Preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds

Abstract

The present invention discloses a preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds, which comprises the following steps: (1) subjecting a phenolic compound II and 3-halo-3,3-difluoropropanoyl chloride to an esterification reaction under the action of a base to obtain a compound III, 3-halo-3,3-difluoropropionic acid aryl ester; (2) subjecting the compound III, 3-halo-3,3-difluoropropionic acid aryl ester to a ring-closing reaction with sodium formaldehyde bisulfite to obtain a compound I, 4,4-difluoro-3,4-dihydrocoumarin compounds. The present invention can synthesize the target product, 4,4-difluoro-3,4-dihydrocoumarin compounds, by a two-step method. The method of the present invention is simple to operate, has a wide substrate adaptability, and a high product yield.

Description

Technical Field

[0001] The present invention relates to a method for preparing 4,4-difluoro-3,4-dihydrocoumarin compounds, belonging to the technical field of organic synthesis. Background Art

[0002] Fluorine-containing compounds often exhibit unique physical and chemical properties, which are mainly due to the many unique properties of fluorine atoms: such as small volume, strong electronegativity, stronger bonding force with carbon than halogen atoms other than hydrogen and fluorine, inflexible bond distance of carbon-fluorine bond, low polarizability, small dispersion force of intermolecular interaction with other substances, high hydrophobicity, high lipophilicity, etc. Therefore, after introducing fluorine atoms into organic small molecules, their lipophilicity can be improved, and if used as drugs, their metabolic stability and biocompatibility can be enhanced; in the field of materials science, the introduction of fluorine atoms can also change the properties of materials, endowing them with unique properties.

[0003] Dihydrocoumarin compounds are widely present in natural products and bioactive substances and are the core skeletons of many natural products. Due to their wide range of physiological activities such as anticoagulant activity, anti-cardiovascular disease activity, anti-HIV activity, anti-tumor activity, antioxidant activity, anti-microbial bacterial activity, anti-inflammatory activity, etc., in recent years, the synthesis of dihydrocoumarin skeletons has attracted more and more attention, and many effective methods for preparing dihydrocoumarin compounds have been reported. However, there are few reports on directly introducing fluorine atoms into the dihydropyran ring of the dihydrocoumarin skeleton, and instead, fluorine-containing groups are all introduced outside the structure of the aromatic ring or the coumarin compound skeleton. Summary of the Invention

[0004] Object of the Invention: The object of the present invention is to provide a simple and efficient method for preparing 4,4-difluoro-3,4-dihydrocoumarin compounds, which can obtain the target product in only two steps.

[0005] Technical Solution: The method for preparing 4,4-difluoro-3,4-dihydrocoumarin compounds according to the present invention includes the following steps:

[0006] (1) Subjecting a phenolic compound II and 3-halo-3,3-difluoropropionyl chloride to an esterification reaction under the action of a base to obtain a compound III, 3-halo-3,3-difluoropropionic acid aryl ester;

[0007] (2) Subjecting the compound III, 3-halo-3,3-difluoropropionic acid aryl ester, to a ring-closing reaction with sodium bisulfite formaldehyde to obtain a compound I, 4,4-difluoro-3,4-dihydrocoumarin compound;

[0008] The synthesis route is as follows:

[0009]

[0010] Among them, R is hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl or benzyl; X is Cl, Br or I.

[0011] Among them, in step (1), the base is pyridine, trialkyl tertiary amine, aromatic tertiary amine; the base is preferably pyridine or triethylamine.

[0012] Among them, in step (1), the reaction conditions are as follows: carried out in an inert gas atmosphere, the reaction temperature is -20°C to 20°C; the reaction solvent can dissolve the raw materials, and the solvent is preferably toluene; 3-halo-3,3-difluoropropionyl chloride is in excess, and the molar ratio of 3-halo-3,3-difluoropropionyl chloride, phenolic compound II and the base is 1-1.6:1:1; the reaction process is detected by TLC, and the developing agent is a mixed solvent of petroleum ether and ethyl acetate mixed in a volume ratio of 4:1.

