A method for preparing alpha-fluoro-beta-hydroxy ester compounds

Abstract

The application discloses a preparation method of an alpha-fluorine-beta-hydroxyl ester compound, and has the structural general formula as shown in the following formula: the preparation method is as follows: a catalyst is added into a reaction bottle, the reaction bottle is replaced with nitrogen for three times, a solvent is added into the reaction bottle by using a syringe under nitrogen protection, then an aldehyde and a monofluorosubstituted enol silyl ether are sequentially added into the reaction bottle by using a micro-injection device; stirring is conducted at room temperature until the reaction is completed; the reaction liquid is transferred into an aqueous phase for quenching, ethyl acetate extraction, drying with anhydrous sodium sulfate, combining organic phases, reducing pressure concentration, and adopting silica gel column chromatography to separate to obtain a pure product; the synthesis route of the alpha-fluorine-beta-hydroxyl ester compound provided by the application has the advantages of novelty, high efficiency, high atom economy, mild reaction conditions, wide substrate application range and the like, and has a potential application prospect in the fields of drug synthesis and the like.

Description

Technical Field

[0001] This invention relates to the technical fields of organic synthesis and drug synthesis, specifically to α-fluoro-β-hydroxy ester compounds and their green and efficient preparation methods. Background Technology

[0002] β-hydroxy esters are widely found in natural products and pharmaceuticals and have become important chemical intermediates. The introduction of fluorine atoms gives fluorinated compounds unique physical and chemical properties that distinguish them from non-fluorinated compounds. In recent years, fluorinated compounds have found wide applications in pharmaceuticals, agrochemicals, and functional materials. Among them, α-fluoro-β-hydroxy esters also play an important role in the pharmaceutical field. For example, these compounds possess important biological activities such as antitumor activity (WOPatent 2,000,069,846) and inhibition of aromatase (J. Pharm. Pharmacol. 2010, 62, 1717-1728).

[0003] The main methods for synthesizing α-fluoro-β-hydroxy esters include: (1) JT Welch et al. used aldehydes to react with lithium enol reagents to obtain α-fluoro-β-hydroxy esters, but the reaction requires the use of a stoichiometric amount of base, resulting in poor atom economy; (2) CF Barbas et al. used aldehydes to react with monofluorinated acetone to obtain α-fluoro-β-hydroxy esters, but the reaction time was long; (3) Professor Chen Qingyun et al. used TMS-OTf under reflux conditions or CuCl in toxic HMPA solvent to react aldehydes with fluorinated enol silyl ethers to obtain α-fluoro-β-hydroxy esters, but the reaction conditions were harsh. Therefore, there is an urgent need in this field for green, efficient, atom-economical, mild reaction conditions, and a wide range of applicable substrates for the preparation of α-fluoro-β-hydroxy esters. Summary of the Invention

[0004] The present invention aims to provide a class of α-fluoro-β-hydroxy ester compounds and their green and efficient preparation method, which is green, efficient, atom-economical, has mild reaction conditions, and has a wide range of applicable substrates.

[0005] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing α-fluoro-β-hydroxy ester compounds.

[0006] The α-fluoro-β-hydroxy ester compounds are The preparation route is as follows:

[0007]

[0008] 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-furanyl, 2-thienyl, phenylpropyl, phenylacrylyl, cyclohexyl, cyclohexenyl, n-pentyl, isopropyl, menthol derivatives, nerol derivatives, adapalene derivatives, oleyl alcohol derivatives, androstenone derivatives, tocopheryl glycoside derivatives, or galactose derivatives;

[0009] The specific preparation method includes the following steps:

[0010] (1) Add a catalyst to the glass reaction flask. The catalyst is one of CsF (cesium fluoride), TBAF (tetrabutylammonium fluoride), or TBAT (tetrabutyldifluorotriphenylammonium silicate).

[0011] (2) Under nitrogen protection, add one of the solvents, acetonitrile or N,N-dimethylformamide, followed by aldehyde compound and monofluorinated enol silyl ether compound in sequence. Continue stirring at room temperature for 3 to 10 minutes to obtain the target product.

[0012] Preferably, the molar ratio of the aldehyde compound, the monofluorosubstituted enol silyl ether compound, and the catalyst is 1:1.5:0.005.

