Tartaric acid pimavanserin impurities and preparation method thereof

A technology of pimavanserin and tartaric acid, which is applied in the field of drug synthesis and can solve problems such as no relevant reports on the synthesis method

Active Publication Date: 2017-09-29
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Current patents US20070260064A1, WO2008144326A2, CN105153016A, and CN101778821A only report two impurities of pimavanserin tartrate: impurity D and impurity F, wherein impurity F is an intermediate, and the synthesis method of impurity D has no relevant reports; impurity A, impurity B, impurity C, impurity E and their directional synthesis methods have not been reported

Method used

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  • Tartaric acid pimavanserin impurities and preparation method thereof
  • Tartaric acid pimavanserin impurities and preparation method thereof
  • Tartaric acid pimavanserin impurities and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1: Preparation of N-(4-isobutoxybenzyl) diphenyl iminodicarboxylate (impurity A)

[0053]Add 5.2g (0.029mol) 4-isobutoxybenzylamine, 11.7g (0.116mol) triethylamine, 3.5g (0.029mol) 4-dimethylaminopyridine (DMAP) to 300ml dichloromethane at room temperature , and cooled the solution to -5°C-0°C. 11.3 g (0.072 mol) of phenyl chloroformate was added dropwise at -5°C-0°C, and after 40 minutes, the solution was transferred to room temperature and heated to 40°C for 12 hours. After completion of the reaction, the reaction solution was washed with 400ml × 2 (8%) dilute hydrochloric acid aqueous solution, separated into layers, the organic layer was washed with 300ml water, 300ml × 2 saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain 11.5 g pale yellow solid crude product, add 60ml petroleum ether and 8ml ethyl acetate, recrystallize at 60°C to obtain 7.8g whi...

Embodiment 2

[0054] Embodiment 2: Preparation of 4-isobutoxybenzyl phenyl carbonate (impurity B)

[0055] Add 50.0g (0.41mol) p-hydroxybenzaldehyde, 84.8g (0.62mol) potassium carbonate, 2.0g (0.012mol) potassium iodide to 200ml N,N-dimethylformamide at room temperature, stir at room temperature for 10min, add 111.4g (0.82mol) of bromoisobutane was heated to 83°C for 24h. After the reaction is complete, filter with suction, pour the filtrate into 300ml of 4% sodium hydroxide aqueous solution and stir for 5min, extract twice with 350×2 ethyl acetate, combine the organic layers, wash the organic layer with 500ml×2 saturated saline, and dry over anhydrous sodium sulfate , evaporate the solvent under reduced pressure to obtain 64.6g light yellow oil crude product 4-isobutoxybenzaldehyde, yield: 88.5%,

[0056] Add 27.6g (0.73mol) of sodium borohydride to 300ml of tetrahydrofuran at room temperature, cool the mixture to 0°C, add 64.6g (0.36mol) of crude 4-isobutoxybenzaldehyde to 100ml of tetra...

Embodiment 3

[0058] Example 3: Preparation of 4-fluorobenzyl (1-methylpiperidin-4-yl)carbonate-4-isobutoxybenzyl ester (impurity C) by method 1

[0059] Method 1: 15.0g (0.035mol) 4-isobutoxybenzyl phenyl carbonate (impurity B) crude product, 7.8g (0.035mol) N-(4-fluorobenzyl)-1-methyl - Add 4-piperidine and 8.0g (0.058mol) potassium carbonate to 80ml N,N-dimethylformamide, heat up to 50°C and react for 5h. After the reaction was completed, filter with suction, add 100ml of water, extract with 150ml×2 ethyl acetate, wash the organic layer with 300ml×3 saturated brine, dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure to obtain 10.5g of crude yellowish-brown oily product, yield 70.0 %. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a colorless transparent liquid. ESI-MS:429.4[M+H] + , 451.3[M+Na] + , 1 H NMR (600MHz, DMSO-d 6 ): δ7.25 (dd, J=8.4Hz, 5.4Hz, 2H, ArH), 7.11 (d, J=8.4H...

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Abstract

The invention discloses tartaric acid pimavanserin impurities, namely N-(4-isobutoxy benzyl) diphenyl aminodiphthalate (impurity A), 4-isobutoxy benzyl carbonic acid phenyl ester (impurity B), 4-fluorobenzyl (1-methylpiperidine-4-yl) carbonic acid-4-isobutoxy benzyl ester (impurity C) and N-( isobutoxy benzyl)-N'-(4-fluorobenzyl) urea (impurity E). In addition, the invention further discloses a preparation method of tartaric acid pimavanserin impurities A, B, C and E and an N,N'-bis(4-isobutoxy benzyl) urea (impurity D). Through application of the tartaric acid pimavanserin impurities as reference substances in research on the quality of the tartaric acid pimavanserin intermediate, a crude drug and a compound preparation thereof, a solid foundation is laid for research on the quality of tartaric acid pimavanserin.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to pimavanserin tartrate impurities and a preparation method thereof. Background technique [0002] Parkinson's disease (PD), also known as Parkinson's paralysis, is a common chronic progressive central nervous system degenerative disease in middle-aged and elderly people, mainly caused by the degeneration of dopamine receptors in the basal ganglia, and the clinical manifestation is resting tremor , muscle rigidity, slowness of movement, and abnormal posture. At present, there are about 7-10 million Parkinson's disease patients in the world, and half of Parkinson's disease patients will develop into mental illness. Parkinson's diseasepsychosis (PDP) often appears in the late stage of Parkinson's disease, and the most common symptom is visual hallucinations. The global cost of treatment and care for Parkinson's disease patients is 41 billion pounds per year, which poses a ...

Claims

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Application Information

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IPC IPC(8): C07C271/66C07C269/04C07C69/96C07C68/00C07C41/26C07C43/23C07D211/58C07C275/24C07C271/48C07C273/18
CPCC07C41/26C07C68/00C07C69/96C07C269/04C07C271/66C07C273/1836C07C275/24C07D211/58C07C43/23C07C271/48
Inventor 王绍杰庞良胜
Owner SHENYANG PHARMA UNIVERSITY
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