(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, short process and high total yield

Active Publication Date: 2008-10-29
ZHEJIANG LEPU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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, but the quantitative analysis and purification of the intermediate is relatively difficult, and the final product often needs to be passed through the column to reach the subsequent response request

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
Effect test

Embodiment 1

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

[0051]Add 65g of zinc foil, 400mL of tetrahydrofuran, and 0.7g of CuBr catalyst into a three-neck flask, stir and raise the temperature to 35°C, add 195g of tert-butyl bromoacetate dropwise, and keep the reaction for 1 hour after dropping. After the incubation, add dropwise a solution composed of 255g (3R)-3-hydroxyl-4-p-toluenesulfonyloxybutyronitrile (I) and 400mL tetrahydrofuran (THF). ). Cool to -5°C, add dropwise 10% sulfuric acid solution to adjust pH=3-4, keep stirring for 3 hours. The reaction solution was extracted with ethyl acetate, anhydrous MgSO 4 Dry, concentrate in vacuo to about 400mL, cool to -15°C, insulate and crystallize for 12 hours, filter, and dry in vacuo to obtain (5S)-5-hydroxy-6-p-toluenesulfonyloxy-3-oxohexanoic acid tert-butyl The ester (II) was 228g, and the content measured by HPLC was 99.0%.

[0052] (2) Synthesis of (3R, 5S)-3,5-dihydrox...

Embodiment 2

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

[0062] Add 65g of zinc foil, 400mL of tetrahydrofuran, and 0.7g of CuBr catalyst into a three-neck flask, stir and raise the temperature to 40°C, add 195g of tert-butyl bromoacetate dropwise, and keep the reaction for 1 hour after dropping. After the incubation, add dropwise a solution composed of 255g (3R)-3-hydroxyl-4-p-toluenesulfonyloxybutyronitrile (I) and 400mL tetrahydrofuran (THF). ). Cool to 0°C, add dropwise 10% sulfuric acid solution to adjust pH=3-4, keep stirring for 3 hours. The reaction solution was extracted with ethyl acetate, anhydrous MgSO 4 Dry, concentrate in vacuo to about 400mL, cool to -10°C, insulate and crystallize for 12 hours, filter, and dry in vacuo to obtain (5S)-5-hydroxy-6-p-toluenesulfonyloxy-3-oxohexanoic acid tert-butyl The ester (II) was 228g, and the content measured by HPLC was 99.2%.

[0063] (2) Synthesis of (3R, 5S)-3,5-dihydrox...

Embodiment 3

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

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