A process for the preparation of a beta-hydroxy-alpha,alpha-difluoro amide compound

Abstract

A method for preparing β-hydroxy-α,α-difluoroamide compounds. This invention belongs to the field of catalytic synthesis technology, specifically relating to a method for preparing β-hydroxy-α,α-difluoroamide compounds. This invention solves the technical problem that existing synthetic methods require the use of photocatalysts or metal catalysts. Method: 1. Under room temperature and a nitrogen atmosphere, a bromodifluoroamide compound, an electrophilic reagent compound, and... n Bu4NBF4 and molecular sieves are added to an ultra-dry solvent and stirred until homogeneous to obtain a mixed solution; then, an electrolytic reaction is carried out, followed by separation and purification. The method of this invention is simple, with mild reaction conditions and readily available raw materials. It can efficiently synthesize β-hydroxy-α,α-difluoroamide compounds without the need for metal reducing agents. This invention has significant potential for large-scale application in the field of organic synthesis.

Description

Technical Field

[0001] This invention belongs to the field of catalytic synthesis technology, specifically relating to a method for preparing β-hydroxy-α,α-difluoroamide compounds. Background Technology

[0002] Fluorine-containing compounds are widely found in natural products, bioactive molecules, and drug molecules. Among them, difluoroamides occupy a very important position, and their synthesis has inspired continuous efforts. The most common method for synthesizing difluoroamides is photoinduced or metal-catalyzed reaction, which involves two basic steps: photoinduced or metal-catalyzed generation of difluoroamide-containing carbon radicals from bromodifluoroamide compounds, followed by radical addition reactions with various acceptors. However, despite numerous efforts, previous reports still suffer from the following problems: the need to introduce expensive photocatalysts; or the need to use metals to activate bromodifluoroamides to form radical sources, resulting in difficult metal recovery after the reaction and an unfriendly reaction environment. These problems limit the large-scale application of the above methods. Therefore, it is necessary to seek a mild, green, efficient, simple, and convenient method for synthesizing difluoroamides. Summary of the Invention

[0003] This invention solves the technical problem that existing synthesis methods require the use of light or metal catalysts, and provides a more convenient, efficient, and scalable method for preparing β-hydroxy-α,α-difluoroamide compounds.

[0004] This invention utilizes an electrocatalytic approach to achieve the nucleophilic addition reaction of bromodifluoroamide with aldehydes and ketones through electroreduction polarity reversal, enabling the efficient preparation of β-hydroxy-α,α-difluoroamide compounds, which differs from common free radical addition reactions (bromodifluoroamide substrates are excellent free radical donors).

[0005] A method for preparing a β-hydroxy-α,α-difluoroamide compound, comprising the following steps:

[0006] I. Under room temperature and a nitrogen atmosphere, bromodifluoroamide compounds, electrophilic compounds, n Bu4NBF4 and Molecular sieves are added to ultra-dry solvent and stirred until homogeneous to obtain a mixed solution;

[0007] The electrophilic reagent compound is a ketone compound, an aldehyde compound, or an electron-deficient olefin compound;

[0008] 2. Under a nitrogen atmosphere and at room temperature, electrolyze the mixed solution obtained in step 1 for 5.0–5.5 h, then remove the solvent by rotary evaporation, and then separate and purify by thin-layer chromatography. The product obtained is a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0009] Furthermore, the bromodifluoroamide compound mentioned in step one is 2-bromo-2,2-difluoro-N-(p-tolyl)acetamide, 2-bromo-2,2-difluoro-N-(p-isopropylphenyl)acetamide, 2-bromo-2,2-difluoro-N-(phenyl)acetamide, or 2-bromo-2,2-difluoro-N-(p-fluorophenyl)acetamide.

[0010] Furthermore, the ketone compound mentioned in step one is acetone, 2-butanone, 2-pentanone, 3-pentanone, cyclobutanone, cyclopentanone, or cyclohexanone.

[0011] Furthermore, the aldehyde compound mentioned in step one is propionaldehyde, butyraldehyde, pentanaldehyde, cyclobutyraldehyde, cyclopentanaldehyde, 4-aldehyde tetrahydropyran, isobutyraldehyde, benzaldehyde, p-methylbenzaldehyde, p-chlorobenzaldehyde, or biphenylaldehyde.

[0012] Furthermore, the electron-deficient olefin compound mentioned in step one is methyl acrylate, ethyl acrylate, or acrylonitrile.

[0013] Furthermore, as described in step one n Bu4NBF4 is tetrabutyltetrafluoroborate amine.

[0014] Furthermore, as described in step one Molecular sieve powder desiccant.

[0015] Furthermore, the ultra-dry solvent mentioned in step one is ultra-dry tetrahydrofuran.

[0016] Furthermore, in step one, the ratio of the bromodifluoroamide compound to the ultra-dry solvent is (0.40–0.42) mmol:4 mL; the ratio of the ketone compound to the ultra-dry solvent is (2.00–2.02) mmol:4 mL; the ratio of the aldehyde compound to the ultra-dry solvent is (2.00–2.02) mmol:4 mL; and the ratio of the electron-deficient olefin compound to the ultra-dry solvent is (2.00–2.02) mmol:4 mL. n The ratio of Bu4NBF4 to ultra-dry solvent is (162-165) mg: 4 mL; The ratio of molecular sieve to ultra-dry solvent is (198-200) mg: 4 mL.

[0017] The reaction principle of this invention is as follows:

[0018]

[0019] Wherein, R is aryl or alkyl; R' is H or methyl;

[0020] Or the principle is:

[0021]

[0022] The bromodifluoroamide compounds of this invention, taking 2-bromo-2,2-difluoro-N-(p-tolyl)acetamide as an example, are synthesized using the following steps:

[0023]

[0024] As shown above, the method involves weighing p-toluidine (10.0 mmol, 1.0 eq) and lanthanum trifluoromethanesulfonate (0.5 mmol, 5% mol) into a 100 mL Shrek flask under air conditions. Immediately afterward, the flask is repeatedly evacuated using a double-row tube and purged with nitrogen. Ethyl dibromofluoroacetate (12.0 mmol, 1.2 eq) is added under nitrogen atmosphere, and the stopper is sealed with a sealing film to prevent leakage. The mixture is then stirred at 50 °C for approximately 12 hours. The reaction is monitored for completeness using a TLC plate. Once complete, the mixture is transferred to a clean round-bottom flask and rotary evaporated. The purified 2-bromo-2,2-difluoro-N-(p-tolyl)acetamide is obtained by column chromatography using petroleum ether at a volume ratio of 20:1.

[0025] Beneficial effects of this invention:

[0026] Compared with existing technologies, this invention uses a simple, green, and efficient electrochemical method to synthesize difluoroamide compounds, which has the following main advantages:

[0027] (1) The reaction can be carried out by electrocatalysis at room temperature and in an inert gas atmosphere to synthesize β-hydroxy-α,α-difluoroamides under mild reaction conditions.

[0028] (2) This reaction is a two-component reaction with a simple reaction system; alkyl ketone compounds, aldehyde compounds, n Bu4NBF4、 Molecular sieves are all simple, inexpensive, and readily available commercial reagents. Bromodifluoroamide is easy to prepare, has good substrate universality, and the entire reaction system is economical and efficient.

[0029] (3) The conditions are green and mild, and no external metal reducing reagent is required; the reaction can be scaled up by applying electricity at room temperature, and the yield is good. The reaction efficiency is high and it has large-scale application value.

[0030] Verification has shown that this invention can achieve gram-scale reaction at room temperature by applying electricity, efficiently synthesizing β-hydroxy-β-dimethyl-α,α-difluoro-N-(p-tolyl)acetamide with a yield of 73%; the use of electron reduction instead of metal reducing reagents demonstrates the green and environmentally friendly nature of the reaction.

[0031] This invention is used to prepare difluoroamide compounds. Attached Figure Description

[0032] Figure 1 It is the β-hydroxy-α,α-difluoroamide compound-1 obtained in Example 1. 1 H NMR spectrum;

[0033] Figure 2 It is the β-hydroxy-α,α-difluoroamide compound-1 obtained in Example 1. 13 C NMR spectrum;

[0034] Figure 3 It is the β-hydroxy-α,α-difluoroamide compound-1 obtained in Example 1. 19 F NMR spectrum. Detailed Implementation

[0035] Specific Implementation Method 1: This embodiment describes a method for preparing a β-hydroxy-α,α-difluoroamide compound, which is carried out according to the following steps:

[0036] I. Under room temperature and a nitrogen atmosphere, bromodifluoroamide compounds, electrophilic compounds, n Bu4NBF4 and Molecular sieves are added to ultra-dry solvent and stirred until homogeneous to obtain a mixed solution;

[0037] The electrophilic reagent compound is a ketone compound, an aldehyde compound, or an electron-deficient olefin compound;

[0038] 2. Under a nitrogen atmosphere and at room temperature, electrolyze the mixed solution obtained in step 1 for 5.0–5.5 h, then remove the solvent by rotary evaporation, and then separate and purify by thin-layer chromatography. The product obtained is a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0039] Specific Implementation Method Two: This implementation method differs from Specific Implementation Method One in that the bromodifluoroamide compound mentioned in step one is 2-bromo-2,2-difluoro-N-(p-tolyl)acetamide, 2-bromo-2,2-difluoro-N-(p-isopropylphenyl)acetamide, 2-bromo-2,2-difluoro-N-(phenyl)acetamide, or 2-bromo-2,2-difluoro-N-(p-fluorophenyl)acetamide. Everything else is the same as in Specific Implementation Method One.

[0040] Specific Implementation Method Three: This implementation method differs from Specific Implementation Method One or Two in that the ketone compound mentioned in step one is acetone, 2-butanone, 2-pentanone, 3-pentanone, cyclobutanone, cyclopentanone, or cyclohexanone. Everything else is the same as in Specific Implementation Method One or Two.

[0041] Specific Implementation Method Four: This implementation method differs from Specific Implementation Methods One to Three in that the aldehyde compound mentioned in step one is n-propanal, butyraldehyde, pentanal, cyclobutyraldehyde, cyclopentanal, 4-aldehydetetrahydropyran, isobutyraldehyde, benzaldehyde, p-methylbenzaldehyde, p-chlorobenzaldehyde, or biphenylaldehyde. Everything else is the same as in Specific Implementation Methods One to Three.

[0042] Specific Implementation Method Five: This implementation method differs from one of Specific Implementation Methods One to Four in that the electron-deficient olefin compound mentioned in step one is methyl acrylate, ethyl acrylate, or acrylonitrile. Everything else is the same as in one of Specific Implementation Methods One to Four.

[0043] Specific Implementation Method Six: This implementation method differs from Specific Implementation Methods One to Five in that: Step One described... n Bu4NBF4 is tetrabutyltetrafluoroborate amine. Other aspects are the same as in any one of embodiments one to five.

[0044] Specific Implementation Method Seven: This implementation method differs from Specific Implementation Methods One through Six in that: Step One described... Molecular sieve powdered desiccant. Other aspects are the same as in any one of embodiments one through six.

[0045] Specific Implementation Method Eight: This implementation method differs from Specific Implementation Methods One to Seven in that the ultra-dry solvent mentioned in step one is ultra-dry tetrahydrofuran. Everything else is the same as in Specific Implementation Methods One to Seven.

[0046] Specific Implementation Method Nine: This implementation method differs from Specific Implementation Methods One to Eight in that: the ratio of the amount of bromodifluoroamide compound to ultra-dry solvent in step one is (0.40-0.42) mmol:4 mL; the ratio of the amount of ketone compound to ultra-dry solvent is (2.00-2.02) mmol:4 mL; the ratio of the amount of aldehyde compound to ultra-dry solvent is (2.00-2.02) mmol:4 mL; and the ratio of the amount of electron-deficient olefin compound to ultra-dry solvent is (2.00-2.02) mmol:4 mL. n The ratio of Bu4NBF4 to ultra-dry solvent is (162-165) mg: 4 mL; The ratio of molecular sieve to ultra-dry solvent is (198-200) mg: 4 mL. Other aspects are the same as in specific embodiments one through eight.

