KR102500124B1 - Production method for 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl]-n-methylmethanamine monofumarate - Google Patents

Abstract

Method for producing 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde by formylation and deprotection reaction and 1-[5-(2-fluorophenyl)-1-(by sulfonylation, etc. It relates to the production of pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate.

Description

Method for producing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate {PRODUCTION METHOD FOR 1-[5 -(2-FLUOROPHENYL)-1-(PYRIDIN-3-YLSULFONYL)-1H-PYRROL-3-YL]-N-METHYLMETHANAMINE MONOFUMARATE}

The present invention relates to 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate, which is an acid secretion inhibitor, and It relates to a method for preparing the intermediate.

1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate represented by the following formula (hereinafter referred to as bonofra Zanfumarate) is a potassium ion-competitive acid blocker, inhibits the binding of potassium ions to H+, K±ATPase, and inhibits gastric acid secretion, so it is used for treatment or prevention of gastric and duodenal ulcers, and eradication of Helicobacter pylori. It is used to adjust pH in the stomach. Compared to conventional proton pump inhibitors, vonoprazan fumarate is known to be stable against acid, reach an effective concentration quickly, and show action from ingestion to onset quickly, strongly inhibiting gastric acid over a long period of time.

[Formula 1]

Regarding the production method of vonoprazan fumarate, for example, Patent Document 1 discloses a method of synthesizing a pyrrole-3-carboxyaldehyde derivative, which is a synthetic intermediate, from a cyano compound represented by the following formula via a pyrrole form. .

[Formula 2]

In this method, [2-(2-fluorophenyl)-2-oxoethyl]propanedinitrile (a) is used as a raw material. It is described that this raw material can be produced by the method described in Patent Document 2, and it is disclosed that it is synthesized by reaction of malononitrile from 2-fluorophenacyl bromide. In addition, it is described that 2-fluorophenacyl bromide can be produced by a generally known method. Although there is no specific description, for example, a method of reacting with bromine in acetic acid (Non-Patent Document 1), a method of reacting with bromine in the presence of aluminum chloride, and the like are known (Non-Patent Document 2). Since two steps are required for the synthesis of raw materials, many steps are required for the production of the target compound. In addition, since these reactions require malononitrile, which is concerned about toxicity and environmental impact, and bromine, which is highly corrosive and irritating, a manufacturing method that takes more safety into consideration for the human body and the environment is required. In addition, 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde is synthesized from raw materials in a yield of 53% to 60%, and improvement in yield is also required.

Therefore, there is a need for a manufacturing method with less impact on the human body or the environment, a shorter process and a higher yield.

Japanese Patent Publication No. 5819494 Japanese Patent Publication No. 3140818

Organic Synthesis, Coll, Vol. 1, 127 (1941) Organic Synthesis, Coll, Vol. 2, 480 (1943) Synthesis, 49(16), 3692-3699; 2017 Journal of Organic Chemistry, 75(9), 3109-3112; 2010

An object of the present invention is to provide a process for producing a synthetic intermediate pyrrole-3-carboxyaldehyde derivative in the production of vonoprazan fumarate and a novel industrial process for producing vonoprazan fumarate using the derivative.

As a result of intensive examination, the present inventors have found that pyrrole-3-carboxyaldehyde can be obtained by using a coupling reaction with readily available fluoroiodobenzene and pyrrole, and a regioselective formylation reaction by appropriately protecting the nitrogen atom on the pyrrole ring. A method for producing a derivative easily and in high yield was discovered, and the present invention was completed.

in other words

[1] The present invention, the following general formula (I),

[Formula 3]

In the pyrrole derivative represented by , a protecting group is introduced to the nitrogen atom of the pyrrole ring,

Formula (II):

[Formula 4]

(wherein P represents a protecting group) to obtain an N-protected pyrrole derivative represented by, and further formylating to obtain the following formula (III)

[Formula 3]

Obtaining a pyrrole-3-carboxyaldehyde derivative represented by, and further deprotection reaction to obtain the following formula (IV)

[Formula 4]

It relates to a method for producing 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde represented by

[2] The present invention also relates to the production method described in [1] above, wherein the protecting group represented by P is a silyl-based protecting group.

[3] The present invention also relates to the production method according to [1] or [2] above, wherein the protecting group represented by P is a triisopropylsilyl group.

