DESC:AN IMPROVED PROCESS FOR THE PREPARATION ALOGLIPTIN AND ITS INTERMEDIATE

FIELD OF THE INVENTION

The present invention provides an improved process for the preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile of formula (II), an intermediate for the preparation of Alogliptin and pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Alogliptin which is chemically known as 2-[6-((3R)-3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile is represented by a compound of formula (I):

Alogliptin is first time disclosed in US 7807689 B2. US ‘689 disclose a process for preparation of Alogliptin as depicted in scheme-1.

Scheme-1

According to US ‘689, 6-Chloro-1H-pyrimidine-2,4-dione is reacted with 2-Bromomethyl-benzonitrile in the presence of sodium hydride (NaH) and Lithium Bromide (LiBr) in a solvent mixture of Dimethyl formamide (DMF) and Dimethylsulfoxide (DMSO) to produce the benzyl substituted uracil derivative in 54% yield. The benzyl substituted uracil derivative is further reacted with iodomethane to give the 1,3-disubstituted uracil. The disubstituted uracil is then reacted with 3(R)-Piperidin-3-ylamine dihydrochloride to provide Alogliptin free base which is converted into its benzoate salt.

The process as disclosed in US ‘689 involves multiple steps for the preparation of Alogliptin. One of the major disadvantages of above described process is the recovery of solvents from the mixture of high boiling solvents (DMF and DMSO), use of hazardous materials such as NaH and low yield in the first step. This process also uses undesirable potential genotoxic compound like methyl iodide and high molar amounts of LiBr in second step.

US 8222411 discloses a reaction of 6-Chloro-3-methyl-1H-pyrimidine-2,4-dione with 2-Bromomethyl-benzonitrile in the presence of Di-isopropylethylamine (DIPEA) as base in a solvent mixture of N-Methylpyrrolidone (NMP) and toluene to give the 1,3-disubstituted uracil as depicted in scheme-2.

Scheme-2

CN 104592195, CN 103980249, CN 102942556 discloses reaction of the 6-Chloro-3-methyl-1H-pyrimidine-2,4-dione with 2-Bromomethyl-benzonitrile in presence of organic bases like DIPEA, triethylamine or tri n-butylamine in toluene as solvent to obtain 1,3-disubstituted uracil. Use of amines makes the recovery of high boiling point solvents after the reaction difficult. Further these processes require longer reaction times for completion of the reaction.

CN 105968091 discloses a process for preparation of 1,3-disubstituted uracil by reacting 6-Chloro-3-methyl-1H-pyrimidine-2,4-dione with 2-Bromomethyl-benzonitrile in presence of triethylamine as base, catalysts such as copper acetate and potassium iodide in acetonitrile as solvent. CN ‘091 uses high molar quantities of both the cataysts i.e. copper acetate and potassium iodide to attain desirable yield and purity. The recovery of solvents from the reaction mixture is also a problem.

IN 1958/MUM/2014, WO 2015092807, CN 103819450 discloses processes for the preparation of compound of formula (II) using high boiling solvents like NMP, DMF or Dimethylacetamide which are difficult to recover for further recycling making these processes industrially non-feasible.

There exist a need for an improved and industrially scalable process for the production of compound of formula (II), in high yields and purity using safer reagents and low quantities of catalysts, shorter reaction times, and amenable to solvent recovery for recycling.

OBJECT OF THE INVENTION

An object of present invention is to provide an improved process for the preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile of formula (II), that is cost effective and commercially feasible.

Another object of the invention is to provide an improved process for the preparation of the compound of formula II in high yields and high purity using safer reagents, shorter reaction times, and amenable to easy solvent recovery for recycling.

Another object of present invention is to provide an improved process for the preparation of Alogliptin of formula (I) and its pharmaceutically acceptable salts at industrial scale.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an improved process for the preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile of formula (II),

which comprises, reacting a compound of formula (III) with a compound of formula (IV),

in the presence of an inorganic base and quaternary ammonium salt in a suitable solvent.

In another aspect, the present invention provides an improved process for the preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile of formula (II),

which comprises, reacting a compound of formula (III) with a compound of formula (IV),

in the presence of an inorganic base and quaternary ammonium salt in aromatic hydrocarbon solvent.

In another aspect, the present invention provides an improved process for the preparation of Alogliptin and its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF INVENTION

In one aspect, the present invention provides an improved process for the preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile of formula (II),

which comprises, reacting a compound of formula (III) with a compound of formula (IV),

in the presence of an inorganic base and quaternary ammonium salt in a suitable solvent.

