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Crystal form of N-(4-fluorobenzyl)-N-(1-methyl piperidine-4-yl)-N'-(4-(2-methylpropanolato)-phenylmethyl)urea hemitartrate and preparation method thereof

A technology of methyl propoxy and hemi-tartrate, which is applied in the field of chemical medicine to achieve the effect of improving bioavailability, low humidity and good repeatability

Active Publication Date: 2015-10-07
CRYSTAL PHARMATECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These psychiatric symptoms are mainly manifested as hallucinations and delusions, which bring greater challenges to the treatment and care of patients with Parkinson's disease

Method used

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  • Crystal form of N-(4-fluorobenzyl)-N-(1-methyl piperidine-4-yl)-N'-(4-(2-methylpropanolato)-phenylmethyl)urea hemitartrate and preparation method thereof
  • Crystal form of N-(4-fluorobenzyl)-N-(1-methyl piperidine-4-yl)-N'-(4-(2-methylpropanolato)-phenylmethyl)urea hemitartrate and preparation method thereof
  • Crystal form of N-(4-fluorobenzyl)-N-(1-methyl piperidine-4-yl)-N'-(4-(2-methylpropanolato)-phenylmethyl)urea hemitartrate and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Preparation of Form I:

[0070] 504.3 mg of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenylmethyl) The powder of urea hemitartrate was dissolved in 10mL of water, placed in the refrigerator to freeze overnight, freeze-dried for 6 hours, and the solid obtained by freeze-drying was added to 16mL of dichloromethane / n-heptane mixed solvent with a volume ratio of 1:4, at room temperature The crystal form I can be obtained by stirring under the same conditions for 6 days. Table 1 shows the X-ray powder diffraction data of Form I obtained in this example.

[0071] Its X-ray powder diffraction pattern is as figure 1 As shown, its differential scanning calorimetry diagram is shown in figure 2 As shown, its thermogravimetric analysis diagram is shown in image 3 .

[0072] Table 1 X-ray powder diffraction data of crystal form Ⅰ

[0073] 2theta d interval Relative Strength% 4.87 18.15 36.81 5.49 16.10 22.82 6.22 14...

Embodiment 2

[0076] Preparation of Form I:

[0077] 1000.4 mg of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenylmethyl) Dissolve the powder of urea hemitartrate in 15 mL of water, freeze overnight in the refrigerator, and freeze-dry for 7 hours to obtain N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N' - (4-(2-Methylpropoxy)-phenylmethyl)urea hemitartrate amorphous powder. Then 22.56 mg of the amorphous solid was weighed and added to 1 mL of dichloromethane / n-heptane mixed solvent with a volume ratio of 1:4, and stirred at room temperature for 1 day to obtain. The X-ray powder diffraction data of the crystal form I obtained in this embodiment are shown in Table 2.

[0078] Table 2 X-ray powder diffraction data of crystal form Ⅰ

[0079] 2theta d interval Relative Strength% 4.76 18.56 100.00 5.39 16.38 49.24 6.12 14.43 74.55 10.76 8.23 17.93 13.99 6.33 32.21 15.49 5.72 16.88 16.98 5.22 33.60 17.65 5...

Embodiment 3

[0081] Stability study of crystal form Ⅰ:

[0082] Take two portions of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenylmethyl)urea The sample of hemitartrate crystal form I is exposed and placed in the constant temperature and humidity chamber of 25 ℃, 60% relative humidity and 40 ℃, 75% relative humidity respectively, after 60 days, sampling measures XRPD (X-ray powder diffraction) and HPLC ( Purity was measured by high performance liquid chromatography. The experimental results are shown in Table 3. Stability study XRPD comparison chart Figure 4 shown.

[0083] Table 3 Stability study of Form Ⅰ

[0084]

[0085]

[0086] The results showed that the crystalline form I was stored for two months under the conditions of 25°C, 60% relative humidity and 40°C, 75% relative humidity, the crystal form remained unchanged and the purity was very high. The test results show that the crystal form I of the present invention has good stability.

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Abstract

The invention provides a crystal form, named as crystal form I, of N-(4-fluorobenzyl)-N-(1-methyl piperidine-4-yl)-N'-(4-(2-methylpropanolato)-phenylmethyl)urea hemitartrate and a preparation method thereof. The crystal form I is characterized by having characteristic peaks in an X-ray powder diffraction pattern when the value of 2theta is 14.0 DEG + / - 0.2 DEG, 17.0 DEG + / - 0.2 DEG, 18.6 DEG + / - 0.2 DEG, 6.1 DEG + / - 0.2 DEG, 4.8 DEG + / - 0.2 DEG and 20.9 DEG + / - 0.2 DEG. The crystal form I has the excellent characteristics of high solubility, good stability and low hygroscopicity, has superiority in industrial production and is applicable to preparation process and long-term storage.

Description

Technical field [0001] The invention relates to the field of chemical medicine, in particular to N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy) -Crystal form of phenylmethyl)urea hemitartrate and preparation method thereof. Background technique [0002] N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenylmethyl)urea (formula Ⅰ The shown compound), also known as Pimavanserin, is an antipsychotic drug developed by American biopharmaceutical company Acadia (Acadia), which is used to improve the psychiatric symptoms of Parkinson's disease and is currently in the clinical stage. [0003] At present, there are about 7 million to 10 million Parkinson's disease patients in the world, and more than 50% of Parkinson's disease patients have had mental symptoms. These psychiatric symptoms mainly manifest as hallucinations and delusions, which bring greater challenges to the treatment and care of patients with Parkinson's disease. Classic...

Claims

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Application Information

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IPC IPC(8): C07D211/58C07C51/43C07C59/255A61K31/4468A61P25/16
CPCC07B2200/13C07D211/58
Inventor 陈敏华张炎锋陆飞杨朝惠张晓宇王鹏李丕旭
Owner CRYSTAL PHARMATECH CO LTD
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