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Novel synthesis method for pimavanserin

A new synthesis technology of pimavanserin, which is applied in the direction of organic chemistry, can solve the problems of optimization of starting material synthesis, difficulty in product purification, and low experimental efficiency, and achieve shortened reaction steps, high product purity, and simple experimental operation Effect

Active Publication Date: 2016-08-03
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The method uses 4-isobutoxybenzylamine to react with carbonyldiimidazole to obtain an active urea intermediate, which is then docked with another fragment to obtain the target molecule. Although this method avoids the use of highly toxic and dangerous reagents, it does not have the effect on the starting materials. The synthesis is optimized, and the intermediates are not purified. The route steps are slightly longer, the experimental efficiency is not high, and the purification of the final product is more difficult.

Method used

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  • Novel synthesis method for pimavanserin
  • Novel synthesis method for pimavanserin
  • Novel synthesis method for pimavanserin

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Experimental program
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Effect test

Embodiment 1

[0048]

[0049]Add 4-fluorobenzaldehyde (12.41g, 100mmol), 4-amino-1-methylpiperidine (11.42g, 100mmol), and dichloromethane (124mL) into a three-necked flask, stir for 1-2 hours, then add acetic acid 25 mL, add sodium acetate borohydride (42.39 g, 200 mmol) in batches, react at room temperature for 6-8 hours, add 100 mL of water to quench the reaction after the reaction, and add 10% sodium hydroxide solution to adjust the pH value to 9-10, and separate , the aqueous phase was extracted twice with dichloromethane (143mL), the combined organic phase was washed twice with saturated brine (143mL), dried over sodium sulfate, and concentrated to obtain an oily product, which was dissolved with isopropanol (200mL) and stirred, heated to 55-60 ℃, 85% phosphoric acid (8.07g, 70mmol) was added dropwise, a small amount of seed crystals were added, the crystallization was carried out at room temperature, filtered, and dried to obtain compound 1a-1 (23.87g, 83%). ESIm / z=223.2(M+1), 1 ...

Embodiment 2

[0051]

[0052] Add 4-fluorobenzaldehyde (12.41g, 100mmol), 4-amino-1-methylpiperidine (11.42g, 100mmol), and dichloromethane (124mL) into a three-necked flask, stir for 1-2 hours, then add acetic acid 25mL, add sodium borohydride (7.57g, 200mmol) in batches, react at room temperature for 6-8 hours, add 100mL of water to quench the reaction after the reaction, and add 10% sodium hydroxide solution to adjust the pH value to 9-10, separate the liquid, The aqueous phase was extracted twice with dichloromethane (143mL), the combined organic phase was washed twice with saturated brine (143mL), dried over sodium sulfate, and concentrated to obtain an oily product which was dissolved by adding tetrahydrofuran (200mL) and stirred, heated to 45-55°C, and dripped Add methanesulfonic acid (19.22g, 200mmol), add a small amount of seed crystals, drop to room temperature for crystallization, filter and dry to obtain compound 1a-2 (29.84g, 72%).

[0053] ESIm / z=223.2(M+1), 1 HNMR(DMSO-d6...

Embodiment 3

[0055]

[0056] Add 4-fluorobenzaldehyde (12.41g, 100mmol), 4-amino-1-methylpiperidine (11.42g, 100mmol), and dichloromethane (124mL) into a three-necked flask, stir for 1-2 hours, then add acetic acid 25mL, add sodium borohydride (7.57g, 200mmol) in batches, react at room temperature for 6-8 hours, add 100mL of water to quench the reaction after the reaction, and add 10% sodium hydroxide solution to adjust the pH value to 9-10, separate the liquid, The aqueous phase was extracted twice with dichloromethane (143mL), and the combined organic phase was washed twice with saturated brine (143mL), dried over sodium sulfate, concentrated to obtain an oily product, added ethyl acetate (200mL), stirred and dissolved, and heated to 45-55°C , dropwise added acetic acid (12.01g, 200mmol), added a small amount of seed crystals, cooled down to room temperature for crystallization, filtered, and dried to obtain compound 1a-3 (27.05g, 79%).

[0057] ESIm / z=223.2(M+1), 1 HNMR(DMSO-d6,400M...

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Abstract

The invention provides a novel synthesis method for pimavanserin. The method comprises the steps that a compound formula (1a) is adopted as a raw material for preparing an active urea compound formula (1) and then subjected to a reaction with a compound formula (2) under an alkaline system to obtain a pimavanserin free alkali formula (3), and then pimavanserin free alkali forms a salt with tartaric acid to obtain a pimavanserin half tartrate formula (4). The method is simple in technological path, low in cost and suitable for industrial production. The formula is shown in the description, wherein HmA is the general formula of m-basic acid, HnA is the general formula of n-basic acid, m and n are 1 or 2 or 3, and the m-basic acid and the n-basic acid are selected from sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, methanoic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid or tartaric acid.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a preparation method of pimavanserin and an intermediate compound used for the preparation of pimavanserin. Specifically, the invention discloses a preparation method of a series of compounds and a preparation method of pimavanserin. A new preparation method. Background technique [0002] At present, there are about 7 million to 10 million Parkinson's disease patients in the world, of which 2.6 million are in China, ranking first in the world. At present, there is a lack of specific drugs for Parkinson's disease. Pimavanserin (or Pimavanserin, Pimavanserin) is a new type of non-dopamine neurotransmitter analogue developed by Arcadia in the United States, which can selectively block the serotonin 2A receptor without affecting the activity of dopamine. Recent clinical trials have shown that it has a good curative effect on patients with Parkinson's disease and related m...

Claims

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Application Information

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IPC IPC(8): C07D211/58C07D401/12
CPCC07D211/58C07D401/12
Inventor 郑旭春张一平
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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