CN115368358A

CN115368358A - Sotorasib novel crystal form and preparation method and application thereof

Info

Publication number: CN115368358A
Application number: CN202211067503.1A
Authority: CN
Inventors: 金从阳; 李永刚; 陈东霞; 闫益妍; 任倩; 徐巧巧; 吴立才
Original assignee: Zhejiang Jiuzhou Pharmaceutical Co Ltd
Current assignee: Zhejiang Jiuzhou Pharmaceutical Co Ltd
Priority date: 2022-09-01
Filing date: 2022-09-01
Publication date: 2022-11-22
Also published as: WO2024045633A1

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a novel crystal form of Sotoranib, a preparation method and application thereof. And the preparation process is simple and easy to implement, is suitable for industrial production, and provides a new choice for the development of Sotorasib preparations.

Description

Sotorasib novel crystal form and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a novel crystal form of Sotorasib, and a preparation method and application thereof.

Background

Sotoraib, chemically (1R) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- [ 4-methyl-2- (1-methylethyl) -3-pyridinyl ] -4- [ (2S) -2-methyl-4- (1-oxo-2-propen-1-yl) -1-piperazinyl ] -pyrido [2,3-D ] pyrimidin-2 (1H) -one, having the following structural formula:

sotorasib is a drug developed by the Anjin company for the treatment of metastatic non-small cell lung cancer (formulation trade name: lumakras) and is approved by the FDA to market 5 months 2021. On 29/1/2021, sotoranib breakthrough therapy was approved by the drug evaluation Center (CDE) of the national drug administration (NMPA).

Sotorasib belongs to water-insoluble substances, and the dosage form is generally oral tablets, so that the Sotorasib has very important significance for researching the crystal form of the Sotorasib. WO2020236947, formerly known by the Ann corporation, discloses sotorasib amorphous, anhydrate forms I, II, III, hydrate forms I, II and various solvates; WO2020236948 discloses sotorasib hydrochloride Form I-VII, phosphate Form I, mesylate Form I. In addition, patent WO2021236920 to Teva discloses sotorasib anhydrous Form IV, hydrate forms H2, H3, H4, and succinate.

Disclosure of Invention

The invention provides a new crystal form of Sotoranib, which is different from various crystal forms disclosed in the prior art, and the structure of the Sotoraib is confirmed by PXRD, NMR, DSC, TGA and GC. The crystal form has stable chemical properties, is easy to store, and is suitable for being prepared into various preparations. Compared with the existing crystal form, the preparation process of the new crystal form is simple and feasible, is suitable for industrial production, and provides a new choice for the development of the Sotoraib preparation.

The novel crystal form of Sotoranib provided by the invention is an acetic acid solvate of Sotoranib.

The crystalline form of sotoranib disclosed in the prior art includes anhydrate, hydrate, and also solvates, such as ethanolate, ethylate, etc., while acetic acid is a weak acid and is generally considered to form an acetate with sotoranib, for example, the prior art discloses the salt of sotoranib with succinic acid.

In the invention, the inventor obtains the acetic acid solvate of Sotoraib by controlling the proportion of acetic acid and Sotoraib, and the acetic acid solvate is a new crystal form of Sotoraib and is different from the prior disclosed Sotoraib crystal form through related characterization confirmation.

In the present invention, the term "solvate" is to be interpreted according to its accepted meaning, i.e. it relates to a solvent molecule incorporated into the crystal structure of sotoraib.

The X-ray powder diffraction of the new crystal form of the Sotoranib at a diffraction angle 2 theta is as follows: one or more characteristic peaks at 7.0 ° ± 0.2 °, 9.1 ° ± 0.2 °, 9.6 ° ± 0.2 °, 10.6 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.2 ° ± 0.2 °, 14.5 ° ± 0.2 °, 16.6 ° ± 0.2 °, 17.0 ° ± 0.2 °, 17.6 ° ± 0.2 °, 18.6 ° ± 0.2 °, 19.1 ° ± 0.2 °, 19.5 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.4 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.1 ° ± 0.2 °, 24.3 ° ± 0.2 °, 24.7 ° ± 0.2 °, 25.3 ° ± 0.2 °, 25.5 ° ± 0.2 ° and 28.5 ° ± 0.2 °.

