Methods for the synthesis of unsymmetrical cycloakyl substituted xanthines
View Patent ↗The present invention provides compounds and pharmaceutical compositions that are selective antagonists of A 2B adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents. Also provided are processes for the preparation of the compounds and their intermediates.
1. A process for preparing a compound of the formula Xa:
R 1 is (C 3-8 )cycloalkyl; and
R 2 is hydrogen, or is selected from the group consisting of (C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkenyl(C 1-8 )alkyl, (C 3-8 )alkynyl, (C 3-8 )alkynyl(C 1-8 )alkyl, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl(C 1-8 ) alkyl-,(C 4-10 ) heterocyclyl, (C 4-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )arloxy, (C 6-10 )aryl(C 1-8 ) alkyl-, (C 5-10 )heteroaryl and (C 5-10 )heteroaryl(C 3-8 )alkyl-;
comprising:
a) contacting a compound of the formula XII:
with a compound of the formula NC—CH 2 —COOH with a dehydrating agent;
b) hydrolyzing the resulting reaction mixture to form a mixture of the compound of the formulae Xa and Xb; and
c) separating the compound of the formula Xa from the formula Xb.
2. The process of claim 1 , wherein the dehydrating agent is selected from the group consisting of acetic anhydride, propionic anhydride and benzoic anhydride.
3. The process of claim 1 , wherein the dehydrating agent is acetic anhydride and the reaction is performed at about 80° C.
4. The process of claim 1 , wherein the hydrolysis is performed with an aqueous alkaline salt in an alcoholic solvent.
5. The process of claim 4 , wherein the aqueous alkaline salt in an alcoholic solvent is aqueous NaOH and methanol.
6. The process of claim 1 , wherein the separation of Xa and Xb to obtain substantially pure Xa is performed by crystallization, chromatography or by derivatizing the compound mixtures into a separable derivatives, isolating the isomers and converting the isolated derivative back to the substantially pure isomer Xa or Xb.
7. The process of claim 1 , wherein R 1 is selected from the group consisting of cyclopropyl and cyclobutyl, and R 2 is selected from the group consisting of (C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkenyl(C 1-8 )alkyl, (C 3-8 )alkynyl, (C 3-8 )alkynyl(C 1-8 )alkyl, (C 1-8 )alkoxy, (C 3-8 cycloalkyl(C 1-8 )alkyl-, (C 4-10 )heterocyclyl, (C 4-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )aryloxy, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl and (C 5-10 )heteroaryl(C 1-8 )alkyl-.
8. The process of claim 7 , wherein R 1 is selected from the group consisting of cyclopropyl and cyclobutyl, and R 2 is selected from the group consisting of (C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkenyl(C 1-8 )alkyl, (C 3-8 )alkynyl and (C 3-8 )alkynyl(C 1-8 )alkyl.
9. The process of claim 7 , wherein R 1 is cyclopropyl or cyclobutyl, and R 2 is a (C 1-8 )alkyl.