[0013] Among them, in step (2), the reaction temperature is 40°C to 90°C.

[0014] Among them, in step (2), the reaction solvent is a mixed solvent of DMF and water, and the mixed volume ratio of DMF and water is 1-3:1.

[0015] Among them, in step (2), the molar ratio of sodium bisulfite formaldehyde to compound III is 1-4:1; the reaction process is detected by TLC, and the developing agent is a mixed solvent of petroleum ether and ethyl acetate mixed in a volume ratio of 4:1.

[0016] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages: The present invention can obtain dihydrocoumarin compounds with 2 fluorine atoms simultaneously introduced at the 4-position of the dihydropyran ring of dihydrocoumarin by a two-step method. Such compounds can combine the characteristics of fluorine atoms and the medicinal value of dihydrocoumarin compounds, thereby more effectively improving the bioavailability and drug activity of dihydrocoumarin compounds; the method of the present invention is simple to operate, has a wide substrate adaptability, and a high product yield. Specific embodiments

[0017] Example 1

[0018] Preparation of Compound III, phenyl 3-bromo-3,3-difluoropropionate: Under nitrogen protection, 50 mmol of phenol (Compound II, R is hydrogen), 50 mmol of pyridine and 30 mL of toluene were added to a reaction flask. After stirring at room temperature for 0.5 h, the temperature of the reaction system was lowered to 0 °C. 50 mmol of 3-bromo-3,3-difluoropropanoyl chloride was dissolved in 20 mL of toluene, and the toluene solution of 3-bromo-3,3-difluoropropanoyl chloride was slowly added dropwise to the above-mentioned toluene solution containing phenol. After the addition, the reaction was stirred at room temperature, and the reaction progress was monitored by TLC. The developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After about 0.5 h, the reaction was completed. 100 mL of water and 100 mL of toluene were added to the reaction solution, stirred for 10 min, and separated. The organic layer was collected and washed with 30 mL of 0.5 M dilute hydrochloric acid and 100 mL of saturated brine respectively, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain light yellow Compound III, phenyl 3-bromo-3,3-difluoropropionate, with a yield of 70%. The obtained product could be directly used for the next reaction without purification.

[0019] The structure of the phenyl 3-bromo-3,3-difluoropropionate obtained in Example 1 was characterized by MS and 1 H NMR. ESI-LRMS m / z: 265.1 [M+H] + , 1 H NMR (500 MHz, CDCl 3 ) δ: 7.25~7.47 (m, 3H), 7.05~7.16 (m, 2H), 2.58 (t, J = 41.8 Hz, 2H).

[0020] 3-Bromo-3,3-difluoropropanoyl chloride was prepared by the acylation reaction of 3-bromo-3,3-difluoropropionic acid with thionyl chloride. The specific method was as follows: 100 mmol of 3-bromo-3,3-difluoropropionic acid, 200 mL of benzene and 3 drops of DMF were added to a reaction flask. After stirring evenly, 15 mL of thionyl chloride was added thereto, and the reaction was refluxed for 3 h. Benzene and unreacted thionyl chloride were evaporated under reduced pressure to obtain 3-bromo-3,3-difluoropropanoyl chloride. Among them, 3-bromo-3,3-difluoropropionic acid: CAS: 130312-65-1, was purchased from Nanjing Shizhou Biotechnology Co., Ltd. Similarly, 3-chloro-3,3-difluoropropanoyl chloride was prepared by the acylation reaction of 3-chloro-3,3-difluoropropionic acid with thionyl chloride; 3-iodo-3,3-difluoropropanoyl chloride was prepared by the acylation reaction of 3-iodo-3,3-difluoropropionic acid with thionyl chloride.

[0021] Example 2

[0022] Preparation of Compound III Phenyl 3-bromo-3,3-difluoropropionate: Under nitrogen protection, 50 mmol of phenol (Compound II, R is hydrogen), 50 mmol of pyridine and 30 mL of toluene were added to a reaction flask. After stirring at room temperature for 0.5 h, the temperature of the reaction system was lowered to 0 °C. 65 mmol of 3-bromo-3,3-difluoropropanoyl chloride was dissolved in 20 mL of toluene, and the toluene solution of 3-bromo-3,3-difluoropropanoyl chloride was slowly added dropwise to the above toluene solution containing phenol. After the addition, the reaction was stirred at room temperature, and the reaction progress was monitored by TLC. The developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After the reaction was completed in about 0.5 h, 100 mL of water and 100 mL of toluene were added to the reaction solution, stirred for 10 min, and separated. The organic layer was collected and washed with 30 mL of 0.5 M dilute hydrochloric acid and 100 mL of saturated brine respectively, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain light yellow Compound III Phenyl 3-bromo-3,3-difluoropropionate with a yield of 86%. The obtained product could be directly used for the next reaction without purification.

[0023] Example 3

[0024] Preparation of Compound III Phenyl 3-bromo-3,3-difluoropropionate: Under nitrogen protection, 50 mmol of phenol (Compound II, R is hydrogen), 50 mmol of pyridine and 30 mL of toluene were added to a reaction flask. After stirring at room temperature for 0.5 h, the temperature of the reaction system was lowered to 0 °C. 80 mmol of 3-bromo-3,3-difluoropropanoyl chloride was dissolved in 20 mL of toluene, and the toluene solution of 3-bromo-3,3-difluoropropanoyl chloride was slowly added dropwise to the above toluene solution containing phenol. After the addition, the reaction was stirred at room temperature, and the reaction progress was monitored by TLC. The developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After the reaction was completed in about 0.5 h, 100 mL of water and 100 mL of toluene were added to the reaction solution, stirred for 10 min, and separated. The organic layer was collected and washed with 30 mL of 0.5 M dilute hydrochloric acid and 100 mL of saturated brine respectively, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain light yellow Compound III Phenyl 3-bromo-3,3-difluoropropionate with a yield of 93%. The obtained product could be directly used for the next reaction without purification.

[0025] Example 4

[0026] Preparation of Compound III, phenyl 3-bromo-3,3-difluoropropionate: Under nitrogen protection, 50 mmol of phenol (Compound II, where R is hydrogen), 50 mmol of pyridine, and 30 mL of toluene were added to a reaction flask. After stirring at room temperature for 0.5 h, the temperature of the reaction system was lowered to 0 °C. 70 mmol of 3-bromo-3,3-difluoropropanoyl chloride was dissolved in 20 mL of ethyl acetate, and the ethyl acetate solution of 3-bromo-3,3-difluoropropanoyl chloride was slowly added dropwise to the toluene solution containing phenol mentioned above. After the addition, the reaction was stirred at room temperature, and the reaction progress was monitored by TLC. The developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After about 0.5 h when the reaction was completed, 100 mL of water and 100 mL of toluene were added to the reaction solution, stirred for 10 min, and then separated. The organic layer was collected and washed with 30 mL of 0.5 M dilute hydrochloric acid and 100 mL of saturated brine respectively, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain light yellow Compound III, phenyl 3-bromo-3,3-difluoropropionate, with a yield of 92%. The obtained product can be directly used for the next reaction without purification.

[0027] From the yields of the products in Examples 1 - 4, it can be seen that as the molar ratio of 3-bromo-3,3-difluoropropanoyl chloride to phenol increases, the reaction is more complete, which is beneficial to improving the yield of the product.

[0028] Based on the reaction conditions in Example 4 (i.e., the molar ratio of 3-halo-3,3-difluoropropanoyl chloride, phenolic compound II, and base is 1.4:1:1), 3-bromo-3,3-difluoropropanoyl chloride can be replaced by 3-chloro-3,3-difluoropropanoyl chloride or 3-iodo-3,3-difluoropropanoyl chloride; R in Compound II can be replaced by halogen, C 1 ~C 4 alkyl, C 1 ~C 4 haloalkyl, C 1 ~C 4 alkoxy, C3 - C6 cycloalkyl, phenyl, benzyl, etc.; thus, a series of Compound III, aryl 3-halo-3,3-difluoropropionates can be obtained; pyridine can be replaced by tertiary amines such as triethylamine, tributylamine, N,N-dimethylaniline, etc.; the reaction system temperature can be adjusted between -20 °C and 20 °C; with other reaction conditions unchanged, some experimental results are shown in the following table.

