Preparation method for pimavanserin

A technology of pimovanserin and equation, applied in the direction of organic chemistry, etc., can solve the problems of many steps and complex synthesis conditions.

Active Publication Date: 2017-03-22
SHANDONG SIMCERE BIO PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method will also go through the 4-isobutoxyphenyl isocyanate intermediate process, and there are many steps, and the synthesis conditions are relatively complicated.

Method used

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  • Preparation method for pimavanserin
  • Preparation method for pimavanserin
  • Preparation method for pimavanserin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Add dichloromethane (5.0g) and 4-isobutoxybenzylamine (1.0g) into the reaction tube, cool down to 0-5°C, add N,N'-carbonyldiimidazole (1.0g) , kept at 0-5°C for half an hour, added N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (1.0 g), stirred at 0-5°C for 6 hours, raised the temperature to 22°C, kept Overnight (12h), water (3×10g) was added for washing, and the organic phase was taken and concentrated to obtain a viscous oil, which was separated by column chromatography as a white powdery solid (1.17g, yield 61.0%).

[0037] 1 H NMR: (400MHz,d-DMSO)δ:7.27-7.23(m,2H),7.13-7.09(m,2H),6.88-6.85(t,1H),6.85-6.83(m,2H),4.41( d,J=5.6Hz,2H),3.93-3.88(m,1H),3.71(d,J=5.6Hz,2H),2.70(d,J=11.2Hz,2H),2.31(s,1H), 2.10(s,3H),2.03-1.96(m,1H),1.90-1.85(m,2H),1.56-1.50(m,2H),1.44-1.41(m,2H),0.98(s,3H), 0.96(s,3H);

[0038] 13 C NMR: (100MHz, d-DMSO) δ: 162.5, 160.1, 158.0, 157.9, 137.8, 137.6, 137.5, 133.6, 129.4, 128.9, 128.8, 128.7, 128.6, 125.8, 115.3, 115.1, 114.5, 74....

Embodiment 2

[0040] Example 2: Dissolve 4-isobutoxybenzylamine (100.0g) in dichloromethane (500ml), cool down to 0-5°C, slowly add N,N'-carbonyldiimidazole (100.0g), and Keep at ~5°C for half an hour, add N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (100.0g), slowly raise the temperature to 18~22°C, keep stirring for 12 hours, add water (3 × 500g) washed the organic phase three times, evaporated the organic phase to remove the solvent under reduced pressure, added isopropyl acetate (600g), stirred and crystallized, filtered, and the filter cake was dried to obtain the target product (white powdery solid 163.0g, 85.0%).

Embodiment 3

[0041]Example 3: Dissolve triphosgene (14.8g) in dichloromethane (200ml), lower the temperature to -5 to 5°C, and slowly add 4-isobutoxybenzylamine (17.9g) and triethylamine (30.3 g), continue to keep for 1 hour after adding, slowly add N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (22.0g) dropwise, slowly heat up to 15-25°C after adding, keep stirring After 5 hours, use water (3 * 200g) to wash the organic phase three times, the organic phase is decompressed to remove the solvent, isopropyl acetate (110g) is added, stirred and crystallized, filtered, and the filter cake is dried to obtain the target product (white powder Solids 34.5 g, 81.6%).

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PUM

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Abstract

The invention relates to a one-pot preparation method for pimavanserin. The method prepares pimavanserin (a compound IV) from 4-isobutoxybenzylamine as shown in a formula (II) or a salt thereof, a carbonylation reagent as shown in a formula (III) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine as shown in a formula (I) by using a one-pot process. The method is highly efficient, high in yield, low in cost, safe, environment friendly and suitable for industrial production, and has great application value.

Description

technical field [0001] The invention relates to the technical field of preparation methods of pimavanserin. Background technique [0002] Pimavanserin (pimavanserin), chemical name 1-(4-fluorobenzyl)-3-(4-isobutyloxybenzyl)-1-(1-methylpiperidin-4-yl)urea Tartrate, its free base structure is as shown in formula (I). Pimavanserin, originally developed by ACADIAP Pharmaceuticals Inc., is a selective 5-HT2A inverse agonist that has been shown to be effective and well tolerated in the treatment of Parkinson's disease psychosis Sex is good, and it doesn't block dopamine receptors, so it won't make Parkinson's symptoms worse. [0003] [0004] The synthesis of pimavanserin has been described in patents CN1443167 and CN1816524. [0005] The following methods have been disclosed at home and abroad to prepare pimavanserin: [0006] a) US2008 / 0280886 discloses the preparation of pimavanserin using methyl 4-hydroxyphenylacetate as a starting material. The route is as follows: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 苗兴亮朱溪张连第
Owner SHANDONG SIMCERE BIO PHARMA CO LTD
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