A Scalable Synthesis of Tofogliflozin Hydrate

Article abstract of DOI:10.1021/acs.oprd.6b00175

A newly process for the synthesis of tofogliflozin hydrate, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, was described. Three improvements were achieved, including the development of a regioselective Friedel-Crafts reaction, a high-yield reduction, and a mild metal-halogen exchange. These improvements ultimately resulted in the isolation of tofogliflozin hydrate as a white solid in >99% purity (HPLC area) and 23% overall yield after 12 steps without column chromatography.

Full text of DOI:10.1021/acs.oprd.6b00175

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Communication
A Scalable Synthesis of Tofogliflozin Hydrate
Xiu-Dong Yang, Zhao-Xi Pan, Da-Jun Li, Guan Wang, Min
Liu, Rong-Gui Wu, Yan-Hua Wu, and Yong-Chen Gao
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00175 • Publication Date (Web): 27 Sep 2016
Downloaded from http://pubs.acs.org on September 27, 2016
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A Scalable Synthesis of Tofogliflozin Hydrate
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XiuꢀDong Yang,* ZhaoꢀXi Pan, DaꢀJun Li, Guan Wang, Min Liu, RongꢀGui
Wu, YanꢀHua Wu and YongꢀChen Gao
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Pharmaceutical Research Center, Disha Pharmaceutical Group Co., Ltd.,
Weihai 264205, China
E-mail: xiudongyang-disha@hotmail.com
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A newly process for the synthesis of tofogliflozin hydrate, a
sodiumꢀglucose coꢀtransporter type 2 (SGLT2) inhibitor, was described.
Three improvements were achieved, including the development of a
regioselective FriedelꢀCrafts reaction, a highꢀyield reduction and a mild
metalꢀhalogen exchange. These improvements ultimately resulted in the
isolation of tofogliflozin hydrate as a white solid in > 99% purity (HPLC
area) and 23% overall yield after 12 steps without column chromatography.
Keywords :
tofogliflozin hydrate
SGLT2
FriedelꢀCrafts reaction
metalꢀhalogen exchange
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Tofogliflozin hydrate (Figure 1), as a novel SGLT2 inhibitor,1 has been
shown that its treatment for Type 2 diabetes is safe and well tolerated to
patients, without any specific or clinically relevant concerns.1c Hence, it has
already been approved and launched in Japan.
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Figure 1. Tofogliflozin Hydrate
There are two scalable synthetic routes reported to prepare tofogliflozin.2
An efficient production synthesis of tofogliflozin hydrate from alcohol 2 was
first described by Murakata et al. (Scheme 1, route 1).2a In 2016, Ohtake et al.
reported an improved synthetic route, which achieved in just 7 linear steps
(Scheme 1, route 2).2b They selected the optimal protecting groups for the
purpose of chemoselective activation and crystalline purification, and
obtained the pure tofogliflozin in a good overall yield. However, these
methods suffer from several drawbacks. Firstly, some reagents, such as BH3
(Scheme 1, route 2) and 2ꢀMethoxyproene (3, Scheme 1), are toxic or highly
volatile. Meanwhile, the use of Palladium reagents may lead to an excess of
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residual heavy metal in the final product. Secondly, manufacturing costs in
these methods are high due to the application of expensive raw materials and
reagents. Last but not least, the key tactical stages that involve Br/Li
exchange of aryl bromide followed by addition to gluconolactone 5 need the
cryogenic conditions (< ꢀ60 oC), and this method is not suitable for industrial
production. Herein, we report a newly developed synthetic method for
tofogliflozin hydrate starting from readily available raw materials and
affording good overall yield.
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Scheme 1. Reported Scalable Synthetic Routes of Tofogliflozin
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Our new retrosynthesis is depicted in Scheme 2, which is partially
inspired from the synthetic route of empagliflozin by Wang’s group.3 As
shown in Scheme 2, the tofogliflozin (1) could be directly prepared from
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advanced fragments 5 and 15 with a metalꢀhalogen exchange and an addition
reaction. Then, the compound 15 could be synthesized from the intermediate
16 by reduction. For the intermediate 16, it could be synthesised from the
precursor 17 and ethylbenzene 18 with a FriedelꢀCrafts reaction. At last, the
aryl iodide 17 could be generated through an iodination from cheap
commercially available 4ꢀ(hydroxymethyl)benzoic acid 19.
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Scheme 2. Retrosynthetic Analysis of Tofogliflozin
The synthesis of tofogliflozin (1) began with the construction of
iodoꢀsubstituted 21 and 22 (Scheme 3). The acid 19 was used as the starting
material and the hydroxyl group was protected through acetylation to afford
ester 20,4 which proceeded smoothly under the Lulinski’s optimized
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condition to provide the desired intermediate 21 in good yield and excellent
regioselectivity.5 Then, the Compound 21 was reacted with thionyl chloride
by using a catalytic amount of N,Nꢀdimethylformamide to obtain
iodoꢀsubstituted 22, which was used in the next step without further
purification.
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Scheme 3. Preparation of Iodo Substituted 21 and 22
ꢀ
With the fragment 22 in hand, the next step was the FriedelꢀCrafts
reaction. In order to convert compound 22 into the ketone 23a, a series of
conditions was explored (Table 1).
Table 1. Optimization of FriedelꢀCrafts Reactiona
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AlCl3
(equiv)
1.1
temperature Yield
para/ortho
18
entry
(23a/23b)e
(equiv)
1.5
(oC)
(%)b
22c
40d
37d
43d
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2.2
1.5
0
3.3
1.5
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0
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3.5
0
2.2
4.5
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3.5
10
20
reflux
2.2
3.5
2.2
3.5
a All reactions were conducted at a concentration of 0.47 M. b Isolated yield from 21. c
Isolated yield after purification by column chromatography. d Isolated yield after
crystallization from isopropanol and water. e Ratio of para to ortho was determined by
HPLC.
The amount of AlCl3 was first investigated, and 2.2 equivalents provided
the best yield (Table 1, entries 1–3). As the amount of ethylbenzene (18)
increased, the yield was improved from 43% to 50% (Table 1, entries 4 and
5). However, a lower yield of 48% was found with the presence of 4.5 equiv
of ethylbenzene (Table 1, entry 6). Then, the results of the following
experiments depicted that the reaction went better with the higher
temperature (Table 1, entries 7–9). Notably, a good yield (64% from 21,
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Table 1, entry 9) was achieved in reflux with the presence of 2.2 equiv of
AlCl3 and 3.5 equiv of ethylbenzene. In addition, the para-selectivities of
the reactions were excellent and no significantly change was found under the
different conditions (Table 1, entries 1–9).
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The next step was the reduction of ketone 23a to aryl iodide 24, and
different reducing conditions were tested (Table 2).
Table 2. Optimization of Reducing Reaction
Lewis
entry acid
(equiv)
AlCl3 (2) NaBH4 (1.5)
Yield
reductant (equiv)
solvent
(%)b
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2
THF
NP
26
–
Et3SiH (2)
Et3SiH (2)
CF3COOH
CH2Cl2/CH3CN
(1:2)
BF3·Et2O
(2)
3a
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43
CH2Cl2/CH3CN
(1:2)
4a
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AlCl3 (2) Et3SiH (2)
AlCl3 (2) 1,1,3,3ꢀtetramethyldisiloxane CH2Cl2/CH3CN 85
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(2)
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1,1,3,3ꢀtetramethyldisiloxane CH2Cl2/CH3CN
6a
7a
AlCl3 (3)
AlCl3 (3)
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34
(2)
(1:2)
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1,1,3,3ꢀtetramethyldisiloxane
toluene
(2)
a the reaction was conducted at a concentration of 0.25 M. b Isolated yield after
purification by column chromatography. NP = no product.
We first used AlCl3 as Lewis acid and NaBH4 as reductant,6 but no desired
product was obtained (Table 2, entry 1). On the basis of the condition
described in Kiuchi’s report,7 the desired product 24 was obtained, albeit
with a low 26% yield (Table 2, entry 2). Our succeeding investigations
found that a very good yield of product 24 could be obtained using BF3 as
Lewis acid in solvent mixtures of CH2Cl2 and CH3CN (Table 2, entry 3).
However, when low toxic reagent AlCl3 was used, the yield was decreased to
43% (Table 2, entry 4). Fortunately, the aryl iodide 24 was obtained in good
yield when 1,1,3,3ꢀtetramethyldisiloxane was used as reductant, and the best
yield (96%) was encountered at the presence of 3 equiv of AlCl3 (Table 2,
entries 5 and 6). However, if the solvent (CH2Cl2/CH3CN) was replaced by
toluene, the reaction, carried out under the same condition as in entry 6,
provided a poor yield (Table 2, entry 7). The LCꢀMS analysis showed that
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the acetoxy group on compound 24 could be reacted with toluene when the
reaction was conducted in presence of AlCl3.8
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The acetate 24 was deprotected by saponification to give alcohol 25 in
high purity and 92% yield over two steps. After protection with TMSCl, The
compound 26 was obtained in nearly quantitative yield and used in the next
step immediately (Scheme 4).
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Scheme 4. Preparation of Aryl Iodide 26
Next, our attention focused on the metalꢀhalogen exchange with
iPrMgCl·LiCl. Taking into account the instability of TMS group, the
protecting groups in oily intermediate 27 were removed using
methanesulfonic acid,9 followed by spirocyclization to afford the stable
compound 1 which could be purified easily. Different reaction temperatures
and the amount of Grignard reagent were tested to determine the effects on
the reaction (Table 3).
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Table 3. Optimization of I/Mg Exchange with iPrMgCl·LiCla
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iPrMgCl·LiCl
isolated yield of 1
entry
temperature (oC)
(equiv)
(%)
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6
1.1
1.1
1.1
1.1
1.5
2.0
0
41b
63b
71b
70b
37b
trace
ꢀ10
ꢀ20
ꢀ30
ꢀ20
ꢀ20
a All reactions were conducted at a concentration of 1.07 M. b Isolated yield after
purification by column chromatography.
o
As shown in Table 3, the data revealed that ꢀ20 C was the best
temperature for the I/Mg exchange (Table 3, entry 3). Further decreasing
reaction temperatures to ꢀ30 °C did not significantly change the yield (Table
3, entry 4). However, the same reactions performed under a higher
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temperature resulted in decreased yields (Table 3, entries 1 and 2). Moreover,
the amount of iPrMgCl·LiCl remarkably affected reaction efficiency. The
more equivalents of Grignard reagent were used, the less compound 1 was
obtained (Table 3, entries 5 and 6). These results were similar to those
published by Wang et al., who observed that excess Grignard reagent was
closely correlated with decreasing amounts of desired product on the
synthesis of empagliflozin.3
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Conversion of crude product 1 obtained in the previous step to highꢀpurity
tofogliflozin hydrate involved three additional manipulations (Scheme 5).
Scheme 5. Preparation of Tofogliflozin Hydrate
According to the reported method,2a when the compound 1 was treated with
methyl chloroformate in the presence of 1ꢀmethylimidazole in acetone and
then crystallized from a mixture of ethanol, methyl tertꢀbutyl ether and
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isopropanol, the crystalline intermediate 14 was obtained with an overall
yield of 60% from 26. Finally, treatment of the compound 14 with NaOH in
solvent mixtures of 1,2ꢀdimethoxyethane and water, followed by
crystallization from aqueous acetone to furnish tofogliflozin hydrate with >
99% purity in 83% yield over two steps.
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In summary, we have developed a practical and scalable synthetic route
for the SGLT2 inhibitor tofogliflozin hydrate which proceeds in 12 linear
steps and in 23% overall yield. One of the key steps involved in the
transformation of aryl iodide 26 to the corresponding crude tofogliflozin 1
was accomplished by a mild process of I/Mg exchange and addition.
Meanwhile, the conditions of FriedelꢀCrafts reaction and reduction have
been optimized. This newly developed synthesis of tofogliflozin, starting
from cheap 4ꢀ(hydroxymethyl)benzoic acid 19 and no using expensive
reagents, is costꢀeffective albeit requiring synthetic steps longer than the
reported routes and has potential for scale manufacturing.
Experimental Section
All starting materials, reagents and solvents were purchased from
commercial suppliers and used without further purification. 1H NMR (400
13
MHz) and C NMR (100 MHz) spectra were measured and chemical shifts
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were reported in ppm using TMS or the residual solvent peak as a reference.
High resonance mass (HRMS) analyses were recorded using ESI mode by
QꢀTOF. Infrared spectra were recorded on FTꢀIR. Optical rotations were
determined on a polarimeter at 589 nm. The water content (KF) was
determined by Karl Fisher titration.
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4ꢀ(acetoxymethyl)benzoic acid (20).4 A 5 L threeꢀnecked flask was
charged with 4ꢀHydroxymethylbenzoic acid 19 (213 g, 1.40 mol), CH2Cl2
(1.40 L), acetic anhydride (700 mL), and pyridine (23.3 mL). The mixture
was heated to reflux and stirred for 2 h. The solvent was evaporated under
reduced pressure. To the resulting residue was added water (4.00 L) and the
mixture was heated to reflux and stirred for 2 h. The reaction mixture was
cooled to 0~5 oC, stirred for 2 h and filtered. The wet cake was washed with
o
water (1.00 L) and dried at 60 C for 8 h to give 20 (239 g, 88%) as a white
o
1
solid. Mp: 127−129 C. H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.8 Hz,
13
2H), 7.46 (d, J = 7.8 Hz, 2H), 5.19 (s, 2H), 2.15 (s, 2H). C NMR (100
MHz, CDCl3) δ 171.8, 170.8, 141.9, 130.4, 129.0, 127.7, 65.4, 20.8. HRMS
(ESI) m/z: [M+NH4]+ Calcd for C10H14NO4 212.0917; Found 212.0905. IR
(KBr, cmꢀ1) ν: 3600, 3079, 2944, 1733, 1683, 1616, 1578, 1517, 1430, 752.
4ꢀ(acetoxymethyl)ꢀ3ꢀiodobenzoic acid (21). A 5 L threeꢀnecked flask
was charged with sodium periodate (143g, 0.670 mol), diiodine (114 g,
0.448 mol), acetic acid (932 mL), and acetic anhydride (466 mL). The
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resulting mixture was vigorously stirred and concentrated sulfuric acid (914
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g, 9.33 mol) was added while keeping the internal temperature below 5 C.
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4ꢀ(acetoxymethyl)benzoic acid 20 (233 g, 1.20 mol) was added portionwise
and the resulting slurry was stirred at 30 oC for 20 h. To the reaction mixture
was added ice water (1.10 L) followed by addition of 15% aqueous Na2SO3
(1.10 L). The slurry was stirred at 20 oC for 0.5 h and filtered. The wet cake
was washed with water (1.00 L) and dried at 70 oC for 8 h to give 21 (346 g ,
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90%) as a offꢀwhite solid. Mp: 170−172 C. H NMR (400 MHz, CDCl3) δ
8.58 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 5.17 (s, 1H),
2.19 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 170.4, 169.5, 144.2, 141.0,
130.3, 130.0, 128.5, 96.9, 69.6, 20.8. HRMS (ESI) m/z: [M+NH4]+ Calcd for
C10H13INO4 337.9884; Found 337.9875. IR (KBr, cmꢀ1) ν: 3427, 3077, 2943,
1728, 1685, 1598, 1557, 1487, 1423, 1236, 759.
4ꢀ(4ꢀethylbenzoyl)ꢀ2ꢀiodobenzyl acetate (23a). A 5 L threeꢀnecked flask
was charged with 4ꢀ(acetoxymethyl)ꢀ3ꢀiodobenzoic acid 21 (320 g, 1.00
mol), CH2Cl2 (2.67 L), and DMF (1.8 mL). The mixture was cooled to 0~5
oC and then thionyl chloride (297 g, 2.50 mol) was added dropwise. The
mixture was heated to reflux, stirred for 3 h and then concentrated under
reduced pressure to give 22 as a offꢀwhite solid without further purification.
A 5 L threeꢀnecked flask was charged with the above residue, CH2Cl2
(2.13 L), and ethylbenzene 18 (427 mL, 3.50 mol). The mixture was cooled
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to 0~5 C and aluminum chloride (293 g, 2.20 mol) was added portionwise
while keeping the internal temperature below 10 oC. The mixture was heated
to reflux and stirred for 0.5 h. Ice water (2.00 L) was added and the resulting
mixture was extracted with ethyl acetate (2.00 L × 3). The combined organic
layer was concentrated under reduced pressure. To the resulting residue was
added isopropanol (1.60 L) and water (533 mL). The mixture was heated to
reflux and then cooled to 20 oC over the course of 2 h. The slurry was stirred
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for additional 2 h at 20 C and filtered. The wet cake was washed with
isopropanol/water (320 mL, v/v = 2:1) and dried at 50 oC for 8 h to give 23a
o
(261 g, 64% from 21) as a white solid. Mp: 69−71 C. 1H NMR (400 MHz,
CDCl3) δ 8.26 (s, 1H), 7.76ꢀ7.72 (m, 3H), 7.47 (d, J = 7.9 Hz, 1H), 7.32 (d, J
= 7.8 Hz, 2H), 5.18 (s, 2H), 2.75 (q, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.29 (t, J
= 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 194.1, 170.3, 149.9, 142.1,
140.4, 139.1, 134.3, 130.3, 129.6, 128.4, 127.9, 97.2, 69.5, 28.9, 20.8, 15.1.
HRMS (ESI) m/z: [M+H]+ Calcd for C18H18IO3 409.0295; Found 409.0287.
IR (KBr, cmꢀ1) ν: 3455, 3056, 2984, 2932, 1744, 1661, 1607, 1595, 1551,
1413, 1226, 1050, 751.
(4ꢀ(4ꢀethylbenzyl)ꢀ2ꢀiodophenyl)methanol (25). A 5 L threeꢀnecked
flask was charged with 4ꢀ(4ꢀethylbenzoyl)ꢀ2ꢀiodobenzyl acetate 23a (250 g,
0.61 mol), dichloromethane (815 mL), acetonitrile (1.63 L), and
1,1,3,3ꢀtetramethyldisiloxane (164 g, 1.22 mol). The mixture was cooled to
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0~5 oC and aluminum chloride (245 g, 1.84 mol) was added portionwise.
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The mixture was warmed to 25 C and stirred for 20 h. To the reaction
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mixture was added ice water (2.00 L) and then stirred for 0.5 h. The
resulting mixture was extracted with ethyl acetate (1.00 L × 3). The
combined organic layer was concentrated under reduced pressure to give
crude 24 as a colorless oil without further purification. A small sample was
obtained as a colorless solid by chromatographic purification on silica gel.
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Mp: 53−54 C. 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.26 (d, J = 8.0
Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.8
Hz, 2H), 5.08 (s, 2H), 3.86 (s, 2H), 2.60 (q, J = 7.6 Hz, 2H), 2.09 (s, 3H),
1.21 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.4, 143.5, 142.2,
139.7, 137.1, 135.9, 129.5, 128.8, 128.7, 128.0, 98.7, 69.8, 40.5, 28.3, 20.8,
15.5. HRMS (ESI) m/z: [M+NH4]+ Calcd for C18H23INO2 412.0768; Found
412.0762. IR (KBr, cmꢀ1) ν: 3437, 3047, 2959, 2922, 1742, 1598, 1557, 1486,
1451, 1239, 1032, 808, 479.
A 5 L threeꢀnecked flask was charged with the above residue, THF (480
mL), methanol (480 mL), and 15% aqueous sodium hydroxide (480 mL).
The slurry was stirred at 25 oC for 4 h and filtered. The wet cake was washed
with water (1.00 L) and dried at 70 oC for 8 h to give 25 (199 g , 92% from
o
23a) as a white solid. Mp: 105−107 C. 1H NMR (400 MHz, CDCl3) δ 7.67
(s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.7
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Hz, 2H), 7.08 (d, J = 7.7 Hz, 2H), 4.64 (s, 2H), 3.89 (s, 2H), 2.62 (q, J = 7.6
Hz, 2H), 1.86 (br s, 1H), 1.22 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 142.9, 142.2, 140.3, 139.4, 137.3, 129.1, 128.7, 128.5, 128.0, 97.8,
69.0, 40.5, 28.4, 15.5. HRMS (ESI) m/z: [M+NH4]+ Calcd for C16H21INO
370.0662; Found 370.0662. IR (KBr, cmꢀ1) ν: 3269, 2921, 2864, 1659, 1512,
1437, 1061, 1027, 556.
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(1S,3’R,4’S,5’S,6’R)ꢀ6ꢀ[(4ꢀethylphenyl)methyl]ꢀ3’,4’,5’,6’ꢀtetrahydroꢀ
3’,4’,5’ꢀtris(methoxycarbonyloxy)ꢀ6’ꢀ[(methoxycarbonyloxy)methyl]ꢀspi
ro[2ꢀbenzofuranꢀ1(3H),2ꢀ[2H]pyran] (14). A 5 L threeꢀnecked flask was
charged with (4ꢀ(4ꢀethylbenzyl)ꢀ2ꢀiodophenyl)methanol 25 (190 g, 0.54
mol), THF (1.80 L), and triethylamine (109 g, 1.08 mol). The mixture was
cooled to 0~5 oC and TMSCl (88.0 g, 0.810 mol) was added dropwise. The
mixture was warmed to 25 oC and stirred for 1 h. To the mixture was added
ice water (2.00 L) and then stirred for 10 min. The resulting mixture was
extracted with CH2Cl2 (2.00 L × 3). The combined organic layers were
washed with brine and dried over anhydrous Na2SO4. The solid was filtered
off, and the mother liquid (water content < 0.1%) was concentrated under
reduced pressure to give 26 (225 g , 98%) as a colorless oil without further
purification.
A 3 L threeꢀnecked flask was charged with the above aryl iodide 26 and
THF (495 mL). The mixture was cooled to ꢀ20~ꢀ25 oC and iPrMgCl·LiCl
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(1.30 M in THF, 448 mL, 0.582 mol) was added dropwise. After stirring at
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ꢀ20~ꢀ25 oC
for
0.5
h,
to
the
mixture
was
added
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(3R,4S,5R,6R)ꢀ3,4,5ꢀtris((trimethylsilyl)oxy)ꢀ6ꢀ(((trimethylsilyl)oxy)methyl)
tetrahydroꢀ2Hꢀpyranꢀ2ꢀone 5 (309 g, 0.662 mol) while keeping the internal
temperature below ꢀ15 oC. The mixture was warmed to 0~5 oC and stirred for
1 h. To the mixture was added 10% aqueous ammonium chloride (1.00 L)
and then warmed to 25 oC. The resulting mixture was extracted with ethyl
acetate (600 mL × 3). The combined organic layers were dried over
anhydrous Na2SO4. The solid was filtered off, and the mother liquid was
concentrated under reduced pressure. the residue was used in the next step
without further purification.
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A 5 L threeꢀnecked flask was charged with the above residue and THF
(1.35 L). The mixture was cooled to 0~5 oC and methanesulfonic acid (0.05
M in methanol, 540 mL, 0.027 mol) was added dropwise. After stirring at
o
0~5 C for 15 h, to the resulting mixture was added saturated aqueous
sodium bicarbonate (900 mL). The mixture was concentrated under reduced
pressure to a low volume (~900 mL). To the mixture was added
1,2ꢀdimethoxyethane (1.80 L), water (1.80 L) and nꢀhexane (2.70 L). The
organic layer was separated and the aqueous layer was extracted with ethyl
acetate (1.20 L × 3). The combined organic layers were dried over
anhydrous Na2SO4. The solid was filtered off, and the mother liquid was
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concentrated under reduced pressure to give crude tofogliflozin 1 as a
colorless foam without further purification.
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A 3 L threeꢀnecked flask was charged with the above product, acetone
(800 mL), and 1ꢀmethylimidazole ( 433 g, 5.27 mol). The mixture was
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cooled to 0~5 C and methyl chloroformate (332 g, 3.51 mol) was added
dropwise. The mixture was warmed to 25 oC and stirred for 1 h. To the
resulting mixture was added water (1.00 L) and then extracted with ethyl
acetate (540 mL × 3). The combined organic layer was concentrated under
reduced pressure. To the residue was added ethanol (1.08 L), methyl
tertꢀbutyl ether (180 mL) and isopropanol (270 mL). The mixture was heated
to reflux and slowly cooled to 25 oC over the course of 4~5 h. The slurry was
stirred for additional 1 h at 25 oC and filtered. The wet cake was washed with
ethanol/isopropanol (100 mL, v/v=3:1) and dried at 60 oC for 6 h to give 14
(196 g, 60% from 26) as a white solid. Mp: 128−130 oC. [α]20D = +30.9 (c =
1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.20 (d, J = 8.0 Hz,
1H), 7.14 (d, J = 8.0 Hz, 1H), 7.12ꢀ7.07 (m, 4H), 5.51 (t, J = 9.6 Hz, 1H),
5.41 (d, J = 9.9 Hz, 1H), 5.21ꢀ5.10 (m, 3H), 4.39ꢀ4.36 (m, 1H), 4.35ꢀ4.31 (m,
1H), 4.25ꢀ4.22 (m, 1H), 3.96 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H),
3.50 (s, 3H), 2.60 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 155.3, 154.9, 154.7, 154.4, 141.9, 141.4, 138.0, 137.9,
135.2, 131.0, 128.7, 127.9, 123.2, 120.9, 108.4, 75.5, 74.6, 73.1, 72.6, 69.4,
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65.6, 55.3, 55.1, 54.9, 54.9, 41.3, 28.3, 15.5. HRMS (ESI) m/z: [M+NH4]+
Calcd for C30H38NO14 636.2287; Found 636.2280. IR (KBr, cmꢀ1) ν: 3485,
2963, 2929, 2880, 1760, 1452, 1272, 808, 785. Spectroscopic data were
identical with those reported.2
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Tofogliflozin hydrate.2a A 3 L threeꢀnecked flask was charged with 14
(193 g, 0.312 mol), 1,2ꢀdimethoxyethane (1.17 L), and 16% aqueous sodium
hydroxide (936 mL). The mixture was stirred for 3 h at 25 oC and then
neutralized to pH 6~7 by the addition of conc. HCl while keeping the
internal temperature below 5 oC. The resulting mixture was extracted with
ethyl acetate (780 mL × 3). The combined organic layers were dried over
anhydrous Na2SO4. The solid was filtered off, and the mother liquid was
concentrated under reduced pressure to give tofogliflozin 1 as a colorless
amorphous solid.
A 3 L threeꢀnecked flask was charged with the above solid, acetone (390
mL), and water (390 mL). The mixture was heated to 50 oC and then cooled
to 5 oC over the course of 1.5 h. Water (1.56 L) was slowly added to the
solution over the course of 3 h while keeping the internal temperature below
10 oC. The slurry was stirred for additional 2 h at 5 oC and filtered. The wet
cake was washed with water (260 mL) and dried at 25 oC in vacuo for 30 h
to give tofogliflozin hydrate (105 g, 83% from 14) as a white solid with
o
99.56% purity by HPLC. Water content: 4.47%. Mp: 71−80 C. [α]20
=
D
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+23.9 (c = 1.0, CH3OH). 1H NMR (400 MHz, CD3OD) δ 7.23ꢀ7.18 (m, 3H),
7.12ꢀ7.08(m, 4H), 5.13 (d, J = 12.4 Hz, 1H), 5.07 (d, J = 12.4 Hz, 1H), 3.96
(s, 2H), 3.83ꢀ3.73 (m, 4H), 3.65 (dd, J = 11.9, 5.5 Hz, 1H), 3.41ꢀ3.47 (m,
1H), 2.59 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz,
CD3OD) δ 143.2, 142.6, 140.2, 139.9, 139.7, 131.2, 129.9, 128.9, 123.6,
121.8, 111.6, 76.4, 76.2, 74.9, 73.4, 71.9, 62.8, 42.3, 29.5, 16.3. HRMS (ESI)
m/z: [M+H]+ Calcd for C22H27O6 387.1802; Found 387.1805. IR (KBr, cmꢀ1)
ν: 3362, 2962, 2927, 1637, 1513, 1429, 1095, 1034, 808, 770. Spectroscopic
data were identical with those reported.1b, 2
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ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR spectra of all compounds.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: xiudongyangꢀdisha@hotmail.com
Notes
The authors declare no competing financial interest.
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REFERENCES
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