Classifications

• • 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
• • 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

Definitions

• the invention belongs to the technical field of synthetizing active pharmaceutical ingredients, and specifically relates to the preparation of Tegoprazan and analogues thereof.
• Tegorazan also known as Tegoprazan or CJ-12420, was approved for marketing by the Korean Ministry of Food and Drug Safety (MFDS) in July, 2018, and is used for the treatment of gastroesophageal reflux disease and erosive esophagitis.
• Tegoprazan was originally developed by Pfizer, then licensed to RaQualia Pharma (spun off from Pfizer) in 2008 for cooperative development, then licensed by RaQualia Pharma to CJ Health Care in 2014, and finally successfully developed by CJ Health Care and marketed in South Korea.
• Tegoprazan is a potassium-competitive acid blocker (P-CAB) and a hydrogen ion /potassium ion exchange ATPase (H + /K + ATPase) inhibitor, works fast and can control the pH of gastric juice for a long time. This drug was first marked in South Korea and is a brand-new drug for the treatment of gastroesophageal reflux disease and erosive esophagitis.
• Gastric proton pump hydrogen ion/potassium ion exchange ATPase is the main pharmacological target for the treatment of gastric acid-related diseases.
• Potassium-competitive acid blocker P-CAB
• Tegoprazan is such a potassium-competitive acid blocker, which is considered the most advanced drug for the treatment of gastroesophageal reflux disease, because proton pump inhibitors are the most commonly used drugs for the treatment of gastroesophageal reflux disease, and Tegoprazan can exactly overcome the shortcomings of proton pump inhibitors.
• Tegoprazan The effectiveness and safety of Tegoprazan are mainly based on two phase III clinical trials.
• One of them was a double-blind, actively controlled phase III study (NCT02456935) , which was conducted in South Korea, and the safety and effectiveness of Tegoprazan and the proton pump inhibitor esomeprazole were compared, by taking 280 patients having erosive esophagitis as the research object, and the cumulative healing rate of erosive esophagitis at the 8th week as the primary endpoint.
• Another phase III clinical trial was a double-blind, randomized, placebo-controlled trial (NCT02556021) . This trial was conducted on 324 patients in South Korea.
• the primary endpoint was the percentage of the patients whose main symptoms (heartburn and reflux) were completely resolved at the 4th week, which was determined by using reflux disease questionnaire (RDQ) , so as to evaluate the safety and effectiveness of the once-daily Tegoprazan tablet (50mg and 100mg) on patients with non-erosive reflux disease.
• RDQ reflux disease questionnaire
• a patent No. CN101341149B discloses the preparation method of Tegoprazan, specifically,
• Tegoprazan mainly involves the condensation reaction of 4-hydroxy-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl] -1H-benzo [d] imidazole-6-methanamide and (S) -5, 7-difluoro-3, 4-dihydro-2H-chromenen-4-ol, this condensation reaction not only involves the use of dangerous reagents tributylphosphine and azo compounds, but also has low yield and high cost.
• the purpose of the present invention is to provide a synthetic method for preparing Tegoprazan and analogues thereof, aiming to avoid the disadvantages of using dangerous condensation reagents and low yield in original drug patents.
• the synthetic route of the present invention is as follows:
• the reaction of the present invention involves the reaction of 4-halo-2-methyl-1H-benzo [d] imidazole-6-carboxylate (Formula I) or 4-halo-2-methyl-1H-benzo [d] imidazole-6-carboxylic acid amide compound (Formula I) with (S) -5, 7-difluoro-3, 4-dihydro-2H-chromene-4-ol in the presence of copper reagent/base/additive/solvent to prepare 4- [ ( (4S) -5, 7-difluoro-3, 4-2H-chromenen-4-yl) oxy] -2-methyl-1H-benzo [d] imidazole-6-carbox ylate (Formula II) or 4- [ ( (4S) -5, 7-difluoro-3, 4-2H-chromenen-4-yl) oxy] -2-methyl-1H-benzo [d] imidazole-6-carbox ylic acid amide (Formula II)
• X in Formula I is Cl, Br, I.
• R 1 in Formula I is H, Ts, Bs, Ms, Bn, alkyl, Ac, Boc.
• R 2 in Formula I is OMe, OEt, O t Bu, O n Bu, O i Pr, O n Pr, NHMe, NHEt, NH i Pr, NH n Pr, N ( i Pr) 2 , N ( n Pr) 2 , NBu 2 , NMe 2 , NEt 2 , NH 2 .
• the copper reagent used in the reaction is CuO, Cu (OAc) 2 , CuI, CuBr, Cu 2 O, Cu (acac) 2 .
• the base used in the reaction is K 3 PO 4 , t BuOK, t BuONa.
• the additives used in the reaction are oxamide compounds, including N 1 , N 2 -bis (2, 4, 6-trimethoxyphenyl) oxamide, N 1 , N 2 -bis (2-phenyl-4-methylphenyl) oxamide, N 1 - (1-naphthyl) -N 2 -alkyl oxamide, N 1 -benzyl-N 2 - (5-methyl- [1, 1'-biphenyl] -2-yl) oxamide, N 1 , N 2 -bis (phenylethyl) oxamide, N 1 , N 2 -bis ( [1, 1'-biphenyl] -2-diyl) oxamide, N 1 -benzyl-N 2 - ( [1, 1'-biphenyl] -2-yl) oxamide, N 1 , N 2 -bis (naphthalene-1-ylmethyl) oxamide, N 1 ,
• the solvent used in the reaction is tert-butanol, 1, 4-dioxane, DMF, acetonitrile, DMSO.
• R 1 in Formula II is H, Ts, Bs, Ms, Bn, alkyl, Ac, Boc.
• R 2 in Formula II is OMe, OEt, O t Bu, O n Bu, O i Pr, O n Pr, NHMe, NHEt, NH i Pr, NH n Pr, N ( i Pr) 2 , N ( n Pr) 2 , NBu 2 , NMe 2 , NEt 2 , NH 2 .
• the reaction used in the invention has simple operations, which uses safe reagents, and is suitable for industrial synthesis of Tegoprazan and analogues thereof.
• the reaction system was then heated to 100°C and reacted for 24 hours with stirring. After the reaction was completed, the system naturally dropped to room temperature.
• the reaction system was diluted by adding ethyl acetate (500 mL) , stirred vigorously for 0.5 hours, and then filtered through Celite. The filtrate was desolventized under reduced pressure to remove the organic solvent.
• the reaction system was then heated to 85°C and reacted for 24 hours with stirring. After the reaction was completed, the system naturally dropped to room temperature.
• the reaction system was diluted with ethyl acetate (200 mL) , stirred vigorously for 0.5 hours, and then filtered through Celite. The filtrate was desolventized under reduced pressure to remove the organic solvent. The residue was purified by column chromatography (ethyl acetate/heptane) to obtain a white solid (3.32 g, 85.7%) .
• the reaction system was then heated to 75°C and reacted for 24 hours with stirring. After the reaction was completed, the system naturally dropped to room temperature.
• the reaction system was diluted with ethyl acetate (200 mL) , stirred vigorously for 1 hour, and then filtered through Celite. The filtrate was desolventized under reduced pressure to remove the organic solvent. The residue was purified by column chromatography (ethyl acetate/heptane) to obtain an off-white solid (2.77 g, 71.5%) .

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Plural Heterocyclic Compounds (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Citations (3)

• 2020
  • 2020-03-19 CN CN202010194067.9A patent/CN111303131B/zh active Active
• 2021
  • 2021-03-15 KR KR1020227036483A patent/KR20220154812A/ko unknown
  • 2021-03-15 WO PCT/CN2021/080657 patent/WO2021185192A1/en active Application Filing

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