N,O-双三甲硅基羟胺

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 5 mL microwave vial, (Z)-methyl N′-cyano-N-(3,5-dichlorophenyl)carbamimidothioate (156 mg, 0.6 mmol, Eq: 1.00) and N,O-bis(trimethylsilyl)hydroxylamine (160 mg, 900 μmol, Eq: 1.5) were combined with CCl4 (1 ml) to give a colorless suspension which was capped and heated in a 80° C. oil bath for 2.5 hr. The mixture was concentrated in vacuo and MeOH added. The mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo and the crude material was purified by preparative TLC (silica gel, 1.0 mm, 9:1 DCM/MeOH) to give product which was recrystallized from MeOH and dried in vacuo (89° C., 2 torr, overnight) to give 32 mg (22%) of desired product as a light brown solid. to give a colorless suspension which was capped The mixture was concentrated in vacuo and MeOH added The reaction mixture was concentrated in vacuo the crude material was purified by preparative TLC (silica gel, 1.0 mm, 9:1 DCM/MeOH) to give product which was recrystallized from MeOH dried in vacuo (89° C., 2 torr, overnight)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 5 mL microwave vial, (Z)-methyl N′-cyano-N-(3,5-dichlorophenyl)carbamimidothioate (156 mg, 0.6 mmol, Eq: 1.00) and N,O-bis(trimethylsilyl)hydroxylamine (160 mg, 900 μmol, Eq: 1.5) were combined with CCl4 (1 ml) to give a colorless suspension which was capped and heated in a 80° C. oil bath for 2.5 hr. The mixture was concentrated in vacuo and MeOH added. The mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo and the crude material was purified by preparative TLC (silica gel, 1.0 mm, 9:1 DCM/MeOH) to give product which was recrystallized from MeOH and dried in vacuo (89° C., 2 torr, overnight) to give 32 mg (22%) of desired product as a light brown solid. to give a colorless suspension which was capped The mixture was concentrated in vacuo and MeOH added The reaction mixture was concentrated in vacuo the crude material was purified by preparative TLC (silica gel, 1.0 mm, 9:1 DCM/MeOH) to give product which was recrystallized from MeOH dried in vacuo (89° C., 2 torr, overnight)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)amino]-3-methylbutyric acid (3.82 g, 8.24 mmol) in dry methylene chloride (20 mL) was added oxalyl chloride (2.2 mL, 24.72 mmol) and a drop of dimethylformamide. The reaction mixture was stirred for 4 h and then concentrated. The residue was dissolved in methylene chloride (20 mL) and N,O-bis-trimethylsilylhydroxylamine (8.8 mL, 41.2 mmol) was added. After 4 h, methanol (1 mL) was added and the stirring was continued for 30 min. Silica gel (10 g) was added and the material was concentrated to dryness. The resultant powder was flash chromatographed on a silica gel column and eluted with 50% ethyl acetate/hexanes to give N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyramide (2.46 g). concentrated The residue was dissolved in methylene chloride (20 mL) After 4 h the stirring was continued for 30 min Silica gel (10 g) was added the material was concentrated to dryness chromatographed on a silica gel column eluted with 50% ethyl acetate/hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxylic acid(288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacuo, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trimethylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stirred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification. The reaction mixture was concentrated in vacuo redissolved in methylene chloride (5 ml) cooled to 0° C the reaction was warmed to RT stirred for 3 h recooled to 0° C the mixture was stirred for an additional 30 min. concentrated in vacuo The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml) the organic layer was separated washed with saturated aqueous sodium bicarbonate dried over MgSO4 concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxylic acid(288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacuo, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trimethylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stirred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification. The reaction mixture was concentrated in vacuo redissolved in methylene chloride (5 ml) cooled to 0° C the reaction was warmed to RT stirred for 3 h recooled to 0° C the mixture was stirred for an additional 30 min. concentrated in vacuo The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml) the organic layer was separated washed with saturated aqueous sodium bicarbonate dried over MgSO4 concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Oxalyl chloride (0.58 ml, 6.7 mmol) and DMF (few drops) were added to a solution of (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1 sulfonyl)amino}-3-methylbutyric acid (1.05 g, 2.7 mmol), [prepared as described in Step 1 above], in methylene chloride (85 ml) and the reaction mixture was stirred overnight at RT. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) and N,O-bis-trimethylsilylhydroxylamine (1.7 g, 9.4 mmol) was added. After 3 h, the reaction was concentrated, methanol (20 ml) was added and after stirring for an additional 30 min., the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgSO4, and concentrated. Chromatography (SiO2, 1-2% methanol/methylene chloride) gave N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl-oxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide as a white solid (35%), mp 97.0-98.4° C. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) After 3 h the reaction was concentrated methanol (20 ml) was added after stirring for an additional 30 min. the solvent was removed in vacuo The residue was dissolved in ethyl acetate washed with water and brine dried over MgSO4 concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxylic acid (288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacuo, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trimethylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stirred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification. The reaction mixture was concentrated in vacuo redissolved in methylene chloride (5 ml) cooled to 0° C the reaction was warmed to RT stirred for 3 h recooled to 0° C the mixture was stirred for an additional 30 min. concentrated in vacuo The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml) the organic layer was separated washed with saturated aqueous sodium bicarbonate dried over MgSO4 concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxylic acid (288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacuo, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trimethylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stirred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification. The reaction mixture was concentrated in vacuo redissolved in methylene chloride (5 ml) cooled to 0° C the reaction was warmed to RT stirred for 3 h recooled to 0° C the mixture was stirred for an additional 30 min. concentrated in vacuo The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml) the organic layer was separated washed with saturated aqueous sodium bicarbonate dried over MgSO4 concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Oxalyl chloride (0.58 ml, 6.7 mmol) and DMF (few drops) were added to a solution of (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1sulfonyl)amino}-3-methylbutyric acid (1.05 g, 2.7 mmol), [prepared as described in Step 1 above], in methylene chloride (85 ml) and the reaction mixture was stirred overnight at RT. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) and N,O-bis-trimethylsilylhydroxylamine (1.7 g, 9.4 mmol) was added. After 3 h, the reaction was concentrated, methanol (20 ml) was added and after stirring for an additional 30 min., the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgSO4, and concentrated. Chromatography (SiO2, 1-2% methanol/methylene chloride) gave N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl-oxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide as a white solid (35%), mp 97.0-98.4° C. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) After 3 h the reaction was concentrated methanol (20 ml) was added after stirring for an additional 30 min. the solvent was removed in vacuo The residue was dissolved in ethyl acetate washed with water and brine dried over MgSO4 concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Oxalyl chloride (0.58 ml, 6.7 mmol) and DMF (few drops) were added to a solution of (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1sulfonyl)amino}-3-methylbutyric acid (1.05 g, 2.7 mmol), [prepared as described in Step 1 above], in methylene chloride (85 ml) and the reaction mixture was stirred overnight at RT. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) and N,O-bis-trimethylsilylhydroxylamine (1.7 g, 9.4 mmol) was added. After 3 h, the reaction was concentrated, methanol (20 ml) was added and after stirring for an additional 30 min., the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgSO4, and concentrated. Chromatography (SiO2, 1-2% methanol/methylene chloride) gave N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl-oxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide as a white solid (35%), mp 97.0-98.4° C. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) After 3 h the reaction was concentrated methanol (20 ml) was added after stirring for an additional 30 min. the solvent was removed in vacuo The residue was dissolved in ethyl acetate washed with water and brine dried over MgSO4 concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of allyl(S)-3-(1H-indol-3-yl)-2-(4-nitrophenylsulfonamido)propyl(3-(isoquinolin-6-yl)isoxazol-5-yl)carbamate (100 mg, 153 μmol) in 2.5 mL of DCM was added Pd(PPh3)4 (5.3 mg, 4.6 μmol) and N,O-bis(trimethylsilyl)hydroxylamine (27 mg, 153 μmol). The mixture was stirred for 15 minutes and was then quenched with 2.5 mL saturated aqueous NH4Cl and the biphasic mixture was stirred for 2 hours. The mixture was then partitioned and the aqueous portion was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative LC to give N-((S)-3-(1H-indol-3-yl)-1-(3-(isoquinolin-6-yl)isoxazol-5-ylamino)propan-2-yl)-4-nitrobenzenesulfonamide (75 mg, 86% yield). MS m/z: 569 (M+1). was then quenched with 2.5 mL saturated aqueous NH4Cl the biphasic mixture was stirred for 2 hours The mixture was then partitioned the aqueous portion was extracted twice with DCM The combined organic layers were dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by preparative LC

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-propen-1-yl((2S)-2-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)propyl)(3-(6-isoquinolinyl)-5-isoxazolyl)carbamate (0.095 g, 0.17 mmol) in 2.5 mL of DCM was added N,O-bis(trimethylsilyl)hydroxylamine (0.11 mL, 0.51 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.0058 g, 0.0051 mmol). The mixture was stirred for 15 minutes. The reaction was quenched with 5 mL of aqueous NH4Cl and the biphasic mixture was stirred for 2 hours. The mixture was then partitioned and the aqueous portion was extracted twice with 5 mL of DCM. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure afforded a residue that was taken up in 3 mL of DCM and 0.5 mL of TFA was then added. After 30 minutes, the reaction was diluted with 20 mL of DCM and transferred to a separatory funnel. 10 mL of 5% aqueous NaOH was added, and the biphasic mixture was shaken vigorously and partitioned. The aqueous portion was extracted twice with 15 mL of DCM, and the combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (2.5 to 7.5% MeOH/CH2Cl2) afforded N-((S)-2-amino-3-(4-chlorophenyl)propyl)-3-(isoquinolin-6-yl)isoxazol-5-amine (0.025 g, 39% yield) as a yellow powder. LCMS (API-ES) m/z: 379 (M+1); 1H NMR (400 MHz, CD3O) δ ppm 9.29 (s, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.29 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.92 (d, J=5.7 Hz, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.60 (s, 1H), 3.45-3.20 (m, 3H), 2.92 (dd, J=5.7 Hz, 13.9 Hz, 1H), 2.72 (dd, J=7.1 Hz, 13.5 Hz, 1H). The reaction was quenched with 5 mL of aqueous NH4Cl the biphasic mixture was stirred for 2 hours The mixture was then partitioned the aqueous portion was extracted twice with 5 mL of DCM The combined organic extracts were dried over MgSO4 Filtration and concentration under reduced pressure afforded a residue that After 30 minutes transferred to a separatory funnel the biphasic mixture was shaken vigorously partitioned The aqueous portion was extracted twice with 15 mL of DCM the combined organic extracts were dried over MgSO4 Filtration and concentration under reduced pressure