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Synthesis method for pimavanserin intermediate

A technology of pimavanserin and synthetic method, which is applied in the field of drug synthesis, can solve the problems of danger, no advantage, and high price in the scale-up production of lithium tetrahydrogen, and achieve good industrial application value, mild reaction conditions, and high yield Effect

Active Publication Date: 2017-08-04
杭州科耀医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Andersen, Valdemar L. et al. (Bioorganic and MedicinalChemistry Letters, 2015, vol.25, #5p.1053-1056) used lithium tetrahydrogen for reduction, and the yield was 54%. Not only the yield was low, but also the enlarged production of lithium tetrahydrogen Dangerous, the raw material p-hydroxybenzonitrile is more expensive than p-hydroxybenzaldehyde
WO2017 / 15272A1 uses hydrogenation reduction to achieve a yield of 80-90%, but the raw material p-hydroxybenzonitrile is expensive compared with p-hydroxybenzaldehyde, and this route has no advantages

Method used

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  • Synthesis method for pimavanserin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Synthesis of 4-isobutoxybenzaldehyde:

[0029] Add 122g of 4-hydroxybenzaldehyde (1mol), 600mL of DMF, 256g of potassium carbonate (1.85mol) and 12g of potassium iodide (0.07mol) into the reaction flask, then raise the temperature to 100°C, and start to add 274g of bromoisobutane dropwise. After completion, react overnight at 100°C, TLC shows that the reaction of 4-hydroxybenzaldehyde is complete and can be processed, the reaction solution is suction filtered, washed with 600mL of dichloromethane, the filtrate is washed twice with 600mL of water, once with 600mL of saturated saline, and separated The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 178 g of the product, which was directly put into the next step reaction.

Embodiment 2

[0030] Example 2 Synthesis of 4-isobutoxybenzyl alcohol:

[0031] Dissolve 178g of 4-isobutoxybenzaldehyde (1mol) obtained in the above steps with 900mL of methanol, cool down to 0°C, then add 38g of sodium borohydride (1mol) in batches, control the temperature of the reaction temperature below 10°C, and complete the addition. Raise the temperature to 25°C for 2 hours, TLC monitors that the reaction is complete, add dropwise 6N hydrochloric acid to quench, spin dry, add 900mL dichloromethane and 900mL water, stir, separate the organic phase, wash the organic phase with 900mL saturated saline, and separate the organic phase , dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 180 g of the product, which was directly put into the next reaction.

Embodiment 3

[0032] Example 3 Synthesis of 4-isobutoxybenzyl chloride:

[0033] Dissolve 180g of 4-isobutoxybenzyl alcohol (1mol) obtained in the above steps in 900mL of dichloromethane, add 18g of DMF, cool down to 0°C, add 357g of thionyl chloride (3mol), and heat up to 25 After reacting overnight at ℃, the reaction was complete as monitored by TLC, and 900 mL of water was added dropwise. After dropping, the organic phase was separated, washed with 900 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 199 g of the product, which was directly put into the next reaction.

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Abstract

The invention discloses a synthesis method for a pimavanserin intermediate. The synthesis method comprises the steps of firstly allowing 4-hydroxybenzaldehyde to react with iso-butyl bromide to obtain 4-isobutoxybenzaldehyde as an initial raw material; and directly carrying out reduction reaction on aldehyde and carrying out a series of steps of chlorination and amination, so that harsh conditions for reducing oxime are avoided; meanwhile, various steps have relatively high yield; and the next step can be carried out on the intermediate without separation, so that industrial production is facilitated.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of a pimavanserin intermediate. Background technique [0002] Pimavanserin is a patented drug independently developed by Acadia Pharmaceuticals in the United States. It is used to treat the mental symptoms of Parkinson's disease. It is a non-dopamine neurotransmitter analog and can selectively block 5- Serotonin 2A receptors without affecting the action of dopamine. Pimavanserin (Nuplazid) was granted breakthrough therapy certification by the US Food and Drug Administration (FDA) on September 3, 2014. On April 29, 2016, it was approved for marketing by FDA. [0003] 4-isobutoxybenzylamine (4-(2-METHYLPROPOXY)-BENZENEMETHANAMI-NE) is a key intermediate for the synthesis of pimavanserin, and its molecular formula is: C 11 h 17 NO, molecular weight: 179.26, structural formula as follows: [0004] [0005] The synthesis of 4-isobutoxybenzylamin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/64C07C47/575C07C41/26C07C43/23C07C41/22C07C43/225C07C213/00C07C217/58C07D209/48C07C51/41C07C53/08
CPCC07C41/22C07C41/26C07C45/64C07C51/41C07C213/00C07D209/48C07C47/575C07C43/23C07C43/225C07C217/58C07C53/08
Inventor 周军明
Owner 杭州科耀医药科技有限公司
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