Description:FIELD OF THE INVENTION:
The present invention relates to an efficient and industrially advantageous process for the preparation of Tegoprazan.
The present invention also relates to a process for the purification of Tegoprazan intermediate namely (-)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl) sulfonyl]-1H-benzimidazole-6-carboxamide of Formula-II, and its use for the preparation of Tegoprazan.
BACKGROUND OF THE INVENTION:
Tegoprazan is chemically known as (-)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide, having the structure of Formula-I.

Tegoprazan has been developed by RaQualia Pharma Inc. and in the partnership with CJ HealthCare Corporation launched in South Korea. Tegoprazan was approved by Korean Food and Drug Administration (KFDA) on July 05th, 2018 under the proprietary name K-CAP®. Tegoprazan is a pharmaceutical ingredient for preventing and treating diseases mediated by an acid pump antagonistic activity, including gastrointestinal diseases, for example, a gastroesophageal disease, a gastroesophageal reflux disease (GERD), a peptic ulcer, a gastric ulcer and a duodenal ulcer, an ulcer induced by NSAID, a gastritis, a Helicobacter pylori infection, a dyspepsia and a functional dyspepsia, a Zollinger-Ellison syndrome, a nonerosive reflux disease (NERD), a visceral pain, a purosis, a nausea, an esophagitis, a dysphagia, a salivation, an airway lesion and an asthma.
US patent number US 7723321 (herein after US ‘321) first discloses Tegoprazan. The process for preparation of racemic Tegoprazan & specific ‘S’ isomer of Tegoprazan has been also disclosed by reacting 4-hydroxy-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide with 5,7-difluoro-3,4-dihydro-2H-chromen-4-ol in presence of triphenylphosphine, toluene and diisopropyl azodicarboxylate. Resulting reaction mixture is stirred at room temperature for 6 hours and concentrated in vacuum followed by column chromatography purification to obtain mixture of 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide and triphenylphosphine oxide. The resulting compound is deprotected by using sodium hydroxide in presence of tetrahydrofuran and methanol to obtain residue. Resulting residue is purified by column chromatography to obtain racemic Tegoprazan having 65% yield.
US ‘321 also discloses process for preparation of ‘S’ isomer Tegoprazan comprising reacting 4-hydroxy-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide with (+)-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol in presence of tributylphosphine, toluene and 1,1'-(azodicarbonyl)dipiperidine to obtain a crude. Resulting crude is purified by column chromatography followed by recrystallization in 2-propanol to obtain (-)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide having 75% yield. The resulting compound further deprotected by using sodium hydroxide in presence of tetrahydrofuran and 2-propanol to obtain residue. The resulting residue is purified by column chromatography to obtain Tegoprazan having 87% yield.
US ‘321 Tegoprazan process requires column chromatography for purification of (-)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl) sulfonyl]-1H-benzimidazole-6-carboxamide and Tegoprazan, which is not suitable for the large industrial scale. Therefore, process as disclosed in US ‘321 is not an attractive option to use for large industrial scale as it requires column chromatography purification, tedious work-up process, and results into lower yield & purity.
The European patent number EP 3517528B1 (herein after EP ‘528) discloses process for preparation of amorphous form of Tegoprazan comprising dissolving Tegoprazan in methanol at 25°C, and then a resulting solution is heated at 50°C, stirred under decompression until a solid is precipitated followed by addition of co-solvent of acetone and ethyl acetate to a concentrate at 25°C at a ratio of acetone: ethyl acetate (1:4) to obtain solution. Resulting solution is stirred agitatedly for 30 minutes. The solid is filtered out under decompression, washed with ethyl acetate, and dried under vacuum at 40°C for 16 hours to obtain amorphous form of Tegoprazan.
The major drawbacks of EP ‘528 process is use of multiple solvents. Further, the process is silent about purity. Therefore, process as disclosed in EP ‘528 is not an attractive option to use for large industrial scale.
The Chinese patent number CN 111303131B (herein after CN ‘131) discloses process for preparation of Tegoprazan comprising reacting 4-bromo-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide with (S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol in presence of cuprous iodide, sodium tert-butoxide, N,N-dimethylformamide and N1,N2-bis(phenylethyl) oxalic diamide at 85? for 24 hours to obtain residue. The resulting residue is purified by column chromatography to obtain Tegoprazan having 85.7% yield.
CN ‘131 process require longer reaction time, higher reaction temperature, and require column chromatography for purification, which is not suitable for large industrial production. Therefore, process as disclosed in CN ‘131 is not an attractive option to use for large industrial scale as it requires column chromatography purification, tedious work-up process, and results into lower yield & purity.
Another Chinese patent application number CN 112851646A (herein after CN ‘646) discloses process for preparation of Tegoprazan comprising reacting 3-((S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yloxy)-4-acetamido-N,N-dimethylbenzamide with diacetyl iodobenzene in presence of 2,2,2-trifluoroethanol, cesium carbonate to obtain oil. The resulting oil is purified by using column chromatography to obtain Tegoprazan having 40.3% yield.
CN ‘646 process also requires column chromatography. Therefore, not an attractive option to use for industrial scale.
All the prior arts discussed above suffer from many disadvantages like tedious work up process, high temperature condition, require longer reaction temperature and time and require column chromatography for purification, which affect the overall yield as well as the purity of the final Tegoprazan product. Therefore, there is an urgent need for an improved process for the preparation of Tegoprazan having high purity and high yield which overcomes the drawbacks of the prior arts process.
The present inventors have developed an efficient process for the preparation of Tegoprazan and improved purification process of Tegoprazan intermediate namely (-)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide which offer advantage over the prior art processes in terms of high yield, high purity and less effluents and simple scalable procedure suitable for large scale industrial production of Tegoprazan.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an efficient and industrially advantageous process for the preparation of Tegoprazan of Formula-I having higher yield and purity.
An another object of the present invention is to provide an industrially advantageous process for purification of Tegoprazan intermediates namely (-)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide of Formula-II and its use for the preparation of Tegoprazan.
Yet another object of the present invention is to provide improved process for preparation of amorphous form of Tegoprazan of Formula-I.
SUMMARY OF INVENTION:
First aspect of the present invention is to provide a process for the preparation of Tegoprazan of Formula-I,

comprising reacting compound of Formula-II,

with base in presence of acetonitrile as solvent to obtain Tegoprazan of Formula-I.
Second aspect of the present invention is to provide a process for the purification of compound of Formula-II,

comprising the steps of:
a) heating compound Formula-II in a solvent to obtain a mixture,
b) cooling mixture of step a); and
c) isolating compound of Formula-II.
Third aspect of the present invention is to provide a process for the preparation of amorphous form of Tegoprazan of Formula-I,

comprising the steps of:
a) reacting compound of formula-II,

with base in presence of first solvent,
b) extracting reaction mixture of step a) in a second solvent; and
c) isolating amorphous form of Tegoprazan of Formula-I.
Fourth aspect of the aspect of the present invention is to provide a process for the preparation of amorphous form of Tegoprazan of Formula-I,

comprising the steps of:
a) dissolving Tegoprazan of Formula-I in an alcohol solvent; and
b) removing solvent from step a) to obtain amorphous form of Tegoprazan of Formula-I.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 01: Illustrates the x-ray powder diffractogram (XRPD) of amorphous form of Tegoprazan.
DEFINITION:
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25ºC and normal pressure unless otherwise designated.
All temperatures used herein are in degree Celsius unless specified otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
The term "about", as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.

DETAILED DESCRIPTION OF INVENTION:
While the following specification concludes with claims particularly pointing out and distinctly claiming the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description and by studying the included examples.
The best methods and materials of performing the present invention are described here.
The present invention provides a novel, efficient and industrially advantageous process for the preparation of Tegoprazan of Formula-I.
According to first embodiment, the present invention is to provides a process for the preparation of Tegoprazan of Formula-I,

comprising reacting compound of Formula-II,

with base in presence of acetonitrile as solvent to obtain Tegoprazan of Formula-I.
In the first embodiment, compound of Formula-II used as a starting material for the preparation of Tegoprazan of Formula-I can be prepared by process known in the prior art.
In the first embodiment, base can be selected from the group consisting of alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate or mixture(s) thereof, preferably base is sodium hydroxide.
In the first embodiment, molar equivalent of base with respect to compound of the Formula-II can be 3.0 to 7.0, preferably 4.5 to 5.5.
In the first embodiment, the reaction of compound of Formula-II with base can be carried in presence of acetonitrile as solvent.
The volume of acetonitrile used in the reaction can be, volume 4.0 to 7.0 with respect to compound of the Formula-II, preferably 4.5 to 5.5
In the first embodiment, the reaction of compound of Formula-II with base can be carried out at temperature of about 40°C to about 70°C, preferably at 45°C to 60°C.
In the first embodiment, the reaction of compound of Formula-II with base can be carried out for 1 hour to 5 hours, preferably for 1 hour to 2 hours.
After, completion of reaction, solvent can be added to the resulting mixture at 25°C to 35°C followed by separation of layers to obtain aqueous layer and organic layer. Resulting aqueous layer can be further extracted with solvent.
Solvent can be selected form the group consisting of dichloromethane, chloroform, methyl tert-butyl ether, toluene, or mixture thereof, preferably dichloromethane.
All the organic layers can be combined and washed with water to obtain final organic layer. Resulting organic layer can be filtered on hyflow bed followed by washing of bed by solvent used. Resulting filtrate can be distilled to obtain pure Tegoprazan of Formula-I.
Tegoprazan of Formula-I can be purified using alcohol solvent to obtain pure Tegoprazan of Formula-I.
Alcohol solvent can be selected from the group consisting of methanol, ethanol, propanol, 2-propanol, butanol, or mixture(s) thereof, preferably solvent is methanol.
In the first embodiment, the pure Tegoprazan of Formula-I may have purity greater than 99%, preferably greater than 99.8% by HPLC (High-performance liquid chromatography).
According to second embodiment, the present invention provides a process for the purification of compound of Formula-II,

comprising the steps of:
a) heating compound Formula-II in a solvent to obtain a mixture;
b) cooling mixture of step a); and
c) isolating compound of Formula-II.
In the second embodiment of step a), solvent can be selected from the group consisting of acetone, methanol, ethanol, propanol, 2-propanol, acetonitrile, or mixture(s) thereof, preferably solvent is acetonitrile.
In the second embodiment of step a), compound Formula-II in presence of solvent can be heated at temperature of 40°C to 70°C, preferably at 50°C to 60°C to obtain a mixture. Resulting mixture can be stirred for 30 minutes to 2 hours.
In the second embodiment of step b), mixture can be cooled at temperature of 0°C to 15°C, preferably at 0°C to 10°C.
In the second embodiment of step c), compound of Formula-II can be isolated from the reaction mixture by filtration and can be dried at 50°C to 60°C to obtain compound of Formula-II.
In the second embodiment of step c), resulting compound of Formula-II is substantially free from triphenylphosphine oxide impurity of compound of Formula-A,

and having less than 0.02% of impurity compound of Formula-B,

In the second embodiment of step c), resulting compound of Formula-II may have purity greater than 99%, preferably greater than 99.5%, more preferably greater than 99.8% by HPLC (High-performance liquid chromatography).
According to third embodiment, the present invention provides a process for the preparation of amorphous form of Tegoprazan of Formula-I,

comprising the steps of:
a) reacting compound of formula-II,

with base in presence of first solvent,
b) extracting reaction mixture of step a) in second solvent; and
c) isolating amorphous form of Tegoprazan of Formula-I.
In the third embodiment, base can be selected from the group consisting of alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate or mixture(s) thereof, preferably base is sodium hydroxide.
In the third embodiment, molar equivalent of base with respect to compound of the Formula-II can be 3.0 to 7.0, preferably 4.5 to 5.5.
In the third embodiment, the reaction of compound of Formula-II with base can be carried in presence of first solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, acetonitrile, tetrahydrofuran, acetone, toluene, or mixtures thereof, preferably acetonitrile.
The volume of solvent used in the reaction can be 4.0 to 7.0 with respect to compound of the Formula-II, preferably 4.5 to 5.5 volume.
In the third embodiment, the reaction of compound of Formula-II with base can be carried out at temperature of about 40°C to about 70°C, preferably at 45°C to 60°C.
In the third embodiment, the reaction of compound of Formula-II with base can be carried out for 1 hour to 5 hours, preferably for 1 hour to 2 hours.
After, completion of reaction, second solvent can be added to the resulting mixture at 25°C to 35°C followed by separation of layers to obtain aqueous layer and organic layer. Resulting aqueous layer can be further extracted with solvent.
Second solvent can be selected form the group consisting of dichloromethane, chloroform, methyl tert-butyl ether, toluene, or mixture thereof, preferably dichloromethane.
All the organic layers can be combined and washed with water to obtain final organic layer. Resulting organic layer can be filtered on hyflow bed followed by washing of bed by solvent used. Resulting filtrate can be distilled to obtain pure Tegoprazan of Formula-I.
Tegoprazan of Formula-I can be purified using alcohol solvent to obtain pure Tegoprazan of Formula-I.
Alcohol solvent can be selected from the group consisting of methanol, ethanol, propanol, 2-propanol, butanol, or mixture(s) thereof, preferably solvent is methanol.
In the third embodiment, the pure Tegoprazan of Formula-I may have purity greater than 99%, preferably greater than 99.8% by HPLC (High-performance liquid chromatography).

According to fourth embodiment, the present invention provides a process for the preparation of amorphous form of Tegoprazan of Formula-I,

comprising the steps of:
a) dissolving Tegoprazan of Formula-I in an alcohol solvent; and
b) removing solvent from step a) to obtain amorphous form of Tegoprazan of Formula-I.
In the fourth embodiment of step a) alcohol solvent can be selected from the group consisting of methanol, ethanol, propanol, 2-propanol, and n-butanol or mixture(s) thereof, preferably alcohol solvent is methanol.
In the fourth embodiment of step a), Tegoprazan of Formula-I can be dissolved in alcohol solvent at 25°C to 40°C, preferably 25°C to 35°C.
In the fourth embodiment of step b) solvent can be removed from the reaction mixture by distillation method and can be carried out at temperature 40°C to 70°C, preferably at 50° to 60°C, followed by resulting solid can be cooled and dried under vacuum to obtain amorphous form of Tegoprazan of Formula-I.
In the fourth embodiment, the resulting amorphous form of Tegoprazan compound of Formula-I may have purity greater than 99%, preferably greater than 99.8% by HPLC (High-performance liquid chromatography).

EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example 01: Preparation of compound of Formula-II

To a stirred solution of toluene (600 mL), compound of Formula-III (100 gm), compound of Formula-IV (65 gm), and triphenyl phosphine (106 gm) was added at 25°C to 35°C. Resulting reaction mixture was cooled at 15°C to 25°C and solution of diisopropyl azodicarboxylate [diisopropyl azodicarboxylate (82 g) + toluene (200 mL)] was added at same temperature for 2 hours. After completion of reaction, reaction mixture was cooled at 0°C to 10°C and water (500 mL) was added for 1 hour at same temperature. Resulting mixture was filtered and washed with toluene (50 mL). Resulting filtrate was allowed to separate the layers and to obtain aqueous and organic layer. The aqueous layer was extracted with toluene (50 mL). both the organic layers were combined, filtered on hyflow bed to obtain filtrate. Resulting filtrate was distilled below 55°C to obtain residue. Methanol (300 mL) was added to resulting residue and stirred at 50°C to 55°C for 1 hour. The resulting mixture was cooled at 0°C to 10°C, filtered and washed with methanol (25 mL) to obtain title compound.
HPLC Purity: 82.27 %
Example 02: Purification of compound of Formula-II
To a stirred solution of compound of Formula-II obtained in Example 01, acetonitrile (2 X 100 mL) was added at 25°C to 35°C followed by distillation at 50°C to 55°C. Acetonitrile (500 mL) was added to distilled mass and heated at 50°C to 55°C for 1 hour. Resulting mixture was cooled at 0°C to 10°C for 1 hour. Resulting mixture was filtered, washed with acetonitrile (25 mL) to obtain a solid. Resulting solid was dried at 60°C to 65°C to obtain pure compound of Formula-II (110 gm)
Yield: 75.86%
HPLC Purity: 99.80%
Example 03: Preparation of amorphous Tegoprazan of Formula-I

To a stirred solution of acetonitrile (500 mL), compound of Formula-II (100 gm) and purified water (1000 mL) was added at 25°C to 35°C. The resulting mixture was stirred and heated at 50°C to 60°C. 48% aqueous sodium hydroxide (77 gm) was slowly added to the resulting mixture at same temperature. After completion of reaction, resulting mixture was cooled at 25°C to 35°C. Dichloromethane (300 mL) was slowly added to resulting mixture at 25° to 35°C and stirred for 30 minutes. Resulting mixture was allowed to settle and layers were separated to obtain aqueous and organic layer. Resulting aqueous layer was extracted with dichloromethane (300 mL). Both the organic layers were combined and washed with water (100 mL). The resulting organic layer was filtered on hyflow bed to obtain filtrate. Resulting filtrate was distilled below 50°C to obtain a title compound (65 gm)
Yield: 91.54%
HPLC Purity: 99.85%
Example 04: Preparation of amorphous form of Tegoprazan of Formula-I
Methanol (400 mL) was added to Tegoprazan of Formula-I (100.0 g) at 25°C to 35°C. The resulting mixture was filtered on hyflow bed and washed with methanol (100 mL). Resulting filtrate was heated at 55°C to 60°C. Resulting mixture was then distilled at same temperature to remove methanol followed by cooling at 25°C to 35°C to obtain a solid. Resulting solid was dried at 50° to 60°C to obtain title compound.
HPLC Purity: 99.85%
, Claims:I / We Claim:
1. A process for the preparation of Tegoprazan of Formula-I,

comprising reacting compound of Formula-II,

with base in presence of acetonitrile as solvent to obtain Tegoprazan of Formula-I.
2. The process as claimed in claim 01; wherein base is selected from the group consisting of alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate or mixture(s) thereof.
3. The process as claimed in claim 01; wherein reaction of compound of Formula-II with base is carried out at temperature of about 40°C to about 70°C.
4. A process for the purification of compound of Formula-II,

comprising the steps of:
a) heating compound Formula-II in a solvent to obtain a mixture;
b) cooling mixture of step a); and
c) isolating compound of Formula-II.
5. The process as claimed in claim 04; wherein solvent in step a) is selected from the group consisting of acetone, methanol, ethanol, propanol, 2-propanol, acetonitrile, or mixture(s) thereof.
6. The process as claimed in claim 04; wherein in step a), compound of the Formula-II is heated at temperature of 40°C to 70°C.
7. The process as claimed in claim 04; wherein mixture of step b) is cooled at temperature of about 0°C to 15°C.
8. A process for the preparation of amorphous form of Tegoprazan of Formula-I,

comprising the steps of:
a) reacting compound of Formula-II,

with base in presence of first solvent,
b) extracting reaction mixture of step a) in second solvent; and
c) isolating amorphous form of Tegoprazan of Formula-I.
9. The process as claimed in claim 08; wherein base in step a) is selected from the group consisting of alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate or mixture(s) thereof.
10. The process as claimed in claim 08; wherein first solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, acetonitrile, tetrahydrofuran, acetone, toluene, or mixture(s) thereof.
11. The process as claimed in claim 08; wherein reaction of compound of Formula-II with base is carried out at temperature of about 40°C to about 70°C.
12. The process as claimed in claim 08; wherein second solvent in step c) is selected from the group consisting of dichloromethane, chloroform, methyl tert-butyl ether, toluene, or mixture(s) thereof.
13. A process for the preparation of amorphous form of Tegoprazan of Formula-I,

comprising the steps of:
a) dissolving Tegoprazan of Formula-I in an alcohol solvent; and
b) removing solvent from step a) to obtain amorphous form of Tegoprazan of Formula-I.
14. The process as claimed in claim 13; wherein alcohol solvent is selected from selected from the group consisting of methanol, ethanol, propanol, 2-propanol, and n-butanol or mixture(s) thereof.

Dated this 22nd October 2022

Dr. Virendra Thakrar,
Sr. Vice- President R&D,
Ami Lifesciences Pvt. Ltd.