CN111527067B - Process for the preparation of 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine monofumarate - Google Patents

Abstract

The present invention relates to a process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde by a formylation and deprotection reaction, and to a process for producing 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine monofumarate by sulfonylation or the like.

Description

Process for the preparation of 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine monofumarate

Technical Field

The present invention relates to a process for producing 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine monofumarate and an intermediate thereof as an acid secretion inhibitor.

Background

1- [5- (2-Fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine monofumarate (hereinafter referred to as Vonoprazan fumarate) represented by the following formula is a potassium competitive acid blocker which inhibits the binding of potassium ions to H+, K+ -ATPase and inhibits gastric acid secretion, and therefore is used for the treatment and prevention of gastric/duodenal ulcers and the like, and for intragastric pH adjustment during helicobacter pylori sterilization. Vonoprazan fumarate is known to be more stable to acids than conventional proton pump inhibitors, to reach an effective concentration rapidly, to rapidly develop an action from administration, and to strongly inhibit gastric acid for a long period of time.

As a method for producing voronoi fumarate, for example, patent document 1 discloses a method for synthesizing pyrrole-3-carbaldehyde derivatives as synthesis intermediates from cyano compounds represented by the following formulas via pyrrole bodies.

In this process, [2- (2-fluorophenyl) -2-oxoethyl ] malononitrile (a) is used as a starting material. It is described that this raw material can be produced by the method described in patent document 2, and it is disclosed that the raw material is synthesized by a reaction between α -bromo-o-fluoroacetophenone and malononitrile. It is also described that α -bromo-o-fluoroacetophenone can be produced by a generally known method. Although not specifically described, a method of reacting with bromine in acetic acid (non-patent document 1) and a method of reacting with bromine in the presence of aluminum chloride (non-patent document 2) are known. Since the synthesis of the raw materials requires 2 steps, the production of the target compound requires a plurality of steps. In addition, in these reactions, malononitrile, which is a concern about toxicity and environmental impact, and bromine, which is highly corrosive and irritating, are used, and thus a production method is desired which is further considered to be safe to the human body and the environment. In addition, 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde is synthesized from the starting materials in a yield of 53% to 60%, and improvement of the yield is also desired.

Therefore, a production method having less influence on the human body and the environment, a shorter process, and a good yield is desired.

Prior art literature

Patent literature

Patent document 1: japanese patent No. 5819494

Patent document 2: japanese patent No. 3140818

Non-patent literature

Non-patent document 1: organic Synthesis, coll, vol.1, 127 (1941)

Non-patent document 2: organic Synthesis, coll, vol.2, 480 (1943)

Non-patent document 3: synthesis,49 (16), 3692-3699;2017

Non-patent document 4: journal of Organic Chemistry,75 (9), 3109-3112;2010

Disclosure of Invention

The purpose of the present invention is to provide a method for producing pyrrole-3-formaldehyde derivatives, which are intermediates for the production of voronoi fumarate, and a novel industrial production method of voronoi fumarate using the same.

As a result of intensive studies, the present inventors have found a method for producing pyrrole-3-carbaldehyde derivatives efficiently and simply by using a coupling reaction based on readily available fluoroiodobenzene and pyrrole and a site-selective formylation reaction based on appropriate protection of the nitrogen atom on the pyrrole ring, and have completed the present invention.

That is to say,

[1] The invention relates to a method for preparing 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde,

A pyrrole derivative represented by the following general formula (I) is obtained by introducing a protecting group to the nitrogen atom of the pyrrole ring, and an N-protected pyrrole derivative represented by the following general formula (II) (wherein P represents a protecting group), is further obtained by formylation, and a pyrrole-3-carbaldehyde derivative represented by the following general formula (III), and is further obtained by deprotection reaction, and is further obtained by the following general formula (IV).

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

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

[4] The present invention also relates to a process for producing the compound (I) described in the above [1] to [3], wherein the pyrrole derivative represented by the general formula (I) is obtained by reacting an o-fluorobenzene derivative represented by the following formula (V) (wherein L represents a leaving group) with pyrrole in the presence of a metal catalyst.

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

[6] The present invention also relates to a process for producing 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methyl methylamine, wherein 5- (2-fluorophenyl) -1H-pyrrol-3-carbaldehyde represented by the general formula (IV) obtained by the process is reacted with pyridine-3-sulfonyl chloride or a salt thereof in the presence of an inorganic or organic base to obtain a pyrrole derivative represented by the following formula (VI), and the pyrrole derivative is further condensed with methylamine, and then subjected to a reduction reaction to obtain 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methyl methylamine represented by the following formula (VII).

[7] The present invention also relates to a process for producing 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine monofumarate, using a compound of the general formula (VII) obtained by the process and fumaric acid.

The present invention can obtain 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde using readily available raw materials such as pyrrole and 2-fluoroiodobenzene in a short time and in a short process and in a good yield (70% or more), and is suitable for industrial production with high economical efficiency and productivity as compared with the conventional methods. Further, the use of the transition metal catalyst is also suppressed to a very small amount and used in the upstream process, whereby the concern of the metal impurities remaining in the final product can be further reduced.

Detailed Description

The present invention will be described in further detail below.

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

In the general formulae (II) and (III), examples of the pyrrole ring nitrogen protecting group represented by P include silyl protecting groups, alkyl protecting groups, heteroaryl protecting groups, acyl protecting groups, and urethane protecting groups, and examples of the silyl protecting groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, and t-butyldiphenylsilyl, and t-butyldimethylsilyl and triisopropylsilyl are preferred.

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-based protecting group include a 2-pyridyl group, a 4-pyridyl group, a 2-pyrazinyl group, a 2-pyrimidinyl group and a 2-triazinyl group.

Examples of the urethane protecting group include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, 2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl, p-methoxyphenylazo benzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 3,4, 5-trimethoxybenzyloxycarbonyl, p-benzisotropyloxycarbonyl, diisopropylmethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, and 9-fluorenylmethoxycarbonyl.

As the other protecting group, an alkylsulfonyl group such as methanesulfonyl, an arylsulfonyl group such as p-toluenesulfonyl, an alkanoyl group such as acetyl, or an aryl acyl group such as benzoyl may be used.

Among these protecting groups, silyl protecting groups are preferred from the viewpoint of yield and the like, and trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and triisopropylsilyl are particularly preferred, and triisopropylsilyl is further preferred.

In the present invention, as the metal catalyst used in the reaction for obtaining the compound (I) from the 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 0-valent nickel catalysts such as bis (1, 5-cyclooctadienyl) nickel, 2-valent nickel catalysts such as nickel chloride and bis (triphenylphosphine) nickel chloride, and phosphine ligands such as triphenylphosphine, 2- (di-t-butylphosphino) biphenyl, xantphos, bis [2- (diphenylphosphino) phenyl ] ether (hereinafter referred to as DPEPhos), (+ -) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (hereinafter referred to as (+ -) -BINAP), and N, N, N ', N' -tetramethyl ethylenediamine may be added as required.

Examples of the palladium catalyst used in the present invention include 0-valent palladium catalysts such as palladium carbon and tetrakis (triphenylphosphine) palladium, 2-valent palladium catalysts such as palladium chloride, palladium acetate and (dichloro bis (tri-o-tolylphosphine)) palladium, and phosphine ligands such as triphenylphosphine, 2- (di-t-butylphosphino) biphenyl, xantphos, DPEPhos, (±) -BINAP, and the like may be added as necessary.

As the base used in the present invention, tertiary amines such as triethylamine and diisopropylethylamine, metal bases such as lithium hydride, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide (hereinafter LDA), lithium hexamethyldisilazide (hereinafter LiHMDS), ethylmagnesium, sodium carbonate, and calcium carbonate, and the like can be added.

The following will illustrate a method for producing pyrrole-3-carbaldehyde derivatives as a synthetic intermediate in the production of voronoi fumarate and a method for producing voronoi fumarate using the same.

