DESC:“AN IMPROVED PROCESS FOR THE PREPARATION OF TEGOPRAZAN”

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Tegoprazan, which provides high yield and high purity. Furthermore, the present invention provides an economical and technically simple process for the preparation of Tegoprazan.

BACKGROUND OF THE INVENTION

Tegoprazan (also known as CJ-12420) is a novel therapeutic agent developed by CJ Healthcare Corp. for the treatment of acid-related gastrointestinal disorders. It functions as a potent and highly selective potassium-competitive acid blocker (P-CAB). Tegoprazan is characterized by a rapid onset of action and the ability to maintain sustained control of gastric pH over an extended period.

Tegoprazan is marketed under the brand name K-CAB®. It was developed and commercialized by HK inno.N (a licensee of RaQualia) and its sublicensees globally. The drug was first launched in South Korea in 2019 as K-CAB® and represents the first human pharmaceutical product introduced by RaQualia to the global market.
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Tegoprazan is chemically known as 7-[[(4S)-5,7-Difluoro-3,4-dihydro-2H-1-benzopyran-4-yl] oxy]-N, N,2-trimethyl-1H-benzimidazole-5-carboxamide, which is represented by the structural formula (I) as follows:

US Patent No. 7,723,321 describes a process for the preparation of Tegoprazan, by reacting a compound of formula (II) with a compound of formula (III) in the presence of triphenylphosphine and diisopropyl azodicarboxylate (DIAD), leading to the formation of a compound of formula (IV). This intermediate (IV) is subsequently deprotected using sodium hydroxide (NaOH) in a mixture of tetrahydrofuran (THF) and 2-propanol, yielding the final compound, Tegoprazan of Formula (I). The reaction sequence is illustrated in the scheme below

However, the prior art process suffers from several significant drawbacks. Notably, it involves prolonged reaction times, generates undesirable impurities, and poses challenges in terms of scalability and commercial feasibility. These limitations affect the overall yield, purity, and cost-effectiveness of the synthesis, making the known process less suitable for large-scale pharmaceutical production.

Hence, the inventors of the present invention have developed an improved process but yet simple, efficient and industrially advantageous for the preparation of Tegoprazan of formula (I), with high yield and high purity. The present invention provides higher reaction conversion, easier removal of by-products formed during the reaction and significantly avoiding the formation of unknown impurities compared to the prior arts.

OBJECTIVE OF THE PRESENT INVENTION
The objective of the present invention is to provide an improved process for the preparation of Tegoprazan of Formula (I), offering high yield and high purity.

Another objective of the present invention is to develop a process that confers multiple advantages, including shorter reaction times, reduced formation of undesirable impurities, ease of scale-up, commercial viability, higher yields, and improved product purity.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Tegoprazan of Formula (I) with high yield and purity.

One aspect of the present invention provides a process for the preparation of Tegoprazan of Formula (I), comprising the steps of:
a) coupling a compound of formula (II) with a compound of formula (III) in the presence of tri-n-octylphosphine, diisopropyl azodicarboxylate (DIAD), and a suitable solvent to obtain a compound of Formula (IV); and

b) deprotecting the compound of formula (IV) with an organic base in a suitable solvent to obtain Tegoprazan of Formula (I).

Another aspect of the present invention provides a process for the preparation of Tegoprazan of Formula (I) comprising:
deprotecting a compound of formula (IV) using an organic base in a suitable solvent to obtain Tegoprazan of Formula (I).

In yet another aspect of the present invention, the organic base is selected from pyridine, trimethylamine, monomethyl amine, methylamine, ethylamine, diethyl amine, diisopropylethylamine, triethylenediamine (DABCO), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo [4.3.0]-5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine, pyridine, or N-methylmorpholine.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Tegoprazan of Formula (I) with high yield and purity.

One embodiment of the present invention provides an improved process for the preparation of Tegoprazan of Formula (I) comprising the steps of:
a) coupling a compound of formula (II) with a compound of formula (III) in the presence of tri-n-octylphosphine, diisopropyl azodicarboxylate (DIAD), and a suitable solvent to obtain a compound of formula (IV); and
b) deprotecting the compound of formula (IV) using an organic base in a suitable solvent to obtain Tegoprazan of formula (I).

According to an embodiment of the present invention, the coupling reaction is typically carried out at a temperature ranging from 0°C to 40°C, more preferably from 10°C to 30°C, and most preferably at room temperature 20°C to 25°C.

Another embodiment of the present invention provides an improved process for the preparation of Tegoprazan of Formula (I), comprising:
deprotecting the compound of Formula (IV) using an organic base in a suitable solvent to obtain Tegoprazan of Formula I.

According to an embodiment of the present invention, wherein the organic base is selected from pyridine, trimethylamine, monomethyl amine, methylamine, ethylamine, diethyl amine, diisopropylethylamine, triethylenediamine (DABCO), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo [4.3.0]-5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine, pyridine, or N-methylmorpholine.

According to an embodiment of the present invention, wherein the suitable solvent is selected from sulfoxides selected from a group of dimethyl sulfoxide and diethyl sulfoxide; alcohols selected from a group of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, and tert-butanol; nitriles selected from a group of acetonitrile and propionitrile; ether selected from a group of tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, and dioxane; amides selected from a group of N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons selected from a group of toluene, anisole, heptane and xylene; esters selected from a group of ethylacetate, methyl acetate, butyl acetate, isopropyl acetate, and methoxy ethyl acetate; ketones selected from a group of acetone, methyl isobutyl ketone, 2-pentanone, ethyl methyl ketone, and diethyl ketone; halogenated hydrocarbons selected from a group of chloroform and dichloromethane; water; cyclohexane, N-methyl-2-pyrrolidone or mixtures thereof.

Advantages of using Tri-n-octylphosphine and Organic Base:
1. Tri-n-octylphosphine offers several advantages over triphenylphosphine. Firstly, it results in higher reaction conversion. Secondly, the by-product formed during the reaction, tri-n-octylphosphine oxide, is easier to remove during the isolation process.
2. The use of an organic base for the deprotection of the tosyl group significantly reduces the formation of unknown impurities. Furthermore, the product can be conveniently isolated without requiring additional reaction workup.
3. The process of the present invention provides several advantages, including shorter reaction times, reduced formation of unwanted impurities, ease of scale-up, commercial viability, higher yields, and improved product purity.

The following examples illustrate the present invention but should not be construed as limiting the scope of the invention.

EXAMPLES:

Examples 1: Preparation of crude (S)-4-((5,7-difluorochroman-4-yl) oxy)-N, N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide
Dichloromethane (40 mL), 4-hydroxy-N,N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide (10.0 g), and (R)-5,7-difluorochroman-4-ol (6.0 g) were added to a round-bottom flask at room temperature and cooled to 10-15°C. Tri-n-octyl phosphine solution (tri-n-octyl phosphine (14.5 g) dissolved in dichloromethane (30.0 mL)) and diisopropyl azodicarboxylate solution (diisopropyl azodicarboxylate (7.0 g) dissolved in dichloromethane (30.0 mL)) were then simultaneously added to the reaction mixture at 10-15°C. The obtained reaction mixture was heated to 25-35°C and stirred for 2-3 hours.

After completion of the reaction, purified water (50.0 mL) was added to the mixture, stirred for 10-15 minutes, and the two layers were separated. The dichloromethane layer was collected, and the solvent was removed under reduced pressure at below 50°C. A mixture of methanol (24.0 mL) and purified water (6.0 mL) was added to the residue at below 50°C. The mixture was stirred for 10-15 minutes at 45-50°C, then cooled to 25-30°C and stirred for 2-3 hours. It was again cooled to 5-10°C. The solid material was filtered and washed with methanol (10.0 mL) to obtain the crude compound of (S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide.
Yield: wet ~13.0 gm; Purity: ~95.0%

Example 2: Purification of (S)-4-((5,7-difluorochroman-4-yl) oxy)-N, N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide
Methanol (30.0 mL), toluene (10.0 mL), and 13.0 g of crude wet material were charged into a reaction flask. The mixture was then heated to 60-65°C and stirred for 10-15 minutes to obtain a clear solution. The reaction mixture was subsequently cooled to 25-30°C and stirred for 1-2 hours. Further, the mixture was cooled to 0-5°C and stirred for 15-30 minutes. The resulting solid was filtered, washed with methanol (5.0 mL), and dried at 60-65°C to yield 10.5 g of the pure product (S)-4-((5,7-difluorochroman-4-yl) oxy)-N, N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide.
Yield: 72.4%; Purity: 99.7%

Example 3: Preparation of Crude Tegoprazan
Methanol (50.0 mL), (S)-4-((5,7-difluorochroman-4-yl) oxy)-N, N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide (10.0 g), and 40% aqueous monomethylamine solution (20.0 mL) were added to a reaction flask. After stirring for 3-4 hours at 65-75°C, the reaction mixture was concentrated by removing the solvent under vacuum. The residue was then treated with 40% aqueous monomethylamine solution (20.0 mL) and cooled to 25-30°C. The mixture was stirred for an additional 1-2 hours. Following this, the obtained solid was filtered, washed with purified water (50.0 mL), and dried at 60-65°C to yield 7.0 g of the crude wet compound of Tegoprazan.
Yield: 97.9%; Purity: ~99.0%

Example 4: Preparation of Pure Tegoprazan
Methanol (20.0 ml) and 10.0 gm of crude wet material were added into a reaction flask. The reaction mixture was stirred and concentrated under reduced pressure at below 60°C. Ethyl acetate (50.0 ml) was added to the reaction mixture and stirred for 15 min at 55-60°C to obtain a clear solution. The reaction mixture was cooled to room temperature and stirred for 24 hours. The resulting solid was filtered, washed with ethyl acetate (10.0 mL), and dried at 60-65°C to yield 6.7 g of pure Tegoprazan

Yield: 93.7%; Purity: 99.8%
,CLAIMS:WE CLAIM:

1) A process for the preparation of Tegoprazan of Formula (I) comprising:

a) coupling a compound of formula (II)

with a compound of formula (III)

in the presence of tri-n-octylphosphine, diisopropyl azodicarboxylate (DIAD), and a suitable solvent to obtain a compound of Formula (IV); and

b) deprotecting the compound of formula (IV) with an organic base in a suitable solvent to obtain the Tegoprazan of Formula (I).

2) A process for the preparation of Tegoprazan of Formula (I) comprising:
deprotecting a compound of formula (IV) using an organic base in a suitable solvent to obtain the Tegoprazan of Formula (I).

3) The process according to any one of the preceding claims, wherein the organic base is selected from pyridine, trimethylamine, monomethyl amine, methylamine, ethylamine, diethyl amine, diisopropylethylamine, triethylenediamine (DABCO), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo [4.3.0]-5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine, pyridine, or N-methylmorpholine.

4) The process according to any one of the preceding claims, wherein the suitable solvent is selected from sulfoxides selected from a group of dimethyl sulfoxide and diethyl sulfoxide; alcohols selected from a group of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, and tert-butanol; nitriles selected from a group of acetonitrile and propionitrile; ether selected from a group of tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, and dioxane; amides selected from a group of N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons selected from a group of toluene, anisole, heptane and xylene; esters selected from a group of ethylacetate, methyl acetate, butyl acetate, isopropyl acetate, and methoxy ethyl acetate; ketones selected from a group of acetone, methyl isobutyl ketone, 2-pentanone, ethyl methyl ketone, and diethyl ketone; halogenated hydrocarbons selected from a group of chloroform and dichloromethane; water; cyclohexane, N-methyl-2-pyrrolidone or mixtures thereof.