Preparation method of pimavanserin intermediate

A reaction system and a technology of isocyanatomethylbenzene are applied in the field of preparation of pimavanserin intermediates, can solve problems such as huge impact on personnel health and environment, inconvenient industrialized production, etc. Reliable quality and reasonable production cost

Inactive Publication Date: 2016-08-31
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Phosgene is a highly toxic chemical with a low boiling point. It has a huge impact on human health and the environment and is strictly regulated. It requires special supporting equipment and is inconvenient for industrial production.

Method used

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  • Preparation method of pimavanserin intermediate
  • Preparation method of pimavanserin intermediate
  • Preparation method of pimavanserin intermediate

Examples

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Embodiment 1

[0022] Step 1: At room temperature, add 840 mL of dichloromethane and 90 g of compound IV into a three-neck flask, stir until completely dissolved, then use an ice-salt bath to cool down to the range of -5 to 0°C and keep it stable. 160 mL of 0.625 mol / L bis(trichloromethyl)carbonate dichloromethane solution was added dropwise into the reaction solution at a rate of 20 mL / min.

[0023] Step 2: After the bis(trichloromethyl) carbonate solution is added dropwise, keep the ice-salt bath in the range of -5 to 0°C, continue to stir the reaction for 2h, then slowly warm up to room temperature within 1h, and continue at room temperature The reaction was stirred for 3h.

[0024] Step 3: add 2000mL of purified water to the reaction system and stir for 30min, remove the water phase after layering, extract twice with 500mL of dichloromethane, and combine the extracted organic phase with the organic phase of the original reaction system. The combined organic phases were washed successive...

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Abstract

The invention relates to a preparation method of a pimavanserin intermediate which is 1-isobutoxy-4-isocyanatomethylbenzene. The preparation method comprises that 4-isobutoxyphenylmethanamine as an initial raw material and a bis(trichloromethyl)carbonate solution undergo a reaction under appropriate conditions to produce a desired product. The preparation method is free of highly toxic chemicals, has stable processes and a high yield and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a pimavanserin intermediate. Background technique [0002] Formula I compound N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-isobutoxy)benzyl)urea, common name Pi Pimavanserin is a specific inverse agonist of 5-hydroxytryptamine 2A subtype, which is 40-fold selective for 5-hydroxytryptamine 2C subtype receptors, and 5-hydroxytryptamine 2B subtype Receptors and dopamine receptors are inactive, so it does not affect the normal function of dopamine. Pimavanserin was researched and developed by Acadia Pharmaceuticals (trade name: Nuplazid) for the treatment of Parkinson's syndrome-related psychiatric diseases. It is currently undergoing phase III clinical trials, September 2014 Granted breakthrough drug status by the US FDA. [0003] [0004] The PCT patent application WO0166521 for the compound of pimavanserin was proposed by Arcadia Pharmaceutical...

Claims

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Application Information

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IPC IPC(8): C07C263/10C07C265/08
CPCC07C263/10C07C265/08
Inventor 袁金桥田文宇王玲刘芳洁
Owner HARVEST PHARMA HUNAN CO LTD
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