The following specification describes the invention:

FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of linagliptin and solid state chemistry of linagliptin.

BACKGROUND OF THE INVENTION

1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl) xanthine, whose international nonproprietary name is Linagliptin [CAS number: 668270-12-0], has the following chemical structure of 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 in which tert-butyloxy carbonyl (Boc) protected linagliptin is deprotected using 5-6 M isopropanolic hydrochloric acid. The process disclosed in US ‘955 is schematically represented in scheme-I.

U.S. Patent No. 7,820,815 (“US ‘815) discloses a process for preparation of linagliptin in which linagliptin 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 of formula IIIa 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-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo xanthine of formula III with (R)-3-phthalimidopiperidine of formula IIa. The process disclosed in US ‘815 is schematically represented in scheme-II.

The synthesis of linagliptin as discussed in US ‘955 and US ‘815 involves protection and deprotection method leading to an increase in the manufacturing cycle time and a decrease in the product yield. Purification by chromatography, as used in US ‘955, is not desirable for commercial-scale manufacturing. There is a continuing need to develop simplified and improved processes for preparing linagliptin which processes are suitable for commercial manufacturing in high purity and yield.

Crystalline linagliptin has been described in U.S. Patent Application Publication No. US 2007/0259900 and in International Patent Application Publication WO 2007/128721. The discovery of new solid states of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.

SUMMARY

Aspects of the present application provide processes for preparing linagliptin using common reagents and process conditions.

In one aspect, the present application provides a one-pot process for preparation of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piper idin-1-yl) xanthine (linagliptin) of formula I comprising:

a) reacting 3-methyl-8-bromo-xanthine of formula VI or a salt thereof with compound of formula VII in presence of a base to obtain 3-methyl-7-(2-butyn-l-yl)-8-bromo-xanthine of formula IV;

b) without isolating, reacting the compound of formula IV with 2-(chloromethyl)-4-methylquinazoline of formula V in presence of a base to obtain 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine of formula III; and

c) without isolating, reacting the compound of formula III with (R)-piperidine-3-amine of formula II or an acid addition salt thereof in presence of a base to obtain linagliptin (I).

In another aspect, the application provides a process for purification of linagliptin, comprising:

a) dissolving crude linagliptin in an aqueous acid solution;

b) optionally, treating the linagliptin solution with a first organic solvent;

c) basifying the linagliptin solution;

d) extracting linagliptin from the solution with a second organic solvent; and

e) isolating pure linagliptin from the second solvent.

In another aspect, the application provides a process for preparation of 3-methyl-8-bromo-xanthine of formula VI, comprising reacting 3-methylxanthine of formula VIII with hydrobromic acid in presence of an oxidizing agent.

In another aspect, the application provides a process for preparation of 3-methyl-8-bromo-xanthine of formula VI, comprising reacting 3-methylxanthine of formula VIII with N-bromosuccinimide (NBS).

In another aspect, the present application further provides the use of linagliptin made by the processes of the application for the manufacture of a pharmaceutical composition.

In another aspect, the application provides amorphous form of linagliptin

In another aspect, the application provides a process for preparation of amorphous form of linagliptin comprising:

a) providing a solution of linagliptin in a solvent which is a C1 to C4 alcohol, a halogenated hydrocarbon, or mixtures thereof; and

b) removal of solvent to obtain amorphous linagliptin.

In another aspect, the present application further provides a process for preparing a pharmaceutical formulation comprising combining amorphous linagliptin of the present application with at least one pharmaceutically acceptable excipient.

In another aspect, the present application further provides the use of amorphous linagliptin of the present application for the manufacture of a pharmaceutical composition.

In another aspect, the present application further provides the use of linagliptin made by the processes of the application for the manufacture of a pharmaceutical composition.

BRIEF DESCRIPTION OF THE FIGURE

Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of an amorphous form of linagliptin prepared according to Example 5.

DETAILED DESCRIPTION

Aspects of the present application provide processes for preparing linagliptin using common reagents and process conditions.

In one aspect, the present application provides a one-pot process for preparation of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piper idin-1-yl) xanthine (linagliptin) of formula I comprising:

a) reacting 3-methyl-8-bromo-xanthine of formula VI or a salt thereof with compound of formula VII in presence of a base to obtain 3-methyl-7-(2-butyn-l-yl)-8-bromo-xanthine of formula IV;

b) without isolating, reacting the compound of formula IV with 2-(chloromethyl)-4-methylquinazoline of formula V in presence of a base to obtain 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine of formula III; and

c) without isolating, reacting the compound of formula III with (R)-piperidine-3-amine of formula II or an acid addition salt thereof optionally in presence of a base to obtain linagliptin (I).

The present invention is represented by the following scheme:

Step (a) involves reaction of 3-methyl-8-bromo-xanthine of formula VI or a salt thereof with compound of formula VII in presence of a base to obtain 3-methyl-7-(2-butyn-l-yl)-8-bromo-xanthine of formula IV. Compound of Formula VI is a known compound and may be prepared by any processes described in the art or by the processes of the present invention. When X is chlorine, the compound of formula VII, i.e. 1-chloro-2-butyne is a known compound and may be obtained by any processes described in the art. When X is bromine, the compound of formula VII, i.e. 1-bromo-2-butyne is a known compound and may be obtained by any processes described in the art.

The base used in step (a) is an organic base or an inorganic base. Suitable organic bases that may be used, but are not limited to triethylamine, tributylamine, diisopropylethylamine (DIPEA), triisopropylamine, N-methyl morpholine, pyridine, 4-dimethylamino pyridine; In one embodiment the organic base is diisopropylethylamine (DIPEA) Suitable inorganic bases that may be used include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, or the like; carbonates of alkali metals such as sodium carbonate, potassium or any mixtures thereof; In one embodiment the inorganic base is potassium carbonate. The amount of base employed is not critical, but good practice recommends an amount of base from about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula VI.

The reaction is effected in the presence of a solvent. The solvents that can be used, include, but or not limited to, a halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, or the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, or the like; ethers such as diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, or the like; or mixtures thereof. In one embodiment the solvent is an aprotic polar solvent such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, or the like. Quantities of solvent used for the process may be from about 2 mL to about 20 mL, in one embodiment the quantity of solvent used is about 3 mL to about 10 mL, per gram of compound of Formula VI.

The reaction of step (a) is suitably carried out at temperatures ranging from about 25°C to about reflux temperature of the solvent used, in one embodiment the temperature is about 50°C to about 80°C.

The time required for the reaction may also vary widely depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above a period from about 30 minutes to till completion of the reaction, in one embodiment the time required for the completion of the reaction is about 2 hours to about 10 hours.

After completion of the reaction of step (a), the reaction mixture may be filtered or may be washed with water. The filtrate containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.

The step (b) involves reaction of the compound obtained in step (a) i.e. 3-methyl-7-(2-butyn-l-yl)-8-bromo-xanthine of formula IV with 2-(chloromethyl)-4-methylquinazoline of formula V in presence of a base to obtain 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine of formula III.

The base used in step (b) is an organic base or an inorganic base. Suitable organic bases that may be used, but are not limited to triethylamine, tributylamine, diisopropylethylamine (DIPEA), triisopropylamine, N-methyl morpholine, pyridine, 4-dimethylamino pyridine; In one embodiment the organic base is diisopropylethylamine (DIPEA) Suitable inorganic bases that may be used include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, lithium carbonate, or the like; bicarbonates of alkali metals, such as sodium bicarbonate, potassium bicarbonate, lithium carbonate, or the like; ammonia; or any mixtures thereof; In one embodiment the inorganic base is potassium carbonate. The amount of base employed is not critical, but good practice recommends an amount of base from about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula IV.

The reaction is effected in the presence of a solvent. The solvents that can be used, include, but or not limited to, a halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile or the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, or the like; ethers such as diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, or the like; or mixtures thereof. In one embodiment the solvent is an aprotic polar solvent. Quantities of solvent used for the process may be from about 1 mL to about 50 mL, per gram of compound of Formula IV. In one embodiment the quantity of solvent used is about 3 mL to about 30 mL of solvent, per gram of compound of Formula IV are used.

The reaction of step (b) is suitably carried out at temperatures ranging from about 25°C to about reflux temperature of the solvent used, in one embodiment temperature is about 50°C to about 100°C.

The time required for the reaction may also vary widely depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above a period from about 30 minutes to till completion of the reaction, preferably form about 2 hours to about 10 hours is sufficient.

After completion of the reaction of step (b), the reaction mixture may be filtered or may be washed with water. The filtrate containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.

The step (c) involves reaction of the compound obtained in step (b) i.e. 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine of formula III with (R)-piperidine-3-amine of formula II or an acid addition salt thereof optionally in presence of a base to obtain linagliptin.

Preferably (R)-piperidine-3-amine of formula II is used as an acid addition salt like hydrochloride, hydrobromide, acetate, sulphate, dihydrochloride and the like; more preferably (R)-piperidine-3-amine acid addition salt is (R)-piperidine-3-amine dihydrochloride.

The base used in step (c) is an organic base or an inorganic base. Suitable organic bases that may be used, but are not limited to triethylamine, tributylamine, diisopropylethylamine (DIPEA), triisopropylamine, N-methyl morpholine, pyridine, 4-dimethylamino pyridine; In one embodiment the organic base is diisopropylethylamine (DIPEA) Suitable inorganic bases that may be used include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, lithium carbonate, or the like; bicarbonates of alkali metals, such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; ammonia; and any mixtures thereof; In one embodiment the inorganic base is potassium carbonate. The amount of base employed is not critical, but good practice recommends an amount of base from about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula III.

The reaction is effected in the presence of a solvent. The solvents that can be used, include, but or not limited to, a halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile or the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, or the like; ethers such as diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, or the like; or mixtures thereof. In one embodiment the solvent is an aprotic polar solvent such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, or the like. Quantities of solvent used for the process may be from about 1 mL to about 20 mL, per gram of compound of Formula II. In one embodiment the quantity is about 3 mL to about 15 mL, per gram of compound of Formula III.

The reaction of step (c) is suitably carried out at temperatures ranging from about 25°C to about reflux temperature of the solvent used, in one embodiment the reaction temperature is about 50°C to about 100°C.

The time required for the reaction may also vary widely depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above a period from about 30 minutes until completion of the reaction, in one embodiment from about 5 hours to about 20 hours is sufficient.

After completion of the reaction of step (c), the reaction mixture may be filtered or may be washed with water. The filtrate containing the product may be distilled completely to produce linagliptin. The linagliptin obtained may be purified to get pure linagliptin.

In another aspect, the present invention provides a process for purification of linagliptin, comprising:

a) dissolving crude linagliptin in an aqueous acid solution,

b) optionally, treating the linagliptin solution with a first organic solvent

c) basifying the linagliptin solution,

d) extracting linagliptin from the solution with a second organic solvent,

e) isolating pure linagliptin from the second organic solvent.

The aqueous acid solution is in one embodiment aqueous hydrochloric acid, aqueous hydrobromic acid, aqueous acetic acid, aqueous sulphuric acid, or aqueous phosphoric acid. In another embodiment the aqueous acid solution is aqueous hydrochloric acid, aqueous acetic acid.

Concentration of the acid in the aqueous acid solution is In one embodiment from about 0.1% to about 20%. In another embodiment concentration of the acid is from about 1% to about 10%.

Linagliptin is added and dissolved in the acid solution and the resulted solution is washed with a first organic solvent. The solvents that can be used for washing include but are not limited to halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, or the like; ester solvents such as ethyl acetate, isopropyl acetate, or the like; ether solvents such as dimethyl ether, diethyl ether, methyl isobutyl ether, or the like; hydrocarbons such as n-pentane, n-hexane, cyclohexane, toluene, xylene, or the like. In one embodiment the first organic solvent is a halogenated solvent such as dichloromethane, ethylene dichloride, chloroform, or the like.

The pH of the aqueous acid solution containing linagliptin is adjusted to about 8 to about 9 using a base. The base used for adjusting pH of the aqueous acid solution containing linagliptin is an organic base or an inorganic base. Suitable organic bases that may be used, but are not limited to triethylamine, tributylamine, diisopropylethylamine (DIPEA), triisopropylamine, N-methyl morpholine, pyridine, 4-dimethylamino pyridine; In one embodiment the organic base is triethylamine. Suitable inorganic bases that may be used include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; carbonates of alkali metals such as lithium carbonate, sodium carbonate, potassium carbonate, or the like; bicarbonates of alkali metals, such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; ammonia; or any mixtures thereof. In one embodiment the inorganic base is sodium bicarbonate.

The base used for basifying the aqueous acid solution may in the form of an aqueous solution having about 1% to about 20% concentration. In one embodiment the base concentration is about 5% to about 10%.

