JP2018002644A - (S)-N-(4-AMINO-5-(QUINOLINE-3-YL)-6,7,8,9-TETRAHYDROPYRIMIDO[5,4-b]INDOLIZINE-8-YL)ACRYLAMIDE CRYSTAL - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel crystal of (S)-N-(4-amino-5-(quinoline-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizine-8-yl)acrylamide and a method for producing the same.SOLUTION: Provided is a crystal of (S)-N-(4-amino-5-(quinoline-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizine-8-yl)acrylamide in which, in the powder X-ray diffraction spectrum, the diffraction angle (2θ±0.2°) has at least three or more peaks selected from 8.9°, 13.7°, 17.3°, 19.5°, 21.8°, 22.8°, 25.4° and 28.1°.SELECTED DRAWING: None

Description

  The present invention relates to (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) The present invention relates to a novel crystal of acrylamide and a method for producing the same. More specifically, the present invention relates to a novel crystal that is excellent in stability and can be industrially produced as a crystal of a drug substance used in the manufacture of a pharmaceutical, a method for producing the crystal, and a pharmaceutical composition containing the crystal as an active ingredient.

  In general, when a compound is used as an active ingredient of a pharmaceutical product, it is necessary that a single crystal having a certain quality is stably obtained with good reproducibility. The obtained single crystal preferably has excellent stability and oral absorbability.

  Patent Document 1 discloses a novel compound that inhibits EGFR (d746-750), EGFR (L858R), EGFR (d746-750 / T790M), and EGFR (T790M / L858R), but does not inhibit EGFR (WT). The following formula (1)

(S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl ) Acrylamide (hereinafter also referred to as “compound 1”). Furthermore, Patent Document 1 discloses that the above compound has a cancer cell growth inhibitory action, and is a useful compound as a medicament for treating cancer.

  (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizine- described in Patent Document 1 As a method for producing 8-yl) acrylamide, the obtained reaction product was purified by silica gel column chromatography, and a foamy substance (amorphous) was obtained.

  As described above, (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [S] -N- (4-amino-5-yl) -6 is preferable as a drug substance crystal used in the manufacture of pharmaceuticals. 5,4-b] Indolizine-8-yl) acrylamide crystals and their production methods are completely unknown.

International Publication WO2013 / 125709

  The present invention is an industrially produced crystal having excellent inhibitory activity against EGFR and cancer cell growth inhibitory activity, excellent oral absorption and stability as a drug substance used in the manufacture of pharmaceuticals, and good acquisition reproducibility. It is intended to be provided in a way that can be produced.

  The present inventor has conducted intensive research to solve the above-mentioned problems. As a result, the crystal I of Compound 1 is excellent in oral absorption and stability, has good acquisition reproducibility, and can be industrially produced. I found out.

  Moreover, the manufacturing method which can produce the crystal | crystallization I of the compound 1 industrially was discovered by adding the process of adding the compound 1 to a solvent, and adding water and crystallizing.

  That is, this invention includes the following aspects.

  Item 1. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydro having at least three peaks selected from 4 ° and 28.1 ° Crystals of pyrimido [5,4-b] indolizine-8-yl) acrylamide.

  Item 2. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Item 2. The crystal according to Item 1, which is a crystal having at least 5 or more peaks selected from 4 ° and 28.1 °.

  Item 3. Item 3. The crystal according to Item 1 or 2, wherein the powder X-ray diffraction spectrum has the following powder X-ray diffraction spectrum.

  Item 4. Item 4. The crystal according to any one of Items 1 to 3, wherein an endothermic top peak temperature is about 271 ° C. ± 5 ° C. in differential scanning calorimetry.

  Item 5. The crystal | crystallization of any one of claim | item 1 -4 which has the following differential scanning calorimetry (DSC) curves in differential scanning calorimetry.

  Item 6. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Item 2. The crystal according to Item 1, wherein the crystal has at least three or more peaks selected from .4 ° and 28.1 °, and has an endothermic top peak temperature of about 271 ° C. ± 5 ° C. in differential scanning calorimetry.

  Item 7. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Item 2. The crystal according to Item 1, having at least 5 or more peaks selected from .4 ° and 28.1 °, and having an endothermic top peak temperature of about 271 ° C. ± 5 ° C. in differential scanning calorimetry.

Item 8. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Having at least three or more peaks selected from .4 ° and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and the infrared (IR) absorption spectrum ^{in, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, at least three or more characteristic absorption band selected from the 956cm ^-1 and 754cm ^-1 (peak) (error: ± The crystal | crystallization of claim | item 1 which has 5 cm <^-1> ).

Item 9. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Having at least five or more peaks selected from .4 ° and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and the infrared (IR) absorption spectrum ^{in, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, at least 5 or more characteristic absorption band selected from the 956cm ^-1 and 754cm ^-1 (peak) (error: ± The crystal | crystallization of claim | item 1 which has 5 cm <^-1> ).

Item 10. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 .4 ° and 28.1 ° peaks, in the differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and in the infrared (IR) absorption spectrum, 1665 cm ⁻¹ , 1600 cm ^{− 1, 1535cm -1, 1438cm -1,} 1233cm -1, characteristic absorption bands of 956cm ^-1 and 754cm ^-1 (peak) (error: ± ^{5 cm -1)} having a crystal according to claim 1.

  Item 11. In the powder X-ray diffraction spectrum, it has the following powder X-ray diffraction spectrum,

In differential scanning calorimetry, it has the following differential scanning calorimetry (DSC) curve,

In the infrared (IR) absorption spectrum analysis near the fingerprint region, it has the IR absorption spectrum shown below,

Item 4. The crystal according to Item 1.

  Item 12. The crystal | crystallization of any one of claim | item 1 -11 whose content of dimethylsulfoxide (DMSO) is 5000 ppm or less.

  Item 13. Methanol content is 3000 ppm or less, ethanol content is 5000 ppm or less, n-propanol content is 5000 ppm or less, isopropanol content is 5000 ppm or less, acetone content is 5000 ppm or less, acetonitrile content is 410 ppm or less, The content of dimethyl sulfoxide (DMSO) is 5000 ppm or less, the content of dimethylformamide (DMF) is 880 ppm or less, the content of dimethylacetamide (DMA) is 1090 ppm or less, and the content of N-methylpyrrolidone (NMP) is 530 ppm or less The crystal | crystallization of any one of claim | item 1 -12 which is these.

