Development of an efficient and sustainable synthesis of 2-(3-methyl-1: H-1,2,4-triazol-1-yl) acetic acid under continuous-flow conditions

Article abstract of DOI:10.1039/c9gc04286e

A novel, metal-free process for the challenging synthesis of 2-(3-methyl-1H-1,2,4-triazol-1-yl) acetic acid is reported, which features an efficient construction of the triazole ring under flow conditions. This continuous, one-pot method is atom economical, highly selective and environmentally benign, due to the avoidance of chromatography and isolation steps. Compared to the earlier batch routes, higher yields were achieved in a flow reactor. In addition, a highly-energetic intermediate could be controlled and handled in a safe manner. To generalize the established route, several triazoles were prepared under the described conditions, confirming that the methodology could find useful applications for the rapid and sustainable construction of differentially-functionalized 1,2,4-triazoles.

Full text of DOI:10.1039/c9gc04286e

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Development of an Efficient and Sustainable
Synthesis of 2-(3-Methyl-1H-1,2,4-triazol-1-yl)
Acetic Acid under Continuous-Flow Conditions
Simone Tortoioli,‡,* Astrid Friedli,† Alice Prud’homme,‡ Sylvia Richard-Bildstein,† Philipp
Kohler,‡ Stefan Abele,‡ and Gianvito Vilé,†,§,*
†Chemistry Technologies & Lead Discovery, Department of Drug Discovery Chemistry, Idorsia
Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
‡Chemical Development & Commercial Manufacturing, Idorsia Pharmaceuticals Ltd.,
Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
§Current address: Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”,
Politecnico di Milano, Piazza Leonardo da Vinci 32, IT-20131 Milano, Italy.
KEYWORDS: Triazole synthesis; alkylation; condensation; flow chemistry;
process intensification; heterocycles.
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2

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ABSTRACT
A novel, metal-free process for the challenging synthesis of 2-(3-methyl-1H-1,2,4-
triazol-1-yl) acetic acid (1) is reported, which features an efficient condensation for the
triazole build-up under flow conditions. This continuous, two-step method is atom
economical, highly selective and environmentally benign, due to the avoidance of
chromatography and isolation steps. Compared to the earlier batch synthetic routes,
higher yields were achieved in a flow reactor. In addition, a highly energetic intermediate
could be controlled and handled in a safe manner. To generalize the established route,
several triazoles were finally prepared under the described conditions, confirming that the
methodology could find useful applications for the rapid and sustainable construction of
differentially functionalized 1,2,4-triazoles.
3

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O
simple & cheap
N
N
continuous & one pot
2.4 g h-1
O
60% tot. yield
H2N
O
N
N
OMe
OMe
OEt
N
N
O
H
N
H2N
OEt
4

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Introduction
Small nitrogen-containing heterocycles are broadly present in molecular frameworks
displaying functional properties of key relevance for the pharmaceutical, agrochemical
and material science fields.1 In this context, 1,2,3- and 1,2,4-triazoles occupy a prominent
role in modern synthetic chemistry2 and, thanks to their modularity, they can either be
‘bought-in’ within larger molecules by N-alkylation strategies, or alternatively ‘built-in’
directly via cyclization reactions. While the first approach is more suited for commercially
1
Katritzky, A. R.; Rachwal, S. Chem. Rev. 2010, 110, 1564-1610. (b) Padwa, A.;
Waterson A. G. Current Org. Chem. 2000, 4, 175-203. (c) Majumdar, K. C.; Debnath, P.;
De, N.; Roy, B. Current Org. Chem. 2011, 15, 1760-1801. (d) Joule, J. A.; Mills, K.
Heterocyclic Chemistry 5th Edition 2010, Ch. 31-33, Wiley-Blackwell.
2 (a) Zhang, S.; Xu, Z.; Gao, C.; Ren, Q.-C.; Chang, L.; Lv, Z.-S.; Feng, L.-S. Eur. J. Med.
