Process for making substituted pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of phosphodiesterase 5

A process for preparing a compound of Formula I:

• wherein R1 is C1-C4 branched or straight chain alkyl;
• R2is H;
• R3 is H;
• C1-C6 branched or straight chain alkyl;
• C2-C4 alkenyl;
• or C2-C4 alkynyl;
• R4 is H;
• C1-C6 branched or straight chain alkyl;
• or C2-C4 alkenyl;
• R5is SO2NR10R11;
• R8 is H;
• or C1-C6 branched or straight chain alkyl;
• R10 and R11 are each independently H;
• C1-C12 branched or straight chain alkyl;
• C1-C3 halogenated branched or straight chain alkyl;
• C2-C6 alkenyl;
• C2-C6 alkynyl or C3-C6 cycloalkyl;
• or R10 and R11 together with their attached nitrogen atom form a pyrrolinyl, pyrrolinone group, piperidyl, morpholinyl, or 4-N(R8)-piperazinyl, the said groups are optionally substituted with OH, CN, CO2R8, C1-C4 branched or straight chain alkyl, or C1-C3 alkoxyl;
• or their pharmaceutically acceptable salts,
• the process comprising reacting compound IE with compound IF:
• wherein R1, R2, R3, R4 and R5 are as defined above, in an inert solvent in the presence of an organic base as a catalyst as well as an acid neutralizer at −20° C. to 80° C., to obtain compound ID:
• heating compound ID in an acidic aqueous solution to obtain the compound IA:
• wherein R1, R2, R3, R4 and R5 are as defined above,
• carrying out a cyclization reaction of compound IA by heating and refluxing in an appropriate solution under acidic, basic or neutral condition to obtain compounds of-Formula I:
• wherein R1, R2, R3, R4 and R5 are as defined above;
• or,
• compounds of Formula I are obtained directly by cyclization of the corresponding compound ID under conditions as follows:
• a) heating to 100-300° C. in mixture of phosphorus pentoxide, water and tertiary amine, or,
• b) reacting at room temperature or reacting by heating in basic hydrogen peroxide aqueous solution, or,
• c) reacting at room temperature or reacting by heating under acidic hydrous or anhydrous condition;
• or,
• specific example of compounds of Formula I wherein R5 is SO2NR10R11 may be prepared by processes as follows:
• compound IC is obtained by reaction between compound IF and compound IE wherein R5 is H;
• wherein R1, R2, R3 and R4 are as defined above,
• then compound IB is obtained by reacting compound IC with chlorosulfonic acid alone or in dichloromethane, chloroform, and other inert or polar non-proton solvents—,
• wherein R1, R2, R3 and R4 are as defined above,
• and then acylation reaction occurs between compound IB and proper amines in dichloromethane, chloroform, tertiary amine or other inert or polar non-proton solvents at −78° C. to 100° C. to obtain compounds of Formula I wherein R5 is SO2NR10R11, and wherein R10and R11 are as defined above;
• or, compounds of Formula I are obtained by reacting compound IG with compound IH
• in the solvents of polar non-proton solvents in the presence of the base as catalyst, wherein R1, R2, R3, R4 and R5 are as defined above and X represents Cl, Br or I;
• and optionally, converting the compounds of Formula I into the corresponding salts thereof by reacting with pharmaceutically acceptable acids.