Details for Patent: 8,268,988
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Title: | Process for preparing an A2A-adenosine receptor agonist and its polymorphs |
Abstract: | Disclosed is a synthesis suitable for large scale manufacture of an A.sub.2A-adenosine receptor agonist, and also relates to polymorphs of that compound, and to methods of isolating a specific polymorph. |
Inventor(s): | Zablocki; Jeff (Mountain View, CA), Elzein; Elfatih (Fremont, CA) |
Assignee: | Gilead Sciences, Inc. (Foster City, CA) |
Filing Date: | Apr 22, 2011 |
Application Number: | 13/092,812 |
Claims: | 1. A method of synthesizing Compound A having the formula: ##STR00025## comprising: (a) contacting compound 1 having the formula: ##STR00026## with a 14.3-16.7 fold molar excess of hydrazine to provide compound 2 having the formula: ##STR00027## (b) contacting compound 2 with an excess of ethyl 2-formyl-3-oxopropionate to provide compound 4 having the formula: ##STR00028## (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.degree. 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.degree. C.; adding a 4.2-4.9 mass equivalent of water while maintaining the temperature at approximately 40.degree. C.; and cooling the mixture to approximately 10.degree. 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.degree. 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.degree. 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.degree. 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.degree. C. 12. The method of claim 1, further comprising wherein (c) is carried out at approximately 2.5-7.5.degree. C. 13. The method of claim 1, further comprising wherein Compound A is isolated by degassing under vacuum at not more than 35.degree. C. to remove excess methylamine; releasing the vacuum and cooling to 0-5.degree. 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.degree. 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.degree. 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.degree. 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. |