Preparation method of pimavanserin

A kind of technology of pimaserin and methyl piperidinyl, which is applied in the field of preparation of pimaserin, and achieves the effects of shortening process steps, mild reaction conditions and low price

Inactive Publication Date: 2018-01-30
FUJIAN INST OF MICROBIOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The original patented method is based on the literature (T.enney L. Davis, et al J. Am. Chem. Soc ., 1923, 45: 1816; Gerhard Müller, et al Chem Ber 1965, 98:1097, and Org. Prep. Proc . 1986,18:149), by reacting N-(4-fluorobenzyl)-1-methylpiperidin-4-amine with urea at 150°C to obtain 1-(4-fluorobenzyl)-1-( 4-methylpiperidinyl)urea, followed by reaction with 4-isobutoxybenzylamine and 1-(4-fluorobenzyl)-1-(4-methylpiperidinyl)urea at 150 °C to give piperidine The method of Marcelin, which eliminates toxic reagents and replaces the original carbonylation reagent with low-cost, environmentally friendly urea, but the patent only gives a synthetic route without a description of the specific process or an implementation case

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] At room temperature, 1-(4-fluorobenzyl)-1-(4-methylpiperidinyl)urea 3.96g (15.0mmol), 4-isobutoxybenzaldehyde 2.67g (15.0mmol) and titanic acid Dissolve 4.26g (15.0mmol) of tetraisopropyl ester in 35mL of tetrahydrofuran, stir for 10h, slowly add 0.224g (6.0mmol) of sodium borohydride at -5 to 0°C for 6h, add 2mL of water to quench the reaction, and diatom Filter on the soil, add 2mol / L dilute hydrochloric acid to the filtrate to adjust the pH to 2~3, add 30mL water to extract, keep the water phase, add sodium hydroxide to adjust the pH to 9~10, add 50mL ethyl acetate to extract, add 15mL saturated salt The organic phase was washed with water, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidine-4 - base) 4.87g of light yellow transparent oily substance of urea, yield 76%.

[0026] 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea: H 1 NMR (500MHz, CDC...

Embodiment 2

[0028] At room temperature, 1-(4-fluorobenzyl)-1-(4-methylpiperidinyl)urea 3.92g (15mmol), 4-isobutoxybenzaldehyde 2.65g (15.0mmol) and tetratitanate Dissolve 4.21g (15.0mmol) of isopropyl ester in 35mL of toluene, stir for 10h, slowly add 0.221g (6.0mmol) of sodium borohydride at -5~0°C to react for 6h, add 2mL of water to quench the reaction, and place on diatomaceous earth Filtrate, add 2mol / L dilute hydrochloric acid to the filtrate to adjust the pH to 2~3, add 30mL water for extraction, keep the water phase, add sodium hydroxide to adjust the pH to 9~10, add 50mL ethyl acetate for extraction, add 15mL saturated saline to wash The organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated to give 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl ) 4.42g of light yellow transparent oily substance of urea, yield 70%.

Embodiment 3

[0030] At room temperature, 1-(4-fluorobenzyl)-1-(4-methylpiperidinyl)urea 5.94g (22.5mmol), 4-isobutoxybenzaldehyde 4.80g (27.0mmol) and titanic acid Dissolve 6.38g (22.5mmol) of tetraisopropyl ester in 55mL of tetrahydrofuran, stir for 10h, slowly add 0.336g (9.0mmol) of sodium borohydride at -5 to 0°C for 6h, add 3mL of water to quench the reaction, and place in diatomaceous earth Add 2mol / L dilute hydrochloric acid to the filtrate to adjust the pH to 2~3, add 45mL water to extract, keep the water phase, add sodium hydroxide to adjust the pH to 9~10, add 70mL ethyl acetate to extract, add 20mL saturated saline The organic phase was washed, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidine-4- Base) 7.98g of light yellow transparent oily substance of urea, yield 83%.

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PUM

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Abstract

The invention discloses a preparation method of pimavanserin. The preparation method comprises the following steps of mixing 1-(4-fluorobenzyl)-1-(4-methylpiperidyl)urea, 4-isobutoxybenzaldehyde and tetraisopropyl titanate in a solvent, reducing through hydroborate, and then obtaining the pimavanserin through purification. A synthesis method provided by the invention is succinct and high-efficiency, mild in reaction condition, easy to control and high in yield.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of pimaserin. Background technique [0002] On April 29, 2016, the U.S. FDA approved the Parkinson’s drug pimaserin (Nuplazid, pimavanserin, 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl) of the U.S. biopharmaceutical company Acadia Pharmaceuticals. yl)-1-(1-methylpiperidin-4-yl)urea), which became the first drug approved to treat psychiatric symptoms such as hallucinations and delusions experienced by Parkinson’s (PD) patients. Conventional Parkinson's disease treatment includes drugs that stimulate dopamine to treat motor symptoms such as tremors, muscle stiffness and difficulty walking. Pimaserin has a novel selective mechanism of action to treat hallucinations and delusions in a new mode of action. The drug does not have dopamine receptor activity and does not interfere with patients' dopaminergic therapy, so it will not affect Parkinson...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
Inventor 林燕琴陈忠成佳威赵学清范琳
Owner FUJIAN INST OF MICROBIOLOGY
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