Citric acid tetrahydrofuran

To a stirred solution of 28.3 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran were added in turn 9.0 g of triethylamine and 12.2 g of isobutyl chloroformate while keeping the temperature at -20°C. After 10 minutes, to this was added 15.2 g of ethyl 4-methyl-2-piperidinecarboxylate and the mixture was stirred for 10 minutes at -20°C. At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken up in 400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate. The solution was evaporated to give 31.5 g (75 %) of ethyl l-[NG-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the form of a syrup. 

Tetrahydrofuran (3.2 ml) and S-(+)-3-chloro-l,2-propanediol (0.299 ml, 3.58 mmol, 1.19 eq) are mixed. The mixture of THF (3.2 ml) and S-(+)-3-chloro-1,2-propanediol (0.299 ml, 3.58 mmol, 1.19 eq) is cooled to -16°C and potassium t-butoxide (3.2 ml, 1.0 M) in THF (3.2 mmol, 1.07 eq) is added at less than -10°C. The resulting slurry is stirred at -14-0°C for 1 hour. Then added to the lithium anion mixture while maintaining both mixtures at 0°C, then rinsed in with THF (2 ml). The resultant slurry is stirred at 20-23°C for 2 hour and then cooled to 6°C and a mixture of citric acid monohydrate (0.4459 g, 2.122 mmol, 0.705 eq) in water (10 ml) is added. The resultant liquid phases are separated and the lower aqueous phase is washed with ethyl acetate (12 ml). The organic layers are combined and solvent is removed under reduced pressure until a net weight of 9.73 g remains. Heptane (10 ml) and water (5 ml) are added and solvent is removed 4-nitrobenzenesulfonyl chloride y reduced pressure until a total volume of 5 ml remains. The precipitated product is collected by vacuum filtration and washed with water (7 ml). The solids are dried in a stream of nitrogen to give (R)-[N-3-(3-fluoro-4-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol. 

This bond strength is considerably higher than any value for the adhesion to smooth dentin surfaces which has been previously reported. The bond strength is slightly decreased when more dilute citric acid solutions are used. Other pretreatments yielding tensile adhesion values above 10 MPa include solutions of 1% alcoholic (1 2) citraconic anhydride, 1% alcoholic tetrahydrofuran -2,3,4,5-tetracarboxylic acid, and 1% aqueous ethylenediamine-tetraacetic acid tetrasodium salt. 

The solution of the chloroformate 545 was added in small portions over a period of 10 min to a solution of the amino acid (0.05 mol) in 1 n sodium hydroxide (200 mL) (L-glutamic acid 1.5 n sodium hydroxide) containing tetrahydrofuran (40 mL) with vigorous stirring at 0-5 °C. Stirring was continued for 2 h then, the reaction mixture was washed with diethyl ether (100 mL) and acidified by the addition of solid citric acid. The product was extracted with ethyl acetate (500 mL). This layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo the residue, which was then crystallized from ethyl acetate/petroleum ether. If the product did not crystallize at this stage, the residue was neutralized with a calculated amount of dicyclohexylamine in diethyl ether and the pMZ-amino acid was crystallized as the dicyclohexylammonium salt. 

The mixed anhydride prepared from 3.2 g (10 mmoles) of Z-Gly-Leu-OH, 1.1 ml (10 mmoles) of iV-methylmorpholine and 1.34 ml (10 mmoles) of iso butyl chloroformate in 60 ml of anhydrous tetrahydrofuran at —10° to —15° is allowed to react with L-phenylalanine chloromethyl ketone hydrobromide and 1.3 ml of fV-methylmorpholine for 1.25 hr while the reaction mixture is allowed to warm to room temperature under anhydrous conditions. Work-up of the reaction mixture involves evaporation of tetrahydrofuran, extraction of the residue into ethyl acetate, washing with citric acid and sodium bicarbonate solutions, drying over magnesium sulfate, and evaporation. The product is recrystallized from ethyl acetate-cyclohexane to yield 3.41 g (68%) of product with m.p. 140.5°-143°. 

Fig. 3.18 The apparent dissociation constants of citric acid (pKp pKj and pK,) at 25 °C in water-organic solvent mixtures as a function of dielectric constant D. pKj values from Table 3.6. - methanol - 1,4-dioxane - tetrahydrofuran and - acetonitrile...

The chemical operations described in the literature to introduce or into citric acid molecule are based essentially on the Grimaux and Adam synthesis. Labeled citric acid was prepared by Wilcox et al. [35] in the reaction of Na CN with 3-chloro-2-carboxy-2-hydroxybutyric acid and the formed nitrile was hydrolyzed directly with hydrochloric acid. From this solution, citric acid was isolated in the form of calcium citrate and finally converted to the acid. An alternative procedme was proposed by Rothchild and Fields [36] to obtain trimethyl citrate from labeled sodium cyanide and di-chloromethyl glycolate. A more complex synthesis of C labeled citric acid is described by Winkel et al. [39]. They used labeled methyl acetate and acetyl chloride (in the presence of hthium 1,1,1,3,3,3,-hexamethyldisilazide, [(CH3)2Si]2NLi which was dissolved in tetrahydiofuran) to obtain methyl acetoac-etate. It reacts in the presence of lithium diisopropylamide, [(CH3)2CH]2NLi, also dissolved in tetrahydrofuran, with dimethyl carbonate to give dimethyl 1,3-ace-tonedicaiboxylate. It is dicarboxylated by the action of bisulfite and potassium cyanide is converted to 3-cyano-3-hydroxy-l,5 pentanedioate and finally hydrolyzed by hydrochloric acid to citric acid. 

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