Process for preparing an A2A-adenosine receptor agonist and its polymorphs
View Patent ↗Disclosed is a synthesis suitable for large scale manufacture of an A 2A -adenosine receptor agonist, and also relates to polymorphs of that compound, and to methods of isolating a specific polymorph.
1. A method of synthesizing Compound A having the formula:
comprising:
(a) contacting compound 1 having the formula:
with a 14.3-16.7 fold molar excess of hydrazine to provide compound 2 having the formula:
(b) contacting compound 2 with an excess of ethyl 2-formyl-3-oxopropionate to provide compound 4 having the formula:
(c) contacting compound 4 with methylamine.
2. The method of claim 1 , further comprising wherein the hydrazine in (a) is first heated to approximately 60-65° C. followed by addition of compound 1.
3. The method of claim 1 , further comprising wherein compound 2 is isolated by:
cooling the reaction mixture to approximately 40° C.;
adding a 4.2-4.9 mass equivalent of water while maintaining the temperature at approximately 40° C.; and
cooling the mixture to approximately 10° C. and maintaining at that temperature for at least approximately 1 hour.
4. The method of claim 3 , further comprising:
filtering the isolated compound 2;
washing the contents of the filter with water followed by ethanol; and
drying the solid that remains under vacuum at a temperature that does not exceed 30° C. for at least 12 hours.
5. The method of claim 1 , wherein the excess ethyl 2-formyl-3-oxoproionate is about a 5-10 fold molar excess.
6. The method of claim 1 , wherein the excess ethyl 2-formyl-3-oxoproionate is about a 6.8-7.5 fold molar excess.
7. The method of claim 1 , wherein (b) further comprises adding HCl as a catalyst.
8. The method of claim 7 , wherein the HCl is added in an amount of about 0.1 equivalents or less.
9. The method of claim 7 , wherein the HCl is added in an amount of about 0.05 equivalents.
10. The method of claim 1 , further comprising wherein (b) is carried out at about 80° C. and further comprises ethanol as a solvent.
11. The method of claim 1 , further comprising wherein compound 4 is isolated by
cooling the completed reaction mixture to approximately 10° C.;
filtering;
washing the contents of the filter with ethanol; and
drying the solid that remains under vacuum at a temperature that does not exceed 40° C.
12. The method of claim 1 , further comprising wherein (c) is carried out at approximately 2.5-7.5° C.
13. The method of claim 1 , further comprising wherein Compound A is isolated by
degassing under vacuum at not more than 35° C. to remove excess methylamine;
releasing the vacuum and cooling to 0-5° C. for approximately 15-minutes to an hour;
filtering the slurry formed;
washing the contents of the filter with water followed by ethanol; and
drying the solid that remains under vacuum at a temperature that does not exceed 40° C.
14. The method of claim 13 , further comprising wherein the Compound A is further purified by
(i) dissolving the dried solid in a solvent;
(ii) filtering any solid impurities from the solution;
(iii) rinsing with additional solvent;
(iv) adding solution to purified water that is maintained at approximately 78-88° C. thereby forming a slurry;
(v) stirring the slurry;
(vi) cooling the slurry;
(vii) filtering;
(viii) washing the contents of the filter with water followed by ethanol; and
(ix) drying the solid that remains under vacuum at a temperature that does not exceed 40° C.
15. The method of claim 14 , further comprising wherein the solvent used in (i) and (iii) comprises dimethylsulfoxide.
16. The method of claim 14 , wherein the residual water content of the Compound A product is not more than 5.5% and the residual ethanol of the Compound A product is not more than 2000 ppm.