# US 2022/0033355 A1 · Crystal form a of 2-(2, 5-dioxopyrrolidin-1yl) ethyl methyl fumarate, preparation method therefor and use thereof

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- Number: US 2022/0033355 A1
- Document ID: US20220033355A1
- Status: Published application
- Kind: A1
- Application number: 17/487,106
- Filed: 2021-09-28
- Published: 2022-02-03
- Earliest claimed: 2019-03-29
- Applicants: Shenzhen Rentai Pharmatech Ltd.
- Inventors: Guobin REN; Dongxu YI; Weijie JI; Jiajun HUANG
- Web page: https://patentgrep.com/patent/US20220033355A1

## CPC

- C07D 207/404: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
- A61K 31/225: Polycarboxylic acids
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61P 25/00: Drugs for disorders of the nervous system
- C07C 69/60: Maleic acid esters; Fumaric acid esters
- C07C 69/90: with esterified hydroxyl and carboxyl groups
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

A crystal form A of 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate has a good light irradiation stability, high-temperature stability and high-humidity stability.

## Claims

### Claim 1

A crystal form A of 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate, wherein the X-ray powder diffraction thereof using Cu-Kα radiation has characteristic peaks at 2θ diffraction angles of 13.5±0.2°, 17.9±0.2°, 23.0±0.2° and 27.3±0.2°.

### Claim 2 (depends on 1)

The crystal form A of claim 1, wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 13.3±0.2°, and 18.2±0.2°.

### Claim 3 (depends on 2)

The crystal form A of claim 2, wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 19.3±0.2°, and 19.6±0.2°.

### Claim 4 (depends on 3)

The crystal form A of claim 3, wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 16.6±0.2°, 20.9±0.2°, 22.0±0.2°, 24.3±0.2°, 25.3±0.2°, and 30.6±0.2°.

### Claim 5 (depends on 4)

The crystal form A of claim 4, wherein the X-ray powder diffraction thereof using Cu-Kα radiation has further characteristic peaks at 2θ diffraction angles of 6.92±0.2°, 11.5±0.2°, 16.1±0.2°, 23.7±0.2°, 26.9±0.2°, and 31.1±0.2°.

### Claim 6 (depends on 1)

The crystal form A of claim 1, wherein the crystal form A has following characteristic peaks in X-ray powder diffraction pattern:
No. of Peaks
2θ (°)
I %
1
13.3
72.3
2
13.54
19.8
3
17.878
82.2
4
22.962
100
5
27.34
97.2

### Claim 7 (depends on 1)

The crystal form A of claim 1, wherein the crystal form A has following characteristic peaks in X-ray powder diffraction pattern:
No. of Peaks
2θ (°)
I %
1
6.92
12.8
2
11.481
6.1
3
13.3
72.3
4
13.54
19.8
5
16.562
14.5
6
17.878
82.2
7
18.24
5.1
8
19.282
2.5
9
19.644
2.9
10
20.901
53
11
21.98
18.4
12
22.962
100
13
24.26
25.7
14
26.858
13.5
15
27.34
97.2

### Claim 8 (depends on 1)

The crystal form A of claim 1, wherein the crystal form A has following characteristic peaks in X-ray powder diffraction pattern:
No. of Peaks
2-Theta
I %
d (Å)
1
6.92
12.8
12.764
2
11.481
6.1
7.7013
3
13.3
72.3
6.6517
4
13.54
19.8
6.5344
5
16.562
14.5
5.3481
6
17.878
82.2
4.9572
7
18.24
5.1
4.8597
8
19.282
2.5
4.5995
9
19.644
2.9
4.5155
10
20.901
53
4.2467
11
21.98
18.4
4.0405
12
22.962
100
3.87
13
23.681
7.3
3.754
14
24.26
25.7
3.6657
15
25.34
8.2
3.5119
16
26.858
13.5
3.3167
17
27.34
97.2
3.2593
18
30.621
14.4
2.9171
19
31.099
11.6
2.8734

### Claim 9 (depends on 1)

The crystal form A of claim 1, wherein the crystal form A has an X-ray powder refraction pattern substantially as shown in FIG. 4.

### Claim 10 (depends on 1)

The crystal form A of claim 1, wherein the crystal form A has a characteristic endothermic peak in a temperature range of 96.0° C.-107.0° C. measured by differential scanning calorimetry.

### Claim 11 (depends on 1)

The crystal form A of claim 1, wherein the crystal form A has a differential scanning calorimetry curve substantially as shown in FIG. 5.

### Claim 12 (depends on 1)

The crystal form A of claim 1, wherein the crystal form A has a weight loss of less than 0.01% before a temperature of 125° C. in its thermo gravimetric analysis curve.

### Claim 13 (depends on 1)

The crystal form A of claim 1, wherein the crystal form A has a thermo gravimetric analysis curve substantially as shown in FIG. 6.

### Claim 14 (depends on 1)

A method for preparing the crystal form A of claim 1, comprising the following steps of: dissolving 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate by adding a good solvent thereto, evaporating the solvent or cooling to give a solid, and drying the solid to obtain the crystal form A as a powder.

### Claim 15 (depends on 14)

The method of claim 14, wherein said dissolving is performed by adding the good solvent at a temperature of 50° C. to 65° C., and said cooling is performed at a temperature of −18° C. to 4° C. to give a solid.

### Claim 16 (depends on 1)

A method for preparing the crystal form A of claim 1, comprising the following steps of: dissolving 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate by adding a good solvent thereto, then adding a poor solvent, separating a solid and drying to obtain the crystal form A as a powder.

### Claim 17 (depends on 16)

The method of claim 16, wherein the good solvent is added at a temperature of 15° C. to 35° C. for dissolving, and the poor solvent is added at a temperature of 15° C. to 35° C. to obtain a solid.

### Claim 18 (depends on 14)

The method of claim 14, wherein the good solvent is an organic solvent selected from the group consisting of a lower alcohol, a lower ketone, a lower ester, a lower nitrile, and a lower ether;
preferably, the lower alcohol is selected from the group consisting of methanol, ethanol, isopropanol or n-butanol, the lower ketone is acetone or 4-methyl-2-pentanone, the lower ester is ethyl acetate, the lower ether is tetrahydrofuran or dioxane, and the lower nitrile is acetonitrile.

### Claim 19 (depends on 14)

The method of claim 14, wherein a ratio of 2-(2, 5-dioxopyrrolidin-1yl)ethyl methyl fumarate to the good solvent is (10-40) mg:(0.1-5) mL.

### Claim 20 (depends on 16)

The method of claim 16, wherein the poor solvent is select from n-heptane, n-hexane, or absolute ethyl ether.

### Claim 21 (depends on 1)

A pharmaceutical composition, comprising the crystal form A of claim 1 and a pharmaceutically acceptable excipient.

### Claim 22 (depends on 1)

A method for treating a neurological disease, comprising administering a pharmaceutically effective amount of the crystal form A of claim 1 or a pharmaceutical composition comprising the same.

### Claim 23 (depends on 22)

The method of claim 22, wherein the neurological disease is multiple sclerosis or psoriasis.

### Claim 24 (depends on 22)

The method of claim 22, wherein the medicament is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal, sublingually rectally, as a topical, inhalation, intranasal, or transdermally.