Further, the differential scanning calorimetry thermogram of the new crystalline form of sotoranib of the present invention comprises an endotherm starting at 172-175 ℃.

Further, the thermogravimetric analysis heat map of the new crystalline form of Sotoranib of the present invention comprises a weight loss of 9.7-10.2% upon heating from 35-40 ℃ to 195-200 ℃.

Further, the residual solvent of the gas phase detection of the new crystal form of Sotoranib of the present invention contains 88000-95000 ppm of acetic acid.

The invention also provides a preparation method of the new crystal form of Sotoranib, which comprises the following steps:

1) The Sotoranib solid is dissolved by acetic acid and filtered;

2) Adding the acetic acid solution of Sotoranib dropwise into a solvate of water and acetic acid;

3) The precipitated solid is filtered by suction and dried.

Further, the mass-to-volume ratio of the Sotoranib solid to acetic acid in the step 1) is 1-1.

Further, the solid solution temperature and crystallization temperature of Sotoranib in the step 1) and the step 2) are both 30-50 ℃.

The invention also provides application of the novel crystal form of Sotoranib in preparation of a medicine for treating related diseases caused by KRAS G12C gene mutation.

The invention also provides a pharmaceutical composition which comprises an effective treatment amount of the novel Sotoraib crystal form and a pharmaceutically acceptable excipient.

By implementing the technical scheme, the invention has the following advantages:

the invention provides a novel crystal form of Sotorasib, which is stable in chemical property, easy to store and suitable for being prepared into various preparations. And the preparation process is simple and feasible, and is suitable for industrial production.

Drawings

FIG. 1 shows a new crystal form of Sotoraib obtained by the invention ¹ H NMR spectrum;

FIG. 2 shows a new crystal form of Sotoraib obtained by the present invention ¹³ A C NMR spectrum;

FIG. 3 is a PXRD pattern of a new crystal form of Sotoraib obtained by the present invention;

FIG. 4 is a DSC chart of the new crystal form of Sotoranib in accordance with the present invention;

FIG. 5 is a TGA profile of a novel crystalline form of Sotorasib obtained in accordance with the present invention;

FIG. 6 is a PXRD pattern of a new crystal form of Sotoranib in comparative example 1.

Detailed Description

The invention is illustrated in detail by the following examples describing in detail the methods of making and using the crystalline forms of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Example 1:

preparation of Sotorasib acetic acid solvate

10mL of acetic acid was added to 5g of Sotoraib solid, warmed to 35 ℃ to clear, and filtered. Mixing 7mL of acetic acid and 30mL of water uniformly, heating to 35 ℃, and slowly dripping the obtained filtrate for 30 min. After the dripping is finished, stirring for 1.0h at the temperature of 35 ℃ to separate out more solids. Suction filtration, washing the filter cake with a little water, vacuum drying at 40 ℃ to obtain white powder 4.8g, namely acetic acid solvate.

¹ The H NMR spectrum is shown in the attached figure 1, ¹³ the C NMR spectrum is shown in figure 2. The nuclear magnetic characterization results of the product are as follows:

¹ H NMR(400MHz,DMSO-d6)，δ11.96(1H，s),10.21(1H，s),8.39(1H，d),8.29(1H，t),7.27(1H，q),6.90(1H，d),6.91～6.82(1H，m)，6.74～6.66(2H，m)，6.23～6.18(1H，m)，5.78～5.75(1H，dd)，4.90(1H，s)，4.39～4.31(2H，m)，4.16～4.01(1H，m)，3.70～3.49(2H，m)，3.28～3.12(1H，m),2.71(1H，t),1.91(2.5H，s,HOAc),1.90(3H，s),1.34(3H，s),1.07(3H，s),0.93(3H,s)。

