Recrystallization decoloration

The total yield amounts to 260-266 g. (48.5-49.5 per cent of the theoretical amount). The product is contaminated by slight traces of d-glucose and possesses a very faint reducing power towards Fehling s solution. For complete purification it is recrystallized (with practically no loss and practically no change in melting point) from five parts of methyl alcohol with the use, if necessary, of decolorizing carbon. 

The free base tends to become oxidized in the air but may be preserved as the hydrochloride. This is prepared by transferring it as soon as possible to 1500 cc. of distilled water containing 100 cc. of concentrated hydrochloric acid. The sparingly soluble hydrochloride separates at once. It is recrystallized from the mixture with the use of a little decolorizing carbon, whereupon it separates as colorless needles. A further crop is obtained on concentrating the mother liquor under reduced pressure to about 200 cc. The yield is no g. (82.1 per cent of the theoretical amount). 

In a 500-ml round-bottom flask is placed a mixture of 25 g (0.178 mole) of dimedone, 21.8 g (0,22 mole, 25 % excess) of pulverized maleic anhydride, 0.1 g of /7-toluenesulfuric acid, and 150 ml of isopropenyl acetate. The mixture is refluxed for 72 hours, then cooled, and the acetone is removed at room temperature on a rotary evaporator. The resulting solution is cooled to —20° in a Dry Ice bath, whereupon the product crystallizes. It is collected by filtration to yield the crude product in about 80% yield. Recrystallization from hexane-ethyl acetate and decolorization by Norit gives colorless crystals, mp 164-166°. 

Four 250-ml fractions were collected followed by 150 ml fractions. The residues from fractions B to 16 were combined and rechromatographed over a 125-g column of magnesium silicate. The solumn was eluted with 6% acetone in hexanes which was collected in 150 ml portions. Fractions IB to 29 were combined and dissolved in acetone, decolorized with charcoal, and recrystallized from acetone. One gram of a crystalline mixture of the 7-epimers of 7,17-dimethyltestosterone was obtained melting at 120° to 140°C. 

The following method is described in U.S. Patent 2,430,891. To a solution of 10 parts of tris-p-methoxyphenyl ethylene in 35 to 40 parts of carbon tetrachloride Is added a solution of 2.0 parts of chlorine in 50 parts of carbon tetrachloride, with stirring, and over a period of Vj hour. The carbon tetrachloride is then removed by distillation on a steam bath and the residual oil is recrystallized from 250 to 400 parts of methanol, decolorizing with charcoal or the like if necessary. Tris-p-methoxyphenyl chloroethylene is obtained in a yield of 65 to 75%. It melts at 113° to 114°C. 

The oil that separates is extracted with ether, the extract dried over anhydrous sodium sulfate and then evaporated at reduced pressure. The residue is dissolved in boiling benzene (75 ml) treated with decolorizing charcoal, filtered, treated with boiling cyclohexane (275 milliliters) and cooled to give 22.3 grams of 2,3-dichloro-4-butyrylphenoxyacetic acid. After several recrystallizations from a mixture of benzene and cyclohexane, then from methyl-cyclohexane, next from a mixture of acetic acid and water, and finally from methylcyclo-hexane, the product melts at 110° to 111°C (corr). 

Drying over anhydrous sodium sulfate containing decolorizing carbon followed by removal of the solvent by distillation at reduced pressure affords an oil which solidifies on standing. Recrystallization of that solid by dropwise dilution with water of a methanol solution affords 17o -ethvnvl-19-norandrost-4-ene-3(3,17(3-diol 3,17-diacetate, melting at about 126° to 127°C. 

After 2 hours the mixture is cooled to about 0°C and the crude product Is collected by filtration, washed with diethyl ether and dried in a vacuum oven. After treatment with decolorizing charcoal and recrystallization from an equivolume mixture of isopropanol and methanol, the product, 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide hydrochloride has a MP of 228°C to 229°C. 

To a solution of 20 parts of thiamine hydrochloride in 30 parts of water is added an aqueous solution of sodium hydroxide (7.2 parts of NaOH in 30 parts of water), and the mixture is cooled with water. The mixture is allowed to stand for 30 minutes, 60 parts of chloroform is added, followed by a solution of 30 parts of crude sodium tetrahydrofurfurylthiosulfate in 30 parts of water, and the whole is stirred for 30 minutes. The chloroform layer is separated and the aqueous layer is extracted twice with 20 parts of chloroform. All the chloroform solutions are combined and shaken with 50 parts of 5% hydrochloric acid. The acid solution is decolorized and neutralized with alkali carbonate, whereupon thiamine tetrahydrofurfuryl disulfide separates out in the resinous state but soon solidifies [MP 129 (decomp.)]. The yield is 16 parts. Recrystallization from ethyl acetate gives colorless prisms melting at 132°C (decomp.). 

The crude iodinated acid was then dissolved in 500 ml of 95% alcohol, 10 g of dimethyl-aminoethanol was added, the solution was decolorized with activated charcoal and filtered at 70°C. After keeping the filtrate for several hours at 5°C, the heavy crystalline precipitate which formed was collected by filtration and washed with acetone. The mother liquors were concentrated to 150 ml and cooled to give a second crop which was further purified by recrystallization from 50 ml of 95% alcohol. In this way a total of 36.0 g of dimethyl-aminoethanol salt of dextro-/3-(3,5-diiodo-4-hydroxy)-o-phenylpropionic acid, MP 151° to 153°C, was obtained. The melting point of the dimethylaminoethanol salt of unresolved /3-(3,5-diiodo-4-hydroxy)-o-phenylpropionic acid was 142° to 144°C. 

The mixture is then cooled and sodium bisulfite added to decolorize. Recrystallization of the product from methanol gives about 8 g, MP 147° to 150°C. The /3-(3-amino-2,4,6-triiodophenyl)-0 -ethylpropionic acid may be purified further by precipitation of the morpholine salt from ether solution and regeneration of the free amino acid by treatment of a methanol solution of the morpholine salt with sulfur dioxide. The pure amino acid has the MP 155° to 156.5°C. 

The temperature Is then raised to 170° to 200°C when the excess water and o-toluidine is gradually distilled off, finally maintaining the temperature at 180° to 200°C for 2 hours. After cooling to about 100°C dilute hydrochloric acid (3 parts) is added and the mixture boiled and stirred. The solution is then neutralized with NaOH with stirring and the product which separates is recrystallized twice from alcohol after decolorizing with carbon. Yield 70% of theoretical, MP 114° to 115°C. 

The crude 2-(p-nitrobenzenesulfonamido)-pyrimidine from the preceding step was suspended in 130 parts alcohol and 1.5 parts of concentrated hydrochloric acid were added. The suspension was then heated to reflux and 30 parts of iron powder were added with mechanical stirring. The mixture was refluxed and stirred for 24 hours with r"-asional addition of concentrated hydrochloric acid. The reaction mixture was then made slightly basic and filtered hot and the residues were extracted with several portions of boiling alcohol. The filtrate and wash solutions were combined and evaporated. The 2-(sulfanilamido)-pyr-imidine was recrystallized from boiling water with decolorizing charcoal added, according to U.S. Patent 2,410,793. 

A solution of 5.0 g of a-ethyl-(3-(aminophenyl)propionic acid in 100 ml of water containing 5 ml of concentrated hydrochloric acid was added over a period of h hour to a stirred solution of 3.2 ml of Iodine monochioride in 25 ml of water and 25 ml of concentrated hydrochloric acid heated to 60°C. After addition was complete, the heating was continued for h hour longer at 60° to 70°C. A black oil separated which gradually solidified. The mixture was then cooled and sodium bisulfite was added to decolorize. Recrystallization of the product from methanol gave about 8 g of a-ethyl-(3-(2,4,6-triiodo-3-aminophenyl-pro-pionic acid, MP 147° to 150°C. The product could be further purified by precipitation of its morpholine salt from ether solution and regeneration of the free amino acid by treatment of a methanol solution of the morpholine salt with sulfur dioxide. The pure amino acid had the MP 155° to 156.5°C (corr). 

The checkers dissolved the crude acid in the minimum amount of 2N sodium hydroxide (about 3 ml./g.) and reprecipitated it in 5 portions with IN hydrochloric acid recovery 75-85%. Alternatively, they added the acid to boiling ethyl acetate (9 ml./g.), added decolorizing carbon to the solution, boiled the mixture for 5 minutes, separated the carbon by filtration, and cooled the hot filtrate recovery 45-55%. The checkers found no difference in the infrared spectra of material purified in the two ways, but recrystallized material was reduced more quickly by hydrogen. 

Diethyl malonate or a derivative (0.25 mol) and benzene-1,2-diamine (27 g, 0.25 mol) were added to a solution of NaOEt prepared from sodium (11.5 g. 0.5 g-atom) and EtOH (300 mL). The EtOH was distilled off, finally under reduced pressure, and the residue was heated at 180-200 C under N2 for 4 h and then stirred with ice. The mixture was acidified with coned HC1 and the resulting solid was collected, washed with H20 and recrystallized (EtOH) with the addition of decolorizing charcoal if necessary. 

A solution of 1 l,12-dihydrodibenzo[r,g][l,2]diazocine (1 1.5 g, 7.1 mmol) in CC14 (120mL) was stirred with NBS (1.5 g. 8.43 mmol) and refluxed for 12 h. The mixture was cooled and filtered, the filtrate was evaporated to dryness, and the resulting dark residue was extracted with boiling cyclohexane (100 mL). The extract was decolorized with charcoal and the filtrate was evaporated to dryness to afford crude 11-bromo-l l,12-dihydrodibenzo[c,g][l,2]diazocine (2) yield 1.1 g (54%) mp 105-106 C (after recrystallization from cyclohexane). 

The tetraketone can be obtained in a pure form by recrystallizing it first from ether with the addition of decolorizing carbon and then from -butanol yield 50-58% m.p. 68-72°. 

The recrystallized products were pure, but considerable losses were entailed. Recrystallized from aqueous ethanol (decolorized with activated carbon). Recrystallized from ethyl acetate-petroleum ether at - 30°. 

The submitters reported a melting point of 114-116°. The checkers obtained analytically pure material with a recovery of 80% after decolorization with activated carbon and recrystallization from 2-3 ml. of hexane at 0°. The product was also purified with comparable efficiency by sublimation at 85-90° (10 mm.). A small amount of a yellow, volatile impurity was removed from the cold finger before the product began to sublime. The melting point of the product after purification by the checkers was 110-112°. The reported melting point is 114-116°. 

If the solution is appreciably colored it may be treated with decolorizing carbon at this point. Toluene or dilute ethanol may also be used for the recrystallization, but these solvents are less satisfactory. 

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