Review

pubs.acs.org/OPRD

Large-Scale Applications of Amide Coupling Reagents for the

Synthesis of Pharmaceuticals
Joshua R. Dunetz,*,† Javier Magano,*,‡ and Gerald A. Weisenburger*,‡
†
Process Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United States
‡
Chemical Research & Development, Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340,
United States

ABSTRACT: This review showcases various coupling reagents which have been implemented specifically for large-scale amide
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synthesis via the condensation of an acid and amine, while highlighting the benefits and drawbacks of each reagent on an
industrial scale.

■
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CONTENTS 4.4.1. n-Propanephosphonic Acid Anhydride

(T3P) 157
1. Introduction 140 4.4.2. Ethylmethylphosphinic Anhydride
2. Reagents for Amide Coupling 141 (EMPA) 158
2.1. Coupling via Acid Chloride 141 4.5. Coupling via CDI 158
2.2. Coupling via Acid Anhydride 142 4.6. Coupling via Carbodiimide 159
2.2.1. Carboxylic/Carbonic Acid Anhydrides 142 4.6.1. DCC 159
2.2.2. Sulfonate-Based Mixed Anhydrides 144 4.6.2. DIC 160
2.2.3. Phosphorus-Based Mixed Anhydrides 144 4.6.3. EDC 161
2.2.4. CDI 144 4.7. Coupling via Phosphonium Salt 162
2.3. Coupling via Activated Ester 144 4.7.1. BOP 162
2.3.1. Carbodiimides 144 4.8. Coupling via Guanidinium and Uronium Salt 163
2.3.2. Phosphonium Salts 145 4.8.1. HBTU 163
2.3.3. Guanidinium and Uronium Salts 146 4.8.2. HATU 163
2.3.4. Triazine-Based Coupling Reagents 147 4.8.3. TBTU 165
2.4. Coupling via Boron Species 148 4.8.4. TPTU 165
3. Other Methods for Amide Bond Formation 149 4.8.5. TOTU 165
3.1. Synthesis of Amides from Esters 149 4.9. Coupling via Triazine Reagent 166
3.2. Synthesis of Amides via Transamidation 149 4.9.1. Cyanuric Chloride 166
3.3. Synthesis of Amides Catalyzed by Brö nsted 4.9.2. CDMT 166
Acids 149 4.9.3. DMTMM 167
4. Case Studies 149 4.10. Coupling via Boron Reagent 167
4.1. Coupling via Acid Chloride 149 4.10.1. Boric Acid 167
4.1.1. Thionyl Chloride 149 4.10.2. 3-Nitrophenylboronic Acid 168
4.1.2. Oxalyl Chloride 150 5. Conclusions 168
4.1.3. Phosphorus Oxychloride 152 Author Information 169
4.1.4. Commercial Vilsmeier Reagent 152 Corresponding Authors 169
4.2. Coupling via Carboxylic or Carbonic Acid Notes 169
Mixed Anhydride 153 Abbreviations 169
4.2.1. Acetic Anhydride 153 References 170
4.2.2. Pivaloyl Chloride (PivCl) 153
4.2.3. Ethyl Chloroformate (ECF) 154
4.2.4. Isobutyl Chloroformate (IBCF) 154
4.2.5. Boc Anhydride 155
4.2.6. EEDQ 155 1. INTRODUCTION
4.3. Coupling via Sulfonate-Based Mixed Anhy- Many reviews of amide bond formation have already been
dride 156 written.1 This manuscript differentiates itself by evaluating
4.3.1. Methanesulfonyl Chloride (MsCl) 156 coupling reagents used in the large-scale condensation of an acid
4.3.2. p-Toluenesulfonyl Chloride (TsCl) 156 and amine for the synthesis of drug candidates, while
4.4. Coupling via Phosphorus-Based Mixed An-
hydride 157
Received: September 20, 2014
Published: November 15, 2015

© 2015 American Chemical Society 140 DOI: 10.1021/op500305s

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Chart 1. Found Number of References Included in This Review for Each Coupling Reagent for Amide Bond Formation above
100 mmol Scale through June 2015
highlighting the benefits and drawbacks of each reagent on
plant scale.
Amide bonds are very frequently incorporated into active
pharmaceutical ingredients (API).2 In fact, amide bond
formation is one of the most prevalent transformations in the
pharmaceutical industry, accounting for 16% of all reactions
carried out in medicinal chemistry laboratories.3 However, the
ideal method for amide synthesis, i.e., the direct condensation
of a carboxylic acid and an amine with the formation of one
equivalent of water as the only byproduct,4 is not practical due
to proton exchange between the coupling partners leading to an
ammonium carboxylate salt. Only under forcing conditions
(such as high temperature5 and microwave irradiation6) can
this coupling take place, which makes it incompatible with the
chemical complexity displayed by current drug candidates. As a
result, acid activation is required to promote the coupling with
an amine, and the development of safe and efficient processes
for acid activation and amine condensation on industrial scale is
of paramount importance.
There are many considerations when selecting an amide
coupling reagent for plant production. The ideal reagent is
inexpensive, widely available, nontoxic, safe, simple to handle,
easy to purge from reaction mixtures, and contributes only
minimally to waste streams. Furthermore, the detection and
purging of coupling byproducts to regulatory limits is high
priority when performing the amidation near the end of a
manufacturing route.7 Of course, not all coupling reagents
perform equally well for a given pair of acid and amine
substrates, and the aforementioned process considerations must
be balanced against the need for amidation conditions that
proceed with high yield and selectivity, excellent reproduci-
bility, and in the case of substrates bearing stereocenters, low
epimerization.
The first half of this review introduces the various amide
coupling reagents and compares the merits of each for large-
scale amidation. The second half of this review details case
studies in which these reagents were applied in an industrial
setting. As with our previous reviews,8 the referenced examples
are limited to couplings which contain a detailed experimental
procedure above 100 mmol scale, which spans laboratory to
plant reactions on grams to hundreds of kilograms of substrate.
This manuscript only covers examples which have appeared in
141
Review
the peer-reviewed journals; while the patent literature contains
many instances of amide coupling, the scientific details within
these legal documents are often limited. Finally, the references
at the end of this review are labeled to provide quick access to
lists of large-scale examples for each coupling reagent.
2. REAGENTS FOR AMIDE COUPLING
Chart 1 describes the number of reports above 100 mmol scale
found in the mainstream literature for each coupling reagent
through June 2015. Based on the number of publications, the
preferred methods for large-scale acid activation are (1)
activated ester formation with carbodiimides (71 instances),
with EDC and DCC as the top choices, (2) acid chloride
formation (70 instances) with thionyl chloride and oxalyl
chloride as the preferred reagents, and (3) CDI (38 instances).
Other reagents that have received considerable attention are
pivaloyl chloride (PivCl), isobutyl chloroformate (IBCF), and
n-propanephosphonic acid anhydride (T3P) for the preparation
of mixed anhydrides.
2.1. Coupling via Acid Chloride. Activation of a
carboxylic acid as the corresponding acid chloride and
subsequent reaction with an amine is one of the oldest
approaches to amide bond formation.9 The high reactivity of
acid chlorides toward amines generally leads to fast couplings
which can be especially useful for sterically hindered substrates.
However, epimerization via the ketene or azlactone is a
potential problem if the acid contains an α-stereocenter.
Several reagents have been employed on large scale for acid
chloride preparation: thionyl chloride (SOCl2), oxalyl chloride
((COCl)2), phosphorus oxychloride (POCl3), and Vilsmeier
reagent (Figure 1). SOCl2 and (COCl)2 are, by far, the two
most widely employed reagents for acid chloride formation in
Figure 1. Structures of reagents for amide bond formation via acid
chloride.
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Scheme 1. Mechanism of Acid Chloride Formation with SOCl2 Catalyzed by DMF
process chemistry. A drawback of these methods is that HCl is
a byproduct of acid chloride generation, which can lead to
incompatibility with acid-sensitive functional groups.
With reagents such as thionyl chloride, oxalyl chloride, and
phosphorus oxychloride, a small amount of DMF is typically
added to serve as a catalyst for acid chloride formation. Scheme
1 details the mechanism for acid chloride formation via SOCl2
and catalytic DMF, which proceeds via Vilsmeier−Haack
intermediate (Vilsmeier reagent10) and regenerates DMF
together with the desired acid chloride.11 The Vilsmeier
reagent is commercially available as a stable, free-flowing,
crystalline solid which allows the purchasing chemist to bypass
its preparation and the associated safety risks related to the
handling of SOCl2 or (COCl)2 (vide infra). However,
commercial Vilsmeier reagent is relatively expensive compared
to alternatives for amide bond formation, which contributes to
the limited use of this preformed reagent in process
chemistry.12
The subsequent reaction of the acid chloride with an amine
can be implemented under anhydrous conditions using an
organic base, such as Et3N, i-Pr2NEt, or pyridine, to neutralize
byproduct HCl. Despite their water sensitivity, acid chlorides
can react with amines in the presence of an aqueous base
(NaOH, NaHCO3, K2CO3, K3PO4) under Schotten−Baumann
conditions.
Thionyl chloride is the most common reagent in process
chemistry for the conversion of a carboxylic acid to an acid
chloride.13 One of the primary factors is cost, since the reagent
is inexpensive and represents one of the most cost-efficient
ways of preparing acid chlorides.14 However, one disadvantage
of thionyl chloride is the potential formation of dimethylcarba-
moyl chloride, a known carcinogen in animal models, when
used in combination with DMF as catalyst.15 The mechanisms
for the formation of this side product are shown in Scheme 2.16
Common solvents for acid chloride formation with SOCl2
include toluene, THF, n-heptane, MeCN, and DME. However,
it is also possible to employ SOCl2 as both reactant and solvent.
Upon reaction completion, excess thionyl chloride can be
removed by distillation before isolating the acid chloride or
telescoping the reaction mixture directly into the amidation.
Oxalyl chloride has also been commonly employed in
process chemistry for acid chloride generation.17 Advantages of
this reagent relative to SOCl2 include: (1) its lower boiling
point (61 °C versus 75 °C) which allows for easier removal of
excess reagent via distillation, and (2) unlike the SOCl2/DMF
combination, (COCl)2/DMF does not form dimethylcarba-
moyl chloride.15 However, equivalents of CO2 and highly toxic
CO are generated as byproducts, and adequate safety and
engineering controls are required to accommodate the
offgassing.
142
Review
Scheme 2. Mechanisms for the Formation of
Dimethylcarbamoyl Chloride
Acid chloride formation via (COCl)2 can be scaled in a
number of solvents, such as toluene, THF, EtOAc, i-PrOAc, or
MeCN. Upon reaction completion, distillation can remove
excess oxalyl chloride; however, the acid chloride thus obtained
is not usually isolated, but carried directly into the amide bond
formation with the corresponding amine.
Phosphorus oxychloride (phosphoryl chloride) has been
rarely reported on large scale for carboxylic acid activation,18
although this reagent is readily available in bulk and represents
a cost-effective alternative to SOCl2.
No examples with phosphorus trichloride or phosphorus
pentachloride for acid chloride generation on a large scale have
been found in the peer-reviewed literature, despite the fact that
these reagents are readily available in bulk and are very
competitive in cost.
Finally, amide bond formation through the acylation of
commercially available acid chlorides is also common practice
on large scale and circumvents the need for acid activation.19
On the other hand, commercially available acid bromides have
seen a much more limited use,20 most likely due to the higher
cost and far smaller number of choices.
2.2. Coupling via Acid Anhydride. 2.2.1. Carboxylic/
Carbonic Acid Anhydrides. Amide bond formation via mixed
anhydride is one of the oldest approaches and only the acyl
chloride and acyl azide methods predate it. Carbon-based
mixed anhydrides can be subdivided into two categories
depending on the type of activating reagent (Figure 2):
1. Mixed carboxylic acid anhydrides, which are formed with
reagents such as acetic anhydride or pivaloyl chloride.
There are two major drawbacks associated with
carboxylic acid mixed anhydrides: (1) regiochemical
control, which can be avoided by increasing the steric
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Figure 2. Reagents for amide coupling via mixed carboxylic and carbonic anhydrides.
Scheme 3. Amide Bond Formation via Acid Activation with EEDQ
bulk of the reagent that is used to form the mixed
anhydride; (2) disproportionation to a mixture of the
two possible symmetrical anhydrides. However, dis-
proportionation can be avoided by forming the mixed
anhydride immediately prior to reaction with the amine.
2. Mixed carbonic acid anhydrides, which are the result of
carboxylic acids undergoing reaction with reagents such
as chloroformates or EEDQ. The two carbonyls of these
substrates are not equivalent, and amines typically add to
the desired carbonyl due to the lower electrophilicity of
the undesired carbonyl (i.e., carbonate). That is the
reason why ethyl chloroformate affords good selectivity
for amide bond formation at the desired carbonyl despite
lacking steric bulk.
Reagents to prepare these mixed carboxylic or carbonic
anhydrides are typically added to a solution of the carboxylic
acid in the presence of a base, such as NMM or N-
methylpiperidine. These mixed anhydrides commonly are
carried into coupling with the amine without isolation.
Acetic anhydride (Ac2O) is commonly used on large scale as
an electrophile for amine acetylation;13ah,21 however, it is rarely
used as a reagent for acid activation in amide couplings13a as the
resulting mixed anhydride demonstrates poor regioselectivity in
reactions with amines.
There are several large-scale examples in which pivaloyl
chloride (PivCl), or trimethylacetyl chloride, has been used to
activate acids for amide coupling on large scale.13aj,17d,22
Pivaloyl chloride affords mixed anhydrides with imposing steric
bulk to drive the desired regioselectivity for amine addition.
Furthermore, PivCl seems to be the coupling reagent of choice
for the acylation of chiral amine auxiliaries
(oxazolidinones22a,c,g−i or pseudoephedrine13aj) on an industri-
al scale. The advantages of PivCl for scaleup include its
relatively low cost, wide availability, and nontoxic pivalic acid as
a byproduct after aqueous workup. As an acid chloride,
however, this reagent is an irritant, can cause chemical burns on
skin contact, and must be handled on large scale with proper
ventilation.
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Review
Ethyl chloroformate (ECF) has been used as a coupling
reagent on a large scale,19j,23 although less commonly than
isobutyl chloroformate. The benefits of ethyl chloroformate
include its low cost (less expensive than isobutyl chlorofor-
mate) and widespread availability. Although this reagent is
highly toxic and more volatile than its isobutyl analog, its
byproducts (EtOH and CO2) are relatively benign, and EtOH
is typically easier to remove via aqueous extraction than the
isobutanol byproduct of isobutyl chloroformate.23c The off-
gassing of byproduct CO2 requires that waste streams are
properly quenched to avoid the buildup of pressure in sealed
waste disposal containers.
Isobutyl chloroformate (IBCF) is a fairly common coupling
reagent for large-scale amide bond formations.13d,17d,19ah,24,25
This reagent is widely available in bulk quantities and
inexpensive. Compared to ethyl chloroformate, the isobutyl
reagent is less toxic, and its mixed anhydride shows greater
selectivity in the reaction of the amine (due to the greater steric
demand of isobutyl vs ethyl). Its byproducts, namely,
isobutanol and CO2, are relatively innocuous, but as for ethyl
chloroformate, IBCF must be properly quenched to avoid
pressurization of drummed waste streams via the offgassing of
CO2.
Boc anhydride, or di-tert-butyl dicarbonate (Boc2O), is not a
common acid-activating reagent for large-scale amide cou-
plings.26 As a low-melting solid (23 °C), this reagent is more
easily handled as a solution.
Finally, EEDQ, or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-
quinoline, was first described as a reagent for amide couplings
in 1968.27 The reagent converts a carboxylic acid to the same
mixed anhydride expected from ethyl chloroformate activation
(Scheme 3). EEDQ is similar to CDI and carbodiimides (vide
infra) in that it mediates amide coupling without requiring
additional base. This reagent is relatively inexpensive, widely
available, and its coupling byproducts (quinoline, EtOH) can
be purged by extraction into acidic aqueous media. Despite its
longevity, only one example of EEDQ on large scale has been
found in the peer-reviewed literature.28
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2.2.2. Sulfonate-Based Mixed Anhydrides. Methanesulfonyl
chloride (MsCl) and p-toluenesulfonyl chloride (TsCl) are the
two reagents in this category that have been employed on large
scale for amide bond formation (Figure 3). Sulfonate-based
Figure 3. Reagents for amide coupling via sulfonate-based anhydrides.
mixed anhydrides derived from either reagent display excellent
selectivity in which amines add preferentially to the activated
carbonyl instead of the sulfonate ester.
MsCl has not been used commonly for large-scale amide
couplings.22f,29 MsCl is highly toxic, corrosive, moisture-
sensitive, and a lachrymator,30 and these properties contribute
to the challenge of handling this reagent in industrial processes.
However, MsCl is relatively inexpensive and has been shown to
suppress epimerization for the coupling of chiral acids.29b
TsCl is used even less frequently than MsCl for large-scale
amide formation.31 TsCl is widely available and inexpensive,
but also toxic and hygroscopic.
2.2.3. Phosphorus-Based Mixed Anhydrides. The first
example of a mixed carboxylic−phosphoric anhydride was
reported in 1972 using diphenylphosphoryl azide.32 However,
no examples using this reagent for acid activation have been
found in the large scale literature, most likely due to the cost
and high energy and toxicity of the azido group. On the other
hand, more scale-friendly reagents such as n-propanephos-
phonic acid anhydride (T3P) and ethylmethylphosphinic
anhydride (EMPA) (Figure 4) have been applied by process
chemistry groups for the synthesis of drug candidates.
Figure 4. Reagents for amide coupling via phosphorus-based
anhydrides.
n-Propanephosphonic acid anhydride, more commonly
referred to as T3P (or PPA), was developed in 198033 as a
reagent for peptide couplings (Scheme 4).34 The past decade
has realized an uptake in this reagent for large-scale amide
couplings.26,31a,35 Several factors contribute to the attractiveness
Scheme 4. Mechanism of Acid Activation with T3P
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Review
of T3P on industrial scale. This reagent has low toxicity (LD50
> 2000 mg/kg),33b long shelf life stability, easy handling
(commercially available as 50% solutions in organic solvents,
such as EtOAc, DMF, or MeCN), and its water-soluble
byproducts are extracted readily into aqueous waste streams.
Furthermore, T3P appears to be a reagent of choice for
suppressing epimerization in the coupling of chiral acids
bearing a sensitive α-stereocenter.26,35a,c,f−h Drawbacks of this
reagent include its moderate cost and the environmental impact
of generating phosphonate waste streams.
Ethylmethylphosphinic anhydride (EMPA) is far less
common than T3P as a coupling reagent for large-scale
amidations.36 EMPA demonstrates enhanced stability toward
hydrolysis which allows for peptide synthesis in aqueous media;
however, its relatively high toxicity (LD50 = 7 mg/kg) and the
need for its low level purging from drug substances have
contributed to the limited use of this reagent on industrial
scale.33b The mechanism of acid activation with EMPA is
similar to the one with T3P.
2.2.4. CDI. CDI, or 1,1′-carbonyldiimidazole, is a very
attractive reagent for amide coupling on a large
scale.13aa,19ac,ae,35b,37 It is inexpensive, widely available on
kilogram scale as a crystalline solid, relatively safe, and its
byproduct imidazole is easily purged with aqueous workup. The
reaction of a carboxylic acid with CDI generates a transient
mixed anhydride that rearranges to a carbonyl imidazolide
(Scheme 5). This carbonyl imidazolide is relatively easy to
handle and may be isolated if necessary. Rearrangement of the
initial mixed anhydride to the carbonyl imidazolide generates
an equivalent of CO2 which can accelerate the rate of
subsequent amide coupling.38 An additional advantage is that
CDI-promoted couplings are often performed without addi-
tional base, as the liberated imidazole can serve this function.
One drawback of this reagent is its sensitivity toward
atmospheric moisture.39
2.3. Coupling via Activated Ester. 2.3.1. Carbodiimides.
The use of DCC, or N,N′-dicyclohexylcarbodiimide, for the
formation of peptide and other amide bonds was first reported
by Sheehan and Hess in 1955.40 Since that time, carbodiimides
have been an extremely important class of compounds for the
efficient preparation of amide bonds.41 Many carbodiimides
have been investigated as coupling reagents, but only a few are
routinely used on large scale based on availability, cost,
isolation, and environmental considerations (Figure 5). This
group is comprised of DCC, DIC (N,N′-diisopropylcarbodii-
mide), and EDC (1-ethyl-3-(3′-dimethylaminopropyl)-carbo-
diimide hydrochloride, also known as EDAC, EDCI, or WSC
(water-soluble carbodiimide)). These compounds are skin
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Scheme 5. Mechanism for CDI-Mediated Amide Coupling
Figure 5. Carbodiimides routinely used on scale.
sensitizers to varying degrees and should be handled with
caution.
A primary consideration when selecting a carbodiimide is the
preferred workup since the method for removal of the urea
byproduct can vary widely. For example, dicyclohexylurea from
DCC has very limited solubility in most organic solvents and,
therefore, is typically removed by filtration. Diisopropylurea
from DIC has reasonable solubility in CH2Cl2 and is normally
removed by aqueous extraction. Finally, the byproduct urea
from EDC is water-soluble and can be removed by aqueous
workup.
The mechanism of carbodiimide-mediated coupling is
complex and begins with proton transfer from the carboxylic
acid to the weakly basic nitrogen on the carbodiimide to give an
ion pair (Scheme 6). Addition of the resulting carboxylate
Scheme 6. Pathways for Carbodiimide-Mediated Amidation
anion forms the O-acylisourea, a very reactive acylating agent
that rapidly undergoes aminolysis with an amine to give the
desired amide. Alternatively, excess carboxylic acid can react
with the O-acylisourea to form the symmetrical anhydride,
which is also a good acylating agent. Acylation of an amine with
the symmetrical anhydride also produces an equivalent of the
starting acid.
145
Review
The O-acylisourea can also rearrange by intramolecular acyl
transfer to give the N-acylurea, which is an irreversible pathway
that does not lead to desired amide. The use of auxiliary
nucleophiles is a common practice to reduce N-acylurea
formation and α-stereocenter epimerization by increasing the
overall rate of amide coupling. Although many additives have
been reported, 1-hydroxybenzotriazole (HOBt)42 is by far the
most commonly used for carbodiimide-mediated reactions in
either stoichiometric or catalytic fashion (Figure 6). HOBt is
Figure 6. Epimerization suppressants HOBt and HOAt.
shock sensitive and subject to travel regulations,49 whereas
analog 1-hydroxy-7-azabenzotriazole (HOAt) is more stable
but considerably more expensive. These additives function by
intercepting the O-acylisourea before intramolecular acyl
transfer to the N-acylurea. The resulting activated ester is
active enough to couple with the amine, which circumvents
epimerization in many cases.
The application of DCC for amide bond formation is
showcased in the numerous reports from pharmaceutical
companies.22d,24a,35a,43 Despite being a strong sensitizer, its
low cost is one of the main drivers for its widespread use.
Compared to DCC, DIC has seen more limited use in
process chemistry groups,24d,44 despite being a liquid which
makes it easier to handle on plant scale.
EDC45 is by far the most widely used carbodiimide for the
synthesis of drug candidates.13r,17k,l,v,19m,n,21l,24b,28,35b,46 The
fact that the urea byproduct is water-soluble and can be
removed during the aqueous workup offers a clear advantage
over other carbodiimides such as DCC and DIC. However, the
high cost of this reagent is an issue that may disfavor its use
over other alternatives on scale, especially in late development.
2.3.2. Phosphonium Salts. BOP ((benzotriazol-1-yloxy)tris-
(dimethylamino)phosphonium hexafluorophosphate, Castro’s
reagent, Figure 7)47 was the first reagent of the HOBt-based
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Figure 7. BOP and PyBOP coupling reagents.

onium salts to be introduced for amide bond formation to

avoid epimerization and other side reactions that can take place
with carbodiimide reagents. Despite promoting fast couplings
and containing the epimerization suppressant HOBt in its
structure, BOP has seen limited use in process chemistry due to
the generation of one equivalent of hexamethylphosphoramide
(HMPA), a known carcinogen. As an alternative, PyBOP
((benzotriazol-1-yloxy)tris(pyrrolidine)phosphonium hexa-
fluorophosphate, Figure 7) was developed,48 which produces
the more benign tris(pyrrolidin-1-yl)phosphine oxide, but this
reagent is relatively expensive, and no examples have been
found describing its use on large scale. Another important
consideration is the presence of the high-energy benzotriazole
moiety, which requires the implementation of thorough safety
studies to determine the viability of the protocol.49
The mechanism of acid activation with BOP is shown in
Scheme 7. In the presence of a base such as Et3N or the Figure 8. Guanidinium and uronium salts HBTU, HATU, TBTU,
preferred i-Pr2 NEt, the acid carboxylate displaces the TPTU, and TOTU.
benzotriazolyloxy anion from the phosphonium center to
produce an acyloxyphosphonium intermediate. This species
then reacts with the benzotriazolyloxy anion to give an thanaminium hexafluorophosphate N-oxide), TBTU (N-[(1H-
activated benzotriazole ester and water-soluble HMPA as the benzotriazol-1-yl) (dimethylamino)methylene]-N-methylme-
byproduct. The final step involves the reaction of the thanaminium tetrafluoroborate N-oxide), TPTU (2-(2-oxo-
benzotriazole ester with the amine nucleophile to afford the 1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate),
desired amide product and HOBt as byproduct. and TOTU (O-[(cyano(ethoxycarbonyl)methyleneamino]-
The application of BOP in process chemistry has been very N,N,N′,N′-tetramethyluronium tetrafluoroborate) have found
limited due to the drawbacks mentioned above, and only one their way into large scale applications for the synthesis of
example is included in this review.50 pharmaceuticals (Figure 8). In comparative studies between
2.3.3. Guanidinium and Uronium Salts. Benzotriazole- HATU and HBTU, it has been shown that the counteranion
based HBTU, or N-[(1H-benzotriazol-1-yl) (dimethylamino)- has no appreciable effect on the outcome of the reaction.51a,52
methylene]-N-methylmethanaminium hexafluorophosphate N- Some reasons for the limited application of these reagents in
oxide,51 was introduced shortly after BOP for amide coupling process chemistry include their high molecular weight (which
(Figure 8). Since then, a large number of guanidinium and translates to high cost per mole),14 the formation of cytotoxic
uronium salts have been reported,1k and the structural N,N,N′,N′-tetramethylurea as a byproduct,53 and the presence
elucidation of these reagents as guanidinium versus uronium of high energy functional groups such as the triazolyl moiety in
salts has been investigated.51c These reagents afford fast amide HBTU, HATU, and TBTU and the N−O bonds in TPTU and
bond formations and can be very useful for the coupling of TOTU. Nevertheless, the use of these reagents may be justified
sterically hindered amino acids in peptide synthesis. Despite in situations where sensitive functionality is present on the
these advantages, only HBTU, HATU (N-[(dimethylamino)- coupling partners, and as a consequence, mild reaction
1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylme- conditions are required. A typical example is when the

Scheme 7. Mechanism of Acid Activation with BOP

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Scheme 8. Acid Activation and Amide Bond Formation with HBTU
carboxylic acid contains an epimerizable α-stereocenter. In
these cases, the addition of 1 equiv of either HOBt or HOAt
(Figure 6) may further suppress epimerization.
The mechanism of amide bond formation using guanidinium
and uronium salts is similar to the one described above for BOP
and is exemplified in Scheme 8 for HBTU. Acid activation
requires the formation of the corresponding carboxylate anion
with bases such as Et3N or i-Pr2NEt as the first step. The
carboxylate anion then reacts with HBTU to form an activated
HOBt ester and tetramethylurea as byproduct, which is the
driving force for acid activation. The reaction of the amine with
the HOBt ester yields the desired amide product.
Interestingly, although HBTU is widely used for solid-phase
peptide synthesis, only one application of this reagent has been
found among process chemistry groups for the manufacture of
drug candidates.54
HATU55 is a structurally very close analog to HBTU, but it
provides faster couplings with less epimerization. This reagent
has seen widespread use as coupling reagent for amide bond
formation due to the mild reaction conditions and the usually
high yields of amide product that it provides. It is also
particularly efficient for sterically hindered couplings.55,56 For
these reasons, several process groups in pharmaceutical
companies have reported HATU applications for the synthesis
of drug candidates.57
Several examples on the application of TBTU52 by process
chemistry groups have been reported.17d,37ae,58 The reagent
provides very fast couplings, and it can be particularly attractive
when the carboxylic acid contains an epimerizable α-stereo-
center. HOBt can be used in combination with TBTU to
reduce epimerization further.
TPTU46b and TOTU35a,36 have seen very limited application
on large scale, most likely due to cost reasons.
2.3.4. Triazine-Based Coupling Reagents. This family of
reagents encompasses several compounds that have been
employed on scale (Figure 9). Due to conflicting reports on
their type of acid activation (as acid chloride or activated ester;
vide infra), these reagents are grouped together in this section
as converting carboxylic acids to activated triazine esters.
Cyanuric chloride (1,3,5-trichlorotriazine) is a highly reactive
coupling reagent produced on the industrial scale by the
hundreds of thousands of metric tons per year via trimerization
of cyanogen chloride. As a result, it is one of the most cost-
effective coupling reagents for amide bond formation. Due to
the presence of three chlorine atoms on the molecule acting as
leaving groups, this reagent can be employed in substoichio-
147
Review
Figure 9. Structure of triazine-derived cyanuric chloride, CDMT, and
DMTMM.
metric quantities. The mechanism for acid activation with
cyanuric chloride has generally been described as proceeding
via acid chloride formation (Scheme 9).1b The acid must be in
the carboxylate form to displace the chloride and form the
activated ester intermediate, which then reacts with the chloride
to afford the desired acid chloride and byproduct 1,3-dichloro-
5-hydroxytriazine. Reaction of the latter with another two
molecules of carboxylic acid can afford cyanuric acid as
byproduct.
However, there has also been a report from the process
chemistry group at Rohm and Haas Company in which an acid
chloride from cyanuric chloride was not detected; instead, acid
activation was proposed to take place via an activated ester
(Scheme 10).59
Amine bases such as Et3N and NMM are commonly used
with cyanuric chloride, but inexpensive inorganic bases such as
NaOH can also be employed and the reaction can be
conducted in the presence of water. The resulting cyanuric
acid byproduct can be easily removed during workup via
filtration or basic washes. In spite of these clear advantages,
cyanuric chloride has received little attention from process
chemists in the pharmaceutical industry.17i,59
CDMT, or 2-chloro-4,6-dimethoxy-1,3,5-triazine,60 can be
easily synthesized from the reaction of cyanuric chloride and 2
equiv of methanol in the presence of Na2CO3 as base. It is a
stable, crystalline solid that is commercially available in bulk.
This reagent has been shown to be effective at reducing
epimerization and, also, to work with sterically hindered
primary and secondary alkyl and aryl amines.61 CDMT usually
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Scheme 9. Mechanism for Acid Chloride Generation with Cyanuric Acid1b

Scheme 10. Mechanism for Activated Ester Generation with Cyanuric Acid59

requires the use of a tertiary amine base, such as NMM, for acid Scheme 11. Acid Activation Mechanism with DMTMM via
activation, and the coupling can be carried out in solvents such Activated Ester
as THF, DMF, and EtOAc. In comparison to cyanuric chloride
and DMTMM (vide infra), CDMT has seen more widespread
use across process groups in the pharmaceutical industry13d,61,62
despite the relatively high cost per mole. A typical experimental
procedure is the addition of the tertiary amine base to a mixture
of acid, amine, and CDMT.61 The mechanism for acid
activation with CDMT is also a matter of debate, and as for
cyanuric chloride, activation via acid chloride1a,d or via activated
ester59 have been proposed. Regardless of the mode of
activation, 1-hydroxy-3,5-dimethoxytriazine is generated as
byproduct.
DMTMM, or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-
morpholinium chloride,63 an air and water-stable solid that can
be easily prepared from CDMT by treatment with NMM, has
been scarcely used in process chemistry.62c An advantage of this
reagent is that it can be employed for amide bond formation in
alcoholic or aqueous solvents without the generation of the Many boron-based reagents have been reported for amide
corresponding esters or hydrolysis product.64 DMTMM bond formation outside of process chemistry: boric acid,70
activation provides an activated ester with NMM·HCl as trimethoxyborane,66a boron trifluoride-etherate,66c catecholbor-
byproduct (Scheme 11).1d The reagent can be added to a ane,66d borane−trimethylamine,66e phenylboronic acid,71 o-
mixture of the acid and amine coupling partners. The addition bromo and o-iodoarylboronic acid,72,73 3,4,5-trifluorophenyl-
of acid carboxylate to DMTMM liberates NMM which acts as a boronic acid,68a,74 N,N-diisopropylbenzylamine-2-boronic
base to promote the amide coupling. 1-Hydroxy-3,5-dimethox- acid,74b,75 trifluoroethoxyborane,76 borate esters,77 3,5-bis-
ytriazine is a water-soluble byproduct that can be removed by (perfluorodecyl)phenylboronic acid,68b N-alkyl-4-boronopyridi-
aqueous workup. However, as was mentioned previously for nium halides,78 4,5,6,7-tetrachlorobenzo[d][1,3,2]dioxaborol-2-
CDMT, the relatively high cost per mole of DMTMM is a ol,79 and 3-nitrophenylboronic acid.68a However, despite the
deterring factor for its application on large scale. many choices available, boric acid clearly stands out as a very
2.4. Coupling via Boron Species. The use of boron- desirable reagent since it is inexpensive and displays excellent
derived reagents as catalysts for amide bond formation has atom economy (Figure 10). In addition, after reaction
increased considerably in recent years.1g,65 The original reports completion, the water-soluble reagent can be extracted into
required the use of stoichiometric amounts of boron an aqueous workup. On the other hand, drawbacks of boric acid
reagents,66,67 but more recently, Yamamoto and co-workers are reproductive toxicity at high doses80 and that the European
have described the first examples with substoichiometric Chemical Agency may include it on the list of high concern
amounts.68,69 substances which would restrict its use in Europe.81
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Figure 10. Boron-derived reagents used on scale.
Boron reagents for amide bond formation82 have seen
limited use in process chemistry, and only examples with boric
acid83 and 3-nitrophenylboronic acid84 have been found
(Figure 10).
The proposed mechanism for amide formation catalyzed by
boric acid is shown in Scheme 12,70 and a similar mechanism
Scheme 12. Mechanism for Carboxylic Acid Activation and
Amide Bond Formation with Boric Acid
can be envisioned for arylboronic acids.85 Reaction of a
carboxylic acid and boric acid leads to the formation of an
activated mixed anhydride intermediate after the loss of a
molecule of water (water must be removed azeotropically to
displace the equilibrium toward the acylated boronic acid
intermediate). This intermediate then reacts with the amine to
afford the amide product and regenerate boric acid, which
restarts the catalytic cycle.
The mechanism for amide bond formation with arylboronic
acids has also been investigated in silico.86
3. OTHER METHODS FOR AMIDE BOND FORMATION
Not all of the following large-scale examples fall into the
category of acid activation for amide bond formation; however,
they are referenced in this review since some approaches have
been employed frequently.
3.1. Synthesis of Amides from Esters. Esters have been
converted to amides by direct treatment with the correspond-
ing amine. Reports employing methyl esters,21p,43i,46u,z,87 ethyl
esters,19e,ah,ap,88 tert-butyl esters,89 isobutyl esters,90 benzyl
esters, 19aa lactones, 91 thioesters, 92 pentafluorophenyl
esters,24i,93 and N-hydroxysuccinimido esters18,43d,94 have
been published.
3.2. Synthesis of Amides via Transamidation. Although
not commonly practiced, one example of intramolecular
transamidation has been reported on large scale for amide
synthesis.22h
3.3. Synthesis of Amides Catalyzed by Brö nsted
Acids. Finally, Brönsted acids can catalyze amide bond
formation, as has been reported for AcOH,95 H2SO4,96 and
TFA.97
4. CASE STUDIES
4.1. Coupling via Acid Chloride. 4.1.1. Thionyl Chloride.
Stoner and co-workers at Abbott Laboratories have reported
the preparation of HIV protease inhibitor 4 (Scheme 13).13g
The last step of the synthesis involved the coupling of acid 1
149
Review
Scheme 13. Amide Bond Formation during the Synthesis of
API 4
and amine 3, which the medicinal chemistry group had carried
out using the EDC/HOBt combination. However, the high cost
and limited commercial availability of EDC as well as the
hazards involved in the handling of HOBt49 led to the search
for a coupling method more amenable for large-scale
operations. In addition, it was necessary to obtain full
consumption of amine 3; otherwise, the isolation of 4 proved
to be difficult. T3P/NMM gave partial conversion and some
degradation byproducts, whereas the preparation of activated
esters (N-hydroxysuccinimide (NHS), N-hydroxybenzotriazole
(HOBt)) via treatment with (COCl)2, acid chlorides, or
chloroformates provided low yields of the activated esters and
polymeric byproducts derived from acid 1. However, treatment
of 1 with either SOCl2 or POCl3 led to the formation of acid
chloride 2, which could be isolated as a crystalline solid. In
order to get full conversion to the desired API 4, a screen was
carried out that looked at both organic (pyridine, DMAP,
NMM, imidazole) and inorganic (Na2CO3, NaHCO3) bases,
which revealed imidazole as the best choice. On laboratory
scale, acid 1 in THF was treated with 1.25 equiv of SOCl2 and,
after stirring at 0 °C for 1 h, the mixture was concentrated
followed by coevaporation with n-heptane to azeotropically
distill SOCl2. The residue was redissolved in DMF and this
solution was added to a solution of amine 3 and imidazole in
EtOAc at 0 °C. After stirring overnight at rt, an aqueous
workup, and crystallization from n-heptane/EtOAc, amide 4
was isolated in 92% yield (two crops).
Walker and co-workers at Parke-Davis have described the
synthesis of compounds 8 and 9, two candidates evaluated as
antiretroviral agents for the treatment of AIDS (Scheme 14).13e
The synthesis of 8 commenced with the preparation of diacid
chloride 6, which was obtained after treating diacid 5 with
SOCl2 (2.8 equiv) and catalytic DMF in toluene. After 16 h at
70−75 °C, residual SOCl2 was removed by distillation, and 6
was crystallized from toluene in 83% yield on multikilogram
scale. With diacid chloride 6 on hand, the researchers
investigated the amide bond formation leading to 8. Several
esters of L-isoleucine (methyl, benzyl, allyl) were tested in
amide coupling, but the subsequent ester cleavage step was not
satisfactory in all three cases. As a result, the direct coupling
with L-isoleucine itself was attempted. Thus, a solvent screen
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Scheme 14. Synthesis of Drug Candidates 8 and 9 via
Diamide Bond Formation
(dioxane, MTBE, di-n-butyl ether, THF) revealed that THF
provided the best yield and purity. Further optimization
showed that inorganic bases such as NaHCO3 led to improved
yields and purities (NaHCO3 performed better than Na2CO3
and K2CO3 in this respect). In the plant, a mixture of acid
chloride, L-isoleucine, and NaHCO3 in THF was heated at 60−
65 °C for 2 h. After reaction completion, the mixture was
quenched into diluted aqueous HCl (to neutralize the base)
and MTBE. Phase separation was greatly facilitated when the
aqueous layer was kept acidic. Following workup, diamide 8
was crystallized from n-hexane/THF and recrystallized from the
same solvent mixture to generate 53.6 kg of material in 75%
yield and excellent purity (98.7%, area % by HPLC). The
experimental conditions including the use of L-isoleucine rather
than an ester derivative contributed to maintaining the chiral
integrity of 7. The only two relevant impurities detected in 8
were half acid 10 and compound 11 (Figure 11), which is
produced due to the presence of trace amounts of L-valine in
commercial L-isoleucine.
Figure 11. Impurities detected during the synthesis of diamide 8.
Sugaya and co-workers at Sakai Research Laboratories in
Japan have reported the synthesis of L-alanyl-L-glutamine (16),
a compound employed as a component of parenteral nutrition
(Scheme 15).13j The preparation of intermediate 15 involved
the amide bond formation between acid chloride 13 and amine
14. Originally, the α-bromo analogue of 12 was employed and
treated with SOCl2 to generate the corresponding acid chloride.
On scale, however, this acid chloride tended to decompose
under Schotten−Baumann conditions, and the resulting amide
showed epimerization and lower purity than in laboratory
experiments. As a result, D-2-chloropropionyl-L-glutamine (12)
150
Review
Scheme 15. Amide Bond Formation En Route to L-Alanyl-L-
glutamine (16)
was chosen for further development due to the enhanced
chemical and optical stability of this substrate compared to the
bromo analogue. In addition, 12 could be prepared in higher
optical purity than D-2-bromopropionyl-L-glutamine from D-
alanine, L-lactate, or via enzymatic resolution of D , L-
chloropropionic acid or its ester. In the plant, acid 12 was
treated with a slight excess of SOCl2 at 85 °C for 1 h followed
by dilution with toluene to afford acid chloride 13 as a toluene
solution. This mixture was then added to a cold (0−5 °C)
solution of L-glutamine (14) in an aqueous NaOH/toluene
mixture and further stirred at 10 °C and pH = 10 for 1 h. After
reaction completion and aqueous workup, the aqueous layer
containing the Na salt of 15 was acidified to pH 2 with HCl
which crystallized the carboxylic acid in 82% yield and 99.7%
de.
Zanka and co-workers at Fujisawa Pharmaceutical Co. Ltd.
have reported the synthesis of compound 23, a nonxanthine
adenosine A1 receptor antagonist for the regulation of renal
function (Scheme 16).13i The penultimate step of the synthesis
involved the coupling of acid 17 and amine 19. Acid 17 was
activated through treatment with equimolar amounts of SOCl2
and DMF (in situ generation of Vilsmeier reagent) to afford
acid chloride 18. Prior to the amide-forming step, the hydroxy
group in amine 19 was protected as the TMS ether through
reaction with N,N′-bis(trimethylsilyl)urea (20) in CH2Cl2.
During optimization of the amide coupling, the use of NMM as
base led to low yields, whereas other bases such as Et3N or
i-Pr2NEt generated dark impurities. However, the addition of
catalytic DMAP increased the coupling rate when using Et3N as
base and provided amide 22 in excellent yield. In the plant, a
mixture of acid 17 and SOCl2 in CH2Cl2 was dosed with DMF
(equimolar amount per SOCl2) to generate acid chloride 18.
Separately, a cooled solution of amine 21 in CH2Cl2 was dosed
with DMAP and Et3N followed by the solution of acid chloride
18. After 1 h, the reaction underwent an aqueous workup, and
TMS-protected intermediate 22 was treated with methanolic
K2CO3 to cleave the TMS ether and afford crude 23.
Recrystallization from EtOH/H2O afforded over 17 kg of
API in 99.8% chemical purity and 99% ee.
4.1.2. Oxalyl Chloride. The process group at Albany
Molecular Research has reported the coupling of acid chloride
25 and trimethylhydrazine (26) as part of the synthesis of 28, a
drug candidate with growth hormone-releasing properties
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Scheme 16. Amide Coupling of an Amino Alcohol via
Transient Hydroxy Protection
(Scheme 17).17e Several methods were attempted for the
coupling of acid 24 and trimethylhydrazine. Initial efforts with
Scheme 17. Coupling of Acid Chloride 25 and
Trimethylhydrazine En Route to Drug Candidate 28
PyBrop (bromotripyrrolidinophosphonium hexafluorophos-
phate), T3P, CDI, or EDC led to poor conversion or
decomposition. The researchers mentioned that these attempts
afforded the activated acid species, but the subsequent coupling
failed likely due to the steric hindrance provided by the
quaternary center at the α position. Despite the presence of the
acid-sensitive Boc protecting group in 24, the researchers
attempted this coupling through the preparation of acid
chloride 25. Thus, acid 24 was treated with 1.6 equiv of
(COCl)2 followed by the addition of catalytic DMF (in situ
151
Review
Vilsmeier reagent generation) and Et3N as base in CH2Cl2 to
generate 25 which, without isolation, underwent reaction with a
solution of trimethylhydrazine in dioxane at −20 °C to provide
27 in 82−90% yield after aqueous workup and purification via
silica gel plug. Key to the success of this approach was the order
of addition of reagents. Thus, when Et3N was added prior to
the (COCl)2 and DMF, only unreacted 24 was recovered,
presumably due to the different reactivity of the ammonium salt
of acid 24. In addition, the Boc-protecting group was found to
be compatible with these reaction conditions, and this protocol
was carried out to produce 3.2 kg of amide 27.
Magnus and co-workers at Eli Lilly have described the
synthesis of glucokinase activator 32 for the treatment of type 2
diabetes (Scheme 18).17q The last step of the synthesis involved
Scheme 18. Amide Bond Formation as the Last Step of the
Synthesis of API 32
the amide coupling of carboxylic acid 29 and 2-aminopyrazine
(31). During a previous synthesis implemented by the
pharmaceutical company Prosidion,98 the aminopyrazine was
added to acid chloride 30 at −45 °C which led to the formation
of peracylated products. The formation of these impurities was
prevented by reversing the order of addition. Thus, acid
chloride 30, generated with (COCl)2 and catalytic DMF in
THF below 30 °C, was added to a solution of aminopyrazine
and pyridine while still maintaining the internal temperature
below 30 °C. After 1 h, the byproduct pyridine·HCl was
removed via filtration. Following an aqueous workup to remove
excess pyridine and 4−5% of acid 29 via acid−base extractions,
API 32 was crystallized from MeOH in 74% yield (88−94% in
situ yield). Despite the presence of an epimerizable chiral
center on the acid moiety, this protocol avoided racemization,
and 32 was obtained in >99% ee.
Another report from the process group at Eli Lilly describes
the synthesis of compound 38, a PPARα agonist for the
potential treatment of dyslipidemia, coronary heart disease, and
diabetes (Scheme 19).17g The synthesis of intermediate amide
36 was initiated by treating carboxylic acid 33 with 1.15 equiv
of (COCl)2 and catalytic DMF in EtOAc below 30 °C which,
after distillation of excess (COCl)2, afforded acid chloride 34 as
a solution in EtOAc. The removal of excess (COCl)2 was
required to keep the level of impurity 39 below 1% (Figure 12).
Acid chloride 34 was then added to a solution of amine salt 35
and pyridine in EtOAc. Although the coupling product 36
could be isolated via crystallization, the researchers decided to
telescope it into the subsequent cyclization involving
camphorsulfonic acid at reflux to afford 37 and side-product
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Scheme 19. Amide Bond Formation during the Synthesis of PPARα Agonist 38

