A method for the difluoromethyl etherification reaction of fatty alcohols and its application

Abstract

The present invention discloses a method for the difluoromethyl etherification reaction of fatty alcohols and its application, which relates to the technical field of the synthesis of alkyl difluoromethyl ether compounds. A method for the difluoromethyl etherification reaction of fatty alcohols, in which a fatty alcohol compound and a difluoromethyl reagent undergo an etherification reaction in a solvent to obtain a fatty alcohol difluoromethyl ether compound; the structural formula of the difluoromethyl reagent is as follows: The present invention can carry out an efficient difluoromethyl etherification reaction by simply stirring a fatty alcohol compound and a difluoromethyl reagent in a solvent at room temperature without adding any catalyst, initiator, activator, additive or base. The method is simple, the process is simple, green and environmentally friendly, low in cost, highly efficient in reaction, and economically practical.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of alkyl difluoromethyl ether compounds, and particularly relates to a method for the difluoromethyl etherification reaction of fatty alcohols and its application. Background Art

[0002] The introduction of difluoromethyl building blocks can endow compounds with special physical, chemical and biological properties, and can often effectively improve the biological activity and target specificity of compounds, which makes it play a very important role in the design of innovative drugs. Therefore, introducing a difluoromethyl group into organic small molecules is an important method and approach for drug structure modification and transformation to obtain potential drug molecules. In particular, difluoromethoxy building blocks (OCF2H) often appear in drug molecules, such as enzyme inhibitors / agonists, anti-AIDS drugs, antibacterial drugs and anesthetics.

[0003] The strong electron-withdrawing property of difluoromethoxy (OCF2H) can reduce the electron density of drug molecules, thereby reducing the possibility of drug molecules being oxidized and metabolized by cytochrome P450 enzymes in the body and prolonging the half-life of the drug. In addition, the proton in the OCF2H group as a hydrogen bond donor can improve the affinity and selectivity of drug molecules for targets, thereby improving the pharmacological activity and specificity of drugs. In recent years, a variety of alkyl difluoromethyl ether compounds with antiviral activity and kinase inhibitory activity have applied for compound patents. Such as T cell activator A [WO2020006018 A1], RORγ antagonist B [WO2020011147A1], anti-hepatitis B virus (HBV) compounds C [WO2020086533 A1] and D [WO2019086142 A1], kinase inhibitors E [WO2019074962A1] and F [WO 2019147782 A1], anti-HIV G [WO 2019209667 A1] and H [EP3305789A1], MCL-1 inhibitor I [US2019352271A1], etc.

[0004] Difluoromethyl ether compounds have never been found in nature or natural products, and the only way to obtain them currently is through artificial synthesis. However, due to the lack of environmentally friendly, stable and efficient difluoromethyl reagents, there are currently not many effective synthesis methods for difluoromethyl ether compounds. Although some methods have been reported, due to the inherent defects of the fluorination reagents and their fluorination methods themselves, most of them have problems such as low efficiency, low yield, poor generality, large waste, and serious pollution. For example, Freon R22 gas (HCF2Cl) has a large usage amount, low efficiency, destroys the ozone layer (ODS), and has great environmental harm. Therefore, it is particularly important to develop convenient, efficient and environmentally friendly green synthesis methods, which have high academic significance and application value. Moreover, most of the existing methods are used for the O-difluoromethylation of (thio)phenols to prepare aryl difluoromethyl (thio)ethers. However, the method for preparing alkyl difluoromethyl (thio)ethers by the O-difluoromethylation reaction of aliphatic alcohols is still very lacking.

[0005] In 2016, the Shen Qilong group used difluoromethylsulfonium ylide as a difluoromethyl reagent to carry out difluoromethyl etherification of alkyl alcohols [J. Zhu, Y. Liu and Q. Shen, Angew. Chem., Int. Ed., 2016, 55, 9050]. In 2017, Professor Hu Jinbo et al. used Me3SiCF2Br as a difluorocarbene precursor reagent to achieve difluoromethyl etherification of alkyl alcohols [Q. Xie, C. Ni, R. Zhang, L. Li, J. Rong and J. Hu, Angew. Chem., Int. Ed., 2017, 56, 3206]. In 2016, Mykhailiuk et al. reported a copper-catalyzed difluoromethyl etherification of aliphatic alcohols using FSO2CF2COOH [Kostiantyn Levchenko, Olexandr P. Datsenko, Oleh Serhiichuk, Andrei Tolmachev, Viktor O. Iaroshenko, and Pavel K. Mykhailiuk, J. Org. Chem. 2016, 81, 5803-5813]. In 2019, a stable S-(difluoromethyl) diaryl sulfonium salt was disclosed as a difluorocarbene precursor reagent to achieve the difluoromethyl etherification and derivation of aliphatic alcohols [G. K. Liu, X. Li, W. B. Qin, X. S. Peng, Henry. N. C. Wong, L. Zhang, X. Zhang, Chem. Commun. 2019, 55(52), 7446-7449]. However, these several reported methods require the addition of a variety of excessive activators and / or bases, or excessive fluorinating agents, or require transition metal catalysts.

