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11.A Preparation of a Compound of Formula I from Other Compounds of Formula I
A. Preparation of a Compound of Formula I where R4 is acetyl, and R5 is Hydrogen 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.5 g) was dissolved in acetic anhydride (10 ml) and 4-dimethylaminopyridine (0.125 g) was added. The reaction mixture was stirred overnight at room temperature, then heated at 75° to 80°C for a total of 4 hours, and evaporated to dryness under vacuum. The residue was partitioned between water and ethyl acetate and then dried over magnesium sulfate.
11.D Conversion of Compounds of Formula I where R1, R3 and are as defined in the Summary of the Invention, and R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R1 and/or R5
D. Preparation of I where R4 is Phenylamido and R5 is Hydrogen 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (288.3 mg) was dissolved in benzene (50 mL) and phenyl isocyanate (119.1 mg) was added. The reaction mixture was heated to reflux for 48 hours, and the solvent was removed under vacuum. The residue was chromatographed on silica gel, eluding with hexane/ethyl acetate, to yield 1-[4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidin-2-yl]-3-phenylurea (49.1 mg), m.p. 117°-178° C.
In benzene
11.D Conversion of Compounds of Formula I where R1, R2 and R3 are as defined in the Summary of the Invention, and R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R4 and/or R5
D. Preparation of I where R4 is Phenylamido and R5 is Hydrogen 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (288.3 mg) was dissolved in benzene (50 mL) and phenyl isocyanate (119.1 mg) was added. The reaction mixture was heated to reflux for 48 hours, and the solvent was removed under vacuum. The residue was chromatographed on silica gel, eluding with hexane/ethyl acetate, to yield 1-[4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidin-2-yl]-3-phenylurea (49.1 mg), m.p. 117-178° C.
In benzene for 48h; Heating / reflux;
11.B Preparation of a Compound of Formula I from Other Compounds of Formula I
B. Preparation of a Compound of Formula I where R4 is Phenylaminocarbonyl, and R5 is Hydrogen 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (288.3 mg) was dissolved in benzene (50 ml) and phenylisocyanate (119.1 mg) was added. The reaction mixture was heated to reflux for 48 hours, and the solvent was removed under vacuum. The residue was chromatographed on silica gel, eluding with 80:20 hexane:ethyl acetate, to yield 4-(4-fluoronaphth-1-yl)-6-isopropyl-2-phenylureidopyrimidine (49.1 mg, m.p. 117-178).
With dmap; sodium hydrogencarbonate In methanol; acetic anhydride
11.A Conversion of Compounds of Formula I where R1, R3 and are as defined in the Summary of the Invention, and R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R1 and/or R5
A. Preparation of I where R4 is acetyl and R5 is Hydrogen 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.5 g) was dissolved in acetic anhydride (10 mL) and 4-dimethylaminopyridine (0.125 g) was added. The reaction mixture was stirred overnight at room temperature, then heated at 75° to 80° C. for a total of 4 hours, and evaporated to dryness under vacuum. The residue was partitioned between water and ethyl acetate and then dried over magnesium sulfate. The diacetyl compound was isolated as an oil by evaporation and then dissolved in methanol (20 mL). The solution was treated with saturated sodium bicarbonate solution (2 mL) and allowed to stir overnight. The resulting monoacetyl derivative was isolated by evaporation to dryness and thorough drying under vacuum. The residue was taken up in boiling hexane and decanted from a small amount of insoluble residue and crystallized to yield 2-acetylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, m.p. 115.4°-116.7° C. Similarly, 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-1-N-oxide may be reacted with acetic anhydride to give directly the monoacetyl product of Formula I, 2-acetylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-1-N-oxide, 1 H-NMR (200 MHz), J 1.39 (d,6h), 2.51(s,3H) 3.81(m,1H), 7.21-7.27(m,2H), 7.62-7.68(m,3H), 8.10-8.23(m,1H), 8.38°-8.41(m,1H).
With dmap; sodium hydrogencarbonate In methanol; acetic anhydride
11.A Conversion of Compounds of Formula I where R1, R2 and R3 are as defined in the Summary of the Invention, and R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R4 and/or R5
A. Preparation of I where R4 is acetyl and R5 is Hydrogen 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.5 g) was dissolved in acetic anhydride (10 mL) and 4-dimethylaminopyridine (0.125 g) was added. The reaction mixture was stirred overnight at room temperature, then heated at 75° to 80° C. for a total of 4 hours, and evaporated to dryness under vacuum. The residue was partitioned between water and ethyl acetate and then dried over magnesium sulfate. The diacetyl compound was isolated as an oil by evaporation and then dissolved in methanol (20 mL). The solution was treated with saturated sodium bicarbonate solution (2 mL) and allowed to stir overnight. The resulting monoacetyl derivative was isolated by evaporation to dryness and thorough drying under vacuum. The residue was taken up in boiling hexane and decanted from a small amount of insoluble residue and crystallized to yield 2-acetylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, m.p. 115.4-116.7° C. Similarly, 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-1-N-oxide may be reacted with acetic anhydride to give directly the monoacetyl product of Formula I, 2-acetylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-1-N-oxide, 1 H-NMR (200 MHz), J 1.39 (d,6h), 2.51(s,3H), 3.81(m,1H), 7.21-7.27(m,2H), 7.62-7.68(m,3H), 8.10-8.23(m,1H), 8.38-8.41(m,1H).
