Crystal form a of 2-(2,5-dioxopyrrolidin-1 base) ethyl methyl fumarate and its preparation method and application

A technology of ethyl methyl fumarate and dioxopyrrolidine, which is applied to the crystal form A of 2-ethyl methyl fumarate and its preparation field, can solve the problem that it cannot be used as a pharmaceutical raw material and a product Physical state instability and other problems, to achieve good light stability, mild conditions, good efficacy

Active Publication Date: 2022-06-21
SHENZHEN RENTAI PHARMATECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The present inventor prepares the compound shown in formula (I) according to the method disclosed in Chinese authorized patent document CN105452213B and analyzes the results, and finds that the compound shown in formula (I) will crystallize when stored under high temperature, high humidity and light conditions. Type transformation, the physical state of the obtained product is unstable, so it cannot be used as a pharmaceutical raw material, and strict management is required during use, so it is not suitable for use as a pharmaceutical raw material

Method used

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  • Crystal form a of 2-(2,5-dioxopyrrolidin-1 base) ethyl methyl fumarate and its preparation method and application
  • Crystal form a of 2-(2,5-dioxopyrrolidin-1 base) ethyl methyl fumarate and its preparation method and application
  • Crystal form a of 2-(2,5-dioxopyrrolidin-1 base) ethyl methyl fumarate and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1 Characterization of bulk drug crystal properties

[0088] 2-(2,5-Dioxopyrrolidin-1-yl)ethyl methyl fumarate was purchased from Shanghai Haoyuan Biomedical Technology Co., Ltd., and the chemical purity was greater than 98%.

[0089] The XRPD pattern of the obtained API is as follows: figure 1 As shown, the characteristic peaks are shown in the following table, indicating that the compound prepared according to the method disclosed in the patent document CN105452213B is in a crystalline state, and is denoted as crystal form I.

[0090] Table 1 Characteristic peaks of crystal form I

[0091]

[0092] Further detection of the DSC and TGA curves of the drug substance such as figure 2 and 3 As shown, in the DSC curve, there is an endothermic peak at 94.0-107.0°C, and in the TGA curve, the weight loss of crystal form I before 125°C is 0.2220%.

Embodiment 2

[0093] Example 2 Preparation of Crystal Form A

[0094] Weigh 10.8 mg of raw materials into a sample bottle, add 0.4 ml of methanol to dissolve and clarify, slowly volatilize to obtain a solid, and vacuum dry at room temperature to obtain a white powder. The measured XRPD pattern is shown in Figure 4 The characteristic peaks are shown in the table below.

[0095] Table 2 Characteristic peaks of crystal form A

[0096]

[0097]

[0098] Further detection of the DSC and TGA curves of the white powder is as follows Figure 5 and 6 As shown, in the DSC curve, the crystal form A has an absorption peak at 96.0-107.0°C, and in the TGA curve, the weight loss of the crystal form A before 125°C is 0.002563%, indicating that the crystal form A is an ansolvate.

Embodiment 3

[0099] Example 3 Preparation of Crystal Form A

[0100] Weigh 8.3 mg of raw materials into a sample bottle, add 0.2 ml of ethyl acetate to dissolve and clarify at room temperature, slowly volatilize to obtain a solid, and vacuum dry at room temperature to obtain a white powder. The measured XRPD pattern is shown in Figure 7 shown, as in Example 2 Figure 4 Basically the same.

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Abstract

The present invention provides the crystal form A of 2-(2,5-dioxopyrrolidinyl) ethyl methyl fumarate, which has good light stability, high temperature stability and high humidity stability sex.

Description

technical field [0001] The invention relates to the technical field of crystal form preparation, in particular to a crystal form A of 2-(2,5-dioxopyrrolidin-1-yl)ethylmethyl fumarate and a preparation method and application thereof. Background technique [0002] 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate of the following formula (I), also known as ALKS8700, is a fumarate prodrug, developed by Alkmes Developed by Pharmaceutical Ireland Co., Ltd. (Alkermes), it is known as a drug for the treatment of psoriasis and multiple sclerosis (China authorized patents CN105452213B and 107205985B), fumarate has been approved in Germany for the treatment of psoriasis, at this time in The treatment of psoriasis and multiple sclerosis is being evaluated in the United States and has been proposed for the treatment of a wide range of immune, autoimmune and inflammatory diseases. However, fumarate has many disadvantages in use, such as side effects such as gastrointestinal reactions an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/60C07C69/90C07D207/404A61K31/40A61K31/225A61P25/00
CPCA61K31/225A61K31/40A61P25/00C07C69/60C07C69/90C07D207/404C07B2200/13
Inventor 任国宾弋东旭季伟杰黄嘉骏
Owner SHENZHEN RENTAI PHARMATECH LTD
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