RU2009146829A - METHOD OF OBTAINING A2A-ADENOSINE RECEPTOR AGONIST AND ITS POLYMORPHIC MODIFICATIONS - Google Patents

Abstract

 1. The method of obtaining (1- {9 - [(4S, 2R, 3R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl] -6-aminopurin-2-yl} pyrazol-4 -yl) -N-methylcarboxamide! ! by contacting the compounds of formula (4):! ! with aqueous methylamine at a temperature of approximately 2.5-7.5 ° C. ! 2. The method according to claim 1, where the reaction is carried out in a sealed reactor under pressure. ! 3. The method according to claim 2, where the product is isolated by! (a) degassing under vacuum at a temperature not exceeding 35 ° C to remove excess methylamine,! (b) venting and cooling to 0-5 ° C for approximately 15 minutes to an hour,! (c) filtering the suspension thus formed,! (d) washing the contents of the filter with water and then with ethanol and! (e) drying the remaining solid under vacuum at a temperature that does not exceed 40 ° C. ! 4. The method according to claim 3, where the final product is (1- {9 - [(4S, 2R, 3R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl] -6-aminopurine- 2-yl} pyrazol-4-yl) -N-methylcarboxamide is further purified by! (i) dissolving the dried solid obtained in step (e) according to claim 3 in a solvent,! (ii) filtering any solid impurities from the solution,! (iii) rinsing with additional solvent,! (iv) adding a solution to the purified water, which is maintained at a temperature of about 78-88 ° C. to thereby form a suspension! (v) stirring the suspension! (vi) cooling the suspension,! (vii) filtering,! (viii) washing the contents of the filter with water and then with ethanol and! (ix) drying the remaining solid under vacuum at a temperature that does not exceed 40 ° C. ! 5. The method according to claim 4, where the solvent used in stages (i) and (iii) is dimethyl sulfoxide. ! 6. The method according to claim 5, gd

Claims (16)

1. The method of obtaining (1- {9 - [(4S, 2R, 3R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl] -6-aminopurin-2-yl} pyrazol-4 -yl) -N-methylcarboxamide

by contacting a compound of formula (4):

with aqueous methylamine at a temperature of approximately 2.5-7.5 ° C. 2. The method according to claim 1, where the reaction is carried out in a sealed reactor under pressure. 3. The method according to claim 2, where the product is isolated by (a) degassing under vacuum at a temperature of not more than 35 ° C to remove excess methylamine, (b) venting and cooling to 0-5 ° C. for about 15 minutes to an hour, (c) filtering the suspension thus formed, (d) washing the contents of the filter with water and then ethanol; and (e) drying the remaining solid under vacuum at a temperature that does not exceed 40 ° C. 4. The method according to claim 3, where the final product is (1- {9 - [(4S, 2R, 3R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl] -6-aminopurine- 2-yl} pyrazol-4-yl) -N-methylcarboxamide is further purified by (i) dissolving the dried solid obtained in stage (e) according to claim 3 in a solvent, (ii) filtering any solid impurities from the solution, (iii) rinsing with an additional solvent, (iv) adding a solution to the purified water, which is maintained at a temperature of about 78-88 ° C, thereby forming a suspension, (v) mixing the suspension, (vi) cooling the suspension, (vii) filtering, (viii) washing the contents of the filter with water and then ethanol; and (ix) drying the remaining solid under vacuum at a temperature that does not exceed 40 ° C. 5. The method according to claim 4, where the solvent used in stages (i) and (iii) is dimethyl sulfoxide. 6. The method according to claim 5, where the residual water content in the final product is not more than 5.5%, and the residual ethanol is not more than 2000 ppm. 7. A method of obtaining a compound of formula (4):

comprising contacting a compound of formula (2):

with an excess of ethyl 2-formyl-3-oxopropionate, optionally in the presence of acid. 8. The method according to claim 6, where the reaction is carried out in ethanol. 9. The method according to claim 6, where an acid is used, which is HCl in an amount of up to 0.1 molar equivalent. 10. The method according to claim 9, where the reaction is carried out at the boil under reflux. 11. The method according to claim 6, where an approximately 5-10-fold molar excess of ethyl 2-formyl-3-oxopropionate is used. 12. The method according to claim 11, where approximately 6.8-7.5-fold molar excess of ethyl 2-formyl-3-oxopropionate is used. 13. The method according to item 12, where the product is isolated by (a) cooling the mixture obtained after completion of the reaction to about 10 ° C, (b) filtering, (c) washing the contents of the filter with ethanol; and (d) drying the remaining solid under vacuum at a temperature that does not exceed 40 ° C. 14. The method of obtaining the compounds of formula (2):

comprising the interaction of the compounds of formula (1)

(one) with a 14.3-16.7-fold molar excess of hydrazine at a temperature of approximately 60-65 ° C. 15. The method according to p. 14, where hydrazine is initially heated to a temperature of approximately 60-65 ° C, followed by the addition of a compound of formula (1). 16. The method according to 14, where the compound of formula (2) is isolated by (a) cooling the reaction mixture to about 40 ° C, (b) adding 4.2-4.9 weight equivalents of water while maintaining a temperature of approximately 40 ° C, (c) cooling the mixture to a temperature of approximately 10 ° C and maintaining this temperature for at least 1 hour, (d) filtering, (e) washing the contents of the filter with water and then ethanol; and (f) drying the remaining solid in vacuo at a temperature that does not exceed 30 ° C. for at least 12 hours