Ethyl 2-fluoro-2- acetate

LIkik. E., and Imbeaux, M., A convenient synthesis of ethyl (diethoxyphosphoryl)fluoroacetate from ethyl fluoro acetate. Synthesis, 861, 1989. 

Similarly, the 6-(tetraethyl phosphorodiamide) of l,2 3,4-di-0-iso-propylidene-a-D-galactopyranose gives the corresponding halogen derivative with methyl iodide, benzyl bromide, benzyl chloride, and ethyl fluoro-acetate. ... 

Insects utilize propionate and methylmalonate in the biosynthesis of ethyl branched juvenile hormones and methyl branched cuticular hydrocarbons. The sources of propionate and methylmalonate in some insects appear to differ from those in mammals. Succinate is the precursor of propionate and methylmalonate in a termite, whereas valine and probably other amino acids are the sources of propionate and methylmalonate in several other species. An unusual pathway for propionate metabolism has been shown to occur in insects and it may be related to the absence or low levels of vitamin B found in many species. Propionate is converted directly to acetate with carbon 1 of propionate lost as C02> carbon 2 of propionate becoming the methyl carbon of acetate and carbon 3 of propionate becoming the carboxyl carbon of acetate. This pathway suggested the possibility that 2-fluoropropionate might be selectively metabolized in insects to the toxic 2-fluoro-acetate. However, preliminary data indicate that 2-fluoropropionate is not toxic to the housefly or the American cockroach. 

A two-step synthesis of modified 2 -C-nucleoside precursor, ethyl [2-(5-methyl-2,4-dioxo-3,4-dihydro-2i/-pyrimidin-l-yl)-4-hydroxyl-5-hydroxymethyltetra-hydrofuran-3-yl]fluoro-acetate 172, from protected glycal 170 and xanthate has been developed following the same idea, and a diastereomeric 1 1 mixture of 2,3-trans product 171 was obtained in 57% yield (O Scheme 46). The use of triethylborane as a free-radical initiator was less successful and a longer reaction time was also required. Interestingly, introducing th)miine at C-1 in the presence of silver triflate at 0°C was highly stereoselective, and only a C, C2-trans linked product was detected. 

In view of these facts and of the known toxic action of fluoro-acetates it seemed worth while investigating compounds containing both fluorine and the above-mentioned groups. We prepared the flrst of a series of nitrogen compounds in 1943, namely, ethyl jluoroacetamidoacetate, CHjF CO NH CHg COjEt (XH). It was a colourless crystalline solid which, when injected into mice, had a l.d. 50 of 20 mg./kg. The corresponding figure for methyl fluoroacetate is 6 mg. /kg. The symptoms were similar in each case (delayed convulsant action). 

The very high toxicity of ethyl 5-fluoropentanecarboxylate and its derivatives and the fluoroacetate-like symptoms produced seemed to us to be of particular interest, since by a process of ) -oxidation in the animal body 5-fluoropentanecarboxyhc acid would readily give rise to the toxic fluoroacetic acid. Similar remarks apply to y-fluorobutyric acid and its derivatives prepared independently by American workers. The non-toxicity of y -fluoropropionic acid and its derivatives may, on the other hand, be due to the inability of this acid to give the toxic fluoro-acetic acid by a process of yff-oxidation. 

C4H6C1F02 1661 C4H6C1F02 1662 C4H6C1F30 chloro-acetic acid 2-fluoro-ethyl ester chloro-fluoro-acetic acid ethyl ester 2-chloro-l-ethoxy-l,l 2-trifluoro-ethane 589-84-4 401-56-9 310-71-4... 

C4H6F2O2 fluoro-acetic acid 2-fluoro-ethyl ester 459-99-4... 

C4H7FO2 fluoro-acetic acid ethyl ester 459-72-3... 

C4 H6 Cl F 02 chloro-fluoro-acetic acid ethyl ester 401-56-9 RI Temp/C Lambda/nm Ref. 

Electrochemical fluorination of a-cyclohexenyl-substituted carboxylic (acetic, propanoic, butanoic, and pentanoic) acid esters (methyl, ethyl, and propyl) results in a series of both perfluoro-9-alkyl-7-oxabicyclo[4 3 OJnonanes and per-fluoro-8-alkoxy-9-alkyl-7-oxabicyclo[4.3.0]nonanes [<8S] (equation 19)... 

FluorO-11/3-hydrOxy-16/3-methyl-170 .21-(r-ethyl-1 -ethoxy methylenedioxyipreg-na-1,4-dlene-3.20-dione Acetic Acid Propionyl Chloride... 

A solution of 90 -fluoro-11/3-hydroxy-16/3-methyI-170 ,21-(1 -ethyl-1 -ethoxymethylenedioxy) pregna-1,4-dlene-3.20-dione (538 mg) in acetic acid (20 ml), containing 2 drops of water, was allowed to stand at room temperature for 5 hours. Dilution of the mixture with water gave a white solid (457 mg) which, after being filtered off and dried, was recrystallized from acetone to afford 90 -fluoro-11/3,21 -dihydroxy-16/3-methy 1-170 -propionyloxypregna-1,4-diene-3, 20-dione (361 mg), MP 230°-235°C. 

To 6a-fluoro-16a-hydroxy-hydrocortisone 21-acetate, described by Mills et al, J. Am. Chem. Soc., volume 81, pages 1264 to 1265, March 5, 1959, there was added acetic anhydride in dry pyridine. The reaction mixture was left at room temperature overnight and was then poured with stirring into ice water. The resulting precipitate was filtered, washed with water and crystallized from acetone-hexane to give 6a-fluoro-16a-hydroxy-hydrocortisone-16a,21-diacetate. This was reacted with methane-sulfonyl chloride in dimethyl formamide in the presence of pyridine at 80°C for 1 hour. The mixture was cooled, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By recrystallization of the residue from acetone-hexane there was obtained 6a-fluoro-A <" -pregnadiene-16o ,17a,21-triol-3,20-dione 16a,21 diacetate. 

A sodium carbonate solution of the crude acetic acid was washed with ether and then acidified with hydrochloric acid the required acid was isolated via an ether extraction and was esterified by refluxing for 6 hr with ethanol (370 ml) and concentrated sulfuric acid (15 ml). Excess alcohol was distilled, the residue diluted with water and the required ester isolated in ether. Distillation finally gave ethyl 2-fluoro-4-biphenylacetate,BP 134°C to 136°C/0.25 mm. 

A) 1-(2-Amino-5-chlorophenyll-1-(2-fluorophenyll-2-a2a-but-1-en-4-ol A mixture of 40 g of 2-methylimidazole hydrochloride and of 90 g of 2-amino-5-chloro-2 -fluoro-benzophenone in 240 ml of ethanolamine is heated at 135 for 2 hours. After cooling, the reaction mixture is poured into an aqueous sodium bicarbonate solution. The mixture is extracted with ether, the organic phase is washed repeatedly with water and is dried over sodium sulfate, and the solvent is evaporated to dryness. The residual oil is chromatographed on a silica column, elution being carried out with a 50/50 mixture of cyclohexane and ethyl acetate. 

C. The precipitated product is filtered, dried and recrystallized from ethyl acetate to give 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid. Upon repeated recrystallization from ethylacetate there is obtained cis-5-fluoro-2-methyl-1-(p-methylsulfinyl-benzylidene)-3-indenylacetic acid (MP 184° to 186°C). 

Paper strip chromatography showed approximately equal amounts of substrate and a more polar product (A -pregnadiene-9a-fluoro-11/3,l6a,17a,21-tetrol-3,20-dione 16,21-diacetate) together with very small amounts of two less polar products. Partition chromatography of 0.25 gram of the residue (diatomaceous earth column system 2 parts ethyl acetate,... 

B. Reactions.—(/) Halides. Whereas ylides are alkylated in the normal way on treatment with a-bromo- or a-iodo-esters, quite different reactions occur with a-fluoro- and a-chloro-acetates. When salt-free ylides were refluxed in benzene with ethyl fluoroacetate or trifluoroacetate normal Wittig olefin synthesis took place with the carbonyls of the ester groups to give vinyl ethers, e.g. (14). On the other hand, methyl chloroacetate with... 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

The synthesis of compound 27 was initiated with the treatment of ke-toester 29, reported by Yoshida et al. [25], with ethyl orthoformate in acetic acid, followed by reaction with (l.R,2S)-2-fluoro-1-cyclopropylamine p-toluenesulfonic acid salt in the presence of triethylamine to yield an enam-inoketoester intermediate, cyclization of which under NaH in dioxane yields the 5-nitroquinolone derivative (30). Reduction of the nitro group of compound 30 followed by acid hydrolysis provides compound 27 via the amino-quinolone derivative (31), according to Scheme 7. 

---