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Chiral purification method of compound C

A purification method and compound technology, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of cumbersome operation, low ee value, high production cost, etc., and achieve the effects of high yield, less three wastes, and simple operation

Active Publication Date: 2021-03-30
TAIAN HAVAY CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] According to market understanding and laboratory verification, the above-mentioned process route (S,S)-2,8-diazabicyclo[4.3.0]nonane has low yield (<30%), low ee value (<98% ), in order to achieve high chiral purity, it is necessary to add a resolving agent several times to resolve and refine (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane, The operation is cumbersome, the split yield is low, and the production cost is high.

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  • Chiral purification method of compound C
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  • Chiral purification method of compound C

Examples

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Embodiment 1

[0033] A method for purifying (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane with a chiral purity ee value of 90.2%, comprising the following steps:

[0034] (1) Preparation of acid salt: 20.0 g of crude product 1 with an ee value of 90.2%, namely (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane, 100 mL of ethanol, Add 31% hydrochloric acid solution to control pH 1-2, then distill off ethanol under reduced pressure to obtain (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane hydrochloride 23.4 g. Then add 120mL of anhydrous methanol, heat up to 80°C for 1 hour, slowly lower to room temperature 20-30°C for 1 hour to crystallize, filter and wash with absolute ethanol, and dry the solid to obtain 20.2g of refined acid salt. 86.4%, ee value 99.6%;

[0035] (2) Stripping alkaloids: Add 50mL purified water, 3.2g caustic soda and 50mL*2 dichloromethane to the refined acid salt obtained in step (1) for extraction, dry over anhydrous sodium sulfate and distill off dichloromethane 17 g of (S,S)-...

Embodiment 2

[0037] A method for purifying (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane with a chiral purity ee value of 95.2%, comprising the following steps:

[0038](1) Preparation of acid salt: 20.0 g of crude product 1 with an ee value of 95.2%, namely (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane, 100 mL of ethanol, Add 31% hydrochloric acid solution to control pH 1-2, then distill ethanol off under reduced pressure to obtain (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane hydrochloride 23.4g. Then add 120mL of absolute ethanol, raise the temperature to 60°C for 2 hours, lower the temperature to 20-30°C for 1 hour to crystallize, filter and wash with absolute ethanol, and then dry the solid to obtain 21.3g of refined acid salt with a yield of 91.3%. , ee value 99.9%;

[0039] (2) Stripping alkaloids: Add 50mL of purified water and 3.5g of caustic soda to the refined acid salt obtained in step (1), and then add 50mL*2 cyclohexane to extract, dry over anhydrous sodium sulfate, and evapor...

Embodiment 3

[0041] A method for purifying (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane with a chiral purity ee value of 95.2%, comprising the following steps:

[0042] (1) Preparation of acid salt: 20.0 g of crude product 1 with an ee value of 95.2%, namely (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane, 100 mL of ethanol, Add 31% hydrochloric acid solution to control pH 1-2, then distill ethanol off under reduced pressure to obtain (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane hydrochloride 23.4g. Then add 120mL mixed solvent (acetone / ethanol=9), raise the temperature to 70°C and keep it for 1 hour, lower it to room temperature at 20-30°C and keep it for 1 hour to crystallize, filter and wash with absolute ethanol, and then dry the solid to obtain refined acid salt 21.8 g, yield 93.4%, ee value 99.9%;

[0043] (2) Stripping alkaloids: Add 50mL purified water, 3.5g caustic soda and 50mL*2 toluene to the refined acid salt obtained in step (1) for extraction, then dry with anhydrous sodium s...

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Abstract

The invention provides a chiral purification method of a compound C. The compound C is a crude product (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane with chiral purity ee of 90%-98%. The chiral purification method comprises the following steps: forming haloid salt from the compound C, and further crystallizing and purifying the compound C haloid salt to obtain a high-purity refined product haloid;carrying out alkali treatment and toluene extraction on the refined high-purity haloid acid salt to obtain the high-chiral-purity (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane. According to the process, a relatively expensive optical resolving agent is prevented from being used for secondary resolution, and the whole process is simple to operate due to the fact that the refined product is insolublein water and an organic solvent is easy to extract; besides, the refining yield is greater than 90%, which is far higher than the yield of secondary resolution of the resolving agent, so that the method is easy to amplify and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, in particular to the preparation of the chiral intermediate side chain (S,S)-2,8-diazabicyclo[4.3.0]nonane of moxifloxacin hydrochloride, a quinolone antibacterial drug. Preparation technology field. Background technique [0002] Moxifloxacin hydrochloride is a fluoroquinolone antibiotic drug developed by Bayer Pharmaceuticals in Germany. It belongs to the fourth-generation quinolone broad-spectrum antibacterial drug. Compared with other fluoroquinolone drugs, the Gram-positive bacteria resistant to this product Little or very slow development of resistance, cross-resistance to other fluoroquinolones has been found in Gram-negative bacteria and enterococci. [0003] (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (the refined product of the following formula) can be quantitatively obtained by hydrogenation debenzylation of palladium carbon to obtain moxifloxacin ...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04C07B2200/07
Inventor 孙桂彬李贺存王加旺张亦林
Owner TAIAN HAVAY CHEM
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