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WO2025173852A1 - Procédé de préparation d'un intermédiaire-clé du tégoprazan, et nouveaux intermédiaires utilisant celui-ci - Google Patents

Procédé de préparation d'un intermédiaire-clé du tégoprazan, et nouveaux intermédiaires utilisant celui-ci

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Publication number
WO2025173852A1
WO2025173852A1 PCT/KR2024/015694 KR2024015694W WO2025173852A1 WO 2025173852 A1 WO2025173852 A1 WO 2025173852A1 KR 2024015694 W KR2024015694 W KR 2024015694W WO 2025173852 A1 WO2025173852 A1 WO 2025173852A1
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Prior art keywords
chemical formula
compound represented
preparation
fluid
preparing
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English (en)
Inventor
Liu-Lan Shen
Yong Ho Sun
Ha-Na Na
Mingyun KIM
Myeonggeuk KIM
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Smartbiopharm Co ltd
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Smartbiopharm Co ltd
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Publication of WO2025173852A1 publication Critical patent/WO2025173852A1/fr
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Classifications

    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a preparation method for a tegoprazan intermediate and a novel intermediate used therein. Specifically, the present invention relates to a novel preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan, and a novel intermediate used therein.
  • Tegoprazan is a potassium-competitive acid blocker (P-CAB) indicated for the prevention or treatment of diseases mediated by acid pump antagonist activity, such as gastrointestinal diseases including gastroesophageal disease, gastroesophageal reflux disease, peptic ulcer, gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, dysphagia, sialorrhea, airway lesion, and asthma.
  • P-CAB potassium-competitive acid blocker
  • tegoprazan (4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide) exhibits a structure where a benzimidazole moiety is linked to a 3,4-dihydrochromene moiety, as shown in the following Chemical Formula I:
  • the key intermediates in the preparation of tegoprazan are the benzimidazole moiety intermediate 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide and the 3,4-dihydrochromene moiety intermediate 5,7-difluoro-3,4-dihydro-2H-chromen-4-ol.
  • An object of the present invention is to provide a novel preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan, with the use of inexpensive reagents, high yield, low difficulty in post-processing, and high purity product.
  • Another object of the present invention is to provide a novel intermediate capable of being used in the above preparation method.
  • the present invention provides a preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate used in the preparation of tegoprazan.
  • the preparation method may comprise Steps (A-1) to (A-5) below:
  • Steps (A-1) to (A-5) will be specifically described.
  • Step (A-1) of the present invention is a step of preparing the compound represented by Chemical Formula A2 by acetylating the compound represented by Chemical Formula A1.
  • Step (A-1) may be performed by reacting 4-aminobenzoic acid represented by Chemical Formula A1 with an acetylating reagent.
  • the acetylating reagent may be an acid anhydride or an acyl halide.
  • acetic anhydride or acetyl chloride may be used.
  • the present invention is not limited thereto.
  • Step (A-1) may be performed by adding, as an acid or dehydrating agent, at least one selected from the group consisting of sulfuric acid, acetic acid, acetic anhydride, or a combination thereof, together with the acetylating reagent.
  • the present invention is not limited thereto.
  • Step (A-1) may be performed by adding a reactant under ice bath conditions, heating the reaction solution to about 15°C to about 30°C, followed by stirring the reaction solution under reflux at about 120°C to about 140°C.
  • a temperature during the heating may be room temperature or ambient temperature, and for example, may be raised to a range of one lower limit and one upper limit selected from the group consisting of about 15°C, about 20°C, about 25°C, and about 30°C.
  • the stirring under reflux may be performed in a range of one lower limit and one upper limit selected from the group consisting of about 120°C, about 125°C, about 130°C, about 135°C, and about 140°C.
  • Step (A-1) may be performed in a non-alcoholic polar solvent.
  • Step (A-1) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile.
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • acetonitrile acetonitrile
  • Step (A-1) may be performed in a continuous flow process.
  • Step (A-2) of the present invention is a step of preparing the compound represented by Chemical Formula A3 by subjecting the compound represented by Chemical Formula A2 to an amide coupling reaction.
