Editing Synthesis of oleylamine (section)

=== 1.4. Purification of oleylamine  ===

<br><br>To the stirred crude amine solution in TBME (~90 L) pf step 1.3, 6.7 Kg (1.2 eq) (±2%) of concentrated (37%) '''hydrochloric acid''' are added via dosing pump, over 15-30 minutes, at a temperature of 20-30°C (exothermic addition). Approximate volume is 95 L. The clear monophasic solution is stirred for at least 30 minutes at 20-30 °C and '''acetonitrile''' (225.0 L, 176.85 Kg) (±5&nbsp;%) is charged to the paired reactor. The hydrochloride salt solution is charged to the acetonitrile over 30-60 minutes to form a white precipitate. Approximate volume is 320 L.<br><br>The precipitate is cooled to 0-6°C, hold for at least 1 hour and filtered. The cake volume is about 90 L. The precipitate is washed with 2 x 35 L of chilled acetonitrile and the solid is dried at 25-30°C to constant weight (DSC performed).<br><br>The dried solid is transferred back into the reactor and 10 weight volumes (-135 L, 100 Kg) of TBME are added. The reaction medium is stirred until a solution is obtained. Approximate volume is 150 L.<br><br>2 equivalents (~50.5 L) of 2M sodium hydroxide solution in water are added over 15-30 minutes at 15-25°C (addition is slightly endothermic). Approximate volume is 200 L and the biphasic mixture is stirred for at least 1 hour at 15-25°C and allows separating. The lower aqueous layer is removed and discarded. The organic solution is washed with water (2 x 35L), azeo-dried by distillation at atmospheric (b.p. TBME 58°C) and then concentrated to dryness under full house vacuum until residual levels of TBME are within ICH guidelines by headspace GC.<br> 

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==== Lab scale purification<br> ====

To a 250 cm3 round-bottomed flask fitted with magnetic stirrer, nitrogen inlet, temperature probe, condenser and a 100 cm3 pressure-equalized dropping funnel, was charged crude elaidylamine (17.0 g, 63.6 mmol) and '''t-butyl methyl ether''' (85 cm3, 5 volumes). The substrate did not dissolve, so an additional 85 cm3 of TBME was added. Although a solution was not obtained, the resultant slurry was deemed adequate for further processing. The stirred slurry was treated with 37% '''hydrochloric acid''' (7.6 g, 1.2 eq.). During this addition the slurry became very thick and difficult to stir, suggesting that '''elaidylamine hydrochloride is poorly soluble in TBME'''. '''Water (100 cm3) was therefore added''' which eventually yielded a clear monophasic solution. The hydrochloride was then precipitated by addition to excess '''acetonitrile''' (750 cm3). The resultant suspension was cooled to 0-5°C, stirred for 30 minutes, filtered and washed with cold acetonitrile (2 x 200 cm3). The solid was then dried under vacuum at 30-35°C to yield elaidylamine hydrochloride as a white crystalline powder (12.1 g, 63%) The hydrochloride (12.1 g) was then slurried in TBME (180 cm3, 15 volumes) and treated with 2M sodium hydroxide solution (40 cm3, 2 eq.). During the addition the solid dissolved to give a bi-phasic solution which was stirred overnight. The mixture was then transferred to a separating funnel, the'''lower aqueous layer removed,''' and the organic phase washed with water (2 x 50 cm3). The resultant product solution was then evaporated to yield elaidylamine as clear oil, which solidified upon cooling to room temperature (10.7 g, 100% from hydrochloride, 63% from crude amine).<br>

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