An economical and facile method to synthesize vildagliptin

Article abstract of DOI:10.14233/ajchem.2014.17621

A facile and economical synthefic method to prepare vildagliption with-reported.It was started from L proline via succsessful reaction with chloried in tetrahydrofuran to-afford 1(2-chloroacetyl) pyrrolidine-2-carboxylic-acid, followed by reacting with 2-chloro-46-dimethoxy-1,3,5-triazine,N-methylmorpholine and 2,4,6-triazine,N-methlmorpholine-2,4,6-trichloro-1,3,5-triazine-to-give 1-(2-chloroacetyl)-pynolidine 2-carbonitrile which was-reacfed-with 3-aminoadmantanol to get the-forget-compound-of-vildagliption.

Full text of DOI:10.14233/ajchem.2014.17621

Asian Journal of Chemistry; Vol. 26, No. 18 (2014), 6275-6278
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17621
An Economical and Facile Method to Synthesize Vildagliptin
*
YU DENG, ANMIN WANG, ZHU TAO, YINGJIE CHEN, XINMEI PAN and XIANGNAN HU
College of Pharmaceutical Sciences, Chongqing Medical University, Chongqing 400016, P.R. China
*
Corresponding author: E-mail: huxiangnan62@163.com
Received: 18 March 2014; Accepted: 19 May 2014;
Published online: 1 September 2014;
AJC-15898
A facile and economical synthetic method to prepare vildagliptin with three steps was reported. It was started from L-proline via successful
reaction with chloroacetyl chloride in tetrahydrofuran to afford 1-(2-chloroacetyl)-pyrrolidine-2-carboxylic acid, followed by reacting
with 2-chloro-4,6-dimethoxy-1,3,5-triazine, N-methyl morpholine and 2,4,6-trichloro-1,3,5-triazine to give 1-(2-chloroacetyl)-pyrrolidine-
2-carbonitrile which was reacted with 3-aminoadmantanol to get the target compound of vildagliptin.
Keywords: 2-Chloro-4,6-dimethoxy-1,3,5-triazine, 2,4,6-Trichloro-1,3,5-triazine, N-Methyl morpholine, Vildagliptin.
endogenous GLP-1 and thereby indirectly increase insulin
secretion, inhibit glucagon secretion, protect the islet β-cells,
restore the sensitivity of insulin and slow gastric emptying,
which lead to normal blood glucose concentration.
Vildagliptin (1) was one of the efficient and competitive
DPP-IV inhibitors, which was developed by Novartis and
marketed in Europe as the antidiabetic drug in 2007. Its curative
effect on type II diabetes is remarkable when used alone or in
combination with other drugs.Along with the traditional drugs
gradually fading out of the market, it is urgent to research the
method with a good yield to prepare vildagliptin with a high
purity.
INTRODUCTION
1
Diabetes mellitus is due to insufficient secretion of insulin
or the impaired physiological effects of insulin caused by
different causes, resulting in abnormal metabolism of carbohy-
drate, fat and protein, with main symptoms including chronic
hyperglycemia and multisystem chronic lesions. Diabetes
mellitus has become the third most wide-spread chronic
diseases which threatened human health, following tumor and
cardiovascular disease. Its incidence is increasing rapidly,
especially in China, Africa and other developing countries.
Diabetes mellitus can be divided into two types, insulin
dependent diabetes (type I) and non-insulin dependent diabetes
(
type II). In addition, type II diabetes mellitus accounts for
OH
more than 90 % of the type suffered by patients. Current treat-
ment of type II is mainly pharmacotherapy. A large number of
patients with diabetes have promoted the antidiabetic drugs
market. Therefore, new effective antidiabetic agents with fewer
side effects, such as glucagon-like peptide-1 (GLP-1) analogs
and dipeptidyl peptidase IV (DPP-IV) inhibitors, have become
O
H
N
N
NC
1
2
the new research focus of global pharmaceutical companies .
GLP-1 is an incretin hormone secreted by intestinal L-
3
cells , which plays an important role in stimulating insulin
EXPERIMENTAL
release, slowing gastric emptying and inhibiting glucagon
release. All of these effects are beneficial to patients with type
II diabetes. However, in human bodies GLP-1 will be cleaved
within minutes by the enzyme dipeptidyl peptidase IV (DPP-
The target compound of vildagliptin synthesized was
1
1
characterized by H NMR, IR, HPLC and LC/MS. The H
NMR spectra were recorded on a Bruker Avance 400 spectro-
meter (400 MHz). IR spectra were recorded on a PerkinElmer
UK spectrum one with KBr tablet. HPLC purity was deter-
mined with anAgilent (model 1200) equipped with a Lichrospher
4
IV) , so its half-life is very short. Moreover, the hydrolyzates
of GLP-1 not only lose insulin secretagogue activity but also
block the GLP-1 receptors. The DPP-IV inhibitors will inhibit
the activity of DPP-IV and in turn prolong the half-life of
C18 column, 250 × 4.6 mm, 5 µm [buffer: 1000 mL 0.1 %
phosphate solution of pH 4 with TFA, mobile phase, buffer:

6
276 Deng et al.
Asian J. Chem.
methanol (30:70), 55 min, 214 nm, 1 mL/min]. LC/MS spectra
were recorded on an Agilent 6120 single quadrupole LC/MS
δ 22.5, 24.5, 25, 30, 32.3, 41.7, 46.5, 46.8, 47.1, 117.9, 164.5,
5
165; MS (m/z): 173.1 [M + 1] .
(
model G6120B) equipped with an Agilent C18 column, 50 ×
Preparation of 1-[[(3-hydroxytricyclo[3.3.1.1(3,7)]dec-
1-yl)amino]acetyl]-2-pyrrolidine carbonitrile (vildgliptin)
(1): 3-Aminoadamantanol (3 g,18 mmol), 2-butanone (21 mL),
potassium carbonate (10 g, 72.5 mmol) and potassium iodide
(0.25 g, 1.5 mmol) were added to a 150 mL three-neck round
bottom flask which was equipped with a condenser pipe, a
thermometer and a constant pressure funnel. The mixture was
heated to 40 °C under stirring and then the compound 4 (3 g,
16.5 mmol) dissolved in 22 mL THF was added dropwise for
1.5 h. After dropped over, the reaction mixture was stirred at
40 °C for 1 h and then heated up to reflux for 0.5 h. The reaction
2
.1 mm, 1.8 µm and a ESI (+) scan mode detector [buffer:
000 mL water with 1 mL formic acid, mobile phase, buffer:
1
acetonitrile (30:70), 20 min, 210 nm, 0.3 mL/min].
Preparation of 1-(2-chloroacetyl)-pyrrolidine-2-carbo-
xylic acid (3): The L-proline (10 g, 0.087mol) dissolved in
1
00 mL THF was added to a 250 mL three-neck round bottom
flask. Then chloroacetyl chloride (10.5 mL, 0.132 mol) was
added dropwise in ice-bath. The reaction mixture was refluxed
under stirring for 2.5 h and monitored by TLC (25 % MeOH-
2 2
CH Cl ).After completing the reaction, the mixture was cooled
to about 25 °C, diluted with 20 mL water and stirred for 15 min.
Then 20 mL saturated brine and 50 mL ethyl acetate were
added and the organic layer was collected. The aqueous layer
was re-extracted with ethyl acetate (3 × 30 mL). The combined
organic layers were dried over anhydrous sodium sulfate for
3 2 2
was monitored by TLC (5 % CH OH-CH Cl ). After comple-
ting the reaction, the hot mixture was filtered and the filter
cake was washed with hot 2-butanone (3 × 20 mL). The collec-
ted filtrate was concentrated under vacuum and stirred under
slowly cooling.After the mixture became viscous, it was stirred
in the ice-bath. The resulting white crystalline solid was filtered
and washed with ethyl acetate (3 × 20 mL) and then dried at
45 °C under vacuum to afford the target compound of vildagliptin
(4.1 g, 82 %). HPLC purity 99.17 %, m.p. 148-150 °C, IR
2
4 h and then concentrated under vacuum. The semisolid
residue was stirred in 30 mL diisopropyl ether for 20 min at
about 25 °C and then cooled to 0 °C for 24 h to give crystalline
white solid which was filtered and washed with cold diiso-
propyl ether, then dried at 45 °C under vacuum to afford com-
-1
1
(KBr, νmax, cm ): 3293, 2915, 2848, 2241, 1656, 1405; H NMR
(400 MHz, DMSO-d ) 1.41-1.49 (m, 14H, CH ), 1.97-2.02
(m, 2H, OH, NH), 3.44-3.63 (m, 2H, COCH ), 4.70-4.73 (t,
1H, CHCN), 2.10-2.14 (m, 4H, CH ), 3.26-3.32 (t, 2H, NCH );
) δ 22.07, 34.22, 38.79, 39,
-1
pound 3 (15.8 g, 95 % ). m.p. 106-108 °C, IR (KBr, νmax, cm ):
1
420, 3050, 2988, 2941, 2810, 1723, 1610, 1475,1462; H
6
2
3
2
NMR (400 MHZ, CDCl ): δ 2.02-2.4 (m, 4H), 3.55-3.8 (m,
3
2
2
1
3
13
2
H), 4-4.2 (m, CH
2
Cl), 4.65 (m, H, CHCOOH); C NMR (75
C NMR (75 MHz, DMSO-d
6
6
) : δ 22, 24.5, 28.5, 31.5, 41.6, 41.8, 47.2,
MHz, DMSO-d
6
39.21, 39.43, 39.64, 39.85, 40.06, 44.62, 47.09, 47.09, 47.16,
4
7.6, 59.3, 60, 166.2, 166.5, 174.9, 175.1.
Preparation of 1-(2-chloroacetyl)-pyrrolidine-2-carbo-
52.72, 68.39, 120.03, 171.32; MS m/z 304.2 [M + 1], 305.2
13
[M + 2] .
11,12
nitrile (4):Acetonitrile (50 mL), CDMT (homemade , 3.85
g, 3.85 mol), NH HCO (9.12 g, 0.12 mol) and compound 3
3.85 g, 0.02 mol) were added to a 150 mL three-neck flask
RESULTS AND DISCUSSION
4
3
(
There are several reported approaches to synthesize com-
pound 1shown in Scheme-I, but all the methods more or less
had some disadvantages.Villhauer et al. prepared vildagliptin
which was equipped with a thermometer, a condenser pipe and
a constant pressure funnel. N-Methyl morpholine (2.4 mL,
5
0
.022 mol) was added after the mixture stirred for 10 min.
The reaction mixture was stirred at room temperature for 4.5 h
and monitored by TLC (95 % CH Cl -CH OH). After comp-
started from expensive L-prolinamide as shown in route 1. It
involved the expensive and corrosive reagent trifluoro acetic
acid. Moreover, the purity of the target product could be lowered
because the excessive 3-aminoadamantanol was difficult to
be removed. Besides, the reaction time was as long as 6 days
2
2
3
letion of the reaction, the mixture was filtered and the filter
cake was washed with methylene chloride (3 × 40 mL). The
filtrates were collected, combined and concentrated under
vacuum to give some oily mass. To this oily mass was added
DMF (20 mL) and TCT (2 g, 0.011 mol) and the reaction
mixture was then stirred at 40 °C for 4 h. The reaction was
6
and the yield was not reported. Singh et al. synthesized vildag-
liptin not only using the expensive trifluoro acetic acid but
also the unstable DCC as shown in route 2. Furthermore, the
total yield of the target compound was only 18 %. Route 3
7
monitored by TLC (95 % CH
2
Cl
2
-CH OH). After completing
3
was designed by Manne et al. to prepare vildagliptin. The
the reaction, water (100 mL) and ethyl acetate (100 mL) were
added and the organic layer was collected. The aqueous layer
was re-extracted with ethyl acetate (3 × 30 mL). The combined
organic layers were washed with saturated sodium bicarbonate
solution (3 × 30 mL) and dried over anhydrous sodium sulfate,
then concentrated under vacuum to give a honey-like residue.
To this residue 15 mL isopropyl ether was added under stirring,
the resulting crystalline solid was filtered and dried at 45 °C
under vacuum to afford compound 4 (2.4 g, 70 %). m.p. 62-
2
use of (Boc) O made the reaction process cumbersome and
the operation complicated. Moreover, it involved large number
of expensive reagents. So it was not suitable for industrial
production. Route 4 was the latest reported method to prepare
8
vildagliptin which was researched by our laboratory . This
method could afford target compound with relatively good
yield and high purity, but it involved four steps and consumed
large amounts of reagents, which made the process complex.
Therefore, it was not the most efficient way to reduce costs.
In our study, we designed a facile and economical method
to afford vildagliptin (1) just with three steps (Scheme-II) using
commercially available and inexpensive raw materials. It was
an optimization and improvement of route 4. It was started
-1
1
6
3 °C, IR (KBr, νmax, cm ): 2952, 2887, 2241, 1655; H NMR
400 MHz, CDCl ): δ 2.15-2.4 (m, 4H, CH ), 3.55-3.65 (m,
), 3.7-3.8 (m, 1H, CH ), 4.075-4.125 (s, 2H, CH Cl),
.725-4.875 (m, 1H, CHCN); C NMR (75 MHz, DMSO-d
(
3
2
1
H, CH
2
2
2
13
4
6
)

Vol. 26, No. 18 (2014)
An Economical and Facile Method to Synthesize Vildagliptin 6277
OH
CONH2
CN
ClCH COCl
2
TFAA
O
Route 1:
CONH2
N
N
3-aminoadamantanol
K CO /THF
H
N
N
H
N
THF
O
O
2
3
Cl
Cl
NC
1
COOH
CONH2
ClCH
2
COCl
DCC
N
N
COOH
Route 2:
N
H
THF
NH HCO
O
4
3
O
Cl
Cl
OH
CN
TFAA
O
3
-aminoadamantanol
N
H
N
N
THF /KI/K CO
O
2
3
Cl
NC
1
Route 3:
HNO / H SO
4
Tert-Butyl chloracetate
(
1)
2)
3
2
OH
OH
H N
2
H N
2
HN
CH COOC(CH )
(
2
3 3
NH .H O
3
2
CON
COOCH3
(Boc) O
2
CONH2
N
H
N
N
H
Boc
OH
OH
HN
CH COOC(CH )
O
H
N
2
3 3
TFAA
CN
N
N
Boc
CN
N
1
Route 4:
COOH
CONH
2
ClCH COCl
2
TCT
NH HCO
N
COOH
N
H
THF
O
4
3
O
Cl
Cl
OH
CN
N
TCT
DMF
O
3
-aminoadamantanol
H
N
N
THF /KI/K CO
2
O
3
Cl
1
NC
OH
Scheme-I: Earlier routes to synthesize vildagliptin
ClCH COCl
2
COOH
COOH a.CDMT/NMM/NH HCO3
4
CN
3
-aminoadamantanol
THF/KI/K CO3
N
H
THF
N
N
O
H
N
b.TCT/DMF
2
O
N
O
Cl
Cl
NC
2
3
4
1
Scheme-II: Synthesis of vildagliptin

6
278 Deng et al.
Asian J. Chem.
from L-proline (2) which was N-acylated with chloroacetyl
chloride in refluxing THF to afford 1-(2-chloroacetyl)-
pyrrolidine-2-carboxylic acid (3) as the first step. Chloroacetyl
group protected the secondary amino and avoided the
procedure of protection and deprotection.
easily available L-proline as starting materials instead of
L-prolinamide. Moreover, we synthesized the target product
just with three steps, which was beneficial to reducing the
reaction time and the costs of vildagliptin.
ACKNOWLEDGEMENTS
The second step was giving 1-(2-chloroacetyl)-pyrrolidine-
-carbonitrile (4). Compound 3 was stirred with CDMT, NMM
2
This work was supported by Natural Science Foundation
of Chongqing (CSTC, 2006BB5286). The authors also thank
the Chongqing Medical University for partial financial support
to this work.
(
N-methyl morpholine) and NH HCO in acetonitrile at room
4
3
temperature. After completion of the reaction, the mixture was
filtered and the filtrates were concentrated under vacuum. To
9,10
the residue were added TCT and DMF (dimethyl formamide),
then stirred for 4.5 h to afford compound 4. The intermediate
REFERENCES
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Conclusion
In conclusion, we have developed a facile and cost-effec-
tive method to prepare vildagliptin. This method employed