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Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof

A technology of pimavanserin and compounds, which is applied to the preparation of organic compounds, chemical instruments and methods, and the preparation of carbamic acid derivatives, etc., can solve problems such as potential safety hazards, and achieve low price, simple operation, and easy separation and purification Effect

Active Publication Date: 2016-03-23
SUZHOU PENGXU PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method reported in US2008 / 0280886A1 uses a relatively expensive reagent such as DPPA. During the reaction process, an azide intermediate will be passed through to generate azide by-products, which have potential safety hazards such as explosion and severe toxicity, while US7790899B2 uses highly toxic light. Gas, large-scale production has certain safety hazards

Method used

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  • Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof
  • Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof
  • Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment 1 prepares compound 8 by compound 7

[0057]

[0058] Add compound 7 (10.0g, 81.9mmol), anhydrous potassium carbonate (22.6g, 163.8mmol), potassium iodide (1.4g, 8.2mmol) and 50mL DMF into a 250mL three-necked flask, heat to 85°C, and slowly add bromine to the reaction system Substituted isobutane (22.4g, 163.8mmol), after addition, the system was reacted at 85°C for 3h, then continued to slowly add bromoisobutane (11.2g, 81.9mmol) to the system, and the system was continued at 85°C Reaction 3h. The reaction was stopped, the system was cooled to room temperature, filtered, and the filter cake was washed twice with 100 mL of ethyl acetate. Pour the filtrate into 250mL water, separate the organic phase, extract the water phase with 100mL ethyl acetate three times, combine the organic phases, wash once with 150mL saturated NaCl aqueous solution, dry over anhydrous sodium sulfate, filter after drying, and spin the filtrate to obtain 14.0 g of compound 8, li...

Embodiment 2

[0060] Embodiment 2 prepares compound 9 by compound 8

[0061]

[0062] Add compound 8 (10.0g, 56.1mmol), 250mL ethanol, K 2 CO 3 (38.7g, 280.5mmol); Hydroxylamine hydrochloride (19.5g, 280.5mmol) was dissolved in 15mL of water, and then added to the system, after addition, the system was heated and refluxed for 2h, the reaction was stopped, cooled to room temperature, and the system was filtered. The filtrate was rotary evaporated to 100 mL, poured into 250 mL of water, and extracted three times with 100 mL of ethyl acetate. The organic phases were combined, washed once with 150 mL of saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (developer polarity: petroleum ether / ethyl acetate=20 / 1) 8.1 g of compound 9 was obtained as a white solid with a yield of 75%.

[0063] The NMR data of compound 9 are as follows: 1 HNMR(400MHz,DMSO)δ10.9...

Embodiment 3

[0064] Embodiment 3 prepares compound 10 by compound 9

[0065]

[0066] Compound 9 (4.0 g, 20.7 mmol), 60 mL of ethanol, acetic acid (2.0 g, 33.1 mmol) and Pd / C (1.2 g, Pd content 10%) were added to a 250 mL three-necked flask. After the addition, the system was catalytically hydrogenated at room temperature and atmospheric pressure. After reacting for 12 hours, filter, wash the filter cake with 30 mL of ethanol, combine the filtrate, and concentrate the filtrate to obtain an oil. Add 50 mL of ethyl acetate and 100 mL of petroleum ether to the oily matter and shake well. After standing still for 3 h, a large amount of white solid (the acetate form of compound 10) precipitates. Filter to obtain 2.3 g of white solid, add 20 mL of 30% NaOH aqueous solution, extract three times with ethyl acetate (15 mL × 3), combine the organic phases, wash with 10 mL of water and 10 mL of saturated NaCl solution once, dry over anhydrous sodium sulfate, filter, and the filtrate Concentrat...

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Abstract

The present invention relates to an intermediate of pimavanserin and a similar compound thereof, and a preparation method thereof, and a method for preparing pimavanserin and a similar compound thereof. According to the present invention, the raw materials required by the intermediate have characteristics of low price, easy obtaining, easy separation purification and no requirement of post-treatment, the next step reaction can be directly performed through the one-pot method to prepare the pimavanserin and the similar compound thereof, the operation is simple, and the economical, efficient, safe and environmentally friendly synthesis process is provided for the preparation of the pimavanserin and the similar compound thereof; and with the application of the intermediate to prepare the pimavanserin, the high toxicity and the use of the difficultly-operated phosgene can be avoided, and the total yield of the reaction can achieves the level in the prior art even the higher level.

Description

technical field [0001] The present invention relates to the synthesis of pimavanserin and similar compounds. Background technique [0002] Neurodegenerative disorders (NDs) are a group of human-associated diseases with common pathophysiological features and progressive degenerative changes of selected neural populations over a period of time. These neurodegenerative diseases include, but are not limited to, Alzheimer's disease and related dementias, Parkinson's disease, Huntington's disease, Lewy Body disease and related movement disorders, and spinocerebellar ataxia (Friedrich' sAtaxia) and related spinocerebellar ataxias. [0003] Arcadia Pharmaceuticals found that N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)- Phenylmethyl)urea (Pimavanserin) and related compounds can be used to control the behavioral and neuropsychiatric manifestations that occur in all of these disease states. Pimavanserin is a selective inverse agonist of serum 5-hydroxytrypt...

Claims

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Application Information

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IPC IPC(8): C07C269/04C07C271/16C07C271/48C07D211/58
Inventor 王鹏李丕旭刘远华杜强强
Owner SUZHOU PENGXU PHARM TECH CO LTD
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