial to environmental protection. Implementation
[0022] The following examples provide further non-limiting illustrations of the technical solutions of the present invention. Example
[0023] A method for synthesizing epiriprazole comprises the following steps: 1. Synthesis of Compound 2 (7-(4-(1-(4-(2-formyl-3-chlorophenyl))piperazinyl)butoxy)quinolin-2(1H)-one) Add 300ml of DMF, 17.43g (300mmol) of potassium fluoride, and 30.14g (100mmol) of 7-(4-(1-piperazinyl)butoxy)quinoline-2(1H)-one to the reactor, stir until dissolved, add 2-chloro-6-fluorobenzaldehyde, heat to 120-130℃ and keep warm for 10 hours. After the reaction is completed, cool to room temperature, pour the reaction solution into 500ml of ice water, stir for 2 hours, filter, and collect the filter cake. Mix the filter cake with 100ml of isopropanol, stir for 1h, filter, collect the filter cake, and dry to obtain 38.21g, with a yield of 86.4%.
[0024] 2. Synthesis of Epiprazole Under nitrogen protection, 300 ml of N-methylpyrrolidone, 30.80 g (70 mmol) of compound 2, and 11.78 g (210 mmol) of potassium hydroxide were added to the reactor, stirred until dissolved, methyl thioglycolate was added, the temperature was raised to 90-100 ° C and the reaction was kept warm for 5 hours, and then the temperature was raised to 120-130 ° C and the reaction was kept warm for 4 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was poured into 500 ml of ice water, stirred for 2 hours, filtered, and the filter cake was collected. The filter cake was mixed with 100 ml of isopropanol, stirred for 1 hour, filtered, and the filter cake was collected and dried to obtain 24.13 g, with a yield of 79.5%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.54 (s,1H), 7.64 (d, J =7.6Hz, 1H), 7.60 (d, J=7.6Hz, 1H), 7.55 (d, J =7.6Hz, 1H),7.51 (d, J=7.5Hz, 1H), 7.35 (d, J =7.3Hz, 1H), 7.23 (t, J =7.2Hz, 1H), 6.82 (d, J =7.6Hz, 1H), 6.82 (d, J =6.8Hz, 1H), 6.76-6.74 (m, 2H), 6.26 (d, J = 6.3 Hz,1H), 4.06 (t, J=4.2Hz, 2H), 3.06-2.98 (m, 4H), 2.66-2.56(m,4H),2.47 -2.38 (m,2H), 1.89-1.71(m, 2H) 1.70~1.55(m,2H). Example
[0025] A method for synthesizing epiriprazole comprises the following steps: 1. Synthesis of Compound 2 (7-(4-(1-(4-(2-formyl-3-chlorophenyl))piperazinyl)butoxy)quinoline-2(1H)-one) Add 300ml of DMF, 17.43g (300mmol) of potassium fluoride, and 30.14g (100mmol) of 7-(4-(1-piperazinyl)butoxy)quinoline-2(1H)-one to the reactor, stir until dissolved, add 2-chloro-6-fluorobenzaldehyde, heat to 120-130°C and keep warm for 10 hours. After the reaction is completed, cool to room temperature, pour the reaction solution into 500ml of ice water, stir for 2 hours, filter, and collect the filter cake. Mix the filter cake with 100ml of isopropanol, stir for 1h, filter, collect the filter cake, and dry to obtain 38.36g, with a yield of 86.7%.
[0026] 2. Synthesis of Epiprazole Under nitrogen protection, 300 ml of N-methylpyrrolidone, 30.80 g (70 mmol) of compound 2, and 8.4 g (210 mmol) of sodium hydroxide were added to the reactor, stirred until dissolved, methyl thioglycolate was added, the temperature was raised to 90-100 ° C and the reaction was kept warm for 5 hours, and then the temperature was raised to 120-130 ° C and the reaction was kept warm for 4 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was poured into 500 ml of ice water, stirred for 2 hours, filtered, and the filter cake was collected. The filter cake was mixed with 100 ml of isopropanol, stirred for 1 hour, filtered, and the filter cake was collected and dried to obtain 20.51 g, with a yield of 67.6%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.54 (s, 1H),7.64 (d,J =7.6Hz, 1H), 7.60 (d, J=7.6Hz, 1H), 7.55 (d, J =7.6Hz, 1H), 7.51(d, J =7.5Hz, 1H), 7.35 (d, J =7.3Hz, 1H), 7.23 (t, J =7.2Hz, 1H), 6.82 (d, J =7.6Hz, 1H), 6.82 (d, J =6.8Hz, 1H), 6.76-6.74 (m, 2H), 6.26 (d, J = 6.3 Hz,1H), 4.06 (t, J=4.2Hz, 2H), 3.06-2.98 (m, 4H), 2.66-2.56(m,4H),2.47 -2.38 (m,2H), 1.89-1.71(m, 2H) 1.70~1.55(m,2H)。。
Claims
1. A method for synthesizing epiriprazole, characterized in that: 7-(4-(1-piperazinyl)butoxy)quinolin-2(1H)-one is used as an intermediate and reacts with 2-halogenated-6-fluorobenzaldehyde under the action of an alkaline reagent to undergo a nucleophilic substitution reaction to obtain compound 3 (7-(4-(1-(4-(2-aldehyde-3-halogenatedphenyl))piperazinyl)butoxy)quinolin-2(1H)-one). Compound 3 undergoes a condensation / decarboxylation reaction with thioglycolate under alkaline conditions to obtain epipiprazole.
2. A method for synthesizing epiriprazole according to claim 1, characterized in that: The following steps are involved: A. Synthesis of compound 2 (7-(4-(1-(4-(2-formyl-3-chlorophenyl))piperazinyl)butoxy)quinoline-2(1H)-one): Add solvent, base and 7-(4-(1-piperazinyl)butoxy)quinoline-2(1H)-one into a reactor, stir until dissolved, add 2-halogenated-6-fluorobenzaldehyde, heat to 100-140°C and keep warm for 10 hours. After the reaction is completed, cool to room temperature, pour the reaction solution into ice water, stir for 2 hours, filter, and collect the filter cake. Mix the filter cake with isopropanol, stir for 1 hour, filter, collect the filter cake, and dry to obtain compound 2. B. Synthesis of epiriprazole: Under nitrogen protection, add the solvent, 30.80 g (70 mmol) of compound 2, and a base to the reactor, stir until dissolved, add thioglycolate, heat to 90-130°C and keep the reaction for 5 hours, then heat to 120-130°C and keep the reaction for 4 hours. After the reaction is completed, cool to room temperature, pour the reaction solution into ice water, stir for 2 hours, filter, and collect the filter cake. Mix the filter cake with isopropanol, stir for 1 hour, filter, collect the filter cake, and dry to obtain epiriprazole.
3. A method for synthesizing epiriprazole according to claim 2, characterized in that: The base in step A is one or more of potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, and N,N-diisopropylethylamine.
4. A method for synthesizing epiriprazole according to claim 2, characterized in that: The solvent in step A is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone or 1,4-dioxane. The reaction temperature in step 1 is in the range of 100-140°C.
5. The method for synthesizing epiriprazole according to claim 2, wherein: In the step A, the molar ratio of 7-(4-(1-(4-(2-aldehyde-3-chlorophenyl))piperazinyl)butoxy)quinoline-2(1H)-one) and the base is 1:0.8~3:1~10.
6. The method for synthesizing epiriprazole according to claim 2, wherein: The 2-halogeno-6-fluorobenzaldehyde in step A, wherein the halogen is fluorine, chlorine, bromine or iodine atom.
7. The method for synthesizing epiriprazole according to claim 2, characterized in that: The base in step B is one or more of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, and N,N-diisopropylethylamine.
8. The method for synthesizing epiprazole according to claim 2, characterized in that: The solvent in step B is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,4-dioxane, sulfolane or dimethyl sulfoxide; preferably, the solvent in step 1 is N,N-dimethylformamide.
9. The method for synthesizing epiriprazole according to claim 2, characterized in that: The reaction temperature in step B ranges from 90 to 130°C.
10. The method for synthesizing epiriprazole according to claim 2, characterized in that: The molar ratio of compound 3, thioglycolate and base in step 2 described in step B is 1:1-5:1-10.