Methods for the synthesis of substituted purines
AssigneeIRM LLC, a Delaware Limited Liability Company
InventorsSheng Ding, Qiang Ding, Nathanael S. Gray, Peter G. Schultz
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Abstract
The invention provides general methods for preparing 2,9-, 2,6,9-, O6-aryl- and O6-alkyl-substituted purines in a combinatorial and traceless fashion. The methods involve, in some embodiments, Mitsunobu alkylation of 2-fluoro-6-phenylsulfenylpurine at N9 with alcohols in solution, followed by C2-capture of the purine core with a resin-bound amine and subsequent oxidation and displacement of the C6 sulfonyl group with amines and anilines.
Claims27
A method of preparing a 2,6,9-substituted purine compound having the Formula I:
- 185
- wherein:
- R1 and R2 are independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl;
- R3 is hydrogen and R4 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl or R3 and R4 when taken together with the nitrogen and carbon atoms to which they are respectively attached form an optionally substituted saturated heterocyclic ring;
- the method comprising:
- a) oxidizing a resin-bound compound of Formula II
- 186
- wherein:
- R1 and R2 are as defined above and n is 0 or 1;
- to provide a resin-bound compound of Formula III
- 187
- wherein R1, R2 and n are as defined above;
- b) reacting the compound of Formula III with an amine of Formula IV
- NR3R4 IV
- wherein R3 and R4 as defined above,
- to provide a resin-bound compound of Formula V
- 188
- wherein R1, R2, R3 and R4 are as defined above;
- and
- c) cleaving the resin-bound compound of Formula V from the resin to provide the substituted purine compounds of Formula I.
A compound of the Formula VI
- 194
- wherein X is fluoro, chloro, or bromo and n is 0 to 1.
A method of preparing 2,9-substituted purine compounds having the Formula X
- 195
- wherein R1 and R2 are independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl;
- the method comprising:
- a) oxidizing a resin-bound compound of Formula II
- 196
- wherein R1 and R2 are as defined above and n is 0 or 1;
- to provide a resin-bound compound of Formula III
- 197
- wherein R1, R2 and n are as defined above;
- b) hydrolyzing the sulfonyl group at the 6-position of the resin-bound compound of Formula III and cleaving the hydrolyzed resin-bound compound from the resin to provide the substituted purine compounds of Formula X.
A method for preparing O6-alkyl-purine compounds of Formula XI
- 203
- wherein R1 and R2 are independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl;
- and R3 is selected from the group consisting of alkyl and substituted alkyl;
- the method comprising:
- a) oxidizing a resin-bound compound of Formula II
- 204
- wherein R1 and R2 are as defined above and n is 0 or 1;
- to provide a resin-bound compound of Formula III
- 205
- wherein R1, R2 and n are as defined above;
- b) hydrolyzing the sulfonyl group at the 6-position of the resin-bound compound of Formula III to form a resin-bound compound of Formula XII
- 206
- wherein R1 and R2 are as defined above;
- and
- c) alkylating the resin-bound compound of Formula XII and cleaving the resin-bound alkylated compound from the resin to provide a compound of Formula XI.
A method for preparing O6-aryl purine compounds of Formula XIII
- 211
- wherein R1 and R2 are independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl and heterocyclyl;
- and R3 is aryl or substituted aryl;
- the method comprising:
- a) oxidizing a resin-bound compound of Formula II
- 212
- wherein R1 and R2 are as defined above and n is 0 or 1;
- to provide a resin-bound compound of Formula III
- 213
- wherein R1, R2 and n are as defined above;
- and
- b) reacting the resin-bound compound of Formula III with an aryl compound followed by cleavage of the resin-bound compound to provide a compound of Formula XIII.
A method of preparing a compound of Formula VI
- 218
- wherein X is fluoro, chloro or bromo and n is 0 or 1;
- the method comprising:
- reacting a 2-halo-6-chloro-purine with a compound of Formula IX
- 219
- wherein n is as defined above to provide the compound of Formula VI.
A method for synthesis of a C2-substituted purine, the method comprising reacting a C6-sulfenylpurine with a nucleophile, wherein X is halogen, and the nucleophile is substituted at the C2 position of the purine.
Dependencies are inferred from the claim text.