CN-115724737-B - Preparation method of alpha-fluoro-beta-hydroxy ester compound

CN115724737BCN 115724737 BCN115724737 BCN 115724737BCN-115724737-B

Abstract

The invention discloses a preparation method for preparing an alpha-fluoro-beta-hydroxy ester compound, which has the following structural general formula: The preparation method comprises the steps of adding a catalyst into a reaction bottle, replacing the reaction bottle with nitrogen for 3 times, adding a solvent into the reaction bottle by using a syringe under the protection of nitrogen, sequentially adding aldehyde and monofluoro-substituted enol silyl ether by using a microsyringe, stirring at room temperature until the reaction is finished, transferring the reaction liquid into a water phase for quenching, extracting by using ethyl acetate, drying by using anhydrous sodium sulfate, merging organic phases, concentrating under reduced pressure, and separating by using silica gel column chromatography to obtain a pure product.

Inventors

JIA ZHENHUA
Zong Xinlong
Liu Shuanglei
ZHANG ZHENGUO
JI LIANG
ZHANG TING

Assignees

南京工业大学

Dates

Publication Date: 20260508
Application Date: 20210831

Claims (10)

1. A preparation method of an alpha-fluoro-beta-hydroxy ester compound is characterized by comprising the following steps: the alpha-fluoro-beta-hydroxy ester compound is The preparation route is as follows: ; Wherein R is p-tolyl, o-tolyl, m-tolyl, p-methoxyphenyl, p-trifluoromethylphenyl, p-cyanophenyl, p-bromophenyl, p-chlorophenyl, p-fluorophenyl, p-vinylphenyl, p-ethynylphenyl, m-phenoxyphenyl, 2-naphthyl, 2-furyl, 2-thienyl, phenylpropyl, or phenylpropenyl; The preparation method comprises the following steps: (1) Adding a catalyst into a glass reaction bottle, wherein the catalyst is one of CsF (cesium fluoride), TBAF (tetrabutylammonium fluoride) and TBAT (tetrabutylammonium difluorotriphenyl silicate); (2) Under the protection of nitrogen, adding one solvent of acetonitrile or N, N-dimethylformamide, then sequentially adding aldehyde compounds and monofluoro-substituted enol silicon ether compounds, and continuously stirring at room temperature for 3-10 min to obtain the target product.
2. The method for producing an alpha-fluoro-beta-hydroxy ester compound according to claim 1, wherein the mass ratio of the aldehyde compound, the monofluoro-substituted enol silicone ether compound and the catalyst is 1:1.5:0.005, respectively.
3. The method for preparing the alpha-fluoro-beta-hydroxy ester compound according to claim 1, wherein the preparation route of the alpha-fluoro-beta-hydroxy ester compound is as follows: ; (1) Adding five to one per thousand mole percent of catalyst, which is one of CsF (cesium fluoride), TBAF (tetrabutylammonium fluoride) and TBAT (tetrabutylammonium difluorotriphenyl silicate), into a glass reaction bottle, and replacing the reaction bottle with nitrogen for 3 times; (2) Under the protection of nitrogen, adding one solvent of acetonitrile or N, N-dimethylformamide, then sequentially adding an aldehyde compound and a monofluoro-substituted enol silicon ether compound, and continuously stirring at 22 ℃ for 3 min to obtain a target product; (3) Transferring the reaction solution into a water phase for quenching, extracting by ethyl acetate, drying by anhydrous sodium sulfate, combining organic phases, concentrating under reduced pressure, and separating by adopting silica gel column chromatography to obtain a pure product.
4. The method for producing an α -fluoro- β -hydroxy ester compound according to claim 1, characterized in that (2 s,3 r) -2-fluoro-3-hydroxy-3- (naphthalen-2-yl) propionic acid ethyl ester is synthesized: ; Adding cesium fluoride into a glass reaction bottle, replacing the reaction bottle with nitrogen for 3 times, adding N, N-dimethylformamide under the protection of nitrogen, sequentially adding 2-naphthaldehyde and monofluoro-substituted enol silicon ether compound under stirring, stirring at 22 ℃ for 3min hours, rapidly pouring the reaction liquid into an aqueous phase for quenching after the reaction is finished, extracting with ethyl acetate for 4 times, merging organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating by adopting silica gel column chromatography to obtain a pure product, wherein the yield is 86%.
5. A preparation method of an alpha-fluoro-beta-hydroxy ester compound is characterized in that (2S, 3R) -2-fluoro-3-hydroxy-3-phenyl ethyl propionate is synthesized: ; Adding cesium fluoride into a glass reaction bottle, replacing the reaction bottle with nitrogen for 3 times, adding N, N-dimethylformamide under the protection of nitrogen, sequentially adding benzaldehyde and monofluoro-substituted enol silicon ether compound under stirring, stirring at 22 ℃ for 3min hours, rapidly pouring the reaction liquid into an aqueous phase for quenching after the reaction is finished, extracting with ethyl acetate for 4 times, merging organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating by adopting silica gel column chromatography to obtain a pure product, and obtaining the yield of 71%.
6. The method for producing an α -fluoro- β -hydroxy ester compound according to claim 1, characterized in that (2 s,3 r) -2-fluoro-3-hydroxy-3- (p-tolyl) propionic acid ethyl ester is synthesized: ; Adding cesium fluoride into a glass reaction bottle, replacing the reaction bottle with nitrogen for 3 times, adding acetonitrile under the protection of nitrogen, sequentially adding 4-methylbenzaldehyde and monofluoro-substituted enol silicon ether compound under stirring, stirring at 22 ℃ for 3 min hours, rapidly pouring the reaction liquid into an aqueous phase for quenching after the reaction is finished, extracting with ethyl acetate for 4 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by adopting silica gel column chromatography to obtain a pure product with the yield of 92 percent.
7. The method for producing an α -fluoro- β -hydroxy ester compound according to claim 1, characterized in that (2 s,3 r) -2-fluoro-3-hydroxy-3- (2-methoxyphenyl) propionic acid ethyl ester is synthesized: ; Adding cesium fluoride into a glass reaction bottle, replacing the reaction bottle with nitrogen for 3 times, adding acetonitrile under the protection of nitrogen, sequentially adding 2-methylbenzaldehyde and monofluoro-substituted enol silicon ether compound under stirring, stirring at 22 ℃ for 3 min hours, rapidly pouring the reaction liquid into an aqueous phase for quenching after the reaction is finished, extracting with ethyl acetate for 4 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating by adopting silica gel column chromatography to obtain a pure product, wherein the yield is 78%.
8. The method for producing an α -fluoro- β -hydroxy ester compound according to claim 1, characterized in that (2 s,3 r) -2-fluoro-3-hydroxy-3- (3-methoxyphenyl) propionic acid ethyl ester is synthesized: ; Adding TBAF (tetrabutylammonium fluoride) into a glass reaction bottle, replacing the reaction bottle with nitrogen for 3 times, adding N, N-dimethylformamide under the protection of nitrogen, sequentially adding 3-methylbenzaldehyde and monofluoro-substituted enol silicon ether compound under stirring, stirring at 22 ℃ for 3min ℃, quenching the reaction liquid in an aqueous phase rapidly after the reaction is finished, extracting with ethyl acetate for 4 times, merging the organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by adopting silica gel column chromatography to obtain a pure product with the yield of 78%.
9. The method for producing an α -fluoro- β -hydroxy ester compound according to claim 1, characterized in that (2 s,3 r) -2-fluoro-3-hydroxy-3- (4-methoxyphenyl) propionic acid ethyl ester is synthesized: ; Adding TBAT (tetrabutyl difluorotriphenylammonium silicate) into a glass reaction bottle, replacing the reaction bottle with nitrogen for 3 times, adding N, N-dimethylformamide under the protection of nitrogen, sequentially adding 4-methoxybenzaldehyde and monofluoro substituted enol silicon ether compound under stirring, stirring at 22 ℃ for 3min ℃, rapidly pouring the reaction liquid into an aqueous phase for quenching after the reaction is finished, extracting with ethyl acetate for 4 times, merging organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by adopting silica gel column chromatography to obtain a pure product with the yield of 92%.
10. The method for producing an α -fluoro- β -hydroxy ester compound according to claim 1, wherein (2 s,3 r) -2-fluoro-3-hydroxy-3- (4- (trifluoromethyl) phenyl) propionic acid ethyl ester: ; adding cesium fluoride into a glass reaction bottle, replacing the reaction bottle with nitrogen for 3 times, adding N, N-dimethylformamide under the protection of nitrogen, sequentially adding 4-trifluoromethyl benzaldehyde and monofluoro-substituted enol silicon ether compound under stirring, stirring at 22 ℃ for 3 min ℃, rapidly pouring the reaction solution into an aqueous phase for quenching after the reaction is finished, extracting ethyl acetate for 4 times, merging organic phases, drying anhydrous sodium sulfate, concentrating under reduced pressure, separating by adopting a silica gel column chromatography to obtain a pure product, wherein the yield is 78%.

Description

Preparation method of alpha-fluoro-beta-hydroxy ester compound Technical Field The invention relates to the related technical fields of organic synthesis and drug synthesis, in particular to an alpha-fluoro-beta-hydroxy ester compound and a green and efficient preparation method thereof. Background Beta-hydroxy ester compounds are widely existing in natural products and medicines, and have been developed as one of important chemical intermediates, and introduction of fluorine atoms causes fluoro compounds to exhibit special physical and chemical characteristics different from non-fluoro compounds, and in recent years, fluoro compounds have been widely applied to medicines, agrochemicals and functional materials. Wherein, the alpha-fluoro-beta-hydroxy ester compound plays an important role in the field of medicine. For example, such compounds have important biological activities such as antitumor (WO Patent 2,000,069,846), aromatase inhibition (J.Pharm. Pharmacol.2010,62, 1717-1728) and the like. The main method for synthesizing the alpha-fluoro-beta-hydroxy ester compound at present comprises the steps of (1) reacting aldehydes with enol lithium reagent by J.T.Welch and the like to obtain the alpha-fluoro-beta-hydroxy ester compound, wherein the reaction requires a stoichiometric amount of alkali, and the atom economy is poor, (2) reacting aldehydes with monofluoro-substituted acetone by C.F.Barbas and the like to obtain the alpha-fluoro-beta-hydroxy ester compound, wherein the reaction time is long, and (3) reacting aldehydes with fluoro-substituted enol silicon ether under reflux condition by TMS-OTf or CuCl in toxic HMPA solvent by using Chen Qingyun professor and the like to obtain the alpha-fluoro-beta-hydroxy ester compound, wherein the reaction condition is harsh. Therefore, the method for preparing the alpha-fluoro-beta-hydroxy ester compound has the advantages of green, high efficiency, high atom economy, milder reaction condition and wider substrate application range. Disclosure of Invention The invention aims to provide an alpha-fluoro-beta-hydroxy ester compound and a green and efficient preparation method thereof, which are green, efficient, high in atomic economy, mild in reaction condition and wide in substrate application range. In order to achieve the aim, the invention provides the following technical scheme that the preparation method of the alpha-fluoro-beta-hydroxy ester compound, The alpha-fluoro-beta-hydroxy ester compound isThe preparation route is as follows: Wherein R is p-tolyl, o-tolyl, m-tolyl, p-methoxyphenyl, p-trifluoromethylphenyl, p-cyanophenyl, p-bromophenyl, p-chlorophenyl, p-fluorophenyl, p-vinylphenyl, p-ethynylphenyl, m-phenoxyphenyl, 2-naphthyl, 2-furyl, 2-thienyl, phenylpropyl, phenylpropenyl, cyclohexyl, cyclohexenyl, n-pentyl, isopropyl, menthol derivatives, nerol derivatives, adapalene derivatives, oleyl derivatives, androsterone derivatives, helicid derivatives or galactose derivatives; The preparation method comprises the following steps: (1) Adding a catalyst into a glass reaction bottle, wherein the catalyst is one of CsF (cesium fluoride), TBAF (tetrabutylammonium fluoride) and TBAT (tetrabutylammonium difluorotriphenyl silicate); (2) Under the protection of nitrogen, adding one solvent of acetonitrile or N, N-dimethylformamide, then sequentially adding aldehyde compounds and monofluoro-substituted enol silicon ether compounds, and continuously stirring at room temperature for 3-10 min to obtain the target product. Preferably, the mass ratio of the aldehyde compound to the monofluoro-substituted enol silicone ether compound to the catalyst is 1:1.5:0.005 respectively. Preferably, the preparation route of the alpha-fluoro-beta-hydroxy ester compound is as follows: (1) Adding five to one per thousand mole percent of catalyst, which is one of CsF (cesium fluoride), TBAF (tetrabutylammonium fluoride) and TBAT (tetrabutylammonium difluorotriphenyl silicate), into a glass reaction bottle, and replacing the reaction bottle with nitrogen for 3 times; (2) Under the protection of nitrogen, adding one solvent of acetonitrile or N, N-dimethylformamide, then sequentially adding an aldehyde compound and a monofluoro-substituted enol silicon ether compound, and continuously stirring at 22 ℃ for 3min to obtain a target product; (3) Transferring the reaction solution into a water phase for quenching, extracting by ethyl acetate, drying by anhydrous sodium sulfate, combining organic phases, concentrating under reduced pressure, and separating by adopting silica gel column chromatography to obtain a pure product. Preferably, synthesis of ethyl (2 s,3 r) -2-fluoro-3-hydroxy-3- (naphthalen-2-yl) propionate: Adding cesium fluoride into a glass reaction bottle, replacing the reaction bottle with nitrogen for 3 times, adding N, N-dimethylformamide under the protection of nitrogen, sequentially adding 2-naphthaldehyde and monofluoro-substituted enol silyl ether compound under stirrin