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CN-122029159-A - Preparation scheme of benzimidazole compound

CN122029159ACN 122029159 ACN122029159 ACN 122029159ACN-122029159-A

Abstract

The present invention relates to a process for the preparation of benzimidazole derivatives, which are useful as pharmaceutical products, in particular as acid secretion inhibitors, to a process for the preparation of intermediates used in the process, and to novel intermediates.

Inventors

  • Da Jianren
  • FU YUANFENG

Assignees

  • 拉夸里亚创药株式会社

Dates

Publication Date
20260512
Application Date
20241101
Priority Date
20231101

Claims (20)

  1. 1. A process for producing a compound represented by the general formula (IX) or a pharmaceutically acceptable salt thereof, which comprises the steps of: (1) Reacting a compound represented by the general formula (I) with a compound represented by the general formula (II) to obtain a compound represented by the general formula (III); (2) Halogenating the compound represented by the general formula (III) to obtain a compound represented by the general formula (IV); (3) Cyclizing the compound represented by the formula (IV) to obtain the compound represented by the formula (V), and (4) Reacting the compound represented by the general formula (V) with the compound represented by the general formula (VI) to obtain the compound represented by the general formula (VII); Wherein R 1 is-N (C 1-6 alkyl) (C 1-6 alkyl) wherein 2 (C 1-6 alkyl) can form a 4-to 6-membered heterocyclyl, -O-C 1-6 alkyl or hydroxy, R 2 is C 1-6 alkyl, R 3 and R 4 are independently C 1-6 alkyl or halogen, and prot. Is a protecting group, { Chemical formula 1} , { Chemical formula 2} , { Chemical formula 3} , { Chemical formula 4} , { Chemical formula 5} , { Chemical formula 6} , { Chemical formula 7} , { Chemical formula 8} 。
  2. 2. A process for producing a compound represented by the general formula (III) or a salt thereof, { Chemical formula 9} , Comprising the step of reacting a compound represented by the general formula (I) with a compound represented by the general formula (II) to obtain a compound represented by the general formula (III) or a salt thereof, Wherein R 1 and R 2 are defined in claim 1 and prot.
  3. 3. A process for producing a compound represented by the general formula (IV) or a salt thereof, which comprises the step of halogenating a compound represented by the general formula (III) to obtain a compound represented by the general formula (IV), Wherein R 1 and R 2 are defined in claim 1 and prot is a protecting group, { Chemical formula 10} 。
  4. 4. A process for producing a compound represented by the general formula (V) or a salt thereof, which comprises the step of cyclizing a compound represented by the general formula (IV) to obtain a compound represented by the general formula (V), Wherein R 1 and R 2 are defined in claim 1 and prot is a protecting group, { Chemical formula 11} 。
  5. 5. A method for producing a compound represented by the general formula (IX) or a pharmaceutically acceptable salt thereof, comprising the following 1 or 2 steps: (1) Reacting a compound represented by the general formula (I) with a compound represented by the general formula (II) to obtain a compound represented by the general formula (III), and (3) Cyclizing the compound represented by the general formula (IV) to obtain a compound represented by the general formula (V); Wherein R 1 and R 2 are defined in claim 1 and prot.
  6. 6. A process for producing a compound represented by the general formula (IX) or a pharmaceutically acceptable salt thereof, which comprises the steps of: (1) Reacting a compound represented by the general formula (I) with a compound represented by the general formula (II) to obtain a compound represented by the general formula (III); (2) Halogenating the compound represented by the general formula (III) to obtain a compound represented by the general formula (IV); (3a) Cyclizing the compound represented by the formula (IV) to obtain the compound represented by the formula (VIII), and (4A) Reacting a compound represented by the general formula (VIII) with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (VII); Wherein R 1 is-N (C 1-6 alkyl) (C 1-6 alkyl) wherein 2 (C 1-6 alkyl) can form a 4-to 6-membered heterocyclyl, -O-C 1-6 alkyl or hydroxy, R 2 is C 1-6 alkyl, R 3 and R 4 are independently C 1-6 alkyl or halogen, and prot. Is a protecting group, { Chemical formula 12} 。
  7. 7. A production method of a compound represented by the general formula (VIII) or a salt thereof, which comprises a step of cyclizing a compound represented by the general formula (IV) to obtain a compound represented by the general formula (VIII); Wherein R 1 and R 2 are defined in claim 6 and prot is a protecting group, { Chemical formula 13} 。
  8. 8. A method for producing a compound represented by the general formula (IX) or a salt thereof, comprising the steps of: (3a) Cyclizing the compound represented by the general formula (IV) to obtain a compound represented by the general formula (VIII); wherein R 1 is-N (C 1-6 alkyl) (C 1-6 alkyl), 2 of which (C 1-6 alkyl) can form a 4-to 6-membered heterocyclic group, -O-C 1-6 alkyl, C 1-6 alkyl or hydroxy, R 2 is C 1-6 alkyl, R 3 and R 4 are independently C 1-6 alkyl or halogen, and prot is a protecting group, { Chemical formula 14} , { Chemical formula 15} 。
  9. 9. The method according to any one of claims 1 to 8, wherein, R 1 is-N (methyl) 2 and R 2 is methyl.
  10. 10. The method according to any one of claims 1 to 8, wherein, The protecting group is selected from the group consisting of methyl, t-butyl, allyl, benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, methoxymethyl, 2- (trimethylsilyl) ethoxymethyl, trityl, benzhydryl, dimethylbenzyl, tetrahydropyranyl, t-butoxycarbonyl, benzyloxycarbonyl, methylsulfonyl, 4-toluenesulfonyl, acetyl and benzoyl.
  11. 11. The method of any one of claim 1, claim 5, claim 6, claim 8, claim 9, and claim 10, wherein, R 3 and R 4 are fluorine.
  12. 12. The method according to any one of claims 1 to 8, wherein, Cyclization is carried out in the presence of a metal catalyst and a ligand.
  13. 13. The method of claim 12, wherein, The metal catalyst is one or more copper catalysts selected from the group consisting of Cu (0), copper (I) acetate, copper (I) bromide, copper (I) chloride, copper (I) iodide, copper (I) oxide, copper (II) triflate, copper (II) acetate, copper (II) bromide, copper (II) chloride, copper (II) iodide, copper (II) oxide, copper (II) sulfate, copper (I) tetra (acetonitrile) hexafluorophosphate, and copper (II) acetylacetonate.
  14. 14. The method of claim 12, wherein, The ligand is selected from the group consisting of ethane-1, 2-diamine, N1, N2-dimethylethane-1, 2-diamine, N1, N2, N2-tetramethylethane-1, 2-diamine, cyclohexane-1, 2-diamine, N1, N2-dimethylcyclohexane-1, 2-diamine, quinolin-8-ol, 1, 10-rphine, proline, oxamide derivatives such as N1, N2-bis (4-hydroxy-2, 6-xylyl) oxamide, N1, N2-bis (1-naphthylmethyl) ethanediamide, N '-dibenzyl oxamide, N1, N2-bis (2, 4, 6-trimethoxyphenyl) ethanediamide, N' -bis (2-phenylethyl) ethanediamide, 6-hydroxymethylpyridinamide derivatives such as N- (2, 6-xylyl) -6-hydroxypyridinamide, 6-hydroxy-N- (2, 4, 6-trimethoxyphenyl) formamide, 6-hydroxy-N- (2, 6-hydroxyphenylcarboxamide, N- (1, 4, 6-hydroxyphenylcarboxamide) and N- (1, 4, 6-hydroxyphenylcarboxamide) m-1, 6-hydroxyphenylcarboxamide 6-hydroxy-N-phenylpicolinamide, 6-hydroxy-N- (thiophen-2-ylmethyl) picolinamide, 6-hydroxy-N- (naphthalen-1-ylmethyl) picolinamide, N- (2, 6-diisopropylphenyl) -6-hydroxymethylpicolinamide, N- (2, 6-difluorophenyl) -6-hydroxymethylpicolinamide, N- (2, 6-dimethoxyphenyl) -6-hydroxymethylpicolinamide and one of the group of 6-hydroxy-N- (4-hydroxy-2, 6-xylyl) picolinamides, 4-hydroxyquinoline-2-carboxamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxamide and N- (2, 6-xylyl) -4-hydroxyquinoline-2-carboxamide and 6-hydroxymethylpyridinamide derivatives such as N- (1, 3-dimethyl-9H-carbazol-9-yl) -6-hydroxymethylpyridinamide, N- (2, 7-dimethyl-9H-carbazol-9-yl) -6-hydroxymethylpyridinamide and N- (2, 7-di-tert-butyl-9H-9-yl) -6-hydroxypyridine carboxamide.
  15. 15. The method of any one of claim 1, claim 5, claim 6, claim 8, claim 9, and claim 10, wherein, The general formula (IX) is an (S) -chiral compound represented by the general formula (X), { Chemical formula 16} 。
  16. 16. The method of claim 15, wherein, The chiral compound represented by the general formula (X) is tergolian, wherein R 1 is-N (methyl) 2 ;R 2 is methyl, and R 3 and R 4 are fluorine.
  17. 17. A compound represented by the general formula (III) or a geometric isomer thereof tautomers or salts: { chemical formula 17} , Wherein R 1 is-N (C 1-6 alkyl) (C 1-6 alkyl), 2 (C 1-6 alkyl) of which can form 4-6 membered heterocyclic group, -O-C 1-6 alkyl, C 1-6 alkyl or hydroxy, R 2 is C 1-6 alkyl, and prot.
  18. 18. A compound represented by the general formula (IV) a geometric isomer, tautomer or salt thereof: { chemical formula 18} , Wherein R 1 is-N (C 1-6 alkyl) (C 1-6 alkyl), 2 (C 1-6 alkyl) of which can form 4-6 membered heterocyclic group, -O-C 1-6 alkyl, C 1-6 alkyl or hydroxy, R 2 is C 1-6 alkyl, and prot.
  19. 19. Use of a compound represented by the general formula (III), a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof as an intermediate compound for preparing a compound represented by the general formula (IX): { chemical formula 19} , { Chemical formula 20} , { Chemical formula 21} , Wherein R 1 is-N (C 1-6 alkyl) (C 1-6 alkyl), 2 (C 1-6 alkyl) of which can form 4-6 membered heterocyclyl, -O-C 1-6 alkyl, C 1-6 alkyl or hydroxy, R 2 is C 1-6 alkyl, R 3 and R 4 are independently C 1-6 alkyl or halogen, and prot.
  20. 20. A pharmaceutical composition comprising a compound of claim 17 or 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Description

Preparation scheme of benzimidazole compound Technical Field The present invention relates to a process for the preparation of benzimidazole derivatives, which are useful as pharmaceutical products, in particular as acid secretion inhibitors, to a process for the preparation of intermediates used in the process, and to novel intermediates. Background Benzimidazole compounds having a substituted amide group at the 6-position are useful as potassium ion competitive acid blockers (p-cab), i.e., therapeutic agents for acid-related diseases (patent document 1 and patent document 2). Patent document 1 discloses a compound represented by the general formula (a), which is useful for treating/preventing a disease state mediated by acid pump inhibitory activity. { Chemical formula 1} Wherein; -a-B-represents-O-CH 2-、-S-CH2-、-CH2 -O-or-CH 2 -S-; x represents an oxygen atom or NH; R 1 represents C 1-C6 alkyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of hydroxyl and C 1-C6 alkoxy, R 2 and R 3 independently represent a hydrogen atom, C 1-C6 alkyl, C 3-C7 cycloalkyl or heteroaryl, R 4、R5、R6 and R 7 independently represent a hydrogen atom, halogen atom, hydroxyl, C 1-C6 alkyl or C 1-C6 alkoxy, and R 8 represents a hydrogen atom, hydroxyl or C 1-C6 alkoxy. Patent document 1 discloses a general synthesis method of a benzimidazole derivative using an aniline derivative as a starting material. Benzimidazole derivatives can be prepared by concentrating reaction of Benzimidazole Intermediate (BI) with a chromanol derivative followed by chiral separation as follows. { Chemical formula 2} Tergolian (Tegoprazan) is a drug for treating acid related diseases, inhibits hydrogen ions/potassium ions exchange ATPase (H +/K+ -ATPase) in a potassium ion competitive mode, namely, a potassium ion competitive acid blocker (p-cab) reacts rapidly, and can control the pH value of gastric juice for a long time. Tergolian has the chemical name (S) -4- ((5, 7-difluorochroman-4-yl) oxy) -N, 2-trimethyl-1H-benzo [ d ] imidazole-6-carboxamide, the chemical structure comprising a benzimidazole structure with a substituted amide group in the 6-position and a chiral 5, 7-difluorochroman-4-oxy radical structure. { Chemical formula 3} Examples 1 to 3 of patent document 1 also disclose a process for producing a Benzimidazole Intermediate (BI) using 4-bromo-2-nitro-6- ((benzyl) oxy) aniline (B). { Chemical formula 4} Further, the compound (B) is produced by a method described in WO2004/054984 (patent document 8) using a commercially available aniline (C) as a starting material. In general, the Benzimidazole Intermediate (BI) of tergolian is prepared from commercially available aniline (C) by nine steps according to the previous method. { Chemical formula 5} Recently, some patent documents (patent documents 3 to 7 and 9) disclose an improved preparation method of Benzimidazole Intermediate (BI), a key intermediate of tergoraprazan. Patent document 3 discloses a seven-step preparation method of Benzimidazole Intermediate (BI) to obtain tergoraprazan from commercially available 4-aminobenzoic acid (D) as follows. The synthetic scheme for tergolian involves mainly a concentration reaction of Benzimidazole Intermediate (BI) with 5, 7-difluorochroman-4-ol followed by a deprotection reaction. The existing preparation method of tergolian has the problems of complex process, environment friendliness, multiple steps, high cost, low yield and the like. Therefore, it is required to provide a simple, high-yield, safe and environment-friendly process for preparing tergolian, which is very important for industrial development of tergolian. Technical literature of the prior art Patent literature { Patent document 1} wo2007/072146 { Patent document 2} WO2016/200148 { Patent document 3} CN115597639 { Patent document 4} WO2015/005615 { Patent document 5} WO2023/128525 { Patent document 6} CN112851846 { Patent document 7} CN114805317 { Patent document 8} WO2004/054984 { Patent document 9} cn116789654 { Patent document 10} CN111303131 { Patent document 11} CN115108994 { Patent document 12} CN116253685 Summary of the invention Technical problem to be solved by the invention There is a need for a cost effective short-step preparation process for benzimidazole derivatives useful as pharmaceutical products. In addition, it is desirable to provide a key intermediate for use in the process. The present invention has conducted intensive studies on a cost-effective, short-step and environmentally friendly process for preparing benzimidazole derivatives including tergolilazan or a pharmaceutically acceptable salt thereof and an improved process for preparing a key intermediate used in the process. As a result, a new and improved three-step process for obtaining a key Benzimidazole Intermediate (BI) from a commercially available aniline derivative (I) has been discovered. In addition, important novel intermediates (III)