(Production of Compound (I))

The compound (I) can be produced by a cross-coupling reaction described in non-patent document 3 and non-patent document 4. For example, by using a non-halogenated unsubstituted pyrrole by a root-side coupling reaction, the above-mentioned base, preferably a metal base, more preferably diethyl ether of sodium hydride, cyclopropylmethyl ether, tetrahydrofuran, 4-methyltetrahydropyran, or ditetrahydrofuran is added in an amount of 1 to 3 equivalents under an inert gas atmosphere such as nitrogen or argonTo a solvent suspension of an ether such as an alkane, monoglyme, diglyme, or the like, an aromatic hydrocarbon such as benzene, toluene, xylene, or the like, 1 to 3 equivalents of a solution of pyrrole/the solvent is added dropwise at-10 to room temperature and stirred for 10 minutes to 1 hour, and then 1 to 3 equivalents of an inorganic zinc such as zinc halide (zinc chloride, zinc bromide), or an organic zinc such as zinc dipentamyl (preferably zinc halide, particularly preferably zinc chloride) is added and stirred at room temperature for 10 minutes to 1 hour. Then, the compound (I) can be produced by adding 1 to 3 equivalents of the compound (V), 0.0001 to 1.0 equivalent (preferably 0.001 to 0.003 equivalent) of the catalyst such as palladium, and 0.0001 to 1.0 equivalent (preferably 0.001 to 0.003 equivalent) of the phosphine ligand, and reacting at room temperature to 150℃for 5 minutes to 24 hours (preferably 90 to 130 ℃).

(Production of Compound (II))

The compound (II) can be produced by introducing a protecting group into the compound (I), and the method for producing the protecting group may be different depending on the protecting group selected, but a generally known method may be employed. For example, when a silyl group protecting group is introduced, 1 to 1.5 equivalents of the above base, preferably a metal base, more preferably diethyl ether of sodium hydride, cyclopropylmethyl ether, tetrahydrofuran, 4-methyltetrahydropyran, or ditetrahydropyran are addedThe compound (II) can be produced by adding dropwise the compound (I) to a suspension of an aprotic polar solvent such as an alkane, monoglyme, diglyme or the like, or an aprotic polar solvent such as N, N-dimethylformamide or a mixed solvent thereof, preferably an ether or the like at-10 to room temperature, then adding a metal chelating agent such as a crown ether, tetraethylene diamine, dimethylimidazolidinone, preferably dimethylimidazolidinone, followed by adding dropwise 1 to 1.5 equivalents of a protecting group introducing reagent to react for 5 minutes to 3 hours.

In addition, when introducing the urethane-based protecting group, the reaction conditions may be different depending on the kind of the urethane-based protecting group, and for example, when introducing a tert-butoxycarbonyl group (Boc group), a tert-pentoxycarbonyl group (Aoc group) or a benzyloxycarbonyl group (Z group), a 9-fluorenylmethoxycarbonyl group (Fmoc) group, a 2, 2-trichloroethoxycarbonyl group, a 2- (trimethylsilyl) ethoxycarbonyl group, or the like, into the compound (I), the reaction may be carried out by the use of a di-catalystAlkane, two/>The solvent such as alkane, water, methylene chloride, tetrahydrofuran, etc., and in the presence of an organic base such as triethylamine, pyridine, etc., an inorganic base such as sodium hydride, potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, etc., 1 to 1.5 equivalents of a generally known introducing reagent such as Boc group such as di-tert-butyl dicarbonate ((Boc) ₂ O), tert-butoxycarbonyl chloride, benzyloxycarbonyl chloride, tert-pentoxycarbonyl chloride, 9-fluorenylmethoxycarbonyl chloride, 2-trichloroethyl chloroformate, 2- (trimethylsilyl) ethoxymethyl chloride, tert-butoxycarbonyl azide, benzyloxycarbonyl azide, etc., are reacted at 0 to 100 ℃ for 5 minutes to 10 hours.

(Production of Compound (III))

The compound (III) can be produced by a generally known formylation reaction, such as Vilsmeier reaction, rieche reaction, daff reaction, reimer-Tieman reaction, etc., for example, in which Vilsmeier reaction a Vilsmeier reagent ((chloromethylene) dimethyl ammonium chloride) is prepared from N, N-Dimethylformamide (DMF), N-Methylformanilide (MFA), N-formylmorpholine, N-diisopropylformamide and the like and phosphorus oxychloride, oxalyl chloride, thionyl chloride, triphenylphosphine-bromine, hexachlorocyclotriphosphazene and the like, or commercially available products are obtained, and the compound (II) is dissolved in a solvent such as phosphorus oxychloride; or halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, etc.; aromatic hydrocarbons such as benzene, toluene, and nitrobenzene; tetrahydrofuran, methyltetrahydropyran, diThe compound (III) can be produced by stirring ethers such as an alkane, ethyl acetate, acetonitrile, N-dimethylformamide, or a mixed solvent thereof, preferably an ether-based solvent, an aromatic hydrocarbon, an aprotic polar solvent, or a mixed solvent thereof, more preferably methyltetrahydropyran, at 0 to 100 ℃ (preferably 40 to 80 ℃) for 0.5 to 12 hours and then reacting the mixture.

(Production of Compound (IV))

The compound (IV) can be produced by deprotection reaction of the compound (III). The deprotection reaction varies depending on the protecting group, and can be produced by a generally known method, for example, when the protecting group is a silyl protecting group, the deprotection reaction can be carried out by reacting a fluorine source such as tetrabutylammonium fluoride, HF pyridine complex, HF triethylamine complex, etc. in a solution such as tetrahydrofuran at-10℃to room temperature. In addition, the deprotection reaction of the silyl group functionalized protecting group is similarly carried out under acidic conditions such as hydrochloric acid and trifluoroacetic acid, and basic conditions such as aqueous sodium hydroxide solution, and thus the compound (IV) can be produced. The deprotection reagent may be used in an amount of 3 to 10 equivalents (preferably 5 equivalents) of an aqueous sodium hydroxide solution relative to the compound (III).

In the case of the urethane-based protecting group, the reaction conditions may be different depending on the kind of the urethane-based protecting group, and the reaction may be performed by a generally known method, for example, by catalytic reduction in the presence of palladium black, palladium carbon or the like under a hydrogen atmosphere, or by appropriately selecting acetic acid/hydrogen bromide, trifluoroacetic acid, hydrochloric acid/an organic solvent or the like depending on the protecting group.

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

The compound (IV) may be produced by a one-pot operation without separating the compound (II) and the compound (III) from the compound (I), for example, by adding a reagent for the production of the compound (IV) to the reaction system after the completion of the reaction in the production of the compound (III), and by adding a reagent for the deprotection reaction to the reaction system after the completion of the reaction, and then carrying out the reaction in the same manner. The same amount as described above can be used for the relation between the amounts of the reagents in any of the production processes.

(Production of Compound (VI))

To a suspension of 1 to 1.5 equivalents of sodium hydride/tetrahydrofuran at-10 to room temperature, a solution of compound (IV) such as tetrahydrofuran is added dropwise, and after stirring for 0.5 to 1 hour, the mixture is further stirred at-10 to room temperature for 0.5 to 1 hour in the presence of a metal chelating agent such as crown ether, tetramethyl ethylenediamine, dimethyl imidazolidinone, etc., and then pyridine-3-sulfonyl chloride is added, and stirring is carried out at 0℃for 0.5 hour. Further, pyridine-3-sulfonyl chloride is added and stirred at-10℃to room temperature for 0.5 to 1 hour, whereby compound (VI) can be produced.

The compound (VI) can be produced by adding a base such as triethylamine or N, N-diisopropylamine to a solution of the compound (IV) such as dichloromethane or acetonitrile at 0℃to room temperature, and a catalytic amount of 4-dimethylaminopyridine or pyridine-3-sulfonyl chloride, and stirring the mixture at room temperature to 100℃for 0.5 to 12 hours.