[0013] Preferably, the preparation route of the α-fluoro-β-hydroxy ester compound is as follows:

[0014]

[0015] (1) Add 0.5% to 1% of a catalyst to the glass reaction flask. The catalyst is one of CsF (cesium fluoride), TBAF (tetrabutylammonium fluoride), or TBAT (tetrabutyldifluorotriphenylammonium silicate); purge the reaction flask with nitrogen three times.

[0016] (2) Under nitrogen protection, add one of the solvents, acetonitrile or N,N-dimethylformamide, followed by aldehyde compound and monofluoro-substituted enol silyl ether compound in sequence. Stir at 22°C for 3 min to obtain the target product.

[0017] (3) The reaction solution was transferred to the aqueous phase for quenching, extracted with ethyl acetate, dried with anhydrous sodium sulfate, the organic phases were combined, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product.

[0018] Preferred synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(naphth-2-yl)propionate:

[0019]

[0020] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 2-naphthaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench the reaction, extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 86%.

[0021] Preferred synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-phenylpropionate:

[0022]

[0023] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by benzaldehyde and a monofluorosubstituted enol silyl ether compound in sequence with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench the reaction, extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 71%.

[0024] Preferred synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(p-tolyl)propionate:

[0025]

[0026] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, acetonitrile was added, followed by the sequential addition of 4-methylbenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 92%.

[0027] Preferred synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(2-methoxyphenyl)propionate:

[0028]

[0029] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, acetonitrile was added, followed by the sequential addition of 2-methylbenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 78%.

[0030] Preferred synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(3-methoxyphenyl)propionate:

[0031]

[0032] TBAF (tetrabutylammonium fluoride) was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 3-methylbenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 78%.

[0033] Preferred synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(4-methoxyphenyl)propionate:

[0034]

[0035] TBAT (tetrabutyldifluorotriphenylammonium silicate) was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 4-methoxybenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 92%.

[0036] Preferred, ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionate:

[0037]

[0038] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 4-trifluoromethylbenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 78%.

[0039] Compared with the prior art, the beneficial effects of the present invention are:

[0040] (1) Under mild reaction conditions, this invention catalyzes the condensation reaction of monofluorosubstituted enol silyl ethers with aldehydes to readily and rapidly construct α-fluoro-β-hydroxy ester compounds. The chemical formula of the reaction is as follows:

[0041]

[0042] (2) As can be seen from (1), the reaction conditions are room temperature (22℃), which is relatively mild. The target product is obtained from the raw materials and products without producing any by-products, which has excellent atom economy.

[0043] (3) The raw materials used in the preparation process are cheap and readily available, the catalyst is inexpensive, the reaction time is short, and the target product can be obtained in high yield, indicating that the method is economically efficient.

[0044] (4) The method for preparing α-fluoro-β-hydroxy ester compounds provided by the present invention has good functional group tolerance. By introducing different substituents into the substrate, polysubstituted α-fluoro-β-hydroxy ester compounds can be constructed in one step.

[0045] (5) The solvent is a highly polar aprotic solvent such as acetonitrile or N,N-dimethylformamide. In other solvents, such as 1,4-dioxane, tetrahydrofuran, dichloromethane, 1,2-tetrachloroethane, toluene, and methanol, an increased amount of catalyst and a longer reaction time are often required for the reaction to proceed.

[0046] (6) Under nitrogen protection, add one of the solvents, acetonitrile and N,N-dimethylformamide, followed by aldehydes and monofluorosubstituted enol silyl ethers. Continue stirring at 22°C for 3 minutes, while existing reactions often require several hours or even longer.

[0047] Therefore, the preparation route for α-fluoro-β-hydroxy esters provided by this invention has the advantages of being novel, efficient, atom-economical, having mild reaction conditions, and having a wide range of applicable substrates, and has important potential application prospects in the fields of organic synthesis and drug synthesis. Attached Figure Description

[0048] Figure 1 The 1H NMR spectrum of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(naphth-2-yl)propionate in Example 1 of this invention;

[0049] Figure 2 This is the carbon NMR spectrum of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(naphth-2-yl)propionate in Example 1 of this invention;

[0050] Figure 3 The nuclear magnetic resonance fluorine spectrum of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(naphth-2-yl)propionate in Example 1 of this invention;

[0051] Figure 4 The 1H NMR spectrum of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-phenylpropionate in Example 2 of this invention;

[0052] Figure 5 This is the carbon NMR spectrum of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-phenylpropionate in Example 2 of the present invention.

[0053] Figure 6 The nuclear magnetic resonance fluorine spectrum of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-phenylpropionate in Example 2 of this invention; Detailed Implementation

[0054] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0055] Example 1

[0056] Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(naphth-2-yl)propionate:

[0057]

[0058] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 2-naphthaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench the reaction, extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 86%.

[0059] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz, CDCl3) δ7.86-7.82(m,2H),7.50-7.47(m,2H),5.34-5.26(m,1H),5.20-5.04(m,1H),4.25-4.14(m,2H),2.36(brs,1H),1.18and 1.14(t,J=7.6Hz,3H).

[0060] Example 2

[0061] Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-phenylpropionate:

[0062]

[0063] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by benzaldehyde and a monofluorosubstituted enol silyl ether compound in sequence with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench the reaction, extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 71%.

[0064] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz, CDCl3) δ7.42-7.32(m,5H),5.17-4.95(m,2H),4.27-4.18(m,2H),2.68(brs,1H),1.22and 1.19(t,J=7.2Hz,3H).

[0065] Example 3

[0066] Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(p-tolyl)propionate:

[0067]

[0068] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, acetonitrile was added, followed by the sequential addition of 4-methylbenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 92%.

[0069] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz, CDCl3) δ7.29-7.26(m,2H),7.20-7.16(m,2H),5.13-4.92(m,2H),4.26-4.17(m,2H),3.17(brs,1H),2.35and 2.34(s,3H),1.23and 1.21(t,J=7.2Hz,3H).

[0070] Example 4

[0071] Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(2-methoxyphenyl)propionate:

[0072]

[0073] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, acetonitrile was added, followed by the sequential addition of 2-methylbenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 78%.

[0074] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz, CDCl3) δ7.53-7.48(m,1H),7.25-7.21(m,2H),7.18-7.15(m,1H),5.40-5.33(m,1H),5 .00(dt,J=48.1,4.0Hz,1H),4.25-4.17(m,2H),2.74(brs,1H),2.36(s,3H),1.21(q,J=7.5Hz,3H).

[0075] Example 5

[0076] Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(3-methoxyphenyl)propionate:

[0077]

[0078] TBAF (tetrabutylammonium fluoride) was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 3-methylbenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 78%.

[0079] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz, CDCl3) δ7.28-7.13(m,4H),5.11-4.92(m,2H),4.25-4.16(m,2H),2.92(brs,1H),2.36and 2.35(s,3H),1.24-1.17(m,3H).

[0080] Example 6

[0081] Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(4-methoxyphenyl)propionate:

[0082]

[0083] TBAT (tetrabutyldifluorotriphenylammonium silicate) was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 4-methoxybenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 92%.

[0084] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz; CDCl3): δ7.37(d,J=7.9Hz,2H),7.30-7.24(m,3H),7.19(t,J=7.6Hz,2H),6.98 (t,J=7.5Hz,2H),6.81(d,J=8.6Hz,2H),6.51(s,2H),5.82(s,1H),3.77(s,3H),3.66(s,6H).

[0085] Example 7

[0086] Ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionate:

[0087]

[0088] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 4-trifluoromethylbenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 78%.

[0089] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz; CDCl3): δ7.65 (t, J=7.2Hz, 2H), 7.54 (dd, J=7.9, 5.1Hz, 2H), 5.2 5-5.18(m,1H),5.03(ddd,J=48.0,4.3,2.5Hz,1H),4.29-4.19(m,2H),2.99and 2.79(brs,1H),1.23(dt,J=15.4,7.2Hz,3H).

[0090] Example 8

[0091] Synthesis of ethyl (2S,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxypropionate:

[0092]

[0093] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 4-fluorobenzaldehyde and a monofluoro-substituted enol silyl ether compound with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The mixture was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 88%.

[0094] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz; CDCl3): δ7.37 (dt, J=10.0, 5.2Hz, 2H), 7.1 (td, J=8.7, 5.7Hz, 2H), 5.1 5-4.90(m,2H),4.25-4.17(m,2H),2.87(brs,1H),1.24-1.18(dt,J=8.8,7.2Hz,3H).

[0095] Example 9

[0096] Synthesis of ethyl (2S,3R)-2-fluoro-3-(furan-2-yl)-3-hydroxypropionate:

[0097]

[0098] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 2-furan carboxaldehyde and a monofluorosubstituted silane ether compound with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench the reaction. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 84%.