The aqueous solution containing linagliptin is extracted with a second organic solvent. The second organic solvent is a water immiscible solvent and include but are not limited to aromatic hydrocarbons such as toluene, xylene, or the like; esters such as ethyl acetate, methyl acetate, or the like; ethers such as diethyl ether, methyl ethyl ether, methyl isopropyl ether, or the like; halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, or the like. In one embodiment the solvent is dichloromethane.

Pure linagliptin is isolated by removing solvent from the resulting organic solvent extracts methods known in the art, for example distillation, evaporation, rotavapor drying, freeze-drying, fluidized bed drying, flash drying, spin flash drying, or the like, In one embodiment the separation technique is distillation under vacuum.

In another aspect, the invention provides a process for preparation of 3-methyl-8-bromo-xanthine of formula VI, comprising reacting 3-methylxanthine of formula VIII with hydrobromic acid in presence of an oxidizing agent.

3-methylxanthine (compound of formula VIII) is a known compound and may be obtained by any processes described in the art.

3-methylxanthine is reacted with aqueous hydrobromic acid in presence of an oxidizing agent such as hydrogen peroxide, sodium hypochlorite, tertiary butyl peroxide, metachloro per benzoic acid or a mixture of alkali metal bromide and an acid. Preferably the oxidizing agent is sodium hypochlorite. The concentration of the oxidizing agent may vary from about 1% to about 50%. In one embodiment the concentration of the oxidizing agent is about 5%. The hydrobromic acid may be generated in situ by the reaction of an alkali metal bromide with an acid. The reaction is suitably carried out at temperatures ranging from about 5°C to about 100°C, in one embodiment temperature is about 20°C to about 50°C.

The time required for the reaction may also vary widely depending on many factors, notably the reaction temperature and the nature of the reagents. However provided that the reaction is effected under the preferred conditions outlined above a period from about 2 hours to about 30 hours, In one embodiment from about 5 hours to about 20 hours is sufficient.

The reaction optionally carried out in presence of an electromagnetic light source like UV light, visible light, or near infrared light. In one embodiment the electromagnetic light source is visible light.

After completion of the reaction, the reaction mixture may be quenched by adding water to it and the solid formed is isolated by filtration.

In another aspect, the application provides a process for preparation of 3-methyl-8-bromo-xanthine of formula VI, comprising reacting 3-methylxanthine of formula VIII with N-bromosuccinimide (NBS).

3-methylxanthine (compound of formula VIII) is a known compound and may be obtained by any processes described in the art.

3-methylxanthine is reacted with N-bromosuccinimide in presence of a solvent. The solvent that can be used, include, but or not limited to, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, acetic acid or the like; or mixtures thereof. In one embodiment the solvent is acetonitrile. Quantities of solvent used for the process may be from about 1 mL to about 30 mL, per gram of compound of Formula VIII. In one embodiment the quantity is about 3 mL to about 20 mL, per gram of compound of Formula VIII.

The amount of N-bromosuccinimide employed is not critical, but good practice recommends an amount of N-bromosuccinimide from about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula VIII.

The reaction is suitably carried out at temperatures ranging from about 5°C to about 100°C, in one embodiment the temperature is about 20°C to about 50°C.

The time required for the reaction may also vary widely depending on many factors, notably the reaction temperature and the nature of the reagents. However provided that the reaction is effected under the preferred conditions outlined above a period from about 30 minutes to about 30 hours, In one embodiment from about 2 hours to about 10 hours is sufficient.

After completion of the reaction, the reaction mixture may be quenched by adding water to it and the solid formed is isolated by filtration.

In another aspect, the present invention further provides use of 3-methyl-8-bromo-xanthine made by the processes of the invention for the preparation of linagliptin.

In another aspect, the present invention further provides the use of linagliptin made by the processes of the invention for the manufacture of a pharmaceutical composition.

In another aspect, the invention provides amorphous form of linagliptin

In another aspect, the invention provides a process for preparation of amorphous form of Linagliptin comprising: providing a solution of Linagliptin in a solvent selected from C1 to C4 alcohols or haloalkanes and removal of solvent to obtain amorphous Linagliptin.

In another aspect, the present invention further provides a process for preparing a pharmaceutical formulation comprising combining amorphous linagliptin of the present invention with at least one pharmaceutically acceptable excipient.

In another aspect, the present invention further provides the use of amorphous linagliptin of the present invention for the manufacture of a pharmaceutical composition.

In another aspect, the present invention provides a process for preparing amorphous Linagliptin comprising: providing a solution of Linagliptin in a solvent selected from C1 to C4 alcohols or haloalkanes and removal of solvent to obtain amorphous Linagliptin. Linagliptin that may be used as the input for the process of the present invention may be obtained by the processes of the present invention or any process including the processes described in the art. For example linagliptin may be prepared by the processes described in US 7407955 or US 7820815. The solution of Linagliptin can be prepared by dissolving in the selected solvent. The dissolution of Linagliptin in the solvent can be carried out at room temperature or dissolution can be assisted by heating to a temperature of about 20°C to about reflux, in one embodiment to a temperature of about 40°C to about 100°C. In one embodoment, the C1 to C4 alcohols are methanol, ethanol or a mixture thereof. The ratio of Linagliptin to solvent can be in a ratio of about 1:1 to about 1:100, in one embodiment Linagliptin to solvent can be in a ratio of about 1:3 to about 1:50 (grams/ml).

Solvent removal may be by any number of means such as evaporation, including fast evaporation or spray drying. Solvent removal is usually complete after dryness. In one embodiment, solvent removal is performed under vacuum.

Spray-drying broadly refers to processes involving breaking up liquid mixtures into small droplets. In one embodiment pray-drying refers to atomization, and rapidly removing solvent from the mixture. In a typical spray-drying apparatus, there is a strong driving force for evaporation of solvent from the droplets, which may be provided by a heated drying gas. Spray-drying processes and equipment are described in Perry''s CHEMICAL ENGINEER''S HANDBOOK, pgs 20-54 to 20-57 (Sixth Edition 1984), which is incorporated by reference in its entirety.

The gas inlet temperature during spray drying is about 25°C to about 70°C. In another embodiment, the gas inlet temperature is about 30°C to about 50°C. An "inlet temperature" is the temperature at which the solution enters the spray dryer.

The outlet temperature is In one embodiment below the inlet temperature. In another embodiment, the outlet temperature is from about 20°C to about 45°C. In another embodiment, the outlet temperature is from about 25°C to about 42°C. An "outlet temperature" is the temperature at which the gas exits the spray dryer. Inlet or outlet temperatures may be varied, if necessary, depending on the equipment, gas, or other experimental parameters. For example, it is known that the outlet temperature may depend on parameters such as aspirator rate, air humidity, inlet temperature, spray air flow, feed rate or concentration.

In another aspect, the present invention provides a process for preparing amorphous linagliptin by a fast evaporation process comprising dissolving linagliptin in an organic solvent, feeding the solution into a chamber maintained at a reduced pressure (pressure of less than one atmosphere) and a temperature of less than about 100°C until obtaining a precipitate. The temperature can be about 30°C to about 100°C.

In one embodiment, the solvent is an C1 to C4 alcohol, a C3 to C7 ketone, a C3 to C7 ester, a C5 to C7 straight or cyclic saturated hydrocarbon, a C4 to C8 ether, a C2 to C6 nitrile, or mixtures thereof. In another embodiment, the solvent is methanol, ethanol, acetone, toluene, acetonitrile, ethyl acetate, heptane, hexane, diethyl ether, methyl isobutyl ether, di-isopropyl-ether, or mixtures thereof. In another embodiment, the solvent is methanol, ethanol, or dichloromethane.

In another aspect, the present invention provides a process for preparing a solid containing pharmaceutical formulation comprising combining amorphous linagliptin of the present invention with at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical formulation is completely solid.

Pharmaceutically acceptable carriers that may be used in this step include a polyvinylpyrrolidone (povidone or PVP), a hydroxypropyl cellulose (HPC), a hydroxypropyl methylcellulose (hypromellose or HPMC), a hydroxyethyl cellulose (HEC), and the like. Any mixtures of two or more thereof also will be useful. In specific embodiments, a pharmaceutically acceptable carrier is a povidone K-30 grade.

The present invention further encompasses the use of amorphous linagliptin of the present invention for the manufacture of a solid containing pharmaceutical composition.

The present invention further encompasses the use of amorphous linagliptin made by the processes of the invention, for the manufacture of a solid containing pharmaceutical composition.

Methods of administration of a pharmaceutical composition of the present invention may comprise administration in various preparations depending on the age, sex, and symptoms of the patient.

The bulk properties of the amorphous form of linagliptin are advantageous compared to those of the prior art, crystalline linagliptin. The flowability of materials with spherical particles is better than the flowability of those with rod shaped particles. Flowability is a very important factor for the manufacturing process, as it affects all the processes that involve powder-handling, including blending, feeding, compaction and fluidization. The smaller particle size of amorphous linagliptin is also advantageous in comparison to crystalline linagliptin, in particular for preparing homogenous composition.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosures of the references referred to in this patent application are incorporated herein by reference.

DEFINITIONS

The following definitions are used in connection with the present invention unless the context indicates otherwise. The term “amorphous” refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.

As used herein, the term "vacuum" refers to a reduced pressure of below about 100 mm Hg. In another embodiment, the pressure is below about 50 mm Hg. In another embodiment, the pressure is below about 30 mm Hg. As used herein, the term "reduced pressure" refers to a pressure below 760 mm Hg or 1 atmosphere.

As used herein, the term "room temperature" refers to a temperature of about 20°C to about 35°C, In another embodiment about 20°C to about 25°C and in another embodiment about 25°C. As used herein, the term "therapeutically effective amount" means the amount of the amorphous linagliptin of the present invention that, when administered to a patient for treating a disease or other undesirable medical condition, is sufficient to have a beneficial effect with respect to that disease or condition. The "therapeutically effective amount" will vary depending on the disease or condition and its severity, and the age, weight, etc., of the patient to be treated. Determining the therapeutically effective amount is within the ordinary skill of the art, and requires no more than routine experimentation.

An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcohol solvents” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C1-6alcohols, or the like.

An “aliphatic or alicyclic hydrocarbon solvent” refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvents include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8aliphatic hydrocarbons, petroleum ethers, or mixtures thereof.

“Aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of aromatic hydrocarbon solvents include, but are not limited to, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10aromatic hydrocarbons, or mixtures thereof.

An “ester solvent” is an organic solvent containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “Ester solvents” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3-6esters, or the like.

A “halogenated hydrocarbon solvent” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbon solvents” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6ketones, 4-methyl-pentane-2-one or the like.

A “polar aprotic solvent” has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO).

An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like.

The term “oxidizing agent” (also called an oxidant, oxidizer) refers to a chemical compound that readily transfers oxygen atoms or a substance that gains electrons in a chemical reaction.

“Leaving group” refers to an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction. For example, in the heterolytic solvolysis of benzyl bromide in acetic acid: the leaving group is bromide. In the reaction of N,N,N-trimethyl-1-phenylmethanaminium ion with methanethiolate, the leaving group is trimethylamine. In the electrophilic nitration of benzene, it is H+. The term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates (i.e. CH3COO-, CF3CO2-, or (CH3)2CH2COO-), F-, water, Cl-, Br-, I-, N3-, SCN-, trichloroacetimidate, thiopyridyl, tertiary amines (i.e. trimethylamine), phenoxides (i.e. o-nitrophenoxide), and sulfonates (i. e. tosylate, mesylate, or triflate).

The invention is further defined by reference to the following examples describing in detail the processes of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Instrument

The amorphous form of linagliptin, produced by the methods of the present invention can be analyzed by Powder X-ray Diffraction (PXRD) was performed on an X-ray Powder Diffractometer, equipped with a Cu-anode (?=1.54 Angstrom), X-ray source operated at 45 kV, 40 mA, and a Ni filter is used to strip K-beta radiation. Two theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range= 2-50° 2?, step width=0.017°; and measuring time per step 22 sec.

Example1: Preparation of 3-methyl-8-bromo-xanthine (compound of formula VI)

a) Using N-bromosuccinimide
3-Methylxanthine (2 gm) is charged into 250 mL round bottomed flask equipped with mechanical stirrer. Acetonitrile (40 mL) and N-bromosuccinimide (6.4 gm) are added at room temperature. Reaction mixture stirred for about 4 hours at same temperature. After completion of the reaction water (20 mL) is added to the reaction mixture and cooled to about 5°C. The resulted solution is stirred for about 2 hours at 5°C. The solid formed was collected by filtration and washed with water (10 mL). The compound was dried under vacuum at about 50°C to yield 1.6 gm of 3-methyl-8-bromo-xanthine. Purity by HPLC: 98.42%.

b). Using hydrobromic acid and hydrogen peroxide
3-Methylxanthine (2 gm) is charged into 500 mL round bottomed flask equipped with mechanical stirrer and aqueous hydrobromic acid (5.1 mL) is added. Aqueous hydrogen peroxide (2.7 mL) and water (7 mL) are added drop wise to the mixture. The reaction mixture was stirred at room temperature for about 20 hours. Water (50 mL) and 2% aqueous sodium sulphite solution (100 mL) were added to the reaction mixture and stirred the resulted solution for about 30 minutes at room temperature. The solid formed was collected by filtration and washed with water (10 mL). The compound was dried under vacuum at about 50°C to yield 900 mg of 3-methyl-8-bromo-xanthine. Purity by HPLC: 97.95%.

c). Using hydrobromic acid and hydrogen peroxide under photochemical conditions
3-methylxanthine (5 gm) is charged into 500 mL round bottomed flask equipped with mechanical stirrer and a visible light source of 100 watts. Aqueous hydrobromic acid (13 mL), aqueous hydrogen peroxide (6.8mL) and water (17.2 mL) are added. Stirred the reaction mixture at room temperature in presence of light for about 5 hours. After completion of the reaction water (50 mL) and 2% aqueous sodium sulphite solution (100 mL) are added to the reaction mixture and stirred the resulted solution for about 30 minutes at room temperature. The solid formed is collected by filtration and washed with water (10 mL). The compound is dried under vacuum at about 50°C to yield 5.7 gm of 3-methyl-8-bromo-xanthine. Purity by HPLC: 97.34%.

d) Using hydrobromic acid and sodium hypochlorite
3-Methylxanthine (2 gm) is charged into 500 mL round bottomed flask equipped with mechanical stirrer, aqueous hydrobromic acid (6.1 mL) is added, and the mixture is stirred at room temperature for 15 minutes. Aqueous sodium hypochlorite (44.6 mL) is added drop wise to the mixture, and stirred the reaction mixture at room temperature for about 5 hours. Water (20 mL) and 10% aqueous sodium sulphite solution (20 mL) are added to the reaction mixture and the resulting solution is stirred for about 30 minutes at room temperature. The solid formed is collected by filtration, washed with water (10 mL), and dried under vacuum at about 50°C to yield 3-methyl-8-bromo-xanthine.

Example 2: Preparation of Linagliptin
a). Preparation of 3-methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (compound of formula IV)
3-Methyl-8-bromo-xanthine (30 gm) and N,N-dimethylformamide (170 mL) are charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Diisopropylethylamine (DIPEA, 15.9 gm) and 1-bromo-2-butyne (16.2 gm) are added at room temperature. The reaction mixture is heated to about 85°C and maintained the temperature for about 4 hours. The reaction mixture is cooled to about 30°C and pre cooled water (300 mL) is added. The solid formed is collected by filtration and washed with pre cooled water (150 mL) and diethyl ether (30 mL). The solid is dried in oven under vacuum at about 50°C to get 30.9 gm of the title compound.

b). Preparation of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (compound of formula III)
3-Methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (35 gm) and N,N-dimethylformamide (875 mL) are charged into a 3000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (25.9 gm) and 2-(chloromethyl)-4-methylquinazoline (25.2 gm) are added to the reaction mixture at room temperature. The reaction mixture is heated to about 85°C and maintained the temperature for about 4 hours. The reaction mixture is cooled to about 30°C and water (1050 mL) is added. The solid formed is collected by filtration and washed with water (525 mL). The solid is dried in oven under vacuum at about 50°C to get 42.4 gm of the title compound.

c). Preparation of Linagliptin
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (5 gm) and N,N-dimethylformamide (DMF, 50 mL) are charged into a 500 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (4.57 gm) and (R)-piperidine-3-amine dihydrochloride (2.86 gm) are added to the reaction mixture at room temperature. The reaction mixture is heated to about 80°C and maintained at that temperature for about 8 hours. The reaction mixture is cooled to room temperature and DMF is evaporated under vacuum, then dichloromethane (DCM, 50 mL) is added, and stirred for about 15 minutes. The reaction mixture is filtered to separate out the non-dissolved material and the non-dissolved material is washed with 15 mL of dichloromethane. The dichloromethane is evaporated under vacuum to give 4 gm of crude linagliptin.

Example 3: One pot process for preparation of linagliptin
3-Methyl-8-bromo-xanthine (5 gm) and N,N-dimethylformamide (DMF, 28.5 mL) are charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Diisopropylethylamine (DIPEA, 2.6 gm) and 1-bromo-2-butyne (2.7 gm) are added at room temperature. The reaction mixture is heated to about 85°C and maintained at this temperature for about 4 hours. The reaction mixture is cooled to about 30°C and N,N-dimethylformamide (DMF, 100 mL) is added. Potassium carbonate (4.4 gm) and 2-(chloromethyl)-4-methylquinazoline (4.2 gm) are added to the reaction mixture at room temperature. The reaction mixture is heated to about 85°C and maintained at this temperature for about 4 hours. The reaction mixture is cooled to about 30°C and N,N-dimethylformamide (DMF, 90 mL) is added. Potassium carbonate (8.3 gm) and (R)-piperidine-3-amine dihydrochloride (5.2 gm) are added to the reaction mixture at room temperature. The reaction mixture is heated to about 80°C and maintained at this temperature for about 8 hours. The reaction mixture is cooled to room temperature and DMF is evaporated under vacuum. Dichloromethane (DCM, 30 mL) is added and stirred for about 15 minutes. The reaction mixture is filtered to separate out the undissolved material and the undissolved material is washed with dichloromethane (30 mL). The dichloromethane is evaporated under vacuum and 10% acetic acid (100 mL) is added. The resulted solution is stirred for about 30 minutes and washed with dichloromethane (25 mLx3). The pH of the aqueous layer is adjusted to about 8.5 with 10% aqueous sodium bicarbonate solution. The aqueous layer is extracted with dichloromethane (25 mLx2) and the dichloromethane is evaporated under vacuum to get 1.2 gm of linagliptin.

Example 4: Purification of Linagliptin

Linagliptin (3.5 gm) is dissolved in 10% aqueous acetic acid and stirred for about 15 minutes. Dichloromethane (50 mL) is added to the solution and stirred for about 30 minutes. The aqueous layer is separated and the pH of this layer is adjusted to about 8.5 using 10% aqueous sodium bicarbonate solution. The aqueous layer is extracted with dichloromethane (50 mLx2). The dichloromethane is evaporated under vacuum to get 3 gm of pure linagliptin.

Example 5: Preparation of amorphous form of linagliptin.

Linagliptin (2 gm) and dichloromethane (100 mL) are charged into a round bottom flask at 28°C and stirred to form a solution. The solution is filtered and the filtrate is evaporated by spray drying, using a Büchi® MINI Spray Dryer B-290 with Büchi® Inert Loop B-295, to afford 0.9 gm of amorphous linagliptin. PXRD pattern: Fig. 1.

Parameters for the spray drier of the above experiment:

Aspirator: 70%.

Feed rate: 10%.

N2 pressure: 6-6.5 Kgf/cm2.

Inlet temperature: 70°C.

Claims We claim

1. A process for preparing linagliptin of Formula (I) comprising:

a) reacting 3-methyl-8-bromo-xanthine of formula VI or a salt thereof with compound of formula VII in presence of a base and a suitable solvent to obtain 3- methyl-7-(2-butyn-l-yl)-8-bromo-xanthine of formula IV;
X is a leaving group

b) reacting the compound of formula IV with 2-(chloromethyl)-4-methylquinazoline of formula V in presence of a base and a suitable solvent to obtain 1 -[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8- bromoxanthine of formula III; and

c) reacting the compound of formula III with (R)-piperidine-3-amine of formula II or an acid addition salt thereof in presence of a base and a suitable solvent to obtain linagliptin (I);

with the proviso that at least two of the steps (a) to (c) are carried out in one pot.

2. The process according to claim 1, wherein the leaving group is selected form the group comprising chloro, bromo, methane sulfonyloxy, benzene sulfonyloxy, para methyl benzenesulfonyloxy.

3. The process according to claim 1, wherein the leaving group is bromo and the compound of formula VII is 1-bromo-2-butyne.

4. The process according to claim 1, wherein the base is selected from the group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, diisopropylethylamine.

5. The process according to claim 4, wherein the base is diisopropylethylamine.

6. The process according to claim 4, wherein the base is potassium carbonate.

7. The process according to claim 1, wherein the solvent is selected from the group comprising dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran.

8. The process according to claim 1, wherein the solvent is dimethylacetamide.

9. A process for preparing 3-methyl-8-bromo-xanthine comprising reacting 3- methylxanthine of formula VIII with (a) hydrobromic acid and an oxidizing agent

(b) with N-bromosuccinimide

10. The process according to claim 9, wherein the oxidizing agent is selected from the group comprising hydrogen peroxide, sodium hypochlorite, tertiary butyl peroxide, metachloro per benzoic acid or a mixture of alkali metal bromide and an acid.