Scheme 20. Amide Bond Formation with POCl3 en Route to

45

Figure 12. Side-products from the coupling of 34 and 35 in the

presence of excess (COCl)2.

40 in 15:1 ratio. Treatment of the resulting solution with

Amberlyst-15 resin allowed for the selective removal of 40 via
filtration, and 37 was crystallized from MTBE with an overall
yield of 55% from acid 33.
4.1.3. Phosphorus Oxychloride. An example of amide
coupling via POCl3 has been reported by scientists at Otsuka
Pharmaceutical during the preparation of drug candidate 45, an
inhibitor of superoxide anion generation for the treatment of
ischemia and inflammation (Scheme 20).18 Prior to the
pyrazinone cyclization, the required amide bond was generated
from carboxylic acid 41 via POCl3 activation in the presence of
catalytic DMF to produce acid chloride 42, which was
telescoped as a CH2Cl2 solution. The amine coupling partner
43 was freebased with aqueous K2CO3 and telescoped as a
CH2Cl2 solution. In the amidation step, the acid chloride was
added to 43 while holding the temperature between 4−19 °C,
and after an aqueous workup, amide 44 was crystallized from
cold IPA/H2O in 88% yield on multikilogram scale.
4.1.4. Commercial Vilsmeier Reagent. The process group at of a mixed anhydride with isobutyl chloroformate (IBCF) was
Novartis in Switzerland has described the preparation of drug clean but led to considerable amounts of recovered 46 due to
candidate 50 for the treatment of inflammation (Scheme competitive addition of amine to the undesired carbonyl of the
21).12e The medicinal chemistry group employed EDC/DMAP mixed anhydride. Other reagents such as CDI and CDMT gave
for the coupling of acid 46 and L-tert-leucine-N-methylamide poor results as well. However, commercial Vilsmeier reagent
(48), but epimerization (>5%) was observed. As a result, afforded a very clean coupling without detectable epimerization
alternative coupling reagents were investigated. The formation and was therefore chosen for further development. On the
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Scheme 21. Amidation via Vilsmeier Reagent Acid
Activation en Route to API 50
laboratory scale, acid 46 was treated with 1.5 equiv of Vilsmeier
reagent in THF to afford acid chloride 47. After the resulting
suspension was stirred at 0 °C for 1 h, the addition of NMM
followed by a solution of amine 48, and catalytic DMF in THF
provided almost 50 g of amide 49 (98% yield).
4.2. Coupling via Carboxylic or Carbonic Acid Mixed
Anhydride. 4.2.1. Acetic Anhydride. As noted above, acetic
anhydride is not a common reagent for acid activation en route
to amide coupling. However, one such example was
demonstrated by Hoekstra and co-workers at Parke−Davis
for the synthesis of pregabalin (Lyrica, 54).13a As demonstrated
in Scheme 22, 3-isobutylglutaric acid (51) and Ac2O were
Scheme 22. Activation of a Symmetrical Diacid with Acetic
Anhydride
heated at reflux for cyclization to the symmetrical anhydride 52.
Excess Ac2O (and AcOH byproduct) were distilled from the
tank, and the anhydride was treated with ammonium hydroxide
to provide amide 53. The amide was crystallized directly from
the reaction mixture after distillation of MTBE and acidification
of the resulting aqueous solution to pH 1.
153
Review
4.2.2. Pivaloyl Chloride (PivCl). Li and co-workers at
Neurocrine Biosciences synthesized amide 57 via the PivCl-
mediated coupling of acid 55 and pseudoephedrine (56) en
route to valnoctamide (59), a mild sedative (Scheme 23).13aj
Scheme 23. PivCl-Mediated Coupling of Acid 55 and
Pseudoephedrine
The mixed anhydride was first prepared by dosing a cooled
solution of acid 55 and Et3N in CH2Cl2 with PivCl. After
treating this mixed anhydride with a second charge of Et3N,
pseudoephedrine was added portionwise while maintaining a
temperature below 5 °C. The amine was added as a solid to
minimize reaction volume, and <1% of N,O-diacylated
byproduct was formed. Aqueous workup with successive acid
and base washes removed any residual coupling partners and
reagents, and concentration of the organic layer provided the
pseudoephedrine amide 57 as an oil in quantitative yield.
Interestingly, α-substitution on the acid reversed the
regioselectivity of coupling. The addition of pseudoephedrine
to mixed anhydride 60, derived from α-ethyl acid 58, provided
the undesired acylation product 61.
As an alternative to forming the mixed anhydride prior to
charging the amine, it is also possible to add PivCl to a solution
of combined acid and amine. Alimardanov and co-workers at
Wyeth used this approach for the coupling of acrylic acid 62
and chiral oxazolidinone 63 (Scheme 24).22i In a one-pot
process, the acid and oxazolidinone in THF were premixed
Scheme 24. N-Acylation of Chiral Oxazolidinone via PivCl-
Activated Acid
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with LiCl and cooled as PivCl and Et3N were charged Scheme 26. Synthesis of Singh’s Organocatalyst 73 via
sequentially. After aqueous workup and solvent exchange, the ClCO2Et-Mediated Amidation
amide was crystallized from IPA/H2O to provide 64 in 93%
yield. These coupling conditions were derived from a previous
report by Merck Process Research on the N-acylation of 2-
oxazolidinones mediated by PivCl, LiCl, and Et3N.99
4.2.3. Ethyl Chloroformate (ECF). Davulcu, Parsons, and co-
workers at Bristol−Myers Squibb employed ethyl chlorofor-
mate for the coupling of serine 65 and 2-chloroethylamine·HCl
(66) in their synthesis of 69, an agonist of the human growth
hormone secretagogue receptor (Scheme 25).23b In the first

Scheme 25. Coupling of Serine Derivative and 2-

Chloroethylamine with Ethyl Chloroformate

carried directly into acid-catalyzed deprotection and freebasing.

The overall process provided 25 g of Singh’s organocatalyst 73
in 70% overall yield.
4.2.4. Isobutyl Chloroformate (IBCF). In a series of
publications,24a,f,25 Novartis described the coupling of amino
acid 74 and N-methylbenzylamine (BnNHMe) via isobutyl
chloroformate (IBCF) for the synthesis of a tachykinin receptor
antagonist (Scheme 27). The original development route

Scheme 27. Investigating the Mechanism of Amidation via

IBCF

step of a telescoped process, serine 65 was first converted to the

mixed anhydride using a slight excess of ethyl chloroformate
and NMM, and then chloroethylamine was dosed along with a
second charge of base. The authors noted that the chloroethyl-
amine, a strong vesicant, was safely and easily handled as the
HCl salt. Its chemoselective addition to the mixed anhydride
was controlled by cooling the mixture between −30 and 0 °C,
and byproducts from addition to the undesired carbonyl were
not detected. Furthermore, splitting the NMM charge into two
portions minimized the racemization (<2%) of mixed
anhydride from exposure to excess base. Aqueous workup
converted excess chloroethylamine to ethanolamine which was
extracted into water alongside the EtOH derived from ethyl
chloroformate. In fact, ethyl chloroformate was specifically
chosen over isobutyl chloroformate for this coupling as the
latter degrades to isobutanol which was difficult to purge via
similar aqueous extraction. The solution of amide 67 was
carried forward to tetrazole 68 for a 75% isolated yield over
four steps.
As shown in Scheme 26, chemists from the Universities of
Cologne and Bielefeld in Germany prepared Singh’s organo-
catalyst 73 on l00 mmol scale via the coupling of proline (70) converted acid 74 to mixed anhydride 76 via IBCF and NMM
and amino alcohol 71.23c While both ethyl and isobutyl in EtOAc, and subsequent treatment with BnNHMe and HCl
chloroformate performed well as the coupling reagent, the provided deprotected amide 75.24a However, this approach
former was chosen for scale up due to its lower cost. A one-pot posed several processing issues, including the need for multiple
process was developed in which proline was first protected at charges of IBCF and BnNHMe to drive the amidation of 74 to
the amine via Boc2O and excess Et3N under conditions which completion. The need for multiple reagent charges was
do not carbonylate the acid. Subsequent charging of ethyl attributed to one of two pathways: (1) the reaction of
chloroformate provided the mixed anhydride which was then BnNHMe at the undesired carbonyl (b) of mixed anhydride 76,
treated with amino alcohol 71 in portions via powder funnel. or (2) the competitive addition of amino acid to 74 to provide
The crude mixture of amide 72 was evaporated to dryness and symmetrical anhydride 78 (via CO2 evolution), which in turn
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reacts with BnNHMe to form the desired amide and
regenerates amino acid 74.25 Either of these pathways would
also lead to the observed urethane 77 as a byproduct. (The
pathway via symmetrical anhydride 78 leaves unconsumed
IBCF to react with BnNHMe.) To better understand the
mechanism for amidation and avoid the need for multiple
reagent charges, the offgassing of CO2 was analyzed from the
initial reaction of amino acid 74 and IBCF.25 The substantial
amount of CO2 measured in this first step is consistent with the
formation of symmetrical anhydride 78. It was rationalized that
the large excess of amino acid relative to mixed anhydride 76
during slow chloroformate addition favors the symmetrical
anhydride and that reversing the order of reagent addition
would suppress this undesired pathway. Thus, the inverse
addition of amino acid 74 and base to IBCF provided the mixed
anhydride cleanly, and subsequent charging of BnNHMe
generated the desired amide without requiring additional
charges of chloroformate or amine.24g Other process changes
included replacing NMM with BnNMe2 as the base, as the
latter is easier to remove from aqueous waste streams (which
facilitates aqueous waste disposal). The solvent was also
changed from EtOAc to toluene for greater compatibility
with concentrated HCl in the downstream Boc removal, which
provided the deprotected amide 75 in 93% overall yield.
Busacca, Wei, and co-workers at Boehringer−Ingelheim
completed their synthesis of HCV protease inhibitor 82 via the
amide coupling of proline 79 and cyclopropylamine 80
followed by methyl ester saponification (Scheme 28).24j Initial
Scheme 28. IBCF-Mediated Coupling of Proline 79 and
Cyclopropylamine 80
couplings of 79 and 80 using EDC and HOBt provided amide
81 in high yield; however, HOBt is relatively expensive and
shock sensitive, and the latter attribute makes it subject to
transportation and storage restrictions.100 Furthermore, cou-
plings with HOBt alternatives in conjunction with EDC led to
detectable amounts of proline epimerization. Ultimately, the
process group was able to replace EDC/HOBt with the
inexpensive IBCF and generate optically pure amide 81 by
maintaining careful temperature control during acid activation
and amination. The chloroformate was added slowly to a THF
solution of proline 79 and NMM while holding the internal
temperature at −10 °C. The resulting mixed anhydride was
treated sequentially with cyclopropylamine salt 80 and
155
Review
additional NMM at rates which kept the internal temperature
below −8 °C. The mixture was warmed to 10 °C, and after
aqueous workup and solvent exchange, amide 81 was
crystallized from aqueous EtOH in 88% yield.
4.2.5. Boc Anhydride. Patterson and co-workers at
GlaxoSmithKline employed Boc2O for the conversion of acid
83 to amide 86 en route to denagliptin (87), a drug candidate
for the treatment of type 2 diabetes (Scheme 29).26 The initial
Scheme 29. Anhydride Intermediates in Boc2O-Mediated
Amide Coupling en Route to Denagliptin
reaction of acid 83, Boc2O, and pyridine provided equal
amounts of mixed anhydride 84 and symmetrical anhydride 85.
Whereas the addition of NH4OH solution converted the mixed
anhydride to desired amide 86, ammonolysis of the sym-
metrical anhydride formed one equivalent each of amide and
starting acid. However, since the overall transformation of acid
83 to amide 86 proceeded to completion without additional
reagent charges, the authors suggested that regenerated acid is
recycled to anhydride (via remaining Boc2O) at a faster rate
than the side reaction of Boc2O and NH3. This rationale is
consistent with another experiment in which the overall amide
coupling still proceeded to >80% conversion when NH4OH
solution was present before charging the Boc2O. On large scale,
charging the preformed mixture of anhydrides 84 and 85 with
NH4OH solution led to strong offgassing from CO2 evolution,
and after 3 h at 25 °C, standard workup and crystallization
provided 95.6 kg of amide 86 for an excellent 96% yield.
4.2.6. EEDQ. As shown in Scheme 30, Ormerod, Willemsens,
and co-workers at Johnson & Johnson reported an amide
coupling using EEDQ for the synthesis of cholecystokinin-2
receptor antagonist 91.28 The process chemistry team retained
EEDQ from the discovery synthesis for the scaled coupling of
amino acid 88 and aniline 89, as alternative reagents induced
racemization. Efforts to preactivate the amino acid with EEDQ
prior to introducing the aniline led to the evolution of CO2
(presumably from the addition of byproduct EtOH to the
resulting mixed anhydride) and up to 20% of the corresponding
ethyl ester of 88. This impurity was overcome by adding EEDQ
to a 1:1 mixture of amino acid and aniline, which provided
amide 90 with negligible racemization and excellent reprodu-
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Scheme 30. EEDQ as the Activating Agent for the Synthesis
of Amide 90
cibility. Solvent exchange to propylene glycol monomethyl
ether crystallized 90 in 92% yield.
4.3. Coupling via Sulfonate-Based Mixed Anhydride.
4.3.1. Methanesulfonyl Chloride (MsCl). Liu and co-workers
from Novartis used MsCl for a pair of amide couplings in their
synthesis of peptide deformylase inhibitor 98 (Scheme 31).22f
Scheme 31. Amide Couplings via MsCl Activation
The coupling of acid 92 and 3-aminopyridazine (93) was very
difficult due to the poor nucleophilicity of the latter, and
reagents such as Ph2POCl, CDMT, and EDCI/HOBt provided
the amide with low conversion or modest yield. Following a
report in which proline carboxylic acids are coupled via mixed
sulfonic anhydrides,101 92 was activated with MsCl and N-
methylimidazole (NMI) and then treated with 93. Performing
this condensation in CH2Cl2 at 40 °C led to epimerization of
the amide product 94, but changing the solvent to DMF and
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Review
cooling at −10 °C minimized epimerization to 1−2% while
improving the yield from 65% to 77%. Amide 94 was
crystallized directly from the reaction mixture by diluting
with NaCl solution. After Boc removal from 94, the liberated
pyrrolidine was subjected to a second amide coupling in which
acid 95 was activated as the mixed sulfonic anhydride via the
same MsCl conditions. The resulting amide 97 was formed in
85% yield (in situ) and telescoped into hydrogenolysis of the
benzyl ether leading to the active pharmaceutical ingredient.
4.3.2. p-Toluenesulfonyl Chloride (TsCl). Campeau and co-
workers at Merck prepared the amide bond of 102, a potent
renin inhibitor for the treatment of hypertension, by activating
acid 99 with TsCl in the presence of NMI and then adding
cyclopropylamine·MsOH 100 (Scheme 32).31a In this case,
Scheme 32. TsCl Activation of Acid 99 for Amide Coupling
TsCl was chosen as a cheaper alternative to HATU from the
medicinal chemistry synthesis. A mixture of acid 99 and TsCl in
MeTHF/MeCN was cooled at −20 °C as NMI was dosed in
portions to control an exotherm. While still cooling the mixed
anhydride (or acylimidazolium intermediate102) at −20 °C, a
solution of amine·MsOH 100 in CH 2 Cl 2 was added
portionwise while controlling the internal temperature below
−5 °C to suppress epimerization. The product amide 101 was
treated to an aqueous workup and carried directly into Boc
removal under acidic conditions to provide the drug substance
in 83% overall yield.
Haddad and co-workers at Boehringer Ingelheim Pharma-
ceuticals have reported the synthesis of dipeptide intermediate
108 en route to HCV protease inhibitor faldaprevir (109,
Scheme 33).31b Initial attempts to activate acid 103 via mixed
anhydride formation with isobutyl chloroformate or pivaloyl
chloride (monitored by ReactIR for the latter, with fast
formation of the mixed anhydride) and subsequent reaction
with hydroxyproline ester 106 resulted in moderate yields
(70%) of desired product due to poor regioselectivity and the
formation of the corresponding acylated byproducts of 106. In
addition, slow reactions rates were observed with the mixed
anhydride of PivCl. In an effort to avoid these issues, the
researchers investigated the use of MsCl and TsCl, which are
known to promote faster reactions103 and be less electrophilic
groups104 and, therefore, provide better regioselectivity. After
base and solvent screens, NMM and MeCN were selected to
afford over 90% isolated yield of 107 without any appreciable
epimerization. TsCl was preferred over MsCl for acid activation
to avoid the possibility of sulfene formation associated with the
use of the latter. In the plant, to a mixture of 103 and NMM in
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Scheme 33. Amide Bond Formation with TsCl for the Synthesis of Faldaprevir
MeCN at −20 °C was added a solution of TsCl in MeCN over
80−100 min. After 1 h at 0 °C, a slurry of amine HCl salt 106
was added, and the resulting mixture was stirred at 0−15 °C for
1.5 h. Without isolation, the ester was cleaved by adding
aqueous LiOH, and subsequent addition of 6 N HCl promoted
the crystallization of dipeptide 108 in 91% yield from 103
(99.91% HPLC purity). This report provides a very detailed
study on ReactIR to monitor intermediate formation and
consumption to generate valuable kinetic data. Also discussed
are safety studies including calorimetry data used to develop a
safe telescoped process.
4.4. Coupling via Phosphorus-Based Mixed Anhy-
dride. 4.4.1. n-Propanephosphonic Acid Anhydride (T3P).
Dunetz, Berliner, and co-workers at Pfizer employed T3P for
the synthesis of amide 112 en route to glucokinase activator
113 (Scheme 34).35h Various coupling reagents for the
Scheme 34. T3P and Pyridine To Suppress Epimerization in
Amidation
condensation of α-imidazolyl acid 110 and aminonicotinate
111 led to racemization, including T3P in initial screens, but
the epimerization from T3P was reduced when switching the
base from Et3N to bulkier (TMP) or weaker alternatives
(pyridines, morpholines). Several evolutions of this coupling
were demonstrated in the pilot plant, and ultimately the pairing
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Review
of T3P and pyridine afforded the amide with negligible
epimerization. In the pilot plant, T3P was dosed to a mixture of
acid, amine, and pyridine in 2:1 v/v MeCN/EtOAc. This
solvent ratio, upon quenching with 0.5 M aqueous HCl,
provided the direct-drop crystallization of free base amide 112
(34.1 kg, 88% yield) with high purity (>99% achiral, 0.5% ent-
112) and purging of pyridine, excess aminonicotinate 111, and
T3P byproducts to the mother liquor. A related study from
Pfizer demonstrated the combination of T3P and pyridine as a
general method for suppressing epimerization in the amide
coupling of other carboxylic acids bearing a sensitive α-
stereocenter.35g
Patterson and co-workers at GlaxoSmithKline developed a
one-pot amidation/dehydration to complete their large-scale
synthesis of denagliptin (87), a treatment for type II diabetes
(Scheme 35).26 The coupling of acid 114 and pyrrolidine 115
with T3P and Hünig’s base provided amide 116 without any
epimerization. The subsequent dehydration of primary
carboxamide to nitrile proved more difficult, as several reagents
led to degradation or incomplete conversion. Initially, the
dehydration was accomplished on 150 kg scale by treating a
Scheme 35. Synthesis of Denagliptin via One-Pot Amidation
and Dehydration Using T3P
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solution of 116 in EtOAc (after aqueous workup and Scheme 37. Forming a Piperidine Amide via
azeotropic drying distillation) with methanesulfonic anhydride Ethylmethylphosphinic Anhydride
and pyridine to afford the nitrile in 90% yield. However, it was
discovered that performing the T3P coupling of acid 114 and
pyrrolidine 115 at higher temperature led to 87 as a
dehydration byproduct, and this observation led to a second-
generation process for a one-pot amidation/dehydration with
both steps facilitated by T3P. In this streamlined approach, the
amide bond was formed with an initial dose of T3P (1.5 equiv)
in EtOAc at 50 °C. After reaction completion, a second dose of
T3P (1.5 equiv) was added, and the mixture was heated at
reflux (∼78 °C) to effect the dehydration. After aqueous
workup, 123 kg of denagliptin was crystallized from IPA for an
excellent 97% yield over two steps.
Gudmundsson, Xie, and co-workers at GSK used T3P to
convert picolinate salt 117 to picolinamide 118, a treatment for
human papillomavirus infections (Scheme 36).35d This is an

Scheme 36. T3P-Mediated Conversion of Picolinate Salt to

Picolinamide Scheme 38. Amide Coupling via Imidazolide 123 for
Synthesis of Trimethobenzamide (125)

interesting case in which amine 117 was crystallized previously

with one equivalent of 2-picolinic acid, the same acid to be
incorporated into the active pharmaceutical ingredient. A
solution of the amine salt and Hünig’s base in CH2Cl2 at 0
°C was dosed with T3P to cleanly generate picolinamide 118,
and an additional 0.1 equiv of 2-picolinic acid were added to
ensure reaction completion. After aqueous workup to remove
the T3P byproducts, solvent exchange and crystallization from
EtOH provided 9.7 kg of picolinamide 118. The authors
mentioned that this T3P procedure was more practical than
alternative acylations via the acid chloride or O-benzotriazole
activation.
4.4.2. Ethylmethylphosphinic Anhydride (EMPA). Col-
leagues at Hoechst AG and Behring Werke used EMPA to
install a piperidine amide in their kilogram-scale synthesis of
thrombin inhibitor 121 (Scheme 37).36 A solution of acid 119
and piperidine in EtOAc was dosed with a solution of EMPA in
EtOAc to form amide 120. Aqueous workup and solvent
evaporation provided 5.7 kg of 120 as a yellow oil. The authors
also described similar EMPA-mediated couplings of two other
acids with piperidine on multigram scale.
4.5. Coupling via CDI. Neelakandan and co-workers at
Emcure Pharmaceutical Limited and Annamalai University identified 1.25 equiv of CDI as optimal for efficient coupling
incorporated CDI into an improved amidation process for the while maintaining impurities 126−128 below regulatory limits
synthesis of trimethobenzamide (125; Tigan), an antiemetic after crystallizing the product trimethobenzamide from acetone
agent for nausea (Scheme 38).37ac Various reagents for the and aqueous HCl.
coupling of trimethoxybenzoic acid 122 and benzylamine 124, Weisenburger and co-workers at Pfizer reported the process
including SOCl2, tert-butyl chloroformate, DCC/DMAP, EDC/ development of a CDI-mediated peptide coupling for the
HOBt, and boric acid, led to demethylation impurities 126 and preparation of αvβ3 integrin antagonist 132 (Scheme 39).37q
127 that were difficult to purge from the desired amide without The original route for preclinical supplies of 132 involved the
yield loss. Alternatively, CDI provided a relatively clean reaction of amine 130 with the N-hydroxysuccinimide (NHS)
amidation from the demethylation impurities; however, the ester of N-Boc glycine (129), but the high cost of this NHS
formation of urea 128 became an issue if this coupling reagent ester prompted the team to explore alternative reagents for the
were used in too large an excess. Stoichiometry studies coupling of 129. Ultimately, CDI was chosen for its relatively
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Scheme 39. Inverse Addition of Carbonyl Imidazolide to
Amine 130
low cost and the ease of removing imidazole salt byproducts by
aqueous extraction. On laboratory scale, the carbonyl
imidazolide of 129 was prepared by charging solvent to
dissolve equal amounts of amino acid and CDI (both solids);
however, this approach led to the rapid release of CO2 which
was unsuitable for pilot plant production. Alternatively, on large
scale, the imidazolide formation was controlled by adding a
solution of 129 to a slurry of CDI, which led to minor foaming
but no increase in pressure. The subsequent addition of amine
130 to the activated glycine led to a mixture of amide 131 and
byproduct from the O-acetylation of 132 at the phenolic
alcohol. Aging this mixture for several hours improved the ratio
of 131 to overacetylation byproduct, presumably from the
addition of unreacted amine 130 to the byproduct’s phenolic
ester to provide two molecules of 131. The rate of O-
acetylation increased exponentially as the concentration of
amine decreased, and the byproduct was held to <1% during
the initial stages of inverse addition of carbonyl imidazolide to a
solution of amine 130. This inverse addition to a solution of
amine had the added practical benefit of avoiding solid charges
of agglomerated 130 to the tank in the pilot plant. The
resulting solution of amide 131 was washed with 1 M aqueous
HCl to remove imidazole and trace unreacted amine (<3%),
and the amide was crystallized from the ternary solvent system
of EtOAc, toluene, and n-heptane. This process furnished 342
kg of amidation product over two batches.
Twiddle and co-workers at Pfizer used CDI for an improved
amide coupling in the synthesis of β-2 adrenoreceptor agonist
137 (Scheme 40).37ab In a previous commercial route,105 the
condensation of acid 133 and benzylamine 134 was mediated
by EDC·HCl and HOBt in CH2Cl2, but this combination of
reagents and solvent led to a protracted aqueous workup.
Alternatively, a revised coupling with CDI in EtOAc stream-
lined the aqueous workup via easy-to-purge byproducts
(imidazole) and facilitated solvent exchange to chloroacetoni-
trile and TFA for a telescoped Ritter reaction. An interesting
consideration for the CDI activation of acid 133 was
competitive activation of the tertiary alcohol, which becomes
dominant only after all the carboxylic acid is consumed. This
issue was circumvented by charging one equivalent of coupling
reagent in portions and tracking CDI consumption by in situ
mid-IR monitoring. Furthermore, avoiding an excess of CDI
minimized the formation of urea derived from amine 134. The
159
Review
Scheme 40. CDI-Mediated Amide Coupling and Ritter
Reaction
addition of 134 to the carbonyl imidazolide provided amide
135. After an aqueous workup which included citric acid washes
to extract imidazole, solvent exchange to ClCH2CN and TFA
promoted a subsequent Ritter reaction. The resulting diamide
136 was crystallized in 88% overall yield on multikilogram
scale.
Kuethe and co-workers at Merck concluded the synthesis of
potent cholecystokinin 1R receptor agonist 141 with the CDI-
mediated condensation of acid 138 and piperazine 139.37p As
shown in Scheme 41, a solution of 138 in DMAc was charged
with solid CDI in one portion and aged at rt for 1 h. The amine
was added to the resulting carbonyl imidazolide as the solid
HCl salt in one portion, and the slurry was warmed to 50 °C
(heating was required for complete conversion to amide 140).
The liberated imidazole from acid activation was an effective
base for neutralizing the HCl salt of 139, and the amide bond
was formed without the requirement of additional base.
Telescoped saponification of the methyl ester with aqueous
NaOH followed by pH adjustment with aqueous H3PO4
crystallized the drug substance in 86% overall yield.
4.6. Coupling via Carbodiimide. 4.6.1. DCC. Prashad and
co-workers at Novartis Pharma AG reported the synthesis of
compound 144, a human NK-1 tachykinin receptor antagonist
for the treatment of chronic inflammatory and neuropathic pain
(Scheme 42).24a The last step of the synthesis involved an
amide coupling to generate the third amide bond on the
molecule. Previous work carried out with N-Boc-L-proline and
143 generated API that required chromatographic purification.
With the goal of developing a chromatography-free process, the
synthetic route was redesigned and focused on the coupling of
L-proline derivative 142 with the free base of 143. An extensive
coupling agent screen was then implemented. Reactions that
employed IBCF, HBTU, or 2,2′-dithiobis(benzothiazole)
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Scheme 41. CDI-Mediated Coupling of Acid 138 and HCl
Salt 139 without Added Base
Scheme 42. DCC-Mediated Coupling To Avoid
Chromatography
yielded API that required chromatographic purification.
Cyanuric chloride in combination with pyridine provided
clean material but this base is undesirable on scale due to its
toxicity and smell. EDC also afforded pure API, but the high
cost of this coupling reagent made this process not amenable to
scaleup. Finally, DCC and HOBt (1 equiv each) was identified
as an inexpensive combination that resulted in the generation of
144 in high yield with the desired purity. On laboratory scale,
to a solution of 142 and 143 in THF at rt was added HOBt.
After cooling to 0 °C, DCC was added as a THF solution, and
the reaction was warmed up to 22 °C. Upon reaction
completion (4 h), the mixture was filtered to remove some
of the 1,3-dicyclohexylurea byproduct. Following an aqueous
workup that purged some impurities and extraction of 144 into
toluene, the remaining 1,3-dicyclohexylurea was filtered off.
After concentration, amorphous 144 was obtained from an
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Review
EtOH/H2O solvent mixture. A final crystallization from EtOH
afforded crystalline API in 81% overall yield with no detectable
amounts of the other diastereomers.
Another example using DCC on scale has been reported by
Storace and co-workers at Bristol-Myers Squibb from the
synthesis of human leukocyte elastase inhibitor 148 for the
treatment of cystic fibrosis and rheumatoid arthritis (Scheme
43).22d The amide forming step to generate the acyl piperazine
Scheme 43. DCC-Mediated Synthesis of Amide 147
was carried out through two different approaches. The first
involved the use of PivCl in the presence of Et3N as base, which
afforded 147 in 67% yield on kilogram scale. Alternatively, the
researchers developed a second method that employed DCC.
On laboratory scale, N-methylpiperazine (146) was added to
acid 145 in EtOAc at 50−70 °C to generate the corresponding
ammonium salt, followed by the addition of a solution of DCC
in EtOAc over 1.5 h at 70−78 °C. After refluxing for 1 h and
cooling, 2 M HCl was added, and the dicyclohexylurea
byproduct was filtered off. Following an aqueous workup,
amide 147 was crystallized from n-BuOH in 84% yield. Due to
the presence of the phenol functionality in 145, DCC also
reacted with the phenol, but heating shifted the equilibrium
toward the formation of the desired amide product. The need
for high temperature in this coupling is in contrast with the
milder conditions typically employed for DCC-mediated amide
bond formation (0 °C to ambient temperature).
4.6.2. DIC. Clark and co-workers at Pfizer employed DIC for
the synthesis of αvβ3 integrin antagonist 132 by coupling acid
149 with amine 150 followed by ester hydrolysis (Scheme
44).44a A screen of coupling reagents revealed multiple options,
but the authors chose DIC because it was highly chemo-
selective, easy to source, cost-effective, and known to provide
greater operator safety relative to DCC. The optimal solvent
system of DMF/CH2Cl2 4.7:1 (v/v) provided the best balance
of efficiencies between coupling and isolation. Several auxiliary
nucleophiles were investigated, and 0.2 equiv of a 12 wt%
solution of HOBt in DMF was selected because it accelerated
the rate and reduced impurities. In the plant, a solution of DIC
in CH2Cl2 was added to a mixture of 149, 150, and HOBt in
DMF at 20 °C. After stirring for 6 h, the sodium carboxylate of
151 was accomplished by the addition of 2.5 M aqueous NaOH
to the crude coupling reaction mixture. After saponification was
complete, the mixture was extracted with CH2Cl2 to remove
the isopropylurea byproduct, HOBt, and some DMF. Careful
adjustment to pH 5.8 with HCl solution resulted in
precipitation of the zwitterion of 132. Chromatography and
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Scheme 44. DIC/HOBt-Mediated Amidation
salt formation provided the desired monohydrate, mono-
phosphoric acid salt 132 in 62% overall yield on multikilogram
scale.
The process group at LG Life Sciences in Korea has
described the preparation of HIV-1 protease inhibitor 155
(Scheme 45).24d A reagent screen was carried out to couple
Scheme 45. Amidation with DIC during the Synthesis of
HIV-1 Protease Inhibitor 155
acid 152 with phenylvalinone·HCl (153) to produce amide
154. The researchers found that BOP, HATU, and EDC
provided yields in the 70−75% range, but the high cost of these
reagents triggered a search for a less expensive alternative. MsCl
and IBCF afforded slightly lower yields of 154 (60% and 72%,
respectively). On the other hand, DCC and DIC afforded 154
in 77−78% yield, and the addition of HOBt increased these
yields to 83% and 94%, respectively. As a result, the DIC/
HOBt combination with NMM as base was chosen to generate
154. On laboratory scale, DIC was added dropwise to a mixture
of acid 152 and HOBt in CH2Cl2 while the internal
temperature was held below 15 °C. After warming up to rt
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Review
for acid activation, the mixture was cooled to 5−10 °C, and
NMM and amine·HCl 153 were added. Upon reaction
completion and following an aqueous workup, amide 154
was telescoped into the next step (epoxide formation) as a
CH2Cl2 solution.
4.6.3. EDC. Researchers at Takeda Chemical Industries in
Japan have employed EDC/HOBt to couple acid 156 with 4-
aminopiperidine 157 for the synthesis of 158, a compound
found to reduce plasma total- and low-density lipoprotein
(LDL) (Scheme 46).46d Initial attempts to couple 156 and 157
Scheme 46. EDC/HOBt-Mediated Amidation with Direct-
Drop Amide Crystallization
via the acid chloride generated from (COCl)2 or SOCl2 gave
yields in the 71−78% range that suffered from the
hygroscopicity of the two coupling partners. As an alternative,
EDC was tested in combination with N-hydroxyphthalimide,
NHS, HONB, and HOBt, and the best yield was obtained with
the latter. In the plant, amine 157·bis-HCl salt was freebased
with Et3N in DMF and treated with carboxylic acid 156, HOBt
(0.23 equiv), and EDC (1.05 equiv). The resulting mixture was
heated at 70−80 °C for 2 h. The addition of aqueous NaHCO3
resulted in the direct crystallization of amide 158 which, after
filtration and recrystallization from EtOH/water, was obtained
in 76% yield on kilogram scale.
Pu and co-workers at Lilly Research Laboratories have
reported on a method for peptide or amide bond formation
using EDC in aqueous EtOH (Scheme 47).46s The process
development of tripeptide 164 required two amide couplings
and previous work had carried them out in CH2Cl2 with
equimolar amounts of EDC and HOBt. These conditions did
not produce any loss of chirality and allowed the couplings to
proceed without the need for protecting the hydroxy group in
valine. Further development focused on improving the yield,
and the researchers tried to apply aqueous conditions for the
couplings, as has been previously demonstrated for the
synthesis of peptides and proteins.
When the coupling of 159 and 160 was carried out in water
with EDC and stoichiometric HOBt, followed by in situ Boc
cleavage with HCl, the subsequent coupling of deprotected
amine 162 and acid 163 did not take place. A two-step process
via isolation of amide 161 did provide tripeptide 164 in 85%
yield, but the first coupling reaction was sluggish at rt after the
uncontrolled crystallization of 161 led to a heterogeneous
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Scheme 47. Aqueous EtOH Media with EDC as an Activator
mixture with impeded agitation. On the other hand, the
addition of an alcoholic solvent such as EtOH and a slightly
elevated temperature (40 °C) increased the reaction rate 5-fold.
It was also discovered that catalytic HOBt afforded high yields
of tripeptide 164 without observable epimerization or detection
of residual HOBt in the coupling product. In the plant, the first
coupling was carried out by adding EDC (1.1 equiv) to a
mixture of acid 159, amine·HCl 160, catalytic HOBt (0.05
equiv), and NMM in EtOH. After stirring the resulting mixture
at rt for 10 h, the addition of water precipitated amide 161
which was isolated via filtration in 91% yield. Prior to the
second amide coupling, the Boc group was removed from 161
with concentrated HCl in EtOH, and the solution of liberated
amine was then treated with NMM, HOBt (0.1 equiv), hydroxy
acid 163 (1.1 equiv), and EDC (1.2 equiv) and stirred at 40 °C
for 3 h. Water addition and seeding crystallized 164 from
solution on 41 kg scale and 99.5% ee.
In the same article, the researchers also explored the scope
and generality of the methodology by applying the process to
several other coupling partners.
Chung and co-workers at Merck reported an aqueous
i-PrOAc, two-phase amidation using EDC toward the synthesis
of fibrinogen receptor antagonist 168, a drug candidate with a
wide-spectrum platelet inhibitory activity (Scheme 48).46a The
penultimate step of the synthesis involved the coupling of the
sodium salt of acid (R)-165 with 3-(R)-aminobutyrate
Scheme 48. EDC Activation in Biphasic Aqueous/i-PrOAc
Media To Prevent Polyamidation
162
Review
hemisulfate (166) in the presence of EDC. Thus, the quinine
salt of acid 165 was converted to the corresponding sodium
salt, which was isolated as an aqueous solution. To this solution
was added amine salt 166, i-PrOAc, HOBt (0.075 equiv), and
EDC (1.2 equiv). After reaction completion and aqueous
workup, amide 167 was telescoped in i-PrOAc (∼95% assay
yield) into the hydrogenolysis of the benzyl ester to provide
API 168. The authors reported that substantial polyamidation
of 167 occurred in the absence of i-PrOAc, since the organic
phase efficiently removed 167 from the aqueous phase and
hence protected it from further reaction with 166.
Although HOBt is widely used as the auxiliary nucleophile of
choice in carbodiimide-based amidations, it is not always
effective. Researchers at GlaxoSmithKline found that HOBt
actually increased epimerization in the synthesis of amide 171
en route to cathepsin K inhibitor 172, a therapy for the
prevention of bone degradation (Scheme 49).46x EDC-
promoted coupling of the side chain 169 with azepane amino
alcohol 170 gave 10% epimerization in the absence of any
additive. When either DMAP or HOBt were employed as
auxiliary nucleophiles, the epimerization level increased to 32%
and 25%, respectively. Alternatively, HOOBt (173) was found
to considerably reduce this side reaction. Thus, 1 mol%
HOOBt at rt or 0 °C afforded 1.2% and 0.4% epimerization,
respectively, whereas only 0.1 mol% at rt provided a higher
level (5.3%). Based on these results, the process that was
implemented in the plant called for the addition of acid 169 (1
equiv) and HOOBt (1.1 mol%) to a CH2Cl2 solution of amino
alcohol 170 (telescoped from the previous step) and cooling to
0 °C. EDC (1.1 equiv) was then added, and the resulting
mixture was stirred at 0 °C for 5 h. After an aqueous quench
and workup, amide 171 was crystallized from MTBE/toluene
on 50-kg scale in 82% yield over two steps from a preceding
olefin reduction to generate the saturated ring of azepane
amino alcohol 170. No information was provided in the
experimental section of the article on the level of epimerization
observed on scale.
4.7. Coupling via Phosphonium Salt. 4.7.1. BOP. A
recent application of BOP on large scale has been reported by
Ishikawa and co-workers at Meiji Seika Kaisha in Japan, who
have described the synthesis of drug candidate 177, an
antagonist for integrins αVβ3 and αIIbβ3 for the treatment of
coronary thrombosis (Scheme 50).50 The amide bond
formation had been originally carried out by the medicinal
chemistry group using EDC and HOBt, but it required 12 h to
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Scheme 49. HOOBt as an Alternative to HOBt To Prevent Epimerization
Scheme 50. Synthesis of Intermediate 176 via Amide Bond
Formation with BOP
proceed to completion and chromatography to purify amide
176. As a consequence, the researchers developed a more
efficient protocol that involved the addition of BOP (1.15
equiv) to a cold (4 °C) suspension of benzoic acid 174 and
NMM in DMF. After acid activation for 30 min, amine 175 was
added, while the internal temperature was held below 7 °C and
the resulting mixture was stirred for a further 23 h at 3−8 °C.
Amide 176 was isolated by pouring the reaction mixture into
Scheme 51. Amide Coupling with HBTU in the Synthesis of Ipatasertib·HCl (182)
163
Review
water followed by filtration to afford over 200 g of material in
96% yield.
4.8. Coupling via Guanidinium and Uronium Salt.
4.8.1. HBTU. A very recent example on the use of HBTU for
amide bond formation has been reported through a
collaboration between the process chemistry group at
Genentech and scientists at Array BioPharma during the
synthesis of ipatasertib·HCl (182), an Akt inhibitor for the
treatment of cancer (Scheme 51).54 The penultimate step of
the synthesis involved the coupling of piperidine bis-HCl 179
and chiral acid 180. Thus, Boc-protected piperazine 178 was
treated with ethanolic HCl to effect Boc-removal and generate
bis-HCl salt 179, which was telescoped into the next step as a
toluene suspension since its very high hygroscopicity made its
isolation difficult. To this suspension were added CH2Cl2,
i-Pr2NEt, acid 180, and finally HBTU as a solid in two portions.
After 3 h, the reaction underwent a complex aqueous workup to
remove HBTU related impurities. Thus, the organic phase was
first washed with saturated, aqueous NaHCO3 and NH4Cl to
remove HOBt. A solvent switch to i-PrOAc and thorough
extraction of the organic phase with 0.6 N NH4OH, 25 wt%
NH4Cl, and water removed tetramethylurea and PF6 salts. After
slurrying the product-rich i-PrOAc phase with charcoal and
SiliaMetS thiol (to scavenge ruthenium from a previous
asymmetric ketone reduction which set the alcohol of 178),
crystallization from MTBE/n-heptane provided 4.7 kg of amide
181 in 81% yield from 179. Besides HBTU, no other
information was provided in the article on alternative methods
tested for amide bond formation.
4.8.2. HATU. O’Shea and co-workers at Merck have
described the preparation of odanacatib (185), a cathepsin K
inhibitor for the treatment of osteoporosis (Scheme 52).57b
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Scheme 52. HATU-Mediated Amide Bond Formation during Scheme 53. Synthesis of Amide 188 via HATU-Promoted
the Synthesis of Odanacatib Coupling

The last step of the synthesis involved the coupling of acid 183 Scheme 54. HATU-Mediated Amide Coupling en Route to
and cyclopropylamine·HCl 184, and a screen of conditions was HIV Entry Inhibitor 192
implemented. Simple protocols, such as (COCl)2, SOCl2 or
mixed anhydride formation with pivaloyl chloride afforded low
yields of product. Higher conversions and yield were observed
with PyBOP, TBTU, and HATU, and the latter was selected for
further development. The experimental protocol called for the
addition of i-Pr2NEt over 1.5 h to a slurry of 183, 184, and
HATU in DMAc at 3 °C, while the internal temperature was
held below 10 °C. By the time the base addition was finalized,
the reaction had gone to completion, and the addition of water
precipitated odanacatib from solution in 79% yield and 98.5%
de. A recrystallization from THF/water increased the optical
purity to 99.9% de for an overall 76% yield.
Fei and co-workers at Novartis in China and the United
States have reported the preparation of hydroxamic acid 189, a
LpxC inhibitor for the treatment of bacterial infectious diseases
(Scheme 53).57c The synthesis of intermediate 188 required
the coupling of benzoic acid 186 and amine 187 (freebased
from its HCl salt by treatment with aqueous NaOH). Since
amide 188 is an oil and cannot be purified by crystallization, an
efficient coupling protocol and workup were needed to
minimize impurities. Thus, the use of 1.2 equiv of amine 187
was necessary to completely consume the benzotriazolyl-ester
intermediate resulting from activation of 186 with HATU, since previous work on a similar substrate, the researchers tried the
this activated ester could not be removed during the aqueous direct coupling of the methyl ester derivative of 190 with 191 in
workup. Upon reaction completion, the mixture was diluted the presence of bases such as NaHMDS, LiHMDS, or
with i-PrOAc and washed sequentially with aqueous HCl to NaOt-Bu, but no desired API was obtained. As a result, an
remove i-Pr2NEt and remaining amine 187, aqueous Na2CO3 amide coupling reagent screen was performed and it was found
to remove the byproduct HOAt, and water. After concen- that acid chloride formation with (COCl)2 afforded 192 in only
tration, 188 was isolated as an oil in 94% yield and >99% ee 20% yield, and the addition of HOBt generated multiple
and used in the next step without any further purification. byproducts. The final conditions to couple 190 and 191 called
Another example of amide bond formation promoted by for the addition of a DMF solution of HATU to a mixture of
HATU comes from a collaboration between Princeton API 190, 191, and i-Pr2NEt in the same solvent at 25 °C. Upon
Services, J-Star Research, ScinoPharm Taiwan, and the reaction completion, EtOH was added to precipitate crude 192.
International Partnership for Microbicides. This group This material was further purified via treatment with Darco KB
published the kilogram-scale synthesis of HIV entry inhibitor in CH2Cl2 at 30 °C followed by crystallization from n-heptane.
192 (Scheme 54).57e The last step of the synthesis effected the A final slurry in n-propanol at 90 °C to obtain the desired
coupling of α-keto acid 190 and piperidine 191. Based on polymorph afforded 953 g of API in 84% overall yield.
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Scheme 55. Amide Bond Formation during the Synthesis of Renin Inhibitor 196

4.8.3. TBTU. TBTU has been employed by Simoneau and co- Scheme 56. Amide Bond Formation with TBTU en Route to
workers at Boehringer-Ingelheim in Canada for the large-scale HCV NS3 Protease Inhibitor 200
preparation of orally active renin inhibitor 196 for the
treatment of hypertension (Scheme 55).17d The amide coupling
to introduce amine fragment 194 had been previously carried
out with the fully elaborated 2-amino-4-thiazolylmethyl group
on the carboxylic acid moiety, which led to the formation of a
substantial amount of the 2(R)-butanediamide epimer. As an
alternative, the coupling of thiazole precursor 193 and amine
194 was investigated through the screening of numerous
coupling reagents (list not provided in the article). Many of
these reagents provided low epimerization levels (<1%), and
the team selected TBTU for further development. The
experimental protocol called for the addition of i-Pr2NEt
portionwise to a solution of 193, 194, and TBTU in MeCN at
0−5 °C followed by warming to 20 °C. After an aqueous
workup and two filtrations through a pad of silica gel, 195 was
crystallized from a concentrated EtOAc solution to afford 1.2
kg of material. A second crop was obtained from the filtrates
(189 g) for a combined 70% yield. The small amount of 2(R)-
epimer (∼0.5%) could be removed via crystallization.
A second application on the use of TBTU has also been Scheme 57. Synthesis of 203 via Amide Coupling with TPTU
reported by researchers at Boehringer-Ingelheim in Canada
during the multigram preparation of macrolactam 200, an HCV
NS3 protease inhibitor for the treatment of hepatitis C
(Scheme 56).58a The formation of amide 199 was carried out
through the addition of TBTU (1.1 equiv) and Hünig’s base to
a mixture of acid 197 and amine·HCl 198. After an aqueous
workup and concentration of the organic phase, 72 g of crude
199 was isolated as a yellow foam and carried into the next step
without any additional purification.
4.8.4. TPTU. An example of TPTU on large scale has been
reported by scientists at Ciba-Geigy in Switzerland during the
preparation of aza-peptide 203, a treatment of AIDS (Scheme
57).46b The last step of the synthesis involved the bis-coupling
between diamine 201 and N-(methoxycarbonyl)-L-tert-leucine
(202). On laboratory scale, Hünig’s base (6 equiv) was added
to an ice-cooled suspension of 202 (3 equiv) and TPTU (3
equiv) in CH2Cl2. The activated ester was then treated with
trihydrochloride salt 201. Upon reaction completion, the
reaction was subjected to an aqueous workup to remove 4.8.5. TOTU. Process chemists at Hoechst AG in Germany
TPTU byproducts followed by silica filtration and slurry in i- demonstrated two examples of amide coupling via TOTU.
Pr2O to afford over half a kilogram of 203 in 73% yield. This First, they reported the synthesis of thrombin inhibitor 207 for
material could be further purified via recrystallization from the treatment of unstable angina pectoris, myocardial infarction,
water/EtOH. venous thrombosis, and stroke (Scheme 58).36 The penulti-
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Scheme 58. TOTU as a Coupling Agent during the Synthesis Scheme 59. TOTU-Mediated Amidation en Route to
of Thrombin Inhibitor 207 Protease Inhibitor 211

mate step in the synthesis coupled amine 204 and cyclo-

hexylammonium carboxylate salt 205 to generate amide 206. In
the plant, NMM and TOTU (1.07 equiv) were added
sequentially to a solution of 204 and 205 in DMF at 0 °C. Scheme 60. Cyanuric Acid-Mediated Amide Bond
After 15 min at this temperature, DMF was removed under Formation To Complete the Synthesis of Taranabant
vacuum, and the residue was subjected to an aqueous workup
to afford 206. This crude amide was carried into the subsequent
benzyl ester cleavage with ethanolic HCl to generate the HCl
salt of API 207. A potential problem in this coupling is the
presence of cyclohexylamine in the reaction medium coming
from 205, which could give rise to the corresponding amide,
but this point was not discussed in the article.
A second example from Hoechst AG reported on the use of
TOTU for the preparation of C2-symmetrical HIV protease
inhibitor 211 (Scheme 59).35a Intermediate 210 was generated
via double amide bond formation by treating a mixture of 208
(2.5 equiv) and 209 in DMF at 0 °C with Hünig’s base (8
equiv) followed by ethyl cyanooximoacetate (2.5 equiv; the
reason for using this reagent was not mentioned in the article,
but it may perform as an epimerization suppressant) and
TOTU (2.5 equiv). Upon warming to rt, the removal of DMF
under vacuum and addition of aqueous KHCO3 crystallized
210, which was then recrystallized from MTBE to give 1.23 kg
of 210 in 88% yield. the other hand, the addition of NMM to a mixture of the acid,
4.9. Coupling via Triazine Reagent. 4.9.1. Cyanuric amine, and cyanuric chloride (only 0.6 equiv required) at 50 °C
Chloride. The process group at Merck has published the large- over 4 h provided taranabant in 94% yield after an aqueous
scale preparation of taranabant (214), a cannabinoid-1 receptor workup and crystallization from MTBE/n-heptane (seeding
inverse agonist for the treatment of obesity (Scheme 60).17i with the hemisolvate was required to induce crystallization).
The last step of the synthesis involved the amide bond The chiral purity of this material could be upgraded from 94%
formation between amine 212 and acid 213 to afford API 214. to 99% ee by slurrying in EtOH/H2O, filtering off insoluble
Originally, this step was carried out with EDC/HOBt and Et3N material with low ee (approximately 5% by weight with 31%
as base, but this led to taranabant with a yellow color that could ee), and recrystallizing taranabant with 90% recovery.
not be removed using Ecosorb. Further optimization led to the 4.9.2. CDMT. Johnson and co-workers at Novartis have
replacement of Et3N with pyridine and the elimination of reported the synthesis of compound 218, a neutral
HOBt, but the high cost of EDC required the identification of a endopeptidase/angiotensin-converting enzyme dual inhibitor
more economical alternative, and thus, the researchers for the treatment of hypertension, and mitigation of congestive
investigated the use of cyanuric chloride. When the typical heart failure, diuresis, natriuresis, and vasodilation (Scheme
protocol was employed (preformation of the activated acid 61).13d In previous work by this group, amine 216 had been
species through reaction of the acid with cyanuric chloride in coupled with (S)-2-acetylthio-3-methylbutanoic acid using a
the presence of base), unsatisfactory results were obtained. On number of coupling reagents (IBCF, PivCl, DCC/HOBt,
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Scheme 61. CDMT-Promoted Amide Formation en Route to 218
CDMT), but considerable impurity formation and loss of
enantiomeric purity was observed. As an alternative, (R)-2-
bromoisovaleric acid was investigated as a coupling partner.
When this acid, as its stable i-Pr2NH salt (215, > 98% ee), was
treated with IBCF, significant amounts of urethane and
symmetrical urea were produced (similar to what had been
observed with (S)-2-acetylthio-3-methylbutanoic acid). Alter-
natively, the addition of CDMT and NMM as base at −10 °C
for 2 h afforded the corresponding activated acid. Without
isolation, amine·HCl 216 was added to generate amide 217,
which could be precipitated from solution upon water addition
to provide material with minor epimerization (>97% de).
Further purification by recrystallization from EtOH/water
afforded amide product with >99% de in 74% yield.
The process group at Lilly has described the preparation of
drug candidate 222, a multitargeted antifolate for the treatment
of cancer (Scheme 62).62a Acid 219 was activated using CDMT
Scheme 62. Synthesis of API 222 via CDMT-Promoted
Amide Formation
in DMF at 25 °C for 1 h followed by the addition of L-glutamic
acid diethyl ester·HCl (220). Upon reaction completion, an
aqueous workup isolated the free base of 221 as a CH2Cl2
solution, which was converted to over 11 kg of the p-TsOH
salt. An interesting observation is that the amino group on the
pyrimidone did not require protection prior to the amide bond
step.
4.9.3. DMTMM. An example of the application of DMTMM
in process chemistry is found in the preparation of cannabinoid-
1 antagonist 226, a drug candidate for the treatment of obesity
and diabetes, by Villhauer, Shieh, and co-workers at Novartis
167
Review
(Scheme 63).62c One of the challenges associated with the
coupling of mandelic acid derivative 223 and secondary amine
Scheme 63. DMTMM as Coupling Reagent en Route to
Drug Candidate 226
224 was the epimerization of the chiral center in 223. Initial
experiments with DMTMM, CDMT, and IBCF led to
considerable racemization (8−30%), most likely due to the
increased acidity of the benzylic proton in 223 upon activated
ester formation. At lower temperature, DMTMM provided the
best results compared to CDMT and IBCF, and by using free
base 224 rather than its HCl salt, an increased reaction rate was
observed which also contributed to minimizing racemization to
only 1.5% epimer. On laboratory scale, 224·HCl was treated
with Cs2CO3 in aqueous THF (19:1 v/v THF:H2O) at ambient
temperature to generate the free base of 224. To this mixture
was then added a solution of acid 223 in toluene. Solid
DMTMM was added in several portions, and the reaction was
cooled at −5 °C for 16 h. Following an aqueous workup, amide
225 was isolated as a toluene solution that was telescoped into
the next step (ester and amide reduction with BH3·THF).
Amide 225 was obtained in 96:4 er with only 2% epimerization
from acid 223 (98:2 er).
4.10. Coupling via Boron Reagent. 4.10.1. Boric Acid.
Boric acid has been employed by the process chemistry group
at GlaxoSmithKline for the preparation of efaproxiral (230), a
commercial drug for the treatment of cancer (Scheme 64).83a
Substrates such as carboxylic acid 228, with a phenol
functionality on the molecule, usually need protection of the
hydroxy group prior to amide bond formation. However, the
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Scheme 64. Synthesis of Amide 229 en Route to Efaproxiral
use of B(OH)3 (0.1 equiv) allowed for the coupling of
unprotected 228 and aniline 227 in toluene at reflux under
Dean−Stark conditions. The resulting amide crystallized upon
cooling and was isolated in 86−95% yield on multigram scale.
The addition of boric acid dramatically reduced the reaction
time and temperature in comparison to the protocol reported
by the medicinal chemistry group, which coupled 227 and 228
in xylene at reflux for 3 days with no catalyst.
Mathad and co-workers at Megafine Pharma and the
chemistry department at B. H. Commerce and A. M. Science
College in India have published the syntheses of several
impurities detected during the industrial preparation of
cinacalcet·HCl (231; Sensipar, Mimpara; Figure 13), a
calcimimetic agent for the treatment of hyperparathyroidism.83c
Figure 13. Structure of cinacalcet·HCl.
One of the impurities described in the article is compound
235 (Scheme 65), which contains a cyclohexyl ring in place of
the phenyl ring in cinacalcet. (The origin of this impurity was
tracked to 1-(3-bromopropyl)-3-(trifluoromethyl)benzene, one
of the reagents employed in a previous N-alkylation step.) The
preparation of amide 234 was carried out by heating a solution
Scheme 65. Boric Acid-Promoted Synthesis of Cinacalcet-
Related Impurity
168
Review
of acid 233 and chiral amine 232 to reflux in the presence of
catalytic boric acid (5.5 mol%) under Dean−Stark conditions.
After 16−18 h, an aqueous workup was performed, and crude
amide 234 was isolated in 76% yield and used in the next step
(amide reduction) without further purification.
4.10.2. 3-Nitrophenylboronic Acid. Brookes and co-workers
at Celltech−Chiroscience in the U.K. have reported the large-
scale preparation of the two enantiomers of verapamil·HCl
(235; Figure 14), a commercial drug for the treatment of
Figure 14. Structure of (±)-verapamil·HCl.
cardiovascular conditions.84 Verapamil is currently adminis-
tered as the racemate, but due to the different biological effects
of the two enantiomers, the development of routes to each
individual enantiomer would be advantageous. For the
preparation of (S)-verapamil·HCl ((S)-236, Scheme 66), chiral
acid 238 was obtained via classical resolution of its racemate
with (S)-α-methylbenzylamine (both enantiomers of this amine
are readily available and, thus, either enantiomer of the acid is
accessible) to give diastereomeric salt 237. After salt break, acid
238 (>95% ee) was telescoped as a xylene solution into
reaction with amine 239 in the presence of catalytic 3-
nitrophenylboronic acid68a (0.5 mol%) at reflux. Following an
aqueous workup and concentration, the amide solution was
seeded with 240 and cooled to afford 480 g of desired amide in
85% yield. This amide bond formation step could also be
carried out with catalytic boric acid, but this reagent was less
efficient and higher loadings were required (10−20 mol%).
5. CONCLUSIONS
The importance of amide bond formation in process chemistry
for the synthesis of drug candidates cannot be overstated.
Process chemists have a wide array of methods at their disposal
to generate amides, but the limitations imposed by large-scale
operations have focused the selection to a narrower field of
reagents. Based on the number of examples included in this
review, the top choices for acid activation by reagent are EDC,
SOCl2, CDI, and (COCl)2, followed by a second group that
includes PivCl, IBCF, T3P, and DCC.
Most of the reagents presented in this review are used in
stoichiometric amounts, and some of them, such as the
guanidinium and uronium salts, are very atom-inefficient. As a
consequence, the American Chemical Society Green Chemistry
Pharmaceutical Roundtable has selected the development of
more environmentally friendly and efficient methods for amide
bond formation as one of their top priorities.106
The development of catalytic processes for amide bond
formation has seen a resurgence in recent years. Boron-derived
reagents, such as the ones described in sections 2.4 and 4.10 of
this review, have already been implemented on large scale in
several instances. Besides boron, catalytic methods that employ
zinc,107 titanium,108 zirconium,109 aluminum,110 indium,111
silica,112 and niobium113 are very promising discoveries that,
with further development, may have the chance to enter the
process chemistry arena and displace some of the more
traditional stoichiometric approaches. Also, enzymes have
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Scheme 66. Amide Bond Formation Catalyzed by 3-Nitrophenylboronic Acid en Route to (S)-Verapamil·HCl

received considerable attention recently as a green approach to

synthesizing primary, secondary, and tertiary amides,1p with
■ ABBREVIATIONS

lipases encompassing most examples. This family of catalysts is API: active pharmaceutical ingredient(s)
highly selective, and the amidation can be carried out in a aq: aqueous
number of green solvents such as water and alcohols. However, Bn: benzyl
current technologies show very limited substrate scope and Boc: tert-butoxycarbonyl
often require long reaction times (days). BOP: (benzotriazol-1-yloxy)tris(dimethylamino)-
Other efforts have investigated safer alternatives to phosphonium hexafluorophosphate
benzotriazole-based coupling reagents. As a result, oxyma- Cbz: carbonylbenzyloxy
based reagents such as COMU (1-[(1-cyano-2-ethoxy-2- CDI: 1,1′-carbonyldiimidazole
oxoethylideneaminooxy)-dimethylamino- CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine
morpholinomethylene)]methanaminium hexafluorophos- CSA: camphorsulfonic acid
DCC: N,N′-dicyclohexylcarbodiimide
phate)114 have emerged as safer replacements with comparable
DCU: N,N′-dicyclohexylurea
reactivities. de: diastereomeric excess
Finally, alternatives to the traditional coupling between a DIC: N,N′-diisopropylcarbodiimide
carboxylic acid and an amine for amide synthesis have also been DMAc: N,N-dimethylacetamide
pursued. A remarkable example is the ruthenium-catalyzed DMAP: N,N-dimethylaminopyridine
coupling of an amine and an alcohol which generates one DME: 1,2-dimethoxyethane
equivalent of dihydrogen as the only byproduct.115 High yields DMF: N,N-dimethylformamide
were obtained with as little as 0.1 mol% Ru catalyst, and no DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-
additives or stoichiometric oxidant were needed. This trans- morpholinium chloride
formation has also been accomplished with catalytic ZnI2 and ECF: ethyl chloroformate
stoichiometric tert-butyl hydroperoxide.107b Another example is EDAC: 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide
the preparation of amides from functionalized aldehydes EDC or EDCI: 1-ethyl-3-(3′-dimethylaminopropyl)-
(formylcyclopropanes, α,β-unsaturated aldehydes, α-haloalde- carbodiimide
hydes, epoxyaldehydes).116 EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
Regardless of reagent choice, amide bond formation will EMPA: ethylmethylphosphinic anhydride
undoubtedly continue to be one of the most important ee: enantiomeric excess
transformations in process chemistry for the synthesis of equiv: equivalent(s)
pharmaceuticals. Societal and economic pressures are already er: enantiomeric ratio
having a clear effect on driving safer, greener, and cheaper GC: gas chromatography
HATU: N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]-
reagents and methods. We are confident that, if proven scalable,
pyridin-1-ylmethylene]-N-methylmethanaminium hexafluor-
many of these new technologies will be routinely incorporated ophosphate N-oxide
into large-scale operations for the synthesis of API. HBTU: N-[(1H-benzotriazol-1-yl) (dimethylamino)-

■ AUTHOR INFORMATION
Corresponding Authors
methylene]-N-methylmethanaminium hexafluorophosphate
N-oxide
HCV: hepatitis C virus
HOAt: 1-hydroxy-7-azabenzotriazole
*E-mail: Joshua.Dunetz@Gilead.com.
HOBt: N-hydroxybenzotriazole
*E-mail: Javier.Magano@Pfizer.com.
HONB: N-hydroxy-5-norbornene-endo-2,3-dicarboxylic acid
*E-mail: Gerald.A.Weisenburger@Pfizer.com.
imide
Notes HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-(1,2,3)-benzotriazine
The authors declare no competing financial interest. HPLC: high performance liquid chromatography
169 DOI: 10.1021/op500305s
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Organic Process Research & Development Review

IBCF: isobutyl chloroformate (7) Wigman, L.; Remarchuk, T.; Gomez, S. R.; Kumar, A.; Dong, M.
IPA: isopropanol, or 2-propanol W.; Medley, C. D.; Chetwyn, N. P. Am. Pharm. Rev. 2014, 17, 20.
LD50: median lethal dose (8) (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177.
LDA: lithium diisopropylamide (b) Magano, J.; Dunetz, J. R. Org. Process Res. Dev. 2012, 16, 1156.
(9) Fischer, E.; Otto, E. Ber. Dtsch. Chem. Ges. 1903, 36, 2106.
LiHMDS: lithium hexamethyldisilazide
(10) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley:
MsCl: methanesulfonyl chloride New York, 1969; Vol. 1, p 286.
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177 DOI: 10.1021/op500305s

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