Efficient synthesis of empagliflozin, an inhibitor of SGLT-2, utilizing an AlCl3-promoted silane reduction of a β-glycopyranoside

Article abstract of DOI:10.1021/ol501755h

An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin (5) from acid 1 is described. The key tactical stage involves I/Mg exchange of aryl iodide 2 followed by addition to glucono lactone 3 in THF. Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces β-anomeric methyl glycopyranoside 4 which is, without isolation, directly reduced with Et₃SiH mediated by AlCl₃ as a Lewis acid in CH ₂Cl₂/MeCN to afford 5 in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch.

Full text of DOI:10.1021/ol501755h

Letter
pubs.acs.org/OrgLett
Efficient Synthesis of Empagliflozin, an Inhibitor of SGLT-2, Utilizing
an AlCl3‑Promoted Silane Reduction of a β‑Glycopyranoside
Xiao-jun Wang,* Li Zhang, Denis Byrne, Larry Nummy, Dirk Weber,† Dhileep Krishnamurthy,
Nathan Yee, and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, United States
S
* Supporting Information
ABSTRACT: An efficient production synthesis of the SGLT-2 inhibitor
Empagliflozin (5) from acid 1 is described. The key tactical stage involves I/
Mg exchange of aryl iodide 2 followed by addition to glucono lactone 3 in THF.
Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces
β-anomeric methyl glycopyranoside 4 which is, without isolation, directly
reduced with Et3SiH mediated by AlCl3 as a Lewis acid in CH2Cl2/MeCN to
afford 5 in 50% overall yield. The process was implemented for production on a
metric ton scale for commercial launch.
mpagliflozin (5), currently in late phase development
Scheme 2. Synthesis of Iodo- and Bromo-Substituted 2a/b
E
along with other similar compounds including Dapagli-
flozin and Canagliflozin, is a medicinally important aryl
glycoside intended for treatment of type 2 diabetes.1 Due to
potentially high commercial importance, we required develop-
ment of an efficient process to satisfy the need for metric ton
production of 5.2
Based on the popular methodology developed by Kishi and
others3 that addresses the diastereoselective synthesis of β-
anomers of C-glycosides utilizing an α-face hydride reduction of
an anomerically stabilized carbenium intermediate,4 a retro-
synthetic pathway was proposed (Scheme 1). Empagliflozin 5,
Scheme 1. Retrosynthetic Analysis of Empagliflozin 5
Aromatic substitution of 7a/b was performed with
commercially available (S)-3-hydroxytetrahydrofuran D and
tBuOK in THF at 15−25 °C to afford benzophenones 8a/b in
80−87% isolated yields after a solvent switch and direct
crystallization from aqueous isopropanol. It is worthy to note
that a high water content in the THF solution of 7a/b and (S)-
3-hydroxytetrahydrofuran led to an undesirable level of
degradation products 9a/b and 10, leading to lower recovery
of benzophenones 8a/b. Reduction of 8a/b was achieved using
1,1,3,3-tetramethyldisiloxane in the presence of aluminum
chloride in toluene. The reduced products 2a/b were isolated
in 92% yield by crystallization from aqueous acetonitrile after
basic treatment of the crude reaction mixture with 10% NaOH
to destroy polymeric siloxane byproducts.
bearing a β-aryl substituent at the C-1 position, can be
disconnected to the key aryl-metal A and δ-gluconolactone
derivative B. Aryl-metal species A can be readily obtained via
fluorobenzophenone C and chiral 3-hydroxy tetrahydrofuran D.
Our studies began by focusing on obtaining access to aryl-
metal species A. We first utilized a highly regioselective
Friedel−Crafts reaction of 5-halo-2-chlorobenzoyl chlorides
6a/b,5 which were prepared from commercially available 5-
halo-2-chlorobenzoic acids 1a/b (Scheme 2). Fluorobenzophe-
nones 7a/b were subsequently isolated in ∼95% yield following
recrystallizations from aqueous isopropanol.
