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1. WO2019049021 - A PROCESS FOR PREPARATION OF TRIAMINOPYRIMIDINE COMPOUND AND INTERMEDIATES THEREOF

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[ EN ]

We claim:

1. A triaminopyrimidine compound 1,


1

or pharmaceutically acceptable salts thereof, or hydrates, or solvates, or polymorphs, or optically active forms thereof, in solid state forms.

2. A crystalline triaminopyrimidine compound 1.

3. A crystalline Form I of triaminopyrimidine compound 1 characterized by powder x-ray diffraction pattern having peaks expressed in degrees 2Θ at 6.3° and 9.8° + 0.2 2Θ.

4. The crystalline Form I according to claim 3 further characterized by powder x-ray diffraction pattern having peaks expressed in degrees 2Θ at 6.3°, 7.8, 9.8°, 15.4°, and 20.0°+ 0.2 2Θ; a differential scanning calorimetry analysis having onset at about 179 °C+ 5 °C and endothermic peak at about 181 °C+ 5 °C; a powder x-ray diffraction pattern substantially same as depicted in FIG. l; and differential scanning calorimetry substantially same as depicted in FIG.2.

5. A crystalline Form II of triaminopyrimidine compound 1 characterized by powder x-ray diffraction pattern having peaks expressed in degrees 2Θ at 13.8°, 21.9°, and 23.7°+ 0.2

2Θ.

6. The crystalline Form II according to claim 5 further characterized by powder x-ray diffraction pattern having peaks expressed in degrees 2Θ at 8.3°, 12.1°, 13.8°, 21.9°, and 23.7°+ 0.2 2Θ; a differential scanning calorimetry analysis having atleast one onset at about 161 °C+ 5 °C and endothermic peak at about 163 °C+ 5 °C; a differential scanning calorimetry having one onset at about 161 °C+ 5 °C and second onset at about 179 °C+ 5 °C; a differential scanning calorimetry having one endothermic peak at about 163 °C+ 5 °C and second endothermic peak at about 181 °C+ 5 °C; powder x-ray diffraction pattern substantially same as depicted in FIG.3; and differential scanning calorimetry substantially same as depicted in FIG.4.

7. Compound 5, or a hydrate thereof,


The compound 5 according to claim 7 is crystalline monohydrate.

The crystalline monohydrate according to claim 8 characterized by powder x-ray powder diffraction pattern having peaks expressed in degrees 2Θ at 10.5°, 12.7°, and 25.1°+ 0.2

2Θ.

10. The compound 5 according to claim 7 is substantially pure having a purity of about 98% or more, of about 99 % or more, of about 99.5% or more, of about 99.8% or more, by weight by area percentage by HPLC.

11. The compound 5 according to claim 9 is substantially free from one or more of compounds 4b or 4c,


4b

12 Compound 5b, which is a free base.


A free base compound 2, which is an intermediate for the preparation triaminopyrimidine compound 1,


14. A process for the preparation of compound 5, or a hydrate thereof,


the process comprising:

(a) reacting compound 4a with cyclopropane carboxylic acid in one or more solvents to obtain compound 3 a;


(b) reacting the compound 3 a with diphenylmethanimine in one or more solvents to obtain compound 2a;


(c) reacting the compound 2a with hydrochloric acid in one or more solvents to obtain the compound 5; and

(d) obtaining the compound 5 or a hydrate thereof by crystallizing in one or more solvents.

15. The process according to claim 14, which is performed in a single solvent in one -pot.

16. A process for the preparation of compound 6,


the process comprising:

(a) halogenating 2-butenenitrile to obtain compound 2,3-dihalobutanenitrile; and

(b) reacting the compound 2,3-dihalobutanenitrile with methyl hydrazine or salts thereof in the presence of a base to obtain compound 6.

17. The process according to claim 16, wherein the halogenation in step (a) comprises chlorination, bromination, fluorination, or iodination.

18. The process according to claim 17, wherein the halogenation is bromination using a brominating agent selected from bromine, HBr- Acetic acid, 1,4-dibromo- dimethylhydantoin, and N-bromosuccinimide.

19. The process according to claim 16, wherein the compound 2,3-dihalobutanenitrile is 2,3- dibromobutanenitrile .

20. The process according to claim 16, wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, STB, PTB, pyridine, piperidine, morpholine, TEA, DIPEA, DBU, or

DABCO.

21. A triaminopyrimidine compound 1 having a purity of about 99% or more and total impurities of about 1.0% or less, when measured by area percentage by HPLC.

22. The triaminopyrimidine compound 1 according to claim 21, which is substantially free from one or more of compound 11, compound 12, compound 13, compound 14 and compound 15.


23. A composition comprising triaminopyrimidine compound 1 having a purity of about 99%

2 4 or more by weight, and (S)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N -(1,5- dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethyl- Piperazine-l-yl)pyrimidine-2,4-diamine (relative to triaminopyrimidine) present in an amount of about 0.5% or less, by weight by area percentage of HPLC.

24. A composition comprising triaminopyrimidine compound 1 having a purity of about 99% or more by weight, and (R)-4-cyclopropyl-6-((4-((l,5-dimethyl-lH-pyrazol-3-yl)amino)- 5-(3,4-dimethylpiperazin-l-yl)pyrimidin-2-yl)amino)-3-fluoro-2-methylpyridine-l-oxide (relative to triaminopyrimidine) present in an amount of about 0.5% or less, by weight by area percentage of HPLC.

25. A process for the preparation of triaminopyrimidine compound 1, the process comprising: (a) reacting compound 10 with compound 9 in one or more solvents to obtain compound 8;

(b) reacting the compound 8 with a chlorinating agent in one or more solvents to obtain compound 7;


7

(c) reacting the compound 7 with compound 6 in one or more solvents in the presence of a base to obtain compound 4;


4

(d) reacting the compound 4 with compound 5 or a hydrate thereof in one or more solvents in the presence of a base to obtain compound 3 or solution thereof;


(e) reacting the compound 3 or solution thereof with an acid in one or more solvents to obtain compound 2 free base;


2

(f) reacting the compound 2 free base with a methylating agent in one or more solvents to obtain the compound 1 ; and

(g) optionally crystallizing the compound in one or more solvents.

26. The process according to claim 25, wherein the chlorinating agent in step (b) is selected from phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, and thionyl chloride.

27. The process according to claim 25, wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, piperidine, morpholine, TEA, DIPEA, DBU, STB, PTB, or

DABCO.

28. The process according to claim 25, wherein the acid comprises one or more of hydrochloric acid, hydrobromic acid, acetic acid, phosphoric acid, and trifluroacetic acid.

29. The process according to claim 25, wherein the solvent in step (e) comprises one or more of methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, isopropyl acetate, butyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile and water, or mixtures thereof.

. A process for obtaining free base compound 2 comprising crystallizing from one or more solvents selected from methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, isopropyl acetate, butyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, water, or mixtures thereof.

31. A process for the preparation of triaminopyrimidine compound 1 comprising methylating free base compound 2 with a methylating agent, optionally in the presence of a reducing agent, in one or more solvents.

32. The process according to claim 31, wherein the methylating agent comprises one or more of diazomethane, 2,2-dimethoxypropane, dimethyl carbonate, dimethyl sulfide, dimethyl zinc, methyl flouro sulfonate, methyl iodide, methyl bromide, methyltrifluoro methane sulfonate, trimethoxonium tetraflouroborate, formaldehyde, and mixture of formic acid and formaldehyde.

33. The process according to claim 31, wherein the reducing agent comprises one or more of sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminium hydride, and sodium borohydride.

34. A process for the preparation of crystalline triaminopyrimidine compound 1 by crystallizing in one or more solvents selected from methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, isopropyl acetate, butyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, water, or mixtures thereof.

35. A pharmaceutical composition comprising crystalline triaminopyrimidine compound 1, and pharmaceutically acceptable carrier, diluents and excipients.

36. A pharmaceutical composition comprising substantially pure triaminopyrimidine compound 1, and one or more of pharmaceutically acceptable carrier, diluents and excipients.

37. A pharmaceutical composition comprising crystalline triaminopyrimidine compound 1 useful for the treatment of malaria.