Process for the Preparation of Pyrimidine Compounds

A compound of Formula (2a), and tautomers thereof:

• wherein
• R is H or an alkyl group;
• R2 is H, an alkyl or aryl group;
• R3 and R4 are each independently H, alkyl, or aryl;
• provided that R3 and R4 are not both unsubstituted alkyl;
• and
• E is an unsubstituted alkyl group, an aryl groups or an electron withdrawing group;
• further provided that R1 is not —CH3 when R2 is unsubstituted phenyl or o-nitrophenyl.

A process for the preparation of a compound of Formula (2a) and tautomers thereof:

• which comprises
• a) reacting a compound of formula R1—CO—CH2-E with a compound of formula R2—CHX1X2 in the presence of a compound of formula R3R4N—C(═NH)NH2 and a catalyst, thereby forming the compound of Formula (2a)
• wherein
• R1 is an H or an alkyl group;
• R2 is an H, an alkyl, or aryl group;
• R3 and R4 are each independently H, alkyl or aryl;
• or R3 and R4 are linked to form, together with the nitrogen to which they are attached, a 5 to 7 membered heterocyclic ring;
• E is H, an unsubstituted alkyl group, an aryl groups or an electron withdrawing group;
• and
• X1 and X2 are each independently leaving groups;
• or X1 and X2 together are ═O.

A process for the preparation of a compound of Formula (1):

• which comprises oxidising a compound of Formula (2a):
• wherein
• R1 is H or an alkyl group;
• R2 is an H, an alkyl or aryl group;
• R3 and R4 are each independently H, alkyl, or aryl;
• or R3 and R4 are linked to form, together with the nitrogen to which they are attached, a 5 to 7 membered heterocyclic ring;
• and
• E is H, an unsubstituted alkyl group, an aryl group, or an electron withdrawing group.

A process for the preparation of a compound of Formula (3):

• which comprises
• a) reacting a compound of formula R1—CO—CH2-E with a compound of formula R2—CHX1X2 in the presence of a compound of formula R7HN—C(═NH)NH2 and a catalyst, thereby forming a dihydropyrimidine;
• b) oxidising the dihydropyrimidine produced in a) to form a compound of Formula (4)
• and
• c) reacting the compound of Formula (4) with a compound of formula R6SO2—X4 to give a compound of Formula (3);
• wherein
• R1 is H or an alkyl group;
• R2 is H, an alkyl, or aryl group;
• E is H, an unsubstituted alkyl group, an aryl group, or an electron withdrawing group;
• X1 and X2 are each independently leaving groups;
• or X1 and X2 together are ═O;
• R6 alkyl or aryl;
• R7 is H, alkyl or aryl;
• and
• X4 is a leaving group.

A process for the preparation of a compound of Formula (3):

• which comprises
• a) reacting a compound of formula R1—CO—CH2-E with a compound of formula R2—CHX1X2 in the presence of a compound of formula R7HN—C(═NH)NH2 and a catalyst, thereby t forming a dihydropyrimidine comprising an exocyclic group formula —NHR7;
• b) reacting a compound of Formula (4)
• with a compound of formula R6SO2—X4 to form a dihydropyrimidine comprising an exocyclic group formula —N(R7)SO2R6;
• c) oxidising the dihydropyrimidine produced in b) to form a compound of Formula (3);
• wherein
• R1 is H or an alkyl group;
• R2 is H, an alkyl or aryl group;
• E is H, an unsubstituted alkyl group, an aryl group, or an electron withdrawing group;
• X1 and X2 are each independently leaving groups;
• or X1 and X2 together are ═O;
• R6 is alkyl or aryl;
• R7 is H, alkyl or aryl;
• and
• X4 is a leaving group.