[0099] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz; CDCl3): δ7.42-7.41(m,1H),6.42-6.36(m,2H),5.26-5.13(m,2H ), 4.27 (dq, J = 19.7, 7.1 Hz, 2H), 2.69 ( brs, 1H), 1.27 ( dt, J = 20.4, 7.4 Hz, 3H).

[0100] Example 10

[0101] Synthesis of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-((1R,2S)-3-ethoxy-2-fluoro-1-hydroxy-3-oxopropyl)benzoate:

[0102]

[0103] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl-4-carboxybenzoate and a monofluorosubstituted enol silyl ether compound, with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The mixture was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 69%.

[0104] The 1H NMR spectrum data for this product are as follows: 1H NMR (400MHz; CDCl3): δ8.04 (dd, J=8.2, 6.5Hz, 2H), 7.49-7.46 (m, 2H), 5.25-4.89 ( m,3H),4.30-4.18(m,2H),2.73(brs,1H),2.11(d,J=11.9Hz,1H),1.93(dtt,J=13.2 ,6.6,2.8Hz,1H),1.73(dt,J=11.8,2.8Hz,2H),1.58-1.51(m,2H),1.27-1.23(m,2 H), 1.21-1.19 (m, 1H), 1.15-1.05 (m, 2H), 0.93-0.90 (m, 7H), 0.78 (d, J = 7.0Hz, 3H).

[0105] Example 11

[0106] Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(3-phenoxyphenyl)propionate:

[0107]

[0108] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 3-phenoxybenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench the reaction, extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 89%.

[0109] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz; CDCl3): δ7.36-7.31(m,3H),7.14-6.96(m,6H),5.14-4.93(m,2H),4.28-4.17(m,2H),2.82(brs,1H),1.23(dt,J=16.6,7.1Hz,3H).

[0110] Example 12

[0111] Synthesis of ethyl (2S,3R)-3-([1,1'-biphenyl]-4-yl)-2-fluoro-3-hydroxypropionate:

[0112]

[0113] Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, N,N-dimethylformamide was added, followed by the sequential addition of 4-biphenylformaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22°C for 3 minutes. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench the reaction, extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 58%.

[0114] The 1H NMR spectrum data for this product are as follows: 1 H NMR (400MHz; CDCl3): δ7.63-7.58(m,4H),7.49-7.35(m,4H),7.39-7.35(m,1H),5 .23-5.00(m,2H),4.28-4.20(m,2H),2.78(brs,1H),1.23(dt,J=10.6,7.2Hz,3H).

[0115] Comparative Example 1

[0116]

[0117] Replacing N,N-dimethylformamide with dichloromethane as the reaction solvent requires increasing the amount of catalyst to 5 mol% and extending the reaction time to 12 hours to obtain the target compound with a separation yield of 78%.

[0118] Comparative Example 2

[0119]

[0120] Replacing N,N-dimethylformamide with methanol as the reaction solvent, even with an increased catalyst amount of 5 mol% and a reaction time of 12 hours, did not result in the formation of the target compound.

[0121] Comparative Example 3

[0122]

[0123] Even when sodium fluoride was used to replace potassium fluoride as the catalyst and DCM was used to replace N,N-dimethylformamide as the reaction solvent, no target compound was detected, even when the amount of catalyst was increased to 5 mol% and the reaction time was extended to 12 hours.

Claims

1. A kind α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: The aforementioned α -fluorine- β -Hydroxy ester compounds are 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-furanyl, 2-thienyl, phenylpropyl, phenylacrylyl; The specific preparation method includes the following steps: (1) Add a catalyst to the glass reaction flask. The catalyst is one of CsF (cesium fluoride), TBAF (tetrabutylammonium fluoride), or TBAT (tetrabutyldifluorotriphenylammonium silicate). (2) Under nitrogen protection, add acetonitrile or N , N A solvent of dimethylformamide is used, followed by the sequential addition of an aldehyde compound and a monofluoro-substituted enol silyl ether compound. The mixture is stirred at room temperature for 3 to 10 minutes to obtain the target product.

2. As described in claim 1 α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: The molar ratios of the aldehyde compounds, monofluorosubstituted enol silyl ether compounds, and catalysts are 1:1.5:0.005, respectively.

