Method for preparing pyrimidone compound

Abstract

A method for preparing a pyrimidone compound and an important intermediate in which raw materials of the preparation method are cheap, the reaction condition of preparation method is mild, the preparation method is simple to operate, and is safe and controllable, has high total yield, and thus is suitable for industrial production.

Claims

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), ##STR00029##

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); ##STR00030##

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); ##STR00031## 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), ##STR00032## 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), ##STR00033## 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.sub.3SiCl or SOCl.sub.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) ##STR00034## 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.sub.2 or a hydrate thereof, Na.sub.2S or a hydrate thereof, a mixture of Na.sub.2S or a hydrate thereof and S, Na.sub.2S.sub.2 or a hydrate thereof, PtO.sub.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.sub.4Cl.

17. A method for preparing a compound having Formula (II) comprising: ##STR00035## 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); ##STR00036## 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); ##STR00037## wherein, the solvent 9 is methanol, ethanol, isopropanol, water or any combination thereof; the reductant is Na.sub.2S or a hydrate thereof, or a mixture of Na.sub.2S 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), ##STR00038## 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.sub.3SiCl; 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), ##STR00039## 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); ##STR00040## 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: ##STR00041## 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); ##STR00042## 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); ##STR00043## wherein, the solvent 9 is methanol, ethanol, isopropanol, water or any combination thereof; the reductant is Zn, Fe, Na.sub.2S or a hydrate thereof, a mixture of Na.sub.2S 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), ##STR00044## 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.sub.3SiCl; 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), ##STR00045## 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); ##STR00046## 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.sub.4Cl.

21. A compound having Formula (V), ##STR00047##

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), ##STR00048## 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.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) The examples of the present invention disclose a method for preparing a pyrimidinone compound having Formula (I) or (II). Skilled in the art can learn from this article to properly improve the process parameters to implement the preparation. Of particular noted is that all similar replacements and modifications are apparent to the skilled person, and they are deemed to be included in the present invention. The method of the present invention has been described by preferred Examples. And skilled person can clearly achieve and apply the techniques disclosed herein by making some changes, appropriate alterations or combinations to the methods of the invention without departing from spirit, principles and scope of the present disclosure.

(2) In order to make the present invention to be better understood, it is detailed below through examples.

EXAMPLES

Example 1 2-fluoro-N,N-dihexyl-4-nitrophenylamine

(3) Method One:

Embodiments 1-4

(4) To a solvent (50 mL) were added 3,4-difluoronitrobenzene (4.77 g, 30 mmol), di-n-hexane (5.84 g, 31.5 mmol), base (60 mmol) and cuprous iodide (0.285 g, 1.5 mmol). The mixture was heated and stirred overnight. After the reaction was completed, a sample of the reaction mixture was taken and detected by HPLC, and the reaction mixture was cooled to room temperature, filtered and evaporated to give yellow liquid. The reaction temperatures, the solvents and the bases used in Embodiments 1-4 were shown in table A.

(5) TABLE-US-00007 TABLE A Content Reaction of the Embodiment Solvent temperature Base product Embodiment Acetonitrile 82 C. Potassium 92.63% 1 carbonate Embodiment Acetonitrile 82 C. Potassium 92.80% 2 phosphate Embodiment Acetonitrile 90 C. Lithium 97.48% 3 hydroxide monohydrate Embodiment N,N- 90 C. Potassium 92.73% 4 Dimethylformamide phosphate Embodiment Acetonitrile 90 C. Potassium 72.65% 5 hydroxide Embodiment N,N- 90 C. Potassium 55.60% 6 Dimethylformamide hydroxide
Method Two:

(6) To a 1000 mL single-neck flask were added lithium hydroxide monohydrate (28.00 g, 667.3 mmol), 3,4-difluoronitrobenzene (50.00 g, 314.3 mmol), di-n-hexylamine (70.00 g, 377.7 mmol) and acetonitrile (400.0 g). The mixture was heated to 80 C. and refluxed under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to about 25 C., and stirred at this temperature for 2 hours, then filtered by suction. The filtrate was distilled under reduced pressure, and the concentrated residue was dissolved in ethyl acetate (400.0 g) uniformly by stirring, then the mixture was washed with saturated aqueous ammonium chloride (400 mL) and water (400 mL2). The organic layer was distilled under reduced pressure to give yellow liquid which was used directly in the next reaction without further treatment.

