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Method for preparing moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane

A technology of diazabicyclo and moxifloxacin, which is applied in the field of organic synthesis, can solve the problems of complicated reaction, increased cost and high price of chiral inducing reagent, and achieve the effect of improving product purity

Active Publication Date: 2021-06-08
TAIZHOU BIOMEDICAL & CHEM IND RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the routes for industrially synthesizing (S,S)-2,8-diazabicyclo[4,3,0]nonane are basically divided into two categories: (1) reduction of the pyridine ring by palladium carbon, and then by manual The total yield of this route is between 30%~40%, and the yield is relatively low, and the cost is high; (2) by chiral inducing reagents, such as (S)-4-benzene Base-2-oxazolidinone, asymmetric synthesis, this route is generally more complicated, the reaction steps are long, and the price of the chiral inducing reagent is high, which increases the cost

Method used

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  • Method for preparing moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane
  • Method for preparing moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane
  • Method for preparing moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane

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Embodiment 1

[0065] Preparation of moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane, the method is as follows:

[0066] (1) Preparation of (4aR,7aS)furo[3,4-b]piperidin-5(1H)-one: take 40g of azaphthalide, dissolve it in a 250mL autoclave with 100mL of toluene, and Replaced three times, then replaced with hydrogen, added chiral catalyst 0.002g ([Ir(cod)Cl] 2 ·2(R)-(+)-BINAP) and 1g of iodine are then replaced with hydrogen, the temperature is raised to 65°C, and the pressure is increased to 1.5MPa for hydrogenation reduction. After the reaction was completed, the resulting hydrogenation reduction reaction was hydraulically filtered into a common reactor, washed twice with saturated aqueous sodium bicarbonate solution, refluxed with water for 2 hours, and then toluene was recovered, and the recovery was completed to obtain (4aR,7aS)furo[3, 4-b] Piperidin-5(1H)-one, under the protection of nitrogen, was dissolved in 200mL DMF and directly used in the next reaction.

[0067] (2...

Embodiment 2

[0074] Preparation of moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane, the method is as follows:

[0075] (1) Preparation of (4aR,7aS)furo[3,4-b]piperidin-5(1H)-one: Take 40g of azaphthalide, dissolve it in a 250ml autoclave with 100mL of toluene, and first use nitrogen Replaced three times, then replaced with hydrogen, added chiral catalyst 0.002g ([Ir(cod)Cl] 2 ·(R)-(+)-BINAP) and 0.5g of bromochlorohydantoin are then replaced with hydrogen, the temperature is raised to 70°C, and the pressure is increased to 1.7MPa for hydrogenation reduction. After the reaction was completed, the resulting hydrogenation reduction reaction was hydraulically filtered into a common reactor, washed twice with saturated aqueous sodium bicarbonate solution, refluxed with water for 2 hours, and then toluene was recovered, and the recovery was completed to obtain (4aR,7aS)furo[3, 4-b] Piperidin-5(1H)-one, under the protection of nitrogen, was dissolved in 200mL DMF and directly used ...

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Abstract

The invention provides a method for preparing a moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane, and relates to the technical field of organic synthesis. According to the method, the azaphthalide is used as a raw material, and due to the ring structure of the azaphthalide, the other two non-corresponding chiral isomers which are not needed in chiral reduction are almost not generated; the chiral purity of the intermediate obtained through reduction is very high, resolution is not needed, and (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane can be obtained directly through ammonolysis, reduction, chlorination and cyclization subsequently. According to the method provided by the invention, chiral resolution is not needed, the process is simple, the process steps are short, the cost is low, and the product is high in chiral purity and high in total yield. Furthermore, in the subsequent product salifying and refining step, carboxylic acid with a chiral structure does not need to be used for salifying, and common achiral carboxylic acid can be used for refining, so the product purity is further improved.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane. Background technique [0002] As a new generation of quinolone antibiotics, moxifloxacin has good economic value and broad market prospects. (S,S)-2,8-diazabicyclo[4,3,0]nonane is a synthetic moxifloxacin An important intermediate of cifloxacin. At present, the routes for industrially synthesizing (S,S)-2,8-diazabicyclo[4,3,0]nonane are basically divided into two categories: (1) reduction of the pyridine ring by palladium carbon, and then by manual The total yield of this route is between 30%~40%, and the yield is relatively low, and the cost is high; (2) by chiral inducing reagents, such as (S)-4-benzene Base-2-oxazolidinone, carry out asymmetric synthesis, this kind of route generally has more complex reactions, long reaction steps, and the price of chiral inducing reagent is high,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04C07B2200/07
Inventor 韩得满李运广武承林贺娇娇
Owner TAIZHOU BIOMEDICAL & CHEM IND RES INST CO LTD
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