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Accepted Article
Title: Highly enantioselective synthesis of sitagliptin#

Authors: Kishor V. Khopade, Anirban Sen, Rajkumar S. Birajdar,

Uday P. Paulbudhe, Dattatry S. Kavale, Prashant S. Shinde,
Santosh B. Mhaske, and Samir Hujur Chikkali

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To be cited as: Asian J. Org. Chem 10.1002/ajoc.201900709

Link to VoR: http://dx.doi.org/10.1002/ajoc.201900709

A Journal of A sister journal of Chemistry – An Asian Journal

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Asian Journal Of Organic Chemistry 10.1002/ajoc.201900709

COMMUNICATION
Highly enantioselective synthesis of sitagliptin#
Kishor V. Khopade,[a] Anirban Sen,[a][c] Rajkumar S. Birajdar,[a][c] Uday P. Paulbudhe,[a] Dattatry S.
Kavale,[b] Prashant S. Shinde,[b] Santosh B. Mhaske [b] and Samir H. Chikkali *[a][c]
[a] K. V. Khopade, A. Sen, R. S. Birajdar, U. P. Paulbudhe, Dr. S. H. Chikkali.
Polymer Science and Engineering Division,
CSIR-National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune-411008, India.
E-mail: s.chikkali@ncl.res.in
[b] D. S. Kavale, P. S. Shinde, Dr. S. B. Mhaske.
Organic Chemistry Division,

Accepted Manuscript
CSIR-National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune-411008, India.
[c] A. Sen, R. S. Birajdar, Dr. S. H. Chikkali.
Academy of Scientific and Innovative Research (AcSIR),
Anusandhan Bhavan, 2 Rafi Marg, New Delhi-110001, India.

Abstract: Highly enantioselective synthesis of sitagliptin, a potent Scheme 1. Asymmetric synthesis of sitagliptin.
DPP-4 inhibitor, has been reported. Explicitly identified chiral
FerroLANE ligands in presence of rhodium, catalyze asymmetric
hydrogenation of enamine to yield sitagliptin with an excellent
enantioselectivity of 98%. The process has been scaled to 5 g scale
and the final product is isolated as a phosphate salt with >99% ee.

Last two decades have witnessed increasing cases of type 2

diabetes mellitus (T2DM), which has been categorised as an
epidemic.[1] T2DM is a long-term metabolic disorder characterized
by high blood sugar, insulin resistance and relative lack of
insulin.[2] Sitagliptin has been approved as a potent DPP-4
(dipeptidyl peptidase IV) inhibitor for the treatment of T2DM and
is an active ingredient in commercial drugs such as JANUVIA and
JANUMET.[3] These have been listed in the top 200 drugs list in
2018 and are being produced by Merck.[4] In 2005, Hansen and
co-workers reported one of the most effective methods to prepare
sitagliptin on multi-kilogram scale.[5] However, the overall
approach was multistep and led to 52% yield. [5] In 2009, the same
authors reported a new route with reduced number of synthetic
steps. In this advanced route, asymmetric hydrogenation of
enamine (1) using rhodium complex of tBu-JOSIPHOS afforded
sitagliptin in 98% conversion along with 95% enantiomeric excess
(ee) (scheme 1, A).[6]
In an almost parallel development, Steinhuebel et. al reported
direct asymmetric reductive amination of unprotected β-keto
amide to sitagliptin with an excellent enantiomeric excess of
>99%.[7] This was achieved using ruthenium and (R)-dm-
SEGPHOS as ligand (scheme 1, B). Apart from above
asymmetric reduction routes, sitagliptin is prepared using,
traditional chiral auxiliary based organic synthesis, [8] chiral
ammonia equivalents,[9,10] allylic amination,[11] enolate
alkylation,[12] enzymatic synthesis[13] and organocatalytic
synthesis.[14] Even a continues manufacturing process using
microreactors has been recently developed for the synthesis of
sitagliptin.[15] Among the available methods for sitagliptin
synthesis, asymmetric reduction reported by Merck, spread over
three generations, has been the most atom economic and
successful method.[5,6,16] The increasing number of T2DM patients
worldwide, demands selective and efficient synthesis of sitagliptin
and the quest to introduce novel routes has begun. [17]
Herein, we report highly enantioselective process for the
synthesis of sitagliptin using a family of specifically identified
FerroLANE ligands.
Industrially practised 1st and 2nd generation Merck processes
employ chiral di-phosphine ligands. Therefore, we anticipated that
electron rich di-phosphine ligands would be potential candidates
for the asymmetric synthesis of sitagliptin. Enamine 1 was
prepared from the ketoamide intermediate using a modified
procedure on 50 g scale.[18] A set of 10 electron rich di-phosphine
ligands L1-L10 was screened in a preliminary investigation (chart
1). Chart 1 summaries the most important results for enamine
hydrogenation to sitagliptin. A typical asymmetric hydrogenation
experiment was carried out in a high pressure autoclave with 4 ml
glass vials at 90 °C and 20 bar hydrogen pressure for 18 hours. [18]
To our delight, ligand L3 {1,1′-Bis[(2S,5S)-2,5-
dimethylphospholano]ferrocene} (Me-FerroLANE) in presence of
rhodium precursor revealed a significant enantiomeric excess
(ee) of 88% along with 89% conversion. While, all other ligands
failed to show considerable conversion (only 1-3% conversion
was observed, see chart 1) to sitagliptin.

1
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Asian Journal Of Organic Chemistry 10.1002/ajoc.201900709

COMMUNICATION
Chart 1. Ligands tested in asymmetric hydrogenation of enamine (1) to
sitagliptin (2). [Conditions: Enamine: 86.3 mg (0.21 mmol); [Rh]: 1 mg (1 mol%);
Rh:L = 1:1; Solvent: Methanol (2 mL); H2 pressure: 20 bar; Time: 18 hr; Temp:
90 °C; NO = No conversion; Conversion and enantiomeric excess was
determined by HPLC].
results under identical conditions. As evident, the ethyl substituted
ligand L11 displayed similar enantiomeric excess as L3, while,
the isopropyl analogue L12 revealed a higher enantiomeric
excess of 91%. Given the astonishing performance of L12 (91%
ee), it was chosen for further optimization and effect of various
parameters was investigated.

Table 1. Asymmetric hydrogenation of enamine (1) to sitagliptin (2) using

rhodium complexes of FerroLANE ligands.a

Accepted Manuscript
Run L (L/Rh) T (°C) Time (h) Conv.% Ee%

1b L3 (1:1) 70 17 92 82

2b L11(1:1) 70 17 95 83

3b L12(1:1) 70 17 30 91

4c L12(1:1) 70 17 70 90

5 L12(1:1) 70 17 95 92

6 L12(1:1) 70 17 95 92

7 L12(2:1) 70 17 95 92

8 L12(3:1) 70 17 95 92

9 L12(2:1) 70 17 95 92

10 L12(2:1) 60 17 95 94

11 L12(2:1) 50 17 90 95

12 L12(2:1) 45 17 85 98
Excited by the performance of L3, this ligand was chosen for
further screening and various reaction parameters were optimized. 13 L12(2:1) 40 17 60 95
Protic and aprotic solvents were screened and among 11 different
14 L12(2:1) RT 17 10 96
solvents, methanol was found to outperform others (see SI Table
S2, runs 1-11). Solvent combinations were also evaluated, which a
Conditions: Substrate (1): 86.3 mg (0.21 mmol, 1 equv.); [Rh]: 1 mg (1 mol%);
revealed better conversion but displayed reduced [Rh]:L = 1; Salicylic acid: 2 equivalents; Solvent: Methanol (2 mL); H2 pressure:
enantioselectivity (see SI Table S3, runs 1-5). After identifying 30 bar. RT = ~30 °C. bAdditive: NH4Cl (0.1 equivalent). cAdditive: salicylic acid
suitable solvent, effect of temperature on conversion and ee was (0.1 equivalent).
investigated. It was found that with increasing temperature, the
Among a set of 11 additives (see SI Table S8, runs 1-11), salicylic
conversion increased. There was no conversion at room
acid revealed 90% ee along with sizeable conversion of 70%
temperature (~30°C), while 89% conversion was observed at
(Table 1, run 3 vs 4). While increasing the equivalents of salicylic
90 °C (see SI Table S4, runs 1-6). Hydrogen pressure
acid to 2, increased the conversion to 95%, along with 92% ee
optimization revealed 30 bar as the optimum pressure (see SI
(Table 1, run 5). In the hope of increasing ee, ligand to metal ratio
Table S5, runs 1-3). Literature report indicate that additives play
was screened (run 6-8). However, it appears that, ligand to metal
an important role in the asymmetric synthesis of sitagliptin. [6]
ratio does not really affect selectivity (ee) and conversion. Next,
Therefore, effect of various additives on ee and conversion was
the effect temperature on enantiomeric excess and conversion
studied. Enantiomeric excess of up to 86% could be observed in
was investigated and runs 9-14 (Table 1) report the results. As
presence of additives such as ammonium chloride, while other
the temperature of the reaction was decreased from 70 °C to room
additives displayed ee in the range of 80-85% (see SI Table S6,
temperature (~30 °C), the enantiomeric excess increased from 92
runs 1-8). Thus, after screening various reaction parameters, we
to 98%, however, at the cost of slightly reduced conversion. Thus,
concluded that L3 can yield, at the best, 86% ee.
the optimal reaction conditions after screening various
In our efforts to improve the enantioselectivity further, we
parameters are, 1 mol% catalyst, 30 bar pressure, 45-50 °C
screened bulkier analogues of L3, i.e. ethyl and isopropyl
temperature and a time span of 17 hours. Sitagliptin (1) was
substituted FerroLANE ligands L11 ({1,1′-Bis[(2S,5S)-2,5-
isolated as free base (Fig. S24) and was converted to stable
diethylphospholano]ferrocene) and L12 ({1,1′-Bis[(2S,5S)-2,5-
diisopropylphospholano]ferrocene). Table 1 lists the comparative
2

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Asian Journal Of Organic Chemistry
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sitagliptin-phosphate salt in 73% isolated yield with >99%
enantiomeric excess (Fig. S27).
Subsequently, the reaction was scaled up to 1 g and 5 g. Three 1
g batches were carried out directly in a metal reactor with
magnetic needle placed at the bottom of the reactor. While, 5 g
batches were carried out in a Parr 450 mL reactor equipped with
overhead stirrer and heating jacket.[18] As evident from Table 2
run 1 and 2, about 90% conversion along with 94% ee was
observed on this scale. While, slightly lower conversion and ee
was found in case of 5 g batch (Table 2, run 3). In our attempts
to improve the conversion on 1 g scale, we performed the reaction
with increased amount of salicylic acid (1.5 equivalent) (Table 2,
run 5). Indeed, 99% conversion was observed within 4 hours
without affecting ee (94%). However, we noticed a tailing at the
end of HPLC chromatogram (Fig. S21).
Table 2. Asymmetric synthesis of sitagliptin on large scale.
Run 1 (g) Time (h) Salicylic Conv. % c Ee% c
acidb
1# 1 18 1 89 94
2# 1 18 1 93 94
3a 5 8 1 85 93
4d 5 4.5 1 96 (40) 96
5b 1 4 1.5 99 (48) 94
6e 0.03 3 1.5 80 94
#
Conditions: [Rh(COD)2OTf]: 12 mg (1 mol%); [Rh]:L = 1:1.2; Methanol (20 mL);
Time: 18 hr; Temp: 50°C; H2 pressure: 30 bar. a[Rh(COD)2OTf]: 60 mg (1 mol%);
L12: 77.95 mg (1.2 mol%): [Rh]:L = 1:1.2; Methanol (100 mL); Time: 8 hr; Temp:
45 °C; H2 pressure: 30 bar. b[Rh(COD)2OTf]: 60 mg (5 mol%); L12: 134.78 mg
(10 mol%): [Rh]:L = 1:2; Methanol (20 mL); Time: 4 hr; Temp: 50 °C ; H2
pressure: 30 bar, impurity observed. cMeasured by HPLC, isolated yield has
been provided in bracket. d[Rh(COD)2OTf]: 116 mg (2 mol%); Ligand L12: 156.3
mg (2.4 mol%); Methanol (100 mL); Temp: 45°C; H2 pressure: 30 bar
e
[Rh(COD)2OTf]: 1.8 mg (5 mol%); Ligand L12: 3.9 mg (10 mol%); Methanol (1
mL); Temp: 50°C; H2 pressure: 30 bar.
A new HPLC method was developed to detect this impurity and
after careful examination the new peak is assigned to sitagliptin
dimer (4).[18] Formation of such dimer has been reported earlier. [18]
We could also observe a peak at 17.4 minutes, which upon 1-2D
NMR characterization was found to be deaminated product 3. In
the above 1 g batch about 38% dimer formation was observed.
This was further reduced to 24% after increasing the catalyst
loading (Table 2, run 6) (Fig. S22).[19]
Ligand coordination determines the selectivity in asymmetric
hydrogenation.[20] Therefore, coordination behaviour of L12 was
investigated by NMR spectroscopy. 5 mg of [Rh(COD) 2OTf] was
treated with 1.1 equivalent of L12 (5.95 mg) in CDCl3. 31P NMR of
the above solution revealed a doublet at 28.4 ppm with a one
bond 1JRh-P = 144.1 Hz (SI, Fig. S23). The above 31P NMR
chemical shift and Rh-P coupling constant is in line with literature
reports and confirms bidentate coordination of L12 to rhodium.[21]
Thus, it is anticipated that the L12 coordinated rhodium complex
catalyses the asymmetric hydrogenation of enamine 1 to
sitagliptin 2.
In summary, highly enantioselective reduction of enamine 1 to
sitagliptin 2, a potent DPP-4 inhibitor, is developed. A new class
of FerroLANE ligands L3, L11 and L12 was identified and
This article is protected by copyright. All rights reserved.
10.1002/ajoc.201900709
examined in the asymmetric hydrogenation of 1. Among the three
ligands, the isopropyl substituted ligand L12 was undoubtedly the
best and displayed excellent performance. Employing L12, an
excellent enantiomeric excess of 98% was achieved in the AH of
1 to 2. To demonstrate the practical significance of our method,
the process has been scaled up to 5g.[22] The free base sitagliptin
was finally converted to phosphate salt with an enantiomeric
excess of >99%. Further optimization on large scale and efforts
to curb the formation of dimer are in progress.
Acknowledgements:
We thank CSIR-NCL (HCP 0011) for financial support. SHC is
indebted to DST-SERB (EMR/2016/005120) and AvH foundation
Accepted Manuscript
Bonn, Germany.
Keywords: Asymmetric hydrogenation • FerroLANE ligands •
Catalysis • Sitagliptin • Rhodium
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Asian Journal Of Organic Chemistry 10.1002/ajoc.201900709

COMMUNICATION
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[19] See reference 6 and 7 for catalyst loading in asymmetric synthesis of
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Accepted Manuscript
[22] A provisional patent has been filed, see: S. H. Chikkali, K. V. Khopade,
IN201811046767.

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Asian Journal Of Organic Chemistry 10.1002/ajoc.201900709

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Entry for the Table of Contents

Accepted Manuscript
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Asymmetric hydrogenation of enamine to sitagliptin has been investigated and initial screening indicated FerroLANE as suitable
candidates. Thus, Rh-FerroLANE catalyzed, highly enantioselective (>99%) synthesis of sitagliptin, a potent DPP-4 inhibitor, has
been reported. The synthetic utility of the process has been demonstrated by scaling the reaction to 5 g and by isolating sitagliptin in
its stable form.

5
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