Example 2 2-fluoro-N.SUP.1.,N.SUP.1.-dihexylbenzene-1,4-diamine

(7) Method One:

Embodiments 1-3

(8) To a 100 mL round bottom flask were added water (10 mL) and concentrated hydrochloric acid (2.0 mL), then iron powder (3.35 g, 60.0 mmol) was added in one time. The mixture was stirred and heated to 65 C. to activate the iron powder for 50 minutes, then the aqueous layer was poured and abandoned. 2-Fluoro-N,N-dihexyl-4-nitrophenylamine (3.24 g, 10.0 mmol) was dissolved in a solvent, and the obtained solution was added into the iron powder. The resulting mixture was adjusted with hydrochloric acid to pH 2, and then heated overnight. After the reaction was completed, the mixture was cooled to room temperature and adjusted with triethylamine to basicity. The mixture was filtered, and concentrated in vacuo to remove the solvent. To the residue was added water (50 mL), and the mixture was extracted with ethyl acetate (100 mL2). The combined organic layers were washed with saturated brine (80 mL2), dried over anhydrous sodium sulfate and concentrated in vacuo to remove the solvent and give brown liquid. The activation conditions of the iron powder, the reaction solvents, the reaction temperatures, and the experimental results in Embodiments 1-3 were shown in Table B.

(9) TABLE-US-00008 TABLE B The activation condition of Reaction Reaction Embodiment the iron powder solvent temperature Yield Embodiment 1 Heating to 65 C. Methanol 65 C. 93.4% and activating (10 mL) and for 50 minutes tetrahydrofuran (20 mL) Embodiment 2 Heating to 70 C. Methanol 70 C. 90.1% and activating (30 mL) for 1 hour Embodiment 3 Heating to 70 C. Ethanol 70 C. 98.0% and activating (30 mL) for 1 hour
Method Two:

(10) To a 100 mL round bottom flask were added water (10 mL) and concentrated hydrochloric acid (2.0 mL), then iron powder (1.96 g, 35.0 mmol) was added in one time. The mixture was stirred and heated to 100 C. to activate the iron powder for 1 hour, then the aqueous layer was poured and abandoned. A solution of 2-fluoro-N,N-dihexyl-4-nitrophenylamine (3.24 g, 10.0 mmol) in ethanol (30 mL) and ammonium chloride (5.35 g, 100 mmol) were added into the iron powder. The resulting mixture was adjusted with hydrochloric acid to pH 2, and then heated to 100 C. and stirred overnight. After the reaction was completed, the mixture was filtered, and the filtrate was evaporated in vacuo to remove the solvent. To the residue was added water (50 mL), and the mixture was extracted with ethyl acetate (100 mL2). The combined organic layers were washed with saturated brine (80 mL2), dried over anhydrous sodium sulfate and concentrated in vacuo to remove the solvent and give brown liquid (2.80 g, 95.2%).

(11) Method Three:

(12) To a 100 mL round bottom flask were added 2-fluoro-N,N-dihexyl-4-nitrophenylamine (3.24 g, 10.0 mmol) and ethanol (30 mL). The mixture was stirred at room temperature, then stannous chloride dihydrate (9.026 g, 40.0 mmol) was added in portions. After addition, the mixture was heated to 85 C. and stirred for 4.5 hours. After the reaction was completed, the mixture was cooled to room temperature, and evaporated in vacuo to remove the solvent. To the residue were added water (50 mL) and ethyl acetate (50 mL), and the mixture was adjusted with saturated aqueous sodium bicarbonate solution to pH 7. The mixture was filtered, and the filtrate was extracted with ethyl acetate (100 mL2). The combined organic layers were washed with saturated brine (60 mL2), dried over anhydrous sodium sulfate and concentrated in vacuo to remove the solvent and give brown liquid (2.74 g, 93.2%).

(13) Method Four:

(14) To a 100 mL round bottom flask were added 2-fluoro-N,N-dihexyl-4-nitrophenylamine (3.24 g, 10.0 mmol) and ethyl acetate (30 mL). The mixture was stirred at room temperature, then stannous chloride dihydrate (9.026 g, 40.0 mmol) was added in portions. After addition, to the mixture was added dropwise concentrated hydrochloric acid (2.5 mL, 30 mmol), then the mixture was heated to 75 C. and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was adjusted with saturated aqueous sodium bicarbonate to pH 7. The mixture was filtered, and the filtrate was extracted with ethyl acetate (100 mL2). The combined organic layers were washed with saturated brine (60 mL2), dried over anhydrous sodium sulfate and concentrated in vacuo to remove the solvent and give brown liquid (2.83 g, 96.3%).

