O-(2-methoxypropan-2-yl)hydroxylamine

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

Procedure: To a suspension of the compound prepared in Example 9(54) (120 mg) and (1-methoxyisopropyl)oxyamine (31 mg) in dimethylformamide (1.6 ml) was added diisopropylethylamine (68 μl), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.hydrochloride (56 mg) and 1-hydroxybenztriazole (40 mg). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was added 1N hydrochloric acid (2 ml) and stirred for 15 minutes at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride and the obtained residue was dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained residue in methanol was added 4N hydrogen chloride/ethyl acetate solution and concentrated. The obtained residue was washed with ethyl acetate to give the title compound (116 mg) having the following physical data. stirred for 15 minutes at room temperature extracted with ethyl acetate The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride the obtained residue was dried over anhydrous sodium sulfate concentrated To a solution of the obtained residue in methanol was added 4N hydrogen chloride/ethyl acetate solution concentrated The obtained residue was washed with ethyl acetate

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

Procedure: To a suspension of the compound prepared in Example 9(54) (120 mg) and (1-methoxyisopropyl)oxyamine (31 mg) in dimethylformamide (1.6 ml) was added diisopropylethylamine (68 μl), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.hydrochloride (56 mg) and 1-hydroxybenztriazole (40 mg). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was added 1N hydrochloric acid (2 ml) and stirred for 15 minutes at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride and the obtained residue was dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained residue in methanol was added 4N hydrogen chloride/ethyl acetate solution and concentrated. The obtained residue was washed with ethyl acetate to give the title compound (116 mg) having the following physical data. stirred for 15 minutes at room temperature extracted with ethyl acetate The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride the obtained residue was dried over anhydrous sodium sulfate concentrated To a solution of the obtained residue in methanol was added 4N hydrogen chloride/ethyl acetate solution concentrated The obtained residue was washed with ethyl acetate

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

Procedure: To a solution of 0.425 g (1 mmol) of desired {[4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)-amino}-acetic acid and 0.27 g (2 mmol) of HOBT in 4 ml of DMF, a solution of 0.116 g of O-(1-methoxy-1-methyl-ethyl)-hydroxylamine in 1 ml of DMF and 0.23 g of WSCD were successively added at 0–5° C. and the mixture was stirred for 1 h. After stirring for additional 2 h at r.t., the mixture is diluted with H2O and extracted with AcOEt. The combined extracts are dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; AcOEt:n-hexane=1:1) to give 2-{[4-(4-fluorobutoxy)-benzenesulfonyl]-4-methoxy-benzyl)-amino}-N-(1-ethoxy-1-methyl ethoxy) acetamide; NMR (CDCl3): 1.35 (s, 6H), 1.83–2.0 (m, 4H), 3.29 (s, 3H), 3.70 (s, 2H), 3.78 (s, 3H), 4.08–4.11 (m, 2H), 4.32 (s, 2H), 4.47–4.49 (m, 1H), 4.60 (br s, 1H), 6.80–6.90 (m, 2H), 6.95–7.05 (m, 2H), 7.10–7.25 (m, 2H), 7.79 (d, 2H, J=9.06 Hz), 8.46 (br s, 1H). After stirring for additional 2 h at r.t. extracted with AcOEt The combined extracts are dried over MgSO4 concentrated under reduced pressure The residue is purified by column chromatography on silica gel (eluent; AcOEt:n-hexane=1:1)

