5-methoxy-4,4-dimethyl-3-oxopentanenitrile

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1.68 g (10.8 mmol) of 5-methoxy-4,4-dimethyl-3-oxo-pentanenitrile and 0.49 g (11.9 mmol) of sodium hydroxide in water (13 mL) is added a solution of 0.98 g (5.9 mmol) of hydroxylamine sulfate in water (4 mL). The reaction mixture is heated to 100° C. for 1.5 h. After this time, the reaction mixture is cooled to room temperature and 0.8 mL (9.7 mmol) of 37% aqueous HCl solution is added. The reaction is heated to 100° C. for 0.5 h. After cooling, the pH of the reaction mixture is adjusted to pH˜12 by addition of 1M aqueous NaOH solution and extracted with DCM (3×20 L). The organic layers are combined and washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residual brown oil is purified by column chromatography (Biotage, eluent DCM, MeOH) to yield 0.94 g of 5-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-3-ylamine as a yellow oil. Yield 51%; m/z 171 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (6H, 2), 3.22 (3H, s), 3.26 (2H, s), 5.40 (2H, m) 5.53 (1H, s). After this time, the reaction mixture is cooled to room temperature The reaction is heated to 100° C. for 0.5 h After cooling extracted with DCM (3×20 L) washed with brine (20 mL) dried over Na2SO4 filtered The filtrate is concentrated under reduced pressure The residual brown oil is purified by column chromatography (Biotage, eluent DCM, MeOH)

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

Procedure: A solution of 1.74 g (12 mmol) of 3-methoxy-2,2-dimethyl-propionic acid methyl ester and 0.9 mL (17 mmol) of acetonitrile in toluene (5 mL) is added dropwise to the refluxing suspension of 0.67 g (17 mmol) of sodium hydride (60% in mineral oil) in toluene (5 mL). After the addition, the reaction mixture is stirred at reflux for 3 h. After this time, the reaction mixture is cooled to room temperature and neutralized to pH˜6-7 by adding 1M aqueous HCl solution. The aqueous layer is extracted with ethyl acetate (3×20 mL). The organic layers are combined, washed with brine (1.5 L), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield 1.69 g of 5-methoxy-4,4-dimethyl-3-oxo-pentanenitrile as a brown oil, which is used in the next step without further purification. Yield: 91%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (6H, s), 3.2 (3H, s), 3.3 (sH, s), 4.2 (2H, s). After the addition at reflux for 3 h The aqueous layer is extracted with ethyl acetate (3×20 mL) washed with brine (1.5 L) dried over Na2SO4 filtered The filtrate is concentrated under reduced pressure

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

Procedure: A solution of hydroxylamine sulfate (976 mg; 5.947 mmol) in water (4 mL) is added to a stirred solution of 5-methoxy-4,4-dimethyl-3-oxo-pentanenitrile (1.678 g; 10.812 mmol) and sodium hydroxide (490.3 mg; 11.89 mmol) in water (13 mL). The reaction mixture is heated to reflux over 30 minutes and kept at reflux for 1 hour. After cooling, 37% HCl aqueous solution (0.8 mL; 9.73 mmol) is added and the mixture is heated to reflux for 20 minutes. After cooling, the mixture's pH is adjusted to ˜12 by adding 40% sodium hydroxide aqueous solution. The mixture is extracted with methylene chloride 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound, m/z 171 [M+H+]. The reaction mixture is heated to reflux over 30 minutes at reflux for 1 hour After cooling the mixture is heated to reflux for 20 minutes After cooling The mixture is extracted with methylene chloride 3 times washed with brine dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: 60% sodium hydride in mineral oil (667.2 mg, 16.68 mmol) in toluene (15 mL) is heated to reflux. A solution of 3-methoxy-2,2-dimethyl-propionic acid methyl ester (1.742 g, 11.916 mmol) and acetonitrile (0.878 mL, 16.68 mmol) in toluene (5 mL) is added dropwise through an additional funnel into the NaH suspension in toluene. After the addition, the reaction is stirred at reflux for 3 hours. After cooling, the reaction mixture is neutralized to PH˜7 by adding 1N HCl aqueous solution. The mixture is extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound. After the addition at reflux for 3 hours After cooling The mixture is extracted with ethyl acetate 3 times washed with brine dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: To a mixture of 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 6.5 mmol) in ethanol (100 mL), was added 96% sodium hydroxide (308 mg, 7.70 mmol). To this was added a solution of hydroxylamine hydrochloride (537 mg, 7.70 mmol) in water (100 mL). The resulting solution (pH 7.8) was stirred at 60° C. for 22 h, then cooled to room temperature. To this was added concentrated hydrochloric acid (3 mL, 36 mmol) and the mixture refluxed (80° C.) for 1 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and the residue was mixed with 30% sodium hydroxide (2.1 g). The mixture was shaken with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. Purification via silica gel chromatography afforded 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine as a colorless solid (350 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 5.60 (s, 1H), 3.39 (s, 2H), 3.32 (s, 3H), 2.94 (brs, 2H), 1.28 (s, 6H); LC-MS (ESI) m/z 171 (M+H)+. the mixture refluxed (80° C.) for 1 h The reaction mixture was concentrated under reduced pressure to remove ethanol the residue was mixed with 30% sodium hydroxide (2.1 g) The chloroform layer was washed with water dried over anhydrous sodium sulfate concentrated under reduced pressure to give an oil Purification via silica gel chromatography

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

Procedure: Prepared from 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (500 mg, 3.22 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-amine as a orange oil (380 mg, 69%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.08 (s, 1H), 4.41 (brs, 2H), 3.39 (s, 2H), 3.35 (s, 3H), 1.28 (s, 6H).

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

Procedure: Prepared from 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (500 mg, 3.22 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-amine as a orange oil (380 mg, 69%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.08 (s, 1H), 4.41 (brs, 2H), 3.39 (s, 2H), 3.35 (s, 3H), 1.28 (s, 6H).

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

Procedure: Prepared from methyl 3-methoxy-2,2-dimethylpropanoate (8 g, 54.7 mmol) according to the method described in Example 122A Step 1 for 4-methyl-3-oxopentanenitrile. Purification via silica gel chromatography eluting with mixtures of petroleum ether and ethyl acetate afforded 5-methoxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (2.5 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.72 (s, 2H), 3.32-3.33 (m, 5H), 1.18 (s, 6H). Purification via silica gel chromatography eluting with mixtures of petroleum ether and ethyl acetate

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

Procedure: To a mixture of 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 6.5 mmol) in ethanol (100 mL), was added 96% sodium hydroxide (308 mg, 7.70 mmol). To this was added a solution of hydroxylamine hydrochloride (537 mg, 7.70 mmol) in water (100 mL). The resulting solution (pH 7.8) was stirred at 60° C. for 22 h, then cooled to room temperature. To this was added concentrated hydrochloric acid (3 mL, 36 mmol) and the mixture refluxed (80° C.) for 1 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and the residue was mixed with 30% sodium hydroxide (2.1 g). The mixture was shaken with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. Purification via silica gel chromatography afforded 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine as a colorless solid (350 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 5.60 (s, 1H), 3.39 (s, 2H), 3.32 (s, 3H), 2.94 (brs, 2H), 1.28 (s, 6H); LC-MS (ESI) m/z 171 (M+H)+. the mixture refluxed (80° C.) for 1 h The reaction mixture was concentrated under reduced pressure to remove ethanol the residue was mixed with 30% sodium hydroxide (2.1 g) The chloroform layer was washed with water dried over anhydrous sodium sulfate concentrated under reduced pressure to give an oil Purification via silica gel chromatography

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

Procedure: Prepared from 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (500 mg, 3.22 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-amine as a orange oil (380 mg, 69%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.08 (s, 1H), 4.41 (brs, 2H), 3.39 (s, 2H), 3.35 (s, 3H), 1.28 (s, 6H).

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

Procedure: Prepared from methyl 3-methoxy-2,2-dimethylpropanoate (8 g, 54.7 mmol) according to the method described in Example 122A Step 1 for 4-methyl-3-oxopentanenitrile. Purification via silica gel chromatography eluting with mixtures of petroleum ether and ethyl acetate afforded 5-methoxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (2.5 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.72 (s, 2H), 3.32-3.33 (m, 5H), 1.18 (s, 6H). Purification via silica gel chromatography eluting with mixtures of petroleum ether and ethyl acetate

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

Procedure: Prepared from methyl 3-methoxy-2,2-dimethylpropanoate (8 g, 54.7 mmol) according to the method described in Example 122A Step 1 for 4-methyl-3-oxopentanenitrile. Purification via silica gel chromatography eluting with mixtures of petroleum ether and ethyl acetate afforded 5-methoxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (2.5 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.72 (s, 2H), 3.32-3.33 (m, 5H), 1.18 (s, 6H). Purification via silica gel chromatography eluting with mixtures of petroleum ether and ethyl acetate