The present invention involves conversion of Linagliptin Dimer into Linagliptin using n-Pentanesulphonic acid sodium salt & orthophosphoric acid or Methanesulphonic acid to give highly pure Linagliptin free from Linagliptin Dimer (Formula II) Impurity, in particular. According to yet another embodiment of the current invention, Linagliptin was converted to its respective benzoic acid salt or R(-) Mandelic acid followed by its re-conversion to Linagliptin free from Linagliptin Dimer (Formula II). As per various prior art reported in background of the invention, this impurity Linagliptin Dimer (Formula II) is very difficult to remove from API incase formed during the process. This impurity can be easily formed in Linagliptin if material is treated with acidic condition.

Formula II

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 treatment of type II diabetes mellitus. Its international nonproprietary name is Linagliptin [CAS number: 668270-12-0] which has the following chemical structure of formula I.

Formula I
US patent number 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
US patent number 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 leads 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 III as well as TFAL impurity of formula IV.

Formula III

Formula IV: 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 US 20070259900 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 the filtrate is distilled off to get the 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. By further cooling 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.
Morepen’s own patent application IN201611032051 gives an improved process for the synthesis of highly pure Linagliptin along with new polymorph & novel processes for preparation of various polymorphs of Linagliptin. Herein, novel method of preparation of Forms A & B were disclosed along with novel polymorphic Form M.
SUMMARY OF THE INVENTION:
The present invention involves conversion of Linagliptin Dimer into Linagliptin using n-Pentanesulphonic acid sodium salt & orthophosphoric acid or methanesulphonic acid to give highly pure Linagliptin free from Linagliptin Dimer (Formula II) impurity in particular. As per various prior arts reported in the Background of the Invention, this impurity Linagliptin Dimer (Formula II) is very difficult to remove from API incase formed during process. This impurity can be easily formed in Linagliptin if material is treated with acidic condition.
It was found that n-Pentanesulphonic acid or Methanesulphonic acid are having inherent tendency to remove or reduce the Linagliptin Dimer content to zero. The solvent that was used in this process is methylene dichloride or similar halogenated hydrocarbon. n-Pentanesulphonic acid & Methanesulphonic acid are used alone or in conjugation with orthophosphoric acid. The details are as given in the next section.
According to yet another embodiment of the current invention, Linagliptin was converted to its respective benzoic acid salt or R(-) Mandelic acid followed by its re-conversion to Linagliptin free from Linagliptin Dimer (Formula II). The salt formation takes place in isopropyl alcohol & water. The details are as provided in the next section.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, an improved process for removal of Linagliptin Dimer (II) from Linagliptin i.e. “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” which comprises (Example 1):
1) dissolving 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 in aliphatic halogenated hydrocarbon;
2) adding n-Pentanesulphonic acid sodium salt at 20-30°C;
3) adjusting pH of the reaction mass to 2-3 pH using Orthophosphoric acid at 20-30°C;
4) heating the reaction mass to reflux for 1-2 hours;
5) reducing the temperature to room temperature & water washing of reaction mass;
6) completely recovering the organic layer below 50°C;
7) to the residue of step 6), adding C1-C4 aliphatic straight chain or branched chain alcohol or a mixture thereof with stirring at 20-30°C;
8) stirring till complete crystallization;
9) cooling the reaction mass to 0-5°C & stirring further;
10) isolating the product as wet cake by filtration & running washing with C1-C4 aliphatic straight chain or branched chain alcohol or mixture thereof with methyl tert butyl ether; and
11) drying the wet cake at 50-60°C for 10-20 hours till the moisture content is below desired level.
According to another aspect of the first embodiment, the C1-C4 aliphatic straight chain or branched chain alcohol used in step 7) & 10) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, isopropyl alcohol, monoethylene glycol & diethylene glycol or a mixture thereof.
According to yet another aspect of the first embodiment, the halogenated hydrocarbon used in step 1) is selected from methylene chloride, chloroform or carbon tetrachloride or a mixture thereof.
According to the second embodiment of the present invention, an improved process for removal of Linagliptin Dimer from “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 (Example 2):
1) dissolving 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 in aliphatic halogenated hydrocarbon;
2) adjusting pH of the reaction mass to 2-3 using Methanesulphonic acid at 20-30°C;
3) heating the reaction mass to reflux for 1-2 hours;
4) reducing the temperature to room temperature & water washing of reaction mass of step 3);
5) completely recovering the organic layer below 50°C;
6) to the residue of step 5), adding C1-C4 aliphatic straight chain or branched chain alcohol or mixture thereof with stirring at 20-30°C;
7) stirring till complete crystallization;
8) cooling the reaction mass to 0-5°C & stirring further;
9) isolating the product as wet cake by filtration & running washing with C1-C4 aliphatic straight chain or branched chain alcohol or mixture thereof with methyl tert butyl ether; and
10) drying the wet cake at 50-60°C for 10-20 hours till the moisture content is below desired level.
According to another aspect of the first embodiment, the C1-C4 aliphatic straight chain or branched chain alcohol used in step 6) & 9) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, isopropyl alcohol, monoethylene glycol & diethylene glycol or a mixture thereof.
According to yet another aspect of the first 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 process for removal of Linagliptin Dimer (II) from “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 (Example 3 & 4):
1) dissolving 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 in the C1-C4 aliphatic straight chain or branched chain alcohol or a mixture thereof with water;
2) adding benzoic acid or R(-) Mandelic acid to the reaction mas above;
3) stirring of the reaction mixture at 20-30°C for 4-6 hours till proper crystallization;
4) isolating the solid residue by routine filtration;
5) drying the solid of step 4) for 6-8 hours at 50-60°C;
6) dissolving the Linagliptin Benzoate or Mandelate salt in a halogenated hydrocarbon alongside 10% aqueous caustic solution;
7) stirring the reaction mass for some time followed by its layer separation;
8) washing organic layer with brine solution;
9) completely recovering the organic layer below 50°C;
10) to the residue of step 9), adding C1-C4 aliphatic straight chain or branched chain alcohol or mixture thereof of step 1) with stirring at 20-30°C;
11) stirring till complete crystallization;
12) cooling the reaction mass to 0-5°C & stirring further;
13) isolating the product as wet cake by filtration & running washing with C1-C4 aliphatic straight chain or branched chain alcohol or mixture thereof; and
14) drying the wet cake at 50-60°C for 10-20 hours, till the moisture content is below desired level.
According to another aspect of the second embodiment, the C1-C4 aliphatic straight chain or branched chain alcohol used in step 1), 10) & 13) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, isopropyl alcohol, monoethylene glycol & diethylene glycol or a mixture thereof.
According to yet another aspect of the second embodiment, the halogenated hydrocarbon used in step 6) is selected from methylene chloride, chloroform or carbon tetrachloride or a mixture thereof.
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: Linagliptin as per prior art
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]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 (50 g) 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, Trifluoroacetic acid (225 g) is slowly added 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 stirring & layer separation at room temperature. The organic layer containing the 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 %
Linagliptin Dimer = 200 ppm or 0.02%.
Total Impurities = 0.73%
Example 1:
10g of Linagliptin (Linagliptin Dimer content 0.02%) was dissolved in methylene dichloride (100 ml) with stirring at 20-30°C. n-Pentanesulphonic acid sodium salt (50 mg) was added to the organic layer at 20-30°C followed by its pH adjustment (pH 2-3) using orthophosphoric acid. The reaction mixture was heated to reflux for 1-2 hours, followed by its water washing twice (with 20 ml each) at 20-30°C. Then, the resulting organic layer was concentrated at maximum 45°C to get the crude material. Methanol (5 ml) & isopropanol (50 ml) were added & the contents were stirred at 20-30°C till complete crystallization. The material was further stirred for 2 hours at 0-5°C. The material was filtered & washed with isopropanol (5 ml) & methyl tertbutyl ether (5 ml) followed by drying at 50-60°C for 10-20 hours.
Yield = 9.3 g.
HPLC purity = 100%
Linagliptin Dimer Impurity = Not Detected
Example 2:
10g of Linagliptin (Linagliptin Dimer content 0.02%) was dissolved in methylene dichloride (100 ml) with stirring at 20-30°C. Then, its pH was adjusted to 2-3, using Methanesulphonic acid. The reaction mixture was heated to reflux for 1-2 hours, followed by its water washing twice (with 20 ml each) at 20-30°C. Then the resulting organic layer was concentrated at maximum 45°C to get the crude material. Methanol (5 ml) & isopropanol (50 ml) was added & the contents were stirred at 20-30°C till complete crystallization. The material was further stirred for 2 hours at 0-5°C. The material was filtered & washed with isopropanol (5 ml) & methyl tertbutyl ether (5 ml) followed by drying at 50-60°C for 10-20 hours.
Yield=9.5 g
HPLC purity = 100%
Linagliptin Dimer Impurity = Not Detected

Example 3:
10 g of Linagliptin (Linagliptin Dimer content 0.02%) was stirred in isopropyl alcohol (60 ml) and water (4 ml) followed by addition of Benzoic acid (3 gm). The resulting Linagliptin solution was stirred for 4-6 hours at 20-30°C till proper crystallization. The benzoate salt thus produced was filtered & given running washing with isopropyl alcohol (2ml). The wet cake was dried at 50-60°C for 6-8 hours.
The Linagliptin benzoate salt as obtained was re-dissolved in methylene chloride (50 ml) & water (50ml) by adding 10% aqueous potassium hydroxide (10 ml). The aqueous layer was extracted with methylene chloride (4 ml). The combined organic layer was washed with 10% sodium chloride solution (50 ml). The organic layer was completely evaporated using vacuum to get crude Linagliptin. This crude material was crystallized in methanol (5ml) & isopropyl alcohol (50 ml) at 20-30°C. After complete crystallization, pure linagliptin was filtered & washed with isopropyl alcohol (4ml). The wet cake was dried at 50-60°C for 10-20 hours.
Yield=8.0 g
HPLC purity = 100%
Linagliptin Dimer Impurity = Not Detected
Example 4:
10g of Linagliptin (Linagliptin Dimer content 0.02%) was stirred in isopropyl alcohol (60 ml) and water (4 ml) followed by addition of R(-) Mandelic acid (3.5 gm). The resulting Linagliptin solution was stirred for 4-6 hours at 20-30°C till proper crystallization. The mandelate salt thus produced was filtered & given running washing with isopropyl alcohol (2ml). The wet cake was dried at 50-60°C for 6-8 hours.
The Linagliptin Mandelate salt as obtained was re-dissolved in methylene chloride (50 ml) & water (50 ml) by adding 10% aqueous potassium hydroxide (10 ml). The aqueous layer was extracted with methylene chloride (4 ml). The combined organic layer was washed with 10% sodium chloride solution (50 ml). The organic layer was completely evaporated using vacuum to get crude Linagliptin. This crude material was crystallized in methanol (5ml) & isopropyl alcohol (50 ml) at 20-30°C. After complete crystallization pure Linagliptin was filtered & washed with isopropyl alcohol (4ml). The wet cake was dried at 50-60°C for 10-20 hours.
Yield=8.2 g
HPLC purity = 100%
Linagliptin Dimer Impurity = Not Detected
Example 5:
10g of Linagliptin (Linagliptin Dimer content 0.02%) was stirred in isopropyl alcohol (60 ml) and water (4 ml) followed by addition of benzoic acid (3 gm). The resulting Linagliptin solution was stirred for 4-6 hours at 20-30°C till proper crystallization. The benzoate salt thus produced was filtered & given running washing with isopropyl alcohol (2ml). The wet cake was dried at 50-60°C for 6-8 hours.
Yield=14 g
HPLC purity = 100%
Linagliptin Dimer Impurity = Not Detected.
Example 6:
10g of Linagliptin (Linagliptin Dimer content 0.02%) was stirred in isopropyl alcohol (60 ml) and water (4 ml) followed by addition of R(-) Mandelic acid (3.5 gm). The resulting Linagliptin solution was stirred for 4-6 hours at 20-30°C till proper crystallization. The mandelate salt thus produced was filtered & given running washing with isopropyl alcohol (2ml). The wet cake was dried at 50-60°C for 6-8 hours.
Yield=14 g
HPLC purity = 100%
Linagliptin Dimer Impurity = Not Detected
Example 7:
10g of Linagliptin (Linagliptin Dimer content 0.02%) was dissolved in methylene dichloride (100 ml) with stirring at 20-30 °C. n-Pentanesulphonic acid sodium salt (50 mg) was added to the organic layer at 20-30 °C followed by its pH adjustment (pH 2-3) using orthophosphoric acid or Methanesulphonic acid. The Linagliptin thus obtained after performing complete recovery of organic layer was free from Linagliptin Dimer.
Yield=7.5 g
HPLC purity = 100%
Linagliptin Dimer Impurity = Not Detected

WE CLAIM:

1.An improved process for removal of Linagliptin Dimer (II) from 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” which comprises:
i. dissolving 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 in aliphatic halogenated hydrocarbon selected from methylene chloride, chloroform or carbon tetrachloride or a mixture thereof;
ii. adding n-Pentanesulphonic acid sodium salt at 20-30°C;
iii. adjusting the pH of reaction mass to 2-3 pH using Orthophosphoric acid at 20-30°C;
iv. heating the reaction mass to reflux for 1-2 hours;
v. reducing the temperature to room temperature & water washing of reaction mass;
vi. completely recovering the organic layer below 50°C;
vii. to the residue of step vi., adding C1-C4 aliphatic straight chain or branched chain alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, isopropyl alcohol, monoethylene glycol & diethylene glycol or a mixture thereof with stirring at 20-30°C;
viii. stirring till complete crystallization;
ix. cooling the reaction mass to 0-5°C & stirring further;
x. isolating the product as wet cake by filtration & running washing with solvent of step vii. followed by running washing with methyl tert butyl ether; and
xi. drying the wet cake at 50-60°C for 10-20 hours, till the moisture content is below the desired level.
2. An improved process for removal of Linagliptin Dimer from “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 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 in aliphatic halogenated hydrocarbon selected from methylene chloride, chloroform or carbon tetrachloride or a mixture thereof;
ii. adjusting the pH of reaction mass to 2-3 using methanesulphonic acid at 20-30°C;
iii. heating the reaction mass to reflux for 1-2 hours;
iv. reducing the temperature to room temperature & water washing of reaction mass of step iii.;
v. completely recovering the organic layer below 50°C;
vi. to the residue of step v., adding C1-C4 aliphatic straight chain or branched chain alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, isopropyl alcohol, monoethylene glycol & diethylene glycol or a mixture thereof with stirring at 20-30°C;
vii. stirring till complete crystallization;
viii. cooling the reaction mass to 0-5°C & stirring further;
ix. isolating the product as wet cake by filtration & running washing with solvent of step vi. followed by methyl tert butyl ether; and
x. drying the wet cake at 50-60 °C for 10-20 hours, till the moisture content is below desired level.
3. An improved process for removal of Linagliptin Dimer from “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 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 in the C1-C4 aliphatic straight chain or branched chain alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, isopropyl alcohol, monoethylene glycol & diethylene glycol or a mixture thereof with water;
ii. adding benzoic acid or R (-) Mandelic acid;
iii. stirring of the reaction mixture at 20-30 °C for 4-6 hours;
iv. isolating the solid residue by filtration;
v. drying the wet cake of step iv) for 6-8 hours at 50-60°C;
vi. dissolving the respective salt as prepared in step ii. in a halogenated hydrocarbon selected from methylene chloride, chloroform or carbon tetrachloride alongside 10% aqueous caustic solution;
vii. stirring the reaction mass for some time followed by its layer separation;
viii. washing the organic layer with brine solution;
ix. completely recovering organic layer below 50°C;
x. to the residue of step ix., adding C1-C4 aliphatic straight chain or branched chain alcohol or mixture thereof of step i. with stirring at 20-30°C;
xi. stirring till complete crystallization;
xii. cooling the reaction mass to 0-5°C & stirring further;
xiii. isolating as wet cake by filtration & running washing with C1-C4 aliphatic straight chain or branched chain alcohol of step i. or mixture thereof; and
xiv. drying the wet cake at 50-60 °C for 10-20 hours.