Distillation notes

The flask was charged with 2.0 mol of dry, freshly distilled (note 1) methyl propargyl ether (VIII-6, Exp. 7), potassium iert.-butoxide (note 2) (5 g) was added with stirring and the mixture was heated under reflux. The reaction was... 

In a 3-I. round-bottomed flask are placed 500 cc. (400 g., 8.7 moles) of absolute alcohol which has been saturated in the cold with hydrochloric acid gas (Note i), 870 cc. (6S0 g., 20 moles) of 96 per cent alcohol (Note 2) and 70 g. (1.03 moles) of methyleneaminoacetonitrile (Note 3). This mixture is refluxed on a steam bath for three hours (Note 4). During the refluxing, ammonium chloride separates. After the reaction is complete, the hot alcohol solution is filtered with suction and the filtrate cooled, thus allowing the glycine ester hydrochloride to separate out in fine white needles. The product is filtered with suction, sucked as dry as possible on the filter, and then allowed to dry in the air. The yield is about no g. The alcohol from the filtrate is distilled (Note 5) until about one-third of its volume is left and again cooled and a second crop of crystals is obtained. The total yield of product, m.p. 142-143, varies from 125 to 129 g. (89-91 per cent of the theoretical amount). If a very pure product is desired, it may be recrystallized from absolute alcohol. 

B. a-Ketoglularic acid. The ester obtained by the foregoing procedure is mixed with 600 ml. of concentrated hydrochloric acid and left overnight. The mixture is concentrated by distillation (Note 5) until the temperature of the liquid reaches 140°. It is poured into an evaporating dish and allowed to cool. The solid mass, weighing 11(3-112 g., is then pulverized. The yield of a-ketoglutaric acid is 92-93% of the theoretical for the last step, or 75-77% based upon diethyl succinate. The light tan product, obtained as described above, is suitable for most purposes, but a purer add, m.p. 109-110° (corr.) may be obtained by recrystallization from an acetone-benzene mixture. 

Ice (about 100 g.) and then 100 ml. of cold water are added, the mixture is stirred for 10 minutes, and then the ether is removed by distillation (Note 5). To the residue in the flask is added sufficient water to make the total volume about 300 ml. Steam distillation is then carried out until the distillate comes over clear. This process requires about 1 hour. The aldehyde is extracted from the steam distillate with three equal portions of the ether recovered above, and the ether solution is dried for several hours over anhydrous sodium sulfate. 

After dilution with 200 ml. of benzene, the solution is transferred to a 2-1. separatory funnel containing 800 ml. of ice water and shaken thoroughly. The aqueous layer is separated, acidified to pH 3-4 with 2-3 ml. of concentrated hydrochloric acid, and extracted with three 100-ml. portions of benzene. All the organic layers are then combined and dried over anhydrous sodium sulfate. Filtration and concentration of the solution with a rotary evaporator, followed by exposure to high vacuum for 2-3 hours, affords 17.3-19.3 g. of the crude product (Note 3). Low-boiling impurities are removed by vacuum distillation (Note 4), the residual oil (14-15 g.) is transferred to a 50-ml. flask equipped with a short-path distillation apparatus, and vacuum distillation is continued. A forerun is taken until no rise in boiling point is observed, and then 7.2-8.6 g. (23-27%) of dimethyl nitrosuccinate is collected as a colorless oil, b.p. 85° (0.07 mm.), 1.4441 (Note 5). 

The distillate is extracted with five 50-cc. portions of benzene, and the benzene solution is dried thoroughly with powdered sodium hydroxide and distilled (Note 5). Most of the amine distfls at 184-186°, but the fraction distilling at 180-190° is sufficiently pure for most purposes (Note 6). The yield of this fraction is 80-88 g. By combining the benzene fore-run with the distillation residue, extracting with dilute acid, and recovering the amine as above, an additional 10-12 g. of material can be obtained (Note 7), making the total yield po-ioo g. (60-66 per cent of the theoretical amount based on the acetophenone taken) (Note 8). 

The pure malate (mol. wt. 255) is decomposed by warming with very slightly more (Note 5) than two equivalents of approximately 2 N sodium hydroxide. The amine is extracted, after cooling with three or four 25-cc. portions of pure benzene, the solution is dried thoroughly with powdered sodium hydroxide, and the pure amine, b.p., 184-185°, [app + 39.2° to +39.7° (without solvent), is obtained by distillation (Note 6). A small amount of the amine distils with the benzene. The yield is 35-40 g. (92-94 per cent of the theoretical amount based on the pure malate). 

The filtrate is transferred to a flask which is placed on a rotary evaporator. The ethanol is then removed under reduced pressure on a steam bath. Using ether as a washing solvent, the residue is transferred to a small distilling flask and the ether distilled. Ihe ethyl -dimcthylaminophenylacetate is then distilled (Notes 6, 7) at reduced pressure, affording 27 7-31.8 g. (67-77%) of colorless product, bp. 122-124° (0.4 mm), n23u 1.5358. 

