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Preparation method of (S, S)-octahydro-6H-pyrrolo[3, 4-b]pyridine

A 4-b, pyrrole technology, applied in the field of preparing -octahydro-6H-pyrrolo[3, can solve problems such as being unsuitable for industrial production, and achieve the effects of avoiding high temperature and high pressure by-products, reducing energy consumption, and mild reaction conditions

Active Publication Date: 2013-03-13
中国中化股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In summary, this route is not suitable for industrial production

Method used

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  • Preparation method of (S, S)-octahydro-6H-pyrrolo[3, 4-b]pyridine
  • Preparation method of (S, S)-octahydro-6H-pyrrolo[3, 4-b]pyridine
  • Preparation method of (S, S)-octahydro-6H-pyrrolo[3, 4-b]pyridine

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example 1

[0033] Synthesis of Example 1, 6-benzyl-hexahydro-pyrrolo[3,4-b]pyridine-5,7-dione

[0034] Add 76.44g of dipicolinic acid and 170ml of acetic anhydride into the reactor, and reflux the reaction for 4.5 hours under stirring. Desolvate under reduced pressure, add 200ml of dioxane to the residue, turn on the stirrer, and add 20.5ml dropwise at room temperature After adding benzylamine, keep it warm for 1.5 hours, remove the solvent under reduced pressure, add 190ml of acetic anhydride and 5.54g of sodium acetate to the residue, react at 125°C for 3.5 hours, cool down to room temperature, and filter to obtain 100g of 6-benzyl-pyrrole [3,4-b]pyridine-5,7-dione.

[0035] Add 800ml of 10% dilute hydrochloric acid, 100g 6-benzyl-pyrrole[3,4-b]pyridine-5,7-dione, 10g palladium carbon catalyst (5%) in the autoclave, then replace the high pressure with nitrogen Oxygen in the autoclave, replace the nitrogen in the autoclave with hydrogen, turn on the agitator, and react for 4 hours at 2...

example 2

[0037] Synthesis of Example 2, 6-benzyl-hexahydro-pyrrolo[3,4-b]pyridine-5,7-dione

[0038] Add 500ml of 15% dilute sulfuric acid in the autoclave, 100g 6-benzyl-pyrrole [3,4-b] pyridine-5,7-dione, 10g palladium carbon (5%), then replace the high pressure with nitrogen Oxygen in the autoclave, feed hydrogen to replace the nitrogen in the autoclave, turn on the agitator, and react for 6 hours at 30-40°C, 3.5-4.5Mpa for reverse hydrogenation, and take a sample TLC thin layer chromatography to analyze that the raw material disappears. At this time, it is At the end of the reaction, filter and concentrate under reduced pressure to obtain 98.5 g of 6-benzyl-hexahydro-pyrrolo[3,4-b]pyridine-5,7-dione, a light yellow viscous liquid. HPLC analysis content 97.85%, yield 96.50%.

example 3

[0039] Synthesis of Example 3, 6-benzyl-hexahydro-pyrrolo[3,4-b]pyridine-5,7-dione

[0040] Add 800ml of 5% acetic acid methanol solution in the autoclave, 100g 6-benzyl-pyrrole [3,4-b] pyridine-5,7-dione, 6g palladium carbon (10%), then replace with nitrogen Oxygen in the autoclave, feed hydrogen to replace the nitrogen in the autoclave, turn on the agitator, and react for 8 hours at 20-30°C and 3-5Mpa for reverse hydrogenation, take a sample TLC thin layer chromatography and analyze that the raw material disappears, then it is At the end of the reaction, filter and concentrate under reduced pressure to obtain 96.5 g of 6-benzyl-hexahydro-pyrrolo[3,4-b]pyridine-5,7-dione, a light yellow viscous liquid. HPLC analysis content 97.12%, yield 94.50%.

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Abstract

The invention discloses a preparation method of (S, S)-octahydro-6H-pyrrolo[3, 4-b]pyridine. The method includes: taking dipicolinic acid as the raw material, which is subjected to dehydration, ammonolysis, cyclization, pyridine ring hydrogenation, imide reduction, chiral separation, amino amidation, deamination, hydrogenation debenzylation, and deamidation, thus obtaining a target product. Specifically, the pyridine ring hydrogenation reaction is finished in a short time under low temperature and low pressure conditions. The imide reduction reaction adopts a cheap reducing agent, and has the characteristics of mild conditions, high yield, low cost, safety and reliability. The hydrogen debenzylation reaction undergoes under normal atmospheric pressure and normal temperature, thus avoiding the formation of by-products and lowering energy consumption. The preparation method provided by the invention has the advantages of simple process, low cost, mild and easily controllable reaction conditions, as well as safe and reliable production process, thus being suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and relates to a method for preparing a side chain intermediate of medicine moxifloxacin, in particular to a method for preparing (S, S)-octahydro-6H-pyrrolo[3,4-b]pyridine. Background technique [0002] Moxifloxacin (chemical name: 1-cyclopropyl-6-fluoro-1,4-dihydro-7-[4aS,7aS)-6H-pyrrolo[3,4-b]pyridine-6- Base]-4-oxo-3-quinolinic acid) is the fourth-generation fluoroquinolone antibiotic developed by Bayer Company in Germany. It has a wide range of antibacterial effects and can effectively treat infections caused by various bacteria. , including Streptococcus, Staphylococcus aureus, and Streptococcus pyogenes, it has better antibacterial activity than sparfloxacin and ciprofloxacin. Formula I is the side chain of moxifloxacin, which is the key intermediate (S, S)-octahydro-6H-pyrrolo[3,4-b]pyridine for the synthesis of moxifloxacin. [0003] [0004] The synthetic method of structure such a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 李学敏王瑛尉宏伟苗雨黄振斌
Owner 中国中化股份有限公司
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