Field of the Invention
The present invention relates to an improved process for the preparation of
vildagliptk or salts thereof. In particular, the present invention relates to the process
for the preparation of Vildagliptin having high purity with less number of impurities.
Background of the Invention
Vildagliptinis an oral anti-hyperglycemic agent (anti-diabetic drug) of the
new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the
inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the
secretion of insulin in the beta cells and suppress glucagon release by the alpha cells
of the islets of Langerhans in the pancreas. Vildagliptin has been shown to reduce
hyperglycemia in type 2 diabetes mellitus.
Vildagliptin is chemically known as (S)- 1 -[2-(3-hydroxyadamantan- 1 -yl-amino)
acetyllpyrrolidine-2-carbonitrile, having molecular weight 303.39 glmol and formula
C17H2~N302V. ildagliptin can be structurally represented as Formula 1:
Formula 1
Vildagliptin or a pharmaceutically acid addition salt thereof were first disclosed in US
6,166,063. Example of said patent described process for preparation of vildagliptin by
reacting L-prolinarnide of Formula 2 with chloroacetyl chloride of Formula 3 in the
presence of potassium carbonate followed by treating with trifluoroacetic anhydride
to provide 1-chloroacetyl-2-cyanopyrrolidine of Formula 4, followed by coupling
with 1-aminoadamantane-3-01 of Formula 5 to obtain vildaglitin as per below
mentioned Scheme 1 :
Scheme 1
( )-CONH2 +
CI 1. K2CO3
c l q ' - N
H 0 2. TFAA
Formula 2 Formula 3 c I
Formula 4
OH
' Formula 5
OH.
b N H T Q0 N
Vildagliptin
I This process involves the use of trifluoroacetic anhydride which is corrosive as well
as expensive, moreover less environment friendly. In addition of this, the patent
discloses purification of vildagliptin by flash chromatography, which is not suitable
for commercial scale production of the drug substance useful in diabetes.
I Journal of Medicinal Chemistry (2003), Vol. 46, page 2774-2789 discloses the similar
process for the preparation of vildagliptin.
US7,375,238B2 discloses a process for the preparation of vildagliptin by reacting Lprolinamide
of Formula 2 with chloroacetyl chloride of Formula 3, followed by
treating with Vilsmeier reagent to obtain (S)- 1 -chloroacetyl-pyrrolidine-2-
carbonitrile. Further the obtained solution of (S)-1-chloroacetyl-pyrrolidine-2-
carbonitrile of Formula 4 coupled with 3-hydroxyaminoadamantane of Formula 5 and
adding 1,8-diazabicyclo[5 .4.0]undec-7-ene, 'isopropanol, t-butylmethylether to obtain
vildaglitin. This process for the preparation of vildagliptin is cumbersome, which
involves many number of steps and costlier reagent like 1,s-diazabicyclo[5.4.0]undec-
7-ene. The process is relatively less safe and more time-consuming. Hence, this
process is also not suitable for commercial production.
Many other patent publications have also been disclosed so far, which describes the
process for the preparation of Vildagliptin or salts thereof. Still there is a need to
develop a simple, cost effective, high yielding and easy to implement on industrial
scale process for the preparation of Vildagliptin or salts thereof.
Object of the invention
The principal object of the present invention is to provide a process for the
preparation of Vildagliptin or salts thereof, which alleviates the drawbacks of prior art
process.
One object of the present invention is to provide an improved, efficient, safe and
convenient process for preparation of Vildagliptin or salts thereof.
Another object of the present invention is to provide a process for preparation of
vildagliptin by coupling of 1-chloroacetyl-2-cyanopyrrolidine of Formula 4 and 3-
aminoadamantan- 1-01 of Formula 5 in the presence of calcium hydride.
Summarv of the invention
In accordance with principal embodiment, the present invention provides a process for
the preparation of Vildagliptin or salts thereof, comprising the steps of:
(a) coupling of L-prolinamide of Formula 2
Formula 2
with haloacetyl chloride in presence of one or more suitable solvent,
optionally using base, to provide compound of Formula 6
Formula 6
wherein, X represents chloro, bromo, iodo and the like thereof; haloacetyl
chloride comprises of chloro, bromo, iodo acetyl chloride;
'(b) dehydrating the compound of Formula 6 using a suitable dehydrating agent, in
the presence or absence of solvent, to provide compound of Formula 4A;
Formula 4A
(c) condensing compound of Formula 4A with 3 -arninoadamantan- 1 -01 of
Formula 5 using suitable base in the presence of suitable solvent to provide
vildagliptin; and,
(d) optionally purifying or converting to salts thereof.
In accordance with one embodiment, the present invention provides a process for the
preparation of Vildagliptin or salts thereof, comprising the steps of:
(a) coupling of L-prolinamide of Formula 2
Formula 2
with chloroacetyl chloride in the presence of mixture of dichloromethane and
N,N-dimethyl fbrmamide to provide compound of Formula 6A;
Formula 6A
(b) dehydrating the compound of Formula 6A using phosphorous oxychloride to
provide 1 -chloroacetyl-2-cyanopyrrolidine of Formula 4;
Formula 4
(c) condensing 1 -chloroacetyl-2-cyanopyrrolidine of Formula 4 with 3-
aminoadamantan-1-01 of Formula 5 using calcium hydride in presence of
dimethyl sulfoxide as solvent to provide vildagliptin; and,
(d) optionally purifying or converting to salts thereof.
In accordance with another embodiment, the present invention provides a process for
the preparation of Vildagliptin or salts thereof, comprising the steps of
(a) condensing 1-chloroacetyl-2-cyanopyrrolidine of Formula' 4 with 3-
aminoadamantan-1-01 of Formula 5 using calcium hydride in presence of
dimethyl sulfoxide as a solvent to provide vildagliptin; and,
(b) optionally purifying or converting to salts thereof.
Detail description of the drawings:
Fig.1: Illustrates the X-ray powder diffraction (XRPD) pattern of Vildagliptin free
base.
Fig.2: Illustrates the differential scanning calorimetry (DSC) of Vildagliptin free base.
Fig.3: Illustrates the thermogravimetric analysis (TGA) of Vildagliptin free base.
Detail description of the invention
The present invention provides an efficient and industrially advantageous process for
the preparation of Viladaglitin or salts thereof.
In accordance with the principal embodiment, the present invention provides a
process for the preparation of Vildagliptin or salts thereo'f, comprising the steps of
(a) coupling of L-prolinamide of Formula 2
Formula 2
with haloacetyl chloride in presence of one or more suitable solvent,
optionally using base, to provide compound of Formula 6,
Formula 6
wherein, X represents chloro, bromo, iodo and the like thereof; haloacetyl
chloride comprises of chloro, bromo, iodo acetyl chloride;
(b) dehydrating the compound of Formula 6 using a suitable dehydrating agent, in
the presence or absence of solvent, to provide compound of Formula 4A;
Formula 4A
(c) condensing compound of Formula 4A with 3-aminoadamantan-1-01 of
Formula 5 using suitable base in the presence of suitable solvent to provide
vildagliptin; and,
(d) optionally purifying or converting to salts thereof.
First step involves coupling of L-prolinamide o f Formula 2
with haloacetyl chloride in presence of one or more suitable solvent, optionally using
base, to provide Formula 6.
After completion of reaction, compound of Formula 6 with or without isolation is
treated with a dehydrating agent in the presence or absence of suitable solvent to
provide compound of Formula 4A.
Next step involves condensation of compound of Formula 4A with 3-
arninoadamantan-1-01 of Formula 5 using suitable base in the presence of suitable
solvent to provide vildagliptin, which may be optionally purified or converted into
salts thereof.
