General and scalable amide bond formation with epimerization-prone substrates using T3P and pyridine

Article abstract of DOI:10.1021/ol201875q

The mild combination of T3P (n-propanephosphonic acid anhydride) and pyridine has been developed for low-epimerization amide bond formation and implemented for the synthesis of a key intermediate to a glucokinase activator. This robust method is general for the coupling of various racemization-prone acid substrates and amines, including relatively non-nucleophilic anilines, and provides amides in high yields with very low epimerization. With easy reaction setup and product isolation, this protocol offers several practical and experimental benefits.

Full text of DOI:10.1021/ol201875q

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5048–5051
General and Scalable Amide Bond
Formation with Epimerization-Prone
Substrates Using T3P and Pyridine
Joshua R. Dunetz,*,† Yanqiao Xiang,‡ Aaron Baldwin,‡ and Justin Ringling‡
Pfizer Worldwide Research and Development, Eastern Point Road, Groton,
Connecticut 06340, United States
joshua.r.dunetz@pfizer.com
Received July 12, 2011
ABSTRACT
The mild combination of T3P (n-propanephosphonic acid anhydride) and pyridine has been developed for low-epimerization amide bond
formation and implemented for the synthesis of a key intermediate to a glucokinase activator. This robust method is general for the coupling of
various racemization-prone acid substrates and amines, including relatively non-nucleophilic anilines, and provides amides in high yields with
very low epimerization. With easy reaction setup and product isolation, this protocol offers several practical and experimental benefits.
Amides are widespread in compounds of biological and
pharmaceutical importance; in fact, a survey found these
structures present in 25% of known pharmaceuticals.1 Not
surprisingly, amide bond formations via the coupling of
amines and carboxylic acid derivatives are the most com-
mon transformations for the synthesis of drug candidates.2
Despite continuing advances in methods to prepare amide
bonds,3 a recurring challenge involves avoiding epimeriza-
tion of activated carboxylic acid substrates at stereogenic
centers adjacent to the carbonyl. This epimerization typi-
cally occurs via deprotonation of the R-carbon, and sub-
strates which can better stabilize the resulting carbanion
through resonance are more susceptible to racemization.
Herein, we describe the development of high-yielding amide
coupling conditions that suppressthe epimerization of acid
substrates which are particularly sensitive to racemization.
These conditions have been applied successfully to
various acids and amines, including relatively non-
nucleophilic anilines.
Our work in this area stems from development efforts to
manufacture clinical API supplies of a glucokinase activa-
tor. Glucokinase is an enzyme in the liver and pancreas
which regulates glucose metabolism,4 and compounds
which activate this enzyme are promising therapies
for type II diabetes.5 We needed to develop a robust
process for the multikilogram synthesis of amide 1, a key
† Chemical Research and Development.
‡ Analytical Research and Development.
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Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606. (c) Bode, J. W.
Curr. Opin. Drug Discovery Dev. 2006, 9, 765. (d) Montalbetti, C. A. G.
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r
10.1021/ol201875q
Published on Web 08/29/2011
2011 American Chemical Society

intermediate to the API (active pharmaceutical ingre-
dient). The medicinal chemistry preparation of 1 coupled
acid 2 and amine 3 in a two-step procedure via the acid
chloride derivative of 2. This approach proved effective
for the synthesis of amide 1 on gram scale, but several
issues had to be addressed to enable the preparation of 1
on kilogram scale. First, we strongly preferred coupling
2 and 3 in a one-pot procedure with minimal handling of
a sensitive activated acid intermediate. In addition, other
factors besides yield and chiral purity of 1 influenced our
optimization of this reaction for scaleup. These included
the ease of reaction workup and product purification, as
well as reagent costs and health safety issues (e.g.,
toxicity, sensitization).
Table 1. Survey of Coupling Reagents and Conditions
Our investigation of reagents for the one-pot condensa-
tion of acid 2 and amine 3 quickly revealed an obstacle to
oursynthesisof1: activated couplingintermediatesderived
from acid 2 are highly susceptible to epimerization.6
Among the conditions outlined in Table 1, reactions with
DCC7 provided the amide with the greatest enantiopurity
(entries 2ꢀ3); however, this reagent (and its dicyclohex-
ylurea byproduct) can be difficult to purge without chro-
matography and poses significant handling concerns due
to toxicity and sensitization risks. Related carbodiimide
EDC8 has an amino side chain that allows for its easy
extraction from reaction mixtures via acidic workup, but
couplings of2 and 3 withthisreagent either proceededwith
epimerization or too sluggishly to be useful (entries 4ꢀ6).
Only slight racemization was observed from our best
HATU9 conditions (entry 10), but this uronium com-
pound is expensive and, much like DCC, degrades to
byproducts via coupling that are difficult to remove with-
out chromatography. Initial efforts to couple 2 and 3 via
CDI,10 CDMT,11 or DEPBT12 also proceeded with race-
mization (entries 11ꢀ14) and were abandoned.
a All reactions at room temperature. DCC = N,N0-dicyclohexylcarbo-
diimide; HOAt=1-hydroxy-7-azabenzotriazole; EDC=N-(3-dimethyla-
minopropyl)-N0-ethylcarbodiimide; CDI=carbonyldiimidazole; HATU=N,
N,N0,N0-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluoropho-
sphate; CDMT=2-chloro-4,6-dimethoxy-1,3,5-triazine; NMM=N-met-
hylmorpholine; DEPBT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-
4(3H)-one.
30years ago,14,15 wefound onlytwo examples16 outside the
patent literature using T3P to prepare amide bonds from
nonamino acid substrates containing an epimerizable
R-stereocenter.17 Of these two examples, one employs race-
mic acid16a and the other was not reported with an
We also explored T3P (4; n-propanephosphonic acid
anhydride13) for the one-pot condensation of acid 2
and amine 3. Although this reagent was developed over
(17) Despite the prevalence of peptide couplings, we also found
relatively few examples in which T3P mediates the coupling of an amino
acid containing an R-stereocenter: (a) Morales-Avila, E.; Ferro-Flores,
(6) In control experiments, amide 1 did not epimerize when exposed
to coupling conditions. Furthermore, acid 2 did not epimerize under the
same conditions excluding coupling reagent.
(7) (a) Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067.
(b) HOAt as additive: Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
(8) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org. Chem.
1961, 26, 2525.
(9) Carpino, L. A.; El-Faham, A.; Albericio, F. Tetrahedron Lett.
1994, 35, 2279.
(10) (a) Anderson, G. W.; Paul, R. J. Am. Chem. Soc. 1958, 80, 4423.
(b) Paul, R.; Anderson, G. W. J. Am. Chem. Soc. 1960, 82, 4596.
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G.; Ocampo-Garcıa, B. E.; De Leon-Rodrıguez, L. M.; Santos-Cuevas,
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a-Becerra, R.; Medina, L. A.; Gomez-Olivan, L. Bioconju-
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2010, 12, 4928. (c) Thoss, M.; Seidel, R. W.; Feigel, M. Tetrahedron 2010,
66, 8503. (d) Vasantha, B.; Hemantha, H. P.; Sureshbabu, V. V. Synthe-
sis 2010, 2990. (e) Patterson, D. E.; Powers, J. D.; LeBlanc, M.; Sharkey,
T.; Boehler, E.; Irdam, E.; Osterhout, M. H. Org. Process Res. Dev. 2009,
€
13, 900. (f) Wehner, M.; Janssen, D.; Schafer, G.; Schrader, T. Eur. J.
Org. Chem. 2006, 138. (g) Lange, U. E. W.; Baucke, D.; Hornberger, W.;
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(11) Kaminski, Z. J. Synthesis 1987, 917.
(12) Li, H.; Jiang, X.; Ye, Y.-h.; Fan, C.; Romoff, T.; Goodman, M.
€
Mack, H.; Seitz, W.; Hoffken, H. W. Bioorg. Med. Chem. Lett. 2006, 16,
2648. (h) Mack, H.; Baucke, D.; Hornberger, W.; Lange, U. E. W.; Seitz,
Org. Lett. 1999, 1, 91.
€
W.; Hoffken, H. W. Bioorg. Med. Chem. Lett. 2006, 16, 2641. (i)
(13) T3P is a registered trademark of Archimica Gmbh.
(14) (a) Wissmann, H.; Kleiner, H.-J. Angew. Chem., Int. Ed. 1980,
19, 133. (b) Wissmann, H. Phosphorus and Sulfur 1987, 30, 645.
´
(15) For reviews of T3P chemistry: (a) Llanes Garcıa, A. L. Synlett
2007, 1328. (b) Wu, C.-z.; He, X.-r.; Hu, X.-m. Huaxue Shiji 2007, 29,
719. (c) Schwarz, M. Synlett 2000, 1369.
(16) (a) Kopach, M. E.; Singh, U. K.; Kobierski, M. E.; Trankle,
W. G.; Murray, M. M.; Pietz, M. A.; Forst, M. B.; Stephenson, G. A.;
Mancuso, V.; Giard, T.; Vanmarsenille, M.; DeFrance, T. Org. Process
Res. Dev. 2009, 13, 209. (b) Fish, P. V.; Deur, C.; Gan, X.; Greene, K.;
Hoople, D.; Mackenny, M.; Para, K. S.; Reeves, K.; Ryckmans, T.; Stiff,
C.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. Bioorg. Med. Chem. Lett.
2008, 18, 2562.
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Z.; Liu, J. O. Tetrahedron Lett. 2000, 41, 6295. (k) Klose, J.; Bienert, M.;
Mollenkopf, C.; Wehle, D.; Zhang, C.-w.; Carpino, L. A.; Henklein, P.
Chem. Commun. 1999, 1847. (l) Hiebl, J.; Alberts, D. P.; Banyard, A. F.;
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M.; Bodenteich, M.; Chen, T.; Esch, P. M.; Kollmann, H.; Lantos, I.;
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Org. Lett., Vol. 13, No. 19, 2011
5049

experimental procedure.16b Furthermore, only recently
has this relatively underappreciated reagent been reported
for any amide bond formation on kilogram scale,17e,i,18
which is surprising as this phosphonic acid anhydride offers
several practical and experimental benefits. First, its bypro-
ducts (e.g., 5) from coupling are water-soluble and easily
separated from reaction mixtures, which greatly simplifies
the purification of amide product without chromatography
and minimizes the environmental impact of this coupling
reagent. In addition, commercially available T3P solutions
(50% in various solvents) are easily handled, are moderately
priced, and have long shelf-life stability. Furthermore,
Table 2. Optimization of T3P-Catalyzed Amide Coupling
this reagent lacks the toxicity and shock sensitivity asso-
ciated with other coupling reagents and additives.
Table 2 shows our optimization of the T3P-catalyzed
coupling of 2 and 3 with respect to epimerization. Negli-
gible product was obtained in the absence of added base
(entry 1). As racemization involves deprotonation at the
stereogenic center of the T3P-activated intermediate, we
hypothesized that weaker and bulkier bases would mini-
mize the loss of chiral purity in converting acid 2 to amide
1.6,19 Indeed, replacing Et3N with hindered TMP for this
T3P-catalyzed amide coupling suppressed epimerization
considerably (entries 2ꢀ4). Additional improvements were
realized using weaker morpholine and lutidine bases
(entries 5ꢀ10), with N-methylmorpholine (NMM) indu-
cing more racemization than the bulkier N-ethylmorpho-
line (NEM). Switching from 2,6-lutidine to pyridine, a
weaker base, further reduced epimerization (entries 12ꢀ14).
Interestingly, we observed enhanced racemization using
DMAP as an additive; the resulting acylpyridinium appears
more susceptible to epimerization than its T3P-activated
precursor, and sufficient reaction rates were observed without
this nucleophilic catalyst. In the end, we achieved the best
results with pyridine at 0 °C, providing 1 with near-complete
preservation of enantiopurity (entry 14). This combination of
T3P and pyridine is particularly well-suited for amide bond
formation from epimerization-prone substrates (vide infra),
a DMAP=4-(dimethylamino)pyridine; TMP=2,2,6,6-tetramethylpipe-
ridine; NMM=N-methylmorpholine; NEM=N-ethylmorpholine. b Either
no DMAP or 0.2 equiv of DMAP.
and although pyridine has greater toxicity than other bases,
it is easily purged via acidic workup.20,21
These conditions were incorporated into an operation-
ally simple procedure for the synthesis of 1 on gram to
kilogram scale (eq 2). T3P (50% in EtOAc) is added to a
mixture of 2 and 3 in pyridine and EtOAc, and the resulting
homogeneous solution is held at 0 °C as amide is formed
with low epimerization (1.0ꢀ1.5% epi-1 from 0.3ꢀ0.6%
epi-2).22 Cooling minimizes racemization and mitigates a
mild exotherm from T3P addition. Using only a slight
excessof 3 iscost-effectiveand simplifiesthe purification of
amide product. Alternatively, T3P is inexpensive relative
to 2 and 3, and although the coupling proceeds well with
only 1.2 equiv of T3P on laboratory scale, a larger excess
on kilogram scale ensures robustness and reproducibility.
In fact, the reaction does not require anhydrous-grade
(18) (a) Campeau, L.-C.; Dolman, S. J.; Gauvreau, D.; Corley, E.;
Liu, J.; Guidry, E. N.; Ouellet, S. G.; Steinhuebel, D.; Weisel, M.;
O’Shea, P. D. Org. Process Res. Dev. 2011, ASAP (DOI: 10.1021/
op2001063). (b) Guercio, G.; Castoldi, D.; Giubellina, N.; Lamonica,
A.; Ribecai, A.; Stabile, P.; Westerduin, P.; Dams, R.; Nicoletti, A.;
Rossi, S.; Bismara, C.; Provera, S.; Turco, L. Org. Process Res. Dev.
2010, 14, 1153. (c) Boggs, S. D.; Cobb, J. D.; Gudmundsson, K. S.;
Jones, L. A.; Matsuoka, R. T.; Millar, A.; Patterson, D. E.; Samano, V.;
Trone, M. D.; Xie, S.; Zhou, X.-m. Org. Process Res. Dev. 2007, 11, 539.
(19) It is possible that epimerization occurs via deprotonation and
ketene formation, although trapping studies failed to capture evidence
for ketene as an intermediate.
(20) The ICH limit for pyridine in drug substances is 200 ppm.
(21) After optimizing this chemistry, we found a single report in
which T3P and pyridine were applied to the synthesis of amide polymers
via condensations of achiral acids and dianilines in NMP at 80 °C: Ueda,
M.; Honma, T. Polym. J. 1988, 20, 477.
(22) Supporting Information contains full experimental details on
gram and kilogram scale. Volume (vol) is a unit for mL/g or L/kg. In this
case, 1 mL of pyridine and 2 mL of EtOAc per gram of 2 (limiting
reagent).
5050
Org. Lett., Vol. 13, No. 19, 2011

solvents with 2 equiv of the water-scavenging T3P, and on
gram scale this coupling is typically performed without
inert atmosphere.
reslurry the filtered amide in water to remove 5 (without loss
of yield). Ultimately, we scaled this process to manufacture
over 20 kg of amide 1 per batch in our cGMP facility.
We next explored the generality of these low-epimeriza-
tion conditions for the condensation of acid 2 with other
amines on gram scale. As shown in Table 3, the T3P-
catalyzed coupling of 2 with various aryl and alkylamines
provided amides in very high yields and enantiopurities.
These conditions accommodate both primary and second-
ary amines, even bulky substrates (e.g., 6d). As a trend,
epimerization increases with the basicity of the amine
coupling partner, which is consistent with observations
from reaction optimization (Table 2). However, even
isopropylamine, the most basic coupling partner in this
study, provided amide 7g with 94:6 er.
The reaction workup is equally straightforward. Quench-
ing with 0.5 M aqueous HCl (3 vol) precipitates 1 as the
freebase with >99% achiral purity and >99:1 er while
purging pyridine and excess 3. The filtered amide is
typically isolated in 80ꢀ85% yield with traces of 5, a T3P
byproduct which inhibits downstream chemistry. On gram
scale, 5 is easily removed by simple water rinses of the filter
cake; however, on kilogram scale, it proved more efficient to
Table 3. Scope of Amines in T3P-Catalyzed Couplings of 2
These conditions also effect amide formation from other
acids whose activated derivatives might be sensitive to
racemization. Condensations of 2-phenylpropanoic acid,
N-Cbz-alanine, and N-Cbz-phenylglycine (all >99:1 er)
with PhNH2 or BnNH2 provided amides 8ꢀ10 in high
yield and without detection of epimerization. Not surpris-
ingly, the application of T3P/pyridine to N-Ac-alanine and
PhNH2 provided azlactone byproducts.3
In conclusion, we have developed mild and general
conditions for amide bond formation on gram to kilogram
scale using T3P and pyridine. This method provides
amides in high yields with very low epimerization and is
particularly well-suited for the coupling of racemization-
prone acids and amines, including relatively non-nucleo-
philic anilines. With easy reaction setup and product
isolation, this protocol offers several practical and experi-
mental benefits to the synthetic chemist.
Acknowledgment. We gratefully thank our Pfizer col-
leagues Martin A. Berliner, for helpful discussions while
designing this amide coupling and for proofreading this
manuscript, and Victor Soliman and Ronald Morris, for
acquiring HRMS data for amide products.
Supporting Information Available. Experimental pro-
cedures and characterization data for all amides. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a R = cyclopentylmethyl; Het = 4-CF3-imidazolyl. b Enantiomeric
ratios unchanged by workup. c Isolated yields.
Org. Lett., Vol. 13, No. 19, 2011
5051