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WO2015005615A1 - Procédé de préparation de dérivés de benzimidazole - Google Patents

Procédé de préparation de dérivés de benzimidazole Download PDF

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Publication number
WO2015005615A1
WO2015005615A1 PCT/KR2014/005996 KR2014005996W WO2015005615A1 WO 2015005615 A1 WO2015005615 A1 WO 2015005615A1 KR 2014005996 W KR2014005996 W KR 2014005996W WO 2015005615 A1 WO2015005615 A1 WO 2015005615A1
Authority
WO
WIPO (PCT)
Prior art keywords
chemical formula
compound represented
imidazole
ethyl
benzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2014/005996
Other languages
English (en)
Inventor
Jae Hong Kweon
Eun Sun Kim
Seog Beom Song
Sung Ah Lee
Ji Yun Lee
Kwang Do Choi
Young Joon Park
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HK Inno N Corp
Original Assignee
CJ Healthcare Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020130114349A external-priority patent/KR101472686B1/ko
Application filed by CJ Healthcare Corp filed Critical CJ Healthcare Corp
Priority to US14/903,793 priority Critical patent/US9493425B2/en
Priority to JP2016525274A priority patent/JP6306173B2/ja
Priority to CN201480038908.XA priority patent/CN105377819B/zh
Publication of WO2015005615A1 publication Critical patent/WO2015005615A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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

Definitions

  • the present invention relates to a method for preparing benzimidazole derivatives.
  • Benzimidazole has been known as a very important pharmacophore in medicinal and chemical fields. In terms of chemical structure, the compound has a fused form between a benzene ring and an imidazole ring, and has various pharmaceutical characteristics. In the 1990s, numerous benzimidazole derivatives having substituents such as fluoro and propylene were synthesized, and they were shown to have stability, bioavailability and bioactivities.
  • Oxidazol-1H-benzimidazole as a representative compound, has been known to have antimicrobial activity and has also been reported to have inhibitory activity against fungi as well.
  • benzimidazole derivatives have been developed as HIV inhibitors.
  • One representative example is tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one, which is an antiretroviral agent acting on a particular allosteric binding site of HIV-1 reverse transcriptase.
  • N-alkoxy-2-alkyl-benzimidazole has an EC 50 below 600 nM and shows an inhibitory activity on reverse transcriptase with excellent selectivity.
  • benzimidazole-based compounds having a sulfoxide group and a methylene group are known to inhibit gastric acid secretion by inhibiting a proton pump and protecting gastric mucosa.
  • benzimidazole-based compounds are also known to have antiviral and antihypertensive effects.
  • Benzimidazole derivatives are also very useful in the textile industry, and are mainly used as a dye dispersant or a softening agent.
  • benzimidazole is a pharmacophore with extremely high applicability in the medicinal and chemical fields, and its synthesis has been developed by numerous research groups and suggested in many documents.
  • An object of the present invention is to provide a method for preparing a compound with a benzimidazole structure with an excellent yield using a low-cost starting material, not requiring an additional separation process, or not using a dangerous reagent during the manufacturing process.
  • Another object of the present invention is to provide an intermediate and a final product produced by the preparing method.
  • the present invention provides a method for preparing a compound represented by the Chemical Formula 1 comprising:
  • R 1 and R 2 are independently C 1-4 alkyl
  • R 3 is C 1 -4 alkyl, C 1 -4 haloalkyl or phenyl.
  • R 1 and R 2 are independently methyl, ethyl, propyl or tert-butyl.
  • R 3 is methyl, trifluoromethyl or phenyl.
  • the method of preparing benzimidazole of the present invention unlike the conventional methods in the related art, employs a low-cost starting material, does not require an additional separation process during the preparation, and does not use a dangerous reagent, thus being suitable for large-scale production, and also exhibiting an excellent manufacturing yield.
  • the step 1) is a Stobbe condensation reaction, in which a compound represented by the Chemical Formula 8 may be reacted with a compound represented by the Chemical Formula 9 to obtain a compound represented by the Chemical Formula 10.
  • the step 1) may be performed in the presence of a base, and the base is preferably selected from the group consisting of potassium tert-butoxide, sodium ethoxide and sodium methoxide.
  • the base is preferably selected from the group consisting of potassium tert-butoxide, sodium ethoxide and sodium methoxide.
  • reaction is preferably performed using a solvent selected from the group consisting of methanol, ethanol, acetonitrile and methylene chloride.
  • the reaction is preferably performed at a temperature in the range of 50°C to 55°C.
  • the molar ratio between the compound represented by the Chemical Formula 8 and the compound represented by the Chemical Formula 9 is preferably in the range of 1:1 to 1:4, and more preferably is 1:1.4.
  • the step 2) is a cyclization reaction of benzimidazole, in which the compound represented by the Chemical Formula 10 may be reacted with a compound represented by the Chemical Formula 11 to obtain the compound represented by the Chemical Formula 1.
  • the step 2) is performed using acetonitrile as a solvent.
  • reaction is preferably performed at a temperature in the range of 80°C to 85°C.
  • molar ratio between the compound represented by the Chemical Formula 10 and the compound represented by the Chemical Formula 11 is preferably in the range of 1:1 to 1:4, and more preferably is 1:2.8.
  • the compound represented by the Chemical Formula 8 may be prepared by a method comprising:
  • R 1 is C 1 -4 alkyl
  • R 4 is C 1 -4 alkyl.
  • R 1 is methyl, ethyl, propyl or tert-butyl.
  • R 4 is methyl or ethyl.
  • the step a), a Pinner reaction is a hydrolysis reaction of nitrile groups, in which a compound represented by the Chemical Formula 4 is obtained by reacting a compound represented by the Chemical Formula 2 with a compound represented by the Chemical Formula 3.
  • the reaction is performed under acidic conditions, and thus hydrochloric acid, bromic acid or acetic acid is preferably added in the reaction.
  • a material that can produce an acidic material during the reaction may be added. For example, it is possible to add acetyl chloride in the reaction thereby producing hydrochloric acid.
  • the reaction may be performed at a temperature in the range of -10°C to 0°C.
  • the molar ratio between the compound represented by the Chemical Formula 2 and the compound represented by the Chemical Formula 3 is preferably in the range of 1:1 to 1:4, and more preferably is 1:2.4.
  • the step b) is a reaction for introducing a benzyl group, in which a compound represented by the Chemical Formula 6 is obtained by reacting the compound represented by the Chemical Formula 4 with a compound represented by the Chemical Formula 5.
  • the reaction is performed using methanol or ethanol as a solvent.
  • the reaction is preferably performed at a temperature in the range of 23°C to 25°C.
  • the molar ratio between the compound represented by the Chemical Formula 4 and the compound represented by the Chemical Formula 5 is preferably in the range of 1:1 to 1:4, and more preferably is 1:1.
  • the step c) is a cyclization reaction of imidazole, in which a compound represented by the Chemical Formula 8 is obtained by reacting the compound represented by the Chemical Formula 6 with a compound represented by the Chemical Formula 7.
  • the reaction is performed in the presence of a base, which is more preferably selected from the group consisting of potassium carbonate, triethylamine, sodium hydroxide and diisopropylethylamine, and most preferably potassium carbonate.
  • a base which is more preferably selected from the group consisting of potassium carbonate, triethylamine, sodium hydroxide and diisopropylethylamine, and most preferably potassium carbonate.
  • reaction is preferably performed using a solvent selected from the group consisting of methanol, ethanol, isopropanol, methylene chloride, chloroform, water and a mixed solution thereof, and most preferably a mixed solution of methylene chloride and water.
  • a solvent selected from the group consisting of methanol, ethanol, isopropanol, methylene chloride, chloroform, water and a mixed solution thereof, and most preferably a mixed solution of methylene chloride and water.
  • reaction is preferably performed at a temperature of in the range of 40°C to 45°C (reflux). Also, in the reaction, the molar ratio between the compound represented by the Chemical Formula 6 and the compound represented by the Chemical Formula 7 is preferably in the range of 1:0.5 to 1:4, and more preferably is 1:0.93.
  • the present invention provides a method of preparing a compound represented by the Chemical Formula 1-1 by reacting a compound represented by the Chemical Formula 1 in the presence of a base selected from potassium carbonate or sodium bicarbonate:
  • R 1 and R 2 are independently C 1 -4 alkyl, and preferably methyl, ethyl, propyl or tert-butyl.
  • the reaction is performed using a solvent selected from the group consisting of methanol, ethanol, water and a mixed solution thereof.
  • the reaction is preferably performed at a temperature of in the range of 23°C to 25°C.
  • the molar ratio between the compound represented by the Chemical Formula 1 and the base is preferably in the range of 1:1 to 1:4, and more preferably is 1:1.4.
  • the present invention provides a method of preparing a compound represented by the Chemical Formula 1-2 by reacting a compound represented by the Chemical Formula 1 in the presence of a base selected from sodium hydroxide or potassium hydroxide:
  • R 1 is C 1-4 alkyl, and preferably, methyl, ethyl, propyl or tert-butyl.
  • the reaction is performed using a solvent selected from the group consisting of methanol, ethanol, water and a mixed solution thereof.
  • the reaction is preferably performed at a temperature of in the range of 70°C to 80°C.
  • the molar ratio between the compound represented by the Chemical Formula 1 and the base is preferably in the range of 1:1 to 1:10, and more preferably is 1:5.
  • the present invention provides a method of preparing a compound represented by the Chemical Formula 1-3 by reacting a compound represented by the Chemical Formula 1-2 with dimethylamine in the presence of thionyl chloride:
  • R 1 is a C 1-4 alkyl, and preferably, methyl, ethyl, propyl or tert-butyl.
  • the reaction is performed in a two-step process.
  • a chloro group is introduced into the compound represented by the Chemical Formula 1-2 using thionyl chloride.
  • acetonitrile is used as a solvent, and the reaction is performed at 80°C.
  • an amine group is introduced via amidation reaction.
  • the amine is dimethylamine, and its salt (e.g., hydrochloride) may be used as well.
  • the reaction is preferably performed at 0°C.
  • the molar ratio between the compound represented by the Chemical Formula 1-2 and the amine is preferably in the range of 1:1 to 1:1.8, and more preferably is 1:1.8.
  • the present invention provides compounds represented by the Chemical Formula 1, the Chemical Formula 1-1, the Chemical Formula 1-2, or the Chemical Formula 1-3 produced by the methods described above:
  • R 1 , R 2 and R 3 are the same as defined above.
  • the representative examples of the compounds represented by the Chemical Formula 1, the Chemical Formula 1-1, the Chemical Formula 1-2, or the Chemical Formula 1-3 are as follows.
  • the method of preparing a compound having a benzimidazole structure of the present invention uses a low-cost starting material, does not require an additional separation process during the manufacturing process, and does not use a dangerous reagent thus being advantageous for a large-scale production, and also has an excellent manufacturing yield.
  • an intermediate and a final product produced by the preparing method of the present invention may be used for preparing other compounds having a benzimidazole structure, and in particular, utilized as an intermediate for preparing compounds which can be used for antibacterial agent, antiulcer agent or antiinflammatory therapeutic agents.
  • Example 7 Preparation of Compound represented by Chemical Formula 1-2(1-benzyl-4-hydroxy-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid)
  • Example 8 Preparation of Compound represented by Chemical Formula 1-3(1-benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxyamide)
  • reaction solvent was removed at 45°C under reduced pressure. Water in the amount of 22.5 kg was added thereto and stirred for 12 hours. The resulting solid was filtered, washed with 6.75 kg of ethanol/water (1:2 volume ratio) and vacuum-dried at 40°C to obtain 2.10 kg of 1-benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxyamide of the Chemical Formula 1-3.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (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)

Abstract

Cette invention concerne un procédé de préparation d'un composé doté d'une structure de benzimidazole à un excellent rendement à l'aide d'un matériau de départ à bas prix, ne nécessitant aucun procédé de séparation supplémentaire, ou n'utilisant aucun réactif dangereux pendant le procédé de préparation. Un intermédiaire et un produit final obtenus par le procédé de préparation selon l'invention sont en outre décrits.
PCT/KR2014/005996 2013-07-09 2014-07-04 Procédé de préparation de dérivés de benzimidazole Ceased WO2015005615A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US14/903,793 US9493425B2 (en) 2013-07-09 2014-07-04 Method for preparation of benzimidazole derivatives
JP2016525274A JP6306173B2 (ja) 2013-07-09 2014-07-04 ベンズイミダゾール誘導体の製造方法
CN201480038908.XA CN105377819B (zh) 2013-07-09 2014-07-04 制备苯并咪唑衍生物的方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2013-0080389 2013-07-09
KR20130080389 2013-07-09
KR10-2013-0114349 2013-09-26
KR1020130114349A KR101472686B1 (ko) 2013-07-09 2013-09-26 벤즈이미다졸 유도체의 제조방법

Publications (1)

Publication Number Publication Date
WO2015005615A1 true WO2015005615A1 (fr) 2015-01-15

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PCT/KR2014/005996 Ceased WO2015005615A1 (fr) 2013-07-09 2014-07-04 Procédé de préparation de dérivés de benzimidazole

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115108994A (zh) * 2022-06-23 2022-09-27 江苏威奇达药业有限公司 一种特戈拉赞中间体及其制备方法与应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5294631A (en) * 1990-04-13 1994-03-15 Smithkline Beecham Corporation Substituted benzimidazoles useful as angiotension II receptor antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5294631A (en) * 1990-04-13 1994-03-15 Smithkline Beecham Corporation Substituted benzimidazoles useful as angiotension II receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MATTHIAS WEBEL ET AL.: "Development of an Efficient Process Towards the Benz imidazole BYK308944: A Key Intermediate in the Synthesis of a Potassium-Comp etitive Acid Blocker.", ORGANIC PROCESS RESEARCH & DEVELOPMENT., vol. 14, no. 1, 2010, pages 142 - 151 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115108994A (zh) * 2022-06-23 2022-09-27 江苏威奇达药业有限公司 一种特戈拉赞中间体及其制备方法与应用
CN115108994B (zh) * 2022-06-23 2024-05-31 江苏威奇达药业有限公司 一种特戈拉赞中间体及其制备方法与应用

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