WO2019131695A1 - Production method for 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl]-n-methylmethanamine monofumarate - Google Patents

Abstract

The present invention relates to methods for producing 5-(2-fluorophenyl)-1H-pyrrole-3-carboxyaldehyde by formylation and deprotection and producing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate by sulfonylation, etc.

Description

Process for producing 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine monofumaric acid salt

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

1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine monofumaric acid salt represented by the following formula , Bonoprazan fumarate) is a potassium ion competitive acid blocker, which inhibits the binding of potassium ion to H + and K ± ATPase and suppresses gastric acid secretion, thereby treating gastric and duodenal ulcers, etc. It is used for pH control in the stomach at the time of prevention and Helicobacter-Helicobacter pylori eradication. Bonoprazan fumarate is stable against acids, rapidly reaches effective concentration, and rapidly suppresses the action of gastric acid for a long time, compared to existing proton pump inhibitors It is known.

With regard to a method for producing vonoprazan fumarate, for example, Patent Document 1 discloses synthesis of a pyrrol-3-carboxaldehyde derivative, which is a synthetic intermediate, from a cyano compound represented by the following formula via a pyrrol compound. Methods are disclosed.

In this method, [2- (2-fluorophenyl) -2-oxoethyl] propanedinitrile (a) is used as a raw material. It is described that this raw material can be produced by the method described in Patent Document 2, and it is disclosed that it is synthesized from 2-fluorophenacyl bromide by the reaction of malononitrile. In addition, it is described that 2-fluorophenacyl bromide can be produced by a generally known method. Although there is no specific description, for example, a method of reacting with bromine in acetic acid (Non-patent Document 1), a method of reacting with bromine in the presence of aluminum chloride, and the like are known (Non-patent Document 2). Since two steps are required to synthesize the raw materials, multiple steps are required to produce the target compound. In addition, since these reactions require malononitrile, which may cause toxicity or environmental impact, or corrosive or irritant bromine, a production method more in consideration of human and environmental safety is desired. In addition, 5- (2-fluorophenyl) -1H-pyrrole-3-carboxaldehyde is synthesized from a raw material in a yield of 53% to 60%, and improvement of the yield is also desired.
Therefore, a production method with less yield to human bodies and the environment and better yield in a shorter process is desired.

Patent No. 5819494 gazette Patent No. 3140818 gazette

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 process for producing a synthetic intermediate pyrrol-3-carboxaldehyde derivative in the production of bonoprazan fumarate, and an industrial process for producing a novel bonoprazan fumarate using the derivative. The purpose is

As a result of intensive studies, the present inventors have found that coupling reactions with readily available fluoroiodobenzene and pyrrole and regioselective formylation reactions by appropriate protection of nitrogen atoms on the pyrrol ring The present invention has been accomplished by finding a method for easily producing a-3-carboxaldehyde derivative in a high yield.

[1] The present invention relates to 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 pyrrol derivative represented by the above, a protecting group is introduced to the nitrogen atom of the pyrrol ring,
The following formula (II):

（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 pyrrol derivative, which is further formylated to give the following formula (III)

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）

The pyrrole-3-carboxaldehyde derivative represented by

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）：

In the present invention of the 5- (2-fluorophenyl) -1H-pyrrole-3-carboxaldehyde represented by the present invention, the protective group represented by P is a silyl-based protective group as described above. 1] It relates to the manufacturing method described.
[3] The present invention also relates to the process according to the above [1] or [2], wherein the protective group represented by P is a triisopropylsilyl group.
[4] Further, according to the present invention, the pyrrole derivative of the above general formula (I) is
Following formula (V):

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

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）：

The pyrrole derivative represented by formula (IV) is condensed with methylamine and then reduced to give a compound of 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。

The present invention relates to a method for producing 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine represented by .
[7] Further, the present invention provides 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H with fumaric acid and a compound of the general formula (VII) obtained by the above-mentioned production method The present invention relates to a process for producing -pyrrol-3-yl] -N-methylmethanamine monofumaric acid salt.

In the present invention, 5- (2-fluorophenyl) -1H-pyrrole-3-carboxaldehyde is good in an inexpensive, short and short process using easily available raw materials such as pyrrole and 2-fluoroiodobenzene. It is possible to obtain a yield (70% or more), is more economical and productivity than conventional methods, and is suitable for industrial production. Furthermore, the use of the transition metal catalyst can be kept to a very small amount, and by using it in the upstream process, it is possible to reduce the concern about metal impurities remaining in the final product.

Hereinafter, the present invention will be described in more detail.
As the leaving group represented by L in the general formula (V), halogen atoms of chlorine, bromine and iodine, lower alkanesulfonyloxy groups such as methanesulfonyloxy group and trifluoromethanesulfonyloxy group, benzenesulfonyloxy And arylsulfonyloxy groups such as p-toluenesulfonyloxy group can be mentioned.

In the general formulas (II) and (III), as a pyrrol ring nitrogen protecting group represented by P, a silyl protecting group, an alkyl protecting group, a heteroaryl protecting group, an acyl protecting group, a car Examples of silyl-based protective groups include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl and the like, and a preferred example is tert. -Butyldimethylsilyl group, triisopropylsilyl group and the like.
Examples of the alkyl 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 2-pyridyl group, 4-pyridyl group, 2-pyrazyl group, 2-pyrimidyl group and 2-triazyl group.
As a carboxyl group protecting group, a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a tert-amyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a p-chloro group 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, diisopropyl methyloxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group, 9-fluorenyl Etc. chill oxycarbonyl group.
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, a silyl protecting group is preferable as a protecting group from the viewpoint of yield etc., and a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group and a triisopropylsilyl group are particularly preferable. Preferably it is a triisopropyl silyl group.

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 the compound (I) from the compound (V).
Examples of nickel catalysts used in the present invention include zero-valent nickel catalysts such as bis (1,5-cyclooctadienyl) nickel, and divalent nickel catalysts such as nickel chloride and bis (triphenylphosphine) nickel chloride. Triphenylphosphine, 2- (di-tert-butylphosphino) biphenyl, Xantphos, bis [2- (diphenylphosphino) phenyl] ether (hereinafter referred to as DPEPhos), (±) -2, Adding a phosphine ligand such as 2′-bis (diphenylphosphino) -1,1′-binaphthyl (hereinafter, (±) -BINAP), N, N, N ′, N′-tetramethylethylenediamine, etc. it can.
The palladium catalyst used in the present invention may be a zero-valent palladium catalyst such as palladium carbon or tetrakistriphenylphosphine palladium or a divalent palladium such as palladium chloride, palladium acetate or (dichlorobis (tri-o-tolylphosphine)) palladium. A catalyst may 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 the base used in the present invention include tertiary amines such as triethylamine and diisopropylethylamine, lithium hydride, sodium hydride, potassium hydrogen, sodium amide, lithium diisopropylamide (hereinafter referred to as LDA), lithium hexamethyl disilazide (hereinafter referred to as (LiHMDS), ethylmagnesium, sodium carbonate, calcium carbonate and other metal bases can be added.

The process for producing the synthetic intermediate pyrrol-3-carboxaldehyde derivative in the production of bonoprazan fumaric acid salt according to the present invention and the process for producing bonoprazan fumaric acid salt using the derivative are shown below.

(Production of Compound (I))
Compound (I) can be produced by the cross coupling reaction described in Non-Patent Document 3 or Non-Patent Document 4, or the like. For example, it is possible to use unsubstituted pyrrole which is not halogenated by using Negishi coupling reaction, 1 to 3 equivalents of the aforementioned base, preferably a metal base, under an inert gas atmosphere such as nitrogen or argon Preferably, ethers such as diethyl ether of sodium hydride, cyclopropyl methyl ether, tetrahydrofuran, 4-methyltetrahydropyran, dioxane, monoglyme, diglyme and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like A solution of 1 to 3 equivalents of pyrrole / the solvent is added dropwise at -10 ° C to room temperature and stirred for 10 minutes to 1 hour, and then 1 to 3 equivalents of zinc halide (zinc chloride, zinc bromide Etc.), organic zinc such as dipivaloyl zinc (preferably zinc halide, particularly preferably zinc chloride) and It is stirred in 10 minutes to 1 hour. Next, the catalyst such as 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, etc. and 0.0001 to 1.0 equivalents (preferably) (0.001 to 0.003 equivalents) of the above phosphine ligand, and reacting at room temperature to 150 ° C. (preferably 90 to 130 ° C.) for 5 minutes to 24 hours to produce compound (I) it can.

(Production of Compound (II))
The compound (II) can be produced by introducing a protecting group into the compound (I), and the introduction of the protecting group may vary depending on the selected protecting group, but a generally known method can be adopted. For example, in the introduction of a silyl-based protecting group, 1 to 1.5 equivalents of the above-mentioned bases, preferably metal bases, more preferably sodium hydride diethyl ether, cyclopropyl methyl ether, tetrahydrofuran, 4 -Aprotic polar solvents such as ethers such as methyl tetrahydropyran, dioxane, monoglyme and diglyme, or N, N-dimethylformamide or mixed solvents thereof, preferably in the solvent suspension such as ethers I) is added dropwise at -10 ° C to room temperature, and then a metal chelating agent such as crown ether, tetraethylenediamine or dimethylimidazolidinone, preferably dimethylimidazolidinone is added, and then 1 to 1.5 equivalents of protecting group introducing reagent Can be added dropwise and reacted for 5 minutes to 3 hours to produce compound (II). Can.
In the case of introducing a cationic protecting group, the reaction conditions vary depending on the kind of the cationic protecting group, and for example, tert-butoxycarbonyl (Boc group), tert- for compound (I), etc. Amidoxy carbonyl (Aoc group) or benzyloxycarbonyl (Z group), 9-fluorenylmethyloxycarbonyl (Fmoc) group, 2,2,2-trichloroethoxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group, etc. When introduced, in a solvent such as dioxane, dioxane / water, methylene chloride, tetrahydrofuran, etc., an organic base such as triethylamine or pyridine, sodium hydride, potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, hydrogencarbonate Di-tert-butyl dicarbonate in the presence of an inorganic base such as sodium ((Bo c) ₂ O) or tert-butoxycarbonyl chloride, benzyloxycarbonyl chloride, tert-amyloxycarbonyl chloride, 9-fluorenylmethyloxycarbonyl chloride, 2,2,2-trichloroethyl chloroformate, 2- (trimethylsilyl) The reaction is carried out by reacting 1 to 1.5 equivalents of a reagent to be introduced such as a commonly known Boc group such as ethoxymethyl chloride, tert-butoxycarbonyl azide, benzyloxycarbonyl azide, etc. at 0 ° C. to 100 ° C. for 5 minutes to 10 hours. Can.

(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-Tiemann reaction, etc. For example, in Vilsmeier reaction, N, N-dimethylformamide (DMF), N- N, N-disubstituted formamide such as methylformanilide (MFA), N-formyl morpholine, N, N-diisopropylformamide, and phosphorus oxychloride, oxalyl chloride, thionyl chloride, triphenylphosphine-bromine, hexachlorotriphospazatriene, etc. The Vilsmeier reagent ((chloromethylene) dimethyliminium chloride) is prepared from the acid chloride of or commercially available, and this and the compound (II) are used as a solvent such as phosphorus oxychloride; Halogenated hydrocarbons such as ethane, chloroform, carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as benzene, toluene and nitrobenzene; ethers such as tetrahydrofuran, tetramethylhydropyran and dioxane or ethyl acetate, acetonitrile, N, Aprotic polar solvents such as N-dimethylformamide or mixed solvents thereof, preferably ether solvents, aromatic hydrocarbons, aprotic polar solvents or mixed solvents thereof, more preferably in tetramethyl hydropyran The compound (III) can be produced by reaction after stirring at -100 ° C. (preferably 40-80 ° C.) for 0.5-12 hours.

