DESC: “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 with high yield and purity.

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.

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 (VIII) is reacted with compound of formula (IX) in presence of sodium hydride (NaH)/ tetrahydrofuran (THF) to obtain the compound of formula (X). The compound of formula (X) is reacted with hydrogen chloride-ethyl acetate (EtOAc.HCl) to obtain the compound of formula (XI). The compound of formula (XI) is reacted with 10% Pd/C in presence of EtOH to obtain the compound of formula (VI). The 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 above 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. The present invention is providing a simple, cost effective 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 (I) with high yield and purity.

SUMMARY OF THE INVENTION

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 (II) is reacting with compound of formula (III) in presence of farmamide and trimethylsilyl halides to obtain the compound of formula (IV),

b) compound of formula (IV) is reacting with dehydrating agent in presence of base to obtain compound of formula (V),

c) compound of formula (V) is reacting with ethyl acrylate in present of base to obtain compound of formula (VI),

d) compound of formula (VI) is reducing with reducing agent to obtain compound of formula (VII), and

e) compound of formula (VII) is oxidizing with oxidizing agent to obtain compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (I) with high yield and purity.

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 (II) is reacting with compound of formula (III) in presence of farmamide and trimethylsilyl halides to obtain the compound of formula (IV),

b) compound of formula (IV) is reacting with dehydrating agent in presence of base to obtain compound of formula (V),

c) compound of formula (V) is reacting with ethyl acrylate in present of base to obtain compound of formula (VI),

d) compound of formula (VI) is reducing with reducing agent to obtain compound of formula (VII), and

e) compound of formula (VII) is oxidizing with oxidizing agent to obtain compound of formula (I).

In an embodiment of the present invention, compound of formula (II) is reacting with compound of formula (III) in presence of farmamide and trimethylsilyl halides and the reaction is carried out at 45-55°C for 14-16 hours to obtain the compound of formula (IV). compound of formula (IV) is reacting with dehydrating agent in presence of base and the reaction is carried out at 08-12°C for 1-3 hours to obtain the compound of formula (V). compound of formula (V) is reacting with ethyl acrylate in present of base and the reaction is carried out at 03-06°C for 1-3 hours to obtain the compound of formula (VI). compound of formula (VI) is reducing with reducing agent and the reaction is carried out at -5 to 5°C for 1-2 or at 50 to 75°C for 4-8 hours to obtain the compound of formula (VII), and compound of formula (VII) is oxidizing with oxidizing agent and the reaction is carried out at 0-5°C for 1-3 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 trimethylsilyl halides is selected from trimethylsilyl chloride and trimethylsilyl iodide.

According to an embodiment of the present invention, wherein the dehydrating agent is selected from phosphorus oxychloride and (chloromethylene)dimethyliminium chloride (Vilsmeier reagent).

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.

According to an embodiment of the present invention, wherein the reducing agent is selected from 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 and tetramethylammonium triacetoxyborohydride.

According to an embodiment of the present invention, wherein the oxidizing agent is selected from tetrapropylammonium perruthenate (TPAP)/N-methylmorpholine N-oxide (NMMO), tetrabutylammonium perrhenate, dess–martin periodinane (DMP) or 2-iodoxybenzoic acid, TEMPO/excess bleach (NaOCl), pyridinium chlorochromate (PCC), pyridine trioxochromium (collins reagent), pyridinium dichromate (PDC) and manganese dioxide.

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) or mixtures thereof.

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

EXAMPLES
Example 1:
Synthesis of sodium 4-methylbenzenesulfinate
Sodium bicarbonate (86 g, 1.02 mol) and sodium sulphite (123 g, 0.97mol) were dissolved in water (500 mL) and heated to 80-85oC, followed by addition of P-toluene sulfonyl chloride (100g, 0.52 mol). The resultant mixture was stirred for 2 hrs at 80-85 oC, further it was slowly allow to cooled at 5-10oC. The obtain solid was filtered and washed with ice cold water to afford sodium 4-methylbenzenesulfinate as an off-white solid.
Yield: 90.94 % (85 g).
Purity: 99.0 %

Example 2:
Synthesis of 4-methylbenzenesulfinic acid (II)
37% HCl (45 mL) was slowly added to a solution of sodium 4-methylbenzenesulfinate (85 g, 0.47 mol) in water (425 mL) and methyl tert butyl ether (425 mL) for 20 min, further the reaction mixture was stirred for 20 min. The layers were separated, the aqueous layers was further extracted with MTBE (200 ml). The combined organic layers were dried over sodium sulphate. The resultant product was filtered and concentrated into 80% n-heptane (100 mL). The obtain solid was filtered to afford 4-methylbenzenesulfinic acid as an off- white solid.
Yield: 96.62 % (72 g).
Purity: 99.2 %

Example 3:
Synthesis of N-((2-fluorophenyl)(tosyl)methyl)formamide (IV)
2-Fluoro benzaldehye (39.7g, .32 mol) in acetonitrile (150 mL), toluene (150 mL) were added into formamide (36 g, 0.8 mol), trimethyl silyl chloride (51 g, 0.42 mol) and heated to 50-55oC. The reaction mixture was stirred for 3h at same temperature, followed by addition of 4-methylbenzenesulfinic acid (75 g, 0.42 mol). The resultant mixture was stirred for 16h at 50-55oC. The reaction was mixture was allowing to cooled at room temperature. The resultant reaction mixture was diluted with water (900 mL) and MTBE (150 mL). The obtained reaction mas was allow to cooled at 0oC and stirred for 30 min. The afford solid was filtered to get N-((2-fluorophenyl)(tosyl)methyl)formamide as an off-white solid.
Yield: 63 % (90 g)
Purity: 99.5%

Example 4:
Synthesis of 1-fluoro-2-(isocyano(tosyl)methyl)benzene (V)
POCl3 (63.7 g, 0.4 mol) was added to a solution of N-((2-fluorophenyl)(tosyl)methyl)formamide (64 g, 0.2 mol) in THF (300 mL) and stirred at room temperature for 15 min. The reaction mixture was allow to cooled at 5oC, followed by addition of trimethylamine (126 g, 1.24 mol). The resultant mixture was stirred for 2h at 10oC. The reaction was quenched with ice water (100 mL) and extracted with ethyl acetate (200 mL). The combined extracts were washed with 5% sodium bicarbonate solution (50 mL). The obtained product was dried over sodium sulphate and filtered to give a brownish sticky liquid. The resultant liquid was added into IPA (100 mL), stirred for 20 min at 0oC and filtered. The afford solid dried to get a 1-fluoro-2-(isocyano(tosyl)methyl)benzene (34 g) as light brown solid.
Yield: 73 % (44 g)
Purity: 99.5 %

Example 5:
Synthesis of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (VI)
Ethyl acrylate (13.8 g, 0.13 mol) was added to a solution of 1-Fluoro-2-(isocyano(tosyl)methyl)benzene (40 g, 0.14 mol) in DMF (200 mL) and it was allow to cooled at 5oC, followed by addition of sodium hydride (55% in paraffin oil, 11.06 g, 0.27 mol). The reaction mixture was stirred for 2h at 5oC. The resultant reaction mass was diluted with ice water to obtained solid. The obtained solid was filtered and washed with n-hexane to get ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate as a light brown solid.
Yield: 96% (31 g)
Purity: 99.2 %

Example 6:
Synthesis of (5-(2-fluorophenyl)-1H-pyrrol-3-yl)methanol (VII)
Ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (10 g, 0.04 mol) in MDC (150 mL) was allow to cooled at 0oC, followed by addition of DiBAl-H (1M in Toluene, 128 mL, 0.12 mol). The resultant mixture was stirred for 1h at 0oC. The obtained reaction mas was quenched with sodium potassium tartrate (10% in water, 100 mL) and stirred for 1h at 0oC. The emulsion was filtered through the celite bed, the obtain filtrate was washed with water, brine solution and dried over sodium sulphate. The resultant liquid was filtered and concentrated to give (5-(2-fluorophenyl)-1H-pyrrol-3-yl) methanol as a reddish liquid.
Yield: 73 % (6 g)
Purity: 99.5 %

Example 7:
Synthesis of (5-(2-fluorophenyl)-1H-pyrrol-3-yl) methanol (VII)
Sodium borohydride (12.3 g, 0.325 mol) was added to a solution of Ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (10 g, 0.04 mol) in THF (100 mL) and heated to 60-65oC, followed by dropwise addition of methanol (5 g, 0.15 mol). The resultant mixture was stirred for 5-6h at same temperature, further it was slowly allow to cooled at 5-10oC. The obtained reaction mas diluted with toluene and adjusted pH 4-5 with 1N hydrochloric acid. The organic layer was separated and washed with water, dried over sodium sulphate and concentrated under reduced pressure to give (5-(2-fluorophenyl)-1H-pyrrol-3-yl) methanol as a reddish liquid.
Yield: 79% (6.5 g)
Purity: 99.4%

Example 8:
Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (I)
Dess Martin Periodinane (4.43 g, 0.01 mol) was added to a solution of (5-(2-Fluorophenyl)-1H-pyrrol-3-yl) methanol (2 g, 0.01 mol) in MDC (20 v) at 0oC. The reaction mixture was stirred for 1h at 0oC. The reaction mas was quenched with 1N NaOH (10 mL) and extracted with ethyl acetate (40 mL). The combined extracts were washed with water (10 mL) and 5% brine solution (10 mL). The organic layer was dried over sodium sulphate, filtered and concentrated. The obtained crude was further precipitated with ethyl acetate and n-hexane (1:10), filtered to give 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde as a light brown solid.
Yield: 75 % (1.5 g)
Purity: 99.9%

Example 9:
Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (I)
10% sodium carbonate solution (pH-9-10) was slowly dropwise addition to sodium hypochlorite (15 mL, 0.015 mol) at 0oC, followed by addition of dichloromethane (10 mL) and TEMPO (0.018g, 0.05 mmol), further added (5-(2-fluorophenyl)-1H-pyrrol-3-yl) methanol (2 g, 0.01 mol). The reaction mixture was stirred for 1h at 0oC. The reaction mas was quenched with 1N HCl (10 mL) and extracted with dichloromethane (40 mL). The combined organic phase was washed with water, brine solution and dried over sodium sulphate. The obtained solid concentrated to give 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde as a light brown solid.

Yield: 70% (1.4 g)
Purity: 99.9%
,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 (II) is reacting with compound of formula (III) in presence of farmamide and trimethylsilyl halides to obtain the compound of formula (IV),

b) compound of formula (IV) is reacting with dehydrating agent in presence of base to obtain compound of formula (V),

c) compound of formula (V) is reacting with ethyl acrylate in present of base to obtain compound of formula (VI),

d) compound of formula (VI) is reducing with reducing agent to obtain compound of formula (VII), and

e) compound of formula (VII) is oxidizing with oxidizing agent to obtain compound of formula (I).

2. The process as claimed in claim 1, wherein the trimethylsilyl halides is selected from trimethylsilyl chloride and trimethylsilyl iodide.

3. The process as claimed in claim 1, wherein the dehydrating agent is selected from phosphorus oxychloride and (chloromethylene)dimethyliminium chloride (Vilsmeier reagent).

4. 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.

5. The process as claimed in claim 1, wherein the reducing agent is selected from 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 and tetramethylammonium triacetoxyborohydride.

6. The process as claimed in claim 1, wherein the oxidizing agent is selected from tetrapropylammonium perruthenate (TPAP)/N-methylmorpholine N-oxide (NMMO), tetrabutylammonium perrhenate, dess–martin periodinane (DMP) or 2-iodoxybenzoic acid, TEMPO/excess bleach (NaOCl), pyridinium chlorochromate (PCC), pyridine trioxochromium (collins reagent), pyridinium dichromate (PDC) and manganese dioxide.

7. 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) or mixtures thereof.

8. The process for the preparation of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (I) as claimed in claim 1, having HPLC purity = 99.5%.