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org/OrgLett Letter

Efficient Route to Canagliflozin via Anhydroketopyranose

Ch.V. A. Sasikala, Ratnamala Annapragada,* Debjit Basu, Kiran Kumar Singarapu, Aaseef Mohammad,
and Rakeshwar Bandichhor*
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ABSTRACT: The development of an efficient route for the synthesis of Canagliflozin is reported. The anhydroketopyranose
intermediate was isolated as a novel intermediate, which was used to prepare Canagliflozin API in high purity.

C anagliflozin is a sodium-glucose cotransporter 2

(SGLT2) inhibitor used to improve glycemic control in
patients with type 2 diabetes.1a,b SGLT2 is an enzyme in
production, primarily due to a lack of crystalline isolable
intermediates, and thus contains cumbersome purification
protocols.14a−c Thus, the primary objective of the present
kidney tubules responsible for glucose reabsorption from endeavor is to develop a cost-effective and expeditious process
urine.2 Canagliflozin blocks the action of SGLT2. Thus, for the synthesis of Canagliflozin, preferably via crystalline
Canagliflozin reduces the reabsorption of glucose from renal isolable intermediates which can be employed for large-scale
tubules, leading to more excretion of glucose in urine, and synthesis.15
reduces the overall sugar load in the blood.3 Canagliflozin was Herein, we report an efficient synthetic route for the
the first SGLT2 inhibitor approved by the FDA in March synthesis of Canagliflozin A via novel anhydroketopyranose
2013, marketed as Invokana by Johnson & Johnson.4 In the intermediate 8a. The formation of 8a includes an innovative
past decade, several other modified C-arylglucosides were purification protocol enabling the synthesis of Canagliflozin in
synthesized in pursuit of achieving better efficacy. In addition high yields and purity.15 The anhydroketopyranoses that have
to this, a myriad of novel synthetic routes were also explored to 6,8-dioxabicyclo[3.2.1]octane structures are widely present in
obtain cost-effective processes to address the needs of diabetic nature as biologically relevant natural products. These are also
patients.5 Several of these C-arylglucosides, namely, Dapagli- considered as chiral building blocks in synthetic organic
chemistry.14 These have been mainly prepared from aldoses by
flozin,6 Empagliflozin,7 Tofogliflozin,8 Sotagliflozin,9 Ipragli-
acid-catalyzed reactions and are limited to the synthesis of the
flozin,10 Luseogliflozin,11 PF-04971729,12 and YM543 (Figure
anhydroheptulopyranoses having a 6,8-dioxabicyclo[3.2.1]-
1),13 are currently under different stages of clinical trials, and a
octane structural framework.16
few of them have been approved. Alternative synthetic pathways to 8a have been reported
At the outset, we embarked on the development of an (Scheme 1). Francisco et al.17 developed a methodology to
efficient process amenable to commercial production of obtain these anhydroketopyranoses from C-glycopyranosides
Canagliflozin. The existing process for Canagliflozin was by intramolecular hydrogen abstraction reactions via radical
deemed challenging yet not impossible for large-scale species.17 Further, the development of a different methodology
based on hemiketals by Yamonoi et al. led to intramolecular
glycosidation products using a catalytic amount of Lewis acids
in good yields.18 However, the synthetic strategy developed did
not disclose the robustness of the process particularly with
unprotected 1-C-substituted carbohydrates (hemiketals).
In our endeavor, we have successfully developed a
methodology to obtain anhydroketopyranose 8a from a

Received: March 20, 2022

Published: May 6, 2022

Figure 1. Structures of SGLT-2 inhibitors.

© 2022 American Chemical Society https://doi.org/10.1021/acs.orglett.2c00980

3450 Org. Lett. 2022, 24, 3450−3454
Organic Letters pubs.acs.org/OrgLett Letter

Scheme 1. Synthesis of Anhydroketopyranose trifluoromethanesulfonic acid (TfOH). Each reaction involved

10 mol % of CSA or TfOH as a Brønsted acid in MeCN at 0
°C and was stirred for 2 h, affording the desired
anhydroketopyranose 8a as a major product along with 8b18
as a minor one as an impurity (Table 2, entries 1 and 2).
Compounds 8a and 8b were obtained as an inseparable
mixture. The intramolecular glycosidation attempts with
trifluoroacetic acid produced exclusively 8a in low yield
(17%) (Table 2, entry 3). The structure of anhydroketopyr-
anose was confirmed by complete spectral analysis using
various orthogonal techniques.17 To delineate the factors
controlling the stereochemical event toward the formation of
both 8a and 8b, we planned to investigate the effect of hydroxy
and methoxy groups at C-1 of trimethylsilyl ether deprotected
methylketal (1-C-arylhexopyranose) 7. Elimination of the C-arylglucoside toward the intramolecular glycosidation.
−OMe group from the anomeric position of 7 resulted in Accordingly, lactol 6 was treated with MsOH (methane
oxonium species (not shown) which were reduced by using sulfonic acid) in MeOH to obtain compound 7. In this event,
silane to obtain C-glycoside 8a in high yield and purity compound 7 was low in yield along with the formation of a
(Scheme 1). The advanced intermediate 8a was finally used in substantial quantity of des-halo derivatives 9 (Table 1, entries
the synthesis of Canagliflozin A.
As a starting point for a scalable synthesis of Canagliflozin A, Table 1. Optimization of the Coupling Stage Starting from 5
our study began with the preparation of aglycon aryl halide
intermediates 4a and 4b (Scheme 2). Highly regioselective entry reaction conditions product (yield)a
1 5, 4a, n-BuLi, THF, −78 °C, 2 h 7 (65%),b 9 (21%)
Scheme 2. Synthesis of Aglycon Moieties 4a and 4b 2 5, 4a, n-BuLi, THF, n-BuMgCl, −20 °C, 2 h 7 (37%),b 9 (49%)
3 5, 4a, n-BuLi, iPrMgCl, −20 °C, 2 h 7 (56%),b 9(31%)
4 5, 4b, n-BuLi, THF, −78 °C, 2h 7 (43%),b 9 (37%)
5 5, 4b, n-BuLi, THF, n-BuMgCl-20 °C, 2 h 7 (53%),b 9 (39%)
6 5, 4b, n-BuLi, THF:toluene (1:1) −78 °C, 7 (82%), 9 (4%)
2h
a
Area % by HPLC of crude reaction mixture over two steps. bAs an
inseparable mixture.

Friedel−Crafts reaction of commercially available 1a and 1b 1 and 4) over two steps. The reactions (Table 1, entries 2, 3,
with 2 afforded requisite intermediates 3a and 3b, respectively, and 5) that employed the magnesium “ate” complex were
as reported in the literature.15,19 Compounds 3a and 3b were found to proceed slowly even at −20 °C and led to the
subjected to trifluoroacetic acid and TMDS-mediated reduc- formation of des-halo derivative 9 in a substantial quantity.
tion to obtain compounds 4a and 4b, respectively, in good The desired lactol 6 was formed in high yield by the addition
yields. Compounds 4a and 4b were isolated as yellow solids of n-BuLi in a mixture of iodo-aglycon 4b and 2,3,4,6-tetra-O-
from respective reactions in high yields and purity just by trimethylsilyl-β-D-gluconolactone 5 dissolved in THF and
trituration with hexane. toluene (1:1) at −78 °C. Upon addition of MsOH in
The aglycon counterpart was tethered with the glycon MeOH, the resulting anomeric mixture of lactol 6 was
moiety by a halide-metal exchange reaction. Initially, glycon 4a immediately converted into desilylated methyl ethers 7 in
was dissolved in THF and treated with n-BuLi at −78 °C to 82% yield along with 9 (4%) over two steps (Table 1, entry 6).
generate aryl lithium followed by the addition of commercially Thereafter, compound 7 was subjected to an intramolecular
available 2,3,4,6-tetra-O-trimethylsilyl-β-D-gluconolactone (gly- glycosidation reaction using 10 mol % of TfOH in THF (10
con) 519 that afforded unstable intermediate lactol 6 (Scheme vol. %) at 0 °C, and the reaction mixture was stirred for 2 h,
3). Thereafter, crude lactol 6 was subjected to intramolecular which afforded a mixture of anhydroketopyranoses 8a and 8b
glycosidation using L-Camphor-10-sulfonic acid (CSA) or in a combined yield of 56% (Table 2, entry 4). The same
reaction when performed in MeCN (40 vol. %) produced 8a
Scheme 3. Optimization of the Coupling Stage and and 8b with a combined yield of 79% (68% of 8a and 11% of
Synthesis of 8a and 8b 8b) (Table 2, entry 5). We speculated that methyl-α/β-
arylpyranoketal anomers 7 led to the formation of desired
anhydroketopyranose 8a and traces of undesired species 8b via
SN2 reaction. The structures of 8a and 8b were determined by
detailed 1D and 2D NMR experiments. In 8a, the character-
istic NOE cross peaks between H2/H11, H2/H15, H11/H17,
H14/H16, H16/H17, H17/H19, and H20/H27 and HMBC
correlations of H8/C1, H9/C1, H11/C1, H15/C1, H2/C10,
H17/C11, H17/C13, H14/C16, H17/C19, and H20/C22
were observed. In 8b, NOE cross peaks between H2/H11,
H2/H15, H11/H17, H14/H16, H16/H17, H17/H19, and
H20/H27 and critical HMBC correlations of H4/C1, H6/C1,
3451 https://doi.org/10.1021/acs.orglett.2c00980
Org. Lett. 2022, 24, 3450−3454
Organic Letters pubs.acs.org/OrgLett Letter

Table 2. Synthesis of Anhydroketopyranose Derivatives from Compounds 6, 7, 10, and 11

entry SMb Bronsted acid (mol %) solvent (vol. %) product (yield)a
c
1 6 CSA (10) MeCN (10) 8a (59%), 8b (6%)
2 6 CF3SO3H (10) MeCN (10) 8a (66%), 8b (9%)
3 6 TFA (300) CH2Cl2 (10) 8a (17%)
4 7 CF3SO3H (10) THF (10) 8a (50%), 8b (6%)
5 7 CF3SO3H (10) MeCN (40) 8a (68%), 8b (11%)
6 10b CSA (10) THF (10) + MeCN (10) 8a (54%)
7 10b TMSOTf (10) THF (40) 8a (55%), 8b (38%)
8 10b CF3SO3H (10) THF (10) + MeCN (10) 8a (55%), 8b (38%)
9 7 CF3SO3H (10) THF (40) 8a (80%), 8b (trace)
a
Yield was determined by area % by HPLC of the crude reaction mixture. bSM: starting material. cCSA: L-camphor-10-sulfonic acid.

H9/C1, H11/C1, H15/C1, H17/C11, H17/C13, H14/C16, Scheme 4. Synthesis of Canagliflozin via
H17/C19, and H20/C22 were observed, as shown below in Anhydroketopyranose Intermediate 8a
Figure 2 and used to determine the stereochemistry and
structures of 8a and 8b.
Next, we turned our attention to obtaining highly pure
methyl-β-arylpyranoketal derivative 7. This was planned from
the pentahydroxy lactol 10b (Scheme 4). To obtain compound
10b, the crude lactol 6 was treated with aqueous trifluoroacetic
acid at 0 °C and stirred for 2 h to obtain lactol 10b (Scheme

4). Thereafter, it was purified by crystallization from n-heptane

in high purity as a solid in 69% yield. Thereafter, lactol 10b was
treated with MsOH in MeOH to obtain the β-pyranoketal
derivative 7 as a major product along with traces of the
corresponding α-pyranoketal in 82% yield and a trace amount
of impurity 12.
As expected, the methyl-β-arylpyranoketal 7 underwent
smooth conversion to anhydroketopyranose 8a in 80% yield
along with a trace amount of undesired isomer 8b (Table 2,
entry 9) with 10 mol % of TfOH in THF (40 vol. %) at room
temperature over 2 h (de > 99.9%) of stirring. The
pentahydroxy derivative 10b was also subjected to intra-
molecular glycosidation using 10 mol % of CSA in a mixture of
THF/MeCN (1:1) to obtain exclusively the isomer 8a.
Interestingly, when pentahydroxy derivative 10b was subjected
to 10 mol % of TMSOTf or TfOH in THF (40 vol. %) at 0 °C
for 2 h of stirring, the desired anhydroketopyranose 8a was
formed in 55% yield along with the isomer 8b in 38% yield
(Table 2, entries 7 and 8). The question arises why a globally
deprotected pentahydroxy species 10b did not yield selective
product 8a, whereas methyl-β-arylpyranoketal 7 afforded the
product in an excellent yield. Mechanistically, compound 10b
can exist in an equilibrium mixture of various species (10, 10a,
and 10b), as shown in Figure 3.

Figure 2. Characteristic NOE and HMBC correlations used to

determine the structures of 8a and 8b. Figure 3. Potential equilibrium mixture of 10b.

3452 https://doi.org/10.1021/acs.orglett.2c00980
Org. Lett. 2022, 24, 3450−3454
Organic Letters pubs.acs.org/OrgLett Letter

This equilibrium mixture, during chemical transformation, produced similar results (Table 3, entry 3). Shuto et al. have
would potentially lead to the formation of a significant quantity developed highly stereoselctive reduction of hemiketals using
of undesired isomer 8b. The fate of these species can be Et3SiH and TMSOTf in CH2Cl2 at −78 °C based on the
understood by cascading transformations, as shown in Figure conformational restriction strategy.22 However, under the same
4. Various synthetic events indicate that methyl-β-arylpyr- conditions, compound 7 led to a mixture of compound A and
12 (Table 3, entry 4). The reduction of anhydroketopyranose
8a with triisopropylsilane using boron trifluoride-diethyl
etherate also led to the formation of a mixture of compounds
A and 12 (entry 5). Eventually, by following a methodology
developed by Kishi and others,21b we were pleased to find that
addition of borontrifluoride-diethyl etherate to a solution of 8a
and Et3SiH in CH2Cl2 at −25 °C led to the formation of the β-
C-glucoside A in good yield (Table 3, entry 1) exclusively.
Mechanistically, we hypothesized that a stereoselective
reduction event would have occurred toward giving rise to
Canagliflozin A. In this case, a novel anhydroketopyranose
intermediate 8a is found to be conformationally restricted, and
it accepts the delivery of hydride from the less hindered face,
giving rise to the desired product, Canagliflozin, in excellent
yields (93%) and selectivity (de > 99.9%).
In conclusion, we have developed a novel and efficient
synthetic route to produce Canagliflozin A. The synthesis
features an isolable solid novel anhydroketopyranose inter-
mediate 8a which was isolated in high yield and purity. It was
found that anydroketopyranose 8a can be reduced to β-C-
glucoside in high yields. This eventually facilitated the
preparation of Canagliflozin with precise control with an
excellent purity profile. The intramolecular glycosidation route
can potentially be applied to the scalable synthesis of other
Figure 4. Cascading transformations leading to the formation of 7. flozins.

anoketal 7 is a safer resort in comparison to the lactol 10b and ■ ASSOCIATED CONTENT
associated hemiketal or methylketal intermediates (10, 10a, *
sı Supporting Information
10c, 10d, and 11). However, the spectroscopic data of the
isolated solid lactol 10b indicated that the structure was not in The Supporting Information is available free of charge at
fact of the compound 10 or 10a but 10b. The conclusive https://pubs.acs.org/doi/10.1021/acs.orglett.2c00980.
indicator of molecular identity of 10b was established by solid- Complete experimental procedures and spectral data
state IR via KBr disc analysis. (PDF)
Subsequently, we focused on the Lewis acid promoted silane
reduction of hemiketals to β-C-glucoside utilizing the α-face AUTHOR INFORMATION
hydride reduction of an anomerically stabilized transient
oxonium species (not shown).20,21a,b Compound 8b along
■
Corresponding Authors
with traces of 8a when subjected to silane reduction, up to 4% Rakeshwar Bandichhor − API R&D, IPDO, Dr. Reddy’s
of compound A, along with 84% of compound 12 were Laboratories Ltd., Hyderabad, Telangana 500090, India;
observed (Table 3, entry 2). The crude mixture of 8a and 8b orcid.org/0000-0003-2673-1429; Email: rakeshwarb@
drreddys.com
Table 3. Lewis Acid Promoted Silane Reduction of 8a in the Ratnamala Annapragada − Department of Chemistry,
Synthesis of Canagliflozina GITAM University, Hyderabad, Telangana 502329, India;
Phone: 91 40 4434 6430; Email: [email protected];
Fax: 9140 4434 6285
Authors
Ch.V. A. Sasikala − API R&D, IPDO, Dr. Reddy’s
entry substrate (purity)b Lewis acid silane product, A (yield)c
Laboratories Ltd., Hyderabad, Telangana 500090, India;
1 8a (97%) BF3·Et2O Et3SiH A (93%) Department of Chemistry, GITAM University, Hyderabad,
2 8b (97%) BF3·Et2O Et3SiH A (4%), 12 (84%) Telangana 502329, India
3 8a (80%) + 8b (7%) BF3·Et2O Et3SiH A (77%), 12 (5%) Debjit Basu − API R&D, IPDO, Dr. Reddy’s Laboratories
4 7 (crude) TMSOTf Et3SiH A (49%), 12 (21%) Ltd., Hyderabad, Telangana 500090, India
i
5 8a (97%) BF3·Et2O Pr3SiH A (66%), 12 (14%) Kiran Kumar Singarapu − API R&D, IPDO, Dr. Reddy’s
a
Laboratories Ltd., Hyderabad, Telangana 500090, India
Reaction was performed with 3 equiv of BF3·Et2O and silylhydride in Aaseef Mohammad − API R&D, IPDO, Dr. Reddy’s
dichloromethane at −25 °C to 0−60 °C for 2 h. bPurity was
determined by HPLC of isolated compound. cYield was determined
Laboratories Ltd., Hyderabad, Telangana 500090, India
by area % by HPLC of the crude reaction mixture. Complete contact information is available at:
3453 https://doi.org/10.1021/acs.orglett.2c00980
Org. Lett. 2022, 24, 3450−3454
Organic Letters pubs.acs.org/OrgLett Letter

https://pubs.acs.org/10.1021/acs.orglett.2c00980 (15) Srinivas, S.; Bhaskar, K.; Vilas, D.; Praveen, C.; Asif, M.; Venu,
N.; Murali, K.; Debjit, B.; Sasi Kala, C. V.; Rakeshwar, B.; Murugan,
Notes A.; Archan, D.; Ramakrishna Reddy, K.; Jithin, J.; Srividya, R.;
Rajasekhar, T.; Sharad Santu, P.; Sateesh, M.; Sravan Kumar, B.;
The authors declare no competing financial interest. Dattatray, M.; Meter Joseph, M.; Vema Reddy, V. V. Patent WO
2016/098016 A1, 2016.
ACKNOWLEDGMENTS (16) (a) Haricoviniova-Bilikova, Z.; Petrus, L. Carbohydr. Res. 1999,
■
We thank the management of Dr. Reddy’s Laboratories Ltd.
320, 31. (b) Haricoviniova-Bilikova, Z. Synthesis 2001, 343, 751.
(17) Francisco, C. G.; Herrera, A. J.; Suarez, E. J. Org. Chem. 2002,
for supporting this work. 67, 7439.
(18) Yamanoi, T.; Matsumura, K.; Matsuda, S.; Oda, Y. Synlett 2005,
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Org. Lett. 2022, 24, 3450−3454