DESC:Field of Invention:

The present invention related to an improved process for the preparation of Infigratinib and its pharmaceutical salts. The present invention provides purification of Infigratinib from novel salts and intermediates.

Background of the invention:

The 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea phosphate is commonly known as Infigratinib phosphate which is represented by the following structural formula:

Formula-I
Infigratinib was approved by the USFDA for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement under brand name TRUSELTIQ.
The process of Infigratinib was disclosed in US 8552002, US 9067896 which involves the usage of column chromatography techniques. Hence, the said process is not suitable for commercial scale.
Thus, there remains a need to develop a process, which overcomes one or more of the drawbacks of the prior art and thereby develop an improved process for preparing Infigratinib. The present inventors have developed an improved process for preparing Infigratinib wherein surprisingly, found that the formation of impurity can be substantially reduced by using the novel intermediates and salts.

Summary of invention:
The present invention provides a process for the preparation of Infigratinib. The present invention provides the removal of impurities by using novel Infigratinib salts. The invention further provides the process for the preparation of novel salts of Infigratinib intermediates.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig-1: Illustrates the characteristic powder X-ray diffraction (XRPD) pattern of the crystalline Infigratinib TFA salt.
DETAILED DESCRIPTION
The object of the present invention is to provide an improved process for preparing Infigratinib phosphate of formula-I comprising the steps of:

Formula-I
a) reacting the compound of formula-A with triphosgene in presence of base to obtain the compound of formula-B;

b) without isolating the compound of formula-B, add to compound of formula- C, in presence of base to obtain the compound of formula-D, with/without isolating add acid to obtain the compound of formula-E as acid salt with or without isolating compound of formula E;

c) add the base to obtain Infigratinib free base;
d) add phosphoric acid to obtain the compound of formula-I.
The base in step-a), step-b) & step-c) is selected from organic bases such as methylamine, ethyl amine, propylamine, diisopropylethylamine and thereof.
The acid used in step-b) is selected from organic or inorganic acids such as HCl (hydrochloric acid), HBr (hydrobromic acid), HI (hydroiodic acid), H2SO4 (sulfuric acid), H3PO3 (phosphorous acid); organic acid selected from Methanesulfonic acid, Ethanesulfonic acid, para-toluene sulfonic acid, Acetic acid, Citric acid, Formic acid, Lactic acid, Malic acid, Oxalic acid, Tartaric acid, Succinic acid, glutaric acid, Trifluoroacetic acid and thereof.
In an embodiment provides a process for preparing Infigratinib acid salt comprising the steps:

a) reacting the compound of formula-A with triphosgene in presence of base to obtain the compound of formula-B;

b) without isolating the compound of formula- B, add to compound of formula- C of the step-a) in presence of base to obtain the compound of formula-D, which with/without isolating, reacted with acid to obtain the compound of formula E Infigratinib acid salt.
The base in step-a) & step-b) is selected from organic bases such as methylamine, ethylamine, propylamine, diisopropylethylamine and thereof.
The acid used in step-b) is selected from organic or inorganic acids; inorganic acids such as HCl (hydrochloric acid), HBr (hydrobromic acid), HI (hydroiodic acid), H2SO4 (sulfuric acid), H3PO3 (phosphorous acid); organic acids selected from Methanesulfonic acid, Ethanesulfonic acid, para-toluene sulfonic acid, Acetic acid, Citric acid, Formic acid, Lactic acid, Malic acid, Oxalic acid, Tartaric acid, Succinic acid, glutaric acid, Trifluoroacetic acid and thereof.
In one embodiment, the present invention provides a process for the preparation of Infigratinib trifluoroacetic acid comprising;
a) reacting the compound of formula-A with triphosgene in presence of base to obtain the compound of formula-B;

b) without isolating the compound of formula-B, add compound of formula- C in presence of base to obtain the compound of formula-D, which with/without isolating reacted with acid to obtain the compound Infigratinib trifluoroacetic acid.

The base in step-a) & step-b) is selected from organic bases such as methyl amine, ethyl amine, propyl amine, diisopropylethylamine.
The acid used in step-b) is Trifluoroacetic acid.
In further embodiment, the present invention provides a process for preparation of 4-(4-ethylpiperazin-1-yl) aniline acetate of formula-IA comprising the steps of:

Formula-IA
a) Reacting 1-Fluoro-4-nitrobenzene with 1-ethylpiperazine in presence of inorganic base in polar solvent to obtain the compound formula IB;

b) reducing the compound of formula-IB in presence of acid to obtain compound of formula-IA;
c) optionally, purifying the compound of formula-IA in a solvent.
The base used in step-a) selected from inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, Cesium carbonate and thereof.
The polar solvent used in step-a) is selected from alcohols such as methanol, propanol, butanol, water, Dimethylsulfoxide, dimethyl formamide and mixture thereof.
The reduction of step-b) is performed by using reagents such as Pd/c, Raney Nickel, iron (Fe), zinc (Zn), tin(II) chloride, Sodium sulfide (Na2S), Lithium aluminum hydride (LiAlH4) and thereof.
The acid used in step-b) is selected from organic acids Methanesulfonic acid, Para-toluene sulfonic acid, Acetic acid, Citric acid, Formic acid, Lactic acid, Malic acid, Oxalic acid, Tartaric acid, Trifluoroacetic acid thereof.
The solvent used in step-c) is selected from mixture of solvents such as polar and non-polar solvent; such as alcohol and hydrocarbon solvents; such as Methanol, Ethanol, Isopropyl alcohol, mixture of methanol: water, ethanol: water, Isopropyl alcohol: water, methanol: hexane, Isopropyl alcohol :hexane, propanol:hexane and mixture thereof.
In further embodiment, the present invention provides highly pure Infigratinib and its pharmaceutical salts comprising the steps of:
a) reacting the compound of formula-B with formula-C in presence of base;
b) after the reaction completion add the acid;
c) filter the reaction mixture;
d) add the base;
e) filter the pure compound.

In further embodiment, the present invention provides a novel crystalline form of Infigratinib Trifluoroacetic acid salt compound of formula-E, which is characterized by:
i) Its powder X-ray diffractogram having peaks at about 6.3, 8.9, 10.0, 12.6, 13.6, 14.1, 16.9, 18.6, 20.1, 20.9, 21.3, 23.0 and 24.6± 0.2 degrees 2-theta.
ii) Its powder X-ray diffraction pattern as shown in figure-1.

PXRD method of analysis:
PXRD analysis of the crystalline form of Infigratinib and its salts were carried out using Panlytical Expert Pro DY3248 X-ray powder diffractometer using Cu-Ka radiation of 10 wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples provide as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of 1-ethyl-4-(4-nitrophenyl)piperazine (Formula-3):

Charged Formula-1(50.0 g) into a round bottomed flask. Slowly added Fromula-2 (48.55 g) into flask under stirring at 25-35?. Slowly added NaOH solution (28.34 g dissolved in 100.0 mL of water) to reaction mass at 25-35oC over a period of 15-20 min. Raised the reaction mass temperature to 50-55? and maintain the reaction mass at 50-55 ºC for 5-6 hrs. After complete consumption of 1-fluoro-4-nitrobenzene, cooled the reaction mass temperature to 25-35 ºC. Charged DM water (250 ml) to the reaction mass. Filtered and washed the wet cake with water. Suck dried for 20-30 min to obtain wet material. Dried the wet material to obtain 1-ethyl-4-(4-nitrophenyl)piperazine of formula-3.
Yield: 96%; Purity: > 99.5% by HPLC.

Example-2: Preparation of 4-(4-ethyl-1-piperazin-1-yl)aniline acetate (Formula-IA):

Charged Methanol (10 vol) in to a round bottomed flask under stirring. Charged 1-ethyl-4-(4-nitrophenyl)piperazine of formula-3 (150 g) and acetic acid (38.25 g) into flask under stirring at 25-35 oC. Charged 1.5 g of 5% Pd/C into the reaction mass. Bubbled the hydrogen gas into the reaction mass at 25-35 ºC for 10-12 hrs. After consumption of the 1-ethyl-4-(4-nitrophenyl)piperazine, filter the reaction mass on a Buchner funnel. Distilled out the solvent completely from the reaction mass to obtain crude compound. To the crude, charged 1500.0 ml of 10% IPA in hexane. Heated to temperature 50-60? and maintain for 45-60 min. Then cooled the reaction mass temperature to 25-35?. Filtered and dried the wet cake to obtain 4-(4-ethyl-1-piperazin-1-yl) aniline acetate of formula-IA.
Yield: 88%; Purity> 99.5% by HPLC.
Example-3: Preparation of N-[4-(4-Ethyl-1-pierazinyl) phenyl] N-methyl-4-6-pyrimidineamine (Formula-C)

Charged 4-(4-ethyl-1-piperazin-1-yl)aniline acetate [Formula-IA] (200 g) and DM water (1200 ml) in to a round bottomed flask and stirred the reaction mixture for 10 min at 25-30°C. Charged 6-Chloro-N-methyl-4-pyrimidinamine [Formula-4] (111.45 g) and Acetic acid (181.1 g) to the reaction mass at 25-30°C and stirred for 10 min. Raised the reaction mass temperature to 95-100°C and maintain for 8 hrs. After completion of reaction, cooled the reaction mass to 45±5°C. Washed the reaction mass with toluene to remove starting material and impurities. Charged methanol (1000 ml) to the aq layer at 25-30°C, added aq sodium hydroxide solution to the reaction mass to precipitate out N-[4-(4-Ethyl-1-pierazinyl)phenyl]N-methyl-4-6-pyrimidineamine (Formula-C) crude compound. Filtered the solid and purified the compound in a mixture of isopropyl alcohol and acetone to obtain N-[4-(4-Ethyl-1-pierazinyl) phenyl] N-methyl-4-6-pyrimidineamine (Formula-C).
Yield: 175 g (80%); Purity: >98% by HPLC.

Example-4: Preparation of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)phenylamino]pyrimidin-4-yl}-1-methylurea (Formula-D)

Charged Toluene (3125 ml) and 2, 6-dichloro-3,5-dimethoxyaniline (Formula-A) (177.7 g) and Triphosgene (118.73 g) into a round bottomed flask under nitrogen atmosphere. Stirred the reaction mixture for 10 min at 25-35ºC. Cooled the reaction mass temperature to 0-5ºC. N,N-diisopropyl ethylamine (181 g) was added to the reaction mass stirred for 15 min at 0-5ºC. Raised the reaction mass temperature to 25-35ºC and maintained for 2-3hrs. After completion of reaction, distilled-off the solvent to obtain 2,4-dichloro-3-isocyanato-1,5-dimethoxybenzene Formula-B as a residue. Charged Toluene (3125 ml) to the above obtained residue in hot condition under nitrogen atmosphere. Stirred the reaction mass for 20 min at 50-60ºC.
Charged Toluene (2750 ml) and N-[4-(4-Ethyl-1-pierazinyl)phenyl]-N-methyl-4-6-pyrimidineamine (Formula-C) (125 g) and N,N-diisopropyl ethylamine (181 g) into another 4N round bottomed flask under nitrogen atmosphere. Stirred the reaction mixture for 10 min at 25-35ºC. Raised the reaction mass temperature to 80-90ºC.
The isocyanate reaction mass of formula-B was added to the reaction mass containing formula-C and stirred for 90 min at 80-90ºC. Raised the reaction mass temperature to 95-100ºC and maintained for 6 hrs. Cooled the reaction mass temperature to 25-35ºC. Charged DM water (1500 ml) to the reaction mass and stirred for 1 hr at the same temperature. Filtered the mass and washed the wet cake with Toluene (250 ml) and dried under vacuum to get the crude compound of formula-D.
Charged dimethylsulfoxide (DMSO) (1210 ml) in 4N round bottomed flask under nitrogen atmosphere. Charged above obtained crude compound of formula-D (220 g) and stirred for 10 min. Trifluoroacetic acid (67.13 g) was added to the reaction mass and stirred for 30 min at 25-35ºC. Filtered the reaction mass and washed the undissolved material with DMSO. Filtered the solid, washed with DM water and dried the wet material at 50-60ºC under vacuum for 7.0-8.0 hrs to obtain trifluoroacetic acid salt of Infigratinib (Formula-E).
Charged trifluoroacetic acid salt of Infigratinib (Formula-E) and triethylamine (119.16) in to another round bottomed flask. Stirred the reaction mass for 3 hrs at 25-35ºC. Filtered the reaction mass, washed with isopropyl alcohol and dried to get the Infigratinib base Formula-D.
Yield: 128 g (60 %); Purity: >99.5 % by HPLC.

Example-5: Preparation of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)phenylamino]pyrimidin-4-yl}-1-methylurea phosphate (Formula-I)
Charged Infigratinib base of formula-D (120 g) and dimethylsulfoxide (600 ml) in 4N round bottomed flask and stirred for 15 min at 25-35ºC. The orthophosphoric acid (76.5 g) was added to reaction mass and stirred for 15 min at the same temperature. Charged isopropyl alcohol (1440 ml) and DM water (1440 ml) in another round bottomed flask under stirring. Added the above obtained orthophosphoric acid reaction mass to the mixture containing isopropyl alcohol and DM water and stirred for 6 hrs at 25-35ºC. Filtered the reaction mass, washed with isopropyl alcohol and dried to get the Infigratinib phosphate of formula-I.
Yield: 122 g (88 %); Purity: 99.9% by HPLC.
,CLAIMS:We Claim:

1. An improved process for the preparation of Infigratinib of formula-D,

comprising of:
a) Treating compound of formula-A with triphosgene in presence of diisopropylethylamine in toluene to provide compound of formula-B,
b) reacting the compound of formula-B in-situ with compound of formula-C in presence of diisopropylethylamine in toluene to provide Infigratinib base of formula-D,
c) treating the formula-D with a suitable acid to provide the acid addition salt of formula-E,
d) treating the formula-E with a suitable base to provide the pure Infigratinib compound of formula-D.

2. The process as claimed in claim-1, wherein,
In step-c) the suitable acid used is selected from organic or inorganic acids such as
HBr (hydrobromic acid), HI (hydroiodic acid), H2SO4 (sulfuric acid), H3PO3 (phosphorous acid); organic acid selected from methanesulfonic acid, ethanesulfonic acid, para-toluene sulfonic acid, acetic acid, citric acid, formic acid, lactic acid, malic acid, oxalic acid, tartaric acid, succinic acid, glutaric acid, Trifluoroacetic acid and the like.
In step-d) the suitable base used is selected from organic base such as
dimethylamine, diethylamine, diisopropylamine, N,N-diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP) and the like.

3. An improved process for the preparation of high pure Infigratinib of formula-D, comprising of:
a) Treating compound of formula-A with triphosgene in presence of diisopropylethylamine in toluene to provide compound of formula-B,
b) reacting the compound of formula-B in-situ with compound of formula-C in presence of diisopropylethylamine in toluene to provide Infigratinib base of formula-D,
c) treating the formula-D with Trifluoroacetic acid to provide the Trifluoroacetic acid salt of formula-E,
d) treating the formula-E with triethylamine to provide the pure Infigratinib compound of formula-D.

4. The Trifluoroacetic acid salt of Infigratinib compound of formula-E:

5. A novel crystalline form of Infigratinib Trifluoroacetic acid salt compound of formula-E, which is characterized by:
i) Its powder X-ray diffractogram having peaks at about 6.3, 8.9, 10.0, 12.6, 13.6, 14.1, 16.9, 18.6, 20.18, 20.97, 21.34, 23.0 and 24.6± 0.2 degrees 2-theta.
ii) Its powder X-ray diffraction pattern as shown in figure-1.

6. A process for the preparation of crystalline Form of Infigratinib Trifluoroacetic acid salt compound of formula-E as claimed in claim-5, comprising of:
a) reacting the compound of formula-B in-situ with compound of formula-C in presence of diisopropylethylamine in toluene to provide Infigratinib base of formula-D,
b) treating the formula-D with Trifluoroacetic acid in dimethyl sulfoxide to provide the Trifluoroacetic acid salt of formula-E.

7. The Trifluoroacetic acid salt of Infigratinib and its crystalline form obtained from the claims 4 to 6 are useful in the preparation of highly pure Infigratinib and its phosphate salt.

8. The Infigratinib phosphate obtained from the present invention is having purity more that 99.9 % by HPLC.