Claims:20
WE CLAIM:
1. A process for effective control on the trifluoroacetyl amino Linagliptin impurity
(Formula III) for the preparation of highly pure Linagliptin, which comprises the
steps of:
i. dissolving 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-tetrahydro-1H-purin-8-yl}piperidin-3-
yl]carbamate or 8-[(3R)-3-Boc-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-
1-[(4-methylquin azolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione in an
halogenated hydrocarbon, which is distilled azeotropically for removal of
moisture;
ii. slowly adding Trifluoroacetic acid to the solution of step i. at 0-5 °C;
iii. stirring at 0-5 °C for 20-24 hours;
iv. cooling of reaction mass to -15 °C after completion of reaction;
v. quenching of reaction mass by adding water at temperature -15 to 10 °C;
vi. separating the aqueous layer;
vii. adjusting pH of reaction solution in MDC to 12.5-14.0 using aqueous potassium
hydroxide solution at -15 °C temperature;
viii. further adding potassium hydroxide followed by layer separation;
ix. water washing of the organic layer, followed by complete recovery of solvent
MDC under vacuum at temperature below 50°C;
x. cooling of reaction mass and addition of a C1-C4 aliphatic straight chain or
branched chain alcohol which is selected from methanol, ethanol, 1-propanol, 2-
propanol, butanol, isopropyl alcohol, monoethylene glycol & diethylene glycol or
a mixture thereof;
xi. stirring for 5-10 hours followed by isolation of product as wet cake by filtration;
21
and
xii. drying at 50-60 °C for 10-20 hours to give the desired product.