¹³ C NMR(100MHz,DMSO-d6)，δ172.5,165.5,163.9,163.0,161.9,159.4,157.4,157.3,154.3,153.7,151.2,150.0,148.8，145.8,144.9,144.7,132.1,132.0,131.3,128.4,128.2,123.7,123.4,123.2,112.2,110.3,110.2,110.1,110.1,106.3，106.1，105.8,105.8,51.9,51.5,49.4,45.9,45.1,44.1,42.1,40.6,40.4,39.5,39.3,30.3,22.4,22.1,21.5,17.5,16.0,15.3。

NMR 0.8mol HOAc。

PXRD patterns are collected on a Bruker D2 Phaser type X-ray diffractometer, and the specific parameters are as follows:

light source: cu Ka (1.5406A)

Pipe pressure: 30KV

Pipe flow: 10mA

Divergent slit: 1.0mm

Receiving a slit: 3.0mm

Air-scattering prevention slit (knife edge): 1.0mm

2 θ scanning range: 2-4 degree

Scanning speed step time: 0.2s/step

Step length: 0.02 degree

The PXRD spectrum is shown in figure 3, and the PXRD peak table is shown in table 1.

TABLE 1 PXRD Peak Table

Angle (2 theta)	Relative Strength (%)	Angle (2 theta)	Relative Strength (%)
				7.0	67.6	24.3	9.9
9.1	79.9	24.7	13.7
				9.6	34.3	25.3	42.8
10.6	100.0	25.5	29.7
				11.1	6.0	26.2	5.0
11.8	2.0	27.0	8.9
				13.7	29.8	27.6	4.2
14.2	95.5	28.1	6.2
				14.5	17.5	28.5	10.7
16.6	90.5	28.7	5.0
				17.0	50.5	29.4	5.3
17.6	38.5	30.3	3.8
				18.6	34.0	30.9	5.7
19.1	38.4	31.2	3.2
				19.5	27.6	33.0	2.3
20.3	6.2	33.6	4.2
				21.0	16.7	33.9	4.2
21.4	46.0	34.6	1.8
				22.4	17.5	35.5	2.0
22.8	12.4	36.4	2.5
				23.1	13.1	36.7	5.4
23.8	7.0	37.7	3.6

The DSC endotherm begins at about 174 ℃, see figure 4. The TGA contained a weight loss of about 10.1% when heated from about 39 ℃ to about 197 ℃, see figure 5. (1.0 mol of HOAc).

Residual solvent determination by GC: HOAc 93358ppm (1.0 mol HOAc).

Example 2:

preparation of Sotoranib acetic acid solvate

To 5g of Sotoraib solid, 15mL of acetic acid was added, warmed to 50 ℃ to clear, and filtered. 8mL of acetic acid and 40mL of water are mixed uniformly, the temperature is raised to 50 ℃, and the obtained filtrate is slowly dripped for 30 min. After dripping, stirring for 1.0h at the temperature of 50 ℃ to separate out more solids. Suction filtration, washing the filter cake with a little water, vacuum drying at 40 deg.C to obtain 3.9g white powder, i.e. acetic acid solvate.

The product characterization results are the same as in example 1.

Example 3:

preparation of Sotoranib acetic acid solvate

5mL of acetic acid was added to 5g of Sotoraib solid, warmed to 40 ℃ to clear, and filtered. Mixing 7mL of acetic acid and 30mL of water uniformly, heating to 40 ℃, and slowly dripping the obtained filtrate for 30 min. After dripping, stirring for 1.0h at the temperature of 40 ℃ to separate out more solids. Suction filtration, washing the filter cake with a little water, vacuum drying at 40 ℃ to obtain 4.7g of white powder, namely acetic acid solvate.

The product characterization results were the same as in example 1.

