JP7227925B2 - Method for producing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate - Google Patents

Description

The present invention provides an acid secretion inhibitor, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine mono It relates to a method for producing a fumarate salt and intermediates thereof.

1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate represented by the following formula (hereinafter , vonoprazan fumarate) is a potassium ion-competitive acid blocker that inhibits the binding of potassium ions to H +, K ± ATPase and suppresses gastric acid secretion, so it is used in the treatment of gastric and duodenal ulcers. It is used for the prevention of infection and for adjusting the intragastric pH when eradicating Helicobacter pylori. Compared to existing proton pump inhibitors, vonoprazan fumarate is stable against acid, reaches an effective concentration quickly, takes a short time from administration to manifestation of action, and strongly suppresses gastric acid over a long period of time. It is known.

Regarding the method for producing vonoprazan fumarate, for example, in Patent Document 1, a pyrrole-3-carboxaldehyde derivative, which is a synthetic intermediate, is synthesized from a cyano compound represented by the following formula via a pyrrole form. A method for doing so is disclosed.

In this method, [2-(2-fluorophenyl)-2-oxoethyl]propanedinitrile (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 it is synthesized from 2-fluorophenacyl bromide by reacting malononitrile. It also describes 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) and a method of reacting with bromine in the presence of aluminum chloride are known (Non-Patent Document 2). Since two steps are required to synthesize the raw materials, multiple steps are required to produce the desired compound. In addition, since these reactions require malononitrile and bromine, which is highly corrosive and irritating, which are concerned about toxicity and environmental impact, a production method that is more safe for the human body and the environment is desired. In addition, 5-(2-fluorophenyl)-1H-pyrrol-3-carboxaldehyde is synthesized from raw materials with a yield of 53% to 60%, and an improvement in yield is desired.
Therefore, there is a demand for a production method which has less impact on the human body and the environment, which involves a shorter process and which has a high yield.

Japanese Patent No. 5819494 Japanese Patent 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

The present invention provides a method for producing a synthetic intermediate pyrrole-3-carboxaldehyde derivative in the production of vonoprazan fumarate and a novel industrial production method for vonoprazan fumarate using the derivative. for the purpose.

As a result of intensive studies, the present inventors have found that by using a coupling reaction with easily available fluoroiodobenzene and pyrrole and a regioselective formylation reaction by appropriately protecting the nitrogen atom on the pyrrole ring, The present inventors have found a method for producing a -ru-3-carboxaldehyde derivative in a high yield and in a simple manner, thereby completing the present invention.

That is, [1] the present invention provides the following general formula (I),

で表されるピロ－ル誘導体において、ピロ－ル環の窒素原子に保護基を導入し、
下記式（ＩＩ）：

In the pyrrole derivative represented by, a protecting group is introduced to the nitrogen atom of the pyrrole ring,
Formula (II) below:

（式中、Ｐは保護基を表す）で表されるＮ保護ピロ－ル誘導体を得、さらにホルミル化により下記式（ＩＩＩ）

(Wherein, P represents a protecting group) to obtain an N-protected pyrrole derivative represented by the following formula (III) by formylation

で表されるピロ－ル－３－カルボキシアルデヒド誘導体を得、さらに脱保護反応により下記式（ＩＶ）

To obtain a pyrrole-3-carboxaldehyde derivative represented by the following formula (IV) by further deprotection reaction

で表される５－（２－フルオロフェニル）－１Ｈ－ピロ－ル－３－カルボキシアルデヒドの［２］また本発明は、前記Ｐで表される保護基が、シリル系保護基である前記［１］記載の製造方法に関するものである。
［３］また本発明は、前記Ｐで表される保護基が、トリイソプロピルシリル基である前記［１］又は［２］記載の製造方法に関するものである。
［４］また本発明は、前記一般式（Ｉ）のピロール誘導体が、
下記式（Ｖ）：

[2] of 5-(2-fluorophenyl)-1H-pyrrol-3-carboxaldehyde represented by [2] The protecting group represented by P is a silyl-based protecting group [ 1] relates to the production method described above.
[3] The present invention also relates to the production method according to [1] or [2], wherein the protective group represented by P is a triisopropylsilyl group.
[4] The present invention also provides the pyrrole derivative of the general formula (I),
Formula (V) below:

（式中、Ｌは脱離基を表す）で表されるオルトフルオロベンゼン誘導体を、金属触媒存在下、ピロ－ルと反応させることにより得られたものである前記［１］～［３］記載の化合物（Ｉ）の製造方法に関するものである。
［５］また本発明は、前記金属触媒がパラジウム触媒である前記［４］記載の製造方法に関するものである。
［６］また本発明は、前記製造方法により得られた一般式（ＩＶ）で表される５－（２－フルオロフェニル）－１Ｈ－ピロ－ル－３－カルボキシアルデヒドを、無機塩基または有機塩基の存在下、ピリジン－３－スルホニルクロリドまたはその塩と反応させ、
下記式（ＶＩ）：

(wherein L represents a leaving group), which is obtained by reacting an orthofluorobenzene derivative represented by with pyrrole in the presence of a metal catalyst, according to [1] to [3] above. It relates to a method for producing compound (I) of
[5] The present invention also relates to the production method according to the above [4], wherein the metal catalyst is a palladium catalyst.
[6] Further, the present invention provides 5-(2-fluorophenyl)-1H-pyrrol-3-carboxaldehyde represented by the general formula (IV) obtained by the above-described production method with an inorganic base or an organic base. reacting with pyridine-3-sulfonyl chloride or a salt thereof in the presence of
Formula (VI) below:

で表されるピロ－ル誘導体を得、さらにメチルアミンと縮合させた後、還元反応により、下記式（ＶＩＩ）：

to obtain a pyrrole derivative represented by the following formula (VII):

で表される１－［５－（２－フルオロフェニル）－１－（ピリジン－３－イルスルホニル）－１Ｈ－ピロ－ル－３－イル］－Ｎ－メチルメタンアミンの製造方法に関するものである。
［７］また本発明は、前記製造方法により得られた一般式（ＶＩＩ）の化合物とフマル酸による１－［５－（２－フルオロフェニル）－１－（ピリジン－３－イルスルホニル）－１Ｈ－ピロ－ル－３－イル］－Ｎ－メチルメタンアミンモノフマル酸塩の製造方法に関するものである。

It relates to a method for producing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine represented by .
[7] The present invention also provides 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H produced by the compound of general formula (VII) obtained by the above production method and fumaric acid. -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-pyrrol-3-carboxaldehyde at a low cost in a short time and in a short process. It can be obtained with a high yield (70% or more), is more economical and more productive than conventional methods, and is suitable for industrial production. Furthermore, by limiting the amount of transition metal catalyst to be used and using it in the upstream process, it is possible to further reduce concerns about metal impurities remaining in the final product.

The present invention will be described in more detail below.
In the general formula (V), the leaving group represented by L includes halogen atoms of chlorine, bromine and iodine, lower alkanesulfonyloxy groups such as methanesulfonyloxy and trifluoromethanesulfonyloxy, and benzenesulfonyloxy. and an arylsulfonyloxy group such as a p-toluenesulfonyloxy group.

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 car Bamate-based protecting groups and the like, and silyl-based protecting groups include trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group and the like, preferably tert. -Butyldimethylsilyl group, triisopropylsilyl group and the like.
Examples of alkyl protecting groups include allyl group, dimethoxymethyl group, diethoxymethyl group, tert-butyl group, triphenylmethyl group, benzyl group, 4-methoxybenzyl group and the like.
Heteroaryl protecting groups include 2-pyridyl, 4-pyridyl, 2-pyrazyl, 2-pyrimidyl and 2-triazyl groups.
Carbamate-based protective groups include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-amyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-chloro benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group and the like.
As other protective groups, alkylsulfonyl groups such as methanesulfonyl group, arylsulfonyl groups such as p-toluenesulfonyl group, alkylacyl groups such as acetyl group, and arylacyl groups such as benzoyl group can be used.
Among these protecting groups, the protecting group is preferably a silyl-based 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. A triisopropylsilyl group is preferred.

In the present invention, a nickel catalyst, a palladium catalyst, or the like can be used as the metal catalyst used in the reaction for obtaining compound (I) from compound (V).
Examples of the nickel catalyst used in the present invention include zerovalent nickel catalysts such as bis(1,5-cyclooctadienyl)nickel, divalent nickel catalysts such as nickel chloride and bis(triphenylphosphine)nickel chloride. optionally triphenylphosphine, 2-(di-tert-butylphosphino)biphenyl, Xantphos, bis[2-(diphenylphosphino)phenyl]ether (hereinafter DPEPhos), (±)-2, A phosphine ligand such as 2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as (±)-BINAP), N,N,N',N'-tetramethylethylenediamine, etc. can be added. can.
The palladium catalyst used in the present invention includes zerovalent palladium catalysts such as palladium carbon and tetrakistriphenylphosphine palladium, or divalent palladium catalysts such as palladium chloride, palladium acetate, and (dichlorobis(tri-o-tolylphosphine))palladium. Catalysts can be mentioned, and if necessary, phosphine ligands such as triphenylphosphine, 2-(di-tert-butylphosphino)biphenyl, Xantphos, DPEPhos, (±)-BINAP and the like can be added.
Examples of bases used in the present invention include tertiary amines such as triethylamine and diisopropylethylamine, lithium hydride, sodium hydride, potassium hydrogen, sodium amide, lithium diisopropylamide (hereinafter LDA), lithium hexamethyldisilazide (hereinafter , LiHMDS), metal bases such as ethylmagnesium, sodium carbonate, calcium carbonate, and the like can be added.

A method for producing a pyrrole-3-carboxaldehyde derivative, which is a synthetic intermediate in the production of vonoprazan fumarate in the present invention, and a method for producing vonoprazan fumarate using the derivative are described below.

(Production of compound (I))
Compound (I) can be produced by the cross-coupling reaction described in Non-Patent Document 3 and Non-Patent Document 4, and the like. For example, non-halogenated unsubstituted pyrrole can be used by using a Negishi coupling reaction, and 1 to 3 equivalents of the above base, preferably a metal base, under an inert gas atmosphere such as nitrogen or argon. Ethers such as sodium hydride diethyl ether, cyclopropyl methyl ether, tetrahydrofuran, 4-methyltetrahydropyran, dioxane, monoglyme and diglyme; aromatic hydrocarbons such as benzene, toluene and xylene are preferred. 1 to 3 equivalents of pyrrole / solution of the above solvent was added dropwise at -10 ° C. to room temperature and stirred for 10 minutes to 1 hour, then 1 to 3 equivalents of zinc halide (zinc chloride, zinc bromide ), 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 is 0.001 to 0.003 equivalent) of the phosphine ligand and reacted at room temperature to 150° C. (preferably 90 to 130° C.) for 5 minutes to 24 hours to produce compound (I). can.

(Production of compound (II))
Compound (II) can be produced by introducing a protecting group into compound (I). Although the production method for introducing the protecting group varies depending on the selected protecting group, 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 aforementioned base, preferably a metal base, more preferably sodium hydride diethyl ether, cyclopropyl methyl ether, tetrahydrofuran, 4 -Methyltetrahydropyran, dioxane, monoglyme, diglyme and other ethers or N,N-dimethylformamide and other aprotic polar solvents or mixed solvents thereof, preferably ethers, are added to a suspension of the compound ( After I) is added dropwise at -10°C to room temperature, a metal chelating agent such as crown ether, tetraethylenediamine, or dimethylimidazolidinone, preferably dimethylimidazolidinone, is added, and then 1 to 1.5 equivalents of a protecting group-introducing reagent is added. is added dropwise and reacted for 5 minutes to 3 hours to produce compound (II).
When a carbamate-based protecting group is introduced, the reaction conditions vary depending on the type of carbamate-based protecting group. amyloxycarbonyl (Aoc group) or benzyloxycarbonyl (Z group), 9-fluorenylmethyloxycarbonyl (Fmoc) group, 2,2,2-trichloroethoxycarbonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, etc. When introducing, in a solvent such as dioxane, dioxane/water, methylene chloride, tetrahydrofuran, an organic base such as triethylamine or pyridine, sodium hydride, potassium hydroxide, sodium hydroxide, potassium hydrogen carbonate, hydrogen carbonate In the presence of an inorganic base such as sodium, di-tert-butyl dicarbonate ((Boc) ₂ O), tert-butoxycarbonyl chloride, benzyloxycarbonyl chloride, tert-amyloxycarbonyl chloride, 9-fluorenylmethyloxycarbonyl 1 to 1.5 equivalents of an introduction reagent such as a generally known Boc group such as chloride, 2,2,2-trichloroethyl chloroformate, 2-(trimethylsilyl)ethoxymethyl chloride, tert-butoxycarbonyl azide, benzyloxycarbonyl azide, etc. It can be produced by reacting at 0° C. to 100° C. for 5 minutes to 10 hours.

(Production of compound (III))
Compound (III) can be produced by a generally known formylation reaction such as Vilsmeier reaction, Rieche reaction, Daff reaction, Reimer-Tiemann reaction, etc. For example, Vilsmeier reaction uses N,N-dimethylformamide (DMF), N- N,N-disubstituted formamides such as methylformanilide (MFA), N-formylmorpholine, N,N-diisopropylformamide and phosphorus oxychloride, oxalyl chloride, thionyl chloride, triphenylphosphine-bromine, hexachlorotriphosphazatriene, etc. Prepare or purchase commercially available Vilsmeier reagent ((chloromethylene)dimethyliminium chloride) from the acid chloride of and combine this with compound (II) in a solvent such as phosphorus oxychloride; or dichloromethane, dichloroethane, chloroform, carbon tetrachloride. , chlorobenzene and other halogenated hydrocarbons; benzene, toluene, nitrobenzene and other aromatic hydrocarbons; tetrahydrofuran, tetramethylhydropyran, dioxane and other ethers or ethyl acetate, acetonitrile, N,N-dimethylformamide and other non- Protic polar solvents or mixed solvents thereof, preferably ether solvents, aromatic hydrocarbons, aprotic polar solvents or mixed solvents thereof, more preferably tetramethylhydropyran, in 0 to 100 ° C. (preferably 40 ~80°C) for 0.5 to 12 hours followed by reaction, compound (III) can be produced.

(Production of compound (IV))
Compound (IV) can be produced from a deprotection reaction of compound (III). The deprotection reaction differs depending on the protecting group, but a generally known method can be used. , HF-pyridine complex, HF-triethylamine complex, or other fluorine source. In addition, the deprotection reaction of the silyl-based protecting group proceeds similarly under acidic conditions such as hydrochloric acid or trifluoroacetic acid, or under basic conditions such as aqueous sodium hydroxide solution, whereby compound (IV) can be produced. As a deprotecting reagent, 3 to 10 equivalents (preferably 5 equivalents) of sodium hydroxide aqueous solution can be used with respect to compound (III).
In the case of a carbamate-based protecting group, reaction conditions vary depending on the type of carbamate-based protecting group, but the reaction can be carried out by a generally known method. , catalytic reduction in the presence of palladium on carbon, etc., or by appropriately selecting acetic acid/hydrogen bromide, trifluoroacetic acid, hydrochloric acid/organic solvent, etc. according to the protective group.
Also, compound (IV) can be produced by a one-pot operation without isolating compound (III) from compound (II). In this case, after completion of the reaction of compound (II) to compound (III), the deprotection reagent can be added to the reaction system.
Compound (IV) can also be produced by a one-pot operation without isolating compound (II) and compound (III) from compound (I). A reaction reagent for the production of compound (IV) is added to the reaction system, and after completion of the reaction, a reagent for the deprotection reaction is further added to the reaction system and reacted in the same manner to produce compound (IV). be able to. As for the amount relationship of the reagents in any production, the same amount as described above can be used.

(Production 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 added with crown ethylenizer. - In the presence of a metal chelating agent such as tel, tetramethylethylenediamine, or dimethylimidazolidinone, the mixture is stirred at -10°C to room temperature for 0.5 to 1 hour, then pyridine-3-sulfonyl chloride is added, and the mixture is heated to 0°C at 0°C. Stir for 5 hours. 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.
Further, compound (VI) can be prepared by adding a base such as triethylamine or N,N-diisopropylamine, a catalytic amount of 4-dimethylaminopyridine, pyridine-3- It can be produced by adding sulfonyl chloride and stirring at room temperature to 100° C. for 0.5 to 12 hours.

(Production 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 hydrogenated at 0°C to room temperature. Compound (VII) can be obtained by adding 1 to 3 equivalents of a reducing agent such as sodium boron and reacting for 0.5 to 1 hour.

(Production 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, and the mixture is stirred for 0.5 to 1 hour. Vonoprazan fumarate can be prepared by recrystallization with methanol/water according to .

EXAMPLES The present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples below, but the present invention is not limited to these.

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), pyro-pyrrole was added under ice-cooling. (2.1 mL, 30.0 mmol) was added dropwise and stirred for 0.5 hours, then zinc chloride (4.1 g, 30.0 mmol) was added and stirred at room temperature for 0.5 hours. followed by 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) was added, and after degassing, the mixture was stirred at 60°C for 6 hours. Water was added dropwise to the reaction mixture while cooling it at 0° C., insoluble matter was filtered, and the mixture was separated with ethyl acetate. Ethyl acetate was added to the aqueous layer and extracted again, and then the organic layers were combined and washed with saturated brine. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography and dried under reduced pressure to obtain the title compound (1.18 g, yield 74%).

Mass (ESI): m / zcalcdfor C10H7FN [MH]-: 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
Preparation of 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole Suspension of sodium hydride (dispersed in 60% liquid paraffin, 64 mg, 1.61 mmol) and tetrahydrofuran (2 mL) A solution of 2-(2-fluorophenyl)-1H-pyrrole (172 mg, 1.07 mmol) in tetrahydrofuran (2 mL) was added dropwise to the solution under ice cooling, and the mixture was stirred for 0.5 hour. Teru (0.32 mL, 1.61 mmol) was added and the mixture was stirred at 0° C. for 0.5 hours. Subsequently, 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 the mixture was separated with ethyl acetate. Ethyl acetate was added to the aqueous layer and extracted again, and then the organic layers were combined and washed with saturated brine. After evaporating the solvent under reduced pressure, the residue was purified with a silica gel column and dried under reduced pressure to obtain the title compound (272 mg, yield 80%).

Mass (ESI): m / zcalcdforC19H28FNNaSi [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, 2.0 Hz, 1H), 7.03-7.12 (m, 2H), 7.29-7.37 (m, 2H).

Example 3
Preparation of 5-(2-fluorophenyl)-1H-pyrrol-3-carboxaldehyde 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole (100mg, 0.32mmol) Under ice-cooling, Vilsmeier reagent (123 mg, 0.96 mmol) was added to a dichloromethane (3.0 mL) solution of and stirred at 40° C. for 0.5 hour. After evaporating the solvent 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 to separate the layers. Ethyl acetate was added to the aqueous layer and extracted again, and then 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 (ESI): m / zcalcdfor C11H8FNNaO [M + Na] +: 212.05; found: 212.03; 1H-NMR (400 MHz, 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
Preparation of 5-(2-fluorophenyl)-1H-pyrrol-3-carboxaldehyde sodium hydride (dispersed in 60% liquid paraffin, 1.2 g, 30.0 mmol) and 4-methyltetrahydropyran (10 mL). Pyrrole (2.1 mL, 30.0 mmol) was added dropwise to the suspension under ice cooling and stirred for 0.5 hours, then zinc chloride (4.1 g, 30.0 mmol) was added and stirred at room temperature for 0.5 hours. bottom. followed by 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) was added and stirred at 100° C. for 0.5 hours. While cooling the reaction mixture at 0° C., 28% aqueous ammonia was added dropwise, insoluble matter was filtered, and the mixture was separated with ethyl acetate. After evaporating the solvent under reduced pressure, 2-(2-fluorophenyl)-1H-pyrrole was obtained as a crude product.
2-(2-fluorophenyl)-1H-pyrrole 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 in tetrahydrofuran (2 mL) was added dropwise under ice-cooling, and the mixture was stirred for 0.5 hour. Subsequently, 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 distilling off the solvent under reduced pressure, separation was performed again with heptane and water, and the solvent was distilled off under reduced pressure to obtain 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole. was obtained as a crude product.
Vilsmeier reagent (3.8 g, 30 mmol) was added under ice-cooling to a dichloromethane (50 mL) solution of the obtained crude product of 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole. Stir at 40° C. for 0.5 hours. After evaporating the solvent 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 to separate the layers. After the organic layer was washed with saturated brine, the solvent was distilled off under reduced pressure. Recrystallization was performed with heptane and ethyl acetate, and the title compound (1.34 g, yield 70%) was obtained by drying under reduced pressure.

Example 5
Preparation of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-carboxaldehyde sodium hydride (dispersed in 60% liquid paraffin, 32 mg, 0.79 mmol) and To a suspension of tetrahydrofuran (2 mL) was added dropwise a solution of 5-(2-fluorophenyl)-1H-pyrrol-3-carboxaldehyde (100 mg, 0.53 mmol) in tetrahydrofuran (2 mL) under ice cooling. After stirring for 1 hour, 15-crown-5-ether (0.16 mL, 0.79 mmol) was added and stirred at 0°C for 0.5 hour. Pyridine-3-sulfonyl chloride (95 μL, 0.79 mmol) was then added and 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. Ethyl acetate was added to the aqueous layer and extracted again, and then the organic layers were combined and washed with saturated brine. After evaporating the solvent under reduced pressure, the residue was purified with a silica gel column and dried under reduced pressure to obtain the title compound (167 mg, yield 95%).

Mass (ESI): m / zcalcdfor 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, 1.5 Hz, 1H), 9.90 (s, 1H).

Example 6
Preparation of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate 5-(2-fluoro Phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-carboxaldehyde (100 mg, 0.30 mmol) in methanol (3 mL) was added at room temperature to methanol solution of methylamine ( 2.0 M, 1.06 mL, 2.12 mmol) was added dropwise and stirred for 0.5 hours. After cooling to 0° C., sodium borohydride (34 mg, 0.91 mmol) was added and stirred for 0.5 hour. 1N 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 to separate the layers. 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, 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, 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%).

Mass (ESI): m / zcalcdfor C17H17FN3NaO2S "M + H" +: 346.09; found: 346.11; 1H-NMR (400 MHz, 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 not detected.

Example 7
Preparation of 5-(2-fluorophenyl)-1H-pyrrol-3-carboxaldehyde Sodium hydride (dispersed in 60% liquid paraffin, 8.8 g, 220.0 mmol) and 4-methyltetrahydropyran (100 mL) Pyrrole (15.7 mL, 220.0 mmol) was added dropwise to the suspension under ice cooling and stirred for 0.5 hours, then zinc chloride (30.3 g, 220.0 mmol) was added and stirred at room temperature for 0.5 hours. bottom. followed by 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) was added and stirred at about 100° C. for 1 hour. An aqueous sodium hydroxide 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 hours. After filtering 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 evaporating the solvent under reduced pressure, toluene (167 mL) was added to the residue. By evaporating the solvent under reduced pressure, 2-(2-fluorophenyl)-1H-pyrrole was obtained as a crude product (20.9 g).
The resulting 2-(2 A tetrahydrofuran (10 mL) solution of the crude product of -fluorophenyl)-1H-pyrrole was added dropwise under ice cooling, washed with tetrahydrofuran (10 mL), and stirred for 0.5 hour. Subsequently, 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 evaporating the solvent under reduced pressure, toluene (167 mL) was added to the residue. After evaporating the solvent under reduced pressure, 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole was obtained as a crude product (45.2 g) by evaporating the solvent under reduced pressure. Obtained.
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 obtained crude 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole in 4-methyltetrahydropyran (100 mL) was added at once and stirred at about 50° C. for 3 hours. bottom. An aqueous sodium hydroxide solution (5.0 M, 100 mL) was added under ice-cooling, and the mixture was stirred overnight at room temperature. 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 dissolution at about 70° C., heptane (300 mL) was added. After allowing to cool to 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 at 50° C. under reduced pressure for 1.5 hours.

Example 8
Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (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. Subsequently, triisopropylsilyl chloride (14.6 mL, 68.2 mmol) was added dropwise, and the mixture was stirred under ice cooling for 2 hours. The reaction solution of 2-(2-fluorophenyl)-1H-pyrrole was added 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). The mixture was added all at once under cooling, washed with 4-methyltetrahydropyran (20 mL), and stirred at about 60° C. for 2 hours. An aqueous sodium hydroxide solution (2.0 M, 310 mL) was added under ice-cooling, and the mixture was stirred overnight at room temperature. 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 dissolution at about 70° C., heptane (180 mL) was added. After allowing to cool to 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 (8)

Formula (I) below:

In the pyrrole derivative represented by, a protecting group is introduced to the nitrogen atom of the pyrrole ring,
The following general formula (II):

(Wherein, P represents a protecting group) to obtain an N-protected pyrrole derivative represented by the following general formula (III) by formylation

A pyrrole-3-carboxaldehyde derivative represented by the following formula (IV), characterized in that it is further deprotected.

A method for producing 5-(2-fluorophenyl)-1H-pyrrol-3-carboxaldehyde represented by 2. The production method according to claim 1, wherein the protecting group represented by P is a silyl protecting group. 3. The production method according to claim 1 or 2, wherein the protective group represented by P is a triisopropylsilyl group. The pyrrole derivative of formula (I) is
The following general formula (V):

(wherein L represents a leaving group), obtained by reacting an orthofluorobenzene derivative represented by the formula with pyrrole in the presence of a metal catalyst. The manufacturing method described in the item . 5. The production method according to claim 4, wherein said metal catalyst is a palladium catalyst. The compound represented by the formula (IV) is obtained by the production method according to any one of claims 1 to 5 , and then the compound represented by the formula (IV) is treated in the presence of an inorganic base or an organic base. Below, it is reacted with pyridine-3-sulfonyl chloride or a salt thereof, and the following formula (VI)

The following formula (VII), characterized in that a pyrrole derivative represented by is obtained, further condensed with methylamine, and then subjected to a reduction reaction:

A method for producing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine represented by 1-[5-(2-fluorophenyl)-1-(pyridine), wherein the compound represented by the formula (VII) is obtained by the production method according to claim 6, and fumaric acid is added. -3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate. 2-(2-fluorophenyl)-1-(triisopropylsilyl)-1H-pyrrole.