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A kind of chiral purification method of compound c

A purification method and compound technology, applied in the directions of organic chemistry methods, organic chemistry, etc., can solve the problems of low nonane yield, low resolution yield and high production cost, and achieve high yield, simple operation, and high yield of the process. The effect of rate increase

Active Publication Date: 2021-12-31
TAIAN HAVAY CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

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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.

Method used

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  • A kind of chiral purification method of compound c
  • A kind of chiral purification method of compound c
  • A kind of chiral purification method of compound c

Examples

Experimental program
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Effect test

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 of purified water and 3.2g of caustic soda to the refined product salt obtained in step (1), then add 50mL of dichloromethane*2 for extraction, dry over anhydrous sodium sulfate, and distill off the dichl...

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 23.4 g. 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 evapo...

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 23.4 g. 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 ...

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Abstract

The invention provides a chiral purification method of compound C, which is a crude product (S,S)-8-benzyl-2,8-diazabicyclo with a chiral purity ee of 90%-98% [4.3.0] Nonane, the chiral purification method is to further crystallize and purify compound C after forming a hydrohalide salt to obtain a high-purity refined hydrohalide salt. The refined high-purity hydrohalide salt is treated with alkali and extracted with toluene (S,S)‑8Benzyl‑2,8‑diazabicyclo[4.3.0]nonane was obtained in high chiral purity. This process avoids the use of more expensive optical resolution agents for secondary resolution, and because the refined product is insoluble in water and the organic solvent is easy to extract, the entire process is easy to operate; in addition, the refined yield is greater than 90%, which is much higher than the resolution The yield of the secondary resolution of the reagent is high, easy to scale up, 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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Patent Type & Authority Patents(China)
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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