Synthesis of Organic Azides via Flow ChemistrySilver, J.E. (jack.silver@teledyne.com), Lewis, R.L., Fowler, N., Letteney, E.N., Clay, D.

Teledyne Isco

The synthesis of an organic azide using flow chemistry is described using a reaction apparatus constructed with an inexpensive continuous flow pump and 316 stainless steel HPLC tubing. There are safety issues with azide synthesis; in protic solvent systems hazardous hydrazoic acid can easily form. Azide reactions are often run below hydrazoic acid’s boiling point of 36 °C to avoid accumulation of this toxic and shock-sensitive compound. As flow chemistry has no headspace to accumulate hydrazoic acid, reactions can safely be run at a higher temperature without the accumulation of hydrazoic acid allowing shorter reaction time and synthesis of larger amounts of the desired azides than traditional batch methods.

Flow chemistry has some advantages over traditional batch chemistry. Since only a small volume of reactants are combined at any one time, the actual reaction volume is quite small, typically milliliters. The nature of the reaction apparatus lends itself to accurate temperature control; the high surface area of the apparatus allows rapid heat dissipation or heat adsorption. Flow chemistry reactions are easily scalable. Flow chemistry reactions are easily scalable and can be run with the same apparatus in parallel or simply increasing the volume of the reactants, and running the reaction for a longer time. Scaling up tradition reaction vessels often involves heat transfer issues.

1-(Azidomethyl)-3,5-bis-(trifluoromethyl)benzene 1 is an intermediate to an NK1-II antagonist 2 and investigational compounds 3 and 41.

All chemicals were purchased from Sigma Aldrich unless otherwise specified. Sodium Azide (2.2 g, 33.8 mmol) was dissolved in 15.0 mL LC-MS grade water. 3,5-Bis-(trifluoromethyl)benzyl chloride (1.0 g, 3.84 mmol) was dissolved in 10.0 mL DMSO.

Azides are useful functional groups. They are used for azide-alkyne cycloadditions, reduction to 1° amines, production of amides, and cyclization via the Schmidt reaction. There are safety issues with azide synthesis; in protic solvent systems hydrazoic acid can easily form. Azide reactions are run below hydrazoic acid’s boiling point of 36 °C to avoid accumulation of this toxic and shock-sensitive compound. As flow chemistry has no headspace to accumulate hydrazoic acid, reactions can safely be run at higher temperatures without accumulation of hydrazoic acid.

The reaction was essentially clean via UHPLC (Agilent 1290, 2x50 mm C18 UHPLC column, gradient 5-100% methanol over 5 minutes, 0.50 mL/min, 220 nm)

Abstract

Background

Experimental and Results

Conclusion

Two ReaXus™ 6010R pumps (Teledyne Isco, Lincoln, NE, PN 69-2253-332) were used; one for each reactant. The pumps were connected via a T connector to 30.5 meters (25 mL volume) of 316 stainless steel tubing (1/16 inch OD, 0.040” ID, Idex Life and Science). The end of the tubing was connected to a 250 psi back pressure regulator (Idex Life and Science); ~29 meters of the tubing was coiled and placed in a 90 °C constant temperature bath. Most of the remaining tubing was coiled placed in an ice bath. The outlet with the back pressure regulator was di-rected into a flask containing ~60 mL each of water and cyclohexane.

The pump delivering 3,5-Bis-(trifluoromethyl)benzyl chloride was flushed with DMSO prior to the run. The refill line for this pump was placed in DMSO after the vial containing this reactant was empty. The sodium azide pump was flushed with water and with the sodium azide solution; the refill line was placed in water after the sodium azide solution was used solution. The 3,5-Bis (trifluoromethyl)benzyl chloride solution was delivered at 0.5 mL/minute; the sodium azide solution was delivered at 0.5 mL/minute. After the vials were empty, 20 mL of DMSO and were pumped followed by 20 mL water.

The cyclohexane layer was separated, dried over sodium sulfate, and evaporated to yield 0.84 g clear oil (1.03 g expected, 81% yield).

The ReaXus pumps are useful to deliver reactants to tubing reactor. The pulse dampener in the pump allowed a constant flow of both reactants into the reaction tubing during pump refill strokes. The pumps are suitable for a small scale (milligram to low gram scale) reactions due to the easy set-up and small pump head volumes. The pumps allow the reaction, in a safe manner, an azide reaction with a total synthesis time of 50 minutes through the use of elevated temperature. The reaction is very clean with pure 1-(Azidomethyl)-3,5-bis-(trifluoromethyl)benzene as determined with UHPLC.

1Kopach, M.E., Murray, M.M, Braden, T.M., Kobierski, M.E., Williams, O.L. Improved Synthesis of 1-(Azidomethyl)-3,5-bis-(trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes. Org. Process Res. Dev.2009, 13, 152-160

Sodium Azide

ReaXus 1 ReaXus 2

Reaction coilheated to 90 ˚C

3,5-Bis-(tritluoromethyl)benzyl chloridedissolved in DMSO

Sodium Azidedissolved in water

Cooling coil inice bath

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