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A process for the preparation of pyridine compounds

A compound and isomer mixture technology, applied in the field of pathological pyridine compounds, can solve the problems of safety hazards, long post-processing time, and reduced yield

Inactive Publication Date: 2007-10-24
DIPHARMA FRANCIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the handling of large quantities of hydrogen peroxide involves significant hazards in terms of operator safety
In addition, oxidation of the thioether (-S-) intermediate may also generate undesired sulfone (-SO 2 -)derivative
This involves lower yields and longer workup times

Method used

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  • A process for the preparation of pyridine compounds
  • A process for the preparation of pyridine compounds
  • A process for the preparation of pyridine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] 2-(4-Chloro-3-methoxypyridin-2-yl)methylsulfinyl-5-difluoromethoxy-1H-benzimidazole

[0066] RuCl was added to a 50 mL three-necked round bottom flask equipped with a magnetic stirrer, reflux condenser and under a nitrogen atmosphere. 3 (63.1 mg, 0.30 mmol), THF (2.0 mL) and 1,4-dioxane (2.0 mL). Then, an aqueous solution of ETDA trisodium (0.13M, 2.37mL, 0.30mmol) was added, and then 2-(4-chloro-3-methoxy-1-oxypyridine-2 A solution of -(methylsulfanyl)-5-difluoromethoxy-1H-benzimidazole (1.178 g, 3.05 mmol) in 1,4-dioxane (12 mL). After 1 hour, the mixture was cooled, the solvent was evaporated in vacuo and the desired product was purified by flash chromatography.

[0067] 1 H NMR (300MHz, CDCl 3 ): δ8.12 (1H, d, J = 5.0Hz), 7.54 (1H, d, J = 8.7Hz), 7.33 (1H, s), 7.25 (1H, d, J = 5.0Hz), 7.08 (1H , dd, J=8.7, 2.4Hz), 6.52 (1H, t, J=74.1Hz), 4.87 & 4.78 (2×1H, AB system, J=13.2Hz), 3.85 (3H, s).

[0068] Following the same procedure, starting from the respective 1...

Embodiment 2

[0075] 2-(3,4-Dimethoxypyridin-2-yl)methylsulfinyl-5-difluoromethoxy-1H-benzimidazole (pantoprazole)

[0076] RuCl was added to a 25 mL three-necked round bottom flask equipped with a magnetic stirrer, reflux condenser, and under a nitrogen atmosphere. 3 (27.0mg, 0.13mmol), THF (1.0mL), H 2 O (0.05 mL), ETDA trisodium hydrate (46.7 mg, 0.13 mmol). Then, 2-(3,4-dimethoxy-1-oxypyridin-2-ylmethylsulfanyl)-5-difluoromethoxy-1H-benzimidazole (500.0mg, 1.30 mmol) in 1,4-dioxane (6 mL) and the mixture was heated to reflux (ca. 80° C.). After 1 hour, the mixture was cooled, the solvent was evaporated in vacuo and the desired product was purified by flash chromatography.

[0077] 1H NMR (300MHz, d6-DMSO+NaOD) δ8.23 (1H, d, J=5.4Hz), 7.46 (1H.d, J=8.7Hz), 7.26 (1H, d, J=4.8Hz), 7.08 (1H, d, J=5.7Hz), 7.03 (1H, t, JHF=84Hz), 6.74 (1H, dd, J=5.7, 2.4Hz), 4.63 & 4.38 (2×1H, AB system, J=12Hz ), 3.90 (3H, s), 3.78 (3H, s).

Embodiment 3

[0079] 2-(4-Chloro-3-methoxypyridin-2-yl)methylsulfinyl-5-difluoromethoxy-1H-benzimidazole

[0080] To a 100 mL three-neck round bottom flask equipped with a magnetic stirrer, reflux condenser and under nitrogen atmosphere was added 4-chloro-2-chloromethyl-3-methoxypyridine N-oxide ( 8.9g, 43mmol), then, add 5-difluoromethoxy-2-mercapto-1H-benzimidazole (9.3g, 43mmol) and a solution of triethylamine (13g, 128mmol) in 20mL THF, keep it The temperature is below 40°C. After 3 hours, water (30 mL) was added to give a clear solution, and 10% HCl was added to pH=5.

[0081] Then, ETDA trisodium monohydrate (1.54 g, 4.3 mmol) and RuCl were added 3 (0.9g). The mixture was heated at 60°C under nitrogen for 8 hours, filtered through celite and the solvent was evaporated under vacuum. The residue was extracted with ethyl acetate and purified by flash chromatography to afford the title compound.

[0082] Following the same method, the following compounds can be obtained:

[0083] 5-...

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Abstract

A process for the preparation of a compound of formula (I) or a salt thereof, both as the isomeric mixture and the individual isomers, wherein Q is =CR 8 - or =N-; each R 1 , R 2 , R 3 and R 4 is independently selected from hydrogen, halogen, hydroxy; nitro; C 1 -C 6 alkyl optionally substituted with hydroxy; alkylthio C 1 -C 6 ; C 1 -C 6 alkoxy optionally substituted with halogen or C 1 -C 6 alkoxy; phenyl-C 1 -C 6 alkyl; phenyl-C 1 -C 6 alkoxy; and - N(RaRb) wherein each Ra and Rb is independently hydrogen or C 1 -C 6 alkyl or Ra and Rb, taken together with the nitrogen atom they are linked to, form a saturated heterocyclic ring; and each R 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, halogen, hydroxy; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C 1 -C 6 ; C 1 -C 6 alkoxy optionally substituted with halogen; C 1 -C 6 alkyl-carbonyl, C 1 -C 6 alkoxy-carbonyl, and oxazol-2-yl; comprising converting a compound of formula (IV), or a salt thereof, wherein Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, to said compound of formula (I), or a salt thereof, in the presence of a catalyst, if necessary in an organic solvent; and, if desired, converting a compound of formula (I) to a salt thereof to another compound of formula (I); and / or, if desired, resolving an isomeric mixture of a compound of formula (I) in the individual isomers.

Description

field of invention [0001] The present invention relates to a novel process for the preparation of pyridine compounds for use in the treatment of, in particular, pathologies associated with increased secretion of gastric juice. technical background [0002] Sulfinyl compounds useful as proton pump inhibitors are used in the treatment of pathologies associated with increased gastric secretion. Examples of such compounds known as "prazoles" are omeprazole, esomeprazole, pantoprazole, rabeprazole, lansoprazole, tenatoprazole and hydroxyomeprazole. [0003] The synthesis of these products is basically carried out according to the scheme reported herein, wherein R 1 -R 7 and Q have the meanings defined eg in this disclosure. [0004] [0005] Obviously, their preparation method requires many complicated steps. In addition, the key step in the known method is to oxidize the thioether (-S-) intermediate to obtain the corresponding sulfinyl (-SO-) derivative. Hydrogen peroxid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D471/04
Inventor P·阿莱格里尼M·拉斯帕瑞尼G·拉泽蒂R·罗西G·文蒂米利亚
Owner DIPHARMA FRANCIS
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