[0029] Table 1 shows the preparation conditions and results of Examples 5 - 49

[0030]

[0031]

[0032]

[0033] Example 50

[0034] Preparation of Compound I 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III 3-bromo-3,3-difluoropropionic acid phenyl ester prepared in Example 4, 50 mmol of sodium bisulfite formaldehyde, 100 mL of DMF and 100 mL of water were successively added. The reaction system was heated to 90 °C with stirring and kept stirring for reaction; the progress of the reaction was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate mixed in a volume ratio of 4:1. After 8 h, the reaction was completed, the heating was stopped, and it was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, stirred for 10 min, and the layers were separated. The organic layer was collected, washed 3 times with 120 mL of saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I 4,4-difluoro-3,4-dihydrocoumarin with a yield of 50% (calculated based on Compound II).

[0035] The structure of 4,4-difluoro-3,4-dihydrocoumarin obtained in Example 50 was characterized by MS and 1 1H NMR. ESI-LRMS m / z: 185.2 [M+H] + , 1 1H NMR (500 MHz, CDCl 3 3) δ: 3.21 (t, J = 2.2 Hz, 2H), 7.27 - 7.41 (m, 4H).

[0036] Example 51

[0037] Preparation of Compound I 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III 3-bromo-3,3-difluoropropionic acid phenyl ester prepared in Example 4, 100 mmol of sodium bisulfite formaldehyde, 100 mL of DMF and 100 mL of water were successively added. The reaction system was heated to 90 °C with stirring and kept stirring for reaction; the progress of the reaction was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate mixed in a volume ratio of 4:1. After 7 h, the reaction was completed, the heating was stopped, and it was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, stirred for 10 min, and the layers were separated. The organic layer was collected, washed 3 times with 120 mL of saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I 4,4-difluoro-3,4-dihydrocoumarin with a yield of 61% (calculated based on Compound II).

[0038] Example 52

[0039] Preparation of Compound I, 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III, phenyl 3-bromo-3,3-difluoropropionate prepared in Example 4, 150 mmol of sodium bisulfite formaldehyde, 100 mL of DMF, and 100 mL of water were successively added. The reaction system was heated to 90 °C with stirring and maintained at this temperature with stirring for the reaction. The progress of the reaction was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After 6 h, the reaction was completed. Heating was stopped and the reaction mixture was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, and the mixture was stirred for 10 min. The layers were separated, and the organic layer was collected. The organic layer was washed three times with 120 mL of saturated brine, and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, and the mixture was stirred and allowed to stand at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I, 4,4-difluoro-3,4-dihydrocoumarin, with a yield of 68% (calculated based on Compound II).

[0040] Example 53

[0041] Preparation of Compound I, 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III, phenyl 3-bromo-3,3-difluoropropionate prepared in Example 4, 200 mmol of sodium bisulfite formaldehyde, 100 mL of DMF, and 100 mL of water were successively added. The reaction system was heated to 90 °C with stirring and maintained at this temperature with stirring for the reaction. The progress of the reaction was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After 6 h, the reaction was completed. Heating was stopped and the reaction mixture was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, and the mixture was stirred for 10 min. The layers were separated, and the organic layer was collected. The organic layer was washed three times with 120 mL of saturated brine, and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, and the mixture was stirred and allowed to stand at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I, 4,4-difluoro-3,4-dihydrocoumarin, with a yield of 69% (calculated based on Compound II).