[4] Another aspect of the present invention is that the pyrrole derivative of the general formula (I)

Formula (V):

[Formula 5]

(Wherein, L represents a leaving group) Obtained by reacting an orthofluorobenzene derivative represented by pyrrole in the presence of a metal catalyst, the method for producing the compound (I) described in [1] to [3] above will be.

[5] The present invention also relates to the production method described in [4] above, wherein the metal catalyst is a palladium catalyst.

[6] In addition, the present invention relates to the preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde represented by the general formula (IV) obtained by the above production method in the presence of an inorganic base or an organic base, reacting with pyridine-3-sulfonyl chloride or a salt thereof;

Formula (VI):

[Formula 6]

After obtaining a pyrrole derivative represented by and further condensing with methylamine, by a reduction reaction, the following formula (VII):

[Formula 7]

It relates to a method for producing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine represented by

[7] Also, the present invention relates to 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H obtained by the compound of formula (VII) obtained by the above production method and fumaric acid. It relates to a method for producing -pyrrol-3-yl] -N-methylmethanamine monofumarate.

The present invention uses readily available raw materials such as pyrrole and 2-fluoroiodobenzene, and produces 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde in good yield by a low-cost, short-time and short process. (70% or more), and is suitable for industrial production because of its economical efficiency and higher productivity than conventional methods. Further, by suppressing the use of the transition metal catalyst to a very small amount and using it in an upstream process, it is possible to further reduce concerns about residual metal impurities in the final product.

Hereinafter, the present invention will be described in more detail.

In the above general formula (V), as the leaving group represented by L, a halogen atom of chlorine, bromine, or iodine, a lower alkanesulfonyloxy group such as a methanesulfonyloxy group or trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, or p - arylsulfonyloxy groups such as toluenesulfonyloxy groups; and the like.

In the general formulas (II) and (III), the pyrrole ring nitrogen protecting group represented by P includes a silyl protecting group, an alkyl protecting group, a heteroaryl protecting group, an acyl protecting group, a carbamate protecting group, and the like, Examples of the silyl protecting group include a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group, and a tert-butyldiphenylsilyl group, preferably a tert-butyldimethylsilyl group, A triisopropylsilyl group etc. are mentioned.

Examples of the alkyl-based protecting group include an allyl group, a dimethoxymethyl group, a diethoxymethyl group, a tert-butyl group, a triphenylmethyl group, a benzyl group, and a 4-methoxybenzyl group.

Examples of the heteroaryl protecting group include a 2-pyridyl group, a 4-pyridyl group, a 2-pyrazyl group, a 2-pyrimidyl group and a 2-triazyl group.

Examples of the carbamate protecting group include a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a tert-amyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-tri A methoxybenzyloxycarbonyl group, p-biphenyl isopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, etc. are mentioned.

In addition, as another protecting group, an alkylsulfonyl group such as methanesulfonyl group, an arylsulfonyl group such as p-toluenesulfonyl group, an alkylacyl group such as acetyl group, and an arylacyl group such as benzoyl group can be used.

Among these protecting groups, the protecting group is preferably a silyl protecting group from the viewpoint of yield and the like, particularly preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, and a triisopropylsilyl group, and more preferably More specifically, it is a triisopropylsilyl group.

In the present invention, as a metal catalyst used in the reaction for obtaining compound (I) from compound (V), a nickel catalyst, a palladium catalyst, or the like can be used.

Examples of the nickel catalyst used in the present invention include a zero-valent nickel catalyst such as bis(1,5-cyclooctazienyl)nickel, a divalent nickel catalyst such as nickel chloride and bis(triphenylphosphine)nickel chloride, and the like. and, if necessary, triphenylphosphine, 2-(di-tert-butylphosphino)biphenyl, Xantphos, bis[2-(diphenylphosphino)phenyl]ether (hereinafter referred to as DPEPhos), (±)- Phosphine ligands such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as (±)-BINAP), N,N,N',N'-tetramethylethylenediamine etc. can be added.

As the palladium catalyst used in the present invention, a zero-valent palladium catalyst such as palladium carbon or tetrakistriphenylphosphine palladium, or a 2-valent catalyst such as palladium chloride, palladium acetate, (dichlorobis(tri-o-tolylphosphine))palladium, etc. A valent palladium catalyst can be mentioned, and phosphine ligands such as triphenylphosphine, 2-(di-tert-butylphosphino)biphenyl, Xantphos, DPEPhos, and (±)-BINAP can be added as needed. .

As the base used in the present invention, tertiary amines such as triethylamine and diisopropylethylamine, lithium hydride, sodium hydride, potassium hydrogen, sodium amide, lithium diisopropylamide (hereinafter referred to as LDA), lithium hexamethyl Metal bases such as disilazide (hereinafter referred to as LiHMDS), ethyl magnesium, sodium carbonate, calcium carbonate, and the like may be added.

The production method of the synthetic intermediate pyrrole-3-carboxyaldehyde derivative in the production of vonoprazan fumarate in the present invention and the production method of vonoprazan fumarate using the derivative are shown below.

[Formula 10]

(Preparation of compound (I))

Compound (I) can be produced by the cross-coupling reaction described in Non-Patent Document 3 or Non-Patent Document 4 or the like. For example, a non-halogenated unsubstituted pyrrole can be used by using the Negishi coupling reaction, and in an inert gas atmosphere such as nitrogen or argon, 1 to 3 equivalents of the above-mentioned base, preferably a metal base, more preferably ethers such as diethyl ether of sodium hydride, cyclopropylmethyl ether, tetrahydrofuran, 4-methyltetrahydropyran, dioxane, monoglyme, and diglyme; A solution of 1 to 3 equivalents of pyrrole/the above solvent is added dropwise to a solvent suspension of aromatic hydrocarbons such as benzene, toluene, and xylene at -10°C to room temperature, stirred for 10 minutes to 1 hour, and then 1 to 3 equivalents of Inorganic zinc such as zinc halide (zinc chloride, zinc bromide) or organic zinc such as dipivaloyl zinc (preferably zinc halide, particularly preferably zinc chloride) is added and stirred at room temperature for 10 minutes to 1 hour. Next, 1 to 3 equivalents of Compound (V), 0.0001 to 1.0 equivalents (preferably 0.001 to 0.003 equivalents) of the catalyst such as palladium and 0.0001 to 1.0 equivalents (preferably 0.001 to 0.003 equivalents) of the above phosphine Compound (I) can be produced by adding a ligand and reacting at room temperature to 150°C (preferably 90 to 130°C) for 5 minutes to 24 hours.

(Preparation of compound (II))

Compound (II) can be produced by introducing a protecting group into Compound (I). Although the production method for introducing a protecting group differs depending on the protecting group selected, a generally known method can be employed. For example, in the introduction of a silyl-based protecting group, 1 to 1.5 equivalents of the above-mentioned base, preferably a metal base, more preferably diethyl ether of sodium hydride, cyclopropylmethyl ether, tetrahydrofuran, 4-methyl A compound in a solvent suspension of ethers such as tetrahydropyran, dioxane, monoglyme, and diglyme, or aprotic polar solvents such as N,N-dimethylformamide, or mixed solvents thereof, preferably ethers, etc. After adding (I) dropwise at -10°C to room temperature, a metal chelating agent such as crown ether, tetraethylenediamine, or dimethylimidazolidinone, preferably dimethylimidazolidinone, is added, followed by 1 to 1.5 equivalents of Compound (II) can be produced by adding a protecting group introduction reagent dropwise and reacting for 5 minutes to 3 hours.

In the case of introducing a carbamate-based protecting group, the reaction conditions are different depending on the type of carbamate-based protecting group. For example, for compound (I), tert-butoxycarbonyl (Boc group), tert- Amyloxycarbonyl (group Aoc) or benzyloxycarbonyl (group Z), 9-fluorenylmethyloxycarbonyl (Fmoc) group, 2,2,2-trichloroethoxycarbonyl group, 2-(trimethylsilyl) When an ethoxycarbonyl group or the like is introduced, organic bases such as triethylamine and pyridine, sodium hydride, potassium hydroxide, sodium hydroxide, and hydrogen carbonate in solvents such as dioxane, dioxane/water, methylene chloride, and tetrahydrofuran Di-tert-butyl dicarbonate ((Boc) ₂ O), tert-butoxycarbonyl chloride, benzyloxycarbonyl chloride, tert-amyloxycarbonyl chloride, in the presence of an inorganic base such as potassium or sodium hydrogen carbonate, 9-fluorenylmethyloxycarbonyl chloride, 2,2,2-trichloroethyl chloroformate, 2-(trimethylsilyl)ethoxymethyl chloride, tert-butoxycarbonyl azide, benzyloxycarbonyl azide, etc. It can be produced by reacting 1 to 1.5 equivalents of a generally known Boc group introduction reagent at 0°C to 100°C for 5 minutes to 10 hours.

(Preparation of compound (III))

Compound (III) can be prepared by a generally known formylation reaction such as Vilsmeier reaction, Rieche reaction, Daff reaction, Reimer-Tiemann reaction, etc., and for example, N,N-dimethylformamide (DMF ), N-methylformanilide (MFA), N-formylmorpholine, N,N-2 substituted formamides such as N,N-diisopropylformamide and phosphorus oxychloride, oxalyl chloride, thionyl chloride, tri Prepare or purchase a commercially available Vilsmeier reagent ((chloromethylene)dimethyliminium chloride) from an acid chloride such as phenylphosphine-bromine or hexachlorotriphosphazatriene, and mix this and compound (II) in a solvent such as phosphorus oxychloride; or halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, and chlorobenzene; Aromatic hydrocarbons, such as benzene, toluene, and nitrobenzene; Ethers such as tetrahydrofuran, tetramethylhydropyran, and dioxane, or aprotic polar solvents such as ethyl acetate, acetonitrile, and N,N-dimethylformamide, or mixed solvents thereof, preferably ether-based solvents and aromatics Compound (III ) can be produced.

(Preparation of compound (IV))

Compound (IV) can be prepared from the deprotection reaction of compound (III). The deprotection reaction differs depending on the protecting group, but a generally known method can be used. For example, when the protecting group is a silyl protecting group, tetrabutylammonium fluoride or tetrabutylammonium fluoride in a solution such as tetrahydrofuran at -10 ℃ to room temperature It can be produced by reacting a fluorine source such as HF pyridine complex and HF triethylamine complex. Further, under acidic conditions such as hydrochloric acid or trifluoroacetic acid or under basic conditions such as sodium hydroxide aqueous solution, the deprotection reaction of the silyl-based protecting group proceeds in the same way, and compound (IV) can be produced. As the deprotection reagent, 3 to 10 equivalents (preferably 5 equivalents) of sodium hydroxide aqueous solution can be used relative to compound (III).

In addition, in the case of a carbamate-based protecting group, the reaction conditions are different depending on the type of carbamate-based protecting group, but it can be carried out by a generally known method, for example, palladium black or palladium carbon in a hydrogen atmosphere. It can be carried out by catalytic reduction in the presence of the like, or by appropriately selecting acetic acid/hydrogen bromide, trifluoroacetic acid, hydrochloric acid/organic solvent or the like according to the protecting group.

In addition, compound (IV) can be produced by a one-pot operation without isolating compound (III) from compound (II). In this case, it can be carried out by adding the reagent for deprotection to the reaction system after completion of the reaction of compound (III) from compound (II).

In addition, compound (IV) can also be produced by a one-pot operation without isolating compound (II) or compound (III) from compound (I). After that, the reaction reagent for producing compound (IV) is added to the reaction system, and after completion of the reaction, the reagent for the deprotection reaction is further added to the reaction system and reacted in the same way to obtain compound (IV). can be manufactured Regarding the amount relationship of the reagent in any production, the same amount as described above can be used.

(Preparation of compound (VI))

A solution of compound (IV) in tetrahydrofuran or the like is added dropwise to a suspension of 1 to 1.5 equivalents of sodium hydride/tetrahydrofuran at -10°C to room temperature, stirred for 0.5 to 1 hour, and then crown ether or In the presence of a metal chelating agent such as tetramethylethylenediamine or dimethylimidazolidinone, stirring is performed at -10°C to room temperature for 0.5 to 1 hour, pyridine-3-sulfonyl chloride is subsequently added, and the mixture is stirred at 0°C for 0.5 hour. Stir. Compound (VI) can be produced by further adding pyridine-3-sulfonyl chloride and stirring at -10°C to room temperature for 0.5 to 1 hour.

In addition, compound (VI) is obtained from a solution of compound (IV) in dichloromethane or acetonitrile at 0°C to room temperature with a base such as triethylamine or N,N-diisopropylamine, or a catalytic amount of 4-dimethylaminopyridine. , It can manufacture by adding pyridine-3-sulfonyl chloride and stirring at room temperature - 100 degreeC for 0.5 to 12 hours.

(Preparation of compound (VII))

A solution of methylamine in methanol or the like is added dropwise to a solution of compound (VI) in methanol or the like at 0°C to room temperature, stirred for 0.5 to 1 hour, and then added with a reducing agent such as sodium borohydride at 0°C to room temperature. Compound (VII) can be obtained by adding 3 equivalents and reacting for 0.5 to 1 hour.

(Preparation of vonoprazan fumarate)

A solution of fumaric acid in methanol or the like is added to a solution of compound (VII) in ethyl acetate or methanol at 0°C to room temperature, stirred for 0.5 to 1 hour, and the precipitated crystals are collected by filtration and, if necessary, recrystallized from methanol/water. By doing so, vonoprazan fumarate can be produced.

Example

The present invention will be described in more detail below with examples, comparative examples and test examples, but the present invention is not limited thereto.

Example 1

Preparation of 2-(2-fluorophenyl)-1H-pyrrole

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 1.2 g, 30.0 mmol) and tetrahydrofuran (10 mL), pyrrole (2.1 mL, 30.0 mmol) was added dropwise under ice-cooling, stirred for 0.5 hour, and zinc chloride (4.1 g, 30.0 mmol) was added and stirred at room temperature for 0.5 hour. Then palladium acetate (11 mg, 0.05 mmol), 2-(di-tert-butylphosphino)biphenyl (15 mg, 0.05 mmol) and 1-fluoro-2-iodobenzene (1.1 mL, 10.0 mmol) were added. After adding and degassing, it stirred at 60 degreeC for 6 hours. Water was added dropwise while cooling the reaction mixture at 0°C, and after filtering the insoluble matter, the mixture was separated with ethyl acetate. After adding ethyl acetate to the aqueous layer and extracting again, the organic layers were combined and washed with saturated brine. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and dried under reduced pressure to obtain the title compound (1.18 g, yield 74%).

Example 2

Preparation of 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole

In a suspension of sodium hydride (60% dispersed in liquid paraffin, 64 mg, 1.61 mmol) and tetrahydrofuran (2 mL), 2-(2-fluorophenyl)-1H-pyrrole (172 mg, 1.07 mmol) was added under ice-cooling. A solution of tetrahydrofuran (2 ml) was added dropwise and stirred for 0.5 hour, then 15-crown-5-ether (0.32 ml, 1.61 mmol) was added and stirred at 0°C for 0.5 hour. Then, triisopropylsilyl chloride (0.35 ml, 1.61 mmol) was added dropwise, and the mixture was stirred at room temperature for 4 hours. After cooling to 0°C, water was added dropwise and partitioned with ethyl acetate. After adding ethyl acetate to the aqueous layer and extracting again, the organic layers were combined and washed with saturated brine. The solvent was distilled off under reduced pressure, purified with a silica gel column, and dried under reduced pressure to obtain the title compound (272 mg, yield 80%).

Example 3

Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde

Vilsmeier's reagent (123 mg, 0.96 mmol) was added to a solution of 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole (100 mg, 0.32 mmol) in dichloromethane (3.0 mL) under ice-cooling. It was added and stirred at 40 degreeC for 0.5 hour. After distilling off the solvent under reduced pressure, sodium hydroxide aqueous solution (1.0 M, 3 ml) was added, and the mixture was stirred at room temperature for 6 hours, and then ethyl acetate was added to separate the mixture. After adding ethyl acetate to the aqueous layer and extracting again, the organic layers were combined and washed with saturated brine. Purification with a silica gel column and drying under reduced pressure gave the title compound (48 mg, yield 80%).

Example 4

Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde

Pyrrole (2.1 ml, 30.0 mmol) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 1.2 g, 30.0 mmol) and 4-methyltetrahydropyran (10 ml) under ice-cooling, stirred for 0.5 hour, and then chlorinated. Zinc (4.1 g, 30.0 mmol) was added and stirred at room temperature for 0.5 hour. Then palladium acetate (11 mg, 0.05 mmol), 2-(di-tert-butylphosphino)biphenyl (15 mg, 0.05 mmol) and 1-fluoro-2-iodobenzene (1.1 mL, 10.0 mmol) were added. It was added and stirred at 100 degreeC for 0.5 hour. 28% aqueous ammonia was added dropwise while cooling the reaction mixture at 0°C, and after filtering the insoluble matter, the mixture was separated with ethyl acetate. After distilling off the solvent under reduced pressure, 2-(2-fluorophenyl)-1H-pyrrole was obtained as a crude product.

2-(2-fluorophenyl)-1H- obtained in a suspension of sodium hydride (60% dispersed in liquid paraffin, 600 mg, 15 mmol) in tetrahydrofuran (10 mL) and dimethylimidazolidinone (2 mL) A solution of the crude product of pyrrole in tetrahydrofuran (2 ml) was added dropwise under ice-cooling, followed by stirring for 0.5 hour. Then, triisopropylsilyl chloride (3.2 ml, 15 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water was added dropwise while cooling to 0°C, and the mixture was separated with ethyl acetate. After the solvent was distilled off under reduced pressure, 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole was crudely obtained by performing a liquid separation operation again with heptane and water and distilling off the solvent under reduced pressure. obtained as a product.

To a solution of the obtained crude product of 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole in dichloromethane (50 mL) was added Vilsmeier reagent (3.8 g, 30 mmol) under ice-cooling. It stirred at 40 degreeC for 0.5 hour. After distilling off the solvent under reduced pressure, an aqueous solution of sodium hydroxide (1.0 M, 100 ml) was added, and the mixture was stirred at room temperature for 6 hours, and ethyl acetate was added to separate the mixture. After washing the organic layer with saturated brine, the solvent was distilled off under reduced pressure. The title compound (1.34 g, yield 70%) was obtained by recrystallization from heptane and ethyl acetate and drying under reduced pressure.

Example 5

Preparation of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde

A suspension of sodium hydride (60% dispersed in liquid paraffin, 32 mg, 0.79 mmol) and tetrahydrofuran (2 mL) was added with 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde (100 mg) under ice-cooling. , 0.53 mmol) in tetrahydrofuran (2 ml) was added dropwise and stirred for 0.5 hour, then 15-crown-5-ether (0.16 ml, 0.79 mmol) was added and stirred at 0°C for 0.5 hour. Subsequently, pyridine-3-sulfonyl chloride (95 µL, 0.79 mmol) was added, and the mixture was stirred at 0°C for 0.5 hour. Further, pyridine-3-sulfonyl chloride (95 µl, 0.79 mmol) was added, and the mixture was stirred at 0°C for 0.5 hour. Water was added dropwise, and the mixture was separated with ethyl acetate. After adding ethyl acetate to the aqueous layer and extracting again, the organic layers were combined and washed with saturated brine. The solvent was distilled off under reduced pressure, purified with a silica gel column, and dried under reduced pressure to obtain the title compound (167 mg, yield 95%).

Example 6

Preparation of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

To a solution of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde (100 mg, 0.30 mmol) in methanol (3 mL) at room temperature, add methylamine to methanol A solution (2.0 M, 1.06 ml, 2.12 mmol) was added dropwise and stirred for 0.5 hour. After cooling to 0°C, sodium borohydride (34 mg, 0.91 mmol) was added and the mixture was stirred for 0.5 hour. 1 normal hydrochloric acid (3 ml) was added dropwise at 0°C, and the mixture was stirred at room temperature for 0.5 hour. Saturated sodium bicarbonate water and ethyl acetate were added and separated. After adding ethyl acetate to the aqueous layer and extracting again, the organic layers were combined and washed with saturated brine. After concentrating the organic layer, ethyl acetate (3 mL) was added, followed by a solution of fumaric acid (39 mg, 0.30 mmol) in methanol (0.3 mL). After stirring at room temperature for 30 minutes, the precipitated crystals were filtered and washed with ethyl acetate and methanol to obtain a crude product. The obtained crude crystals were recrystallized from methanol and water, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain the title compound (90 mg, yield 64%).

Example 7

Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde

Pyrrole (15.7 mL, 220.0 mmol) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 8.8 g, 220.0 mmol) and 4-methyltetrahydropyran (100 mL) under ice-cooling, stirred for 0.5 hour, and then chlorinated. Zinc (30.3 g, 220.0 mmol) was added and stirred at room temperature for 0.5 hour. Then palladium acetate (56.1 mg, 0.25 mmol), 2-(di-tert-butylphosphino)biphenyl (74.6 mg, 0.25 mmol) and 1-fluoro-2-iodobenzene (11.5 mL, 100.0 mmol) were added. It was added and stirred at about 100 degreeC for 1 hour. Sodium hydroxide aqueous solution (5.0 N, 220.0 mmol) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour. After filtration of the insoluble matter and washing with toluene (100 ml), the organic layer was separated and the aqueous layer was extracted with toluene (100 ml). The organic layers were combined and washed with distilled water (167 mL) and saturated brine (167 mL). After distilling off the solvent under reduced pressure, toluene (167 ml) was added to the residue. By distilling off the solvent under reduced pressure, 2-(2-fluorophenyl)-1H-pyrrole was obtained as a crude product (20.9 g).

2-(2-fluorophenyl) obtained in a suspension of sodium hydride (60% dispersed in liquid paraffin, 4.4 g, 110.0 mmol) in tetrahydrofuran (100 mL) and dimethylimidazolidinone (32.6 mL, 300.0 mmol) A solution of the crude product of -1H-pyrrole in tetrahydrofuran (10 ml) was added dropwise under ice-cooling, washed with tetrahydrofuran (10 ml), and stirred for 0.5 hour. Then, triisopropylsilyl chloride (23.5 ml, 110.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Distilled water (17 ml) was added dropwise under an ice bath, and further distilled water (167 ml) was added. Extraction was performed twice using ethyl acetate (84 ml), and washed with distilled water (167 ml) and saturated brine (167 ml). After distilling off the solvent under reduced pressure, toluene (167 ml) was added to the residue. After distilling off the solvent under reduced pressure, the solvent was distilled off under reduced pressure to obtain 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole as a crude product (45.2 g).

Oxalyl chloride (17.2 ml, 200.0 mmol) was added to dichloromethane (100 ml), DMF (15.5 ml, 200.0 mmol) was added dropwise under ice-cooling, and the mixture was stirred for 0.5 hour. A 4-methyltetrahydropyran (100 ml) solution of the obtained crude product of 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole was added at once and stirred at about 50°C for 3 hours. did Under ice-cooling, aqueous sodium hydroxide solution (5.0 M, 100 ml) was added, and the mixture was stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was partitioned with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (200 ml), and the solvent was distilled off under reduced pressure. Ethyl acetate (47 ml) was added to the obtained solid residue, and after dissolving at about 70°C, heptane (300 ml) was added. After cooling at room temperature, the mixture was stirred in an ice bath for 1 hour, and the precipitated crystals were collected by filtration and washed with cooled ethyl acetate:heptane (1:6, 70 ml). The title compound (13.6 g, yield 72%) was obtained by drying under reduced pressure at 50°C for 1.5 hours.

Example 8

Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde (one pot synthesis from 2-(2-fluorophenyl)-1H-pyrrole)

After adding dimethylimidazolidinone (20.0 mL, 186 mmol) to a solution of 2-(2-fluorophenyl)-1H-pyrrole (10.0 g, 62.0 mmol) in 4-methyltetrahydropyran (62 mL), Sodium hydride (dispersed in 60% liquid paraffin, 2.7 g, 68.2 mmol) was slowly added under ice-cooling, followed by stirring for 10 minutes. Then, triisopropylsilyl chloride (14.6 ml, 68.2 mmol) was added dropwise, and the mixture was stirred for 2 hours under ice-cooling. A reaction solution of 2-(2-fluorophenyl)-1H-pyrrole in dichloromethane (90 mL) solution of Vilsmeier's reagent prepared from oxalyl chloride (10.6 mL, 124 mmol) and DMF (9.65 mL, 124 mmol) was added to ice. It was added at once under cooling, washed with 4-methyltetrahydropyran (20 ml), and stirred at about 60°C for 2 hours. Under ice-cooling, aqueous sodium hydroxide solution (2.0 M, 310 ml) was added, and the mixture was stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was partitioned with ethyl acetate (120 mL). The organic layers were combined, washed with saturated brine (120 ml), and the solvent was distilled off under reduced pressure. Ethyl acetate (29 ml) was added to the obtained solid residue, and after dissolving at about 70°C, heptane (180 ml) was added. After cooling at room temperature, the mixture was stirred in an ice bath for 1 hour, and the precipitated crystals were collected by filtration and washed with cooled ethyl acetate:heptane (1:6, 42 ml). The title compound (8.30 g, yield 71%) was obtained by drying under reduced pressure at 50°C for 1.5 hours.

Claims (1)

2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole.