2-hydroxypropanenitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:51.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Anhydrous magnesium sulfate (12.04 g, 0.1 mol) was added to diisopropylamine (12.14 g, 0.12 mol), followed by lactonitrile (7.73 g of 92% aqueous solution, 0.1 mol) added all at once with stirring. The reaction mixture spontaneously warmed up to 51° C. It was left overnight at room temperature. Diethyl ether (50 ml) was added, and magnesium sulfate was filtered off and washed with ether (50 ml). The product was isolated by distillation, 11.57 g, 75% yield, bp 49°-50° C./0.1 mm Hg. 1H NMR CDCl3 δ ppm, 1.02 (d, J=6.5 Hz, 6H, CH3), 1.17 (d, J=6.5 Hz, 6H, CH3), 1.41 (d, J=6.5 Hz, 3H, CH3, 3.21 (sep, J=6.5 Hz, 2H,=CH) , 3.89 (q, J=6.5 Hz, 1H, CH) . added all at once magnesium sulfate was filtered off washed with ether (50 ml) The product was isolated by distillation, 11.57 g, 75% yield, bp 49°-50° C./0.1 mm Hg

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

Procedure: To a stirred solution of 2-(benzo[1,3]dioxol-5-yloxy)-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamide (5 g, 13.1 mmol), (+/−)-lactonitrile (0.93 g, 13.1 mmol) and triphenylphosphine (3.78 g, 14.4 mmol) in tetrahydrofuran (200 mL) at room temperature, diethyl azodicarboxylate (2.3 mL, 14.4 mmol) was added dropwise with stirring. The mixture was stirred at room temperature overnight. Solvents were stripped in vacuo, diluted with ethyl acetate and washed with dilute aqueous sodium hydroxide, brine, and dried (MgSO4). Solvents were stripped in vacuo. The resulting oil was washed with diethyl ether and the precipitate was filtered off. The mother liquor was purified by flash column chromatography (35% ethyl acetate/hexane), affording 1.5 g white solid (26% yield). The mixture was stirred at room temperature overnight washed with dilute aqueous sodium hydroxide, brine dried (MgSO4) The resulting oil was washed with diethyl ether the precipitate was filtered off The mother liquor was purified by flash column chromatography (35% ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 3.7 grams (0.052 mole) of 2-hydroxypropionitrile in 8.9 grams (0.10 mole) of pyridine was prepared. To this stirred solution at ambient temperature was added 10.4 grams (0.05 mole) of 2,6-dichlorobenzoyl chloride dropwise during a 20 minute period. The exothermic reaction caused the temperature of the reaction mixture to rise to 50°. The reaction mixture was heated at 75°-80° for 75 minutes. The cooled reaction mixture was poured into 150 ml of water and the mixture was stirred. The mixture was extracted with 200 ml of diethyl ether. The extract was washed with three portions of 30 ml each of an aqueous solution of 3% hydrochloric acid, then three portions of 30 ml each of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to an amber oil. The oil solidified and the solid was recrystallized from hexane-diethyl ether to give an oily semi-solid. The semi-solid and mother liquor were combined and concentrated under reduced pressure to an oil. An attempt to sublime the oil failed. The oil was distilled under reduced pressure using a short-path distilling system to give 3.1 grams of 2-cyanoethyl 2,6-dichlorobenzoate; bp 117°/0.005 mm. The oil product solidified; mp 45°-46° C. The nmr and the ir spectra were consistent with the proposed structure. The exothermic reaction to rise to 50° The reaction mixture was heated at 75°-80° for 75 minutes The cooled reaction mixture The mixture was extracted with 200 ml of diethyl ether The extract was washed with three portions of 30 ml each of an aqueous solution of 3% hydrochloric acid The organic layer was dried with sodium sulfate filtered The filtrate was concentrated under reduced pressure to an amber oil the solid was recrystallized from hexane-diethyl ether to give an oily semi-solid concentrated under reduced pressure to an oil The oil was distilled under reduced pressure

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

Procedure: A solution of lactonitrile (378 g, 5.32 mol) in ethyl ether (1.46 L) and ethanol (0.34 L) was saturated with hydrogen chloride gas at 0-5° C. for 0.5 h and kept at 5° C. for 60 h. The resulting precipitate was filtered off and washed twice with ethyl ether to give the title compound of Preparation Twelve, Step A as a solid, 815 g (99%). mp: 165-168° C.; 1H NMR (CD3OD, 250 MHz) δ 1.45-1.53 (c, 6H), 4.40-4.61 (c, 3H). The resulting precipitate was filtered off washed twice with ethyl ether to give

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

Procedure: A solution of lactonitrile (378 g, 5.32 mol) in ethyl ether (1.46 L) and ethanol (0.34 L) was saturated with hydrogen chloride gas at 0-5° C. for 0.5 h and kept at 5° C. for 60 h. The resulting precipitate was filtered off and washed twice with ethyl ether to give the title compound of Preparation Twelve, Step A as a solid, 815 g (99%). mp: 165-168° C.; 1H NMR (CD3OD, 250 MHz) δ 1.45-1.53 (c, 6H), 4.40-4.61 (c, 3H). The resulting precipitate was filtered off washed twice with ethyl ether to give

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 138.5 g (1.95 moles) of acetaldehyde cyanohydrin were added dropwise to a solution of 176 g (2 moles) of 2,3-diaminobutane in 250 ml of water, with cooling at 25° C. The mixture was then heated at the boil for 8 hours, until no more ammonia was split off. The reaction mixture was then distilled under reduced pressure to give 200 g (72% of theory) of 2,5,6-trimethyl-3-oxo-piperazine of boiling point 123° C./0.5 mbar. was split off The reaction mixture was then distilled under reduced pressure

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

Procedure: Lactonitrile (71.08 g.) is added in a dropwise manner to a stirred solution of 100.1 g. of 1-methyl-piperazine in 500 ml. of benzene. The resulting warm solution is heated at reflux under a water separator until the theoretical amount of water is collected (about 4 hours). The solution is evaporated at reduced pressure and the residue is fractionated. The product, 2-(4-methyl-1-piperazinyl)propionitrile, is obtained as an oil, b.p. 128°-130° C./23 mm. The resulting warm solution is heated is collected (about 4 hours) The solution is evaporated at reduced pressure

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

Procedure: Lactonitrile (71.08 g.) is added in a dropwise manner to a stirred solution of 100.1 g. of 1-methyl-piperazine in 500 ml. of benzene. The resulting warm solution is heated at reflux under a water separator until the theoretical amount of water is collected (about 4 hours). The solution is evaporated at reduced pressure and the residue is fractionated. The product, 2-(4-methyl-1-piperazinyl)propionitrile, is obtained as an oil, b.p. 128°-130° C./23 mm. The resulting warm solution is heated is collected (about 4 hours) The solution is evaporated at reduced pressure

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

Procedure: A solution of lactonitrile (378 g, 5.32 mol) in ethyl ether (1.46 L) and ethanol (0.34 L) was saturated with hydrogen chloride gas at 0-5° C. for 0.5 h and kept at 5° C. for 60 h. The resulting precipitate was filtered off and washed twice with ethyl ether to give the title compound of Preparation Twelve, Step A as a solid, 815 g (99%). mp: 165-168° C.; 1H NMR (CD3OD, 250 MHz) δ 1.45-1.53 (c, 6H), 4.40-4.61 (c, 3H). The resulting precipitate was filtered off washed twice with ethyl ether to give

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Hydroxypropanenitrile (26-1) (5.0 g, 70 mmol, 1 eq) in toluene (60 mL) was added dropwise to a stirring solution of oxalyl chloride (24.6 mL, 281 mmol, 4 eq) in toluene (165 mL) at 0° C. After 30 minutes, the reaction mixture was heated to 90° C. and triethylamine hydrochloride (4.8 g, 35.2 mmol, 0.5 eq) was added. The mixture stirred for 4 hours at the same temperature and then was concentrated in vacuo at 60° C. The resulting mixture was suspended in Et2O (300 mL), filtered washing with Et2O (3×100 mL), and the filtrates were combined and concentrated. Purification by flash chromatography (330 g SiO2, 0-50% EtOAc in hexanes) afforded 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one (26-2) as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H). was concentrated in vacuo at 60° C filtered washing with Et2O (3×100 mL) concentrated Purification by flash chromatography (330 g SiO2, 0-50% EtOAc in hexanes)