FIELD OF THE INVENTION
The present invention relates to a process for preparation of sitagliptin phosphate.
More particularly, the present invention relates to a process for the preparation of
crystalline anhydrous form of sitagliptin phosphate.
BACKGROUND OF THE INVENTION
Sitagliptin phosphate is known from U.S patent No. 7,326,708 and is represented
by structural Formula 1.
F
f > % . H,P04
CF3
Formula 1
Sitagliptin phosphate is marketed in the USA under the proprietary name
"JANUVIA" and is indicated as an adjunct to diet and exercise to improve*
glycemic control in adults with type 2 diabetes mellitus.
US patent number 7,326,708 discloses crystalline sitagliptin phosphate
monohydrate having characteristic diffraction peaks corresponding to d-spacings
of 7.42, 5.48, 5.85, 5.21, and 3.52 angstroms. The crystalline monohydrate formof
sitagliptin phosphate is being prepared by reacting one equivalent of sitagliptin
free base with one equivalent of aqueous phosphoric acid at 75°C and the
resulting solution is cooled to 68°C and then held at that temperature for 2 hr to
form a slurry and the slurry thus formed is cooled at a rate of 4° C/h to 21°C/h and
kept overnight. To the slurry was added IPA (105 mL) and after 1 hr, the slurry
was filtered and washed with 45 ml IPA. The solid so obtained was dried on the
frit with open to air. It is observed that monohydrate form as obtained by the
process of the above patent disclosure is not suitable for formulation of
pharmaceutical dosage form.
1 8 - 8 8 2
US patent application 2006/0287528 discloses crystalline anhydrous Form I of
sitagliptin phosphate having characteristic reflections obtained from the X-ray
powder diffraction pattern at spectral d-spacings of 18.42, 9.35, 6.26 ,5.78, 4.71,
and 3.67 angstroms. US'528 also discloses crystalline desolvated anhydrate Form
II of sitagliptin phosphate characterized by characteristic reflections obtained from
the X-ray powder diffraction pattern at spectral d-spacings of 7.09, 5.27,4.30
18.56, 9.43, and 4.19 angstroms. This application further discloses crystalline
anhydrate Form III of sitagliptin phosphate characterized by characteristic
reflections obtained from the X-ray powder diffraction pattern at spectral dspacings
of 17.88, 6.06, 4.26, 9.06, 5.71, and 4.55 angstroms. The disclosed Form-
1 was prepared by reacting sitagliptin free base and 85% aqueous phosphoric acid
at a temperature of 75 to 78° C. A thick white precipitate formed at lower
temperatures which get dissolved upon reaching 75° C. The solution was cooled
to 68° C and then held at this temperature for 4-8 h. A slurry bed of solids of
ethanol solvate was formed during this age time. The slurry was then cooled at a.
rate of 4° C/hr to 21° C and then held overnight. 70 mL of ethanol was then added
to the slurry of ethanol solvate. After 1 hr the slurry of ethanol solvate was filtered
and washed with 45 mL ethanol. The solids were dried in a vacuum oven at 40° C
for 18 hr. Mixture of Form I and Form III was then obtained with Form I
predominating. Polymorphic forms as disclosed in US patent application
2006/0287528 are not stable and they tend to interconvert in one another on
different temperature condition.
US patent application 2007/0021430 discloses a crystalline anhydrate Form IV of
sitagliptin phosphate characterised by X-ray powder diffraction pattern at spectral
d-spacings of 17.94, 7.95, and 6.16 angstroms. The disclosed Form IV was
prepared by heating the monohydrate of sitagliptin phosphate at 120° C. for about
2 h or by heating the monohydrate above 58° C. for about 8 h. Form IV is
metastable and converts into the crystalline monohydrate slowly under ambient
conditions and rapidly under high relative humidity (98%) at room temperature.
Form IV can also be converted to anhydrate Form I in about 1 hr at a temperature
above 140° C.
US patent number 9,409,912 discloses a process for the preparation of anhydrous
form of sitagliptin phosphate wherein said process involves treating one
equivalent of sitagliptin free base with 1.4 equivalent of phosphoric acid in
presence of water and isopropyl alcohol followed by cooling at 0 to 5°C.
US patent application No. 2010/0041885 discloses a crystalline form of sitagliptin
phosphate characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7,
18.3, and 23.7±0.2°29 and is referred as Form II. Crystalline form disclosed is
prepared by reacting sitagliptin base and phosphoric acid in a solvent selected
from ethyl acetate, methyl isobutyl ketone, dioxane, dimethyl carbonate, acetone,
tetrahydrofuran, acetonitrile, ethanol, methyl acetate, propylene glycol methyl
ether, dimethyl formamide, dimethylsulfoxide, a mixture of acetonitrile and
toluene, or a mixture of tetrahydrofuran and water, forming a slurry; and obtaining
the crystalline form of sitagliptin phosphate. The obtained slurry is formed either
by adding the phosphoric acid to a slurry of the sitagliptin base in the organic
solvent, or by adding the Sitagliptin base into a slurry of the phosphoric acid in
the organic solvent. Process disclosed in US patent application No. 2010/0041885
is time consuming as it involves drying of final compound for 16 hour.
The discovery of new polymorphic forms and solvates of a pharmaceutical^
useful compound provides a new opportunity to improve the performance
characteristics of a pharmaceutical product. It enlarges the repertoire of materials
that a formulation scientist has available for designing, for example, apharmaceutical
dosage form of a drug with a targeted release profile or other
desired characteristic.
In view of the above disclosure, it is observed that polymorph reported in prior
published references are not stable and process to prepare those polymorphs are,
I 1 D - 0 8 - 2 0 1 3 1 7 : 20
time consuming and commercially uneconomical, hence there is a need to develop
a commercially viable process that produced stable crystalline anhydrous form of
sitagliptin phosphate.
OBJECT OF THE INVENTION
The main object of the present invention is to provide commercially viable
process for preparing crystalline anhydrous form of sitagliptin phosphate.
Another object of the present invention is to provide pharmaceutical composition
comprising crystalline anhydrous of sitagliptin phosphate and pharmaceutical^
acceptable carrier.
SUMMARY OF THE INVENTION
In the first aspect, the present invention relates to a process of preparing
crystalline anhydrous form of sitagliptin phosphate of Formula (I),
F
N
N
N • H3PO4
Formula I
comprising the steps of;
(a) coupling (3R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl)
butanoic acid of Formula (II),
F
Formula II
g*IPQ
with 3-(trifluoromethyl)-5, 6, 7 ,8-tetrahydro-l ,2,4-triazolo-[4,3-a]pyrazine or its
hydrochloride of Formula (III),
41 I O - 8 8 - ^ U J L © & / * £& c
HN"~VN\,
I N
CF3 .HCI
Formula III
in presence of a coupling agent and a base in a suitable solvent to obtain tertbutyl
(R)-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-
a]pyrazin-7(8H)-yl)-l -(2,4,5-trifluorophenyl)butan-2-yl)carbamate compound of
Formula IV,
Formula (IV)
(b) deprotecting the compound of Formula (IV) with an acid in presence of a
solvent to obtain sitagliptin free base of Formula (VI),
F
O
- - ? r
F
Formula (VI)
(c) treating the sitagliptin free base of Formula (VI) with orthophosphoric acid in
presence of a solvent; and
d) isolating crystalline anhydrous form of sitagliptin phosphate of structural
Formula I.
In another aspect, the present invention further relates to a process of preparing a
crystalline anhydrous form of sitagliptin phosphate of Formula I,
41. 1 G - G 8 - 2 G 1 8 1 1•? • •> n
. H3P04
Formula I
comprising the steps of:
a) deprotecting tert-butyl (R)-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro [1,2,4]
triazolo [4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-yl)carbamate
compound of Formula (IV),
N k.N-f
F formula (IV)
to give sitagliptin free base compound of Formula (VI),
H
NH2
O
formula (VI)
9
b) reacting sitagliptin free base obtained in step a) with orthophosphoric acid in a
mixture of solvent containing water and an organic solvent at a temperature 30-
35°C to obtain a reaction mixture;
c) heating the reaction mixture of step b) at a temperature in the range of 75-80°C
to obtain a clear solution;
d) cooling the clear solution obtained in step c) to 20-25°C to get a reaction mass;
e) adding an organic solvent to the reaction mass of step d); and
f) filtering to get crystalline anhydrous form of sitagliptin phosphate of Formula I.
•-"t. •£=• •* .TV 1 f
In another aspect, the present invention provides a crystalline anhydrous form of
sitagliptin phosphate, wherein said polymorphic form is characterised by
characteristic reflections obtained from the X-ray powder diffraction pattern at
spectral d-spacings of 18.92, 9.47, 6.32, 4.74, 3.68,2.71, and 2.67 A.