Description:FIELD OF INVENTION:
The present invention discloses new polymorph of Linagliptin along with novel processes for various polymorphs of Linagliptin. It also reports an improved methodology for large scale production of highly pure Linagliptin. The process/ technology described herein is capable of producing highly pure Linagliptin consistently.
BACKGROUD OF 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 nonproprietary name is Linagliptin [CAS number: 668270-12-0], 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) protected Linagliptin 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 ofLinagliptin 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 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 leads to the formation of bromobutene 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 form e.g. US 9,266,888 or US2007 0259900 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 clear solution followed by its fine filtration. The filtrate upon cooling below -10 °C to get 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.
SUMMARY OF INVENTION:
The present invention relates to an improved process for synthesis of Linagliptin, which give highly pure Linagliptin in high yield. The traditional approach of making 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]carbamateor 8-[(3R)-3-Boc-aminopiperidin-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 aq sodium hydroxide. But it results in increased TFAL impurity formation which once formed, is very difficult to reduce. Therefore, according to present invention to sort out this problem, various organic as well as inorganic base like TEA, DIPEA, LiOH, KOH, Ca(OH)2 were used for quenching of reaction mass after deprotection with TFA but only the aq potassium hydroxide along with modified process was able to control the formation of TFAL impurity (Formula III). In other words, the modified/ improved process describes herein, resulted in highly pure Linagliptin with controlled TFAL as well as BBL impurities.
The present invention also reports the novel processes for the synthesis of various known polymorphic forms of Linagliptin e.g. novel process developed for the preparation of form A & C of Linagliptin basically involves dissolution of any polymorphic form of Linagliptin in an aliphatic straight or branched chain alcohol such as methanol and an halogenated hydrocarbon containing 2-5 carbon atoms such as methylene chloride respectively, followed by the addition of resulting solution in an aliphatic ether with stirring to give Linagliptin form A and Form C respectively.
The present invention also relates to one new polymorphic form of Linagliptindeveloped by Morepen and designated it as “Form M”. Its synthesis involves dissolution of any form of Linagliptin in either a halogenated hydrocarbon such as methylene chloride or and aliphatic straight chain or branched chain alcohol such as methanol, followed by its complete recovery under vacuum to obtain New crystalline form M of Linagliptin.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention is explained in detail below. This description is not intended to be a detailed catalogue of all the different ways in which the invention may be implemented, or all features that may be added to the instant invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof.
According to the first embodiment of the present invention, an improved process for preparation of Linagliptin “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:
1) A solution of 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-tetrahydro-1H-purin-8-yl}piperidin-3-yl]carbamate or
8-[(3R)-3-Boc-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione in an halogenated hydrocarbon is distilled azeotropically for removal of moisture
2) slow addition of Trifluoroacetic acid to the solution of step 1 at 0-5 °C.
3) stirring of the reaction mixture at 0-5 °C for 20-24 hours.
4) lowering of temperature to -15 °C after completion of reaction.
5) Quenching of the of reaction mass by adding water.
6) separation of aq layer
7) adjusting pH of reaction mass to 12.5-14.0 using aq potassium hydroxide solution at -15 °C temperature.
8) addition of further aq potassium hydroxide
9) layer separation & water washing of the organic layer at room temperature
10) complete recovery of organic solvent below 50 °C.
11) again triturated the oily mass using anC1-C4 aliphatic straight chain or branched chain alcohol so as to remove traces of solvent keeping temperature Below 50 °C.
12) cooling the reaction mass to room temperature.
13) addition of an aliphaticC1-C4 straight chain or branched chain alcohol or a mixture thereof.
14) stirring to ensure complete crystallization for 5-10 hours
15) isolation of product as wet cake by filtration.
16) drying the wet cake at 50-60 °C for 10-20 hours, till moisture content is below desired level.
According to one aspect of the first embodiment, the quenching in 5 should be done at -15°C to -10°C to control TFAL impurity.
According to another aspect of the first embodiment the pH in step 7 should be towards higher range i.e. towards 14 to control TFAL impurity.
According to still another aspect of the first embodiment, the C1-C4 aliphatic straight chain or branched chain alcohol used in step 11 & 13 is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, Isopropyl alcohol, monoethylene glycol & diethylene glycol or a mixture thereof.
According to still another aspect of first embodiment, the halogenated hydrocarbon used in step 1 is selected from methylene chloride, chloroform or carbon tetrachloride or a mixture thereof.
According to another aspect of first embodiment the pH in step 7 should be towards higher range i.e. towards 14 to control TFAL impurity.
According to the second embodiment of the present invention, an improved process for preparation of Linagliptin “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:
1) A solution of 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-tetrahydro-1H-purin-8-yl}piperidin-3-yl]carbamate or 8-[(3R)-3-Boc-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione in an halogenated hydrocarbon is distilled azeotropically for removal of moisture
2) slow addition of Trifluoroacetic acid to the solution of step 1 at 0-5 °C.
3) stirring of the reaction mixture at 0-5 °C for 20-24 hours.
4) lowering of temperature to -15 °C after completion of reaction .
5) quenching of the of reaction mass by adding water.
6) adjusting pH of organic layer reaction mass to 12.5-14.0 using aq Potassium hydroxide solution at -15 °C temperature.
7) addition of further aq potassium hydroxide
8) layer separation & water washing of the organic layer at room temperature
9) complete recovery of organic solvent below 50 °C.
10) again triturated the oily mass using an C1-C4 aliphatic straight chain or branched chain alcohol so as to remove traces of various solvent keeping temperature round about 50 °C.
11) cooling the reaction mass to room temperature.
12) addition of an aliphatic C1-C4 straight chain or branched chain alcohol or a mixture thereof.
13) stirring to ensure complete crystallization for 5-10 hours
14) isolation of product as wet cake by filtration
15) drying the wet cake at 50-60 °C for 10-20 hours, till moisture content is below desired level.
According to one aspect of the second embodiment, the quenching in 5 should be done at -15°C to -10°C to control TFAL impurity.
According to another aspect of the second embodiment, the pH in step 6 should be towards higher range i.e. towards 14 to control TFAL impurity.
According to still another aspect of the second embodiment, the C1-C4 aliphatic straight chain or branched chain alcohol used in step 10 & 12 is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, Isopropyl alcohol, monoethylene glycol & diethylene glycol or a mixture thereof.
According to another aspect of second embodiment, the halogenated hydrocarbon used in step 1 is selected from methylene chloride, chloroform or carbon tetrachloride or a mixture thereof.
According to the third embodiment of the present invention, a novel process for preparation of Crystalline form A of Linagliptin “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 halogenated hydrocarbon.
ii. slow addition of the solution of step (i) to an aliphatic ether under stirring
iii. stirring of reaction mass to ensure complete crystallization
iv. isolation of product as wet cake by filtration.
v. drying of wet cake at 50-60 °C to give Crystalline form A of Linagliptin
According to one aspect of third embodiment, the halogenated hydrocarbon used in step (i) is selected from methylene chloride, chloroform or carbon tetrachloride or a mixture thereof.
According to still another aspect of the third embodiment, the aliphatic straight chain or branched chain ether used in step (ii) can be selected from dimethyl ether, diethyl ether, diisopropyl ether or methyl tert butyl ether or a mixture thereof
XRD of form A obtained is as given in Fig 1 and have following peaks as given in Table I below
S.No 2 theta Relative intensity (%)
1. 7.246 32.47
2. 7.695 100.00
3. 8.614 17.93
4. 11.213 15.89
5. 11.725 44.73
6. 12.454 80.22
7. 15.302 15.68
8. 19.620 15.42
9. 22.494 17.47
10. 23.122 69.42
11. 25.173 62.97
12. 25.731 52.86
13. 28.849 23.67

According to the fourth embodiment of the present invention, a novel process for preparation of Crystalline form C of Linagliptin “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 polymorph of Linagliptin in a C1-C4 aliphatic straight chain or branched chain alcohol
ii. slow addition of this solution of step 1 to an aliphatic ether under stirring
iii. stirring of reaction mass to ensure complete crystallization
iv. isolation of wet cake by filtration .
v. drying of wet cake at 50-60 °C to give Crystalline form C of Linagliptin
According to one aspect of the fourth embodiment, the C1-C4 aliphatic straight chain or branched chain alcohol used in step (i) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, Isopropyl alcohol, monoethylene glycol &diethylene glycol or a mixture thereof.
According to still another aspect of fourth embodiment, the aliphatic straight chain or branched chain ether used in step (ii) can be selected from dimethyl ether, diethyl ether, diisopropyl ether or methyl tert butyl ether or a mixture thereof

XRD of form C obtained is as given in Fig 2 and have following peaks as given in Table II below:
S.No 2 theta Relative intensity (%)
1. 7.0054 100.00
2. 8.1910 54.64
3. 13.950 26.42
4. 22.693 15.75
5. 23.859 17.14

According to the fifth embodiment of the present invention, a novel polymorphic form of Linagliptin designated as “form M”& process for preparation of Linagliptin Form M is disclosed which comprises:
i. dissolving any polymorphic form of Linagliptin in a C1-C4 aliphatic straight chain or branched chain alcohol or analiphatic halogenated hydrocarbon.
ii. complete recovery of solvent under vacuum to obtain desired polymorphic form M of Linagliptin.
According to one aspect of the fifth embodiment, the C1-C4 aliphatic straight chain or branched chain alcohol used in step (i) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, Isopropyl alcohol, monoethylene glycol &diethylene glycol or a mixture thereof.
According to another aspect of the fifth embodiment, the halogenated hydrocarbon used in step (i) is selected from methylene chloride, chloroform or carbon tetrachloride or mixture thereof.
XRD of form M disclosed herein is as given in Fig 3 and have following peaks as given in Table III below
S.No 2 theta Relative intensity (%)
1. 7.249 15.72
2. 10.570 42.68
3. 13.549 16.49
4. 14.125 65.72
5. 15.642 35.65
6. 16.311 24.48
7. 16.690 52.02
8. 19.563 52.50
9. 20.112 30.26
10. 21.775 100.00
11. 23.250 38.14
12. 23.646 61.48
13. 24.350 47.38
14. 26.066 30.96
15. 26.55 15.29
16. 27.14 19.26
17. 27.261 15.33
18. 33.63 18.28

BRIEF DESCRIPTION OF FIGURES:
1) Figure 1 – Linagliptin Form A
2) Figure 2 – Linagliptin Form B
3) Figure 3 – Morepen’s Linagliptin Form M
The above mentioned inventions are supported by the following non limiting examples. Reference example 1 is given to give overview of existing Linagliptin synthesis on the basis of various processes as discussed in prior art.
Reference Example 1:
The 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-tetrahydro-1H-purin-8-yl}piperidin-3-yl]carbamateor 8-[(3R)-3-Boc-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione(50g) is dissolved in methylene dichloride (500 ml) with stirring at 20-30 °C. The reaction solution is heated & azeotropic recovery of methylene dichloride is done to remove moisture followed by cooling of reaction mass to 0-5 °C. Then slow addition of Trifluoroacetic acid (225 g) is done followed by stirring of the reaction mass for 15-20 hours at same temperature. After reaction completion, the reaction mass is cooled to -15 °C and quenching is done by addition of water to it followed by adjusting the pH to 9.5-10.5 using NaOH solution (70 g) with stirred & layer separation at room temperature. The organic layer containing product is given three water washing followed by brine washing. The recovery of solvent is done followed by isolation of Linagliptin in MeOH-MTBE.
Yield = 0.55
Purity by HPLC =99.27 %
Single highest impurity = 0.50 %
Total Impurities = 0.73%

Example 1:
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-tetrahydro-1H-purin-8-yl}piperidin-3-yl]carbamate or 8-[(3R)-3-Boc-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione (50 g) is dissolved in methylene dichloride (500 ml) with stirring at 20-30 °C on heating followed by partial recovery of methylene dichloride azeotropically to remove moisture. The resulting solution is cooled to 0-5 °C and slowly added Trifluoroacetic acid (225 g) to it. The reaction mixture is stirring for 15-20 hours at same temperature. After reaction completion, the reaction mass is cooled to -15 °C and quenching by addition of water (350 ml) to it followed by adjusting the pH to 12.5-14 using aq potassium hydroxide solution (120 g) and layer separation to discard aq layer followed by water and brine washing of the organic layer containing product. Then complete recovery of solvent is done and product Linagliptin is isolated in MeOH 25ml) and isopropyl alcohol (250ml) followed by slurry washing of wet cake with Methyl tert-butyl ether (25 ml) and drying at 50-60 °C for 12-15 hours to give pure Linagliptin.
Yield = 0.60
Purity by HPLC =99.89 %
Single highest impurity =0.06 %
TFAL Impurity = 0.05%
Total Impurities = 0.11 %
S-isomer = Not detected.

Example 2:
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-tetrahydro-1H-purin-8-yl}piperidin-3-yl]carbamate or 8-[(3R)-3-Boc-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione(50 g) is dissolved in methylene dichloride (500 ml) with stirring at 20-30 °C. on heating followed by partial recovery of methylene dichloride azeotropically to remove moisture. The resulting solution is cooled to 0-5 °C and slowly added Trifluoroacetic acid (225 g) to it. The reaction mixture is stirring for 15-20 hours at same temperature. After reaction completion, the reaction mass is cooled to -15 °C and quenching by addition of water (350 ml)followed by layer separation to discard the aqueous layer & added water (50 ml) to the organic layer, followed by adjusting the pH to 12.5-14 using aq potassium hydroxide solution (120 g) and layer separation to discard aq layer followed by water and brine washing of the organic layer containing product. Then complete recovery of solvent is done and product Linagliptin is isolated in MeOH 25ml) and isopropyl alcohol (250ml) followed by slurry washing of wet cake with Methyl tert-butyl ether (25 ml) and drying at 50-60 °C for 12-15 hours to give pure Linagliptin.
Yield = 0.62
Purity by HPLC = 100.00%
Single highest impurity = 0.00 %
Total Impurities = 0.00 %
S-isomer = Not detected.

Example 3:
Linagliptin (4 g) is dissolved in methylene chloride (8 ml) and the resulting Linagliptin solution is added to the Methyl tert butyl ether (20 ml) with stirring at 20-30 °C in 10-15 minutes followed by stirring of reaction mass for 3-4 hours to ensure complete crystallization. Then the reaction mass is cooled to 0-5 °C and product is isolated by filtration and running washing of wet cake with methyl tert butyl ether (2 ml). The wet cake is dried at 50-60 °C for 6-7 hrs under vacuum to give Linagliptin Form A having XRD reported in Figure 1 (Yield = 0.82).
Example 4:
Linagliptin (4 g) is dissolved in Methanol (8 ml) and the resulting Linagliptin solution is added to the Methyl tert butyl ether (20 ml) with stirring at 20-30 °C in 10-15 minutes followed by stirring of reaction mass for 3-4 hours to ensure complete crystallization. Then the reaction mass is cooled to 0-5 °C and product is isolated by filtration and running washing of wet cake with methyl tert butyl ether (2 ml). The wet cake is dried at 50-60 °C for 6-7 hrs under vacuum to give Linagliptin Form C having XRD reported in Figure 2 (Yield = 0.84).
Example 5:
Linagliptin (4 g) was dissolved in methylene chloride (8 ml)by stirring the reaction mass for 20-30 minutes. The resulting solution was heated to 40-45 °C followed by complete recovery of solvent under vacuum followed by its further drying at 50-60 °C for 6-7 hours to get new polymorphic form M of Linagliptin having XRD reported in Figure 3.
Yield = 0.97

Example 6:
Linagliptin (4 g) was dissolved in Methanol (8 ml) by stirring the reaction mass for 20-30 minutes. The resulting solution was heated to 40-45 °C followed by complete recovery of solvent under vacuum followed by its further drying at 50-60 °C for 6-7 hours to get new polymorphic form M of Linagliptin having XRD reported in Figure 4.
Yield = 0.94
While at least some exemplary embodiment has been presented in the foregoing detailed description of the invention, it should be appreciated that a vast number of variations exist. It should also be appreciated that the exemplary embodiment are not intended to limit the scope, applicability, or configuration of the invention in any way. It is being understood that various changes may be made in the function and arrangement of elements described in an exemplary embodiment without departing from the scope of the invention.