(Production of Compound (IV))
Compound (IV) can be produced from the deprotection reaction of compound (III). Although the deprotection reaction varies depending on the protecting group, generally known methods can be used. For example, when the protecting group is a silyl protecting group, tetrabutylammonium fluoride is allowed to react at −10 ° C. to room temperature in a solution such as tetrahydrofuran. It can be produced by reacting a fluorine source such as HF pyridine complex or HF triethylamine complex. Further, the deprotecting reaction of the silyl protecting group proceeds similarly under acidic conditions such as hydrochloric acid and trifluoroacetic acid, and under basic conditions such as aqueous sodium hydroxide solution, and compound (IV) can be produced. The deprotecting reagent can be 3 to 10 equivalents (preferably 5 equivalents) of aqueous sodium hydroxide solution relative to compound (III).
Further, in the case of a protecting group of a carboxylate type, reaction conditions may differ depending on the kind of the protecting group of a carboxylate type, but the reaction can be carried out by a generally known method, for example, palladium black under hydrogen atmosphere It can be carried out by catalytic reduction in the presence of palladium carbon or the like, or by appropriately selecting acetic acid / hydrogen bromide, trifluoroacetic acid, hydrochloric acid / organic solvent etc. as a protective group.
Compound (IV) can also be produced by one-pot operation without isolating Compound (III) from Compound (II). In this case, the reaction can be carried out by adding the reagent for the deprotection to the reaction system after completion of the reaction of the compound (II) to the compound (III).
The compound (IV) can also be produced by a one-pot operation without isolating the compound (II) and the compound (III) from the compound (I). For example, after completion of the reaction in the production of the compound (III), The reaction reagent in the production of the compound (IV) is added to the reaction system, and after completion of the reaction, the reagent for the above-mentioned deprotection reaction is further added to the reaction system, and the compound (IV) is produced by the same reaction. be able to. With regard to the amount relationship of 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, and the mixture is stirred for 0.5 to 1 hour. -Stir at -10 ° C to room temperature for 0.5 to 1 hour in the presence of metal chelating agent such as teryl, tetramethylethylenediamine, dimethylimidazolidinone etc., add pyridine-3-sulfonyl chloride, then add to 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.
Compound (VI) can be prepared by using triethylamine, a base such as N, N-diisopropylamine, a catalytic amount of 4-dimethylaminopyridine, or pyridine-3-3 in a solution of compound (IV) in dichloromethane or acetonitrile at 0 ° C. to room temperature. It can be prepared 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, and stirred for 0.5 to 1 hour, and this is 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.

(Manufacture of Bonoprazan fumaric acid salt)
A solution of fumaric acid methanol or the like is added to a solution of compound (VII) such as ethyl acetate or methanol at 0 ° C to room temperature, stirred for 0.5 to 1 hour, and the precipitated crystals are collected by filtration and necessary Depending on recrystallization with methanol / water, Bonoprazan fumarate can be produced.

Hereinafter, the present invention will be described in more detail by way of Examples, Comparative Examples and Test Examples, but the present invention is not limited thereto.

Example 1
Preparation of 2- (2-fluorophenyl) -1H-pyrrole A suspension of sodium hydride (dispersed in 60% liquid paraffin, 1.2 g, 30.0 mmol) and tetrahydrofuran (10 mL) under ice-cooling under ice-cooling After adding dropwise (2.1 mL, 30.0 mmol) and stirring for 0.5 hours, zinc chloride (4.1 g, 30.0 mmol) was added and the mixture was stirred at room temperature for 0.5 hours. Subsequently, 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) The mixture was degassed and then stirred at 60 ° C. for 6 hours. Water was added dropwise while cooling the reaction mixture at 0 ° C., and the insoluble matter was filtered off and partitioned with ethyl acetate. After ethyl acetate was added to the aqueous layer to extract again, 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 / z calcd for C 10 H 7 FN [M−H] −: 160.06; found: 160.18; 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 6.30 to 6.33 (m, 1 H) , 6.64-6.67 (m, 1 H), 6.90-6.93 (m, 1 H), 7.07-7.16 (m, 1 H), 7.13-7. 17 (m, 1 H) 2H), 7.60-7.65 (m, 1 H), 9.05 (brs, 1 H).

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) To the mixture was added dropwise a solution of 2- (2-fluorophenyl) -1H-pyrrole (172 mg, 1.07 mmol) in tetrahydrofuran (2 mL) under ice-cooling and stirred for 0.5 hours. Ter (0.32 mL, 1.61 mmol) was added and stirred at 0 ° C. for 0.5 hour. Subsequently, triisopropylsilyl chloride (0.35 mL, 1.61 mmol) was added dropwise and stirred at room temperature for 4 hours. The mixture was cooled to 0 ° C., water was added dropwise, and the mixture was partitioned with ethyl acetate. After ethyl acetate was added to the aqueous layer to extract again, 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 and dried under reduced pressure to obtain the title compound (272 mg, yield 80%).

Mass (ESI): m / z calcd for C 19 H 28 FN Na Si [M + Na] +: 340. 19; found: 340. 16; 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 1.01 (d, J = 6.9 Hz, 18 H) , 1.13-1.21 (m, 3H), 6.25 (dd, J = 3.2, 1.2 Hz, 1 H), 6.37 (t, J = 3.2 Hz, 1 H), 6. 93 (dd, J = 2.8, 2.0 Hz, 1 H), 7.03-7.12 (m, 2 H), 7.29-7.37 (m, 2 H).

Example 3
Preparation of 5- (2-fluorophenyl) -1H-pyrrole-3-carboxaldehyde 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole (100 mg, 0.32 mmol) 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. The solvent was evaporated under reduced pressure, aqueous sodium hydroxide solution (1.0 M, 3 mL) was added, and the mixture was stirred at room temperature for 6 hours, and ethyl acetate was added to separate the layers. After ethyl acetate was added to the aqueous layer to extract again, the organic layers were combined and washed with saturated brine. The residue was purified by silica gel column and dried under reduced pressure to give the title compound (48 mg, yield 80%).

Mass (ESI): m / z calcdfor C11 H 8 FN NaO [M + Na] +: 212.05; found: 212.03; 1 H-NMR (400 MHz, CDCl3) δ (ppm): 7.07 (dd, J = 2.0, 1. 2 Hz, 1 H), 7.12-7.26 (m, 3 H), 7.53 (dd, J = 2.8, 1.2 Hz, 1 H), 7.64 (dt, J = 7.6, 1 .6 Hz, 1 H), 9.45 (brs, 1 H), 9.86 (s, 1 H).

Example 4
Preparation of 5- (2-fluorophenyl) -1H-pyrrole-3-carboxaldehyde Sodium hydride (dispersed in 60% liquid paraffin, 1.2 g, 30.0 mmol) and 4-methyltetrahydropyran (10 mL) Pyrrolyl (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 hour did. Subsequently, 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, and the insoluble matter was filtered off and partitioned 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 suspension of sodium hydride (dispersed in 60% liquid paraffin, 600 mg, 15 mmol) and tetrahydrofuran (10 mL) and dimethylimidazolidinone (2 mL) A solution of the crude product in tetrahydrofuran (2 mL) was added dropwise with ice-cooling and stirred for 0.5 hours. Subsequently, 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., and the mixture was partitioned with ethyl acetate. After distilling off the solvent under reduced pressure, the liquid separation operation is performed again with heptane and water, and the solvent is distilled off under reduced pressure to obtain 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole. Was obtained as a crude product.
To a solution of the obtained 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole crude product in dichloromethane (50 mL) was added Vilsmeier reagent (3.8 g, 30 mmol) under ice-cooling The mixture was stirred at 40 ° C. for 0.5 hours. The solvent was evaporated under reduced pressure, aqueous sodium hydroxide solution (1.0 M, 100 mL) was added, and the mixture was stirred at room temperature for 6 hours, and ethyl acetate was added to separate the layers. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. Recrystallization from heptane and ethyl acetate and drying under reduced pressure gave the title compound (1.34 g, yield 70%).

Example 5
Preparation of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carboxaldehyde Sodium hydride (dispersed in 60% liquid paraffin, 32 mg, 0.79 mmol) and A solution of 5- (2-fluorophenyl) -1H-pyrrole-3-carboxaldehyde (100 mg, 0.53 mmol) in tetrahydrofuran (2 mL) was added dropwise to a suspension of tetrahydrofuran (2 mL) under ice-cooling to 0.5. After stirring for 15 hours, 15-crown-5-ether (0.16 mL, 0.79 mmol) was added and the mixture was stirred at 0 ° C. for 0.5 hour. Subsequently, pyridine-3-sulfonyl chloride (95 μL, 0.79 mmol) was added and stirred at 0 ° C. for 0.5 hours. Further, pyridine-3-sulfonyl chloride (95 μL, 0.79 mmol) was added and stirred at 0 ° C. for 0.5 hour. Water was added dropwise and partitioned with ethyl acetate. After ethyl acetate was added to the aqueous layer to extract again, 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 and dried under reduced pressure to obtain the title compound (167 mg, yield 95%).

Mass (ESI): m / z calcd for C 16 H 11 FN 2 NaO 3 S “M + Na” +: 353.04; found: 353.00; 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 6.68 (d, J = 1.7 Hz, 1 H) , 7.01-7.05 (m, 1H), 7.16-7.18 (m, 2H), 7.37-7.40 (m, 1H), 7.45-7.51 (m, 1 H) 1H), 7.69-7.72 (m, 1H), 8.15 (d, J = 1.8 Hz, 1 H), 8.58 (d, J = 1.7 Hz, 1 H), 8.82 ( dd, J = 4.8, 1.5 Hz, 1 H), 9.90 (s, 1 H).

Example 6
Preparation of 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine fumarate 5- (2-fluoro) A solution of methylamine in methanol (3 mL) at room temperature in a solution of phenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carboxaldehyde (100 mg, 0.30 mmol) 2.0 M (1.06 mL, 2.12 mmol) was added dropwise and stirred for 0.5 hours. The mixture was cooled to 0 ° C., sodium borohydride (34 mg, 0.91 mmol) was added, and the mixture was stirred for 0.5 hours. 1N hydrochloric acid (3 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 0.5 hour. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to separate the layers. Ethyl acetate was added to the aqueous layer to extract again, and then the organic layer was combined and washed with saturated brine. After concentration of 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 for 30 minutes at room temperature, the precipitated crystals were filtered and washed with ethyl acetate and methanol to obtain a crude product. The obtained crude crystals were recrystallized from methanol and water, and the precipitated crystals were collected by filtration and then dried under reduced pressure to give the title compound (90 mg, yield 64%).

Mass (ESI): m / z calcd for C 17 H 17 FN 3 NaO 2 S “M + H” +: 346.09; found: 346.11; 1 H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.39 (s, 3 H), 3.76 (S, 2 H), 6.44 (d, J = 2.0 Hz, 1 H), 6.47 (s, 2 H), 7.10 to 7.13 (m, 1 H), 7.20 to 7.26 (M, 2H), 7.50 to 7.56 (m, 1 H), 7. 70 to 7.67 (m, 2 H), 7.85 to 7.89 (m, 1 H), 8.56 (d , J = 2.8 Hz, 1 H), 8.87-8.89 (m, 1 H). 3H not detected.

Example 7
Preparation of 5- (2-fluorophenyl) -1H-pyrrole-3-carboxaldehyde Sodium hydride (dispersed in 60% liquid paraffin, 8.8 g, 220.0 mmol) and 4-methyltetrahydropyran (100 mL) To the suspension is added dropwise pyrol (15.7 mL, 220.0 mmol) under ice-cooling and stirred for 0.5 hours, then zinc chloride (30.3 g, 220.0 mmol) is added and stirred at room temperature for 0.5 hour did. Subsequently, 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 solution of sodium hydroxide (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. The insolubles were filtered and washed with toluene (100 mL), then 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. The solvent was evaporated under reduced pressure to give 2- (2-fluorophenyl) -1H-pyrrole as a crude product (20.9 g).
2- (2) obtained in suspension of sodium hydride (dispersed in 60% liquid paraffin, 4.4 g, 110.0 mmol) and tetrahydrofuran (100 mL) and dimethylimidazolidinone (32.6 mL, 300.0 mmol) A solution of the crude product of -fluorophenyl) -1H-pyrrole in tetrahydrofuran (10 mL) was added dropwise with ice-cooling, washed with tetrahydrofuran (10 mL) and stirred for 0.5 hours. Subsequently, 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. The mixture was extracted twice with 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 distilling off the solvent under reduced pressure, the solvent is distilled off under reduced pressure to obtain 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole as a crude product (45.2 g). 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 hours. A 4-methyltetrahydropyran (100 mL) solution of the obtained crude product of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole was added in one portion and stirred at about 50 ° C. for 3 hours did. Under ice-cooling, aqueous sodium hydroxide solution (5.0 M, 100 mL) was added and the mixture was stirred overnight at room temperature. The organic layer was separated, and the aqueous layer was partitioned with ethyl acetate (200 mL). The organic layer was combined, washed with saturated brine (200 mL), and the solvent was evaporated 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 cooling at room temperature, the mixture was stirred for 1 hour under an ice bath, and the precipitated crystals were collected by filtration and washed with cooled ethyl acetate: heptane (1: 6, 70 mL). The title compound (13.6 g, yield 72%) was obtained by drying under reduced pressure at 50 ° C. for 1.5 hours.

Example 8
Preparation of 5- (2-fluorophenyl) -1H-pyrrole-3-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 stirred for 2 hours under ice-cooling. A solution of 2- (2-fluorophenyl) -1H-pyrrole in ice-cold dichloromethane (90 mL) solution of Vilsmeier reagent prepared from oxalyl chloride (10.6 mL, 124 mmol) and DMF (9.65 mL, 124 mmol) The mixture was cooled in one portion, washed with 4-methyltetrahydropyran (20 mL) and stirred at about 60 ° C. for 2 hours. Under ice-cooling, aqueous sodium hydroxide solution (2.0 M, 310 mL) was added and the mixture was stirred overnight at room temperature. The organic layer was separated, and the aqueous layer was partitioned with ethyl acetate (120 mL). The organic layer was combined, washed with saturated brine (120 mL), and the solvent was evaporated 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 cooling at room temperature, the mixture was stirred 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). The title compound (8.30 g, yield 71%) was obtained by drying under reduced pressure at 50 ° C. for 1.5 hours.

Claims (7)

The following formula (I):

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

(Wherein P represents a protecting group) to obtain an N-protected pyrrol derivative, which is further formylated to give the following formula (III)

The pyrrole-3-carboxaldehyde derivative represented by

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

The compound according to any one of claims 1 to 3, which is obtained by reacting an orthofluorobenzene derivative represented by (wherein L represents a leaving group) with pyrrole in the presence of a metal catalyst ( Method I). The method according to claim 4, wherein the metal catalyst is a palladium catalyst. The 5- (2-fluorophenyl) -1H-pyrrole-3-carboxaldehyde represented by the general formula (IV) obtained by the above-mentioned production method is treated with pyridine-3- in the presence of an inorganic base or an organic base. It is made to react with sulfonyl chloride or its salt, and the following formula (VI)

The pyrrole derivative represented by formula (IV) is condensed with methylamine and then reduced to give a compound of the following formula (VII):

A process for producing 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethanamine represented by the formula: 1- [5- (2-Fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl with fumaric acid and the compound of the general formula (VII) obtained by the above process ] The manufacturing method of-N-methyl methanamine monofumaric acid salt.