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Method for splitting docetaxel side chain intermediate

A technique for docetaxel and intermediates, applied in the field of resolution of chiral compounds

Inactive Publication Date: 2011-05-11
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the content of the non-target optical isomer (b) is relatively large, if the side chain of docetaxel is directly synthesized with the mixture of (a) and (b) without resolution, the by-products will increase. Lower yields and more complex purification operations
The separation method disclosed in the above-mentioned literature adopts medium-pressure silica gel column chromatography to separate the target optical isomers. Those skilled in the art know that the medium-pressure silica gel column chromatography is relatively cumbersome to operate, takes a long time, and requires pressurized equipment. Not suitable for industrial scale production

Method used

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  • Method for splitting docetaxel side chain intermediate
  • Method for splitting docetaxel side chain intermediate
  • Method for splitting docetaxel side chain intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 20 g of the intermediate 1-[(1S)-1(4-methoxyphenyl)ethyl]-2-phenyl-3-acetoxyazetidin-4-one synthesized according to the method of Preparation Example Dissolve in 50ml of ethyl acetate, add 400ml of petroleum ether dropwise to the above ethyl acetate solution, stir while adding, continue to stir at 10°C for 10 hours to crystallize after the dropwise addition, the stirring speed is 100 rpm. Suction filtration under reduced pressure, the filter cake was washed with 50ml of petroleum ether, and vacuum-dried at 30°C for 6 hours. White crystals were obtained as intermediate (2S,3R)-1-[(1S)-1(4-methoxyphenyl)ethyl]-2-phenyl-3-acetoxyazetidin-4- Ketones 12g. Its melting point is 144-145°C; specific rotation [α] 25 D +10.8(c0.8, CH 2 Cl 2 ). Detected by high performance liquid chromatography, the ee value was 94.4%. As shown in the accompanying drawing, the retention time of the non-target optically pure isomer is 11.015 minutes, and the percentage calculated by the area ...

Embodiment 2

[0030] Dissolve 20 g of the prepared synthetic intermediate 1-[(1S)-1(4-methoxyphenyl)ethyl]-2-phenyl-3-acetoxyazetidin-4-one in ethyl acetate Add 800ml of n-pentane dropwise to the above-mentioned ethyl acetate solution in 80ml of ester, stir while adding, and continue to stir at 20°C for 20 hours after the dropwise addition, at a stirring speed of 200 rpm. Suction filtration under reduced pressure, the filter cake was washed with 50ml of n-pentane, and vacuum-dried at 30°C for 6 hours. 11.2 g of white crystal (2S,3R)-1-[(1S)-1(4-methoxyphenyl)ethyl]-2-phenyl-3-acetoxyazetidin-4-one was obtained . Its melting point is 144-145°C; specific rotation [α] 25 D +10.9 (c0.8, CH 2 Cl 2 ). Detected by high performance liquid chromatography, the ee value is 93.6%.

Embodiment 3

[0032] Dissolve 20 g of the prepared synthetic intermediate 1-[(1S)-1(4-methoxyphenyl)ethyl]-2-phenyl-3-acetoxyazetidin-4-one in ethyl acetate Add 1200ml of petroleum ether dropwise to the above ethyl acetate solution in 100ml of ester, stir while adding, and continue stirring at 20°C for 15 hours after the dropwise addition. The stirring speed is 300 rpm. Suction filtration under reduced pressure, the filter cake was washed with 50ml of petroleum ether, and vacuum-dried at 30°C for 6 hours. White crystals (2S,3R)-1-[(1S)-1(4-methoxyphenyl)ethyl]-2-phenyl-3-acetoxyazetidin-4-one 11.5 g. Its melting point is 144-145°C; specific rotation [α] 25 D +10.8(c0.8, CH 2 Cl 2 ). After detection by high performance liquid chromatography, the ee value was 92.8%.

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Abstract

The invention discloses a method for splitting a docetaxel side chain midbody 1-[(1S)-1(4-methoxyphenyl)ethyl]-2-phenyl-3-acetoxy-aza-cyclo-4-ketone. The method comprises the following steps: the docetaxel side chain midbody to be split is dissolved in acetic ether or methyl acetate; an organic solvent of at least one of petroleum ether, n-pentane, n-hexane, n-heptane and toluene is added into the solution; the volume ratio of the added organic solvent to the acetic ether or methyl acetate is 3-25:1; and the mixture is stirred, crystallized, filtered and dried in vacuum to obtain the target optical isomer. Through HPLC detection, the excess value of enantiomer of the obtained target optical isomer reaches over 90 percent. The method has simple and practical operation and is suitable for industrial scale production.

Description

technical field [0001] The invention relates to a resolution method of chiral compounds, in particular to a resolution method of a docetaxel side chain intermediate. Background technique [0002] Docetaxel (DOC) is a semi-synthetic taxane antineoplastic drug, its structural formula is: [0003] [0004] The source of docetaxel is semi-synthesized from the precursor 10-deacetylbaccatin III (10-deacetylbaccatin III, 10-DABIII for short) extracted from Taxus chinensis. It is obtained by introducing an active side chain intermediate at the C-13 position based on 10-DABIII. The introduced active side chain contains a chiral center. If there is a non-optically pure intermediate during the synthesis of docetaxel, it should be resolved as soon as possible to obtain an optically pure intermediate, and then further synthesized to obtain optically pure docetaxel, otherwise the docetaxel The yield of taxel will be low, and the operation is cumbersome during purification. [0005] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/08C07B57/00C07D305/14
Inventor 王建新钱建彬张广明韦旭华
Owner 深圳万乐药业有限公司