Another aspect of the present invention is to provide a pharmaceutical
composition comprising crystalline anhydrous form of sitagliptin phosphate and
pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF INVENTION
Brief Description of Drawings
Fig. 1 represents X-ray powder diffraction (XRD) pattern of crystalline anhydrous
form of present invention
Fig. 2 represents Differential Scanning Calorimetry (DSC) of crystalline
anhydrous form of present invention
Fig. 3 represents Thermogravimetric analysis (TGA) of anhydrous form of
present invention. .
The present invention will now be explained in details. While the invention is
susceptible to various modifications and alternative forms, specific embodiment
thereof will be described in detail below. It should be understood, however that it
is not intended to limit the invention to the particular forms disclosed, but on the
contrary, the invention is to cover all modifications, equivalents, and alternative
falling within the scope of the invention as defined by the appended claims.
In one embodiment, the present invention provides a crystalline anhydrous form
of sitagliptin phosphate characterized by characteristic reflections obtained from
the X-ray powder diffraction pattern at spectral d-spacings of 18.92, 9.47, 6.32,
2.71 and 2.67 A.
I 1 6 - 0 8 - 2 8 1 8 1? : 2 B R
In one another embodiment, the crystalline anhydrous form of present invention is
further characterised by X-Ray diffraction pattern having following XRD peaks
(29 values) and d-spacing:
Pos.[°28]
4.6652
9.3297
11.0044
11.7630
12.8094
13.4569 •
13.9952
14.3522
15.0213
15.5102
16.5552
17.4308
17.6373
18.3083
18.6864
19.1201
19.5087
20.0272
21.4732
21.7394
23.2788
23.6383
24.1316
24.9619
25.2814
25.4724
25.8276
26.2323
26.6462
27.0014
27.5776
28.1478
28.7420
29.2858
30.0357
30.2842
30.8990
31.6487
d-spacing [A]
18.92597
9.47162
8.03367
7.51719
6.90539
6.57453
6.32284
6.16637
5.89316
5.70850
5.35045
5.08360
5.02454
4.84186
4.74474
4.63808
4.63808
4.43001
4.13485
4.08482
3.81805
3.76080
3.68502
3.56430
3.51998
3.49401
3.44676
3.39450
3.34270
3.29953
3.23188
3.16769
3.10355
3.04715
2.97275
2.94892
2.89164
2.82483
PQ. DELHI 1 Q - Q a - 2 0 1 8 1 7 : 2 0 9
32.9863
33.5171
35.0721
2.71327
2.67151
2.55654
Table 1
In another embodiment, the crystalline anhydrous form of sitagliptin phosphate of
present invention may be characterized by X-ray diffraction pattern as depicted in-
Figl.
In another aspect, the present invention further relates to a process of preparing
crystalline anhydrous form of sitagliptin phosphate of Formula (I),
F
? " > N N - H3P04
CF3
Formula I
comprising the steps of:
(a) coupling (3R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl)
butanoic acid of Formula (II),
F
Formula II
with 3-(trifluoromethyl)-5, 6, 7, 8-tetrahydro-l, 2, 4-triazolo-[4,3-a]pyrazine or its
hydrochloride of Formula (III),
I 2 8 - 0 8 - 2 8 : 1 8 17 : 28
HN- ^ N
N
CF3 .HCI
Formula
in presence of a coupling agent and a base in a suitable solvent to obtain tertbutyl
(R)-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-
a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-yl)carbamate of Formula IV,
Formula (IV)
(b) deprotecting the compound of Formula (IV) with an acid in presence of a
solvent to obtain sitagliptin free base of Formula (VI),
F
Formula (VI)
(c) treating the sitagliptin free base of Formula (VI) with orthophosphoric acid in
presence of a solvent; and
d) isolating the crystalline anhydrous form of sitagliptin phosphate of Formula I.
In another embodiment, the sitagliptin free base of Formula (VI) may be isolated
as wet material and the wet mass of free base may further be reacted with
orthophosphoric acid.
In another embodiment, sitagliptin free base of Formula (VI) may be isolated and
dried and the dried free base may further be reacted with orthophosphoric acid.
§>IPQ D E L H I 1 8 - 8 8 - 2 8 1 8 1 7 : 2 8 n
In one another embodiment, sitagliptin free base of Formula (VI) may not be
isolated and the reaction mixture comprising free base may further be reacted with
orthophosphoric acid.
In other embodiment, the coupling agent in step (a) is selected from one or more
of N,N'-dicyclohexyl carbodiimide (DCC) , l-ethyl-3-(3-dimethyl aminopropyl)
carbodimide (EDC), hydroxybenzotriazole (HOBT) or O-benzotriazol-l-yl-1,1,3-'
tetramethyluroniumtetrafluoroborate.
In other embodiment, acid used in step b) for the deprotection of compound of
Formula (IV) may be selected from hydrochloric acid, triflouroacetic acid,
sulfuric acid, pivalic acid, acetic acid, formic acid and the like. In particularhydrochloric
acid or triflouroacetic acid may be used.
In other embodiment, solvent used in step b) may be selected from one or more
alcohols selected from the group consisting of methanol, ethanol, n -propanol,
isopropanol, and n-butanol; a ketone selected from the group consisting of.
acetone, methyl ethyl ketone and methyl isobutyl ketone; a chloro solvents
selected from the group consisting of methylene dichloride (MDC), chloroform,
ethylene dichloride and chlorobenzene; a hydrocarbons selected from the group
" consisting of toluene, xylene, and ethylbenzene; an ester selected from the group
consisting of ethyl acetate, isopropyl acetate, and n-butyl acetate; an ether selected
from the group consisting of tetrahydrofuran,. diethyl ether, diisopropyl ether, and
methyl tert-butyl ether or a polar solvents selected from the group consisting of
water, dimethyl formamide (DMF), dimethyl acetamide (DMAc), dimethyl
sulfoxide {DMSO), and N-methyl-2-pyrrolidone (NMP). In particular methanol or
isopropyl alcohol may be used.
In another embodiment, the mole ratio of orthophosphoric acid used in step (c)
may be selected from 1.01 to 1.39, preferably 1.15 to 1.30, more preferably the
mole ratio is 1.15
I 1 0 - 8 : 8 - 2 8 1 8 17 : 20 „
In another embodiment, isolation in step (d) is carried out by the techniques
known in prior art such as filtration, precipitation, centrifugation, evaporation,
decantation or by distillation. In particular filtration and distillation may be used.
In further embodiment, the process used for the preparation of crystalline
anhydrous of sitagliptin phosphate according to present application is described in
the scheme 1 as represented below:
MeOH,Conc.HCI(aq)
;N MDC,Na2C03,MTBE
Formula (IV) . Formula (VI)
.IPA.H3P04 U x
Formula (I)
Scheme 1
In certain embodiments, the crystalline anhydrous form of sitagliptin phosphate of
present application is stable on storage when, stored at a temperature of about 25
°C (± 2 °C) and a relative humidity of about 60% (± 5% RH). Below given Table -
2 shows the data related to moisture content of two batches of stable anhydrous
form measured by Karl Fischer method.
Storage
condition
25°C±2°C,
60%±5% (RH)
•
After 1 month
0.29
0.26
Water content by KF (wt.
After 2 month
Batch 1
0.21
Batch 2
0.21
% )
After 3 month
0.20
0.17
Table 2
In further embodiment, the present invention provides a crystalline anhydrous
form of sitagliptin phosphate substantially free of impurities of Formula A, B, C,
? I P O DELHI 1 8 - 8 : 8 - 2 8 1 8 i ? : 2 8 13
D, E, F, G and H wherein each impurity is less than about 0.15%w/w and wherein
total impurity is less than 1% w/w
Impurity A
Impurity D
.HCI
HN N
F
Impurity G
Impurity B
Impurity E
Impurity C
Impurity F
Impurity H
In most preferred embodiment, the present invention provides a substantially pure
crystalline anhydrous form of sitagliptin phosphate of Formula-I, wherein said
crystalline anhydrous form is substantially free of impurities of Formula A, B, C,
D, E, F, G and H
Another aspect of the present invention is to provide a pharmaceutical
composition comprising crystalline anhydrous form of sitagliptin phosphate of the
present invention and a pharmaceutical acceptable carrier, which may be in the
form of a tablet, capsule, syrup, powder or granulate for reconstitution. In
particular tablet or capsule may be prepared.
In another embodiment, pharmaceutical acceptable carrier is preferably a
polymeric carrier, and more preferably at least one from the group consisting of
starches, modified starches, cellulose, methyl cellulose (MC), microcrystalline
n> -sf" r*s /"v ELBX 1Q-08- 2818. 14
cellulose (MCC), ethyl cellulose (EC),hydroxyethylcelIulose (HEC),
hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC),
hydroxypropylmethylcellulose acetate succinate (HPMC AS), polycarbophil,
polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives,
polymethacrylates, polyvinyl pyrrolidone (PVP), PVP K-30, polyvinyl acetate
(PVAc), PVP vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a
vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol,
saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, p-cyclodextrins, ycyclodextrins,
hydroxyl-propyl-cyclodextrins, hydroxyl propyl-cyclodextrin,
sodium carboxymethyl cellulose cross-linked polyacrylic acid (carbipol), or a
mixture thereof.
Further, the present invention is illustrated in detail by way of the following
examples. The examples are given herein for illustration of the invention and are
not intended to be limiting thereof.
EXAMPLES
EXAMPLE 1
Preparation of tert-butyl (R)-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro
[1,2,4] triazolo [4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-
yl)carbamate:
(3R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl) butanoic acid
compound of formula (II) was dissolved in 1200 ml of ethyl acetate to this 232
gm of N,N-diisopropylethylamine , 138 gm EDC and 85.2 gm of HOBT was.
added at a temperature of 25-30°C and the reaction mass was stirred for 10-15
minute. To the reaction mass 150 gm 3-(trifluoromethyl)-5, 6, 7, 8-tetrahydro-l,
2, 4-triazolo-[4, 3-a]pyrazine or its hydrochloride compound of Formula (III) was
added and reaction mass was stirred at 55-60°C. After the completion of reaction
ethyl acetate was distilled out under reduced pressure to the residue 10% sodium
carbonate solution was added and reaction mass was stirred. Material thus
x 18-88 2018 17 : 20
obtained was filtered and washed with water to obtain the title compound.
Material obtained was dried. Purity 95%, yield 90-95%.
EXAMPLE 2
Preparation of crystalline anhydrous form of sitagliptin phosphate:
tert-butyl (R)-(4-oxo-4-(3-(trifluoromethyl)-5?6-dihydro [1,2,4] triazolo [4,3-
a]pyrazin-7(8H)-yl)-l -(2,4,5-trifluorophenyl)butan-2-yl)carbamate (compound of
formula IV) 280 gm was dissolved in 1960 ml methanol. Added 102 ml cone
HCl(aq) and the reaction mass was stirred at a temperature of 50°C to 60 °C till -
the completion of reaction. Methanol was distilled out under reduced pressure and
added 1200 ml MDC, to this added 15% Na2CC>3 to adjust the pH to 8. Reaction
mass was stirred to separate the organic layer. Organic layer was distilled out and
560 ml of Methyl tertiary butyl ether (MTBE) was added to the reaction mass
followed by steering at a temperature 25-30°C, to obtain the precipitate. Obtained.
precipitate was further washed with Methyl tertiary butyl ether (MTBE). To the
wet material added 370 ml of water and 930 ml isopropyl alcohol, to this added
85% orthophosphoric acid 69.9 gm at a temperature 30-35°C and stirred the
reaction mass. Temperature was raised to 75-80°C to obtain a clear solution. The
solution was slowly cooled to 20-25°C and to this 930 ml isopropyl alcohol was
added. Reaction mass thus obtained was stirred and filter to obtain the final
product. The material was further dried in hot air oven.
EXAMPLE 3
Preparation of crystalline anhydrous form of sitagliptin phosphate:
tert-butyl (R)-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [453-
a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-yl)carbamate (compound of
formula IV) 280 gm was dissolved in 1960 ml methanol. Added 102 ml cone
HCl(aq) and the reaction mass was stirred at a temperature of 50°C to 60 °C till
the completion of reaction. Methanol was distilled out under reduced pressure and
added 1200 ml MDC, to this added 15% Na2C03 to adjust the pH to 8. Reaction'
mass was stirred to separate the organic layer. Organic layer was distilled out and
I io-aa-2018 i? :28
560 ml of Methyl tertiary butyl ether (MTBE) was added to the reaction mass
followed by steering at a temperature 25-30°C, to obtain the precipitate. Obtained
precipitate was further washed with Methyl tertiary butyl ether (MTBE) to obtain
sitagliptin free base 250 gm. In a round bottom flask added 250 gm (0.614 mol)
sitagliptin free base to this added 370 ml of water and 930 ml isopropyl alcohol, to
this added 81.5 gm orthophosphoric acid (85%) (0.706 mol) at a temperature 30-"
35°C and stirred the reaction mass. Temperature was raised to 75-80°C to obtain a
clear solution. The solution was slowly cooled to 20-25°C and to this 930 ml
isopropyl alcohol was added. Reaction mass thus obtained was stirred and filter to
obtain the final product. The material was further dried in hot air oven.
3 - 8 ' g - 2 8 1 a 17 : 2 0 17
WE CLAIM
1. A process for preparation of a crystalline anhydrous form of sitagliptin
phosphate of Formula (I),
N ' ^ \ .H3P04
comprising the steps of:
(a) coupling (3R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,435-trifluorophenyl)
butanoic acid of Formula (II),
F
with 3-(trifluoromethyl)-5,6,7J8-tetrahydro-l,2J4-triazolo-[4,3-a]pyrazine or its
hydrochloride of Formula (III),
N
.HCI
H N I N
CF3
cu , Formuta
o
Q.
CD in presence of a coupling agent and a base in a suitable solvent to obtain tert-.
butyl (R)-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-
a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-yl)carbamate compound of
Formula IV,
I P O D E L H I • 1 8 - 8 8 - 2 8 1 & 17 : 2 8 18
N
Formula (IV)
(b) deprotecting the compound of Formula (IV) with an acid in presence of a
solvent to obtain sitagliptin free base of Formula (VI),
CF3 Formula (VI)
(c) treating the sitagliptin free base of Formula (VI) with orthophosphoric acid in
presence of a solvent; and
d) isolating crystalline anhydrous form of sitagliptin phosphate of Formula I.
2. The process as claimed in claim 1, wherein mole ratio of orthophosphoric acid
and sitagliptin free base used in step (c) is 1.15 to 1.35.
3. The process as claimed in claim 1, wherein the coupling agent is selected from
the group comprising of N,N'-dicyclohexyl carbodiimide (DCC) , l-ethyl-3-(3-
dimethyl aminopropyl) carbodimide (EDC),. hydroxybenzotriazole (HOBT), Obenzotriazol-
l-yl-l,l,3-tetramethyluronium tetrafluoroborate and mixture thereof.
4. The process as claimed in claim 1, wherein the base is selected from the group
comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide,
sodium carbonate, potassium carbonate, sodium bicarbonate, potassium
bicarbonate, ammonia, aqueous ammonia, methyl amine, ethyl amine, triethyl"
amine, tert-butyl amine, diisopropyl amine, diisopropyl ethyl amine, pyridine,
piperidine, morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-
PO DELHI 10-88-2013 17:28 ig
diazabicyclo[2.2.2]octane (DABCO) and l,5-diazabicyclo[4.3.0]non-5-ene
(DBN).
5. The process as claimed in claim 1, wherein the solvent is selected from the
group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol,
acetone, methyl ethyl ketone, methyl isobutyl ketone, methylene dichloride,
chloroform, ethylene dichloride, chlorobenzene, toluene, xylene, ethylbenzene,
ethyl acetate, isopropyl acetate, n-butyl acetate, tetrahydrofiiran, diethyl ether,
diisopropyl ether, methyl tert-butyl ether, water, dimethyl formamide, dimethyl
acetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and mixture thereof.
6. A process of preparing a crystalline anhydrous form of sitagliptin phosphate of
Formula I,
F
N
N . H3PO4
Formula
comprising the steps of:
a) deprotecting tert-butyl (R)-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro [1,2,4]
triazolo [4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-yl)carbamate
compound of Formula (IV),
Formula (IV)
to give sitagliptin free base compound of Formula (VI),
J—
C-lL. * IO-8:8- 2818 17 : 28 20
Formula (VI)
b) reacting sitagliptin free base of formula (VI) obtained in step a) withorthophosphoric
acid in a mixture of solvent containing water and an organic
solvent at a temperature 30-35°C to obtain a reaction mixture;
c) heating the reaction mixture of step b) at a temperature in the range of 75-80°C
to obtain a clear solution;
d) cooling the clear solution obtained in step c) to 20-25°C to get a reaction mass; .
e) adding an organic solvent to the reaction mass of step d); and
f) filtering to get crystalline anhydrous form of sitagliptin phosphate of Formula I.
7. The process as claimed in claim 6, wherein the organic solvent is selected from
group comprising of methanol, ethanol, propanol, isopropanol or mixture thereof.
8. The process as claimed in claims 1 and 6, wherein said crystalline anhydrous
form is characterized by X-ray powder diffraction pattern at spectral d-spacings of
18.92, 9.47, 6.32, 4.74, 3.68, 2.71 and 2.67 A.
9. The process as claimed in claims 1 and 6, wherein said crystalline anhydrous
form is characterized by X-ray powder diffraction and d-spacing as mentioned in
table below: