Method for producing pyrazolopyrazine compounds and their crystalline forms.

Abstract

This invention discloses a method for producing pyrazolopyrazine compounds and their crystalline forms, and in particular a method for producing the compound of formula (I) and its crystalline form. JPEG2026518967000048.jpg54108

Claims

1. A method for producing a compound of formula (I), characterized by including a method for the chiral resolution of compound q. 【Chemistry 1】 (Here, The chiral reagent is selected from chiral reagent 1 or chiral reagent 2; The chiral reagent 1 is (R)-(+)-N-benzyl-1-phenethylamine, and the chiral reagent 2 is (S)-(-)-N-benzyl-1-phenethylamine; The mixed solvent is selected from solvent 2 and solvent 3; The solvent 2 is tetrahydrofuran, and the solvent 3 is water.

2. A method for producing the compound of formula (I) according to claim 1, wherein the molar ratio of compound q to chiral reagent is 1:2 to 1:2.5, preferably 1:2.

1.

3. A method for producing the compound of formula (I) according to claim 1, wherein the volume ratio of the mixed solvent is tetrahydrofuran:water = 15:1 to 20:1, preferably 16.5:

1.

4. A method for producing the compound of formula (I) according to claim 1, wherein the chiral resolution of compound q further comprises a further purification step.

5. The process includes a step of selectively alkylating compound d and compound e, 【Chemistry 1】 Here, Reagent 1 is magnesium bromide; The aforementioned base 2 is DIEA; A method for producing the compound of formula (I) according to claim 1, wherein the solvent 4 is tetrahydrofuran.

6. A method for producing the compound of formula (I) according to claim 5, wherein the molar ratio of compound e, compound d, and reagent 1 is 1:0.8:0.1 to 1:1.2:0.3, preferably 1:1:0.

2.

7. This includes a method for synthesizing intermediate k. 【Chemistry 1】 The reagent 1 is selected from magnesium bromide; The aforementioned base 2 is selected from DIEA; The solvent 4 is selected from tetrahydrofuran; The reagent 2 is selected from ammonium acetate; The solvent 5 is selected from ethanol; The halogenating reagent is selected from phosphoryl chloride; The solvent 6 is selected from acetonitrile; The catalyst is selected from [1,1-bis(diphenylphosphin)ferrocene]dichloropalladium; The aforementioned base 3 is selected from sodium carbonate; The solvent 7 is selected from dioxanes; The solvent 8 is selected from water; The aforementioned acidic system 2 is selected from hydrochloric acid / ethyl acetate solution; The method for producing the compound of formula (I) according to claim 1, wherein the solvent 9 is selected from dichloromethane.

8. The method further includes a method for synthesizing the compound of formula (I) from compound l, 【Chemistry 1】 The aforementioned acidic system 3 is selected from sulfuric acid; The solvent 10 is selected from ethanol; The aforementioned base 4 is selected from triethylamine; The solvent 11 is selected from tetrahydrofuran; The reagent 3 is selected from lithium bromide; The solvent 1 is selected from acetonitrile; The basic system 1 is selected from aqueous sodium hydroxide solution; The aforementioned acidic system 1 is selected from concentrated hydrochloric acid; The chiral reagent is selected from chiral reagent 1 or chiral reagent 2; The chiral reagent 1 is (R)-(+)-N-benzyl-1-phenethylamine, and the chiral reagent 2 is (S)-(-)-N-benzyl-1-phenethylamine; The mixed solvent is selected from solvent 2 and solvent 3; The solvent 2 is tetrahydrofuran, and the solvent 3 is water; The reagent 4 is selected from ammonium chloride; The aforementioned base 5 is selected from DIEA; The aforementioned coupling agent is selected from HATU; The solvent 12 is selected from DMF; The reagent 4 is selected from trifluoroacetic anhydride; The aforementioned base 6 is selected from triethylamine; The solvent 13 is selected from dichloromethane; The method for producing the compound of formula (I) according to claim 1, wherein the solvent 14 is selected from methanol.

9. A type 1 crystal of the compound of formula (I), characterized in that the powder X-ray diffraction spectrum using Cu Kα rays has characteristic diffraction peaks at 2θ angles of 8.087±0.200°, 9.379±0.200°, 11.188±0.200°, and 12.852±0.200°. 【Chemistry 1】

10. A type 1 crystal of the compound of formula (I) according to claim 9, wherein the powder X-ray diffraction spectrum contains at least 6, 7, 8, or 9 diffraction peaks selected from 8.087±0.200°, 9.379±0.200°, 11.188±0.200°, 12.852±0.200°, 16.163±0.200°, 18.306±0.200°, 18.626±0.200°, 19.105±0.200°, 19.447±0.200°, and 20.666±0.200°, expressed in terms of 2θ angle.

11. A type 1 crystal of the compound of formula (I) according to claim 10, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 8.087±0.200°, 9.379±0.200°, 11.188±0.200°, 12.852±0.200°, 16.163±0.200°, 18.306±0.200°, 18.626±0.200°, and 19.105±0.200°.

12. A type 1 crystal of the compound of formula (I) according to claim 11, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 8.087±0.200°, 9.379±0.200°, 11.188±0.200°, 12.852±0.200°, 16.163±0.200°, 18.306±0.200°, 18.626±0.200°, 19.105±0.200°, 19.447±0.200°, 20.666±0.200°, 20.875±0.200°, and 21.210±0.200°.

13. Powder X-ray diffraction spectra were 8.087±0.200°, 9.379±0.200°, 11.188±0.200°, 12.852±0.200°, 16.163±0.200°, 18.306±0.200°, 18.626±0.200°, 19.105±0.200°, 19.447±0.200°, 20 A type 1 crystal of the compound of formula (I) according to claim 12, having characteristic diffraction peaks at 2θ angles of 666±0.200°, 20.875±0.200°, 21.210±0.200°, 22.417±0.200°, 23.446±0.200°, 24.043±0.200° and 24.402±0.200°.

14. The powder X-ray diffraction spectra were 6.516°, 8.087°, 9.378°, 11.188°, 11.881°, 12.852°, 13.880°, 14.564°, 15.615°, 16.163°, 18.306°, 18.626°, 19.105°, 19.477°, 20.666°, 20.875°, 21.210°, 22.417°, 23.446°, 23.715°, 24.043°, 24.402°, 25. A type 1 crystal of the compound of formula (I) according to claim 13, having characteristic diffraction peaks at 2θ angles of 159°, 25.663°, 26.227°, 26.742°, 26.897°, 27.127°, 27.752°, 28.341°, 29.332°, 30.727°, 30.956°, 31.678°, 32.197°, 32.574°, 34.479°, 35.051°, 35.341°, 35.873°, and 36.960°.

15. A type 1 crystal of the compound of formula (I) according to claim 9, wherein the XRPD spectrum is as shown in Figure 1.

16. A type 1 crystal of the compound of formula (I) according to claim 9, wherein the differential scanning calorimetry (DSC) curve shows that the starting point of an endothermic peak is at 161.77°C ± 3.00°C.

17. A type 1 crystal of the compound of formula (I) according to claim 9, wherein the thermogravimetric analysis (TGA) curve shows a weight loss of 0.3182% at 150.00°C ± 3.00°C.

18. Use of type 1 crystals of the compound of formula (I) according to any one of claims 9 to 17 in the manufacture of a therapeutic agent for psoriasis and / or inflammatory bowel disease.

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