Item 14. Step (1) (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) Step of adding acrylamide to the solvent, and Step (2) (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9- obtained in step (1) Produced by a method comprising the steps of stirring the solvent and adding water while maintaining the solvent to which tetrahydropyrimido [5,4-b] indolizine-8-yl) acrylamide has been added at 50 to 150 ° C. Of (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) acrylamide crystal.

  Item 15. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Item 15. The crystal according to Item 14, which is a crystal having at least 3 or more peaks selected from 4 ° and 28.1 °.

  Item 16. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Item 16. The crystal according to Item 14 or 15, which is a crystal having at least 5 or more peaks selected from 4 ° and 28.1 °.

Item 17. Item 17. The crystal according to any one of Items 14 to 16, which is a crystal having the following powder X-ray diffraction spectrum in a powder X-ray diffraction spectrum.

  Item 18. Item 18. The crystal according to any one of Items 14 to 17, wherein an endothermic top peak temperature is about 271 ° C. ± 5 ° C. in differential scanning calorimetry.

  Item 19. The crystal | crystallization of any one of claim | item 14 -18 which has the following differential scanning calorimetry (DSC) curves in differential scanning calorimetry.

  Item 20. Item 20. The crystal according to any one of Items 14 to 19, wherein in the step (1), the solvent is dimethyl sulfoxide.

  Item 21. Item 21. The crystal according to any one of Items 14 to 20, wherein the suspension is maintained at 70 to 120 ° C. in the step (2).

  Item 22. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Item 15. The crystal according to Item 14, which has at least three or more peaks selected from .4 ° and 28.1 °, and has an endothermic top peak temperature of about 271 ° C. ± 5 ° C. in differential scanning calorimetry.

  Item 23. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Item 15. The crystal according to Item 14, which has at least 5 or more peaks selected from 4 ° and 28.1 °, and has an endothermic top peak temperature of about 271 ° C. ± 5 ° C. in differential scanning calorimetry.

Item 24. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Having at least three or more peaks selected from .4 ° and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and the infrared (IR) absorption spectrum ^{in, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, at least three or more characteristic absorption band selected from the 956cm ^-1 and 754cm ^-1 (peak) (error: ± Item 15. The crystal according to Item 14, having 5 cm ⁻¹ ).

Item 25. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Having at least five or more peaks selected from .4 ° and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and the infrared (IR) absorption spectrum ^{in, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, at least 5 or more characteristic absorption band selected from the 956cm ^-1 and 754cm ^-1 (peak) (error: ± Item 15. The crystal according to Item 14, having 5 cm ⁻¹ ).

Item 26. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 .4 ° and 28.1 ° peaks, in the differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and in the infrared (IR) absorption spectrum, 1665 cm ⁻¹ , 1600 cm ⁻ Item 1. The crystal according to Item 1, having characteristic absorption bands (peaks) (error: ± 5 cm-1) of ¹ , 1535 cm ^-1 , 1438 cm ^-1 , 1233 cm ^-1 , 956 cm ^-1 and 754 cm ^-1 .

  Item 27. The powder X-ray diffraction spectrum has the following powder X-ray diffraction spectrum,

In differential scanning calorimetry, it has the following differential scanning calorimetry (DSC) curve,

In infrared (IR) absorption spectrum analysis near the fingerprint region, it has the following IR absorption spectrum,

Item 15. The crystal according to Item 14.

  Item 28. Item 28. The crystal according to any one of Items 14 to 27, wherein the content of dimethyl sulfoxide (DMSO) is 5000 ppm or less.

  Item 29. Methanol content is 3000 ppm or less, ethanol content is 5000 ppm or less, n-propanol content is 5000 ppm or less, isopropanol content is 5000 ppm or less, acetone content is 5000 ppm or less, acetonitrile content is 410 ppm or less, The content of dimethyl sulfoxide (DMSO) is 5000 ppm or less, the content of dimethylformamide (DMF) is 880 ppm or less, the content of dimethylacetamide (DMA) is 1090 ppm or less, and the content of N-methylpyrrolidone (NMP) is 530 ppm or less The crystal according to any one of Items 14 to 28, wherein

  Item 30. Item 30. A pharmaceutical composition comprising the crystal according to any one of items 1 to 29.

  Item 31. Item 32. The pharmaceutical composition according to Item 31, which is an antitumor agent.

Item 32. Step (1) (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) Step of adding acrylamide to the solvent, and Step (2) (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9- obtained in step (1) Tetrahydropyrimido [5,4-b] indolizin-8-yl) acrylamide added to the solvent while stirring the solvent while maintaining the solvent at 50-150 ° C. and adding water;
(S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) acrylamide crystals Production method.

  Item 33. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Item 33. The method according to Item 32, which is a method for producing a crystal having at least three or more peaks selected from 4 ° and 28.1 °.

  Item 34. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Item 34. The method according to Item 32 or 33, which is a method for producing a crystal having at least 5 or more peaks selected from 4 ° and 28.1 °.

Item 35. Item 35. The method according to any one of Items 32 to 34, which is a method for producing a crystal having the following powder X-ray diffraction spectrum in a powder X-ray diffraction spectrum.

  Item 36. Item 36. The method according to any one of Items 32 to 35, which is a method for producing a crystal having an endothermic top peak temperature of about 271 ° C. ± 5 ° C. in differential scanning calorimetry.

Item 37. Item 37. The method according to any one of Items 32 to 36, which is a method for producing a crystal having the following differential scanning calorimetry (DSC) curve in differential scanning calorimetry.

  Item 38. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 A method for producing a crystal having at least three or more peaks selected from .4 ° and 28.1 ° and having an endothermic top peak temperature of about 271 ° C. ± 5 ° C. in differential scanning calorimetry. 33. The method according to 32.

  Item 39. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 A method for producing a crystal having at least five or more peaks selected from .4 ° and 28.1 ° and having an endothermic top peak temperature of about 271 ° C. ± 5 ° C. in differential scanning calorimetry. 33. The method according to 32.

Item 40. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Having at least three or more peaks selected from .4 ° and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and the infrared (IR) absorption spectrum ^{in, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, at least three or more characteristic absorption band selected from the 956cm ^-1 and 754cm ^-1 (peak) (error: ± Item 33. The method according to Item 32, which is a method for producing a crystal having 5 cm ⁻¹ ).

Item 41. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Having at least five or more peaks selected from .4 ° and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and the infrared (IR) absorption spectrum ^{in, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, at least 5 or more characteristic absorption band selected from the 956cm ^-1 and 754cm ^-1 (peak) (error: ± Item 33. The method according to Item 32, which is a method for producing a crystal having 5 cm ⁻¹ ).

Item 42. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 .4 ° and 28.1 ° peaks, in the differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and in the infrared (IR) absorption spectrum, 1665 cm ⁻¹ , 1600 cm ^{− 1, 1535cm -1, 1438cm -1,} 1233cm -1, characteristic absorption bands of 956cm ^-1 and 754cm ^-1 (peak) (error: ± ^{5 cm -1)} is a method for producing a crystal having, in section 32 The method described.

Item 43. In the powder X-ray diffraction spectrum, it has the following powder X-ray diffraction spectrum,
In differential scanning calorimetry, it has the following differential scanning calorimetry (DSC) curve,

Infrared (IR) absorption spectrum analysis near the fingerprint region has the following IR absorption spectrum

Item 33. The method according to Item 32, which is a method for producing a crystal.

  Item 44. Item 44. The method according to any one of Items 32 to 43, which is a method for producing a crystal having a dimethyl sulfoxide (DMSO) content of 5000 ppm or less.

  Item 45. Methanol content is 3000 ppm or less, ethanol content is 5000 ppm or less, n-propanol content is 5000 ppm or less, isopropanol content is 5000 ppm or less, acetone content is 5000 ppm or less, acetonitrile content is 410 ppm or less, The content of dimethyl sulfoxide (DMSO) is 5000 ppm or less, the content of dimethylformamide (DMF) is 880 ppm or less, the content of dimethylacetamide (DMA) is 1090 ppm or less, and the content of N-methylpyrrolidone (NMP) is 530 ppm or less Item 45. The method according to any one of Items 32 to 44, which is a method for producing a crystal.

  Item 46. Item 46. The method according to any one of Items 32 to 45, wherein in the step (1), the solvent is dimethyl sulfoxide.

  Item 47. Item 47. The method according to any one of Items 32 to 46, wherein in the step (2), the specific temperature is 70 to 120 ° C.

  According to the present invention, the crystal I of the compound 1 can be obtained industrially as a new crystal having excellent oral absorbability and stability, and good acquisition reproducibility. Can be used. Moreover, the manufacturing method which can produce the crystal | crystallization I of the compound 1 industrially was discovered by adding water and crystallizing the process of adding the compound 1 to a solvent, and maintaining specific temperature.

1 shows a powder X-ray diffraction spectrum of Crystal I of Compound 1 (the vertical axis represents intensity (counts) and the horizontal axis represents diffraction angle (2θ ± 0.2 °)). 1 shows a differential scanning calorimetry (DSC) curve of Compound I Crystal I. The differential thermal-thermogravimetric simultaneous measurement (TG-DTA) curve of the crystal | crystallization I of the compound 1 is shown. 2 shows an infrared (IR) absorption spectrum of Compound I Crystal I. The vicinity of the fingerprint region of the infrared (IR) absorption spectrum of Compound I Crystal I is shown. 2 shows a moisture adsorption isotherm (DVS) curve of Compound I Crystal I. 1 shows a powder X-ray diffraction spectrum of crystal II of Compound 1 (the vertical axis represents intensity (counts) and the horizontal axis represents diffraction angle (2θ ± 0.2 °)). 2 shows a differential scanning calorimetry (DSC) curve of Compound 1 Crystal II. 1 shows an infrared (IR) absorption spectrum of Compound II Crystal II. The vicinity of the fingerprint region of the infrared (IR) absorption spectrum of Compound II Crystal II is shown.

  Hereinafter, the present invention will be described in detail.

  A crystal is a solid in which atoms or molecules are arranged in a regular repeating structure, and is different from an amorphous (amorphous) solid having no repeating structure. Powder X-ray diffraction measurement (XRD measurement), differential scanning calorimetry (DSC measurement), thermogravimetry-differential thermal analysis (TG-DTA), infrared spectroscopy (IR), etc. Alternatively, it can be determined that the solid is an amorphous solid, and if the solid state is crystalline, the crystalline polymorph can be determined.

  A crystal may have a polymorphism that is the same molecule but has a different arrangement of molecules in the crystal. In that case, it is known that a characteristic peak obtained by powder X-ray diffraction measurement (XRD measurement) differs between crystal polymorphs. Moreover, it is known that solubility, oral absorbability, stability, etc. differ between each crystal polymorph, and it is required to find an optimal crystal in developing a pharmaceutical from various viewpoints.

  In the present specification, the term “crystal” is used in the usual sense, means a solid having a spatially regular atomic arrangement, and may be a solvate or a hydrate. Further, the label of Compound 1, that is, a compound in which one or more atoms are substituted with a radioisotope or a non-radioisotope is also included in the present invention.

  As a result of intensive studies, the present inventors have found that compound 1 has at least two crystal polymorphs (crystal I, crystal II).

  There is a possibility that the crystal II undergoes a phase transition due to an increase in temperature, and the stability is not sufficient, and the crystal may change during the production process. Therefore, it is not considered suitable for pharmaceutical crystals.

  On the other hand, the phase transition due to the temperature rise is not confirmed in the crystal I, and the possibility that the crystal changes in the manufacturing process is low and it can be said that the crystal I is excellent in stability. Moreover, it can be said that the crystal I is excellent in oral absorptivity from evaluation of the measurement of the blood concentration in oral administration.

  The crystal of the present invention is not limited as long as it contains the crystal I of the compound 1, and may be a single crystal of the crystal I or a polymorphic mixture containing other crystals. When the crystal of the present invention is a polymorph mixture, the purity is preferably 90% by weight or more of the crystal, more preferably 95% by weight or more, and more preferably 99% by weight or more. Crystal I is particularly preferred.

In this specification, the purity is the purity when measured by high performance liquid chromatography, and when described as the purity of compound 1, it means the purity when compound 1 is measured by high performance liquid chromatography. At that time, the wavelength of the detector used for purity measurement can be set as appropriate.

  In the present specification, the term “stability” refers to the purity of Compound 1 and the fact that the crystal does not change to an amorphous state and does not change to another crystal polymorph under long-term storage, heating conditions, or humidifying conditions.

  Further, the crystal of the present invention includes crystal habits having different outer shapes due to differences in crystal plane growth. For this reason, the peak pattern of the diffraction angle 2θ in the powder X-ray diffraction spectrum of the crystal I is the same, but those having different peak relative intensities are included. Here, the relative intensity is a relative value of each peak area when the peak of the diffraction area 2θ in the powder X-ray diffraction spectrum having the maximum peak area is taken as 100.

  In addition, the error of the peak at the diffraction angle 2θ in the powder X-ray diffraction spectrum of the present invention is ± 0.2 °. This is an error caused by the instrument used for measurement, sample preparation, data analysis method, and the like.

  In the DSC measurement, the measured endothermic peak (peak top value) may vary depending on the temperature rise rate per minute, the weight of the sample, the purity of the sample, and the like. Therefore, the error of the measured endothermic peak (peak top value) is ± 5 ° C.

  The crystal of the present invention has a diffraction angle (2θ ± 0.2 °) of 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 ° in the powder X-ray diffraction spectrum, It has at least three or more characteristic peaks selected from 22.8 °, 25.4 ° and 28.1 °. Preferably, the crystal of the present invention has a diffraction angle (2θ ± 0.2 °) of 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21. It has at least five characteristic peaks selected from 8 °, 22.8 °, 25.4 ° and 28.1 °. More preferably, the crystal of the present invention has a diffraction angle (2θ ± 0.2 °) of 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21 in the powder X-ray diffraction spectrum. It has characteristic peaks of .8 °, 22.8 °, 25.4 ° and 28.1 °.

  In one preferred embodiment of the present invention, the crystal of the present invention has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG.

  The crystal of the present invention has an endothermic top peak temperature of about 271 ° C. ± 5 ° C. in differential scanning calorimetry.

  The crystal of the present invention has a diffraction angle (2θ ± 0.2 °) of 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 in the powder X-ray diffraction spectrum. Having at least three or more characteristic peaks selected from °, 22.8 °, 25.4 °, and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C. Preferably, the crystal of the present invention has a diffraction angle (2θ ± 0.2 °) of 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21. It has at least 5 or more characteristic peaks selected from 8 °, 22.8 °, 25.4 ° and 28.1 °, and in the differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C. More preferably, the crystal of the present invention has a diffraction angle (2θ ± 0.2 °) of 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21 in the powder X-ray diffraction spectrum. It has characteristic peaks of .8 °, 22.8 °, 25.4 ° and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C.

In the infrared (IR) absorption spectrum measurement, the measured peak value may vary depending on the weight of the sample and the measuring instrument. Therefore, the measured peak error is ± 5 cm ⁻¹ .

Crystals of the invention, in the infrared (IR) absorption ^{spectrum, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, at least three or more selected from the 956cm ^-1 and 754cm ^-1 Characteristic absorption band (peak) (error: ± 5 cm ⁻¹ ). Preferably, the crystal of the present invention, in the infrared (IR) absorption ^{spectrum, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, at least selected from 1233cm ^-1, 956cm -1 and 754cm ^-1 It has five or more characteristic absorption bands (peaks) (error: ± 5 cm ⁻¹ ). More preferably, the crystal of the present invention, in the infrared (IR) absorption ^{spectrum, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, characteristic of the 956cm ^-1 and 754cm ^-1 It has an absorption band (peak) (error: ± 5 cm ⁻¹ ).

  In one preferred embodiment of the present invention, the crystal of the present invention has an infrared (IR) absorption spectrum substantially the same as the infrared (IR) absorption spectrum shown in FIGS.

  The crystal of the present invention can be obtained, for example, by the following crystal production method. The present invention also provides a method for producing the following crystal and a crystal obtained by the method.

  The crystal of the present invention can be produced by crystallization of amorphous compound 1, crystallization from a reaction product after synthesizing compound 1, or recrystallization.

  As the compound 1 used, what was manufactured according to the method of patent document 1 is mentioned, for example. In crystallization, it is possible to use a compound 1 that has not been extracted as a crystal after synthesis, or a compound that has been once extracted as a crystal (crude crystal). In order to further improve the crystal purity, It is preferable to use a crystal taken out. As a crystal once taken out, any of crystal polymorphs of crystal I or crystal II or crystal polymorphs other than these can be used.

  The crystal of the present invention can be crystallized under appropriate conditions by adding a solvent such as alcohol or ester to the compound 1, for example, n-propanol, to make it into a suspended state. The amount of the solvent used can be 1 to 50 times, preferably about 10 times. The compound 1 is dissolved in the vicinity of the boiling point temperature of the solvent to be used, and then allowed to cool to precipitate a white solid. The crystals of the present invention can be obtained by drying the precipitated white solid under reduced pressure.

  In a preferred embodiment of the present invention, the crystal of the present invention can be obtained by a method for producing a crystal comprising a step of adding Compound 1 to a solvent and a step of adding water to crystallize while maintaining a specific temperature. it can. Such a production method is a production method excellent in production efficiency of the crystal of the present invention and capable of industrial production of the crystal of the present invention.

Therefore, the present invention
Step (1) Step of adding Compound 1 to the solvent, and Step (2) While maintaining the solvent to which Compound 1 obtained in Step (1) was added at 50 to 150 ° C., water was added to the solvent, Also provided is a crystal I of compound 1 produced by the process comprising the step of obtaining solid compound 1.

In addition, the present invention includes a step (1) a step of adding compound 1 to the solvent, and a step (2) while maintaining the solvent to which compound 1 obtained in step (1) is added at 50 to 150 ° C. Also provided is a method for producing Compound 1 Crystal I, which comprises the step of adding water to obtain Compound 1 in solid form.

