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Preparation method of substituted urea derivative

An intermediate, isobutoxybenzyl technology, applied in the field of chemical pharmacy, can solve the problems of raw material toxicity, high price, side reactions, etc., and achieve the effects of high product purity and simple steps

Inactive Publication Date: 2015-12-02
ANHUI YIXINMING PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The raw materials used in the above methods ②~⑤ are extremely toxic. The raw materials used in method ⑥ are not easy to obtain and are expensive. In method ①, CO 2 Although it is cheap and easy to obtain, it requires high temperature and high pressure. It has great advantages in the preparation of urea derivatives with symmetrical structure, but in the preparation of urea derivatives with asymmetric structure, the side reaction is as high as 35%.

Method used

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  • Preparation method of substituted urea derivative
  • Preparation method of substituted urea derivative
  • Preparation method of substituted urea derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0031] 1. Preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine hydrochloride (intermediate of formula III)

[0032] In a 10L dry reaction kettle, add 6000ml of isopropanol and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (Formula V) (555g, 2.5mol), stir, and cool to 0~ Add a hydrogen chloride solution of isopropanol dropwise at 5°C, adjust the pH to 1-2, keep stirring for 1 hour, filter, wash the solid with an appropriate amount of isopropanol, and dry it under vacuum at 70-80°C to obtain N-(4-fluorobenzyl)- 674g of 1-methylpiperidin-4-amine hydrochloride, yield 91.3%.

[0033] 2. N-(4-isobutoxybenzyl)-1 H - Preparation of imidazole-carboxamide (formula II intermediate)

[0034] In a 20L dry reaction kettle, at room temperature, add 2500ml of dry N,N'-dimethylformamide, 8500ml of dry acetonitrile, and add (4-isobutoxyphenyl)-methylamine (formula IV ) (538g, 3.0mol) and N,N'-carbonyldiimidazole (CDI) (584g, 3.6mol), stirred at 20-25°C for 15h, after the reaction was c...

Embodiment 2

[0046] 1. Preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine hydrochloride (intermediate of formula III)

[0047] In a 2000ml dry three-necked flask, add 600ml of isopropanol and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (Formula V) (55.5g, 0.25mol), stir and cool to 0 ~5°C, add isopropanol hydrogen chloride solution dropwise, adjust the pH to 1~2, keep stirring for 1 hour, filter, wash the solid with an appropriate amount of isopropanol, and dry under vacuum at 70~80°C to obtain N-(4-fluorobenzyl) -1-methylpiperidin-4-amine hydrochloride 68g, yield 91.4%.

[0048] 2. N-(4-isobutoxybenzyl)-1 H - Preparation of imidazole-carboxamide (formula II intermediate)

[0049] In a 2000ml dry three-necked flask, at room temperature, add 250ml of dry N,N'-dimethylacetamide, 850ml of dry acetonitrile, and add (4-isobutoxyphenyl)-methylamine (formula IV ) (53.8g, 0.3mol) and N,N'-carbonyldiimidazole (CDI) (58.4g, 0.36mol), stirred and reacted at 20-25℃ for 15h, after the reac...

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Abstract

The invention relates to a novel preparation method of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidyl-4-yl)urea hemitartrate (pimavanserin tartrate), particularly a pharmaceutical compound for treating Parkinson's disease, of which the structural formula is disclosed as Formula (I). The invention also relates to a novel intermediate of the preparation method.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and more specifically relates to a new preparation method of a drug compound pimavanserin tartrate for treating Parkinson's disease psychosis and a new intermediate of the preparation method. Background technique [0002] At present, there are about 7 million to 10 million Parkinson's disease patients in the world, and China has 2.6 million people, ranking first in the world, and there will be an increase of 100,000 new patients every year. More than 50% of patients with Parkinson's disease have had psychotic symptoms (PDP). These psychiatric symptoms mainly manifest as hallucinations and delusions, which bring greater challenges to the treatment and care of patients with Parkinson's disease. Dopamine is the main target of Parkinson's disease treatment. Since most antipsychotic drugs block dopamine in the brain and lead to worsening of motor dysfunction in Parkinson's patients, they ar...

Claims

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Application Information

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IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 徐奎刘经星王会山
Owner ANHUI YIXINMING PHARMA TECH
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