(4R-cis)-6-formyl-2,2-dimethyl-1,3- dioxane -4- tertiary butyl acetate synthesis method

A technology of tert-butyl acetate and dioxane, applied in directions such as organic chemistry, can solve problems such as quantitative analysis of intermediates and difficulty in purification, and achieve the effects of improving purity, easy analysis and control, and short process

Active Publication Date: 2006-12-13
ZHEJIANG LEPU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0036] It can be seen from the above literature reports that the target product synthesized by using the chiral compound as the starting material has the characteristics of high optical purity, bu

Method used

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  • (4R-cis)-6-formyl-2,2-dimethyl-1,3- dioxane -4- tertiary butyl acetate synthesis method
  • (4R-cis)-6-formyl-2,2-dimethyl-1,3- dioxane -4- tertiary butyl acetate synthesis method
  • (4R-cis)-6-formyl-2,2-dimethyl-1,3- dioxane -4- tertiary butyl acetate synthesis method

Examples

Experimental program
Comparison scheme
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Example Embodiment

[0049] Example 1

[0050] (1) Synthesis of (5S)-5-hydroxy-6-p-toluenesulfonyloxy-3-oxohexanoate tert-butyl ester (II)

[0051] Add 65 g of zinc foil, 400 mL of tetrahydrofuran, and 0.7 g of CuBr catalyst to a three-necked flask, stir and raise the temperature to 35° C., add 195 g of tert-butyl bromoacetate dropwise, and complete the heat preservation reaction for 1 hour. After incubation, add dropwise a solution consisting of 255g (3R)-3-hydroxy-4-p-toluenesulfonyloxybutyronitrile (I) and 400mL tetrahydrofuran. After the incubation reaction, the content of (I) is basically unchanged (HPLC tracking) ). Cool to -5°C, add dropwise 10% sulfuric acid solution to adjust pH=3~4, keep warm and stir for 3 hours. The reaction solution is extracted with ethyl acetate, anhydrous MgSO 4Dry, vacuum concentrate to about 400mL, cool to -15°C, keep crystallization for 12 hours, filter, and vacuum dry to obtain (5S)-5-hydroxy-6-p-toluenesulfonyloxy-3-oxohexanoic acid tert-butyl 228 g of ester (II),...

Example Embodiment

[0060] Example 2

[0061] (1) Synthesis of (5S)-5-hydroxy-6-p-toluenesulfonyloxy-3-oxohexanoate tert-butyl ester (II)

[0062] Add 65 g of zinc foil, 400 mL of tetrahydrofuran, and 0.7 g of CuBr catalyst to a three-necked flask, stir and raise the temperature to 40° C., add 195 g of tert-butyl bromoacetate dropwise, and complete the heat preservation reaction for 1 hour. After the incubation, a solution consisting of 255g (3R)-3-hydroxy-4-p-toluenesulfonyloxybutyronitrile (I) and 400mL tetrahydrofuran was added dropwise. After the incubation, the content of (I) remained basically unchanged (HPLC tracking) ). Cool to 0°C, add dropwise 10% sulfuric acid solution to adjust pH=3~4, keep warm and stir for 3 hours. The reaction solution is extracted with ethyl acetate, anhydrous MgSO 4 Dry, concentrate in vacuum to about 400mL, cool to -10°C, keep crystallization for 12 hours, filter and dry in vacuum to obtain (5S)-5-hydroxy-6-p-toluenesulfonyloxy-3-oxohexanoic acid tert-butyl 228 g of...

Example Embodiment

[0071] Example 3

[0072] This example is the synthesis of (3R,5S)-3,5-dihydroxy-6-p-toluenesulfonyloxyhexanoate tert-butyl ester (III).

[0073] Add 186g (5S)-5-hydroxy-6-p-toluenesulfonyloxy-3-oxohexanoate tert-butyl ester (II), 500mL tetrahydrofuran and methanol mixed solvent into a three-necked flask, and cool to -35℃, 300mL of 2mol / L ethoxydiethylborane was added, and the reaction was incubated for 2.5 hours. Cool down to -75℃, add KBH 4 30g, stir the reaction until the (II) reaction is complete (HPLC tracking), heat to 0-10°C, add glacial acetic acid to neutralize to pH4 After drying, the ethyl acetate was removed by distillation under reduced pressure to obtain (3R,5S)-3,5-dihydroxy-6-p-toluenesulfonyloxyhexanoic acid tert-butyl ester (III) 183g, measured by HPLC chiral column ( The content of 3R, 5S) isomer (III) is 98.1%.

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Abstract

The invention relates the synthesis of (4R-cis)-6- formyl -2, 2- dimethyl-1, 3- dioxide hexanaphthene-4- acid tertbutyl ester. The now technology has the defect that is hard to quantitative analysis and purify. The method adds p-toluenesulfonyl to raw material, so it is easy to control and analyze intermediate, the fusing point of intermediate is improved, and the purity of intermediate is improved. The invention has the advantages of simple technology, high productivity and high content.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a new method for synthesizing (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester. technical background [0002] (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester is an intermediate in the synthesis of the hypolipidemic drug Rosuvastatin . There have been many reports about its synthetic route in the literature. According to the different starting materials and synthesis techniques, they can be roughly divided into the following two categories: [0003] 1. Using chiral compounds as starting materials, synthesize target products through chiral-induced reduction [0004] Using chiral compounds as starting materials, first condensation and then chiral-induced reduction to synthesize (4R-cis)-6-formyl (or hydroxymethyl)-2,2-dimethyl-1,3-dioxo Hexylcyclo-4-acetic acid tert-butyl ester (VI) is a more commonly used method. [0005] G...

Claims

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Application Information

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IPC IPC(8): C07D319/06
Inventor 陈志荣王志华颜剑波
Owner ZHEJIANG LEPU PHARMA CO LTD
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