FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION
"PROCESS FOR THE PREPARATION OF ANAGLIPTIN"
Glenmark Pharmaceuticals Limited;
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957 and having its registered
office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099
The following specification particularly describes the invention and the manner in which it is to be performed.

Field Of Invention
The present invention relates to a process for preparation of anagliptin. Background of the Invention
Anagliptin chemically known as N-[2-[2-[2(S)-cyanopyrrolidin-l-yl]-2-oxoethylamino]-2-methylpropyl]-2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamide is represented by the snuctural formula:

Anagliptin is a dipeptidyl peptidase IV- inhibitor. United States Patent No 7345180 (US'180)
discloses anagliptin.
Presently, we have developed a cost effective, industrially feasible process for the preparation
and purification of anagliptin which is less time consuming.
Summary of the Invention
In one embodiment, the present invention provides a process for the preparation of a compound

comprising dehydrating a compound of formula IV

of formula I
In one embodiment, the present invention provides process for purification of a compound of formula I, comprising:
a) convening a compound of formula I to an acid addition salt; and
b) basifying the acid addition salt and isolating the compound of formula I. In one embodiment, the present invention provides a compound of formula IV


In one embodiment, the present invention provides a salt of compound of formula I with succinic
acid.
In one embodiment, the present invention provides a process for preparation of compound of
formula I, comprising isolating compound of formula I from a solvent selected from the group
consisting of water, ethyl acetate, pentane, diisopropylether, methyl tert-butyl ether, hexane,
heptane, ethanol or mixtures thereof.
In one embodiment, the present invention provides a crystalline form I of compound of formula I
characterized by X-ray diffraction pattern having peak reflections at about 17.62, 18.83, 19.33,
25.46 and 26.07 ± 0.2 degrees 2 theta and Differential Scanning Calorimetric (DSC) thermogram
having an endothermic peak at about 116.0 ±3°C.
In one embodiment, the present invention provides a crystalline form II of compound of formula
I characterized by X-ray diffraction pattern having peak reflections at about 17.62,18.83, 19.33,
25.46 and 26.07 ± 0.2 degrees 2 theta and Differential Scanning Calorimetric (DSC) thermogram
having an endothermic peak at about 123.0 ±3°C.
In one embodiment, the present invention provides use of compound of formula III or IV in the
preparation of compound of formula I.
Brief Description Of The Accompanying Figures
Fig. 1: PXRD pattern of anagHptin, which is substantially in accordance with example 6.
Fig 2: IR pattern of anagliptin, which is substantially in accordance with example 6.
Fig 3: PXRD of anagliptin, which is substantially in accordance with example 9.
Fig 4. DSC of form I of anagliptin , which is substantially in accordance with example 6.
Fig 5. DSC of form 11 of anagliptin , which is substantially in accordance with example 8.
Fig. 6: PXRD pattern of anagliptin, which is substantially in accordance with example 8.
Detailed Description of the Invention
In one embodiment the present invention provides a process for the preparation of compound of
formula I

comprising dehydrating a compound of formula IV

In one embodiment the present invention provides a process for the preparation of compound of
formula I comprising dehydrating a compound of formula IV to a compound of formula I in the
presence of a suitable solvent and a suitable dehydrating agent.
A suitable solvent may be selected from the group consisting of alcohols such as methanol,
ethanol, isopropanol, n-propanol, butanol. polyethylene glycol and the like; esters such as ethyl
acetate, isopropyl acetate, butyl acetate; amides such as dimethyl formamide, dimethyl acetamide
and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, t-butyl methyl ether,
1,4-dioxane; halogenated hydrocarbons such as methylene chloride, ethylene chloride,
chloroform, carbon tetrachloride; hydrocarbons methyl cyclohexane, cyclohexane, toluene,
xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; sulfolane; ketones such
as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, butyronitrile
and the like; water, polyethylene glycol or mixtures thereof. Preferably the solvent is
tetrahydrofuran or methylene dichloride.
A suitable dehydrating agents may be selected from the group consisting of cyanuric acid halide,
trifluoroacetic anhydride, vilsemeir reagents, phosphorous oxy chloride (POCl3), thionyl chloride
(SOCl2), sulfuric acid (H2SO4), carbonyldiimidazole. (CDI), N,N'-dicyclohexylcarbodiimide
(DCC), hydroxybenzotriazole (HOBt), polyphosphoric acid(PPA), methane sulphonic acid.
Preferably, the dehydrating agent is trifluoroacetic anhydride.
The dehydration reaction may be carried out in presence or absence of a suitable base.
The dehydration of the compound of formula IV to a compound of formula I may be carried out
in presence of a suitable organic or inorganic base. The inorganic base may be selected from, but
is not limited to hydroxides such as sodium hydroxide, potassium hydroxide; carbonates such as

sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium
bicarbonate, hydrides such as sodium hydride; alkoxides such as sodium mefhoxide, potassium
methoxide, tert-butoxide and the like; while the organic base may be selected from, but is not
limited to triethyl amine, trimethyl amine, pyridine, dimethyl amino pyridine, 3-methoxy
pyridine, ethyl nicotinate, quinoline, 3-acetoxypyridine. Preferably, the base is triethyl amine.
In one embodiment the present invention provides a process for the preparation of compound of
formula I comprising dissolving compound of formula IV in methylene dichloride.
Triethylamine and trifiuoroacetic anhydride are added to the solution of the compound of
formula IV at a temperature of about -100°C to about 40°C.
The reaction transpires at a temperature of about 20°C to about 40°C, Preferably the reaction
transpires at about 25-30°C.
In one embodiment the present invention provides a process for the preparation of compound of
formula I comprising dehydrating a compound of formula IV in the absence of a base.
In one embodiment the present invention provides a process for the preparation of compound of
formula I, wherein the reaction is carried out in the absence of a base, comprising dissolving a
compound of formula IV in a suitable solvent and adding a suitable dehydrating agent.
In one embodiment the present invention provides a process for the preparation of compound of
formula I comprising dehydrating a compound of formula IV wherein the dehydrating agent is
trifiuoroacetic anhydride.
In one embodiment the present invention provides a process for the preparation of compound of
formula I, wherein the reaction is carried out in the absence of a base, comprising dissolving a
compound of formula IV in tetrahydrofuran; then adding trifiuoroacetic anhydride to the solution
of compound of formula IV at a temperature of about -5°C to about 35°C.
The reaction transpires at a temperature of about 15-35°C. Preferably the reaction transpires at
about 25-30°C.
In one embodiment the present invention provides a process for the preparation of compound of
formula IV comprising reacting a compound of formula II with a compound of formula III ,
wherein X is any halogen,


to obtain a compound of formula IV.
In one embodiment, the compound of formula II reacts with compound of formula III wherein X is any, halogen selected from the group consisting of chlorine, bromine or iodine in presence of a suitable solvent and a base. In one embodiment, in the above process X is chloro.
A suitable solvent may be selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol. polyethylene glycol and the like; esters such as ethyl acetate, isopropyl acetate, butyl acetate; amides such as dimethyl formamide,. dimethyl acetamide and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran; tetrahydropyran, 1,4-dioxane; halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform,
carbon tetrachloride; hydrocarbons methyl cyclohexane, cyclohexane, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; sulfolane; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, butyronitrile and the like; and water or mixtures thereof. Preferably the solvent is acetone.
The reaction" may be carried out in presence of suitable base selected from the group consisting of organic or an inorganic base. The inorganic base may be selected from, but is not limited to hydroxides such as sodium hydroxide, potassium hydroxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, hydrides such as sodium hydride; alkoxides such as sodium methoxide, potassium methoxide, tert-butoxide and the like; while the organic base may be selected from, but is not limited to triethyl amine, trimethyl amine, pyridine, dimethyl amino pyridine. Preferably, the base is potassium carbonate.
The reaction may be carried out in presence or absence of suitable catalyst selected from the group consisting of tetrabulyl ammonium bromide, sodium iodide, sodium bromide, potassium bromide, potassium iodide and the like. Preferably the catalyst used is sodium iodide. In one embodiment, the compound of formula II reacts with (2S)-l-(chloroaceryl) pyrrolidine-2-carboxamide in the presence of acetone and potassium carbonate. The reaction is carried out in presence of sodium iodide. The reaction transpires at a temperature of about 0- 35°C. Preferably the reaction transpires at a temperature of about 25-30°C. In one embodiment, the compound of formula IV may be purified in a suitable solvent.

A suitable solvent may be selected from the group consisting of alcohols such as methanol. ethanol, isopropanol, n-propanol, and the like; esters such as ethyl acetate, isopropyl acetate, butyl acetate; amides such as dimethyl formamide, dimethyl acetamide and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran; halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform: hydrocarbons methyl cyclohexane, cyclohexane, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like: sulfolane; ketones such as acetone, methyl ethyl ketone,; nitriles such as acetonitrile, butyronitrile and the like; and water or mixtures thereof. Preferably the solvent is ethanol. In one embodiment, the compound of formula IV is treated with ethanol to get a reaction mixture. The reaction mixture is heated to a temperature of about 30 to about reflux temperature of the solvent. Preferably, the reaction mixture is heated to reflux temperature of the solvent. The clear solution obtained is stirred for a period of about 1-2 hour and cooled to about 25-30°C, The compound of formula IV may be isolated by methods known in the art such as filtration. centrifugation and the like. Preferably, the compound of formula IV is isolated by filtration. In one embodiment the present invention provides a process for the preparation of compound of formula II comprising reacting a compound of formula VII, wherein R is H, alky], aryl, alkylaryl or arylalkyl with 2-amino-2-methylpropyl amine to obtain a compound of formula II.

The term "alkyl" as used herein includes a straight or branched chain hydrocarbon containing
from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, n-butyl. sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl,
n-hexyl.
The term "aryl" as used herein, refers to aromatic ring systems, which may include fused rings.
Representative examples of aryl include, but are not limited to, phenyl, and naphthyl,
anthracenyl, phenanthrenyl.
The term "alkylaryl" as used herein, refers to an aryl group, as defined herein, appended to the
parent molecular moiety through an alkyl group, as defined herein. Representative examples of

alkylaryl include, but are not limited to,' benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-
yl ethyl.
The term "arylalkyl" as used herein, refers to an aryl group, as defined herein, appended to the
parent molecular moiety and substituted with an alkyl group, as defined herein. Representative
examples of arylalkyl include, but are not limited to tolyl and phenyl ethyl.
In one embodiment, in the above process R is H.
In one embodiment the present invention provides a process for the preparation of the compound
of formula II comprising when R is H, the compound of formula Vila, is reacted with

2-amino-2-methylpropyl amine in the presence of a suitable solvent.
A suitable solvent may be selected from the group consisting of alcohols such as methanol,
efhanol, isopropanol, n-propanol, butanol and the like; esters such as ethyl acetate, isopropyl
acetate, butyl acetate; amides such as dimethyl formamide, dimethyl acetamide and the like;
ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran, 1,4-dioxane;
halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, carbon
tetrachloride; hydrocarbons methyl cyclohexane, cyclohexane, toluene, xylene and the like;
sulfoxides such as dimethyl sulfoxide and the like; sulfolane; ketones such as acetone, methyl
ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, butyronitrile and the like; and
water or mixtures thereof. Preferably the solvent is tetrahydrofuran or methylene dichloride.
In one embodiment, the reaction may be carried out in presence of a suitable acid activator
selected from the group consisting of 1, 1-carbonyldiimidazole(CDI), dimethyl formamide,
dimethyl amine, oxalyl chloride, thionyl chloride, N,N'-dicyclohexylcarbodiimide (DCC),
hydroxybenzotriazole (HOBt). l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCl) or
mixtures thereof. Preferably the reaction is carried out in presence of N, N dimethylformamide
/oxalyl chloride or CDI, EDCI/HOBt, DCC.
The reaction may be carried out in presence or absence of a base.
A suitable base may be selected from the group consisting of organic or an inorganic base. The
inorganic base may be selected from, but is not limited to hydroxides such as sodium hydroxide,

potassium hydroxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates
such as sodium bicarbonate, potassium bicarbonate, hydrides such as sodium hydride; alkoxides
such as sodium methoxide, potassium methoxide, tert-butoxide and the like; while the organic
base may be selected from, but is not limited to triethyl amine, trimethyl amine, pyridine,
dimethyl amino pyridine. Preferably, the base is triethyl amine.
In one embodiment the present invention provides a process for the preparation of compound of
formula II, in the absence of a base, comprising reacting a solution of compound of formula Vila
in tetrahydrofuran with 2-amino-2-methylpropyI amine in the presence of 1,
l'carbonyldiimidazole (CDI).
In one embodiment the present invention provides a process for the preparation of compound of
formula II, in the absence of a base, comprising reacting a solution of compound VIIa in
dichloromethane with CDI with 2-amino-2-methylpropyI amine.
The reaction transpires at a temperature of about -100°C to reflux temperature of the solvent.
Preferably the reaction transpires at a temperature of about 25 to 30°C.
In one embodiment, the present invention provides a process for the preparation of compound of
formula II in the presence of triethyl amine as a base comprising reacting a solution of compound
of formula VIIa in methylene dichloride with N, N dimethylformamide and oxalyl chloride; then
reacting this mixture with 2-amino-2-methylpropylamine.
The reaction transpires at a temperature of about -100°C to reflux temperature of the solvent.
Preferably the reaction transpires at a temperature of about -78 to -75 °C.
In one embodiment, the present invention provides a process for the preparation of the
compound of formula IV comprising the steps as represented schematically in scheme 1:


In one embodiment, the present invention provides the preparation of a compound of formula IV comprising reacting a compound of formula IIIa with N-(2-amino-2-methylpropyl)-2, 2-dimethylpropanamide to obtain a compound of formula IX; then reacting the compound of formula IX with compound of formula VII to obtain the compound of formula IV. In one embodiment the present invention provides a compound of formula IV

In one embodiment, the present invention provides a process for the preparation of compound of formula I, comprising the steps as represented schematically in scheme 2:

In one embodiment, the present invention provides a process for the preparation of compound of formula I comprising:

- a) reacting a compound of formula VII. wherein R is H, alkyl, aryl, alkylaryl or arylalkyl

with 2-amino-2-methylpropyl amine to obtain a compound of formula II;
b) reacting the compound of formula II, wherein X is any halogen with a compound of formula
III

to obtain a compound of formula IV; and
c) dehydrating the compound of formula IV to a compound of formula I..
In one embodiment, in a) of the above process the compound of formula VII is reacted with 2-
amino-2-methylpropyl amine to obtain a compound of formula II.
In one embodiment, in a) of the above process when R is H, the compound of formula Vila is
reacted with 2-amino-2-methylpropyl amine to obtain a compound of formula II.
In one embodiment, the compound of formula VIIa is reacted with 2-amino-2-methyIpropyl
amine to obtain a compound of formula II in the presence of a suitable acid activator.
In one embodiment, in b) of the above process the compound of formula II is reacted with the
compound of formula III. wherein X is any halogen selected from the group consisting of chloro,
bromo or iodo to obtain a compound of formula IV.
In one embodiment, in b) of the above process the compound of formula II is reacted with the
compound of formula III, wherein X is chloro, in the presence of a suitable base to obtain a
compound of formula IV.
In one embodiment, the present invention provides a process for the preparation of compound of
formula VIIa comprising reacting ethyl 3,3-diethoxypropionate with ethyl formate to obtain a
compound of formula V. The compound of formula V is reacted with 3-methyl-lH-pyrazol-5-
amine to obtain the ester of formula Vllb. The compound of formula VIIb is hydrolysed to
obtain the compound of formula VIIa. The process is schematically depicted below:


In one embodiment, the present invention provides a process for the preparation of compound of formula IIIa comprising reacting (2S)-pyrrolidine-2-carboxamide with chloroacetyl chloride to obtain compound of formula IIIa. The process is schematically depicted below:

In one embodiment, the present invention provides yet another process for the preparation of compound of formula I, comprising the steps as represented schematically in scheme 3:

In one embodiment, the present invention provides a process for the preparation of compound of formula I comprising steps as depicted in scheme 3 comprising reacting a compound of formula II with a 2-haloester, wherein X is a halogen selected from the group consisting of chloro, bromo or iodo and R is an alkyl, aryl, alkylaryl or arylalkyl to obtain a compound of formula VIII; then reacting the" compound of formula VIII with (2S)-cyanopyrrolidine to obtain compound of
formula I.
In one embodiment, the terms of "alkyl", "aryl", "alkylaryl" or "arylalkyl" is as disclosed supra. In one embodiment, the present invention provides a process for the purification of a compound of formula I, comprising:
a) converting a compound of formula I to an acid addition salt; and
b) basifying the acid addition salt and isolating the compound of formula I.

In one embodiment, in a) of the process above, a compound of formula I is reacted with a suitable acid in presence of suitable solvent.
A suitable acid may be selected from the group consisting of organic and inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, oxalic acid, malonic acid, maleic acid, succinic acid, phosphoric acid, fumaric acid, paratoluene sulfonic acid, methane sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid or camphorsulfonic acid. Preferably, the succinate salt of compound of formula I is prepared. In one embodiment, the acid addition salt is prepared by reacting the compound of formula I with an acid selected from the group consisting of oxalic acid, succinic acid, maleic acid, paratoluene sulfonic acid, methane sulfonic acid, hydrobromic acid, phosphoric acid and fumaric acid. Preferably the acid additional salt is a succinic acid salt.
A suitable solvent may be selected from the group consisting of alcohols such as methanol, ethanol, isopropanol. n-propanol, butanol, polyethylene glycol and the like; esters such as ethyl acetate, isopropyl acetate, butyl acetate; amides such as dimethyl formamide, dimethyl acetamide and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran; halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride; hydrocarbons methyl cyclohexane, cyclohexane, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; sulfolane; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, butyronitrile and the like: and water or mixtures thereof. Preferably the solvent is ethyl acetate.
In one embodiment, in b) of the above process the salt of compound of formula is subjected to basification with a suitable base selected from the group consisting hydroxides such as sodium hydroxide, potassium hydroxide and the like; carbonates such as sodium carbonate, potassium carbonate, bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. Preferably the base is sodium bicarbonate.
in one embodiment succinic acid is added to a solution of compound of formula I in ethyl acetate to obtain the succinate salt of compound of formula I. The succinate salt of compound of formula I is basified.using sodium bicarbonate and the aqueous layer is extracted with a suitable solvent. The compound formula I is isolated by removing the solvent.
In one embodiment, a suitable solvent for extraction of the compound of formula I may be selected from the group consisting of alcohols such as methanol, ethanol. isopropanol. n-

prdpanol, butanol, polyethylene glycol and the like; esters such as ethyl acetate, isopropyl
acetate, butyl acetate; amides such as dimethyl formamide, dimethyl acetamide and the like;
ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran; halogenated hydrocarbons such
as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride; hydrocarbons methyl
cyclohexane, cyclohexane, toiuene, xylene and the like; sulfoxides such as dimethyl sulfoxide
and the like: sulfolane; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone;
nitriles such as acetonitrile, butyronitrile and the like; and water or mixtures thereof. Preferably
the solvent is methylene dichloride.
In one embodiment, the solvent is removed by methods known in the art such as filtration,
centrifugation and concentration. Preferably, the solvent is removed by concentration.
In one embodiment, the present invention provides a salt of the compound of formula I.
In one embodiment, the present invention provides the compound of formula I obtained by the
above purification process, wherein the isolated compound of formula I has a purity not less than
97%.
In one embodiment, the present invention provides the salt of the compound of formula I with
succinic acid.
In one embodiment, the present invention provides amorphous anagliptin.
In one embodiment, the present invention provides a process for the preparation of amorphous
compound of formula I comprising isolating the amorphous compound of formula I by
concentrating a solution containing the compound of formula I.
In one embodiment, the present invention provides purification of compound of formula I by
solvent/anti-solvent method.
In one embodiment the present invention provides a process for preparation of compound of
formula I, comprising isolating the compound of formula I from a solvent selected from the
group consisting of water, ethyl acetate, pentane .diisopropylether, methyltert-butyl ether,
methylene dichloride, hexane or mixtures thereof. The solvents mixture may be selected from
the group consisting of methylene dichloride / diisopropyl ether, methylene dichloride/ methyl
tert-butyl ether and ethyl acetate /Hexane and the like.
In one embodiment the present invention provides a compound of formula I having a purity not
less than 99% as measure by high performance chromatography (HPLC).

In one embodiment the present invention provides a compound of formula I having a purity not
less than 99.9% as measure by high performance chromatography (HPLC).
In one embodiment, the present invention provides compound of formula I having a chiral purity
of about 100% and chemical purity of about 100% as measured by HPLC (high performance
liquid chromatography).
In one embodiment, the present invention provides a compound of formula I having less than
0.1 % of compound of formula IV. as measured by high performance liquid chromatography.

In one embodiment, the present invention provides a compound of formula I The present
invention provides the compound of formula I having less than about 1 % of total impurities as
measured by high performance liquid chromatography (HPLC).
In one embodiment, the present invention provides a crystalline form I of compound of formula I
characterized by XRPD having peak reflections at about 17.62, 18.83, 19.33, 25.46 and 26.07 ±
0.2 degrees 2 theta .
In one embodiment, the present invention provides a crystalline form I of compound of formula I
characterized by XRPD having peak reflections at about 17.62, 18.83, 19.33, 25.46 and 26.07 •
0.2 degrees 2 theta substantially as shown in Fig 1.
In one embodiment the present invention provides a crystalline form I of compound of formula I
characterized by IR values 3339.46, 3281.47, 2963.14, 2249.5, 1663.81, 1625.65, 1544.13,
1323.15,1196.6cm-1.
In one embodiment the present invention provides a crystalline form I of compound of formula I
characterized by IR values 3339.46, 3281.47, 2963.14, 2249.5, 1663.81, 1625.65, 1544.13,
1323.15, 1196.6cm-1 substantially as shown in Fig 2.
In one embodiment, the present invention provides a crystalline form I of compound of formula I
characterized by Differential Scanning Calorimetric (DSC) thermogram having an endothermic
peak at about 116.0±3°C.

In one embodiment, the present invention provides a crystalline form II of compound of formula
I characterized by Differential Scanning Calorimetric (DSC) thermogram having an endothermic
peak at about 123.0 ±3°C.
In one embodiment, the present invention provides a crystalline form I of compound of formula I
characterized by XRPD having peak reflections at about 17.62, 18.83, 19.33, 25.46 and 26.07 ±
0.2 degrees 2 theta and Differential Scanning Calorimetric (DSC) thermogram having an
endothermic peak at about 116.0 ±3°C.
In one embodiment, the present invention provides a crystalline form II of compound of formula
I characterized by XRPD having peak reflections at about 17.62,18.83,19.33, 25.46 and 26.07 ±
0.2 degrees 2 theta and Differential Scanning Calorimetric (DSC) thermogram having an
endothermic peak at about 123.0 ±3°C.
In one embodiment, the present invention provides a process for the preparation of crystalline
form I of compound of formula I comprising :
a) treating the compound of formula I with methyl tert-butyl ether;
b) optionally, heating the mixture of step "a"; and
c) crystallizing the compound of formula I from the mixture.
In one embodiment, as used herein the term "treating" refers to contacting, suspending or
slurrying.
In one embodiment, in a) of the above process the compound of formula I is suspended in methyl
tertiary butyl ether to obtain a reaction mixture.
In one embodiment, in b) of the above process the reaction mixture of the compound of formula I
in methyl tert butyl ether is optionally heated to a temperature of about 45°C.
In one embodiment, in c) of the above process the reaction mixture of the compound of formula I
in methyl ten. butyl ether is stirred for a period of about 30 min to about 5 hours. Preferably, the
reaction mixture is stirred for a period of about 2 to 4 hours.
In one embodiment, the reaction mixture is stirred at a temperature of about 25-30°C.
In one embodiment, in c) of the above process the crystalline form I of the compound of formula
I is isolated from the reaction mixture after stirring for a period of about 2 to 4 hours at a
temperature of about 25-30°C.

In one embodiment, the present invention provides a process for the preparation of crystalline
form I compound of formula I comprising isolating the crystalline form I of the compound of
formula I from methyl tertiary butyl ether.
In one embodiment, the isolation is carried out by methods known in the art such as filtration,
concentration and the like.
In one embodiment, the present invention provides a process for the preparation of crystalline
form II of the compound of formula I comprising:
a) treating the compound of formula I with ethyl acetate;
b) optionally, heating the mixture of step "a"; and
c) crystallizing the compound of formula I from the above step "a".
In one embodiment, in a) of the above process the compound of formula I is treated with ethyl
acetate to obtain a reaction mixture.
In one embodiment, in b) of the above process the reaction mixture of step "a" is heated to a
temperature of about 30 to about reflux temperature of the solvent. Preferably, the compound of
formula I is dissolved in ethyl acetate at the reflux temperature of the solvent.
In one embodiment, in c) of the above process the solution of the compound of formula I in ethyl
acetate is cooled to a temperature of about 0 to 30°C. Preferably, the solution is cooled to a
temperature of about 25 to about 30°C. The crystalized form II of the compound of formula I is
isolated from the mixture of the compound of formula I in ethyl acetate by methods known in the
art such as filtration, centrifugation and the like.
In one embodiment, the present invention provides a process for the preparation of the crystalline
form II of the compound of formula I comprising stirring the compound of formula I in ethyl
acetate to obtain a solution. The reaction mixture is stirred for a period of about 30 minutes to
about 5 hr. Preferably, the reaction mixture is stirred for about 1-2 hr. The precipitated solid is
isolated by methods known in the art such as filtration, centrifugation and the like.
In one embodiment, the present invention provides a process for the preparation the crystalline
form II of the compound of formula I comprising isolating crystalline form II of the compound
of formula I from ethyl acetate.
In one embodiment, the present invention provides a compound of formula IV


In one embodiment the present invention provides use of compound of formula III or IV in the preparation of compound of formula I.
The compound of formula I of a defined particle size may be produced by various methods using recrystallization from different solvents. Particle size plays of the active pharmaceutical ingredient (API) plays a vita) role in the solubility properties. The reduction in particle size results in an increase in surface area of the solid phase that is in contact with the liquid phase, thus leading to increased solubility. The bioavailability depends vastly on the rate of dissolution of the poorly soluble drug. As dissolution of drug limit its rate of absorption. Thus, particle size reduction may enhance the absorption thereby improving the bioavailability. Further, particle size can also affect how freely crystals or a powdered form of a drug will flow past each other. which in turn, has consequences in the production process of pharmaceutical products containing the drug. Various techniques are known in the art to get a defined particle size. These methods include pH adjustment, cooling, evaporation of solvent, addition of antisolvent to a solution or by co-precipitation to obtain a precipitate with a defined particle size. Particle size of the compound of formula I may be further adjusted by employing known methods of particle size reduction like compaction, milling or micronizing and sorting the milled product according to particle size.
In one embodiment the present invention provides a composition comprising crystalline compound of formula I wherein 90% of the particles have a particle size less than 450 μ.. In one embodiment the present invention provides a composition comprising crystalline compound of formula I wherein 90% of the particles have a particle size less than 350 μ. In one embodiment the present invention provides a composition comprising crystalline compound of formula I wherein 90% of the particles have a particle size in between 200- 350 μ. In one embodiment the present invention provides a composition comprising crystalline compound of formula I wherein 50% of the particles have a particle size in between 50-250 μ. In one embodiment the present invention provides a composition comprising crystalline compound of formula I wherein 50% of the particles have a particle size in between 50-100 μ..

Particle Size: Particle size of the compound of formula I was measured by Malvern Mastersizer
2000®.
HPLC method: High performance liquid chromatography (HPLC) was performed with the
conditions described below for detecting chiral purity:
Apparatus: A High Performance Liquid Chromatograph equipped with quaternary
gradient pumps, variable wavelength UV detector attached with data recorder and Integrator
software or equivalent. Column: Zorbax SB Phenyl, 150 X 4.6 mm, 5μ, Column temperature: 25
°C, Mobile phase: A=Buffer, B= Methanol (Gradient Program) , Buffer: 0.1% trifluoroacetic
acid in water, pH adjusted to 2.5 with triethyl amine, Diluent: Buffer: Methanol (50:50 v/v).
Flow Rate: 1.0 mL/minute, Detection wavelengths: UV 245 nm,, Injection volume:
10DL, Run time: 60 minutes. The retention time of the compound of formula I is about 26.66
minutes under these conditions. Relative retention time for the compound of formula IV with
respect to the main peak is 0.72.
Instrumental settings for XRPD of stable the compound of formula I.
The measurements were performed on Philips X-Ray Diffractometer model XPERT-PRO
(Panalytical) Detector: X'celerator [1] using Cu lamp with type and wavelength of the X-ray
radiation: K-Alphal [A] and 1.54060 under the following conditions: Generator settings:
40mA/45kV: Time per step: 50, Step size: 0.0167, Peak width 2.00 and start angle (°) 2.0 and
End angle: 50.0, Scan type: continuous; measurement performed at 25°C. The XRPD instrument
is calibrated using NIST SRM 6-40C silicon standard and NIST SRM 1976 Alumina.
Instrumental settings for DSC: The DSC thermogram was measured by a Differentia]
Scanning Calorimeter (DSC 822, Mettler Toledo) at a scan rate of 10oC per minute in the
temperature range of range is "30oC to 350oC. The DSC module was calibrated with Indium and
zinc standard.
The following examples are provided to enable one skilled in the art to practice the invention and
are merely illustrative of the invention. The examples should not be read as limiting the scope of
the invention.

Examples:
Example 1: Synthesis of (2S)-l-(chloroacctyl) pyrrofidine-2-carboxamide
To a solution of L-Prolinamide (50g) and potassium carbonate (151.22 g) in acetonitrile (1.0 lit)
was slowly added chloroacetyl chloride (54.38 g) at about 10-15° C and stirred for about 30-45
min at about 25-30°C. The reaction mass was filtered through celite bed. The filtrate was
concentrated under reduced pressure. The residue was stirred in ethyl acetate and the solid was
collected by filtration and dried to get 70g of (2S)-1-(chloroacetyl) pyrrolidine-2-carboxamide.
1H NMR (300 MHz, CDCl3): δ 1.85-2.36 (m, 4H), 3.55-3.71 (m; 2H), 4.02{m, 0.4H, CH2C1),
4.15 (m, 1.6H, CH2C1), 4.57-4.60 (m, 1H, CHCONH2); 5.70 (s, 1H, NH2), 6.84 (s, 1H, NH2)
IR (KBr, CM-1): 3384, 3158, 2981, 2884 and 2764 Cm-1, Melting Point: 133-137oC
Chemical Purity by HPLC: 91.75%, Chiral purity by HPLC: 100%
Example 2: Synthesis of 2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxylic acid
Step-1: Synthesis of ethyl-2-formyl-3-oxopropanoate
To a stirred solution of ethyl-3, 3-diethoxypropionate (6.45g) in tetrahydrofuran (64.5 ml),
sodium hydride 60% suspension in mineral oil (2.12 g) was added and the reaction mixture was
cooled at about 0-5°C. Ethyl formate (25.7g) was added to the reaction mass at about 0-5°C. The
reaction was stirred for about 4 to 5hrs at about 25-30°C. The reaction mixture was quenched in
cold water. Subsequently aqueous layer was extracted with methyl t-butyl ether. The aqueous
phase was acidified with conc, hydrochloric acid to a pH of about 1 to 1.5. The aqueous layer
was extracted with methylene dichloride. The organic layers were dried over sodium sulphate.
The solvent was removed under reduced pressure to obtain title compound 3.2 g.
1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H, J = 7.0Hz), 4.30 (q, 2H, J = 7.0Hz), 9.13 (s, 2H),
13.12 (br s lH).
Step-2: Synthesis of 3-Amino-5-methylpyrazole
Method -I To a stirred solution of 3-aminocrotononitrile (20 g) in ethanol (120 ml), hydrazine
hydrate (11.90g) was added at about 25-30°C. The reaction mass was heated to 65-70 °C and
maintained for about 16-18 h. After cooling the reaction mass to about 25-30°C, the solvent was
distilled under reduced pressure to obtain residue. This residue was then purified by column
chromatography to yield the title compound (16g).
1H NMR (400 MHz, CDCl3): δ 2.14 (s; 3H)5 5.36 (s, 1H), 5.76 (br s 3H).
Method-2:

To a stirred solution of 3-aminocrotononitrile (1.0 Kg) in ethanol (6.0 Lit), hydrazine hydrate
(0.73 Kg) was added at about 25-30°C and stirred for 30 min, The reaction mass was heated to
75-80 °C and maintained for about 16-18 hrs. After cooling the reaction mass to about 55-60°C,
the solvent in reaction mass was distilled under reduced pressure to yield the title compound
(1-10 Kg).
HPLC: 97.9%
Step-3: Synthesis of Ethyl 2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxylate
Ethyl-2-formyl-3-oxopropanoate (2g, O.Olmol) and 3-Amino-5-methylpyrazole (1.34g), 0.138
mol) was dissolved in acetic acid (10 ml). Reaction mass was stirred for about 2-3 hrs at about
25-30°C. To the reaction mass, water was added and stirred for 30 mins. The precipitated solid
was isolated by filtration, washed with water, followed by hexane and then dried at about 30-
35°C for about 5-6 hrs to obtain title compound 2.0 gram.
1H NMR (400 MHz, CDCl3): δ 1.33 (t, 3H), 2.44 (s, 3H), 4.33 (q, 2H), 6.65(s, IH), 8.79(d, IH),
9.40(q, IH).
Step-4: Synthesis of 2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxylic acid
To a stirred reaction mass of ethyl 2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxylate (2g) in
ethanol (10 ml) was added 5N aq. NaOH solution (2.5 ml) and the reaction mass stirred for 2-
3hrs at about 25-30°C. After completion of reaction, water was added and acidified with cone.
hydrochloric acid to a pH of about 1-1.5. The reaction mass was further stirred for 30 min. at 25-
30°C. The precipitated solid was isolated by filtration, washed with water, followed by hexane
and then dried at 50-55°C for about 5-6 hrs to obtain title compound (1.6 g).
1H NMR (300 MHz, CDCl3): δ 2.445 (s,3H), 6.633 (s, IH), 8.792 (d, IH, J = 2.0 Hz), 9.339
(d, ]H,J = 0.8Hz),13.504(brslH).
Example 3: Synthesis of N-(2-amino-2-methylpropyl)-2-methylpyrazolo [1, 5-a] pyrimidine-
6-carboxamide
Method-1:
To a stirred solution of 2-methylpyrazolo[l,5-a]pyrirnidine-6-carboxylic acid (1.8g. methylene
dichloride (50 ml) and N,N-dimethyl formamide (0.5ml) a solution of oxalyl chloride was slowly
added over a period of 15 minutes at about 0-5 C. The reaction mass was stirred for about an
hour at 0-5oC and then further stirred for about 5.0 hr at about 25-30°C. This is referred as
solution-A.

Triethyl amine (3.3ml) was added to the solution of 2-amino-2-methylpropylamine (l.lg, 0.012 mol) and methylene dichloride (30 ml) at about 25-30°C. The reaction mixture was cooled to about -78 C and stirred for about 10-15 minutes. The solution A previously prepared as described was slowly added to the cooled reaction mixture over a period of 30 minutes. The reaction mixture was stirred for about 30 minutes at about -78°C; then the temperature was raised gradually to about 25-30°C. Subsequently water was added to the reaction mixture. The layers were separated and the aqueous layer was acidified with conc. HC1 and further washed with chloroform. The aqueous layer was basified with NaOH solution and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulphate and further concentrated to get 600 mg of titled compound as off white solid.
1H NMR (400 MHz, DMSO-d6): δ 1.032 (6H, s), 2.46 (3H, s), 3.21 (2H, s), 6.61 (1H, s), 8.45 (1H, brs), 8.85 (1H, d, J= 2.16Hz), 9.47 (1H, q, J=0.68Hz, J=0.68Hz). Method-2:
A solution of 2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxylic acid (5.0g) in tetrahydrofuran (THF) (50.0ml) was treated with 1, l'-carbonyldiimidazole (4.58g) and stirred for about an hour. To this reaction mixture a solution of 2-amino-2-mefhylpropylamine (2.5g) in THF (25ml) was added at about 0°C. The reaction mixture was stirred at 0°C for 1 hr and further stirred for about 12-18 hour at about 25-30°C. The reaction mass was filtered and the clear filtrate was concentrated under reduced pressure to obtain a residue. The residue was treated with diisopropyl ether (50.0 ml) and solid material was isolated by filtration. (4.0 gm). 1H NMR (400 MHz, DMSO-d6): δ 1.032 (6H, s), 2.46 (3H, s), 3.21 (2H, s), 6.61 (1H, s), 8.45 (1H, brs), 8.85 (1H, d, J= 2.16Hz), 9.47 (1;H, q, J=0.68Hz, J=0.68Hz). Method - 3:
A solution-'of 2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxylic acid (100g. 0.56mol) in methylene dichloride (l.Olit) was treated with 1, l'-carbonyldiimidazole (100g. 0.61 mol) and stirred for about 3h at 25-30°C. The reaction mass was filtered. To the solution of above wet cake material in methylene dichloride (l.Olit) was added a solution of 2-amino-2-methylpropylamine (50 g, 0.36mol) in methylene dichloride (250 ml) at 25-30°C. The resulting reaction mixture was maintained for 12 - 14 hr. The reaction mass was filtered over hyflobed and the clear filtrate was concentrated and co-distilled with ethyl acetate (200 ml) under reduced pressure to obtain a residue. The residue was treated with ethyl acetate and stirred for 2hr at 25-

30°C. The solid was isolated by filtration to give'(80 g, 57%) of the title compound as off white solid, HPLC purity: 99.8%, DSC: 138.96°C.
Example 4: Synthesis of N-[2-2[2(S)-carboxamide pyrroIidine-l-y]]-2-oxoethylamino]-2-methylpropyl]-2-methyalpyrazolo [1, 5-a] pyrimidinc-6-carboxamide: Method-1:
To a solution of N-(2-amino-2-methy]propyl)-2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxamide (16.0g) in acetone (320ml) was added potassium carbonate (12.06 g) at 0 - 5°C and stirred for about 30 min. Separately sodium iodide (14.54g) and a solution of (2S)-1-(chloroacetyl) pyrrolidine-2-carboxamide (13.5g) in acetone were stirred at about 0-5°C and subsequently this solution was added to the reaction mass and stirred for further 18 h at 25-30°C. The reaction mass was filtered through celite and the clear filtrate was concentrated under reduced pressure to obtain the crude mass. This crude mass was then diluted with methylene dichloride and extracted with saturated with brine soln. The methylene dichloride layer was dried over anhydrous sodium sulfate and further concentrated under reduced pressure to yield crude solid mass. The crude mass was stirred in acetone for about 5h at about 25-30°C. The precipitated solid was isolated by filtration to give 10 g of the title compound as off white solid. 1H NMR (300 MHz, DMSO): δ 1.04 (s, 6H), 1.87-1.98(m, 4H), 2.50(s: 3H), 3.23-3.54 (m, 4H)), 3.52-3.54 (in, 2H), 6.61 (s, 1H), 6.94 (s, 1H, D20 exchangeable), 7.27 (s, 1H, D20 exchangeable),8.51-8.53 (s, 1H, D20 exchangeable), 8.832-8.839 (d, 1H), 9.41-9.04 (d, 1H) HPLC Purity: 98.15%, Chiral purity by HPLC: 100% Method-2:
To a solution of N-(2-arnino-2-methylpropyl)-2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxamide (25g, 0.1 Omol) in acetone (50ml) were added powdered potassium carbonate (20.26 g, 0.14mol), sodium iodide (1.26gs 0.0084mol), and (2S)-l-(chloroacetyl) pyrrolidine^-carboxamide (22.5g, 0.11 mole) at 25-30°C. The resulting reaction mass was stirred for 4 h at 25-30°C. To the resulting mixture was added chloroform and stirred for 1 hr at 25-30°C. The reaction mass was filtered. The clear filtrate was concentrated and co-distilled with acetone under reduced pressure to obtain crude residue. This crude residue was then treated with acetone and stirred for 4 - 5 hr at 25-30°C. The solid was isolated by filtration and further dried to give (36g, 88%) of the title compound as off white solid. HPLC purity: 98.28%, DSC: 180.74°C.

Purification: Dissolution of above isolated material (l0.0g) in ethanol (80ml) was accomplished at reflux temperature. The clear solution was then cooled gradually at 25-30°C. The solid mass was stirred at room temperature for 2hr, filtered and dried to give 8.0g title compound as off white compound. HPLC purity: 99.53%, DSC: 185.25°C. Method-3:
To a solution of N-(2-amino-2-methylpropyJ)-2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxamide (5g, 0.02mol) in acetone (50 ml) were added powdered potassium carbonate (4g, 0.028mol), sodium iodide (0.25g, O.OOlmol), and (2S)-l-(chloroacetyl) pyrrolidine-2-carboxamide (4.5 g, 0.023mol) at 25-30°C. The resulting reaction mass was stirred for 4 h at 25-30°C. After the completion of reaction, the reaction mass was filtered and the wet solid cake was dissolved in chloroform and water. To this subsequently was added 20% aq. NaOH solution slowly under stirring at 25-30°C. The layers were separated and extracted aqueous layer with additional chloroform. The total organic layers was washed with brine solution and dried over anhydrous sodium sulphate and filtered through hyflobed. The clear filtrate was concentrated and co-distilled with acetone under reduced pressure to obtain as crude residue. This crude residue was then treated with acetone and stirred for 6 hr at 25-30°C. The precipitated solid was isolated by filtration and dried to give (7.34g, 91%) the title compound as off white solid. HPLC purity: 99.25%, IR (cm-1): 3310.88, 1647.77, 1562.73, 1504.89, 1195.45, 1042.62, 912.57, 790.58,DSC: 181.45°C. Method-4:
To a solution of N-(2-amino-2-methylpropyl)-2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxamide (40.0 g, 0.161mol) in dimethyl formamide (DMF, 800 ml) were added powdered potassium carbonate (32.Og, 0.23mol). sodium iodide (2g, 0,0134mol), and (2S)-l-(chloroacetyl) pyrrolidine-2-carboxamide (36g, 0.18mol) at 25-30°C. The resulting reaction mass was stirred for 16h at 25-30°C. The reaction mass was filtered through hyflobed, The clear filtrate was concentrated and co-distilled with acetone under reduced pressure to obtain as crude residue. This crude residue was then treated with acetone and stirred for 12 hr at 25-30°C. The solid was isolated by filtration and dried to give (47g. 73%) of the title compound as off white solid. HPLC purity: 98.20%, IR (cm-1): 3310.96, 1645.01, 1563.2, 1500.64, 1194.49, 1042.85, 912.34, 790.15, DSC: 182.8°C.

Example 5: Synthesis of N-[2-2[2(S)-Cyano pyrro]idin-l-y]]-2-oxoethyIaminoJ-2-mcthyIpropyl]-2-methyalpyrazolo [1, 5-a] pyrimidine-6-carboxamide (I).
In a dry three-neck flask under nitrogen atmosphere N-[2-2[2(S)-carboxamide pyrrolidine-1-yl]-2-oxoethylamino]-2-methylpropyl]-2-methylpyrazoIo [1. 5-a] pyrirnidine-6-carboxamide (500 mg) in methylene dichloride (10 ml) was stirred and cooled down to -75° C. Triethyl amine (130 mg) was added under stirring at -75°C. After 30 min, trifhioro acetic anhydride (500 mg) was added drop wise at -75°C. Slowly the reaction temperature was raised to 25-30°C and reaction mass was stirred for another 2 h. The reaction mixture was quenched into crushed ice solution and extracted with methylene dichloride . The combined methylene dichloride layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give residue. This residue was then purified by silica gel column chromatography to obtain title comp as an amorphous solid. (180 mg).
1H NMR (300 MHz, DMSO): δ 1.16 (s, 6H), 2.23(m, 4H), 2.54(s, 3H), 3.25-3.51 (m, 6H), 4,78 (m, 1H), 6.53 (s, 1H), 8.05 (s, 1H), 8.93 (s, 1H), 9.22(s, 1H) HPLC Purity: 99.71%, Chiral purity: 100%
Example 6: Synthesis of form I of N-[2-2[2(S)-Cyano pyrrolidin-l-yl]-2-oxoethylamino]-2-mcthylpropyl]-2-methyalpyrazolo [1,5-a] pyrimidine-6-carboxamide (I, anagliptin). To a solution of N-[2-2[2(S)-carboxamide pyrrolidine-l-yl]-2-oxoethylamino]-2-methylpropyl]-2-mefhyalpyrazolo [], 5-a] pyrimidine-6-carboxamide (340.0g. 0,84mol) in tetrahydrofuran (THF) (3.4 Lit) was slowly added trifluoroacetic anhydride (264.6g. 1.26mol) solution prepared in 680 ml THF at 0- 5°C. The resulting mixture was stirred at 0 - 5°C for about 30 - 60min. The reaction mass was quenched in aqueous sodium carbonate solution followed by addition of methylene dichloride under stirring. The layers were separated and aqueous layer was extracted with methylene dichloride . The organic layer was dried over anhydrous sodium sulphate and concentrated and co-distill with ethanol (680 ml) under reduced pressure to obtain crude residue. To the above crude residue was added ethanol (2.0 Lit), succinic acid (115 g) and stirred for 12 hr at 25-30°C for salt formation. The succinate salt of compound of formula I was isolated by filtration. The isolated succinate salt was treated with water and further washed with ethyl acetate. The pH of aqueous layer was then adjusted to ~8 by sodium carbonate and again extracted with methylene dichloride. The organic layer was washed by brine solution, dried over sodium sulfate, concentrated and co-distilled with methyl tert butyl ether (MTBE. 680 ml) under

reduced pressure to give crude residue. This crude residue was treated with MTBE and stirred the reaction mass for about 2 to 4 hour. The precipitated solid was isolated by filtration to yield (208g, 64%) of N-[2-2[2(S)-cyano pyrroIidin-l-yl]-2-oxoethylamino]-2-methylpropyl]-2-methyalpyrazolo [1, 5-a] pyrimidine-6-carboxamide compound as a crystalline white solid. 1H NMR (300 MHz, CDCl3): δ 1.17 (s, 6H), 2.15-2.30 (m, 4H), 2.53 (s, 3H), 333 - 3.65 (m, 6H), 4.70- 4.73 (m, 1H), 6.50 (s, 1H), 8.05 (s, 1H), 8.94 (s, 1H), 9.28 (s, 1H). IR(cm-1): 3339.46,3281.47,2963.14,2249.5,1663.81,1625.65,1544.13, 1323.15,1196.6 DSC: 116.4°C, HPLC Purity: 99.9%, Chiral HPLC: 100%
Example 7: Synthesis of form I of N-[2-2[2(S)-Cyano pyrrolidin-l-yl]-2-oxoethy!amino]-2-methylpropyl]-2-methyalpyrazo!o [1,5-a] pyrimidine-6-carboxamidc (I, anagliptin). To a solution of N-[2-2[2(S)-carboxamide pyrrolidine-l-yl]-2-oxoethylamino]-2-methylpropyl]-2-methyalpyrazolo [1, 5-a] pyrimidine-6-carboxamide ( 90g, 0.22mol) in tetrahydrofuran (THF, 0.9 Lit) was slowly added trifluoroacetic anhydride (70.65g, 0.33mol) solution in 180 ml THF at 0- 5°C. The resulting mixture was stirred at 0 - 5°C for about 30 - 60min. The reaction mass was quenched in aqueous sodium carbonate solution and extracted with methylene dichloride under stirring. The layers were separated and aqueous layer was extracted with methylene dichloride. The total organicjayer was dried over anhydrous sodium sulphate and concentrated and co-distill with ethyl acetate (270 ml,) under reduced pressure to obtain crude residue (78.24% purity). To the above crude residue was added ethyl acetate ( 450ml), succinic acid (30.5 g) and stirred for 12 hr at 25-30°C. The succinate salt of compound of formula I was isolated by filtration. The succinate salt was dissolved in water and aqueous layer was washed with ethyl acetate. The pH of aqueous layer was then adjusted to ~8 by sodium carbonate and again extracted with methylene dichloride. The total organic layer was washed by brine solution, dried over sodium sulfate, concentrated and co-distilled with methyl tert butyl ether (MTBE, 270 ml) under reduced pressure to give crude residue. This crude residue was treated with MTBE and collected the solid by filtration to yield (50g, purity:98.7%) of N-[2-2[2(S)-cyano pyrrolidin-l-yl]-2-oxoethylarnmo]-2-methylpropyl]-2-methyalpyrazolo [1, 5-a] pyrimidine-6-carboxamide compound as a crystalline solid.
Example 8: Synthesis of form II of N-[2-2[2(S}-Cyano pyrrolidin-l-yl]-2-oxoethylamino]-2-methy]propyl]-2-methyalpyrazoIo [1,5-a] pyrimidinc-6-carboxamidc (I, anagliptin).

The N-[2-2[2(S)-cyano pyrrolidin-1 -yl]-2-oxoethylamino]-2-methylpropy]]-2-methyalpyrazolo
[1, 5-a] pyrimidine-6-carboxamide crude (50 g), compound of formula I, was dissolved in ethyl
acetate ( ml) at 75-80°C. The resultant mixture was filtered through hyflobed . The clear filtrate
was heated to 75-80°C to get clear solution. The resultant mixture was cooled gradually at 25-
30°C and was stirred for about 8 - 10 hr. The solid material was then collected by filtration and
dried to yield 40 gm of title compound as a crystalline white solid.
1H NMR {300 MHz, CDCl3):δ 1.17 (s, 6H), 2.15-2.30 (m, 4H), 2.53 (s, 3H), 3.33-3.65 (m,
6H), 4.70- 4.73 (m, 1H), 6.50 (s, 1H), 8.05 (s, 1H), 8.94 (s, 1H), 9.28 (s, 1H).
IR(cm-1): 3339.46,3281.47, 2963.14,2249.5, 1663.81,1625.65, 1544.13,1323.15, 1196.6cm"'
DSC: 123.17°C, HPLC Purity: 99.75% Chiral purity: 100%.
Example 9: Synthesis of amorphous form of N-[2-2[2(S)-Cyano pyrrolidin-l-yl]-2-
oxoethylamino]-2-methyl propyl]-2-methyaIpyrazolo [1, 5-a] pyrimidinc-6-carboxamide(l,
anagliptin).
To a solution of N-[2-2[2(S)-carboxamide pyrrolidine-l-yl]-2-oxoethylamino]-2-methylpropyl]-
2-methyalpyrazolo [1, 5-a] pyrimidine-6-carboxamide (9.0 g) in tetrahydrofuran (THF) (90 ml)
was slowly added trifluoroacetic anhydride (7.0 g) solution prepared in 18 ml THF at 0- 5°C. The
reaction mixture was stirred at 25-30°C for about 2- 3 h. Water was added to the reaction mass,
The solvent was evaporated under reduced pressure to obtain oily residue. The oily residue was
treated with saturated NaHCO.i solution and extracted with methylene dichloride. The methylene
dichloride was dried over anhydrous sodium sulphate and evaporated under reduced pressure to
obtain 8 gram of product.
To the above product ethyl acetate (40ml) and succinic acid (2.14 g) was added and the reaction
mixture was stirred at 25-30°C for about 12-18 hour. The succinate salt of compound of formula
I was collected by filtration. The succinate salt was treated with aqueous sodium bicarbonate
solution and extracted with ethyl acetate. The solvent was evaporated under reduced pressure to
yield 5.5 gram of N-[2-2[2(S)-Cyano pyrrolidin-l-yI]-2-oxoethylamino]-2-methylpropyl]-2-
methyalpyrazolo [1, 5-a] pyrimidine-6-carboxamide compound as an amorphous white solid.
Example 10: Synthesis of form II of N-[2-2|2(S)-Cyano pyrrolidin-l-yI]-2-oxoethyIamino]-
2-methyl propyl]-2-methyalpyrazolo [1, 5-a] pyrimidine-6-carboxamide(I, anagliptin).
The N-[2-2[2(S)-cyano pyrrolidin-l-yl]-2-oxoethylamino]-2-methylpropyl]-2-methyalpyrazolo
[1, 5-a] pyrimidine-6-carboxamide crude 5.5g, compound of formula I, was dissolved in ethyl

acetate (27.5ml) at 25-30°C. The solution was stirred for about 1- 2 hr. The solid material was
then collected by filtration and dried to yield 3.5 gm of title compound as a crystalline white
solid.
1H NMR {300 MHz, CDCl3):δ 1.17 (s, 6H), 2.15-2.30 (m, 4H), 2.53 (s, 3H), 3.33 - 3.65 (m,
6H), 4.70- 4.73 (m, 1H), 6.50 (s, 1H), 8.05 (s, 1H), 8.94 (s, 1H), 9.28 (s, 1H).
HPLC Purity: 99.95%, Chiral Purity: 100.0%
PXRD:

Pos.[°2Th] d-space [A°] Rel. int [%) Pos.[°2Th] d-space [A0] Rel. int
[%] Pos[°2Th] d-space [A°] Rel. int
[%]
8.95 9.87 12.7 21.09 4.21 2.37 31.14 2.87 8.31
9.58 9,22 4.09 22.3 3.98 4.86 31.64 2.82 1.99
10.05 8.8 29,07 22.53 3,94 10.75 32,99 2.71 1.77
11.28 7.83 19.93 24.25 3,66 7 33.5 2.67 3.22
13,09 6.76 19.31 25.46 3.49 42.08 34.28 2.61 3.25
15,27 5.8 18.58 26.07 3.41 43.97 34.85 2.57 4.83
16,57 5.34 26.35 26.87 3.31 9,53 35.79 2.5 1.04
16,81 5.27 26.85 28.06 3.17 7,26 36.76 2.44 1.51
17.62 5.03 87.03 28,97 3,08 9,72 37.18 2.41 1.66
18.83 4.71 100 29.47 3.03 12.62 38 2.36 1.29
19.33 4.59 41.64 30.2 2.95 4.05 39.15 2.3 2.78
20.23 4.38 33.13 30.69 2.91 4,33 39.75 2.26 3.85

We Claim:
1] A process for the preparation of a compound of formula I

comprising dehydrating a compound of formula IV

2] The process as claimed in claim 1 wherein the compound of formula IV is prepared by reacting a compound of formula II with a compound of formula III, wherein X is any halogen.

to obtain a compound of formula IV.
3] The process as claimed in claim 2, wherein the compound of formula II is prepared by a process comprising reacting a compound of formula VII, wherein R is H, alkyl, aryl group, alkylaryl or arylalkyl

with 2-amino-2-methylpropyl amine to obtain a compound of formula II. 4] A process for purification of a compound of formula I, comprising:
a) converting a compound of formula I to an acid addition salt; and
b) basifying the acid addition salt and isolating the compound of formula I. 5] A compound of formula IV.


6] A salt of the compound of formula I with succinic acid.
7] A process for the preparation of compound of formula I, comprising isolating compound of
formula I from a solvent selected from the group consisting of water, ethyl acetate, pentane,
diisopropylether, methyl tert-butyl ether, hexane or mixtures thereof.
8] A crystalline form I of compound of formula I characterized by X-ray diffraction pattern
having peak reflections at about 17.62,18.83,19.33,25.46 and 26.07 ± 0.2 degrees 2 theta and '
Differential Scanning Calorimetric (DSC) thermogram having an endothermic peak at about
116.0 ±3°C.
9] A crystalline form II of compound of formula I characterized by X-ray diffraction pattern
having peak reflections at about 17.62, 18.83, 19.33, 25.46 and 26.07 ± 0.2 degrees 2 theta and
Differential Scanning Calorimetric (DSC) thermogram having an endothermic peak at about
123.0 ±3°C.
10] Use of compound of formula III or IV in the preparation of compound of formula I.