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Preparation method for chiral 4-chloro-3-hydroxybutyrate

A hydroxybutyrate, chiral technology, applied in the field of preparation of chiral 4-chloro-3-hydroxybutyrate, can solve the low yield of methyl 4-chloro-3-hydroxybutyrate, operating conditions Harshness and other problems, to achieve the effect of easy realization of reaction conditions, mild reaction conditions and low cost

Inactive Publication Date: 2013-12-04
SUZHOU OST ADVANCED MATERIALS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In fact, as early as 1967, McClure reported that Co 2 (CO) 8 Catalyze the hydroesterification reaction of epichlorohydrin (J.D.McClure, J.Org.Chem., 1967, 32, 3888-3894), but the operating conditions are relatively harsh, and the carbon monoxide pressure needs to be above 12.0MPa. The obtained product The yield of methyl 4-chloro-3-hydroxybutyrate is low (11~53%)

Method used

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  • Preparation method for chiral 4-chloro-3-hydroxybutyrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] In an autoclave with a volume of 600 mL, add 200 mL of anhydrous methanol, 200 mmol of (S)-epichlorohydrin (ee>99.9%), 2.5 mmol of dicobalt octacarbonyl, and 10 mmol of ZnBr 2 (pyridine) 2 . Seal the reactor, replace the reactor with carbon monoxide 3 times, and seal the reactor. In the Schlenk vacuum line, the reaction system was replaced three times with carbon monoxide gas at room temperature, and the pressure of CO gas was charged at 6.0 MPa. The temperature was controlled by a temperature controller to slowly rise to 60° C., reacted for 8 hours, cooled to room temperature, and unloaded.

[0034] The liquid obtained by the reaction is qualitatively analyzed by Agilent 6890 / 5973 GC / MS, and quantitatively analyzed by Agilent 7890 gas chromatography: the conversion rate of (S)-epichlorohydrin is 99%, and the conversion rate of (S)-4-chloro-3-hydroxybutyrate Acid methyl ester selectivity 94%. Distilled under reduced pressure to obtain (S)-4-chloro-3-hydroxybutyric ac...

Embodiment 2

[0036] In an autoclave with a volume of 600 mL, add 200 mL of anhydrous methanol, 200 mmol of (R)-epichlorohydrin (ee>99.9%), 2.5 mmol of dicobalt octacarbonyl, and 10 mmol of ZnBr 2 (pyridine) 2 . Close the reactor, in the Schlenk vacuum line, replace the reaction system with carbon monoxide gas three times at room temperature, fill the CO gas with a pressure of 6.0MPa, and slowly increase the temperature to 60°C under the control of the temperature controller, react for 8 hours, and cool to room temperature , Unload the kettle.

[0037] The liquid obtained by the reaction is qualitatively analyzed by Agilent 6890 / 5973 GC / MS, and quantitatively analyzed by Agilent 7890 gas chromatography: the conversion rate of (R)-epichlorohydrin is 99%, and the conversion rate of (R)-4-chloro-3-hydroxybutyrate Acid methyl ester selectivity 96%. Distilled under reduced pressure to obtain (R)-4-chloro-3-hydroxybutyric acid methyl ester 27.8g (yield 96%, purity 99%), gas chromatography (Chi...

Embodiment 3

[0039] Add 200 mL of absolute ethanol, 200 mmol of (S)-epichlorohydrin (ee>99.9%), 2.5 mmol of dicobalt octacarbonyl, and 10 mmol of 3-Hydroxypyridine into an autoclave with a volume of 600 mL. Close the reactor, in the Schlenk vacuum line, replace the reaction system with carbon monoxide gas three times at room temperature, fill the CO gas with a pressure of 6.0MPa, and slowly increase the temperature to 60°C under the control of the temperature controller, react for 8 hours, and cool to room temperature , Unload the kettle.

[0040] The liquid obtained by the reaction is qualitatively analyzed by Agilent 6890 / 5973 GC / MS, and quantitatively analyzed by Agilent 7890 gas chromatography: the conversion rate of (S)-epichlorohydrin is 95%, and the conversion rate of (S)-4-chloro-3-hydroxybutyrate Ethyl acid selectivity 93%. Distilled under reduced pressure to obtain 28.0 g of ethyl (S)-4-chloro-3-hydroxybutyrate (yield 95%, purity 99%), gas chromatography (Chiraldex G-TA column) ...

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Abstract

The invention discloses a preparation method for chiral 4-chloro-3-hydroxybutyrate. The preparation method specifically comprises: adding chiral chloropropylene oxide, an alcohol, a catalyst into a high-pressure reaction vessel, introducing carbon monoxide, heating for a reaction, and obtaining chiral 4-chloro-3-hydroxybutyrate after the reaction. The preparation method has the advantages of being cheap and easily-available in raw materials, mild in reaction conditions, high in yield, low in cost, and the like. Compared with conventional synthetic methods for chiral 4-chloro-3-hydroxybutyrate, the preparation method employs a reaction with atom economical efficiency of 100%, is environment friendly, low in 'three wastes (waste gas, waste water and industrial residue) ' and applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of chiral 4-chloro-3-hydroxybutyrate. Background technique [0002] 4-Chloro-3-hydroxybutanoate esters (4-chloro-3-hydroxybutanoate esters, CHBE) as a versatile building block, because it contains three multifunctional groups (-Cl, -OH, -COOR), can introduce various drug intermediates through chlorine displacement reaction, reduction reaction, etc. Among them, (R)-CHBE is a key chiral intermediate for the synthesis of L-carnitine (L-carnitine), (R)-γ-amino-β-hydroxybutyric acid (GABOB) and the like. (S)-CHBE is widely used in the synthesis of lipid-lowering statins—hydroxymethylglutaryl CoA (HMG-CoA) reductase inhibitors, alkaloids Slagenins B and C, and 4-hydroxypyrrolidone (Q .Ye,et al.Appl.Microbiol.Biotechnol.,2011,89,513-522; D.S.Karanewsky,et al.J.Med.Chem.,1990,33,2925-2956;B.Zhou,et al.J.Am . Chem. Soc., 1983, 105, 5925-5926.). As chiral 4-chloro-3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/675C07C67/37
Inventor 陈静刘建华夏春谷许传芝
Owner SUZHOU OST ADVANCED MATERIALS
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