A process for the preparation of pimavanserin

Abstract

This invention discloses a method for preparing pimozide, which involves acylation of 4-isobutoxybenzylamine acetate with carbonyl diimidazole under alkaline conditions, followed by condensation reaction with N-(4-fluorobenzyl)-1-methylpiperidine-4-amine in a reducing solvent, and then post-treatment to obtain the product. The method uses stable 4-isobutoxybenzylamine acetate as raw material, which avoids the introduction of impurities by 4-isobutoxybenzylamine. Combined with the condensation reaction under a reducing solvent, the generation of impurities can be effectively avoided. The product has stable quality, is simple to operate, has low production cost, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, and more specifically, to a method for preparing pimovaserine. Background Technology

[0002] Pimovanserin tartrate, chemically named N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N'-[[4-(2-methylpropoxy)phenyl]methyl]-urea,(2R,3R)-2,3-dihydroxybutyrate (2:1), CAS: 706782-28-7, is a novel non-dopamine neurotransmitter analog developed by ACADIA, Inc., primarily used to treat hallucinations, delusions, and other psychotic symptoms associated with Parkinson's disease.

[0003] Patent publication WO2006036874A1 uses p-hydroxybenzaldehyde as a starting material, and synthesizes 4-isobutoxybenzylamine through etherification, oximeization, and reduction. Then, it undergoes acylation with phosgene to generate 4-isobutoxybenzyl isocyanate, followed by ureation with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to obtain pimovasselin. Finally, it reacts with tartaric acid to form a salt to prepare pimovasselin tartrate. The synthetic route is as follows:

[0004]

[0005] The above process route has the following drawbacks: the synthesis route is relatively long and the atom economy is not high; 4-isobutoxybenzylamine is a liquid raw material that is not easy to purify and there is no commercially available product; the preparation of 4-isobutoxybenzyl isocyanate requires the use of phosgene, a highly toxic asphyxiating gas, which increases the danger of industrial production and the investment in tail gas absorption equipment; and because phosgene has high reactivity, symmetrical urea impurities are generated during the preparation of 4-isobutoxybenzyl isocyanate.

[0006]

[0007] Patent publication CN105153016A uses 4-isobutoxybenzylamine as a raw material, which is acylated with carbonyl diimidazole (CDI) in toluene to obtain N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide, and then condensed with N-(4-fluorobenzyl)-1-methylpiperidine-4-amine to prepare pimovaserin. The synthetic route is as follows.

[0008]

[0009] as follows:

[0010] The above process avoids the use of highly toxic phosgene, and the synthetic route is shorter and reduces environmental pollution. However, this route also has drawbacks: 4-isobutoxybenzamide is not commercially available and needs to be prepared in-house; this liquid raw material is unstable, difficult to store, and easily reacts with carbon dioxide in the air to form carbonates; after the reaction of 4-isobutoxybenzamide with carbonyl diimidazole (CDI) ends, no quenching treatment is performed, and the residual carbonyl diimidazole can continue to participate in the reaction, thus generating other impurities; and during the condensation of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide with N-(4-fluorobenzyl)-1-methylpiperidine-4-amine to prepare pimova serine, oxidative impurities are also generated.

[0011]

[0012] The raw materials 4-isobutoxybenzylamine acetate and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine are readily available and of stable quality. 4-isobutoxybenzylamine acetate is a solid powder, with a liquid phase purity of over 99.5% for commercially available products; N-(4-fluorobenzyl)-1-methylpiperidin-4-amine has a liquid phase purity of over 98.5% for commercially available products. These two raw materials can meet the needs of large-scale production of pimovaserine tartrate API.

[0013] The literature “Research Progress on Synthesis of Pimovanserine, a Parkinson’s Disease Drug” (Guangdong Chemical Industry, 2017, 44(11):177) reported three routes for preparing pimovaserine tartrate using commercially available key intermediates 4-isobutoxybenzylamine acetate and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine as starting materials. Among them, method 2 describes that using 4-isobutoxybenzylamine acetate as a starting material, it is necessary to first alkalize and release 4-isobutoxybenzylamine, and then react it with carbonyl diimidazole (CDI) to obtain N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide. The existing alkali-free production process involves adding an aqueous sodium hydroxide solution to 4-isobutoxybenzylamine acetate in an organic solvent for alkali-free reaction. After the reaction is complete, the aqueous layer is separated, the organic layer is washed with water, refluxed to remove water, and then cooled before adding carbonyl diimidazole (CDI) to the organic solvent for reaction. After the reaction is complete, the mixture is washed with water, then with saturated brine, dried with anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to obtain N-(4-isobutoxyphenyl)-1H-imidazolium-1-carboxamide. This preparation process is complex, involving multiple steps such as alkali-free reaction, washing, drying, and concentration, which significantly increases the production cycle and cost.

[0014]

[0015] Patent publication CN105820110A describes a method that involves reacting 4-isobutoxybenzamide with carbonyl diimidazole (CDI) in a mixed solvent of N,N-dimethylformamide and acetonitrile. After the reaction, the solvent is evaporated, dichloromethane is added for extraction, and the dried filtrate is concentrated under reduced pressure to obtain N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide. This method uses a mixed solvent reaction, employs two concentration steps, and adds an extraction process, which will increase raw material costs and production cycle. Summary of the Invention

[0016] In view of this, the present invention provides a method for preparing pimovaserin, which solves the defects of the prior art, such as complex preparation process, low efficiency, high cost, and easy introduction of impurities that affect product quality.

[0017] Based on this, the technical solution of the present invention is as follows:

[0018] A method for preparing pimovaserin involves acylation of 4-isobutoxybenzylamine acetate with carbonyl diimidazole under alkaline conditions, followed by condensation reaction with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine in a reducing solvent, and then post-treatment to obtain the product.

[0019] Furthermore, the preparation method of the pimovaserin includes the following steps:

[0020] S1,4-isobutoxybenzylamine acetate and carbonyl diimidazole undergo an acylation reaction in a nonpolar solvent and an organic base to give a solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide.

[0021] S2. Add a reducing solvent and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to the product solution from step S1 to carry out a condensation reaction. Quench the reaction after it is complete. Wash the solution with water and saturated brine in sequence. Then concentrate the solution, replace it with an ester solvent, add a solvent, cool and crystallize the solution. Filter the solution to obtain pimovaserin.

[0022] Preferably, in the preparation method, the nonpolar solvent is selected from dichloromethane, toluene, or tetrahydrofuran.

[0023] Preferably, the organic base is an organic amine.

[0024] Preferably, the reducing solvent is isopropanol.

[0025] Preferably, after the acylation reaction in step S1 is completed, purified water is added for washing, and the aqueous layer is discarded.

[0026] Preferably, the ester solvent in step S2 is ethyl formate or ethyl acetate.

[0027] Preferably, the solvent in step S2 is petroleum ether.

[0028] The pimova serine prepared by the above-described preparation method of the present invention has an HPLC purity greater than 99.5% and an oxidative impurity content of less than 0.05%.

[0029] The beneficial effects of this invention are as follows:

[0030] 1. The preparation method of this invention uses readily available and stable-quality 4-isobutoxybenzylamine acetate and N-(4-fluorobenzyl)-1-methylpiperidine-4-amine as raw materials. It eliminates the alkalization and release steps (layering, water washing, reflux dehydration) required in the preparation of N-(4-isobutoxyphenyl)-1H-imidazolium-1-carboxamide in existing technologies. Furthermore, it replaces the cumbersome water washing, saturated brine washing, anhydrous sodium sulfate drying, filtration, and filtrate concentration under reduced pressure with a simple water washing layering method after the acylation reaction. Adding a reducing solvent to the N-(4-isobutoxyphenyl)-1H-imidazolium-1-carboxamide solution obtained after water washing and layering effectively avoids the formation of oxidative impurities. This invention is simple to operate, has low production costs, and provides a new path for industrial production.

[0031] 2. The preparation method described in this invention yields a product with a purity greater than 99.5%, an oxidation impurity content of less than 0.05%, stable and controllable quality, and high reliability for industrial production. Detailed Implementation

[0032] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] In the field of pharmaceutical chemistry, drug synthesis pathways not only need to consider product quality, such as purity and yield, but also the risks of impurities introduced during intermediate processes due to raw material selection and the impact of intermediate processing steps. In industrial production, the integrity of the reaction pathway, the convenience of the operation, and its impact on quality must be fully considered. Generally, simply optimizing intermediate processes or substituting raw materials using conventional methods is insufficient. Furthermore, while the basic chemical reaction principles are well-known to those skilled in the art, the impact of raw material selection on the overall process is uncertain. Without mastering the ability to combine multiple methods to improve quality while simplifying preparation steps, it is unpredictable whether attempting multiple methods can solve the aforementioned technical problems. Therefore, unlike existing preparation processes, combining multiple methods is considered a creative process.

[0034] To address the shortcomings of existing technologies using 4-isobutoxybenzylamine (benzylamine), such as unstable raw material, easy reaction with carbon dioxide in the air to form carbonates affecting quality, and easy introduction of oxidative impurities during condensation reaction, this invention provides reasonable solutions through optimization of raw materials and processes.

[0035] In one embodiment, a method for preparing pimovaserin is provided, comprising acylation of 4-isobutoxybenzylamine acetate with carbonyl diimidazole under alkaline conditions, followed by condensation reaction with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine in a reducing solvent, and then post-treatment to obtain the product. Specific steps include:

[0036] S1,4-isobutoxybenzylamine acetate and carbonyl diimidazole undergo an acylation reaction in a nonpolar solvent and an organic base to give a solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide.

[0037] S2. Add a reducing solvent and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to the product solution from step S1 to carry out a condensation reaction. Quench the reaction after it is complete. Wash the solution with water and saturated brine in sequence. Then concentrate the solution, replace it with an ester solvent, add a solvent, cool and crystallize the solution. Filter the solution to obtain pimovaserin.

[0038] The reaction route is as follows:

[0039]

[0040] This scheme selects 4-isobutoxybenzylamine acetate as the raw material. Firstly, commercially available products have controllable quality, and secondly, they are less prone to deterioration upon contact with air during industrial production. However, this choice may introduce new problems. The acetic acid in 4-isobutoxybenzylamine acetate needs to be removed before the acylation reaction, complicating the process. If the neutralizing alkali is added to the acylation reaction system, its potential adverse effects on the acylation reaction must also be considered. Furthermore, the condensation reaction is intense and easily oxidizes, introducing impurities. This scheme uses an organic alkali solution to pre-remove acetic acid in the solvent system, eliminating the need for pre-alkalization and reducing the impact on the acylation reaction. The condensation reaction is carried out in a reducing solvent and quenched afterward, effectively reducing the formation of oxidative impurities. The pimozantril obtained by this preparation method has an HPLC purity greater than 99.5% and an oxidative impurity content of less than 0.05%.

[0041] In a preferred embodiment, the nonpolar solvent is selected from dichloromethane, toluene, or tetrahydrofuran; the organic base is an organic amine, intended to neutralize and remove acetic acid from the added 4-isobutoxybenzamine acetate. The organic amine is preferably an alkylamine, such as triethylamine or diethylamine. The amount of organic amine added is 0.8 to 1.5 ml based on 1 g of 4-isobutoxybenzamine acetate added.

[0042] In a preferred embodiment, the purpose of the reducing solvent is to prevent the introduction of oxidative impurities during the condensation reaction, and isopropanol is preferred as the reducing solvent.

[0043] In a preferred embodiment, after the acylation reaction in step S1 is completed, purified water is added for washing, and the aqueous layer is discarded, in order to remove some impurities in advance.

[0044] In a preferred embodiment, the ester solvent in step S2 is ethyl formate or ethyl acetate, and the purpose of adding the precipitating agent is to precipitate the product, preferably petroleum ether.

[0045] In the above embodiments, the amounts of various solvents used are within the range that can be selected by those skilled in the art, with the aim of fully dissolving to form a reaction or operating system.

[0046] The following are preferred embodiments of the present invention, used to verify the technical solution and effects of the invention.

[0047] In the examples, all raw materials involved are commercially available industrial raw materials, with industrial-grade standards, and the same raw materials have the same purity.

[0048] Example 1

[0049] Add 700 ml of toluene, 50 g of carbonyl diimidazole, and 80 ml of triethylamine to a reaction flask, stir, and cool to 5℃~10℃. Add 60 g of 4-isobutoxybenzylamine acetate and react at 5℃~10℃ for 2 hours. After the reaction is complete, wash the organic layer with 100 ml × 3 of purified water, discard the aqueous layer, and obtain a toluene solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide.

[0050] To a toluene solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide obtained from the previous step, 20 ml of isopropanol was added and stirred until homogeneous. Then, 57.6 g of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine was added, and the mixture was heated to 50-60°C and maintained at this temperature for 4 hours. After the reaction was completed, the temperature was lowered to 20-30°C, 100 ml of purified water was added, and the mixture was stirred for 15 minutes. The aqueous layer was separated by standing. The organic layer was then washed sequentially with 100 ml of purified water and 100 ml of saturated brine. The organic layer was concentrated under reduced pressure to remove the solvent, and 150 ml of ethyl acetate was added. The mixture was heated to 50-60°C to dissolve the organic layer. 450 ml of petroleum ether was added dropwise, and the mixture was stirred at 50-60°C for 1 hour. The temperature was then lowered to 5-10°C to allow crystallization for 2 hours. The crystals were filtered and dried to obtain 93.8 g of pimozantrone with an HPLC purity of 99.93%. No oxidizing impurities were detected.

[0051] Example 2

[0052] Add 600 ml of dichloromethane, 50 g of carbonyl diimidazole, and 50 ml of diethylamine to a reaction flask, stir, and cool to 5℃~10℃. Add 60 g of 4-isobutoxybenzylamine acetate and react at 5℃~10℃ for 2 hours. After the reaction is complete, wash the organic layer with 100 ml × 3 of purified water, discard the aqueous layer, and obtain a dichloromethane solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide.

[0053] In the dichloromethane solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide obtained from the previous step, 30 ml of isopropanol was added, and the mixture was stirred until homogeneous. Then, 57.5 g of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine was added, and the reaction was maintained at 30℃~35℃ for 8 hours. After the reaction was completed, the temperature was lowered to 20℃~25℃, 100 ml of purified water was added, and the mixture was stirred for 15 minutes. The aqueous layer was separated by standing, and the organic layer was washed successively with 100 ml × 1 of purified water and 100 ml × 1 of saturated brine. The organic layer was concentrated under reduced pressure to remove the solvent, and 300 ml of ethyl formate was added. The temperature was raised to 40℃~50℃ to dissolve the organic layer, and 900 ml of petroleum ether was added dropwise. The mixture was kept at 40℃~50℃ and stirred for 1 hour. The temperature was lowered to 5℃~10℃ to crystallize, and the crystallization was allowed to proceed for 2 hours. The crystals were filtered and dried to obtain 91.9 g of pimozantrone with an HPLC purity of 99.90% and an oxidation impurity content of 0.01%.

[0054] Example 3

[0055] Add 700 ml of toluene, 50 g of carbonyl diimidazole, and 50 ml of diethylamine to a reaction flask, stir, and cool to 5℃~10℃. Add 60 g of 4-isobutoxybenzylamine acetate and react at 5℃~10℃ for 2 hours. After the reaction is complete, wash the organic layer with 100 ml × 3 of purified water, discard the aqueous layer, and obtain a toluene solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide.

[0056] To a toluene solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide obtained from the previous step, 20 ml of isopropanol was added and stirred until homogeneous. Then, 57.6 g of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine was added, and the mixture was heated to 50℃~60℃ and reacted for 4 hours. After the reaction was completed, the temperature was lowered to 20℃~30℃, 100 ml of purified water was added, and the mixture was stirred for 15 minutes. The aqueous layer was separated by standing, and the organic layer was washed successively with 100 ml × 1 of purified water and 100 ml × 1 of saturated brine. The organic layer was concentrated under reduced pressure to remove the solvent, and 300 ml of ethyl formate was added and heated to 40℃~50℃ to dissolve it. 900 ml of petroleum ether was added dropwise, and the mixture was stirred at 40℃~50℃ for 1 hour. The temperature was lowered to 5℃~10℃ to crystallize, and the crystallization was allowed to proceed for 2 hours. The crystals were filtered and dried to obtain 93.3 g of pimozantrone with an HPLC purity of 99.91% and no oxidizing impurities were detected.

[0057] Comparative Example 1

[0058] 100 g (0.558 mol) of 4-isobutoxybenzylamine was added to 500 mL of toluene and stirred until dissolved. Then, 100 g (0.627 mol) of carbonyl diimidazole was added at room temperature, and the mixture was stirred for 2 hours at room temperature to obtain a toluene solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide. A 500 mL toluene solution of 124 g (0.558 mol) of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine was added dropwise to the toluene solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide prepared above. The mixture was refluxed for 5 hours, and after the reaction was complete, it was cooled to room temperature.

