FIELD OF INVENTION:
The present invention discloses several novel processes for the preparation of anhydrous crystalline Sitagliptin phosphate.

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. This invention describes the use of (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluoro phenyl)butan-2-yl)carbamate (Boc-Sitagliptin of Formula II) intermediate or (R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl) butan-1-one mandelate (Sitagliptin Mandelate of Formula III), and subsequently converts it to Anhydrous Sitagliptin Phosphate of formula Ia.

Boc-Sitagliptin or Formula II

Formula III or Sitagliptin Mandelate Salt

BRIEF DESCRIPTION OF THE DRAWINGS:
The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
Figure 1 shows the XRD of highly pure Crystalline anhydrous Sitagliptin Phosphate (73.5 g)
Figure 2 shows the XRD of highly pure Crystalline anhydrous Sitagliptin Phosphate (43.5 g).
Figure 3 shows the XRD of Anhydrous crystalline Sitagliptin Phosphate.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a novel process of preparation of Crystalline anhydrous Sitagliptin Phosphate is disclosed which comprises (Example 1):
1) Charging of (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluoro phenyl)butan-2-yl)carbamate (Boc-Sitagliptin or Formula II) in round bottom flask.
2) Charging of C1 – C4 aliphatic alcohol to it with stirring for complete dissolution
3) Cooling of reaction mass to 0-5°C.
4) Addition of anhydrous Methanolic.Hydrogen chloride gas to it
5) Stirring for 20-30 minutes at this temperature.
6) Allowed the temp to rise to 20-30 °C.
7) Stirring the reaction mass till reaction completion
8) Cooling of reaction mass to -10°C to -5°C.
9) Adjust pH with caustic solution
10) Stirring for 20-30 minutes at -10°C to -5°C.
11) Extraction of product using a halogenated hydrocarbon
12) Layer separation
13) Washing of organic layer with water
14) Complete recovery of solvent under vacuum at 35-45 °C to get crude Sitagliptin base.
15) Charging of C1 – C4 aliphatic alcohol into crude Sitagliptin base of step 14
16) Addition of orthophosphoric acid & water
17) Stirring for dissolution
18) Heating to 55-65 °C & stirring
19) Cooling to room temperature & stirring for complete crystallization
20) Filtration of resulting solid to obtain the product as wet cake
21) Charging of wet cake of step 20 in a C1-C4 aliphatic straight chain or branched chain alcohol
22) Heating to 35-40 °C.
23) Stirring for 1-2 hrs
24) Filtration of resulting solid to obtain the product as wet cake
25) Drying of wet cake at 50-60°C for 10-20 hours to give desired anhydrous Crystalline Sitagliptin phosphate. XRD as per figure 1.
According to one aspect of the present invention, the C1-C4 aliphatic alcohol used in step 2, 15 & 21 is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof.
According to another aspect of first embodiment, the halogenated hydrocarbon used in step 11 is selected from methylene chloride, chloroform or carbon tetrachloride or mixture thereof.
According to the second embodiment of the present invention, a novel process of preparation of Crystalline anhydrous Sitagliptin Phosphate is disclosed which comprises (Example 2):
1) Charging of (R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl) butan-1-one mandelate (Sitagliptin Mandelate, Formula III) in round bottom flask.
2) Charging of a halogenated hydrocarbon & water
3) Stirring to dissolve
4) pH adjustment of reaction mass to 11-13 using aq caustic solution.
5) Settling & layer separation
6) Washing of organic layer with water followed by brine washing.
7) Fine filtration of the organic layer through hyflo bed.
8) Complete recovery of solvent under vacuum at 35-45 °C to get crude Sitagliptin base.
9) Charging of C1 – C4 aliphatic alcohol into crude Sitagliptin base of step 8
10) Addition of orthophosphoric acid & water
11) Stirring for dissolution
12) Heating to 55-65 °C & stirring
13) Cooling to room temperature & stirring for complete crystallization
14) Filtration of resulting solid to obtain the product as wet cake
15) Charging of wet cake of step 14 in a C1-C4 aliphatic straight chain or branched chain alcohol
16) Heating to 35-40 °C.
17) Stirring for 1-2 hrs
18) Filtration of resulting solid to obtain the product as wet cake
19) Drying of wet cake at 50-60°C for 10-20 hours to give desired anhydrous Crystalline Sitagliptin phosphate. XRD as per figure 2.
According to first aspect of second embodiment, the halogenated hydrocarbon used in step 2 is selected from methylene chloride, chloroform or carbon tetrachloride or mixture thereof.
According to Second aspect of the current embodiment, the C1-C4 aliphatic alcohol used in step 9 & 15 is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof.

According to the third embodiment of the present invention, a novel process of preparation of Crystalline anhydrous Sitagliptin Phosphate is disclosed which comprises (Example 3):
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[4,3-a]pyrazine phosphate Monohydrate in round bottom flask
b) Charging of C1-C4 aliphatic straight chain or branched chain alcohol to it
c) Heating of reaction mass to 40-50°C.
d) Stirring for 1-2 hrs
e) Cooling of reaction mass to 25-35°C.
f) Filtration of resulting solid to get wet cake
g) Running washing of wet cake of step (f) with C1-C4 aliphatic straight chain or branched chain alcohol.
h) Drying of wet cake under vacuum at 50-60 °C for 10-20 hours to get anhydrous crystalline Sitagliptin Phosphate. XRD as per figure 3.
According to first aspect of the third embodiment, the C1-C4 aliphatic alcohol used in step b, & g, is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof.

According to yet another major embodiment of current invention, it is disclosed that Anhydrous Crystalline Sitagliptin phosphate prepared as per any of the process as disclosed earlier, is novel & its having XRD pattern with peaks as tabulated below:
S.No 2-Theta Value Intensity
1. 4.8222(19) 40.74
2. 13.616(3) 30.05
3. 14.115(5) 21.36
4. 14.453(7) 72.94
5. 15.225(4) 26.29
6. 15.576(5) 77.71
7. 18.4458(18) 64.11
8. 18.799(5) 40.71
9. 19.592(5) 100.00
10. 20.154(3) 32.00
11. 21.627(17) 34.57
12. 22.289(9) 37.10
13. 23.809(4) 75.51
14. 24.442(4) 60.08
15. 25.545(10) 71.66
16. 26.765(8) 44.80
17. 27.170(6) 49.83
18. 30.206(19) 23.57
19. 33.616(7) 21.15
20. 35.395(12) 30.78

The above mentioned invention is supported by the following non limiting examples.
EXAMPLES:
Example 1:
(R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluoro phenyl)butan-2-yl)carbamate (Boc-Sitagliptin or Formula II) (50 g) is taken in an RBF along with Methanolic HCl (300 ml) under cooling at 0-5 °C. Stirring & raising the temperature to 20-30 °C & stirred the reaction mass till reaction completion. After reaction completion reduced the temperature to -10 to -5 °C & adjusted the pH of reaction mass with 20% NaOH Solution. Continued stirring of reaction mass for 1-2 hours at this temperature. Charged methylene chloride (250 ml) to reaction mass & extracted product in organic layer. Performed layer separation & extracted aq. Layer twice with methylene chloride (100 ml). Combined all organic layers & provided water washing to it. After water washing, fine filtered reaction mass from hyflo bed & performed complete solvent recovery under vacuum keeping temperature below 45 °C. Dissolved material thus obtained in Methanol (150 ml) & stirred followed by addition of Orthophosphoric acid (15 g) & water (100 ml) to it. Heated the reaction mass to 50-60 °C & stirred till reaction completion. Then allowed the reaction mass to cool to room temperature & stirred till complete crystallization. After crystallization filtered tth reaction mass & slurry washed the wet cake in methanol (25 ml) 35-40 °C for 1-2 hours. Then filtered the reaction mass & dried under vacuum at 50-60 °C for 10-20 hour to give highly pure Crystalline anhydrous Sitagliptin Phosphate (73.5 g). The XRD is attached herewith as 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:
(R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4, 5-trifluorophenyl) butan-1-one mandelate (Sitagliptin Mandelate, Formula III) (50 g) is taken in Methylene chloride (250 ml) & stirred to dissolve. Charged water to reaction mass & stirred. Adjusted pH of reaction mass to 11-12.8 with NaOH solution. Stirred the reaction mass for one hour to ensure complete conversion of starting material at room temperature. After reaction completion confirmation, performed layer separation of biphasic reaction mass. Organic layer containing product was fine filtered thorough hyflo bed to remove insoluble impurities. Performed complete recovery of solvent under vacuum to get crude material keeping temperature below 45 °C. Dissolved material thus obtained in Methanol (150 ml) & stirred followed by addition of Orthophosphoric acid (15 g) & water (100 ml) to it. Heated the reaction mass to 50-60 °C & stirred till reaction completion. Then allowed the reaction mass to cool to room temperature & stirred till complete crystallization. After crystallization filtered tth reaction mass & slurry washed the wet cake in methanol (25 ml) 35-40 °C for 1-2 hours. Then filtered the reaction mass & dried under vacuum at 50-60 °C for 10-20 hour to give highly pure Crystalline anhydrous Sitagliptin Phosphate (43.5 g). The XRD is attached herewith as 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:
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 (50 g) is taken in 2-propanol (125 ml) & stirred the reaction mass. Heating the reaction mass to to 40-50 °C for 1-2 hours. Then cooling the reaction mass to 25-35 °C. Filtered the reaction mass & running washed the wet cake with 2-propanol (200 ml). Re-filtered the reaction mass & dried product at 50-60 °C for 1-20hours to give Anhydrous crystalline Sitagliptin Phosphate. The XRD is attached herewith as 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:
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 (50 g) is taken in Methanol (125 ml) & stirred the reaction mass. Heating the reaction mass to to 40-50 °C for 1-2 hours. Then cooling the reaction mass to 25-35 °C. Filtered the reaction mass & running washed the wet cake with methanol (50 ml). Re-filtered the reaction mass & dried product at 50-60 °C for 10-20 hours to give Anhydrous crystalline Sitagliptin Phosphate. The XRD is attached herewith as Figure 3.
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.

CLAIMS:
1. A novel process for preparation of Crystalline anhydrous Sitagliptin Phosphate which comprises:
i. dissolving (R)-tert-butyl(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole[4,3-a] pyrazin-7(8H)-yl)-1-(2,4,5-trifluoro phenyl)butan-2-yl) in a aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof;
ii. cooling of reaction mass to 0-5°C & addition of methanolic HCl solution followed by stirring at this temperature for 10-20 min;
iii. heating the reaction mass to 20-30 °C followed by stirring till reaction completion;
iv. again cooling reaction mass to -5 to -10°C & pH adjustment using caustic solution;
v. stirring at -5 to -10 °C for 30 min;
vi. extracted product from aq. layer using a halogenated hydrocarbon which may be selected from methylene dichloride, chloroform, carbon tetrachloride or mixture thereof;
vii. isolating Sitagliptin base by complete solvent recovery keeping temperature below 45 °C;
viii. redissolving Sitagliptin base as obtained in previous step in a aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof;
ix. adding orthophosphoric acid & water followed by stirring;
x. heating the reaction mass to 55-65 °C with continued stirring;
xi. cooling reaction mass to room temperature followed by stirring till proper crystallization of material;
xii. filtering of product as wet cake & slurry washing in a aliphatic alcohol as used in step VII above at 35-40 °C;
xiii. again filtering ofproduct as wet cake;
xiv. drying of wet cake at 50-60°C for 10-20 hours to give desired product, which is anhydrous Crystalline Sitagliptin phosphate.

2. A novel process for preparation of Crystalline anhydrous Sitagliptin Phosphate which comprises:
i. Dissolving (R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl) butan-1-one mandelate or Sitagliptin mandelate salt in a halogenated hydrocarbon which may be selected from methylene dichloride, chloroform, carbon tetrachloride or mixture thereof & water;
ii. stirring to dissolve & adjusted its pH to 11-13 using caustic solution;
iii. layer separation & washing of organic layer with brine;
iv. fine filtration of organic layer via hyflow bed;
v. isolation of Sitagliptin base from organic layer by complete solvent recovery keeping temperature below 45 °C;
vi. re-dissolving Sitagliptin base as obtained in previous step in a aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof;
vii. addition of orthophosphoric acid & water followed by stirring;
viii. heating the reaction mass to 55-65 °C with continued stirring;
ix. cooling reaction mass to room temperature followed by stirring till proper crystallization of material;
x. filtration of product as wet cake & slurry washing in a aliphatic alcohol as used in step VI above at 35-40 °C;
xi. again filtration of product as wet cake;
xii. drying of wet cake at 50-60°C for 10-20 hours to give desired product, which is anhydrous Crystalline Sitagliptin phosphate.

3. A novel process for preparation of Crystalline anhydrous Sitagliptin Phosphate using any polymorphic form of Sitagliptin phosphate which comprises:
i. adding any polymorphic form of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoro methyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate to an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof;
ii. stirring & heating of reaction mass to 40-50 °C for 1-2 hours;
iii. cooling of reaction mass to 25-35 °C;
iv. continued stirring at this temperature for ensure proper crystallization;
v. filtration of product as wet cake with running washing with aliphatic alcohol as used in step I) earlier;
vi. drying of wet cake at 50-60°C for 10-20 hours to give desired product, which is anhydrous Crystalline Sitagliptin phosphate.

4. A novel polymorphic form of anhydrous Sitagliptin phosphate prepared using any of process as claimed in claim 1-3.

5. The novel polymorphic crystalline form of anhydrous Sitagliptin phosphate of claim 4, having characteristic peaks as given below:

S. No 2-Theta Value Intensity
1. 4.8222(19) 40.74
2. 13.616(3) 30.05
3. 14.115(5) 21.36
4. 14.453(7) 72.94
5. 15.225(4) 26.29
6. 15.576(5) 77.71
7. 18.4458(18) 64.11
8. 18.799(5) 40.71
9. 19.592(5) 100.00
10. 20.154(3) 32.00
11. 21.627(17) 34.57
12. 22.289(9) 37.10
13. 23.809(4) 75.51
14. 24.442(4) 60.08
15. 25.545(10) 71.66
16. 26.765(8) 44.80
17. 27.170(6) 49.83
18. 30.206(19) 23.57
19. 33.616(7) 21.15
20. 35.395(12) 30.78