Note: Descriptions are shown in the official language in which they were submitted.
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SAXAGLIPTIN SALTS
Field of the Invention
The present invention provides saxagliptin bisulphate, saxagliptin acetate,
saxagliptin oxalate, saxagliptin bicarbonate, and saxagliptin carbonate, their
polymorphic
forms, processes for their preparation, and pharmaceutical compositions
thereof.
Background of the Invention
Saxagliptin of Formula A, an orally-active inhibitor of the dipeptidyl
peptidase IV
enzyme, chemically designated as (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-
hydroxytricyclo
[3.3.1.13'7]dec-1-yDacetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, is
indicated as an
adjunct to diet and exercise to improve glycemic control in adults with type 2
diabetes
mellitus.
H2N
o
CN
Formula A
U.S. Patent No. 6,395,767 (hereinafter "the '767 patent") provides a process
for the
preparation of the saxagliptin trifluoroacetate salt The '767 patent also
provides the
hydrochloride salt of saxagliptin.
U.S. Patent No. 7,943,656 provides a process for the preparation of
crystalline
forms of saxagliptin free base, hydrochloride, hydrobromide, hydroiodide,
fumarate (2:1),
tartrate, benzoate, trifluoroacetate, ammonium sulfate complex, and nitrate.
PCT Publication No. WO 2010/115974 provides a process for the preparation of
anhydrous crystalline forms of saxagliptin hydrochloride.
PCT Publication No. WO 2012/017028 provides a process for the preparation of
crystalline forms of saxagliptin phosphate.
PCT Publication No. WO 2012/017029 provides a process for the preparation of a
crystalline compound comprising a mixture of saxagliptin and an organic C4-
diacid,
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wherein the organic C4-diacid is selected from maleic acid, malic acid, L-
malic acid, D-
malic acid, and succinic acid.
PCT Publication No. WO 2012/047871 provides a process for the preparation of
crystalline Form K, Form Z, Form D, and amorphous saxagliptin hydrochloride.
Chinese Publication No. CN 102086172 provides a process for the preparation of
mesylate, maleate, malate, succinate, and citrate salts of saxagliptin.
Several processes are known in the literature for making saxagliptin, or a
salt
thereof, for example, PCT Publication Nos. WO 2004/052850, WO 2005/115982, WO
2005/106011 and WO 2005/094323.
In the pharmaceutical industry there is a constant need to identify the
critical
physicochemical parameters such as novel salts and novel polymorphic forms
that affect
the drug's performance, stability, etc., which may play a key role in
determining a drug's
market acceptance and success.
Since saxagliptin or its salts constitute an important therapeutic agent,
additional
saxagliptin salts are of value to pharmaceutical science. Thus, there is a
need for the
development of novel saxagliptin salts having improved solubility, stability,
bioavailability, storage and handling stability, and less susceptibility to
degradation at
lower temperatures.
Accordingly, the present inventors have prepared saxagliptin bisulphate,
saxagliptin acetate, saxagliptin oxalate, saxagliptin bicarbonate, and
saxagliptin carbonate
salts. The salts of the present invention are easy to prepare and isolate in
solid forms,
particularly, in crystalline forms. Further, they can be prepared by an
efficient,
economical, and reproducible process, which is particularly suited to large
scale
preparation.
Summary of the Invention
A first aspect of the present invention provides saxagliptin bisulphate.
A second aspect of the present invention provides a crystalline form of
saxagliptin
bisulphate.
A third aspect of the present invention provides saxagliptin acetate.
2
=
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A fourth aspect of the present invention provides a crystalline form of
saxagliptin
acetate.
A fifth aspect of the present invention provides saxagliptin oxalate.
A sixth aspect of the present invention provides a crystalline form of
saxagliptin
oxalate.
A seventh aspect of the present invention provides a process for the
preparation of
a compound of Formula I
HO giti
H2N = HA
0 CN
Formula I
which comprises treating saxagliptin or its salt with HA, wherein HA is
selected from
sulphuric acid, acetic acid, and oxalic acid.
An eighth aspect of the present invention provides saxagliptin bicarbonate of
Formula II.
40: =CN
0
0
OH NH30
0
Formula II
A ninth aspect of the present invention provides a crystalline form of
saxagliptin
bicarbonate.
A tenth aspect of the present invention provides a process for the preparation
of
saxagliptin bicarbonate, which comprises contacting saxagliptin or its salt
with a suitable
carbonate source.
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An eleventh aspect of the present invention provides saxagliptin carbonate of
Formula III.
40: .C1
OH NH: 0-
2 ()-
Formula III
A twelfth aspect of the present invention provides a crystalline form of
saxagliptin
carbonate.
A thirteenth aspect of the present invention provides a process for the
preparation
of saxagliptin carbonate, which comprises heating saxagliptin bicarbonate,
optionally in
the presence of water.
A fourteenth aspect of the present invention provides the use of saxagliptin
salts
selected from saxagliptin bisulphate, saxagliptin acetate, saxagliptin
oxalate, saxagliptin
bicarbonate, or saxagliptin carbonate for the preparation of saxagliptin or
salts, solvates, or
polymorphs thereof.
A fifteenth aspect of the present invention provides a pharmaceutical
composition
comprising saxagliptin salts selected from saxagliptin bisulphate, saxagliptin
acetate,
saxagliptin oxalate, saxagliptin bicarbonate, or saxagliptin carbonate, and a
pharmaceutically acceptable carrier.
A sixteenth aspect of the present invention provides a method of treating type
2
diabetes mellitus which comprises administering to a patient in need thereof a
therapeutically effective amount of saxagliptin salts selected from
saxagliptin bisulphate,
saxagliptin acetate, saxagliptin oxalate, saxagliptin bicarbonate, or
saxagliptin carbonate,
and a pharmaceutically acceptable carrier.
Detailed Description of the invention
A first aspect of the present invention provides saxagliptin bisulphate.
A second aspect of the present invention provides a crystalline form of
saxagliptin
bisulphate. The crystalline form of saxagliptin bisulphate of the present
invention may be
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characterized by an XRPD pattern substantially the same as depicted in Figure
1,
exhibiting interplanar spacing (d) values at about 3.63, 3.39, 3.27, and 3.20
(A), and
further exhibiting interplanar spacing (d) values at about 4.22, 3.89, 3.09,
3.05, 2.98, 2.91,
2.79, and 2.63 (A). The crystalline form of saxagliptin bisulphate has an XRPD
pattern
with characteristic peak values (20) at about 24.50, 26.26, 27.25, and 27.84
0.2 , and
additional characteristic peak values (20) at about 21.04, 22.82, 28.89,
29.26, 29.98, 30.71,
32.05, and 34.06 0.2 . The crystalline form of saxagliptin bisulphate of the
present
invention may be characterized by FTIR as depicted in Figure 2. The
crystalline form of
saxagliptin bisulphate of the present invention may be characterized by DSC as
depicted in
Figure 3, with a characteristic endothermic peak value at about 100.90 C in
the DSC
thermogram.
A third aspect of the present invention provides saxagliptin acetate.
A fourth aspect of the present invention provides a crystalline form of
saxagliptin
acetate. The crystalline form of saxagliptin acetate of the present invention
may be
characterized by an XRPD pattern substantially the same as depicted in Figure
4,
exhibiting interplanar spacing (d) values at about 11.97, 9.84, 5.98, 4.96,
and 4.91 (A), and
further exhibiting interplanar spacing (d) values substantially at about 6.27,
5.16, 4.71,
4.68, 4.50, 4.45, 3.99, and 3.87 (A). The crystalline form of saxagliptin
acetate has an
XRPD pattern with characteristic peak values (20) at about 7.38, 8.98, 14.79,
17.85, and
18.03 0.2 , and additional characteristic peak values (20) at about 14.12,
17.17, 18.82,
18.92, 19.70, 19.94, 22.26, and 22.97 0.2 . The crystalline form of
saxagliptin acetate of
the present invention may be characterized by FTIR as depicted in Figure 5.
The
crystalline form of saxagliptin acetate of the present invention may be
characterized by
DSC as depicted in Figure 6, with characteristic endothermic peak values at
about 68.12,
79.62, 152.38, and 161.14 C in the DSC thermogram.
A fifth aspect of the present invention provides saxagliptin oxalate.
A sixth aspect of the present invention provides a crystalline form of
saxagliptin
oxalate. The crystalline form of saxagliptin oxalate of the present invention
may be
characterized by an XRPD pattern substantially the same as depicted in Figure
7,
exhibiting interplanar spacing (d) values substantially at about 12.99, 6.28,
4.96, 4.91, and
4.67 (A), and further exhibiting interplanar spacing (d) values at about 5.99,
5.93, 5.69,
4.59, 4.32, 4.01, and 3.08 (A). The crystalline form of saxagliptin oxalate
has an XRPD
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pattern with characteristic peak values (20) at about 6.80, 14.06, 17.88,
18.06, and 18.98
0.2 , and additional characteristic peak values (20) at about 14.76, 14.93,
15.56, 19.30,
20.54, 22.15, and 28.97 0.2 . The crystalline form of saxagliptin oxalate of
the present
invention may be characterized by FTIR as depicted in Figure 8. The
crystalline form of
saxagliptin oxalate of the present invention may be characterized by DSC as
depicted in
Figure 9, with a characteristic endothermic peak value at about 61.67 C, and a
characteristic exothermic peak value at about 186.24 C in the DSC thermogram.
A seventh aspect of the present invention provides a process for the
preparation of
a compound of Formula I
HO
H2N = HA
=
CN
Formula I
which comprises treating saxagliptin or its salt with HA, wherein HA is
selected from
sulphuric acid, acetic acid, or oxalic acid.
The saxagliptin or its salt used as the starting material may be prepared by
any of
the methods known in the art including those described in, for example, U.S.
Patent Nos.
6,395,767, and 7,943,656; PCT Publications WO 2004/052850, WO 2005/115982, WO
2005/106011, WO 2005/094323, WO 2010/115974, WO 2012/017028, WO 2012/017029,
and WO 2012/047871.
The saxagliptin or its salt prepared by any of the methods known in the art
may be
isolated or directly treated with HA.
The saxagliptin or its salt prepared by any of the methods known in the art
may be
optionally purified prior to treatment with HA to remove foreign particulate
matter.
Alternatively, it may be treated with activated charcoal to remove coloring
and other
related impurities in a suitable solvent. The solution of saxagliptin or its
salt may be
optionally concentrated to reduce the amount of solvent. The saxagliptin salt
may
optionally be converted to saxagliptin base before treatment with HA.
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Treating saxagliptin or its salt with HA may include adding, dissolving,
slurrying,
stirring, or a combination thereof. Saxagliptin or its salt may be treated
with HA directly,
or in the presence of a suitable solvent at a suitable temperature.
The term "solvent" includes any solvent, or a solvent mixture, including for
example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers,
polar aprotic
solvents, or mixtures thereof.
Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate,
and n-
butyl acetate. Examples of alkanols include those primary, secondary, and
tertiary
alcohols having from one to six carbon atoms. Examples of suitable alkanols
include
methanol, ethanol, n-propanol, isopropanol, and butanol. Examples of
halogenated
hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
Examples of
ketones include acetone and methyl ethyl ketone. Examples of ethers include
diethyl ether
and tetrahydrofuran. Examples of polar aprotic solvents include N,N-
dimethylformamide,
N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-
methylpyrrolidone.
Saxagliptin or its salt is treated with HA at a temperature of from about -10
C to
about 10 C, preferably, from about -5 C to about 5 C. The formation of the
saxagliptin
salt may be accelerated by stirring the reaction mixture for about 10 minutes
to about 4
hours at a temperature of from about -5 C to about 40 C, preferably from about
0 C to
about 25 C. After completion of the reaction, the saxagliptin salt of Formula
I may be
isolated by filtration, decantation, solvent precipitation, trituration,
evaporation,
distillation, or combinations thereof.
An eighth aspect of the present invention provides a saxagliptin bicarbonate
of
Formula II.
ieCrACN
0
()-
OH NH30
0
Formula II
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A ninth aspect of the present invention provides a crystalline form of
saxagliptin
bicarbonate. The crystalline form of saxagliptin bicarbonate of the present
invention may
be characterized by an XRPD pattern substantially the same as depicted in
Figure 10,
exhibiting interplanar spacing (d) values at about 3.70, 2.99, and 2.86 (A),
and further
exhibiting interplanar spacing (d) values at about 7.45, 3.17, 3.12, 2.64,
2.39, and 2.30
(A). The crystalline form of saxagliptin bicarbonate has an XRPD pattern with
characteristic peak values (20) at about 24.05, 29.84, and 31.18 0.2 , and
additional
characteristic peak values (20) at about 11.86, 28.13, 28.60, 33.88, 37.55,
and 39.01
0.2 . The crystalline form of saxagliptin bicarbonate of the present invention
may be
characterized by FTIR as depicted in Figure 11. The crystalline form of
saxagliptin
bicarbonate of the present invention may be characterized by DSC as depicted
in Figure
12, with a characteristic endothermic peak value at about 76.94 C in the DSC
thermogram.
A tenth aspect of the present invention provides a process for the preparation
of
saxagliptin bicarbonate, which comprises contacting saxagliptin or its salt
with a suitable
carbonate source.
The saxagliptin or its salt prepared by any of the methods known in the art
may be
isolated or directly treated with a suitable carbonate source.
The saxagliptin or its salt prepared by any of the methods known in the art,
before
treatment with a suitable carbonate source, may be optionally purified to
remove foreign
particulate matter or treated with activated charcoal to remove coloring and
other related
impurities in a suitable solvent. The solution of saxagliptin or its salt may
be optionally
concentrated to reduce the amount of solvent. The saxagliptin salt may
optionally be
converted to saxagliptin base before treatment with a suitable carbonate
source, optionally
in the presence of a base.
The term "carbonate source" includes carbon dioxide gas, dry ice, and carbonic
acid prepared in situ by dissolving carbon dioxide gas in water.
The term "base" includes hydroxides, carbonates, and bicarbonates of alkali
and
alkaline earth metals; ammonia; alkyl amines; hydrazine; and the like.
Examples of
hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals
may include
lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate,
potassium
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carbonate, sodium bicarbonate, or potassium bicarbonate. Examples of alkyl
amines may
include diethyl amine, triethyl amine, or methyl diethyl amine.
Treating saxagliptin or its salt with a suitable carbonate source may include
adding,
dissolving, slurrying, stirring, or combinations thereof. Saxagliptin or its
salt may be
treated with a suitable carbonate source directly or in the presence of a
suitable solvent at a
suitable temperature.
The term "solvent" includes any solvent, or a solvent mixture, including for
example, water, alkanols, esters, ketones, polar aprotic solvents, or mixtures
thereof.
Examples of alkanols include primary, secondary and tertiary alcohols having
from one to
six carbon atoms. Examples of suitable alkanols include methanol, ethanol, n-
propanol,
isopropanol, and butanol. Examples of esters include ethyl acetate, n-propyl
acetate,
isopropyl acetate, and n-butyl acetate. Examples of ketones include acetone
and methyl
ethyl ketone. Examples of polar aprotic solvents include N,N-
dimethylformamide, N,N-
dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
In a specific embodiment of this aspect, saxagliptin is treated with dry ice
at a
temperature of from about 20 C to about 30 C, in ethanol while stirring for
about 30
minutes to about 1 hour, preferably, from about 35 minutes to about 45
minutes. Ethanol
is removed by distillation under vacuum, followed by the addition of ethyl
acetate while
stirring. Saxagliptin bicarbonate of Formula II may be isolated by filtration,
decantation,
solvent precipitation, trituration, evaporation, distillation, or combinations
thereof.
An eleventh aspect of the present invention provides saxagliptin carbonate of
Formula III.
q0
0-
-Z3
OH
- 2 -
Formula III
A twelfth aspect of the present invention provides a crystalline form of
saxagliptin
carbonate. The crystalline form of saxagliptin carbonate of the present
invention may be
characterized by FTIR as depicted in Figure 13. The crystalline form of
saxagliptin
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carbonate of the present invention may be characterized by DSC as depicted in
Figure 14.
The crystalline form of saxagliptin carbonate has a characteristic endothermic
peak value
at about 113.45 C in the DSC thermogram.
A thirteenth aspect of the present invention provides a process for the
preparation
of saxagliptin carbonate, which comprises heating saxagliptin bicarbonate,
optionally in
the presence of water.
In a specific embodiment of this aspect, saxagliptin bicarbonate is dissolved
in
water and stirred at a temperature of from about 50 C to about 100 C,
preferably, from
about 65 C to about 70 C, for about 3 hours to about 6 hours, preferably, for
about 4 hours
to about 5 hours. Water is then removed by distillation under vacuum. The
residue
obtained is stirred with ethyl acetate and then removed by distillation under
vacuum to
obtain the solid. The solid may be washed with ethyl acetate, and is then
isolated by
filtration, decantation, solvent precipitation, trituration, evaporation,
distillation, or
combinations thereof to obtain the saxagliptin carbonate.
A fourteenth aspect of the present invention provides the use of saxagliptin
salts
selected from saxagliptin bisulphate, saxagliptin acetate, saxagliptin
oxalate, saxagliptin
bicarbonate, or saxagliptin carbonate for the preparation of saxagliptin or
salts, solvates, or
polymorphs thereof.
Saxagliptin salts may be used for the preparation of saxagliptin by contacting
with
a base or heating, optionally in the presence of water. The base may be
selected from the
group comprising of hydroxides, carbonates, and bicarbonates of alkali and
alkaline earth
metals; ammonia; alkyl amines; hydrazine; and the like. Examples of
hydroxides,
carbonates, and bicarbonates of alkali and alkaline earth metals include
lithium hydroxide,
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
sodium
bicarbonate, or potassium bicarbonate. Examples of alkyl amines may include
diethyl
amine, triethyl amine, or methyl diethyl amine. Saxagliptin thus obtained may
be
converted to salts, solvates, or polymorphs thereof.
A fifteenth aspect of the present invention provides a pharmaceutical
composition
comprising saxagliptin salts selected from saxagliptin bisulphate, saxagliptin
acetate,
saxagliptin oxalate, saxagliptin bicarbonate, or saxagliptin carbonate, and a
pharmaceutically acceptable carrier.
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A sixteenth aspect of the present invention provides a method of treating type
2
diabetes mellitus which comprises administering to a patient in need thereof a
therapeutically effective amount of saxagliptin salts selected from
saxagliptin bisulphate,
saxagliptin acetate, saxagliptin oxalate, saxagliptin bicarbonate, or
saxagliptin carbonate,
and a pharmaceutically acceptable carrier.
Brief Description of the Figures
Figure 1 and Figure la depict the X-Ray Powder Diffractogram (XRPD) of
saxagliptin bisulphate and the associated values, respectively, prepared as
per Example 1.
Figure 2 depicts the Fourier-Transform Infra-red (FTIR) spectrum of
saxagliptin
bisulphate prepared as per Example 1.
Figure 3 depicts the Differential Scanning Calorimetry (DSC) of saxagliptin
bisulphate prepared as per Example 1.
Figure 4 and Figure 4a depict the XRPD of saxagliptin acetate and the
associated
values, respectively, prepared as per Example 2.
Figure 5 depicts the FTIR spectrum of saxagliptin acetate prepared as per
Example
2.
Figure 6 depicts the DSC of saxagliptin acetate prepared as per Example 2.
Figure 7 and Figure 7a depict the XRPD of saxagliptin oxalate and the
associated
values, respectively, prepared as per Example 4.
Figure 8 depicts the FTIR spectrum of saxagliptin oxalate prepared as per
Example
4.
Figure 9 depicts the DSC of saxagliptin oxalate prepared as per Example 4.
Figure 10 and Figure 10a depict the XRPD of saxagliptin bicarbonate and the
associated values, respectively, prepared as per Example 5.
Figure 11 depicts the FTIR spectrum of saxagliptin bicarbonate prepared as per
Example 5.
Figure 12 depicts the DSC of saxagliptin bicarbonate prepared as per Example
5.
Figure 13 depicts the FTIR spectrum of saxagliptin carbonate prepared as per
Example 6.
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Figure 14 depicts the DSC of saxagliptin carbonate prepared as per Example 6.
The XRPD of the samples were determined by using Instrument: PANalytical;
Mode: Expert PRO; Detector: Xcelerator; ScanRange: 3-40; Step size: 0.02;
Range: 3-40
degree 2 theta; CuKa radiation at 45kV.
FTIR of the samples was determined by using Instrument: Perkin Elmer; SCAN:
16 scans, Resolution: 4.0 cm-I; potassium bromide pellet method.
DSC of the samples was determined by using Instrument: Perkin Elmer, Diamond
DSC. Data collection parameters: Scanning rate: 10 C/min; Temperature: 30 C -
300 C.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those
skilled in the
art, and are intended to be included within the scope of the present
invention.
EXAMPLES
Example 1: Preparation of Saxagliptin bisulphate
A mixture of saxagliptin (1.5 g) and ethyl acetate (30 mL) was stirred and
cooled
to -5 C, followed by drop-wise addition of sulphuric acid solution (0.466 g)
in ethyl
acetate (15 mL) at -5 C to 0 C for 5 minutes. The temperature of the reaction
mixture was
raised to 15 C with continuous stirring for 15 minutes, followed by the
addition of
methanol (4.5 mL), and then stirred for 30 minutes at 15 C to 20 C. The
solvent was
distilled off from the reaction mixture completely under vacuum at 35 C. Ethyl
acetate
(45 mL) was charged, and stirred at 20 C to 22 C for 14 hours to obtain the
solid. The
solid was filtered under vacuum in nitrogen environment, washed with n-hexane
(20 mL),
and dried under vacuum at 35 C to 40 C for about 7 hours to obtain the title
compound.
Yield: 1.5 g
Example 2: Preparation of Saxagliptin acetate
A mixture of saxagliptin (1.13 g) and isopropanol (10 mL) was stirred, and
cooled
to 5 C, followed by the addition of acetic acid (0.22 g) at 5 C to 10 C, and
then stirred for
1 hour while gradually raising the temperature to about 20 C to 25 C. The
reaction
mixture was cooled to 0 C to 5 C, and then stirred for 4 hours, maintaining
the same
temperature, to obtain a white solid. The solid was filtered through a
sintered funnel under
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vacuum in a nitrogen environment, washed with isopropanol (10 mL), and dried
under
vacuum at 40 C to 45 C for 12 hours to 14 hours to obtain the title compound.
