Organic Process Research & Development
Article
̈
T. Org. Process Res. Dev. 2009, 13, 1401−1406. (e) Otvos, S. B.; Fulop,
̈
̈
̈
and EDTA (tetrasodium salt, 0.38 M). After 19.5 h of
continuous manufacturing corresponding to 3507 mL of Na-
azide solution consumed (5.26 mol), sodium nitrite (36.3 g,
526.05 mmol) and water (1 L) were added and the
homogeneous blue solution was heated to 40 °C under a
strong flow of nitrogen and with no external cooling of a
condenser. A scrubber containing 1 M NaOH was connected,
and a pH-probe was installed. The mixture was then slowly
acidified through slow addition (2.5 h) of concentrated H2SO4
(∼2.1 L). When pH reached ∼7, some minor gas evolution was
observed. At pH = 5.6, ethyl acetate (7.5 L) was added. When
pH 2 had been attained, agitation was stopped and the layers
were separated. Some precipitation occurred of presumed
copper salts, but it was still possible to separate the layers. The
aqueous layer was extracted with EtOAc (2 × 5 L + 1 × 2.5 L)
after which at most only traces of product remained in the
aqueous layer (checked by 1H NMR). The combined brownish
organic layer was washed with brine (3 L + 1 L) to give a clear
organic brown phase. The organic layer was concentrated under
reduced pressure to give the crude acid 1 as a brown solid (955
g, 88% w/w, 94% from Na-azide). The crude compound was
suspended in acetonitrile (2.5 L) followed by concentration to
remove traces of residual water. Acetonitrile (2.5 L) was again
added followed by heating to 60 °C. The brown suspension was
stirred at 60 °C for 1 h followed by slow cooling to 16 °C
overnight. The mixture was then filtered, and the solid collected
was washed with ice-cold acetonitrile (1.5 L). This was
followed by drying under reduced pressure at 44 °C for 20 h
to give 1 as a colorless solid (770 g, 100% w/w, 86% yield based
on Na-azide). Mp 176−178 °C, 1H NMR [400 MHz,
(CD3)2SO] δ 1.23 (d, J = 6.9 Hz, 6H); 2.97 (hept., J = 6.9
Hz, 1H); 5.20 (s, 2H); 7.80−7.82 (m, 1H); 13.35 (s, br, 1H).
13C NMR (100.6 MHz, C2D6SO) δ 22.5 (2 Cs), 25.3, 50.5,
121.9, 153.1, 168.8. HRMS: [M + H]+ m/z calcd for
C7H12N3O2 170.0929, found 170.0925.
F. Catal. Sci. Technol. 2015, 5, 4926−4941.
(7) Wiss, J.; Fleury, C.; Heuberger, C.; Onken, U.; Glor, M. Org.
Process Res. Dev. 2007, 11, 1096−1103.
(8) Compound 1 and esters thereof showed no explosive properties
according to our internal explosive screening protocol.
(9) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057−3064.
(10) For example, see: (a) Salvador, C. E. M.; Pieber, B.; Neu, P. M.;
Torvisco, A.; Andrade, C. K. Z.; Kappe, C. O. J. Org. Chem. 2015, 80,
4590−4602. (b) Zhang, P.; Russell, M. G.; Jamison, T. F. Org. Process
Res. Dev. 2014, 18, 1567−1570. (c) Bogdan, A. R.; Sach, N. W. Adv.
Synth. Catal. 2009, 351, 849−854.
(11) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596−2599.
(12) For example, see: (a) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.;
Fokin, V. V. Org. Lett. 2004, 6, 2853−2855. (b) Gonzal
Espinoza-Vazquez, A.; Negron-Silva, G. E.; Palomar-Pardave,
Romero-Romo, M. A.; Santillan, R. Molecules 2013, 18, 15064−15079.
(c) Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn, M. G. J. Am.
