Process for preparing trisubstituted pyrimidine compounds

A method for regioselectively preparing a compound represented by formula (I):

• or a salt thereof, wherein:
• X is —NH—;
• G is —O—, —O—C(O)—NH—, —O—C(O)—NRf—, —O—C(S)—NH—, —NH—C(S)—O—, —O—C(S)—NRf—, —NR−C(S)—O—, —P(O)(Rc)—, —P(O)(Rc)—O—, —P(O)(Rc)—NRc—, -Cyclyl-, -Heterocycloalkyl-, -Aryl-, -Heteroaryl-, -Heteroaralkyl-, -Heteroaryl-NH—, -Heteroaryl-S—, -Heteroaralkyl-O—, —Si(OH)2—, —B(OH)—, —P(O)2O—, —P(O)2N(Rc)—, —N(Rc)P(O)2, or —OP(O)2—;
• wherein Rf for each occurrence is H, alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, or heterocycloalkyl;
• R2 and R4 are each H;
• R3 is Rc, alkenyl, alkynyl, —ORc, —OC(O)Rc, —SO2Rc, —S(O)Rc, —S(O)2NRcRd, —SRc, —NRcRd, —NRcCORd, —NRcC(O)Rd, —NRcC(O)ORd, —NRcC(O)NRcRd, —NRcSO2Rd, —C(O)Rc, —C(O)ORc, —C(O)NRcRd, —P(O)ORcORd, or —S(O)2NRcRd;
• R7 is an optionally substituted indolyl or an optionally substituted phenyl;
• R8 and R9, taken together with the nitrogen to which they are attached, are an optionally substituted heterocycloalkyl, wherein the heterocycloalkyl is morpholine;
• R10 is H or methyl;
• n is 1 or 2;
• m is 0 or 1;
• Y is O, S, or NRc;
• and
• Rc and Rd, for each occurrence, are, independently, H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, —C(O)-alkyl, or —S(O)2Rf;
• the method comprising the steps of:
• a) reacting HNR8R9 with a 2,4,6-trihalopyrimidine in a solution of alcohol and water, wherein HNR8R9 is present in an excess amount compared to the 2,4,6-trihalopyrimidine, to form a first mixture of regioisomers represented by formulas (IIIa) and (IIIb):
• wherein R6, for each occurrence, is independently F, CI, Br, or I;
• b) adding a strong base to the first mixture in at least 2 separate portions, and the mixture is maintained at a temperature of between about −20° C. and about 10° C., comprising the regioisomers represented by formulas (IIIa) and (IIIb) and a compound represented by formula (II):
• thereby forming a second mixture of regioisomers represented by formulas (IVa), (IVb), and (IVc):
• c) adding a hydrocarbon solvent to the second mixture after the reaction is substantially complete and stirring the mixture for between about 1 hour to about 2 hours;
• d) heating a suspension comprising hydrazine, and the regioisomers represented by formulas (IVa), (IVb), and (IVc) in a polar solvent, thereby forming a third mixture comprising regioisomers represented by formulas (VIa), (VIb) and (VIc):
• e) adding water to the third mixture of regioisomers represented by formulas (VIa), (VIb), and (VIc), wherein the volume of water added is about 1 to about 4 times the volume of the polar solvent;
• f) allowing the compound represented by formula (VIa) to selectively precipitate out of the mixture at room temperature;
• g) collecting the precipitate comprising a compound represented by formula (VIa);
• h) heating in the presence of a catalytic amount of an acid the precipitate comprising a compound represented by formula (VIa) and a compound represented by the formula R7—C(O)R10, thereby regioselectively forming a compound represented by formula (I).