Comparative example 1:

10mL of acetic acid was added to 5g of Sotoraib solid, warmed to 60 ℃ to clear, and filtered. Mixing 7mL of acetic acid and 30mL of water uniformly, heating to 60 ℃, and then slowly dripping the obtained filtrate for 30 min. After dripping, stirring for 1.0h at the temperature of 60 ℃, and separating out more solids. Suction filtration, washing the filter cake with a little water, vacuum drying at 40 ℃ to obtain 4.2g of white powder.

The characterization result of product PXRD is the same as that of anhydrous Form I of the original patent WO2020236947, and the detailed description is shown in figure 6.

Comparative example 2:

5mL of acetic acid was added to 5g of Sotoraib solid, warmed to 40 ℃ to clear, and filtered. Heating 40mL of water to 40 ℃, and slowly dripping the obtained filtrate for 30 min. After dripping, stirring for 1.0h at the temperature of 40 ℃ to separate out more solids. Suction filtration, filter cake washing with a little water, 40 degrees vacuum drying, get white powder 4.4g.

The product PXRD characterization results were the same as in comparative example 1.

Claims

1. A novel crystalline form of Sotorasib which is an acetic acid solvate of Sotorasib.

2. The novel crystalline form of Sotorasib according to claim 1, characterized by an X-ray powder diffraction at diffraction angles 2 Θ:7.0 ^o ±0.2 ^o 、9.1 ^o ±0.2 ^o 、9.6 ^o ±0.2 ^o 、10.6 ^o ±0.2 ^o 、13.7 ^o ±0.2 ^o 、14.2 ^o ±0.2 ^o 、14.5 ^o ±0.2 ^o 、16.6 ^o ±0.2 ^o 、17.0 ^o ±0.2 ^o 、17.6 ^o ±0.2 ^o 、18.6 ^o ±0.2 ^o 、19.1 ^o ±0.2 ^o 、19.5 ^o ±0.2 ^o 、21.0 ^o ±0.2 ^o 、21.4 ^o ±0.2 ^o 、22.4 ^o ±0.2 ^o 、22.8 ^o ±0.2 ^o 、23.1 ^o ±0.2 ^o 、24.3 ^o ±0.2 ^o 、24.7 ^o ±0.2 ^o 、25.3 ^o ±0.2 ^o 、25.5 ^o ±0.2 ^o And 28.5 ^o ±0.2 ^o At one or more characteristic peaks.

3. The novel crystalline form of Sotorasib according to claim 1, wherein the differential scanning calorimetry thermogram of the novel form comprises an endotherm starting at 172 to 175 ℃.

4. The novel crystalline form of Sotorasib according to claim 1, wherein the thermogravimetric analysis heat map of the novel form comprises a weight loss of 9.7 to 10.2% when heated from 35 to 40 ℃ to 195 to 200 ℃.

5. The novel crystalline form of Sotorasib according to claim 1, wherein the novel crystalline form has a residual solvent from gas phase detection of 88000 to 95000ppm of acetic acid.

6. A process for the preparation of a new crystalline form of Sotorasib according to any one of claims 1 to 5, comprising the steps of:

1) The Sotoranib solid is dissolved by acetic acid and filtered;

2) Adding the acetic acid solution of Sotorasib dropwise into a solvate of water and acetic acid;

3) The precipitated solid is filtered by suction and dried.

7. The method as claimed in claim 6, wherein the mass-to-volume ratio of Sotoraib solid to acetic acid in step 1) is 1-3 g/mL.

8. The method for preparing the novel crystal form of Sotoraib according to claim 6, wherein the solid solution temperature and crystallization temperature of Sotoraib in step 1) and step 2) are both 30-50 ℃.

9. The novel crystal form of Sotoranib according to any one of claims 1 to 5 for use in the preparation of a medicament for the treatment of diseases associated with mutations in the KRAS G12C gene.

10. A pharmaceutical composition comprising a therapeutically effective amount of a novel crystalline form of Sotorasib according to any one of claims 1 to 5 and pharmaceutically acceptable excipients.