Process for preparing trisubstituted pyrimidine compounds

1. 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)—NR f —, —O—C(S)—NH—, —NH—C(S)—O—, —O—C(S)—NR f —, —NR − C(S)—O—, —P(O)(R c )—, —P(O)(R c )—O—, —P(O)(R c )—NR c —, -Cyclyl-, -Heterocycloalkyl-, -Aryl-, -Heteroaryl-, -Heteroaralkyl-, -Heteroaryl-NH—, -Heteroaryl-S—, -Heteroaralkyl-O—, —Si(OH) 2 —, —B(OH)—, —P(O) 2 O—, —P(O) 2 N(R c )—, —N(R c )P(O) 2 , or —OP(O) 2 —; wherein R f for each occurrence is H, alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, or heterocycloalkyl;

R 2 and R 4 are each H;

R 3 is R c , alkenyl, alkynyl, —OR c , —OC(O)R c , —SO 2 R c , —S(O)R c , —S(O) 2 NR c R d , —SR c , —NR c R d , —NR c COR d , —NR c C(O)R d , —NR c C(O)OR d , —NR c C(O)NR c R d , —NR c SO 2 R d , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —P(O)OR c OR d , or —S(O) 2 NR c R d ;

R 7 is an optionally substituted indolyl or an optionally substituted phenyl;

R 8 and R 9 , taken together with the nitrogen to which they are attached, are an optionally substituted heterocycloalkyl, wherein the heterocycloalkyl is morpholine;

R 10 is H or methyl;

n is 1 or 2;

m is 0 or 1;

Y is O, S, or NR c ; and

R c and R d , for each occurrence, are, independently, H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, —C(O)-alkyl, or —S(O) 2 R f ;

the method comprising the steps of:

a) reacting HNR 8 R 9 with a 2,4,6-trihalopyrimidine in a solution of alcohol and water, wherein HNR 8 R 9 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 R 6 , 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 R 7 —C(O)R 10 , thereby regioselectively forming a compound represented by formula (I).

2. The method of claim 1 , further comprising the step of recrystallizing the compound represented by formula (I) in ethanol.

3. The method of claim 1 , wherein the polar solvent in step d) is selected from the group consisting of an ether, dimethylacetamide (DMA), N-methylpyrrolidine (NMP), tetrahydrofuran (THF), a dioxane, hexamethylphosphoramide (HMPA), or mixtures thereof.

4. The method of claim 1 , wherein the polar solvent is 1,4-dioxane and the reaction mixture in step d) is heated to between about 80° C. and about 105° C.

5. The method of claim 1 , wherein the compound represented by formula (VIa) is allowed to precipitate for between about 2 to about 12 hours in step f).

6. The method of claim 1 , wherein the compound represented by formula (VIa) and R 7 —C(O)R 10 are heated in ethyl acetate in the presence of a catalytic amount of an acid.

7. The method of claim 1 , wherein the compound represented by formula (I) is at least about 70% pure.

8. The method of claim 1 , wherein the compound represented by formula (I) is at least about 80% pure.