Method for preparing pyrimidone compound

A method for preparing a compound having Formula (II) comprising:

• Step I):
• reacting 3,4-difluoronitrobenzene with dihexylamine in the presence of base 3 in solvent 8 at about 80° C. to give a compound having Formula (VII);
• wherein, the solvent 8 is N,N-dimethylformamide, toluene, acetonitrile, isopropanol, ethanol, or any combination thereof;
• the base 3 is lithium hydroxide or a hydrate thereof, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, or any combination thereof;
• Step II):
• reacting the compound having Formula (VII) in the present of a reductant in solvent 9 at about 80° C. to give compound having Formula (VI);
• wherein, the solvent 9 is methanol, ethanol, isopropanol, water or any combination thereof;
• the reductant is Na2S or a hydrate thereof, or a mixture of Na2S or a hydrate thereof and S;
• Step III):
• reacting a compound having Formula (VI) with a suitable reagent in solvent 7 at room temperature to give the compound having Formula (V),
• wherein, the solvent 7 is ethyl acetate, methanol, ethanol, or a combination thereof;
• the suitable reagent is hydrogen chloride, a hydrogen chloride solution, or Me3SiCl;
• Step IV):
• reacting a compound having Formula (V) with an acetoacetate in solvent 6 at about 105° C. to about 110° C. to give the compound having Formula (IV),
• wherein the solvent 6 is toluene, water, or any combination thereof;
• the acetoacetate is methyl acetoacetate, ethyl acetoacetate, isopropyl acetoacetate or tert-butyl acetoacetate;
• Step V):
• reacting a compound having Formula (IV) with an ammonium salt in solvent 5 at about 25° C. to about 40° C. to give the compound having Formula (III);
• wherein the solvent 5 is methanol, ethanol, isopropanol, water, or any combination thereof;
• the ammonium salt is ammonium chloride, ammonium bromide, ammonium acetate, ammonium formate, or ammonium bicarbonate;
• Step VI):
• reacting a compound having Formula (III) with triethyl orthoacetate at 80° C.-140° C.,
• wherein the amount of triethyl orthoacetate is 2.0 to 4.0 molar equivalents relative to the amount of the compound having Formula (III).

A method for preparing a compound having Formula (II) comprising:

• Step Ia):
• reacting 3,4-difluoronitrobenzene with dihexylamine in the presence of base 3 in solvent 8 at about 80° C. to give a compound having Formula (VII);
• wherein, the solvent 8 is N,N-dimethylformamide, toluene, acetonitrile, isopropanol, ethanol, or any combination thereof;
• the base 3 is lithium hydroxide or a hydrate thereof, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, or any combination thereof;
• Step IIa):
• reacting the compound having Formula (VII) in the present of a reductant in solvent 9 at about 80° C. to give compound having Formula (VI);
• wherein, the solvent 9 is methanol, ethanol, isopropanol, water or any combination thereof;
• the reductant is Zn, Fe, Na2S or a hydrate thereof, a mixture of Na2S or a hydrate thereof and S;
• Step IIIa):
• reacting a compound having Formula (VI) with a suitable reagent in solvent 7 at room temperature to give the compound having Formula (V),
• wherein, the solvent 7 is ethyl acetate, methanol, ethanol, or a combination thereof;
• the suitable reagent is hydrogen chloride, a hydrogen chloride solution, or Me3SiCl;
• Step IVa):
• reacting a compound having Formula (V) with diketene in the present of base 2 in solvent 6 at room temperature to give the compound having Formula (IV),
• wherein the solvent 6 is dichloromethane, tetrahydrofuran, toluene, acetone, acetonitrile, water, or any combination thereof;
• the base 2 is triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate;
• Step Va):
• reacting a compound having Formula (IV) with a solution of ammonia in alcohol in solvent 5 at about 40° C. to about 65° C. to give the compound having Formula (III);
• wherein the solvent 5 is methanol, ethanol, isopropanol, water, or any combination thereof;
• the solution of ammonia in alcohol is a solution of ammonia in methanol;
• the amount of ammonia in the solution of ammonia in methanol is 2.0 to 4.0 molar equivalents relative to the amount of the compound having Formula (IV);
• Step VIa):
• reacting a compound having Formula (III) with triethyl orthoacetate at 80° C.-140° C.;
• wherein the amount of triethyl orthoacetate is 2.0 to 4.0 molar equivalents relative to the amount of the compound having Formula (III).