Methylamine hydrochloride from acetamide

METHYLAMINE HYDROCHLORIDE (from Acetamide) Place 25 g. of dry acetamide in a 350 ml. conical or flat-bottomed flask, and add 69 g. (23 ml.) of bromine (CAUTION ) a deep red liquid is produced. Cool the flask in ice water and add 10 per cent, sodium hydroxide solution (about 210 ml.) in small portions and with vigorous shaking until the solution acquires a pale yellow colour. At this stage the bromoacetamide is present in the alkaline solution. If any solid should crystallise out, add a little water. 

Assemble the apparatus shown in Fig. 111,56, 1, using a 1-litre distilling flask replace the filter flask receiver by a small funnel attached to the end of the condenser by a short length of rubber tubing and dipping about 0-5 cm. below 100 ml. of dilute hydrochloric acid (1 1) contained in a beaker. Place a solution of 60 g. of sodium hydroxide in 150 ml. of water, together with a few fragments of porous porcelain, in the flask and the bromoacetamide solution in the separatory funnel. Warm the solution in the flask until the thermometer in the liquid reads 60-70°. Allow the bromoacetamide solution to run slowly into the flask at such a rate that the temperature does not rise above about 70° heat is evolved 

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A mixture of acetamide (30 g. = 0-5 mole) and bromine (80 g. = 26 c.c.) in a half-litre flask is kept well cooled with water while enough of a solution of 50 g. of potassium hydroxide in 350 c.c. of water is added to change the initially red-brown colour into a pale yellow this requires most of the alkali. The solution is now run from a dropping funnel in an unbroken jet into a solution of 80 g. of potassium hydroxide in 150 c.c. of water, maintained at 70°-75° in a litre flask. The operation lasts for several minutes. Until the reaction mixture becomes colourless (one quarter to half an hour) the temperature is maintained at 70°-75°, and then the methylamine is distilled with steam. An adapter is fixed to the lower end of the condenser and dips 1 cm. below the surface of the liquid in the receiver (100 c.c. of approximately 5 N-hydrochloric acid2). As soon as the liquid which forms in the condenser is no longer alkaline the distillation is discontinued and the contents of the receiver are evaporated to dryness in a porcelain basin on the water bath. The last traces of water are removed by allowing the basin to stand over night in a vacuum desiccator. The dried material is boiled with absolute alcohol, which dissolves the methylamine hydrochloride but not the ammonium chloride with which it is mixed. The clear filtrate obtained when the ammonium chloride is removed by filtration is concentrated to a small volume and the methylamine hydrochloride is allowed to crystallise out in the cold. The salt is filtered with suction, washed with a little alcohol, and dried in a desiccator. Yield 15-20 g. 

Preparation qf2-amino-2-(4 -hydroxyphenyl)-N-methyl acetamide 190 [125] Tri-methylsilyl chloride (64.6 mL, 0.75 mol, 2.5 equiv.) was added dropwise over 30 min to a suspension of 4-hydroxyphenylglycine 189 (50 g, 0.3 mol, 1 equiv.) in MeOH (500 mL) at 0 °C and the resulting clear solution was stirred at 35 °C for 48 h. Evaporation of the solvent from an aliquot (1 mL) gave the hydrochloride salt as a white solid. The reaction mixture was diluted with a further volume of MeOH (250 mL), Amberlyst21 (500 g, 1.5 mol, 5 equiv., 3 inmolg Fluka Cat. No. 06424) 191 was added, and the mixture was shaken at ambient temperature for 2 h (Caution this process was mildly exothermic ). The resin was then removed and washed with MeOH (3 x 150 mL). Removal and concentration of a second ahquot (1 mL) of the pale-yellow filtrate gave an off-white solid, which was characterized as the free base. The bulk solution was then reduced in volume to one half of the original, methylamine (31.06 g, 0.9 mol, 3 equiv.) was added, and the mixture was... 

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