# US 11,299,462 B2 · Crystal form of oxopicolinamide derivative and preparation method therefor

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,299,462 B2
- Document ID: US11299462B2
- Status: Granted
- Kind: B2
- Application number: 16/971,352
- Filed: 2019-02-26
- Published: 2020-12-10
- Granted: 2022-04-12
- Earliest claimed: 2018-02-27
- Assignees: Jiangsu Hengrui Medicine Co., Ltd.
- Applicants: Jiangsu Hengrui Medicine Co., Ltd.
- Inventors: Junran Yang; Lin Wang; Qiyun Shao; Zhenxing Du; Likun Wang
- Web page: https://patentgrep.com/patent/US11299462B2

## CPC

- C07D 213/69: Two or more oxygen atoms
- A61P 9/00: Drugs for disorders of the cardiovascular system
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Provided are a crystal form of an oxopicolinamide derivative and a preparation method therefor. In particular, provided are crystal forms A, B, C, D, E, and F of a compound as shown in formula (I) and a preparation method therefor. Crystal forms A, B, C, D, E, and F of the compound of formula (I) obtained in the present disclosure have good crystal stability and chemical stability, and can be better used in clinical treatment.

## Claims

### Claim 1

A crystal form of a compound of formula (I):
selected from the group consisting of:
(1) crystal form A having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 5.9, 8.8, 9.6, 13.8, 15.7 and 16.8;
(2) crystal form B having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 7.5, 12.4, 13.1, 16.8 and 19.9;
(3) crystal form C having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 7.4, 9.2, 13.3, 15.6, 15.9, 19.2, 21.7, 24.1, 24.9 and 27.3;
(4) crystal form D having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 5.3, 6.4, 8.7, 11.5, 15.9, 16.3, 20.0 and 24.7;
(5) crystal form E having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 6.6, 7.0, 8.9, 11.9, 15.1, 15.4, 16.3, 19.1, 19.9, 20.9, 23.5, 23.8, 24.3, 25.4, 26.6, 28.9 and 30.1; and
(6) crystal form F having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 6.5, 7.51, 9.9, 11.3, 13.6 and 16.5.

### Claim 2 (depends on 1)

The crystal form according to claim 1, being crystal form A having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 4.50, 5.86, 8.78, 9.60, 11.89, 12.57, 13.21, 13.76, 14.35, 15.68, 16.78, 18.01, 19.42, 19.95, 22.57, 23.76, 25.14, 27.03, 27.42 and 27.92.

### Claim 3 (depends on 1)

A method for preparing the crystal form A according to claim 1, the method comprising:
(1) adding the compound of formula (I) to a solvent (I) to obtain a mixture, and slurrying the mixture to obtain the crystal form A, wherein the solvent (I) is an ester solvent; or
(2) dissolving the compound of formula (I) in a solvent (II) to obtain a mixture, and crystallizing the crystal form A from the mixture, wherein the solvent (II) is an ester solvent, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal.

### Claim 4 (depends on 1)

The crystal form according to claim 1, being crystal form B having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 6.98, 7.53, 11.24, 12.36, 13.13, 13.59, 16.02, 16.79, 17.21, 18.12, 19.06, 19.87, 20.56, 21.65, 22.70, 23.73, 23.94, 24.50, 25.58, 25.98, 26.33, 27.87, 28.48, 28.96, 30.19, 30.77, 33.01, 34.13, 35.13, 37.83, 38.74, 41.03, 41.74, 42.91, 44.03 and 45.46.

### Claim 5 (depends on 1)

A method for preparing the crystal form B according to claim 1, the method comprising:
(1) adding the compound of formula (I) to a solvent (III) to obtain a mixture, and slurrying the mixture to obtain the crystal form B, wherein the solvent (III) is selected from the group consisting of water, an alcohol solvent, a mixed solvent of an alcohol solvent and water, a mixed solvent of an ether solvent and an alcohol solvent, and a mixed solvent of an ether solvent and water; or
(2) dissolving the compound of formula (I) in a solvent (IV) to obtain a mixture, and crystallizing the crystal form B by adding a solvent (V) to the mixture, wherein the solvent (IV) is an ether solvent, and the solvent (V) is selected from the group consisting of water, an alcohol solvent, and a mixed solvent of an alcohol solvent and water.