3. As described in claim 1 α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: The aforementioned α -fluorine- β The preparation route for hydroxy ester compounds is shown below: ; (1) Add 0.5% to 0.1% of a catalyst to the glass reaction flask. The catalyst is one of CsF (cesium fluoride), TBAF (tetrabutylammonium fluoride), or TBAT (tetrabutyldifluorotriphenylammonium silicate); replace the reaction flask with nitrogen three times. (2) Under nitrogen protection, add acetonitrile or N , N A solvent of dimethylformamide was added, followed by an aldehyde compound and a monofluoro-substituted enol silyl ether compound. The mixture was stirred at 22°C for 3 min to obtain the target product. (3) The reaction solution was transferred to the aqueous phase for quenching, extracted with ethyl acetate, dried with anhydrous sodium sulfate, the organic phases were combined, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product.

4. As described in claim 1 α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(naphth-2-yl)propionate: ； Add cesium fluoride to the glass reaction flask, and purge the reaction flask with nitrogen three times; And under nitrogen protection, add N , N Dimethylformamide was added sequentially with 2-naphthaldehyde and monofluorosubstituted enol silyl ether compound under stirring. The mixture was stirred at 22 °C for 3 min. After the reaction was completed, the reaction solution was quickly poured into the aqueous phase to quench it. The mixture was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 86%.

5. A kind α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-phenylpropionate: ； Add cesium fluoride to the glass reaction flask, and purge the reaction flask with nitrogen three times; And under nitrogen protection, add N , N Dimethylformamide was added sequentially with benzaldehyde and monofluorosubstituted enol silyl ether compound under stirring. The mixture was stirred at 22 °C for 3 min. After the reaction was completed, the reaction solution was quickly poured into the aqueous phase to quench it. The mixture was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 71%.

6. The method according to claim 1 α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(p-tolyl)propionate: ； Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Under nitrogen protection, acetonitrile was added, followed by the sequential addition of 4-methylbenzaldehyde and monofluorosubstituted enol silyl ether compounds with stirring. The mixture was stirred at 22 °C for 3 min. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 92%.

7. The method according to claim 1 α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(2-methoxyphenyl)propionate: ； Cesium fluoride was added to a glass reaction flask, and the flask was purged with nitrogen three times. Acetonitrile was added under nitrogen protection, and 2-methylbenzaldehyde and monofluorosubstituted enol silyl ether compound were added sequentially with stirring. The mixture was stirred at 22 °C for 3 min. After the reaction was completed, the reaction solution was quickly poured into an aqueous phase to quench it. The solution was extracted four times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the pure product. The yield was 78%.

8. The method according to claim 1 α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(3-methoxyphenyl)propionate: ； Add TBAF (tetrabutylammonium fluoride) to the glass reaction flask, and purge the reaction flask with nitrogen three times; And under nitrogen protection, add N , N Dimethylformamide was added sequentially with 3-methylbenzaldehyde and monofluorosubstituted enol silyl ether compound under stirring. The mixture was stirred at 22 °C for 3 min. After the reaction was completed, the reaction solution was quickly poured into the aqueous phase to quench it. The mixture was extracted four times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 78%.

9. The method according to claim 1 α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: Synthesis of ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(4-methoxyphenyl)propionate: ； Add TBAT (tetrabutyldifluorotriphenylammonium silicate) to the glass reaction flask, purge the flask three times with nitrogen, and then add [other ingredients] under nitrogen protection. N , N Dimethylformamide was added sequentially with 4-methoxybenzaldehyde and monofluorosubstituted enol silyl ether compound under stirring. The mixture was stirred at 22 °C for 3 min. After the reaction was completed, the reaction solution was quickly poured into the aqueous phase to quench it. The mixture was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 92%.

10. The claim 1 α -fluorine- β A method for preparing hydroxy ester compounds, characterized in that: Ethyl (2S,3R)-2-fluoro-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionate: ； Cesium fluoride was added to the glass reaction flask, and the flask was purged with nitrogen three times; then, under nitrogen protection, cesium fluoride was added. N , N Dimethylformamide was added sequentially with 4-trifluoromethylbenzaldehyde and monofluorosubstituted enol silyl ether compound under stirring. The mixture was stirred at 22 °C for 3 min. After the reaction was completed, the reaction solution was quickly poured into the aqueous phase to quench it. The mixture was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the pure product. The yield was 78%.

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