[0006] Therefore, it is particularly important to develop a greener, more economical and efficient method for the difluoromethyl etherification of fatty alcohols, which has high practical value and broad application prospects. Summary of the Invention

[0007] Aiming at the lack of existing methods for the difluoromethyl etherification of fatty alcohols, and the existing difluoromethyl etherification methods require the addition of a variety of excessive activators and / or bases, or excessive fluorinating agents, or require transition metal catalysts, which are not green, environmentally friendly and economical technical problems.

[0008] The present invention aims to invent a method for the difluoromethyl etherification reaction of fatty alcohols, which can carry out an etherification reaction between fatty alcohol compounds and special difluoromethyl reagents in a solvent without adding a phase transfer catalyst. During the reaction process, no excessive activators and / or bases are added, and no excessive fluorinating agent or transition metal catalyst is required, which is green, environmentally friendly, low-cost and economical.

[0009] The technical route and method of the present invention are realized through the following technical solutions: The present invention provides a method for the difluoromethyl etherification reaction of fatty alcohols, in which fatty alcohol compounds and difluoromethyl reagents undergo an etherification reaction in a solvent to obtain fatty alcohol difluoromethyl ether compounds;

[0010] The structural formula of the difluoromethyl reagent is as follows:

[0011]

[0012] Preferably, the solvent is selected from at least one of ethyl acetate, ethyl formate, acetonitrile, dichloromethane, chloroform, and tetrahydrofuran. More preferably, the solvent is dichloromethane.

[0013] Preferably, the reaction temperature of the etherification reaction is -30 to 80 °C. More preferably, the reaction temperature of the etherification reaction is 0 - 50 °C.

[0014] Preferably, the reaction time of the etherification reaction is 6 - 24 h.

[0015] Preferably, water is added during the etherification reaction.

[0016] The present invention also provides the application of the above-mentioned method for the difluoromethyl etherification reaction of fatty alcohols in the preparation of fatty alcohol difluoromethyl ether compounds.

[0017] Beneficial Effects:

[0018] The present invention uses a special difluoromethyl reagent to carry out an etherification reaction with fatty alcohol compounds in a solvent. During the reaction process, no catalysts, initiators, activators, additives and / or bases, or excessive fluorinating agents need to be added. At the same time, the reaction has a high yield and has the characteristics of being green, environmentally friendly, economical, convenient and efficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for the description of the embodiments will be briefly introduced below. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0020] Figure 1 It is a schematic diagram of the implementation process of the preparation reaction of the difluoromethyl reagent of the present invention;

[0021] Figure 2 It is a schematic diagram of the implementation process of the method for the difluoromethyl etherification reaction of fatty alcohols of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0023] It should be understood that when used in this specification and the appended claims, the terms "comprises" and "comprising" indicate the presence of the described features, wholes, steps, operations, elements, but do not exclude the presence or addition of one or more other features, wholes, steps, operations, elements and / or their combinations.

[0024] It should also be understood that the terms used in this specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. It should be further understood that the term " / and" used in this specification of the present invention and the appended claims refers to any combination and all possible combinations of one or more of the related listed items, and includes these combinations.

[0025] I. Synthesis of Difluoromethyl Reagent

[0026] As Figure 1 , the implementation process of the synthesis of the difluoromethyl reagent:

[0027] The first step: Implementation process Take a dry 500 mL round-bottom flask, add 2-bromobenzenethiol (5.7 g, 30.0 mmol, 1.0 eq.), then add 100 mL of pure water and 100 mL of acetonitrile. After adding a stir bar of appropriate size, add sodium hydroxide (3.6 g, 90.0 mmol, 3.0 eq.) at zero degree Celsius. After 10 minutes, add diethyl (bromodifluoromethyl)phosphonate (16.0 g, 60.0 mmol, 2.0 eq.) dropwise. React overnight. After completion of the reaction, extract the reaction solution twice with 100 mL of petroleum ether, collect the petroleum ether, remove the solvent by distillation under reduced pressure, and purify the crude product by silica gel column chromatography to obtain 2-bromo-(difluoromethyl)phenyl sulfide. [1-3] 。

