N-tert-butylhydroxylamine;hydrochloride

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

Procedure: By anaolgy to the procedure for the synthesis described above, 5.024 g (40.0 mmol) of N-tert-butylhydroxylamine hydrochloride (1) were reacted with 6.476 g (35.0 mmol) of 4-bromobenzaldehyde (2c) in 100 mL of anhydrous toluene, and in the presence of 4.554 g (45 mmol, 6.27 mL) of Et3N and 8.425 g (70.0 mmol) of MgSO4. Purification of the crude yellow oil by column chromatography (silica gel, EtOAc/hexanes=1:6 to 1:3) yielded 8.95 g (quant.) of colorless crystals. Rf: 0.25 (EtOAc/hexanes=1:4, UV254-quenching). 1H NMR (300 MHz, CDCl3, room temp.): δ8.14 (dt, J=8.7,2.4 Hz, 2H, Ar-H), 7.49 (dt, superimposed, J=8.7,2.4 Hz, 2H, Ar-H), 7.48 (s, superimposed, 1H, HC(═N)), 1.56 (s, 9H, C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3, room temp.): δ131.53, 130.06, 129.81, 128.92, 123.73, 71.09, 28.20 ppm. Purification of the crude yellow oil by column chromatography (silica gel, EtOAc/hexanes=1:6 to 1:3) yielded 8.95 g (quant.) of colorless crystals

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: According to a protocol of A. Dondoni, et al., (Synth. Commun. 1994, 24, 2537-2550), an ovendried 250 mL round-bottomed flask equipped with a magnetic stir bar, reflux condenser and adapter to an argon line was charged with 2.512 g (20.0 mmol) of N-tert-butylhydroxylamine hydrochloride (1), 2.144 g (20.0 mmol) of pyridine-3-carboxaldehyde (2b), and 2.889 g (22.0 mmol) of MgSO4.100 mL of anhydrous toluene were added followed by 2.024 g (20.0 mmol, 2.79 mL) of anhydrous Et3N. The reaction mixture was heated to 100-110° C. under atmosphere of argon, and the reaction course was followed by t.l.c. and GC/MS. After 3-5 h, the reaction was cooled to room temperature, MgSO4 was filtered off, and the solvent was evaporated under reduced pressure to yield a dark yellow-green mixture of product and Et3N HCl. The solids were dissolved in EtOAc and the solution was subsequently washed with a saturated aq. NaHCO3-solution (50 mL) to remove Et3N HCl, water (50 mL), and brine (50 mL), dried over MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by passing through a short plug of silica gel (EtOAc/hexanes (1: 1) to yield after evaporation 3.000 g (84%) of a pale yellow solid. Rf: 0.61 (EtOAc/hexanes=1:9, UV254-quenching). GC: Rt: 3.92 min. 1H NMR (300 MHz, CDCl3, room temp.): δ9.06 (dt, J=8.4,1.8 Hz, 1H, Ar-H), 8.93 (d, J=1.8 Hz, 1H, Ar-H), 8.53 (dd, J=8.8, 1.8 Hz, 1H, Ar-H), 7.56 (s, 1H, HC(═N)), 7.31 (dd, J=8.1, 4.8 Hz, 1H, Ar- H), 1.54 (s, 9H, C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3, room temp.): δ150.20, 150.09, 134.57, 127.49, 126.91, 123.40, 71.43, 28.24 ppm. MS: m/z=178 (M+), 147, 122 (b.p., M+—H2C═C(CH3)2), 106, 79, 57. Dondoni, et al., (Synth. Commun. 1994, 24, 2537-2550), an ovendried 250 mL round-bottomed flask equipped with a magnetic stir bar reflux condenser and adapter to an argon line the reaction was cooled to room temperature MgSO4 was filtered off the solvent was evaporated under reduced pressure to yield the solution was subsequently washed with a saturated aq. NaHCO3-solution (50 mL) to remove Et3N HCl, water (50 mL), and brine (50 mL) dried over MgSO4 filtered evaporated under reduced pressure The crude product was purified to yield after evaporation 3.000 g (84%) of a pale yellow solid

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-tert-butylhydroxylamine hydrochloride (2.512 g, 20.0 mmo 1), pyridine-3 -carboxaldehyde (2.144 g, 20.0 mmol), and MgSO4 (2.889 g, 22.0 mmol) was added 100 mL of anhydrous toluene followed by 2.024 g (20.0 mmol/2.79 mL) of Et3N. The reaction mixture was heated to 100-110° C. under argon atmosphere, and the reaction course was followed by t.l.c. and GC/MS. After 3-5 hours, the reaction was cooled to room temperature, Mg SO4 was filtered off, and the solvent was evaporated under reduced pressure to yield a dark yellow-green mixture of product and Et3N.HCl. The crystals were dissolved in EtOAc and the solution was subsequently washed with saturated aqueous NaHCO3, water and saturated aqueous NaCl, dried (MgSO4 or Na2SO4, ca. 30 min), filtered, and evaporated under reduced pressure. The crude product was purified by passing through a short plug of silica gel (1:1 EtOAc/hexanes) to yield after evaporation 3.00 g (84%) of a pale yellow solid. TLC (1:9 EtOAc/hexanes): Rf=0.61; GC: Rt: 3.92 min; MS: 178 (M+.), 147, 122 (b.p.), 106, 79, 57; 1H NMR (300 MHZ, CDCl3): D=1.54 (s, 9H, C(CH3)3), 7.31 (dd, J=8.1,4.8 Hz, 1H, C(5)-H), 7.56 (s, 1H, HC=N), 8.53 (dd, J=4.8,1.8 Hz, 1H, C(6)-H), 8.93 (d, J=1.8 Hz, 1H, C(2)-H), 9.06 (dt, J=8.4,1.8 Hz, 1H, C(4)-H) ppm; 13C NMR (75 MHZ, CDCl3): D=28.24 71.43, 123.40, 126.91, 127.49, 134.57, 150.09, 150.20 ppm. the reaction was cooled to room temperature Mg SO4 was filtered off the solvent was evaporated under reduced pressure to yield the solution was subsequently washed with saturated aqueous NaHCO3, water and saturated aqueous NaCl dried (MgSO4 or Na2SO4, ca. 30 min) filtered evaporated under reduced pressure The crude product was purified to yield after evaporation 3.00 g (84%) of a pale yellow solid

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using the procedure of Example 1, the above-named compound is prepared from 5.0 g (40 mmol) of N-tert-butylhydroxylamine hydrochloride, 2.4 g (80 mmol) of paraformaldehyde, 9.0 g (41 mmol) of dibenzyl phosphite, 3.0 g (40 mmol) of sodium bicarbonate and 200 ml of tetrahydrofuran (THF) by heating at 55° C. for 14 hours. The residue is purified by recrystallization from a mixture of methylene chloride and hexane to give 9.2 g (64% yield) of a white solid melting at 106°-107° C. The residue is purified by recrystallization from a mixture of methylene chloride and hexane

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

Procedure: To 0.15 g (3 mmol) of (1R,2R)-1-fluoro-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid in DMF (4 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (0.16 g, 1.2 eq), tert-butyl hydroxylamine hydrochloride (0.078 g, 2 eq) and diisopropylethylamine (0.22 mL, 4 eq). The resulting reaction mixture was stirred for 18 h, and then taken up in ethyl acetate, washed with brine, dried over Mg2SO4, filtered and concentrated. The residue was purified using silica chromatography, eluting with a gradient of 50-80% ethyl acetate/hexanes to afford (1R,2R)-N-(tert-butoxy)-1-fluoro-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (0.14 g, 60%, 2 steps). MS: 530.2 (M+H)+. The resulting reaction mixture washed with brine dried over Mg2SO4 filtered concentrated The residue was purified eluting with a gradient of 50-80% ethyl acetate/hexanes

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

Procedure: To 0.15 g (3 mmol) of (1R,2R)-1-fluoro-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid in DMF (4 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (0.16 g, 1.2 eq), tert-butyl hydroxylamine hydrochloride (0.078 g, 2 eq) and diisopropylethylamine (0.22 mL, 4 eq). The resulting reaction mixture was stirred for 18 h, and then taken up in ethyl acetate, washed with brine, dried over Mg2SO4, filtered and concentrated. The residue was purified using silica chromatography, eluting with a gradient of 50-80% ethyl acetate/hexanes to afford (1R,2R)-N-(tert-butoxy)-1-fluoro-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (0.14 g, 60%, 2 steps). MS: 530.2 (M+H)+. The resulting reaction mixture washed with brine dried over Mg2SO4 filtered concentrated The residue was purified eluting with a gradient of 50-80% ethyl acetate/hexanes

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Example 81C (0.45 g, 1.1 mmol) and N-(tert-butyl)hydroxylamine hydrochloride (0.28 g, 2.3 mmol) in THF (20 mL) was added potassium tert-butoxide (0.19 g, 1.7 mmol). The mixture was warmed to 40° C. and stirred for 18 hours then additional potassium tert-butoxide was added (0.40 g). The mixture was stirred for an additional 1 hour then partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 50% hexanes/EtOAc then 100% EtOAc then 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (0.41 g, 0.88 mmol, 78% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J=7.3 Hz, 3H) 1.20 (s, 9H) 1.34-1.43 (m, 2H) 1.42 (s, 9H) 1.64-1.72 (m, 2H) 3.72 (s, 3H) 4.27 (dd, J=7.5 Hz, 2H) 5.75 (s, 1H) 7.01 (s, 1H) 7.46 (dd, J=8.6, 1.9 Hz, 1H) 7.67 (d, J=8.8 Hz, 1H) 8.10 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 469 (M+H)+; Anal. calculated for C24H35F3N4O2: Calc: C, 61.52; H, 7.53; N, 11.96. Found: C, 61.18; H, 7.26; N, 11.92. The mixture was stirred for an additional 1 hour then partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL) The layers were separated the aqueous phase was extracted with EtOAc (3×10 mL) The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated Purification by column chromatography (SiO2, 50% hexanes/EtOAc

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Example 81C (0.45 g, 1.1 mmol) and N-(tert-butyl)hydroxylamine hydrochloride (0.28 g, 2.3 mmol) in THF (20 mL) was added potassium tert-butoxide (0.19 g, 1.7 mmol). The mixture was warmed to 40° C. and stirred for 18 hours then additional potassium tert-butoxide was added (0.40 g). The mixture was stirred for an additional 1 hour then partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 50% hexanes/EtOAc then 100% EtOAc then 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (0.41 g, 0.88 mmol, 78% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J=7.3 Hz, 3H) 1.20 (s, 9H) 1.34-1.43 (m, 2H) 1.42 (s, 9H) 1.64-1.72 (m, 2H) 3.72 (s, 3H) 4.27 (dd, J=7.5 Hz, 2H) 5.75 (s, 1H) 7.01 (s, 1H) 7.46 (dd, J=8.6, 1.9 Hz, 1H) 7.67 (d, J=8.8 Hz, 1H) 8.10 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 469 (M+H)+; Anal. calculated for C24H35F3N4O2: Calc: C, 61.52; H, 7.53; N, 11.96. Found: C, 61.18; H, 7.26; N, 11.92. The mixture was stirred for an additional 1 hour then partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL) The layers were separated the aqueous phase was extracted with EtOAc (3×10 mL) The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated Purification by column chromatography (SiO2, 50% hexanes/EtOAc

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

Procedure: To a solution of 4-cyclohexyl-cyclohexanecarboxylic acid (1.47 g, 7 mmol) in 20 ml of tetrahydrofuran was added oxalyl chloride (0.67 ml, 7.7 mmol) and a few drops of dimethylformamide. After stirring for one hour, the reaction mixture was added dropwise into a cold (~0° C.), stirred solution of N-(1,1-dimethylethyl)hydroxylamine hydrochloride (1.75 g, 14 mmol) in 40 ml of 1N sodium hydroxide. The mixture was stirred for two hours, from 0° C. to room temperature and extracted three times with ethyl acetate. The combined ethyl acetate extracts were then washed twice with water, dried with anhydrous sodium sulfate and concentrated. Purification by flash chromatography provided 0.186 g of the 4-cyclohexyl-N-(1,1-dimethylethyl)-N-hydroxy-cyclohexane-carboxamide as a white solid (m.p. 119°-120° C.). the reaction mixture was added dropwise into a cold (~0° C.) The mixture was stirred for two hours, from 0° C. to room temperature extracted three times with ethyl acetate The combined ethyl acetate extracts were then washed twice with water dried with anhydrous sodium sulfate concentrated Purification by flash chromatography

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

Procedure: A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione (400 mg, 1.37 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (334 mg, 2.06 mmol) in N,N-dimethylformamide (16 mL) was stirred for 1 hour. In one portion, N-tert-butylhydroxylamine hydrochloride (516 mg, 4.11 mmol) was added and the solution was stirred for 17 hours at room temperature. To the resulting solution was added water (20 mL). The insoluble material was filtered and washed with hot methanol (3×20 mL) to give the title compound (300 mg, 61% yield, m.p. 258° C.). The insoluble material was filtered washed with hot methanol (3×20 mL)

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

Procedure: By anaolgy to the procedure for the synthesis described above, 5.024 g (40.0 mmol) of N-tert-butylhydroxylamine hydrochloride (1) were reacted with 6.476 g (35.0 mmol) of 4-bromobenzaldehyde (2c) in 100 mL of anhydrous toluene, and in the presence of 4.554 g (45 mmol, 6.27 mL) of Et3N and 8.425 g (70.0 mmol) of MgSO4. Purification of the crude yellow oil by column chromatography (silica gel, EtOAc/hexanes=1:6 to 1:3) yielded 8.95 g (quant.) of colorless crystals. Rf: 0.25 (EtOAc/hexanes=1:4, UV254-quenching). 1H NMR (300 MHz, CDCl3, room temp.): δ8.14 (dt, J=8.7,2.4 Hz, 2H, Ar-H), 7.49 (dt, superimposed, J=8.7,2.4 Hz, 2H, Ar-H), 7.48 (s, superimposed, 1H, HC(═N)), 1.56 (s, 9H, C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3, room temp.): δ131.53, 130.06, 129.81, 128.92, 123.73, 71.09, 28.20 ppm. Purification of the crude yellow oil by column chromatography (silica gel, EtOAc/hexanes=1:6 to 1:3) yielded 8.95 g (quant.) of colorless crystals

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: According to a protocol of A. Dondoni, et al., (Synth. Commun. 1994, 24, 2537-2550), an ovendried 250 mL round-bottomed flask equipped with a magnetic stir bar, reflux condenser and adapter to an argon line was charged with 2.512 g (20.0 mmol) of N-tert-butylhydroxylamine hydrochloride (1), 2.144 g (20.0 mmol) of pyridine-3-carboxaldehyde (2b), and 2.889 g (22.0 mmol) of MgSO4.100 mL of anhydrous toluene were added followed by 2.024 g (20.0 mmol, 2.79 mL) of anhydrous Et3N. The reaction mixture was heated to 100-110° C. under atmosphere of argon, and the reaction course was followed by t.l.c. and GC/MS. After 3-5 h, the reaction was cooled to room temperature, MgSO4 was filtered off, and the solvent was evaporated under reduced pressure to yield a dark yellow-green mixture of product and Et3N HCl. The solids were dissolved in EtOAc and the solution was subsequently washed with a saturated aq. NaHCO3-solution (50 mL) to remove Et3N HCl, water (50 mL), and brine (50 mL), dried over MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by passing through a short plug of silica gel (EtOAc/hexanes (1: 1) to yield after evaporation 3.000 g (84%) of a pale yellow solid. Rf: 0.61 (EtOAc/hexanes=1:9, UV254-quenching). GC: Rt: 3.92 min. 1H NMR (300 MHz, CDCl3, room temp.): δ9.06 (dt, J=8.4,1.8 Hz, 1H, Ar-H), 8.93 (d, J=1.8 Hz, 1H, Ar-H), 8.53 (dd, J=8.8, 1.8 Hz, 1H, Ar-H), 7.56 (s, 1H, HC(═N)), 7.31 (dd, J=8.1, 4.8 Hz, 1H, Ar- H), 1.54 (s, 9H, C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3, room temp.): δ150.20, 150.09, 134.57, 127.49, 126.91, 123.40, 71.43, 28.24 ppm. MS: m/z=178 (M+), 147, 122 (b.p., M+—H2C═C(CH3)2), 106, 79, 57. Dondoni, et al., (Synth. Commun. 1994, 24, 2537-2550), an ovendried 250 mL round-bottomed flask equipped with a magnetic stir bar reflux condenser and adapter to an argon line the reaction was cooled to room temperature MgSO4 was filtered off the solvent was evaporated under reduced pressure to yield the solution was subsequently washed with a saturated aq. NaHCO3-solution (50 mL) to remove Et3N HCl, water (50 mL), and brine (50 mL) dried over MgSO4 filtered evaporated under reduced pressure The crude product was purified to yield after evaporation 3.000 g (84%) of a pale yellow solid