́
ez-Olvera, R.;
M. E.;
́
́
́
̈
Chem. Soc. 2004, 126, 9152−9153. (d) Ozcubukcu, S.; Ozkal, E.;
̀
Jimeno, C.; Pericas, M. A. Org. Lett. 2009, 11, 4680−4683.
(e) Presolski, S. I.; Hong, V.; Cho, S.-H.; Finn, M. G. J. Am. Chem.
Soc. 2010, 132, 14570. (f) Díez-Gonzalez, S. Catal. Sci. Technol. 2011,
1, 166−178.
́
(13) Sonication was applied to facilitate the dissolution of the CuI.
(14) Higher concentrations of the alkyne 3 resulted in precipitation
of CuI, and a two-phase inhomogenous mixture was obtained.
(15) Starting from 2-bromoacetic acid instead of 6 was also
considered as an alternative, but due to the high risk of generating
hydrazoic acid or the need for an external base which might give rise to
solubility problems, this approach was abandonned.
(16) By adding NaNO2 to the hydrolysis mixture followed by slow
acidification, any residual trace of Na-azide is destroyed. A scrubber
containing NaOH and the application of a strong nitrogen flow in the
workup further reduces the risks associated with hydrazoic acid.
(17) Presumably, the preciptate was due to insoluble copper
hydroxides.
(18) By adding Et3N in excess to affect hydrolysis we were able to
obtain a homogeneous solution. However, the reaction was deemed
too slow to be practical in a continuous process.
(19) EDTA was added both to obtain a homogeneous solution which
resulted in a more easily operational process and to make a complex
with the copper salts and thereby minimize risks of formation of
hazardous copper azides.
(20) Although an excess of alkyne 3 is undesirable in the workup
reaction mixture, most of the excess of this was removed during the
nitrogen purging in the receiver batch reactor. It is advised for further
scale-up to optimize the conditions so that as little excess as possible of
alkyne 3 is used.
AUTHOR INFORMATION
Corresponding Author
■
ORCID
Notes
The authors declare no competing financial interest.
REFERENCES
■
(21) For future manufacturing of 1, further optimization is
recommended for the workup procedure. Screening of scavengers
for copper salt is advised to facilitate the extraction procedure.
(1) David, A. M.; Kaur, B. S.; Graham, B. D.; Richard, G. K.;
Kiyoyuki, O.; Thomas, R.; Yogesh, S.; Elizabeth, S. S.; Anthony, S. P.
Patent WO2014053967, 2014.
(2) Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952−3015.
(3) Urben, P. G., Ed. Bretherick’s Handbook of Reactive Chemical
Hazards, 7th ed.; Academic Press: Oxford, 2007; Vol. 2, p 51.
(4) Tickner, C. A.; Gillespie, P. M.; Hoyle, M. Screening Protocol to
Identify Potentially Explosive Compounds in Early Stage Develop-
ment. HAZARDS 25 Symposium Series NO 160 2015, 31, 742−746.
(5) Urben, P. G., Ed. Bretherick’s Handbook of Reactive Chemical
Hazards, 7th ed.; Academic Press: Oxford, 2007; Vol. 1, p 1564.
(6) For examples of similar continuous approaches, see: (a) Teci, M.;
Tilley, M.; McGuire, M. A.; Organ, M. G. Org. Process Res. Dev. 2016,
20, 1967−1973 and references cited therein. (b) Sadler, S.; Sebeika, M.
M.; Kern, N. L.; Bell, D. E.; Laverack, C. A.; Wilkins, D. J.; Moeller, A.
R.; Nicolaysen, B. C.; Kozlowski, P. N.; Wiles, C.; Tinder, R. J.; Jones,
G. B. J. Flow Chem. 2014, 4, 140−147. (c) Baxendale, I. R.; Ley, S. V.;
Mansfield, A. C.; Smith, C. D. Angew. Chem., Int. Ed. 2009, 48, 4017−
4021. (d) Tinder, R.; Farr, R.; Heid, R.; Zhao, R.; Rarig, R. S., Jr; Storz,
G
Org. Process Res. Dev. XXXX, XXX, XXX−XXX