Preparation method of pimavanserin

A technology of pimavanserin and formamide, applied in the field of medicinal chemistry, can solve the problems of causing pulmonary edema, difficult reaction control, increasing the risk of operators, etc. Environmentally friendly effect

Active Publication Date: 2015-12-16
NKD PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main defects in the method reported in this patent are: (1) Phosgene is a severe suffocating poisonous gas, high concentration inhalation can cause pulmonary edema, increases the danger of operators in the production process, and requires high equipment and tail gas treatment. At the same time, it is not conducive to environmental protection
(2) In the process of preparing compound 8, the reaction control is relatively difficult, and a large amount of symmetrical urea impurity A is produced:

Method used

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  • Preparation method of pimavanserin

Examples

Experimental program
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Effect test

Embodiment 1

[0036] The preparation of embodiment 1N-(4-isobutoxyphenyl)-1H-imidazole-1-carboxamide (intermediate 2)

[0037] Add 100g (0.558mol) of 4-isobutoxybenzylamine to 500ml of toluene, stir to dissolve, add 100g (0.627mol) of carbonyldiimidazole at room temperature, and stir at room temperature for 1 to 2 hours to obtain N-(4-isobutyl The toluene solution of oxyphenyl)-1H-imidazole-1-carboxamide was directly used in the next reaction.

Embodiment 2

[0038] The preparation of embodiment 2N-(4-isobutoxyphenyl)-1H-imidazole-1-carboxamide (intermediate 2)

[0039] According to the method of Example 1, after the reaction, the reaction solution was concentrated under reduced pressure to constant weight to obtain N-(4-isobutoxyphenyl)-1H-imidazole-1-carboxamide.

Embodiment 3

[0040] The preparation of embodiment 3 pimavanserin

[0041] Add 124g (0.558mol) of N-(4-fluorophenyl)-1-methylpiperidin-4-amine in 500ml of toluene solution dropwise to N-(4-isobutoxyphenyl)-1H-imidazole- In the toluene solution of 1-formamide (prepared in Example 1), the temperature was raised and refluxed for 5 to 8 hours. After the reaction was completed, the temperature was lowered to room temperature, and 2.5 L of ethyl acetate was added to the reaction system, and washed twice with 1 L of saturated brine. Dry over anhydrous sodium sulfate. Suction filtration, adding 10 g of activated carbon to the filtrate, stirring at 80-85°C for 0.5-1 hour for decolorization, cooling to room temperature, suction filtration, evaporation under reduced pressure at 40°C to remove the solvent to obtain crude pimavanserin.

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Abstract

The invention discloses a preparation method of pimavanserin. The method comprises the following two steps: firstly, 4-isobutoxy benzene methylamine and carbonyl diimidazole are subjected to acylation reaction to obtain N-(4-isobutoxy phenyl)-1H-imidazole-1-formamide, and the N-(4-isobutoxy phenyl)-1H-imidazole-1-formamide and N-(4-fluorophenyl)-1-methylpiperidine-4-amine are subjected to urea reaction, so as to obtain the pimavanserin. The prepared pimavanserin is good in quality and high in yield, the reagent toxicity is relatively low, the operation is simple and easy to control, and the pimavanserin is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a preparation method of a pharmaceutical compound, especially N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxy The preparation method of benzyl) urea (pimavanserin). Background technique [0002] WO2006036874A1 discloses pimavanserin (English name: pimavanserin), namely N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxy Benzyl) urea, its tartrate and polymorphs, as well as its preparation and use. [0003] [0004] The compound can treat neuropsychiatric disorders such as schizophrenia and related idiopathic psychosis, depression, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, depression with psychotic features, and Touré Teddy's Syndrome. Other beneficial treatments may be treatment of drug-induced psychosis and side effects of Parkinson's disease and psy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 陶秀梅尚丽霞牟昳田力文严智
Owner NKD PHARMA CO LTD
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