We initiated formation of the aryl-metal species A using
bromide 2a first. It was found that Br/Mg exchange of 2a with
i
the PrMgCl·LiCl complex proceeded slowly, even at an
elevated temperature of up to 40 °C which also led to
6
n
simultaneous decomposition. Br/Li exchange with BuLi or
Received: June 17, 2014
Published: July 25, 2014
© 2014 American Chemical Society
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Letter
n
the BuLi/nBuMgCl complex was successful, and subsequent
<0.1 A% of α-anomer detected after crystallization from
addition to commercially available persilylated gluconolactone
37 gave rise to the desired methyl β-lactol 4. Considering the
demanding requirements associated with the use of nBuLi, such
as cryogenic conditions (←40 °C) and reagent handling, the
analogous iodide 2b was chosen for the process even though
bromide 2a is more desirable from an economical standpoint.
isopropyl acetate (IPAc, Table 1).
Table 1. Lewis Acid Promoted Reduction of 4 and 13a−c
with Et3SiH
i
Although complete I/Mg exchange of 2b with PrMgCl was
reached in 30 min at −20 °C, the subsequent addition to 3 was
sluggish even at room temperature, resulting in decomposition
of the arylmagnesium chloride throughout the course of the
prolonged reaction. However, by employing Knochel’s
iPrMgCl·LiCl complex for exchange, the addition to 3 was
proven to be effective to yield intermediate lactol 11 (Scheme
3).
a
entry substrate Lewis acid β:α (area %)
isolated yield of 5, 16a−c
b
1
2
3
4
5
6
7
4
BF3·Et2O
AlCl3
>99:1
>99:1
15:1
5:1
63
b
4
67
b
13a
13b
13b
13c
13c
AlCl3
58 (R: Ac)
c
BF3·Et2O
AlCl3
83 (R: Bn)
c
5:1
87 (R: Bn)
c
Scheme 3. Preparation of Methyllactol 4 and Methyl Tetra-
O-protected Lactols 13a−c
BF3·Et2O
AlCl3
7:1
90 (R = allyl)
c
7:1
87 (R = allyl)
a
b
Area % by HPLC of the reaction mixture. Crystallization from IPAc.
c
As an inseparable β/α mixture by chromatography.
It was anticipated that the reduction would produce <5% of
furanosides 15a/b since the crude 4 contained 2%−3% of
furanoketal 11. However, up to 20% of this byproduct was
generated in some pilot plant batches as a 1:1 mixture of α/β
anomers (Figure 1). A careful study revealed that the water
Without workup, the resulting mixture was subjected to
treatment with 5 N HCl in methanol to a pH of 2−3 at about
40 °C. Following pH adjustment, latol 11 was completely
converted to a 1:1 mixture of α/β methyl furanoketal 12 as the
dominant components. This mixture was transformed to
methyl β-pyranoketal 4 over about 3−5 h monitored by
HPLC. After workup and solvent switch to methylene chloride,
the resultant solution of 4 (crude product is an oil; 85% HPLC
assay yield from 2b) was directly used for the reduction to 5.
Next, our attention focused on the desired reduction of
glucopyranoside 4. In general, the diastereoselectivity of Lewis
acid mediated silane reductions of tetra-O-protected glycopyr-
anosides to β-C-glycosides varies from moderate to high.3,4,8
Better results are typically achieved with conformationally
restricted substrates.9 While few accounts were reported for O-
unprotected substrates, no details on β-selectivity were
discussed.1b,c We felt that methyl β-glycopyranoside 4, though
conformationally flexible, would be practically advantageous
with no O-protection if good diastereoselectivity could be
achieved during reduction.
Figure 1. Effect of water content on the formation of impurity 15 (α/
β 1:1).
content of the reaction mixture was attributable to this side
reaction through a fast interconversion of 4 to lactol 14.
Furanosides 15a/b were found to be the major products when
the water content was >4000 ppm. Therefore, a low KF of the
reaction mixture was specified in order to prevent the formation
of 15a/b.
Next, we focused on the Lewis acid used to mediate
reduction. To the best of our knowledge, pyranoside reduction
using AlCl3 as a Lewis acid had not appeared in the literature
prior to our studies; this reagent is much more preferable over
BF3·OEt2 for practical reasons. We were pleased to find that
addition of 4 in CH2Cl2 to Et3SiH and a suspension of AlCl3 in
CH3CN produced results comparable to BF3·OEt2.11 Fur-
thermore, the reaction with AlCl3 was much less sensitive to
For our studies, several tetra-O-protected derivatives 13a−c
were prepared (via 4, Scheme 3) for investigation in parallel
with 4. When a mixture of crude 4 and Et3SiH in CH3CN/
10
CH2Cl2 was treated with BF3·OEt2, the reaction proceeded
smoothly at 15−20 °C. To our surprise, β-C-glycoside 5 was
obtained almost exclusively in about 65% isolated yield with
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Letter
water content, which allowed for development of a more robust
process. After 30 min at room temperature, the reaction
mixture was quenched by careful addition of water. Azeotropic
distillation and a solvent switch to IPAc was followed by
crystallization and isolation of 5 crystallized in 60−70% yield.
In contrast to the excellent selectivity observed for O-
unprotected 4, the reduction of 13b−c using BF3·OEt2
generated significant amounts of α-anomers with a β/α ratio
of 5−7:1. Using AlCl3 as a Lewis acid provided no
improvements, as we anticipated that a possible chelation
effect may restrict the confirmation which would enhance the
anomeric effect (Table 1). The reduction of substrate 13a with
BF3·OEt2 was very sluggish, even after the addition of water as
described in the literature.14 AlCl3 was proven to be much more
effective, giving the desired product 16a in 15:1 selectivity.
In order to confirm the relative stereochemistry and obtain
material for use as an analytical standard, β/α-anomeric
mixtures of 16b−c were used to prepare quantities of the
pure α-anomer 18 (Scheme 4). Deprotection of O-tetra-allyl
Table 2. Formation of Impurity 19
Grignard
(equiv)
a
a
b
entry
4 (area %) 19 (area %) isolated yield of 19
1
2
3
4
1.1
1.2
1.5
2.2
84
75
41
<1
<3
10
38
77
/
/
20
57
a
b
Area % by HPLC of the reaction mixture. Crystallization from
MeOH.
side. The selectivity of reduction of O-unprotected glycopyr-
anosides to β-C-glycosides was also better understood. The
one-stage process involves four chemical transformations from
2 to 5 without isolation of intermediates and precise control
over the purity profile of the final drug substance.
Scheme 4. Preparation of α-Anomer 18
ASSOCIATED CONTENT
* Supporting Information
■
S
Spectroscopic data and copies of 1H/13C NMR spectra for 2a−
b, 4, 5, 6a/b−8a/b, 12, 13a−c, 15a/b, 16a/c, 18, 19. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xiao-jun.wang@boehringer-ingelheim.com.
Present Address
†Department of Process Development, Boehringer Ingelheim
GmbH & Co.KG, 55216 Ingelheim am Rhein, Germany.
protected 16c with a 7:1 of β/α ratio was performed using 10%
palladium on carbon in the presence of p-TsOH in n-propanol
at 90 °C for 5 days. The resulting product was transformed to
O-tetra-acetate 17c, which was further subjected to crystal-
lization in a 2:1 mixture of hexane/EtOAc in order to remove
the β-anomer. This sequence upgraded the filtrate α/β anomer
ratio to 5:1 from the original 1:7. The crude 17c filtrate was
then treated with hydrazine in THF, and α-anomer 18 of >99%
purity crystallized from a mixture of EtOAc and MTBE with an
overall yield of 3% from 16c.
Notes
The authors declare no competing financial interest.
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the production of SGLT-2 inhibitor Empagliflozin (5) on a
metric ton scale. The synthesis features a highly β-selective
AlCl3-promoted silane reduction of a methyl β-glycopyrano-
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Letter
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