Large-Scale Carbonyl Reductions in the Pharmaceutical Industry
Javier Magano* and Joshua R. Dunetz*
Chemical Research and Development, Pharmaceutical Sciences, Pfizer Worldwide Research and Development, Eastern Point Road,
Groton, Connecticut 06340, United States
ABSTRACT: Herein we present a review on methods for carbonyl reductions on large scale (≥100 mmol) applied to the
synthesis of drug candidates in the pharmaceutical industry. We discuss the most common and reliable methods for the reduction
of aldehydes, ketones, carboxylic acids, esters, amides, imides, and acid chlorides. Representative examples illustrate detailed
reaction and workup conditions and highlight the advantages and limitations of each reducing agent with special emphasis on
safety, cost, and amenability to scale-up.
■ CONTENTS
1. Introduction 1156
2. Aldehyde Reduction 1157
2.1. Aldehyde Reduction to Alcohol 1157
2.2. Aldehyde Reduction to Alkane 1157
3. Ketone Reduction 1158
3.1. Nonasymmetric Ketone Reduction to
Alcohol 1158
3.2. Substrate-Controlled, Diastereoselective
Ketone Reduction to Alcohol 1158
3.3. Reagent-Controlled, Asymmetric Ketone
Reduction to Alcohol 1160
3.4. Ketone Reduction to Alkane 1164
4. Carboxylic Acid Reduction to Alcohol 1164
5. Ester Reduction 1166
5.1. Acyclic Ester Reduction to Aldehyde 1166
5.2. Acyclic Ester Reduction to Alcohol 1167
5.3. Lactone Reduction to Lactol 1170
5.4. Lactone Reduction to Diol 1172
6. Amide Reduction 1172
6.1. Amide Reduction to Aldehyde 1172
6.2. Amide Reduction to Alcohol 1173
6.3. Amide Reduction to Saturated Amine 1174
7. Imide Reduction 1176
7.1. Imide Reduction to Saturated Amine 1176
7.2. Imide Reduction to Hemiaminal 1177
8. Acid Chloride Reduction to Aldehyde 1178
9. Conclusions 1179
Author Information 1180
Corresponding Author 1180
Notes 1180
Acknowledgments 1180
Abbreviations 1180
References 1180
1. INTRODUCTION
Reductions and oxidations are among the most important and
prevalent transformations in organic chemistry. In the
pharmaceutical industry, the synthesis of drug candidates often
requires functional group manipulations via reductants or
oxidants during the early stages of compound preparation.
Successful compound progression requires greater quantities of
active pharmaceutical ingredient (API), and process chemists
are responsible for the manufacture of high-quality API under
the guidelines of current Good Manufacturing Practices
(cGMP) to meet the stringent requirements for clinical testing.
As a result, early synthetic routes are often revised for safe and
efficient implementation on large scale.
One goal of process development is redox economy,1 or the
minimization of changes to oxidation states throughout a
synthesis. For this reason, there is a strong preference to design
process routes from raw materials having the desired oxidation
states; however, the increasing complexity of drug candidates
makes it impossible to avoid reductions or oxidations in process
chemistry. Reductions are preferred to oxidations on large scale,
as the latter can be more difficult to implement due to process
safety and toxicity concerns surrounding many oxidants (which
can make the disposal of waste streams difficult and
expensive).2 As a result, reductions are much more frequent
than oxidations for the synthesis of pharmaceuticals on large
scale and, as many examples in this review will showcase, can be
implemented reliably on multikilogram scale.
Both industry and academia place special emphasis on
carbonyl reductions due to the versatility of this transformation
for the generation of a wide range of products.3 Hydrogen gas is
the ideal reducing agent in terms of cost and atom efficiency,
and has very broad applicability for the reduction of carbonyls.
Hydrogenation chemistry is well established (first catalytic
example reported in 1874 for olefin reduction4) and reliable,
and typically affords reduction products in high yield and purity
with minimal workup.5 Its drawbacks include the flammability
of H2 gas, the frequent need for specialized equipment, and
the lack of reactivity toward certain carbonyl groups (e.g.,
carboxylic acids, esters, amides). The discovery of LiAlH4 in
1947 (prepared by treating AlCl3 with LiH)
6 and NaBH4 in
1953 (prepared by treating B(OMe)3 with NaH)
7 set the
foundation for the development of new and more chemo-
selective reagents that have considerably expanded the scope
of reducing agents.8 For example, reductions using boron-
based reagents now comprise a mature technology routinely
Received: December 23, 2011
Published: February 14, 2012
Review
pubs.acs.org/OPRD
© 2012 American Chemical Society 1156 dx.doi.org/10.1021/op2003826 | Org. Process Res. Dev. 2012, 16, 1156−1184
implemented in the pharmaceutical industry with numerous
applications in process chemistry where robustness and reliability
are fundamental.9 Further research in this field has led to the
development of chiral reagents for asymmetric reductions.10
To the best of our knowledge, a general review covering large-
scale processes for carbonyl reduction has not been published.
Herein we intend to describe technologies that are reliable and well-
established or have the possibility of being useful for carbonyl
reduction on large scale. For easy reference, this review has been
divided into sections and subsections based on functional group
conversion (e.g., aldehyde to alcohol). Each subsection contains an
introduction citing all the examples we found for a given trans-
formation that meet the following two criteria: (a) implementation
on at least 100 mmol scale and (b) the presence of a detailed
experimental procedure. The body of each subsection then contains
representative examples which highlight the most commonly
employed methods for substrate reduction. These examples have
been selected because the researchers provided details on decisions
leading to the development of reaction and quench conditions. We
captured this information in the schemes and text of this review
and, where appropriate, commented on the advantages and
limitations of processes with respect to safety, cost, and amenability
to scale-up. In reaction schemes, Roman numerals indicate steps
performed within a single process (e.g., i. LAH; ii. MeOH quench),
whereas Arabic numerals designate discrete transformations
separated by reaction workups or product isolations.
We have thoroughly reviewed the mainstream, large-scale
literature from the early 1990s through December 2011 and
believe that we have captured most of the examples from the
past 20 years. The patent literature has not been covered in this
review since, in our opinion, the most representative examples
have been reported in the mainstream literature.
2. ALDEHYDE REDUCTION
2.1. Aldehyde Reduction to Alcohol. Surprisingly, the
reduction of aldehydes to alcohols is not commonly found in the
process literature.11 Sodium borohydride is the preferred reagent
for this transformation on large scale since it is reliable,
commercially available in bulk and in various forms (powder,
pellets, caustic solution), and cost efficient (least expensive metal
hydride on a hydride equivalent basis).12 NaBH4 reductions of
aldehydes are typically carried out in THF, alcohols (MeOH,
EtOH), or combinations thereof, and may be performed under
aqueous or anhydrous conditions. Other solvent combinations
include toluene/MeOH11j and MTBE/H2O (biphasic mixture
with n-Bu4NCl as phase-transfer agent).
11i Sodium hydroxide is
sometimes added to stabilize the reagent and avoid decomposition
(and the need for a large excess) in protic solvents such as MeOH.
An aqueous quench, sometimes acidic depending on product
stability (e.g., HCl,11b,d H2SO4
11j), typically follows NaBH4
reduction to destroy residual borohydride. Safety concerns
with aqueous quench include hydrogen gas evolution and
concurrent exotherm, and acetone may be employed as an
alternative quench reagent to avoid offgassing and minimize
heat generation.11i,13 Acetic acid is another alternative when
anhydrous quench conditions are required.
