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Pyrazole compound, crystal form thereof and preparation method of crystal form

A technology of compound and pyrazoles, which is applied in the field of pyrazoles, can solve the problems of TM2002 hydrochloride crystal form, which has no relevant literature reports and XRPD data, and achieves good fluidity, stable yield, and reduced The effect of impurities

Pending Publication Date: 2017-11-21
CHINA NAT MEDICINES GUORUI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] As we all know, crystal form is very important to the stability and solubility of raw materials and preparations, but there is no relevant literature report on the crystal form of TM2002 hydrochloride
In the patent document WO2005054205, methanol and 2N hydrochloric acid methanol were used to crystallize, and concentrated with ethanol to obtain crystalline TM2002 hydrochloride powder, but its XRPD data was not reported

Method used

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  • Pyrazole compound, crystal form thereof and preparation method of crystal form
  • Pyrazole compound, crystal form thereof and preparation method of crystal form
  • Pyrazole compound, crystal form thereof and preparation method of crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Dissolve 1 g of crude TM2002 in a mixed solvent of 2.5 mL of concentrated hydrochloric acid, 5 mL of water and 10 mL of acetone at 40 °C, heat to reflux for 0.5 h, filter while hot, and cool the filtrate to precipitate a solid. The initial temperature of crystallization is 42 °C, 0 Keep warm in an ice-water bath at ~5°C for 1.5 hours, filter, wash the filter cake with acetone, and dry at 30°C to obtain 0.65 g of TM2002 hydrochloride. After testing, the purity was >99.0%, and the yield was 65%.

[0089] In the present embodiment, the MS and NMR data of product are as follows:

[0090] EMS-MS m / z:324.1[M+H] + ;

[0091] 1 H-NMR (400MHz, CDCl 3 +CF 3 COOH)δ: 2.35(s,3H,CH 3 ),2.68(s,3H,CH 3 ),5.32-5.43(m,2H,CH 2 ), 6.64 (s, 1H, CH), 7.26-7.51 (m, 7H), 8.10 (s, 1H).

[0092] Tested by XRPD and DSC, the test results are as follows Figure 7 with Figure 8 As shown, the specific XRPD data are shown in Table 5. The TM2002 hydrochloride prepared in Example 1 is record...

Embodiment 2

[0098] Carry out single crystal cultivation on crystal II to obtain single crystal, the specific preparation method is as follows:

[0099] Dissolve 1 g of TM2002 crude product in 4 mol / L hydrochloric acid aqueous solution (30ml), heat to 90°C to completely dissolve the TM2002 crude product, leave it at room temperature overnight to cool the material slowly, and precipitate solid at 48°C, taking granular crystals is the present invention A single crystal of the crystal, which was determined to be Form II by XRPD, was designated as single crystal II.

[0100] The obtained single crystal II was subjected to single crystal X-ray diffraction experiment, and the results are as follows:

[0101] 1 Diffraction experiment

[0102] The crystal of the present invention is colorless and transparent columnar, and the crystal size used in diffraction experiment is 0.12×0.13×0.18mm, belongs to monoclinic system, space group P21 / c, unit cell parameters: a=6.8753(14), b=27.905(6 ), α=γ=90...

Embodiment 3

[0112] Dissolve 30g of crude TM2002 in a mixed solvent of 135mL of concentrated hydrochloric acid, 15mL of water and 900mL of ethanol, heat to 80°C until the crude TM2002 is completely dissolved, add 1g of activated carbon, reflux for 15min, filter while it is hot, cool the filtrate to 48°C, and add seed crystals Ⅱ. The seed crystal Ⅱ is a solid particle determined to be crystal form Ⅱ by XRPD detection. The solid was precipitated at 48°C, kept in an ice-water bath for 1h, filtered, the filter cake was washed with ethanol, and dried at 50°C to obtain 24.9g of TM2002 hydrochloride . After testing, the purity was 99.9%, and the mono-heterohydrochloride was less than 0.1%. The obtained TM2002 hydrochloride was determined to be the same as the sample in Example 1 by XRPD. It was TM2002 monohydrochloride monohydrate, and the corresponding crystal form was crystal form II.

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Abstract

The invention discloses a pyrazole compound, a crystal form thereof and a preparation method of the crystal form. The pyrazole compound is a 1-(5-hydroxyl-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol monohydrochloride monohydrate. The TM2002 monohydrochloride monohydrate and the crystal form thereof have favorable flowability, and are beneficial to the operation of preparations in the preparation process, thereby improving the quality of the product. The preparation method disclosed by the invention is simple, quick, mild in preparation conditions and stable in yield, thereby being suitable for large-scale production.

Description

technical field [0001] The invention relates to a pyrazole compound, its crystal form and a preparation method thereof. Background technique [0002] 1-(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridine-7 -Alcohol hydrochloride (hereinafter referred to as TM2002 hydrochloride), is a protein modification generation inhibitor, its structural formula is as shown in formula 1: [0003] [0004] TM2002 hydrochloride, as an inhibitor of protein modification, has no side effects (such as vitamin B6 deficiency) of other protein modification inhibitors (such as edaravone), and has a protective effect on the kidney. [0005] As we all know, crystal form is very important to the stability and solubility of raw materials and preparations, but there is no relevant literature report on the crystal form of TM2002 hydrochloride. In the patent document WO2005054205, methanol and 2N hydrochloric acid methanol were used to crystallize, and then concentra...

Claims

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Application Information

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IPC IPC(8): C07D491/048
CPCC07B2200/13C07D491/048
Inventor 裘鹏程张福利潘林玉余俊蒋敏王震宇
Owner CHINA NAT MEDICINES GUORUI PHARMA
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