Facile and green synthesis of dapagliflozin

Article abstract of DOI:10.1080/00397911.2019.1666283

A facile and green synthetic route was developed for the preparation of dapagliflozin (1), a selective sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes. Key reaction steps include a direct Friedel–Crafts acylation and a synthesis of diaryl ketal moiety in one-pot manner without waste water generation. Furthermore, the reduction of the diaryl ketone and C-phenylglucoside were achieved in one-pot manner to generate dapagliflozin (1) more efficiently. The synthetic route featured the usage of commercial available and easily handling reagents with shorter reaction steps and less waste disposal.

Full text of DOI:10.1080/00397911.2019.1666283

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Facile and green synthesis of dapagliflozin
Lin Hu, Ping Zou, Wanguo Wei, Xi-Meng Yuan, Xiao-Long Qiu & Shao-Hua
Gou
To cite this article: Lin Hu, Ping Zou, Wanguo Wei, Xi-Meng Yuan, Xiao-Long Qiu & Shao-
Hua Gou (2019): Facile and green synthesis of dapagliflozin, Synthetic Communications, DOI:
10.1080/00397911.2019.1666283
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https://doi.org/10.1080/00397911.2019.1666283
Facile and green synthesis of dapagliflozin
Lin Hua,b, Ping Zoua,b, Wanguo Weib, Xi-Meng Yuanb, Xiao-Long Qiub, and Shao-
Hua Goua
aPharmaceutical Research Center, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-
Tech Key Laboratory for Bio-medical Research, Southeast University, Nanjing, Jiangsu, P. R. China;
bWisdom Pharmaceutical Co. Ltd, Haimen, Jiangsu, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 24 July 2019
A facile and green synthetic route was developed for the preparation
of dapagliflozin (1), a selective sodium-dependent glucose cotrans-
porter 2 inhibitor for the treatment of type 2 diabetes. Key reaction
steps include a direct Friedel–Crafts acylation and a synthesis of dia-
ryl ketal moiety in one-pot manner without waste water generation.
Furthermore, the reduction of the diaryl ketone and C-phenylgluco-
side were achieved in one-pot manner to generate dapagliflozin (1)
more efficiently. The synthetic route featured the usage of commer-
cial available and easily handling reagents with shorter reaction steps
and less waste disposal.
KEYWORDS
Dapagliflozin; di-aryl ketal;
glycoside; green chemistry;
one-pot synthesis
GRAPHICAL ABSTRACT
Introduction
C-glycosides are ubiquitous natural products with great importance in medicinal chem-
istry.[1] One class of medicinally important aryl glycosides active against diabetes are the
selective sodium-dependent glucose cotransporter 2 (SGLT-2) inhibitors,[2–3] several
exemplified by dapagliflozin (1), canagliflozin (2), empagliflozin (3) and ipragliflozin
(4), as shown in Figure 1.
The typical synthesis method of these aryl glycosides was based on the reaction of
protected aldonolactones with aryllithium or aryl Grignard reagents to generate lactols,
CONTACT Shao-Hua Gou
sgou@seu.edu.cn
Pharmaceutical Research Center, School of Chemistry and Chemical
Engineering, Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, Southeast University, Nanjing 210096, P.
R. China.; Xiao-Long Qiu
chemqiu@jfzhiyao.com
Wisdom Pharmaceutical Co. Ltd, No. 18, Qinghua Road, Haimen
226123, Jiangsu, P. R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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L. HU ET AL.
Figure 1. Representative SGLT-2 inhibitors.
which needs to be reduced in the next reaction step.[3–5] Alternative method included
the cross-coupling reaction between glycosyl bromides and arylzinc reagents, leading to
b-arylated glycosides.[3] Specifically, for the preparation of dapagliflozin (1), there are
two main reported strategies as shown in Scheme 1 (routes 1 and 2).[3,6,7] A similar
method was disclosed in patent WO2013068850, in which direct C-glycosylation
between the Grignard reagent 6 and the protected levoglucosan 12 was achieved to give
b-arylated glycosides 13 (Scheme 1, route 3).[8] As a common starting material in differ-
ent methods according to the literature, the aryl halide 5 was synthesized from
5-bromo-2-chlorobenzoic acid 14 in three steps.[9] Initially, acylation was achieved by
thionyl chloride or oxalyl chloride. Then, a Friedel–Crafts acylation mediated by AlCl3
in anhydrous CH2Cl2 was carried out. Finally, reduction of the diaryl ketone intermedi-
ate was achieved by using Et3SiH in the presence of BF3ꢀEt2O in dichloromethane to
give 5 in excellent overall yield.
Classical Friedel–Crafts acylation of aromatic compounds required more than one
equivalent of Lewis acid such as AlCl3. This was due to the complexation of AlCl3 with
ketone intermediate. A large amount of toxic waste was generated in this step.
Considering the ecological and economical problems associated with the waste disposal,
the usage of oxalyl chloride and AlCl3 was not recommended for the large-scale prepar-
ation of dapagliflozin. Furthermore, the preparation of the common intermediate 5 and
late-stage transformations involving two reduction steps, diaryl ketone reduction and
1 C-phenylglucoside, needed to be performed. Therefore, it was highly desirable to
develop environmentally friendly protocols to prepare dapagliflozin. Scientists were try-
ing to pursue direct and eco-friendly Friedel–Crafts acylations. Indeed, anisole and phe-
netole were electron-rich arene and active reagents in Friedel–Crafts acylation reaction.
Progress has been made to achieve greener Friedel–Crafts acylations by using inorganic
solid supported reagents[10] or solid acids[11–12] as catalysts. Direct Friedel–Crafts acyl-
ation of aromatic carboxylic acid with anisole has also been reported. For instance, the
combination of graphite with methylsulfonic acid[13] or p-toluenesulfonic acid,[14] the
combination of TFAA with BF3ꢀEt2O[15] and methanesulfonic anhydride[16–17] were
investigated to promote this reaction.
Results and discussion
Based on the information above and the fact that both diaryl ketone and 1 C-phenylglu-
coside could be reduced by silane in the presence of catalytic amount of

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Scheme 1. The reported synthetic routes to dapagliflozin (1).
BF3ꢀEt2O,[6,7,9,18] we herein have developed a green synthetic strategy for dapaglifozin
(1) as shown in Scheme 2.
Our synthesis started from commercially available 5-bromo-2-chlorobenzoic acid 14
and gluconolactone. An interesting result lied in the fact that both Friedel–Crafts acyl-
ation and ketallization could be realized by catalytic amount of BF3ꢀEt2O to afford 15 in
76% overall yield in a one-pot manner. Gratifyingly, the diaryl ketal 15 could be easily
crystallized from the reaction mixture without any other work-up operations. Similar to
the reported processes,[8] a condensation between 15 and 7 was carried out under
–78 ꢁC in THF, followed by full deprotection of silyl groups in the presence of
CF3CO2H in CH3OH in a one-pot manner to yield compound 17 in 68% overall yield.
It was satisfying that the intermediate 17 was also easy to crystallize from the reaction
mixture in good quality. The single crystal of compound 17 was obtained in THF, and
its structure was confirmed by X-ray diffraction analysis (Figure 2). In contrast, com-
pound 8 was a syrupy foaming solid, which was very difficult to crystallize, as reported
in the previous literatures.[8] Finally, Reduction of 17 was conducted by Et3SiH in the
presence of BF3ꢀEt2O in CH2Cl2/CH3CN to provide dapagliflozin (1) in high yield. The
product could be purified in >98% purity upon crystallization from ethyl acetate
and heptanes.
Compared with the previous synthetic strategies, obvious improvement includes the
conduction of the reduction of diaryl ketone and 1 C-phenylglucoside in one step
(17!1). This method could minimize the waste generation and improve the productiv-
ity. Additionally, it is well known that the control of genotoxic impurities is difficult
and very important for APIs (active pharmaceutical ingredients). For example, the sul-
fonate is a typical genotoxic impurity with very low limitation requirements in drugs.
At the beginning of this research, compound 14 was selected as the starting material,

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L. HU ET AL.
Scheme 2. Green synthesis of dapaglifozin (1).
Figure 2. X-ray structure of intermediate 17.
which was converted to ketal 15 by using catalytic amounts of CH3SO3H and CH3OH.
Similarly, methylsulfonic acid and methanol were also used in the quenching stage of
condensation reaction to yield C-phenylglucoside 17 following a reported literature.[7]
These procedures inevitably introduced methanesulfonate as the genotoxic impurity into
APIs. In order to avoid the generation of sulfonate, ketalization was attempted with

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5
weak acids. Fortunately, BF3Et2O and CF3CO2H were used to replace methylsulfonic
acid successfully in this report, which avoided the possibility of generating geno-
toxic impurities.
Experimental
General
1H NMR and 13C NMR spectra were recorded with a Bruker WM-400 MHz spectrom-
1
eter. The chemical shifts (d scale) of the H NMR data are indicated in ppm relative to
1
tetramethyl silane (TMS) (d ¼ 0.00 ppm). The H NMR data are reported as follows:
chemical shift (d, ppm), multiplicity [s (singlet), d (doublet), t (triplet), q (quarterlet), m
(multiplet or unresolved)], coupling constant (J) in Hz, integration. The LC–MS data
were recorded with Shimadzu LCMS-2010EV Mass spectrometers. The melting point
was recorded with a digital melting point meter (Hanon MP490). All reagents were
commercially obtained and used as received.
Synthesis of dapaglifozin (1)
Under N2 atmosphere, to a four-necked round-bottom flask equipped with a mechanical
stirrer, a thermometer and an addition funnel, was added 16 (9.1 g, 20 mmol), CH3CN
(27 mL), CH2Cl2 (27 mL) and Et3SiH (13.4 g, 120 mmol). The resulting suspension was
cooled to –25 ꢁC, and a solution of BF3ꢀEt2O (14.2 g, 100 mmol) in CH2Cl2 (14.2 mL)
was added dropwise to the reaction mixture over 15 min, keeping the temperature below
–20 ꢁC. The reaction mixture was stirred at –20 ꢁC for 3 h and then warmed to 35 ꢁC
and kept stirring for additional 4 h. Aqueous NaHCO3 (90 mL) was added slowly to
quench the reaction and the organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (20 mL ꢂ 2). The combined organic layers were concentrated
under reduced pressure to obtain dapaglifozin as a light yellow solid: yield (7.8 g, 95%);
1
melting point (m.p.) 88–90 ꢁC; H NMR (400 MHz, DMSO-d6): d ¼ 7.37 (d, J ¼ 8.0 Hz,
1H), 7.32 (d, J ¼ 1.6 Hz, 1H), 7.23 (dd, J ¼ 8.0, 1.6 Hz, 1H), 7.09 (d, J ¼ 8.4 Hz, 2H), 6.82
(d, J ¼ 8.4 Hz, 2H), 4.94–4.95 (m, 2H), 4.82 (d, J ¼ 5.6 Hz, 1H), 4.44 (t, J ¼ 6.0 Hz, 1H),
3.93–4.02 (m, 5H), 3.68–3.72 (m, 1H), 3.42–3.48 (m, 1H), 3.08–3.29 (m, 4H), 1.29
(t, J ¼ 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) d 15.15, 38.13, 61.83, 63.36,
70.78, 75.18, 78.78, 81.17, 81.68, 114.77, 127.82, 129.13, 130.03, 131.27, 131.69, 132.39,
138.27, 140.14, 157.37; LC–MS (ESIþ): m/z (%) ¼ 431 (Mþ þ Na, 100), 433 (32). Anal.
calcd. for C21H25ClO6: C, 61.69; H, 6.16; Cl, 8.67; found C, 61.72; H, 6.18; Cl, 8.64.
1
Full experimental detail, copies of H and 13C NMR spectra of compound 1, 15, 17,
and X-ray data of 17 are provided. This material can be found via the “Supplementary
content” section of this article’s webpage.
Conclusions
In summary, we have developed a facile and green protocol for the preparation of
SGLT-2 inhibitor dapaglifozin (1) in four overall steps from readily available 5-bromo-
2-chlorobenzoic acid 14 and gluconolactone. The direct Friedel–Crafts reaction and the

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L. HU ET AL.
synthesis of diaryl ketal 15 were successfully performed in a one-pot manner without
waste water generation. Furthermore, the reduction of diaryl ketone and C-phenylgluco-
side moieties was also achieved in one step, leading to shorter synthetic route and less
waste. The intermediate 15 and 17 could be easily purified via crystallization.
Considering the control of genotoxic impurity, CH3SO3H was replaced by CF3CO2H/
.
BF3 Et2O. Thus, this method provided an efficient strategy to prepare dapaglifozin (1),
which was suitable for large-scale production and expected to be extended to the prep-
aration of other similar SGLT-2 inhibitors.
Funding
The authors thank the Wisdom Pharmaceutical Co. Ltd. for financial support.
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