The versatility of NaBH4 for the large-scale reduction of
aldehydes to alcohols has been demonstrated in the literature.11
For example, NaBH4 has been used to convert the aldehyde
generated from alkene ozonolysis directly to the alcohol.11f,g
This reagent has also been employed for the reduction of
a lactol to the corresponding diol (CH2Cl2/MeOH mixture at
reflux).14
Cabaj and co-workers at Cedarburgh Pharmaceuticals have
described the synthesis of anabolic steroid oxandrolone (3), a
compound to promote weight gain and relieve the bone pain
caused by osteoporosis (Scheme 1).11d The lactone of the
molecule was assembled in a one-pot, three-step sequence that
started with the sodium salt formation of acid 1 via treatment
with aqueous, ethanolic NaOH. The resulting solution was dosed
with NaBH4 at 0−10 °C (added in four portions) to reduce the
aldehyde group to the corresponding alcohol. Alternatively, a
commercially available caustic solution of NaBH4 could be
employed, which is more easily handled on scale. After complete
reduction of aldehyde to alcohol, 6 M aqueous HCl was added
to quench excess NaBH4 and promote the cyclization to the
lactone. Oxandrolone (3) was then collected by filtration in 94%
yield. This material could be further purified by performing a
charcoal treatment in MeOH followed by recrystallization from
MeOH/H2O (85% yield). The researchers mentioned that when
the reduction was carried out in water, product filtration after
acidification was very slow.
In addition to sodium borohydride, both LAH (conversion
of an α,β-unsaturated aldehyde to the allylic alcohol; THF,
−78 °C, basic quench)15 and catalytic hydrogenation
(conversion of furan-2-carbaldehyde to 2-hydroxymethyltetra-
hydrofuran, 60 psig, Ra-Ni, MeOH, 60 °C)16 have been
employed for the large-scale reduction of aldehydes to alcohols.
The Meerwein−Ponndorf−Verley reduction (IPA/Al(Oi-Pr)3)
17
is another useful method that has not yet been reported in the
mainstream literature for the large-scale reduction of aldehydes,
although an example for ketone reduction has been reported
(section 3.2). As a special case of aldehyde reduction, an
interesting example of diastereoselective pinacol homocoupling
of an aldehyde to a vicinal diol mediated by VCl3 has been
described by researchers at Hoechst AG.18
2.2. Aldehyde Reduction to Alkane. Aldehydes can also
be reduced to alkanes, although this transformation rarely
appears in the large-scale literature. An example is the reduction
of benzaldehyde 4 to toluene 6, reported by Connolly and co-
workers at Roche Palo Alto LLC en route to benzoic acid 9
(Scheme 2).19 Aldehyde 4 was hydrogenated at 5 psig with 10%
Pd/C (5 wt%; 50% water-wet) in EtOAc to provide transient
benzylic alcohol 5, which upon further reduction afforded
dimethoxytoluene 6. Initial experiments with only 2.5 wt%
catalyst showed quick reduction to alcohol 5 followed by slow
conversion to the alkane over 48 h. The amount of catalyst was
Scheme 1. Synthesis of oxandrolone (3) via aldehyde
reduction with NaBH4 followed by lactonization
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doubled in the plant to decrease the reaction time; as a result,
the aldehyde was fully consumed after 3 h with only 4% residual
alcohol 5. After 15 h, essentially complete reduction of 5 to toluene
6 was observed (only 0.4% of residual 5). After filtration through
Celite or Solka-Floc (cellulose), the EtOAc solution of 6 under-
went bromination with 1,3-dibromo-5,5-dimethylhydantoin (7) to
provide aryl bromide 8. This material was isolated via crystallization
from H2O/MeOH in 96% yield on multikilogram scale.
3. KETONE REDUCTION
The large-scale reduction of ketones to alcohols in both non-
asymmetric and asymmetric fashion is a very general practice
and numerous examples can be found in the literature. In
particular, the preparation of chiral, secondary alcohols with
high optical purity from prochiral ketones is of paramount
importance, and many methods are currently available to
medicinal and process chemists,20 including biocatalysis.20h,21
In this review, the asymmetric reductions have been divided into
two categories: substrate-controlled and reagent-controlled.
