Ethyl 2-chloro-2-(hydroxyimino)acetate

off-white solid

A mixture of solution of amino-acetic acid ethyl ester (5 g, 48.53 mmol) in water (5 ml) and cone. HCl (8 ml), NaNO26 g of glycine ethyl ester hydrochloride, 40 g of water, 25 g of hydrochloric acid, dissolved and cooled to -5 ° C, sodium nitrite solution (13.2 g + 23 g of water) was added dropwise, and the reaction was completed for 1 hour. It was extracted with 40 ml of dichloromethane, dried over anhydrous MgSO 4 and evaporated to dryness to afford ethyl 2-chloro-2-(hydroxyimino)acetate(3) 20 g.(2) In 1 L round bottom flask equipped with stir bar added amino-acetic acid ethyl ester hydrochloride (20 g, 143 mmol) and water (30 ml). The solution was cooled down to [0°C] followed by sequential addition of concentrated hydrochloric acid (11.8 ml, 143 mmol) and dropwise addition of sodium nitrite (9. [89] g, 143 mmol) solution in water (15 ml). After 10 min added another equivalent each of concentrated hydrochloric acid and sodium nitrite solution in water. The reaction mixture was left stirring at [0°C] for 1 h. Reaction mixture was extracted with ether [(4X100] ml). Combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo to isolate a lemon yellow solid. The solid was recrystallized from hexanes to isolate a white solid (11 g, 51percent). 1H-NMR [(CDC13), ] d (ppm): 9.98 (bs, 1H), 4.40 (q, 2H), 1. 38 (t, 3H).5-5chloro-2-fluorophenyl)isoxazole-3-carbaldehyde; (i) ethyl chloro(hydroxyimino)acetate; Concentrated hydrochloric acid (5.9 ml, 71.65 mmol) was added in a drop-wise manner to a solution of glycine ethyl ester hydrochloride (10 g, 71.65 mmol) in water (15 ml) at 0° C. Sodium nitrite (4.94 g, 71.65 mmol) in water (7.5 ml) was then added in a drop-wise manner to the resulting mixture, keeping the temperature below 5° C. After 10 min., the second equivalent of hydrochloric acid (5.9 ml, 71.65 mmol) as added drop-wise, followed by sodium nitrite (4.94 g, 71.65 mmol) in water (7.5 ml), again keeping the temperature below 5° C. The reaction mixture was stirred at 0° C. for 45 min., and then washed with ether. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield a yellow solid. The solid was recrystallized from hexanes, filtered and washed with hexanes to isolate a white crystalline solid (5.4153 g, 49.9percent). A. Synthesis of ethyl chloro(hydroxyirnino)acetate (C87). Ethyl 2-aminoacetate hydrochloride (40 g, 286.57 mmol) was added to a solution of water (54 ml) and concentrated hydrochloric acid (36 mL) and the reaction was cooled to -5°C. The solution was then treated drop-wise with a solution of sodium nitrite (19.77 g, 286.57 mmol) in water(36 ml) while maintaining the reaction temperature below -5°C, The mixture was stirred for 0.5 h and treated with another portion of concentrated hydrochloric acid (36 ml) followed by the drop-wise addition of a solution of sodium nitrite (19.77 g, 286.57 mmol) in water (36 mL). The reaction was further stirred for 2 h at -5°C. The mixture was then extracted with diethyl ether (400 mL). The resultant organic layer was collected, washed with water (100 mL), saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate and concentrated, The resultant residue was recrystallized from hexanes to provide C87 as a white solid. Yield; 19.10 g, 44percent, Step 1 A 250 mL round bottom flask was charged with glycine ethyl ester hydrochloride (40 g, 0.29 mol), concentrated HCl (24 mL, 0.29 mol) and water (55 mL). To the above was added dropwise a solution of sodium nitrite (20 g, 0.29 mol) in water (30 mL) at -5 °C. A second equivalent of hydrochloric acid and sodium nitrite were then added in the same manner. The resulting mixture was stirred at -5 °C for 20 min then extracted with ethyl ether (250 mL). The extract was dried over anhydrous MgS0EXAMPLE 11Laboratory-Scale Production of ECHAEthyl 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 (32percent) 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.EXAMPLE 12Large-Scale Production of ECHAGlycine ethyl ester hydrochloride (6.3 kg, 0.045 kmol) was dissolved in hydrochloric acid (32percent, 5.13 kg). The solution was cooled to 0° C. and hydrochloric acid gas was bubbled into the reactor via a sparging tube for 1 hour while maintaining the temperature at <5° C. The reaction mixture was then cooled to -5° C. A solution of sodium nitrite (3.11 kg) in water (4.5 L) was then dosed into the reactor using a diaphragm pump while maintaining the temperature at -5° C. to 0° C. This operation was complete within an hour. A second portion of gaseous HCl was sparged into the reactor over 1 hour at 0 to 5° C. This was followed by a second portion of sodium nitrite (3.11 kg) in water (4.5 L) which was added over one hour while maintaining the temperature at -5° C. to 0° C. The reaction mixture was stirred for a further hour and was then extracted with chloroform (3.x.2 kg) at ambient temperature. The organic extracts were combined, dried (MgSOTo a 200 mL round bottom flask glycine ethyl ester hyrochloride (35.8 mmol, 5.0 g) cooled to -5 °C 5.9 mL of 12M HCl were added and followed by addition of NaNO

Molecular Weight:151.55
XLogP3:2.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:151.0036207
Monoisotopic Mass:151.0036207
Topological Polar Surface Area:58.9
Heavy Atom Count:9
Complexity:134
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes