Description:FIELD OF THE INVENTION:
The present invention discloses three new crystalline Forms of Linagliptin designated as Form M1, M2 & M3 and novel processes for preparation of highly pure Linagliptin polymorphic Forms M1, Form M2 & Form M3. The present invention also discloses novel processes for the preparation of polymorphic Forms C and Form XXII of Linagliptin.
BACKGROUND OF THE INVENTION:
Linagliptin, namely 8-(3R)-3-aminopiperidinyl)-7-butyn-2-yl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione or 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino- piperidin-1-yl) xanthine, of formula I, is a long acting inhibitor of dipeptidylpeptidase-IV (DPP-IV) activity, at present under development for the treatment of type II diabetes mellitus. Its international non-proprietary name is Linagliptin [CAS number: 668270-12-0] which has the following chemical structure of formula I.

Formula I
U.S. Patent No. 7,407,955 (US '955) discloses Linagliptin, related compounds, and their pharmaceutical compositions. Further, it describes a process for the preparation of Linagliptin wherein tert-butyloxy carbonyl (Boc) protectedLinagliptin is deprotected using 5-6 M isopropanolic hydrochloric acid or equivalent acid, followed by purification using chromatography. The process disclosed in US '955 is schematically represented in scheme-l.

Scheme-1
U.S. Patent No. 7,820,815 (US '815) discloses a process for preparation of Linagliptin wherein it is prepared by deprotecting 1 -[(4-methyl-quinazolin-2-yl)methyl]-3- methyl-7-(2-butyn-1-yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthine in the presence of ethanolamine. The 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)phthalimidopiperidin-1-yl)-xanthine is prepared by condensing 1-[(4- l methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine with (R)-3-phthalimidopiperidine. The process disclosed in US '815 is schematically represented in scheme-II.
Scheme II
The prior art processes as disclosed in US '955 and US '815 involve protection-deprotection method, leading to an increase in the manufacturing cycle time, decrease in the product yield and further requires purification by chromatography that is not suitable for commercial-scale manufacturing. In addition to this, the prior art processes lead to the formation of bromo butene impurity (i.e. 1 -[(4-Methyl-quinazolin-2-yl)methyl]-3- methyl-7-(3-bromobut-2-e -1 -yl)-8-(3-(R)-amino-piperidin-1 -yl) xanthine of formula II as well as TFAL impurity of formula III.

Formula II

Formula III: Trifluoro acetyl amino Linagliptin / TFAL
Linagliptin is known to exhibit polymorphism and is available in various polymorphic forms, e.g. US 9,266,888 or US20070259900 of Boehringer claims two anhydrous forms- A & B. It involves crude Linagliptin refluxing in ethanol and its hot filtration after charcoalization followed by cooling of the filtrate to 20°C & addition of MTBE at <5°C to give anhydrous Form A. This anhydrous Form A on cooling below 10°C, leads to the formation of anhydrous Form B. Furthermore, Forms C, D & E are also reported. The crude Linagliptin is refluxed in methanol followed by its charcoaling and then filtrate is distilled off to get residue. The resulting residue is cooled to 45-55°C followed by addition of MTBE and further cooling to 20-25°C to get Form C of Linagliptin. Further cooling of Form C to 0-5°C to enhance crystallization, Form D & E can be obtained.
US Patent Application US2013/0123282 of Teva discloses preparation of amorphous Linagliptin which involves partial dissolution of Linagliptin in ethanol followed by evaporation of solvent under reduced pressure to get amorphous Linagliptin.
PCT patent application WO2013128379 of Dr. Reddy Limited reports heating of Linagliptin in ethanol and heating to 78-79°C to get a clear solution followed by its fine filtration. The filtrate upon cooling below -10°C gives Form I of Linagliptin.
Linagliptin Form II is reported to form by dissolution of Linagliptin in methanol on heating followed by its recrystallization by slow addition of MTBE.
Another US Patent Application US2013/0123282 of Teva reports preparation of various new crystalline forms II, III, IV, V, VI, VII, VIII, IX, X, XI, XI’, XII, XIII, XIII’, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII & XXIV using amorphous Linagliptin.
Morepen’s own patent application IN201611032051 also discloses an improved process for the synthesis of highly pure Linagliptin.
Reported polymorphic Forms A, B of Linagliptin reported by its innovator Bohreinger are enantiotropically related and convert reversibly into each other at different temperatures. Linagliptin Form C also converts into Form A by slurry washing in water or solvent. Therefore, there was a need to develop stable polymorphic forms of Linagliptin.
SUMMARY OF THE INVENTION:

The present invention relates to new polymorphic forms of Linagliptin designated as Forms M1, M2, M3 and novel processes for the synthesis of highly pure new polymorphic Forms M1, M2, M3 of Linagliptin.
The traditional approach of making various known polymorphic forms of Linagliptin using intermediate tert-butyl-[(3R)-1-{7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-2,6-dioxo-2,3,6,7-tetra hydro-1H-purin-8-yl}piperidin-3-yl]carbamate or 8-[(3R)-3-Boc-amino piperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H -purine-2,6-dione as described in Scheme I or analogously in Scheme II involves deprotection using Trifluoroacetic acid and quenching by aqueous sodium hydroxide or potassium hydroxide. It further gives rise to various polymorphic Forms A, B or C or any other polymorphic form as described in prior art.
The present invention reports new polymorphic Forms M1, M2 & novel processes for their preparation. It involves dissolution of any known polymorphic form from processes of prior art in an halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or a mixture and its crystallization using an aliphatic ether which can be selected from dimethyl ether, diethyl ether, diisopropyl ether or methyl tert butyl ether or a mixture thereof at different temperatures.
The present invention also reports new polymorphic Form M3 & novel process for its preparation. It involves dissolution of any known polymorphic form reported in prior art in an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof and its crystallization using an acyclic aliphatic hydrocarbon which is selected from, n-pentane, n-hexane, n-heptane, octane or a mixture thereof at different temperatures.
Another aspect of the present invention is that novel process for preparation of polymorphic Form XXII of Linagliptin is disclosed which comprises a similar process as Form M3 but with different temperature for addition of acyclic aliphatic hydrocarbon.
Still another aspect of the present invention is that novel process for preparation of polymorphic Form C of Linagliptin is disclosed which comprises dissolving any form of Linagliptin in aliphatic alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof and its crystallization using direct or reverse addition of cyclic aliphatic hydrocarbon selected from cyclopentane, cyclohexane, cycloheptane, etc. or a mixture thereof at 20-30°C.
The detailed invention is described in elaborated manner in the next section of this patent application.

DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a new crystalline Form M1 of “8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1H-purine-2,6-dione or Linagliptin” & novel process for their preparation is disclosed which comprises:
i. Dissolving any polymorphic form of Linagliptin in a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or a mixture thereof at 20-30°C.
ii. Removing the solvent of step (i) by vacuum distillation till residue formation.
iii. Slowly adding an aliphatic ether selected from diethyl ether, diisopropyl ether or methyl tert butyl ether, etc. or a mixture thereof to the solution of step (ii) with stirring at 20-30 °C.
iv. Stirring of reaction mass till crystallization.
v. Cooling the reaction to 0-10°C & stirring further for 1-2 hours to ensure proper crystallization.
vi. Isolation of product as wet cake by filtration.
vii. Drying of wet cake at 50-60°C for 15-25 hours to give the desired novel crystalline Form M1 of Linagliptin.
XRD of Morepen’s crystalline Form M1 obtained is as given in Fig. 1 and has the following peaks as given in Table 1 below
Pos. [°2?] d-spacing [Å] Rel. Int. [%]
7.1241 12.39821 67.53
7.5745 11.66203 100.00
10.5950 8.34317 54.49
12.3250 7.17568 68.72
13.4467 6.57953 30.03
14.0699 6.28945 68.17
15.6483 5.65844 37.54
16.6513 5.31977 41.17
19.5543 4.53607 33.59
21.6441 4.10259 61.27
23.2563 3.82171 36.32
23.5954 3.76754 50.66
25.0458 3.55255 34.35
25.6055 3.47615 37.19

Table 1
According to the second embodiment of the present invention, a new crystalline Form M2 of “8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1H-purine-2,6-dione or Linagliptin” & novel process for preparation thereof is disclosed which comprises:
i. Dissolving any polymorphic form of Linagliptin in a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or a mixture thereof at 20-30 °C.
ii. Adding an aliphatic ether which can be selected from dimethyl ether, diethyl ether, diisopropyl ether or methyl tert butyl ether or a mixture thereof to the solution of step i under stirring at 20-30 °C.
iii. Stirring of reaction mass till crystallization.
iv. Cooling the reaction to 0-10°C & stirring further for 1-2 hours to ensure proper crystallization.
v. Isolating the product as wet cake by filtration.
vi. Drying of wet cake at 50-60°C for 15-25 hours to give the desired new crystalline Form M2 of Linagliptin.
XRD of Morepen’s crystalline Form M2 obtained is as given in Fig. 2 and has following peaks as given in Table 2 below
Pos. [°2?] d-spacing [Å] Rel. Int. [%]
7.2152 12.24194 84.90
8.1305 10.86569 34.13
9.8755 8.94936 31.41
10.6740 8.28157 80.79
13.5101 6.54875 42.66
14.1816 6.24018 100.00
15.6840 5.64563 40.79
16.6836 5.30956 39.54
21.7340 4.08581 90.65
23.6773 3.75470 56.82

Table 2
According to the third embodiment of the present invention, a new crystalline Form M3 of “8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1H-purine-2,6-dione or Linagliptin” & novel process for preparation thereof is disclosed which comprises:
i. Dissolving any polymorphic form of Linagliptin in an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof, at 50-60 °C.
ii. Adding acyclic aliphatic hydrocarbon selected from n-pentane, n-hexane, n-heptane, n-octane or a mixture thereof to the solution of step i under stirring at 40-50 °C.
iii. Stirring of reaction mass till crystallization.
iv. Cooling the reaction to 0-10°C & stirring further for 1-2 hours to ensure proper crystallization.
v. Isolating the product as wet cake by filtration.
vi. Drying of wet cake at 50-60 °C for 15-25 hours to give the desired novel crystalline Form M3 of Linagliptin.
XRD of Morepen’s crystalline Form M3 obtained is as given in Fig. 3 and has the following peaks as given in Table 3 below
Pos. [°2?] d-spacing [Å] Rel. Int. [%]
6.9621 12.68643 100.00
7.1704 12.31833 30.21
8.1589 10.82803 23.36
10.6252 8.31951 23.54
14.0752 6.28710 31.47
21.7811 4.07710 28.33
23.6344 3.76140 27.32

Table 3
According to the fourth embodiment of the present invention, a novel process for preparation of crystalline Form XXII of “8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1H-purine-2,6-dione or Linagliptin” is disclosed which comprises:
i. Dissolving any polymorphic form of Linagliptin in an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof, at 50-60 °C.
ii. Adding acyclic aliphatic hydrocarbon selected from n-pentane, n-hexane, n-heptane, n-octane or a mixture thereof to the solution of step i under stirring at 20-30°C.
iii. Stirring the reaction mass till crystallization.
iv. Cooling the reaction to 0-10°C & stirring further for 1-2 hours to ensure proper crystallization.
v. Isolating the product as wet cake by filtration.
vi. Drying of wet cake at 50-60°C for 15-25 hours to give desired Linagliptin Crystalline form XXII.
XRD of Linagliptin crystalline Form XXII obtained is as given in Fig. 4.
According to the fifth embodiment of the present invention, a novel process for the preparation of crystalline Form C of “8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1H-purine-2,6-dione or Linagliptin” which comprises:
i. Dissolving any polymorphic form of Linagliptin in an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof at 50-60°C.
ii. Adding cyclic aliphatic hydrocarbon selected from cyclopentane, cyclohexane, cycloheptane, etc. or a mixture thereof to the solution of step i under stirring at 20-30°C. or adding a solution of step i to cyclic aliphatic hydrocarbon selected from cyclopentane, cyclohexane, cycloheptane, etc. or a mixture thereof under stirring at 20-30°C.
iii. Stirring of reaction mass till crystallization.
iv. Cooling the reaction to 0-10°C & stirring further for 1-2 hours to ensure proper crystallization.
v. Isolation of product as wet cake by filtration.
vi. Drying of wet cake at 50-60°C for 15-25 hours to give the desired crystalline Form C of Linagliptin as shown in Figures 5 and 6.
Brief Description of figures:
1) Figure 1 – Morepen’s Linagliptin Form M1
2) Figure 2 – Morepen’s Linagliptin Form M2
3) Figure 3 – Morepen’s Linagliptin Form M3
4) Figure 4 – XRD of Linagliptin Form XXII as per novel process
5) Figure 5 – Linagliptin Form C prepared by direct addition of cyclohexane
6) Figure 6 – Linagliptin Form C prepared by reverse addition of cyclohexane
The above-mentioned invention is supported by the following non-limiting examples.
Example 1:
Linagliptin (20 g) was dissolved in methylene chloride (60 ml) at 20-30°C. After dissolution, the solvent was completely removed under vacuum at 35-45°C to form residue. Then, methyl tert-Butyl ether (60 ml) was added to the residue and stirred till crystallization. The resulting mass was cooled to 0-10°C and stirred further for 1-2 hours to ensure proper crystallization. The product was isolated as wet cake by filtration & dried at 50-60°C for 15-25 hours under vacuum to give Linagliptin Form M1 (yield = 0.96) having XRD as reported in Figure 1.
Example 2:
To a solution of Linagliptin (20 g) in methylene chloride (60 ml), methyl tert-butyl ether (60 ml) was added at 20-30°C and the resulting solution was stirred at the same temperature till complete crystallization. The resulting mass was cooled to 0-10°C and stirred further for 1-2 hours to ensure proper crystallization. The product was filtered as wet cake & dried at 50-60 °C for 15-25 hours under vacuum to give Linagliptin Form M2 (yield = 0.92) having XRD as reported in Figure 2.
Example 3:
To a solution of Linagliptin (20 g) in methanol (50ml), n-Heptane (60 ml) was added at 40-50°C and stirred till complete crystallization. The resulting mass was cooled to 0-10°C and stirred further for 1-2 hours to ensure proper crystallization. The product was isolated by filtration & the wet cake was dried at 50-60°C for 15-25 hours under vacuum to give Linagliptin Form M3 (yield = 0.90) having XRD as reported in Figure 3.
Example 4:
To a solution of Linagliptin (20 g) in methanol (50 ml), n-Heptane (60 ml) was added at 20-30°C and stirred till complete crystallization. The resulting mass was cooled to 0-10°C and stirred further for 1-2 hours to ensure proper crystallization. The product was isolated by filtration & the wet cake was dried at 50-60°C for 15-25 hours under vacuum to give Linagliptin Form XXII (yield = 0.92) having XRD as reported in Figure 4.

Example 5:
To a solution of Linagliptin (20 g) in methanol (50 ml), cyclohexane (60 ml) was added at 20-30°C and stirred till complete crystallization. The resulting mass was cooled to 0-10°C and stirred further for 1-2 hours to ensure proper crystallization. The product was isolated by filtration & the wet cake was dried at 50-60°C for 15-25 hours under vacuum to give Linagliptin Form C (yield = 0.95) having XRD as reported in Figure 5.
Example 6:
A solution of Linagliptin (20 g) in methanol (50 ml) was added to cyclohexane (60 ml) at 20-30°C and stirred till complete crystallization. The resulting mass was cooled to 0-10°C and stirred further for 1-2 hours to ensure proper crystallization. The product was isolated by filtration & the wet cake was dried at 50-60°C for 15-25 hours under vacuum to give Linagliptin Form C (yield = 0.93) having XRD as reported in Figure 6.
, C , Claims:WE CLAIM:

1. An improved process for preparation of crystalline Form M2 of “8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1H-purine-2,6-dione or Linagliptin comprising:
i. dissolving any polymorphic form of Linagliptin in a halogenated hydrocarbon selected from methylene dichloride, chloroform, carbon tetrachloride or a mixture thereof at 20-30°C;
ii. slowly adding an aliphatic ether selected from diethyl ether, diisopropyl ether or methyl tert butyl ether or a mixture thereof under stirring at 20-30°C;
iii. stirring & cooling the reaction mass at 0-10°C for 1-2 hours;
iv. isolating the product as wet cake by filtration; and
v. drying of the wet cake at 50-60°C for 15-25 hours to give the desired novel crystalline Form M2 of Linagliptin having characteristic peaks at 2theta value 7.2152, 8.1305, 9.8755, 10.6740, 13.5101, 14.1816, 15.6840, 16.6836, 21.7340, 23.6773 in the XRD spectrum.