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Synthetic method of atorvastatin calcium intermediate

A technology of atorvastatin calcium and synthesis method, applied in microorganism-based methods, biochemical equipment and methods, microorganisms and other directions, can solve problems such as long steps, and achieve the effects of shortening steps, high yield and reducing costs

Inactive Publication Date: 2014-03-05
SUZHOU HEALTH COLLEGE
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Problems solved by technology

In the prior art ( S )-3,4-dihydroxybutyric acid methyl ester, 3,4-epoxybutyrate or ethyl chloroacetoacetate as raw material, the same intermediate [(4 R ,6 S )-6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl] tert-butyl acetate, and then through oxidation, condensation and reduction reaction to obtain [(4 R ,6 R )-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester, a longer step, [(4 R ,6 S )-6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl] tert-butyl acetate yields were 44.5%, 55.1% and 25.9%, respectively

Method used

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  • Synthetic method of atorvastatin calcium intermediate

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Embodiment Construction

[0016] The present invention will be described in detail below in conjunction with embodiments.

[0017] Step 1) Add THF (50 ml) into a 1 L three-necked flask, and add (3 S )-4-bromo-3-hydroxybutyric acid ethyl ester (purity 97%, 15.7 g, 75 mmol) and tert-butyl acetate (17.4 g, 150 mmol), continue to stir under argon protection at 0-5 ℃, dropwise Add 1 mol / L toluene-THF solution of tert-butylmagnesium chloride (1:2.5, 75 ml), and continue stirring at 5°C for 30 min. Add 1 mol / L lithium diisopropylamide in n-hexane (240 ml) dropwise, and continue stirring at the same temperature for 16 h after the drop. Separately take concentrated hydrochloric acid (60.4 g), water (31.3 g) and ethyl acetate (50 ml), stir and mix, add to the above reaction solution, stir for 10 min, then pour into a 2 L separatory funnel and let stand to separate. layer, the organic layer was washed with water (100 ml × 2) and concentrated under reduced pressure to obtain a reddish-brown oil (5 S )-tert-buty...

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Abstract

The invention discloses a synthetic method of an atorvastatin calcium intermediate. The synthetic method comprises the following steps: preparing [(4R, 6S)-6- brooethyl-2,2-diemthyl-1,3-dioxane-4-group] tert-butyl acetate (5) by (3S)-4-bromine-3-hydroxyl ethyl butyrate through condensation, asymmetric biological catalytic reduction and hydroxyl protection; and preparing an atorvastatin calcium intermediate [(4R, 6S)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-group] tert-butyl acetate through catalytic hydrogenation reduction of raney nickel after 5 is condensed with nitromethane under action of cuprous bromide and a nitrogen-containing compound ligand. According to the synthetic method disclosed by the invention, steps are shortened, cost is lowered, and therefore, the synthetic method is more suitable for large-scale preparation.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to a method for synthesizing an atorvastatin calcium intermediate. Background technique [0002] [(4 R ,6 R )-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl] tert-butyl acetate is a synthetic hypolipidemic drug atorvastatin calcium ( important intermediate of atorvastatin calcium). In the prior art ( S )-3,4-dihydroxybutyric acid methyl ester, 3,4-epoxybutyrate or ethyl chloroacetoacetate as raw material, the same intermediate [(4 R ,6 S )-6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl] tert-butyl acetate, and then through oxidation, condensation and reduction reaction to obtain [(4 R ,6 R )-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester, a longer step, [(4 R ,6 S The yields of )-6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester were 44.5%, 55.1% and 25.9%, respectively. Existing technology with (3 S )-4-chloro-3-hydroxybutyric a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/06C07D319/06C12R1/72
Inventor 张立光
Owner SUZHOU HEALTH COLLEGE
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