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

Abstract

The invention belongs to the technical field of medicine, and specifically relates to a new crystal form of Sotorasib and its preparation method and application. The new crystal form is an acetic acid solvate of Sotorasib, has stable chemical properties, is easy to store, and is suitable for making various preparations. Moreover, the preparation process is simple and easy, suitable for industrial production, and provides a new option for the development of Sotorasib preparations.

Description

A new crystal form of Sotorasib and its preparation method and application

technical field

The invention belongs to the technical field of medicine, and specifically relates to a new crystal form of Sotorasib and a preparation method and application thereof.

Background technique

Sotorasib, chemical name (1R)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridyl ]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]-pyrido[2,3-D]pyrimidine-2 (1H)-ketone, its structural formula is as follows:

Sotorasib is a drug developed by Amgen for the treatment of metastatic non-small cell lung cancer (preparation trade name: Lumakras), which was approved by the FDA in May 2021. On January 29, 2021, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China granted breakthrough therapy designation to sotorasib.

Sotorasib is a poorly water-soluble substance, and its dosage form is generally oral tablets, so the research on its crystal form is of great significance. The patent WO2020236947 of Yuanyan Amgen Company discloses sotorasib amorphous form, anhydrous Form I, II, III, hydrate Form I, II and various solvates; WO2020236948 discloses sotorasib hydrochloride FormI-VII, phosphate Form I, mesylate salt Form I. In addition, Teva's patent WO2021236920 discloses sotorasib anhydrate Form IV, hydrate Form H2, H3, H4, and succinate.

Contents of the invention

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

The new crystal form of Sotorasib provided by the present invention is the acetic acid solvate of Sotorasib.

The crystal forms of Sotorasib disclosed in the prior art include anhydrous, hydrate, and solvate, such as alcoholate, ethyl acetate, etc., and acetic acid is a weak acid, which is generally considered to form acetate with Sotorasib, such as the present Salt formation of Sotorasib with succinic acid is disclosed in the prior art.

In the present invention, the inventor obtained the acetic acid solvate of Sotorasib by controlling the ratio of acetic acid and Sotorasib, the conditions of dissolution and crystallization, and confirmed by relevant characterization that it is a new crystal form of Sotorasib, which is different from the existing disclosed crystal form of Sotorasib. Types are not the same.

In the present invention, the term "solvate" is interpreted according to its accepted meaning, ie it refers to solvent molecules incorporated into the crystal structure of Sotorasib.

The above-mentioned new crystal form of Sotorasib, its X-ray powder diffraction at diffraction angle 2θ is: 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 one or more characteristic peaks at 28.5°±0.2°.

Further, the differential scanning calorimetry thermogram of the new crystal form of Sotorasib of the present invention contains an endotherm starting at 172-175°C.

Further, the thermal gravimetric analysis thermogram of the new crystal form of Sotorasib of the present invention includes a weight loss of 9.7-10.2% when heated from 35-40°C to 195-200°C.

Furthermore, the residual solvent of the new crystal form of Sotorasib in the present invention is detected by gas phase, and contains 88,000-95,000 ppm of acetic acid.

The present invention also provides a preparation method of a new crystal form of Sotorasib, comprising the following steps:

1) Dissolving the Sotorasib solid with acetic acid and filtering;

2) the acetic acid solution of Sotorasib is added dropwise in the solvate of water and acetic acid;

3) Suction filter and dry the precipitated solid.

Further, the mass volume ratio of Sotorasib solid to acetic acid in step 1) is 1:1-1:3g/mL.

Further, the solid dissolution temperature and crystallization temperature of Sotorasib in step 1) and step 2) are both 30-50°C.

The present invention also provides the use of the above-mentioned new crystal form of Sotorasib for the preparation of medicines for treating related diseases caused by KRAS G12C gene mutation.

The present invention also provides a pharmaceutical composition, comprising the therapeutically effective amount of the above-mentioned new crystal form of Sotorasib and a pharmaceutically acceptable excipient.

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

The invention provides a new crystal form of Sotorasib, which has stable chemical properties, is easy to store, and is suitable for making various preparations. Moreover, the preparation process is simple and easy, and is suitable for industrial production.

Description of drawings

Accompanying drawing 1 is the ¹ H NMR spectrum of the new crystal form of Sotorasib obtained in the present invention;

Accompanying drawing 2 is the ¹³ C NMR spectrum of the new crystal form of Sotorasib obtained in the present invention;

Accompanying drawing 3 is the PXRD collection of illustrative plates of the new crystal form of Sotorasib gained in the present invention;

Accompanying drawing 4 is the DSC collection of illustrative plates of the new crystal form of Sotorasib obtained in the present invention;

Accompanying drawing 5 is the TGA collection of illustrative plates of the new crystal form of Sotorasib gained in the present invention;

Accompanying drawing 6 is the PXRD spectrum of the new crystal form of Sotorasib obtained in Comparative Example 1 of the present invention.

Detailed ways

The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use methods of the crystal form of the present invention. It will be apparent to those skilled in the art that many changes in both materials and methods can be made without departing from the scope of the invention.

Example 1:

Preparation of Sotorasib acetic acid solvate

Add 10 mL of acetic acid to 5 g of Sotorasib solid, heat up to 35 ° C to dissolve, and filter. Mix 7mL of acetic acid and 30mL of water evenly, raise the temperature to 35°C, and then slowly add the above-mentioned filtrate into the mixture, and the dripping is completed in 30 minutes. After dripping, keep stirring at 35°C for 1.0h, and more solids precipitate out. After suction filtration, the filter cake was washed with a small amount of water, and dried under vacuum at 40°C to obtain 4.8 g of white powder, namely acetic acid solvate.

¹ H NMR spectrum is shown in Figure 1, and ¹³ C NMR spectrum is shown in Figure 2. The NMR 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, 1381.3 ,128.2,123.7,123.4,123.2,112.2,110.3,110.2,110.1,110.1,106.3,106.1,105.8,105.8,51.9,51.5,49.4,45.9,45.1,44.1,42.1,40.6,30.3,4.9,39 , 22.4, 22.1, 21.5, 17.5, 16.0, 15.3.

NMR 0.8 mol HOAc.

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

Light source: Cu Ka (1.5406A)

Pipe pressure: 30KV

Pipe flow: 10mA

Divergence slit: 1.0mm

Receiving slit: 3.0mm

Anti-air scattering slit (knife edge): 1.0mm

2θ scanning range: 2°～4°

Scan rate step: 0.2s/step

Step size: 0.02°

PXRD spectrum is shown in accompanying drawing 3, and PXRD peak list is shown in Table 1.

Table 1 PXRD peak table

Angle (2θ) Relative Strength(%) Angle (2θ) 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 starts at about 174°C, see Figure 4. The TGA contained about 10.1% weight loss when heated from about 39°C to about 197°C, see Figure 5. (1.0 mol HOAc).

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

Example 2:

Preparation of Sotorasib acetic acid solvate

Add 15 mL of acetic acid to 5 g of Sotorasib solid, heat up to 50 ° C to dissolve, and filter. Mix 8mL of acetic acid and 40mL of water evenly, raise the temperature to 50°C, and then slowly add the above-mentioned filtrate into the mixture, and the dripping is completed in 30 minutes. After dripping, keep stirring at 50°C for 1.0h, and more solids precipitate out. After suction filtration, the filter cake was washed with a small amount of water, and dried under vacuum at 40°C to obtain 3.9 g of white powder, ie, acetic acid solvate.

Product characterization results are the same as in Example 1.

Example 3:

Preparation of Sotorasib acetic acid solvate

Add 5 mL of acetic acid to 5 g of Sotorasib solid, heat up to 40°C to dissolve, and filter. Mix 7mL of acetic acid and 30mL of water evenly, raise the temperature to 40°C, and then slowly add the above-mentioned filtrate into the mixture, and the dripping is completed in 30 minutes. After dripping, keep stirring at 40°C for 1.0h, and more solids precipitate out. After suction filtration, the filter cake was washed with a small amount of water, and dried under vacuum at 40°C to obtain 4.7 g of white powder, namely acetic acid solvate.

Product characterization results are the same as in Example 1.

Comparative example 1:

Add 10 mL of acetic acid to 5 g of Sotorasib solid, heat up to 60 ° C to dissolve, and filter. Mix 7mL of acetic acid and 30mL of water evenly, raise the temperature to 60°C, and then slowly add the above-mentioned filtrate into the mixture, and the dripping is completed in 30 minutes. After dripping, keep stirring at 60°C for 1.0 h, and a lot of solids precipitate out. Suction filtration, the filter cake was washed with a small amount of water, and vacuum-dried at 40°C to obtain 4.2 g of white powder.

The PXRD characterization results of the product are the same as the anhydrous Form I of the original patent WO2020236947, see Figure 6 for details.

Comparative example 2:

Add 5 mL of acetic acid to 5 g of Sotorasib solid, heat up to 40°C to dissolve, and filter. Warm up 40mL of water to 40°C, then slowly add the filtrate obtained above dropwise, and finish dropping in 30min. After dripping, keep stirring at 40°C for 1.0h, and more solids precipitate out. Suction filtration, the filter cake was washed with a small amount of water, and vacuum-dried at 40°C to obtain 4.4 g of white powder.

The PXRD characterization results of the product are the same as in Comparative Example 1.

Claims (10)

1. A new crystal form of Sotorasib, characterized in that the new crystal form is the acetic acid solvate of Sotorasib. 2. A new crystal form of Sotorasib according to claim 1, characterized in that its X-ray powder diffraction at diffraction angle 2θ is: 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° ^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. A new crystal form of Sotorasib according to claim 1, wherein the differential scanning calorimetry heat map of the new crystal form includes an endotherm starting at 172-175°C. 4. A new crystal form of Sotorasib according to claim 1, wherein the thermogravimetric analysis heat map of the new crystal form contains 9.7-10.2% of weight loss. 5. the new crystal form of a kind of Sotorasib according to claim 1, is characterized in that, the gas phase detection residual solvent of described new crystal form contains the acetic acid of 88000～95000ppm. 6. A preparation method of the new crystal form of Sotorasib as described in any one of claims 1-5, characterized in that, comprising the following steps: 1) Dissolve the Sotorasib solid with acetic acid and filter; 2) Add the acetic acid solution of Sotorasib dropwise to the solvate of water and acetic acid; 3) Suction filter and dry the precipitated solid. 7. the preparation method of the new crystal form of a kind of Sotorasib according to claim 6, is characterized in that, the mass volume ratio of the Sotorasib solid in step 1) and acetic acid is 1:1～1:3g/mL. 8. The preparation method of a new crystal form of Sotorasib according to claim 6, characterized in that, the solid solution temperature and crystallization temperature of Sotorasib in step 1) and step 2) are both 30-50°C. 9. The new crystal form of Sotorasib according to any one of claims 1-5, which is used for the preparation of medicines for treating related diseases caused by KRAS G12C gene mutation. 10. A pharmaceutical composition, comprising a therapeutically effective amount of the new crystal form of Sotorasib according to any one of claims 1-5, and a pharmaceutically acceptable excipient.

Images