O-prop-2-ynylhydroxylamine;hydrochloride

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

Procedure: 1,3-diaminoacetone dihydrochloride monohydrate (1.10 g, 6.14 mmol) was dissolved in refluxing methanol and O-(2-propynyl)hydroxylamine hydrochloride (0.730 g, 6.75 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture and heated to reflux. After 24 hours the solvent was removed in vacuo. Crystallization from methanol/ethyl acetate afforded 410 mg (36%) of light-brown material. Mp. 205.0° C. was added After refluxing for 48 hours the solvent was evaporated The crude product was dissolved in methanol an excess of trimethylorthoformate was added to the reaction mixture heated to reflux After 24 hours the solvent was removed in vacuo Crystallization from methanol/ethyl acetate

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

Procedure: 1,3-diaminoacetone dihydrochloride monohydrate (1.10 g, 6.14 mmol) was dissolved in refluxing methanol and O-(2-propynyl)hydroxylamine hydrochloride (0.730 g, 6.75 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture and heated to reflux. After 24 hours the solvent was removed in vacuo. Crystallization from methanol/ethyl acetate afforded 410 mg (36%) of light-brown material. Mp. 205.0° C. was added After refluxing for 48 hours the solvent was evaporated The crude product was dissolved in methanol an excess of trimethylorthoformate was added to the reaction mixture heated to reflux After 24 hours the solvent was removed in vacuo Crystallization from methanol/ethyl acetate

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

Procedure: 1.8 g of 3-acetyl quinuclidine hydrochloride and 1.02 g of O-2-propynyl-hydroxylamine hydrochloride are heated for 20 minutes to reflux in 30 cm3 of methanol. After evaporating to dryness, the residue is chromatographed on silica (eluant: methanol-ethyl ether). An aqueous solution of potassium carbonate is added and extraction is carried out with ethyl acetate. The extracts are dried and distilled at 170° C. under 0.2 mbar. After cooling, 1.1 g of expected product is obtained. M.p.=56°-58° C. After evaporating to dryness the residue is chromatographed on silica (eluant: methanol-ethyl ether) An aqueous solution of potassium carbonate is added extraction The extracts are dried distilled at 170° C. under 0.2 mbar After cooling

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

Procedure: The operation is carried out as in Example 1 using 1.75 g of 3-methoxy methylidene quinuclidine, 3.8 cm3 of perchloric acid and 1.22 g of O-2-propynylhydroxylamine hydrochloride (U.S. Pat. No. 3,398,180 (1968)). After the ethyl ether has been evaporated off, the residue is chromatographed on silica (eluant: chloroform-methanol 7-3) then distilled at 190° C. under 0.05 mbar and 1.35 g of expected product is obtained. After the ethyl ether has been evaporated off the residue is chromatographed on silica (eluant: chloroform-methanol 7-3) then distilled at 190° C. under 0.05 mbar

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

Procedure: 1.8 g of 3-acetyl quinuclidine hydrochloride and 1.02 g of O-2-propynyl-hydroxylamine hydrochloride are heated for 20 minutes to reflux in 30 cm3 of methanol. After evaporating to dryness, the residue is chromatographed on silica (eluant: methanol-ethyl ether). An aqueous solution of potassium carbonate is added and extraction is carried out with ethyl acetate. The extracts are dried and distilled at 170° C. under 0.2 mbar. After cooling, 1.1 g of expected product is obtained. M.p.=56°-58° C. After evaporating to dryness the residue is chromatographed on silica (eluant: methanol-ethyl ether) An aqueous solution of potassium carbonate is added extraction The extracts are dried distilled at 170° C. under 0.2 mbar After cooling

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

Procedure: The operation is carried out as in Example 1 using 1.75 g of 3-methoxy methylidene quinuclidine, 3.8 cm3 of perchloric acid and 1.22 g of O-2-propynylhydroxylamine hydrochloride (U.S. Pat. No. 3,398,180 (1968)). After the ethyl ether has been evaporated off, the residue is chromatographed on silica (eluant: chloroform-methanol 7-3) then distilled at 190° C. under 0.05 mbar and 1.35 g of expected product is obtained. After the ethyl ether has been evaporated off the residue is chromatographed on silica (eluant: chloroform-methanol 7-3) then distilled at 190° C. under 0.05 mbar

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (500 mg, 2.281 mmol) in ethanol (6.912 mL) was added O-(prop-2-ynyl)hydroxylamine hydrochloride (368 mg, 3.42 mmol) and HCl 4N in dioxane (1.711 mL, 6.84 mmol). The mixture was stirred at 50° C. for 2 hours and then concentrated in vacuo. Saturated sodium bicarbonate was added, extracted with ethyl acetate twice, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (60-100% ethyl acetate/heptane, and then 5% MeOH/ethyl acetate) giving (E)-4-(4-(1-(prop-2-ynyloxyimino)ethyl)phenyl)-1,2,4-triazolidine-3,5-dione (I-6a: 46 mg, 7%) as a white solid. LC-MS (M+1) 273.1, t=0.81 minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H) 3.48 (t, J=2.40 Hz, 1 H) 4.80 (d, J=2.27 Hz, 2 H) 7.53 (d, J=8.59 Hz, 2 H) 7.76 (d, J=8.59 Hz, 2 H) 10.52 (s, 2 H). concentrated in vacuo Saturated sodium bicarbonate was added extracted with ethyl acetate twice dried over MgSO4 filtered concentrated in vacuo The residue was purified by silica gel chromatography (60-100% ethyl acetate/heptane

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

Procedure: 1,3-diaminoacetone dihydrochloride monohydrate (1.10 g, 6.14 mmol) was dissolved in refluxing methanol and O-(2-propynyl)hydroxylamine hydrochloride (0.730 g, 6.75 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture and heated to reflux. After 24 hours the solvent was removed in vacuo. Crystallization from methanol/ethyl acetate afforded 410 mg (36%) of light-brown material. Mp. 205.0° C. was added After refluxing for 48 hours the solvent was evaporated The crude product was dissolved in methanol an excess of trimethylorthoformate was added to the reaction mixture heated to reflux After 24 hours the solvent was removed in vacuo Crystallization from methanol/ethyl acetate