[0028] Characterization of the spectral data of the product:

[0029] According to the above method, the following compound is prepared:

[0030] 2-bromo-(difluoromethyl)phenyl sulfide

[0031] (2-bromophenyl)(difluoromethyl)sulfane

[0032]

[0033] White liquid; Rf = 0.8 (petroleum ether); 6.57 g, 92% isolated yield; 1 1H-NMR (CDCl3): 6.87 (t, 1H, JH-F = 57.50 Hz), 7.20 - 7.26 (m, 1H), 7.28 - 7.34 (m, 1H), 7.60 - 7.68 (m, 2H). 13 13C-NMR (CDCl3): 120.6 (t, J = 277 Hz), 128.50, 128.52, 129.3, 131.2, 134.0, 136.6 19 19F-NMR (CDCl3): -92.65 (d, J = 57.50 Hz).

[0034] The second step:

[0035] Implementation process: Take a dry 250 mL round-bottom flask, add 2-bromo-(difluoromethyl)phenyl sulfide (7.17 g, 30.0 mmol, 1.0 eq.), then add 100 mL of dichloromethane. Under zero degree Celsius condition, slowly add meta-chloroperoxybenzoic acid (5.2 g, 30.0 mmol, 1.0 eq.). React overnight. After completion of the reaction, extract the reaction solution twice with 100 mL of saturated sodium carbonate aqueous solution, collect the dichloromethane phase, remove the solvent by distillation under reduced pressure, and purify the crude product by silica gel column chromatography to obtain 1-((difluoromethyl)sulfinyl)-2-bromobenzene. [4] 。

[0036] According to the above method, the following compound is prepared:

[0037] 1-((Difluoromethyl)sulfinyl)-2-bromobenzene

[0038] 1-((difluoromethyl)sulfinyl)-2-phenoxybenzen

[0039]

[0040] White solid; Rf = 0.4 (petroleum ether: ethyl acetate = 10:1); 6.71 g, 88% isolated yield; 1 H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 7.9, 1.6 Hz, 1H), 7.72–7.62 (m, 2H), 7.52 (dd, J = 7.6, 1.6 Hz, 1H), 6.36 (s, 1H). 19 F NMR (377 MHz, CDCl3) δ -105.44–-130.57 (m).

[0041] The third step:

[0042] In the implementation process, a dry 100 mL reaction flask was charged with 1-((difluoromethyl)sulfinyl)-2-bromobenzene (7.6 g, 30.0 mmol, 1.0 equiv), then phenol (5.6 g, 60.0 mmol, 2.0 equiv), copper(I) iodide (5.7 g, 30.0 mmol, 1.0 equiv) and n-butylimidazole (3.7 g, 30.0 mmol, 1.0 equiv) were added. It was placed in a glove box, 30 mL of toluene was added, sealed, taken out, and reacted at 150 °C for 12 hours. After completion of the reaction, the reaction solution was extracted twice with 50 mL of dichloromethane, the dichloromethane phase was collected, the solvent was removed by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 1-((difluoromethyl)sulfinyl)-2-phenoxybenzene.

[0043] According to the above method, the following compound is prepared:

[0044] 1-((Difluoromethyl)sulfinyl)-2-phenoxybenzene

[0045] 1-((difluoromethyl)sulfinyl)-2-phenoxybenzen

[0046]

[0047] Pale yellow liquid; Rf = 0.3 (petroleum ether: ethyl acetate = 10:1); 6.67 g, 83% isolated yield; 1HNMR(500MHz,CDCl3)δ7.93(dd,J=7.8,1.5Hz,1H),7.51–7.44(m,1H),7.41(t,J=7.7Hz,2H),7.35(t,J=7.6Hz,1H),7.23(t,J=7.5Hz,1H),7.09–7.05(m,2H),6.86(d,J=8.3Hz,1H),6.41(t,J=54.8Hz,1H). 13 C NMR(151MHz,CDCl3)δ155.03,154.81,133.77,130.27,126.83,125.24,124.05,120.35,120.32(t,J=293.9Hz),119.91,116.75. 19 F NMR(471MHz,CDCl3)δ-120.01(ddd,J=2688.0,252.6,54.5Hz).HRMS(ESI):m / z[M+H]+calcd forC14H10F2O2S+269.0403,found269.0440.

[0048] Step 4:

[0049] Implementation process: Take a dry 250 mL round-bottom reaction flask, add 1-((difluoromethyl)sulfinyl)-2-phenoxybenzene (24.1 g, 90.0 mmol, 1.0 equiv), then add 90 mL of diethyl ether. At 0 °C, dropwise add trifluoromethanesulfonic anhydride (25.6 g, 90.0 mmol, 1 equiv). After 15 minutes, confirm the complete reaction by thin-layer chromatography silica gel. After the reaction is complete, remove the diethyl ether, add 100 mL of dichloromethane to dissolve the reactants, and then perform negative ion exchange 4 times with 100 mL of sodium tetrafluoroborate (1 M). Finally, distill the dichloromethane phase under reduced pressure until it becomes viscous, and dropwise add diethyl ether at -10 °C to recrystallize to obtain the product S-(difluoromethyl)phenoxathiinium tetrafluoroborate.

[0050] According to the above method, the following compound was prepared:

[0051] S-(Difluoromethyl)phenoxathiinium tetrafluoroborate

[0052] Difluoromethyl Phenoxathiinium Tetrafluoroborate

[0053]

[0054] Pale yellow solid; 25.25 g, 84% recrystallization yield; 1 H NMR(500MHz,CDCl3 ) δ 8.23 (dd, J = 8.0, 1.4 Hz, 2H), 7.93 (td, J = 7.9, 1.6 Hz, 2H), 7.71–7.56 (m, 4H), 7.56–7.34 (t, 1H). 19 19F NMR (471 MHz, CDCl3) δ -103.96 (d, J = 54.7 Hz), -148.95 (d, J = 25.3 Hz). 13 13C NMR (101 MHz, CDCl3) δ 152.53, 138.29, 133.46, 127.40, 120.27, 118.77 (t, J = 303.3 Hz), 95.72. HRMS (ESI): m / z [M - BF4]+ calcd for C13H10F2OS+ 251.0337, found 251.0335. Melting point: 97 - 99 °C.

[0055] II. Method for the difluoromethyl etherification reaction of fatty alcohols

[0056] A method for the difluoromethyl etherification reaction of fatty alcohols

[0057] The fatty alcohol compound and the difluoromethyl reagent are subjected to an etherification reaction in a solvent to obtain the fatty alcohol difluoromethyl ether compound;

[0058] The structural formula of the difluoromethyl reagent is as follows:

[0059]

[0060] The solvent is selected from at least one of ethyl acetate, ethyl formate, acetonitrile, dichloromethane, chloroform, and tetrahydrofuran, and is preferably dichloromethane.

[0061] The reaction temperature of the etherification reaction is -30 to 80 °C. Preferably, the reaction temperature is 0 - 50 °C, and more preferably at room temperature; the reaction time of the etherification reaction is 6 - 24 hours. Preferably, the reaction time is 10 - 18 h, and more preferably 12 h.

[0062] During the etherification reaction, a phase transfer catalyst can also be added, and the catalyst is selected from at least one of 20% Bu4NI, 20% Bu4NBF4, and 20% Bu4NOTF (herein, “%” is the mole percentage).

[0063] Preferably, water is added during the etherification reaction.

[0064] And after the etherification reaction, distillation and purification are carried out to separate the fatty alcohol difluoromethyl ether compound; the purification can be silica gel column chromatography.

[0065] Implementation process:

[0066] Optimization process:

[0067] Reaction conditions and parameters: Using 2-(naphthalen-1-yl)ethanol as the template substrate (1aa), reagent 1 as the difluoromethyl reagent, whether to add water to the reaction conditions, preferably add water; whether to add a phase transfer catalyst 20% Bu4NI, 20% Bu4NBF4, 20% Bu4NOTF (wherein, "%" is the mole percentage), preferably do not add a phase transfer catalyst; the reaction solvent is selected from at least one of ethyl acetate, ethyl formate, acetonitrile, dichloromethane, chloroform, and tetrahydrofuran, preferably the solvent is dichloromethane; the reaction temperature is from -30 °C to 80 °C, preferably from 0 °C to 50 °C, more preferably at room temperature; after the reaction is completed (monitored by TLC), stop stirring, distill off the solvent under reduced pressure, and purify the crude product by silica gel column chromatography to obtain the pure product 1-(2-(difluoromethoxy)ethyl)naphthalene (3a).

