Description:FIELD OF INVENTION:
The present invention primarily discloses several novel processes for the preparation of anhydrous crystalline Sitagliptin phosphate using various solvent systems such as Ethyl acetate, Dimethylsulfoxide & Tetrahydrofuran or mixture thereof. This patent also discloses novel method of preparation of Sitagliptin Oxalic acid salt & Benzoic acid salt using Isopropyl alcohol. Apart from these two primary inventions, also disclosed is a novel method of preparation of Sitagliptin Phosphate monohydrate.

BACKGROUD OF INVENTION:
Sitagliptin phosphate having chemical name 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate salt has the following structural formula I:

Formula I

Formula Ia
Sitagliptin is disclosed in WO 03/004498 and U.S. Pat. No. 6,699,871. Sitagliptin phosphate salt is disclosed in US patent application 7,326,708. Sitagliptin or Sitagliptin phosphate is a dipeptidyl peptidase- IV (DPP-IV) inhibitor and is useful for the treatment and prevention of Type 2 diabetes, hyperglycemia, insulin resistance, obesity, and high blood pressure. Sitagliptin hydrochloride is prepared from 2,4,5-trifluorobenzyl chloride. The major disadvantages of this process are that it involves multi-step synthesis; use of hazardous chemicals such as butyl lithium, diazomethane and silver benzoate; and low overall yield (18%).

U.S. Patent application 2005/0032804 discloses a (2R)-4-oxo-4-[3-( trifluoromethy I)-5,6-dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)yl]-1-(2,4,5-trifluorophenyl)butan-2-amine dihydro gen phosphate monohydrate, also known as Sitagliptin phosphate monohydrate. The commercial JANUVIA tablets contain Sitagliptin phosphate monohydrate.

U.S. Patent application 2006/0287528 discloses three polymorphic forms (Form I, Form II and Fom1 III) of anhydrous Sitagliptin phosphate and crystalline solvates of Sitagliptin phosphate (e.g., ethanol solvate). This publication reports that Form II is a desolvated anhydrate form, which is metastable and converts into anhydrous forms such as Form I or Form III or mixtures thereof in about 2 hours at about 45° C. The ethanol solvate is also not a stable form and can be converted to desolvated Form II by (a) drying with nitrogen flow over the sample for about 5 hours at about 25° C. or (b) drying in vacuum for about 5 hours at about 25° C. Upon grinding or compaction of Form I, Form I can be converted into Form III. However, Form III is a stable form at low temperature and is stable below 34o C.
U.S. Patent application 2007/0021430 (or WO 2005/030127) discloses an anhydrous polymorph form of Sitagliptin phosphate (Form IV). Form IV is prepared by heating Sitagliptin phosphate monohydrate above 58° C. for about 8 hours. This publication reports that Form IV is also a metastable form and it converts into a crystalline Sitagliptin phosphate monohydrate slowly under ambient conditions and rapidly under high relative humidity (98%) condition at room temperature.
U.S. Patent application 2007/028194 discloses a composition comprising an amorphous form of Sitagliptin phosphate, which is obtained by freeze-drying of Sitagliptin Phosphate in aqueous solutions. Amorphous Sitagliptin Phosphate is usually less stable, both chemically and physically in comparison to crystalline forms.
W0201000469 discloses crystalline hydrochloride, fumarate, malate, sulfate, phosphate, succinate, lactate, glycolate, maleate, citrate and mesylate salts of Sitagliptin.
W02010012781 discloses novel crystalline forms of galactarate, hemi-L-malate, D­ gluconate, sucinate, hydrobromide, thiocyanate, oxalate, L-asparate, ethanedisulfonate, pyroglutamate, glutarate, acetate forms of Sitagliptin.
WIPO patent application WO2010/131035 Sitagliptin dihydrogenphosphate form M, characterized by an XRPD spectrum comprising the following degrees 28 peaks: 5.0, 14.3, 18.6, 24.0 ± 0.2 degrees 28. Preferably Sitagliptin dihydrogenphosphate form M is characterized by an XRPD spectrum comprising four or more (preferably five or more, preferably six or more, preferably seven or more, preferably eight or more, preferably nine or more, preferably ten or more, preferably eleven or more, preferably twelve or more preferably thirteen or more, preferably fourteen or more, preferably fifteen) of the following degrees 28 peaks: 5.0, 9.7, 13.7, 14.3, 15.4, 18.6, 19.5, 19.7, 20.3, 22.4, 24.0, 24.5, 25.7, 27.0, 27.3 ± 0.2 degrees 2 theta.

WO2012025944A2 of USV Limited discloses new polymorphic forms of Sitagliptin Hydrochloride and Sitagliptin Esylate and processes thereof.
Morepen’s own patent application 1788/DEL/2013 disclosed four new polymorphic forms of Sitagliptin Phosphate mainly M1, M2, M3 & M4 and processes for the preparation thereof.
SUMMARY OF INVENTION:
The present invention reports the novel processes for the preparation of anhydrous crystalline Sitagliptin phosphate using Dimethylsulfoxide, Tetrahahydrofuran & Ethyl acetate or mixture Thereof. The preparation of Crystalline form was confirmed by the XRD pattern of the final material obtained.
This patent also gives novel method of preparation of preparation of Sitagliptin Benzoate & Oxalate salts in Isopropyl alcohol with respective XRD pattern.
This patent gives yet another novel method of preparation of Sitagliptin Phosphate monohydrate of Formula I, using a ketone-water solvent system.
.C6H5COOH
Sitagliptin Benzoate Salt or Formula II
.(COOH)2
Sitagliptin Oxalate or Formula III
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, novel benzoic acid salt and novel crystalline polymorphic “Form B” of Sitagliptin Benzoate salt is disclosed
.C6H5COOH
Sitagliptin Benzoate Salt or Formula II
having characteristic peaks as given below.

2- Theta Relative intensity (%)
(Peaks having > 20% Intensity are mentioned)

7.27 20.56
18.16 58.36
18.46 39.46
18.74 46.01
19.41 61.11
20.45 24.25
21.85 100.00
22.29 23.49
27.57 31.26

According to another aspect of current invention a novel process of preparation of Crystalline Sitagliptin benzoate is disclosed which comprises (Example 1):
1) Charging of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo or Sitagliptin Base in a C1-C4 aliphatic straight chain or branched chain alcohol selecting from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof.
2) Charging of Benzoic acid
3) Stirring the reaction mass for 3-5 hours at 20-30°C.
4) Filtration of resulting solid to obtain the product as wet cake
5) Drying of wet cake at 50-60°C for 10-20 hours to give desired Crystalline Sitagliptin benzoate.
According to the Second embodiment of the present invention, Novel oxalic acid salt and Novel Crystalline polymorphic “Form O” of Sitagliptin oxalate salt is disclosed
.(COOH)2
Sitagliptin Oxalate or Formula II

having structure as given above and characteristic peaks as given below.

2- Theta Relative intensity (%)
(Peaks having > 20% Intensity are mentioned)

8.37 25.38
11.18 44.43
16.98 21.27
17.50 100.00
20.58 40.65
20.89 50.34
21.12 26.83
25.34 54.30
27.00 26.80

According to yet another aspect of current invention, a novel process of preparation of Crystalline Sitagliptin oxalate is disclosed which comprises (Example 2):
1) Charging of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo or Sitagliptin Base in a C1-C4 aliphatic straight chain or branched chain alcohol selecting from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof.
2) heating to 75-85°C.
3) stirring till complete dissolution.
4) Charging of mixture of oxalic acid & C1-C4 aliphatic straight or branched chain alcohol as used in step 1.
5) Stirring the reaction mass for 30 min at 75-85°C.
6) Cooled the reaction mass to 20-30°C.
7) Further stirring for 2-3 hours.
8) Filtration of resulting solid to obtain the product as wet cake
9) Drying of wet cake at 50-60°C for 10-20 hours to give desired Crystalline Sitagliptin oxalate.
According to the third embodiment of the present invention, a novel crystalline Form AS-1 of anhydrous Sitagliptin phosphate having XRD pattern with characteristic peaks as tabulated below:
2- Theta Relative intensity (%)
(Peaks having > 40% Intensity are mentioned)

13.85 61.84
15.99 65.44
18.50 62.85
18.65 49.02
19.19 44.78
23.72 67.35
24.09 100.00
24.40 75.65
24.99 50.59

According to the fourth embodiment of the present invention, a novel process of preparation of Crystalline anhydrous Sitagliptin Phosphate is disclosed which comprises (Example 3, 4 & 5):
a) Charging of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo or Sitagliptin Base in a C1-C3 aliphatic ester. e.g. ethyl acetate, propyl acetate, butyl acetate or a mixture thereof or dimethylsulfoxide or cyclic or acyclic ethers like tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether or a mixture thereof.
b) Heating to 40-50°C
c) Stirring to ensure complete dissolution
d) Adding orthophosphoric acid to the reaction mass of step c)
e) Cooling the reaction mass to 20-30°C
f) Stirring for 3-5 hours to ensure complete crystallization.
g) Filtration of resulting solid to obtain the product as wet cake
h) Drying of wet cake under vacuum at 50-60 °C for 10-20 hours to get anhydrous crystalline Sitagliptin Phosphate.

According to the fifth embodiment of the present invention, a novel process of preparation of Crystalline Sitagliptin Phosphate monohydrate is disclosed which comprises (Example 6):
a) Charging of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo or Sitagliptin Base in a C1-C3 straight or branched chain ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone Or cyclic or acyclic ethers like tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether or a mixture thereof.
b) Adding orthophosphoric acid & water under stirring
c) Heating & stirring to ensure complete dissolution
d) Cooled the reaction mass to 20-30 °C.
e) Further added C1-C3 straight or branched chain ketone of step a).
f) Stirring for 4-8 hours to ensure complete crystallization
g) Filtration of resulting solid to get product as wet cake
h) Drying of wet cake under vacuum at 50-60 °C for 4-8 hours to get crystalline Sitagliptin Phosphate monohydrate.

The above disclosed invention is supported by the following non limiting examples.
EXAMPLES:
Example 1:
Process for the preparation of Sitagliptin Benzoate:
To a suspension of 50 g Sitagliptin base in Isopropyl alcohol (250 ml) in a round bottom flask, benzoic acid (15 g) was added at 20-30°C & resulting reaction mixture was stirred for 3-5 hours. The crystallized material was isolated by filtration & dried at 50-60°C for 10-20 hours to get 60 g of Sitagliptin Benzoate (92.33% yield). The Sitagliptin Benzoate thus obtained is crystalline in nature having XRD pattern as shown in Figure 1.
Yield = 1.47
Purity by HPLC = 99.67 %
Single highest impurity = 0.15 %
Total Impurities = 0.33 %
Moisture Content = 0.09% w/w by KF.
Example 2:
Process for the preparation of Sitagliptin Oxalate:
50 g of Sitagliptin base was dissolved in Isopropyl alcohol (250 ml) in a round bottom flask at 75-85°C with stirring until clear solution. After complete dissolution, a mixture of Oxalic acid (1 g) & Isopropyl alcohol (100 ml) was added in reaction mass at 75-85°C and stirred for 30 minutes. The mass was cooled to 20-30°C for 2-3 hours. The crystallized material was isolated by filtration & dried at 50-60°C for 10-20 hours to get 55 g of Sitagliptin Oxalate (90.16% yield). The Sitagliptin Oxalate thus obtained is crystalline in nature having XRD pattern as shown in Figure 2
Yield = 0.87
Purity by HPLC = 99.95%
Single highest impurity = 0.03 %
Total Impurities = 0.05%
Moisture Content = 0.16% w/w by KF.
Example 3:
Process for the preparation of Anhydrous Sitagliptin Phosphate:
50 g of Sitagliptin base was dissolved in Ethyl acetate (250 ml) in a round bottom flask at 40-50°C with stirring until clear solution. After complete dissolution, a mixture of Orthophosphoric acid (15 g) & ethyl acetate was added. The reaction mass was cooled to 20-30°C & stirred for 3-5 hours. The crystallized material was isolated by filtration & dried at 50-60°C for 10-20 hours to get 57.5 g of anhydrous Sitagliptin Phosphate (92.74% yield). The anhydrous Sitagliptin Phosphate thus obtained is crystalline in nature having XRD pattern as shown in Figure 3.
Yield = 0.95
Purity by HPLC = 99.99%
Single highest impurity = 0.01 %
Total Impurities = 0.01%
Moisture Content = 0.19% w/w by KF.
Example 4:
Process for the preparation of Anhydrous Sitagliptin Phosphate:
50 g of Sitagliptin base was dissolved in DMSO (250 ml) in a round bottom flask at 40-50°C with stirring until clear solution. After complete dissolution, a mixture of Orthophosphoric acid (15 g) & DMSO (25 ml) was added. The reaction mass was cooled to 20-30°C & stirred for 3-5 hours. The crystallized material was isolated by filtration & dried at 50-60°C for 10-20 hours to get 50 g of anhydrous Sitagliptin Phosphate (80.64% yield). The anhydrous Sitagliptin Phosphate thus obtained is crystalline in nature having XRD pattern as shown in Figure 4.
Yield = 0.93
Purity by HPLC = 99.95%
Single highest impurity = 0.02 %
Total Impurities = 0.05%
Moisture Content = 0.17% w/w by KF.

Example 5:
Process for the preparation of Anhydrous Sitagliptin Phosphate:
To a solution of Sitagliptin base (50g) in Tetrahydrofuran (400 ml) in a round bottom flask at 40-50°C, Orthophosphoric acid (15 g) was added and the reaction mixture was stirred for 1-2 hrs followed by cooling to 20-30°C & stirring for 3-5 hours. The crystallized material was isolated by filtration & dried at 50-60°C for 10-20 hours to get 53 g of anhydrous Sitagliptin Phosphate (85.48% yield). The anhydrous Sitagliptin Phosphate thus obtained is crystalline in nature having XRD pattern as shown in Figure 5.
Yield = 0.93
Purity by HPLC = 99.95%
Single highest impurity = 0.02 %
Total Impurities = 0.05%
Moisture Content = 0.17% w/w by KF.
Example 6:
Process for the preparation of Sitagliptin Phosphate Monohydrate:
To a suspension of 50g Sitagliptin base in Acetone (250 ml) in a round bottom flask, Orthophosphoric acid (15g) & water (45ml) were added & heated to 50-60°C with stirring until clear solution. After complete dissolution, the reaction mass was cooled to 20-30°C, Acetone (300 ml) was added & stirred for 4-8 hours. The crystallized material was isolated by filtration & dried at 50-60°C for 4-8 hours to get 58g of Sitagliptin Phosphate Monohydrate (90.62% yield). The Sitagliptin Phosphate Monohydrate thus obtained is having XRD pattern as shown in Figure 6.
Yield = 0.93
Purity by HPLC = 99.95%
Single highest impurity = 0.02 %
Total Impurities = 0.05%
Moisture Content=0.17% w/w by K

, Claims:WE CLAIM:

1. The novel process for the preparation of Crystalline anhydrous Sitagliptin Phosphate, which comprises:
i. Dissolving 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(tri fluoromethyl)-1,2,4-triazolo or Sitagliptin Base in a C1-C3 aliphatic ester. e.g. ethyl acetate, propyl acetate, butyl acetate or a mixture thereof or dimethylsulfoxide or cyclic or acyclic ethers like tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether or a mixture thereof.

ii. Heating the reaction mass to 40-50°C, stirring to dissolve completely

iii. adding orthophosphoric acid to reaction mass

iv. Cooling the reaction mass to 20-30 °C

v. Stirring for 3-5 hours to ensure proper crystallization

vi. Filtration of resulting solid to obtain the product as wet cake

vii. Drying of wet cake at 50-60°C for 10-20 hours to give desired Crystalline anhydrous Sitagliptin Phosphate.