Yield: 400 mg
Example 3: Preparation of Saxagliptin acetate from Saxagliptin
trifluoroacetate
A mixture of saxagliptin trifluoroacetate (1.5 g) and dichloromethane (30 mL)
was
charged in a round bottomed flask, stirred, and cooled to 0 C. 8% Aqueous
sodium
bicarbonate solution (9 mL) was added drop-wise to the reaction mixture over 5
minutes at
0 C to 2 C. The mixture was stirred, and the temperature was raised to 18 C.
Sodium
chloride (4.5 g) was added, and stirred at 17 C to 19 C for 25 minutes, and
filtered
through a cotton plug. The filtrate obtained was allowed to settle for 10
minutes. The
aqueous layer was extracted thrice with dichloromethane (10 mL). All the
organic layers
were combined. Sodium sulphate was added, and filtered through a cotton plug.
The
filtrate was cooled to 15 C in 5 minutes. Dichloromethane-acetic acid solution
(2 mL of
dichloromethane in 0.2 mL of acetic acid) was added to the filtrate at 15 C.
The solvent
was distilled off to the maximum extent under reduced pressure at 15 C, and
then ethyl
acetate (15 mL) was added, and stirred at 15 C for 30 minutes. The solid
obtained was
filtered under vacuum, washed with chilled ethyl acetate (5 mL), and kept
under vacuum
suction for 5 minutes. The material obtained was dried under vacuum at 20 C to
25 C for
14 hours to 16 hours to obtain the title compound.
Yield: 840 mg
Example 4: Preparation of Saxagliptin oxalate
A mixture of saxagliptin (1.0 g) and dichloromethane (15 mL) was stirred and
cooled to 0 C, followed by the addition of oxalic acid (0.358 g) and
isopropanol (3 mL) at
0 C. The reaction mixture was stirred for 2 hours at 0 C to 5 C, and further
stirred for
another 2 hours at 8 C to 10 C to obtain the white solid. The solid was
filtered under
vacuum, washed with dichloromethane (5 mL), and dried under vacuum at 33 C to
37 C
for 8 hours to obtain the title compound.
Yield: 200 mg
Example 5: Preparation of Saxagliptin bicarbonate
Saxagliptin hydrochloride (5 g) was dissolved in water (50 mL) at 22 C,
stirred,
and cooled to 1 C in 15 minutes, followed by drop-wise addition of 10% aqueous
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potassium carbonate solution (20 mL) at 0 C to 5 C over 10 minutes to adjust
the pH to
8.3. The reaction mixture was stirred for 10 minutes at 5 C and the pH was
checked and
adjusted to 8.3. The water in the reaction mixture was distilled off under
vacuum at 25 C
in 2 hours, followed by the addition of ethanol (60 mL). The inorganic
substances in the
reaction mixture were filtered under vacuum. The inorganic substances were
washed with
ethanol (15 mL) and filtered to obtain filtrate. The obtained filtrates were
distilled off
under vacuum at 25 C in 1 hour to obtain an oily mass.
The oily mass of saxagliptin free base (6.2 g) was dissolved in ethanol (15
mL) at
25 C, and stirred for 10 minutes. Dry ice (50 g) was added slowly under
stirring in 35
minutes. Ethanol was distilled off under vacuum completely at 25 C in 30
minutes to
obtain a sticky mass. Ethyl acetate (60 mL) was added to the sticky mass, and
stirred at
25 C for 30 minutes to obtain a solid. The solid obtained was filtered, washed
with ethyl
acetate (10 mL), and then dried under vacuum for 14 hours at 25 C to obtain
the title
compound.
Yield: 2.52 g
Example 6: Preparation of Saxagliptin carbonate
Saxagliptin bicarbonate (300 mg) obtained as per Example 5 was dissolved in
water (30 mL) and stirred for 4 hours at 65 C to 70 C. The water in the
reaction mixture
was recovered at 65 C to 70 C under vacuum to obtain a residue. To the
residue, ethyl
acetate (20 mL) was added, stirred for 10 minutes at 55 C, and the solvent was
recovered
under vacuum at 50 C to 55 C to obtain a solid mass. To the solid mass, ethyl
acetate (10
mL) was added, and stirred for 15 minutes. The solid obtained was filtered,
then dried
under vacuum at 65 C for 14 hours to obtain the title compound.
Yield: 150 mg
14