[0059] 2.5 L of ethyl acetate was added to the reaction system, and the mixture was washed twice with 1 L of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and 10 g of activated carbon was added to the filtrate. The mixture was stirred at 80-85 °C for 0.5 hours to decolorize. After cooling to room temperature, the mixture was filtered again, and the solvent was removed by vacuum evaporation at 40 °C to obtain crude pimova serline. 100 g of the crude pimova serline was added to 500 mL of ethyl acetate and dissolved under reflux. 1.0 L of n-hexane was added dropwise. After the addition was complete, the mixture was cooled to room temperature and stirred at room temperature for 4 hours. The mixture was filtered and dried under vacuum at 40-50 °C for 5 hours to obtain a pale yellow solid pimova serline. The content of oxidizing impurities was determined to be 0.17%.

[0060] Comparative Example 2

[0061] The preparation method and conditions for N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide are the same as in Example 3, except that 20 ml of toluene is added to the toluene solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide, and after stirring evenly, 57.6 g of N-(4-fluorobenzyl)-1-methylpiperidine-4-amine is added, and the temperature is raised to 50℃~60℃ and kept at the temperature for 4 hours. After the reaction was completed, the temperature was lowered to 20℃~30℃, 100ml of purified water was added and stirred for 15 minutes. The aqueous layer was separated by standing. The organic layer was then washed sequentially with 100ml of purified water and 100ml of saturated brine. The organic layer was concentrated under reduced pressure to remove the solvent. 300ml of ethyl formate was added and the temperature was raised to 40℃~50℃ to dissolve the organic layer. 900ml of petroleum ether was added dropwise, and the mixture was kept at 40℃~50℃ and stirred for 1 hour. The temperature was then lowered to 5℃~10℃ to allow crystallization. Crystallization was allowed to occur for 2 hours. The crystals were filtered and dried to obtain 92.6g of pimozantrone with an HPLC purity of 99.52% and an oxidizing impurity content of 0.15%.

[0062] The results of Examples 1-3 clearly show that the proposed method utilizes 4-isobutoxybenzylamine acetate, which can still undergo acylation under organic amine conditions, eliminating the need for pre-alkalization. The reducing solvent added during the condensation reaction effectively suppresses the formation of oxidative impurities. Since the structure of these oxidative impurities is very similar to that of the product pimova serine, they are difficult to remove during post-processing. Comparative Example 1, as a prior art, did not add a reducing solvent during the condensation process, resulting in oxidative impurities in the final product. This is likely because oxidation occurs during the condensation reaction, and the oxidative impurities are difficult to separate during post-processing, leading to a decrease in product quality. Comparative Example 2, as a comparison with Example 3, more significantly demonstrates that when the reducing solvent is replaced with toluene, the protective effect disappears, resulting in the formation of oxidative impurities.

[0063] Finally, it should be noted that although the present invention has been described in detail above with general descriptions and specific embodiments, the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing pimova serine, characterized in that the steps include... include: S1. 4-Isobutoxybenzamide acetate and carbonyl diimidazole undergo an acylation reaction in a nonpolar solvent and an organic base to give a solution of N-(4-isobutoxyphenyl)-1H-imidazol-1-carboxamide; S2. After washing with purified water and removing the aqueous layer in the product solution from step S1, add isopropanol and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to carry out a condensation reaction. Quench the reaction after it is completed. Wash with water and saturated brine in sequence. Then concentrate and replace with ester solvent. Add solvent, cool and crystallize. Filter to obtain pimovaserin.

2. The preparation method according to claim 1, characterized in that, The nonpolar solvent is selected from dichloromethane, toluene, or tetrahydrofuran.

3. The preparation method according to claim 1, characterized in that, The organic base is an organic amine.

4. The preparation method according to claim 1, characterized in that, The ester solvent mentioned in step S2 is ethyl formate or ethyl acetate.

5. The preparation method according to claim 1, characterized in that, The solvent used in step S2 is petroleum ether.

6. The preparation method according to claim 1, characterized in that, The pimozantrone obtained by the preparation method has an HPLC purity greater than 99.5% and an oxidative impurity content of less than 0.05%.

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