[0047] Specific Implementation Method 10: This implementation method differs from Specific Implementation Methods 1 to 9 in that: in step 2, the current is controlled to be 10mA; the anode material is a magnesium rod, and the cathode material is a carbon rod;

[0048] The solvent used for separation and purification is a mixture of petroleum ether and ethyl acetate. Other aspects are the same as in any of the specific embodiments one through nine.

[0049] The scope of this invention is not limited to the above-described embodiments; a combination of one or more specific embodiments can also achieve the purpose of the invention.

[0050] Example 1:

[0051] This embodiment describes a method for preparing a β-hydroxy-α,α-difluoroamide compound, which is carried out according to the following steps:

[0052] 1. Under a nitrogen atmosphere at room temperature, mix 0.4 mmol of 2-bromo-2,2-difluoro(p-tolyl)acetamide, 2.0 mmol of acetone, 0.5 mmol of tetrabutyltetrafluoroborate amine, and 200 mg of... Molecular sieves were added to 4 mL of ultra-dry tetrahydrofuran and stirred for 10 min to obtain a mixed solution;

[0053] 2. Under room temperature and nitrogen atmosphere, the mixed solution obtained in step 1 was electrolyzed for 5.5 hours, with the current controlled at 10 mA. The anode material was a magnesium rod and the cathode material was a carbon rod. The reaction progress was monitored by TLC. Then, the solvent was removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The solvent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. The obtained product was a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0054] The product prepared in this embodiment was identified as β-hydroxy-α,α-difluoroamide compound-1 using 1H NMR, 1C NMR, and mass spectrometry, with the following structural formula:

[0055]

[0056] The product purity was 99%, and the yield was 76%; its NMR data analysis was as follows: 1 H NMR (400MHz, CDCl3) δ8.18 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 3.31 (s, 1H), 2.34 (s, 3H), 1.42 (s, 6H). 13C NMR (100MHz, CDCl3) δ 162.1 (t, J = 28.8 Hz), 135.6, 133.3, 129.7, 120.5, 118.3 (t, J = 259.1 Hz), 73.2 (t, J = 25.1 Hz), 23.2, 21.0. 19 F NMR (CDCl3, 376MHz): δ-117.8 (2F, s).

[0057] Example 2:

[0058] This embodiment describes a method for preparing a β-hydroxy-α,α-difluoroamide compound, which is carried out according to the following steps:

[0059] 1. Under a nitrogen atmosphere at room temperature, mix 0.4 mmol of 2-bromo-2,2-difluoro(p-tolyl)acetamide, 2.0 mmol of cyclobutanone, 0.5 mmol of tetrabutyltetrafluoroborate amine, and 200 mg of... Molecular sieves were added to 4 mL of ultra-dry tetrahydrofuran and stirred for 10 min to obtain a mixed solution;

[0060] 2. Under room temperature and nitrogen atmosphere, the mixed solution obtained in step 1 was electrolyzed for 5.5 hours, with the current controlled at 10 mA. The anode material was a magnesium rod and the cathode material was a carbon rod. The reaction progress was monitored by TLC. Then, the solvent was removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The solvent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. The obtained product was a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0061] The product prepared in this embodiment was identified as β-hydroxy-α,α-difluoroamide compound-2 using 1H NMR, 1C NMR, and mass spectrometry, with the following structural formula:

[0062]

[0063] The product purity was 99%, and the yield was 67%; its NMR data analysis was as follows: 1 H-NMR (400MHz, CDCl3) δ8.25 (s, 1H), 7.42-7.40 (m, 2H), 7.14 (d, J = 5.6Hz, 2H), 3.62 (s, 1H) ,2.64-2.57(m,2H),2.32(s,3H),2.18-2.10(m,2H),1.96-1.94(m,1H),1.83-1.77(m,1H). 13C NMR (100MHz, CDCl3) δ 162.1 (t, J = 29.0Hz), 135.6, 133.3, 129.7, 120.5, 114.9 (t, J = 256.4Hz), 76.1 (t, J = 27.6Hz), 30.3, 21.0, 12.8. 19 F NMR (CDCl3, 376MHz): δ-119.8 (s, 2F).

[0064] Example 3:

[0065] This embodiment describes a method for preparing a β-hydroxy-α,α-difluoroamide compound, which is carried out according to the following steps:

[0066] 1. Under a nitrogen atmosphere at room temperature, mix 0.4 mmol of 2-bromo-2,2-difluoro(p-tolyl)acetamide, 2.0 mmol of n-propionaldehyde, 0.5 mmol of tetrabutyltetrafluoroborate amine, and 200 mg of... Molecular sieves were added to 4 mL of ultra-dry tetrahydrofuran and stirred for 10 min to obtain a mixed solution;

[0067] 2. Under room temperature and nitrogen atmosphere, the mixed solution obtained in step 1 was electrolyzed for 5.5 hours, with the current controlled at 10 mA. The anode material was a magnesium rod and the cathode material was a carbon rod. The reaction progress was monitored by TLC. Then, the solvent was removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The solvent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. The obtained product was a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0068] The product prepared in this embodiment was identified as β-hydroxy-α,α-difluoroamide compound-3 using 1H NMR, 1C NMR, and mass spectrometry, with the following structural formula:

[0069]

[0070] The product purity was 99%, and the yield was 84%; its NMR data analysis was as follows: 1 H NMR (400MHz, CDCl3) δ8.07(s,1H),7.43(d,J=8.0Hz,2H),7.16(d,J=8.0Hz,2H),4.14-4.05(m ,1H),2.42(s,1H),2.33(s,3H),1.83-1.71(m,1H),1.66-1.55(m,1H),1.07(t,J=7.6Hz,3H). 13C NMR (100MHz, CDCl3) δ 162.0 (t, J = 28.0Hz), 135.6, 133.3, 129.7, 120.4, 120.3, 118.2 (t, J = 259.0Hz), 72.8 (t, J = 27.6Hz), 22.4, 21.0, 9.9. 19 F NMR (CDCl3, 376MHz): δ-113.0-122.6 (m, 2F).

[0071] Example 4:

[0072] This embodiment describes a method for preparing a β-hydroxy-α,α-difluoroamide compound, which is carried out according to the following steps:

[0073] 1. Under a nitrogen atmosphere at room temperature, mix 0.4 mmol of 2-bromo-2,2-difluoro(p-tolyl)acetamide, 2.0 mmol of cyclobutyraldehyde, 0.5 mmol of tetrabutyltetrafluoroborate amine, and 200 mg of... Molecular sieves were added to 4 mL of ultra-dry tetrahydrofuran and stirred for 10 min to obtain a mixed solution;

[0074] 2. Under room temperature and nitrogen atmosphere, the mixed solution obtained in step 1 was electrolyzed for 5.5 hours, with the current controlled at 10 mA. The anode material was a magnesium rod and the cathode material was a carbon rod. The reaction progress was monitored by TLC. Then, the solvent was removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The solvent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. The obtained product was a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0075] The product prepared in this embodiment was identified as β-hydroxy-α,α-difluoroamide compound-4 using 1H NMR, 1C NMR, and mass spectrometry, with the following structural formula:

[0076]

[0077] The product purity was 99%, and the yield was 87%; its NMR data analysis was as follows: 1 H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 7.42 (d, J = 8.0Hz, 2H), 7.16 (d, J = 8.0Hz, 2H), 4.12 -4.06(m,1H),2.88-2.63(m,2H),2.33(s,3H),2.03-1.90(m,5H),1.82-1.73(m,1H). 13C NMR (100MHz, CDCl3) δ162.0 (t, J = 27.7Hz), 135.6, 133.3, 129.4, 120.4, 118.4 (t, J = 258.2Hz), 73.9 (t, J = 25.5Hz), 34.7, 24.6, 24.0, 21.0, 18.9. 19 F NMR (CDCl3, 376MHz): δ-112.5–121.3 (m, 2F).

[0078] Example 5:

[0079] This embodiment describes a method for preparing a β-hydroxy-α,α-difluoroamide compound, which is carried out according to the following steps:

[0080] 1. Under a nitrogen atmosphere at room temperature, mix 0.4 mmol of 2-bromo-2,2-difluoro(p-tolyl)acetamide, 2.0 mmol of benzaldehyde, 0.5 mmol of tetrabutyltetrafluoroborate amine, and 200 mg of... Molecular sieves were added to 4 mL of ultra-dry tetrahydrofuran and stirred for 10 min to obtain a mixed solution;

[0081] 2. Under room temperature and nitrogen atmosphere, the mixed solution obtained in step 1 was electrolyzed for 5.5 hours, with the current controlled at 10 mA. The anode material was a magnesium rod and the cathode material was a carbon rod. The reaction progress was monitored by TLC. Then, the solvent was removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The solvent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. The obtained product was a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0082] The product prepared in this embodiment was identified as β-hydroxy-α,α-difluoroamide compound-5 using 1H NMR, 1C NMR, and mass spectrometry, with the following structural formula:

[0083]

[0084] The product purity was 99%, and the yield was 80%; its NMR data analysis was as follows: 1 H NMR (400MHz, DMSO) δ10.40 (s, 1H), 7.59 (d, J = 8.4Hz, 2H), 7.49 (d, J = 6.8Hz, 2H), 7.45-7. 35(m,3H),7.18(d,J=8.4Hz,2H),6.57(d,J=5.6Hz,1H),5.28-5.20(m,1H),2.29(s,3H). 13C NMR (100MHz, DMSO) δ 162.5 (t, J = 29.0Hz), 137.4, 135.3, 134.3, 129.6, 128.8, 128.4, 121.3, 118.7 (t, J = 250.0Hz), 72.0 (t, J = 23.0Hz), 71.5, 21.0. 19 F NMR (CDCl3, 376MHz): δ-110.1-122.7 (m, 2F).

[0085] Example 6:

[0086] This embodiment describes a method for preparing a β-hydroxy-α,α-difluoroamide compound, which is carried out according to the following steps:

[0087] 1. Under a nitrogen atmosphere at room temperature, mix 0.4 mmol of 2-bromo-2,2-difluoro(p-tolyl)acetamide, 2.0 mmol of p-tolualdehyde, 0.5 mmol of tetrabutyltetrafluoroborate amine, and 200 mg of... Molecular sieves were added to 4 mL of ultra-dry tetrahydrofuran and stirred for 10 min to obtain a mixed solution;

[0088] 2. Under room temperature and nitrogen atmosphere, the mixed solution obtained in step 1 was electrolyzed for 5.5 hours, with the current controlled at 10 mA. The anode material was a magnesium rod and the cathode material was a carbon rod. The reaction progress was monitored by TLC. Then, the solvent was removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The solvent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. The obtained product was a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0089] The product prepared in this embodiment was identified as β-hydroxy-α,α-difluoroamide compound-6 using 1H NMR, 1C NMR, and mass spectrometry, with the following structural formula:

[0090]

[0091] The product purity was 99%, and the yield was 81%; its NMR data analysis was as follows: 1 H NMR (400MHz, DMSO) δ10.38(s,1H),7.59(d,J=8.4Hz,2H),7.36(d,J=7.6Hz,2H),7. 22-7.17(m,4H),6.48(d,J=5.6Hz,1H),5.22-5.14(m,1H),2.31(d,J=12.8Hz,6H). 13C NMR (100MHz, DMSO) δ162.5 (t, J = 26.9Hz), 138.1, 135.3, 134.4, 134.3, 129.6 ,129.0,128.3,121.2,118.7(t,J=261.3Hz),71.8(t,J=22.5Hz),21.3,21.0. 19 F NMR (CDCl3, 376MHz): δ-110.2-122.6 (m, 2F).

[0092] Example 7:

[0093] This embodiment describes a method for preparing a β-hydroxy-α,α-difluoroamide compound, which is carried out according to the following steps:

[0094] 1. Under a nitrogen atmosphere at room temperature, mix 0.4 mmol of 2-bromo-2,2-difluoro(p-tolyl)acetamide, 2.0 mmol of p-chlorobenzaldehyde, 0.5 mmol of tetrabutyltetrafluoroborate amine, and 200 mg of... Molecular sieves were added to 4 mL of ultra-dry tetrahydrofuran and stirred for 10 min to obtain a mixed solution;

[0095] 2. Under room temperature and nitrogen atmosphere, the mixed solution obtained in step 1 was electrolyzed for 5.5 hours, with the current controlled at 10 mA. The anode material was a magnesium rod and the cathode material was a carbon rod. The reaction progress was monitored by TLC. Then, the solvent was removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The solvent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. The obtained product was a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0096] The product prepared in this embodiment was identified as β-hydroxy-α,α-difluoroamide compound-7 using 1H NMR, 1C NMR, and mass spectrometry, with the following structural formula:

[0097]

[0098] The product purity was 99%, and the yield was 70%; its NMR data analysis was as follows: 1 H NMR (400MHz, DMSO) δ10.19(s,1H),7.35(d,J=8.0Hz,2H),7.26(s,4H),6.95(d,J=8.4Hz,2H),6.44(d,J=5.6Hz,1H),5.07-4.99(m,1H),2.07(s,3H). 13C NMR (100MHz, DMSO) δ162.2 (t, J = 27.6Hz), 136.4, 135.2, 134.4, 133.5, 130.2, 129.6, 128.5, 121.3, 118.5 (t, J = 251.1Hz), 71.3, (t, J = 22.9Hz), 21.0. 19 F NMR (CDCl3, 376MHz): δ-110.0-122.7 (m, 2F).

[0099] Example 8:

[0100] This embodiment describes a method for preparing a β-hydroxy-α,α-difluoroamide compound, which is carried out according to the following steps:

[0101] 1. Under a nitrogen atmosphere at room temperature, mix 0.4 mmol of 2-bromo-2,2-difluoro(p-tolyl)acetamide, 2.0 mmol of ethyl acrylate, 0.5 mmol of tetrabutyltetrafluoroborate, and 200 mg of... Molecular sieves were added to 4 mL of ultra-dry tetrahydrofuran and stirred for 10 min to obtain a mixed solution;

[0102] 2. Under room temperature and nitrogen atmosphere, the mixed solution obtained in step 1 was electrolyzed for 5.5 hours, with the current controlled at 10 mA. The anode material was a magnesium rod and the cathode material was a carbon rod. The reaction progress was monitored by TLC. Then, the solvent was removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The solvent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. The obtained product was a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0103] The product prepared in this embodiment was identified as β-hydroxy-α,α-difluoroamide compound-8 using 1H NMR, 1C NMR, and mass spectrometry, with the following structural formula:

[0104]

[0105] The product purity was 99%, and the yield was 40%; its NMR data analysis was as follows: 1 H NMR (400MHz, CDCl3) δ7.95 (s, 1H), 7.44 (d, J = 8.4Hz, 2H), 7.17 (d, J = 8.4Hz, 2H) ,4.16(q,J=7.2Hz,2H),2.61-2.50(m,4H),2.33(s,3H),1.26(t,J=6.8Hz,3H). 13C NMR (100MHz, CDCl3) δ171.7, 161.7 (t, J = 28.0Hz), 135.5, 133.4, 129.8, 120.3, 120.0 (t, J = 253.0Hz), 61.0, 29.7 (t, J = 24.0Hz), 27.0, 27.0, 26.9, 21.0, 14.2. 19 F NMR (CDCl3, 376MHz): δ-106.2 (t, 2F).