Chem. 2017, 138, 501-513. (b) Kumar, V.; Kaur, K. J. Nat. Prod. 2014, 4, 115-130. (c)
Díaz-Ortiz, A.; Prieto, P.; Carrillo, J. R.; Martín, R.; Torres, I. Current Org. Chem. 2015,
19, 568-584. (d) Song, M. X.; Deng, X.-Q. J. Enzyme Inhib. Med. Chem. 2018, 33, 453-
478. (e) Zhou, C. H.; Wang, Y. Current Med. Chem. 2012, 19, 239-280. (f) Al-Masoudi,
A.; Al-Soud, Y. A.; Al-Salihi, N. J.; Al-Masoudi, N. A. Chem. Heterocycl. Compd. 2006,
42, 1377-1403.
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available unsubstituted triazoles, the latter is addressing at best the need of adjustable
mono-, bis- and tris- substituents on the triazole ring.3
We became interested in developing a method to rapidly supply kilogram amounts of
2-(3-methyl-1H-1,2,4-triazol-1-yl)acetic acid (1). An obvious approach able to furnish
initial multi-grams amount of material relied on the ‘buy-in’ strategy from commercial 3-
methyl-1H-1,2,4-triazole (3) through alkylation with bromoacetate 2 (Scheme 1). Since
moderate selectivity on the N-alkylation was anticipated, a chromatography to purify the
desired N-1 isomer was deemed necessary.
O
O
O
N
N
N
NH
N
N
+
OR
OH
OR
N
N
N
Br
1
N-1,2,4 isomers
2
3
Scheme 1. Initial synthetic ‘buy-in’ approach to acid 1.
3
Zhang, H.-Z.; Damu, G. L. V.; Cai, G.-X.; Zhou, C.-H. Current Org. Chem. 2014, 18,
359-406.
6

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While on the short term this approach was a good fit, on the longer run we aimed to
have a more efficient route achieving higher yields and devoid of chromatographic
purifications, which are particularly problematic for large scale applications, due to the
economic and environmental impacts associated with the use and disposal of large
amounts of organic solvents.
Looking at alternative synthetic strategies for a more sustainable and efficient process,
we rapidly realized that the selectivity problem associated with the N-alkylation of 2 could
be overcome only with a ‘built-in’ approach, i.e. via the formation of 3-methyl triazole
moiety by cyclization.4 To be competitive, the new strategy would require simple,
commercially available starting materials and mild reaction conditions. A possible
alternative, where the triazole could be assembled through condensation between simple
4 Screening of bases, solvents, temperatures and type of nucleophiles for the alkylation
of 2 was performed (but not detailed here for the sake of conciseness), showing only a
very limited effect on the selectivity. For a similar result, see: Fox, R. J.; Tripp, J. C.;
Schultz, M. J.; Payack, J. F.; Fanfair, D. D.; Mudryk, B. M.; Murugesan, S.; Chen, C. P.
H.; La Cruz, T. E.; Ivy, S. E.; Broxer, S.; Cullen, R.; Erdemir, D.; Xu, P. G. Z.; Fritz, A.;
Doubleday, W. W.; Conlon, D. A. Org. Process Res. Dev. 2017, 21, 1095-1109.
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ethyl hydrazinoacetate 4 as hydrazine synthon and acetimidamide 5 as electrophilic
partner, was proposed from a different retrosynthetic disconnection (Scheme 2). The
latter could be derived from commodity chemicals such as formamide and
dimethylacetamide dimethylacetal 6.
O
O
O
OMe
OMe
N
3
N
+
N
N
N
OH
H2N
N
1
5
6
formamide
O
H
N
H2N
OEt
4
Scheme 2. New retrosynthetic ‘built-in’ plan to acid 1.
A similar approach was previously reported for the preparation of 5-methyl-1,2,4-
triazole derivatives.5 In those cases, acetamide was employed to generate reactive amide
derivative 8 which underwent cyclization to 5-methyltriazoles 10 (Scheme 3).
5
(a) Naidu, B. N.; Ueda, Y.; Matiskella, J. D.; Walker, M. A.; Banville, J.; Beaulieu, F.;
Ouellet, C.; Plamondon, S. US2007/0111984 A1, 2007 (assigned to Bristol-Meyer
Squibb). (b) Nosse, B.; Eckhardt, M.; Himmelsbach, F.; Langkopf, E.; Ashweek, N. J.;
Harriot, N. WO2014/019967 A1, 2014 (assigned to Boehringer Ingelheim GmbH). (c)
Heckel, A.; Himmelsbach, F.; Langkopf, E.; Nosse, B.; Ashweek, N. J.; Harriot, N.
US2013/0143892 A1, 2013 (assigned to Neurocrine Biosciences Inc. and Boehringer
8

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H
N
H2N
R
OMe
OMe
H
O
R
N
O
9
-MeOH
N
H
+
N
N
N
C-5
AcOH
H2N
acetamide
N
7
8
10
Scheme 3. Literature precedent for the synthesis of 5-methyltriazole derivative through
cyclization with amide derivative 8.5
Although the analogous acetimidamide 5 has never been described before and the
preparation of 3-methyl-1,2,4-triazole derivatives has not been reported with such
synthetic strategy,6 the existing precedents gave us good confidence about the
Ingelheim GmbH). (d) For a large-scale example of 5-substituted 1,2,4-triazole, see:
Huang, Q.; Richardson, P. F.; Sach, N. W.; Zhu, J.; Liu, K. K.-C.; Smith, G. L. Org.
Process Res. Dev. 2011, 15, 556-564.
6 Dimethylacetamide dimethylacetal 6 has been condensed with various primary amides
for the preparation of 3-methyl-5-substituted-1,2,4-triazoles. For representative
examples, see: Bist, S.; Dangel, B.; Sherer, B. WO2009/106885, 2009 (assigned to
AstraZeneca UK Ltd.). (b) Czollner, L.; Szilágyi G.; Langó, J.; Janáky, J. Arch. Pharm,
1990, 323, 225-227. (c) Wang, W.; Zhao, X.; Zhang, H.; Fang, B.; Rong, Y.; Yuan, Q.;
Tian, Q.; Fu, J.; Deng, J.; Zeng, F.; Lin, M. WO2014/75317, 2014 (assigned to Shanghai
Fochon Pharmaceutical Co. Ltd.). (d) McComas, C.; Liverton, N. J.; Habermann, J.; Koch,
U.; Njares, F.; Li., P.; Peng, X.; Soll, R.; Wu, H.; Palani, A.; He, S.; Dai, X.; Liu, H.; Lai,
9

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alternative route. In addition, we aimed to develop a process under continuous flow
conditions due to the well-recognized advantages of improving efficiency, selectivity, safety
and reproducibility as compared to traditional batch chemistry.7 Making use of this principle, we
describe herein the successful development of a new, scalable and concise synthesis of triazole
acetic acid 1 and how the application of continuous-flow conditions allowed increased waste and
yield efficiencies along with improved process safety.
Results and Discussion
Z.; London, C.; Xiao, D.; Zorn, N.; Nargund, R WO2013/33971, 2013 (assigned to Merck
& Co.). (e) Tereshchenko, A. D.; Myronchuk, J. S.; Leitchenko, L. D.; Knysh IV, L. D.;
Tokmakova, G. O.; Litsis, O. O.; Tolmachev A.; Liubchak K.; Mykhailiuk P. Tetrahedron
2017, 73, 750-757.
7
(a) Vaccaro, L.; Lanari, D.; Marrocchi, A.; Strappaveccia, G. Green Chem. 2014, 16,
3680-3706. (b) Koenig, S. G.; Sneddon, H. F. Green Chem. 2017, 19, 1418-1419. (c)
Contente, M. L.; Farris, S.; Tamborini, L.; Molinari, F.; Paradisi, F. Green Chem. 2019,
21, 3263-3266. (d) Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem. Int. Ed. 2015,
54, 6688-6728. (e) Hessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.; Wang, Q.
ChemSusChem 2013, 6, 746-789. (f) Amini-Rentsch, L.; Vanoli, E.; Richard-Bildstein, S.;
Marti, R.; Vilé, G. Ind. Eng. Chem. Res. 2019, 58, 10164-10171. (g) Baxendale, I. R.;
Schou, S. C.; Sedelmeier, J.; Ley, S. V. Chem. Eur. J. 2010, 16, 89-94. (h) Martin, R. E.
Science 2016, 352, 44-45.
10

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1st generation batch process. The triazole N-alkylation synthesis used at the beginning of our
investigation to satisfy the need of the first multi-gram amount of carboxylic acid 1 is outlined in
Scheme 4. The choice of benzyl bromoacetate 2a was dictated by the high polarity and hydrophilic
nature of acid 1. Extraction of the free acid from aqueous phases was, in fact, not possible with
conventional organic washes. The benzyl group decreased the polarity of the corresponding ester
11a while improving its UV detection by conventional LC/MS and allowed the ester cleavage in
the last step to be performed in the absence of water. N-alkylation of the triazole 3, performed
under acetone/K2CO3 conditions, afforded in quantitative yields an isomeric mixture with no
selectivity towards the N-1 isomer 11a which was present in a poor 46% a/a purity.
O
OBn
N
O
N
Br
plug
O
OBn
N
N
2a
N
NH
N
+
+
N
OBn
EtOAc/hept 9:1
K2CO3,
acetone
quant.
N
N
N
OBn
N
O
3
11a
11a
11a
N-4- (14%)
N-2-
(40%)
(46%)
O
O
recryst
H2, Pd/C
O
O
OBn
N
N
N
N
N
N
N
+
N
OH
OBn
OBn
TBME
20% tot.
MeOH
95%
N
N
N
N
11a
11a
1
11a
N-2-
Scheme 4. 1st generation batch synthesis of 2-(3-methyl-1H-1,2,4-triazol-1-yl)acetic acid
(1).
Since the crude mixture appeared as an oily residue and attempts of purification by direct
precipitation were unsuccessful, a silica gel plug was required to remove the N-4 isomer, while the
N-2 isomer could not be separated at this stage from 11a due to the very similar retention factor.
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The plug was highly efficient and required only 1.8 wt. silica and 23 vol. solvent relative to the
crude isomeric mixture. From the purified ca. 1:1 mixture obtained after the plug, a selective
crystallization from TBME gave ester 11a as a white solid. The price to pay for this tedious
purification sequence was reflected by a total yield of only 20%. Hydrogenation occurred with no
issue and the acid product 1 was obtained in high purity with excellent yield for this step. Even if
the limitations of this ‘built-in’ approach are undeniable, the process was robust enough to be used
several times and fulfill material needs, with a maximum scale of 1.6 kg of triazole 3 as input and
498 g of acid 1 as output (see experimental part for details).
2nd generation batch process. According to the alternative synthetic strategy outlined in
Scheme 2, acetimidamide 5 was obtained in good yields by simply heating a mixture of
formamide and N-N’-dimethylacetamide dimethylacetal (6) in dioxane at 50 °C and
removal of the generated methanol under reduced pressure (Scheme 5).8
8
For representative applications of amidines of type 5 besides heterocycles formation,
see: Dineen, T. A., Zajac, M. A.; Myers, A. G. J. Am. Chem. Soc. 2006, 128, 16406-
16409, and references cited therein. (b) Blake, A. J.; McNab, H.; Murray, M. E.-A. J.
