O-trimethylsilylhydroxylamine

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

Procedure: Prepared according to Method D of the General Procedures for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(4″-(un)substituted amino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from 5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one (0.046 g, 0.1 mmol) and O-trimethylsilylhydroxylamine (0.052 mL, ca. 0.5 mmol) in tetrahydrofuran (1 mL). The synthesis was performed for 2 h at r.t. Diethyl ether (4 mL) was added, the precipitated product washed with diethyl ether, tetrahydrofuran (2×0.5 mL), excess ether, and dried in vacuo. MS: 312 [M+H]+. Rt 2.8 min. 1H NMR. Prepared the precipitated product washed with diethyl ether, tetrahydrofuran (2×0.5 mL), excess ether dried in vacuo

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

Procedure: A stirred solution of (±)-3-(3-cyclopentyloxy-4-methoxyphenyl)sulfanyl-7-phenylheptanoic acid (0.40 g, Example 4) in a mixture of dimethylformamide (0.07 ml) and dichloromethane (20 ml) was treated dropwise with a solution of oxalyl chloride in dichloromethane (1.17 ml, 2.0 M). After stirring at room temperature for a further 30 minutes the mixture was treated dropwise with O-(trimethylsilyl)hydroxylamine (0.57 ml). The resulting white suspension was stirred for 10 minutes then partitioned between hydrochloric acid (50 ml, 1N) and ethyl acetate (50 ml). The aqueous layer was extracted twice with ethyl acetate (50 ml). The combined organic phases were washed with water (50 ml), then with brine (50 ml), then dried over magnesium sulphate and then evaporated to give the title compound (0.26 g) as a white foam. NMR (CDCl3): δ1.60 (m,8H), 1.86 (m,6H), 2.35 (br d,2H), 2.60 (br t,2H), 3.30 (m,1H), 3.80 (s,3H), 3.73 (m,1H), 6.76 (d,1H), 6.95 (d,2H), 7.10-7.30 (m,5H). Mass spectrum (FAB): m/z 444 (M+H)+. The resulting white suspension was stirred for 10 minutes then partitioned between hydrochloric acid (50 ml, 1N) and ethyl acetate (50 ml) The aqueous layer was extracted twice with ethyl acetate (50 ml) The combined organic phases were washed with water (50 ml) with brine (50 ml), then dried over magnesium sulphate evaporated

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

Procedure: 0.78 g of 2-morpholino-ethyl isocyanide was added at 22° to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine from Example 11 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of t-butyl methyl ether and 0.23 ml of water, stirred for 11/2 hrs. at 22°, the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-ethyl]propionyl]piperidine I, MS (EI): 436 (40%). stirred for 2 hrs The reaction mixture was washed with saturated NaHCO3 solution and with water evaporated The residue was dissolved in 20 ml of t-butyl methyl ether 0.23 ml of water, stirred for 11/2 hrs at 22°, the suspension was diluted with 10 ml of hexane filtered the residue was dried at 22°/11 mbar, there

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

Procedure: O-Trimethylsilylhydroxylamine (0.37 ml, 3.0 mmol) and 5-(S)-acetamidomethyl-3-[4′-cyano-3′-fluorophenyl]oxazolidine-2-one (0.277 g, 1.0 mmol) in ethanol (3.0 ml) were stirred at 80° C. in a sealed reaction vial for 2.5 h. The mixture was left at r.t. for 48 h, and the crystallized product filtered, rinsed with ethanol (ca. 0.75 ml), washed with ether, and dried under vacuum. Yellow crystals. Yield 0.260 g (84%). HPLC: Rt 2.6 min. MS (m/z): [M+H]+=311. the crystallized product filtered rinsed with ethanol (ca. 0.75 ml) washed with ether dried under vacuum

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

Procedure: Intermediate (27) (0.0128 mol), 1,4-dioxane (50 ml), and O-(trimethylsilyl)hydroxyl-amine, (0.134 mol) were combined under argon. The reaction mixture was stirred at RT for 20 hours. The reaction mixture was concentrated and DCM (50 ml), NaOH (1 N; 50 ml), and HCl (1N; 100 ml) were added. The solution was stirred for one hour. The precipitate was filtered off and recrystallized from methanol. The precipitate was filtered off and dried, yielding 2.96 g (59.8%) of 4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]benzonitrile monohydrochloride monohydrate (compound 21). The reaction mixture was concentrated DCM (50 ml), NaOH (1 N; 50 ml), and HCl (1N; 100 ml) were added The solution was stirred for one hour The precipitate was filtered off recrystallized from methanol The precipitate was filtered off dried

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

Procedure: Intermediate (27) (0.0128 mol), 1,4-dioxane (50 ml), and O-(trimethylsilyl)hydroxyl-amine, (0.134 mol) were combined under argon. The reaction mixture was stirred at RT for 20 hours. The reaction mixture was concentrated and DCM (50 ml), NaOH (1 N; 50 ml), and HCl (1N; 100 ml) were added. The solution was stirred for one hour. The precipitate was filtered off and recrystallized from methanol. The precipitate was filtered off and dried, yielding 2.96 g (59.8%) of 4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]benzonitrile monohydrochloride monohydrate (compound 21). The reaction mixture was concentrated DCM (50 ml), NaOH (1 N; 50 ml), and HCl (1N; 100 ml) were added The solution was stirred for one hour The precipitate was filtered off recrystallized from methanol The precipitate was filtered off dried

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

Procedure: (±)-3-(4-Methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.38 g, 1.1 mmol) is dissolved in CH2Cl2 (1 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (0.7 mL, 1.4 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 3 hours. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (3 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.4 mL, 3.4 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to yield (±)-3-(4-methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid hydroxyamide (0.37 g, 90%) which is used without further purification: 1H NMR (300 MHz, CDCl3) δ 7.30-7.18 (m, 4H), 7.14-7.07 (m, 3H), 7.80-7.73 (m, 2H), 3.73 (s, 1.5H), 3.72 (s, 1.5H), 3.12-3.06 (m, 0.5H), 2.97-2.90 (m, 0.5H), 2.53 (m, 2H), 2.32-2.19 (m, 1H), 1.68-1.25 (m, 6H) 1.16 (d, J=7.0 Hz, 1.5H), 1.11 (d, J=7.0 Hz, 1.5H); MS (FAB) m/e 374 (M+H)+. the bath removed to warm The reaction is then concentrated in vacuo azeotroped with CHCl3 The resulting oil is dissolved in CH2Cl2 (3 mL) cooled to 0° C. The bath is removed to warm to 20° C The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL) The organic layer is then separated washed with water (10 mL) dried (MgSO4) concentrated in vacuo

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

Procedure: (±)-(2R*,3S*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylmethyl)heptanoic acid (0.42 g, 0.84 mmol) is dissolved in CH2Cl2 (3 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (1.5 mL, 3 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 1 hour. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (2 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.3 mL, 2.6 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to yield (±)-(2R*,3S*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylmethyl)heptanoic acid hydroxyamide (0.37 g, 87%) The material obtained from the reaction is analytically pure: 1H NMR (300 MHz, CD3OD) δ 7.74-7.69 (m, 2H), 7.32-7.17 (m, 1H), 7.15-7.08 (m, 1H), 7.06-7.01 (m, 4H), 3.87 (s, 3H), 3.49 (dd, J=13.8, 5.3 Hz, 1H), 3.39 (q, J=5.3 Hz, 1H), 3.21 (dd, J=13.8, 9.8 Hz, 1H), 2.98-2.85 (m, 1H), 2.43 (t, J=7.3 Hz, 2H), 1.78-1.71 (m, 2H), 1.41-1.10 (m, 4H); MS (FAB) m/e 514 (M+H)+ ; Anal. (C27H31NO5S2) C, H, N. the bath removed to warm The reaction is then concentrated in vacuo azeotroped with CHCl3 The resulting oil is dissolved in CH2Cl2 (2 mL) cooled to 0° C. The bath is removed to warm to 20° C The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL) The organic layer is then separated washed with water (10 mL) dried (MgSO4) concentrated in vacuo

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

Procedure: (±)-(2R*,3S*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylmethyl)heptanoic acid (0.42 g, 0.84 mmol) is dissolved in CH2Cl2 (3 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (1.5 mL, 3 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 1 hour. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (2 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.3 mL, 2.6 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to yield (±)-(2R*,3S*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylmethyl)heptanoic acid hydroxyamide (0.37 g, 87%) The material obtained from the reaction is analytically pure: 1H NMR (300 MHz, CD3OD) δ 7.74-7.69 (m, 2H), 7.32-7.17 (m, 1H), 7.15-7.08 (m, 1H), 7.06-7.01 (m, 4H), 3.87 (s, 3H), 3.49 (dd, J=13.8, 5.3 Hz, 1H), 3.39 (q, J=5.3 Hz, 1H), 3.21 (dd, J=13.8, 9.8 Hz, 1H), 2.98-2.85 (m, 1H), 2.43 (t, J=7.3 Hz, 2H), 1.78-1.71 (m, 2H), 1.41-1.10 (m, 4H); MS (FAB) m/e 514 (M+H)+ ; Anal. (C27H31NO5S2) C, H, N. the bath removed to warm The reaction is then concentrated in vacuo azeotroped with CHCl3 The resulting oil is dissolved in CH2Cl2 (2 mL) cooled to 0° C. The bath is removed to warm to 20° C The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL) The organic layer is then separated washed with water (10 mL) dried (MgSO4) concentrated in vacuo

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

Procedure: (±)-(2R*,3R*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid (0.17 g, 0.34 mmol) is dissolved in CH2Cl2 (1 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (0.5 mL, 1 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 3 hours. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (3 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.16 g, 1.7 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo. The product is purified by reverse phase HPLC (65% CH3CN in 0.1% TFA/H2O) to yield (±)-(2R*, R*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid hydroxyamide (0.12 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.8 Hz, 2H), 7.28-7.14 (m, 5H), 7.08 (d, J=7.0 Hz, 2H), 6.97-6.89 (m, 3H), 6.73 (d, J=8.1 Hz, 2H), 3.89-3.71 (m, 5H), 3.27-3.20 (m, 2H), 2.51 (t, J=7.2 Hz, 2H), 2.45-2.32 (m, 1H), 1.98-1.75 (m, 3H), 1.55-1.38 (m, 3H), 1.35-1.22 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 168.74, 164.06, 158.25, 141.93, 130.70, 129.46, 128.88, 128.34, 128.30, 125.78, 121.06, 114.63, 114.36, 66.37, 65.16, 55.67, 38.36, 35.30, 31.00, 30.35, 27.75, 25.34; MS (FAB) m/e 512 (M+H)+ ; Anal. (C28H33NO6S.0.2 H2O) C, H, N. the bath removed to warm The reaction is then concentrated in vacuo azeotroped with CHCl3 The resulting oil is dissolved in CH2Cl2 (3 mL) cooled to 0° C. The bath is removed to warm to 20° C The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL) The organic layer is then separated washed with water (10 mL) dried (MgSO4) concentrated in vacuo The product is purified by reverse phase HPLC (65% CH3CN in 0.1% TFA/H2O)

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

Procedure: (±)-(2R*,3R*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid (0.17 g, 0.34 mmol) is dissolved in CH2Cl2 (1 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (0.5 mL, 1 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 3 hours. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (3 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.16 g, 1.7 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo. The product is purified by reverse phase HPLC (65% CH3CN in 0.1% TFA/H2O) to yield (±)-(2R*, R*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid hydroxyamide (0.12 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.8 Hz, 2H), 7.28-7.14 (m, 5H), 7.08 (d, J=7.0 Hz, 2H), 6.97-6.89 (m, 3H), 6.73 (d, J=8.1 Hz, 2H), 3.89-3.71 (m, 5H), 3.27-3.20 (m, 2H), 2.51 (t, J=7.2 Hz, 2H), 2.45-2.32 (m, 1H), 1.98-1.75 (m, 3H), 1.55-1.38 (m, 3H), 1.35-1.22 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 168.74, 164.06, 158.25, 141.93, 130.70, 129.46, 128.88, 128.34, 128.30, 125.78, 121.06, 114.63, 114.36, 66.37, 65.16, 55.67, 38.36, 35.30, 31.00, 30.35, 27.75, 25.34; MS (FAB) m/e 512 (M+H)+ ; Anal. (C28H33NO6S.0.2 H2O) C, H, N. the bath removed to warm The reaction is then concentrated in vacuo azeotroped with CHCl3 The resulting oil is dissolved in CH2Cl2 (3 mL) cooled to 0° C. The bath is removed to warm to 20° C The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL) The organic layer is then separated washed with water (10 mL) dried (MgSO4) concentrated in vacuo The product is purified by reverse phase HPLC (65% CH3CN in 0.1% TFA/H2O)

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

Procedure: (2R,3S)-3-(3,4-Dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.46 g, 1.2 mmol) is dissolved in CH2Cl2 (4.5 mL) and cooled to 0° C. and to this is added 2 M oxalyl chloride in CH2Cl2 (1.9 mL, 3.8 mmol) over 5 minutes. The ice bath is removed and the reaction allowed to warm to room temperature. After 1.5 hours, the reaction is concentrated in vacuo and azeotroped with chloroform several times. The crude residue is dissolved in CH2Cl2 (4 mL) and O-trimethylsilylhydroxylamine (0.4 g, 3.6 mmol) is added slowly. After 5 minutes, the reaction is diluted with CH2Cl2 (20 mL) and washed with 2 N HCl (15 mL). The aqueous layer is back-extracted with CH2Cl2 (10 mL) and the combined organic layers are washed with water (50 mL), dried over MgSO4 and concentrated in vacuo. The crude residue is azeotroped with ether/petroleum ether and triturated with a large volume of petroleum ether to give (+)-(2R,3S)-3-(3,4-dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid hydroxyamide (0.45 g, 94%): [a]D23 +22° (c=1.0, CHCl3); 1H NMR (300 MHz, CD3OD) δ 7.25-7.21 (m, 2H), 7.15-7.10 (m, 3H), 7.05-6.98 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.17-3.14 (m,1H), 2.58-2.52 (m, 2H), 2.35-2.30 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.40 (m, 5H), 1.17 (d, J=7.0 Hz, 3H); MS (ion spray) m/e 404 (M+H)+ ; Anal. (C22H29NO4S) C, H, N. The ice bath is removed to warm to room temperature the reaction is concentrated in vacuo azeotroped with chloroform several times The crude residue is dissolved in CH2Cl2 (4 mL) After 5 minutes washed with 2 N HCl (15 mL) The aqueous layer is back-extracted with CH2Cl2 (10 mL) the combined organic layers are washed with water (50 mL) dried over MgSO4 concentrated in vacuo The crude residue is azeotroped with ether/petroleum ether triturated with a large volume of petroleum ether