Method for preparing pyrimidone compound

1. A method for preparing a compound having Formula (II) comprising reacting a compound having Formula (III) with triethyl orthoacetate at 80° C.-140° C. to give the compound having Formula (II),

2. The method according to claim 1 , wherein the reaction is carried out at 80° C.-120° C.

3. The method according to claim 1 , wherein the amount of triethyl orthoacetate is 2.0 to 4.0 molar equivalents relative to the amount of compound having Formula (III).

4. The method according to claim 1 , wherein the compound having Formula (II) can be further purified by the following steps:

Step (A): Reacting the compound having Formula (II) with p-toluenesulfonic acid or a p-toluenesulfonic acid hydrate in solvent 1 to give a compound having Formula (II-a);

Step (B): Reacting the compound having Formula (II-a) with base 1 in solvent 2 to give the purified compound having Formula (II);

5. The method according to claim 4 , wherein the solvent 1 is dichloromethane, acetonitrile, toluene, isopropanol, 1-propanol, n-butanol, tetrahydrofuran, t-butanol, ethyl acetate, isobutanol, isopentanol, n-propyl acetate, isopropyl acetate, 4-methyl-2-pentanone, dimethyl phthalate, methyl methacrylate, 1,4-dioxane, ethyl formate, xylene, water, or any combination thereof; and

wherein the reaction in step (A) is carried out at room temperature or by heating.

6. The method according to claim 4 , wherein the solvent 2 is methanol, ethanol, isopropanol, acetonitrile, or any combination thereof;

wherein the base 1 is potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, or any combination thereof; and

the reaction in step (B) is carried out at room temperature or by heating.

7. The method according to claim 1 further comprising a method for preparing the compound having Formula (III) which comprises reacting a compound having Formula (IV) with a solution of ammonia in alcohol or an ammonium salt in solvent 5 to give the compound having Formula (III);

wherein the solvent 5 is methanol, ethanol, isopropanol, water, or any combination thereof;

the reaction is carried out at 20° C.-65° C.; or the reaction is carried out at room temperature;

the solution of ammonia in alcohol is a solution of ammonia in methanol; and

the ammonium salt is ammonium chloride, ammonium bromide, ammonium acetate, ammonium formate, or ammonium bicarbonate.

8. The method according to claim 7 , wherein the reaction of compound having Formula (IV) with an ammonium salt is carried out in the presence of base a;

wherein the base a is triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, or any combination thereof.

9. The method according to claim 7 , wherein 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).

10. The method according to claim 7 further comprising a method for preparing the compound having Formula (IV) which comprises reacting a compound having Formula (V) with diketene or an acetoacetate in solvent 6 to give the compound having Formula (IV),

wherein the solvent 6 is dichloromethane, tetrahydrofuran, toluene, acetone, acetonitrile, water, or any combination thereof;

wherein the reaction is carried out at 0° C.-110° C.; and

the acetoacetate is methyl acetoacetate, ethyl acetoacetate, isopropyl acetoacetate or tert-butyl acetoacetate.

11. The method according to claim 10 , wherein the reaction is carried out in the presence of base 2;

wherein the base 2 is triethylamine, N,N-diisopropylethylamine, pyridine, methylmorpholine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, or any combination thereof.

12. The method according to claim 10 , wherein the reaction of compound having Formula (V) with diketene is carried out at 0° C.-42° C., or about 0° C., or room temperature, or about 42° C.;

the reaction of the compound having Formula (V) with an acetoacetate is carried out by heating at 105° C.-110° C., or about 105° C., or about 110° C.

13. The method according to claim 10 , wherein the amount of diketene is 1.0 to 2.0 molar equivalents relative to the amount of the compound having Formula (V); or,

the amount of diketene is about 1.0, 1.2, 1.5 or 2.0 molar equivalents relative to the amount of the compound having Formula (V).

14. The method according to claim 10 further comprising a method for preparing the compound having Formula (V) which comprises reacting a compound having Formula (VI) with a suitable reagent in solvent 7 to give the compound having Formula (V),

wherein the solvent 7 is ethyl acetate, acetone, toluene, acetonitrile, methanol, ethanol, dichloromethane or a combination thereof;

the suitable reagent is hydrogen chloride or a hydrogen chloride solution, Me 3 SiCl or SOCl 2 ; and

the reaction is carried out at room temperature.

15. The method according to claim 14 further comprising a method for preparing the compound having Formula (VI)

which comprises

Step (i): Reacting 3,4-difluoronitrobenzene with dihexylamine in the presence of base 3 in solvent 8 to give a compound having Formula (VII);

wherein, the reaction is carried out at 80° C.-90° C.;

the solvent 8 is N,N-dimethylformamide, toluene, ethyl acetate, acetonitrile, acetone, 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, triethylamine, pyridine, or any combination thereof; and

Step (ii): Reacting the compound having Formula (VII) in the presence of a reductant in solvent 9 to give the compound having Formula (VI);

wherein, the reaction is carried out at room temperature or at 65° C.-100° C.;

the solvent 9 is methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, water or any combination thereof;

the reductant is Zn, Fe, SnCl 2 or a hydrate thereof, Na 2 S or a hydrate thereof, a mixture of Na 2 S or a hydrate thereof and S, Na 2 S 2 or a hydrate thereof, PtO 2 or Raney nickel.

16. The method according to claim 15 , wherein, the reaction in step (i) is further carried out in the presence of cuprous iodide; and

the reaction in step (ii) is further carried out in the presence of an acidic reagent, wherein the acidic reagent is HCl, AcOH or NH 4 Cl.

17. 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 Na 2 S or a hydrate thereof, or a mixture of Na 2 S 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 Me 3 SiCl;

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).

18. The method according to claim 17 , wherein the reaction of Step IV) may be carried out in the present of base 2 which is triethylamine, N,N-diisopropylethylamine, pyridine, methylmorpholine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or any combination thereof; and

the reaction of Step V) may be carried out in the present of base a which is potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or any combination thereof.

19. 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, Na 2 S or a hydrate thereof, a mixture of Na 2 S 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 Me 3 SiCl;

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).

20. The method according to claim 19 , wherein the reaction of Step Ia) is further carried out in the presence of cuprous iodide; and

the reaction of Step IIa) is further carried out in the presence of an acidic reagent, wherein the acidic reagent is HCl, AcOH or NH 4 Cl.

21. A compound having Formula (V),

22. A method for preparing a compound having Formula (I) comprising reacting a compound having Formula (II) prepared by the method of claim 1 with hydrogen chloride or a hydrogen chloride solution in solvent 3 to give the compound having Formula (I),

wherein the solvent 3 is dichloromethane, ethyl acetate, ethanol, isopropanol, tert-butanol, water, or any combination thereof;

the hydrogen chloride solution is a solution of hydrogen chloride in water, a solution of hydrogen chloride in ethyl acetate or a solution of hydrogen chloride in isopropanol; and

the reaction is carried out at room temperature or by heating; wherein heating refers to heating to reflux, or heating to about 80° C.