In accordance with one embodiment, the present invention provides a process for the
preparation of Vildagliptin or salts thereof, comprising the steps of:
(a) coupling of L-prolinamide of Formula 2 with chloroacetyl chloride in the
presence of the mixture of dichloromethane and N,N-dimethyl formamide to
provide compound of Formula 6A;
(b) dehydrating the compound of Formula 6A using phosphorous oxychloride to
provide 1- chloroacetyl-2-cyanopyrrolidineo f Formula 4;
(c) condensing 1-chloroacetyl-2-cyanopyrrolidine of Formula 4 with 3-
aminoadamantan-1-01 of Formula 5 using calcium hydride in the presence of
dimethyl sulfoxide as solvent to provide vildagliptin; and,
(d) optionally purifying or converting to salts thereof. ,
First step involves coupling of L-prolinamide of Formula 2
with haloacetyl chloride in the presence of one or more suitable solvent, optionally
using base, to provide compound of Formula 6. Generally reaction may be carried out
at a temperature of -10 to 50°C for few minutes to few hours or till completion of
reaction. Preferably reaction is conducted at a temperature of 10 to 40°C, more
preferably reaction is conducted at room temperature and it takes 2 to 5 hours for
completion of the reaction.
After completion of reaction, compound of Formula 6 with or without isolation may
be taken for next step.
-
Next step involves dehydrating the compound of Formula 6 using a suitable
I dehydrating agent, in the presence or absence of solvent, to provide compound of'
I Formula 4A. Generally reaction may be carried out at a temperature of -30°C to room
I temperature for few minutes to few hours or till completion of reaction. Preferably
I reaction is conducted at a temperature of -10 to 15"C, more preferably reaction is
conducted at a temperature of.-10 to 5OC for 2 to 4 hours.
I Further, condensing compound of Formula 4A with 3-aminoadamantan- 1-01 of
I Formula 5 using suitable base in presence of suitable solvent to provide vildagliptin.
I Generally condensation may be carried out at room temperature to reflux temperature
I for few minutes to few hours, preferably at a temperature of 20 to 60°C, more
preferably reaction is conducted at a temperature of 40 to 50°C for 2 to 3 hours.
I Suitable solvent used for coupling and dehydration in step a) and b) includes but not
I limited to organic solvents selected fiom the group comprising of sulfoxide, amide,
I. esters, ,ketone, nitrile, aliphatic or aromatic hydrocarbons, chloro solvents, cyclic
I .ethers and mixture thereof, preferably, selected fiom dimethyl sulfoxide (DMSO),
I N,N-dimethylformamide (DMF), N,N-dimethyl acetamide (DMAC), ethyl acetate,
I propyl acetate, butyl acetate, acetone, propanone, butanone, methyl isobutyl ketone,
I acetonitrile, butyronitrile, pentane, hexane, heptane, cyclohexane, toluene, xylene,
i methylene dichloride (MDC), ethylene dichloride, chloroform, tetrahydrofuran,
I methyl tetrahydrofuran, dioxane and' the like or mixture thereof, more preferably
solvents used are N,N-dimethylformamide and methylene dichloride (MDC).
The base used for coupling in step a) may be selected from inorganic or organic base,
wherein inorganic base is selected from alkali or alkaline earth metal hydroxides,
carbonates, bicarbonates such as sodium hydroxide, potassium hydroxide, calcium
hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium
E
L carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium
0
bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate,
cesium bicarbonate, sodium with liquid ammonia, sodamide or the like and mixture
thereof. Organic base is selected from diisopropyl ethyl amine, triethyl amine, tributyl
amine, N-methyl morpholine, 1,s-diazabicyclo[5.4.0]undec-7-ene (DBU) and
pyridine or like thereof.
The suitable dehydrating agent used in step b) may be selected from but not limited to
Vilsmeier's reagent, phosphorous oxychloride, trifluoroacetic anhydride, phosphorous
pentoxide, diethylchloro phosphate, cyanuric chloride, trifluoroacetic acid, thionyl
chloride and the like thereof, preferably, dehydrating agent used is phosphorous
oxychloride.
The base used during condensation in step c) may be selected from inorganic or
organic. base, wherein inorganic base is selected from alkali or alkaline earth metal
hydrides, hydroxides, carbonates, bicarbonates such as sodium hydride, calcium
hydride, lithium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide,
magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate,
calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate,
potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium
bicarbonate, sodium with liquid ammonia, sodamide or like and mixture thereof;
organic bases may be selected fiom diisopropyl ethyl amine, triethyl amine, tributyl
amine, N-methyl morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
pyridine or like thereof, preferably base used is calcium hydride.
The suitable solvent for condensation in step c) is selected fiom group comprising of
water, sulfoxides, alcohols, halogenated hydrocarbons, ethers, amides, hydrocarbons, and
the like or mixture thereof such as dimethyl sulfoxide (DMSO), methanol, ethanol, npropanol,
isopropanol, n-butanol, dichloromethane (DCM), chloroform, dichloroethane,
chlorobenzene, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether,
tetrahydrofuran (THF), dioxane N,N-dimethylformamide (DMF), N, Ndimethylacetamide
(DMAC), N-methylformamide, N-methylpyrrolidone, pentane, hexane,
heptane, octane,. cyclohexane, cyclopentane, toluene, xylene and the like or mixture
thereof, preferably, solvents used are water and dimethyl sulfoxide (DMSO).
In accordance with another embodiment, the present invention provides a process for
the preparation of Vildagliptin or salts thereof, comprising the steps of:
(a) condensing compound of Formula 4 with 3 -aminoadmantan- 1-01 of Formula
5 using calcium hydride in presence of dimethyl sulfoxide as solvent to
provide vildagliptin; and,
(b) optionally purifying or converting to salts thereof.
0
9
2 I P O D E L H I 02-CJ5-2o17 15147 4 10
The purification of vildagliptin free base can be conducted by using suitable reagents,
solvents and any suitable method known in the art.
The reaction completion is monitored by suitable techniques such as thin layer
chromatography (TLC), high performance liquid chromatography (HPLC), ultraperformance
liquid chromatography (UPLC), gas chromatography (GC) and the like
thereof.
Accordingly, vildagliptin obtained according to the instant invention possess the
relative particle size distribution, wherein the 10th volume percentile particle size D
(0.1) is less than about 50 pm, the 50th volume percentile particle size D(0.5) is less
than about 100pm, or the 90th volume percentile particle size D(0.9) is less than about
200pm, or any combination thereof.
In general, the particle size measurement is determined by Malvern light scattering,
laser light scattering technique etc. In particular the particle size measurement is
measured using a Malvern particle size analyzer.
In another aspect there is provided a pharmaceutical composition that includes a
therapeutically effective amount of vildagliptin according to the process of the present
invention and one or more pharmaceutically acceptable carriers, excipients or diluents.
Major advantages realized in the present invention are that the process involves the
use of calcium hydride during the reaction of compound of Formula 4 with 3-
aminoadamantan-1-01 compound of Formula 5, which reduces the formation of
dicyano dimer impurity, also the present invention avoids the use of corrosive,
expensive dehydrating reagent such as cyanuric chloride, trifluoro acetic anhydride
and the like thereof. In addition of this the present invention can be easily and
conveniently scaled-up for industrial large scale production. The process is simple,
economical, with high yield throughout and environment friendly.
Although the following examples illustrate the present invention in more detail. but the
examples are not intended in any way to limit the scope of the present invention. It
will thus be readily apparent to the one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from
the scope and spirit of the invention. Thus, it should be understood that although the
present invention has been specifically disclosed by preferred embodiments and
optional features, modifications and variation of the concepts herein disclosed may be
resorted to by those skilled in the art and that such modifications and variations are
considered to be falling within the scope of the invention.
Example 1
'Preparation of 1-chloroacetyl-2-cyanopyrrolidipe:
To solution of chloroacetyl chloride in dichloromethane (54.3. ml in 455 ml) was
cooled to 10 to 15OC and slowly added a solution of L-prolinamide (65g) in dimethyl
formamide (154.3 ml) and dichloromethane ' (65 ml) while maintaining the
temperature. The temperature of the reaction mixture was further raised to room
temperature and stirred for 3 to 4hours. The reaction mixture was further cooled to -5
to O°C and POCb (58.6 ml) was added slowly and stirred at the same temperature for
2 to 3 hours. After the completion of the reaction, water (650 ml) was added slowly to
the reaction mixture, stirred and separated the layers. The aqueous layer was extracted
with dichloromethane (325 ml), combined the organic layers, washed with 7.5% aq.
potassium. hydroxide solution and concentrated under reduced pressure to give pale
yellow oil which solidified upon cooling. To the solidified residue iso-propyl alcohol
(280 ml) was added and heated at 40 to 50°C to obtain a clear solution, further the
reaction mixture was cooled to -10 to -20°C and stirred at same temperature for 3 to 4
hours. The precipitated solid was filtered and washed .with iso-propyl alcohol to
obtain the title compound as off-white solid (Yield: 90 % & purity 99.0%).
Example 2
Preparation of Vidagliptin
To the solution of 3-aminoadamantan-1-01 in DMSO (53.2 g in 100 ml) was added
calcium hydride (13.4 g) at room temperature further raised the temperature of
reaction mixture to 45 to 50°C and the solution of 1-chloroacetyl-2-cyanopyrrolidine
in dimethyl sulfoxide (50 g in 100 ml) was added slowly. The reaction mixture was
stirred at same temperature for 2 to 3 hours. After completion of the reaction, the
0
(V
(D reaction mixture was cooled to 0 to 5OC, dichloromethane (500 ml) was added,
Q)
(D
CO
(V
stirred, filtered and washed the filtrate with 25% aq. sodium chloride solution. To the
b
7
0
organic layer de-ionized water (100 ml) was added and pH of the reaction mixture
9 2 -JPQ f-JEkHI a Z - E B 5 - 2 Q a 7 4.5 147
z I
(V
12
0
was adjusted to 5.0 to 5.5 using 15% aq. potassium hydrogen sulphate solution,
separate the layers and aqueous layer was washed with dichloromethane (100 ml).
Further, aqueous layer was basified using aq. ammonia to pH 8.3 to 9.0 and the
product was extracted from aqueous layer using dichloromethane (500 ml x 2). The
organic layer was concentrated under vacuum till minimum volume of
dichloromethane and add IPA (300 ml), concentrate under vacuum to remove
dichloromethane. To the clear reaction mixture ethyl acetate (500 ml) and heated at 50
to 55OC for 30 minutes. The reaction mixture was cooled to 0 to 5OC and stirred for 4
to 6 hours at same temperature. The solid obtained was filtered and washed with ethyl
acetate to obtain the title compound as white crystalline solid (Yield: 80% and purity:
99.9%).
Example 3
Preparation of Vildagliptin
The solution of 3-aminoadamantan-1-01 (10.6 g) in dimethylsulfoxide (20 ml) and
DM water (2 ml) was cooled to 5 to 10°C and added calcium fiydride (2.7 g) in 3 to 4
lots at the same temperature. Further the temperature of the reaction mixture was
raised to 40 to 50°C and a solution of 1-chloroacetyl-2-cyanopyrrolidine in dimethyl
sulfoxide (log in 20 ml) was added slowly at the same temperature. The reaction
mixture was stirred for 2 to 3 hours and dichloromethane (50 ml) was added. The
reaction mixture was filtered. The obtained filtrate was washed with aq. sodium
chloride solution and solvent was concentrated under.vacuum to obtain the title
compound as white crystalline solid (Yield: 77% and purity 99.9%).
We claim:
1. A process for the preparation of Vildagliptin or salts thereof, comprising the
steps of:
a) coupling of L-prolinamide of Formula 2
ON C OW H 2
H
Formula 2
with haloacetyl chloride in presence of one or more suitable solvent, optionally
using base, to provide compound of Formula 6,
Formula 6
wherein, X represents chloro, bromo, iodo;
haloacetyl chloride comprises of chloro, bromo, iodo acetyl chloride;
b), dehydrating the compound of Formula 6 using a suitable dehydrating agent, in
the presence or absence of solvent, to provide compound of orm mu la 4A;
Formula 4A
c) condensing compound of Formula 4A with 3-aminoadarnantan-1-01 of
Formula 5 using suitable base in the presence of suitable solvent to provide
vildagliptin; and,
CO
(V
b - d) optionally purifying or converting to salts thereof.
2. The process according to claim 1, wherein in step a) and b) suitable solvent
may be selected from group comprising of sulfoxide, amide, esters, ketone,
nitrile, aliphatic or aromatic hydrocarbons, chloro solvents, cyclic ethers and
mixture thereof such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide
(DMF), N,N-dimethyl acetamide (DMAC), ethyl acetate, propyl acetate, butyl
acetate, acetone, propanone, butanone, methyl isobutyl ketone, acetonitrile,
butyronitrile, pentane, hexane, heptane, cyclohexane, toluene, xylene,
methylene dichloride (MDC), ethylene dichloride, chloroform,
tetrahydrofuran, methyl tetrahydrofuran, dioxane and mixture thereof.
3. The process according to claim 1, wherein in step b) dehydrating agent used
may be selected from Vilsmeier's reagent, phosphorous oxychloride,
trifluoroacetic anhydride, phosphorous pentoxide, diethylchloro phosphate,
cyanuric chloride, trifluoroacetic acid, thionyl chloride and mixture thereof.
4. The process according to claim 1, wherein in step a) and c) base used may be
selected from inorganic or organic base, wherein inorganic base is selected
from alkali or alkaline earth metal hydrides, hydroxides, carbonates, .
bicarbonates such as sodium hydride, calcium hydride, lithium hydride,
sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium
hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate,
calcium carbonate, magnesium carbonate, cesium carbonate, sodium
bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium
bicarbonate, cesium bicarbonate, sodium with liquid ammonia, sodamide and
mixture thereof; organic base is selected from diisopropyl ethyl amine, triethyl
amine, tributyl mine, N-methyl morpholine, 1,8-diazabicyclo[5.4~0]undec-7-
ene (DBU), pyridine and mixture thereof.
5. The process according to claim 1, wherein in step c) suitable solvent is
selected from group comprising of sulfoxides, alcohols, halogenated
hydrocarbons, ethers, amides, hydrocarbons such as dimethyl sulfoxide
(DMSO), methanol, ethanol, n-propanol, isopropanol, n-butanol,
7
0
(V
\ dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene, diethyl
(D
Q)
(D
CO
ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran
(V
b
7 (THF), dioxane, N, N-dimethylformamide (DMF), N, N-dimethylacetmide
0
9 s x p ~ @-2-Q5-28B$ 15:47 m z I
(V
15
0
(DMAC), N-methylformamide, ~ - m e t h ~ l ~ ~ ~ o l i dpoenntaen,e , hexane,
heptane, octane, cyclohexane, cyclopentane, toluene, xylene, water and
mixture thereof.
6. A .process for the preparation of Vildagliptin or salts thereof, comprising the
steps of:
a) coupling of L-prolinamide of Formula 2
Formula 2
with chloroacetyl chloride in the presence of mixture of dichloromethane and
N,N-dimethyl formmide to provide compound of Formula 6A;
Formula 6A
b) dehydrating the compound of Formula 6A using phosphorous oxychloride to
provide 1 -chloroacetyl-2-cyanopyrrolidine of Formula 4;
. .
Formula 4
c) condensing 1-chloroacetyl-2-cyanopyrrolidine of Formula 4 with 3-
minoadamantan-1-01 of Formula 5 using calcium hydride in presence of
dimethyl sulfoxide as solvent to provide vildagliptin; and,
d) optionally purifying or converting to salts thereof.
7. A process for the preparation of Vildagliptin or salts thereof, comprising the
steps of: 7

I a) condensing 1 -chloroacetyl-2-cyanopyrrolidine of Formula 4 with
I arninoadarnantan-1-01 of Formula 5 using calcium hydride in presence
dimethyl sulfoxide as a solvent to provide vildagliptin; and,
I b) optionally purifying or converting to salts thereof.