DESC:“AN IMPROVED PROCESS FOR THE PREPARATION OF LINAGLIPTIN”

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Linagliptin (I), comprising reacting the compound of formula (II) with compound of formula (III) in presence of base, solvent and phase transfer catalyst (PTC) to obtain compound of formula (IV), and reacting the compound of formula (IV) with (3R)-piperidin-3-amine dihydrochloride of Formula (V) in absence of water, presence of base and solvent, followed by treating with Boc anhydride (Boc2O).

BACKGROUND OF THE INVENTION
Linagliptin, sold under the brand name Tradjenta among others, is a medication used to treat
diabetes mellitus type 2. It is generally less preferred than metformin and sulfonylureas as an
initial treatment. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth. Common side effects include inflammation of the nose and throat. Serious side effects may include angioedema, pancreatitis, joint pain. Use in pregnancy
and breastfeeding is not recommended. Linagliptin is a dipeptidyl peptidase-4 inhibitor. It works by increasing the production of insulin and decreasing the production of glucagon by the pancreas.

Chemically, Linagliptin is 8-[(3R)-3-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. The empirical formula is C25H28N8O2. Its molecular weight is 472.54 g/mol, and its chemical structure is represented below:

Linagliptin is marketed by Boehringer under the trade names Tradjenta (in the United States) Trajenta (in Europe).
US 7407955 discloses a process for the preparation of Linagliptin of formula (I), which comprises, compound of formula (II) is reacted with compound of formula (VI) in presence of sodium carbonate (Na2CO3)/dimethylsulphoxide (DMSO)/ethyl acetate (EtOAc) to obtain the compound of formula (VII). The compound of formula (VII) is reacted with compound of formula (III) in presence of potassium carbonate (K2CO3)/ dimethylformamide (DMF) to obtain the compound of formula (VIII). The compound of formula (VIII) is reacted with trifluoroacetic acid (TFA) in presence of methylene dichloride (MDC) to obtain the Linagliptin (I). The process is schematically shown as below:

The above processes disclose the preparation of the Linagliptin (I), the reaction can be accomplished without use of the solvent when used the excess of the 3-aminopiperidine of compound of formula (VI) and Boc deprotection was performed using trifluoroacetic acid (TFA) in methylene dichloride (DCM) to yield Linagliptin. The main disadvantage of this route is that, it involves the use of (R)-N-Boc piperidine of compound of formula (VI) is very expensive intermediate and purification by column chromatography.

US 9056112 discloses a process for the preparation of Linagliptin of formula (I), which comprises, compound of formula (II) is reacted with compound of formula (III) in presence of dimethylacetamide (DMAc)/ potassium carbonate (K2CO3) to obtain the compound of formula (IV). The compound of formula (IV) is reacted with compound of formula (V) in presence of water/methyl isobutyl ketone (MIBK)/ potassium carbonate (K2CO3), followed by treated with D-(-)-tartaric acid and NaOH to obtain the Linagliptin (I). The process is schematically shown as below:

The above processes disadvantages, lead to formation of the regioisomer impurity is more than 1%. Hence, this process not suitable for industrial scale and quality not meet as per ICH limit.

Hence, there is consequently a need development for new methods to sort out prior art existing methods. So, our inventors have developed an improved process for the preparation of Linagliptin (I). The present invention advantageous process for preparing Linagliptin, which is relatively simple, less costly and quality as per ICH limit with excellent yield in a high purity, cost effective and industrial applicable process.

OBJECT OF THE INVENTION
The objective of the invention relates to an improved process for the preparation of Linagliptin (I), thereby controlling the formation of regioisomer impurity (compound of formula IX) to obtain Linagliptin in good yield and purity.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Linagliptin (I), thereby controlling the formation of regioisomer impurity (compound of formula IX) to obtain Linagliptin in good yield and purity.

In one embodiment of the present invention provides, an improved process for the preparation of Linagliptin (I), comprising the steps of;
a) reacting the compound of formula (II) with compound of formula (III) in presence of base, solvent and phase transfer catalyst (PTC) to obtain compound of formula (IV), and

b) reacting the compound of formula IV with (3R)-piperidin-3-amine dihydrochloride of Formula (V) in absence of water, presence of base and solvent, followed by treating with Boc anhydride (Boc2O), optionally treated with acetic acid, thereby controlling the formation of regioisomer impurity is below 0.5% to obtain Pure Linagliptin.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Linagliptin (I), thereby controlling the formation of regioisomer impurity (compound of formula IX) to obtain Linagliptin in good yield and purity.

In one embodiment of the present invention provides, an improved process for the preparation of Linagliptin (I), comprising the steps of;
a) reacting the compound of formula (II) with compound of formula (III) in presence of base, solvent and phase transfer catalyst (PTC) to obtain compound of formula (IV), and

b) reacting the compound of formula IV with (3R)-piperidin-3-amine dihydrochloride of Formula (V) in absence of water, presence of base and solvent, followed by treating with Boc anhydride (Boc2O), optionally treated with acetic acid, thereby controlling the formation of regioisomer impurity is below 0.5% to obtain Pure Linagliptin.

According to embodiment of the present invention, reacting the compound of formula (II) with compound of formula (III) in presence of base, solvent and phase transfer catalyst (PTC) and the reaction is carried out at 55 to 70°C for 18-26 hours, followed by purified with methanol at 55 to 70°C to obtain the compound of formula (IV).

According to embodiment of the present invention, reacting the compound of formula (IV) with (3R)-piperidin-3-amine dihydrochloride of Formula (V) in absence of water, presence of base and solvent and the reaction is carried out at 85 to 100°C for 18-24 hours, followed by treating with Boc anhydride (Boc2O) and the reaction is carried out at 20 to 35°C for 1-4 hours, optionally treated with acetic acid or acetic acid solution (acetic acid and water) and adjust pH 10-14 with sodium hydroxide solution, followed by purified with methanol or isopropyl alcohol and MTBE, thereby controlling the formation of regioisomer impurity is below 0.5% to obtain Pure Linagliptin.

According to an embodiment of the present invention provides Linagliptin (I) having HPLC purity = 99.5%.

According to an embodiment of the present invention, wherein the base is selected from inorganic base or organic base; inorganic base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; ammonia; sodium sulphite; organic base is selected from triethylamine, triethanolamine, diisopropylethylamine, di-n-propylamine and 4-dimethylaminopyridine (DMAP).

According to an embodiment of the present invention, wherein the phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), tetraethylammonium p-toluenesulfonate, tetrapropyl ammonium trifluoromethanesulfonate, tetraphenyl phosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenyl phosponium chloride, benzyltriethyl ammonium chloride, benzyltrimethylammonium chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyl triethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyl triphenylphosphonium iodide, phenyl trimethylammonium chloride, tetrabutylammonium hydroxide, tetra butyl ammonium perchlorate, tetra butyl ammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetra fluoroborate, tetra butyl ammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctyl ammonium bromide, tetraphenyl phosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride, tributyl benzyl ammonium bromide, benzyl trimethyl ammonium chloride, tetra butyl ammonium acetate or alkali iodides like sodium iodide, potassium iodide and lithium iodide.

According to an embodiment of the present invention, the reaction carried out suitable solvent is selected from tetrahydrofuran, methyl tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, 2-propanol, 2-butanol, dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone (MIBK), cyclohexanone, n-hexane, diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, chloroform, carbon tetrachloride and chloroform, methyl tert-butyl ether (MTBE) and/or mixtures thereof.

According to embodiment of the present invention, regioisomer impurity (compound of formula IX):

According to embodiment advantages of the present invention, regioisomer impurity removing by using Boc anhydride, thereby controlling the formation of regioisomer impurity is below 0.5% to obtain Pure Linagliptin.

According to the embodiment of the present invention, where regioisomer impurity means herein refers to the level of impurity present in the material which is less than about 0.5% or less than about 0.10% or less than about 0.15% or less than about 0.05 % or less than about 0.005 % or less than about 0.009 or less than about 0.0001.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example 1:
Synthesis of 1-(4-Methyl-quinazolin-2-yl)methyl-3-methyl-7-(2-butyn-1-yl)-8- bromoxanthine (IV)

N,N-Dimethylformamide (850 mL), 2-chloromethyl-4-methylquinazoline (100 gm), potassium carbonate (82.0 gm), 3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine (142.8 gm), and tetrabutylammonium bromide (14.3 gm) were added into a reaction vessel at ambient temperature. The reaction mixture was heated to 60°C to 65°C, then stirred for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to ambient temperature and then deionized water (1700 mL) was added. The reaction mixture was stirred for about 2 hours, filtered, and then washed with deionized water (300 mL). The wet material was charged in Methanol (1000 mL), heated to 60-65oC and then stirred for 1 hour. The reaction mixture was cooled to ambient temperature, stirred for 120 minutes, filtered, and washed with methanol (200 ml) dried at 55°C to 60°C for 12 hours to obtain the 1-(4-Methyl-quinazolin-2-yl)methyl-3-methyl-7-(2-butyn-1-yl)-8- bromoxanthine (185.0 gm).
Yield: 79.0% %
HPLC Purity: = 99.0%

Example 2:
Synthesis of Linagliptin (I)
Methyl isobutylketone (MIBK) (1000 mL) and 1-(4-Methyl-quinazolin-2-yl)methyl-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (100 gm) were added into round bottomed flask equipped with a mechanical stirrer. (R)-piperidine-3-amine dihydrochloride (45.9 gm) and Potassium carbonate (153 gm) were added to the reaction mixture at 30°C. The reaction mixture was heated to 95°C. and maintained at that temperature for 20-22 hours. The reaction mixture was cooled to 30° C, and filtered and washed with MIBK (200 mL). The filtrate was charged into another flask and given water washings, then added Boc Anhydride (2.3 gm) at 30-35oC, stir for 1 hour, added 10% aqueous acetic acid solution and stirred for one hour at room temperature. The aqueous layer was separated and washed with dichloromethane (200 mL). The aqueous layer was charged into another flask and dichloromethane (800 mL) was added, then adjust the PH 11-13 with aqueous sodium hydroxide solution at below 20°C. The mixture was stirred for one hour at 30° C and the organic layer was separated and the aqueous layer was extracted with dichloromethane (200 ml). Combined the organic layers and washed with water, evaporated under vacuum at below 45° C. Isopropyl alcohols (900 mL) was added heated to reflux, stir for 30 mins cool to room temperature stir for 3 hours. Filtered the compound and washed with MTBE (100 mL) and dried the compound at below 75°C. under vacuum to give Linagliptin (89.0 gm).
Yield: 85.0%
HPLC Purity: = 99.60%

Example 3:
Synthesis of Linagliptin (I)
Methyl isobutylketone (MIBK) (810 mL) and 1-(4-Methyl-quinazolin-2-yl)methyl-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (100 gm) were added into round bottomed flask equipped with a mechanical stirrer, (R)-piperidine-3-amine dihydrochloride (50 gm) and Potassium carbonate (153 gm) were added to the reaction mixture at 30°C. The reaction mixture was heated to 95°C and maintained at that temperature for 18 hours. The reaction mixture was cooled to 30° C, and filtered and washed with MIBK (190 mL). The filtrate was charged into another flask and given water washings, then added Boc Anhydride (2.3 gm) at 30-35oC, stir for 1 hour, added 10% aqueous acetic acid solution and stirred for one hour at room temperature. The aqueous layer was separated and washed with dichloromethane (200 mL). The aqueous layer was charged into another flask and dichloromethane (750 mL) was added, then adjust the PH 11-13 with aqueous sodium hydroxide solution at 30°C. The mixture was stirred for one hour at 30° C and the organic layer was separated and the aqueous layer was extracted with dichloromethane (200 ml) Combined the organic layers and evaporated under vacuum at below 45° C. Isopropyl alcohols (450 mL) was added heated to reflux, stir for 30 mins cool to room temperature stir for 3 hours. Filtered the compound and washed with MTBE (110 mL) and dried the compound at below 75°C. under vacuum to give Linagliptin (88.0 gm).
Yield: 84.5%
HPLC Purity: = 99.60%.
,CLAIMS:WE CLAIM:
1. An improved process for the preparation of Linagliptin (I), comprising the steps of;
a) reacting the compound of formula (II) with compound of formula (III) in presence of base, solvent and phase transfer catalyst (PTC) to obtain compound of formula (IV), and

b) reacting the compound of formula IV with (3R)-piperidin-3-amine dihydrochloride of Formula (V) in absence of water, presence of base and solvent, followed by treating with Boc anhydride (Boc2O), optionally treated with acetic acid, thereby controlling the formation of regioisomer impurity is below 0.5% to obtain Pure Linagliptin.

2. The process as claimed in claim 1, wherein the base is selected from inorganic base or organic base; inorganic base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; ammonia; sodium sulphite; organic base is selected from triethylamine, triethanolamine, diisopropylethylamine, di-n-propylamine and 4-dimethylaminopyridine (DMAP).
3. The process as claimed in claim 1, wherein the phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), tetraethylammonium p-toluenesulfonate, tetrapropyl ammonium trifluoromethanesulfonate, tetraphenyl phosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenyl phosponium chloride, benzyltriethyl ammonium chloride, benzyltrimethylammonium chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyl triethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyl triphenylphosphonium iodide, phenyl trimethylammonium chloride, tetrabutylammonium hydroxide, tetra butyl ammonium perchlorate, tetra butyl ammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetra fluoroborate, tetra butyl ammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctyl ammonium bromide, tetraphenyl phosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride, tributyl benzyl ammonium bromide, benzyl trimethyl ammonium chloride, tetra butyl ammonium acetate or alkali iodides like sodium iodide, potassium iodide and lithium iodide.

4. The process as claimed in claim 1, wherein the reaction carried out suitable solvent is selected from tetrahydrofuran, methyl tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, 2-propanol, 2-butanol, dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone (MIBK), cyclohexanone, n-hexane, diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, chloroform, carbon tetrachloride and chloroform, methyl tert-butyl ether (MTBE) and/or mixtures thereof.

5. The process for the preparation of Linagliptin (I) as claimed in claim 1, HPLC purity = 99.5%.

6. The process for the preparation of Linagliptin (I) as claimed in claim 1, regioisomer impurity (compound of formula IX):