(Production of Compound (VII))

The compound (VII) can be obtained by adding dropwise a solution of methylamine in methanol or the like to a solution of compound (VI) in methanol or the like at 0℃to room temperature, stirring for 0.5 to 1 hour, and adding 1 to 3 equivalents of a reducing agent such as sodium borohydride at 0℃to room temperature to react for 0.5 to 1 hour.

(Preparation of Vonoprazan fumarate)

To a solution of compound (VII) in ethyl acetate, methanol or the like, a solution of fumaric acid in methanol or the like is added at 0 to room temperature, stirred for 0.5 to 1 hour, and the precipitated crystals are collected by filtration and recrystallized from methanol/water as necessary, whereby voronoi fumarate can be produced.

Examples

Hereinafter, the present invention will be described in more detail with reference to examples, comparative examples and test examples, but the present invention is not limited to these.

Example 1

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

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 1.2g,30.0 mmol) and tetrahydrofuran (10 mL) was added pyrrole (2.1 mL,30.0 mmol) dropwise under ice-cooling and stirred for 0.5 hours, and then zinc chloride (4.1 g,30.0 mmol) was added and stirred at room temperature for 0.5 hours. Next, palladium acetate (11 mg,0.05 mmol), 2- (di-t-butylphosphino) biphenyl (15 mg,0.05 mmol) and 1-fluoro-2-iodobenzene (1.1 mL,10.0 mmol) were added and after degassing, stirred at 60℃for 6 hours. The reaction mixture was cooled at 0℃and water was then added dropwise thereto, and the insoluble matter was filtered off, followed by separation with ethyl acetate. After ethyl acetate was added to the aqueous layer and extraction was repeated, the organic layers were combined and washed with saturated brine. After the solvent was distilled off under reduced pressure, purification was performed by silica gel column chromatography and drying was performed under reduced pressure, whereby the title compound (1.18 g, yield 74%) was obtained.

Mass spectrometry (ESI)：m/z calcd for C10H7FN[M－H]－：160.06;found：160.18;1H－NMR(400MHz,CDCl3)δ(ppm)：6.30－6.33(m,1H),6.64－6.67(m,1H),6.90－6.93(m,1H),7.07－7.16(m,1H),7.13－7.17(m,2H),7.60－7.65(m,1H),9.05(brs,1H).

Example 2

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

After a solution of 2- (2-fluorophenyl) -1H-pyrrole (172 mg,1.07 mmol) in tetrahydrofuran (2 mL) was added dropwise under ice-cooling to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 64mg,1.61 mmol) and tetrahydrofuran (2 mL) and stirred for 0.5 hours, 15-crown-5-ether (0.32 mL,1.61 mmol) was added and stirred at 0℃for 0.5 hours. Triisopropylsilyl chloride (0.35 mL,1.61 mmol) was then added dropwise and stirred at room temperature for 4 hours. Cooled to 0 ℃, water is added dropwise, and the mixture is separated by ethyl acetate. After ethyl acetate was added to the aqueous layer and extraction was repeated, the organic layers were combined and washed with saturated brine. After the solvent was distilled off under reduced pressure, purification was performed with a silica gel column and drying was performed under reduced pressure, whereby the title compound (272 mg, yield 80%) was obtained.

Mass spectrometry (ESI)：m/z calcd for C19H28FNNaSi[M+Na]+：340.19;found：340.16;1H－NMR(400MHz,CDCl3)δ(ppm)：1.01(d,J＝6.9Hz,18H),1.13－1.21(m,3H),6.25(dd,J＝3.2,1.2Hz,1H),6.37(t,J＝3.2Hz,1H),6.93(dd,J＝2.8,2.0Hz,1H),7.03－7.12(m,2H),7.29－7.37(m,2H).

Example 3

Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde

To a solution of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole (100 mg,0.32 mmol) in dichloromethane (3.0 mL) was added Vilsmeier reagent (123 mg,0.96 mmol) under ice-cooling and stirred at 40℃for 0.5H. After the solvent was distilled off under reduced pressure, an aqueous sodium hydroxide solution (1.0M, 3 mL) was added and stirred at room temperature for 6 hours, and ethyl acetate was added to conduct liquid separation. After ethyl acetate was added to the aqueous layer and extraction was repeated, the organic layers were combined and washed with saturated brine. Purification by silica gel column and drying under reduced pressure gave the title compound (48 mg, yield 80%).

Mass spectrometry (ESI)：m/z calcd for C11H8FNNaO[M+Na]+：212.05;found：212.03;1H－NMR(400MHz,CDCl3)δ(ppm)：7.07(dd,J＝2.0,1.2Hz,1H),7.12－7.26(m,3H),7.53(dd,J＝2.8,1.2Hz,1H),7.64(dt,J＝7.6,1.6Hz,1H),9.45(brs,1H),9.86(s,1H).

Example 4

Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 1.2g,30.0 mmol) and 4-methyltetrahydropyran (10 mL) was added pyrrole (2.1 mL,30.0 mmol) dropwise under ice-cooling and stirred for 0.5 hours, and then zinc chloride (4.1 g,30.0 mmol) was added and stirred at room temperature for 0.5 hours. Palladium acetate (11 mg,0.05 mmol), 2- (di-t-butylphosphino) biphenyl (15 mg,0.05 mmol) and 1-fluoro-2-iodobenzene (1.1 mL,10.0 mmol) were then added and stirred at 100℃for 0.5 hours. The reaction mixture was cooled at 0℃and 28% aqueous ammonia was added dropwise thereto, and the insoluble matter was filtered off, followed by separation with ethyl acetate. After the solvent was distilled off under reduced pressure, 2- (2-fluorophenyl) -1H-pyrrole was obtained as a crude product.

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 600mg,15 mmol) and tetrahydrofuran (10 mL) and dimethylimidazolidinone (2 mL) was added dropwise a solution of the crude product of the obtained 2- (2-fluorophenyl) -1H-pyrrole in tetrahydrofuran (2 mL) under ice-cooling and stirred for 0.5 hours. Triisopropylsilyl chloride (3.2 mL,15 mmol) was then added dropwise and stirred at room temperature for 2 hours. While cooling to 0 ℃, water was added dropwise and the mixture was separated with ethyl acetate. After the solvent was distilled off under reduced pressure, the liquid separation operation was performed again with heptane and water, and the solvent was distilled off under reduced pressure, whereby 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole was obtained as a crude product.

To a solution of the crude product of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole in methylene chloride (50 mL) was added Vilsmeier reagent (3.8 g,30 mmol) under ice-cooling and stirred at 40℃for 0.5 hours. After the solvent was distilled off under reduced pressure, an aqueous sodium hydroxide solution (1.0M, 100 mL) was added and stirred at room temperature for 6 hours, and ethyl acetate was added to conduct liquid separation. The organic layer was washed with saturated brine, and then the solvent was distilled off under reduced pressure. Recrystallization from heptane and ethyl acetate, drying under reduced pressure gave the title compound (1.34 g, yield 70%).

Example 5

Production of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde

After dropwise adding a solution of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (100 mg,0.53 mmol) in tetrahydrofuran (2 mL) under ice-cooling to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 32mg,0.79 mmol) and tetrahydrofuran (2 mL) and stirring for 0.5 hours, 15-crown-5-ether (0.16 mL,0.79 mmol) was added and stirring was carried out at 0℃for 0.5 hours. Next, pyridine-3-sulfonyl chloride (95. Mu.L, 0.79 mmol) was added and stirred at 0℃for 0.5 hours. Pyridine-3-sulfonyl chloride (95. Mu.L, 0.79 mmol) was further added and stirred at 0deg.C for 0.5 hours. Water was added dropwise and the mixture was partitioned with ethyl acetate. After ethyl acetate was added to the aqueous layer and extraction was repeated, the organic layers were combined and washed with saturated brine. After the solvent was distilled off under reduced pressure, it was purified by a silica gel column and dried under reduced pressure, whereby the title compound (167 mg, yield 95%) was obtained.

Mass spectrometry (ESI)：m/z calcd for C16H11FN2NaO3S「M+Na」+：353.04;found：353.00;1H－NMR(400MHz,CDCl3)δ(ppm)：6.68(d,J＝1.7Hz,1H),7.01－7.05(m,1H),7.16－7.18(m,2H),7.37－7.40(m,1H),7.45－7.51(m,1H),7.69－7.72(m,1H),8.15(d,J＝1.8Hz,1H),8.58(d,J＝1.7Hz,1H),8.82(dd,J＝4.8,1.5Hz,1H),9.90(s,1H).

Example 6

Production of 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methyl methylamine fumarate

To a solution of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde (100 mg,0.30 mmol) in methanol (3 mL) was added dropwise a solution of methylamine in methanol (2.0M, 1.06mL,2.12 mmol) at room temperature and stirred for 0.5 hours. Cooled to 0deg.C, sodium borohydride (34 mg,0.91 mmol) was added and stirred for 0.5 hours. 1 equivalent of hydrochloric acid (3 mL) was added dropwise at 0℃and stirred at room temperature for 0.5 hours. Saturated sodium bicarbonate water and ethyl acetate were added to separate the solution. After ethyl acetate was added to the aqueous layer and extraction was repeated, the organic layers were combined and washed with saturated brine. After concentrating the organic layer, ethyl acetate (3 mL) was added, and a solution of fumaric acid (39 mg,0.30 mmol) in methanol (0.3 mL) was added. After stirring at room temperature for 30 minutes, the precipitated crystals were filtered and washed with ethyl acetate and methanol to give a crude product. The obtained crude crystals were recrystallized from methanol and water, and the precipitated crystals were filtered and dried under reduced pressure, whereby the title compound (90 mg, yield 64%) was obtained.

Mass spectra (ESI)：m/z calcd for C17H17FN3NaO2S「M+H」+：346.09;found：346.11;1H－NMR(400MHz,DMSO－d6)δ(ppm)：2.39(s,3H),3.76(s,2H),6.44(d,J＝2.0Hz,1H),6.47(s,2H),7.10－7.13(m,1H),7.20－7.26(m,2H),7.50－7.56(m,1H),7.60－7.67(m,2H),7.85－7.89(m,1H),8.56(d,J＝2.8Hz,1H),8.87－8.89(m,1H).3H were not detected.

Example 7

Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 8.8g,220.0 mmol) and 4-methyltetrahydropyran (100 mL) was added pyrrole (15.7 mL,220.0 mmol) dropwise under ice-cooling and stirred for 0.5 hours, and then zinc chloride (30.3 g,220.0 mmol) was added and stirred at room temperature for 0.5 hours. Next, palladium acetate (56.1 mg,0.25 mmol), 2- (di-t-butylphosphino) biphenyl (74.6 mg,0.25 mmol) and 1-fluoro-2-iodobenzene (11.5 mL,100.0 mmol) were added and stirred at about 100deg.C for 1 hour. Aqueous sodium hydroxide (5.0N, 220.0 mmol) was added dropwise to the reaction mixture under ice-cooling, and stirred at room temperature for 0.5 hours. After insoluble matter was filtered, washed 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 the solvent was distilled off under reduced pressure, toluene (167 mL) was added to the residue. The solvent was distilled off under reduced pressure, whereby 2- (2-fluorophenyl) -1H-pyrrole was obtained as a crude product (20.9 g).

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 4.4g,110.0 mmol) and tetrahydrofuran (100 mL) and dimethylimidazolidinone (32.6 mL,300.0 mmol) was added dropwise a solution of the crude product of 2- (2-fluorophenyl) -1H-pyrrole in tetrahydrofuran (10 mL) under ice-cooling, and the mixture was rinsed with tetrahydrofuran (10 mL) and stirred for 0.5 hours. Triisopropylsilyl chloride (23.5 mL,110.0 mmol) was then added dropwise and stirred at room temperature for 1 hour. Distilled water (17 mL) was added dropwise under ice bath, and distilled water (167 mL) was further added. Extraction was performed 2 times with ethyl acetate (84 mL), and washed with distilled water (167 mL) and saturated brine (167 mL). After the solvent was distilled off under reduced pressure, toluene (167 mL) was added to the residue. After the solvent was distilled off under reduced pressure, whereby 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole was obtained 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 stirring was continued for 0.5 hours. A solution of the crude 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole in 4-methyltetrahydropyran (100 mL) was added in one portion and stirred at about 50℃for 3 hours. Aqueous sodium hydroxide (5.0M, 100 mL) was added under ice-cooling and 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. To the resulting solid residue was added ethyl acetate (47 mL), and after dissolution at about 70℃heptane (300 mL) was added. After cooling at room temperature, stirring was carried out for 1 hour under ice bath, and the precipitated crystals were collected by filtration and washed with cooled ethyl acetate: heptane (1:6, 70 mL). Drying at 50℃under reduced pressure for 1.5 hours gave the title compound (13.6 g, yield 72%).

Example 8

Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (one pot synthesis from 2- (2-fluorophenyl) -1H-pyrrole)

After dimethylimidazolidinone (20.0 mL,186 mmol) was added 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, 2.7g,68.2 mmol) was slowly added under ice-cooling and stirred for 10 minutes. Next, triisopropylsilyl chloride (14.6 mL,68.2 mmol) was added dropwise and stirred under ice-cooling for 2 hours. To a solution of Vilsmeier reagent in dichloromethane (90 mL) prepared from oxalyl chloride (10.6 mL,124 mmol) and DMF (9.65 mL,124 mmol) was added a reaction solution of 2- (2-fluorophenyl) -1H-pyrrole in one portion under ice-cooling, washed with 4-methyltetrahydropyran (20 mL) and stirred at about 60℃for 2 hours. Aqueous sodium hydroxide (2.0M, 310 mL) was added under ice-cooling and 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. To the resulting solid residue was added ethyl acetate (29 mL), and after dissolution at about 70℃heptane (180 mL) was added. After cooling at room temperature, stirring was carried out for 1 hour in an ice bath, and the precipitated crystals were collected by filtration and washed with cooled ethyl acetate: heptane (1:6, 42 mL). Drying at 50℃under reduced pressure for 1.5 hours gave the title compound (8.30 g, yield 71%).

Claims (5)

1. A process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde, characterized by comprising reacting an o-fluorobenzene derivative represented by the following formula (V) with pyrrole in the presence of a zinc halide and a palladium catalyst to give a pyrrole derivative represented by the following formula (I), introducing a protecting group into the nitrogen atom of the pyrrole ring in the pyrrole derivative represented by the following formula (I) to give an N-protected pyrrole derivative represented by the following formula (II), further obtaining a pyrrole-3-carbaldehyde derivative represented by the following formula (III) by formylation with a Vilsmeier reagent, further obtaining 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the following formula (IV) by deprotection reaction, wherein P represents a protecting group in the formula (II), L represents a leaving group,

2. The production method according to claim 1, wherein the zinc halide is zinc chloride.

3. The production process according to claim 1, wherein the protecting group represented by P in the formula (II) is a silyl protecting group.

4. A process for producing 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine, characterized by obtaining 5- (2-fluorophenyl) -1H-pyrrol-3-carbaldehyde represented by the general formula (IV) by the process according to claim 1, reacting 5- (2-fluorophenyl) -1H-pyrrol-3-carbaldehyde represented by the general formula (IV) with pyridine-3-sulfonyl chloride or a salt thereof in the presence of an inorganic base or an organic base to obtain a pyrrole derivative represented by the following formula (VI), condensing the pyrrole derivative with methylamine, and then subjecting the resultant product to a reduction reaction to obtain 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine represented by the following formula (VII),

5. A process for producing 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine monofumarate, characterized in that 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine represented by the general formula (VII) is obtained by the process according to claim 4, and 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine and fumaric acid represented by the general formula (VII) are used to obtain 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine monofumarate.