  • Step (A-2) may be performed by reacting the compound represented by Chemical Formula A2 with dimethyl amine.
  • Step (A-2) may be performed by first reacting the compound represented by Chemical Formula A2 with pivaloyl chloride and then reacting it with dimethyl amine.
  • Step (A-2) may be performed in the presence of a base.
  • the base may be an inorganic base, an amine base, or a heterocyclic base.
  • the base may be sodium hydroxide, calcium hydroxide, sodium bicarbonate, triethylamine, or pyridine.
  • the present invention is not limited thereto.
  • Step (A-2) may be performed by heating to about 15°C to about 30°C after cooling and stirring.
  • a temperature during the heating may be room temperature or ambient temperature, and for example, may be raised to a range of one lower limit and one upper limit selected from the group consisting of about 15°C, about 20°C, about 25°C, and about 30°C.
  • Step (A-2) may be performed in a non-alcoholic polar solvent.
  • Step (A-2) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile.
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • acetonitrile acetonitrile
  • Step (A-2) may be performed in a continuous flow process.
  • Step (A-3) of the present invention is a step of preparing the compound represented by Chemical Formula A4 by subjecting the compound represented by Chemical Formula A3 to a nitration reaction.
  • Step (A-3) may be conducted by reacting the compound represented by Chemical Formula A3 with nitric acid or nitrate to perform a dinitration reaction.
  • the nitrate may be potassium nitrate (KNO 3 ).
  • KNO 3 potassium nitrate
  • the present invention is not limited thereto.
  • Step (A-3) may be performed at about 40°C to about 90°C. Specifically, Step (A-3) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, and about 90°C.
  • Step (A-3) may be performed in a non-alcoholic polar solvent.
  • Step (A-3) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), tetrahydrofuran (THF), and acetonitrile.
  • DCM dichloromethane
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • acetonitrile acetonitrile
  • Step (A-3) may be performed in a continuous flow process.
  • Step (A-3) may be performed by reacting the compound represented by Chemical Formula A3, which is a reactant of Step (A-3), with nitric acid or nitrate, via a continuous flow process.
  • fluids containing the reactants in Step (A-3) above may be supplied to different pumps, respectively, and mixed in a T-shaped connector to perform the reaction. More specifically, Step (A-3) may comprise reacting a fluid a1 containing the compound represented by Chemical Formula A3; and a fluid a2 containing the nitric acid or nitrate.
  • Step (A-4) of the present invention is a step of preparing the compound represented by Chemical Formula A5 by hydrogenating the compound represented by Chemical Formula A4. Specifically, Step (A-4) may be performed by adding hydrogen to the reaction in the presence of a metal catalyst.
  • the metal catalyst may be at least one selected from the group consisting of Raney-Ni, Pd(OAc) 2 , Pd/C, Pt/C, PdO, and Fe powder.
  • the present invention is not limited thereto.
  • Step (A-4) may be performed at about 40°C to about 80°C. Specifically, Step (A-4) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, and about 80°C.
  • Step (A-4) may be performed in a continuous flow process.
  • Step (A-4) may be performed by reacting the compound represented by Chemical Formula A4, which is a reactant of Step (A-4), with hydrogen gas, via a continuous flow process.
  • a flow velocity ratio of the fluid a3 and the fluid a4 may be from about 1 : 4 to about 1 : 8.
  • Step (A-5) may be performed by reacting the compound represented by Chemical Formula A5 with sodium nitrite (NaNO 2 ) in the presence of acid to form an unstable intermediate, a diazonium compound, while simultaneously reacting it with a copper salt.
  • the above copper salt may be Cu 2 O, Cu(NO 3 ) 2 ⁇ 3H 2 O, CuSO 4 , or a combination thereof.
  • the present invention is not limited thereto.
  • Step (A-5) may be performed at about 0°C to about 70°C. Specifically, Step (A-5) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, and about 70°C.
  • Step (A-5) may be performed in a continuous flow process.
  • Step (A-5) may be performed by reacting the compound represented by Chemical Formula A5, which is a reactant of Step (A-5), with sodium nitrite and a copper salt, via a continuous flow process.
