Synthesis of 2-aralkoxyadenosines and 2-alkoxyadenosines

A process for the preparation of a compound of formula I:

• 26
• wherein:
• R1 and R2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, heterocyclic, or if taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing a total of one to four heteroatoms selected from nitrogen, oxygen, and sulfur;
• R3 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, substituted aralkyl, aralkenyl, or substituted aralkenyl;
• the method comprising:
• (a) treating guanosine with an acylating agent;
• (b) treating a compound resulting from step (a) with a halide source;
• (c) hydrolysis of a compound resulting from step (b);
• (d) treating a compound resulting from step (c) with an alkylating agent;
• and
• (e) treating a compound resulting from step (d) with an amine to provide a compound of Formula I.

A process for the preparation of a compound of formula I:

• 27
• wherein:
• R1 and R2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, heterocyclic, or if taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing a total of one to four heteroatoms selected from nitrogen, oxygen, and sulfur;
• R3 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, substituted aralkyl, aralkenyl, or substituted aralkenyl;
• comprising the steps of:
• (a) treating guanosine with an acylating agent in the presence of a base and a solvent at a reaction temperature of about 20° C. to about 120° C. for a period of about 20 minutes to about 30 hours;
• (b) treating the product of step (a) in a solvent with a suitable chloride source, such as phosphorus oxychloride in the presence of a tertiary amine, thionyl chloride/DMF, phosphorus pentachloride, chlorine gas, carbon tetrachloride/triphenylphosphine, dichorotriphenylphosphorane, or triphenylantimony dichloride at a reaction temperature of 10° C. to about 120° C. for a period of about 5 minutes to about 8 hours;
• (c) hydrolytic diazotization of the product from step (b) with an alkyl nitrite or sodium nitrite and an inorganic acid in a mixture of water and a lower alcohol at −10° C. to about 60° C. for a period of about 20 minutes to about 24 hours;
• (d) adding to the protected 6-chloro-2-hydroxy-9-(β-D-ribofuranosyl)-purine in a solvent, a base and a suitable alkylating agent, at a temperature of 10° C. to about 120° C. for a period of about 30 minutes to about 48 hours;
• (e) dissolving the intermediate of step (d) in an alcoholic solvent which is then treated with ammonia or a suitable primary or secondary amine at temperatures of −70° C. to about 120° C. for a period of about 20 minutes to about 48 hours and one to fifty atmospheres of pressure;
• evaporating the reaction mixture;
• then purifying the product by recrystallization from an appropriate solvent or chromatography or a combination of these two methods.

A process for the preparation of 2-[2-(4-chlorophenyl)ethoxy]adenosine comprising:

• (a) treating guanosine with an acylating agent in the presence of a base and a solvent at a reaction temperature of about 20° C. to about 120° C. for a period of about 20 minutes to about 30 hours;
• (b) treating the product of step (a) in a solvent with a suitable chloride source, such as phosphorus oxychloride in the presence of a tertiary amine, thionyl chloride/DMF, phosphorus pentachloride, chlorine gas, carbon tetrachloride/triphenylphosphine, dichlorotriphenylphosphorane, or triphenylantimony dichloride at a reaction temperature of 10° C. to about 120° C. for a period of about 5 minutes to about 8 hours;
• (c) hydrolytic diazotization of the product from step (b) with an alkyl nitrite or sodium nitrite and an inorganic acid in a mixture of water and a lower alcohol at −10° C. to about 60° C. for a period of about 20 minutes to about 24 hours;
• (d) adding to the protected 6-chloro-2-hydroxy-9-(β-D-ribofuranosyl)purine in a solvent, a base and a suitable alkylating agent, at a temperature of 0° C. to about 120° C. for a period of about 30 minutes to about 48 hours;
• (e) dissolving the intermediate of step (d) in an alcoholic solvent which is then treated with a suitable primary or secondary amine at temperatures of −70° C. to about 120° C. for a period of about 20 minutes to about 48 hours and one to fifty atmospheres of pressure;
• evaporating the reaction mixture;
• then purifying the product by recrystallization from an appropriate solvent or chromatography or a combination of these two methods.