The present invention relates to an improved, efficient, and industrially advantageous process for preparation of dipeptidyl peptidase-4 (DPP-4) inhibitor, saxagliptin monohydrate of formula I.
A1
on
.][sO Formula (T)
Particularly, the present invention provides an improved process for the preparation of saxagliptin monohydrate of formula I from saxagliptin hydrochloride in the absence of an organic solvent. BACKGROUND OF THE INVENTION
Saxagliptin monohydrate of formula I, marketed under the trade name ONGLYZA®,
is a cyclopropyl-fused pyrrolidine indicated to improve glycemic control in adults with
type 2 diabetes mellitus.
Saxagliptin monohydrate is described chemically as (lS,3S,5S)-2-[(2S)-2-amino-2-
(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3 -
carbonitrile monohydrate or (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-
yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrate.
Saxagliptin hydrochloride and its process of preparation were first described in US
patent 6,395,767 (reissued asRE44186).
US patent 6,395,767 has also described following process of Scheme 1 for the
preparation of saxagliptin and its pharmaceutically acceptable salts thereof:



I AH
R.-(-)-2-F]ienvl£lyciD<)[
O
nci
fix

m^
COOI1
^"^ NHEiiC
OSiEl,
iA
Y

NFEBot
,TFA
Schpltll! 1
The above process involves the use of toxic potassium cyanide. It also employs use of
highly reactive, hygroscopic, and pyrophoric, lithium aluminium hydride, which is less
favored on commercial scale.
The US patent 7,186,846 has described process for the preparation of saxagliptin base
through the reductive cleavage of a saxagliptin protected with o-trifluoroacetyl group.
US patent 7,214,702 describes process for the preparation of saxagliptin and its
hydrochloride salt.
US patent 8,278,462 describes saxagliptin monohydrate and following process of
Scheme 2 for the preparation from saxagliptin hydrochloride employing sodium
hydroxide and water in an organic solvent.
OH OH OH
.H20
Scheme 2

It has also disclosed process for the preparation of saxagliptin including free base thereof, free base monohydrate thereof, hydrochloric acid thereof and benzoate salt thereof. In the said process hydrochloride salt of saxagliptin (present in organic layer) is treated with methylene chloride and water and 5N sodium hydroxide solution is added dropwise while maintaining reaction temperature between 20 and 25° C to adjust pH between 9 and 10.5. After pH adjustment, saxagliptin free base is isolated by separating the organic layer followed by washing and concentrating organic layer. Finally, the resulting saxagliptin is crystallized with water and ethyl acetate to give saxagliptin monohydrate.
The said process suffers from the draw back such as use of organic solvent for separating layers after pH adjustment and isolation of saxagliptin free base makes the process lengthy and costly.
US patent 7,943,656 describes saxagliptin free base, hydrates thereof (H.5-2 and H-l), pharmaceutically acceptable salts of saxagliptin other than the trifluoroacetic acid salt, and process for the preparation thereof. It has described four hydrate hydrochloride forms of saxagliptin (H2-1, HO.75-3, HI.25-2, HI.67-1), oneanhydrate hydrochloride (P-5) and one dihydrated dihydrochloride(H2-l diHCl) form. US patent 8,501,960 relates to Saxagliptin Schiff bases. It describes preparation of crystalline saxagliptin monohydrate form H-l from amorphous Saxagliptin in an atmosphere of a solvent selected from ethanol, dibutyl ether, and water. It also describes preparation of a mixture of crystalline Saxagliptin monohydrate form H-l and crystalline Saxagliptin hemihydrate form HO .5-2.
US patent 9,199,933 describes process for the preparation of the saxagliptin. It has also disclosed preparation of saxagliptin monohydrate from saxagliptin hydrochloride employing water and adjusting pH with sodium carbonate solution in presence of organic solvents such as, methylene chloride and ethyl acetate and methylene chloride layer is separated and distilled under vacuum. The resulting residue is treated with ethyl acetate and purified water.

Indian patent application, IN 201611035865 describes process for the preparation of saxaghptin monohydrate from saxaghptin hydrochloride employing ammonia solution in presence of organic solvents for adjusting pH to 9.5 to 10.5 and methylene chloride layer is separated and distilled off. The resulting residue is treated with ethyl acetate and purified water to give saxaghptin monohydrate.
Organic Process Research and Development 2009, 13, 1169-1176 reports process for the preparation of saxaghptin monohydrate from saxaghptin hydrochloride in the presence of organic solvent. In the said process pH of reaction mixture is adjusted to ~9 with potassium carbonate. The obtained methylene chloride solution was partially distilled to a constant volume under atmospheric conditions. The remaining methylene chloride was chased with sufficient amount of ethyl acetate and adjusted the moisture content in ethyl acetate solution 5 to-1.5-2.0%.
There are also several patent applications disclosing polymorphs of saxaghptin and other specific salts of saxaghptin.
The prior art methods for the preparation of saxaghptin monohydrate described in literature and as detailed in above paragraphs particularly involve organic solvents followed by layer separation and/or distillation of solvent, which is neither cost-effective nor environment friendly instead of it is lengthy in process. None of theprior art publication described or suggested saxaghptin monohydratefrom saxaghptin hydrochloride in the absence of organic solvent or in presence of water, wherein layer separation and distillation of organic solvent is not done after pH adjustment.
Particularly, the prior art references are silent about the preparation of saxaghptin monohydrate in the absence of organic solvent, wherein layer separation and distillation of organic solvent is not done after pH adjustment. Therefore, having a commercially viable process with organic solvent was always a matter of concern. This attracted us to develop an ecofriendly and cost-effective process for the

preparation of saxagliptin monohydrate in the absence of organic solvent and in presence of water.
OBJECT OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of saxagliptin monohydrate of formula I.
on
&S4
iVH, 4__
][sO Formula (TJ
More particularly, the present invention provides an improved process for the
preparation of saxagliptin monohydrate of formula I from saxagliptin hydrochloride
in the absence of organic solvent.
Yet another objective of the present invention is to provide a process for the
preparation of saxagliptin monohydrate of formula I from saxagliptin hydrochloride
in the presence of water.
Yet another objective of the present invention is to provide an ecofriendly, simple,
cost-effective, efficient, and industrially advantageous process for the preparation of
saxagliptin monohydrate of formula I.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of saxagliptin monohydrate of formula I.

on
iVH, *
NH> CN

ILjO Formula (J)

In an aspect, the present invention provides an improved process for the preparation of saxagliptin monohydrate of formula I from saxagliptin hydrochloride of formula II,

on
to
HCI Formula (Hi
in the absence of an organic solvent.
In another aspect, the present invention provides a process for the preparation of saxagliptin monohydrate of formula I comprises:
a) converting saxagliptin hydrochloride of formula II to saxagliptin monohydrate of formula I in the presence of water; and
b) isolating saxagliptin monohydrate of formula I by precipitation.
In an aspect, the present invention provides an improved process for the preparation of substantially pure saxagliptin monohydrate of formula I, comprising the steps of:
on

LjO Formula (I)
iVH, 4
a) adding water to saxagliptin hydrochloride of formula II to get a reaction
mixture;
OH
* A
N \ . HCI Formula (Hi
Nil.. I
b) treating the resulting reaction mixture of step (a) with a suitable base at a suitable temperature;
c) isolating saxagliptin monohydrate of formula I;
d) washing saxagliptin monohydrate of formula I of step (c) with water;
e) optionally, washing saxagliptin monohydrate of formula I of step (c) with a suitable organic solvent; and

f) drying finally isolated substantially pure saxagliptin monohydrate of formula I at a suitable temperature.
In another aspect, the present invention provides a process for the preparation of saxagliptin hydrochloride of formula II.
In another aspect, the present invention provides a process for the preparation of compound of formula IX.
OH
Atf -
0=^ CN
O
-A
In another aspect, the present invention provides a process for the preparation of saxagliptin monohydrate of formula I and saxagliptin hydrochloride of formula II substantially free of impurities.
In another aspect, the present invention provides a process for the preparation of crystalline saxagliptin free base monohydrate Form H-l.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows an X-ray powder diffraction (XRPD)pattern of crystalline saxagliptin
free base monohydrate Form H-l of formula I prepared according to process of present
invention.
Figure 2 shows differential scanning calorimetry (DSC) thermogram of crystalline
saxagliptin free base monohydrate Form H-l of formula I prepared according to
process of present invention.
Figure 3 shows an X-ray powder diffraction (XRPD) pattern of crystalline saxagliptin
hydrochloride dihydrate (H2-1) of formula II prepared according to process of present
invention.

DETAILED DESCRIPTION OF THE INVENTION
The present disclosure encompasses improved process for the preparation of
saxagliptin monohydrate of formula I.
As discussed above, the processes described in the literature have significant
disadvantages. More particularly, the process described in prior art employ organic
solvent i.e. methylene chloride for layer separation which increases environmental
loading and cost.
Therefore, the reported processes may not be considered suitable for large scale
production.
As used herein, the modifier term "about" should be considered as disclosing the range
defined bythe absolute values ofthetwoendpoints. For example, the expression "from
about 5 to about 10" also discloses the range "from 5 to 10." When used to modify a
single number, the term "about" may refer to plus or minus 10% of the indicated
number and includes the indicated number e.g., "about 10%" may indicate a range
from 9% to 11%, and "about 1" may be from 0.9-1.1.
As used herein, and unless otherwise specified, the term "isolated" in reference to the
compounds of the present invention, their salts or solid-state forms thereof corresponds
to compounds that are physically separated from the reaction mixture in which they
are formed.
As used herein, and unless otherwise specified, the term "reduced pressure" refers to
a pressure of about 10 mbar to about 500 mbar, or about 50 mbar.
As used herein, and unless otherwise specified, the term "substantially free" is meant
that the saxagliptin monohydrate of formula I or saxagliptin hydrochloride of formula
II or any other intermediate thereof of the present invention contain about 2% (w/w)
or less, about 1% (w/w) or less, about 0.5% (w/w) or less, or about 0.2% (w/w) or less,
or about 0.1% (w/w) or less of a specified or unspecified impurity.
As used herein, and unless otherwise specified, the term "substantially pure" relates to
compounds having a purity of about 95% or more. In other words, the term relates a

compound, having a purity, measured as % area normalization by HPLC, of about 95%
or more. In other embodiments, the term relates to compounds having a purity of about
more than 97% area normalization by HPLC. In preferred embodiments, the term
relates to compounds having a purity of about more than 98% (by HPLC; area
normalization).
In one aspect, the present invention provides an improved process for the preparation
of saxagliptin monohydrate of formula I.
A*
on
- ILjO Formula {T)
In another aspect, the present invention provides an improved process for the preparation of saxagliptin monohydrate of formula I from saxagliptin hydrochloride of formula II in the absence of an organic solvent. Absence of an organic solvent means use of water only during the conversion of saxagliptin hydrochloride of formula II to saxagliptin monohydrate and use of organic solvent is avoided. The advantage of the said process is that there is no layer separation to get saxagliptin and saxagliptin in-situ converted to saxagliptin monohydrate in the present invention. In another aspect, the present invention provides a process for the preparation of saxagliptin monohydrate of formula I from saxagliptin hydrochloride of formula II in the presence of water and saxagliptin monohydrate of formula I is isolated by precipitation.
In the said process ester solvent is used along with water for preparing saxagliptin monohydrate of formula I. The ester solvent is selected from the group but not limited to ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate and alike or mixture thereof. The saxagliptin monohydrate of formula I prepared by the present invention is isolated by precipitation.

The advantage of the said process is that there is no layer separation and distillation of organic solvent to get saxagliptin and saxagliptin in-situ converted to saxagliptin monohydrate by precipitation method.
In an embodiment, the present invention provides an improved process for the
preparation of substantially pure saxagliptin monohydrate of formula I, comprising the
steps of:
A*
on
. HjO Formula (I)
a) adding water to saxagliptin hydrochloride of formula II to get a reaction
mixture;
Oil
&JL
\ . HCI Formula (II)
b) treating the resulting reaction mixture of step a) with a suitable base at a suitable temperature;
c) isolating saxagliptin monohydrate of formula I;
d) washing saxagliptin monohydrate of formula I of step c) with water;
e) optionally, washing saxagliptin monohydrate of formula I of step c) with a suitable organic solvent; and
f) drying finally isolated substantially pure saxagliptin monohydrate of formula I at a suitable temperature.
The saxagliptin monohydrate of formula I obtained at step c) is isolated by
precipitation.
The reaction mixture formed in the step a) is a clear solution when water as single
solvent is used. The reaction mixture of step a) is optionally filtered to get the clear
solution

In the said process at step a) ester solvent is used along with water to get a reaction mixture. The ester solvent is selected from the group but not limited to ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate and alike or mixture thereof. The saxagliptin monohydrate of formula I prepared by the present invention is isolated by precipitation.
The suitable base in step b) include inorganic and organic base and combination
thereof. Preferably, the base is an inorganic base, selected from, but are not limited to,
sodium hydroxide, ammonium hydroxide, potassium hydroxide, sodium carbonate,
potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixture thereof.
Most preferably, the base is ammonium hydroxide.
The suitable temperature in step b) is in the range of 0°C-50°C. Preferably, the
temperature range is in the range of 15°C-30°C.
The pH in step b) is adjusted in the range of 8-11. Preferably, the pH in step b) is
adjusted in the range of 9-10.5.
The suitable organic solvent in step e) is selected from, but not limited to, ethyl acetate,
methyl tert. butyl ether, diisopropyl ether, cyclohexane, n-heptane, butyl acetate,
isopropyl acetate, methyl acetate, and any mixture thereof. Most preferably, the
organic solvent is ethyl acetate.
In yet another aspect, washing of saxagliptin monohydrate of formula I in step d) is
optionally performed with mixture of water and an organic solvent. The organic
solvent may be selected from, but not limited to, ethyl acetate, methyl tert. butyl ether,
diisopropyl ether, cyclohexane, n-heptane, butyl acetate, isopropyl acetate, methyl
acetate, and any mixture thereof. Most preferably, the organic solvent is ethyl acetate.
The drying in step f) is done by any conventional method known in the prior art.
Preferably the drying is done at temperature in the range of 25°C-50°C. Most
preferably, the temperature range for drying is 35°C-40°C.

In an embodiment, the present invention provides processes for the preparation of saxagliptin monohydrate as depicted in Scheme 3.

OH

o
on

>H

I °
o
~7\ m
MDC.TEA EDAC. HCI HQBT, HCI, NaHCO,,

0 NH;

Oil

(VI)

ElOAc
TFAA Pyridine
*■
HCI NaHCO„

X
FXF
0^*0
o
(VII)

o
N
0^0
O^11 CN
7<> (vim

OH OH OH

INK ^ MHS iN «!,, 1K
Siiiidliftlin E1CI
(1) Saxa£li|)rhl ITiO

Scheme 3

In an embodiment, the present invention provides a process for preparation of saxagliptin monohydrate of formula I, wherein, the compound of formula IX is isolated from cyclohexane to remove non-polar impurities as well as to minimize loss of product. The said process comprises reaction of compound of formula VI with trifluoroacetic anhydride, followed by layer separation and extraction in presence of hydrochloric acid. The resulting organic layer is washed and concentrated. Then, the compound of formula IX is purified with cyclohexane to remove non-polar impurities as well as to minimize loss of

product and the resulting compound of formula IX is converted to saxagliptin monohydrate of formula I.
In another embodiment, compound of formula IX has HPLC purity of more than 99%. In an embodiment, the reaction mass containing compound of formula IX in a suitable solvent is heated at 50°C-70°C.
In another embodiment, saxagliptin hydrochloride of formula II has HPLC purity of more than 99%.
In yet another embodiment, the saxagliptin monohydrate of formula I prepared according to process of the present invention is crystalline saxagliptin free base monohydrate Form H-l.
In another embodiment, saxagliptin hydrochloride of formula II can be isolated or used in the next step without isolation. Preferably, saxagliptin hydrochloride of formula II of present invention is isolated.
OH
?$■ Aft
NH2 (xvm)
CN
In another embodiment, the saxagliptin monohydrate of formula I and saxagliptin hydrochloride of formula II prepared by process of present invention is substantially free of impurities of following formula: OH



OH OH
(xrx) (xx)
In another aspect, the present invention provides a process for the preparation of
saxagliptin hydrochloride of formula II.
The said process for the preparation of saxagliptin hydrochloride of formula II
comprises reaction of saxagliptin monohydrate of formula I with source of
hydrochloride in the presence of solvent at a temperature in the range of 20-35 °C for
1 to 5 hours and followed by cooling the resulting mixture at -5 to 10 °C to get the
solid product. The solid product is filtered, washed, and dried to get saxagliptin
hydrochloride of formula II. In the present invention saxagliptin hydrochloride of
formula II is present in monohydrate form.
The source of hydrochloride is concentrated hydrochloric acid or aqueous hydrogen
chloride and the solvent is selected from the group comprises of water, ethanol,
methanol, isopropanol and alike and/or mixture thereof.
The progress of the reaction can be monitored by suitable chromatographic techniques
such as high-pressure liquid chromatography (HPLC), gas chromatography (GC),
ultra-pressure liquid chromatography (UPLC), thin layer chromatography (TLC) and
the like.
The following examples are provided to describe the invention in further detail.
Although, the following examples illustrate the present invention in more detail but
should not be construed as limiting the scope of the invention.
While the present invention has been described in terms of its specific aspects and
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:

Preparation of compound of formula IX:
OH
Af^ -
0=^H CN
o
7^
Example 1: (As per known method)
(lS,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-(III) (90g, 0.398 mmoles) was treated with trifluoroacetic acid (319g, 2.79 mmoles) in MDC (540ml) at 25-30°C for2h. After completion of reaction, reaction mass was concentrated under reduced pressure at 35-40°C. MTBE (90ml) was added and distilled out at 35-40 °C under reduced pressure. Residue left was crystallized from MTBE (540ml), filtered, and washed with MTBE (180ml) under nitrogen atmosphere. Isolated TFA salt of (lS,3S,5S)-3-carbamoyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (IV) was coupled with Boc-3-hydroxy-l-adamantyl-D-glycine (V) (lOOg, 0.307 mmoles) in the presence of TEA (68g, 0.672 mmoles), 1,2,3-triaza-lH-inden-1-ol (HOBt) (54g, 0.399 mmoles) and l-ethyl-3-(3'-dimethylaminopropyl) carbodiimide HCl (EDC.HCl) (76g, 0.397 mmoles) in MDC (600ml) at 25-30°C for 2h to form (l,S',3)S',5)S)-[2-(3-carbamoyl-2-aza-bicyclo[3.1.0]hex-2-yl)-l-(3-hydroxy-adamantan-l-yl)-2-oxo-ethyl]-(2S)-carbamic acid tert-butyl ester (VI). After completion of reaction, water (400ml) was added, layers were separated, and MDC layer was washed twice with IN HCl (200ml) followed by washing with 10% aqueous sodium bicarbonate solution (4><400ml). Combined aqueous layer was back extracted with MDC (100ml). A combined organic layer was washed with 100 ml water. Organic layer was distilled out at 35-40 °C under atmospheric pressure and degassed. To the residue (VI), ethyl acetate (700ml), pyridine (120g, 1.517 mmoles), trifluoroacetic anhydride (258 g, 1.228 mmoles) were added and stirred for 2h at 0-5°C for 2 hours. After completion of reaction, 10% aqueous sodium bicarbonate

solution (1200ml) was added, and layers were separated. Aq. layer was extracted with ethyl acetate (100ml) and then combined organic layers were washed with IN-HCl (500 ml). Organic layer was treated with 25% aqueous potassium carbonate solution (500 ml) and methanol (250ml) at 45-50 °C for 4-6 hrs. Solvents (ethyl acetate and methanol) were distilled out under reduced pressure at 45 -50 °C. Ethyl acetate (500ml) was added in the reaction mass, stirred for 10 min and then layers were separated. Aqueous layer was again extracted with ethyl acetate (100ml). Combined organic layer was washed with 1NHC1 (500ml). Aq. layer was extracted with ethyl acetate (100ml) followed by washing of combined organic layer with 30% aqueous sodium chloride solution (250ml). The organic layer was concentrated under reduced pressure at 40-45°C. IPA (300ml) was added to the residue, reaction mass was heated to 50-55°C, and water (1000ml) was then added slowly at same temperature in -30 minutes. After addition of water, reaction mass was cooled to 25-30°C, stirred for 6 hours, filtered and washed with mixture ofIPA:water(50ml: 150ml) at25-30°C. The wet product was dried at 40-45°C till Loss on drying NMT 2.0% w/w was achieved. Dry Wt. 80g. HPLC Purity: (IX): 98.72%, Any Individual Unidentified Impurity (AIUI): 0.27%. Theoretical Yield: 1.27 w/w (4 steps); Actual Yield: 0.80 w/w (63%) (4 steps)
Example 2: (lS,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (in) (0.9kg, 3.98 moles) was treated with trifluoroacetic acid (3.19kg, 27.98 moles) in MDC (5.4L)at 25-30 °Cfor2h. After completion of reaction, reaction mass was concentrated under reduced pressure at 3 5 -40 °C, MTBE (0.9L) was added and distilled out at 35-40°C under reduced pressure. Corresponding TFA salt left in the reactor was crystalized from MTBE (5.4L), filtered and washed with MTBE (1.8L) under nitrogen atmosphere.
Isolated TFA salt of (lS,3S,5S)-3-carbamoyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (IV) was coupled with Boc-3-hydroxy-l-adamantyl-D-glycine (V) (1.0kg, 3.07 moles) in the presence of TEA (0.68kg, 6.72 moles), 1,2,3-triaza-lH-inden-1-ol (HOBt) (0.54kg, 3.99 moles) and l-ethyl-3-(3'-dimethylaminopropyl)

carbodiimide HCl (EDC. HCl) (0.76kg, 3.97 moles) in MDC (6.0ml) at 25-30°C for 2h to form (lS,3S,5S)-[2-(3-carbamoyl-2-aza-bicyclo[3.1.0]hex-2-yl)-l-(3-hydroxy-adamantan-l-yl)-2-oxo-ethyl]-(2S)-carbamic acid tert-butyl ester (VI). After completion of reaction, water (4.0L) was added, layers were separated, and MDC layer was washed twice with IN HCl (2.0L) followed by washing with 10% aqueous sodium bicarbonate solution (4x4.0L). Combined aqueous layer was back extracted with l.OL MDC and combined organic layers were washed with l.OL water. Organic layer was concentrated at 35-40°C under atmospheric pressure and degassed. To the residue (VI), ethyl acetate (7.0L), pyridine (1.21kg, 15.3 moles), trifluoroacetic anhydride (2.58 kg, 12.28 moles) were added and stirred for 2h at 0-5°C. After completion of reaction, 10% aqueous sodium bicarbonate solution (12.0L) was added and layers were separated. Aq. layer was extracted with ethyl acetate (l.OL). Combined organic layer was washed with 1N-HC1 (5.0L). Organic layer was treated with 25%) aqueous potassium carbonate solution (5.0L) and methanol (2.5L) at 45-50 °C for 4-6 h. Organic layer was concentrated under reduced pressure at 45 -50°C. Ethyl acetate (5.0L) was added in the reaction mass, stirred for 10 min and then layers were separated. Aqueous layer was again extracted with ethyl acetate (l.OL). Organic layers were combined and washed with IN HCl (5.0L). Aq. layer was extracted with ethyl acetate (l.OL) followed by washing of combined organic layer with 30% aqueous sodium chloride solution (2.5L). The organic layer was concentrated under reduced pressure at 40-45°C. Cyclohexane (2.0L) was added to the degassed mass and distilled off under reduced pressure. Again cyclohexane (2.0L) was added and stirred for 2 hours at 25-30°C, filtered, and washed with cyclohexane (l.OL) at 25-30°C. Crude product was dried for 8-12h till constant weight and IPA (3.0L) was added, reaction mass was heated to 50-55°C, water (10.0L) was added slowly at same temperature. After addition of water, reaction mass was cooled to 25-30°C, stirred for 6 hours, filtered and washed with IPA: water mixture (0.5L: 1.5L) 25-30°C. The wet product

was dried at 40-45°C till Loss on drying (LOD)NMT 2.0% w/w was achieved. Dry
Wt. 0.96Kg.
HPLC Purity: (IX): 99.0%.
Theoretical Yield: 1.27 w/w (4 steps);
Actual Yield: 0.96 w/w (75.6% (4 steps)
Preparation of saxagliptin hydrochloride of formula II:
on
^ Ml.
~\ .HCl Formula (H)
Example 3: (As per known method)
IPA (30ml), water (5ml) and. cone. HCl (6.4ml) were added to (IX) (lOg, 0.024 mmoles) at 25-30°C. Reaction mass was heated to 60-65 °C and stirred for 2 hours. After completion of reaction, reaction mass was cooled to 25-30°C and stirred for 12h. The product was filtered, washed withIPA(15ml) and dried undervacuum at 40-45°C. Dry Wt. 6.3g. HPLC Purity: 99.96%, Any individual unknown impurity (AIUI) = 0.02%, Theoretical Yield: 0.84 w/w; Actual yield: 0.63 w/w (75%)
Example 4:
To (IX) (5g, 0.012 mmoles), IPA (15ml) and cone. HCl (3.2ml) were added at 25-
30°C. Reaction mass was heated to 50-55°C and stirred for 5-6 hours. After completion
of the reaction, reaction mass was cooled to 25-30°C and stirred for 12 hours. The
product was filtered, washed with IPA (7.5ml) and dried under vacuum at 50-55°C.
DryWt.3.2g.
HPLC Purity: 99.92%, (VI): 0.006%, Any individual unknown impurity (AIUI):
0.05%; Theoretical Yield: 0.84 w/w; Actual yield: 0.64 w/w (76.2%).

Example 5:
IP A (2700ml) and water (450ml) were added to (IX) (900g, 2.165 mmoles). Reaction
mass was heated to 60-65°C, cone. HC1 (576ml) was added slowly at 60-65°C and
stirred for 2 hours. After completion of reaction, reaction mass was cooled to 0-5°C
and stirred for 2 hours. The product was filtered, washed with IPA (1350ml) and dried
undervacuum at 45-50°C. Dry Wt. 701g.
HPLC Purity: 99.96 %, Any individual unknown impurity: 0.03%.; Water Content:
6.9% w/w
Theoretical Yield: 0.84 w/w; Actual yield: 0.78 w/w (93%)
Example 6: Saxagliptin monohydrate (10.Og , 0.03moles) was taken in isopropyl alcohol (30.0ml/ 3V) followed by the addition of water (5.0ml/ 5V) and resulting reaction mixture was stirred at 30°C and then cooled to 25°C. Then, to the reaction mixture was added concentrated hydrochloric acid (6.26ml) and stirred for 2.0 hour at 25-30°C. Further, isopropyl alcohol (30ml) was added and reaction mixture was cooled to 0-5°C under stirring for 2 hours to give a solid product. The solid product was filtered, washed with 5% aqueous isopropyl alcohol( 10.0ml) and dried at 25-30 °C for 6-8 hours to get 10.Og of saxagliptin hydrochloride dihydrate. Moisture Content: 9.32%w/w and HC1 content : 9.3%w/w
Example 7: To a mixture of saxagliptin monohydrate (5.0g , 0.015moles) in isopropyl alcohol (15.0ml/ 3V) was added concentrated hydrochloric acid (1.72g, 0.016 moles) and the reaction mixture was stirred for 2.0 hours at 25-30°C. Further, isopropyl alcohol (15ml) was added and reaction mixture was cooled to 0-5°C under stirring at 0-5°C for 2.0 hours to get a solid product. The solid product was filtered, washed with isopropyl alcohol(5.0ml) and dried in VTD at 25-30 °C for 12-16 hours to get 5.5g of saxagliptin hydrochloride dihydrate.

Preparation of saxagliptin monohydrate of formula I:
on
-W
.HjO Formula «T}
Example 7: (As per known method)
To the (II) (lOg, 0.028 mmoles), MDC (100ml) and water (10ml) were added at 25-30°C. 25% aqueous ammonium hydroxide solution (15 ml) was added (pH = 9.0-10.5) and the reaction mass was stirred for 30 min at 25-30°C. Layers were settled and separated. To the aqueous layer, 30% aqueous sodium chloride solution (20ml) was added and then aq. layer was re-extracted with MDC three times (3 x30ml). Combined organic layer was charcoalised with activated carbon and then solvent was distilled out under vacuum completely below 40 °C. To the residue, ethyl acetate (30ml) and water (10ml) were added and stirred for 2h at 25-30°C. Product precipitated was filtered, washed with a mixture of ethyl acetate: water (3:1) (16ml) at 25-30°C and then dried at 35-40°C to get 7.0g product as white powder.
HPLC Purity: (I): 99.62%, Amidine impurity (Impurity-XI): 0.10%, Diketo Impurity (XIH): 0.01%, Amide impurity ((X): 0.04%, AIUI: 0.03%.; Water content: 5.41% w/w; Theoretical Yield: 0.94 w/w Actual Yield: 0.70 w/w (74.5%)
Example 8:
To (II) (20g, 0.056 mmoles), water (80ml) was added, and the reaction mass was heated at 35-40°C to get clear solution. Reaction mass was filtered and washed with water (10ml). Ethyl acetate (20ml) was added to the filtered mass and 25% aqueous ammonium hydroxide solution (20ml) was added slowly to the reaction mass at 25-30°C (pH 9.0-10.5). Reaction mass was cooled to 15-20°C and stirred for 2h. The product precipitated was filtered out, washed with water (10ml) and dried under vacuum at 35-40°C to get 13.5g product as a white powder.

HPLC Purity: (I): 99.75%, Amidine impurity (XI): 0.01%, AIUI: 0.04%. All stereoisomer impurities: <0.02%.; Water content: 5.28% w/w; Theoretical Yield: 0.94 w/w; Actual Yield: 0.67 w/w (71.8%)
Example 9:
To the (II) (lOg, 0.028 mmoles), water (40 ml) was added, and the mass was heated to 35-40 oC to get clear solution. After filtration, reaction mass was washed with water (5ml). pH of the reaction mass was adjusted first to 6.5 to 7.0 with 10% aq. sodium hydroxide solution (3.1ml) at 15-20 °C and then to pH 10.0 to 10.5 with 25% aq. ammonium hydroxide solution (4.5ml). Reaction mass was stirred for 2h at 15-20 °C and filtered. Wet product was washed with water (30 ml) and then dried under vacuum at 35-40 °C to get 7.79g of product as a white powder.
HPLC Purity: (I)= 99.9%, Amidine impurity (XI) = <0.02%, Diketo Impurity (XIII) <0.02%, Amide Impurity (X) 0.02%, Epimer-B (XH)<0.02%.; Water content: 5.6% w/w; Theoretical Yield: 0.94 w/w; Actual Yield: 0.78 w/w (83%)
Example 10:
To (II) (10g, 0.028 mmoles), water (10ml) and ethyl acetate (30ml) were added.
Reaction mass was heated to 35-40 °C and 25% aq. ammonium hydroxide solution (10ml) was added to the reaction mass at 25-30 °C (pH 9.0-10.5). Reaction mass was cooled to 15-20 °C and stirred for 2h. Product formed was filtered out, washed with water and then dried under vacuum at 35-40 °C to get 7g product as a white powder. HPLC Purity: (I): 99.97%, Amidine impurity (XI): <0.02%, Diketo Impurity (XIII): <0.02%, Amide Impurity (X): 0.02%, Epimer-B ((XII): <0.02%, AIUI: 0.02%. Water content: 5.54% w/w; Theoretical Yield: 0.94 w/w; Actual Yield: 0.70 w/w (74.5%)

Example 11:
To (II) (20g, 0.056 mmoles), water (80 ml) was added and heated to 35-40°C to get
clear solution. Reaction mass was filtered and washed with (10ml) of water. 25% Aq.
Ammonium hydroxide solution (20 ml) was added (pH 9.0 - 10.5) to the reaction mass
at 25-30°C, cooled to 15-20°C and stirred for 2h. Product precipitated was filtered,
washed with water and then dried at 35-40°C under vacuum. Dry Wt. 14.8g.
HPLC Purity: (I): 99.93%, Amidine impurity (XI): 0.03%, Diketo Impurity (XIII):
<0.02%, Amide Impurity (X): 0.02%, AIUI: 0.03%. All stereoisomer impurities:
<0.02%. Water content: 5.76% w/w
Theoretical Yield: 0.94 w/w; Actual Yield: 0.74 w/w (88%)
Example 12:
To the (II) (lOOg, 0.28moles), water (1.0L) was added and stir to get clear solution. Reaction mass was filtered and washed with (50ml) of water. 25% Aq. ammonium hydroxide solution (20 ml) was added (pH 9.0 -10.5) to the reaction mass at 25-30°C, cooled to 15-20°C and stirred for 2h. Product formed was filtered, washed with water and then with ethyl acetate and dried at 35-40°C under vacuum. Dry Wt. 67. lOg HPLC Purity: (I): 99.94%, AIUI: 0.03%. All stereoisomer impurities: <0.02%.; Water content: 5.5% w/w Theoretical Yield: 0.94 w/w; Actual Yield: 0.67 w/w (71%)
Example 13:
To the (II) (25g, 0.071moles), water (200ml) was added and stirto get clear solution. Reaction mass was filtered and washed with (12.5ml) of water. 25% Aq. ammonium hydroxide solution (12.5 ml) was added (pH 9.0 - 10.5) to the reaction mass at 25-30°C, cooled to 15-20°C and stirred for 2h. Product formed was filtered, washed with water followed by the washing with ethyl acetate and dried at 35-40°C under vacuum. DryWt. 17.1g

HPLC Purity: (I): 99.91%, Amidine impurity (XI): 0.06%, AIUI: 0.03%; Theoretical Yield: 0.94 w/w; Actual Yield: 0.68w/w (72.34%)
Example 14:
To (II) (90g, 0.26 moles), water (900ml) was added and stir to get clear solution. Reaction mass was filtered and washed with (45ml) of water. 25% Aq. ammonium hydroxide solution (72ml) was added (pH 9.0 - 10.5) to the reaction mass at 25-30°C, cooled to 15-20°C and stirred for 2 hours. Product formed was filtered, washed with water followed by the washing with ethyl acetate and dried at 35-40°C under vacuum. Dry Wt. 66g. HPLC Purity: (I): 99.92%, AIUI: 0.03%. All stereoisomer impurities: <0 02% ; Water content: 5.60% w/w; Theoretical Yield: 0.94 w/w; Actual Yield: 0.66 w/w (70.21%)
Example 15:
To the (II) (180g, 0.51moles), water(1800ml) was added and stir to get clear solution.
Reaction mass was filtered and washed with (90ml) of water. 25% Aq. ammonium hydroxide solution (144ml) was added (pH 9.0- 10.5) to the reaction mass at25-30°C, cooled to 15-20°C and stirred for 2 hours. Product formed was filtered, washed with water followed by the washing with ethyl acetate and dried at 35-40°C under vacuum. Dry Wt. 120g. HPLC Purity: (I): 99.96%, Dehydroxy Impurity (XIV): 0.04%, AIUI: ND., All stereoisomer impurities: <0.02%.; Water content: 5.70% w/w; Theoretical Yield: 0.94 w/w; Actual Yield: 0.66w/w (70.21%).

WE CLAIM

Claim 1. An improved process for the preparation of substantially pure saxagliptin
monohydrate of formula I from saxagliptin hydrochloride of formula II,

OH
. HCI Formula (II) cs
in the absence of an organic solvent.
Claim 2. A process for the preparation of saxagliptin monohydrate of formula I
comprises:
a) converting saxagliptin hydrochloride of formula II to saxagliptin monohydrate of formula I in the presence of water; and
b) isolating saxagliptin monohydrate of formula I by precipitation.
Claim 3. An improved process for the preparation of substantially pure saxagliptin
monohydrate of formula I, comprising the steps of:
on
JW-
.H20 Formula (I)
a) adding waterto saxagliptin hydrochloride of formula II;
b) treating the resulting reaction mixture of step (a) with a base;
c) isolating saxagliptin monohydrate of formula I;
d) washing saxagliptin monohydrate of formula I of step (c) with water;
e) optionally, washing saxagliptin monohydrate of formula I of step (c) with organic solvent; and
f) drying the isolated substantially pure saxagliptin monohydrate of formula I.
Claim 4. The process as claimed in claims 2 and 3, wherein in step a) ester solvent is
used along with water.
Claim 5. The process as claimed in claims 3, wherein in step c) saxagliptin monohydrate of formula I is isolated by precipitation.

Claim 6. The process as claimed in claim 4, wherein ester solvent is selected from
ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate or mixture
thereof.
Claim 7. The process as claimed in claim 3, wherein base used in step b) is selected
from inorganic and organic base selected from sodium hydroxide, ammonium
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate and mixture thereof.
Claim 8. The process as claimed in claim 3, wherein organic solvent used in step e) is
selected from ethyl acetate, methyl tert. butyl ether, diisopropyl ether, cyclohexane, n-
heptane, butyl acetate, isopropyl acetate, methyl acetate, and any mixture thereof.
Claim 9. The process for the preparation of saxaghptin hydrochloride of formula II by
reacting saxaghptin monohydrate of formula I with source of hydrochloride; wherein
saxaghptin monohydrate of formula I is prepared by the process as claimed in claim
1.
Claim 10. The process as claimed in claims 2 and 3, wherein saxaghptin hydrochloride
of formula II used in step a) is prepared from compound of formula IX,
ON
^^ NH *
0=^ CN
O
Qfc**'
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sis ■■• ■■"■-■'*°a- .,-„,
wherein compound of formula IX is purified with cyclohexane.