Ethyl 2,2-difluoro-2 acetate

Earlier, Ruh [120a] reported a similar reaction for l,2-dichloro-l,2-difluoro-ethylene on reaction with sodium ethoxide to give ethyl chlorofluoroortho-acetate (Eq. 39). 

Abramov nucleophilic addition of various phosphorus acid esters to nucleoside aldehyde derivatives yielded the phosphonate-based iso-polar, non-iso-steric 5 -nucleotide analogues (28) containing a geminal hydroxy phosphonate moiety on the 5 -carbon of the pentofuranose ring. The enantiomerically pure D- and l- 2, 3, 5 -trideoxy-4 -[(ethoxyphosphoryl) difluoromethyl] thymidine analogues(29) have been synthesized from (i 5)-( )-2-methyl-5-(4-methyl-phenyl-sulfinyl)pent-2-ene and ethyl 2-(diethoxyphosphoryl)-2,2-difluoro-acetate in 45% overall yield over seven steps. ... 

C4H6F2O2 difluoro-acetic acid ethyl ester 454-31-9... 

R = H, R =Br, R" =Et) was prepared by cyclization of aroylacetate 314 (R = H, R =Br, r2 = H, X = F) (OOMIPIO). 9,10-Difluoro-3(5)-methyl-7-oxo-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylic acid and its racemic form were prepared in the reaction of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-2-ethoxymethyleneacetate and (R)- or (i ,5)-2-aminopropanol and subsequent hydrolysis of the ring closed tricyclic esters (98MI45). Cyclization of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-2-[A-(2-hydroxyethyl)aminomethylene]acetate 315 in the presence of K2CO3 in DMF at 95 °C for 3.5 h yielded 9-iodo-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylate (01MIP2). 

After further working up there is obtained an oily crystalline residue which is subjected to chromatography on silica gel. The 16a-methyl-6a,9a-difluoro-A -pregnadien-11/3,21-diol-3,20-dione is eluated with ethyl acetatereacted with valeric acid chloride to give the valerate ester. 

A mixture of 290 mg of the 16,21-diacetate of 6a,9a-difluoro-16o --hYdroxY-hYdrocortisone, 30 cc of t-butanol, 0.5 cc of pyridine and 150 mg of selenium dioxide was refluxed for 53 hours under an atmosphere of nitrogen and cooled ethyl acetate was added and filtered through celite the solvent was evaporated to dryness under reduced pressure, the residue... 

Ethyl 6-amino-4,5-difluoro-l-methyl-7-oxo-li/,7//-pyrido[3,2,l-i/]cinno-line-8-carboxylate (84, R = H) was prepared from the 6-benzylamino derivative 84 (R = CH2Ph) by catalytic debenzylation over Pd/C in a mixture of ethanol and acetic acid (92EUP470578,92MIP1). 

FLUORINE COMPOUNDS, ORGANIC - FLUORINATED ACETIC ACIDS] (Volll) Ethyl 3-(2,5-difluoro-4-bromophenyl)-3-oxopropanoate [123942-12-1]... 

A mixture of 430 mg of the 16,21-diacetate of 6a,9a-difluoro-16a-hydroxy-prednisolone, 15 cc of methanol and 2.2 cc of a 4% aqueous solution of potassium hydroxide was stirred at 0°C in an atmosphere of nitrogen the material entered rapidly in solution and reprecipitated after 30 minutes. The mixture was then stirred for 1 hour more at 0°C and under an atmosphere of nitrogen, then neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water, the solid was collected, washed with water, dried and recrystallized from ethyl acetate-methanol, thus giving 285 milligrams of the free 6a,9a-difluoro-16a-hydroxy-prednisolone, MP 258° to 260°C the analytical sample showed MP 266° to 268°C. 

A solution of the 6a,9a-difluoro-lip-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17p-carboxylic acid (500 mg) and sodium iodide (1.874 g) in acetone (15 ml) was stirred and heated under reflux for 6.5 h. Ethyl acetate (75 ml) was then added and the solution was washed successively with water, 10% sodium thiosulfate solution, 5% sodium hydrogen carbonate solution and water, dried and evaporated to give an off-white foam (525 mg). PLC in chloroform-acetone (6 1) to give an off-white foam (478 mg) which was crystallised from acetone without being heated above room temperature to give colourless crystals of the S-iodomethyl-6a,9a-difluoro-lip-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17p-carbothioate (241 mg) m.p. 196-197°C, [a]D = -32° (c 1.01). 

A solution of S-iodomethyl-6a,9a-difluoro-lip-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17p-carbothioate (310 mg) in acetonitrile (10 ml) was stirred with silver fluoride (947 mg) for 3 days at room temperature in the dark. Ethyl acetate (100 ml) was added and the mixture was filtered through kieselguhr. The filtrate was washed successively with 2 N hydrochloric acid, water, saturated brine, then dried. The solvent was removed and the residue was subjected to column chromatography in chloroform then chloroform-acetone (19 1). The product was eluted with ethyl acetate and crystallised on concentration of the solution to give S-fluoromethyl 6a,9a-difluoro-lip-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17p-carbothioate (0.075 g) melting point 272-273°C (dec.), [a]D= +30° (c 0.35). 

To a solution of 46 mg (0.11 mmol) of 4,6-di-0-benzoyl-3-deoxy-3,3-difluoro-a/p-D-gluco-pyranoside in water-dioxane 1 2 (2 ml) was added 120 mg (0.56 mmol) of sodium periodate. This resulting solution was stirred at room temperature for 20 h. Then, more sodium periodate (55 mg, 0.26 mmol) was added and stirring was continued for 6 h. After that, the solvents were evaporated and the solid was repeatedly extracted with ethyl acetate (total volume 70 ml). The solvent was then evaporated to give a solid that was treated for 15 min with a diluted (0.1%) methanolic solution of ammonia. THE solution was evaporated and the crude purified by preparative TLC (hexane/ethyl acetate 2 1) to yield 18 mg (0.04 mmol, 43%) of a-3,5-di-0-benzoyl-2-deoxy-2,2-difluoro-D-ribose. 

BF3OEt2 (0.060 ml, 0.48 mmol as a solution of 48% in BF3) and phenylselenol (0.064 ml, 0.60 mmol) were added to a stirred solution of methyl 4,6-di-O-benzoyl-2,3-dideoxy-3,3-difluoro-a-D-erythro-hexopyranoside (100 mg, 0.24 mmol) in anhydrous dichlormethane (2 ml). The solution was heated to reflux for 3 h, neutralized by dropwise addition of pyridine and evaporated to dryness. The residue was purified by column chromatography (hexane/ethyl acetate 10/1) to afford 92 mg (72%) of phenyl 4,6-di-0-benzoyl-2,3-dideoxy-3,3-difluoro-l-seleno-a-D-erythro-hexopyranoside as an anomeric mixture. 

Acetoxymethyl-7,8-difluoro-2,3-dihydro-4H-[l,4]benzoxazine (m.p. 73-74°C) was synthesized by hydrogenation of a compound prepared from 2,3-difluoro-6-nitrophenol, l-acetoxy-3-chloro-2-propane and potassium iodide. The hydrogenation was carried out on Raney nickel. The resulting compound was dissolved in THF, and 3,5-dinitrobenzoyl chloride and pyridine were added thereto, followed by heating at 60°C for 3 hours. The mixture was concentrated, and the concentrate was dissolved in ethyl acetate, washed successively with diluted hydrochloric acid, an aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated. Addition of n-hexane to the concentrate caused precipitation of yellow crystals of a racemate. The yield of 3,5-dinitrobenzoyl derivative of the ()-3-acetoxymethyl-7,8-difluoro-2,3-dihydro-4H-[l,4]benzoxazine 3.93 g. 

To 1.13 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[l,4]benzoxazine was added 1.58 g of diethyl ethoxymethylenemalonate, and the mixture was stirred at 130-140°C for 70 min. The reaction mixture was subjected to column chromatography using 50 g of silica gel and eluted with chloroform to obtain 2.47 g of diethyl [(-)-7,8-difluoro-3-methyl-2,3-dihydro-4H-[l,4] benzoxazin-4-yl]methylenemalonate. This product was dissolved in 5 ml of acetic anhydride, and 10 ml of a mixture of acetic anhydride and concentrated sulfuric acid (2/1 by volume) with stirring under ice-cooling, followed by stirring at 50-60°C for 40 min. To the reaction mixture were added ice and an aqueous solution of sodium bicarbonate, and the product was extracted three times with 150 ml portions of chloroform. The combined extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The precipitate was washed with a small amount of diethyl ether to yield 1.32 g of (-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4] benzoxazine-6-carboxylate. 

The mixture of the ethyl 2-(3-methoxy-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate (6.68 g), sodium fluoride (1.31 g) and anhydrous dimethylformamide (26 ml) was refluxed for 5 h. After cooling, the reaction mixture was poured into ice water (100 ml) and the resulting precipitate was collected by filtration, washed with water and recrystallized from ethyl acetate to give ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate (4.53 g) as colorless needle, melting point 178°-180°C. 

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