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Method for continuously preparing pimavanserin by using micro-channel reactor

A technology of microchannel reactor and pimavanserin, which is applied in the field of medicine and chemical industry, can solve the problems of high price of DPPA, high production risk and difficulty in industrialization, so as to improve the overall safety, occupy less production space and lower the price Effect

Inactive Publication Date: 2020-10-27
杭州珠联医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional key intermediate 4-isobutoxybenzyl isocyanate preparation process requires the use of highly toxic reagents such as hydroxylamine aqueous solution, phosgene, or 4-isobutoxybenzoic acid and diphenylphosphoryl azide (DPPA). Curtius reaction is obtained, but DPPA is expensive and explosive, the production is dangerous, and it is difficult to industrialize

Method used

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  • Method for continuously preparing pimavanserin by using micro-channel reactor
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  • Method for continuously preparing pimavanserin by using micro-channel reactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: the synthesis of hydrazide compound (I)

[0038] Add 100g of p-hydroxyphenylacetic acid into a 500mL four-necked bottle, add 300ml of ethanol, add 83g of thionyl chloride dropwise at 0-10°C, heat up to 65-70°C to react for 2-3 hours, concentrate to remove ethanol, and obtain p-hydroxyl Ethyl phenylacetate. Yield 98%.

[0039] Add 200mL DMF, 115g potassium carbonate, 50g ethyl p-hydroxyphenylacetate and 76g bromoisobutane into a 500mL four-neck flask, stir and heat to 75-80°C for 2 hours, cool and filter to remove solids, add water and ethyl acetate ester, the organic phase was separated and concentrated to obtain the product ethyl 4-isobutoxybenzoate with a yield of 90%.

[0040] Add 100g of ethyl 4-isobutoxybenzoate, 500mL of ethanol, 100mL of 80% hydrazine hydrate into a 1000mL reaction flask, heat and reflux to keep the reaction until the ethyl 4-isobutoxybenzoate is less than 0.5%, and recover ethanol by distillation About 300mL, stop the distillati...

Embodiment 2

[0041] Embodiment 2: microchannel reaction synthesis pimavanserin

[0042]

[0043] Material A: hydrazide compound (I) is dissolved in dichloromethane

[0044] Material B: Sodium Nitrite / Water

[0045] Material C: 30% hydrochloric acid

[0046] Material D sodium hydroxide / water

[0047] Material E: (4-fluorobenzyl)-(1-methylpiperidin-4-yl)amine in dichloromethane

[0048] Silicon carbide reactor holding liquid 20.8mL

[0049] Advection pump 4 sets

[0050] The reactor equipment holds 20 mL of liquid, and there are 10 reaction sheets in total. The first sheet is connected to material A, material B and material C, the fifth sheet is connected to material D, and the sixth sheet is connected to material E. The flow rate of each pump is set according to the molar ratio A: B:C:D:E=1:1.05:1.1:0.95:0.95

[0051] The back pressure valve is connected to the back of the tenth piece, and the set pressure is 1.5MPa

[0052] The temperature of 1-4 reaction sheets is 15-20°C, the tem...

Embodiment 3

[0054] Embodiment 3: microchannel reaction synthesis pimavanserin

[0055] Material A: hydrazide compound (I) is dissolved in dichloromethane

[0056] Material B: Sodium Nitrite / Water

[0057] Material C: 30% hydrochloric acid

[0058] Material D sodium hydroxide / water

[0059] Material E: (4-fluorobenzyl)-(1-methylpiperidin-4-yl)amine in dichloromethane

[0060] Silicon carbide reactor holding liquid 20.8mL

[0061] Advection pump 4 sets

[0062] The reactor equipment holds 20 mL of liquid, and there are 10 reaction sheets in total. The first sheet is connected to material A, material B and material C, the fifth sheet is connected to material D, and the sixth sheet is connected to material E. The flow rates of each pump are set according to the molar ratio A: B:C:D:E=1:1.2:1.25:0.95:0.95

[0063] The back pressure valve is connected to the back of the tenth piece, and the set pressure is 1.5MPa

[0064] The temperature of 1-4 reaction sheets is 15-20°C, the temperature...

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Abstract

The invention discloses a method for continuously preparing pimavanserin by using a micro-channel reactor. The method comprises the following steps: dissolving a reaction substrate in an organic solvent, pumping the material solution into a micro-channel reactor by using a feeding pump, sufficiently mixing, and carrying out continuous Curtius rearrangement and addition reaction to obtain the pimavanserin. According to the invention, the micro-channel reactor is adopted for reaction, so that the mixing uniformity is good, the reaction time is shortened, and the operation is simple and safe; andthe environmental pollution is obviously reduced.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to the continuous preparation of pimavanserin by using a microchannel reactor, which has the advantages of safety, environmental protection and suitability for industrialization. Background technique [0002] The traditional chemical and pharmaceutical industry has always relied on batch production. It is necessary to consider the amplification effect and avoid the influence of some strong exothermic high temperature conditions. Moreover, the quality of products produced in each batch is different. Therefore, the traditional batch production method has been facing problems of quality, Cost, safety, environmental protection and other pressures. [0003] In recent years, flow chemistry technology represented by microchannel reactor has emerged as the times require. Microchannel reactors have incomparable advantages over large reactors in the field of chemistry...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58C07C265/08C07C263/12C07C243/32C07C241/04
CPCC07D211/58C07C263/12C07C241/04
Inventor 陈冲杜小华车大庆
Owner 杭州珠联医药科技有限公司
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