Methyl 2-cyanobenzoate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Two identical reactions were run side by side. A solution of diisopropylamine (0.120 mL, 0.91 mmol) in tetrahydrofuran (5.4 mL) was chilled to -78° C. and butyllithium (0.26 mL, 0.65 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.204 g, 0.70 mmol) in tetrahydrofuran (5 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (1.02 g, 6.33 mmol) in tetrahydrofuran (15 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 1 hour at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues from the two side by side reactions were combined and flash chromatographed on silica gel (40×220 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (250 mL), nil; 20% ethyl acetate/hexane (250 mL), nil; 30% ethyl acetate/hexane (50 mL), unweighed impurity; 40% ethyl acetate/hexane (250 mL), unweighed recovered 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 50% ethyl acetate/hexane (250 mL), nil; 60% ethyl acetate/hexane (250 mL), desired product (tlc Rf =0.3 with 50% ethyl acetate/hexane on silica gel). The product containing fractions were combined and concentrated. The residue was triturated with ether and the light yellow solid which formed was collected and dried to yield 0.093 g (17%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 217-218° C.; 1H NMR δ8.60 (dd, J=3, 5 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.81 (dd, J=2, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.58-7.42 (m, 6 H), 4.98 (s, 1 H). Analysis calculated for C21H12ClFN4O2 : C, 63.09; H, 2.89; N, 13.38. Found: C, 62.90; H, 2.81; N, 13.01. was stirred 30 minutes The resulting mixture was stirred 1 hour at -78° C. quenched with saturated aqueous bicarbonate warmed to ambient temperature The mixture was diluted with water repeatedly extracted with ethyl acetate The combined extracts were washed with water and brine dried over magnesium sulfate concentrated flash chromatographed on silica gel (40×220 mm) with elution proceeding 40% ethyl acetate/hexane (250 mL), unweighed recovered 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one The product containing fractions concentrated The residue was triturated with ether the light yellow solid which formed was collected dried

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (0.046 mL, 0.47 mmol) in tetrahydrofuran (2.7 mL) was chilled to -78° C. and butyllithium (0.13 mL, 0.32 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 6-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (0.10 g, 0.37 mmol) in tetrahydrofuran (0.7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (0.50 g, 3.1 mmol) in tetrahydrofuran (10 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 30 minutes at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20×100 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (50 mL), nil; 20% ethyl acetate/hexane (50 mL), unweighedrecovered 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 30% ethyl acetate/hexane (50 mL), nil; 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate; 50% ethyl acetate/hexane (50 mL), unweighed impurity; 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product; 70% ethyl acetate/hexane (50 mL), product. The product containing fractions were combined and concentrated. The residue was triturated with 1% ethyl acetate/ether and the yellow solid which formed was collected and dried to yield 0.017 g (10%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 213-215° C.; 1H NMR δ8.70 (d, J=4 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.60 (d, J=9 Hz, 1 H), 7.58-7.38 (m, 6 H), 4.94 (s, 1 H), 2.44 (s, 3 H). Analysis calculated for C23H15FN4O2.0.25 H2O: C, 68.57; H, 3.88; N, 13.91. Found: C, 68.52, 68,91; H, 4.13, 4.21; N, 13.25, 13.28. was stirred 30 minutes The resulting mixture was stirred 30 minutes at -78° C. quenched with saturated aqueous bicarbonate warmed to ambient temperature The mixture was diluted with water repeatedly extracted with ethyl acetate The combined extracts were washed with water and brine dried over magnesium sulfate concentrated chromatographed on silica gel (20×100 mm) with elution proceeding 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product The product containing fractions concentrated The residue was triturated with 1% ethyl acetate/ether the yellow solid which formed was collected dried

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (0.046 mL, 0.47 mmol) in tetrahydrofuran (2.7 mL) was chilled to -78° C. and butyllithium (0.13 mL, 0.32 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 6-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (0.10 g, 0.37 mmol) in tetrahydrofuran (0.7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (0.50 g, 3.1 mmol) in tetrahydrofuran (10 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 30 minutes at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20×100 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (50 mL), nil; 20% ethyl acetate/hexane (50 mL), unweighedrecovered 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 30% ethyl acetate/hexane (50 mL), nil; 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate; 50% ethyl acetate/hexane (50 mL), unweighed impurity; 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product; 70% ethyl acetate/hexane (50 mL), product. The product containing fractions were combined and concentrated. The residue was triturated with 1% ethyl acetate/ether and the yellow solid which formed was collected and dried to yield 0.017 g (10%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 213-215° C.; 1H NMR δ8.70 (d, J=4 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.60 (d, J=9 Hz, 1 H), 7.58-7.38 (m, 6 H), 4.94 (s, 1 H), 2.44 (s, 3 H). Analysis calculated for C23H15FN4O2.0.25 H2O: C, 68.57; H, 3.88; N, 13.91. Found: C, 68.52, 68,91; H, 4.13, 4.21; N, 13.25, 13.28. was stirred 30 minutes The resulting mixture was stirred 30 minutes at -78° C. quenched with saturated aqueous bicarbonate warmed to ambient temperature The mixture was diluted with water repeatedly extracted with ethyl acetate The combined extracts were washed with water and brine dried over magnesium sulfate concentrated chromatographed on silica gel (20×100 mm) with elution proceeding 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product The product containing fractions concentrated The residue was triturated with 1% ethyl acetate/ether the yellow solid which formed was collected dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl-2-cyanobenzoate (10 g, 62.11 mmol) in ethyl ether (300 mL) was added dropwise to a slurry of lithium aluminum hydride in ethyl ether (200 mL). After the addition was complete, more ether was added (200 mL) and the mixture heated at reflux for 2 h. The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL). The reaction was filtered and evaporated to give 6.96 g (50.8 mmol) of 2-(aminomethyl)benzyl alcohol. This material was carried on without further purification. After the addition the mixture heated at reflux for 2 h The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL) The reaction was filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl-2-cyanobenzoate (10 g, 62.11 mmol) in ethyl ether (300 mL) was added dropwise to a slurry of lithium aluminum hydride in ethyl ether (200 mL). After the addition was complete, more ether was added (200 mL) and the mixture heated at reflux for 2 h. The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL). The reaction was filtered and evaporated to give 6.96 g (50.8 mmol) of 2-(aminomethyl)benzyl alcohol. This material was carried on without further purification. After the addition the mixture heated at reflux for 2 h The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL) The reaction was filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl-2-cyanobenzoate (10 g, 62.11 mmol) in ethyl ether (300 mL) was added dropwise to a slurry of lithium aluminum hydride in ethyl ether (200 mL). After the addition was complete, more ether was added (200 mL) and the mixture heated at reflux for 2 h. The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL). The reaction was filtered and evaporated to give 6.96 g (50.8 mmol) of 2-(aminomethyl)benzyl alcohol. This material was carried on without further purification. After the addition the mixture heated at reflux for 2 h The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL) The reaction was filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl-2-cyanobenzoate (10 g, 62.11 mmol) in ethyl ether (300 mL) was added dropwise to a slurry of lithium aluminum hydride in ethyl ether (200 mL). After the addition was complete, more ether was added (200 mL) and the mixture heated at reflux for 2 h. The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL). The reaction was filtered and evaporated to give 6.96 g (50.8 mmol) of 2-(aminomethyl)benzyl alcohol. This material was carried on without further purification. After the addition the mixture heated at reflux for 2 h The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL) The reaction was filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-cyanobenzoate (1.0 g, 6.2 mmol) and PtO2 (100 mg) in 20 mL EtOH and 1 ml of chloroform was hydrogenated under 50 psi of hydrogen for 2 h. The reaction mixture was filtered through Celite® in a sintered glass funnel and concentrated on a rotary evaporator to give methyl 2-(aminomethyl)benzoate as a HCl salt and this was carried to the next step crude. The reaction mixture was filtered through Celite® in a sintered glass funnel concentrated on a rotary evaporator

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 2-cyanobenzoate (54 g, 0.33 mole) in D.M.F. (165 ml) was treated with sodium azide (23.4 g, 0.36 mole) and ammonium chloride (19.3 g, 0.36 mole). After the reaction mixture had been stirred on the steam bath for 20 hrs., the D.M.F. was removed under reduced pressure and the residue dissolved in water (200 ml). The solution was filtered, cooled in ice and acidified to give a white precipitate which was filtered, washed with water and dried. This gave methyl 2-(5-2H-tetrazolyl)benzoate, M.P. 132°-5°, 19 g (28%). (Found: C, 53.79, 52.59, 52.33; H, 4.25, 4.17, 4.07; N, 26.79, 26.84, 27.25. C9H8N4O2 requires C, 52.94; H, 3.95; N, 27.44.) was removed under reduced pressure the residue dissolved in water (200 ml) The solution was filtered cooled in ice to give a white precipitate which was filtered washed with water dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phthalamic acid (240 g, 1.37 moles) in methylenechloride (1.7 l) was stirred and cooled to <5° in an ice bath. Triethylamine (244 ml, 176 g, 1.74 moles) was added and a clear solution was obtained. Methyl chloroformate (200 g, 163 ml, 2.1 moles) was added at such a rate that the temperature did not exceed 5°. As the addition continued, triethylamine hydrochloride precipitated and carbon dioxide was evolved. On completion of the addition, the ice bath was removed and stirring was continued for 12-20 hrs. at room temperature. Triethylamine hydrochloride was removed by filtration and the methylene chloride evaporated. The residue was dissolved in ether (2 l), and this ether solution washed with water, dried over anhydrous sodium sulfate and evaporated. Distillation under reduced pressure gave methyl 2-cyanobenzoate, b.p. 125° at 2.5 mm, 215 g (97%), a solid at room temperature, M.P. 45°-6°. cooled to <5° in an ice bath a clear solution was obtained did not exceed 5° As the addition triethylamine hydrochloride precipitated On completion of the addition the ice bath was removed at room temperature Triethylamine hydrochloride was removed by filtration the methylene chloride evaporated The residue was dissolved in ether (2 l) this ether solution washed with water dried over anhydrous sodium sulfate evaporated Distillation under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Two identical reactions were run side by side. A solution of diisopropylamine (0.120 mL, 0.91 mmol) in tetrahydrofuran (5.4 mL) was chilled to -78° C. and butyllithium (0.26 mL, 0.65 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.204 g, 0.70 mmol) in tetrahydrofuran (5 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (1.02 g, 6.33 mmol) in tetrahydrofuran (15 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 1 hour at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues from the two side by side reactions were combined and flash chromatographed on silica gel (40×220 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (250 mL), nil; 20% ethyl acetate/hexane (250 mL), nil; 30% ethyl acetate/hexane (50 mL), unweighed impurity; 40% ethyl acetate/hexane (250 mL), unweighed recovered 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 50% ethyl acetate/hexane (250 mL), nil; 60% ethyl acetate/hexane (250 mL), desired product (tlc Rf =0.3 with 50% ethyl acetate/hexane on silica gel). The product containing fractions were combined and concentrated. The residue was triturated with ether and the light yellow solid which formed was collected and dried to yield 0.093 g (17%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 217-218° C.; 1H NMR δ8.60 (dd, J=3, 5 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.81 (dd, J=2, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.58-7.42 (m, 6 H), 4.98 (s, 1 H). Analysis calculated for C21H12ClFN4O2 : C, 63.09; H, 2.89; N, 13.38. Found: C, 62.90; H, 2.81; N, 13.01. was stirred 30 minutes The resulting mixture was stirred 1 hour at -78° C. quenched with saturated aqueous bicarbonate warmed to ambient temperature The mixture was diluted with water repeatedly extracted with ethyl acetate The combined extracts were washed with water and brine dried over magnesium sulfate concentrated flash chromatographed on silica gel (40×220 mm) with elution proceeding 40% ethyl acetate/hexane (250 mL), unweighed recovered 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one The product containing fractions concentrated The residue was triturated with ether the light yellow solid which formed was collected dried

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (0.046 mL, 0.47 mmol) in tetrahydrofuran (2.7 mL) was chilled to -78° C. and butyllithium (0.13 mL, 0.32 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 6-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (0.10 g, 0.37 mmol) in tetrahydrofuran (0.7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (0.50 g, 3.1 mmol) in tetrahydrofuran (10 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 30 minutes at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20×100 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (50 mL), nil; 20% ethyl acetate/hexane (50 mL), unweighedrecovered 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 30% ethyl acetate/hexane (50 mL), nil; 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate; 50% ethyl acetate/hexane (50 mL), unweighed impurity; 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product; 70% ethyl acetate/hexane (50 mL), product. The product containing fractions were combined and concentrated. The residue was triturated with 1% ethyl acetate/ether and the yellow solid which formed was collected and dried to yield 0.017 g (10%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 213-215° C.; 1H NMR δ8.70 (d, J=4 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.60 (d, J=9 Hz, 1 H), 7.58-7.38 (m, 6 H), 4.94 (s, 1 H), 2.44 (s, 3 H). Analysis calculated for C23H15FN4O2.0.25 H2O: C, 68.57; H, 3.88; N, 13.91. Found: C, 68.52, 68,91; H, 4.13, 4.21; N, 13.25, 13.28. was stirred 30 minutes The resulting mixture was stirred 30 minutes at -78° C. quenched with saturated aqueous bicarbonate warmed to ambient temperature The mixture was diluted with water repeatedly extracted with ethyl acetate The combined extracts were washed with water and brine dried over magnesium sulfate concentrated chromatographed on silica gel (20×100 mm) with elution proceeding 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product The product containing fractions concentrated The residue was triturated with 1% ethyl acetate/ether the yellow solid which formed was collected dried