Chem. Soc., Perkin Trans 1, 1989, 589-595. (c) Bredereck, H.; Simchen, G.; Funke, B.
Chem. Ber. 1971, 104, 2709-2726.
12

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O
HCl
H
dioxane, 50 °C
180-140 mbar
(-MeOH)
N
H2N
OEt
O
HN
NH
N
O
O
OMe
OMe
4a
+
N
N
N
H2N
75-85%
dioxane, rt
6
formamide
5
O
OEt
open form
O
N
N
NH2
N
N
OEt
35%
N
11b
12
Scheme 5. 2nd generation synthesis of 1: formation of the triazole ethyl ester 11b in
batch mode.
Subsequently, by dosing isolated intermediate 5 into a suspension of ethyl
hydrazinoacetate hydrochloride (4a) in dioxane at room temperature, to our delight the
formation of triazole ethyl ester 11b occurred rapidly under mild conditions, with the
observation of the open intermediate as well.9 The resulting suspension was filtered to
remove insoluble salts formed, followed by ordinary aqueous work-up to afford the
product in ca. 80% yield as crude but only 70% purity. After crystallization, triazole 11b
was obtained in a poor 35% yield albeit in pure form (>99% a/a, >98% w/w). Attempts to
9
The open form intermediate was not isolated but only detected by LC-MS and its
structure confirmed by m/z data.
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optimize purity and recovery on this condensation step by looking at solvents, additives
such as acids and bases, order of addition and temperature gave scarce results. The low
recovery of the isolated crude could be attributed to the presence of several polar
impurities, with the major one being hydrazine adduct 12 which precipitated from the
reaction mixture and was subsequently filtered off.
While the hydrazine content in the acetate 4a can in principle be controlled by the purity
of the starting material itself,10 the finding demonstrates no kinetic advantage of the
desired reaction pathway towards possible side-reactions. Impurities either coming from
the starting materials (hydrazine) or from the synthesis could have a detrimental effect on
the reaction performance due to the highly reactive nature of acetimidamide 5.
Not surprisingly, intermediate 5 is also an energetic compound, as shown by the
differential scan calorimetry (DSC) where a H of 328 J/g and a left limit temperature of
10
Different batches and suppliers of ethyl hydrazinoacetate hydrochloride 4a were not
tested and at this stage there is no information about hydrazine content on commercial
supplies of 4a.
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50 °C were found (Figure 1), indicating thermal decomposition and potential hazard for
this compound already at room temperature. Ideally, intermediate 5 should be produced
and reacted in situ avoiding any isolation. This could be practically realized under flow
conditions through the design of a one-pot, two-step continuous process where every
new molecule of acetimidamide 5 formed in a first reactor is directly pumped into a second
reactor with hydrazine 4a for the condensation step, limiting its accumulation and handling.
In this way, we also sought to improve the yield and purity as a direct consequence of the
minimization of thermal stress and concentration effects which might favor decomposition
pathways of intermediate 5.
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1.4
1.2
1
0.8
0.6
Integral
697.07 mJ
normalized 328.81 J g–1
Peak
Left Limit
Right Limit
131.24 °C
50.08 °C
201.44 °C
0.4
0.2
0
40
60
80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400
temperature, T (°C)
Figure 1. DSC of acetimidamide 5 (heat ramp: 4 °C/min).
2nd generation continuous-flow process. To develop a combined, two-step process, we
used a continuous-flow system consisting of coil tubes of 10 mL internal volume coupled
with peristaltic pumps. Each of the two reaction steps was first optimized individually.
For the synthesis of the acetimidamide 5, Figure 2 shows the influence of residence
time, solvent and temperature on the conversion of formamide and purity of 5.
O
O
OMe
OMe
+
N
N
N
H2N
6
formamide
5
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Figure 2. Effect of residence time, temperature and solvent on the conversion of
formamide (white squares) and acetimidamide 5 purity (black circles) under continuous-
flow conditions.
The conversion of formamide increased with the residence time (left graph, Figure 2),
from 33% a/a at a residence time of 2 min to 98% a/a at 20 min, remaining constant
afterwards. The purity of intermediate 5, on the other hand, first increased with the
residence time, reaching a maximum of 60-65% a/a at a residence time of 10-13.3 min,
before starting to drop with prolonged times. Compared to the batch protocols where the
reactions took several hours to complete, it is well known that the use of a continuous
reactor improves the throughput and shorten reaction times thanks to the better transport
phenomena (mixing, diffusion) in the small cross-section of the reactor. The temperature
had a less marked impact on the conversion, since only minor changes could be detected
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in the product feed between 80 and 120 °C (central graph, Figure 2). The product purity,
in contrast, increases with the temperature, from 60% a/a at 80 °C to 85% a/a at 120 °C,
suggesting that higher temperatures accelerate the main reaction while limiting potential
secondary ones. The role of the solvent (dioxane, DMF, and DMSO; right graph, Figure
2) was also studied showing little influence on the conversion but an effect on the purity,
with better results in DMSO and DMF (85.4 and 91% a/a purity, respectively).
Based on these results, our optimal conditions for the acetimidamide 5 formation step
were a temperature of 120 °C, pressure of 1 bar and a residence time of 13.3 min. DMSO
was chosen as solvent over DMF due to easier removal in the aqueous phase during the
work-up (see experimental part for details).
For the subsequent condensation step to form triazole 11b, we also explored the
influence of residence time and temperature on the isolated yield as well as purity of the
final product. The results are reported on Table 1. In this case, the pressure was kept at
1 bar to allow the two steps to be run consecutively without any intermediate work-up or
manipulation.
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Table 1. Influence of residence time and temperature on the synthesis of 11b under
continuous-flow conditions.
O
O
N
4a
+
N
N
N
OEt
N
5
11b
Entry
Solvent T [°C]
τ [min]
Yielda
57%
64%
46%
45%
39%
32%
Purityb
1
2
3
4
5
6
DMSO
DMSO
DMSO
DMSO
DMF
25
25
50
70
25
–30
5.0
6.7
5.0
5.0
5.0
5.0
84% (89%)c
89% (95%)
85% (89%)
89% (91%)
81% (82%)
82% (84%)
DMF
a Upon isolation. b Determined by LC-MS (% a/a). c Determined by 1H-
NMR with internal standard.
The isolated yield of 11b increased with the residence time from 57% at a residence
time of 5 min, to 64% at 6.7 min (entries 1 and 2, respectively). The purity of 11b also
improved, passing from 85-90% at 5 min to 90-95% at 6.7 min. Longer residence times
were also explored (up to 20 min; not shown in the table for the sake of conciseness) but
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did not improve the reaction further. The temperature, also in this case, seemed to have
a less pronounced effect on the reaction, as the yield decreased only slightly going from
25 °C to 70 °C (from 57% to 46%, entries 1, 3 and 4), confirming the findings on the
instability of intermediate 5 and suggesting low temperatures to minimize side reactions.
Analysis of the aqueous aliquots of the reactions at 50 and 70 °C (entries 3 and 4) after
work-up showed a higher fraction of the polar side-products, such as 12, as observed
during the development of the batch process. We then explored the possibility to perform
the reaction below 0 °C using a cryostat to cool the coil. For this purpose, DMF was used
to avoid freezing of the solvent and, as comparison, the reaction at 25 °C was performed
achieving lower isolated yield (39%) and product purity (80-82%, entry 5). At -30 °C, the
result is even worse, with 32% isolated yield and 80-85% purity (entry 6). As a result,
optimal reaction conditions for the second step were therefore T = 25 °C and τ = 6.7 min.
With the two reactions separately optimized, we assembled the system to allow the direct
pumping of the product stream from the acetimidamide formation into the second step using the
conditions outlined above (Figure 3). The excellent heat transfer in the flow reactor allows the
acetimidamide stream to be heated and mixed with the hydrazine stream without any concern due
to heat accumulation. Besides, this system required no additional solvent because the same solvent
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(DMSO) was used in both reactors. To achieve efficient mixing of the stream from the first step
with the stream of hydrazine derivative 4a for the second step, a T-junction was used. This mixer
was kept at 25 °C and proved to mix the two streams effectively. Sampling the stream at the outlet
of the second reactor showed only the presence of product 11b. In a 1 g test experiment, 11b was
obtained in 60% isolated yield with 95% NMR assay purity. The reaction was further intensified
in a large-scale run, yielding 117.1 g of pure product (95% NMR assay purity) over approximately
48 h of continuous operation, with an isolated yield of 57% and a productivity of 2.4 g h–1. This
demonstrated that the method could be efficiently intensified from small (1 gram) to large (100
grams) scale.
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Figure 3. Continuous-flow system set-up used for scale-up experiment.
Having developed an efficient and practical 2nd generation route through a one-pot
continuous flow process to access triazole 11b, we needed the development of a non-
conventional hydrolysis able to convert ethyl ester 11b into target acid 1 with the
avoidance of any aqueous work-up due to the reported high hydrophilic nature of 1 (see
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above). After some experimentation, it was found that ester hydrolysis could be performed
in toluene with only stoichiometric amounts of concentrated aqueous NaOH while residual
water and EtOH were removed by azeotropic distillation upon full conversion. Trituration
with TBME afforded an off-white solid corresponding to the sodium salt 13 in high yield
(Scheme 6).
NaOH
toluene, rt
TFA, MeCN
rt
O
N
O
N
N
N
1
O
N
OEt
92%
98%
N
Na
11b
13
Scheme 6. 2nd generation synthesis of 1: ester 11b hydrolysis in batch mode.
When the salt was treated with trifluoroacetic acid (TFA) in acetonitrile, free acid 1 was
smoothly formed and precipitated as white suspension easily filtered off and recovered in
quantitative yield and high purity. In this way, triazole ethyl ester 11b obtained from the
continuous flow process, could be converted in two simple steps into triazole acid 1 in
high overall yields.
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The development of more sustainable and lower environmental impact manufacturing
processes for API and intermediates is of high priority in the pharmaceutical industry.
Green chemistry metrics are at best used to mirror ecological aspects as well as process
efficiency. Given the short synthesis and the restricted amount of data available at this
early stage of development, a meaningful green score card calculation was not possible
and only some representative parameters such as process mass intensity (PMI), relative
process greenness (RPG), relative process improvement (RPI) besides yield were taken
into consideration to benchmark the 2nd generation flow process with the batch
approaches (Table 1).11
In terms of yield, the winning position of the flow process over the two others by a factor
of 2-3 was anticipated thanks to the minimized handling of unstable intermediate 5 and
to the high selectivity of the new process versus the 1st route, respectively. The impact of
11
Roschangar, F.; Colberg, J.; Dunn, P. J.; Gallou, F.; Hayler, J. D.; Koenig, S. G.;
Kopach, M. E.; Leahy, D. K.; Mergelsberg, I.; Tucker, J. L.; Sheldon, R.; Senanayake, C.
H. Green Chem. 2017, 19, 281-285.
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the chromatography for the 1st generation is reflected in the significantly higher PMI
compared to the more efficient 2nd generation route. The inferior PMI of the flow process
compared to the batch one is explained by the unoptimized work-up which was still
performed in batch mode and accounted for increased volumes and solvent waste. As
consequence of the PMI values, the RPG is for the 1st generation below average with
12%, while with 58 and 44% the 2nd generation batch and flow rank respectively good to
average as manufacturing processes in early development stage.11
Table 2. Green metrics comparison for the different routes to 11.
Yield
12%
29%
57%
PMI
212
91
Complexity
RPG
12%
58%
44%
RPI
-
Scale
1-3 kg
0.1 kg
0.1 kg
1st generation batch
2nd generation batch
2nd generation flow
1
2
2
46%
32%
120
Finally, the benefit of the 2nd generation is illustrated with the RPI values, respectively
of 46% and 32% for the batch and the flow processes which reflect the overall easiness
and efficiency of the new route compared to the 1st generation. Even if the flow approach
suffers from a less competitive PMI (and as consequence lower RPG and RPI) compared
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to the batch process, based on the available data, it should be pointed out that this is due
to the unoptimized work-up at such early phase of development. Significant
improvements in waste reduction could be achieved by implementing, for example,
continuous strategies for work-up and product isolation, such as continuous membrane-
assisted liquid-liquid extraction or continuous crystallization.12
Finally, to demonstrate the generality of the described methodology, the flow conditions
were applied in a small screening of other substrates, as depicted in Table 3. As an
example of the chemical diversification that can be achieved, triazole derivative 14 was
obtained in a straightforward manner and in good yields by using 3-bromo-5-
carboxyamide pyridine as amide source. When different hydrazines were used to couple
with acetimidamide 5, methyl-triazole derivatives 15-18 were obtained. Remarkably, the
same conditions optimized for our target substrate 11b could be applied as well to the
12 (a) Lawton, S.; Steele, G.; Shering, P. Org. Process Res. Dev. 2009, 13, 1357-1363.
(b) Adamo, A.; Beingessner, R. L.; Behnam, M.; Chen, J.; Jamison, T. F.; Jensen, K. F.;
Monbaliu, J.-C. M; Myerson, A. S.; Revalor, E. M.; Snead, D. R.; Stelzer, T.;
Weeranoppanant, N.; Wong, Y. S.; Zhang, P. Science 2016, 352, 61-67.
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new products. The results collected hint to the diversity of substrates that can be obtained
using our novel route and open paths for extended, follow-up synthetic investigations.
Table 3. Substrate scope for the continuous-flow acetamide formation and triazole
cyclisation.
Entry
Product
Yield (%)
N
N
CO2Et
N
N
1
52
Br
14
F
N
N
N
2
63
15
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N
N
3
4
73
66
N
16
N
N
N
O
17
N
N
5
72
N
18
Conclusions
In conclusion, an alternative and novel route for the synthesis of substituted 1,2,4-
triazole acetic acid 1 has been developed and presented herein. The approach
constitutes a significant improvement compared to the more traditional 1st generation
‘buy-in’ approach due to the simple starting materials employed, mild reaction conditions,
and chromatography-free isolations. The implementation of the two reactions into an
integrated and continuous process allowed a modular and efficient scale up and rapidly
provided with multi gram amounts of target triazole 1, avoiding extensive purification and
work-up procedures, and reducing the manual handling of dangerous intermediates. Flow
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chemistry confirmed to be a successful and useful technology for the process/organic
chemist’s toolbox to shorten the time for development and scale-up, enabling rapid
reaction optimization and precise control of the reaction conditions within the small flow
pipes. In this case, remarkable benefits are the almost doubled yield as compared to the
batch process, the safe handling of an unstable and energetic intermediate, with effects
in terms of cost efficiency, sustainability, and process safety.
In our view, the new continuous-flow route constitutes a viable and appealing alternative
to traditional ‘buy-in’ approaches used in the synthesis of 1,2,4-triazole derivative 1. We
believe that the method, which was further demonstrated in the preparation of other
similar 1,2,4-triazoles, will find further useful application in the rapid, modular, and
automated construction of differentially functionalized triazoles.
Experimental Section
1. General
All commercially available chemicals employed were used as such with no further
purification. LC/MS analyses were performed using Aquity Waters system equipped with
29