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

Procedure: To a solution of 0.425 g (1 mmol) of desired {[4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)-amino}-acetic acid and 0.27 g (2 mmol) of HOBT in 4 ml of DMF, a solution of 0.116 g of O-(1-methoxy-1-methyl-ethyl)-hydroxylamine in 1 ml of DMF and 0.23 g of WSCD were successively added at 0–5° C. and the mixture was stirred for 1 h. After stirring for additional 2 h at r.t., the mixture is diluted with H2O and extracted with AcOEt. The combined extracts are dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; AcOEt:n-hexane=1:1) to give 2-{[4-(4-fluorobutoxy)-benzenesulfonyl]-4-methoxy-benzyl)-amino}-N-(1-ethoxy-1-methyl ethoxy) acetamide; NMR (CDCl3): 1.35 (s, 6H), 1.83–2.0 (m, 4H), 3.29 (s, 3H), 3.70 (s, 2H), 3.78 (s, 3H), 4.08–4.11 (m, 2H), 4.32 (s, 2H), 4.47–4.49 (m, 1H), 4.60 (br s, 1H), 6.80–6.90 (m, 2H), 6.95–7.05 (m, 2H), 7.10–7.25 (m, 2H), 7.79 (d, 2H, J=9.06 Hz), 8.46 (br s, 1H). After stirring for additional 2 h at r.t. extracted with AcOEt The combined extracts are dried over MgSO4 concentrated under reduced pressure The residue is purified by column chromatography on silica gel (eluent; AcOEt:n-hexane=1:1)

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

Procedure: The compound (239 mg) prepared in Example 2, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC; 192 mg), 1-hydroxybenzotriazole (HOBt; 135 mg), dimethylformamide (4 ml) and (1-methoxy-1-methylethyl)oxyamine (0.35 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water (twice), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate alone) to thereby obtain the title compound (289 mg) having the following physical properties. washed with water (twice), dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane

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

Procedure: To a dimethylformamide (5 ml) solution of the compound (208 mg) prepared in Example 2 and 2-aminooxy-2-methoxypropane (57.7 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg) and triethylamine (83 μl ) were added, followed by stirring at room temperature overnight. The reaction mixture was concentrated. The residue was diluted with methylene chloride. The diluted solution was washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to thereby obtain the title compound (239 mg) having the following physical data. The reaction mixture was concentrated The residue was diluted with methylene chloride The diluted solution was washed with 1N hydrochloric acid a saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order, dried with anhydrous sodium sulfate concentrated The residue was purified by silica gel column chromatography (chloroform:methanol=50:1)

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

Procedure: To a suspension of the compound prepared in Example 9(54) (120 mg) and (1-methoxyisopropyl)oxyamine (31 mg) in dimethylformamide (1.6 ml) was added diisopropylethylamine (68 μl), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.hydrochloride (56 mg) and 1-hydroxybenztriazole (40 mg). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was added 1N hydrochloric acid (2 ml) and stirred for 15 minutes at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride and the obtained residue was dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained residue in methanol was added 4N hydrogen chloride/ethyl acetate solution and concentrated. The obtained residue was washed with ethyl acetate to give the title compound (116 mg) having the following physical data. stirred for 15 minutes at room temperature extracted with ethyl acetate The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride the obtained residue was dried over anhydrous sodium sulfate concentrated To a solution of the obtained residue in methanol was added 4N hydrogen chloride/ethyl acetate solution concentrated The obtained residue was washed with ethyl acetate

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

Procedure: The compound (239 mg) prepared in Example 2, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC; 192 mg), 1-hydroxybenzotriazole (HOBt; 135 mg), dimethylformamide (4 ml) and (1-methoxy-1-methylethyl)oxyamine (0.35 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water (twice), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate alone) to thereby obtain the title compound (289 mg) having the following physical properties. washed with water (twice), dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane

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

Procedure: The compound (239 mg) prepared in Example 2, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC; 192 mg), 1-hydroxybenzotriazole (HOBt; 135 mg), dimethylformamide (4 ml) and (1-methoxy-1-methylethyl)oxyamine (0.35 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water (twice), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate alone) to thereby obtain the title compound (289 mg) having the following physical properties. washed with water (twice), dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane

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

Procedure: To a suspension of the compound prepared in Example 9(54) (120 mg) and (1-methoxyisopropyl)oxyamine (31 mg) in dimethylformamide (1.6 ml) was added diisopropylethylamine (68 μl), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.hydrochloride (56 mg) and 1-hydroxybenztriazole (40 mg). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was added 1N hydrochloric acid (2 ml) and stirred for 15 minutes at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride and the obtained residue was dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained residue in methanol was added 4N hydrogen chloride/ethyl acetate solution and concentrated. The obtained residue was washed with ethyl acetate to give the title compound (116 mg) having the following physical data. stirred for 15 minutes at room temperature extracted with ethyl acetate The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride the obtained residue was dried over anhydrous sodium sulfate concentrated To a solution of the obtained residue in methanol was added 4N hydrogen chloride/ethyl acetate solution concentrated The obtained residue was washed with ethyl acetate

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

Procedure: To a solution of 0.425 g (1 mmol) of desired ([4-(4-fluorobutoxy)-benzenesulfonyl]-(4-methoxy-benzyl)-amino)-acetic acid and 0.27 g (2 mmol) of HOBT in 4 ml of DMF, a solution of 0.116 g of O-(1-methoxy-1-methyl-ethyl)-hydroxylamine in 1 ml of DMF and 0.23 g of WSCD were successively added at 0-5° C. and the mixture was stirred for 1 h. After stirring for additional 2 h at r.t., the mixture is diluted with H2O and extracted with AcOEt. The combined extracts are dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; AcOEt:n-hexane=1:1) to give 2-([4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)amino)-N-(1-ethoxy-1-methyl ethoxy)acetamide; NMR (CDCl3): 1.35 (s, 6H), 1.83-2.0 (m, 4H), 3.29 (s, 3H), 3.70 (s, 2H), 3.78 (s, 3H), 4.08-4.11 (m, 2H), 4.32 (s, 2H), 4.47-4.49 (m, 1H), 4.60 (br s, 1H), 6.80-6.90 (m, 2H), 6.95-7.05 (m, 2H), 7.10-7.25 (m, 2H), 7.79 (d, 2H, J=9.06 Hz), 8.46 (br s, 1H). After stirring for additional 2 h at r.t. extracted with AcOEt The combined extracts are dried over MgSO4 concentrated under reduced pressure The residue is purified by column chromatography on silica gel (eluent; AcOEt:n-hexane=1:1)

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

Procedure: Ethyl chloroformate (1.26 mmol, 0.12 mL) and triethylamine (1.37 mmol, 0.19 mL) were added to a cooled (0° C.) solution of 3-[4-(2,3-Diphenylpropionylamino)phenyl]-2-propenoic acid (1.05 mmol, 0.39 g) in dry THF (10 mL), and the mixture was stirred for 10 min. The solid was filtered off, and O-(2-methoxy-2-propyl)hydroxylamine (3.15 mmol, 0.23 mL) was added to the filtrate. The solution was stirred for 15 min at 0° C., then was evaporated under reduced pressure, and the residue was diluted in methanol (10 mL). Amberlyst® 15 ion-exchange resin (105 mg) was added to the solution of the O-protected hydroxamate, and the mixture was stirred at room temperature for 1 h. After, the reaction was filtered and the filtrate was concentrated in vacuo to give the crude MC1895 which was purified by crystallization. 1H NMR (DMSO-d6) δ 3.05 (m, 1H, PhCH2), δ 3.60 (m, 1H, PhCH2), δ 3.75 (m, 1H, PhCHCO), δ 6.36 (d, 1H, PhCH═CHCOOEt), δ 7.15-7.70 (m, 15H, benzene protons and PhCH═CHCOOEt), δ 9.00 (s, 1H, OH), δ 10.23 (s, 1H, CONHPh), δ 10.85 (s, 1H, NHOH). Anal. C, H, N, O. The solid was filtered off The solution was stirred for 15 min at 0° C. was evaporated under reduced pressure the residue was diluted in methanol (10 mL) Amberlyst® 15 ion-exchange resin (105 mg) was added to the solution of the O-protected hydroxamate the mixture was stirred at room temperature for 1 h After, the reaction was filtered the filtrate was concentrated in vacuo