CN111527067A - Method for producing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethylamine monofumarate - Google Patents

Abstract

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

Description

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyridine Production method of pyrrole-3-yl]-N-methylmethylamine monofumarate

technical field

The present invention relates to 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monohydrate as an acid secretion inhibitor Methods for the manufacture of fumarate salts and intermediates thereof.

Background technique

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethylamine monofumaric acid represented by the following formula Salt (hereinafter referred to as vonoprazan fumarate) is a potassium ion-competitive acid blocker, which inhibits the combination of potassium ions with H+, K±ATPase, and inhibits gastric acid secretion. Therefore, it is used in the stomach/duodenum Treatment and prevention of ulcers, etc., and pH adjustment in the stomach during sterilization of Helicobacter pylori. It is known that vonoprazan fumarate is more stable to acid than the existing proton pump inhibitors, reaches an effective concentration quickly, takes it quickly until the effect appears, and strongly inhibits gastric acid for a long time.

Regarding the production method of vonoprazan fumarate, for example, Patent Document 1 discloses a method for synthesizing a pyrrole-3-carbaldehyde derivative as a synthesis intermediate from a cyano compound represented by the following formula via a pyrrole body.

In this method, [2-(2-fluorophenyl)-2-oxoethyl]malononitrile (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 the reaction of α-bromo-o-fluoroacetophenone and malononitrile. In addition, it is described that α-bromo-o-fluoroacetophenone can be produced by a generally known method. Although not specifically described, for example, 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 material requires two steps, the production of the target compound requires a plurality of steps. In addition, in these reactions, since malononitrile, which is concerned about toxicity and environmental impact, and bromine, which is corrosive and irritating, are used, a production method that further considers safety to human body and the environment is desired. In addition, 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde was synthesized from the raw materials in a yield of 53% to 60%, and the improvement of the yield was also desired.

Therefore, a production method with less impact on the human body and the environment, shorter steps, and 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

SUMMARY OF THE INVENTION

An object of the present invention is to provide a method for synthesizing an intermediate pyrrole-3-carbaldehyde derivative in the production of vonoprazan fumarate, and an industrial method for producing a novel vonoprazan fumarate using the derivative .

The inventors of the present invention have conducted intensive studies and, as a result, found that it is possible to efficiently and simply use a regioselective formylation reaction based on a coupling reaction of readily available fluoroiodobenzene and pyrrole and a regioselective formylation reaction based on appropriate protection of nitrogen atoms on the pyrrole ring. A method for producing a pyrrole-3-carbaldehyde derivative has led to the completion of the present invention.

which is,

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

In the pyrrole derivative represented by the following general formula (I), a protecting group is introduced into the nitrogen atom of the pyrrole ring to obtain an N-protected pyrrole derivative represented by the following formula (II) (wherein P represents a protecting group), A pyrrole-3-carbaldehyde derivative represented by the following formula (III) was further obtained by formylation, and 5-(2-fluorophenyl)-1H- represented by the following formula (IV) was further obtained by a deprotection reaction. Pyrrole-3-carbaldehyde.

[2] Further, the present invention relates to the production method according to the above [1], wherein the protective group represented by the P is a silyl-based protective group.

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

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

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

[6] In addition, the present invention relates to 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine The production method of the invention comprises combining the 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde represented by the general formula (IV) obtained by the production method with pyridine-3 in the presence of an inorganic base or an organic base - Sulfonyl chloride or its salt is reacted to obtain a pyrrole derivative represented by the following formula (VI), and further condensed with methylamine, and then 1-[5-(2 represented by the following formula (VII) is obtained by a reduction reaction -Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine.

[7] In addition, the present invention relates to 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine The production method of monofumarate utilizes the compound of general formula (VII) obtained by the above production method and fumaric acid.

In the present invention, 5-(2-fluorophenyl)-1H-pyrrole can be obtained in a short time and in a short process and in a good yield (70% or more) using readily available raw materials such as pyrrole and 2-fluoroiodobenzene at low cost. 3-formaldehyde, compared with the existing methods, has high economy and productivity, and is suitable for industrial production. Furthermore, the use of the transition metal catalyst is also suppressed to an extremely small amount, and the use of the transition metal catalyst in the upstream process can further reduce the fear of remaining metal impurities in the final product.

