DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:

“TEGOPRAZAN BENZOATE AND PROCESS FOR THE PREPARATION THEREOF”

2. APPLICANT(S):

a) NAME: Ami Lifesciences Private Limited

b) NATIONALITY: An Indian Company registered under The Companies Act, 1956

c) ADDRESS: 7th Floor, Lilleria 1038, Gotri Sevasi Road, New Alkapuri, Vadodara – 390 021, Gujarat, India.

3. PREAMBLE TO THE INVENTION:

COMPLETE:

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to Tegoprazan benzoate and process for the preparation thereof.

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.

[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.
U.S. patent number US7723321 first discloses Tegoprazan. However, this patent does not disclose specific salt of Tegoprazan.

U.S. patent number US9908870 discloses crystalline Tegoprazan, which is advantageous for preparing a formulation because of being stable under a long-term and stress storage condition, having no crystal transition observed due to a change with the passage of time, having an excellent photostability, and having a low hygroscopicity and a low induction of static electricity.
The above-mentioned compound has a limitation to selection of salts because the compound has a very low water solubility (0.02 mg/ml, pH 6.8), has a solubility increased (0.7 mg/ml, pH 3.0) under an acidic condition, but without a great effect, and has a degradation product increased under an acidic condition, such that the compound does not have a good stability. Also, in case of using a solubilizing agent, such as a surfactant, to improve solubility, excessive amounts of excipients are needed, thus causing a difficulty.

U.S. patent publication number US20210292307 specifically discloses several acid addition salts of Tegoprazan, wherein acid is selected from succinic acid, fumaric acid, oxalic acid, citric acid, L-pyroglutamic acid, 1,5-naphinalene disulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, L-malic acid, nicotinic acid, 2,5-dihydroxybenzoic acid and L-tartaric acid.
The above-mentioned salts are unstable except pidolate and malate salt of Tegoprazan. However, pidolate and malate salt are costly. Further, these salts are prepared using multiple solvents namely methanol, acetone and ethyl acetate. Therefore, not an attractive option for commercial scale production.
Most of the prior art salts have their own disadvantages like higher cost, use of multiple solvents and stability. Thus, there is an urgent need to develop novel salt which solves problems of higher cost, multiple solvents and stability, which is suitable for large scale industrial production.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide Tegoprazan benzoate of Formula-II.
Another object of the present invention is to provide an industrially advantageous process for the preparation of Tegoprazan benzoate of Formula-II.
SUMMARY OF INVENTION:
First aspect of the present invention is to provide a Tegoprazan benzoate of Formula-II,

[Formula-II].
Second aspect of the present invention is to provide a process for the preparation of Tegoprazan benzoate of Formula-II,

[Formula-II]
comprising reacting Tegoprazan of Formula-I,

[Formula-I]
with benzoic acid to obtain a Tegoprazan benzoate of Formula-II.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 01: Illustrates the x-ray powder diffractogram (XRPD) of Tegoprazan benzoate of Formula-II obtained according to example 01.

DETAILED DESCRIPTION OF INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
According to first embodiment, the present invention is to provide a Tegoprazan benzoate of Formula-II,

[Formula-II]
According to second embodiment, the present invention provides a process for the preparation of Tegoprazan benzoate of Formula-II,

[Formula-II]
comprising reacting Tegoprazan of Formula-I,

[Formula-I]
with benzoic acid to obtain a Tegoprazan benzoate of Formula-II.
Tegoprazan of Formula-I used as a starting material can be prepared by processes known in the prior-art.
In the second embodiment, Tegoprazan of Formula-I can be reacted with benzoic acid to obtain Tegoprazan benzoate of Formula-II.
In the second embodiment, Tegoprazan of Formula-I can be reacted with benzoic acid in presence of solvent.
The solvent can be selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the second embodiment, benzoic acid can be used in 1.0 to 1.5 molar equivalent with respect to Tegoprazan of Formula-I.
In the second embodiment, solvent can be used in 5.0 volume to 15. 0 volume with respect to Tegoprazan of Formula-I.
In the second embodiment, Tegoprazan of Formula-I can be reacted with benzoic acid at temperature of 40°C to 70°C for 30 minutes to 2 hours.
Tegoprazan benzoate of Formula-II can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing.
Resulting Tegoprazan benzoate of Formula-II may have purity of greater than 98%, preferably greater than 99.0% by HPLC (High-performance liquid chromatography).
Tegoprazan benzoate of Formula-II can also be isolated by known methods such as crystallization, recrystallization, or solvent-anti solvent methods.
Tegoprazan benzoate of Formula-II can be purified by crystallizing Tegoprazan benzoate using solvent.
Alternatively, Tegoprazan benzoate of Formula-II can be purified using solvent-anti solvent method.
The solvent can be selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
Anti-solvent can be selected from the group consisting of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
Generally, Tegoprazan benzoate of Formula-II can be stirred in presence of solvent at 25°C to 60°C. Resulting mixture can be stirred for 30 minutes to 2 hours. Anti-solvent can be added to resulting mixture at 10°C to 30°C to precipitate the solid.
Resulting solid can be isolated by decantation or filtration followed by drying to obtain a Tegoprazan benzoate of Formula-II.
Resulting Tegoprazan benzoate of Formula-II may have purity of greater than 98%, preferably greater than 99.0% by HPLC (High-performance liquid chromatography).
Resulting Tegoprazan benzoate of Formula-II according to present invention is stable amorphous or crystalline in nature.
Amorphous Tegoprazan benzoate of Formula-II according to present invention is stable at 25°C to 30°C under inert atmosphere.
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 Tegoprazan benzoate of Formula-II
To a stirred solution of methanol (100 mL) and Tegoprazan (10 g), benzoic acid (3.31 g) was added at 25°C to 35°C and stirred for 30 minutes at same temperature. Resulting solution was heated at 50°C to 55°C and stirred for 1 hour. Methanol was distilled completely under vacuum at 40°C to 45°C and resulting solid was dried at same temperature for 16 hours to obtain a title compound (12.8 g) having purity of 99.89% by HPLC.

Example 02: Preparation of Tegoprazan benzoate of Formula-II
To a stirred solution of isopropanol (100 mL) and Tegoprazan (10 g), benzoic acid (3.31 g) was added at 25°C to 35°C and stirred for 30 minutes at same temperature. Resulting solution was heated at 50°C to 55°C and stirred for 1 hour. Isopropanol was distilled completely under vacuum at 40°C to 45°C and resulting solid was dried to obtain a title compound.
Example 03: Preparation of Tegoprazan of Formula-I
To a stirred solution of acetonitrile (750 mL), compound of Formula-III (150 gm) and purified water (1350 mL) was added at 25°C to 35°C. The resulting mixture was stirred and heated at 50°C to 60°C. Aqueous sodium hydroxide [caustic lye (115.41 gm) solution in water (150 mL)] (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 (450 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 and Methanol (600 mL) was added to the distilled mass below 50°C. Resulting mixture was cooled to 25°C to 35°C and benzoic acid (33.82 g) was added at same temperature. Resulting mixture was filtered through hyflow bed and washed with Methanol (150 mL). Resulting filtrate was distilled completely under vacuum at below 60 °C followed by n-heptane stripping (150 mL). n-heptane (600 mL) was added to resulting residue and mixture was stirred for 1 hour at 20°C to 30°C. Resulting solid was filtered and washed with n-heptane (75 mL). Resulting solid was dried under vacuum at 50°C to 60°C for 12 hours to obtain a title compound (129.0 g) having HPLC purity of 99.81%.

Dated this 24th November 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd
I / We Claim:
1. Tegoprazan benzoate of Formula-II,

[Formula-II].
2. Amorphous Tegoprazan benzoate of Formula-II,

[Formula-II].
3. Amorphous Tegoprazan benzoate of Formula-II according claim-2 is stable at 25°C to 30°C under inert atmosphere.
4. A process for the preparation the preparation of Tegoprazan benzoate of Formula-II,

[Formula-II]
comprising reacting Tegoprazan of Formula-I,

[Formula-I]
with benzoic acid to obtain a Tegoprazan benzoate of Formula-II.
5. The process as claimed in claim 04, wherein reaction of Tegoprazan of Formula-I with benzoic acid is carried out in presence of solvent selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol, tert-butyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, water or mixture(s) thereof.
6. The process as claimed in claim 04, wherein molar equivalent of benzoic acid with respect to Tegoprazan of Formula-I is 1.0 to 1.5.
7. A process for the purification of Tegoprazan benzoate of Formula-II by crystallizing Tegoprazan benzoate using solvent or by using solvent-anti solvent method.
8. The process as claimed in claim 07, wherein solvent is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
9. The process as claimed in claim 07, wherein anti solvent is selected from the group consisting of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.

Dated this 24th November 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd

ABSTRACT
“TEGOPRAZAN BENZOATE AND PROCESS FOR THE PREPARATION THEREOF”
The present invention relates to Tegoprazan benzoate of Formula-II.
The present invention also relates to an efficient and industrially advantageous process for the preparation of Tegoprazan benzoate of Formula-II,

[Formula-II].

Dated this 24th November 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd.

Name of the Applicant: Ami Lifesciences Pvt. Ltd. Total No. of Sheets: 1
Sheet No. 1

Figure 01

Dated this 24th November 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd.
,CLAIMS:I / We Claim:
1. Tegoprazan benzoate of Formula-II,

[Formula-II].
2. Amorphous Tegoprazan benzoate of Formula-II,

[Formula-II].
3. Amorphous Tegoprazan benzoate of Formula-II according claim-2 is stable at 25°C to 30°C under inert atmosphere.
4. A process for the preparation the preparation of Tegoprazan benzoate of Formula-II,

[Formula-II]
comprising reacting Tegoprazan of Formula-I,

[Formula-I]
with benzoic acid to obtain a Tegoprazan benzoate of Formula-II.
5. The process as claimed in claim 04, wherein reaction of Tegoprazan of Formula-I with benzoic acid is carried out in presence of solvent selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol, tert-butyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, water or mixture(s) thereof.
6. The process as claimed in claim 04, wherein molar equivalent of benzoic acid with respect to Tegoprazan of Formula-I is 1.0 to 1.5.
7. A process for the purification of Tegoprazan benzoate of Formula-II by crystallizing Tegoprazan benzoate using solvent or by using solvent-anti solvent method.
8. The process as claimed in claim 07, wherein solvent is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
9. The process as claimed in claim 07, wherein anti solvent is selected from the group consisting of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.

Dated this 24th November 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd