Development and Demonstration of a Safer Protocol for the Synthesis of 5-Aryltetrazoles from Aryl Nitriles

Article abstract of DOI:10.1021/acs.oprd.7b00016

The search for a faster, safer protocol for the direct synthesis of 5-aryltetrazoles from aryl nitriles in the presence of sodium azide and an amine hydrochloride salt led to the discovery of a buffered system comprised of BnNH₂, BnNH₂·HCl, and NaN₃. After optimization of reaction conditions and a thorough investigation of reaction safety, the procedure was demonstrated for the synthesis of several hundred grams of 4-chloro-2-(2H-tetrazol-5-yl)phenol. The generality of the developed reaction conditions was established by a small-scale reactivity screen using 16 additional aryl and heteroaryl nitrile substrates.

Full text of DOI:10.1021/acs.oprd.7b00016

Subscriber access provided by Fudan University
Communication
Development and Demonstration of a Safer Protocol
for the Synthesis of 5-Aryltetrazoles from Aryl Nitriles
Daniel S. Treitler, Simon W. Leung, and Mark Lindrud
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00016 • Publication Date (Web): 17 Feb 2017
Downloaded from http://pubs.acs.org on February 19, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 17
Organic Process Research & Development
1
2
3
4
5
Development and Demonstration of a Safer Protocol for the Synthesis of 5-Aryltetrazoles from Aryl
Nitriles
6
7
Daniel S. Treitler,* Simon Leung, Mark Lindrud
8
9
BristolꢀMyers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 17
1
2
3
4
Table of Contents Graphic:
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 3 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ABSTRACT: The search for a faster, safer protocol for the direct synthesis of 5ꢀaryltetrazoles
from aryl nitriles in the presence of sodium azide and an amine hydrochloride salt led to the
discovery of a buffered system comprised of BnNH2, BnNH2 · HCl, and NaN3. After
optimization of reaction conditions and a thorough investigation of reaction safety, the procedure
was demonstrated for the synthesis of several hundred grams of 4ꢀchloroꢀ2ꢀ(2Hꢀtetrazolꢀ5ꢀ
yl)phenol. The generality of the developed reaction conditions was established by a small scale
reactivity screen using 16 additional aryl and heteroaryl nitrile substrates.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KEYWORDS: Tetrazole, Sodium Azide, Hydrazoic Acid, Safety
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 17
1
2
3
4
INTRODUCTION
5
6
7
8
Up until the middle of the 20th century, the most direct method to access 5ꢀaryltetrazoles was by reacting an aryl
nitrile with hydrazoic acid (Scheme 1, Eq A).1 However, hydrazoic acid is not only toxic (Mouse LD50 = 22
mg/kg)2 but also explosive. Based on calculated total energy release and measured detonation velocity, HN3 is a
superior explosive to TNT.3 These hazards are compounded by its volatility (bp = 37 °C) and its propensity to
react with metals to form extremely dangerous shockꢀsensitive metal azides, many of which explode at the
slightest provocation.4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Literature Methods for the Synthesis of 5ꢀAryltetrazoles from Aryl Nitriles
In order to avoid the use of hydrazoic acid, dozens of alternative protocols have since been developed for the
conversion of an aryl nitrile to the corresponding 5ꢀaryltetrazole.5 In the simplest of these procedures, hydrazoic
acid is generated in-situ by the reaction of sodium azide with a weak Brönsted acid, typically ammonium chloride
or triethylamine hydrochloride (Scheme 1, Eq B).6 Alternatively, myriad Lewis acids have been demonstrated to
mediate the reaction between an aryl nitrile and sodium azide. Reported protocols use Lewis acids derived from
Li,6b B,7 Mg,8 Al,9 Si,10 Sc,11 Ti,12 Fe,13 Co,14 Ni,15 Cu,16 Zn,17 Zr,18 Mo,19 Ag,20 Cd,21 In,22 Sb,23 La,24 Ce,25 Yb,24
W,26 Au,27 and Bi19 (Scheme 1, Eq C). Furthermore, there are a number of tetrazole preparations that rely on
more exotic reagents such as azides of boron,28 aluminum,29 silicon,30 or tin31 (Scheme 1, Eq D).
From a safety perspective, tetrazole formation reactions represented by Equations C and D in Scheme 1 appear to
be superior by circumventing hydrazoic acid formation, but it should be noted that the majority of these systems
will react with adventitious water (or other protic solvents, or protic functional groups on the substrate of interest)
to generate hazardous HN3 (aqueous pKa = 4.7).32 Additionally, the traditional acidic aqueous workup would
result in the formation of hydrazoic acid from unconsumed azide reagent.
RESULTS AND DISCUSSION
During the course of a recent synthesis of an intermediate towards a drug candidate it was necessary to produce
several hundred grams of tetrazole 2 (Scheme 2). Since the corresponding nitrile (1) was commercially available,
it was proposed that the tetrazole ring should be introduced directly via azide cycloaddition. We were thus faced
with the task of deciding which of the dozens of tetrazoleꢀforming reaction conditions to employ.6ꢀ31 Considering
ease of operation, reagent cost, and waste minimization, we decided to first investigate the simple conditions
reported by Finnegan, Henry, and Lofquist in 1958: NaN3 in the presence of NH4Cl in DMF.6b While nitrile 1
was successfully transformed to 2 under these conditions, the reaction was unfortunately very sluggish, as is often
the case for orthoꢀsubstituted nitriles.6g,11,17,28 Full consumption of the nitrile starting material required >40 h at
120 °C with a significant excess of reagents (2.0 eq NaN3, 2.5 eq NH4Cl). From a safety perspective, we were
also concerned because a sublimate was observed on the upper portions of the reaction flask, likely ammonium
azide (NH4N3). This relatively volatile salt (vapor pressure at 80 °C is 38 mm Hg) is known to be explosive.33
Scheme 2. Proposed Synthesis of 5ꢀAryltetrazole 2
ACS Paragon Plus Environment

Page 5 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
We hypothesized that an investigation of alternative amine hydrochlorides might uncover one with increased
reactivity, perhaps due to improved solubility or acidity. More importantly, we hoped to introduce a higher
molecular weight amine hydrochloride to decrease the volatility of the corresponding ammonium azide salt
formed in-situ, in order to prevent deposition of a potential explosive salt. Moreover, even if sublimation and
deposition were to occur, an ammonium azide salt with a higher carbon:nitrogen ratio would likely demonstrate
increased thermal stability, mitigating the risk of an explosion.34 Although there have been previous publications
investigating alternative amine hydrochloride promoters, to the best of our knowledge these investigations have
been focused on improving reactivity rather than process safety.6b,c,e,h,k We decided to evaluate 12 amine
hydrochloride salts in the desired transformation and obtain rough kinetic data by HPLC analysis of the reaction
mixture after 2 h, 4 h, and 6 h at 120 °C. The compiled reaction conversion data is plotted in Figure 1, where the
Yꢀaxis illustrates tracks the consumption of aryl nitrile 1. Surprisingly, the most acidic amine hydrochloride salts
employed (pyridine HCl, lutidine HCl, and Nꢀmethylimidazole HCl) exhibited poor reactivity under our
conditions. Nonetheless, we found that three amine hydrochloride salts demonstrated a significantly faster
reaction rate than the original NH4Cl conditions: benzylamine hydrochloride, morpholine hydrochloride, and
DABCO hydrochloride. All three of these amine hydrochloride salts have significantly higher molecular weights
than ammonium chloride, suggesting that the corresponding azide salts should be much less volatile and thus safer
to work with. Among the three contenders, benzylamine hydrochloride was selected for further study since it has
the highest C:N ratio and is also commercially available from several vendors on multiꢀkilo scale.
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Aryl nitrile consumption rates for 12 amine hydrochloride promoters
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 17
1
2
3
4
5
6
7
8
9
Since the combination of benzylamine hydrochloride and sodium azide should lead to the formation of
benzylammonium azide in situ, our next step was to carefully synthesize small amounts of this salt for thermal
decomposition analysis and shock/friction testing. Results are presented in Table 1. The energy released upon
decomposition of 3 is large, but the high temperature threshold for this decomposition was reassuring. Use of
AKTS software to estimate ADT24 (temperature at which time to maximum rate at adiabatic conditions is 24 h)
suggests prolonged stability of 3 in the solid phase at temperatures below 137 °C. Most importantly, 3 exhibited
insensitivity to shock and friction, distinguishing it from ammonium azide, hydrazoic acid, and most metal
azides.3,4,33 With this data in hand, we felt comfortable scaling the benzylamine hydrochloride system with the
caveat that we still needed to understand how much free hydrazoic acid was released during the course of the
reaction. Hydrazoic acid vapor in the headspace is especially dangerous because HN3 is liquid at room
temperature and can condense onto cooler parts of the equipment, potentially leading to an explosion.4a,35 In order
to monitor hydrazoic acid in the headspace, we employed an inꢀline mass spectrometer (MS) to sample gases
from above the reaction solution under a slow flow of nitrogen (~1 headspace volume/10 minutes).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Stability Data for Benzylamine Hydrazoic Acid Salt 3
Test
DSC
DSC
Property Measured
Onset of Exotherm
ꢁHDecomp
Value
172 °C
1782 J/g
137 °C
DSC
ADT24
MPꢀ3 Impact
Test
BAM Friction
Test
Impact Sensitivity
Friction Sensitivity
> 60 J
> 360 N
Inꢀline MS Analysis of the reaction of 1 to 2 under newly optimized conditions revealed that headspace HN3
peaked early in the reaction at approximately 17,000 ppm (See Scheme 3). This level is below hydrazoic acid’s
reported lower decomposition limit (120,000 ppm at 100 °C)3b by less than an order of magnitude. Any
disruption in headspace nitrogen flow or areas of low flow could allow for condensation of these vapors to form
an explosion hazard. Additionally, the inꢀline mass spectrometer detected around 1,000 ppm of methyl azide in
the headspace, which was corroborated by the observation of a demethylated phenol impurity (4) formed at low
levels (~10% by HPLC area percent). Methyl azide in the reaction effluent is especially dangerous because this
volatile explosive compound, in contrast to hydrazoic acid, cannot be trapped by a basic aqueous scrubber
solution.4a
Scheme 3. Optimized Conditions for the Conversion of 1 to 2, with a Kinetic Description Accounting for the
Formation of 4
ACS Paragon Plus Environment

Page 7 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A brief investigation of the demethylation pathway yielded two key observations: 1) 2 does not convert to 4 under
the reaction conditions and 2) the corresponding demethylated nitrile 5 cannot be observed by HPLC at any point
during the course of the reaction. Taken together, these two observations are consistent with the simplified
kinetic model at the bottom of Scheme 3, wherein very slow demethylation of 1 to afford phenol 5 is followed by
rapid formation of 4.
In order to test our hypothesis that phenol substrate 5 reacts significantly faster than methoxy substrate 1, we
subjected commercially available 5 to our reaction conditions. To our delight, >99.8% of 5 was converted to 4
after only 30 minutes at 100 °C. Subsequent experiments established that the rate of conversion of 5 to 4 was
approximately two orders of magnitude faster than the rate of conversion of 1 to 2. Fortunately, at a later step in
our synthetic sequence the phenol moiety could be conveniently methylated to afford the desired methoxy group;
as such we decided to change our initial synthetic target from 2 to 4.
As depicted in Scheme 4 Eq A, the much higher intrinsic reactivity of the phenol substrate allowed for significant
reductions in reaction temperature, reaction time, and reagent loadings. These modifications in turn led to a large
reduction in peak headspace hydrazoic acid detected by our inꢀline MS, down to 900 ppm. Furthermore, it was
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 17
1
2
3
4
5
found that buffering the reaction mixture with 0.5 equivalents of added benzylamine resulted in an additional 5ꢀ
fold reduction in peak headspace hydrazoic acid without compromising on reactivity (Scheme 4, Eq B).a
6
7
Scheme 4. Further Optimization of the Tetrazole Formation Reaction Starting from Substrate 5
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Having devised safer reaction conditions for the tetrazole formation step, we then focused on making the workup
safer as well. Specifically, we took advantage of the fact that Nꢀmethylꢀ2ꢀpyrrolidone (NMP) will phaseꢀsplit
with concentrated aqueous NaOH solutions, allowing for the aqueous extraction of residual azide prior to
acidification of the reaction stream for isolation.36 An HPLC method was developed to quantify the concentration
of azide in basic aqueous solutions (λ = 245 nm). Using this method, we determined that aqueous extraction of
sodium azide from the reaction stream in NMP was surprisingly inefficient, with less than 50% of the azide ion
removed to the aqueous layer with each wash. As shown in Table 2, a survey of other polar aprotic solvents
revealed a similar trend. Gratifyingly, reducing the polarity of the organic layer by introducing tetrahydrofuran
(THF) as a cosolvent improved the purge of sodium azide to the aqueous layer. Additional screening revealed
that increasing the number of aqueous NaOH washes was the most successful approach to residual azide
reduction. Based on a previously published analysis of azide safety, we decided to reduce the level of azide in our
organic stream to <50 ppm prior to acidification.35c With 1.1 – 1.2 equivalents of sodium azide added up front,
we could thus calculate that four aqueous washes would be necessary to purge the unreacted NaN3 to the
appropriate level. Fortunately, product losses to the aqueous washes were minimal (~2% per wash), and upon
dilution of the washed NMP/THF layer with water and acidification with HCl or citric acid, compound 4
crystallized out of solution and could be isolated in 85ꢀ90% yield with >99.5% purity by HPLC.
Table 2. Optimizing Aqueous Extraction of Azide from the Reaction Stream
a The apparent pH of the reaction (measured by diluting 1 part reaction mixture with 3 parts water) was increased from ~5 to
~9 by the addition of 0.5 eq benzylamine.
ACS Paragon Plus Environment

Page 9 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
Entry Reaction Solvent
Cosolvent
ꢀ
Basic Aqueous Wash
25 wt% NaOH (10 L/kg)
25 wt% NaOH (10 L/kg)
25 wt% NaOH (10 L/kg)
25 wt% NaOH (10 L/kg)
25 wt% NaOH (10 L/kg)
25 wt% NaOH (10 L/kg)
25 wt% NaOH (8 L/kg)
40 wt% NaOH (8 L/kg)
40 wt% K3PO4 (8 L/kg)
40 wt% K2HPO4 (8 L/kg)
2 x 25 wt% NaOH (8 L/kg)
3 x 25 wt% NaOH (8 L/kg)
4 x 25 wt% NaOH (8 L/kg)
5 x 25 wt% NaOH (8 L/kg)
Residual N3 Removed
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMP (4 L/kg)
DMAc (4 L/kg)
DMF (4 L/kg)
NMP (3 L/kg)
NMP (3 L/kg)
NMP (3 L/kg)
NMP (2 L/kg)
NMP (2 L/kg)
NMP (2 L/kg)
NMP (2 L/kg)
NMP (2 L/kg)
NMP (2 L/kg)
NMP (2 L/kg)
NMP (2 L/kg)
43%
50%
46%
58%
70%
74%
74%
emulsion
71%
23%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
ꢀ
ꢀ
THF (3 L/kg)
THF (6 L/kg)
THF (9 L/kg)
THF (6 L/kg)
THF (6 L/kg)
THF (6 L/kg)
THF (6 L/kg)
THF (6 L/kg)
THF (6 L/kg)
THF (6 L/kg)
THF (6 L/kg)
90.5%
96.9%
98.9%
99.6%
With small scale optimization complete and a thorough safety understanding in place, we began scaling up the
tetrazole formation reaction (all previous data had been collected on <5 g scale as a safety precaution).
Unfortunately, upon transitioning to jacketed glass reactors with overhead stirring, we discovered that the reaction
no longer reached completion under our previously optimal conditions. After investigating a number of potential
variables including water content, reagent source, and rate of headspace nitrogen flow, we determined that the
method and rate of stirring was likely responsible for the discrepancy. With overhead stirring, even at very
vigorous rates, the reaction consistently failed to reach completion. Since the reaction is heterogeneous, it appears
that the grinding action of a magnetic stirbar was necessary to facilitate complete conversion as observed on small
scale. As further corroboration, smallꢀscale experiments with magnetic stirring at very slow rates were observed
to be much slower, but the reaction rate could be restored by using finely ground sodium azideb or increasing the
stir rate. As for the largerꢀscale reactions with overhead stirring, it was found that a kicker charge of sodium azide
could increase conversion, but this would in turn require additional aqueous extractions to remove the large
excess of reagent present at the end of the reaction prior to acidification.
Ultimately it was observed that added water could reꢀstart a stalled reaction, presumably by increasing the
solubility of sodium azide. Building on this, a scalable process was designed by incorporating 15 – 20% water as
a cosolvent into the reaction mixture. Reactions conducted in either 5:1 NMP:water or 5:1 THF:water reached
complete conversion without introducing new impurities, albeit reaction times were noticeably longer (using 1.10
equivalents of NaN3, reaction time was ~10 h at 75 °C using NMP/water or ~20 h at reflux [64 °C] using
THF/water). Using inꢀline mass spectrometry to evaluate the headspace azide concentrations in the NMP/water
b Not recommended for scaleꢀup, due to safety concerns.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 17
1
2
system,c we found that compared to the pure NMP system there was a 40% increase in the concentration of HN3
in the headspace, but overall values were still more than two orders of magnitude below the lower decomposition
limit and thus considered safe. We ultimately decided to scale up the THF/water procedure, rationalizing that
THF is much more volatile than NMP, such that any condensates observed should consist of mostly THF and not
present an explosion hazard.3b This strategy was vindicated by diverting samples of the distillate for analysis as
the refluxing reaction proceeded, allowing for direct measurement of [N3] in the condensate by HPLC. By this
method we determined that the distillate was >99.8% THF (the concentration of azide in the distillate peaked at
the beginning of the reaction at 1700 ppm and quickly dropped below 1000 ppm as the reaction proceeded).
Upon workup, an additional benefit of the THF/water system was reduction in both the number of solvents and
the total solvent volumes, since the NMP/water procedure required added THF during workup to facilitate azide
purge (vida supra).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The final optimized procedure was scaled up (622 g of 5) in a 20 L jacketed glass reactor inside a walkꢀin hood
(see Scheme 5). Throughout the course of the reaction, a slow aboveꢀsurface nitrogen purge was employed (500
mL/min; ~1.5 headspace volumes/hr) as an additional precaution against hydrazoic acid buildup in the headspace.
The effluent gas exiting the condenser was bubbled through a trap containing 2.5 wt% aqueous sodium hydroxide
to remove any HN3 prior to venting into the hood baffles. Prior to reaction start the metal thermocouple was
removed from the reaction solution in order to mitigate the risk of forming dangerous metal azides.d During the
workup, extractions were performed at elevated temperature (45 °C) to improve the rate of layer separation. The
concentration of azide in each aqueous wash was quantified by HPLC; the calculated amount of residual azide
remaining at the end of the reaction minus the measured amount of azide purged allowed for determination of the
maximum [HN3] in the aqueous THF layer upon acidification for isolation.e This calculated maximum value (22
ppm) was safely below our already conservative limit of 50 ppm. Ultimately, this scaleꢀup effort afforded nearly
700 grams of desired aryltetrazole 4 in very good yield and excellent purity.
Scheme 5. 20 L Batch Procedure for the Synthesis of Aryl Tetrazole 4
c The THF/water system was not compatible with the inꢀline MS instrument because THF has a large ion fragment at 43 amu
that obscures the HN3 signal.
d Reaction temperature could be measured using a glass thermometer instead.
e The HPLC method developed to quantify azide levels could not be used to directly measure the azide level of the reaction
stream because the small N3 peak is obscured by other signals in the crude reaction mixture. The method could only be used
for quantification of azide levels in aqueous washes and distillate.
ACS Paragon Plus Environment

Page 11 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Upon completion of our scaleꢀup activities to prepare triazole 4, a brief screen was undertaken to investigate the
substrate scope amenable to our new reaction conditions. For each of 16 commercially available aromatic nitriles,
two small scale reactions were carried out: one in 5:1 THF:water at 65 °C (Table 3, Procedure A) and one in 5:1
NMP:water at 90 °C (Table 3, Procedure B). Reactions were followed exclusively by HPLC with product identity
confirmed by LC/MS; reaction aliquots were pulled after 1.5 h, 4 h, 8 h, 24 h, and 48 h, or until the conversion by
HPLC area % was >98. All data in Table 3 are based on inꢀprocess uncorrected HPLC area percent. Since the
purpose of this study was only to get a sense of how broadly applicable the developed conditions were, no
products were isolated and no yields are given.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As evident from the results in Table 3, our developed reaction conditions proved general. The reaction rate
appears predictable based on the steric and electronic properties of the substrate. For example, electronꢀdeficient
4ꢀtriflouromethylbenzonitrile (entry 6) reacted faster than benzonitrile (entry 1), which in turn reacted faster than
electronꢀrich 4ꢀmethoxybenzonitrile (entry 8). The least reactive substrate was electronꢀrich and sterically
hindered 2ꢀmethoxybenzonitrile (entry 4). Among the substituted benzonitriles, 2ꢀhydroxybenzonitrile (entry 2)
stands out as an anomaly, exhibiting significantly higher reactivity than both benzonitrile (entry 1), which is less
electronꢀrich, and 4ꢀhydroxybenzonitrile (entry 7), which is less sterically hindered. This rate acceleration is
analogous to what was observed in the synthesis of our desired intermediate, where the conversion of 1 to 2 was
much slower than the conversion of 5 to 4 under the same reaction conditions. The kinetic enhancement of the
orthoꢀphenol substrates may be attributable to an entropyꢀreducing directing effect, perhaps via a hydrogen
bonding interaction with the azide moiety. An alternative explanation invokes hydrogenꢀbond stabilization of a
partial negative charge that builds up on the nitrile nitrogen during the transition state. It is worth noting that this
acceleration was not observed with other, less acidic, protic functional groups in the 2ꢀposition (i.e. – entries 3
and 12). Among the heteroaromatic nitriles screened, only the highly electronꢀrich indole and pyrrole substrates
failed to reach full conversion within the allotted 48 h reaction time.
Table 3. Substrate Scope Investigation
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 17
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 13 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
In most cases, for both heteroaryl and aryl substrates, a single byproduct accounts for the discrepancy between
product area percent and conversion: benzyl amidine 8 (see Scheme 6). Formation of this impurity was
accelerated at higher temperatures, globally resulting in lower levels of this impurity when using Procedure A.
By HPLC, growth of the benzyl amidine byproduct 8 continued after starting material was consumed at the
expense of product, suggesting that loss of N3 from the tetrazole might be possible under the reaction conditions.
Scheme 6. Benzyl Amidine Byproduct
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
A safer procedure for acidꢀmediated tetrazole synthesis from aryl nitriles and sodium azide was developed.
Thermal stability experiments, analysis of headspace gases and condensates, and quantification of azide levels in
waste streams were employed to better understand the safety aspects of the newly developed reaction conditions.
After ensuring that a safe procedure was in place, the protocol was scaled up to afford ~0.7 kg of aryl tetrazole 4,
an early intermediate in the synthesis of a drug candidate. In addition, the generality of the developed reaction
procedure in aqueous THF (65 °C) and aqueous NMP (90 °C) was demonstrated using an array of 16
commercially available aryl and heteroaryl nitriles.
EXPERIMENTAL SECTION
General. All tetrazole formation reactions and other investigations using azide reagents were carried out in a
fume hood behind a blast shield, on small scale (<2.5 g substrate) unless larger amounts were absolutely
necessary. No metal tools or reactor components (i.e. - metal thermocouples, metal spatulae, metal needles,
etc.) were used to avoid the formation of shock-sensitive metal azides. Halogenated solvents were strictly
avoided to prevent formation of highly unstable polyazidoalkanes.37 All azide-containing waste streams were
segregated and diluted with aqueous sodium hydroxide. It is recommended that all attempts to replicate this
chemistry include a careful, holistic evaluation of safety prior to scale-up. Compounds 1 and 5 were purchased
from Ark Pharm and Parchem, respectively, and used as received. Benzylamine, benzylamine hydrochloride, and
sodium azide were purchased from SigmaꢀAldrich and used as received. Tetrahydrofuran (THF) and Nꢀmethylꢀ2ꢀ
pyrrolidone (NMP) were purchased from SigmaꢀAldrich (“anhydrous” grade) and used as received. All reactions
were run under a nitrogen atmosphere, with a slow nitrogen flow through a basic aqueous trap employed in larger
scale reactions to prevent headspace HN3 accumulation. Reverse phase HPLC was used to monitor reaction
progress and assess product purity. Reverse phase HPLC was also used to quantify the azide content of aqueous
washes, distillates, and sublimates. Headspace hydrazoic acid concentration was monitored via inꢀline mass
spectrometry (Ametek® ProMaxionTM process mass spectrometer); the instrument was set to intermittently draw
up headspace gas samples at a flow rate of approximately 9 mL/minute; relative concentrations of HN3 were
derived from the ratio of the HN3 and N2 ion counts; this method of quantification was corroborated by calibration
with dilute samples of known hydrazoic acid concentration.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 17
1
2
3
4
5
6
7
8
9
5-(5-chloro-2-methoxyphenyl)-2H-tetrazole (2). In a 100 mL roundꢀbottomed flask equipped with a magnetic
stirbar, 5ꢀchloroꢀ2ꢀmethoxyꢀbenzonitrile (1, 2.00 g, 11.9 mmol, 1.0 equiv) and benzylamine hydrochloride (4.28
g, 29.8 mmol, 2.5 equiv) were combined and diluted with NMP (8.0 mL, 4 L/kg). The resultant slurry was heated
to 110 °C and solid sodium azide (1.55 g, 23.8 mmol, 2.0 equiv) was added in a single portion. After 18 h at 110
°C, the dark brown reaction mixture was cooled to 20 °C and diluted with additional NMP (8 mL, 4 L/kg). The
diluted reaction stream was washed with 25 wt% aqueous NaOH (2 x 20 mL), then diluted with water (16 mL).
The resultant aqueous NMP solution was washed with MTBE (24 mL), then heated to 70 °C and acidified by
dropwise addition of 25 wt% citric acid (20 mL) [Note: From results obtained after this experiment (see Table 2),
there was probably still a substantial amount of NaN3 in this stream upon acidification; do not attempt to
replicate this procedure]. The resultant slurry was cooled slowly to 20 °C over the course of 1 h, aged at 20 °C
for 1 h more, then filtered. The filter cake was washed with water (3 x 5 mL) and dried under vacuum (150 torr)
at 60 °C with a slow nitrogen purge for 68 h to afford 2 (2.07 g, 82% yield, 99.5% purity by HPLC) as an offꢀ
white crystalline solid. mp 223 – 226 °C (dec). 1H NMR (DMSOꢀD6, 500 MHz): δ 8.04 (d, 1H, J = 2.5 Hz), 7.60
(dd, 1H, J = 9.0, 2.5 Hz), 7.28 (d, 1H, J = 9.0 Hz), 3.96 (s, 3H). 13C NMR (DMSOꢀD6, 125 MHz): δ 155.3, 150.2,
132.4, 128.4, 124.7, 114.2, 113.9, 56.3.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzylamine Hydrazoic Acid Salt (3). A freshly prepared solution of sodium azide (2.26 g, 34.8 mmol, 1.00
equiv) in water (25 mL) was added dropwise over the course of 5 min to a solution of benzylamine hydrochloride
(5.00 g, 34.8 mmol, 1.00 equiv) in water (25 mL) at 20 °C. The resultant homogeneous solution was stirred
gently for 15 min, then decanted into a glass crystallization dish. Evaporation from the dish (no stirring) at 20 °C
over the course of 16 h reduced the overall volume to approximately 25 mL and afforded a number of large
colorless needles, which were collected, rinsed with water (3 mL), and dried under vacuum (150 torr) at 35 °C
with a slow nitrogen purge for 22 h to afford 3 (1.21g, 23% yield) as a colorless crystalline solid. 1H NMR
(DMSOꢀD6, 500 MHz): δ 8.10 (br s, 3H), 7.48 – 7.33 (m, 5H), 3.99 (s, 2H). 13C NMR (DMSOꢀD6, 125 MHz): δ
134.4, 128.9 (2C), 128.7 (2C), 128.4, 42.4. Elemental analysis: theoretical C: 55.98%, H: 6.71%, N: 37.31%, Cl:
0.00%, Na: 0.00%; observed C: 55.74%, H: 6.87%, N: 36.90%, Cl: 0.61%, Na: 0.24%; residual water (Karl
Fischer method): 0.13 wt%.
4-chloro-2-(2H-tetrazol-5-yl)phenol (4). (Reaction vessel: 20 L glass jacketed reactor equipped with a sprayball
inlet, an overhead stirrer, a glass thermometer measuring headspace temperature, a nitrogen inlet [flow rate 500
mL/min], and a condenser cooled to –8 °C connected via plastic tubing to a hydrazoic acid trap consisting of 1.5
liters of 2.5 wt% aqueous NaOH; entire setup enclosed in a walkꢀin hood). With the jacket temperature at 20 °C,
tetrahydrofuran (2.5 L, 4.0 L/kg), 5ꢀchloroꢀ2ꢀhydroxyꢀbenzonitrile (5, 622 g, 4.05 mol, 1.00 equiv) and
benzylamine hydrochloride (668 g, 4.65 mol, 1.15 equiv) were charged into the reactor. Benzylamine (217 g,
2.02 mol, 0.50 equiv) was added [Note: exotherm of 11 °C], followed by sodium azide (290 g, 4.46 mol, 1.10
equiv). The sodium azide charge was rinsed into the reactor with water (0.5 L, 0.8 L/kg) [Note: endotherm of 8
°C]. The reactor jacket was heated to 85 °C and the reactor contents were refluxed at an internal temperature of
~64 °C for 22 h. At the conclusion of the reaction, the reactor contents were cooled to 45 °C and washed with 30
wt% aqueous NaOH (4 x 2.5 L, 4 x 4 L/kg) at 45 °C. The washed organic layer was diluted with water (6.2 L, 10
L/kg) and cooled to 20 °C. Concentrated aqueous HCl (1.86 L, 3 L/kg, ~5.5 equiv) was added dropwise to the
homogeneous solution over the course of 80 min [Note: highly exothermic; temperature is kept <30 °C by slow
addition]. The resultant slurry was aged for 1 h more at 20 °C, then drained and filtered. The filter cake was
washed with water (3 x 2.5 L), then transferred to trays and dried in a vacuum oven (40 h at 150 torr, 60 °C, slow
N2 purge) to afford 4 (687 g, 86.3% yield) as an offꢀwhite crystalline solid. mp 228 – 231 °C (dec). 1H NMR
(DMSOꢀD6, 500 MHz): δ 7.95 (d, 1H, J = 2.5 Hz), 7.43 (dd, 1H, J = 9.0, 2.5 Hz,), 7.08 (d, 1H, J = 9.0 Hz), 3.56
(br s, 1H). 13C NMR (DMSOꢀD6, 125 MHz): δ 154.3, 150.8, 132.3, 128.2, 123.2, 118.3, 112.3.
ACS Paragon Plus Environment

Page 15 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Substrate Scope Evaluation (Table 3). Procedure A: Aryl nitrile (9.00 mmol), benzylamine (0.49 mL, 4.50
mmol, 0.50 equiv), and benzylamine hydrochloride (1.49 g, 10.35 mmol, 1.15 equiv) were suspended in a mixture
of THF (5.0 mL) and water (1.0 mL). Solid sodium azide (644 mg, 9.90 mmol, 1.10 equiv) was added and the
resultant mixture was heated to 65 °C with stirring. Aliquots (5 uL) were removed after 8 h, 24 h, and 48 h and
diluted into 1.0 mL aqueous acetonitrile for HPLC analysis. Procedure B: Aryl nitrile (9.00 mmol), benzylamine
(0.49 mL, 4.50 mmol, 0.50 equiv), and benzylamine hydrochloride (1.49 g, 10.35 mmol, 1.15 equiv) were
suspended in a mixture of NMP (5.0 mL) and water (1.0 mL). Solid sodium azide (644 mg, 9.90 mmol, 1.10
equiv) was added and the resultant mixture was heated to 90 °C with stirring. Aliquots (5 uL) were removed after
1.5 h, 4 h, 8 h, 24 h, and 48 h and diluted into 1.0 mL aqueous acetonitrile for HPLC analysis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SUPPORTING INFORMATION
1H and 13C NMR spectra for compounds 2, 3, and 4.
AUTHOR INFORMATION
*Eꢀmail: Daniel.Treitler@bms.com
ORCID: 0000ꢀ0001ꢀ5375ꢀ4920
ACKNOWLEDGMENTS
The authors would like to thank Sergei Kolotuchin for his contributions to the early development of this chemistry
and his edits to the manuscript. The authors would also like to thank Ian Young, Rebecca Greene, and Chris
Sfouggatakis for their valuable feedback regarding this manuscript.
REFERENCES
(1) Mihina, J. S.; Herbst, R. M. J. Org. Chem. 1950, 15, 1082.
(2) (a) Lewis, R. J. Sr. (Ed) Sax’s Dangerous Properties of Industrial Materials; Wiley & Sons, Inc.:
Hoboken, 2004. (b) Trout, D.; Esswein, E. J.; Hales, T.; Brown, K.; Solomon, G.; Miller, M. Am. J. Ind.
Med. 1996, 30, 343.
(3) (a) Pepekin, V. I. Pol. J. Chem. 1981, 55, 1405. (b) Wiss, J.; Fleury, C.; Heuberger, C.; Onken, U. Org.
Process Res. Dev. 2007, 11, 1096.
(4) (a) Urben, P. G. (Ed) Bretherick’s Handbook of Reactive Chemical Hazards; Academic Press: Boston,
2007. (b) Patnaik, P. A Comprehensive Guide to the Hazardous Properties of Chemical Substances; Van
Nostrand Reinhold: California, 1992.
(5) For a review, see: Roh, J.; Vávrová, K.; Hrabálek, A. Eur. J. Org. Chem. 2012, 6101.
(6) (a) Herbst, R. M.; Wilson, K. R. J. Org. Chem. 1957, 22, 1142. (b) Finnegan, W. G.; Henry, R. A.;
Lofquist, R. J. Am Chem. Soc. 1958, 80, 3908. (c) Titova, I. E.; Poplavskii, V. S.; Koldobskii, G. I.;
Ostrovskii, V. A.; Nikolaev, V. D.; Erusalimskii, G. B. Khim. Geterotsikl. Soedin. 1986, 1086. (d)
Bernstein, P. R.; Vacek, E. P. Synthesis 1987, 1133. (e) Ostrovskii, V. A.; Poplavskii, V. S.; Koldobskii,
G. I.; Erusalimskii, G. B. Khim. Geterotsikl. Soedin. 1992, 1214. (f) Koguro, K.; Oga, T.; Mitsui, S.;
Orita, R. Synthesis 1997, 910. (g) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984. (h)
Vereshchagin, L. I.; Verkhozina, O. N.; Pokatilov, F. A.; Strunevich, S. K.; Proidakov, A. G.; Kizhnyaev,
V. N. Russ. J. Org. Chem. 2007, 43, 1710. (i) Das, B.; Reddy, C. R.; Kumar, D. N.; Krishnaiah, M.;
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 17
1
2
3
4
5
6
7
8
9
Narender, R. Synlett 2010, 391. (j) Gutmann, B.; Roduit, J.ꢀP.; Roberge, D.; Kappe, C. O. Angew. Chem.
Int. Ed. 2010, 49, 7101. (k) Zhou, Y.; Yao, C.; Ni, R.; Yang, G. Synth. Commun. 2010, 40, 2624. (l)
Shelkar, R.; Singh, A.; Nagarkar, J. Tetrahedron Lett. 2013, 54, 106. (m) Nowrouzi, N.; Farahi, S.;
Irajzadeh, M. Tetrahedron Lett. 2015, 56, 739. Alternatively, a protic solvent can act as the acid if the
temperature is high enough: (n) Palde, P. B.; Jamison, T. F. Angew. Chem. Int. Ed. 2011, 50, 3525. (o)
Nandre, K. P.; Salunke, J. K.; Nandre, J. P.; Patil, V. S.; Borse, A. U.; Bhosale, S. V. Chin. Chem. Lett.
2012, 23, 161. For mechanistic investigations, see: (p) Cantillo, D.; Gutmann, B.; Kappe, C. O. J. Org.
Chem. 2012, 77, 10882.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) see reference 6b. (b) Kumar, A.; Narayanan, R.; Shechter, H. J. Org. Chem. 1996, 61, 4462. (c)
Prajapti, S. K.; Nagarsenkar, A.; Babu, B. N. Tetrahedron Lett. 2014, 55, 3507.
(8) Sugi, K.; Katsura, T.; Itatani, N. Preparation of Tetrazoles. JP 11171873 A, 1999.
(9) (a) Fauchere, J. L.; Kucharczyk, G. N.; Paladino, J.; Bonnet, J.; Canet, E.; Birrell, G. New Pseudopeptides
as Neurokinin Anatagonists. FR 2719312 A1, 1995. (b) Matthews, D. P.; Green, J. E.; Shuker, A. J. J.
Comb. Chem. 2000, 2, 19. (c) Sajadi, S. M.; Khalaj, M.; Jamkarani, S. M. H.; Mahame, M.; Kashefib, M.
Synth. Commun. 2011, 41, 3053.
(10) Cantillo, D.; Gutmann, B.; Kappe, C. O. J. Am. Chem. Soc. 2011, 133, 4465.
(11) Coca, A.; Turek, E.; Feinn, L. Synth. Commun. 2015, 45, 218.
(12) HosseiniꢀSarvari, M.; NajafvandꢀDerikvandi, S. C. R. Chim. 2014, 17, 1007.
(13) Nasrollahzadeh, M.; Bayat, Y.; Habibi, D.; Moshaee, S. Tetrahedron Lett. 2009, 50, 4435.
(14) Rama, V.; Kanagaraj, K.; Pitchumani, K. J. Org. Chem. 2011, 76, 9090.
(15) Chermahini, A. N.; Teimouri, A.; Moaddeli, A. Heteroat. Chem. 2011, 22, 168.
(16) Akhlaghinia, B; Rezazadeh, S. J. Braz. Chem. Soc. 2012, 23, 2197.
(17) (a) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945. (b) Himo, F.; Demko, Z. P.;
Noodleman, L.; Sharpless, K. B. J. Am. Chem. Soc. 2003, 125, 9983.
(18) Gowd, M. R. M. B.; Pasha, M. A. J. Chem. Sci. 2011, 123, 75.
(19) Takale, S.; Manave, S.; Phatangare, K.; Padalkar, V.; Darvatkar, N.; Chaskar, A. Synth. Commun. 2012,
42, 2375.
(20) Mani, P.; Singh, A. K.; Awasthi, S. K. Tetrahedron Lett. 2014, 55, 1879.
(21) Venkateshwarlu, G.; Premalatha, A.; Rajanna, K. C.; Saiprakash, P. K. Synth. Commun. 2009, 39, 4479.
(22) Sun, H.ꢀB.; Chen, W.; Sun, Y.; Qin, P.; Qi, X. Adv. Mater. Res. 2012, 398, 2416.
(23) Venkateshwarlu, G.; Rajanna, K. C.; Saiprakash, P. K. Synth. Commun. 2009, 39, 426.
(24) Coca, A.; Turek, E. Tetrahedron Lett. 2014, 55, 2718.
(25) (a) see reference 19. (b) Kumar, S.; Dubey, S.; Saxena, N.; Awasthi, S. K. Tetrahedron Lett. 2014, 55,
6034.
(26) (a) He, J.; Li, B.; Chen, F.; Xu, Z.; Yin, G. J. Mol. Catal. A: Chem. 2009, 135. (b) Kong, D.; Liu, Y.;
Zhang, J.; Li, H.; Wang, X.; Liu, G.; Li, B.; Xu, Z. New J. Chem. 2014, 38, 3078.
(27) Kumar, S.; Kumar, A.; Agarwal, A.; Awasthi, S. K. RSC Adv. 2015, 5, 21651.
(28) Yao, Y.ꢀW.; Zhou, Y.; Lin, B.ꢀP.; Yao, C. Tetrahedron Lett. 2013, 54, 6779.
(29) (a) Behringer, H.; Kohl, K. Chem. Ber. 1956, 89, 2648. (b) Arnold, C.; Thatcher, D. N. J. Org. Chem.
1969, 34, 1141. (c) Aureggi, V.; Sedelmeier, G. Angew. Chem. Int. Ed. 2007, 46, 8440.
(30) (a) Ettenhuber, E.; Rühlmann, K. Chem. Ber. 1968, 101, 743. (b) Washburne, S. S.; Peterson Jr., W. R.
J. Organomet. Chem. 1970, 21, 427. (c) Huff, B. E.; Staszak, M. A. Tetrahedron Lett. 1993, 34, 8011.
(d) Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58, 4139. (e) Amantini, D.; Beleggia, R.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2004, 69, 2896. (f) Bonnamour, J.; Bolm, C. Chem.
Eur. J. 2009, 15, 4543.
(31) (a) Sisido, K.; Nabika, K.; Isida, T.; Kozima, S. J. Organomet. Chem. 1971, 33, 337. (b) Duncia, J. V.;
Pierce, M. E.; Santella III, J. B. J. Org. Chem. 1991, 56, 2395. (c) Curran, D. P.; Hadida, S.; Kim, S.ꢀY.
Tetrahedron 1999, 55, 8997.
(32) McDonald, J. R.; Rabalais, J. W.; McGlynn, S. P. J. Chem. Phys. 1970, 52, 1332.
(33) Williams, W. O. Gun Propellant Containing Ammonium Azide and an Inert Casing. US 5,081,930, 1992.
ACS Paragon Plus Environment

Page 17 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(34) Smith, P. A. S. The Chemistry of Open-Chain Organic Nitrogen Compounds; W. A. Benjamin, Inc: New
York, 1966.
(35) (a) Wiss, J.; Fleury, C.; Onken, U. Org. Process Res. Dev. 2006, 10, 349. (b) Scott, J. P.; Alam, M.;
Bremeyer, N.; Goodyear, A.; Lam, T.; Wilson, R. D.; Zhou, G. Org. Process Res. Dev. 2011, 15, 1116.
(c) GonzálezꢀBobes, F.; Kopp, F.; Li, L.; Deerberg, J.; Sharma, P.; Leung, S.; Davies, M.; Bush, J.;
Hamm, J.; Hrytsak, M. Org. Process Res. Dev. 2012, 16, 2051.
(36) Miranda, E. I.; Vlaar, C.; Zhu, J. A Method for Preparing Irbesartan and Intermediates Thereof via
Alkylation with Mixed Bromides using Aqueous Bases, a PhaseꢀTransfer Catalyst, and a Reducing
Agent. US 20060041147.
(37) (a) Peet, N. P.; Weintraub, P. M. Chem. Eng. News 1993, 71: 16, 4. (b) Hruby, V. J.; Boteju, L.; Li, G.
Chem. Eng. News 1993, 71: 41, 2. (c) Peet, N. P.; Weintraub, P. M. Chem. Eng. News 1994, 72: 11, 4.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment