FIELD OF INVENTION:
The present invention discloses improved process for Sitagliptin phosphate which
involve reaction of (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-
[1,2,4]triazole[4,3-α]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)
carbamate (Formula 3) in C1-C4 alcohol saturated with hydrogen chloride gas
followed by its quenching in suitable base to give Sitagliptin base , without in
between recovery of C1-C4 alcohol, therefore keeping content of 3-amino-4-(2,4,5-
trifluorophenyl)butanoic acid impurity or hereinafter called as Amino TFPBA
(Formula 5) impurity to <0.10% by HPLC which is normally 8-15% in routine
process reported in literature. The final API Sitagliptin Phosphate, thus prepared,
is having Amino TFPBA impurity (Formula 5) content < 0.1% only which
otherwise present in the level of 0.3-1.0% in routine process.
Formula – 1 (Sitagliptin Phosphate Monohydrate)
Chemical Name – [(3R)-3-Amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6,7,8-
tetrahydro-3- (trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine Phosphate
3
COOH
F
F
F
NH
O O
Formula -2
Chemical Name: (R)-3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic
acid
F
F
F
NH O
N
N
N
N
CF3
O O
Formula -3
Chemical Name: (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-
[1,2,4]triazole[4,3-α]pyrazin-
7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate
4
F
F
F
NH2 O
N
N
N
N
CF3
Formula -4
Chemical Name: [(3R)-3-Amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6,7,8-
tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine
F
F
F
NH2 O
OH
Formula -5 (Amino-TFPBA)
Chemical Name: 3-Amino-4-(2,4,5-trifluorophenyl)butanoic acid
BACKGROUD OF INVENTION:
Sitagliptin phosphate, its chemical name is dihydrogenphosphate salt of (2R)-4-oxo-4-[3-
(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7-(8H)yl]-1-(2,4,5-
trifluorophenyl) butan-2-amine, has the following structural formula as given in formula 1
above.
5
Sitagliptin base and Sitagliptin Phosphate are disclosed in WO 03/004498/ U.S. Pat. No.
6,699,871 and US patent application 2005/0032804 respectively Sitagliptin base or
Sitagliptin phosphate are dipeptidyl peptidase- IV (DPP-IV) inhibitor and is useful for the
treatment and prevention of Type 2 diabetes, hyperglycemia, insulin resistance, obesity,
and high blood pressure. Sitagliptin hydrochloride is prepared from 2,4,5-trifluorobenzyl
chloride. The major disadvantages of this process are that it involves multi-step synthesis;
use of hazardous chemicals such as butyl lithium, diazomethane and silver benzoate; and
low overall yield (18%).
U.S. Patent application 2005/0032804 & US 7,326,708 discloses a (2R)-4-oxo-4-[3-(
trifluoromethyl-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)yl]-1-(2,4,5-trifluorophenyl)
butan-2-amine dihydrogen phosphate, also known as Sitagliptin phosphate. The
commercial JANUVIA tablets contain Sitagliptin phosphate.
International Application Publication No.: WO 2004/085661 discloses a process for the
preparation of Sitagliptin in which S-phenyl glycine amide is used as a chiral auxilary to
form an intermediate that subsequently provides the required enantiomer (i.e., Sitagliptin).
However, the processes disclosed in patent application WO 2004/085661 are not suitable
for industrial production as they involve expensive agents like PtO2 and palladium
hydroxide and require reaction at high pressure for more than 24 hours.
International Application Publication No.: WO 2004/087650 discloses another process in
which N-protected 3-((R)-amino)-4-(2,4,5-trifluorophenyl)-butyric acid is synthesized
enantio-selectively, condensed with a pyrazine intermediate, and deprotected to provide
6
Sitagliptin. US Patent No. 7,326,708 discloses the dihydrogen phosphate salt of Sitagliptin
and processes for the preparation thereof. However, the processes disclosed in patent
application WO 2004/087650 are not suitable for industrial production as they involve a
very expensive chiral catalyst and require reaction at high pressure
International Application Publication No.: WO 2004/085378 discloses a process for the
preparation of Sitagliptin, wherein the reduction of the Sitagliptin intermediate is carried
out by using rhodium metal and a chiral ferrocenyl diphosphine.
In another prior art process, disclosed in patent application US 2006/194977,
Sitagliptin dihydrogen phosphate salt was prepared by reaction of Meldrum's adduct and 3-
trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, was further
converted into enamine by use of ammonium acetate in methanol. The enamine was
further converted into enantiomerically enriched Sitagliptin free base by asymmetric
reduction using Josiphos catalyst and chloro(1,5-cyclooctadiene)rhodium(I) dimer. The
asymmetric synthesis involves hydrogenation of the enamine at 200 psi at 50° C. for 13
hours to obtain enantiomerically enriched Sitagliptin free base. However, this process is not
suitable for industrial production as it involves a very expensive chiral catalyst and requires
reaction at high pressure for more than 10 hours.
In US. Patent Application No.: US 20120108598 the inventors have developed a
method of resolution of racemic β-amino acid derivatives, in particular β-amino esters, to
obtain enantiomerically enriched β-amino acid derivatives which are extremely suitable for
the synthesis of enantiomerically pure Sitagliptin and salts thereof.
7
U.S. Patent 8,309,724 includes processes for the preparation of Sitagliptin, which
processes comprise at least one of the steps of:
(i) reacting 7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-
tetrahydro-1,2,4-triazolo[4,3-a]pyrazine with a first reagent to afford 7-(1-oxo-3-amino-4-
(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-
a]pyrazine;
(ii) converting the 7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-
trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine with a second reagent to 7-
(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-
1,2,4-triazolo[4,3-a]pyrazine;
(iii) treating the 7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-butyl)-3-(trifluoromethyl)-
5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine with a third reagent to afford a
diastereomeric salt of 7-(1-oxo-3((R)-amino)-4-(2,4,5-trifluorophenyl)-butyl)-3-
(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine;
(iv) isolating the diastereomeric salt;
(v) treating the diastereomeric salt with an acid or a base to afford Sitagliptin free base; and
(vi) optionally treating the Sitagliptin free base with an acid to afford an acid addition
salt of Sitagliptin.
Indian patent application 1788-DEL-2013, cites four new polymorphic form namely M1,
M2, M3, M4 along with their XRD & processes for the preparation thereof.
8
SUMMARY OF INVENTION:
The present invention describes a novel process for the preparation of Sitagliptin phosphate
from (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole[4,3-α]pyrazin-
7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate (Formula 3) with reduced
impurity content which is normally around 0.5-1.0% by various processes described in
prior art. Hence in order to compete in various regulated markets where impurity limits are
very stringent, there was a need of cost effective process of Sitagliptin phosphate which
give consistent good quality high enantiomeric purity along with proper yields.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, an improved process of
making of Sitagliptin base, having low 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid
impurity (Amino TFPBA; Formula 5) content, which comprises (Example 1):
i. adding the C1-C4 aliphatic alcohol saturated with Hydrogen chloride gas (25-30%)
at 0-5 °C.
ii. charging of (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-
[1,2,4]triazole[4,3-α]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-
yl)carbamate (Formula 3).
iii. heating the reaction mass.
iv. stirring for reaction completion.
v. checking for reaction completion by HPLC/TLC.
9
vi. quenching of reaction mass in aq. caustic solution.
vii. stirring for 1-3 hours.
viii. charging of a halogenated hydrocarbon to extract product from aq. layer.
ix. stirring and layer separation.
x. complete recovery of solvent under vacuum to yield 7-[(3R)-3-Amino-1-oxo-4-
(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-
triazolo[4,3-a] pyrazine or Sitagliptin base (Formula 4).
xi. drying it for 10-12 hours to get Sitagliptin base having low amino TFPBA impurity.
According to one aspect of the present invention, the C1-C4 aliphatic alcohol used in step i)
is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, Isopropyl alcohol,
monoethylene glycol & diethylene glycol or a mixture thereof.
According to yet another aspect of present invention, the temperature in step iii) is 20-40
ºC, and most preferably 20-30 ºC.
According to yet another aspect of present invention, the halogenated hydrocarbon used in
step viii) is selected from methylene chloride, chloroform or carbon tetrachloride or
mixture thereof.
According to the second embodiment of the present invention, an improved process of
making of Sitagliptin phosphate monohydrate, having low 3-amino-4-(2,4,5-
10
trifluorophenyl)butanoic acid impurity (Amino TFPBA; Formula 5) content, which
comprises (Example 2):
a) charging of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-
tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine or Sitagliptin base as
obtained from first embodiment in an aliphatic alcohol
b) stirring at room temperature
c) charging of orthophosphoric acid
d) charging of de-ionized water & stirring at room temperature
e) heating & stirring
f) refluxing the reaction mass for 60-75 minutes.
g) cooling of reaction mass
h) further stirring to ensure proper crystallization
i) seeding with Sitagliptin phosphate crystals if required
j) further cooling of reaction mass
k) stirring
l) addition of an aliphatic alcohol
m) stirring
11
n) filtration
o) running washing of wet cake with aliphatic alcohol
p) unloading of wet cake
q) drying to get pure 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-
tetra hydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine phosphate salt
monohydrate or Sitagliptin phosphate monohydrate.
According to one aspect of the current invention, the aliphatic alcohol used in step a), l) &
o) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, Isopropyl alcohol,
monoethylene glycol & diethylene glycol or a mixture thereof.
According to yet another aspect of present invention, the temperature in step e) is 75-85 ºC,
step g) is 55-60 °C, step j) is 20-25 °C & step q) is 50-60 °C.
According to still another aspect of present invention, the stirring time in step h) is 3-5
hours, step k) is 3-4 hours & step m) is 6-8 hours.
According to one more aspect of present invention, the 3-amino-4-(2,4,5-trifluorophenyl)
butanoic acid impurity (Amino TFPBA; Formula 5) content, in Sitagliptin phosphate
monohydrate as obtained in step q) is in region 0-0.10%.
The above mentioned invention is supported by the following non limiting examples.
EXAMPLES:
12
Comparative Example 1: Preparation of (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-
5,6-dihydro-[1,2,4]triazole[4,3-α]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-
yl) carbamate as per US 6,699,871.
(R)-3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic acid (100 g) & 3-
(trifluoro methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride are taken
in methylene chloride (1000 ml) at room temperature. Then the reaction mass is cooled to
0-5 °C followed by addition of N-Hydroxybenzotriazole (50 g). The reaction mass is then
stirred for half an hour followed by addition of 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide (75 g). Now the temperature is elevated to 25-35 °C followed by its stirring
for 16-24 hours so as to complete the reaction. After reaction completion is confirmed by
HPLC/TLC, the reaction mass is quenched by addition water (500 ml). The reaction mass
is then fine filtered from hyflow so as to remove any undesired particles. The aq. layer is
then extracted with methylene chloride (200 ml) twice. The organic layer is then washed
with brine solution followed by its complete recovery under vacuum, keeping temperature
40-45 °C, to give 145 g (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-
[1,2,4]triazole[4,3-α]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl) butan-2-yl)carbamate.
Yield = 1.45
Purity by HPLC = 94.35 %
Highest Individual Impurity = 2-5 % (HOBT)
Total Impurities = 5.65 %
13
Comparative Example 2: Preparation of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluoro
phenyl) butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine or
Sitagliptin Base as per US 6,699,871.
(R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole[4,3-α]pyrazin-
7(8H)-yl)-1-(2,4,5-trifluorophenyl) butan-2-yl)carbamate (eq. to 100 g of (R)-3-((tertbutoxycarbonyl)
amino)-4-(2,4,5-trifluorophenyl)butanoic acid) is taken in flask and
Methanolic.HCl (25-30%) is slowly added it at 0-5 °C. The temperature was increased to
20-30 ºC followed by stirring of reaction mass till reaction completion. After the
confirmation of reaction completion by HPLC/TLC, complete recovery of reaction mass is
done. After complete solvent recovery under vacuum, caustic solution is added to the
reaction mass followed by stirring for 1-3 hours. The reaction mass is then extracted with
methylene chloride (200 ml) twice. This methylene chloride layer is then recovered under
vacuum to give 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-
3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine or Sitagliptin base.
Yield = 0.68
Purity by HPLC = 85-92%
Amino-TFPBA impurity Content = 8-15 %
Total Impurities = 10-15 %.
14
Comparative Example 3: Preparation of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluoro
phenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine
Phosphate or Sitagliptin Phosphate as per US 7,326,708.
7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-
(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine or Sitagliptin base (100.0 g) was taken in
isopropyl alcohol (210 ml) and stirred. Now 85% aqueous phosphoric acid (28.30 g) is
charged along with de-ionized water (90 ml). The resulting reaction mass is now stirred at
75 °C till dissolution. Then reaction mass is cooled to 68 °C and stirred for 2 hours. After
stirring the reaction mass is seeded with crystals of alpine milled small particle size
Sitagliptin phosphate monohydrate (0.5 to 5.0%). Now the temperature is further reduced
21 °C and stirred overnight. Isopropyl alcohol (700 ml) is further added to the above
slurry/reaction mass and stirred for 1 hour for complete crystallization. This was followed
by its filtration and running washing with isopropyl alcohol (300 ml). The resulting solid is
dried to get 124 g Sitagliptin phosphate monohydrate.
Yield = 1.24
Purity by HPLC = 99.47 %
Amino-TFPBA impurity Content = 0.5-2.0 %
Total Impurities = 0.63%
Example 1:
R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole[4,3-α]pyrazin-7(8H)-
yl)-1-(2,4,5-trifluorophenyl) butan-2-yl)carbamate (eq. to 100 g of (R)-3-((tert15
butoxycarbonyl) amino)-4-(2,4,5-trifluorophenyl)butanoic acid) which was prepared as
per comparative example 1 as described earlier, is taken in flask and Methanolic.HCl (25-
30%) is slowly added it at 0-5 °C. The temperature was increased to 20-30 ºC followed by
stirring of reaction mass till reaction completion. After the confirmation of reaction
completion by HPLC/TLC, instead of performing routine complete recovery of reaction
mass, caustic solution is added to the reaction mass followed by stirring for 1-3 hours. The
reaction mass is then extracted with methylene chloride (200 ml) twice. This methylene
chloride layer is then recovered under vacuum to give 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-
trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine
or Sitagliptin base.
Yield = 0.71
Purity by HPLC = 99.82%
Amino-TFPBA impurity Content = 0 - 0.10 %
Total Impurities = 0.18 %.
Example 2:
7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-
(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine or Sitagliptin base (100.0 g) as prepared in
example 1 was taken in isopropyl alcohol (250 ml) and stirred. Now orthophosphoric acid
(30 g) is charged along with de-ionized water (90 ml). The resulting reaction mass is now
stirred at room temperature for 20-30 minutes, followed by its refluxing at 75-85 °C for 60-
75 minutes. Then reaction mass is cooled to 55-60 °C and stirred for 3-5 hours. After
stirring the reaction mass is seeded with crystals of Sitagliptin phosphate (2.5 g). Now the
16
temperature is further reduced 20-25 °C and stirred for 3-4 hours. Isopropyl alcohol (600
ml) is further added to the above reaction mass and stirred for 6-8 hours for complete
crystallization. This was followed by its filtration and running washing with isopropyl
alcohol (30 ml). The resulting solid is dried at 50-60 ºC for 4-8 hours to get high purity
Sitagliptin phosphate monohydrate.
Yield = 1.20
Purity by HPLC = 99.97 %
Amino TFPBA impurity content = 0.01%
Total Impurities = 0.03 %

We Claim:
1. An improved process for the preparation of Sitagliptin Phosphate, having low 3-amino-
4-(2,4,5-trifluorophenyl)butanoic acid impurity (Amino TFPBA; Formula 5) content,
which comprises:
a) Charging of (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-
[1,2,4]triazole [4,3-α]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-
yl)carbamate (Formula 3) in a Hydrogen chloride saturated (25-30% ) C1-C4
alcohol
b) Heating & stirring for reaction completion
c) Checking of reaction completion by HPLC/TLC
d) Quenching of reaction mass in aq. caustic solution or vise versa
e) Stirring of reaction mass for 1-3 hours.
f) Charging of a halogenated hydrocarbon for extraction of product from aqueous
layer.
g) Stirring & layer separation
h) Complete recovery of solvent to give pure 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-tri
fluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]
pyrazine or Sitagliptin base
i) Drying for 10-12 hours to get pure Sitagliptin base or 7-[(3R)-3-Amino-1-oxo-4-
(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-
triazolo[4,3-a] pyrazine with low impurity content of Amino TFPBA (Formula
5).
18
2. A process of claim 1, in which the preferred temperature in step a) is 0-5°C.
3. A process of claim 1, in which the temperature of step b) is 20-40 °C or preferably
20-35 °C or even more preferably 20-30 °C.
4. A process of claim 1, in which the halogenated hydrocarbon used in step f) is selected
from methylene chloride, chloroform or carbon tetrachloride or mixture thereof.
5. A process for preparation of highly pure 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluoro
phenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine
phosphate monohydrate or Sitagliptin phosphate monohydrate which comprises
a) Charging of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-
tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine or Sitagliptin base
as per claim 1, in an C1-C4 alcohol
b) Addition of orthophosphoric acid & water to it
c) Stirring of reaction mass for 20-30 min at ambient temperature
d) Heating of reaction mass to reflux & further stirring for 60-75 min.
e) Cooling of reaction mass & stirring for 4-5 hours.
f) Seeding
g) Further cooling of reaction mass to 20-25 °C & stirring for 3-4 hours.
h) Addition of C1-C4 alcohol to the reaction masss.
i) Further stirring of reaction masss. for 6-8 hours.
19
j) Isolation of highly pure 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluoro
phenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-
a]pyrazine phosphate monohydrate or Sitagliptin phosphate monohydrate by
filtration.
k) Drying of isolated solid at 50-60 °C for 4-8 hours
l)
6. A process of claim 5, wherein the C1-C4 alcohol used in step a) & h) is selected from
methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene
glycol or a mixture thereof..
7. A process of claim 5, wherein the temperature for crystallization in step e) is sensitive
for proper crystallization of product and is preferably 50-65 °C, more preferable 55-65
°C and even more preferably 55-60 °C.