12.C Alternative Conversion of Compounds of Formula I where R1 is Isopropyl, R3 is, 4-Fluoronaphth-1-yl, and R2, R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R2 or R3
C. Preparation of I where R2 is Hydrogen and R3 is 4-Aminonaphth-1-yl 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.288 g) was dissolved in N-methyl pyrrolidinone (5 mL) and sodium azide (0.288 g) was added. The mixture was brought to a temperature of 160° C. under an inert atmosphere for 16 hours. After cooling the reaction mixture was poured into water (50 mL) and the reaction product was extracted with ethyl acetate (3*30 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The product was purified by column chromatography on silica gel, eluding with hexane/ethyl acetate, and recrystallized from tert-butyl methyl ether to give 2-amino-4-(4-aminonaphth-1-yl)-6-isopropyl-pyrimidine (0.151 g), m.p. 185°-186° C.
In N-methy pyrrolidinone
12.C Alternative Conversion of Compounds of Formula I where R1 is Isopropyl, R3 is 4-Fluoronaphth-1-yl, and R2, R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R2 or R3
C. Preparation of I where R2 is Hydrogen and R3 is 4-Aminonaphth-1-yl 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.288 g) was dissolved in N-methy pyrrolidinone (5 mL) and sodium azide (0.288 g) was added. The mixture was brought to a temperature of 160° C. under an inert atmosphere for 16 hours. After cooling the reaction mixture was poured into water (50 mL) and the reaction product was extracted with ethyl acetate (3*30 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The product was purified by column chromatography on silica gel, eluding with hexane/ethyl acetate, and recrystallized from tert-butyl methyl ether to give 2-amino-4-(4-aminonaphth-1-yl)-6-isopropyl-pyrimidine (0.151 g), m.p. 185-186° C.
In N-methy pyrrolidinone
12.C Alternative Conversion of Compounds of Formula I where R1 is Isopropyl, R3 is 4-Fluoronaphth-1-yl, and R2, R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R2 or R3
C. Preparation of I where R2 is Hydrogen and R3 is 4-Aminonaphth-1-yl 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.288 g) was dissolved in N-methy pyrrolidinone (5 mL) and sodium azide (0.288 g) was added. The mixture was brought to a temperature of 160° C. under an inert atmosphere for 16 hours. After cooling the reaction mixture was poured into water (50 mL) and the reaction product was extracted with ethyl acetate (3*30 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The product was purified by column chromatography on silica gel, eluding with hexane/ethyl acetate, and recrystallized from tert-butyl methyl ether to give 2-amino-4-(4-aminonaphth-1-yl)-6-isopropylpyrimidine (0.151 g), m.p. 185-186° C.
11.B Conversion of Compounds of Formula I where R1, R3 and are as defined in the Summary of the Invention, and R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R1 and/or R5
B. Preparation of I where R4 and R5 are Methanesulfonyl 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.374 g) was dissolved in dichloromethane (25 mL) and cooled to 0° C. Triethyl amine (0.5 mL) was added to the solution and methanesulfonyl chloride (0.12 mL) in dichloromethane (5 mL) was added dropwise. After stirring the mixture for 15 minutes, another portion of triethyl amine (0.25 mL) and methanesulfonyl chloride (0.12 mL) were added sequentially. After 15 minutes, the process was repeated and tlc examination showed a single new product. The reaction mixture was evaporated to dryness and purified by silica gel chromatography, eluding with ethyl acetate/hexane mixture. The colorless crystalline material was recrystallized from hexane-ether to afford 2-(bis-methanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, (354 mg), m.p. 143.8°-144.2° C.
With triethylamine In dichloromethane
11.B Conversion of Compounds of Formula I where R1, R2 and R3 are as defined in the Summary of the Invention, and R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R4 and/or R5
B. Preparation of I where R4 and R5 are Methanesulfonyl 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.374 g) was dissolved in dichloromethane (25 mL) and cooled to 0° C. Triethyl amine (0.5 mL) was added to the solution and methanesulfonyl chloride (0.12 mL) in dichloromethane (5 mL) was added dropwise. After stirring the mixture for 15 miutes, another portion of triethyl amine (0.25 mL) and methanesulfonyl chloride (0.12 mL) were added sequentially. After 15 minutes, the process was repeated and tlc examination showed a single new product. The reaction mixture was evaporated to dryness and purified by silica gel chromatography, eluding with ethyl acetate/hexane mixture. The colorless crystalline material was recrystallized from hexane-ether to afford 2-(bis-methanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, (354 mg), m.p. 143.8-144.2° C.
With triethylamine In dichloromethane
11.B Conversion of Compounds of Formula I where R1, R2 and R3 are as defined in the Summary of the Invention, and R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R4 and/or R5
B. Preparation of I where R4 and R5 are Methanesulfonyl 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.374 g) was dissolved in dichloromethane (25 mL) and cooled to 0° C. Triethyl amine (0.5 mL) was added to the solution and methanesulfonyl chloride (0.12 mL) in dichloromethane (5 mL) was added dropwise. After stirring the mixture for 15 miutes, another portion of triethyl amine (0.25 mL) and methanesulfonyl chloride (0.12 mL) were added sequentially. After 15 minutes, the process was repeated and the examination showed a single new product. The reaction mixture was evaporated to dryness and purified by silica gel chromatography, eluding with ethyl acetate/hexane mixture. The colorless crystalline material was recrystallized from hexane-ether to afford 2-(bis-methanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, (354 mg), m.p. 143.8-144.2° C.
12.B Alternative Conversion of Compounds of Formula I where R1 is Isopropyl, R3 is, 4-Fluoronaphth-1-yl, and R2, R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R2 or R3
B. Preparation of I where R2 is Hydrogen and R3 is 4-Thiomethylnaphth-1-yl 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.281 g) was dissolved in dimethyl sulphoxide (DMSO) (10 mL) and sodium thiomethoxide (0.070 g) was added. The reaction mixture was stirred at room temperature for 2 hours at which time another equivalent of thiomethoxide was added and the reaction stirred for another 2 hours. The mixture was poured into water (100 mL) and the product was extracted into ethyl acetate/hexane (3*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The reaction product was purified by column chromatography on silica gel, eluding with hexane/ethyl acetate to give 2-amino-4-(4-methylthionaphth-1-yl)-6-isopropylpyrimidine (0.303 g), m.p. 139°-140° C.
In dimethyl sulphoxide (DMSO)
12.B Alternative Conversion of Compounds of Formula I where R1 is Isopropyl, R3 is 4-Fluoronaphth-1-yl, and R2, R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R2 or R3
B. Preparation of I where R2 is Hydrogen and R3 is 4-Thiomethylnaphth-1-yl 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.281 g) was dissolved in dimethyl sulphoxide (DMSO) (10 mL) and sodium thiomethoxide (0.070 g) was added. The reaction mixture was stirred at room temperature for 2 hours at which time another equivalent of thiomethoxide was added and the reaction stirred for another 2 hours. The mixture was poured into water (100 mL) and the product was extracted into ethyl acetate/hexane (3*50 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The reaction product was purified by column chromatography on silica gel, eluding with hexane/ethyl acetate to give 2-amino-4-(4-methylthionaphth-1-yl)-6-isopropylpyrimidine (0.303 g), m.p. 139-140° C.
12.A Alternative Conversion of Compounds of Formula I where R1 is Isopropyl, R3 is, 4-Fluoronaphth-1-yl, and R2, R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R2 or R3
A. Preparation of I where R2 is Bromo and R3 is 4-Fluoronanhth-1-yl To a solution of 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (free base, 0.100 g) in carbon tetrachloride (10 mL) was added iron powder (0.002 g) and bromine (0.074 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, after which time it was poured into sodium bicarbonate solution (saturated, 30 mL). The layers were separated and the aqueous layer was extracted three times with methylene chloride (3*10 mL). The combined organic layers were evaporated to dryness. The residue was purified by preparative thin layer chromatography, eluding with hexane/ethyl acetate, and recrystallized from ether/hexane to give 2-amino-5-bromo-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.072 g), m.p. 176°-180° C.
With bromine In tetrachloromethane
12.A Alternative Conversion of Compounds of Formula I where R1 is Isopropyl, R3 is 4-Fluoronaphth-1-yl, and R2, R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R2 or R3
A. Preparation of I where R2 is Bromo and R3 is 4-Fluoronaphth-1-yl To a solution of 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (free base, 0.100 g) in carbon tetrachloride (10 mL) was added iron powder (0.002 g) and bromine (0.074 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, after which time it was poured into sodium bicarbonate solution (saturated, 30 mL). The layers were separated and the aqueous layer was extracted three times with methylene chloride (3*10 mL). The combined organic layers were evaporated to dryness. The residue was purified by preparative thin layer chromatography, eluding with hexane/ethyl acetate, and recrystallized from ether/hexane to give 2-amino-5-bromo-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.072 g), m.p. 176-180° C.
With bromine In tetrachloromethane
12.A Alternative Conversion of Compounds of Formula I where R1 is Isopropyl, R3 is 4-Fluoronaphth-1-yl, and R2, R4 and R5 are Hydrogen to Other Compounds of Formula I, varying R2 or R3
A. Preparation of I where R2 is Bromo and R3 is 4-Fluoronaphth-1-yl To a solution of 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (free base, 0.100 g) in carbon tetrachloride (10 mL) was added iron powder (0.002 g) and bromine (0.074 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, after which time it was poured into sodium bicarbonate solution (saturated, 30 mL). The layers were separated and the aqueous layer was extracted three times with methylene chloride (3*10 mL). The combined organic layers were evaporated to dryness. The residue was purified by preparative thin layer chromatography, eluding with hexane/ethyl acetate, and recrystallized from ether/hexane to give 2-amino-5-bromo-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.072 g), m.p. 176-180° C.