DESC:“AN IMPROVED PROCESS FOR THE PREPARATION OF 5-(2-FLUOROPHENYL)-1H-PYRROLE-3-CARBALDEHYDE”

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde by using novel compound of formula (XIIA), an intermediate in the synthesis of Vonoprazan Fumarate.

BACKGROUND OF THE INVENTION
5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde as a key intermediate for the preparation of potassium ion-competitive acid blocker (P-CAB), this intermediate is also used in the preparation of Vonoprazan Fumarate, which is treated of gastroduodenal ulcer (including some drug-induced peptic ulcers) and reflux esophagitis.

5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde, is represented by structural Formula (I).

5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde of formula (I), which is a key intermediate for the preparation of Vonoprazan Fumarate.

US 5122615, US 8048909 and US 7977488 discloses a process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde of formula (I), which comprises compound of formula (VI) is reacted with diisobutylaluminum hydride (DIBAL-H)/ tetrahydrofuran (THF) in presence of toluene to obtain the compound of formula (VII). The compound of formula (VII) is reacted with tetrapropylammonium perruthenate (TPAP)/ N-methylmorpholine N-oxide (NMMO) in presence of acetonitrile (ACN) and molecular sieves 4A powder to obtain the compound of formula (I). The process is schematically shown as below:

The above processes disclose the preparation of the 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde is difficult for bulk manufacturing process commercially. Impurities are generated in the preparation process of the 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde, and the impurities affect the purity of the Vonoprazan Fumarate.

Hence, there is consequently a need development for new methods to sort out prior art existing methods. So, our inventors have developed a method for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde by using novel compound of formula (XIIA). The present invention advantageous process for preparing 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde, an intermediate in the synthesis of Vonoprazan Fumarate, which is relatively simple and less costly than the prior art processes and which provides 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde in an excellent yield in a high purity with low costs and industrial applicable process.

OBJECT OF THE INVENTION
The present invention relates to an improved process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde by using novel compound of formula (XIIA), an intermediate in the synthesis of Vonoprazan Fumarate

SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde by using novel compound of formula (XIIA), an intermediate in the synthesis of Vonoprazan Fumarate.

In one embodiment of the present invention provides, an improved process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (I), comprising the steps of;
a) compound of formula (VI) is hydrolysing with base to obtain compound of formula (XII),

b) compound of formula (XII) is treating with chlorinating agent to obtain in-situ compound of formula (XIIA), followed by treating with weinreb amine (N,O-dimethylhydroxylamine) to obtain compound of formula (XIII),

c) compound of formula (XIII) is protecting with di-tert-butyl dicarbonate (Boc anhydride) in presence of base to obtain compound of formula (XIV), and

d) compound of formula (XIV) is reducing with reducing agent to obtain compound of formula (I).

In yet another embodiment of the present invention, a compound of formula (XIIA).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde by using novel compound of formula (XIIA), an intermediate in the synthesis of Vonoprazan Fumarate.

In one embodiment of the present invention provides, an improved process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (I), comprising the steps of;
a) compound of formula (VI) is hydrolysing with base to obtain compound of formula (XII),

b) compound of formula (XII) is treating with chlorinating agent to obtain in-situ compound of formula (XIIA), followed by treating with weinreb amine (N,O-dimethylhydroxylamine) to obtain compound of formula (XIII),

c) compound of formula (XIII) is protecting with di-tert-butyl dicarbonate (Boc anhydride) in presence of base to obtain compound of formula (XIV), and

d) compound of formula (XIV) is reducing with reducing agent to obtain compound of formula (I).

According to embodiment of the present invention, compound of formula (VI) is hydrolysing with base and the reaction is carried out at 75 to 90°C for 6-10 hours, followed by acidified pH 1-4 with conc. HCl to obtain the compound of formula (XII).

According to embodiment of the present invention, compound of formula (XII) is treating with chlorinating agent to obtain in-situ compound of formula (XIIA) and the reaction is carried out at -5 to 10°C for 20-30 minutes, followed by treating with weinreb amine (N,O-dimethylhydroxylamine) and the reaction is carried out at room temperature for 10-13 hours to obtain the compound of formula (XIII).

According to embodiment of the present invention, compound of formula (XIII) is protecting with di-tert-butyl dicarbonate (Boc anhydride) in presence of base and the reaction is carried out at room temperature for 10-14 hours to obtain the compound of formula (XIV), and compound of formula (XIV) reducing with reducing agent and the reaction is carried out at -5 to 10°C for 2-6 hours to obtain the compound of formula (I).

According to an embodiment of the present invention provides 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (I) having HPLC purity = 99.5%.

According to an embodiment of the present invention, wherein the base is selected from inorganic base or organic base; inorganic base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; ammonia; sodium sulphite; organic base is selected from triethylamine, triethanolamine, diisopropylethylamine, di-n-propylamine and 4-dimethylaminopyridine (DMAP).

According to an embodiment of the present invention, wherein the chlorinating agent is selected from oxalyl chloride, sodium hypochlorite (NaOCl), thionyl chloride (SOCl2), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorus oxychloride (POCl3), CCl4, N-chlorosuccinimide (NCS), sulfuryl chloride, malonyl chloride, succinyl chloride, glutaryl chloride, adipoyl chloride, pimeloyl chloride, suberoyl chloride, azelaoyl chloride, sebacoyl chloride and/or mixture thereof.

According to an embodiment of the present invention, wherein the reducing agent is selected from Red-Al (Vitride), diisobutylaluminum hydride (DIBAL-H), lithium aluminium hydride (LiAlH4), sodium borohydride (NaBH4), lithium borohydride (LiBH4), potassium borohydride (KBH4), calcium borohydride (Ca(BH4)2), sodium cyanoborohydride (NaBH3CN), tetramethylammonium borohydride, tetraethylammonium borohydride, benzyltriethylammonium borohydride, tetrabutylammonium borohydride, tetramethylammonium triacetoxyborohydride, dithionates and thiosulfates.

According to an embodiment of the present invention, the reaction carried out suitable solvent is selected from tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, n-hexane, diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, carbon tetrachloride and chloroform, methyl tert-butyl ether (MTBE) and/or mixtures thereof.

In yet another embodiment of the present invention, a compound of formula (XIIA).

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

EXAMPLES
Example 1:
Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylic acid (XII)
1N NaOH (200 mL) was added to ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (40 g, 0.171 mol) at 0oC and heated to 80-85oC. The reaction mixture was stirred for 8h at 80-85oC. The reaction mixture was washed with ethyl acetate (50 mL). The aqueous layer was cooled to 0oC and acidified pH: 2-3 with conc. HCl. The obtained precipitated solid was filtered, washed with water and dried to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylic acid as an off white solid.
Yield: 82.5% (29g)

Example 2:
Synthesis of Synthesis of 5-(2-fluorophenyl)-N-methoxy-N-methyl-1H-pyrrole-3-carboxamide (XIII)

Oxalyl chloride (24 g, 0.19 mol) was added to a solution of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylic acid (20 g, 0.13 mol) in DCM (100 mL) at 0oC and stirred at same temperature for 30 min. The obtain reaction was concentrated under reduced pressure and add DCM (100 mL), followed by added drop wise weinreb amine (N, O- dimethylhydroxylamine) (12.8 g, 0.13 mol) and DIPEA (50.1g, 0.39 mol) at 0oC. The reaction mixture was stirred for 12h at room temperature. The reaction was diluted with water (50 mL). The organic layer was separated, washed with water and brine solution. The combined organic layers were dried over sodium sulphate, filtered and concentrated. to give 5-(2-fluorophenyl)-N-methoxy-N-methyl-1H-pyrrole-3-carboxamide as an off-white solid.
Yield: 91% (22g)

Example 3:
Synthesis of tert-butyl 2-(2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-1H-pyrrole-1-carboxylate (XIV)
Di-tert-butyl dicarbonate (17.1g, 0.08mol) was added to solution of 5-(2-fluorophenyl)-N-methoxy-N-methyl-1H-pyrrole-3-carboxamide (13g, 0.05 mol) in THF (75 mL) at room temperature, followed by added triethyl amine (15.2g, 0.16 mol) and DMAP (0.61 g, 0.005 mol). The reaction mixture was stirred at room temperature for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with 1N HCl, water and brine solution. organic layer was dried over sodium sulphate and concentrated to obtain tert-butyl 2-(2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-1H-pyrrole-1-carboxylate as light brown liquid.
Yield: 92.8% (17.5 g)

Example 4:
Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (I)
Tert-butyl 2-(2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-1H-pyrrole-1-carboxylate (2 g, 0.005 mol) in Toluene (10 mL) at 0oC, followed by added Vitride (80% in Toluene, 1.4 mL, 0.015 mol). The reaction mixture was stirred for 3h at same temperature. The reaction was quenched with 1 N HCl (20 mL) and stirred for 30 min at 0oC. The reaction was diluted with ethyl acetate (100 mL). The organic layer was separated, washed with saturated sodium bicarbonate solution (50 mL), water (50 mL) and brine solution (50 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated. The residue was taken in methanol (100 mL), potassium phosphate tribasic (2.4 g, 0.01 mol) was added and heated to 65-70oC for 15 min. The reaction mixture was allow to cooled at 0oC and add water and methanol. The precipitate was filtered, washed with water (20 mL) to give 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde as a light brown solid.
Yield: 82% (8.9 g)
,CLAIMS:WE CLAIM:
1. An improved process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (I), comprising the steps of;
a) compound of formula (VI) is hydrolysing with base to obtain compound of formula (XII),

b) compound of formula (XII) is treating with chlorinating agent to obtain in-situ compound of formula (XIIA), followed by treating with weinreb amine (N,O-dimethylhydroxylamine) to obtain compound of formula (XIII),

c) compound of formula (XIII) is protecting with di-tert-butyl dicarbonate (Boc anhydride) in presence of base to obtain compound of formula (XIV), and

d) compound of formula (XIV) is reducing with reducing agent to obtain compound of formula (I).

2. The process as claimed in claim 1, wherein the base is selected from inorganic base or organic base; inorganic base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; ammonia; sodium sulphite; organic base is selected from triethylamine, triethanolamine, diisopropylethylamine, di-n-propylamine and 4-dimethylaminopyridine (DMAP).

3. The process as claimed in claim 1, wherein the chlorinating agent is selected from oxalyl chloride, sodium hypochlorite (NaOCl), thionyl chloride (SOCl2), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorus oxychloride (POCl3), CCl4, N-chlorosuccinimide (NCS), sulfuryl chloride, malonyl chloride, succinyl chloride, glutaryl chloride, adipoyl chloride, pimeloyl chloride, suberoyl chloride, azelaoyl chloride, sebacoyl chloride and/or mixture thereof.

4. The process as claimed in claim 1, wherein the reducing agent is selected from Red-Al (Vitride), diisobutylaluminum hydride (DIBAL-H), lithium aluminium hydride (LiAlH4), sodium borohydride (NaBH4), lithium borohydride (LiBH4), potassium borohydride (KBH4), calcium borohydride (Ca(BH4)2), sodium cyanoborohydride (NaBH3CN), tetramethylammonium borohydride, tetraethylammonium borohydride, benzyltriethylammonium borohydride, tetrabutylammonium borohydride, tetramethylammonium triacetoxyborohydride, dithionates and thiosulfates.

5. The process as claimed in claim 1, wherein the reaction carried out suitable solvent is selected from tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, n-hexane, diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, carbon tetrachloride and chloroform, methyl tert-butyl ether (MTBE) and/or mixtures thereof.

6. A compound of formula (XIIA).