Editing Synthesis of oleylamine

== Preparation of oleoyl chloride<br>  ==

'''Steps'''<br>

a) chlorination of the corresponding acid by treatment with neat thionyl chloride in dichloromethane at reflux temperature, to obtain a solution of corresponding chloride in dichloromethane,<br>(b) addition of the chloride solution of step a) to a solution of liquid ammonia in dichloromethane at a temperature comprised between 0 and 10°C to yield the corresponding amide,<br>(c) reduction of the amide to amine by treatment with lithium aluminium hydride in tetrahydrofuran, followed by extraction of amine by t-butyl methyl ether,<br>(d) purification of amine of step c) by treatment in solution in t-butyl methyl ether by aqueous hydrochloric acid to give a monophasic solution, followed by treatment by acetonitrile to yield amine hydrochloride, and optionally,<br>(e) treatment of amine hydrochloride of step d) by t-butyl methyl ether and a base to yield amine as a free base.<br>

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Due to the very unusual solubility properties of oleylamine and its ammonium salts, it was found that a solution of oleylamine in t-butyl methyl ether could be reacted to the hydrochloride salt by reaction of aqueous hydrochloric acid to give a monophasic solution. This solution could then be precipitated by addition to acetonitrile without need for solvent replacement. The precipitation is extremely tolerant to high levels of water or t-butyl methyl ether giving a very efficient product yield of a white crystalline solid with all non-amine impurities rejected. In&nbsp; step d) high temperature, high vacuum distillation, which would have been time consuming and energy inefficient on a large scale, are avoided. Purification via the ammonium salt effectively reduces any non-amine organic impurities to an acceptable limit (≤0.05% by GC). Precipitation from acetonitrile by TBME avoids the necessity for complete solvent replacement, which is time-consuming on scale. By use of hydrochloric acid (which is used earlier in the process during the amidation quench) no new reagents have been introduced to the process. The return of oleylamine from the hydrochloride was nearly quantitative (95-97%) upon evaporation of the organic phase and the purified product was found to be near 99.5% oleylamine by GC or by acid titration<br>

[[Image:Synthesis_of_oleylamine.png]]<br>

<br>Oleic acid (20.00 kg) (±1%) and dichloromethane (212.00 kg, 160.00 L) (±2%) are charged to the reactor. The stirrer is started. The volume of the medium is about 180 L. The resultant solution is heated to reflux (39-41°C) during about 1 hour.<br><br>To the refluxing solution, a solution of thionyl chloride (10.11 kg) (±1%) is added over 0.75 to 1.25 hours. The volume of the medium is about 186 L.<br><br>The reaction is stirred out at reflux (39-41°C) for 2.75 to 3.25 hours and the yellow coloured acid chloride solution is cooled to 15-25°C and stored under nitrogen for use in the subsequent reaction. The solution should be processed without undue delay.<br> 

=== <br>1.2. Preparation of oleylamide<br>  ===

<br>Dichloromethane (600.00 kg, 452.83 L) (±2%) is charged to the reactor and the stirrer is started. The contents of the reactor are cooled to 0-5 °C. Ammonia (48.00 kg) (±2%) is charged as a liquid over 1.5 to 2.0 hours. To the ammonia solution, the oleoyl chloride solution is added over 1.25 to 1.75 hours at 0-10°C. The volume of the medium is about 580 L.<br><br>The reaction mixture is stirred out at 0-10°C for 1.75 to 2.25 hours. A sample of the reaction mixture is analysed by HPLC (quench sample into MeOH). If the reaction has not proceeded to completion (limit 0.5% acid chloride as the methyl ester by HPLC), then the reaction mixture is stirred out for a further 0.75 to 1.25 hours and resample.<br><br>At the end, the reaction is quenched by addition of 5M hydrochloric acid solution (400.0 L) (±2%). Ammonium chloride formed will dissolve to give two separable layers. The volume of the medium is about 980 L. The lower dichloromethane layer is separated and retained and the upper aqueous layer is removed and discarded. The dichloromethane layer is washed with 1M sodium carbonate solution (2 x 80 L). The maximum approximate volume is 740 L. The combined carbonate washes are extracted and back-extracted with dichloromethane (106.00 kg, 80.00 L) (±2%). The combined dichloromethane layers are washed with water (3 x 100 L) (±2%). The maximum approximate volume is 760 L.<br><br>The dichloromethane solution is distilled to minimum stirred volume at atmospheric pressure and then tetrahydrofuran is charged (426.72 kg, 480.00 L)(±2%) while continuing the distillation until a pot temperature of &gt;65°C is obtained; the distillate is &lt;1% dichloromethane by Gas Chromatography. If level of dichloromethane is &gt; 1% distillation is continued with addition of tetrahydrofuran until specification is met.<br><br>The tetrahydrofuran solution is concentrated to ~10% w/w (~220.0 L), removed from the reactor and stored for use in the subsequent reduction reaction.<br> 

=== <br>1.3. Preparation of oleylamine<br><br>  ===

<br>1.0 M lithium aluminium hydride solution is charged in tetrahydrofuran (160.20 kg, 177.02 L) (±1%) to the reactor and the stirrer is started. The reactor contents are heated to 50-60°C. To the lithium aluminium solution the amide solution in tetrahydrofuran is charged over 1.75 to 2.25 hours, maintaining the reaction temperature between 50-60°C. The approximate volume is 397.0 L. The reaction is stirred at 50-60°C for 1.75 to 2.25 hours. The reaction mixture is sampled and analysed by gas chromatography GC (quench sample into excess 32% NaOH solution and remove lower aqueous layer). The limit is 0.5% oleylamide by GC. If the reaction has not proceeded to completion, the medium is stirred-out for a further 0.75 to 1.25 hours and resampled. The reaction mixture is cooled to 15-25°C.<br><br>Into the larger paired reactor 32% w/w sodium hydroxide solution is charged in water (800.00 Kg) (±5%). Approximate volume is 595 L. The reaction mixture is charged to the sodium hydroxide solution via the charge vessel over 1.0 to 2.0 hours, maintaining the temperature of the reactor contents below 40°C. Approximate volume is 995 L.<br><br>T-butyl methyl ether (148.00 kg, 200.00 L)(±2%) is charged to the reactor and stirred for 0.25 to 0.75 hours. The mixture is allowed to separate. Approximate volume is 1 195 L.<br><br>The lower aqueous layer is separated and retained. The upper organic layer is removed and retained. The aqueous layer is re-extracted with t-butyl methyl ether (74.00 kg, 100.00 L) (±2%). Approximate volume is 670 L. The combined organic layers are washed with deionised water (3 x 200 L) (±5%). Approximate maximum volume is 520 L.<br><br>The resultant organic solution is concentrated to give a ~15-20% w/v solution of crude product in t-butyl methyl ether (containing ~15 Kg of oleylamine). Approximate volume is 90 L.<br><br> 

=== 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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