The solution is filtered if not clear, and the cyanoacetic acid is set free (hood) by adding with thorough stirring 600 cc. (a slight excess) of commercial hydrochloric acid (sp. gr. 1.156). The solution is evaporated on a water bath at 60-70° (Note 3) under a pressure of 20 30 mm. and the evaporation continued until practically 110 more distillate (Note 4) comes over. To... 

From the dropping funnel is next slowly introduced, with stirring, 40 g. (0.5 mole) of dry pyridine (Note 4) in 100 cc. of dry toluene. The ether is then distilled (Note 5) and the residual suspension stirred at no0 (inside temperature) for eight hours. It is then cooled to about 40°, 35 cc. of water cautiously added, and the liquids filtered if necessary (Note 6). The lower layer is separated and discarded. The toluene layer is dried for an hour with 20 g. of pulverized potassium hydroxide, and carefully distilled, using a fractionating flask (Org. Syn. Coll. 

Work-up is initiated by extracting the reaction mixture with three 50-ml. portions of aqueous ] N hydrochloric acid, three 50-ml. portions of aqueous 1AT potassium bicarbonate (Notes 7 and 8), and 50 ml. of saturated aqueous sodium chloride. The organic solution is then dried over sodium sulfate (Note 9), filtered, and concentrated on a rotary evaporator. Purification of t lie residue by bulb-to-bulb distillation (Note 10) at about 140° (5 mm.) provides 1.77-1.98 g. (85-95%) of ethyl 4-acetoxybenzoate as a colorless, viscous liquid (Note 11). 

Concentration of the ethereal solution at reduced pressure gives the epoxyacetate as a colorless oil more viscous than water. The overall yield based on farnesyl acetate is near 60% (Note 11). This material is reasonably pure if the preparation has been executed carefully, but it can be further purified by column chromatography (Note 12) or distillation (Note 13). 

Part of the excess hydrogen chloride is removed by blowing (or drawing) air through the solution for 1 hour. The solution then is made alkaline by the slow addition of 50% aqueous sodium hydroxide (Note 4) with mechanical stirring and cooling in an ice bath. Solid sodium hydroxide (24 g.) is added, and the mixture is steam-distilled until no more ammonia and acetophenone pass into the distillate (Note 5). About 3-41. of distillate is collected (Note 6). 

B. Pyridine-N-oxide. The acetic acid solution is evaporated on the steam bath under the pressure of a water aspirator, and the residue (180-190 g.) is distilled at a pressure of 1 mm. or less in an apparatus suitable for collecting a solid distillate (Note 5). The vacuum pump must be protected with a Dry Ice trap capable of holding about 60 ml. of acetic acid, which distils as the pyridine-N-oxide acetate dissociates at low pressure. Heat is provided by an oil bath, the temperature of which is not allowed to rise above 130° (Note 6). The product is collected at 100-105°/1 mm. (95-98°/0.5 mm.). The yield is 103-110 g. (78-83%) of colorless solid, m.p. 65-66° (sealed capillary). The base is deliquescent and must be stoppered immediately. 

The condenser is then set for downward distillation, and, while the mixture is stirred, about 450 ml. of solvent is distilled (Notes 3 and 4). The condenser is reset in the reflux position, and 300 ml. of ether (commercial anhydrous) is added slowly from the dropping funnel with vigorous stirring. This is followed by 50 ml. of ethyl acetate added very slowly with vigorous stirring and finally by 500 ml. of 6 A hydrochloric acid added in the same manner. 

D. 2,6-Dibromoaniline. In a 2-1. flask, equipped with a two-holed stopper carrying an exit tube to a condenser and an entrance tube for steam, 50 g. of crude 3,5-dibromosulfanilamide (Notes 17 and 18) and 250 ml. (5 ml./g.) of 70% sulfuric acid are heated in an oil bath when the temperature of the bath reaches 175— 180°, steam is passed rapidly through the mixture (Note 19). The hydrolysis is continued in this way for 2 hours small amounts of the dibromoaniline distil (Note 20). The bath is then allowed to cool to 105-110°. At this temperature the main mass of the product is steam-distilled. The slightly colored 2,6-dibromoaniline melts at 84-86° and weighs 25-30 g. (66-79% based on 3,5-dibromosulfanilamide) (Note 21). It may be purified by recrystallization from 70% alcohol (7 ml./g.) after recrystallization the product is obtained as long colorless needles which melt at 87-88°. The recovery is 85-90%. 

The crude product is placed in a 1-L, round-bottomed flask and distilled in an Aldrich Kugelrohr apparatus, heated with an air bath, the receiver bulb being cooled with ice water. Partial condensation of (R)-3-hydroxybutanoic acid to oligomers occurs if the temperature is too high during distillation (Note 12). 

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