(15) Method Five:

(16) To a 100 mL round bottom flask were added 2-fluoro-N,N-dihexyl-4-nitrophenylamine (3.24 g, 10.0 mmol) and ethanol (25 mL). The mixture was stirred at room temperature, and a solution of sodium sulfide nonahydrate (3.60 g, 15.0 mmol) in water (20 mL) was added. After the addition, the mixture was heated to 100 C. and stirred for 13 hours. After the reaction was completed, the mixture was cooled to room temperature and adjusted with saturated aqueous sodium bicarbonate to pH 7. The mixture was filtered, and the filtrate was concentrated to remove the solvent. To the residue were added water (50 mL) and ethyl acetate (50 mL). The mixture was extracted with ethyl acetate (100 mL2). The combined organic layers were washed with saturated brine (60 mL2), dried over anhydrous sodium sulfate and concentrated to remove the solvent and give brown liquid (2.88 g, 98.0%).

(17) Method Six:

Embodiment 1

(18) To a 100 mL single-neck flask were added sodium sulfide nonahydrate (18.5 g, 77.0 mmol), sulfur (2.48 g, 77.4 mmol) and H.sub.2O (10 mL). The mixture was heated to 80 C. and stirred to the solid was dissolved completely, then cooled to 40 C. To the reaction mixture was added a solution of 2-fluoro-N,N-dihexyl-4-nitrophenylamine (5.00 g, 15.0 mmol) in ethanol (30 mL). The mixture was heated to 80 C. and stirred for 5 hours. The mixture was cooled to room temperature, and evaporated under reduced pressure to remove the organic solvent. To the residue was added ethyl acetate (20 mL), then the mixture was stirred for 10 minutes and then stood for partition. The organic layer was washed with water (20 mL), and then evaporated under reduced pressure to remove the solvent and give yellow oil (4.25 g, 93.73%).

Embodiment 2

(19) To a 2000 mL single-neck flask were added water (204 g), sodium sulfide nonahydrate (377.00 g, 1550 mmol) and sulphur powder (51.00 g, 1590.5 mmol), then the mixture was heated to 80 C. and stirred until the solid was dissolved completely. The mixture was cooled to 45 C., and degassed and filled with nitrogen, then kept under nitrogen protection. To the reaction mixture was added a solution of 2-fluoro-N,N-dihexyl-4-nitrophenylamine (102.0 g, 314.4 mmol) in ethanol (360 g) prepared from Method Two of Example 1. After the addition, the mixture was heated to 80 C. and stirred. The reaction was completed through monitoring by HPLC, and the mixture was cooled to room temperature, and evaporated under reduced pressure to remove the ethanol. To the concentrated residue was added ethyl acetate (500 g), and the mixture was stirred until the residue was dissolved completely. The mixture was stood and then aqueous layer was partitioned. The organic layers were washed with water (500 mL2) and saturated aqueous sodium chloride solution (500 mL), and the obtained solution was used directly in the next step.

(20) Method Seven:

Embodiments 1-2

(21) To a 100 mL round bottom flask were added 2-fluoro-N,N-dihexyl-4-nitrophenylamine (3.00 g, 9.25 mmol) and solvent (25 mL), the mixture was stirred at room temperature and then zinc powder (6.05 g, 92.4 mmol) and ammonium chloride (4.95 g, 92.4 mmol) were added. The resulting mixture was stirred at room temperature and the reaction was completed through monitoring by TLC. After post-treatment, brown liquid was obtained. The reaction solvents, reaction times, post-treatment methods of the reactions in Embodiment s1-2 were shown in table C.

(22) TABLE-US-00009 TABLE C Reaction Embodiment Solvent time Post-treatment method Yield Embodiment 1 Ethyl 17 The reaction mixture was 95.2% acetate hours filtered, and the filtrate was washed with water (50 mL) and saturated brine (50 mL), then evaporated under reduced pressure to remove the solvent. Embodiment 2 Ethanol 5.5 The reaction mixture was 95.2% hours filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (50 mL), and the resulting mixture was washed with water (50 mL 2) and saturated brine (50 mL), then evaporated under reduced pressure to remove the solvent.

Example 3 2-Fluoro-N.SUP.1.,N.SUP.1.-dihexylbenzene-1,4-diamine Hydrochloride

(23) Method One:

(24) To a 100 mL round bottom flask were added 2-fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine (2.72 g, 9.24 mmol) and ethyl acetate (20 mL). The mixture was stirred, and methanol (1.5 mL, 37 mmol) was added into the mixture, then trimethylchlorosilane (3.1 g, 28 mmol) was added dropwise into the mixture. After addition, the mixture was stirred at room temperature overnight, and then filtered to give an off-white solid (2.74 g, 80.7%).

(25) Method Two:

(26) To a 100 mL round bottom flask were added 2-fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine (5.00 g, 17.0 mmol) and ethyl acetate (40 g). The mixture was stirred, and hydrochloric acid (3.91 mL, 39.1 mmol) was added dropwise into the mixture. The mixture was stirred at room temperature for 5 hours, and filtered. The filter cake was triturated with ethyl acetate (25 g), and then the mixture was filtered by suction. The filter cake was dried at 50 C. in oven to give an off-white solid (4.92 g, 79.0%).

(27) Method Three:

(28) To a solution of 2-fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine in ethyl acetate prepared from Embodiment 2 of Method Six in Example 2 which was placed in a 1000 mL single-neck flask was added anhydrous ethanol (36.1 g, 784 mmol). The mixture was degassed and filled with nitrogen, then protected in nitrogen atmosphere. To the reaction mixture was added dropwise trimethylchlorosilane (85.7 g, 781 mmol). After the addition, the mixture was stirred at room temperature and monitored by TLC until the reaction material was disappeared, then the reaction was stopped. The mixture was filtered, and the filer cake was washed with ethyl acetate (200 g). Then the filter cake was triturated with ethyl acetate (200 g) for 5 hours, and the mixture was filtered. The filter cake was washed with ethyl acetate (200 g), and dried at 60 C. for 8 hours to give a light yellow solid (115.5 g, 92.6%).

Example 4: N-(4-(dihexylamino)-3-fluorophenyl)-3-oxobutanamide

(29) Method One:

(30) To dichloromethane (10 mL) were added 2-fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride (1.5 g, 5.1 mmol) and diketene (640 mg, 7.6 mmol). The mixture was stirred at room temperature, and triethylamine (1.10 g, 11 mmol) was added dropwise into the mixture. After the addition, the mixture was heated to 42 C. and refluxed for 12 hours. The reaction was completed, and quenched with water (30 mL). The aqueous layer was partitioned, and the organic layer was evaporated to dryness under reduced pressure and give black oil (1.80 g, 93.4%).

(31) Method Two:

(32) To dichloromethane (200 mL) were added 2-fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride (30.00 g, 81.65 mmol) and diketene (6.87 g, 81.7 mmol). The mixture was cooled in an ice-bath, and then triethylamine (26 mL, 187.8 mmol) was added dropwise at a temperature of not more than 5 C. The mixture was stirred under the ice-bath condition for 1.5 hours, and then washed with water (200 mL2) and saturated brine (200 mL). The organic layer was evaporated to dryness under reduced pressure and give black oil (30.00 g, 97.1%).

(33) Method Three:

Embodiments 1-4

(34) 2-Fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride was added into a solvent, then the mixture was stirred at room temperature, and a base was added into the mixture. To the mixture was added dropwise diketene, and the temperature of the reaction mixture was controlled below the boiling temperature of the solvent used. After addition, the reaction mixture was stirred and heated naturally to reflux, then cooled naturally to room temperature and stirred at room temperature. The reaction was completed, and a sample of reaction mixture was taken and detected by HPLC. The reaction was quenched with water (30 mL). The aqueous layer was partitioned, and the organic layer was evaporated to dryness under reduced pressure and give black oil. The specific reaction conditions and results in Embodiments 1-4 were as shown in table D.

(35) TABLE-US-00010 TABLE D Reaction time at room Content Embodi- Hydro- Di- Base/ Solvent/ tempera- of the ment chloride ketene amount amount ture product Embodi- 30 g 1.0 Triethyl- DCM/ 0 93.06% ment 1 equiv amine/ 200 mL 23 mL Embodi- 1.5 g 1.2 Saturated THF/ 3 hours 94.21% ment 2 equiv aqueous 20 mL sodium bicarbonate solution/ 20 mL Embodi- 1.5 g 1.2 Saturated Acetone/ 5 hours 93.86% ment 3 equiv aqueous 8 mL sodium bicarbonate solution/ 20 mL Embodi- 30 g 2.0 Saturated Acetone/ 1 hour 95.86% ment 4 equiv aqueous 150 mL sodium bicarbonate solution/ 60 mL
Method Four:

(36) 2-Fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride (2.03 g, 5.53 mmol) was added into toluene (20 g), then the mixture was stirred at room temperature, and a solution of sodium carbonate (1.33 g, 12.5 mmol) in water (15.0 g) was added into the mixture. The mixture was stirred at room temperature until the solid was dissolved completely, and then stood for partition. The aqueous layer was partitioned, and the organic layer was washed with water (50 mL2). To the organic layer were added methyl acetoacetate (1.00 g, 8.61 mmol) and DIPEA (0.20 g, 1.5 mmol). The mixture was stirred at 105 C. for 24 hours under nitrogen protection. The reaction mixture was cooled to room temperature and washed with water (50 mL), then evaporated under reduced pressure to give brown oil (1.97 g, 94.2%).

(37) Method Five:

(38) 2-Fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride (3.00 g, 8.17 mmol) was added into toluene (30 g), then the mixture was stirred at room temperature, and a solution of sodium carbonate (1.95 g, 18.4 mmol) in water (20.0 g) was added into the mixture. The mixture was stirred at room temperature until the solid was dissolved completely, and then stood for partition. The aqueous layer was partitioned, and the organic layer was washed with water (50 mL2). To the organic layer were added tert-buyl acetoacetate (3.97 g, 24.6 mmol) and DIPEA (0.32 g, 2.5 mmol). The mixture was stirred at 105 C. for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature and washed with water (50 mL), then evaporated under reduced pressure to give brown oil (3.06 g, 99.0%).

(39) Method Six:

Embodiments 1-7

(40) 2-Fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride was added into toluene (10 g/g), then the mixture was stirred at room temperature, and a solution of sodium carbonate (0.65 g/g) in water (6.5 g/g) was added into the mixture. The mixture was stirred at room temperature until the solid was dissolved completely, and then stood for partition. The aqueous layer was partitioned, and the organic layer was washed with water (20 g/g2). To the organic layer were added tert-butyl acetoacetate (1.30 g/g) and base (0.10 g/g). The mixture was heated to a certain temperature and stirred under nitrogen protection. The reaction was completed, and the reaction mixture was washed with water (20 g/g), then evaporated under reduced pressure to give brown oil. The amount of the each reagent described in Embodiments 1-7 was based on the ratio of the amount of the reagent to 2-fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride, i.e., the amount of 2-fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride was benchmark when the amount of each reagent was calculated. The reaction temperatures, the reaction times and the bases used in Embodiments 1-7 were as shown in table E.

(41) TABLE-US-00011 TABLE E Reaction Reaction Embodiment Base temperature time Yield Embodiment 1 Triethylamine 105 C. 4 hours 96.96% Embodiment 2 Pyridine 105 C. 4 hours 96.98% Embodiment 3 DIPEA 105 C. 4 hours 97.63% Embodiment 4 Methylmorpholine 105 C. 4 hours 96.72% Embodiment 5 N/A*.sup.1 105 C. 4 hours 99.3% Embodiment 6*.sup.2 N/A 110 C. 1 hour 98.5% Embodiment 7*.sup.2 N/A 105 C. 2 hours 97.1% Notes: *.sup.1N/A denotes that base was not added in the embodiment; *.sup.2the ratios of the amounts of tert-butyl acetoacetate used in Embodiment 6 and Embodiment 7 to the amount of 2-fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride are independently 1.75 g/g and 0.66 g/g.

Embodiment 8

(42) To a 1000 mL single-neck flask were added toluene (500 g) and 2-fluoro-N.sup.1,N.sup.1-dihexylbenzene-1,4-diamine hydrochloride (50.00 g, 136.1 mmol) prepared from Method Three of Example 3. The mixture was stirred for 15 minutes, then aqueous sodium carbonate (30.0 g) solution was added into the mixture. After addition, the mixture was stirred until the solid was dissolved completely, and then stood for partition. The aqueous layer was partitioned, and the organic layer was washed with water (500 mL2). To the organic layer was added tert-butyl acetoacetate (32.5 g). The reaction mixture was stirred in nitrogen atmosphere for 30 minutes, then heated to 105 C. and refluxed. The reaction was completed through monitoring by HPLC, then cooled to room temperature, washed with water (500 mL2), and evaporated under reduced pressure to give light brown liquid, which was used directly in the next step without further purification.

Example 5: (Z)-3-amino-N-(4-(dihexylamino)-3-fluorophenyl)but-2-enamide

(43) Method One:

Embodiments 1-5

(44) N-(4-(Dihexylamino)-3-fluorophenyl)-3-oxobutanamide (500 mg, 1.39 mmol) was dissolved in methanol (10 mL), then a solution of ammonia in methanol (7 mol/L) was added into the mixture. The resulting mixture was stirred at a certain temperature. After the reaction was completed, a sample of reaction mixture was taken for HPLC detection. The reaction mixture was concentrated in vacuo to give brown black liquid. The reaction temperatures, reaction times, the amounts of a solution of ammonia in methanol and the results of Embodiments 1-5 were shown in table F.

(45) TABLE-US-00012 TABLE F A solution of Proportion ammonia in Reaction Reaction of Embodiment methanol temperature time product Embodiment 1 2.0 equiv 20 C. 21 hours 91.4% Embodiment 2 3.0 equiv 20 C. 21 hours 92.5% Embodiment 3 4.0 equiv 20 C. 21 hours 94.9% Embodiment 4 4.0 equiv 40 C. 6 hours 94.2% Embodiment 5 4.0 equiv 65 C. 6 hours 93.6%
Method Two:

Embodiments 1-2

(46) To a 100 mL single-neck flask were added ethanol, N-(4-(dihexylamino)-3-fluorophenyl)-3-oxobutanamide (4.99 g, 13.2 mmol), ammonium acetate (8.16 g, 106 mmol) and sodium carbonate. The mixture was stirred at 25 C. The reaction was completed through monitoring by HPLC, and the reaction mixture was concentrated. The residue was dissolved in dichloromethane (100 mL), and the mixture was washed with water (100 mL3) and saturated brine (100 mL). The organic layer was concentrated in vacuo to remove the solvent and give brown oil. The amounts of ethanol and sodium carbonate, reaction times and results in Embodiments 1-2 were as shown in table G.

(47) TABLE-US-00013 TABLE G Embodiment Ethanol Sodium carbonate Reaction time Yield Embodiment 1 20 g N/A 24 hours 95.0% Embodiment 2 25 g 8.88 g 20 hours 96.2% Note: N/A denotes that sodium carbonate was not added into the reaction mixture of the Embodiment.
Method Three:

Embodiments 1-2

(48) To a 100 mL single-neck flask were added ethanol (15 g), N-(4-(dihexylamino)-3-fluorophenyl)-3-oxobutanami de (3.00 g, 7.93 mmol) and ammonium bicarbonate (0.96 g, 12.0 mmol). The mixture was stirred at a certain temperature. The reaction was completed through monitoring by HPLC and then filtered. The filtrate was evaporated under reduced pressure to remove the solvent and give black oil. The reaction temperatures, reaction times and results in Embodiment 1-2 were as shown in table H.

(49) TABLE-US-00014 TABLE H Embodiment Reaction temperature Reaction time Yield Embodiment 1 25 C. 13 hours 100% Embodiment 2 40 C. 3 hours 98.6%

Embodiment 3

(50) To N-(4-(dihexylamino)-3-fluorophenyl)-3-oxobutanamide (51.5 g, 136 mmol) prepared from Embodiment 8 of Method Six in Example 4 which was placed in a 1000 mL single-neck flask was added anhydrous ethanol (300.0 g). The mixture was stirred into a clear solution. To the reaction mixture was added ammonium bicarbonate (22.0 g, 276 mmol), and the mixture was degassed and filled with nitrogen. Then the mixture was stirred at 40 C. in nitrogen atmosphere. The reaction was completed through monitoring by HPLC, then the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to give light brown liquid, which was used directly in the next step without further purification.

Example 6: 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one

(51) 6-1) Preparation of the Title Compound

Embodiments 1-7

(52) (Z)-3-Amino-N-(4-(dihexylamino)-3-fluorophenyl)but-2-enamide was added into a certain amount of triethyl orthoacetate. The mixture was heated and stirred at a certain temperature. After the reaction was completed, a sample of reaction mixture was taken for HPLC detection. The reaction mixture was evaporated under reduced pressure to remove the solvent and give black liquid. The specific reaction conditions and results of Embodiments 1-7 were shown in table I.

(53) TABLE-US-00015 TABLE I Triethyl Reaction Proportion Embodiment orthoacetate Temperature time of product Embodiment 2.0 equiv 120 C. 24 hours 95.63% 1 Embodiment 3.0 equiv 120 C. 24 hours 95.21% 2 Embodiment 4.0 equiv 120 C. 24 hours 95.38% 3 Embodiment 3.0 equiv 80 C. 4 hours 52.80% 4 Embodiment 3.0 equiv 100 C. 4 hours 59.20% 5 Embodiment 3.0 equiv 120 C. 4 hours 63.29% 6 Embodiment 3.0 equiv 140 C. 4 hours 52.27% 7

Embodiment 8

(54) To (Z)-3-amino-N-(4-(dihexylamino)-3-fluorophenyl)but-2-enamide (51.4 g, 136 mmol) prepared from Embodiment 3 of Method Three in Example 5 which was placed in a 1000 mL single-neck flask was added triethyl orthoacetate (66.3 g, 409 mmol). The mixture was degassed and filled with nitrogen, and stirred at 120 C. under nitrogen protection, then distilled to remove the low boiling side-product. The reaction was completed through monitoring by HPLC, then the reaction mixture was evaporated under reduced pressure to remove the solvent and give black liquid, which was used directly in the next step without further purification.

(55) 6-2) Further Purification of the Title Compound

(56) Step 1: 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one Tosilate

Embodiments 1-1 to 1-16

(57) 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (0.80 g, 2.0 mmol) prepared from the method of 6-1) was dissolved in a certain solvent (5 mL). p-Toluenesulfonic acid monohydrate (0.76 g, 4.0 mmol) was added into the mixture, and the resulting mixture was stirred for 24 hours and then filtered to give a yellow solid. The solvents used in Embodiments 1-1 to 1-16 and the results were as shown in table J.

(58) TABLE-US-00016 TABLE J Purity of Embodiment Solvent Yield the product Embodiment 1-1 Toluene 80.43% 97.93% Embodiment 1-2 1-Propanol 75.03% 98.81% Embodiment 1-3 n-Butanol 71.10% 98.25% Embodiment 1-4 t-Butanol 83.57% 96.85% Embodiment 1-5 Ethyl acetate 87.14% 97.87% Embodiment 1-6 Propanol 86.44% 98.99% Embodiment 1-7 Isobutanol 80.95% 98.39% Embodiment 1-8 Isopentanol 74.94% 98.20% Embodiment 1-9 n-Propyl acetate 84.87% 98.57% Embodiment 1-10 Isopropyl acetate 86.62% 95.97% Embodiment 1-11 4-Methylpentan-2-one 79.56% 97.79% Embodiment 1-12 Dimethyl phthalate 76.16% 95.31% Embodiment 1-13 Methyl methacrylate 84.35% 97.27% Embodiment 1-14 1,4-Dioxane 82.78% 96.92% Embodiment 1-15 Ethyl formate 84.00% 98.47% Embodiment 1-16 Xylene 82.17% 93.42%

Embodiment 2

(59) 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (660 g, 1.45 mol) prepared from the method of 6-1) was dissolved in isopropanol (4.4 L). A solution of p-toluenesulfonic acid monohydrate (558 g, 2.93 mol) in isopropanol (2.2 L) was added dropwise into the mixture. After addition, the resulting mixture was stirred at 82 C. for 10 hours and filtered by suction. The filter cake was washed with a mixed solvent of isopropanol (660 mL) and ethyl acetate (660 mL) to give a light yellow solid (808 g, 74.6%), and the purity was 98.96%.

(60) Step 2: hydrolysis of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one Tosilate

Embodiment 1

(61) 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one tosilate (5.02 kg, 6.72 mol) and potassium carbonate (3.00 kg, 21.71 mol) were added into acetonitrle (20 L). The mixture was heated to 82 C. and refluxed for 24 hours, then cooled to 30 C. and filtered. The filter cake was washed with ethyl acetate (5 L), and the filtrate was concentrated under reduced pressure to give purified 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one as light yellow liquid, and the purity detected by HPLC was 98.82%.

Embodiment 2

(62) 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one tosilate (3.30 kg, 4.12 mol) and potassium carbonate (1.20 kg, 8.68 mol) were added into ethanol (16 L). The mixture was stirred at room temperature for 5.5 hours, then filtered. The filter cake was washed with dichloromethane (3 L), and the filtrate was concentrated under reduced pressure to give purified 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one as light yellow liquid, and the purity detected by HPLC was 99.43%.

Embodiment 3

(63) 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one tosilate (2.17 kg, 2.90 mol) and sodium carbonate (0.71 kg, 5.14 mol) were added into ethanol (17 L). The mixture was heated to 77 C. and refluxed for 4 hours, then cooled to 30 C. and filtered. The filter cake was washed with dichloromethane (5 L), and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 L), and the mixture was washed with water (10 L) and saturated brine (5 L), concentrated under reduced pressure to give purified 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one as light yellow liquid, and the purity detected by HPLC was 99.49%.

Example 7: 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one Hydrochloride

(64) Method One:

(65) 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (5.00 g, 12.3 mmol, purity: 98.63%) was dissolved in isopropanol (25 mL). The mixture was stirred at room temperature, and hydrochloric acid (1.50 g, 13.0 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours, then heated to reflux and stirred overnight. The mixture was stirred at room temperature for another 3 hours, then filtered by suction, and the filter cake was dried under vacuum in oven at 60 C. to give an off-white solid (5.02 g, 93.3%, purity: 97.12%).

(66) Method Two:

(67) To 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (54.70 g, 98.30 mmol) prepared from Embodiment 8 of 6-1) in Example 6 which was placed in a 250 mL single-neck flask was added ethyl acetate (100.0 g). The mixture was stirred into a clear solution, and then performed in nitrogen atmosphere. Concentrated hydrochloric acid (11.9 g) was added dropwise at room temperature. After addition, the mixture was heated to 80 C. and refluxed for 5 hours while water was distilled out. The reaction mixture was cooled to about 20 C. and stirred at this temperature for 12 hours, and then filtered. The filter cake was washed with ethyl acetate (35.0 g) and dried at 60 C. to give an off-white solid (43.06 g, 61.5%, purity: 99.0%).

(68) Method Three:

Embodiments 1-3

(69) 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one was dissolved in a solvent. The mixture was stirred at room temperature, then to the mixture was added dropwise hydrochloric acid or hydrochloric acid solution. The mixture was stirred at a certain temperature, then filtered, and the filter cake was dried in vacuo to give an off-white solid. The specific reaction conditions and results of Embodiments 1-3 were shown in table K.

(70) TABLE-US-00017 TABLE K Hydrochloric Reaction acid or temperature Purity Solvent/ hydrochloric and/or reaction Output/ of the Embodiment One amount acid solution time Yield product Embodiment 5.00 g Ethyl acetate/ 9.8 mol/L The mixture was 5.02 g, 98.63% 1 (Purity: 50 mL hydrochloric heated to 80 C. 93.3% 98.63%) acid (1.9 mL, and stirred 19 mmol) overnight, then cooled to room temperature and stirred for 6 hours. Embodiment 24.61 g DCM/100 mL A solution of The mixture was 22.73 g, 99.97% 2 (Purity: hydrochloric stirred at room 85.3% 99.24%) acid in ethyl temperature for 2 acetate (30 mL, hours. 30.0 mmol) Embodiment 5.24 g Isopropanol/ A solution of The mixture was 5.29 g, 99.5% 3 (Purity: 40 mL hydrochloric stirred overnight 92.6% 99%) acid in at room isopropanol (1.9 temperature. g, 15.6 mmol)

(71) Reference throughout this specification to an embodiment, some embodiments, one embodiment, another example, an example, a specific example, or some examples, means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as in some embodiments, in one embodiment, in an embodiment, in another example, in an example, in a specific example, or in some examples, in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments or examples of the specification or the features of them as long as they are not contradictory to one another.

(72) Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.