### Claim 6 (depends on 1)

The crystal form according to claim 1, being crystal form C having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 7.38, 9.15, 11.60, 12.82, 13.27, 14.36, 15.60, 15.91, 16.67, 17.21, 18.54, 19.18, 20.15, 21.65, 22.27, 24.06, 24.92, 26.82, 27.34, 28.96, 29.96, 32.24 and 33.08.

### Claim 7 (depends on 1)

A method for preparing the crystal form C according to claim 1, the method comprising:
(1) dissolving the compound of formula (I) in a solvent (VI) to obtain a mixture, and crystallizing the crystal form C from the mixture, wherein the solvent (VI) is selected from the group consisting of a halohydrocarbon solvent and a ketone solvent, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal; or
(2) adding the compound of formula (I) to a solvent (VII) to obtain a mixture, and slurrying the mixture to obtain the crystal form C, wherein the solvent (VII) is selected from the group consisting of a halohydrocarbon solvent, a ketone solvent and a nitrile solvent.

### Claim 8 (depends on 1)

The crystal form according to claim 1, being crystal form D having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 5.34, 6.44, 8.71, 10.85, 11.48, 12.02, 13.24, 15.91, 16.28, 18.08, 20.04, 23.22, 24.69, 25.95 and 27.30.

### Claim 9 (depends on 1)

A method for preparing the crystal form D according to claim 1, the method comprising:
dissolving the compound of formula (I) in a solvent (VIII) to obtain a mixture, and crystallizing the crystal form D from the mixture, wherein the solvent (VIII) is an ether solvent, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal.

### Claim 10 (depends on 1)

The crystal form according to claim 1, being crystal form E having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 3.60, 3.79, 4.76, 6.55, 6.98, 8.92, 11.86, 13.18, 14.33, 15.14, 15.37, 16.32, 17.19, 19.05, 19.86, 20.88, 22.75, 23.50, 23.77, 24.26, 25.38, 26.56, 28.88, 30.05 and 32.19.

### Claim 11 (depends on 1)

A method for preparing the crystal form E according to claim 1, of the method comprising:
dissolving the compound of formula (I) in a solvent (IX) to obtain a mixture, and crystallizing the crystal form E from the mixture, wherein the solvent (IX) is selected from the group consisting of a halohydrocarbon solvent, a mixed solvent of a halohydrocarbon solvent and an ester solvent, and a mixed solvent of a halohydrocarbon solvent and an ether solvent, a mixed solvent of dichloroethane and ethyl acetate, and a mixed solvent of dichloroethane and diisopropyl ether, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal.

### Claim 12 (depends on 1)

The crystal form according to claim 1, being crystal form F having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 6.46, 7.51, 9.92, 11.26, 13.15, 13.58, 15.20, 16.46, 17.38, 17.88, 19.02, 20.10, 21.10, 23.70, 24.10, 26.61, 28.78 and 29.80.

### Claim 13 (depends on 1)

A method for preparing the crystal form F according to claim 1, the method comprising:
(1) adding the compound of formula (I) to a solvent (X) to obtain a mixture, and slurrying the mixture to obtain the crystal form F, wherein the solvent (X) is an alcohol solvent; or
(2) dissolving the compound of formula (I) in a solvent (XI) to obtain a mixture, and crystallizing the crystal form F from the mixture, wherein the solvent (XI) is an alcohol solvent, and the crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatilization crystallization and crystallization induced by addition of a seed crystal.

### Claim 14 (depends on 1)

The crystal form according to claim 1, wherein the error range of 2θ is ±0.2.

### Claim 15 (depends on 1)

A pharmaceutical composition, comprising the crystal form according to claim 1 and optionally a pharmaceutically acceptable carrier, diluent and excipient.

### Claim 16 (depends on 1)

A method for preparing a pharmaceutical composition, comprising mixing the crystal form according to claim 1 with a pharmaceutically acceptable carrier, diluents or excipient.

### Claim 17 (depends on 1)

A method for treating and/or preventing a disease or condition associated with inhibition of factor XIa in a subject in need thereof, comprising administering to the subject an effective amount of the crystal form according to claim 1, wherein the disease or condition is a cardiovascular disease.

### Claim 18 (depends on 1)

The crystal form according to claim 1, being crystal form B having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 7.5, 12.4, 13.1, 13.6, 16.0, 16.8, 17.2, 19.9, 21.7, 22.7 and 23.7.

### Claim 19 (depends on 1)

The crystal form according to claim 1, being crystal form F having an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction 2θ angels of 6.5, 9.9, 11.3, 13.2, 13.6 15.2, 16.5, 17.4, 17.9 and 20.1.