Method for preparing pimavanserin and tartrate thereof

A technology for pimaserin and hemi-tartrate, which is applied in the field of improved preparation of pimaserin and its tartrate, can solve the problem of 4-(2-methylpropoxy)benzene which endangers the health of production members, is unsuitable for storage, and Problems such as poor stability of methyl isocyanate

Inactive Publication Date: 2017-10-24
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In this method, phosgene is used to prepare 4-(2-methylpropoxy) phenylmethyl isocyanate. Phosgene is highly toxic, has a great impact on the environment, and endangers the health of production mem

Method used

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  • Method for preparing pimavanserin and tartrate thereof
  • Method for preparing pimavanserin and tartrate thereof
  • Method for preparing pimavanserin and tartrate thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0054] The preparation of embodiment 1 compound 2

[0055] Dissolve (4.7g, 47.5mmol) BTC in 190ml DCM, cool down to 0°C and stir for 30min. (24g, 108mmol) compound 1 and (21.8g, 216mmol) triethylamine were dissolved in 50ml DCM. At 0°C, slowly drop the mixed solution into the above-mentioned triphosgene-dichloromethane solution, stir for 30 minutes after the dropwise addition, warm up to room temperature (30°C), stir and react for 24 hours, and the remaining amount of compound 1 is controlled by HPLC ≤ 1.0% . After the reaction was completed, the pH was adjusted to 5-6, the liquid was separated, extracted with DCM, the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain 27.63 g of compound 2 with a yield of 90% and a purity of 98.2%.

[0056] LCMS-ESI + Characterization: 285.1[M+H + ].

[0057] 1 HNMR characterization: (400MHz, CDCl 3 )7.28(t, J=8.0,2H),6.99(t,J=10.0,2H),5.19(d,J=12.0,1H),3.93(d,J=16.0,1H),3.58(m,3H ), 3.54(m,1...

Embodiment 2

[0059] The preparation of embodiment 2 compound 2

[0060] 14.7g of BTC (0.44eq, 47.50mmol) was dissolved in 190ml of dichloromethane (8vol), and the temperature was lowered to 0°C and stirred. 24g (107.96mmol) of compound 1 and 21.8g of triethylamine (2.0eq, 215.92mmol) were miscibly dissolved in 50ml of dichloromethane (2vol), and the mixed solution was slowly Add dropwise the above-mentioned triphosgene in dichloromethane solution. After the dropwise addition was completed and stirred for 30 min, the temperature was raised to room temperature (30° C.) for reaction. The reaction was stirred at room temperature for 24 hours, and the detection of compound 1 by HPLC was below 3%. After the reaction was completed, the pH was adjusted, the liquid was separated, extracted, and the organic phase was rotary evaporated in vacuum to obtain 27.63 g of liquid compound 2 with a yield of 90%.

Embodiment 3

[0061] The preparation of embodiment 3 compound 2

[0062] Dissolve 9.4g of BTC (0.44eq, 31.67mmol) in 130ml of dichloromethane (8vol), and stir at -5°C. Mix 16g of compound 1 (71.97mmol) and 11.36g of pyridine (2.0eq, 143.94mmol) in 30ml of DCM (2vol), and slowly drop the mixed solution into the above-mentioned Sanko gas in dichloromethane solution. After the dropwise addition was completed and stirred for 30 minutes, the temperature was raised to room temperature (30° C.) and the reaction was stirred for 18 hours. Compound 1 was detected to be below 1% by HPLC. After the reaction was completed, the pH was adjusted, the liquid was separated, extracted, and the organic phase was rotary evaporated in vacuum to obtain 19.04 g of liquid compound 2 with a yield of 92.9%.

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Abstract

The invention provides an improved method for preparing pimavanserin and tartrate thereof. The method comprises the following steps: taking a compound 4-(4-fluorobenzylamino)-1-methylpiperidine as a starting material and carrying out acylation reaction on the starting material and triphosgene in the presence of triethylamine to prepare a compound (4-fluorobenzyl)-(1-methylpiperidine-4-yl)carbamyl chloride; then taking the (4-fluorobenzyl)-(1-methylpiperidine-4-yl)carbamyl chloride and 4-isobutoxybenzylamine to react in the presence of triethylamine, so as to prepare the pimavanserin and the tartrate thereof. The method provided by the invention is simple, efficient and economical and the quality of an intermediate is controllable, so that the method is suitable for industrial preparation.

Description

technical field [0001] The invention belongs to the technical field of organic and pharmaceutical synthesis, and in particular relates to an improved method for preparing pimaserin and tartrate thereof. Background technique [0002] Pimaserin (also known as Pimavanserin), generic name Pimavanserin, trade name Nuplazid, also known as N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidin Pyridyl)-N'-[[4-(2-methylpropoxy)phenyl]methyl]-urea, 1-(4-fluorobenzyl)-1-(1-methylpiperidine- 4-yl)-3-[4-(2-methylpropoxy)benzyl]urea or, N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl base)-N'-(4-(2-methylpropoxy)phenylmethyl)urea or ACP-103, the structural formula is as follows: [0003] [0004] Formula (I) Pimaserin is a non-dopamine neurotransmitter substance, and as an inverse agonist of 5-HT2A receptor, it can selectively block 5-HT2A receptor without affecting the effect of dopamine. Pimaserin exhibits antipsychotic, antikinesia and antiinsomnia activities. [0005] Formula (...

Claims

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Application Information

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IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 雷鑫田发银何方李东明
Owner SUNSHINE LAKE PHARM CO LTD
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