[0106] Regarding gram-scale reactions, the specific procedures are as follows:

[0107] 1. Under a nitrogen atmosphere at room temperature, mix 2 mmol of 2-bromo-2,2-difluoro(p-tolyl)acetamide, 10.0 mmol of acetone, 2.5 mmol of tetrabutyltetrafluoroborate amine, and 1000 mg of... Molecular sieves were added to 20 mL of ultra-dry tetrahydrofuran and stirred for 10 min to obtain a mixed solution;

[0108] 2. Under room temperature and nitrogen atmosphere, the mixed solution obtained in step 1 was electrolyzed for 5.5 hours, with the current controlled at 10 mA. The anode material was a magnesium rod and the cathode material was a carbon rod. The reaction progress was monitored by TLC. Then, the solvent was removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The solvent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. The obtained product was a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation.

[0109] The prepared product was identified as β-hydroxy-α,α-difluoroamide compound-1 by proton NMR, carbon NMR, and mass spectrometry, with the following structural formula:

[0110]

[0111] The product purity was 99%, and the yield was 73%; its NMR data analysis was as follows: 1 H NMR (400MHz, CDCl3) δ8.18 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 3.31 (s, 1H), 2.34 (s, 3H), 1.42 (s, 6H). 13 C NMR (100MHz, CDCl3) δ 162.1 (t, J = 28.8 Hz), 135.6, 133.3, 129.7, 120.5, 118.3 (t, J = 259.1 Hz), 73.2 (t, J = 25.1 Hz), 23.2, 21.0. 19 F NMR (CDCl3, 376MHz): δ-117.8 (2F, s).

[0112] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

1. A method for preparing a β-hydroxy-α,α-difluoroamide compound, characterized in that... This method is specifically carried out in the following steps: I. Under room temperature and a nitrogen atmosphere, bromodifluoroamide compounds, electrophilic compounds, n Bu4NBF4 and 5Å molecular sieves were added to an ultra-dry solvent and stirred until homogeneous to obtain a mixed solution. The electrophilic reagent compound is an aldehyde compound; 2. Under a nitrogen atmosphere and at room temperature, the mixed solution obtained in step 1 is electrolyzed for 5.0-5.5 h, then the solvent is removed by rotary evaporation, and then separated and purified by thin-layer chromatography. The product obtained is a β-hydroxy-α,α-difluoroamide compound, thus completing the preparation. The aldehyde compounds mentioned in step one are propionaldehyde, butyraldehyde, pentanaldehyde, cyclobutyraldehyde, cyclopentanaldehyde, 4-aldehyde tetrahydropyran, isobutyraldehyde, benzaldehyde, p-methylbenzaldehyde, p-chlorobenzaldehyde, or biphenylaldehyde; The bromodifluoroamide compound mentioned in step one is 2-bromo-2,2-difluoro-N-(p-tolyl)acetamide, 2-bromo-2,2-difluoro-N-(p-isopropylphenyl)acetamide, 2-bromo-2,2-difluoro-N-(phenyl)acetamide, or 2-bromo-2,2-difluoro-N-(p-fluorophenyl)acetamide.

2. The method for preparing a β-hydroxy-α,α-difluoroamide compound according to claim 1, characterized in that... The 5Å molecular sieve powdered desiccant described in step one.

3. The method for preparing a β-hydroxy-α,α-difluoroamide compound according to claim 1, characterized in that... The ultra-dry solvent mentioned in step one is ultra-dry tetrahydrofuran.

4. The method for preparing a β-hydroxy-α,α-difluoroamide compound according to claim 1, characterized in that... The ratio of bromodifluoroamide compounds to ultra-dry solvent in step one is (0.40~0.42) mmol : 4 mL; the ratio of aldehyde compounds to ultra-dry solvent is (2.00~2.02) mmol : 4 mL. n The ratio of Bu4NBF4 to ultra-dry solvent is (162~165) mg : 4 mL; the ratio of 5Å molecular sieve to ultra-dry solvent is (198~200) mg : 4 mL.

5. The method for preparing a β-hydroxy-α,α-difluoroamide compound according to claim 1, characterized in that... Step 2: Control the current to 10mA; the anode material is a magnesium rod, and the cathode material is a carbon rod. The solvent used for separation and purification was a mixture of petroleum ether and ethyl acetate.

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