In another aspect, the present invention provides an improved process for the preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile of formula (II),

which comprises, reacting a compound of formula (III) with a compound of formula (IV),

in the presence of an inorganic base and quaternary ammonium salt in aromatic hydrocarbon solvent.

The quaternary ammonium salt of the present invention can be selected from a group comprising of tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetrabutyl ammonium sulfate, cetyl trimethyl ammonium iodide, tetraethylammonium chloride (TEAC), tetrapropylammonium bromide (TPAB), tetrabutylammonium fluoride (TBAF), tetrapropylammonium perruthenate (TPAP), benzyltrimethylammonium chloride (BTMAC), benzyltriethylammonium chloride (BTAC), tetrabutylammonium hydroxide (TBAH), methyltricaprylammonium chloride (MTCAC), tributylmethylammonium chloride (MTBAC) or trioctylmethylammonium chloride. Preferably quaternary ammonium salt is TBAB.

The inorganic base of the present invention can be selected from a group comprising of carbonates like potassium carbonate (K2CO3), sodium carbonate (Na2CO3); bicarbonates like sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3); hydroxides like sodium hydroxide (NaOH), potassium hydroxide (KOH) or Lithium hydroxide (LiOH); hydrides like sodium hydride or potassium hydride. Preferably base is Na2CO3 or K2CO3.

The suitable solvent of the present invention can be selected from ethers, chlorinated hydrocarbon and aromatic hydrocarbon solvent. Preferred solvent is aromatic hydrocarbon.

The ethers solvent of the present invention can be selected from a group comprising of tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, dioxane, diethylene glycol dimethyl ether or mixtures thereof.

The chlorinated hydrocarbon solvent of the present invention can be selected from a group comprising of methylene dichloride, ethylene dichloride, chloroform or mixtures thereof.

The aromatic hydrocarbon solvent of the present invention can be selected from a group comprising of toluene, xylene, benzene or mixtures thereof. Preferably aromatic hydrocarbon solvent is toluene or xylene.

In general, the compound of formula (II) can be prepared by reacting a compound of formula (III) with a compound of formula (IV) in the presence of an inorganic base and quaternary ammonium salt in aromatic hydrocarbon solvent at any suitable range of temperature generally at 25°C - 140°C, preferably at 80°C - 100°C over a period of about 1 to 5 hours, preferably for 2 to 4 hours. The reaction can be carried out using about 2 to 20 volume of aromatic hydrocarbon solvent with respect to compound of formula (III). Preferably about 4 to 8 volume of aromatic hydrocarbon solvent can be used. The amount of quaternary ammonium salt used can range from 0.001 to 0.5 moles with respect to compound of formula (III). Preferably 0.01 to 0.05 mole of quaternary ammonium salt can be used. The amount of compound of formula (IV) used can range from 1.0 to 2.0 moles, preferably 1 to 1.2 moles with respect to compound of formula (III).

The reaction can be carried out by adding the reactants or reagents in any sequence that is known to one of skill in the art. Preferably, the reaction can be performed by adding compound of formula (IV) to a reaction mixture of compound of formula (III) in an aromatic hydrocarbon solvent followed by addition of an inorganic base and quaternary ammonium salt to the reaction mixture. After the completion of reaction, the compound of formula (II) can be isolated by any conventional methods known in the art.

According to another aspect of the present invention, there is provided an improved process for the preparation of Alogliptin and its pharmaceutically acceptable salts thereof, by converting the compound of formula (II) into Alogliptin and its pharmaceutically acceptable salts thereof, by any method known in the art.

The present inventors have surprisingly found that the compound of formula (II) can be prepared by a commercially scalable process in high yields and purity and amenable to solvent recovery for recycling.

It has surprisingly been found that reactions carried out in the absence of quaternary ammonium salts do not produce the desired results. Similarly reactions carried our using quaternary ammonium salts in solvents other than aromatic hydrocarbons do not produce the desired results. The results of comparative experiments, for the preparation of the compound of formula (II) are given in table-1.

According to another aspect of the present invention, there is provided an improved process for the preparation of Alogliptin and its pharmaceutically acceptable salts from the compound of formula (II) as prepared by the present invention (scheme-3).

Scheme-3

The invention is illustrated with non-limiting examples.

Example-1:
Preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile [Compound of formula (II)]
2-Bromomethyl-benzonitrile (26.9 gm) was added to a stirred solution of 6-Chloro-3-methyl-1H-pyrimidine-2,4-dione (20.0 gm) in toluene (120 ml) at 25°C - 30°C. Na2CO3 (26.4 gm) and TBAB (2.0 gm) were added to the reaction mixture, heated to 80°C - 85°C and maintained for 4-5 hrs. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, water (200 ml) was added slowly to the reaction mixture. The reaction mixture was cooled to 25°C - 35°C, stirred for 1 hr and filtered to obtain 30.22 gm of the compound of formula-(II); Yield: 88.00%; Purity: 99.56%.

Example-2:
Preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile [Compound of formula (II)]
2-Bromomethyl-benzonitrile (26.9 gm) was added to a stirred solution of 6-Chloro-3-methyl-1H-pyrimidine-2.4-dione (20.0 gm) in toluene (200 ml) at 25°C - 30°C. Na2CO3 (26.4 gm) and tetrabutyl ammonium sulfate (3.5 gm) were added to the reaction mixture, heated to 80°C - 85°C and maintained for 4 - 5 hrs. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, water (200 ml) was added slowly to the reaction mixture. The reaction mixture was cooled to 25°C - 35°C, stirred for 1 hr and filtered to obtain 28.50 gm of the compound of formula-(II); Yield: 83.00%; Purity: 99.35%.

Example-3:
Preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile [Compound of formula (II)]
2-Bromomethyl-benzonitrile (26.9 gm) was added to a stirred solution of 6-Chloro-3-methyl-1H-pyrimidine-2,4-dione (20.0 gm) in toluene (200 ml) at 25°C - 30°C. Na2CO3 (26.4 gm) and cetyl trimethyl ammonium iodide (2.8 gm) were added to the reaction mixture, heated to 80°C - 85°C and maintained for 4-5 hrs. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, water (200 ml) was added slowly to the reaction mixture. The reaction mixture was cooled to 25-35°C, stirred for 1 hr and filtered to obtain 28.91 gm of the compound of formula-(II); Yield: 84.20%; Purity: 99.65 %.

Example-4:
Preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile [Compound of formula (II)]
2-Bromomethyl-benzonitrile (26.9 gm) was added to a stirred solution of 6-Chloro-3-methyl-1H-pyrimidine-2,4-dione (20.0 gm) in benzene (200 ml) at 25°C - 30°C. Na2CO3 (26.4 gm) and TBAB (2.0 gm) were added to the reaction mixture, heated to 73°C - 78°C and maintained for 4-5 hrs. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, water (200 ml) was added slowly to the reaction mixture. The reaction mixture was cooled to 25°C - 35°C, stirred for 1 hr and filtered to obtain 28.67 gm of the compound of formula-(II); Yield: 83.50%; Purity: 99.10%.

Example-5:
Preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile [Compound of formula (II)]
2-Bromomethyl-benzonitrile (26.9 gm) was added to a stirred solution of 6-Chloro-3-methyl-1H-pyrimidine-2,4-dione (20.0 gm) in xylene (200 ml) at 25°C - 30°C. Na2CO3 (26.4 gm) and TBAB (2.0 gm) were added to the reaction mixture, heated to 80°C - 85°C and maintained for 4-5 hrs. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, water (200 ml) was added slowly to the reaction mixture. The reaction mixture was cooled to 25°C - 30°C, stirred for 1 hr and filtered to obtain 28.43 gm of the compound of formula-(II); Yield: 82.80%; Purity: 99.73%.

Example-6:
Preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile [Compound of formula (II)]
2-Bromomethyl-benzonitrile (26.3 gm) was added to a stirred solution of 6-Chloro-3-methyl-1H-pyrimidine-2,4-dione (20.0 gm) in toluene (200 ml) at 25°C - 30°C. Na2CO3 (26.4 gm) and TBAB (2.0 gm) were added to the reaction mixture, heated to 80°C - 85°C and maintained for 4-5 hrs. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, water (200 ml) was added slowly to the reaction mixture. The reaction mixture was further cooled to 25°C - 30°C and stirred for 1 hr and filtered to obtain 28.01 gm of the compound of formula-(II); Yield: 81.58%; Purity: 99.25%.

Analogously, the compound of formula (II) is prepared according to Example-6 by using the following solvents, reagents, and reaction conditions mentioned in table-1.
Table-1:
Ex. No. Solvent
(10 Volume) Base Catalyst Temp. Time Yield (%) Purity (%)
7 Toluene Na2CO3 MTCAC 80-85°C 4 hrs 86.2 99.42
8 Toluene Na2CO3 BTAC 80-85°C 5 hrs 83.86 99.59
9 Toluene Na2CO3 TEAC 80-85°C 6 hrs 85.03 99.32
10 Toluene Na2CO3 TBAC 80-85°C 5 hrs 85.9 99.46
11 Toluene K2CO3 TBAB 80-85°C 5 hrs 84.5 98.84

Example-12:
Preparation of Alogliptin Benzoate
3-(R)-Piperidin-3-ylamine dihydrochloride (15 gm) was added to a stirred solution of compound of formula (II) (20.0 gm) in isopropanol (100 ml) at 25°C - 30°C, and heated to 45°C - 50°C. NaHCO3 (27.4 gm) was added to the reaction mixture and maintained for 3 hrs. The reaction progress was monitored by (TLC). After the completion of the reaction, the reaction mixture was cooled to 25°C - 30°C, filtered and washed with isopropanol (5 ml). The filtrate was concentrated under vacuum below 60°C and dissolved in dichloromethane (MDC) (60 ml) at 25°C - 30°C. Water (60 ml) was added to the reaction mixture under stirring. The reaction mixture was acidified to attain a pH of less than 2.0 with dilute hydrochloric acid. After acidification, the aqueous layer was separated and washed with MDC (5 ml). MDC (60 ml) was added to the aqueous layer, and the reaction mixture was basified to attain a pH of 8-9 with 10% aqueous Na2CO3 solution. The aqueous layer was separated after basification and extracted with MDC (10 ml). All the MDC layers were combined, washed with water (60 ml) and concentrated under vacuum below 50°C to obtain Alogliptin free base. The obtained aloglitptin free base was dissolved in isopropanol (60 ml) at 25°C - 30°C and the reaction mixture was heated to 60°C. Benzoic acid (5 g) was added to the reaction mixture, heated to reflux at 80°C - 85°C and maintained for 20 minutes. The reaction mixture was then cooled at 25°C - 30°C, stirred for 60 minutes and filtered. The obtained wet cake was washed with isopropanol (10 ml) and dried under vacuum at 55°C - 60°C to obtain (14.2 gm) crude alogliptin benzoate. Yield: 85.0%; Purity: 99.6%. Crude aloglitpin benzoate was recrystallised from ethanol to obtain (12.72 gm) pure aloglitpin benzoate. Yield: 76.0%; Purity: 99.9%.

Comparative example 1-8:
A compound of formula (II) was also prepared by condensing the compound of formula (III) with compound of formula (IV) by using the following reaction conditions:
Table-2:
No. Solvent Base Catalyst Temp. Time Yield (%)
1 Toluene NaHCO3 Absent 80 - 85°C 10 hrs Reaction was not proceeded for completion
2 DMF K2CO3 Absent 80 - 85°C 4 hrs 44
3 Toluene Tributylamine Absent 80 - 85°C 4 hrs 51
4 Toluene Triethylamine Absent 80 - 85°C 4 hrs 69
5 Toluene Triethylamine TBAB 80 - 85°C 4 hrs 70
6 Isopropanol Na2CO3 TBAB 75 - 80°C 10 hrs Reaction was not proceeded for completion
7 Ethyl acetate Na2CO3 TBAB 70 - 75°C 10 hrs 75
8 Acetonitrile Na2CO3 TBAB 80 - 85°C 10 hrs Reaction was not proceeded for completion

The results of comparative examples as depicted in table-2 clearly show that the Examples 1-11 of the present invention unexpectedly provide high yield in contrast to the comparative examples.
,CLAIMS:We claim

1. A process for the preparation of compound of formula (II)

comprising:
reacting a compound of formula (III) with a compound of formula (IV)

in the presence of inorganic base and quaternary ammonium salt in a suitable solvent.

2. The process as claimed in claim 1, wherein the quaternary ammonium salt is selected from the group comprising of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutyl ammonium sulfate, cetyl trimethyl ammonium iodide, tetraethylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium fluoride, tetrapropylammonium perruthenate, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydroxide, methyltricaprylammonium chloride, tributylmethylammonium chloride or trioctylmethylammonium chloride.

3. The process as claimed in claim 1, wherein the quaternary ammonium salt is tetrabutylammonium bromide.

4. The process as claimed in claim 1, wherein the inorganic base is selected from the group comprising of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride or potassium hydride.

5. The process as claimed in claim 1, wherein the inorganic base is selected from the group comprising of potassium carbonate or sodium carbonate.

6. The process as claimed in claim 1, wherein the solvent is selected from ethers, chlorinated hydrocarbon and aromatic hydrocarbon.

7. The process as claimed in claim 6, wherein aromatic hydrocarbon solvent is selected from the group comprising of toluene, xylene, benzene or mixture thereof.

8. The process as claimed in claim 1, wherein the reaction is carried out at about 25°C - 140°C.

9. The process as claimed in claim 1, wherein the molar ratio of quaternary ammonium salt used to compound of formula (III) is 0.01 to 0.05 mole.

10. A process for preparing Alogliptin and its pharmaceutically acceptable salts comprising converting compound of formula (II) prepared according to claim 1 into Alogliptin and its pharmaceutically acceptable salts.