2-(dimethylamino)-2-oxoacetic acid

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: N,N-Dimethyl-oxalamic acid (34 mg, 0.29 mmol), hydroxybenzotriazole hydrate (45 mg, 0.29 mmol), and tetrahydrofuran (5 ml) were added to tert-butyl{5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-yl}carbamate (150 mg, 0.27 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (56 mg, 0.29 mmol) and triethylamine (74 μl, 0.53 mmol) were added and the resulting mixture was stirred for 18 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give the title compound (148 mg, 84%) as a white solid. The reaction mixture was partitioned with ethyl acetate and water the organic layer was washed with saturated aqueous sodium bicarbonate solution dried over magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography (chloroform:methanol=19:1)

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

Procedure: Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (51 mg, 0.13 mmol) and 2-(dimethylamino)-2-oxoacetic acid (13 mg, 0.13 mmol). Yield 44 mg (69%). Prepared

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

Procedure: Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (51 mg, 0.13 mmol) and 2-(dimethylamino)-2-oxoacetic acid (13 mg, 0.13 mmol). Yield 44 mg (69%). Prepared

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

Procedure: To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-(epoxymethano)pyrimido[1,2-a]azepine-2-carboxamide (70 mg, 0.187 mmol) and 2-(dimethylamino)-2-oxoacetic acid (32.8 mg, 0.280 mmol) in DMF (3 mL) was added diisopropyl-ethylamine (0.175 mL, 1.002 mmol), 4-(dimethylamino)pyridine (DMAP) (4.57 mg, 0.037 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (107 mg, 0.280 mmol) and the resulting mixture stirred at room temperature for 3 h. After work-up the crude was purified by preparative HPLC to afford the title compound as an off-white solid (35 mg, 40% yield). 1H NMR (500 MHz, CDCl3) δ: 12.11 (s, 1H), 8.73 (brs, 1H), 7.47 (s, 1H), 7.34 (dd, 2H, J=8.39 & 5.34 Hz), 6.98-7.03 (m, 2H), 4.62-4.70 (m, 2H), 4.53 (d, 2H, J=6.71 Hz), 4.49-4.52 (m, 1H), 4.29 (d, 1H, J=11.6 Hz), 4.08 (d, 1H, J=16.79 Hz), 3.21 (s, 3H), 2.89 (s, 3H), 2.46-2.53 (m, 1H), 2.33-2.38 (m, 1H), 1.86-1.92 (m, 1H), 1.53-1.58 (m, 1H). LCMS (M+H)=474.24. HPLC purity>95%. After work-up the crude was purified by preparative HPLC

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

Procedure: A solution of benzyl((7S,10R,11R)-2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-10,12,12-trimethyl-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,10-methanopyrimido[1,2-a]azocin-11-yl)carbamate hydrochloride salt (0.0367 g, 0.081 mmol), 2-(dimethylamino)-2-oxoacetic acid (9.53 mg, 0.081 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.031 g, 0.081 mmol) and diisopropyl-ethylamine (0.014 mL, 0.081 mmol) in DMF (3 mL) was stirred at room temperature for 24 h. After this the crude reaction mixture was purified by preparative-HPLC using methanol/water (0.1% trifluoroacetic acid) to afford the title compound (0.0301 g, 0.059 mmol, 72% yield) as a purple solid. 1H NMR (500 MHz, CDCl3) δ: 12.01 (1H, s), 8.76 (1 H, t, J=6.0 Hz), 8.21 (1 H, d, J=9.8 Hz), 7.36-7.41 (2 H, m), 6.99-7.05 (2 H, m), 5.27 (1 H, d, J=9.8 Hz), 5.18 (1 H, dd, J=15.6, 8.9 Hz), 4.50-4.63 (2 H, m), 3.65 (1 H, d, J=15.6 Hz), 3.34 (3 H, s), 2.95 (3 H, s), 2.14 (1 H, t, J=8.2 Hz), 1.83-1.94 (1 H, m), 1.47-1.52 (1 H, m), 1.41 (1 H, dd, J=9.5, 5.2 Hz), 1.36 (3 H, s), 1.06 (1 H, dd, 9.8, 4.6 Hz), 1.03 (3 H, s), 0.97 (3 H, s). LCMS (M+H) calcd for C26H33FN5O5: 514.25; found: 514.29. After this the crude reaction mixture was purified

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred precooled (0° C.) solution of 2-(dimethylamino)-2-oxoacetic acid (101 mg, 0.866 mmol) in CH2Cl2 (5 mL) was added oxalyl chloride (0.083 mL, 0.953 mmol) and 2 drops of DMF and the resulting solution stirred for 1 h at 0° C., then 2 h at room temp. The mixture was then concentrated and dried under high vacuum to give crude acid chloride which was diluted with CH2Cl2 (3 mL)) and added to a pre-stirred solution of ethyl 10-(ethylamino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (100 mg, 0.216 mmol) and diisopropyl-ethylamine (0.165 mL, 0.944 mmol) in CH2Cl2 (5 mL). The resulting solution was stirred at room temperature for 16 h. The reaction mixture was poured into sat. NaHCO3 and extracted with dichloromethane (50×3), then dried (Na2SO4) and concentrated to give a yellow oil, which was diluted with ethanol (2 mL) and treated with 2M dimethylamine (0.095 mL, 0.191 mmol). The resulting mixture was heated at 50° C. for 1 h. (4-Fluorophenyl)methanamine (0.054 mL, 0.477 mmol) followed by triethylamine (0.066 mL, 0.477 mmol) was then added and the mixture heated at 90° C. for 18 h. The reaction mixture was cooled, concentrated and purified by preparative HPLC to afford the title compound (5 mg, 11% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 12.02 (1 H, brs), 9.33 (1 H, s), 7.35-7.38 (2 H, m), 6.95-6.99 (2 H, m), 4.81 (1 H, dd, J=15.26, 7.63 Hz), 4.66 (1 H, dd, J=14.34, 7.02 Hz), 4.42 (1 H, dd, J=14.65, 5.80 Hz), 3.53-3.62 (2 H, m), 3.39-3.47 (1 H, m), 3.26-3.36 (1 H, m), 2.98 (3 H, s), 2.97 (3 H, s), 2.49 (1 H, brs), 1.94-2.17 (4 H, m), 1.77-1.84 (2 H, m), 1.44-1.52 (1 H, m), 1.23 (3 H, t, J=7.02 Hz). LCMS (M+H)=500.08. HPLC purity: >95%. 2 h at room temp The mixture was then concentrated dried under high vacuum to give crude acid chloride which The resulting solution was stirred at room temperature for 16 h extracted with dichloromethane (50×3) dried (Na2SO4) concentrated to give a yellow oil, which was then added the mixture heated at 90° C. for 18 h The reaction mixture was cooled concentrated purified by preparative HPLC

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred precooled (0° C.) solution of 2-(dimethylamino)-2-oxoacetic acid (101 mg, 0.866 mmol) in CH2Cl2 (5 mL) was added oxalyl chloride (0.083 mL, 0.953 mmol) and 2 drops of DMF and the resulting solution stirred for 1 h at 0° C., then 2 h at room temp. The mixture was then concentrated and dried under high vacuum to give crude acid chloride which was diluted with CH2Cl2 (3 mL)) and added to a pre-stirred solution of ethyl 10-(ethylamino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (100 mg, 0.216 mmol) and diisopropyl-ethylamine (0.165 mL, 0.944 mmol) in CH2Cl2 (5 mL). The resulting solution was stirred at room temperature for 16 h. The reaction mixture was poured into sat. NaHCO3 and extracted with dichloromethane (50×3), then dried (Na2SO4) and concentrated to give a yellow oil, which was diluted with ethanol (2 mL) and treated with 2M dimethylamine (0.095 mL, 0.191 mmol). The resulting mixture was heated at 50° C. for 1 h. (4-Fluorophenyl)methanamine (0.054 mL, 0.477 mmol) followed by triethylamine (0.066 mL, 0.477 mmol) was then added and the mixture heated at 90° C. for 18 h. The reaction mixture was cooled, concentrated and purified by preparative HPLC to afford the title compound (5 mg, 11% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 12.02 (1 H, brs), 9.33 (1 H, s), 7.35-7.38 (2 H, m), 6.95-6.99 (2 H, m), 4.81 (1 H, dd, J=15.26, 7.63 Hz), 4.66 (1 H, dd, J=14.34, 7.02 Hz), 4.42 (1 H, dd, J=14.65, 5.80 Hz), 3.53-3.62 (2 H, m), 3.39-3.47 (1 H, m), 3.26-3.36 (1 H, m), 2.98 (3 H, s), 2.97 (3 H, s), 2.49 (1 H, brs), 1.94-2.17 (4 H, m), 1.77-1.84 (2 H, m), 1.44-1.52 (1 H, m), 1.23 (3 H, t, J=7.02 Hz). LCMS (M+H)=500.08. HPLC purity: >95%. 2 h at room temp The mixture was then concentrated dried under high vacuum to give crude acid chloride which The resulting solution was stirred at room temperature for 16 h extracted with dichloromethane (50×3) dried (Na2SO4) concentrated to give a yellow oil, which was then added the mixture heated at 90° C. for 18 h The reaction mixture was cooled concentrated purified by preparative HPLC

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (0.08 g, 0.187 mmol), (2,5-dibromo-4-fluorophenyl)methanamine hydrochloride (0.080 g, 0.250 mmol) and Et3N (0.139 mL, 1 mmol) in EtOH (3 mL) was heated at 90° C. for 22 h. Then, cooled, diluted with Ethyl acetate (50 mL), washed with 1N aq. HCl (2×5 mL), water (10 mL) followed by brine (10 mL), dried (Na2SO4), filtered and concentrated to give light purple foam which was used in the next without purification. To CH2Cl2 (5 mL) solution of this crude material was added HBr/AcOH (1.5 mL, 45% w/v) and the mixture stirred at room temperature for 4 h. The reaction mixture was concentrated and resulting light brown solid was used in the next step without purification. A 10 mL flask was charged with this intermediate and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.190 g, 0.5 mmol). To this was added diisopropyl-ethylamine (0.3 mL, 1.718 mmol), N,N-dimethyloxamic acid (0.117 g, 1 mmol) and DMF (3 mL). After 4 h at room temperature, 2M Me2NH/methanol (2 mL) was added and this was stirred at room temperature overnight (15 h). The solution was diluted with Et2O (50 mL), washed with 1N HCl (10 ml), water (2×5 mL) followed by brine (5 mL), then dried (Na2SO4), filtered, concentrated and purified by preparative-HPLC to afford the title compound (0.0136 g, 0.020 mmol, 11% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 11.84 (1H, s), 8.69 (1H, t, J=5.8 Hz), 7.98 (1H, s), 7.56 (1H, d, J=7.3 Hz), 7.35 (1H, d, J=7.9 Hz), 4.63 (2H, d, J=6.1 Hz), 4.17 (2H, d, J=3.7 Hz), 3.28 (3H, s), 2.89 (3H, s), 2.55-2.49 (3H, m), 2.16-2.10 (2H, m), 2.00-1.93 (2H, m), 1.76-1.69 (2H, m). LCMS (M+H) calcd for C23H25Br2FN5O5: 628.02; found: 629.88. Then, cooled washed with 1N aq. HCl (2×5 mL), water (10 mL) dried (Na2SO4) filtered concentrated to give light purple foam which next without purification To CH2Cl2 (5 mL) solution of this crude material was added HBr/AcOH (1.5 mL, 45% w/v) The reaction mixture was concentrated resulting light brown solid was used in the next step without purification After 4 h at room temperature this was stirred at room temperature overnight (15 h) washed with 1N HCl (10 ml), water (2×5 mL) dried (Na2SO4) filtered concentrated purified by preparative-HPLC