1,1′-carbonyldiimidazole (CDI) mediated coupling and cyclization to generate [1,2,4]triazolo[4,3-a]pyridines

Article abstract of DOI:10.1021/acs.orglett.5b03589

An operationally efficient CDI mediated tandem coupling and cyclization reaction to generate [1,2,4]triazolo[4,3-a]pyridines has been reported. The reaction conditions and scope were investigated, and the methodology was demonstrated in batch mode as well

Full text of DOI:10.1021/acs.orglett.5b03589

Letter
pubs.acs.org/OrgLett
1,1′-Carbonyldiimidazole (CDI) Mediated Coupling and Cyclization
To Generate [1,2,4]Triazolo[4,3‑a]pyridines
Kyle D. Baucom, Sian C. Jones, and Scott W. Roberts*
̂
Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 31320, United States
S
* Supporting Information
ABSTRACT: An operationally efficient CDI mediated
tandem coupling and cyclization reaction to generate [1,2,4]-
triazolo[4,3-a]pyridines has been reported. The reaction
conditions and scope were investigated, and the methodology
was demonstrated in batch mode as well as in a continuous
process.
he [1,2,4]triazolo[4,3-a]pyridine structural motif is found
Tin a variety of molecules of critical use in the pharmaceutical
sciences, agricultural sciences, and material sciences. The
literature reports the use of triazolopyridines as carbohydrate
derivatives,1 C-nucleoside analogs,2 and as potential pharma-
ceuticals in the form of triazolobenzodiazepanes.3 Herbicidal4 as
well as antimycobacterial5 and -microbial6 uses for triazolopyr-
idines have also been reported. Within the pharmaceutical
sciences, a wide range of biological activities have been reported
for these moieties: (a) fibrinogen receptor (GPIIb/IIIa),7 β-
chemokine receptor CCR 5,8 and histamine H3 antagonist
activity;9 (b) farnesyl protein transferase (FPT),10 P38α
mitogen-activated (MAP) kinase,11 receptor tyrosine kinase (c-
Met),12 serine/threonine Akt1/Akt2 kinase,13 and human 11β-
hydroxysteroid dehydrogenase type-1 (11β-HSD-1) inhibitor
activity;14 (c) antiviral activity,15 and (d) anti-inflammatory
activity.16 Given the widespread application of the triazolopyr-
Figure 1. Synthetic approaches toward [1,2,4]triazolo[4,3-a]pyridines.
idine motif, the development of efficient chemistries to access
these structures is of great importance to the synthetic
community.
There are multiple drawbacks to the cyclization strategies
presented above: (a) all strategies require the isolation of either
2-pyridylhydrazide 3 or 2-pyridylhydrazone 7 cyclization
precursors, (b) the reported acidic and/or thermal cyclization
conditions are generally not compatible with diverse function-
ality, and (c) while the use of Burgess’s reagent, Lawesson’s
reagent, or Mitsunobu conditions provide mild cyclization
conditions, these strategies inherently suffer from atom
inefficiencies. Thus, we became interested in the development
of a mild and operationally efficient synthesis of triazolopyridines
using a single dehydration reagent for both coupling and
cyclization events.26 Herein, we describe the use of 1,1′-
carbonyldiimidazole (CDI) as a mild and efficient reagent in
the synthesis of triazolopyridines. This research focused on
identifying a single-flask coupling/cyclization reagent, develop-
ing mild conditions that tolerated diverse functionality, and
assessing this methodology as a continuous manufacturing (CM)
process.
The methods for the synthesis of triazolopyridines generally
involve the dehydration of 2-pyridylhydrazides 3 or oxidative
cyclization of 2-pyridylhydrozones 7 (Figure 1).17 The requisite
2-pyridylhydrazines 1 are readily accessed by SnAr or palladium
catalyzed couplings of hydrazine and 2-halopyridines. Coupling
of 2-pyridylhydrazines 1 with carboxylic acids 218 and/or the
palladium mediated coupling of 2-chloropyridines 4 with aryl
hydrazides 519 has been reported to generate 2-pyridylhydrazides
3, which are converted to the desired triazolopyridines 6 by
dehydration/cyclization. The dehydration/cyclization has been
reported with numerous reagents and conditions: Mitsunobu
conditions,20 Brønsted acids,19,21 Burgess’s reagent,22 Law-
esson’s reagent,18 phosphorus oxychloride,23 and thermal21 as
well as microwave irradiation.19 Alternatively, 2-pyridylhydra-
zones 7 generated either from palladium catalyzed coupling of 2-
chloropyridines and an aldehyde-derived hydrazine24 or from
condensation of an aldehyde and 2-pyridylhydrazines25 have
been reported to generate triazolopyridines 6 after oxidative
cyclization.
Received: December 18, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03589
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Organic Letters
Letter
Our investigations into the single-flask acylation of 2-
pyridylhydrazines and subsequent dehydration to generate
triazolpyridines began by screening typical amide coupling
reagents and monitoring by liquid chromatography−mass
spectrometry (LCMS, Table 1). The screening reactions were
selected for the substrate scope investigations since the addition
of water (10.0 mL/g) to the crude reaction mixture quenched the
remaining CDI and specifically precipitated the desired product
in high yield and purity. It was hypothesized that this MeCN/
water crystallization would be a general and convenient isolation
for the subsequent substrate scope investigations.
Aromatic acid derivatives with a range of different functional
groups were tolerated under the reaction conditions (Table 2).
Table 1. Coupling and Dehydration Reagent Investigations
Table 2. Scope of Tandem Coupling/Cyclization Reactions
with Functionalized Benzoic Acids
a
entry
1
conditions
results
DCC, oxyma, DMF,
ambient temp
cyclic product 10 observed poor
purity profile
2
3
4
5
6
7
DIC, oxyma, DMF,
ambient temp
low conversion to cyclic product 10
SOCl2, DIEA, DMF,
ambient temp
cyclic product 10 observed poor
purity profile
BOP, DIEA, DMF, ambient to linear product 9 only
50 °C
HATU, DIEA, DMF, ambient
to 50 °C
T3P, DIEA, DMA, ambient to high conversion to cyclic product 10
40 °C
CDI, DMF, ambient to 40 °C
high conversion to cyclic product 10
high conversion to cyclic product 10
a
Both 2-fluorobenzoic and 4-fluorobenzoic acid were utilized for the
initial screening experiments.
performed by (1) charging 1.0−1.5 equiv of the coupling reagent
to a solution containing the carboxylic acid 8, (2) charging 1.0
equiv of the 2-pyridylhydrazine (neat), and (3) charging an
additional 1.0−2.0 equiv of coupling reagent. The carbodiimide
reagents DCC/oxyma and DIC/oxyma primarily generated
linear intermediate 9, with only minor conversion to
triazolopyridine 10 observed (entries 1−2). Activation of
carboxylic acid 9 with thionyl chloride, coupling, and attempted
cyclization promoted by an additional charge of thionyl chloride
generated a complicated reaction (entry 3). While phosphonium
reagent BOP generated only linear product 9, HATU
successfully converted 1 and 8 to the desired product 10 (entries
4−5). Additionally, both propylphosphonic anhydride (T3P)
and CDI were also competent in the single-flask conversion of
hydrazine and acid to product 10 in high conversion and purity
(entries 6−7). Due to the relatively low cost, commercial
availability, and demonstrated utility on large scale,27 CDI was
selected for further development.
The reaction was performed by utilizing two separate CDI
charges. In order to design a robust process to accommodate a
diverse substrate scope, 1.2 equiv of the carboxylic acid was
activated with 1.3 equiv of CDI at 40 °C (age time ≥30 min),28
followed by charging 1.0 equiv of the 2-pyridylhydrazine (neat)
and aging at ambient temperature for ≥30 min to generate
hydrazide 9. The dehydration was accomplished by charging an
additional 2.0 equiv of CDI (neat) and aging ≥30 min at ambient
temp.29 Elevated temperature (40 °C) was implemented to
ensure that the acid activation went to completion. If CDI was
still present when 1 was added, then CDI and the 2-
pyridylhydrazine provided the [1,2,4]triazolo[4,3-a]pyridin-3-
ol impurity.
a
Isolated yield after direct crystallization of product from the reaction
mixture.
In general, halogenated benzoic acids provided triazolopyridines
in high isolated yield (80−90%, entries 1−3). Benzoic acids
containing nitrile, methyl ether, and methyl ester functionality
also provided triazolopyridines in high yield (93−100%, entries
4−6). Only in the case of potentially reactive amide functionality
(4-carbamoylbenzoic acid, entry 7) or sterically challenging
functionality (2,4,6-trimethylbenzoic acid, entry 8) did the
reaction fail.31 The furan-2-carboxylic acid provided the desired
triazolopyridine in high yield (88%, entry 9).
Isopropyl acetate (IPAc), dichloromethane (DCM), N,N-
dimethylacetamide (DMA), 2-methyltetrahydrofuran
(MeTHF), and acetonitrile (MeCN) were all proven compatible
with the reaction conditions.30 Acetonitrile (10.0 mL/g) was
B
DOI: 10.1021/acs.orglett.5b03589
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Alkyl substituted carboxylic acids were also well tolerated
under the reaction conditions (Table 3). The branched
Table 3. Scope of the Tandem Coupling/Cyclization
Reactions with Alkyl Substituted Carboxylic Acids
Figure 2. Schematic of [1,2,4]triazolo[4,3-a]pyridine CM process.
solubility of CDI in MeCN necessitated the use of DMA (CDI
solubility approximately 100 mg/mL) to ensure homogeneous
streams. The 4-fluorobenzoic acid (1.2 equiv), first CDI charge
(1.3 equiv), and 2-pyridyl hydrazine (1.0 equiv) were each
dissolved in 10.0 mL/g of DMA. The second CDI charge (2.0
equiv) was dissolved in 20.0 mL/g DMA. This CM design
resulted in a 5× net dilution compared to the batch process.
While the acid activation step is fast at ambient temperature, the
coupling and cyclization reactions were performed at 90 °C to
achieve the desired residence time of 17 min for the coupling and
10 min for the final cyclization.32
The CM system was successfully demonstrated producing 2
mg/min, delivering product with high isolated purity. The first
reaction, 4-fluorobenzoic acid (1.2 equiv, 10.0 mL/g DMA) and
CDI (1.3 equiv, 10.0 mL/g DMA), was performed using a 1 mL
quartz microreactor at ambient temperature (8 min residence
time) to achieve rapid mixing. The second reaction, reaction of
the acyl imidazole with 2-pyridylhydrazine (1.0 equiv, 10.0 mL/g
DMA), was performed using a static micromixing tee and a 1.0
mL capacity HP PFA reactor at 90 °C (17 min residence time).
The third reaction, dehydration of the hydrazide, was performed
using a quartz micromixing chip and 2.0 mL capacity HP PFA
reactor at 90 °C (10 min residence time). The triazolopyridine
product was precipitated by addition to a continuous stirred-tank
reactor (CSTR) containing deionized (DI) water (50.0 mL/g) at
ambient temperature.33
a
Isolated yield after column chromatography.
isobutyric acid and linear 3-phenylpropanoic acid both provided
the desired products in high isolated yield (entries 1−2).
Attempts to crystallize the alkyl substituted triazolopyridines
under the typical conditions were not successful. Thus, products
were purified by column chromatography following aqueous
workup.
The scope of the hydrazine component was also examined
(Table 4). 2-Hydrazinylquinoline and 3-chloro-2-hydrazinylpyr-
Table 4. Scope of the Tandem Coupling/Cyclization Reaction
with Functionalized 2-Pyridylhydrazines
The carbon dioxide (CO2(g)) generated from the initial CDI
activation created segmented flow and impacted the mixing and
conversion of downstream chemistry. Thus, a degassing cell was
implemented whereas the segmented flow was pumped into a
vial (under nitrogen), and the gas was released into the
headspace. The CO2(g) evolution from the CDI mediated
cyclization also created segmented flow and impacted conversion
to the final product due to the decrease in residence time. This
was overcome by subjecting the reaction stream to a quartz
mixing chip before heating to 90 °C and utilizing a longer
residence time (2.0 mL capacity HP PFA reactor, 10 min
residence time). These modifications improved the crude
reaction mixture purity at steady state to 84 liquid chromatog-
a
34
Isolated yield after direct crystallization of product from the reaction
raphy area percent (LCAP)254
.
The final purity profile of the
mixture.
isolated solids was improved to 100 LCAP254 after continuous
precipitation. While high dilution of a category 1B (toxic for
reproduction)35 solvent was utilized for this preliminary
assessment, this feasibility study successfully established a CM
process that generated isolated solids in high purity.
In conclusion, an operationally efficient CDI mediated tandem
coupling and cyclization reaction to generate [1,2,4]triazolo[4,3-
a]pyridines has been reported. This reaction tolerated various
functional groups and was demonstrated in batch mode as well as
in a continuous process.
idine provided the desired triazolopyridines in excellent isolated
yield (93−99%, entries 1−2). However, 5-nitropyridine failed to
perform the final cyclization (entry 3). A higher temperature (40
°C) was required for the hydrazide coupling for all entries, while
chloro-substituted hydrazine 16b required 40 °C to perform the
final cyclization to generate triazolopyridine 17b.
An assessment of this methodology as a continuous
manufacturing process was investigated (Figure 2). The poor
C
DOI: 10.1021/acs.orglett.5b03589
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03589.
Experimental procedures; and characterization data for
new compounds (1H and 13C NMR spectra) (PDF)
(16) Roma, G.; Di Braccio, M.; Grossi, G.; Piras, D.; Ballabeni, V.;
Tognolini, M.; Bertoni, S.; Barocelli, E. Eur. J. Med. Chem. 2010, 45, 352.
(17) For a general review, see: Jones, G. Adv. Heterocycl. Chem. 2002,
83, 1.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: scottr01@amgen.com.
(18) Moulin, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2006,
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Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. Seb Caille, Dr. Shawn Walker, Dr. Jackie
Milne, and Dr. Matthew Bio (Amgen Drug Substance
Technologies) for insightful discussions regarding this project.
The authors additionally thank Dr. Karl Hansen, Dr. Jeroen
Bezemer, and Dr. Margaret Faul (Amgen Drug Substance
Technologies) for support of this research.
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