CN-115677566-B - Preparation method of pimavanserin

Abstract

The invention discloses a preparation method of pimavanserin, which is characterized in that 4-isobutoxy benzyl amine acetate and carbonyl diimidazole are acylated under the condition of alkali liquor, then are subjected to condensation reaction with N- (4-fluorobenzyl) -1-methylpiperidine-4-amine under a reducing solvent, and then are subjected to post-treatment to obtain the pimavanserin; the preparation method selects the 4-isobutoxy benzylamine acetate with stable performance as the raw material, can avoid the easy introduction of impurities into the 4-isobutoxy benzylamine, combines the condensation reaction under the reducing solvent, can effectively avoid the generation of impurities, has stable quality, simple operation and low production cost, and is suitable for industrial production.

Inventors

• LIAO JUN
• FU LIN
• WEI NING
• ZENG JIANHUA
• WU DEQI
• YANG SHENKUN
• Zou Jinshuang
• WANG SHUANG

Assignees

• 华中药业股份有限公司

Dates

Publication Date

20260505

Application Date

20221028

Claims (6)

1. 1. The preparation method of pimavanserin is characterized by comprising the following steps: S1.4-isobutoxy benzylamine acetate and carbonyl diimidazole are subjected to acylation reaction under the action of a nonpolar solvent and an organic base to obtain a solution of N- (4-isobutoxy phenyl) -1H-imidazole-1-formamide; S2, adding purified water into the product solution obtained in the step S1 for washing, removing a water layer, adding isopropanol and N- (4-fluorobenzyl) -1-methylpiperidine-4-amine for condensation reaction, quenching after the reaction is finished, washing with water, saturated brine in sequence, concentrating, replacing an ester solvent, adding a solvent, cooling for crystallization, and filtering to obtain pimavanserin.
2. 2. The method of claim 1, wherein the nonpolar solvent is selected from the group consisting of dichloromethane, toluene, and tetrahydrofuran.
3. 3. The method of claim 1, wherein the organic base is an organic amine.
4. 4. The preparation method according to claim 1, wherein the ester solvent in the step S2 is ethyl formate or ethyl acetate.
5. 5. The method of claim 1, wherein the solvent in step S2 is petroleum ether.
6. 6. The preparation method according to claim 1, wherein the pimavanserin finally obtained by the preparation method has an HPLC purity of more than 99.5% and an oxidized impurity content of less than 0.05%.

Description

Preparation method of pimavanserin Technical Field The invention relates to the technical field of chemical pharmacy, in particular to a preparation method of pimavanserin. Background Pimavanserin tartrate (pimavanserin, PIMAVANSERIN TARTRATE) with chemical name of N- [ (4-fluorophenyl) methyl ] -N- (1-methyl-4-piperidinyl) -N '- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -urea, (2R, 3R) -2, 3-dihydroxysuccinate (2:1), CAS:706782-28-7, which is a novel non-dopamine neurotransmitter analogue developed by Amyda (ACADIA) company in the United states, is mainly used for treating mental symptoms such as illusion, delusions and the like, which are accompanied by patients suffering from Parkinson's disease. Patent publication WO2006036874A1 adopts p-hydroxybenzaldehyde as a starting material, and is subjected to etherification, oximation and reduction to synthesize 4-isobutoxy benzyl amine, then the 4-isobutoxy benzyl isocyanate is produced by acylation with phosgene, then the 4-isobutoxy benzyl isocyanate and N- (4-fluorobenzyl) -1-methylpiperidine-4-amine are subjected to carbamide reaction to obtain pimavanserin, and finally the pimavanserin tartrate is produced by salifying with tartaric acid, wherein the synthetic process route is as follows: The process route has the defects of longer synthetic route, low atom economy, difficult purification of the 4-isobutoxy benzyl amine as a liquid raw material and no commercial product, and the requirement of using severe choking poison gas-phosgene in the preparation of the 4-isobutoxy benzyl isocyanate, increases the danger of industrial production and equipment investment for tail gas absorption, and can generate symmetrical urea impurities when the 4-isobutoxy benzyl isocyanate is prepared due to higher phosgene activity. Patent publication CN105153016A uses 4-isobutoxy benzylamine as raw material, and uses it and Carbonyl Diimidazole (CDI) to make acylation in toluene to obtain N- (4-isobutoxy phenyl) -1H-imidazole-1-carboxamide, then uses it and N- (4-fluorobenzyl) -1-methylpiperidine-4-amine to make condensation reaction so as to obtain pimavanserin The following are provided: The process avoids the use of phosgene which is a highly toxic raw material, has a short synthetic route and reduces environmental pollution. However, this route has the disadvantages that 4-isobutoxy-benzylamine does not need to be prepared by itself because of being supplied by a commercial product, the liquid raw material is unstable and not easy to store, and is easy to react with carbon dioxide in the air to generate carbonate, the reaction of 4-isobutoxy-benzylamine and Carbonyl Diimidazole (CDI) is finished, the residual carbonyl diimidazole can continue to participate in the reaction to generate other impurities without quenching treatment, and oxidized impurities are generated in the process of preparing pimavanserin by condensing N- (4-isobutoxy-phenyl) -1H-imidazole-1-carboxamide with N- (4-fluorobenzyl) -1-methylpiperidine-4-amine. The raw material 4-isobutoxy phenylmethylamine acetate and the raw material N- (4-fluorobenzyl) -1-methylpiperidine-4-amine are sufficient in market supply and stable in quality, wherein the property of the 4-isobutoxy phenylmethylamine acetate is solid powder, the liquid phase purity of a commercial product is more than 99.5%, and the liquid phase purity of the commercial product of the N- (4-fluorobenzyl) -1-methylpiperidine-4-amine is more than 98.5%. The two raw materials can meet the large-scale production requirement of the tartaric acid pimavanserin raw material drug. Three routes for preparing pimavanserin tartrate using the commercially available key intermediate 4-isobutoxy benzylamine acetate and N- (4-fluorobenzyl) -1-methylpiperidine-4-amine as starting materials are reported in the literature (Guangdong chemical, 2017,44 (11): 177), progress in the synthesis of the parkinsonism drug pimavanser, wherein method 2 describes that 4-isobutoxy benzylamine is obtained by first basifying to free 4-isobutoxy benzylamine using 4-isobutoxy benzylamine acetate as starting material and then reacting with Carbonyldiimidazole (CDI) to give N- (4-isobutoxyphenyl) -1H-imidazole-1-carboxamide. The existing alkalization free production process adopts 4-isobutoxy phenylmethylamine acetate to add sodium hydroxide aqueous solution into organic solvent for free, after the reaction is finished, separating a water layer, washing the organic layer, refluxing and separating water to remove water, cooling, then dropwise adding Carbonyl Diimidazole (CDI) into the organic solvent for reaction, completely and successively washing with water, saturated brine, drying with anhydrous sodium sulfate, filtering filtrate and concentrating under reduced pressure to obtain N- (4-isobutoxy phenyl) -1H-imidazole-1-formamide. The preparation process has complex production flow, and the preparation production period and production cost can be greatly increased through the multi-st