[0068] Specifically, Example 1: Take a dry 10 mL Schlenk tube, add the substrate 1aa (for example, 2-(naphthalen-1-yl)ethanol or other fatty alcohols, 0.2 mmol, 1.0 equivalent), the difluoromethyl reagent (200.4 mg, 0.6 mmol, 3.0 equivalents), add 1 mL of dichloromethane and 1 mL of water as solvents, stir at room temperature (about 25 °C) overnight (about 12 h). After the reaction is completed, distill off the solvent under reduced pressure, and purify the crude product by silica gel column chromatography to obtain the fatty alcohol difluoromethyl ether compound 3a.

[0069] Using the specific reaction method of Example 1 as the reaction formula, such as Figure 2 .

[0070] Examples 2 - 16 were carried out for the fatty alcohol difluoromethyl etherification reaction according to the same preparation method as in Example 1. Specifically, the difference between Examples 2 - 16 and Example 1 is only that the fatty alcohol compounds (substrates) used are different. Therefore, the fatty alcohol difluoromethyl ether compounds (target products) obtained are also different.

[0071] The fatty alcohol compounds used in Examples 2 - 16, the generated fatty alcohol difluoromethyl compounds and their separation yields are shown in Table 1.

[0072] Table 1

[0073]

[0074]

[0075] That is, Examples 1 - 16 were prepared according to the same method as in Example 1 to obtain the following compounds (target products), and their structural formulas are as follows:

[0076]

[0077] Characterization of each product data:

[0078] According to the foregoing general formula method, the following compound (Example 1) was prepared:

[0079] 1-(2-(Difluoromethoxy)ethyl)naphthalene

[0080] 1-(2-(difluoromethoxy)ethyl)naphthalene

[0081]

[0082] Colorless transparent liquid; Rf = 0.3 (petroleum ether); 36.4 mg, 82% isolated yield; 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.3 Hz, 1H), 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.52 (ddd, J = 12.9, 8.1, 1.3 Hz, 2H), 7.45–7.36 (m, 2H), 6.21 (t, J = 74.7 Hz, 1H), 4.19 (t, J = 7.4 Hz, 2H), 3.44 (t, J = 7.5 Hz, 2H). 19 F NMR (377 MHz, CDCl3) δ -84.01 (d, J = 74.8 Hz). The compound is known [5] .

[0083] According to the foregoing general formula method, the following compound (Example 2) was prepared:

[0084] 1-(2-(Difluoromethoxy)ethyl)-4-methoxybenzene

[0085] 1-(2-(difluoromethoxy)ethyl)-4-methoxybenzene

[0086]

[0087] Colorless transparent liquid; Rf = 0.3 (petroleum ether / ethyl acetate = 50; 1); 35.9 mg, 89% isolated yield; 1 H NMR (400 MHz, CDCl3) δ 7.17–7.09 (m, 2H), 6.89–6.77 (m, 2H), 6.17 (t, J = 74.9 Hz, 1H), 4.01 (t, J = 7.1 Hz, 2H), 3.78 (s, 3H), 2.89 (t, J = 7.1 Hz, 2H). 1919F NMR (377 MHz, CDCl3) δ -84.02 (d, J = 74.6 Hz). The compound is known. [5] 。

[0088] According to the aforementioned general formula method, the following compound (Example 3) was prepared:

[0089] 1-((Difluoromethoxy)methyl)-4-nitrobenzene

[0090] 1-((difluoromethoxy)methyl)-4-nitrobenzene

[0091]

[0092] Colorless transparent liquid; Rf = 0.3 (petroleum ether / ethyl acetate = 20; 1); 22.3 mg, 55% isolated yield; 1 1H NMR (400 MHz, CDCl3) δ 8.33–8.14 (m, 2H), 7.58–7.48 (m, 2H), 6.38 (t, J = 73.4 Hz, 1H), 5.01 (s, 2H). 19 19F NMR (377 MHz, CDCl3) δ -84.78 (d, J = 73.1 Hz). The compound is known. [5] 。

[0093] According to the aforementioned general formula method, the following compound (Example 4) was prepared:

[0094] 4-((Difluoromethoxy)methyl)-1,1'-biphenyl

[0095] 4-((difluoromethoxy)methyl)-1,1'-biphenyl

[0096]

[0097] Colorless transparent liquid; Rf = 0.3 (petroleum ether / ethyl acetate = 50:1); 35.6 mg, 76% isolated yield; 1 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.4, 6.5 Hz, 4H), 7.44 (t, J = 7.5 Hz, 4H), 7.39–7.32 (m, 1H), 7.13–6.95 (m, 1H), 6.32 (t, J = 74.4 Hz, 1H), 4.93 (s, 2H). 19 19F NMR (377 MHz, CDCl3) δ -84.15 (d, J = 74.6 Hz). The compound is known. [5] 。

[0098] According to the aforementioned general formula method, the following compound (Example 5) was prepared:

[0099] 5-((Difluoromethoxy)methyl)benzo[d][1,3]dioxole

[0100] 5-((difluoromethoxy)methyl)benzo[d][1,3]dioxole

[0101]

[0102] Colorless transparent liquid; Rf = 0.3 (petroleum ether); 25.1 mg, 62% isolated yield; 1 H NMR (400 MHz, CDCl3) δ 6.88 (d, J = 1.4 Hz, 1H), 6.86–6.80 (m, 2H), 6.30 (t, J = 74.5 Hz, 1H), 6.00 (s, 2H), 4.81 (s, 2H). 19 F NMR (377 MHz, CDCl3) δ -84.12 (d, J = 74.5 Hz). The compound is known [5] 。

[0103] According to the aforementioned general formula method, the following compound (Example 6) was prepared:

[0104] 2-((Difluoromethoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxine

[0105] 2-((difluoromethoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxine

[0106]

[0107] Colorless transparent liquid; Rf = 0.3 (petroleum ether: ethyl acetate = 50:1); 22.0 mg, 51% isolated yield; 1 H NMR (400 MHz, CDCl3) δ 6.99–6.67 (m, 1H), 6.28 (t, J = 73.8 Hz, 0H), 4.39 (dtd, J = 7.5, 5.5, 2.3 Hz, 0H), 4.30 (dd, J = 11.5, 2.4 Hz, 0H), 4.18–3.97 (m, 1H). 19 F NMR (377 MHz, CDCl3) δ -85.01 (dd, J = 73.7, 5.2 Hz). The compound is known [5] 。

[0108] According to the aforementioned general formula method, the following compound was prepared (Example 7):

[0109] (5-(Difluoromethoxy)pent-1-yn-1-yl)benzene

[0110] (5-(difluoromethoxy)pent-1-yn-1-yl)benzene

[0111]

[0112] Colorless transparent liquid; Rf = 0.3 (petroleum ether: ethyl acetate = 50:1); 31.9 mg, 76% isolated yield; 1 H NMR (400 MHz, CDCl3) δ 7.39 (h, J = 3.4, 2.8 Hz, 2H), 7.30–7.24 (m, 3H), 6.21 (t, J = 75.0 Hz, 1H), 4.00 (t, J = 6.2 Hz, 2H), 2.53 (t, J = 7.0 Hz, 2H), 1.93 (p, J = 6.6 Hz, 2H). 19 F NMR (377 MHz, CDCl3) δ -83.94 (d, J = 74.8 Hz). The compound is known [5] 。

[0113] According to the aforementioned general formula method, the following compound was prepared (Example 8):

[0114] 3-(3-(Difluoromethoxy)propyl)-1H-indole

[0115] 3-(3-(difluoromethoxy)propyl)-1H-indole

[0116]

[0117] Colorless transparent liquid; Rf = 0.3 (petroleum ether: ethyl acetate = 20:1); 33.3 mg, 74% isolated yield; 1 H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.59 (dd, J = 7.9, 1.1 Hz, 1H), 7.34 (dt, J = 8.2, 0.9 Hz, 1H), 7.22–7.18 (m, 1H), 7.16–7.11 (m, 1H), 7.03 (d, J = 2.3 Hz, 1H), 6.20 (t, J = 75.1 Hz, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H). 19 F NMR (377 MHz, CDCl3) δ -83.65 (d, J = 75.0 Hz). The compound is known[5] .

[0118] According to the aforementioned general formula method, the following compound (Example 9) was prepared:

[0119] 3-(2-(Difluoromethoxy)ethyl)thiophene

[0120] 3-(2-(difluoromethoxy)ethyl)thiophene

[0121]

[0122] Colorless transparent liquid; Rf = 0.3 (petroleum ether); 25.0 mg, 74% isolated yield; 1 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 4.9, 3.0 Hz, 1H), 7.10–7.05 (m, 1H), 7.01 (d, J = 4.9 Hz, 1H), 6.23 (t, J = 74.7 Hz, 1H), 4.09 (t, J = 6.9 Hz, 2H), 3.02 (t, J = 6.9 Hz, 2H). 19 19F NMR (377 MHz, CDCl3) δ -84.18 (d, J = 74.7 Hz). The compound is known [5] .

[0123] According to the aforementioned general formula method, the following compound (Example 10) was prepared:

[0124] 1-Bromo-10-(difluoromethoxy)decane

[0125] 1-bromo-10-(difluoromethoxy)decane

[0126]

[0127] Colorless transparent liquid; Rf = 0.3 (petroleum ether); 50.9 mg, 85% isolated yield; 1 1H NMR (400 MHz, CDCl3) δ 6.18 (t, J = 75.4 Hz, 1H), 3.83 (t, J = 6.6 Hz, 2H), 3.41 (t, J = 6.9 Hz, 2H), 1.85 (p, J = 6.9 Hz, 2H), 1.63 (p, J = 6.7 Hz, 2H), 1.45–1.26 (m, 15H). 19 19F NMR (377 MHz, CDCl3) δ -83.76 (d, J = 75.3 Hz). The compound is known [5] .

[0128] According to the foregoing general formula method, the following compound was prepared (Example 11):

[0129] 1-(difluoromethoxy)octadecane

[0130] 1-(difluoromethoxy)octadecane

[0131]

[0132] Colorless transparent liquid; Rf = 0.3 (petroleum ether); 57.0 mg, 89% isolated yield; 1 1H NMR (400 MHz, CDCl3) δ 6.17 (t, J = 75.3 Hz, 1H), 3.82 (t, J = 6.6 Hz, 2H), 1.63 (p, J = 6.8 Hz, 2H), 1.26 (s, 30H), 0.88 (t, J = 6.9 Hz, 3H). 19 19F NMR (377 MHz, CDCl3) δ -83.81 (d, J = 75.4 Hz). The compound is known [5] 。

[0133] According to the foregoing general formula method, the following compound was prepared (Example 12):

[0134] 2-(difluoromethoxy)tridecane

[0135] 2-(difluoromethoxy)tridecane

[0136]

[0137] Colorless transparent liquid; Rf = 0.3 (petroleum ether); 34.0 mg, 68% isolated yield; 1 1H NMR (400 MHz, CDCl3) δ 6.23 (s, 1H), 4.23 (h, J = 6.2 Hz, 1H), 1.62 (ddd, J = 16.7, 9.1, 4.4 Hz, 1H), 1.50 (ddt, J = 14.1, 10.6, 4.9 Hz, 1H), 1.37–1.25 (m, 21H), 0.91 (t, J = 6.9 Hz, 3H). 19 19F NMR (377 MHz, CDCl3) δ -73.00–-92.52 (m). The compound is known [5] 。

[0138] According to the foregoing general formula method, the following compound was prepared (Example 13):

[0139] (difluoromethoxy)cyclododecane

[0140] (difluoromethoxy)cyclododecane

[0141]

[0142] Colorless transparent liquid; Rf = 0.3 (petroleum ether); 28.2 mg, 61% isolated yield; 1 H NMR (400 MHz, CDCl3) δ 6.21 (t, J = 75.9 Hz, 1H), 4.26 (td, J = 7.4, 3.8 Hz, 1H), 1.74 (dq, J = 13.4, 6.7 Hz, 2H), 1.56 (tt, J = 11.0, 5.8 Hz, 2H), 1.36 (dd, J = 17.8, 6.5 Hz, 18H). 19 F NMR (377 MHz, CDCl3) δ -80.04 (d, J = 75.9 Hz). The compound is known [5] 。

[0143] According to the method of the foregoing general formula, the following compound was prepared (Example 14):

[0144] (3-(difluoromethoxy)-3-methylbutyl)benzene

[0145] (3-(difluoromethoxy)-3-methylbutyl)benzene

[0146]

[0147] Colorless transparent liquid; Rf = 0.3 (petroleum ether); 14 mg, 34% isolated yield; 1 H NMR (400 MHz, CDCl3) δ 7.31–7.27 (m, 2H), 7.21–7.17 (m, 3H), 6.32 (t, J = 76.8 Hz, 1H), 2.75–2.70 (m, 2H), 1.91–1.86 (m, 2H), 1.41 (s, 6H). 19 F NMR (377 MHz, CDCl3) δ -76.49 (d, J = 77.0 Hz). The compound is known [5] 。

[0148] According to the method of the foregoing general formula, the following compound was prepared (Example 15):

[0149] 2-(10-(difluoromethoxy)decyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione

[0150] 2-(10-(difluoromethoxy)decyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione

[0151]

[0152] Yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 10:1); 68 mg, 87% isolated yield; 1 H NMR(400MHz,CDCl3)δ6.19(t,J = 75.4Hz,1H),3.99(d,J = 1.6Hz,6H),3.83(t,J = 6.6Hz,2H),2.49–2.42(m,2H),2.01(s,3H),1.67–1.57(m,2H),1.45–1.28(m,14H). 19 F NMR(377MHz,CDCl3)δ - 83.77(d,J = 75.4Hz). The compound is known [5] 。

[0153] According to the general formula method described above, the following compound (Example 16) was prepared:

[0154] (3S,5S,8R,9R,10S,13S,14S)-3-(difluoromethoxy)-8,10,13-trimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

[0155] (3S,5S,8R,9R,10S,13S,14S)-3-(difluoromethoxy)-8,10,13-trimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

[0156]

[0157] Yellow solid; Rf = 0.3 (petroleum ether / ethyl acetate = 10:1); 68 mg, 87% isolated yield; 11H NMR (400 MHz, CDCl3) δ 6.23 (t, J = 75.8 Hz, 1H), 4.04 (tt, J = 11.3, 5.0 Hz, 1H), 2.44 (ddd, J = 19.2, 9.0, 1.1 Hz, 1H), 2.07 (dt, J = 19.2, 9.1 Hz, 1H), 1.97–1.72 (m, 6H), 1.69–1.45 (m, 6H), 1.37–1.25 (m, 5H), 1.16 (tt, J = 12.2, 3.5 Hz, 1H), 1.05–0.93 (m, 2H), 0.86 (d, J = 5.5 Hz, 6H), 0.70 (ddd, J = 12.2, 10.5, 4.1 Hz, 1H). 19 19F NMR (377 MHz, CDCl3) δ -80.07 (dd, J = 75.8, 8.6 Hz). The compound is known [5] 。

[0158] Among them, the superscripts [1-5] are references, specifically as follows:

[0159] [1]. Prakash, G.K.S.; Krishnamoorthy, S.; Kar, S.; Olah, G.A., Direct S-difluoromethylation of thiols using the Ruppert–Prakash reagent. J Fluorine Chem 2015, 180, 186-191.

[0160] [2]. Wu, J.; Gu, Y.; Leng, X.; Shen, Q., Copper-promoted sandmeyer difluoromethylthiolation of aryl and heteroaryl diazonium salts. Angew Chem Int Ed Engl 2015, 54(26), 7648-52.

[0161] [3]. Wang, W.; Zhang, S.; Zhao, H.; Wang, S., Visible light-promoted difluoromethylthiolation of aryldiazonium salts. Org Biomol Chem 2018, 16(44), 8565-8568.

[0162] [4]. Prakash, G.K.S.; Weber, C.; Chacko, S.; Olah, G.A., New electrophilic difluoromethylating reagent. Organic Letters 2007, 9(10), 1863 - 1866.

[0163] [5]. Liu, G.K.; Li, X.; Qin, W.B.; Peng, X.S.; Wong, H.N.C.; Zhang, L.; Zhang, X., Facile difluoromethylation of aliphatic alcohols with an S-(difluoro - methyl)sulfonium salt: reaction, scope and mechanistic study. Chem Commun 2019, 55(52), 7446 - 7449.

Claims

1. A method for the difluoromethyl etherification reaction of fatty alcohols, characterized in that, An etherification reaction occurs between a fatty alcohol compound and a difluoromethyl reagent in a solvent to obtain a fatty alcohol difluoromethyl ether compound; The structural formula of the difluoromethyl reagent is as follows: The solvent is selected from at least one of ethyl acetate, ethyl formate, acetonitrile, dichloromethane, chloroform, and tetrahydrofuran; Water is added in the etherification reaction.

2. The method for the difluoromethyl etherification reaction of fatty alcohol according to claim 1, wherein, The reaction temperature of the etherification reaction is -30 to 80 °C.

3. The method for the difluoromethyl etherification reaction of fatty alcohol according to claim 1, wherein The reaction time of the etherification reaction is 6 - 24 h.

4. The method for the difluoromethyl etherification reaction of fatty alcohols according to claim 1, wherein The solvent is dichloromethane.

5. The method for the difluoromethyl etherification reaction of fatty alcohols according to claim 2, characterized in that, The reaction temperature of the etherification reaction is 0 - 50 °C.

6. Use of the method for the etherification reaction of fatty alcohol difluoromethyl as described in any one of claims 1 - 5 in the preparation of fatty alcohol difluoromethyl ether compounds.

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