Process for preparation of triaminopyrimidine compound and intermediates thereof
The present invention relates to triaminopyrimidine compound 1, or pharmaceutically acceptable salts thereof, or hydrates, or solvates, or polymorphs, or optically active forms thereof, in solid state forms. The invention also relates to a process for preparation of triaminopyrimidine compound and intermediates thereof. The present invention also relates to a pharmaceutical composition comprising pure triaminopyrimidine compound, useful for preventing or treating malaria.
1. A crystalline triaminopyrimidine compound of formula 1,
which is in crystalline Form I or Form II, wherein the crystalline Form I is characterized by a powder x-ray diffraction pattern having peaks expressed in degrees at 6.3°, 7.8°, 9.8°, 15.4°, and 20.0°±0.2° 2θ, when measured using CuKα source, and the crystalline Form II is characterized by a powder x-ray diffraction pattern having peaks expressed in degrees at 8.3°, 12.1°, 13.8°, 21.9°, and 23.7°±0.2° 2θ, when measured using CuKα source.
2. The crystalline triaminopyrimidine compound according to claim 1 , which is in the crystalline Form I, wherein the crystalline Form I is further characterized by a differential scanning calorimetry analysis having onset at about 179° C.±5° C. and endothermic peak at about 181° C.±5° C., when the differential scanning calorimetry analysis is performed at a heating rate of 10° C./minute.
3. The crystalline triaminopyrimidine compound according to claim 1 , which is in the crystalline Form II, wherein the crystalline Form II is further characterized by one or more of:
(a) a differential scanning calorimetry analysis having at least one onset at about 161° C.±5° C. and endothermic peak at about 163° C.±5° C.;
(b) a differential scanning calorimetry having one onset at about 161° C.±5° C. and second onset at about 179° C.±5° C.; and
(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.;
wherein the differential scanning calorimetry analysis in (a), (b), or (c) is performed at a heating rate of 10° C./minute.
4. A compound of formula 5,
as crystalline monohydrate, characterized by a powder x-ray diffraction pattern having peaks expressed in degrees at 10.5°, 12.7°, 25.1°, and 25.7°±0.2° 2θ, wherein the powder x-ray diffraction pattern is obtained using CuKα source.
5. The compound according to claim 4 that is substantially pure having a purity of about 98% or more, by weight as measured by area percentage by HPLC.
6. The compound according to claim 4 , wherein the compound is substantially free from one or more of compounds of formula 4b or formula 4c,
7. A process for the preparation of the compound of formula 5 according to claim 4 ,
the process comprising:
(a) reacting compound of formula 4a with cyclopropane carboxylic acid in one or more solvents to obtain compound of formula 3a;
(b) reacting the compound of formula 3a with diphenylmethanimine in one or more solvents to obtain compound of formula 2a;
(c) reacting the compound of formula 2a with hydrochloric acid in one or more solvents to obtain the compound of formula 5; and
(d) obtaining the compound of formula 5 as crystalline monohydrate by crystallizing the compound of formula 5 in one or more solvents.
8. The process according to claim 7 , wherein steps (a)-(c) are performed in a single solvent in one-pot.
9. The crystalline triaminopyrimidine compound of formula 1 according to claim 1 , having a purity of about 99% or more and total impurities of about 1.0% or less, by weight as measured by area percentage by HPLC.
10. The crystalline triaminopyrimidine compound of formula 1 according to claim 9 , which is substantially free from one or more of the compounds selected from the group consisting of a compound of formula 11, a compound of formula 12, a compound of formula 13, a compound of formula 14 and a compound of formula 15, wherein the formulas of these compounds are:
11. A composition comprising the crystalline triaminopyrimidine compound of formula 1 according to claim 1 , wherein the triaminopyrimidine compound of formula 1 has a purity of about 99% or more by weight, and(S)-N 2 -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N 4 -(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethyl-piperazine-1-yl) pyrimidine-2,4-diamine (relative to the triaminopyrimidine compound of formula 1) is present in an amount of about 0.5% or less, by weight as measured by area percentage of HPLC.
12. A composition comprising the crystalline triaminopyrimidine compound of formula 1 according to claim 1 , wherein the triaminopyrimidine compound of formula 1 has a purity of about 99% or more by weight, and (R)-4-cyclopropyl-6-((4-((1,5-dimethyl-1H-pyrazol-3-yl) amino)-5-(3,4-dimethylpiperazin-1-yl) pyrimidin-2-yl) amino)-3-fluoro-2-methylpyridine-1-oxide (relative to the triaminopyrimidine compound of formula 1) is present in an amount of about 0.5% or less, by weight as measured by area percentage of HPLC.
13. A process for the preparation of the crystalline triaminopyrimidine compound of formula 1 according to claim 1 , the process comprising:
(a) reacting a compound of formula 10 with a compound of formula 9 in one or more solvents to obtain a compound of formula 8;
(b) reacting the compound of formula 8 with a chlorinating agent in one or more solvents to obtain a compound of formula 7;
(c) reacting the compound of formula 7 with a compound of formula 6 in one or more solvents in the presence of a first base to obtain a compound of formula 4;
(d) reacting the compound of formula 4 with a compound of formula 5 or a hydrate thereof in one or more solvents in the presence of a second base to obtain a compound of formula 3 or solution thereof;
(e) reacting the compound of formula 3 or solution thereof with an acid in one or more solvents to obtain a compound of formula 2, which is a free base;
(f) reacting the compound of formula 2 with a methylating agent in one or more solvents to obtain the compound of formula 1; and
(g) crystallizing the compound of formula 1 in one or more solvents.
14. The process according to claim 13 , wherein the chlorinating agent at step (b) is selected from phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, and thionyl chloride.
15. The process according to claim 13 , wherein the first or second base at step c or d comprises one or more bases selected from 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.
16. The process according to claim 13 , wherein the acid comprises one or more acids selected from hydrochloric acid, hydrobromic acid, acetic acid, phosphoric acid, and trifluroacetic acid.
17. The process according to claim 13 , wherein the solvent at step (e) comprises 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 and water, or mixtures thereof.
18. A process for crystallizing a free base compound of formula 2,
the process comprising crystallizing the free base compound of formula 2 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.
19. A process for the preparation of the crystalline triaminopyrimidine compound of formula 1 according to claim 1 , the process comprising methylating a free base compound of formula 2
with a methylating agent, optionally in the presence of a reducing agent, in one or more solvents.
20. The process according to claim 19 , wherein the methylating agent comprises one or more of diazomethane, dimethyl carbonate, dimethyl sulfide, methyl fluorosulfonate, methyl iodide, methyl bromide, methyltrifluoro methane sulfonate, trimethoxonium tetraflouroborate, formaldehyde, and mixture of formic acid and formaldehyde.
21. The process according to claim 19 , wherein the reducing agent comprises one or more agents selected from sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminium hydride, and sodium borohydride.
22. A process for the preparation of the crystalline triaminopyrimidine compound of formula 1 according to claim 1 , the process comprising crystallizing the triaminopyrimidine compound of formula 1 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.
23. A pharmaceutical composition comprising the crystalline triaminopyrimidine compound of formula 1 according to claim 1 , and pharmaceutically acceptable carrier, diluents and excipients.
24. A pharmaceutical composition comprising the crystalline triaminopyrimidine compound of formula 1 according to claim 9 , and one or more of pharmaceutically acceptable carriers, diluents and excipients.
25. A method of treatment of malaria comprising administering to a subject in need thereof a pharmaceutical composition comprising the crystalline triaminopyrimidine compound of formula 1 according to claim 1 .