[0042] Example 54

[0043] Preparation of Compound I 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III 3-bromo-3,3-difluoropropionic acid phenyl ester prepared in Example 4, 150 mmol of sodium bisulfite formaldehyde, 100 mL of DMF and 100 mL of water were successively added. The reaction system was heated to 40 °C with stirring and kept stirring for reaction; the reaction progress was detected by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate mixed at a volume ratio of 4:1. After 10 h, the reaction was completed. Heating was stopped and the mixture was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, and the mixture was stirred for 10 min. The layers were separated, and the organic layer was collected. The organic layer was washed 3 times with 120 mL of saturated brine, and the organic layers were combined and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, and the mixture was stirred and allowed to stand at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I 4,4-difluoro-3,4-dihydrocoumarin, and the yield was 39% (calculated based on Compound II).

[0044] Example 55

[0045] Preparation of Compound I 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III 3-bromo-3,3-difluoropropionic acid phenyl ester prepared in Example 4, 150 mmol of sodium bisulfite formaldehyde, 100 mL of DMF and 100 mL of water were successively added. The reaction system was heated to 60 °C with stirring and kept stirring for reaction; the reaction progress was detected by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate mixed at a volume ratio of 4:1. After 8 h, the reaction was completed. Heating was stopped and the mixture was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, and the mixture was stirred for 10 min. The layers were separated, and the organic layer was collected. The organic layer was washed 3 times with 120 mL of saturated brine, and the organic layers were combined and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, and the mixture was stirred and allowed to stand at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I 4,4-difluoro-3,4-dihydrocoumarin, and the yield was 54% (calculated based on Compound II).

[0046] Example 56

[0047] Preparation of Compound I 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III 3-bromo-3,3-difluoropropionic acid phenyl ester prepared in Example 4, 150 mmol of sodium bisulfite formaldehyde, 100 mL of DMF and 100 mL of water were successively added. The reaction system was heated to 80 °C with stirring and kept stirring for reaction; the reaction progress was detected by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate mixed at a volume ratio of 4:1. After 6 h, the reaction was completed, heating was stopped, and it was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, stirred for 10 min, separated, and the organic layer was collected. The organic layer was washed 3 times with 120 mL of saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added again, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I 4,4-difluoro-3,4-dihydrocoumarin, and the yield was 65% (calculated based on Compound II).

[0048] Example 57

[0049] Preparation of Compound I 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III 3-bromo-3,3-difluoropropionic acid phenyl ester prepared in Example 4, 150 mmol of sodium bisulfite formaldehyde, 150 mL of DMF and 50 mL of water were successively added. The reaction system was heated to 90 °C with stirring and kept stirring for reaction; the reaction progress was detected by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate mixed at a volume ratio of 4:1. After 6 h, the reaction was completed, heating was stopped, and it was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, stirred for 10 min, separated, and the organic layer was collected. The organic layer was washed 3 times with 120 mL of saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added again, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I 4,4-difluoro-3,4-dihydrocoumarin, and the yield was 64% (calculated based on Compound II).

[0050] Example 58

[0051] On the basis of the reaction conditions in Example 52 (i.e., the reaction temperature was 90 °C; the reaction solvent was a mixed solution of DMF and water at a volume ratio of 1:1; the molar ratio of sodium bisulfite formaldehyde to Compound III was 3:1), Compound III 3-bromo-3,3-difluoropropionic acid phenyl ester prepared in Example 4 was replaced with 3-bromo-3,3-difluoropropionic acid aryl ester prepared in Examples 5 - 22, and other reaction conditions remained unchanged, and a series of Compound I 4,4-difluoro-3,4-dihydrocoumarin could be prepared.

[0052] Example 59

[0053] Preparation of Compound I, 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III, 3-chloro-3,3-difluoropropionic acid phenyl ester prepared in Example 23, 150 mmol of sodium bisulfite formaldehyde, 100 mL of DMF, and 100 mL of water were successively added. The reaction system was heated to 90 °C with stirring and kept stirring for the reaction; the progress of the reaction was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After 8 h, the reaction was completed, the heating was stopped, and it was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, stirred for 10 min, and then separated. The organic layer was collected, washed 3 times with 120 mL of saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I, 4,4-difluoro-3,4-dihydrocoumarin, with a yield of 31% (calculated based on Compound II).

[0054] Example 60

[0055] Preparation of Compound I, 4,4-difluoro-3,4-dihydrocoumarin: To 50 mmol of Compound III, 3-iodo-3,3-difluoropropionic acid phenyl ester prepared in Example 32, 150 mmol of sodium bisulfite formaldehyde, 100 mL of DMF, and 100 mL of water were successively added. The reaction system was heated to 90 °C with stirring and kept stirring for the reaction; the progress of the reaction was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After 5 h, the reaction was completed, the heating was stopped, and it was cooled to room temperature. 400 mL of ethyl acetate and 400 mL of water were added to the reaction solution, stirred for 10 min, and then separated. The organic layer was collected, washed 3 times with 120 mL of saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure until about 40 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound I, 4,4-difluoro-3,4-dihydrocoumarin, with a yield of 67% (calculated based on Compound II).

[0056] Example 61

[0057] On the basis of the reaction conditions of Example 60 (i.e., the reaction temperature is 90 °C; the reaction solvent is a mixed solution of DMF and water with a volume ratio of 1:1; the molar ratio of sodium formaldehyde sulfoxylate to Compound III is 3:1), replace the 3-iodo-3,3-difluoropropionic acid phenyl ester prepared in Example 32 with the 3-iodo-3,3-difluoropropionic acid aryl ester prepared in Examples 33 to 38 for Compound III, and keep other reaction conditions unchanged, then a series of Compound I, 4,4-difluoro-3,4-dihydrocoumarin can be prepared.

Claims

1. A preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds, characterized in that, it comprises the following steps: (1) Subject the phenolic compound II and 3-halo-3,3-difluoropropanoyl chloride to an esterification reaction under the action of a base to obtain the compound III, 3-halo-3,3-difluoropropionic acid aryl ester; wherein, the phenolic compound II is 4-fluorophenol; the 3-halo-3,3-difluoropropanoyl chloride is 3-bromo-3,3-difluoropropanoyl chloride; (2) Subject the compound III, 3-halo-3,3-difluoropropionic acid aryl ester, and sodium formaldehyde bisulfite to a ring-closing reaction to obtain the compound I, 4,4-difluoro-3,4-dihydrocoumarin compounds; The synthetic route is: ； wherein, R is fluorine; X is Br.

2. The preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds according to claim 1, characterized in that: In step (1), the base is one of pyridine, trialkyl tertiary amine or aromatic tertiary amine.

3. The preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds according to claim 1, characterized in that: In step (1), the reaction conditions are: carried out in an inert gas atmosphere, and the reaction temperature is -20°C to 20°C.

4. The preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds according to claim 1, characterized in that: In step (1), the molar ratio of 3-halo-3,3-difluoropropanoyl chloride, phenolic compound II and the base is 1 to 1.6∶1∶1.

5. The preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds according to claim 1, characterized in that: In step (1), the reaction process is detected by TLC, and the selected developing agent is a mixed solvent of petroleum ether and ethyl acetate mixed at a volume ratio of 4∶1.

6. The preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds according to claim 1, characterized in that: In step (2), the reaction temperature is 40°C to 90°C.

7. The preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds according to claim 1, characterized in that: In step (2), the reaction solvent is a mixed solvent of DMF and water, and the mixed volume ratio of DMF and water is 1 to 3∶1.

8. The preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds according to claim 1, characterized in that: In step (2), the molar ratio of sodium formaldehyde bisulfite to compound III is 1 to 4∶1.

9. The preparation method of 4,4-difluoro-3,4-dihydrocoumarin compounds according to claim 1, characterized in that: In step (2), the reaction process is detected by TLC, and the selected developing agent is a mixed solvent of petroleum ether and ethyl acetate mixed at a volume ratio of 4∶1.

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