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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/333—Radicals substituted by oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B61/00—Other general methods
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• 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.
• 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.
• 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.
• Patent No. 5819494 gazette Patent No. 3140818 gazette
• 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
• 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):
• 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.
• L represents a leaving group
• 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.
• 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):
• 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.
• 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.
• 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.
• 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.
• alkyl protecting group examples 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.
• heteroaryl-based protecting group examples include 2-pyridyl group, 4-pyridyl group, 2-pyrazyl group, 2-pyrimidyl group and 2-triazyl group.
• 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-fluoren
• 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.
• 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.
• it is a triisopropyl silyl group.
• 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).
• 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.
• DPEPhos bis [2- (diphenylphosphino) phenyl] ether
• 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.
• tertiary amines such as triethylamine and diisopropylethylamine
• lithium hydride sodium hydride
• potassium hydrogen sodium amide
• lithium diisopropylamide hereinafter referred to as LDA
• LiHMDS lithium hexamethyl disilazide
• ethylmagnesium sodium carbonate, calcium carbonate and other metal bases can be added.
• Compound (I) can be produced by the cross coupling reaction described in Non-Patent Document 3 or Non-Patent Document 4, or the like.
• a base preferably a metal base
• an inert gas atmosphere such as nitrogen or argon
• 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
• 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.
• 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.
• 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 dimethylimid
• 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.
• 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)
• a reagent to be introduced such as a commonly known Boc group such as ethoxymethyl chloride, tert-butoxycarbonyl azide, benzyloxycarbonyl azide, etc.
• the compound (III) can be produced by a generally known formylation reaction such as Vilsmeier reaction, Rieche reaction, Daff reaction, Reimer-Tiemann reaction, etc.
• a generally known formylation reaction such as Vilsmeier reaction, Rieche reaction, Daff reaction, Reimer-Tiemann reaction, etc.
• 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
• Compound (IV) can be produced from the deprotection reaction of compound (III).
• the deprotection reaction varies depending on the protecting group, generally known methods can be used.
• 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.
• 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).
• 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).
• 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).
• 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.
• the amount relationship of reagents in any production the same amount as described above can be used.
• 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.
• 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 ⁇ L, 0.79 mmol) was added and stirred at 0 ° C. for 0.5 hours. Further, pyridine-3-sulfonyl chloride (95 ⁇ L, 0.79 mmol) was added and stirred at 0 ° C. for 0.5 hour. Water was added dropwise and partitioned with ethyl acetate.
• 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.
• 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.
• 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.
• 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.

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