Method for preparing (4R-cis)-6-substituted-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate

A technology of tert-butyl acetate and 4r-cis, which is applied in the field of pharmaceuticals, can solve problems such as difficult control of the operation process and unsatisfactory de values ​​of compounds, and achieve the effects of increasing yield and reducing costs

Active Publication Date: 2013-08-28
VALIANT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] This reaction requires the application of biological enzyme technology in the reduction process. Although the method is novel, its operation process is difficult to control and the de value of the obtained compound is not ideal.

Method used

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  • Method for preparing (4R-cis)-6-substituted-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate
  • Method for preparing (4R-cis)-6-substituted-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate
  • Method for preparing (4R-cis)-6-substituted-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate

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Experimental program
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Effect test

Embodiment 1

[0058] The synthesis of embodiment 1 (S)-4-chloro-3-trimethylsilyloxybutyronitrile (compound II)

[0059] Under nitrogen protection, add 48.0g (0.4mol) (s)-4-chloro-3-hydroxybutyric acid ethyl ester, 59.2g (0.87mol) imidazole, 47.5g (0.44mol) trimethyl chloride Silane and 500 mL tetrahydrofuran were stirred at room temperature for 1 h, filtered with suction, and the filtrate was adjusted to neutrality with saturated ammonium chloride aqueous solution. Take the upper organic phase, wash the organic phase with water, and dry it. The solvent was evaporated to dryness to obtain 75.6 g, the yield was 98.6%, and the content measured by GC was 99.2%, which was (S)-4-chloro-3-trimethylsilyloxybutyronitrile (compound II).

Embodiment 2

[0060] The synthesis of embodiment 2 (S)-6-chloro-5-hydroxyl-3-oxohexanoic acid tert-butyl ester (compound III)

[0061] Under nitrogen protection, add 23.8g (0.36mol) of zinc powder, 0.3g (3mmol) of methanesulfonic acid, 150mL of tetrahydrofuran and 49.8g (0.26mol) of (S)-4-chloro-3 - Trimethylsiloxybutyronitrile (compound II) was heated to reflux for 10 min. Slowly add 60.8g (0.312mol) of tert-butyl bromoacetate dropwise within 1 hour, the reaction solution turns light yellow. After dropping, continue heating to reflux for 3h, cool to room temperature, and add 180mL of 3N hydrochloric acid dropwise. Stir at room temperature for 3 h, evaporate the solvent, and extract the residue with ethyl acetate, wash with water, and dry. The solvent was evaporated to dryness to obtain 54.6 g of a yellow oil, namely (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (compound III). The yield is 89.0%, and the content measured by GC is 98.6%.

Embodiment 3

[0062] The synthesis of embodiment 3 (R, S)-6-chloro-3,5-dihydroxyhexanoate (compound IV)

[0063] Under nitrogen protection, 51.9 g (0.22 mol) of (S)-6-chloro-5-hydroxy-3-oxohexanoic acid tert-butyl ester (compound III) obtained in the previous step, 450 mL of tetrahydrofuran, 360 mL methanol. Cool down to -78°C, add 44.6g of 50% methoxydiethylboron tetrahydrofuran solution dropwise, stir for 0.5h after dropping, add 9.7g (0.26mol) sodium borohydride in batches, and continue stirring at -78°C 6h, 50mL of glacial acetic acid was added dropwise. After dropping, stir and warm to room temperature. The reaction solution was poured into a mixture of 150mL ethyl acetate and 100mL water, the organic phase was taken, washed with water, dried, filtered with suction, and the solvent was evaporated to dryness to obtain 45.0g of a light yellow oil, which was (R,S)-6- Chloro-3,5-dihydroxyhexanoate (compound IV), yield 86.3%.

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Abstract

The invention relates to a method for preparing (4R-cis)-6-substituted-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate with a structural formula (VIII) shown in the specifications. In the formula, R is formaldehyde or methanol. In the preparation method, Blaise reaction is used for replacing complicated Claisen ester condensation reaction with a large number of side reactions, the aim of growing a carbon chain is fulfilled under the mild condition, and expensive lithium diisopropylamide (LDA) and a low-temperature environment is avoided; and a complicated route of oxidizing alcohol into aldehyde is avoided in the process of generating the compound VIII.

Description

technical field [0001] The invention relates to a preparation method of (4R-cis)-6-substituted-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, which belongs to the field of pharmacy. Background technique [0002] (4R-cis)-6-substituted-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate is an important intermediate in the synthesis of the hypolipidemic drug Rosuvastatin . There are many reports about the synthetic route of this compound at present. [0003] G.Wess et al. (Wess, G.et al.Tetrahedron Lett.1990, 31, 2545) reported a kind of (S)-3,4-dihydroxybutyric acid methyl ester as a starting material, through the following steps Generate the target compound. [0004] [0005] The route yield is low, deprotection is difficult, and the de value (diastereoisomeric excess) is not high. And need to use expensive lithium diisopropylamide (LDA) as the catalyst of condensation reaction, the high cost is not suitable for industrial production. [0006] U.S. Patent No. 5,3...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/06
CPCY02P20/55
Inventor 孙蕊张福乾杜体健房立平孟凡民刘立
Owner VALIANT CO LTD
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