Process for preparing an A
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. The A 2A -adenosine receptor agonist has the following formula: This compound is prepared by reacting the ethyl ester with methylamine in a sealed pressure reactor.
1. A method for the large scale preparation of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide:
comprising:
reacting a compound of the formula (3)
with methylamine wherein the compound of formula (3) is reacted with an aqueous solution of methylamine at an initial temperature of about 0-5° C. followed by warming to about 50-70° C. in a sealed pressure reactor.
2. The method of claim 1 , further comprising wherein the (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl)pyrazol-4-yl)-N-methylcarboxamide end product is isolated as the pure monohydrate by
(a) dissolving the product in a solvent,
(b) adding purified water,
(c) filtering the slurry thus formed,
(d) washing the contents of the filter with water followed by ethanol, and
(e) drying the solid that remains under vacuum at a temperature that does not exceed 40° C.
3. The method of claim 2 , wherein the solvent of step (a) is dimethylsulfoxide.
4. A method of preparing a compound of the formula (3):
comprising:
reacting a compound of the formula (2)
with ethyl 2-formyl-3-oxopropionate wherein about 1.1 molar equivalent of ethyl 2-formyl-3-oxopropionate is reacted with the compound of formula (2) in a solvent.
5. The method of claim 4 , wherein the solvent is ethanol.
6. The method of claim 5 , wherein the reaction is conducted at a temperature of about 80° C.
7. A method of synthesizing (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide
comprising by contacting a compound of the formula (4):
with an aqueous solution of methylamine at an initial temperature of about 0-5° C. followed by warming to about 50-70° C. in a sealed pressure reactor.
8. The method of claim 7 , further comprising wherein the (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide end product is isolated as the pure monohydrate by
(a) dissolving the product of claim 7 in a solvent,
(b) adding purified water,
(c) filtering the slurry thus formed,
(d) washing the contents of the filter with water followed by ethanol, and
(e) drying the solid that remains under vacuum at a temperature that does not exceed 40° C.
9. The method of claim 8 , wherein the solvent of step (a) is dimethylsulfoxide.
10. A method of synthesizing a compound of the formula (4):
comprising
contacting a compound of the formula (2):
with an excess of ethyl 2-formyl-3-oxopropionate wherein about a 2-10 fold molar excess of ethyl 2-formyl-3-oxopropionate is reacted with the compound of the formula (2) in a solvent.
11. The method of claim 10 , wherein the solvent is ethanol.
12. The method of claim 11 wherein the reaction is conducted at a temperature of about 80° C.
13. The method of claim 10 , wherein about a 5-10 fold molar excess of ethyl 2-formyl-3-oxopropionate is reacted with the compound of the formula (2).