ethyl (2E)-2-chloro-2-hydroxyiminoacetate

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

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

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

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-t-butyl-5-(4-ethynylphenyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (1.51 g, 3.9 mmol), ethyl 2-chloro-2-hydroxyiminoacetate (1.19 g, 7.8 mmol) and THF (4 mL), triethylamine (1.09 mL, 7.8 mmol) in THF (3 mL) was added dropwise under ice-cooling conditions, and the mixture was stirred at 0° C. for 4 hr. Ethyl 2-chloro-2-hydroxyiminoacetate (1.19 g, 7.8 mmol) was added, and further triethylamine (0.81 mL, 5.9 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at 0° C. for 2 hr and left stand overnight. The precipitate was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 3-t-butyl-5-[4-(3-ethoxycarbonyl-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]-pyrazol-6-one (1.26 g, 64%) as a colorless solid. was added dropwise under ice- cooling conditions The mixture was stirred at 0° C. for 2 hr left stand overnight The precipitate was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane)

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

Procedure: Ethyl chlorohydroxyiminoacetate (ECHA) can be produced from glycine ethyl ester hydrochloride by the in-situ generation of nitrosyl chloride gas from aqueous sodium nitrite and HCl. In particular, Glycine ethyl ester.HCl is dissolved in water. To this is added concentrated HCl solution (32%) and the reaction mixture is cooled to <10° C. HCl gas is then bubbled into the reaction mixture. An aqueous solution of sodium nitrite is dosed into the reactor while maintaining the temperature at <10° C. HCl gas is bubbled into the reactor again followed by a second portion of aqueous sodium nitrite. Finally, the product is purified from the reaction mixture by any appropriate means known to those of skill in the art. For example, the reaction mixture is stirred for a further period and then extracted with a water immiscible solvent (dichloroethane, chloroform, carbon tetrachloride) at room temperature to remove the product from the reaction mixture. The organic extracts are dried with a drying agent and the solvent is flashed off. An oily residue remains, which crystallizes on cooling. The crystals are filtered and washed with a suitable solvent to obtain a purified ECHA. the reaction mixture is cooled to <10° C HCl gas is then bubbled into the reaction mixture while maintaining the temperature at <10° C HCl gas is bubbled into the reactor Finally, the product is purified from the reaction mixture by any appropriate means extracted with a water immiscible solvent (dichloroethane, chloroform, carbon tetrachloride) at room temperature to remove the product from the reaction mixture The organic extracts are dried with a drying agent which crystallizes on cooling The crystals are filtered washed with a suitable solvent

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

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

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

Procedure: 69.8 g of glycine ethyl ester hydrochloride are initially introduced into 120 ml of water and 41 ml of concentrated hydrochloric acid. 38 g of NaNO2 in 60 ml of water are then added dropwise at -10° C. in the course of 1 hour. After half an hour, a further 42.5 ml of concentrated hydrochloric acid are added, and then, in the course of 1 hour, a further 38 g of NaNO2 in 60 ml of water. Stirring is continued for 1 hour at -10° C. The mixture is subsequently extracted with ether, and the ether phase is washed several times with water. The ether is distilled off, and the crystals are dried. In this way, 38 g (50% of theory) of ethyl 2-chloro-2-hydroximinoacetate of a melting point of 81°-82° C. are obtained. After half an hour in the course of 1 hour The mixture is subsequently extracted with ether the ether phase is washed several times with water The ether is distilled off the crystals are dried

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

Procedure: A solution of 2-chloro-2-hydroxyiminoacetic acid ethyl ester (2.2 g, 14.6 mmol) in DCM (20 ml) was slowly added dropwise at 0° C. to a solution of 1-tert-butyl-4-methylenecyclohexane (740 mg, 4.86 mmol) in DCM (20 ml). Subsequently, a solution of triethylamine (1.5 ml) in DCM (10 ml) was slowly added dropwise at 0° C. and the resulting mixture was stirred overnight at RT. The reaction mixture was diluted with water. The aqueous phase was extracted several times with DMC. The combined organic phases were dried and the solvent was removed under vacuum. After purification of the residue (silica gel, hexane/ether 2:1) by column chromatography, the desired product 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid ethyl ester was obtained as a yellowish liquid (1.21 g, 93% of the theoretical amount). The aqueous phase was extracted several times with DMC The combined organic phases were dried the solvent was removed under vacuum After purification of the residue (silica gel, hexane/ether 2:1) by column chromatography

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

Procedure: A solution of 2-chloro-2-hydroxyiminoacetic acid ethyl ester (2.2 g, 14.6 mmol) in DCM (20 ml) was slowly added dropwise at 0° C. to a solution of 1-tert-butyl-4-methylenecyclohexane (740 mg, 4.86 mmol) in DCM (20 ml). Subsequently, a solution of triethylamine (1.5 ml) in DCM (10 ml) was slowly added dropwise at 0° C. and the resulting mixture was stirred overnight at RT. The reaction mixture was diluted with water. The aqueous phase was extracted several times with DMC. The combined organic phases were dried and the solvent was removed under vacuum. After purification of the residue (silica gel, hexane/ether 2:1) by column chromatography, the desired product 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid ethyl ester was obtained as a yellowish liquid (1.21 g, 93% of the theoretical amount). The aqueous phase was extracted several times with DMC The combined organic phases were dried the solvent was removed under vacuum After purification of the residue (silica gel, hexane/ether 2:1) by column chromatography