Detailed ways

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

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

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

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

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 carbamate-based protecting groups include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-amyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and benzyloxy Carbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl, p-methoxyphenylazobenzyloxycarbonyl, 3 ,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, p-biphenylisopropoxycarbonyl, diisopropylmethoxycarbonyl, 2-(trimethylmethyl) Silyl) ethoxycarbonyl, 9-fluorenylmethoxycarbonyl and the like.

In addition, as other protective groups, alkylsulfonyl groups such as methanesulfonyl groups, arylsulfonyl groups such as p-toluenesulfonyl groups, alkyl acyl groups such as acetyl groups, and aryl acyl groups such as benzoyl groups can be used.

Among these protecting groups, from the viewpoint of yield and the like, silyl-based protecting groups are preferable, and trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl are particularly preferable as protecting groups. , a triisopropylsilyl group, more preferably a triisopropylsilyl group.

In the present invention, as the metal catalyst used in the reaction of 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, and divalent nickel catalysts such as nickel chloride and bis(triphenylphosphine)nickel chloride. Nickel catalyst, etc., if necessary, triphenylphosphine, 2-(di-tert-butylphosphino)biphenyl, Xantphos, bis[2-(diphenylphosphino)phenyl]ether (hereinafter DPEPhos), ( Phosphine ligands such as ±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter (±)-BINAP), N,N,N',N'-tetramethyl Ethylenediamine, etc.

Examples of the palladium catalyst used in the present invention include 0-valent palladium catalysts such as palladium carbon and tetrakis(triphenylphosphine)palladium, palladium chloride, palladium acetate, and (dichlorobis(tri-o-tolylphosphine))palladium. Divalent palladium catalysts such as triphenylphosphine, phosphine ligands such as 2-(di-tert-butylphosphino)biphenyl, Xantphos, DPEPhos, (±)-BINAP, etc. 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 hydride, sodium amide, lithium diisopropylamide (hereinafter referred to as LDA), Metal bases such as lithium hexamethyldisilazide (hereinafter, LiHMDS), ethylmagnesium, sodium carbonate, calcium carbonate, and the like.

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

(Production of Compound (I))

烷、单甘醇二甲醚、二甘醇二甲醚等醚类、苯、甲苯、二甲苯等芳香族烃类等的溶剂悬浮液中在－10℃～室温下滴加1～3当量的吡咯/上述溶剂的溶液并搅拌10分钟～1小时后，加入1～3当量的卤化锌(氯化锌、溴化锌)等无机锌、二新戊酰基锌等有机锌(优选为卤化锌、特别优选为氯化锌)并在室温下搅拌10分钟～1小时。接着，加入1～3当量的化合物(V)、0.0001～1.0当量(优选为0.001～0.003当量)的钯等上述催化剂以及0.0001～1.0当量(优选为0.001～0.003当量)的上述膦配体，并在室温～150℃(优选为90～130℃)下反应5分钟～24小时，由此可以制造化合物(I)。Compound (I) can be produced by the cross-coupling reaction described in Non-Patent Document 3 and Non-Patent Document 4, or the like. For example, by using a Negishi coupling reaction using unhalogenated unsubstituted pyrrole, under an inert gas atmosphere such as nitrogen or argon, 1 to 3 equivalents of the above-mentioned base, preferably a metal base, more preferably sodium hydride can be added to Diethyl ether, cyclopropyl methyl ether, tetrahydrofuran, 4-methyltetrahydropyran, diethyl ether

To the solvent suspension of ethers such as alkane, monoglyme and diglyme, aromatic hydrocarbons such as benzene, toluene and xylene, etc., dropwise add 1 to 3 equivalents of After stirring the pyrrole/solvent solution for 10 minutes to 1 hour, 1 to 3 equivalents of inorganic zinc such as zinc halide (zinc chloride, zinc bromide) and organic zinc such as dipivaloyl zinc (preferably zinc halide, zinc bromide, etc.) are added. Particularly preferred is zinc chloride) and stirred at room temperature for 10 minutes to 1 hour. Next, 1 to 3 equivalents of the compound (V), 0.0001 to 1.0 equivalents (preferably 0.001 to 0.003 equivalents) of the above-mentioned catalysts such as palladium, and 0.0001 to 1.0 equivalents (preferably 0.001 to 0.003 equivalents) of the above-mentioned phosphine ligands are added, and Compound (I) can be produced by reacting at room temperature to 150°C (preferably 90 to 130°C) for 5 minutes to 24 hours.

