# US 10,479,789 B2 · Pyrido[1,2-A]pyrimidone analog, crystal form thereof, intermediate thereof and preparation method therefor

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- Number: US 10,479,789 B2
- Document ID: US10479789B2
- Status: Granted
- Kind: B2
- Application number: 16/061,279
- Filed: 2016-12-16
- Published: 2018-11-08
- Granted: 2019-11-19
- Earliest claimed: 2015-12-16
- Assignees: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
- Applicants: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
- Inventors: Tao Yu; Ning Li; Lingwei Kong; Peipei Jiang; Yong Wang; Zhemin Rong; Changjun Wang; Feng Guo; Zongbin Li; Zheng Wang; Jiahu Wu; Chengde Wu
- Web page: https://patentgrep.com/patent/US10479789B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 35/00: Antineoplastic agents
- 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
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Disclosed in the present invention are a crystalline Form of pyrido[1,2-a]pyrimidone analog, a preparation method therefor and an intermediate thereof.

## Claims

### Claim 1

Crystalline forms of Compound 1 as represented by the following formula or salts thereof, wherein crystalline Forms of Compound 1 or the salts thereof are selected from the group consisting of Crystalline Forms I, II, III, IV, V, VI, VII, VIII and IX:

### Claim 2 (depends on 1)

Crystalline forms of Compound 1 or the salts thereof of claim 1, characterized in that crystalline Form IX of Compound 1 has diffraction peaks at 2θ=7.947°, 10.073°, 14.531°, 19.187°, 21.237°, 24.055°, 25.497° in a X-ray diffraction pattern.

### Claim 3 (depends on 2)

Crystalline forms of Compound 1 or the salts thereof of claim 2, characterized in that XRPD pattern analysis data of crystalline Form IX is as follows:
Relative
Nos.
2θ degree
intensity %
1
6.014
2.5
2
7.947
29.0
3
10.073
54.2
4
11.970
23.3
5
13.053
5.9
6
13.468
14.4
7
14.531
62.5
8
14.828
49.7
9
15.911
31.1
10
17.369
21.8
11
17.569
26.1
12
17.941
4.5
13
18.377
1.6
14
19.187
55.2
15
19.561
41.3
16
19.855
61.5
17
20.233
22.2
18
21.237
62.8
19
21.984
22.0
20
22.373
3.2
21
23.073
2.2
22
23.446
32.9
23
24.055
100.0
24
24.847
6.6
25
75.497
60.4
26
26.265
1.3
27
27.074
28.0
28
27.448
10.1
29
27.862
22.8
30
28.081
15.6
31
29.005
4.5
32
29.445
3.3
33
30.171
13.0
34
31.014
1.5
35
31.437
0.7
36
31.963
19.5
37
32.381
23.5
38
33.937
9.1
39
34.565
4.7
40
35.218
6.8
41
36.403
5.8
42
36.897
3.7
43
38.103
7.1
44
38.605
6.8
45
39.502
2.6.

### Claim 4 (depends on 2)

Crystalline forms of Compound 1 or the salts thereof of claim 2, characterized in that a XRPD pattern of crystalline Form IX is as shown in FIG. 25.

### Claim 5 (depends on 1)

Crystalline forms of Compound 1 or the salts thereof of claim 1, wherein the salt is represented by the following formula Compound 2,
characterized in that crystalline Form I of Compound 2 has diffraction peaks at 2θ=10.1540°, 12.285°, 14.511°, 16.328°, 24.311°, 26.188° in a X-ray diffraction pattern.

### Claim 6 (depends on 1)

Crystalline forms of Compound 1 or the salts thereof of claim 1, wherein the salt is represented by the following formula Compound 2,
characterized in that crystalline Form II of Compound 2 has diffraction peaks at 2θ=6.524°, 7.782°, 13.895°, 15.495°, 17.487°, 19.322° in a X-ray diffraction pattern.

### Claim 7 (depends on 1)

Crystalline forms of Compound 1 or the salts thereof of claim 1, wherein the salt is represented by the following formula Compound 2,
characterized in that crystalline Form III of Compound 2 has diffraction peaks at 2θ=6.979°, 9.939°, 14.392°, 16.107°, 20.982°, 25.990° in a X-ray diffraction pattern.

### Claim 8 (depends on 1)

Crystalline forms of Compound 1 or the salts thereof of claim 1, wherein the salt is represented by the following formula Compound 2,
characterized in that crystalline Form IV of Compound 2 has diffraction peaks at 2θ=6.388°, 7.278°, 11.076°, 15.454°, 21.256° in a X-ray diffraction pattern.

### Claim 9 (depends on 1)

Crystalline forms of Compound 1 or the salts thereof of claim 1, wherein the salt is represented by the following formula Compound 2,
characterized in that crystalline Form V of Compound 2 has diffraction peaks at 2θ=7.116°, 14.137°, 15.911°, 22.223°, 24.610° in a X-ray diffraction pattern.

### Claim 10 (depends on 1)

Crystalline forms of Compound 1 or the salts thereof of claim 1, wherein the salt is represented by the following formula Compound 2,
characterized in that crystalline Form VI of Compound 2 has diffraction peaks at 2θ=5.775°, 11.77°, 14.415°, 15.753°, 22.518°, 26.623° in a X-ray diffraction pattern.

### Claim 11 (depends on 1)

Crystalline forms of Compound 1 or the salts thereof of claim 1, wherein the salt is represented by the following formula Compound 3,
characterized in that crystalline Form VII of Compound 3 has diffraction peaks at 2θ=6.325°, 12.677°, 15.813°, 21.395°, 22.519°, 27.133° in a X-ray diffraction pattern.

### Claim 12 (depends on 1)

Crystalline forms of Compound 1 or the salts thereof of claim 1, wherein the salt is represented by the following formula Compound 4,
characterized in that crystalline Form VIII of Compound 4 has diffraction peaks at 2θ=5.889°, 11.002°, 12.518°, 14.906°·17.825°, 22.814°, 25.555° in a X-ray diffraction pattern.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising crystalline forms of Compound 1 or the salts thereof of claim 1, wherein the pharmaceutical composition comprises a therapeutically effective amount of the crystalline forms, and optionally pharmaceutically acceptable carriers, excipients and/or media.

### Claim 14 (depends on 1)

A method for treating colon cancer and/or gastric cancer, comprising administering a therapeutically effective amount of crystalline forms of Compound 1 or the salts thereof of claim 1 to patients in need.

### Claim 15

A method for preparing Compound 1 as represented by the following formula,
comprising the following steps,
wherein
X is selected from Cl or Br;
alkali C is selected from pyridine, 2,6-lutidine, Et3N, 4-DMAP, LiOH, Cs2CO3, or K2CO3;
solvent c is selected from pyridine, dichloromethane, toluene, acetonitrile, acetone, DMF or THF;
a molar ratio of Compound 7 to Compound 8 is 1:1-3;
a molar ratio of Compound 7 to alkali C is 1:1˜3.

### Claim 16 (depends on 15)

The method of claim 15, the method comprises the following steps,
wherein
alkali A is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, or sodium hydroxide;
solvent a is selected from DMF, DMSO, or NMP;
alkali B is selected from potassium carbonate, sodium carbonate, barium hydroxide, potassium phosphate, cesium carbonate, potassium fluoride, cesium fluoride, sodium hydroxide, potassium t-butoxide, sodium t-butoxide, potassium acetate or sodium acetate;
solvent b is selected from 1,4-dioxane, DMSO, THF, 1,4-dioxane/water or THF/water;
a volume ratio of 1,4-dioxane or THE to water in said solvent b is 3˜6:1;
a catalyst is selected from Pd(dppf)Cl2, or Pd(PPh3)4;
2-dimethylaminoethyl chloride or 2-dimethylaminoethyl bromide can be in the form of its salt.

### Claim 17

A compound represented by the following formula, as intermediates for preparation of Compound 1,