Process Development and Scale-up of a Multicomponent Synthesis of a 3-Methyl-1-aryl-1,2,4-triazole Building Block

Article abstract of DOI:10.1021/acs.oprd.9b00337

The classical preparation of 3-methyl-1-aryl-1,2,4-triazoles through an S_NAr reaction pathway results in a mixture of N-regioisomers. Removal of the unwanted isomer reduces the yield and affects processability of the final product. In the prese

Full text of DOI:10.1021/acs.oprd.9b00337

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Communication
Process Development and Scale-up of a Multi-Component
Synthesis of a 3-Methyl-1-Aryl 1,2,4-Triazole Building Block
Thomas Edward La Cruz, Daniel S. Treitler, Annie Tam, Kristine Smith, Simon W.
Leung, Charles Pathirana, Michael Peddicord, Yu Fan, Dale Vanyo, and Joerg Deerberg
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00337 • Publication Date (Web): 30 Jan 2020
Downloaded from pubs.acs.org on January 31, 2020
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Process Development and Scale-up of a Multi-Component Synthesis of a 3-Methyl-1-Aryl 1,2,4-
Triazole Building Block
Thomas E. La Cruz*†, Daniel S. Treitler†, Annie Tam†, Kristine M. Smith§, Simon Leung‡, Charles
Pathirana†, Michael Peddicord†, Yu Fan, Dale Vanyo, and Joerg Deerberg
†Chemical and Synthetic Development, ‡R&D External Manufacturing, and §Drug Product Science and
Technology
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Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States
* To whom correspondence should be addressed: thomas.lacruz@bms.com
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TOC: Table of Contents graphic
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Multi-Component
SNAr
7
8
9
H
N
NO2
NH2
NO2
NO2
N
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N
N
OTs
HC(EtO)3
Steps: 1
Yield: 80%
PMI: 24
Base
F
HO
HO
Steps: 3
Yield: 24%
PMI: 300
F
N
N
NH2
N
Isomers: One
Isomers: ~3:2
4.5 Kg Scale
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ABSTRACT
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The classical preparation of 3-methyl-1-aryl-1,2,4-triazoles through an S Ar reaction pathway results in a
N
7
8
9
mixture of N-regioisomers. Removal of the unwanted isomer reduces the yield and affects processability
of the final product. In the presented case study, the target triazole was prepared by an S Ar route over
N
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three steps, in 24% overall yield, with a prohibitive Process Mass Index (PMI) of 300 that made the S Ar
N
route inadequate for process scale implementation. Bristol-Myers Squibb scientists discovered an
improved strategy that allows access to 3-methyl-1-aryl-1,2,4-triazoles directly from anilines and
completely obviates formation of N-regioisomers. Further development of this new reaction manifold for
process-scale application led to the production of the target triazole in kilogram quantities, as a single
regioisomer, with a three-fold improvement in yield and seven-fold improvement in PMI. Pre-scale-up
thermal analysis indicated that the tosylamide oxime reagent was highly energetic and required proper
controls for its scaled-up preparation and handling.
Keywords: triazole, regioisomer, S Ar, multicomponent, tosylamide oxime, safety, building block
N
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INTRODUCTION
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When designing a chemical process for kilo-scale implementation, process scientists search the literature
for examples of well-established chemical transformations and begin to optimize the chemical reaction
to suit the target substrate by understanding the underlying mechanism, characterizing by-products and
examining the parameters that impact reaction efficiency. However, optimizing a reaction from the
literature may not yield fruitful results. No matter the amount of time and resources invested, sometimes
an inherent limitation in the underlying reaction mechanism limits its efficiency, or proves otherwise
unsuitable for the target substrate. At these junctures, alternative reaction pathways can be sought out
to address the chemical challenge at hand. Creating a chemical methodology can be exciting, but a high-
risk endeavor especially in the development space where meeting product delivery timelines is
paramount.
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1,2,4-Triazoles, which are structural motifs found in several biologically active and polymeric compounds,
can serve as an example where the limits of established chemical methodologies may inhibit development
of an efficient process.1 Out of the many types of 1,2,4-triazoles that exist, 3-methyl-1-aryl-1,2,4-triazoles
can be troublesome to prepare efficiently (Figure 1). For example, a common multistep strategy of
preparing an aryl hydrazine, followed by stepwise condensation with a thioimidate and a trialkyl
orthoformate generates 1-aryl 1,2,4-triazoles (Eq. 1). While this approach provides access to the desired
product, handling toxic, flammable diazo intermediates, or aryl hydrazine derivatives on scale in addition
to multiple linear steps being required, make this approach unattractive for large-scale implementation.2
More convergent chemical routes exist, such as SNAr reactions or metal mediated C-N bond couplings (Eq.
2). However, lack of control around the triazole N-regioisomer is a major limitation of these strategies
that results in complexities when purifying the desired product and ultimately decreased material
throughput.3,4
Figure 1. 1-Aryl 1,2,4-triazole Synthesis
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Eq. 1:
General hydrazine approach, Ref. 2
4
5
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7
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9
S
R
R
R
i. HCl,
NaNO2
ii. SnCl2
N
H
base, then
HC(OMe)3
N
N
N
H2
NH2
H
N
N
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Eq. 2:
General SNAr and metal catalyzed, Ref. 3,4
R
R
R
base
heat
or
Cu(I),
ligand,
heat
H
N
N
+
+
N
N
N
X
N
N
N
N
X = F, Cl, Br, or I
Regioisomer control over 2 and 3 was the core challenge encountered when compound 5 first entered
the development space and required a scalable synthesis (Scheme 1). Published routes to target 5
reported yields of 26-36% after purification and N-regioisomeric ratios of ~1:1 stemming from the SNAr
reaction of 3-methyl-1H-1,2,4-triazole (6) with aryl halides.5 Overall, the most efficient literature example
to access compound 5 required a four-step sequence, which includes masking and unmasking the hydroxyl
group as a PMB ether.6 Attempts at in-house optimization of the SNAr route, summarized in Scheme 1,
began with the reaction between 1,2-difluoro-4-nitrobenzene (1) and 3-methyl-1H-1,2,4-triazole (6),
which consistently gave a 3:2 mixture of triazole products 2 and 3. The inherent lack of selectivity led to
isolated yields of only 38% resulting from complicated work-up and crystallization protocols required to
reduce the amount of undesired triazole isomer in the isolated product. Product 2 was then methoxylated
to give the target triazole 4 in 73% yield (28% overall yield). Demethylation of 4 was performed with
excess BBr3 (4 equiv) in dichloromethane (DCM) to afford compound 5 in 86% yield, 24% overall yield
from 1. The amount of waste generated from this synthetic route was undesirable and processability
issues were evident. Demethylation of 4 generated a thick, gummy-mixture and liberated several molar
equivalents of HBr during the quench.6 Overall, the work-up and crystallization required copious amounts
of water to remove excess inorganic salts, and large volumes of organic solvents were required for
crystallizations, leading to process mass intensities (PMI) of 104 and 300 for compounds 4 and 5,
respectively, starting from 1 in both cases.7 The negative impact of generating isomeric mixtures to
process efficiency was very evident. Incremental processing improvements mainly focused on removing
the undesired N-regioisomer, but did not address the root cause of the issue, which was that SNAr routes
to 3-methyl-1-aryl 1,2,4-triazoles give mixtures of isomers. Thus, a fundamentally different reaction
manifold, which obviates the regiosomeric selectivity challenge, would be highly advantageous.
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Scheme 1. SNAr synthesis of triazoles 4 and 5.
H
N
N
NO2
NO2
NO2
NO2
NO2
N
6
( )
BBr3,
DCM,
35 C, 20 h
NaOMe, MeOH
THF
+
K2CO3, DMF,
80 C, 1 h
F
MeO
HO
F
F
N
N
N
N
N
N
N
N
F
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3:2
1
N
N
N
N
2
3
4
5
73% yield
(28% overall yield from
38% yield
removed by
crystallization
86% yield
(24% overall yield from
1
1
)
)
A more convergent reaction pathway to compounds 4 and 5 would ideally use commercially available
anilines and preclude formation of N-regioisomers. Fortuitously, this alternative route to 3-methyl-1-aryl
1,2,4 triazoles does exist, discovered by BMS scientists and developed as a general chemical methodology
to prepare isomer free 3-methyl-1-aryl-1,2,4-triazoles.8 Figure 2 illustrates a brief summary of this
method. The transformation is an acid catalyzed multi-component reaction of an aniline with
triethylorthoformate and tosylamidoxime (8). At the onset of the reaction an equilibrium mixture of
imidates and amidines forms. Subsequent reaction with 8 and cyclization leads to the desired product.
Through this pathway, convergent access to a wide range of 3-methyl-1-aryl-1,2,4-triazoles can be
achieved. The scope of this methodology includes electron-deficient, electron-rich, and sterically hindered
substrates to provided triazole products in good to excellent yields as summarized in Figure 2. After
establishing its potential utility in a laboratory setting for the synthesis of desired triazole 5, focus turned
to developing and streamlining protocols for process scale application. Our first area of investigation was
to ensure we had a good understanding of the acetamide oxime tosylation procedure to form 8,
optimizing for safety, quality and yield.
Figure 2. Selected examples for the multi-component triazole synthesis methodology
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Imidate
Amidine
4
5
6
R
R
R
R
NH2
N
HC(OEt)3
OTs
8
( )
acid catalyst
7
8
9
NH2
N
N
N
N
R
NH
OEt
N
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NO2
OMe
Bpin
R
i-Pr
i-Pr
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
95%, 4 h
75%, 24 h
76%, 24 h
56%, 24 h
PREPARATION OF TOSYLAMIDOXIME
Preparation of tosylamidoxime 8, a crystalline solid, has been previously reported.9 The procedure entails
tosylation of acetamide oxime (7) with TsCl in the presence of triethylamine using THF as the solvent,
followed by multiple unit operations that include filtrations, aqueous work-up and crystallization.
Although suitable to prepare 8 in small quantities, this approach employed potentially unnecessary
processing steps that could likely be simplified. In addition, compounds with N-O bonds are known to be
energetic substances, thus the chemical and thermal stability of 8 were the primary factors considered
before any activities related to its large scale application could begin.10,11
AKTS (Advanced Thermal Analysis Software) analysis of the DSCs of the solids 7 and 8 gave ADT24
(temperature at which time to maximum rate under adiabatic conditions in 24 h) values of 90 °C and 64
C, respectively (Table 1, entries 1 and 2). The commercially available acetamide oxime 7 was safe to
handle and store utilizing the vendor prescribed conditions.12 However, due to its relatively low ADT24
value, it was imperative that all processing temperatures associated with 8 (reaction, workup, drying,
storage, etc) be kept at or below 60 C. Solid 8 was shown to have limited thermal stability with a
decomposition energy corresponding to TAD of decomposition (DSC) of +429 C (entry 2) and a
decomposition onset temperature of 100 °C. As part of the reaction mixture in THF (10 L/Kg), the
measured TAD substantially improved to +75 C as the solvent provided a heat sink for the decomposition
energy (entry 3). Due to this enhanced thermal stability profile of the solution, it was decided to
implement a telescoped procedure, which had the additional benefit of eliminating unit operations and
waste from the final triazole process.
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Tosylation of amidoxime 7 in THF with triethylamine takes place almost instantaneously. The reaction is
highly exothermic with an adiabatic temperature rise TAD of +111 C (Table 1 entry 4) when tosyl chloride
(TsCl) is added as a single molar equivalent portion. Not surprisingly, 95% of the heat energy was
generated within 1.3 minutes of tosyl chloride addition. To control the exotherm generated by this
reaction and ensure safe scale-up, addition of TsCl in five equal portions to a mixture of 7, Et3N and THF,
with enough time in-between charges to ensure batch temperature control, was designed as part of the
process to sustain the desired internal batch temperature.13 Furthermore, it was advantageous to lower
the processing temperature to 0 C and maintain active batch cooling. This strategy was successful in
lowering the maximum TAD of the reaction to 28 °C and ensured that the reaction temperature could be
maintained below the ADT24 even if cooling were lost (Table 1, entries 5-9). After the tosylation reaction
was complete, the process stream could be warmed to 20 C for further processing without thermal
concerns (entry 10). The metered introduction of the tosylating reagent, along with active batch cooling
and the heat sink effect generated by reaction dilution, safely dissipated the heat associated with the
reaction and enabled scale up activities to take place safely.14
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Performing the tosylation reaction in THF allowed for a simple work-up. Once the reaction had reached
completion, filtering the resulting slurry removes the Et3NHCl salt by-product to afford tosylamidoxime
8 as a THF process stream ready for use in the subsequent cyclo-condensation step. The small amounts
of Et3NHCl salt (~1 mg/mL) that remained in solution did not have an adverse impact on the next reaction.
However, control of reagent stoichiometry was important since a large excess of base or TsCl would inhibit
the acid catalyzed formation of the triazole in the subsequent step. This reaction proceeded safely to give
8 in almost quantitative solution yield. With high quality solutions of 8 now available, focus on the triazole
reaction development was initiated again focusing on safety, quality, and yield.
Scheme 2. Tosylamidoxime 8 preparation
Conditions:
1. THF (10 L/Kg)
2. Et3N (1.05 equiv.)
3. Cool to 0 C
NH2
N
NH2
N
OTs
OH
4. TsCl (5 x 0.0206 equiv.)
5. Filter
acetamide oxime
8
7
6. THF cake wash (5 L/Kg)
solution in THF
~95% yield
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Table 1. Thermal analysis of tosylation reaction components
5
6
7
8
Entry
Compound/Stream
Method
DSC
DSC
ARC
RC1
TAD C ADT24 C Onset C
1
2
3
4
5
6
7
8
9
Acetamide Oxime 7 (Solid)
Tosylamidoxime 8 (Solid)
Tosylamidoxime 8 in THF
TsCl Addition (charge 1 of 1)
TsCl Addition (charge 1 of 5)
TsCl Addition (charge 2 of 5)
TsCl Addition (charge 3 of 5)
TsCl Addition (charge 4 of 5)
TsCl Addition (charge 5 of 5)
587
429
75
90
64
65
136
100
83
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111
19
-
̶
-̶-
--
̶
--
̶
RC1
28
-̶
-̶
RC1
27
-̶
-̶
RC1
23
-̶
-̶
RC1
13
-̶
-̶
RC1
10 Warm stream from 0 to 20 °C
1
-̶
-̶
RC1
MULTICOMPONENT TRIAZOLE REACTION
The reaction between commercially available aniline 9, (EtO)3CH, an acid catalyst (such as citric acid or
EtSO3H) and a THF solution of 8 occurs smoothly at 60 C (reaction conditions 1, Scheme 3). An RC1 study
of the reaction stream showed an exotherm with heat generated over 5 h (TAD 27 °C), which supports 60
C as a safe processing temperature. Furthermore, with a maximum self-heating rate of 4.5 °C/min, a TAD
of 30 °C and an onset of 135 °C in an ARSST study, the cyclo-condensation reaction mixture contained no
significant thermal decomposition risk. The transformation proceeded through a series of expected
intermediates 11a and 12a (Scheme 3) and after 6 h, most of these chemical entities were converted to
triazole 4, with solution yields measured above 90%, while a small excess of 8 remained. Tight control of
residual water (<300 ppm) was necessary to minimize (EtO)3CH hydrolysis and subsequent reaction
stalling. Ethyl tosylate, a known genotoxic impurity (GTI), produced by the condensation of ethanol and
tosic acid, two reaction by-products, does form at significant levels (4 relative area percent by HPLC), but
purges during the crystallization to < 10 ppm.15 As an alternative, the sulfonic acid catalyst could be
substituted with citric acid to preclude formation of ethyl tosylate. An aqueous work-up was unnecessary;
once the reaction reached completion and was cooled to ambient temperature, a thick slurry formed.
Water was then added and triazole 4 was isolated as a crystalline solid in 85% isolated yield, a circa three-
fold improvement from its first generation synthesis. In addition to the dramatic increase in product
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throughput, a PMI of 25 was calculated for the combined preparation of 8 and 4, resulting in a four-fold
reduction from the first generation process. These results underline the utility of the multi-component
triazole methodology with respect to both material throughput and sustainability.
7
8
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Scheme 3. Multi-component synthesis of triazoles 4 and 5
NO2
NO2
NO2
NO2
NH2
N
OTs
Reaction
conditions
1 or 2
RO
RO
RO
RO
8
N
NHAr
NH2
N
OEt
N
N
N
9:
10:
11a:
11b:
12a:
12b:
4:
5:
R = Me
R = H
R = Me
R = H
R = Me
R = H
R = Me, 85% yield
R = H, 80% yield
Reaction conditions 1: 9
8
NO2
(1.0 equiv.), (1.1 equiv.) THF stream, HC(OEt)3 (1.7 equiv.)
Citric Acid (10 mol%), 60 °C, 6 h
Ar =
Reaction conditions 2 10
8
:
(1.0 equiv), (1.2 equiv.) THF stream, DMA, HC(OEt)3 (1.2 equiv.),
RO
EtSO3H (10 mol%), 45 C, 17 h
Successfully optimizing the preparation of triazole 4 improved the formal synthesis of compound 5, but
the demethylation reaction with BBr to access 5 remained an unsustainable option since the process
3
stream generated a thick, difficult to stir, gummy-mixture. An alternative route to directly access triazole
5 was considered as aniline 10 (Scheme 3) is a readily commercially available compound that contains a
free hydroxyl group compatible with the multi-component triazole methodology. Thus, reacting aniline
10, tosylamide oxime, triethyl orthoformate, and an acid catalyst generates triazole 5 in a single step
(Scheme 3, reaction conditions 2).16,17 The use of THF as solvent resulted in a thick difficult-to-stir slurry
that is comprised of the starting material and the highly polar amidine intermediate 12b, ultimately
resulting in an incomplete transformation. Switching to N,N-dimethylacetamide (DMA) affords a
homogeneous reaction. Protection of the hydroxyl group in 10 as an ether or ester was not required. The
reaction of substrate 10 proceeded at a lower batch temperature, albeit with an extended age time, which
led to a more efficient transformation producing triazole 5 in >95% solution yield.18 The reaction profile
contained low levels of aniline-related byproducts, but fortunately no complicated aqueous work-up was
necessary, and the product was crystallized directly from the reaction stream in 80% isolated yield; a more
than three-fold yield improvement compared to the first generation route. An increase in product
throughput (80% vs. 24% yield for the old process) was accompanied by a dramatic drop in waste volumes
for this process. The effect of using a more relevant starting material, a convergent sequence, no aqueous
work-up, and one isolation resulted in a PMI value of 42 for the combined preparation of 8 and 5, which
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is striking when compared to a PMI of 300 associated with the first generation route. This multi-
component reaction was carried out successfully on 4.0 kg scale to generate 4.5 kg of the target triazole
5.
7
8
9
CONCLUSION
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A multi-component synthesis of 1-aryl 1,2,4-traizoles 4 and 5, as single regioisomers, directly from
commercially available anilines, resulted in a three-fold increase in product yield of triazole products
compared to the previously utilized SNAr method (from 28%/24%, respectively, to 85%/80%).
Implementation of this reaction on process scale required understanding of the thermal events associated
with preparation/handling of tosylamidoxime 8 and proper engineering controls to allow for a safe and
successful scale-up. Significant PMI reduction was observed for the multi-component process when
compared to the SNAr (first generation) approach. In addition, the multi-component triazole methodology
substrate scope was expanded from the seminal publication by using two anilines substituted with both
19
an electron- donating and withdrawing group.
The goal to deliver a process to prepare triazole 5 with
a sharp increase in yield and reduction in the waste footprint was achieved and serves as an example of
the magnitude a multi-component reaction can have on increasing process efficiency.
EXPERIMENTAL
General. All reactions were carried out with overhead stirring under a nitrogen atmosphere using
commercially available, anhydrous solvents. Reaction progress was monitored by HPLC unless otherwise
noted.
Due to thermal concerns, all plant-scale manipulations involving 8 as either a product or a reagent utilized
a fully jacketed (ethylene glycol) reactor. Fail temperature set to 55 °C and Fail Set Point set to maximum
cooling (-15 °C ); that is, if the internal temperature of the reaction had exceeded 55 °C, maximum cooling
would have automatically initiated. The Threshold Temperature was set to 55 °C, which prevented an
operator from setting the jacket temperature set point above 55 °C. Even with engineering controls in
place, critical operations involving heating (i.e. – distillation) were supervised at all times. While the
process was not supervised during overnight holds, temperature control was turned off in order to
prevent inadvertent jacket heating. Liquid wastes that were found to contain unreacted 8 by HPLC (i.e. –
mother liquor from the crystallization of 5) were cooled and treated carefully with aqueous sodium
hydroxide in order to destroy any residual 8 prior to disposal.
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Preparation of Triazole 5 (Part 1: Synthesis of 8). In a 100L glass-lined reactor, acetamide oxime (7, 2.31
Kg, 31.2 mol, 1.00 equiv) was added to a solution of triethylamine (3.30 Kg, 32.6 mol, 1.03 equiv) in THF
(49.3 Kg). This heterogeneous mixture (280 ppm water by KF) was cooled to an internal temperature of
5 °C, and then with active cooling, five portions of p-TsCl (5 x 1.20 Kg, 31.5 mol, 1.01 equiv) were charged
over the course of 90 min (each addition resulted in an immediate exotherm of approximately 8 °C; the
next addition was not carried out until the internal temperature had returned to <8 °C). After the final
charge of p-TsCl, an additional charge of THF (2 Kg) was used to rinse any residual reagent from the reactor
walls. The resultant thick white slurry was warmed to 20 °C, aged for 1 h and then filtered. The reaction
vessel and filter cake were washed with THF (2 x 9.2 Kg), the filter cake was discarded, and the combined
mother liquors were returned to the reactor.
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Preparation of Triazole 5 (Part 2: Multi-component reaction). A distillative solvent swap of the solution
prepared in the prior step was effected under reduced pressure (200 torr; jacket temp: 40 °C) using slow
addition of DMA (24.4 Kg) to maintain a nearly constant volume until DMA addition was complete.
Distillation was continued until the molar ratio of DMA:THF was >7:1 (as determined by 1H NMR). To this
resultant DMA solution of 8 (31.2 mol assumed, 1.20 equiv) was added 2-amino-5-nitrophenol (10, 4.00
Kg, 26.0 mol, 1.00 equiv.), triethylorthoformate (4.60 Kg, 31.0 mol, 1.20 equiv), and ethanesulfonic acid
(0.25 Kg, 2.27 mol, 0.1 equiv.). These charges were rinsed into the reactor with additional DMA (2 Kg).
The resultant brown homogeneous solution was aged for 17 h at 45 °C, becoming heterogeneous after
~14 h (Note: in addition to 17 h at 45 °C, the reaction mixture was aged for an additional 24 h at ~20 °C
since heating was turned off f
or two overnight periods to avoid potential overheating while the reaction was not being monitored).
Next, MeOH (44.6 Kg) was charged slowly into the reaction mixture over the course of 2 h, resulting in a
thick slurry, which was cooled slowly to 0 °C over the course of 2 h and then aged for an additional 4 h at
0 °C. The slurry was filtered and the reaction vessel and filter cake were rinsed with MeOH (3 x 6.9 Kg).
The rinsed filter cake was dried in a vacuum oven (50 °C, 100 torr, 48 h) to afford 5 as an off-white
crystalline solid (4.49 Kg, 80% yield). 5: 1H NMR (400 MHz, DMSO-d6) δ 11.77 (br s, 1 H), 9.09 (s, 1 H), 7.92
(d, J = 8.8 Hz, 1 H), 7.86 (d, J = 2.8 Hz, 1 H), 7.80 (dd, J = 8.8, 2.4 Hz, 1 H), 2.37 (s, 3 H) ppm; 13C NMR (100
MHz, DMSO-d6) δ 160.4, 148.6, 145.5, 129.8, 123.4, 114.9, 111.7, 13.6 ppm; HRMS calcd for C9H9N4O3 [M
+ H]+ 221.06692, found 221.06711.
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Preparation of Solid Tosylamidoxime (8) for Characterization. In a 2 L glass reactor equipped with
overhead stirring, acetamide oxime (7, 20.0 g, 0.270 mol, 1.00 equiv) was added to a solution of
triethylamine (40.0 mL, 0.287 mol, 1.06 equiv) in THF (600 mL). While maintaining the jacket temperature
at 0 °C, p-TsCl (56.0 g, 0.294 mol, 1.09 equiv) was added in five equal portions to the reaction mixture over
the course of 1 h (a large exotherm was observed immediately after each addition). The resulting thick
slurry was warmed to 20 °C and aged for an additional 45 min and then filtered. The filter cake was rinsed
with additional THF (200 mL), then the solids were discarded and the mother liquors were concentrated
under reduced pressure to near-dryness. The resulting residue was dissolved in EtOAc (450 mL) and
washed with water (90 mL), then saturated aqueous NaCl (200 mL). The organic layer was dried over
Na2SO4, filtered, and once more concentrated under reduced pressure to near-dryness. MTBE (150 mL)
was then added, resulting in a slurry, which was agitated for 16 h at 20 °C. Vacuum filtration, MTBE rinses
(2 x 30 mL), and vacuum drying at 20 °C afforded 8 as a white powder (53.0 g, 86% yield). (Caution: Do not
heat solid. Store at 0 °C under a nitrogen atmosphere). 8: 1H NMR (500 MHz, CD2Cl2) δ 7.81 (d, J = 8.5 Hz,
2 H), 7.35 (d, J = 8.0 Hz, 2 H), 4.92 (br s, 2 H), 2.44 (s, 3 H), 1.81 (s, 3 H) ppm; 13C NMR (125 MHz, CD2Cl2) δ
157.3, 145.4, 133.7, 130.0 (2 C), 129.1 (2 C), 21.9, 16.8 ppm; HRMS calcd for C9H13N2O3S [M + H]+
229.06414, found 229.06395.
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Lab Scale Preparation of Triazole 4. In a 1 L glass reactor equipped with an overhead stirrer, 9 (29.6 g,
0.176 mol, 1.00 equiv), triethylorthoformate (44.5 g, 0.300 mol, 1.70 equiv), and citric acid (3.6 g, 0.019
mol, 0.11 equiv) were added sequentially to a solution of 8 (44.2 g, 0.194 mol, 1.10 equiv) in THF (220 mL)
at 20 °C (Note: 8 solution is prepared using same procedure described for the synthesis of 5). The resulting
homogeneous brown solution was heated to an internal target temperature of 60–66 °C, which rapidly
afforded a heterogeneous mixture. After 6 h at temperature, the reaction mixture was cooled back down
to 20 °C. Water (444 mL) was added slowly over the course of 60 min, then the resulting slurry was aged
for an additional 2 h at 20 °C and vacuum filtered. The filter cake was washed with a 1:2 mixture of
THF:water (120 mL), then dried to afford 4 (36.7g, 95 LCAP purity, 95.5wt%, 85% yield adjusted for
potency) as an off-white powder [Note: An optional recrystallization from i-PrOH (10 L/Kg) could afford
analytically pure material]. 4: 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1 H), 8.05 (d, J = 8.8 Hz, 1 H), 7.97–7.89
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(m, 2 H), 4.07 (s, 3 H), 2.46 (s, 3 H) ppm; C NMR (100 MHz, CDCl3) δ 161.4, 149.9, 146.5, 145.1, 131.2,
123.4, 116.9, 107.6, 56.7, 13.8 ppm; HRMS calcd for C10H11N4O3 [M + H]+ 235.08257, found 235.08267.
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Liquid wastes that were found to contain unreacted 8 by HPLC (i.e. – mother liquor from the crystallization
of 4) were cooled and treated carefully with aqueous sodium hydroxide in order to destroy any residual 8
prior to disposal.
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ACKNOWLEDGMENTS
We would like to thank the Bristol-Myers Squibb Chemical and Synthetic Development senior leaders Dr.
Robert Waltermire, Dr. Albert DelMonte, Dr. Rodney Parsons, Dr. Michael Randazzo, Dr. Martin Eastgate
and Dr. Jean Tom for their support. Ms. Vera Leshchinskaya (HPLC) for analytical support. BMS Chemical
Development chemists, Dr. Antonio Ramirez and Dr. Tom Razler for thoughtful scientific discussions.
REFERENCES
1 Reviews on applications of 1,2,4-triazoles: (a) Al-Masoudi, A.; Al-Soud, Y. A.; Al-Salihi, N. J.; Al-Masoudi,
N. A. 1,2,4-Triazoles: Synthetic Approaches and Pharmacological Importance (Review), Chem. Heterocycl.
Compd. 2006, 42, 1377–1403. (b) Pibiri, I.; Buscemi, S. A Recent Portrait of Bioactive Triazoles, Current
Bioactive Compounds 2010, 6, 208–242. (c) Sahoo, S.; Veliyath, S. K.; Mahendra Kumar, C. B. Review on
Substituted 1, 2, 4-Triazoles as Potent Antifungal and Antibacterial Agents, Int. J. Res. Pharm. Sci. 2012, 3,
326–333. (d) Shalini, K.; Kumar, N.; Drabu, S.; Sharma, P. K. Advances in Synthetic Approach to and
Antifungal Activity of Triazoles, Beilstein J. Org. Chem. 2011, 7, 668–677. (e) Naik, A. D.; Dîrtu, M. M.;
Railliet, A. P.; Marchand-Brynaert, J.; Garcia, Y. Coordination Polymers and Metal Organic Frameworks
Derived from 1,2,4-Triazole Amino Acid Linkers, Polymers 2011, 3, 1750–1775. (f) Klingele, M. H.; Brooker,
S. The Coordination Chemistry of 4-substituted 3,5-di(2-pyridyl)-4H-1,2,4-Triazoles and Related Ligands,
Coord. Chem. Rev. 2003, 241, 119–132. (g) Haasnoot, J. G. Mononuclear, Oligonuclear and Polynuclear
Metal Coordination Compounds with 1,2,4-Triazole Derivatives as Ligands, Coord. Chem. Rev. 2000, 200–
202, 131–185 and references therein. (h) Guru, M. M.; Punniyamurthy, T. Copper(II)-Catalyzed Aerobic
Oxidative Synthesis of Substituted 1,2,3- and 1,2,4-Triazoles from Bisarylhydrazones via C–H
Functionalization/C–C/N–N/C–N Bonds Formation, J. Org. Chem. 2012, 77, 5063–5073 and references
therein.
2
Terauchi, J.; Koike, T.; Honda, E.; Nakamura, M.; Kajita, Y.; Hoashi, Y.; Morimoto, S.; Fujimoto, T.
Preparation of Piperazines and Related Compounds for Inhibiting Amyloid-β Production. PCT Int. Appl.
WO 2011002067, January 6, 2011.
3 Metal mediated examples: (a) Albrecht, B. K.; Gehling, V. S.; Hewitt, M. C.; Taylor, A. M.; Harmange, J.-
C. Preparation of 4HBenzo[b][1,2,4]Triazolo[4,3-d][1,4]Diazepine Derivatives as Bromodomain Inhibitors.
PCT Int. Appl. WO 2012151512, November 8, 2012. (b) Aspnes, G. E.; Didiuk, M. T.; Filipski, K. J.; Guzman-
Perez, A.; Lee, E. C. Y.; Pfefferkorn, J. A.; Stevens, B. D.; Tu, M. M. Preparation of 3-[4-(Heterocyclyl-
Substituted)-Benzamido]Propanoic Acids as Glucagon Receptor Modulators. U.S. Pat. Appl. US
20120202834, August 9, 2012.
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General SNAr examples: (a) De Cleyn, M. A. J.; Van Brandt, S. F. A.; Gijsen, H. J. M.; Berthelot, D. J-C.;
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Oehlrich, D. Triazole Derivatives as Gamma-Secretase Modulators and Their Preparation and Use for the
Treatment of Diseases. PCT Int. Appl. WO 2011086098, July 21, 2011 (b) Kamenecka, T. M.; Jiang, R.; Song,
X.; Lograsso, P.; Cameron, M. D. Preparation of Phenylaminopyrimidine Derivatives and Analogs as Protein
Kinase Inhibitors. PCT Int. Appl. WO 2009032861, March 12, 2009. (c) Naidu, B. N.; Connolly, T. P.; Ueda,
Y. Cyclic Pyrimidinone Derivatives as HIV Integrase Inhibitors and Their Preparation, Pharmaceutical
Compositions and Use in the Treatment of HIV Infections. US 7419969, September 2, 2008.
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Several examples of an SNAr approach to triazole 4 are reported in the patent literature by different
pharmaceutical institutions, Bristol-Myers Squibb Company, USA , AstraZeneca AB, Swed, Ortho-McNeil-
Janssen Pharmaceuticals, Inc, USA, and Hoffmann-La Roche AG, Switz: (a) Cleyn, M. A. J.; Van Brandt, S.
F. A.; Gijsen, H. J. M.; Berthelot, D. J.-C.; Oehlrich, D. Triazole Derivatives as γ-Secretase Modulators and
Their Preparation and Use for the Treatment of Diseases. PCT Int. Appl. WO 2011086098, July 21, 2011.
(b) Gijsen, H. J. M.; Bischoff, F. P.; Zhuang, W.; Van Brandt, S. F. A.; Surkyn, M.; Zaja, M.; Berthelot, D. J.-
C.; De Cleyn, M. A. J.; Macdonald, G. J.; Oehlrich, D. Substituted Benzoxazole, Benzimidazole,
Oxazolopyridine and Imidazopyridine Derivatives as γ-Secretase Modulators and Their Preparation and
Use for the Treatment of Diseases. PCT Int. Appl. WO 2010094647, August 26, 2010. (c) Van Brandt, S. F.
A.; De Cleyn, M. A. J.; Gijsen, H. J. M.; Berthelot, D. J.-C.; Surkyn, M. Triazole Derivatives as γ-Secretase
Modulators and Their Preparation and Use for the Treatment of Diseases. PCT Int. Appl. WO 2011086099,
July 21, 2011. (d) Gijsen, H. J. M.; MacDonald, G. J.; Bischoff, F. P.; Tresadern, G. J.; Trabanco-Suarez, A.
A.; Van Brandt, S. F. A.; Berthelot, D. J.-C. Preparation of Substituted Bicyclic Imidazole Derivatives as
Gamma Secretase Modulators. PCT Int. Appl. WO 2010070008, June 24, 2010. (e) Boy, K. M.; Guernon,
J. M.; Macor, J. E.; Olson, Richard, E.; Shi, J.; Thompson, L. A., III; Wu, Y.-J.; Xu, Li; Zhang, Y.; Zuev, D. S.
Preparation of Fused Pyrimidine Compounds as Modulators of β-Amyloid Production. PCT Int. Appl. WO
2011014535, February 3, 2011. (f) Marcin, L. R.; Thompson, L. A., III; Boy, K. M.; Guernon, J. M.; Higgins,
M. A.; Shi, J.; Wu, Y.-J.; Zhang, Y.; Macor, J. E. Preparation of Bicyclic Compounds, Especially Bicyclic
Triazoles, for the Reduction of Beta-Amyloid Protein Production. PCT Int. Appl. WO 2010083141, July 22,
2010. (g) Lo-Alfredsson, Y.; Paulsen, K.; Rakos, L.; Rotticci, D.; Waldman, M. Preparation of
Pyridooxazepine Derivatives for Use as Gamma-Secretase Modulators and Treatment of Alpha Beta
Related Pathologies, Such as Alzheimer's Disease. PCT Int. Appl. WO 2010132015, November 18, 2010.
(h) Baumann, K.; Flohr, A.; Goetschi, E.; Jacobsen, H.; Jolidon, S.; Luebbers, T. F. Preparation of
Heteroarylphenylamine Derivatives for Use as Amyloid Beta Modulators. PCT Int. Appl. WO 2009103652,
August 27, 2009.
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Boy, K. M.; Guernon, J. M.; Macor, J. E.; Thompson, L. A., III; Wu, Y.-J.; Zhang, Y. Preparation of
Macrocyclic Compounds Fused to Benzene and Pyrimidine Rings for the Reduction of Beta-Amyloid
Production. PCT Int. Appl. WO 2012009309, January 19, 2012.
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Jimenez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Using the Right Green Yardstick:
Why Process Mass Intensity Is Used in the Pharmaceutical Industry To Drive More Sustainable Processes,
Org. Process Res. Dev. 2011, 15, 912–917.
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8 (a) Tam, A.; Armstrong, I. S.; La Cruz, T. E. Multicomponent Synthesis of 1-Aryl 1, 2, 4-Triazoles, Org. Lett.
2013, 15, 3586–3589. (b) A review of the original article also appears as an abstract by Snieckus, V.; Bian,
J. Synthesis of 1-Aryl 1,2,4-Triazoles by a Three-Component Condensation, Synfacts, 2013, 9, 1047.
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9 (a) Literature preparation of tosylamidoxime 8: Inagaki, T.; Kurita, Y.; Hirakata, K.; Mizutani, A.; Kondo,
M. Preparation of Alkoximino-5-Amino-1,2,4-thiadiazole-3-Acetates. EP 0795551, September 17, 1997.
(b) For a review on the structure and chemistry of hydroxylamidoximes see: Katritzky, A. R.; Huang, L.;
Chahar, M.; Sakhuja, R.; Hall, C. D. The Chemistry of N-Hydroxyamidoximes, N-Aminoamidoximes, and
Hydrazidines, Chem. Rev. 2012, 112, 1633–1649.
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10 The thermal stability studies of tosyl oximes and hydroxylamines have been reported: (a) Am Ende, D.
J.; Ripin, D. H. B.; Weston, N. P. Thermochimica Acta, 2004, 419, 83–88. (b) Cisneros, L. O.; Rogers, W. J.;
Mannan, M. S. Thermochimica Acta, 2004, 414, 177–183.
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The Chemical Synthesis Development department at Bristol-Myers Squibb has published a case study
on the scale-up synthesis of an energetic azide compound: González-Bobes, F.; Kopp, N., Li, L. Deerberg,
J.; Sharma, P.; Leung, S.; Davies, M.; Bush, J.; Hamm, J.; Hrytsak, M. Scale-up of Azide Chemistry: A Case
Study, Org. Process Res. Dev. 2012, 16, 2051−2057.
12 Acetamide oxime (cas 22059-22-9) was purchased from GFS, handled and stored as prescribed by the
vendor’s instructions.
13 Original procedure followed a similar approach, but provided no thermal data analysis or quantitative
basis for TsCl charge amounts and rates.
14 Please refer to experimental section for engineering control details.
15
Lead references on the topic of alkyl tosylates as genotoxic impurities: (a) Guo, T.; Shi, Y.; Zheng, L.;
Feng, F.; Zheng, F; Liu, W. Rapid and Simultaneous Determination of Sulfonate Ester Genotoxic Impurities
in Drug Substance by Liquid Chromatography Coupled to Tandem Mass Spectrometry: Comparison of
Different Ionization Modes, Journal of Chromatography A, 2014, 1355, 73–79. (b) Elder, D.P.; Teasdale,
A.; Lipczynski, A.M. Control and Analysis of Alkyl Esters of Alkyl and Aryl Sulfonic Acids in Novel Active
Pharmaceutical Ingredients (APIs), Journal of Pharmaceutical and Biomedical Analysis, 2008, 46, 1–8. (c)
Elder, D.; Facchine, K. L.; Levy, J. N.; Parsons, R.; Ridge, D.; Semo, L.; Teasdale, A. An Approach to Control
Strategies for Sulfonate Ester Formation in Pharmaceutical Manufacturing Based on Recent Scientific
Understanding, Org. Process Res. Dev. 2012, 16, 1707−1710.
16 The tosylamidoxime reagent was prepared in 25 L/Kg concentration in THF.
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Structure of 5 was confirmed by NMR using H-1H NOE and H-15N HMBC correlations. N chemical
shifts are given in red:
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18 Residual tosylamidoxime 8, 0.03 equiv with respect to input, was still present in the mother liquors after
processing. Please refer to the experimental section for the optional procedure used to treat the waste.
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A few interesting qualitative observations were made about the behavior of anilines 9 and 10 in the
triazole reaction. The multi-component triazole methodology reaction reaches completion faster when
electron-withdrawing groups are present on the arene ring (Figure 2). This is due to the consumption of
the amidine intermediate (such as 12a and 12b, Scheme 3) being rate limiting as observed in the seminal
publication. Electron-donating groups, on the other hand, tended to slow the reaction kinetics, and
required controlled addition of the aniline to achieve the best yields.8 Not surprisingly, anilines 9 and 10
are of mixed electronic nature containing both strong electron-donating and electron-withdrawing
groups, complicating a reaction rate prediction. It was observed that the nitro group on the aniline had
an overriding effect and the triazole reaction behaved as if the methoxy or hydroxyl groups were absent
leading to facile turnover of the amidine. Furthermore, an acceleration of the triazole reaction with the
free hydroxyl group was observed, allowing the transformation to reach completion at temperatures
below 60 C. It is presumed that intramolecular hydrogen bonding between the hydroxyl motif and the
proximal nitrogen atom in amidine 12b assisted in the intermediate’s breakdown and subsequent facile
conversion to the triazole product.
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