(Production of Compound (II))

烷、单甘醇二甲醚、二甘醇二甲醚等醚类或N,N－二甲基甲酰胺等非质子性极性溶剂或者它们的混合溶剂、优选为醚类等的溶剂悬浮液中在－10℃～室温下滴加化合物(I)后，加入冠醚、四乙二胺、二甲基咪唑啉酮等金属螯合剂、优选为二甲基咪唑啉酮，接着滴加1～1.5当量的保护基导入试剂使其反应5分钟～3小时，由此可以制造化合物(II)。The compound (II) can be produced by introducing a protecting group into the compound (I). The production method for introducing the protecting group varies depending on the protecting group selected, but a generally known method can be employed. For example, when introducing 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, cyclopropyl methyl ether, tetrahydrofuran, 4-methyl Tetrahydropyran, Di

Ethers such as alkane, monoglyme, diglyme, etc., or aprotic polar solvents such as N,N-dimethylformamide, or a mixed solvent thereof, preferably a solvent suspension of ethers, etc. After the compound (I) is added dropwise at -10°C to room temperature, a metal chelating agent such as crown ether, tetraethylenediamine, and dimethylimidazolidinone, preferably dimethylimidazolidinone, is added, followed by dropwise addition of 1 to Compound (II) can be produced by reacting 1.5 equivalents of the protecting group-introducing reagent for 5 minutes to 3 hours.

烷、二

烷/水、二氯甲烷、四氢呋喃等溶剂中，在三乙基胺、吡啶等有机碱、氢化钠、氢氧化钾、氢氧化钠、碳酸氢钾、碳酸氢钠等无机碱的存在下，使二碳酸二叔丁酯((Boc)₂O)、叔丁氧基羰基氯化物、苄氧基羰基氯化物、叔戊氧基羰基氯化物、9－芴基甲氧基羰基氯化物、氯甲酸2,2,2－三氯乙酯、2－(三甲基甲硅烷基)乙氧基甲基氯化物、叔丁氧基羰基叠氮化物、苄氧基羰基叠氮化物等一般公知的Boc基等的导入试剂1～1.5当量在0℃～100℃反应5分钟～10小时而制造。In addition, when introducing a carbamate-based protecting group, the reaction conditions differ depending on the type of carbamate-based protecting group. For example, a tert-butoxycarbonyl group (Boc group), a tert-amyloxycarbonyl group ( Aoc group) or benzyloxycarbonyl (Z group), 9-fluorenylmethoxycarbonyl (Fmoc) group, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethyl Oxycarbonyl, etc., can be

alkane, two

In solvents such as alkane/water, dichloromethane, tetrahydrofuran, etc., in the presence of organic bases such as triethylamine and pyridine, and inorganic bases such as sodium hydride, potassium hydroxide, sodium hydroxide, potassium bicarbonate, and sodium bicarbonate, the Di-tert-butyl dicarbonate ((Boc) ₂ O), tert-butoxycarbonyl chloride, benzyloxycarbonyl chloride, tert-amyloxycarbonyl chloride, 9-fluorenylmethoxycarbonyl chloride, chloroformic acid Commonly known Boc such as 2,2,2-trichloroethyl ester, 2-(trimethylsilyl)ethoxymethyl chloride, tert-butoxycarbonyl azide, benzyloxycarbonyl azide, etc. 1 to 1.5 equivalents of introducing reagents such as radicals are produced by reacting at 0°C to 100°C for 5 minutes to 10 hours.

(Production of Compound (III))

烷等醚类或乙酸乙酯、乙腈、N,N－二甲基甲酰胺等非质子性极性溶剂或者它们的混合溶剂、优选为醚系溶剂、芳香族烃类、非质子性极性溶剂或者它们的混合溶剂、更优选为甲基四氢吡喃中，在0～100℃(优选为40～80℃)搅拌0.5～12小时后使其反应，由此可以制造化合物(III)。Compound (III) can be produced by generally known formylation reactions, such as Vilsmeier reaction, Rieche reaction, Daff reaction, Reimer-Tiemann reaction, etc., for example, in Vilsmeier reaction, from N,N-dimethylformamide (DMF) ), N-methylformanilide (MFA), N-formylmorpholine, N,N-diisopropylformamide and other N,N-disubstituted formamides and phosphorus oxychloride, oxalyl chloride, sulfite Acid chlorides, triphenylphosphine-bromide, hexachlorocyclotriphosphazene and other acid chlorides were prepared with Vilsmeier reagent ((chloromethylene)dimethylammonium chloride) or purchased commercially, and mixed with compound (II) in a solvent For example, phosphorus oxychloride; or halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons such as benzene, toluene, and nitrobenzene; tetrahydrofuran, methyltetrahydrofuran, etc. Pyran, Di

Ethers such as alkane, aprotic polar solvents such as ethyl acetate, acetonitrile, N,N-dimethylformamide, or their mixed solvents, preferably ether-based solvents, aromatic hydrocarbons, and aprotic polar solvents Alternatively, compound (III) can be produced by stirring in a mixed solvent of these, more preferably methyltetrahydropyran, at 0 to 100°C (preferably 40 to 80°C) for 0.5 to 12 hours and then reacting.

(Production of Compound (IV))

Compound (IV) can be produced by deprotection reaction of compound (III). The deprotection reaction varies depending on the protecting group, and generally known methods can be used. For example, when the protecting group is a silyl-based protecting group, tetrabutylammonium fluoride can be obtained by deprotecting tetrabutylammonium fluoride in a solution such as tetrahydrofuran at -10°C to room temperature. , HF pyridine complex, HF triethylamine complex and other fluorine sources react to produce. In addition, even under acidic conditions such as hydrochloric acid and trifluoroacetic acid, and under basic conditions such as sodium hydroxide aqueous solution, the deprotection reaction of the silyl-based protecting group proceeds in the same manner to produce compound (IV). As the deprotection reagent, an aqueous sodium hydroxide solution in an amount of 3 to 10 equivalents (preferably 5 equivalents) can be used with respect to compound (III).

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

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

In addition, compound (IV) can also be produced by one-pot operation without separating compound (II) and compound (III) from compound (I). For example, after the reaction in the production of compound (III) is completed, Compound (IV) can be produced by adding the reagent used in the production of the above-mentioned compound (IV) to the reaction system, and after the completion of the reaction, adding the reagent for the above-mentioned deprotection reaction to the reaction system and performing the reaction in the same manner. . The quantitative relationship of the reagents in any production can be used in the same amounts as those described above.

(Production of Compound (VI))

A solution of compound (IV) in tetrahydrofuran, etc. was added dropwise to a suspension of 1 to 1.5 equivalents of sodium hydride/tetrahydrofuran at -10°C to room temperature, and after stirring for 0.5 to 1 hour, the solution was further added to crown ether, tetramethylethylenedi The mixture was stirred at -10°C to room temperature for 0.5 to 1 hour in the presence of a metal chelating agent such as an amine and dimethylimidazolidinone, and then pyridine-3-sulfonyl chloride was added, followed by stirring at 0°C for 0.5 hour. Further, pyridine-3-sulfonyl chloride is added, and the compound (VI) can be produced by stirring at -10°C to room temperature for 0.5 to 1 hour.

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

(Production of Compound (VII))

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

(Manufacture of Vonorazan Fumarate)

A solution of fumaric acid in methanol or the like is added to a solution of compound (VII) in ethyl acetate, methanol, or the like at 0°C to room temperature, followed by stirring for 0.5 to 1 hour. By recrystallization, vornorazan fumarate can be produced.

Example

Hereinafter, the present invention will be described in more detail using Examples, Comparative Examples, and Test Examples, but the present invention is not limited to these.

Example 1

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

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 tetrahydrofuran (10 mL) under ice-cooling, and after stirring for 0.5 hours, zinc chloride ( 4.1 g, 30.0 mmol) and stirred at room temperature for 0.5 h. Next, 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 and degassed Then, it stirred at 60 degreeC for 6 hours. Water was added dropwise to the reaction mixture while cooling at 0°C, and the insoluble matter was filtered, followed by liquid separation with ethyl acetate. After adding ethyl acetate to the aqueous layer and extracting again, the organic layers were combined and washed with saturated brine. After the solvent was distilled off under reduced pressure, it was purified by silica gel column chromatography and dried under reduced pressure to obtain the title compound (1.18 g, yield 74%).

Mass spectrum (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

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 64 mg, 1.61 mmol) and tetrahydrofuran (2 mL) was added dropwise a solution of 2-(2-fluorophenyl)-1H-pyrrole (172 mg, 1.07 mmol) under ice-cooling. After a solution of tetrahydrofuran (2 mL) and stirring for 0.5 h, 15-crown-5-ether (0.32 mL, 1.61 mmol) was added and stirred at 0°C for 0.5 h. Next, triisopropylsilyl chloride (0.35 mL, 1.61 mmol) was added dropwise and stirred at room temperature for 4 hours. It was cooled to 0 degreeC, water was added dropwise, and the liquid 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. After the solvent was distilled off under reduced pressure, it was purified with a silica gel column and dried under reduced pressure to obtain the title compound (272 mg, yield 80%).

Mass spectrum (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) under ice-cooling , 0.96 mmol) and stirred at 40 °C for 0.5 h. After the solvent was evaporated under reduced pressure, an aqueous sodium hydroxide solution (1.0 M, 3 mL) was added, the mixture was stirred at room temperature for 6 hours, and ethyl acetate was added for liquid separation. 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%).

Mass spectrum (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, 1.2 g, 30.0 mmol) and 4-methyltetrahydropyran (10 mL) was added dropwise pyrrole (2.1 mL, 30.0 mmol) under ice cooling and stirred for 0.5 hour After that, 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-tert-butylphosphino)biphenyl (15 mg, 0.05 mmol) and 1-fluoro-2-iodobenzene (1.1 mL, 10.0 mmol) were added at 100°C Stir for 0.5 hour. While cooling the reaction mixture at 0°C, 28% aqueous ammonia was added dropwise, and the insoluble matter was filtered, followed by liquid separation with ethyl acetate. After the solvent was distilled off under reduced pressure, 2-(2-fluorophenyl)-1H-pyrrole was obtained as a crude product.

The obtained 2-(2-fluorophenyl) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 600 mg, 15 mmol), tetrahydrofuran (10 mL) and dimethylimidazolidinone (2 mL) under ice cooling. A solution of the crude product of -1H-pyrrole in tetrahydrofuran (2 mL) was stirred for 0.5 hours. Next, triisopropylsilyl chloride (3.2 mL, 15 mmol) was added dropwise and stirred at room temperature for 2 hours. Water was added dropwise while cooling to 0°C, followed by liquid separation 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 to obtain 2-(2-fluorophenyl)-1-(trisine as a crude product. isopropylsilyl)-1H-pyrrole.

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) and stirred at 40 °C for 0.5 h. After the solvent was distilled off under reduced pressure, an aqueous sodium hydroxide solution (1.0 M, 100 mL) was added, the mixture was stirred at room temperature for 6 hours, and ethyl acetate was added for liquid separation. After the organic layer was washed with saturated brine, the solvent was evaporated under reduced pressure. It was recrystallized from heptane and ethyl acetate, and dried under reduced pressure to obtain the title compound (1.34 g, yield 70%).

Example 5

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

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 32 mg, 0.79 mmol) and tetrahydrofuran (2 mL) was added dropwise 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (100 mg, under ice-cooling) 0.53 mmol) in tetrahydrofuran (2 mL) and stirred for 0.5 h, 15-crown-5-ether (0.16 mL, 0.79 mmol) was added and stirred at 0°C for 0.5 h. Next, pyridine-3-sulfonyl chloride (95 μL, 0.79 mmol) was added, and the mixture was stirred at 0° C. for 0.5 hours. Further, pyridine-3-sulfonyl chloride (95 μL, 0.79 mmol) was added, and the mixture was stirred at 0° C. for 0.5 hours. 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. After the solvent was distilled off under reduced pressure, it was purified with a silica gel column and dried under reduced pressure to obtain the title compound (167 mg, yield 95%).

Mass spectrum (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-methylmethanamine fumarate

Methylamine was added dropwise to a solution of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (100 mg, 0.30 mmol) in methanol (3 mL) at room temperature in methanol (2.0 M, 1.06 mL, 2.12 mmol) and stirred for 0.5 h. Cool to 0°C, add sodium borohydride (34 mg, 0.91 mmol) and stir for 0.5 h. 1 N hydrochloric acid (3 mL) was added dropwise at 0°C, and the mixture was stirred at room temperature for 0.5 hours. Saturated sodium bicarbonate water and ethyl acetate were added for liquid separation. After adding ethyl acetate to the aqueous layer and extracting again, the organic layers were combined and washed with saturated brine. After the organic layer was concentrated, 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 obtain a crude product. The obtained crude crystals were recrystallized from methanol and water, and the precipitated crystals were filtered and dried under reduced pressure to obtain the title compound (90 mg, yield 64%).

Mass spectrum (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 was not detected.

Example 7

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

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 8.8 g, 220.0 mmol) and 4-methyltetrahydropyran (100 mL) was added dropwise pyrrole (15.7 mL, 220.0 mmol) under ice cooling and stirred for 0.5 h After that, zinc chloride (30.3 g, 220.0 mmol) was added and stirred at room temperature for 0.5 hour. Next, 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, Stir at about 100°C for 1 hour. Under ice-cooling, an aqueous sodium hydroxide solution (5.0 N, 220.0 mmol) was added dropwise to the reaction mixture, followed by stirring at room temperature for 0.5 hour. The insoluble matter was filtered and 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 to obtain 2-(2-fluorophenyl)-1H-pyrrole as a crude product (20.9 g).

To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 4.4 g, 110.0 mmol), tetrahydrofuran (100 mL) and dimethylimidazolidinone (32.6 mL, 300.0 mmol) was added dropwise the resulting 2-( A solution of crude 2-fluorophenyl)-1H-pyrrole in tetrahydrofuran (10 mL), rinsed with tetrahydrofuran (10 mL) and stirred for 0.5 h. Next, triisopropylsilyl chloride (23.5 mL, 110.0 mmol) was added dropwise and stirred at room temperature for 1 hour. Distilled water (17 mL) was added dropwise under an ice bath, and distilled water (167 mL) was further added. Extraction was performed twice 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, the solvent was distilled off under reduced pressure to obtain 2-(2-fluorophenyl)-1-(triisopropylsilyl) as a crude product (45.2 g). -1H-pyrrole.

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 solution of the resulting crude 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole in 4-methyltetrahydropyran (100 mL) was added in one portion and heated at about 50 °C was stirred for 3 hours. Aqueous sodium hydroxide solution (5.0 M, 100 mL) was added under ice cooling and stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was separated with ethyl acetate (200 mL). The organic layers were combined, washed with saturated brine (200 mL), and then the solvent was evaporated 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 standing to cool 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). It was dried at 50°C for 1.5 hours under reduced pressure, whereby the title compound (13.6 g, yield 72%) was obtained.

Example 8

Production of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (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 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's reagent in dichloromethane (90 mL) prepared from oxalyl chloride (10.6 mL, 124 mmol) and DMF (9.65 mL, 124 mmol) was added 2-(2-fluorophenyl)-1H-pyrrole in one portion under ice cooling The resulting reaction solution was rinsed with 4-methyltetrahydropyran (20 mL) and stirred at about 60° C. for 2 hours. Aqueous sodium hydroxide solution (2.0 M, 310 mL) was added under ice cooling and stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was separated with ethyl acetate (120 mL). The organic layers were combined, washed with saturated brine (120 mL), and then the solvent was evaporated 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 standing to cool 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). It was dried at 50°C for 1.5 hours under reduced pressure, whereby the title compound (8.30 g, yield 71%) was obtained.

Claims (7)

1. A process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde, which comprises introducing a protecting group to the nitrogen atom of the pyrrole ring in a pyrrole derivative represented by the following formula (I) to obtain an N-protected pyrrole derivative represented by the following formula (II), formylating the N-protected pyrrole derivative to obtain a pyrrole-3-carbaldehyde derivative represented by the following formula (III), and deprotecting the N-protected pyrrole derivative to obtain 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the following formula (IV) wherein P represents a protecting group,

2. the production method according to claim 1, wherein the protecting group represented by P is a silyl protecting group.

3. The production process according to claim 1 or 2, wherein the protecting group represented by P is triisopropylsilyl.

4. A process for producing a compound (I) according to any one of claims 1 to 3, wherein the pyrrole derivative of the general formula (I) is obtained by reacting an o-fluorobenzene derivative represented by the following formula (V) with pyrrole in the presence of a metal catalyst,

in the formula (V), L represents a leaving group.

5. The production method according to claim 4, wherein the metal catalyst is a palladium catalyst.

6. A process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine, which comprises reacting 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the general formula (IV) obtained by the above production process 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), further condensing the pyrrole derivative with methylamine, and then subjecting the condensation reaction to a reduction reaction to obtain 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine represented by the following formula (VII),

7. a process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanamine monofumarate, which comprises using a compound of the general formula (VII) obtained by the above production process and fumaric acid.