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Preparation method of Pimavanserin

A technology of pimavanserin and reaction temperature, applied in the direction of organic chemistry, can solve the problems of unfavorable environmental protection, low safety, expensive palladium carbon, etc., and achieve environmental protection, improve safety, and good safety Effect

Active Publication Date: 2017-09-26
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Disadvantages of this route: (1) The use of hydrogen to participate in the reaction needs to be carried out under high pressure, and the safety is low; the use of palladium carbon in the reaction is expensive
(2) Toxic phosgene is involved in the reaction, which has a great impact on the health of the operator, is not conducive to environmental protection, has low safety, and is not suitable for industrial production
[0009] The DPPA used in this route is expensive, and the azide intermediate will be passed through during the reaction process to generate azide by-products. The azide is unstable and there are safety hazards such as explosion.

Method used

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  • Preparation method of Pimavanserin

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preparation example Construction

[0026] The preparation method of this pimavanserin is to use 4-isobutoxybenzaldehyde as the starting material, react with hydroxylamine hydrochloride to generate 4-isobutoxybenzaldehyde oxime, and then use zinc powder to dissolve 4-isobutoxybenzaldehyde The reduction of benzaldoxime produces 4-isobutoxybenzylamine, followed by the reaction of 4-isobutoxybenzylamine with diphenyl carbonate to give N-(4-isobutoxybenzyl)phenylcarbamate, and finally with N -(4-fluorobenzyl)-1-methylpiperidin-4-amine reacts to obtain pimavanserin; its synthetic route is as follows:

[0027]

[0028] The process of each step is as follows:

[0029] (1) In the reactor, add hydroxylamine hydrochloride and lye to the water, the lye is sodium hydroxide solution or potassium carbonate solution, preferably sodium hydroxide solution; slowly add 4-isobutyric acid dissolved in the solvent dropwise under stirring phenylbenzaldehyde, the solvent is ethanol or THF (tetrahydrofuran), preferably ethanol; the ...

Embodiment 1

[0033] Embodiment 1: The specific process of the preparation method of this pimavanserin is as follows.

[0034] (1) Preparation of 4-isobutoxybenzaldehyde oxime:

[0035]

[0036] Hydroxylamine hydrochloride (15.6g, 0.224mol) and sodium hydroxide (8.98g, 0.224mol) were added to 100g of water at room temperature, stirred for 15 minutes, and 4-isobutoxybenzaldehyde dissolved in 150mL of ethanol was slowly added dropwise (20g, 0.112mol), reacted at room temperature for 40min, TLC detected the reaction, after the reaction, distilled off ethanol under reduced pressure, extracted with water (250mL) and dichloromethane (250mL), separated the organic layer, the water layer was dichloromethane Wash with methane (100mL*2), combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and distill off dichloromethane under reduced pressure to obtain crude 4-isobutoxybenzaldehyde oxime. Recrystallize the crude product, add petroleu...

Embodiment 2

[0050] Embodiment 2: The specific process of the preparation method of this pimavanserin is as follows.

[0051] (1) The preparation of 4-isobutoxybenzaldehyde oxime, except following difference, all the other are the same as embodiment 1:

[0052] The dosage of hydroxylamine hydrochloride is 11.7g, 0.168mol, that is, 4-isobutoxybenzaldehyde: hydroxylamine hydrochloride=1:1.5 (mol); the reaction temperature of 4-isobutoxybenzaldehyde and hydroxylamine hydrochloride is 20-25°C. 19.51g of the product was obtained with a yield of 90%.

[0053] The NMR data of the obtained 4-isobutoxybenzaldoxime are as follows: H1NMR (500MHz, DMSO) δ8.042 (s.1H), 7.482-7.499 (d.2H), 6.923-6.940 (d, 2H), 3.744-3.757 (d.2H), 1.970-2.049(m,1H), 0.969-0.983(d,6H).

[0054] (2) The preparation of 4-isobutoxybenzylamine is the same as in Example 1 except for the following differences:

[0055] The amount of zinc powder is 81.24g, 1.236mol, that is, 4-isobutoxybenzylaldoxime:zinc powder=1:12 (mol); 1...

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Abstract

The invention discloses a preparation method of Pimavanserin. The preparation method comprises the following steps: (1) adopting 4-isobutoxy benzaldehyde to react with hydroxylamine hydrochloride in an alkaline liquor to prepare 4-isobutoxy benzaldoxime; (2) adopting a reducing agent to reduce the 4-isobutoxy benzaldoxime so as to generate 4-isobutoxy benzylamine; (3) adopting a carbonyl compound to react with the 4-isobutoxy benzylamine to prepare N-(4-isobutoxy benzyl) phenyl carbamate; and (4) adopting the N-(4-isobutoxy benzyl) phenyl carbamate to react with N-(4-fluorobenzyl)-1-methyl piperidine-4-amine, and thus obtaining the Pimavanserin. Heating is not needed when the 4-isobutoxy benzaldoxime is prepared in the method, so that the energy consumption is reduced; zinc powder is used for replacing hydrogen and palladium carbon so as to generate the 4-isobutoxy benzylamine, and low-cost easily-obtained diphenyl carbonate is used for replacing hypertoxic carbonyl chloride and expensive DPPA, so that the safety is improved, and the environmental protection is facilitated.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a preparation method of pimavanserin. Background technique [0002] Pimavanserin (generic name: Pimavanserin, trade name: Nuplazid) is a patented drug independently developed by Arcadia Pharmaceuticals for the treatment of Parkinson's disease mental symptoms. It is a non-dopamine neurotransmitter analog and can be selected Sexual blockade of serotonin 2A receptors does not affect the effects of dopamine. [0003] Pimavanserin was granted Breakthrough Therapy Certification by the US Food and Drug Administration (FDA) on September 3, 2014. In April 2016, the FDA approved its treatment for patients with Parkinson's disease psychiatric disorders, in order to relieve the mental symptoms such as hallucinations and delusions in Parkinson's patients. Pimavanserin is an atypical antipsychotic and the first and only FDA-approved drug that selectively targets the 5-HT2A receptor, a high...

Claims

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Application Information

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IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 尚振华贺晓娟
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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