  The crystal I of Compound 1 obtained by the above production method is preferably less than the predetermined value of the residual solvent defined in the Q3C Guidelines (hereinafter also referred to as ICH Q3C Guidelines) of the Japan-US EU Pharmaceutical Regulation Harmonization International Conference (ICH). Specifically, the content of methanol is 3000 ppm or less, the content of ethanol is 5000 ppm or less, the content of n-propanol is 5000 ppm or less, the content of isopropanol is 5000 ppm or less, the content of acetone is 5000 ppm or less, The content is 410 ppm or less, the content of dimethyl sulfoxide (DMSO) is 5000 ppm or less, the content of dimethylformamide (DMF) is 880 ppm or less, the content of dimethylacetamide (DMA) is 1090 ppm or less, and N-methylpyrrolide The content of (NMP) is less than 530 ppm. Thus, the present invention also provides Compound 1 Crystal I below the predetermined value of the residual solvent defined in the ICH Q3C guidelines and a method for producing the same.

  In step (1) of the method for producing a crystal of the present invention, compound 1 is suspended or dissolved in a solvent. As the solvent in the step (1), a solvent that can be uniformly mixed with water can be used. Examples of the solvent that can be uniformly mixed with water include methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, and dimethyl. Examples thereof include sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), a mixed solvent of these solvents and water, and the like. The solvent is preferably dimethyl sulfoxide from the viewpoint of the predetermined value of the residual solvent defined in the ICH Q3C guidelines. The amount of the solvent may be 1 to 50 times the amount of compound 1 used (v / w), preferably 2 to 30 times the amount (v / w), from the viewpoint of the size of the reaction vessel, stirring efficiency, and the like. More preferably 5 to 20 times (v / w).

  In step (1) of the crystal production method of the present invention, when compound 1 is dissolved in a solvent, clarification filtration can be performed. Clarification filtration means removing impurities of a drug substance that is not dissolved in a solvent by filtration, and is a process for maintaining the quality of a drug. In this step, if the compound 1 is dissolved in a solvent, clarification filtration can be performed. Filters such as filter paper and filter cloth used at that time are not particularly limited as long as they are commercially available products, and can be appropriately selected depending on the viscosity of the solution, the time required for the filtration, the size of impurities to be removed, and the like. .

  In step (2) of the crystal production method of the present invention, water is added to the suspension or solution while maintaining the suspension or solution obtained in step (1) at 50 to 150 ° C. Compound 1 is obtained. By maintaining this temperature while adding water, the crystal I of Compound 1 can be obtained with good reproducibility. If the temperature at which the suspension or solution is maintained is lower than the above temperature, the crystal of the present invention cannot be obtained. The temperature at which the suspension or solution is maintained is preferably 70 to 120 ° C., and more preferably, from the viewpoint that the crystals of Compound 1 below the specified value of the residual solvent specified in the ICH Q3C guidelines can be obtained efficiently. 90-110 ° C.

  In step (2) of the crystal production method of the present invention, the amount of water to be added is a compound that is lower than the crystal yield of the present invention, the size of the reaction vessel, and the residual solvent specified in the ICH Q3C guidelines. 1 to 50 times amount (v / w) of compound 1 used in step (1) is mentioned from the viewpoint that 1 crystal can be obtained efficiently, and preferably 2 to 30 times amount (v / w). More preferably, the amount is 5 to 20 times (v / w).

  In the step (2) of the method for producing a crystal of the present invention, the amount of water to be added is 0.3 to 10 times (v / v) of the solvent used in the step (1) from the same viewpoint as described above. Preferably, it is 0.5-2, More preferably, it is 1 time amount (v / v).

  In step (2) of the crystal production method of the present invention, the suspension or solution is preferably stirred when water is added while maintaining the suspension or solution at a specific temperature. Stirring can be performed using a stirrer, a stirring blade, a magnetic stirrer, or the like as appropriate depending on the amount of solvent, the size of the reaction vessel, and the like. Moreover, 1-600 RPM is mentioned as stirring speed, for example, Preferably it is 10-300 RPM.

  In step (2) of the crystal production method of the present invention, the solid compound 1 crystallized can be obtained after maintaining the suspension or solution at a specific temperature and adding water. For example, the crystallized solid compound 1 can be obtained by filtration. The solid compound 1 can be collected by filtration 0.5 to 100 hours after the addition of water, and preferably 2 to 72 hours later. The temperature of the suspension may be any of 0 ° C. to 150 ° C., preferably 70 to 120 ° C., more preferably 90 to 110 ° C., between the addition of water and the start of filtration. The temperature at the time of filtration may be any of 0 to 120 ° C, preferably 5 to 100 ° C, and more preferably room temperature (5 to 40 ° C).

  In the step (2) of the crystal production method of the present invention, the addition of water to the suspension or solution can be dripping water. As long as the internal temperature of the suspension is the above temperature, the time for dropping water may be any.

  In step (2) of the crystal production method of the present invention, an appropriate amount of Compound I of Compound 1 or a mixed crystal containing Crystal I may be added as a seed crystal in order to promote crystallization. The seed crystal to be added is 0.01 to 5 (w / w)%, preferably 0.03 to 1 (w / w)% of the weight of Compound 1 used in Step (1).

  In the step (2) of the crystal production method of the present invention, the acquisition of the solid compound 1 may be performed while maintaining the temperature when water is added, and between the temperature when water is added from room temperature. You may go on. The solid compound 1 can be isolated and purified from the dissolved solution or mixed solution by known separation and purification means such as filtration, washing with an organic solvent, and drying under reduced pressure. Examples of the solvent used for washing include water, dimethyl sulfoxide, lower alcohol, acetone, acetonitrile and the like.

  Thus, crystals of compound 1 of the present invention are produced.

  The crystal of the present invention is useful as an antitumor agent because Compound 1 has excellent EGFR inhibitory activity. The target cancer is not particularly limited, but head and neck cancer, gastrointestinal cancer (esophageal cancer, stomach cancer, gastrointestinal stromal tumor, duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, bile duct cancer, etc.), pancreatic cancer, small intestine Cancer, colorectal cancer (colorectal cancer, colon cancer, rectal cancer, etc.), lung cancer, breast cancer, ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), kidney cancer, bladder cancer, prostate cancer, urinary tract Skin cancer, bone and soft tissue sarcoma, blood cancer (B-cell lymphoma, chronic lymphocytic leukemia, peripheral T-cell lymphoma, myelodysplastic syndrome, acute myeloid leukemia, acute lymphocytic leukemia, etc.), multiple myeloma, skin cancer And mesothelioma.

  The crystals of the present invention may be pulverized or not pulverized, and various forms of pharmaceutical compositions such as tablets, capsules, granules, fine granules, powders, dry syrups and other oral preparations, suppositories, and inhalants These can be processed into external preparations such as nasal drops, ointments, plasters, aerosols, and injections, but are preferably used in oral preparations. These pharmaceutical compositions can be produced by a known and commonly used formulation method of those skilled in the art using a pharmaceutically acceptable carrier.

  The amount of the crystal of the present invention to be blended in the above pharmaceutical composition is not constant depending on the symptoms of the patient to which the crystal is applied or the dosage form thereof, but generally 0.05 to 1000 mg per oral dosage unit form. It is desirable that the dosage is about 0.01 to 500 mg for injections and about 0.1 to 1000 mg for suppositories or external preparations. In addition, the daily dose of the crystal of the present invention in the above pharmaceutical composition cannot be generally determined according to the symptom, administration route, patient age, etc., but is determined by a doctor's prescription, which is determined once or twice a day. It is preferable to administer in about 3 times.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples. While the invention has been fully described by way of example, it will be understood that various changes and modifications may be made by those skilled in the art. Therefore, unless such changes and modifications depart from the scope of the present invention, they are included in the present invention.

Various reagents used in the examples were commercially available unless otherwise specified. ¹ H-NMR spectrum was measured using an AL400 (400 MHz; JEOL), Mercury 400 (400 MHz; Agilent Technology) spectrometer, or an Inova 400 (400 MHz; Agilent Technology) spectrometer equipped with a 400 M NMR probe (Protasis). When tetramethylsilane was included in the heavy solvent, tetramethylsilane was used as the internal standard, and in other cases, the NMR solvent was used as the internal standard, and all δ values were expressed in ppm.

The meanings of the abbreviations are shown below.
s: singlet d: doublet t: triplet q: quartet dd: double doublet dt: double triplet td: triple doublet tt: triple triplet ddd: double double doublet ddt: double double triplet dtd: double triple doublet tdd: triple double doublet m: Multiplet br: Broad brs: Broad singlet

Powder X-ray diffraction measurement Powder X-ray diffraction was measured according to the following test conditions after lightly grinding an appropriate amount of a test substance with an agate mortar as necessary.
Device: Rigaku MiniFlexII
Target: Cu
X-ray output setting: 15 mA, 30 kV
Scanning range: 2.0-40.0 °
Step size: 0.010 °
Scan speed: 5.00 ° C./min.
Divergent slit: 1.25 °
Scattering slit: Opening Receiving slit: Opening Handling of devices including data processing was in accordance with the methods and procedures directed by each device.
Note that numerical values obtained from various spectra may vary somewhat depending on the crystal growth direction, particle size, measurement conditions, and the like. Therefore, those numbers should not be interpreted exactly.

Differential scanning calorimetry (DSC measurement)
The DSC measurement was performed according to the following test conditions.
Equipment: TA Instruments Q1000
Sample: Approximately 1 mg
Sample container: made of aluminum Temperature increase rate: up to 300 ° C. at a rate of 5 ° C./min. Atmosphere gas: nitrogen Nitrogen gas flow rate: 50 ml / min.

Differential thermal-thermogravimetric simultaneous measurement (TG-DTA measurement)
The TG-DTA measurement was performed according to the following test conditions.
Equipment: Hitachi High-Tech Science TG / DTA7200
Sample: Approximately 5mg
Sample container: made of aluminum Temperature increase rate: up to 300 ° C. at 10 ° C./min. Atmosphere gas: air Nitrogen gas flow rate: 100 ml / min.

Infrared (IR) absorption spectrum The infrared (IR) absorption spectrum was measured according to the following test conditions.
Apparatus: Spectrum 100 (manufactured by PerkinElmer)

Dynamic Vapor Adsorption System (DVS) Analysis The dynamic vapor adsorption system (DVS) analysis was measured according to the following test conditions.
Apparatus: VTI-SA + Vapor adsorption / desorption measuring device (TA Instruments)
Conditions etc .: Adsorption and desorption data were collected in the range of 5% to 95% relative humidity (RH) at 5% RH intervals. Before the measurement, the temperature was raised to 60 ° C. at 1 ° C./min under a nitrogen purge and dried for a maximum of 6 hours until the weight change during 5 minutes was less than 0.0100%. At the time of measurement, equilibration was performed for a maximum of 2 hours until the weight change during 5 minutes was less than 0.0100%.

  The handling of devices including various data processing was in accordance with the method and procedure instructed by each device.

Example 1 (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) acrylamide Production of (Crystal I) A crude product of Compound 1 (140 g) synthesized with reference to a known method disclosed in Patent Document 1 was added to dimethyl sulfoxide (1120 ml) and dissolved by heating to 100 ° C. Using a Kiriyama funnel and filter paper (Kiriyama Seisakusho: No.3, 95φ, two layers), a slight insoluble matter in the solution was filtered off, and dimethyl sulfoxide (140 ml) was further added to the solution. Water (1260 ml) was added dropwise over 30 minutes while maintaining the internal temperature of the obtained dimethyl sulfoxide solution of Compound 1 at 96 to 100 ° C., and the mixture was stirred at an internal temperature of 93 ° C. for 2 hours. Thereafter, the suspension solution was slowly cooled to room temperature and stirred overnight. The obtained solid was collected by filtration, washed with water, and dried under reduced pressure at 60 ° C. to obtain Compound 1 Crystal I (127 g, yield 91%). In addition, the same experiment was performed several times, and it was found that the crystal I could be obtained with good reproducibility.

¹ H-NMR (CDCl ₃ ) δ: 2.14 (2H, d, J = 5.6 Hz), 3.04 (2H, t, J = 6.2 Hz), 4.17 (1H, dd, J = 12.7, 5.8 Hz), 4.46 (1H, dd, J = 12.7, 4.5 Hz), 4.70-4.80 (1H, m), 4.89 (2H, brs), 5.71 (1H, d, J = 10.2 Hz), 6.21 (1 H, dd, J = 16.8, 10.2 Hz), 6.39 (1 H, d, J = 16.8 Hz), 6 .50 (1H, d, J = 7.0 Hz), 7.62 (1H, t, J = 7.4 Hz), 7.77 (1H, t, J = 7.4 Hz), 7.87 (1H, d, J = 8.0 Hz), 8.15 (1H, d, J = 8.0 Hz), 8.25 (1H, s), 8.32 (1H, s), 9.00 (1H, s) .
ESI-MS m / z 385 (MH ^<+> ).

Further, powder X-ray diffraction spectrum, differential scanning calorimetry (DSC) curve, differential thermal-thermogravimetric simultaneous measurement (TG-DTA) curve, infrared (IR) absorption spectrum, dynamic vapor adsorption system (crystal 1 of compound 1) The results of DVS analysis are shown in FIGS.
In the powder X-ray diffraction spectrum of Compound I Crystal I, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, The crystals had characteristic peaks at 22.8 °, 25.4 ° and 28.1 °. In the differential scanning calorimetry (DSC) curve, no endotherm or exotherm was observed at a temperature increase of 50 to 250 ° C. Further, infrared (IR) absorption ^{spectrum, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, has a 956cm ^-1 and 754cm ^-1 characteristic absorption band (peak) It was. In addition, the moisture adsorption isotherm (DVS) curve shows that the change in weight due to water adsorption is 1% or less at RH 95%, and even if it is returned from RH 95% to 5%, the change in weight compared to the original weight at RH 5% I could not confirm.

Comparative Example 1 Production of Compound II Crystal II Compound 1 crude product (3.00 g) synthesized with reference to a known method disclosed in Patent Document 1 was added to dimethyl sulfoxide (24 ml) and heated to 80 ° C. To dissolve. The Kiriyama funnel was used to filter out a slight amount of insoluble matter in the solution, and then dimethyl sulfoxide (3 ml) was further added to the solution. The obtained dimethyl sulfoxide solution of Compound 1 was cooled to around room temperature (5 to 40 ° C.), water (27 ml) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 2 hours. Thereafter, the obtained solid was collected by filtration, washed with water, and dried under reduced pressure at 60 ° C. to obtain Compound II Crystal II (2.58 g, yield 86%).

  Further, the results of the powder X-ray diffraction spectrum, differential scanning calorimetry (DSC) curve, and infrared (IR) absorption spectrum of Compound II Crystal II are shown in FIGS.

In the powder X-ray diffraction spectrum of the crystal II of the compound 1, unlike the crystal I, the diffraction angles (2θ ± 0.2 °) are 8.3 °, 12.5 °, 14.0 °, 23.8 °. , 25.3 °, and crystals having characteristic peaks at 26.9 °. In addition, unlike the crystal I, the differential scanning calorimetry (DSC) curve showed endotherm and exotherm when the temperature was increased from 50 to 200 ° C. Therefore, it was found that the crystal II is more likely than the crystal I to change depending on the external environment such as temperature. Further, infrared (IR) absorption spectrum is different from the crystal ^{I, 1646cm -1, 1560cm -1,} 1292cm -1, 1241cm -1, had to 757cm ^-1 characteristic absorption band (peak) .

Test Example 1 Measurement of blood concentration Crystal I of test compound 1 was suspended in a 0.5% HPMC aqueous solution and orally administered to BALB / c mice at 50 mg / kg. Fundus blood was collected 0.5, 1, 2, 4, and 6 hours after administration, and the concentration of Compound 1 in plasma was measured. As a result, the AUC (Area under the curve) of the crystal I of the compound 1 was 10.03 μM · hr, and it was found that the oral absorbability was good.

Test Example 2 Storage Stability Test Using the crystal I obtained in Example 1, the residual ratio during storage under each condition was evaluated.
Storage conditions:
Condition 1: 40 ° C. under airtight condition 2: 40 ° C. relative humidity 75% open condition 3: 60 ° C. under airtight condition 4: 25 ° C. exposed to light (2000 lx · hr)
Measurement point: 1, 3, 6 months Storage amount: about 30mg
Storage container: Brown glass bottle

The amount of related substances in the sample solution was measured by HPLC analysis. In addition, the handling of the apparatus including data processing was in accordance with the method and procedure instructed by each apparatus. (Device: Shimadzu LC-20AB)
Column: YMC Trial C18 [3 × 100 mm, 3 μm]
UV detection: 220 nm
Column temperature: 40 ° C
Column flow rate: 0.6 mL / min
Mobile phase: A; 10 mM phosphate buffer (pH 2.5), B; Acetonitrile Injection volume: 5 μL
Sample concentration: 0.2 mg / mL
Gradient: Table 1

Table 2 shows the test results. The residual rate was calculated as follows.
Residual rate (%) = 100 × (purity of compound 1 at each elapsed time) / (purity of compound at 0 months)

  As shown in Table 2, the crystal I of Compound 1 did not show a significant decrease in purity when stored for 1 month or longer under the above conditions. Further, no remarkable changes were observed in these powder X-ray diffraction spectra and differential scanning calorimetry (DSC) curves. From these results, it became clear that the crystal I has high stability with respect to the above conditions.

Test Example 3 Comparison of dimethyl sulfoxide remaining in crystal I The value of residual dimethyl sulfoxide contained in crystal I obtained according to Example 1 was calculated by proton NMR. The internal temperature in Table 3 below is the temperature of the solution when water is added to dimethyl sulfoxide, and water was added so that the internal temperature was not lower than the stated internal temperature during the addition in Conditions 2 to 4. Crystal I could not be obtained when the internal temperature was 5 to 40 ° C., but could be obtained at 80 ° C., 90 ° C., and 100 ° C. Further, at 90 ° C. and 100 ° C., it was below the limit value (5000 ppm) of dimethyl sulfoxide contained in the drug substance defined in the ICH Q3C guidelines.

Claims (31)

  In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydro having at least three peaks selected from 4 ° and 28.1 ° Crystals of pyrimido [5,4-b] indolizine-8-yl) acrylamide.   In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 The crystal according to claim 1, which is a crystal having at least 5 or more peaks selected from 4 ° and 28.1 °. The crystal according to claim 1 or 2, wherein the powder X-ray diffraction spectrum has the following powder X-ray diffraction spectrum.
  The crystal according to any one of claims 1 to 3, wherein an endothermic top peak temperature is about 271 ° C ± 5 ° C in differential scanning calorimetry. The crystal according to any one of claims 1 to 4, which has the following differential scanning calorimetry (DSC) curve in differential scanning calorimetry.
  In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 The crystal according to claim 1, having at least three or more peaks selected from .4 ° and 28.1 °, and having an endothermic top peak temperature of about 271 ° C ± 5 ° C in differential scanning calorimetry.   In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 The crystal according to claim 1, which has at least 5 or more peaks selected from .4 ° and 28.1 °, and has an endothermic top peak temperature of about 271 ° C ± 5 ° C in differential scanning calorimetry. In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Having at least three or more peaks selected from .4 ° and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and the infrared (IR) absorption spectrum ^{in, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, at least three or more characteristic absorption band selected from the 956cm ^-1 and 754cm ^-1 (peak) (error: ± The crystal according to claim 1, having 5 cm ⁻¹ ). In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 Having at least five or more peaks selected from .4 ° and 28.1 °, and in differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and the infrared (IR) absorption spectrum ^{in, 1665cm -1, 1600cm -1, 1535cm} -1, 1438cm -1, 1233cm -1, at least 5 or more characteristic absorption band selected from the 956cm ^-1 and 754cm ^-1 (peak) (error: ± The crystal according to claim 1, having 5 cm ⁻¹ ). In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 .4 ° and 28.1 ° peaks, in the differential scanning calorimetry, the endothermic top peak temperature is about 271 ° C. ± 5 ° C., and in the infrared (IR) absorption spectrum, 1665 cm ⁻¹ , 1600 cm ^{− 1, 1535cm -1, 1438cm -1,} 1233cm -1, characteristic absorption bands of 956cm ^-1 and 754cm ^-1 (peak) (error: ± ^{5 cm -1)} having a crystal of claim 1. The powder X-ray diffraction spectrum has the following powder X-ray diffraction spectrum,
In differential scanning calorimetry, it has the following differential scanning calorimetry (DSC) curve,
In infrared (IR) absorption spectrum analysis near the fingerprint region, it has the following IR absorption spectrum,
The crystal according to claim 1.   The crystal according to any one of claims 1 to 11, wherein the content of dimethyl sulfoxide (DMSO) is 5000 ppm or less.   Methanol content is 3000 ppm or less, ethanol content is 5000 ppm or less, n-propanol content is 5000 ppm or less, isopropanol content is 5000 ppm or less, acetone content is 5000 ppm or less, acetonitrile content is 410 ppm or less, The content of dimethyl sulfoxide (DMSO) is 5000 ppm or less, the content of dimethylformamide (DMF) is 880 ppm or less, the content of dimethylacetamide (DMA) is 1090 ppm or less, and the content of N-methylpyrrolidone (NMP) is 530 ppm or less The crystal according to any one of claims 1 to 12. Step (1) (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) Step of adding acrylamide to the solvent, and Step (2) (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9- obtained in step (1) Produced by a method comprising the steps of stirring the solvent and adding water while maintaining the solvent to which tetrahydropyrimido [5,4-b] indolizine-8-yl) acrylamide has been added at 50 to 150 ° C. Of (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) acrylamide crystal.   In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 The crystal according to claim 14, which is a crystal having at least three or more peaks selected from .4 ° and 28.1 °.   In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 The crystal according to claim 14 or 15, which is a crystal having at least 5 or more peaks selected from 4 ° and 28.1 °. The powder according to any one of claims 14 to 16, which is a crystal having the following powder X-ray diffraction spectrum in a powder X-ray diffraction spectrum.
  The crystal according to any one of claims 14 to 17, wherein an endothermic top peak temperature is about 271 ° C ± 5 ° C in differential scanning calorimetry. The crystal according to any one of claims 14 to 18, which has the following differential scanning calorimetry (DSC) curve in differential scanning calorimetry.
  The crystal according to any one of claims 14 to 19, wherein in the step (1), the solvent is dimethyl sulfoxide.   The crystal according to any one of claims 14 to 20, wherein the suspension is maintained at 70 to 120 ° C in the step (2).   A pharmaceutical composition comprising the crystal according to any one of claims 1 to 21.   The pharmaceutical composition according to claim 22, which is an antitumor agent. Step (1) (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) Step of adding acrylamide to the solvent, and Step (2) (S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9- obtained in step (1) Tetrahydropyrimido [5,4-b] indolizin-8-yl) acrylamide added to the solvent while stirring the solvent while maintaining the solvent at 50-150 ° C. and adding water;
(S) -N- (4-amino-5- (quinolin-3-yl) -6,7,8,9-tetrahydropyrimido [5,4-b] indolizin-8-yl) acrylamide crystals Production method.   In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 The method according to claim 24, which is a method for producing a crystal having at least three or more peaks selected from .4 ° and 28.1 °.   In the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2 °) are 8.9 °, 13.7 °, 17.3 °, 19.5 °, 21.8 °, 22.8 °, 25 The method according to claim 24 or 25, which is a method for producing a crystal having at least 5 or more peaks selected from 4 ° and 28.1 °. 27. The method according to any one of claims 24 to 26, which is a method for producing a crystal having the following powder X-ray diffraction spectrum in a powder X-ray diffraction spectrum.
  The method according to any one of claims 24 to 27, which is a method for producing a crystal having an endothermic top peak temperature of about 271 ° C ± 5 ° C in differential scanning calorimetry. The method according to any one of claims 24 to 28, which is a method for producing a crystal having the following differential scanning calorimetry (DSC) curve in differential scanning calorimetry.
  30. The method according to any one of claims 24 to 29, wherein in step (1), the solvent is dimethyl sulfoxide.   The method according to any one of claims 24 to 30, wherein in the step (2), the specific temperature is 70 to 120 ° C.