Two methods for the preparation of sitagliptin phosphate: Via chemical resolution and asymmetric hydrogenation

Article abstract of DOI:10.1039/d0ra10273c

Two effective processes have been developed for the preparation of sitagliptin phosphate. The approach of chemical resolution obtained R-sitagliptin in five steps from commercially available starting materials using the inexpensive NaBH4 to reduce the enamine and then using (-)-di-p-toluoyl-l-tartaric acid to resolve racemates in 11% yield overall. The route successfully avoids the use of expensive noble metal as catalysts compared with traditional synthesis methods, resulting in greatly reduced costs and simplified synthetic routes. Other alternative asymmetric hydrogenation of β-ketomide routes for the synthesis of sitagliptin were found, two of the intermediates were synthesized for the first time. This journal is

Full text of DOI:10.1039/d0ra10273c

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Two methods for the preparation of sitagliptin
phosphate via chemical resolution and asymmetric
hydrogenation†
Cite this: RSC Adv., 2021, 11, 4805
*
Fei Ye,
Zhifeng Zhang, Wenxia Zhao, Jianhai Ding, Yali Wang and Xueyan Dang
Two effective processes have been developed for the preparation of sitagliptin phosphate. The approach of
chemical resolution obtained R-sitagliptin in five steps from commercially available starting materials using
the inexpensive NaBH4 to reduce the enamine and then using (ꢀ)-di-p-toluoyl-L-tartaric acid to resolve
racemates in 11% yield overall. The route successfully avoids the use of expensive noble metal as
catalysts compared with traditional synthesis methods, resulting in greatly reduced costs and simplified
synthetic routes. Other alternative asymmetric hydrogenation of b-ketomide routes for the synthesis of
sitagliptin were found, two of the intermediates were synthesized for the first time.
Received 7th December 2020
Accepted 26th December 2020
DOI: 10.1039/d0ra10273c
rsc.li/rsc-advances
groups in sitagliptin. The key problem with the synthesis of
sitagliptin is how to install optically pure chiral central, b-amino
Introduction
acid. In Merck's rst-generation synthesis process (Scheme 1),18
starting from achiral b-keto ester 2, chirality was introduced in
form of a hydroxyl group in b-hydroxy acid 3 through a ruthe-
nium-catalyzed asymmetric hydrogenation.19–21 The hydroxyl
group of 3 was transformed into protected amino acid 5 through
several steps, followed by direct coupling to the triazolopiper-
azine 6 afforded sitagliptin 1 aer cleavage of the N-benzyloxy
group and salt formation. Despite the overall yield being quite
high at 52%, multiple steps and isolations resulted in large
amounts of waste and poor atom-economy.
Type 2 diabetes1–4 mellitus is a commonly and rapidly growing
disease, with millions of new cases reported annually world-
wide. Diabetes has become a serious threat to human health
and brings enormously high economic costs, not only to indi-
viduals and families, but also to the global health system.5 It is
estimated that approximately 5 million people died from dia-
betes and its complications in 2015, representing one of the
leading causes of death globally.6–8 Dipeptidyl peptidase-4 (DPP-
4) inhibitors, enzymes that act to degrade and inactivate
glucagon-like peptide-1 (GLP-1), are a novel class of anti-
hyperglycemic agents for the treatment of Type 2 diabetes
mellitus. GLP-1 is an incretin hormone that stimulates insulin
secretion and biosynthesis, inhibits glucagon release in
a glucose-dependent manner, and also aids gastric emptying
and reducing appetite.9–11 Sitagliptin,12–15 which was originally
known as MK-0431 under the trade name Januvia, is a chiral
beta-amino acid derivative that contains both a triuorophenyl
moiety and a triuoromethylated triazole,16 and also is the rst
agent developed in the class of DPP-4 inhibitors approved by the
FDA in 2006. Because of its safety, efficiency, and being well-
tolerated in various treatment regimens, it has tremendous
commercial value (more than 11.4 billion dollars annually since
2018)17 and thus has captured the interest of many pharma-
ceutical companies and research groups.
Although researchers from Merck have reported three
generations of processes for the preparation of sitagliptin on
a large scale, it does not diminish the interest of other research
School of Chemistry and Chemical Engineering, Ningxia Normal University, Guyuan,
756000, China. E-mail: yefei0310@outlook.com; yefeiqqq@163.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra10273c
Scheme 1 Merck's three generations synthesis processes.
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In their second-generation process,22 dehydrositagliptin 1123
was rstly synthesized by a three-step one-pot process starting
from triuorophenyl acetic acid 8, which contained within its
structure the entire carbon skeleton of 1. Crystallization and
a simple ltration could give 11 in 82% overall yield with 99 wt%
purity. The researchers then used the rhodium complex of t-Bu
JOSIPHOS to asymmetrically hydrogenate the unprotected
enamine amide 11 to install the chiral amine center into 12 in
98% conversion along with up to 95% ee.23,24 Finally, sitagliptin
1 was recrystallized and isolated as its phosphate monohydrate
salt in 84% yield with an upgrade in enantiomeric excess up to
99% ee.25 Although this 2nd generation process for the sita-
gliptin manufacture has led to a signicant reduction in waste
as compared to the 1st generation process, its endgame leover
room for improvement because of the inherent drawbacks of
utilizing an expensive transition metal mediated hydrogenation
step. This process needs the specialized high-pressure equip-
ment and a process for the complete removal of the precious
Scheme 3 The process for the preparation of sitagliptin phosphate via
asymmetric hydrogenation.
process of directly asymmetric hydrogenation of b-ketomide 10
to 14, a chiral intermediate of sitagliptin (Scheme 3).
Results and discussion
Chemical resolution preparation of sitagliptin 1
metal from the product stream, both of which were signicant Meldrum's adduct
9 was rstly prepared from 2,4,5-tri-
cost drivers.
uorophenyl acetic acid 8 utilizing the ability of Meldrum's acid
To circumvent these drawbacks, Merk and Codexis to act as an acyl anion equivalent at 50 ꢁC for 5 h in 87% yield.
researchers have recently developed a highly efficient bio- This process involves the activation of 2,4,5-triuorophenyl
catalytic process (the 3rd generation process)26 to prepare sita- acetic acid 8, and we chose N,N-carbonyl di-imidazole (CDI)32,33
gliptin 1. In the presence of the R-selective transaminase as active agent instead of pivaloyl chloride34 to simplify the
enzyme, direct amination of prositagliptin ketone to enantio- experiment. 9 was then coupled to the 3-(triuoromethyl)-1,2,4-
meric pure sitagliptin 1 (up to 99% ee) was carried out in triazolo-[4,3-a]piperazine hydrochloride 6 using i-Pr2NEt, to
multipurpose under mild conditions, and thus eliminated all provide b-ketomide 10 in 67% yield. Treatment of 10 with
the drawbacks of the 2nd generation process. Not only does the AcONH4 and ammonia water results in formation of enamine
3rd generation process lead to a reduction of the total waste 11. As the reaction temperature was raised to 58 ꢁC, the desired
produced (19%) as compared to the 2nd generation process, but product 11 began to crystallize from the reaction mixture. Upon
also increase the overall yield (13%) and productivity (53%). to the mild temperature, 11 was isolated as a white crystalline
This biocatalytic route should become an important auxiliary solid through simple ltration in 92% yield with 99 wt% purity.
asymmetric synthesis in a pilot-scale production.
Next the reduction of enamine 11 was performed with NaBH4 at
Besides, recently, several synthesis methods of sitagliptin ꢀ15 ꢁC in 4.5 h, monitored by HPLC until enamine 11 dis-
have been reported on laboratory scale, including biocatalytic appeared. It was found that the reductive reaction of 11 and
asymmetric reductive amination of b-ketomide,26,27 enzymatic NaBH4 could not be performed very well. Therefore, several
resolution of racemates,28 chemical kinetic resolution,16,29 and
stereoselective reduction of an enamine derivative using
Table 1 Reductive reaction of enamine 11 to racemates 13a
NaBH4.30,31 Although some of these synthetic routes are very
efficient, given the enormous industrial interest, an inexpen-
sive, convenient, industrially viable, and greener synthetic route
is still in urgent need.
In this work, we report for the rst time the process of
chemical resolution of racemates 13 to sitagliptin 1 followed by
reduction of enamine 11 using NaBH4 (Scheme 2) and the
Conversion
Entry
Reduction
Additive
(%)
1
2
3
4
5
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
None
0
BF3 diethyl etherate
MsOH (methanesulfonic acid)
Acetic acid
95
93
10
2
TFA (triuoroacetic acid)
a
All reactions were carried out as follows: THF (50 mL) was rstly cooled
to ꢀ10 ꢁC. NaBH4 (2.33 g, 61.68 mmol) and an additive such as MsOH
(5.9 g, 61.68 mmol) were added dropwise at ꢀ10 to ꢀ5 ꢁC, and then
enamine 11 (5.0 g, 12.34 mmol) and isopropanol (30 mL) were added.
The reaction mixture was aged at ꢀ15 ꢁC for 4.5 h, monitored by
HPLC. Isolated yield aer ethyl acetate extraction.
Scheme 2 The process for the preparation of sitagliptin phosphate via
chemical resolution.
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Table 2 Effects of resolution agents on the configuration of (R)-1a
Conclusion
In this study, we established two new efficient routes of the
synthesis of sitagliptin phosphate. The approach of chemical
resolution of racemates 13 to sitagliptin 1 not only successfully
obtained R-sitagliptin with up to 96% ee but also afforded S-
sitagliptin with 90% ee by using chiral resolution agent, (ꢀ)-di-
p-toluoyl-L-tartaric acid. Reduction of enamine 11 and chemical
resolution of racemates 13 as two key steps, makes the synthetic
route simple and practical and greatly reduce the cost.
The approach of asymmetric hydrogenation of b-ketoester 10
to 1 using [Ru(cymene)Cl]2 and (s)-Ts-DPEN as a chiral catalyst
to directly hydrogenate 10 and reacts with MsCl to form the
methanesulfonate 15, a key intermediate, and nally success-
fully obtained R-sitagliptin 1. Although this approach failed to
afford idealized optical purity results, an alternative route of the
synthesis of sitagliptin was found, compound 14 and 15 were
rstly synthesized as new substrates.
Conguration
(ee%)
Entry
Resolution agent
Solvent
1
2
(ꢀ)-L-Tartaric acid
MeOH
MeOH
4%
96%
(ꢀ)-Di-p-toluoyl-L-tartaric acid
a
All reactions were carried out using racemates 13 (0.5 g, 1.23 mmol)
and resolution agents such as (ꢀ)-di-p-toluoyl-L-tartaric acid (0.24 g,
0.62 mmol) in solvent (15 mL) at 65 ꢁC for 1 h. White sitagliptin
tartrate was obtained aer ltration. And tartrate was hydrolyzed by
using ammonia water (10 mL), and extracted twice by ethyl acetate
(30 mL ꢂ 2). The organic layer was concentrated and isopropanol (15
mL) was added. Then 85 wt% H3PO4 was added dropwise and the
reaction mixture was aged at 78 ꢁC for 1 h to afford sitagliptin 1.
Experimental section
General
additional chemicals were screened to improve the conversion
of the reduction reaction.
All of the reagents and solvents were purchased from
commercial sources and used without purication. Melting
points were determined on a Reichert micro-hot-stage appa-
ratus. The IR spectra were recorded on an FSM-2201 spec-
trometer with Fourier transform from samples dispersed in
mineral oil. High resolution mass spectra were recorded in ESI
mode using magnetic sector mass analyzer and TOF mass
spectrometer. 1H and 13C spectra were recorded with a 400 MHz
NMR instrument at 295 K. Chemical shis are reported relative
to the residual signals of tetramethylsilane in CDCl3 or
As indicated in Table 1, these additives play a catalyst role in
reaction mixtures, and signicantly improve the conversion of
the reductive reaction. BF3 diethyl etherate yields the highest
conversion (entry 2). However, because of the extreme toxicity of
BF3 diethyl etherate, we chose MsOH as the additive of the
reductive reaction.
Aer the reductive reaction, the resolution of racemates 13
was carried out by treatment with di-p-toluoyl-L-tartaric acid in
MeOH to form R-sitagliptin 1 in 33% yield with 99 wt% purity
and 96% ee. At the same time, we compared the effects of the
two L-tartaric acids on the resolution, as shown in Table 2.
Lastly, the separated ltrate was treated to obtain S-sitagliptin
phosphate with 90% ee.
1
deuterated solvent CDCl3/DMSO-d6 for H and 13C NMR spec-
troscopy, respectively. Multiplicities are reported as follows:
singlet (s), doublet (d), broad singlet (br s), doublet of doublets
(dd), doublet of triplets (dt), triplet (t), quartet (q), and multiplet
(m). All of the reactions were monitored by HPLC or TLC.
Tetrahydrofuran was distilled over sodium before use.
5-[1-Hydroxy-2-(2,4,5-triuorophenyl)ethylidene]-2,2-
Asymmetric hydrogenation of b-ketoester 10 to sitagliptin 1
via three steps
The difficulty of this route (Scheme 3) lies in the asymmetric dimethyl-1,3-dioxane-4,6-dione 9. 2,4,5-Triuorophenyl acetic
reduction of 10. The carbonyl could be reduced by the solution acid 8 (10.0 g, 52.60 mmol) was dissolved in dry THF (80 mL),
of formic acid and Et3N in the presence of a chiral catalyst at activated by N,N0-carbonyl di-imidazole (CDI) (10.0 g, 57.86
room temperature in the literature.35,36 Although the reaction mmol), and then Meldrum's acid (8.4 g, 57.86 mmol) was added
ꢁ
mixture of 10 and formic acid were heated to 80 ꢁC, the reaction at 50 C and aged for 5 h. The reaction mixture changed from
did not proceed. The b-ketoester 10 was hydrogenated by light yellow to orange, and was monitored by TLC. The reaction
hydrogen under 435 psi at 65 ꢁC for 12 h to afford (S)-3-hydroxy- mixture was cooled to room temperature, and the prepared
1-(3-(triuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-
solution of isopropyl acetate/water in 1/1 was added and stirred
7(8H)-yl)-1-(2,4,5-triuorophenyl)butan-1-one 14. Treatment of for 0.5 h. And the pH of the mixture was adjusted to 2–3 with
14 with MsCl resulted in (S)-4-oxo-4-(3-(triuoromethyl)-5,6- concentrated hydrochloric acid. The aqueous layer was sepa-
dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-
rated, and the organic layer was washed with 0.1 M HCl. The
triuorophenyl)butan-2-yl methanesulfonate 15 in 42% yield organic layer was concentrated, ushed with IPAc, and the
with 98 wt% purity and 7% ee. And then methanesulfonate 15 residue was slurried in 2 : 1 heptane/IPAc. The mixture was
reacted with NH3 in MeOH under 145 psi to form R-sitagliptin 1 cooled in an ice-bath and ltered, and then the solid is rinsed
in 33% yield with 99 wt% purity and 7% ee. Although this with 2 : 1 heptane/IPAc. Aer drying, the Meldrum's acid adduct
approach failed to afford adequate results, an alternative route 9 (14.6 g, 99 wt%) was obtained as a white solid in 87% yield. Mp
of the synthesis of sitagliptin was developed, 14 and 15 were 121–123 ꢁC; ESI-MS (m/z): (317, M+ + H); IR (KBr), v, cmꢀ1: 3448,
rstly synthesized as new substrates.
3001, 1734, 1653, 1581, 1525, 1428, 1338, 1307, 1203, 1153,
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1024, 922, 789. 1H NMR (400 MHz, CDCl3) d 15.49 (s, 1H), 7.15
(m, 1H), 6.95 (m, 1H), 4.45 (s, 2H), 1.76 (s, 6H).
Sitagliptin tartrate was directly dissolved in water (30 mL)
and the pH of the mixture was adjusted to 10–12 with 28 wt%
ammonia water (10 mL), and extracted twice by ethyl acetate
4-Oxo-4-[3-(triuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]
pyrazin-7(8H)-yl]-1-(2,4,5-triuorophenyl)bytan-2-one 10. 5-[1- (30 mL ꢂ 2). The organic layer was concentrated and iso-
Hydroxy-2-(2,4,5-triuorophenyl)ethylidene]-2,2-dimethyl-1,3- propanol (15 mL) was added. Then 85 wt% H3PO4 was added
dioxane-4,6-dione 9 (5.0 g, 15.81 mmol), 3-(triuoromethyl)- dropwise and the reaction mixture was aged at 78 ꢁC for 1 h. The
1,2,4-triazolo-[4,3-a]piperazine hydrochloride 6 (3.6 g, 15.81 slurry wan then cooled to room temperature and aged for an
mmol), and isopropyl acetate (50 mL) were charged into additional 0.5 h before ltration. The wet cake was washed with
a 250 mL three-neck ask. i-Pr2NEt (3 mL) was added dropwise 15 mL cold ethanol and dried at 40 ꢁC in a vacuum oven to
at room temperature, and the reaction mixture was aged at 75– afford sitagliptin 1 (0.21 g, 99 wt%) in 33% yield and 96% ee. Mp
80 ꢁC for 5 h. Aer gradually cooled to 30 ꢁC, water (50 mL) was 218–220 ꢁC; ESI-MS (m/z): (408, M+ + H); IR (KBr), v, cmꢀ1: 3196,
added and the mixture was transferred to a separatory funnel. 3027, 2861, 1649, 1521, 1453, 1167, 1093, 850. 1H NMR (400
The aqueous layer was separated and organic layer was washed MHz, DMSO-d6) d 7.29 (m, 1H), 7.16 (m, 1H), 4.94 (s, 2H), 4.30
three times with water (150 mL). The organic layer was (d, J ¼ 17.6 Hz, 1H), 4.27 (d, J ¼ 17.6 Hz, 1H), 4.00 (m, 2H), 3.12
concentrated under diminished pressure to 10 mL and n- (m, 2H), 2.99–3.08 (m, 1H), 2.92 (dd, J ¼ 17.1 Hz, 1H), 2.87 (m,
heptane (50 mL) was added dropwise. The mixture was stirred 1H); 13C NMR (CDCl3) d 36.2, 38.0, 39.1, 40.0, 40.1, 41.6, 42.4,
for 2 h and ltered, the ketoamide 10 (9.2 g, 90 wt%) was ob- 43.2, 43.6, 48.5, 105.6, 118.2, 1119, 121.7, 143.7, 146.6, 148.8,
tained in 67% yield. ESI-MS (m/z): (407, M+ + H). IR (KBr), 149.7, 150.4, 156.1, 170.2, 170.58.
v, cmꢀ1: 3060, 2925, 1725, 1653, 1519, 1435, 1330, 1270, 1207,
(S)-3-Hydroxy-1-(3-(triuoromethyl)-5,6-dihydro[1,2,4]tri-
1154, 1061, 1014, 935, 882, 852, 771, 680. 1H NMR (400 azolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-triuorophenyl)butan-1-
MHz,CDCl3) d 7.13–6.99 (m, 1H), 6.95–6.91 (m, 1H), 5.21–4.90 one 14. [Ru(cymene)Cl]2 (0.4 g, 0.58 mmol) and (s)-Ts-DPEN
(m, 2H), 4.24–4.11 (m, 4H), 3.94–3.83 (m, 4H).
(Z)-3-Amino-1-(3-triuoromethyl-5,6-dihydro-8H-[1,2,4]tri-
azo-lo[4,3-a]pyrazin-7-yl)-4-(2,4,5-triuoro-phenyl)-but-2-en-1-
(0.6 g, 1.64 mmol) was charged into 500 mL ask under
a nitrogen atmosphere. Degassed methanol was added and the
mixture was stirred at room temperature for 1 h. The ketoamide
one 11. Ketoamide 10 (10.0 g, 24.63 mmol) was dissolved in 10 (10.0 g, 24.63 mmol) along with MeOH (100 mL) was charged
MeOH (100 mL), and NH4OAc (9.5 g, 123.13 mmol) and ammonia into the mixture. The ketoamide 10 was hydrogenated under
water (10 mL) was added. The reaction mixture was heated to 435 psi at 65 ꢁC for 12 h aer the slurry was degassed three
58 ꢁC and stirred for 30 min, and white solids began to precipi- times, and monitored by HPLC. When the reaction nished, the
tate. Aer an additional 2 h age, the mixture was cooled to room reaction mixture was concentrated and Brown oily (S)-3-
temperature and ltered. The wet cake was washed with meth- hydroxy-1-(3-(triuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]
anol (100 mL) and dried at ambient temperature in a vacuum pyrazin-7(8H)-yl)-1-(2,4,5-triuorophenyl)butan-1-one 14 (9.9 g)
oven to afford white crystalline 11 (9.2 g, 99 wt%) in 92% yieꢀld1. was obtained in 98% assay yield. ESI-MS (m/z): (409, M+).
+
ꢁ
Mp 196–198 C; ESI-MS (m/z): (406, M + H); IR (KBr), v, cm
:
(S)-4-Oxo-4-(3-(triuoromethyl)-5,6-dihydro-[1,2,4]triazolo
[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-triuorophenyl)butan-2-yl
methanesulfonate 15. The above (S)-3-hydroxy-1-(3-(tri-
uoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-
1-(2,4,5-triuorophenyl)butan-1-one 14 crude solution (10.0 g,
24.63 mmol) and ethyl acetate (100 mL) were charged into
3408, 3043, 2044, 1626, 1516, 1425, 1179, 1013, 886, 750.
Racemates 13
THF (50 mL) was charged into a 250 mL three-neck ask and
cooled to ꢀ10 ꢁC. NaBH4 (2.33 g, 61.68 mmol) and MsOH (5.9 g,
ꢁ
250 mL three-neck ask and cooled to ꢀ10 C. The trimethyl-
ꢁ
61.68 mmol) were added dropwise at ꢀ10 to ꢀ5 C, and then
amine (6 mL 50 mmol) was added and MsCl (18 mL 50 mmol)
was added dropwise at ꢀ10 to ꢀ5 ꢁC. The reaction mixture was
aged at ꢀ10 ꢁC for 2 h, and monitored by HPLC. When the
reaction was nished, the mixture was ltered and the ltrate
was concentrated to dryness to give a residue which was chro-
matographed on silica gel with the solution of ethyl acetate-
petroleum ether (1 : 1) (150 mL). The eluant was cooled to
enamine 11 (5.0 g, 12.34 mmol) and isopropanol (30 mL) were
added. The reaction mixture was aged at ꢀ15 ꢁC for 4.5 h,
monitored by HPLC. When the reaction was nished, water was
added and ethyl acetate (60 mL ꢂ 2) was extracted twice. The
organic layer was dried by MgSO4 and concentrated under
diminished pressure. Oil racemates 13 (3.0 g, 78 wt%) was ob-
tained in 60% yield.
ꢁ
ꢀ10 C and stirred for 2 h, and white solids precipitated. Aer
an additional 2 h age, the mixture was ltered. The wet cake was
Sitagliptin 1
washed with ethyl acetate (50 mL) and dried at ambient
Racemates 13 (0.5 g, 1.23 mmol) was dissolved in methanol (15 temperature in a vacuum oven to obtain white crystalline 15
mL) and solution of (ꢀ)-di-p-toluoyl-L-tartaric acid (0.24 g, 0.62 (5.1 g, 98 wt%) in 42% yield and 7% ee. Mp 157–159 ꢁC; ESI-MS
mmol) in isopropanol (15 mL) was added. Then the mixture was (m/z): (487, M+); IR (KBr), v, cmꢀ1: 3044, 2934, 1658, 1511, 1443,
heated to 65 C and stirred for 1 h, and white solids began to 1338, 1172, 1015, 528. 1H NMR (400 MHz, DMSO-d6) d 7.54–7.44
ꢁ
precipitate. The reaction mixture was cooled to ambient (m, 2H), 5.19 (m, 1H), 4.98 (t, 1H), 4.92–4.84 (m, 1H), 4.24 (m,
temperature and aged for an additional 2 h before ltration. 1H), 4.12–4.08 (m, 1H), 3.96–3.94 (m, 2H), 3.09–3.04 (m, 3H),
The cake was recrystallized by methanol solution in water 3.02 (s, 3H), 2.94–2.83 (m, 1H).
(1 : 1). Sitagliptin tartrate was obtained in 96% ee.
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Engl., 1981, 20, 798–799.
(S)-4-Oxo-4-(3-(triuoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]
pyrazin-7(8H)-yl)-1-(2,4,5-triuorophenyl)butan-2-yl methanesul-
fonate 15 (3.0 g, 6.17 mmol) and the prepared solution of NH3 in
MeOH (13 wt% 60 mL) were charged into the ask. The reaction
ꢁ
mixture was heated to 65 C and stirred for 8 h under 145 psi.
MTBE (methyl tert-butyl ether) (50 mL) and 0.5 M H3PO4 (50 mL)
were added aer concentrated. The pH of the mixture was
adjusted to 8–9 with the solution of NaOH. The aqueous layer was
separated, and the organic layer was concentrated and iso-
propanol (40 mL) and water (40 mL) were added. Then 0.5 M
H3PO4 (1 mL) was added dropwise and the mixture was heated to
70 ꢁC and stirred for 2 h. The slurry was ltered aer cooled to the
room temperature. The wet cake was washed with 15 mL iso-
propanol and dried at 40 ꢁC in a vacuum oven to obtain sita-
gliptin 1 (1.2 g, 99 wt%) in 33% yield and 7% ee. ESI-MS (m/z):
1
(408, M+ + H); H NMR (400 MHz, CDCl3) d 7.00–7.25 (m, 5H),
4.61–4.91 (m, 2H), 4.31–4.36 (m, 1H), 3.84–3.99 (s, 2H), 2.78–3.82
(m, 2H), 2.66–2.72 (m, 1H), 2.59–2.64 (m, 1H), 2.51 (s, 2H); 13C
NMR (D2O) d: 30.9, 33.7, 38.0, 41.8, 43.1, 48.2, 105.8, 115.4, 118.5,
120.9, 145.5, 148.7, 157.2, 170.2.
Conflicts of interest
21 D. Kim, L. Wang, M. Beconi, G. J. Eiermann and
M. H. Fisher, J. Med. Chem., 2005, 48, 141–151.
22 K. B. Hansen, H. Yi, F. Xu, N. Rivera, A. Clausen and
M. Kubryk, J. Am. Chem. Soc., 2009, 131, 8798–8804.
23 F. Xu, J. D. Armstrong, G. X. Zhou and B. Simmons, J. Am.
Chem. Soc., 2004, 126, 13002–13009.
The authors declare that there are no conicts of interest
regarding the publication of this article.
Acknowledgements
24 Y. Hsiao, N. R. Rivera, T. Rosner and S. W. Krska, J. Am.
Chem. Soc., 2004, 126, 9918–9919.
25 A. M. Clausen, B. Dziadul, K. L. Cappuccio and M. Kaba, Org.
Process Res. Dev., 2006, 10, 723–726.
26 C. K. Savile, J. M. Janey, E. C. Mundorff, J. C. Moore, S. Tam,
W. R. Jarvis, J. C. Colbeck, A. Krebber, F. J. Fleitz and
J. Brands, Science, 2010, 329, 305–309.
27 Y. Wei, S. Xia and C. He, Biotechnol. Lett., 2016, 38, 841–846.
28 L. L. Zeng, Y. J. Ding, G. C. Zhang, H. R. Song and W. H. Hu,
Chin. Chem. Lett., 2009, 20, 1397.
This work was partially supported by the Natural Science
Foundation for Ningxia Province (Grants no. 2018AAC03235),
Liupanshan Resources Engineering Technology Central (Grants
no. HGZD19-10), the Research Award Fund for First-class
Discipline Construction (Education Discipline) in Higher
Education
Institutions
of
Ningxia
(Grants
no.
NXYLXK2017B11), Development of Science and Technology of
Ningxia (Grants no. 2019BEB04019).
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© 2021 The Author(s). Published by the Royal Society of Chemistry
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