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WO2024087155A1 - Procédé de synthèse de 4-hydroxy-n, n, 2-triméthylbenzimidazole-6-carboxamide - Google Patents

Procédé de synthèse de 4-hydroxy-n, n, 2-triméthylbenzimidazole-6-carboxamide Download PDF

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Publication number
WO2024087155A1
WO2024087155A1 PCT/CN2022/128206 CN2022128206W WO2024087155A1 WO 2024087155 A1 WO2024087155 A1 WO 2024087155A1 CN 2022128206 W CN2022128206 W CN 2022128206W WO 2024087155 A1 WO2024087155 A1 WO 2024087155A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
add
ammonia
stir
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/CN2022/128206
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English (en)
Chinese (zh)
Inventor
费安杰
叶伟平
周章涛
汪辉
王道功
韩小东
黄富任
于璐
吴春林
严凯伦
张毅琳
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.)
Shenzhen Hwagen Pharmaceutical Co Ltd
Original Assignee
Shenzhen Hwagen Pharmaceutical Co Ltd
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
Application filed by Shenzhen Hwagen Pharmaceutical Co Ltd filed Critical Shenzhen Hwagen Pharmaceutical Co Ltd
Priority to PCT/CN2022/128206 priority Critical patent/WO2024087155A1/fr
Publication of WO2024087155A1 publication Critical patent/WO2024087155A1/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

Definitions

  • the invention relates to the field of organic chemical synthesis, and in particular to a method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide.
  • 4-Hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide is a key intermediate in the synthesis of the proton pump inhibitor tegoprazan.
  • the first two steps of this route require the protection of oxygen and nitrogen atoms in sequence, and the use of an iron powder/glacial acetic acid system in the reduction of the nitro group greatly increases the difficulty of post-processing.
  • the introduction of the carboxyl group requires the introduction of the cyanide group through bromination and metal catalysis, which increases the risk of reagent handling, and the resulting carboxylic acid intermediate has high polarity and is difficult to purify.
  • the invention aims to solve the problems of great difficulty in post-processing, low yield and difficulty in obtaining high-purity products in the existing synthesis route of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, and provides a new method for synthesizing a 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide intermediate.
  • the embodiment of the present invention provides a new method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide.
  • the method comprises the following reaction steps:
  • the method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide comprises the following steps:
  • the condensation reagent in step (1) is selected from at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-propyl phosphoric anhydride, and N,N'-carbonyldiimidazole, preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • the source of ammonia in step (2) is selected from at least one of ammonia gas, ammonia water, an alcoholic solution of ammonia, a 1,4-dioxane solution of ammonia, sodium amide, and potassium amide, preferably an alcoholic solution of ammonia.
  • the condensing agent in step (3) is selected from at least one of acetic acid, acetaldehyde, acetal, orthoacetic acid esters (trimethyl orthoacetate, triethyl orthoacetate, etc.), preferably acetic acid;
  • the transition metal reducing agent is selected from at least one of iron powder, zinc powder, stannous chloride compounds, platinum carbon, palladium carbon, preferably reduced iron powder.
  • the diazotizing agent in step (4) is selected from at least one of sodium nitrite, isopentyl nitrite, and tert-butyl nitrite, preferably sodium nitrite; and the acid is selected from at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, preferably hydrochloric acid.
  • the method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide in the embodiment of the present invention has the characteristics of novel process route, inexpensive and readily available raw materials, high chemical purity (>99.0%), and easy production scale-up (because the method of the present invention has a short synthesis route and simple reaction conditions, it is easy to scale up production and can be scaled up to hundreds of kilograms for production).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Procédé de synthèse de 4-hydroxy-N, N, 2-triméthylbenzimidazole-6-carboxamide. Une voie du procédé est la suivante : [Formule (I)-formule (V)]. Le procédé de synthèse de 4-Hydroxy-N, N, 2-triméthylbenzimidazole-6-carboxamide selon la présente invention présente les caractéristiques suivantes : nouvelle voie de traitement, matières premières bon marché et facilement disponibles, pureté chimique élevée (supérieure à 99,0 %), et facilité de production et de mise à l'échelle.
PCT/CN2022/128206 2022-10-28 2022-10-28 Procédé de synthèse de 4-hydroxy-n, n, 2-triméthylbenzimidazole-6-carboxamide Ceased WO2024087155A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2022/128206 WO2024087155A1 (fr) 2022-10-28 2022-10-28 Procédé de synthèse de 4-hydroxy-n, n, 2-triméthylbenzimidazole-6-carboxamide

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2022/128206 WO2024087155A1 (fr) 2022-10-28 2022-10-28 Procédé de synthèse de 4-hydroxy-n, n, 2-triméthylbenzimidazole-6-carboxamide

Publications (1)

Publication Number Publication Date
WO2024087155A1 true WO2024087155A1 (fr) 2024-05-02

Family

ID=90829662

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/128206 Ceased WO2024087155A1 (fr) 2022-10-28 2022-10-28 Procédé de synthèse de 4-hydroxy-n, n, 2-triméthylbenzimidazole-6-carboxamide

Country Status (1)

Country Link
WO (1) WO2024087155A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005111000A1 (fr) * 2004-05-18 2005-11-24 Altana Pharma Ag Benzimidazoles a substitution 7 et utilisation de ces derniers en tant qu'inhibiteurs de la secretion d'acide gastrique
WO2007023135A1 (fr) * 2005-08-22 2007-03-01 Nycomed Gmbh Derives de benzimidazole a substitution isotopique
CN101341149A (zh) * 2005-12-19 2009-01-07 辉瑞大药厂 经色原烷取代的苯并咪唑类和它们作为酸泵抑制剂的用途
CN113527272A (zh) * 2021-08-06 2021-10-22 西安淳甄新材料有限公司 一种特戈拉赞的合成方法
CN114805317A (zh) * 2022-05-20 2022-07-29 江苏威奇达药业有限公司 一种特戈拉赞的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005111000A1 (fr) * 2004-05-18 2005-11-24 Altana Pharma Ag Benzimidazoles a substitution 7 et utilisation de ces derniers en tant qu'inhibiteurs de la secretion d'acide gastrique
WO2007023135A1 (fr) * 2005-08-22 2007-03-01 Nycomed Gmbh Derives de benzimidazole a substitution isotopique
CN101341149A (zh) * 2005-12-19 2009-01-07 辉瑞大药厂 经色原烷取代的苯并咪唑类和它们作为酸泵抑制剂的用途
CN113527272A (zh) * 2021-08-06 2021-10-22 西安淳甄新材料有限公司 一种特戈拉赞的合成方法
CN114805317A (zh) * 2022-05-20 2022-07-29 江苏威奇达药业有限公司 一种特戈拉赞的制备方法

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