5-hydroxy-4,4-dimethyl-3-oxopentanenitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile from Step B (1 g, 7.09 mmol), sodium hydroxide (378 mg, 9.45 mmol), and hydroxylamine hydrochloride (656 mg, 9.43 mmol) in a mixture of ethanol (100 mL) and water (100 mL), was heated at 60° C. for 22 h. After cooling to rt, concentrated HCl (1 g) was added and stirred at 50° C. for 2 h followed by 80° C. for a further 1 h. After concentration under reduced pressure, the mixture was treated with 30% sodium hydroxide solution and extracted with chloroform (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4, and filtered. Concentrated under reduced pressure, followed by purification via recrystallisation from diethyl ether, afforded 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol as a colorless solid (600 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 3.65 (s, 2H), 2.30 (brs, 2H), 1.31 (s, 6H); LC-MS (ESI) m/z 156 (M+H)+. After cooling to rt followed by 80° C. for a further 1 h After concentration under reduced pressure the mixture was treated with 30% sodium hydroxide solution extracted with chloroform (3×100 mL) The combined organic layers were washed with water (100 mL), brine (100 mL) dried over Na2SO4 filtered Concentrated under reduced pressure followed by purification via recrystallisation from diethyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a refluxing suspension of sodium hydride (1.40 g of a 60% suspension in mineral oil, 35 mmol) in anhydrous toluene (45 mL), was added dropwise (over 1 h) a mixture of methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (6.0 g, 24.39 mmol) from Step A and acetonitrile (1.80 mL, 35 mmol). After refluxing for a further 5 h, the mixture was cooled to rt and the pH was adjusted to 4 with aqueous HCl solution. The mixture was extracted with ethyl acetate (3×200 mL) and the combined organic layers washed with brine (2×200 mL), separated, dried over Na2SO4, and filtered. Concentration under reduced pressure, followed by Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether, afforded 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (1 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.76 (s, 2H), 3.61 (s, 2H), 1.19 (s, 6H). was added dropwise (over 1 h) After refluxing for a further 5 h The mixture was extracted with ethyl acetate (3×200 mL) the combined organic layers washed with brine (2×200 mL) separated dried over Na2SO4 filtered Concentration under reduced pressure followed by Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a refluxing suspension of sodium hydride (1.40 g of a 60% suspension in mineral oil, 35 mmol) in anhydrous toluene (45 mL), was added dropwise (over 1 h) a mixture of methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (6.0 g, 24.39 mmol) from Step A and acetonitrile (1.80 mL, 35 mmol). After refluxing for a further 5 h, the mixture was cooled to rt and the pH was adjusted to 4 with aqueous HCl solution. The mixture was extracted with ethyl acetate (3×200 mL) and the combined organic layers washed with brine (2×200 mL), separated, dried over Na2SO4, and filtered. Concentration under reduced pressure, followed by Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether, afforded 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (1 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.76 (s, 2H), 3.61 (s, 2H), 1.19 (s, 6H). was added dropwise (over 1 h) After refluxing for a further 5 h The mixture was extracted with ethyl acetate (3×200 mL) the combined organic layers washed with brine (2×200 mL) separated dried over Na2SO4 filtered Concentration under reduced pressure followed by Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared from 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 7.90 mmol) according to the method described for 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine. Purification via recrystallisation from diethyl ether afforded 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol as a colorless solid (600 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 3.65 (s, 2H), 2.30 (brs, 2H), 1.31 (s, 6H). Purification via recrystallisation from diethyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared from 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 7.90 mmol) according to the method described for 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine. Purification via recrystallisation from diethyl ether afforded 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol as a colorless solid (600 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 3.65 (s, 2H), 2.30 (brs, 2H), 1.31 (s, 6H). Purification via recrystallisation from diethyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared from methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (6 g, 24.39 mmol) according to the method described for 4-methyl-3-oxopentanenitrile Example XA Step 1. Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether afforded 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (1 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.76 (s, 2H), 3.61 (s, 2H), 1.19 (s, 6H). Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared from 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 7.90 mmol) according to the method described for 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine. Purification via recrystallisation from diethyl ether afforded 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol as a colorless solid (600 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 3.65 (s, 2H), 2.30 (brs, 2H), 1.31 (s, 6H). Purification via recrystallisation from diethyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared from methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (6 g, 24.39 mmol) according to the method described for 4-methyl-3-oxopentanenitrile Example XA Step 1. Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether afforded 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (1 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.76 (s, 2H), 3.61 (s, 2H), 1.19 (s, 6H). Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared from methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (6 g, 24.39 mmol) according to the method described for 4-methyl-3-oxopentanenitrile Example XA Step 1. Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether afforded 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (1 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.76 (s, 2H), 3.61 (s, 2H), 1.19 (s, 6H). Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 9.22 g of 3-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionic acid methyl ester and acetonitrile (2.34 mL, 44.88 mmol) in toluene (25 mL) is added dropwise over 1 h at reflux to a suspension of 1.80 g (44.88 mmol) NaH (60% dispersion in mineral oil) in anhydrous toluene (50 mL). The reaction mixture is heated to 110° C. for 18 h. The reaction mixture is diluted with 1M aqueous HCl solution to pH 7 and extracted with ethyl acetate (3×200 mL). The organic layers are combined, washed with water and brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 4.79 g of 5-hydroxy-4,4-dimethyl-3-oxo-pentanenitrile as a dark biphasic oil which is used crude in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (s, 6H), 3.55 (s, 2H), 3.61 (s, 2H). Spectrum recorded on crude material, signals of TBMDS are present. extracted with ethyl acetate (3×200 mL) washed with water and brine dried over Na2SO4 filtered The filtrate is concentrated under reduced pressure