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New apremilast crystal form H and preparation method thereof

A technology of crystal form and characteristic peaks, applied in the field of medicinal chemistry, to achieve the effect of good stability and strong solubility

Inactive Publication Date: 2018-08-24
WEIHAI DISU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Therefore, the currently known crystal forms of apremilast all have certain defects in solubility properties. The development of a preparation process is simple, the solubility is strong, the stable form is relatively good, and the non-solvated crystal form is still of great value.

Method used

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  • New apremilast crystal form H and preparation method thereof
  • New apremilast crystal form H and preparation method thereof
  • New apremilast crystal form H and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: Preparation of crystal form H

[0037] Put 5.0 g of Apremilast and 150 ml of absolute ethanol into a 250 ml three-neck flask, continue to stir and heat to 78° C. to reflux to dissolve the liquid, and the stirring rate is 200 r / min. After refluxing for 10 minutes, start to lower the temperature of the system to 10°C at a cooling rate of 10°C / h, grow crystals at this temperature for 2 hours, filter, and dry the solid at 50°C with air blast to constant weight. The molar yield of the process is 90.5%, and the measured HPLC purity is 99.96%. The results of X-ray powder diffraction and differential scanning calorimetry analysis showed that the solid was apremilast crystal form H.

Embodiment 2

[0038] Embodiment 2: Preparation of crystal form H

[0039] Put 5.0 g of Apremilast, 130 ml of acetone, and 130 ml of purified water into a 500 ml three-neck flask, continue stirring and heating to 50°C to dissolve, and the stirring rate is 300 r / min. Continue stirring at constant temperature for 10 min after dissolving. Afterwards, the temperature of the system was lowered to 5°C, the cooling rate was 30°C / h, and the crystal was grown at this temperature for 3 hours, filtered, and the solid was air-dried at 50°C until constant weight. The molar yield of the process is 72.1%, and the measured HPLC purity is 99.95%. The results of X-ray powder diffraction and differential scanning calorimetry analysis showed that the solid was apremilast crystal form H.

Embodiment 3

[0040] Embodiment 3: the preparation of crystal form H

[0041] Put 5.0 g of Apremilast and 300 ml of isopropanol into a 500 ml three-necked flask, continue stirring and heating to 75°C to dissolve, and the stirring rate is 300 r / min. Continue stirring at constant temperature for 10 min after dissolving. Then cool the system down to 50°C at a cooling rate of 5°C / h, then add the solid form containing crystal form H as a seed crystal to induce crystallization, and continue to grow crystals at this temperature for 3 hours, filter, and blast the solid at 50°C Dry to constant weight. The molar yield of the process is 81.0%, and the measured HPLC purity is 99.96%. The results of X-ray powder diffraction and differential scanning calorimetry analysis showed that the solid was apremilast crystal form H.

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Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a new apremilast crystal form H and a preparation method thereof. The crystal form H is characterized in that a. differential scanning calorimetry analysis shows that only one endothermic peak exists within a temperature range of 100-180 DEG C, and the endothermic peak top value is 156 + / -3 DEG C; b. the X-ray powder diffraction pattern has the following characteristic peaks at 2theta+ / -0.2: 7.980, 14.494, 14.723, 15.081, 17.317, 18.261, 19.147, 20.362, 21.809, 23.138, 23.505, 25.057; c. the X-ray powder diffraction pattern has no characteristic peak at the position where 2theta+ / -0.2 is 8.443 and 15.482. The invention provides the highly dissolved new apremilast crystal form H.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a new crystal form H of apremilast and a preparation method thereof. Background technique [0002] Apremilast (English name is Apremilast), the chemical name is S-(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl-ethyl] -4-Acetylaminoisoindoline-1,3-dione; molecular formula C 22 h 24 N 2 o 7 S, CAS No. 608141-41-9, is a small molecule selective phosphodiesterase (PDE4) inhibitor, researched and developed by Celgene Biotechnology Company, and was approved by FDA for the treatment of psoriasis in March 2014 disease arthritis, curative effect is definite. Its structural formula is as follows: [0003] [0004] As we all know, drug polymorphism is an important factor affecting the quality of drugs, which has an important impact on the physical and chemical properties of drugs, bioavailability, and the quality of related preparations. At present, this type of p...

Claims

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Application Information

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IPC IPC(8): C07D209/48
CPCC07D209/48C07B2200/13
Inventor 王冠孙详彧姜凯丛日刚
Owner WEIHAI DISU PHARMA CO LTD
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