3.1. Nonasymmetric Ketone Reduction to Alcohol.
Sodium borohydride12 is the preferred reagent for large-scale
ketone reductions22 for the same reasons described in section
2.1. LAH has been employed as an alternative to NaBH4 for
large-scale ketone reduction,23 but the lower chemical selectivity
of this reagent limits its application to relatively simple substrates.
Dowpharma reported ketone hydrogenation in IPA using
(diphosphine)RuCl2(diamine) precatalysts and KOt-Bu
24 as a
practical alternative to NaBH4.
Ikemoto and co-workers at Takeda Chemical Industries in
Japan have reported the preparation of non-peptide CCR5
antagonist candidate 13 for the therapy of HIV-1 (Scheme 3).22h
During the one-pot preparation of α,β-unsaturated acid 12 from
cycloheptanone 10, an intermediate β-keto ester (not shown) was
synthesized by treating 10 with dimethyl carbonate and NaOMe
at reflux. Initial conditions (NaBH4 in CH2Cl2) for ketone
reduction produced the desired β-hydroxy ester 11 with 1,3-diol
as a byproduct from ester reduction, and as a result, the
purification of 11 required chromatography. Alternatively, ketone
reduction in a 10:1 THF/H2O mixture at −15 to −5 °C provided
alcohol 11 without diol after water dilution and product extraction
into diisopropyl ether.25 Dehydration of the β-hydroxy ester via
mesylate elimination and subsequent saponification via aqueous
NaOH in MeOH provided acid 12 in 54% yield from 10 on
kilogram scale.
3.2. Substrate-Controlled, Diastereoselective Ketone
Reduction to Alcohol. NaBH4 is also the most widely used
reagent for the substrate-controlled, diastereoselective reduction
of ketones.26 This reagent has been used in combination with
additives such as CeCl3 (Luche reduction of an enone to allylic
alcohol)27 and Et3B
28 or Et2BOMe
11c (reduction of β-hydroxy
ketone to syn-1,3-diol). NaBH4 has also been employed for the
kinetic resolution of a mixture of diastereomeric, α-substituted
cyclopentanones.26c
Acyloxyborohydrides, prepared from the reaction of NaBH4
and carboxylic acids, are also useful reagents for diastereose-
lective, substrate-controlled reductions.29,30 An attractive feature
of these reductants is that their reactivity can be fine-tuned
by adjusting the stoichiometry of carboxylic acid (1−3 equiv).
Among them, Me4N(OAc)3BH is known to reliably afford
anti-1,3-diols with high diastereoselectivity via reduction of the
corresponding β-hydroxy ketones,31 but we only found a single
application of this technology in the process literature.32
LAH is a cost-effective reagent, but it is less frequently used
for the reduction of ketones to alcohols due to its lower
chemical selectivity.33 Solid LAH is highly flammable and may
ignite in moist or heated air. Commercial LAH solutions in
various solvents (e.g., THF, 2-methoxyethyl ether, DME) are
safer and more practical alternatives for large-scale manufactur-
ing, but careful quenching of LAH reductions with protic solvent
is still required to control the rate of H2 evolution and
accompanying exotherm. In addition, aluminum salts often
complicate reaction workup and product isolation, but the Fieser
conditions34 generally precipitate these salts from solution as a
granular solid that can be easily removed by filtration.
Diisobutylaluminum chloride (DIBAC)35 is a less known
alternative to DIBAL, and only one example has been found in
the large-scale literature for substrate-controlled, diastereose-
lective ketone reduction.36 Another technology that has
received little attention from the process community, despite
being cost-effective and environmentally friendly, is the
Meerwein−Ponndorf−Verley reduction.17,37 This method
employs Al(Oi-Pr)3 as catalyst and IPA (a readily oxidized
secondary alcohol) as solvent to generate acetone as byproduct,
which can be easily removed by distillation to drive the reaction
to completion.
Other reagents and methods implemented on large-scale
for substrate-controlled, diastereoselective ketone reduction to
Scheme 2. Benzaldehyde 4 reduction to alkane 6 via catalytic
hydrogenation
Scheme 3. NaBH4 reduction of β-keto ester intermediate en
route to α,β-unsaturated acid 12
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alcohol are L-Selectride (cyclohexenone reduction to allylic
alcohol during the synthesis of anti-Alzheimer drug (−)-gal-
anthamine),38 catalytic hydrogenation in the presence of
PtO2 (cyclohexanone reduction in steroid substrate),
39 and
Li(Ot-Bu)3AlH (aliphatic ketone reduction during the synthesis
of HIV protease inhibitor atazanavir).40
Beck and co-workers at Hoechst AG in Germany combined
NaBH4 with Et3B (1 M in hexanes) to reduce β-hydroxy ester
14 to syn-1,3-diol 15, an intermediate to side-chain 16 for
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reduc-
tase inhibitors (Scheme 4).28 Similarly, Fuenfschilling and
co-workers at Novartis combined NaBH4 with Et2B(OMe)
(50% in THF) to prepare the racemic syn-1,3-diol 18 for the
synthesis of racemic fluvastatin (19, Scheme 5).11c Both cases
required cryogenic temperatures and provided syn-1,3-diols
with high diastereoselectivities after aqueous quench and
oxidative workup to cleave the initial boronate from reduction.
The Evans−Saksena reduction31 of β-hydroxy ketone 20 was
implemented by researchers at Novartis for the large-scale prep-
aration of the anticancer marine natural product discodermolide
(22, Scheme 6).32 The highly functionalized and advanced
intermediate 20 was treated with Me4N(OAc)3BH at −25 °C in
a mixture of THF and glacial AcOH. After an 18-h period at
0 °C, the reaction was quenched with an aqueous solution
of sodium potassium tartrate (Rochelle salt). Workup and
chromatography afforded anti-1,3-diol 21 in 73% yield and high
diastereoselectivity (exact information on stereoselectivity was
not provided in the article).
Watson and co-workers at the Hoechst Marion Roussel
Research Institute used LAH to effect the diastereoselective
reduction of cyclopentenone 23 to allylic alcohol 24 for their
synthesis of 25 (MDL 201449A), a candidate for the treatment
of multiple inflammatory diseases (Scheme 7).33b A solution
of cyclopentenone 23 in MTBE was added to a mixture of
LAH and LiI in toluene while maintaining batch temperature
between −30 and −20 °C. The additive LiI served two
purposes: (a) it suppressed 1,4-hydride addition to 23, thus
minimizing olefin reduction byproducts; and (b) it allowed the
raising of reaction temperature from −78 to −30 °C. After
reaction completion, the mixture was quenched with aqueous
NH4Cl at a rate to maintain an internal temperature below
10 °C. The aluminum salts were removed by filtration, and
concentration of the organic layer provided alcohol 24 in 76%
yield as a 37:1 mixture of cis/trans isomers. Ethereal cosolvents
were required for LAH solubility, and initial studies using
Et2O/toluene gave more favorable cis/trans ratios; however, the
highly flammable and peroxide-forming Et2O was replaced with
MTBE to avoid the process safety risks associated with the
diethyl ether. Furthermore, to minimize the handling risks
associated with flammable LAH and anhydrous LiI (hygro-
scopic), both materials were purchased in preweighed, toluene-
soluble bags and charged directly to the tank.
Singh and co-workers at Bristol-Myers Squibb employed
DIBAC for the reduction of cyclobutanone 26 to alcohol 27
during the preparation of lobucavir (28), a potent antiviral
agent for the treatment of herpes, hepatitis B, and HIV
(Scheme 8).36 T