Synthesis of sitagliptin phosphate by a NaBH4/ZnCl2-catalyzed diastereoselective reduction

Article abstract of DOI:10.1246/cl.150390

A practical asymmetric synthesis of sitagliptin phosphate, from 1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo-[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl) butane-1,3-dione, in overall 65.3% yield has been reported. The target compound was synth

Full text of DOI:10.1246/cl.150390

CL-150390
Received: April 24, 2015 | Accepted: May 20, 2015 | Web Released: May 30, 2015
Synthesis of Sitagliptin Phosphate by a NaBH4/ZnCl2-catalyzed Diastereoselective Reduction
Xianhua Pan,# Kun Wang,# Wansheng Yu, Ruimin Zhang, Lu Xu, and Feng Liu*
School of Perfume and Aroma Technology, Shanghai Institute of Technology, 100 Haiquan Rd, Shanghai, 201418, P. R. China
(E-mail: liufeng@sit.edu.cn)
F
F
F
F
Ph
CONH2
NH
A practical asymmetric synthesis of sitagliptin phosphate,
from 1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo-[4,3-
a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)butane-1,3-dione,
in overall 65.3% yield has been reported. The target compound
was synthesized via eneamination, diastereoselective reduction,
amine-deprotection, and phosphatization. The key diastereose-
lective reduction was performed with NaBH4 and ZnCl2, and it
gave the product with almost quantitative yield and 68.5% d.e.
value after simple work-up and recrystallization with IPA/PE;
a high enantiopurity (d.e.% = 99.3%) can also be obtained in
57.1% yield.
Ph
CONH2
NH2
NaBH4/ZnCl2
THF, quantitative
F
F
O
O
O
AcOH
N
N
d.e. = 68.5 % and
can be purified to
>99% after
N
N
N
N
i-PrOH, 91.3 %
N
N
CF3
simple recryst.
3
CF3
2
F
F
F
Ph
CONH2
NH
H3PO4
NH2
1) 5% Pd(OH)2/C
F
F
O
O
HCOOH, H2O,MeOH/THF
N
N
N
N
2) H3PO4, i-PrOH/H2O
N
N
F
N
N
89.3 % for 2 steps
CF3
CF3
sitagliptin phosphate
4
1
Scheme 1. Synthesis of sitagliptin phosphate.
Diabetes, a fast growing global epidemic that affects
millions of people, is caused by multiple reasons and can be
characterized by divided levels of plasma glucose in the rapid
or post glucose-challenge state. Two types of diabetes can be
generally recognized: Type 1 diabetes mellitus (T1DM), wherein
patients generate none or trace insulin, which cut down glucose,
and Type 2 diabetes mellitus (T2DM), in which patients can
generate insulin normally, but this insulin has a poor effect in
regulating glucose utilization. In a recent study, inhibitors of
dipeptidyl peptidase IV (DPP-IV) could generate fresh ther-
apeutic agents for T2DM by stimulating GLP-1 (glucagon-like
peptide-1) and GIP (glucose-dependent insulinotropic peptide)
levels, as well as boosting glycemic control for diabetics.
Sitagliptin phosphate 1 (Figure 1), the representative drug
for the treatment of T2DM, was approved by USFDA in 2006,
which received almost 4 billion saleroom in 2013, being worthy
of the name “heavy bomb drug.” Due to the unique structure and
good market performance, a large number of synthetic routes of
sitagliptin phosphate have been developed in the past decade.
Kim et al.1 reported an ingenious way to obtain the target
compound at 2005, but this needs quite strict reaction conditions
such as a low temperature (¹78 °C) and a dangerous reagent
(CH2N2). A method to obtain the key intermediate (β-amino acid
derivative) of sitagliptin phosphate has been developed by Xiao
et al.2 at 2004, which was carried out by metal-catalyzed
asymmetric hydrogenation; however, even if the chiral amido-
gen were created inventively, the cost of using the expensive
([Rh(cod)2]OTf) limited this process to the laboratory and small
scale, so did (S-BINAP),3 RuCl2,3 [(R)-(R)-t-Bu JOSIPHOS],4
(R-DM-SEGPHOS),5 and PtO2.6,7 Therefore, applying a cheap,
safe, and large-scale method to obtain sitagliptin phosphate or its
intermediates has become the scientists’ unremitting goal.
In 2013, a novel method that achieved the intermediate of
sitagliptin phosphate in a certain chiral purity (d.e.% = 50%)
by using a cheap reductant (NaBH4 and aliphatic acid) was
developed by Lin and colleagues,8 which revealed that a cheap
and simple reductive system can also catalyze the substrate
controlled diastereoselective reduction to a certain extent.
As a part of our interests in developing practical and simple
approaches for the synthesis of sitagliptin phosphate and other
active pharmaceutical ingredients (API) as well as the inter-
mediates,9 we report here an efficient approach to the synthesis
of sitagliptin phosphate 1 (Scheme 1) by a NaBH4/Lewis acid-
catalyzed diastereoselective reduction reaction10 and the follow-
ing work-up.11-14
The synthesis began from compound 2,2 after treating it
with (S)-phenylglycine amide in the presence of AcOH in IPA,
compound 3 was obtained in good yield (91%) and high HPLC
purity (99%).
Then, with the key intermediate, enamine compound 3 in
hand, the Lewis acid-catalyzed diastereoselective reduction was
examined carefully. As indicated in Table 1, it could be easily
found that NaBH4-ZnCl2 has better catalytic ability among the
four different NaBH4-Lewis acids (Entries 1-4) at 0 °C in THF,
resulting in 59.4% yield and 51.7% diastereomeric excess.
Then, the reaction mixture was frozen to ¹60 °C to enhance the
chiral selectivity, and a better yield and enantioselectivity were
obtained (Entry 5). We were happy to find that on decreasing
the loading of ZnCl2 to 0.7 equiv (Entry 6), the diastereomeric
pair of 4 could be quantitatively obtained with a satisfactory
diastereoselectivity (d.e.% = 68.5%). However, unfortunately,
further decreasing ZnCl2 to 0.35 equiv gave us a worse result,
and both the yield and d.e. value were reduced (Entry 7). We
then tried to adjust the reaction temperature to a moderate level
in order to reduce the energy consumption, but with the increase
in the temperature, the reaction yield decreased, and the
stereoselectivity was less than satisfactory (Entries 8-10).
CF3
N
N
N
F
F
N
(R)
O
NH2
F
H3PO4
Sitagliptin phosphate
1
Figure 1. Structure of sitagliptin phosphate.
1170 | Chem. Lett. 2015, 44, 1170–1172 | doi:10.1246/cl.150390
© 2015 The Chemical Society of Japan

Table 1. Influence of the sort of Lewis acid, equivalent and
temperature on reactiona
The subsequent synthesis could be carried out by treating 4
with Pd(OH)2/C and HCOOH aq. in MeOH/THF for 16 h; after
a typical work-up, the crude free base was recrystallized from
toluene, and sitagliptin was isolated with 95% yield, and then
adding 85% H3PO4 in IPA/H2O, a phosphoric acid salt 1 was
obtained with 94% yield, 99.2% HPLC purity (single impurity
less than 0.1%) and 99.4% e.e. value after recrystallization from
i-PrOH.
In summary, we have devised a novel asymmetric synthesis
of sitagliptin phosphate via a diastereoselective reduction
reaction, which was performed by NaBH4 and ZnCl2, giving
us the satisfying result with an almost quantitative yield and
68.5% d.e. value. This simple and economical process provides
a novel synthesis of sitagliptin phosphate 1.
F
Ph
CONH2
F
Ph
CONH2
F
F
NH
O
NH
O
N
N
N
N
N
N
F
N
F
N
CF3
4
3
CF3
Temp.
/°C
Yieldb
/%
d.e.
/%
Entry Lewis acid
equiv
1
2
3
4
5
6
7
8
9
CoCl2
MnCl2
CaCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
1.5
1.5
1.5
1.5
1.5
0.7
0.35
0.7
0.7
0.7
0
0
0
38.6
30.0
c
c
®
®
®
®
c
c
0
59.4
74.1
100
60.4
81.6
90.2
60.4
51.7
54.9
68.5d
46.8
59.6
58.3
57.5
¹60
¹60
¹60
¹35
¹15
0
This work was supported by the National Natural Science
Foundation of China (Grants No. 21302126) and Shanghai
Engineering Technology Research Center of Fragrance and
Flavor (No. 12DZ2251400).
10
aAll reactions were run under the following conditions unless
otherwise noted: 3 (0.93 mmol) in 15 mL THF, NaBH4
(1.86 mmol.), 4 h. bYields calculated by HPLC. cTrace product.
dAfter work up and recrystallization, a white powder was
gained with the yield of 57.1%, and d.e.% = 99.3%.
Supporting Information is available electronically on J-STAGE.
References and Notes
#
These two authors (Xianhua Pan and Kun Wang) contributed
equally to this work and should be considered as co-first
authors.
F
Ph
CONH2
NH
1
D. Kim, L. Wang, M. Beconi, G. J. Eiermann, M. H. Fisher,
H. He, G. J. Hickey, J. E. Kowalchick, B. Leiting, K. Lyons,
F. Marsilio, M. E. McCann, R. A. Patel, A. Petrov, G.
Scapin, S. B. Patel, R. S. Roy, J. K. Wu, M. J. Wyvratt, B. B.
Zhang, L. Zhu, N. A. Thornberry, A. E. Weber, J. Med.
Chem. 2005, 48, 141.
Y. Xiao, J. D. Armstrong, III, S. W. Krska, E. Njolito, N. R.
Rivera, Y. Sun, T. Rosner, PCT Int. Appl. WO 2004085378,
2004.
K. B. Hansen, J. Balsells, S. Dreher, Y. Hsiao, M. Kubryk,
M. Palucki, N. Rivera, D. Steinhuebel, J. D. Armstrong, III,
D. Askin, E. J. J. Grabowski, Org. Process Res. Dev. 2005,
9, 634.
F
Ph
CONH2
F
F
O
NH
O
NaBH4/ZnCl2
N
N
N
N
N
N
F
N
F
N
CF3
3
4
CF3
H2
N
H2
N
2
3
Ph
O
H
Ph
H
O
F
F
F
F
H
Zn
H
O
Zn
H
F
H
O
N
F
B
N
B
H
H
N
N
N
N
N
N
N
N
CF3
CF3
3-1
3-2
Scheme 2. Proposed mechanism of the reduction.
4
K. B. Hansen, Y. Hsiao, F. Xu, N. Rivera, A. Clausen, M.
Kubryk, S. Krska, T. Rosner, B. Simmons, J. Balsells, N.
Ikemoto, Y. Sun, F. Spindler, C. Malan, E. J. J. Grabowski,
J. D. Armstrong, III, J. Am. Chem. Soc. 2009, 131, 8798.
D. Steinhuebel, Y. Sun, K. Matsumura, N. Sayo, T. Saito,
J. Am. Chem. Soc. 2009, 131, 11316.
S. D. Dreher, N. Ikemoto, E. Njolito, N. R. Rivera, D. M.
Tellers, Y. Xiao, WO 2004085661.
P. P. Reddy, I. Babu, P. Srinivas, P. Shailaja, N. Kavitha,
R. V. Anand, V. R. Reddy, WO 2009085990.
This result may partly be caused by the balance between the
temperature and the concentration of Zn2+. At the beginning of
the reduction process, conjugated imine-enol intermediate state
3-1 has formed in the coordination of NaBH4 and ZnCl2; then,
imine was stereoselectively reduced to amine 3-2 as the C-N
double bond was linked with the zinc ion at little space steric
hindrance (α-face), and then compound 4 was obtained by the
reduction of intermediate state 3-2 by treatment with NaBH4
(Scheme 2). During the reduction course, the chiral purity would
be reduced while the process temperature is too high or the zinc
ion concentration is too high, which would both affect the
selective annexation of the zinc ions and imine; meanwhile,
when the concentration of zinc ion was too low, a portion of
enamine would be reduced by NaBH4 directly instead of
stereoselective reducing.
5
6
7
8
H. Jona, J. Shibata, M. Asai, Y. Goto, S. Arai, S. Nakajima,
O. Okamoto, H. Kawamoto, Y. Iwasawa, Tetrahedron:
Asymmetry 2009, 20, 2439.
9
a) F. Liu, W. Yu, W. Ou, X. Wang, L. Ruan, Y. Li, X. Peng,
X. Tao, X. Pan, J. Chem. Res. 2010, 34, 230. b) F. Liu, W.
Yu, W. Ou, X. Xu, L. Ruan, X. Wang, Y. Li, X. Peng, X.
Tao, J. Mao, J. Wan, X. Pan, J. Chem. Res. 2010, 34, 517.
c) X. Pan, W. Yu, W. Ou, X. Tao, J. Wan, F. Liu, J. Chem.
Res. 2011, 35, 545. d) X. Pan, X. Tao, L. Ruan, Y. Li, W. Ou,
F. Liu, J. Chem. Res. 2011, 35, 729. e) X. Pan, R. Huang, J.
Zhang, L. Ding, W. Li, Q. Zhang, F. Liu, Tetrahedron Lett.
According to the optimized reaction condition in Table 1,
compound 4 could be obtained in an excellent yield and a
moderate purity (d.e.% = 68.5%); then, after a simple work-
up and recrystallization with IPA/PE, a high enantiopurity
(d.e.% = 99.3%) can also be obtained in 57.1% yield.
Chem. Lett. 2015, 44, 1170–1172 | doi:10.1246/cl.150390
© 2015 The Chemical Society of Japan | 1171

2012, 53, 5364. f) X. Pan, X. Li, Q. Lu, W. Yu, W. Li, Q.
Zhang, F. Deng, F. Liu, Tetrahedron Lett. 2013, 54, 6807.
10 a) J. Seyden-Penne, in Reductions by the Alumino- and
Borohydrides in Organic Synthesis, 2nd ed., ed. by D. P.
Curran, Wiley, New York, 1997. b) S. Narasimhan, S.
Madhavan, K. G. Prasad, J. Org. Chem. 1995, 60, 5314.
11 Compound 2 (10.0 g, 24.6 mmol) and (S)-phenylglycine
amide (4.1 g, 27.1 mmol) were added into i-PrOH (50 mL)
successively, then AcOH (0.8 g, 13.3 mmol) was added
dropwise into the mixture after warmed to 45 °C. After the
addition, the mixture was stirred for another 10 h until the
starting material was disappear (determined by TLC). The
slurry was filtered and washed with cooled i-PrOH (10 mL)
carefully after cooled down the mixture to room temperature.
12.0 g of compound 3 (91.3% yield, 99.0% purity) was
obtained via drying for 12 h under N2.
(0.49 g, almost 100% yield, d.e.% = 68.5%). 0.29 g of
compound 4 (57.1% yield, d.e.% = 99.3%) was obtained
after recrystallized from 1:2 i-PrOH/hexane (5 mL).
13 Compound 4 (5.0 g, 18.6 mmol) and 20% Pd(OH)2/C
(0.25 g, 5 wt %) were slurried in 1:1 MeOH/THF (15 mL),
then a solution of 98% HCOOH (5.0 mL) in 5.0 mL of H2O
was added dropwise to the mixture. After the addition, the
mixture was warmed to 55 °C and stirred for 16 h until the
starting material was disappear (determined by TLC). The
reaction was cooled to room temperature and filtrated to
remove Pd(OH)2/C. After evaporating in vacuo, saturated
Na2CO3 (50 mL) was added and extracted with DCM
(2 © 50 mL). The organic layer was combined and washed
with water and brine, then dried over anhydrous Na2SO4.
The Na2SO4 was removed by filtration and the volatile
removed under reduced pressure to give a pale yellow solid.
9.5 g of sitagliptin (17.6 mmol, 95.2% yield) was obtained
after recrystallized from toluene (40 mL).
14 All sitagliptin obtained above was slurried in 2:1 i-PrOH/
H2O (30 mL), 85% H3PO4 (2.0 g, 17.6 mmol) was then
added dropwise at room temperature. After the addition, the
mixture was warmed to 70 °C to dissolve the solids. The
reaction was aged for 1 h, then cooled down slowly to 0 °C
in about 12 h, a white solid was gained by filtration. Finally
10.5 g of sitagliptin phosphate 1 was obtained with 94%
yield, 99.2% HPLC purity (single impurity less than 0.1%)
and 99.4% e.e after recrystallization from i-PrOH.
12 Compound
3 (0.5 g, 0.93 mmol) and ZnCl2 (0.09 g,
0.65 mmol) were added into anhydrous THF (15 mL), then
NaBH4 (0.07 g, 1.86 mmol) was added into the mixture in
several portions after cooled down to ¹60 °C. After the
addition, the mixture was stirred for another 4 h until the
starting material was disappear (determined by TLC). The
reaction was then diluted with H2O (15 mL) and extracted
with EtOAc (3 © 10 mL). The organic layer was washed
with water, sat. NaHCO3, brine and dried over anhydrous
Na2SO4. The Na2SO4 was removed by filtration and the
volatile removed under reduced pressure to give solid
1172 | Chem. Lett. 2015, 44, 1170–1172 | doi:10.1246/cl.150390
© 2015 The Chemical Society of Japan