  • the preparation method of the present invention may reduce the amount of reagents or solvents, making it environmentally friendly, and also may be performed in a small space and safely as all processes are system-controlled.
  • the present invention provides a novel intermediate capable of being used in preparing 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan.
  • the novel intermediate is a compound represented by the following Chemical Formula A4 or a salt thereof:
  • the present invention provides a preparation method for 4-acetamido-N,N-dimethyl-3,5-dinitrobenzamide, a novel intermediate used in the preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide.
  • the preparation method comprises the following Steps (A-1) to (A-3):
  • Steps (A-1) to (A-3) above is as provided above.
  • the present invention provides a preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate used in the preparation of tegoprazan.
  • the preparation method may comprise the following Steps (B-1) to (B-6):
  • Steps (B-1) to (B-6) will be described in detail.
  • Step (B-1) of the present invention is a step of preparing the compound represented by Chemical Formula B2 by subjecting the compound represented by Chemical Formula B1 to a nitration reaction.
  • Step (B-1) may be performed by adding nitric acid or nitrate to the 4-chlorobenzoic acid represented by Chemical Formula B1 to perform a dinitration reaction.
  • the nitrate may be potassium nitrate (KNO 3 ).
  • KNO 3 potassium nitrate
  • the present invention is not limited thereto.
  • Step (B-1) may be performed by adding, as an acid or dehydrating agent, at least one selected from the group consisting of sulfuric acid, acetic acid, acetic anhydride, or a combination thereof, together with nitric acid or nitrate.
  • an acid or dehydrating agent at least one selected from the group consisting of sulfuric acid, acetic acid, acetic anhydride, or a combination thereof, together with nitric acid or nitrate.
  • the present invention is not limited thereto.
  • Step (B-1) may be performed at about 20°C to about 180°C. Specifically, Step (B-1) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, about 110°C, about 120°C, about 130°C, about 140°C, about 150°C, about 160°C, about 170°C, and about 180°C.
  • Step (B-1) may be performed in a continuous flow process.
  • Step (B-2) of the present invention is a step of preparing the compound represented by Chemical Formula B3 by replacing -Cl in the compound represented by Chemical Formula B2 with -NH 2 .
  • Step (B-2) may be performed by adding aqueous ammonia to the compound represented by Chemical Formula B2.
  • Step (B-2) may be performed at about 40°C to about 80°C. Specifically, Step (B-2) may be performed in a range of one lower limit and one upper limit selected from the group consisting of about 40°C, about 50°C, about 60°C, about 70°C, and about 80°C.
  • Step (B-2) may be performed in an alcoholic solvent.
  • Step (B-2) may be performed in a solvent selected from the group consisting of methanol, ethanol, isopropanol, and butanol.
  • the present invention is not limited thereto.
  • Step (B-2) may be performed in a continuous flow process.
  • Step (B-3) of the present invention is a step of preparing the compound represented by Chemical Formula B4 by subjecting the compound represented by Chemical Formula B3 to an acetylation reaction.
  • Step (B-3) may be performed by reacting an acetylating reagent with the compound represented by Chemical Formula B3.
  • the acetylating reagent may be an acid anhydride or an acyl halide.
  • acetic anhydride or acetyl chloride may be used.
  • the present invention is not limited thereto.
  • Step (B-3) may be performed by adding, as an acid or dehydrating agent, at least one selected from the group consisting of sulfuric acid, acetic acid, acetic anhydride, or a combination thereof, together with the acetylating reagent.
  • the present invention is not limited thereto.
  • Step (B-3) may be performed at about 20°C to about 85°C. Specifically, Step (B-3) may be performed in a range of one lower limit and one upper limit selected from the group consisting of about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, and about 85°C.
  • Step (B-3) may be performed in a non-alcoholic polar solvent.
  • Step (B-3) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile.
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • acetonitrile acetonitrile
  • Step (B-3) may be performed in a continuous flow process.
  • Step (B-4) of the present invention is a step of preparing the compound represented by Chemical Formula B5 by hydrogenating the compound represented by Chemical Formula B4. Specifically, Step (B-4) may be performed by adding hydrogen to the reaction in the presence of a metal catalyst.
  • the metal catalyst may be at least one selected from the group consisting of Raney-Ni, Pd(OAc) 2 , Pd/C, Pt/C, PdO, and Fe powder.
  • the present invention is not limited thereto.
  • Step (B-4) may be performed at about 40°C to about 80°C. Specifically, Step (B-4) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, and about 80°C.
  • Step (B-4) may be performed in an alcoholic solvent.
  • Step (B-4) may be performed in a solvent selected from the group consisting of methanol, ethanol, isopropanol, and butanol.
  • the present invention is not limited thereto.
  • Step (B-4) may be performed in a continuous flow process.
  • Step (B-4) may be performed by reacting the compound represented by Chemical Formula B4, which is a reactant of Step (B-4), with hydrogen gas, via a continuous flow process.
  • fluids containing the reactants in Step (B-4) above may be supplied to different pumps, respectively, and mixed in a T-shaped connector, followed by performing the reaction while passing through a column filled with a metal catalyst.
  • Step (B-4) may comprise reacting a fluid b1 containing the compound represented by Chemical Formula B4; and a fluid b2 containing the hydrogen.
  • the reaction may be performed under conditions where the internal pressure of the pump transporting the fluid is between about 2 bar and about 10 bar.
  • the internal pressure of the pump may be in a range of one lower limit and one upper limit selected from the group consisting of about 2 bar, about 3 bar, about 4 bar, about 5 bar, about 6 bar, about 7 bar, about 8 bar, about 9 bar, and about 10 bar.
  • Step (B-5) of the present invention is a step of preparing the compound represented by Chemical Formula B6 by subjecting the compound represented by Chemical Formula B5 to an amide coupling reaction.
  • Step (B-5) may be performed by reacting the compound represented by Chemical Formula B5 with dimethyl amine.
  • Step (B-5) may be performed by first reacting the compound represented by Chemical Formula B5 with pivaloyl chloride and then reacting it with dimethyl amine.
  • Step (B-5) may be performed in the presence of a base.
  • the base may be an inorganic base, an amine base, or a heterocyclic base.
  • the base may be sodium hydroxide, calcium hydroxide, sodium bicarbonate, triethylamine, or pyridine.
  • the present invention is not limited thereto.
  • Step (B-5) may be performed by heating to about 15°C to about 30°C after cooling and stirring.
  • a temperature during the heating may be room temperature or ambient temperature, and for example, may be raised to a range of one lower limit and one upper limit selected from the group consisting of about 15°C, about 20°C, about 25°C, and about 30°C.
  • Step (B-5) may be performed in a non-alcoholic polar solvent.
  • Step (B-5) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile.
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • acetonitrile acetonitrile
  • Step (B-5) may be performed in a continuous flow process.
  • Step (B-6) of the present invention is a step of preparing the compound represented by Chemical Formula Ia from the compound represented by Chemical Formula B6. Specifically, Step (B-6) may be performed by the Sandmeyer reaction.
  • Step (B-6) may be performed at about 0°C to about 70°C. Specifically, Step (B-6) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, and about 70°C.
  • Step (B-6) may be performed in a continuous flow process.
  • Step (B-6) may be performed by reacting the compound represented by Chemical Formula B6, which is a reactant of Step (B-6), with sodium nitrite and a copper salt, via a continuous flow process.
  • fluids containing the reactants in Step (B-6) above may be supplied to different pumps, respectively, and mixed in a T-shaped connector to perform the reaction. More specifically, Step (B-6) may comprise reacting a fluid b3 containing the compound represented by Chemical Formula B6; and a fluid b4 containing sodium nitrite and a copper salt.
  • the preparation method of the present invention may prepare 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide with a few steps and without post-treatment, thereby shortening the process time to provide excellent efficiency and cost-effectiveness.
  • the preparation method of the present invention may reduce the amount of reagents or solvents, making it environmentally friendly, and also may be performed in a small space and safely as all processes are system-controlled.
  • the 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide prepared by the preparation method of the present invention has excellent yield and purity, and the preparation method of the present invention is highly reproducible.
  • the present invention provides a novel intermediate capable of being used in preparing 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan.
  • the novel intermediate is a compound represented by the following Chemical Formula B4 or a salt thereof:
  • novel intermediate of the present invention enables the preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan, by a novel synthesis pathway.
  • the above synthesis pathway is a very simple process that can significantly reduce process time, resulting in overall excellent efficiency and cost-effectiveness.
  • the novel intermediate of the present invention may be usefully employed as a key intermediate in the preparation method of the present invention capable of being usefully applied to industrial scale production.
  • the present invention provides a preparation method for 4-acetamido-3,5-dinitrobenzoic acid, a novel intermediate used in the preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide.
  • the preparation method comprises the following Steps (B-1) to (B-3):
  • Steps (B-1) to (B-3) above is as provided above.
  • the preparation method of the present invention may utilize a novel intermediate to prepare 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide with a few steps and without post-treatment, thereby shortening the process time to provide excellent efficiency and cost-effectiveness.
  • the preparation method of the present invention may reduce the amount of reagents or solvents, making it environmentally friendly, and also may be performed in a small space and safely as all processes are system-controlled.
  • the 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide prepared by the preparation method of the present invention has excellent yield and purity, and the preparation method of the present invention is highly reproducible.
  • the preparation method of the present invention may be usefully applied to the industrial scale production of tegoprazan (in particular, its key intermediate 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide).
  • FIG. 2 is a schematic diagram of Step A-4 of Example 1 according to the present invention.
  • FIG. 3 is a schematic diagram of Step A-5 of Example 1 according to the present invention.
  • FIG. 4 is a schematic diagram of Step B-4 of Example 2 according to the present invention.
  • Step A-1 Synthesis of 4-acetamidobenzoic acid (Chemical Formula A2)
  • Step A-2 Synthesis of 4-acetamido-N,N-dimethylbenzamide (Chemical Formula A3)
  • Step A-3 Synthesis of 4-acetamido-N,N-dimethyl-3,5-dinitrobenzamide (Chemical Formula A4)
  • the 4-acetamido-N,N-dimethylbenzamide (10 g) prepared in Step A-2 was dissolved in THF (20 mL) and connected to pump A. 60% nitric acid was connected to pump B. Pump A transported the solution at a flow rate of 0.6 mL/min, and pump B transported the solution at a flow rate of 0.2 mL/min. A T-shaped connector was connected and the mixing point was heated to 55°C. The transported reaction product was poured into water, and then DCM (30 mL) was added to extract the organic layer. The organic layer was washed twice with ice water (100 mL). The organic layer was concentrated under reduced pressure at 40°C to obtain the title compound (12.5 g, yield 87%).
  • Step A-4 Synthesis of 4-amino-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Chemical Formula A5)
  • a Raney-Ni catalyst was loaded into a catalyst column with a diameter of 1 cm and a length of 5 cm.
  • the 4-acetamido-N,N-dimethyl-3,5-dinitrobenzamide (5 g) prepared in Step A-3 was dissolved in methanol (100 mL) and connected to a pump.
  • a T-shaped connector was attached to the top of the column to connect both hydrogen gas and the compound solution prepared in Step A-3.
  • Hydrogen gas was transported at a flow rate of 3 mL/min and the compound solution was transported at a flow rate of 0.5 mL/min, while the internal pressure was maintained at 3 bar.
  • the pump was operated, and after 8 minutes, the liquid was collected from the gas-liquid separator. The liquid was transferred to a flask and heated while stirring. After reacting for 2 hours, the reaction product was concentrated under reduced pressure at 40°C to obtain the title compound (3.3 g, yield 90%).
  • Step A-5 Synthesis of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Chemical Formula Ia)
  • the 4-amino-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (5 g) prepared in Step A-4 was dissolved in sulfuric acid (10 mL) and connected to pump A.
  • Sodium nitrite (1.9 g) was dissolved in water (20 mL), and Cu(NO 3 ) 2 ⁇ 3H 2 O (6.5 g) and Cu 2 O (3 g) were added and connected to pump B.
  • a T-shaped connector was connected to transport the solution at a flow rate of 0.5 mL/min.
  • the liquid was collected in a flask, and DCM (50 mL) was added to extract the organic layer.
  • the organic layer was washed twice with water (50 mL).
  • the organic layer was concentrated under reduced pressure at 40°C to obtain the title compound (4.7 g, yield 95%).
  • Step B-2 Synthesis of 4-amino-3,5-dinitrobenzoic acid (Chemical Formula B3)
  • Step B-3 Synthesis of 4-acetamido-3,5-dinitrobenzoic acid (Chemical Formula B4)
  • the 4-amino-3,5-dinitrobenzoic acid (5 g) prepared in Step B-2 was added to acetic anhydride (31 mL). Sulfuric acid (0.1 mL) was added to the reaction solution. The reaction solution was stirred under reflux for 15 minutes. The reaction temperature was lowered to room temperature, and the reaction product was filtered and washed with diethyl ether. The filtrate was poured into ice water and stirred, and the obtained solid was filtered. The filtered solid was dried in a 40°C oven for 24 hours to obtain the title compound (5.3 g, 89% yield).
  • a Raney-Ni catalyst was loaded into a catalyst column with a diameter of 1 cm and a length of 5 cm.
  • the 4-acetamido-3,5-dinitrobenzoic acid (5 g) prepared in Step B-3 was dissolved in methanol (100 mL) and connected to a pump.
  • a T-shaped connector was connected to the top of the column to connect both hydrogen gas and the compound solution prepared in Step B-3.
  • Hydrogen gas was transported at a flow rate of 3 mL/min and the compound solution at a flow rate of 0.5 mL/min, while the internal pressure was maintained at 3 bar.
  • the pump was operated, and after 8 minutes, the liquid was collected from the gas-liquid separator. The liquid was transferred to a flask and heated while stirring. After reacting for 2 hours, the reaction product was concentrated under reduced pressure at 40°C to obtain the title compound (3.2 g, yield 90%).
  • Step B-6 Synthesis of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Chemical Formula Ia)
  • the 4-amino-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (2 g) prepared in Step B-5 was dissolved in sulfuric acid (4 mL) and connected to pump A.
  • Sodium nitrite (0.76 g) was dissolved in water (8 mL), and Cu(NO 3 ) 2 ⁇ 3H 2 O (2.6 g) and Cu 2 O (1.2 g) were added and connected to pump B.
  • a T-shaped connector was connected to transport the solution at a flow rate of 0.5 mL/min.
  • the liquid was collected in a flask, and DCM (20 mL) was added to extract the organic layer.
  • the organic layer was washed twice with water (20 mL).
  • the organic layer was concentrated under reduced pressure at 40°C to obtain the title compound (1.9 g, yield 95%).

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Abstract

La présente invention concerne un nouveau procédé de préparation du 4-hydroxy-N,N,2-triméthyl-1H-benzo[d]imidazole-6-carboxamide, un intermédiaire-clé du tégoprazan ; elle concerne également un nouvel intermédiaire utilisé dans ce procédé Le procédé de préparation de la présente invention peut utiliser un nouvel intermédiaire pour préparer du 4-hydroxy-N,N,2-triméthyl-1H-benzo[d]imidazole-6-carboxamide avec quelques étapes et sans post-traitement, ce qui permet d'obtenir de faibles coûts en matières premières et des temps de traitement raccourcis pour fournir une excellente efficacité et un bon rapport coût- efficacité. En outre, le 4-hydroxy-N,N,2-triméthyl-1H-benzo[d]imidazole-6-carboxamide préparé par le procédé de préparation de la présente invention présente un excellent rendement et une excellente pureté, et le procédé de préparation de la présente invention est hautement reproductible. Ainsi, le procédé de préparation de la présente invention peut être utilement appliqué à la production à l'échelle industrielle du tégoprazan (en particulier, son intermédiaire clé 4-hydroxy-N,N,2-triméthyl-1H-benzo[d] imidazole-6-carboxamide).
PCT/KR2024/015694 2024-02-16 2024-10-16 Procédé de préparation d'un intermédiaire-clé du tégoprazan, et nouveaux intermédiaires utilisant celui-ci Pending WO2025173852A1 (fr)

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