Process for the preparation of 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol

Abstract

The present application relates to a kind of 4-(2,2,2-trifluoro-1-alkoxyethyl) phenol preparation method, it is suitable for process amplification, for industrial production, the feature of preparation method is that, including: step (1), with trifluoro-1-(4-hydroxyphenyl) ethanone as raw material, preparation intermediate A, and, step (2), intermediate A prepared in step (1) is dissolved or dispersed in alkanol B, reaction is carried out in the presence of basic substance, 4-(2,2,2-trifluoro-1-alkoxyethyl) phenol is prepared, the reaction temperature of the reaction is 50~80 DEG C, reaction time is within 3 hours.

Description

Technical Field

[0001] This invention relates to the synthesis of organic compounds, specifically to a method for preparing 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol and a method for preparing the corresponding intermediates. Background Technology

[0002] 4-(2,2,2-trifluoro-1-methoxyethyl)phenol, represented by 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol, is an ethyl-substituted compound with a trifluoromethyl and alkoxy substitution at the para-position of the phenolic hydroxyl group. In the chemical structure of such compounds, the phenolic hydroxyl group can be further modified to form esters or ethers, thereby synthesizing more complex functional organic compounds. The trifluoromethyl group is one of the important groups in the fine synthesis of medicinal chemistry. Due to its high lipophilicity and high electronegativity resulting from perfluorinated substitution, it is widely used in various bioactive molecules. Introducing a trifluoromethyl structure through modification can improve the lipophilicity and metabolic stability of compounds, significantly altering various properties. Including but not limited to, the trifluoromethyl group and its ortho-substituted structures play the role of a "multifunctional modifying group" in drug design through unique electronic effects, steric effects, and metabolic stability. These molecules have broad application prospects in antiviral, anticancer, and central nervous system disease fields. Therefore, 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol is being studied and utilized as a promising intermediate compound in pharmaceutical synthesis and fine chemical synthesis.

[0003] On the other hand, there are currently no patents or literature reports on an industrially feasible synthetic route for 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol. As for synthetic routes for similar structures, such as 2,2,2-trifluoro-1-methoxyethylbenzene, Non-Patent Literature 1 reports a synthesis under light irradiation using 3-phenyl-3-(trifluoromethyl)-3H-bisacrylidine as a starting material, while Non-Patent Literature 2 reports a high-temperature sealed reaction using 1-phenyl-2,2,2-trifluoroethanol as a starting material.

[0004] Existing technical documents

[0005] Non-patent literature 1: Eur. J. Org. Chem. 2019, 7563–7567

[0006] Non-patent literature 2: Angew. Chem. Int. Ed. 2024, 63, e202409931 Summary of the Invention

[0007] Therefore, for a long time, there has been a lack of industrially feasible synthetic techniques for 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol. Among the existing technologies mentioned above, synthetic routes for similar structural molecules also suffer from problems such as high raw material costs, low yields, or the need for photochemical reaction equipment, making them unsuitable for industrial production. Therefore, there is an urgent need to develop an industrially feasible synthetic route for 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol or its derivatives, characterized by mild reaction conditions, high yields, and low impurities.

[0008] To address the aforementioned technical challenges, this invention provides a novel method for preparing 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol. This method, using specific intermediates, prepares 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol, offering the following advantages: (1) The starting materials are inexpensive and readily available. (2) The reaction conditions are simple and mild, particularly requiring only a short reaction time at relatively low temperatures. (3) The yield is high, and the target product can be obtained through simple purification. Therefore, the preparation method provided by this invention is suitable for process scale-up and industrial production.

[0009] In addition, the present invention provides a method for preparing an intermediate with insertion reaction activity, which can be obtained by simple heating under alkaline conditions, and can be used to realize the industrial preparation of 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol, etc.

[0010] Specifically, the present invention includes the following technical solutions.

[0011] [1]. A method for preparing 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol, characterized in that it comprises:

[0012] Step (1): Using trifluoro-1-(4-hydroxyphenyl)ethyl ketone as a raw material, intermediate A is prepared.

[0013]

[0014] as well as,

[0015] Step (2): The intermediate A obtained in step (1) is dissolved or dispersed in alkanol B, and reacted in the presence of an alkaline substance to obtain 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol. The reaction temperature is 50-80°C, and the reaction time is within 3 hours.

[0016]

[0017] [2]. According to the preparation method described in [1], the alkanol B in step (2) is selected from one or more of methanol, ethanol, propanol and butanol.

[0018] [3]. According to the preparation method described in [1], the alkaline substance in step (2) is 1.2 to 4.0 stoichiometric equivalents relative to the added intermediate A.

[0019] [4]. According to the preparation method described in [1], the alkaline substance in step (2) is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide.

[0020] [5]. According to the preparation method described in [1], the reaction temperature in step (2) is below 75°C.

[0021] [6]. According to the preparation method described in [1], the reaction time in step (2) is 30 minutes to 2 hours.

[0022] [7]. The preparation method according to [1] is characterized in that it is a method for preparing 4-(2,2,2-trifluoro-1-methoxyethyl)phenol.

[0023] [8]. A method for preparing an intermediate with insertion reaction activity, characterized in that the p-toluenesulfonate of 4-[3-(trifluoromethyl)-3H-bisacryl-3-yl]phenol is heated at 60-75°C under alkaline conditions.

[0024] [9]. The preparation method according to [8] is characterized in that the heating time is 30 minutes to 2 hours, and 1.2 to 4.0 stoichiometric amounts of an alkaline substance are added relative to the p-toluenesulfonate of 4-[3-(trifluoromethyl)-3H-bisacrylidine-3-yl]phenol, wherein the alkaline substance is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide. Attached Figure Description

[0025] Figure 1 The image shows the 1H NMR spectrum of 4-(2,2,2-trifluoro-1-methoxyethyl)phenol in Example 1.

[0026] Figure 2 The spectrum is shown to display the 1H NMR spectrum of 4-(2,2,2-trifluoro-1-ethoxyethyl)phenol in Example 2. Detailed Implementation

[0027] The method for preparing 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol of the present invention includes: step (1), using trifluoro-1-(4-hydroxyphenyl)ethyl ketone as a raw material to prepare intermediate A, wherein intermediate A is p-toluenesulfonate of 4-[3-(trifluoromethyl)-3H-bis(acrylidine-3-yl)phenol,

[0028]

[0029] as well as,

[0030] Step (2) involves dissolving or dispersing intermediate A obtained in step (1) in alkanol B and reacting it in the presence of an alkaline substance to obtain 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol. The reaction temperature is 50-80°C and the reaction time is within 3 hours.

[0031]

[0032] In step (1) of the preparation method of this invention, intermediate A is synthesized using trifluoro-1-(4-hydroxyphenyl)ethyl ketone as a raw material and following conventional methods reported in the literature. The raw material, 2,2,2-trifluoro-1-(4-hydroxyphenyl)ethyl ketone, also known as TFHA, is typically a colorless liquid or a pale yellow oily substance. As a common organofluorine compound, TFHA has no particularly limited source and can be synthesized in a laboratory or purchased commercially.

[0033] The method for synthesizing intermediate A from TFHA can be the method reported in the usual literature (Organic Letters (2015), 17(3), 616-619), or refer to the Organic Synthesis Handbook to introduce the bisacrylidine structure into TFHA through the following route, and then further esterify the phenolic hydroxyl group with p-toluenesulfonic acid (TsOH).

[0034]

[0035] The present invention employs the following synthetic route, but it should be noted that the synthetic method for synthesizing intermediate A from TFHA is not particularly limited, and any synthetic route existing in the art can be used.

[0036]

[0037] Intermediate A is a p-toluenesulfonate of 4-[3-(trifluoromethyl)-3H-bisacryl-3-yl]phenol, i.e., a p-toluenesulfonyl structure (Tosyl group) is formed at the position of the phenol structure. As described below, the above-mentioned p-toluenesulfonyl structure of intermediate A is extremely important for achieving the technical objectives of this invention.

[0038] In step (2) of the preparation method of the present invention, intermediate A from step (1) is dissolved or dispersed in alkanol B and reacted in the presence of an alkaline substance to prepare alkoxyfluorinated ethylphenol compounds. The reaction temperature is 60-80°C and the reaction time is within 3 hours.

[0039]

[0040] Step (2) employs a one-step reaction to directly prepare 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol, wherein the reaction heating temperature does not exceed 80°C, the reaction time does not exceed 3 hours, and the experimental conditions are extremely mild. For reference, similar reactions typically employ UV light activation as in Non-Patent Literature 1, and even when heating is used, it requires heating to a relatively high temperature.

[0041] The realization of this reaction in this invention, particularly the mildness of the reaction conditions required, exceeds the understanding of those skilled in the art in similar organic synthesis processes. Its mechanism is not yet clear; based on the inventors' experimental verification, it can be inferred that it is due to the effect of the O-Tosyl structure on the benzene ring, as explained below.

[0042] In the one-step reaction of step (2), the bisacrylidine structure in intermediate A is converted to an alkoxy structure, while the O-Tosyl structure is converted to a phenolic hydroxyl group. From an organic synthesis perspective, the change in the phenolic hydroxyl structure during the reaction from trifluoro-1-(4-hydroxyphenyl)ethyl ketone to intermediate A to 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol can be considered a protecting-deprotecting process of the phenolic hydroxyl group. The inventors of this invention accidentally discovered in experiments that the intermediate using the Tosyl protecting group yielded the target product of this invention. Through repeated experiments and adjustments, they found that high yields could be achieved under extremely mild reaction conditions. However, using other phenolic hydroxyl protecting groups, regardless of whether they have higher or lower electronegativity than the Tosyl protecting group or whether they possess an aromatic ring, made it difficult to successfully carry out the reaction.

[0043] Commonly used protecting groups for phenolic hydroxyl groups in this art include ethers such as alkyl, benzyl, and allyl groups; silyl ethers (such as TBS); carboxylic acid esters (such as acetyl or benzoyl); carbonates; carbamates; hypophosphite esters; and sulfonate esters. Based on common understanding, groups that can protect the phenolic hydroxyl group in the reaction and are easily deprotected can be appropriately selected according to the reaction solvent, reaction type, and deprotection conditions, without fully discussing the influence of the protecting group on the reaction. However, in this invention, only the Tosyl protecting group can successfully promote the reaction.

[0044] On the other hand, based on the reaction mechanism of step (2), it may involve the conversion of the bisacrylidine structure at the para position of the -O-Tosyl structure in intermediate A into a carbene structure with insertion reactivity. According to common understanding, stabilizing such a carbene structure requires providing it with as many electrons as possible to make it more stable, thus resulting in milder reaction conditions. However, contrary to this common understanding, the Tosyl protecting group used in this invention is an electron-withdrawing group, making it difficult to explain the mechanism of this invention using conventional mechanisms. Possible guesses include, in addition to moderate intramolecular inductive and conjugation effects, intermolecular interactions among multiple molecules, thereby stabilizing the carbene structure.

[0045] In step (2) of one embodiment of the present invention, the alkanol B is not particularly limited and can be a common lower alcohol that is liquid at room temperature, selected from one or more of methanol, ethanol, propanol (n-propanol, isopropanol) and butanol (n-butanol, sec-butanol, tert-butanol), preferably methanol and ethanol, more preferably methanol. By selecting different alkanol ROH, the corresponding alkoxy structure RO can be obtained.

[0046] In step (2), alkanol B serves as both the reaction medium and reactant, dissolving (or dispersing) intermediate A in alkanol B to carry out the reaction. Therefore, no additional solvent is needed during the reaction process, and the atomic utilization rate of intermediate A can be improved.

[0047] In step (2) of one embodiment of the present invention, the alkaline substance is present in an amount of 1.2 to 4.0 stoichiometric equivalents relative to the added intermediate A. The alkaline substance in step (2) serves two purposes: firstly, to deprotect the Tosyl protecting group, and secondly, to provide an alkaline environment conducive to the reaction. Its content being above the lower limit ensures complete reaction, while its content being below the upper limit avoids unnecessary material waste. The alkaline substance can be a commonly used organic or inorganic base in the art. From a cost and industrial production perspective, the alkaline substance can be sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0048] In one embodiment of the present invention, the 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol is prepared by the same method as for 4-(2,2,2-trifluoro-1-methoxyethyl)phenol, using methanol as alkanol B.

[0049] As described above, the preparation method of the present invention is characterized by sufficiently mild reaction conditions. In one embodiment, in step (2), the reaction temperature is 50–80°C, more preferably below 75°C, and particularly preferably below 70°C, and the reaction time is 30 minutes to 2 hours. By reducing the reaction temperature and shortening the reaction time, the preparation method of the present invention is further suitable for the low energy consumption and high efficiency requirements of industrial production.

[0050] Furthermore, the preparation method of the present invention is characterized by extremely high reaction yield, with a yield of over 70% relative to intermediate A, more preferably over 80%. Therefore, the preparation method of the present invention achieves the combination of high yield and mild reaction conditions, which is difficult to achieve with similar reactions. Due to the high yield, it is easy to understand that the separation and purification steps of the preparation method of the present invention are simple, thus further suitable for the separation and purification needs of industrial production.

[0051] Another aspect of the present invention includes a method for preparing an intercalation-reactive intermediate, characterized in that the p-toluenesulfonate ester of 4-[3-(trifluoromethyl)-3H-bis(acrylidine-3-yl)phenol (intermediate A)) is heated at 60–75°C under alkaline conditions. The aforementioned intercalation-reactive intermediate is not only an intermediate for preparing the 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol of the present invention, but can also be used for the intercalation of CH, OH bonds in other chemical or biological organic structures.

[0052] Other conditions for the preparation method of the intermediate with insertional reactivity of the present invention are as described above for 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol. For example, the heating time may be 30 minutes to 2 hours. The basic condition is that 1.2 to 4.0 stoichiometric amounts of a basic substance may be added relative to the p-toluenesulfonate of 4-[3-(trifluoromethyl)-3H-bis(acrylidine-3-yl)phenol. The basic substance may be sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0053] Example

[0054] The present invention will be described below with reference to examples and comparative examples, but the present invention is not limited thereto.

[0055] Preparation Example

[0056] [Preparation of Intermediate A]

[0057] The specific method for synthesizing intermediate A4-[3-(trifluoromethyl)-3H-bisacryl-3-yl]phenol is as follows:

[0058]

[0059] Synthesis of int-1

[0060] SM1 (9.9 g, 1.0 eq) was dissolved in EtOH (50 mL), followed by the addition of pyridine (24.6 g, 6.0 eq) and hydroxylamine hydrochloride (10.8 g, 3.0 eq). The mixture was heated to reflux and reacted for 4–6 h. TLC monitoring (DCM:MeOH = 5:1) was performed. f (int-1) = 0.4, the raw material disappeared, 10% citric acid aqueous solution was added to the reaction solution, the pH was adjusted to 3-4, and MTBE was used for extraction. The organic phase was washed with brine and dried with anhydrous sodium sulfate. The crude int-1 product was concentrated under reduced pressure to obtain 13g. 1 H NMR (400MHz, DMSO-d6) δ12.52 (s, 1H), 9.99 (s, 1H), 7.36 (d, J = 8.5Hz, 2H), 6.89–6.84 (m, 2H).

[0061] Synthesis of int-2

[0062] The obtained int-1 (12 g, 1.0 eq) was dissolved in DCM (300 mL), cooled to 0 °C, and TEA (17.7 g, 3.0 eq) and DMAP (0.35 g, 0.05 eq) were added under controlled temperature. p-Toluenesulfonyl chloride (22.3 g, 2.0 eq) was dissolved in DCM and added dropwise to the reaction solution. After the addition was complete, the temperature was slowly raised to room temperature, and the reaction was allowed to proceed for 3 h. TLC monitoring (PE:EA = 1:1) was performed. f (int-2) = 0.8, int-1 disappears, the reaction solution is quenched in a saturated ammonium chloride aqueous solution, extracted with DCM, the organic phase is washed with brine and dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 27g of crude int-2. 1 H NMR (400MHz, DMSO-d6) δ7.90–7.85(m,2H),7.83–7.77(m,2H),7.56(dd,J=8.3, 4.5Hz, 4H), 7.50 (d, J = 8.0Hz, 2H), 7.32–7.26 (m, 2H), 2.46 (s, 3H), 2.44 (s, 3H).

[0063] Synthesis of int-3

[0064] Add the obtained int-2 (27g, 1.0eq), THF (55mL), and ammonia (55mL) to a sealed container, heat to 60℃ and react for 12-18h. Cool to 0℃ and open the container. Monitor by TLC (PE:EA = 1:1), R... f(int-3) = 0.6, int-2 disappears, the reaction solution is quenched in saturated brine, extracted with EA, the organic phase is washed with brine and dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 18g of crude int-3. 1 H NMR(400MHz,Chloroform-d)δ7.74–7.69(m,2H),7.59–7.54(m,2H),7.33(d,J=8.0H z,2H),7.08–7.03(m,2H),2.80(d,J=8.8Hz,1H),2.46(s,3H),2.19(d,J=8.8Hz,1H).

[0065] Synthesis of intermediate A

[0066] The obtained int-3 (15 g, 1.0 eq) was dissolved in DCM (150 mL), cooled to 0 °C, and TEA (12.7 g, 3.0 eq) and I2 (11.7 g, 1.1 eq) were added under controlled temperature. The mixture was then slowly heated to room temperature and stirred for 1-2 h. TLC monitoring (PE:EA = 1:1) was performed. f (int-4) = 0.6, int-3 disappears, the reaction solution is quenched in an aqueous sodium thiosulfate solution, extracted with DCM, the organic phase is washed with brine and dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain 15g of crude int-4, and passed through a PE column to obtain 12g of product.

[0067] [Preparation of 4-(2,2,2-trifluoro-1-methoxyethyl)phenol]

[0068] Example 1-1

[0069] Intermediate A (2 g, 5.6 mmol, 1.0 eq) was dissolved in MeOH (20 mL, 10 V) and added to a 100 mL round-bottom flask. K₂CO₃ (1.9 g, 2.4 eq) was added, and the mixture was heated to 65 °C and refluxed for 1–2 h. TLC monitoring (PE:EA = 1:1) showed Rf(DP) = 0.5. After the starting material disappeared, the reaction solution was concentrated to dryness, diluted with 20 mL of ethyl acetate, washed twice with 50 mL of water, and once with 50 mL of saturated sodium chloride solution. The organic phase after washing with brine was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and then eluted by column chromatography using a PE:EA = 1:3 system to obtain 1.12 g of colorless liquid product.

[0070] The colorless liquid was analyzed using a nuclear magnetic resonance spectrometer (Braker 400MHz, Switzerland) and a mass spectrometer (LC Agilent 1260ⅡMS Agilent 96160A). 1H NMR (400MHz, Chloroform-d) δ7.30 (d, J = 8.3Hz, 2H), 6.96–6.81 (m, 2H), 5.06 (s, 1H), 4.44 (q, J = 6.6Hz, 1H), 3.39 (s, 3H).

[0071] It was determined that 1.12 g of 4-(2,2,2-trifluoro-1-methoxyethyl)phenol was synthesized, with a yield of 97%.

[0072] Except for changing the corresponding conditions as shown in the table below, the experiments of Examples 1-2 to 1-7 were carried out in the same manner as in Example 1-1, and the yields are shown in the table below.

[0073] Example alkaline substances Reaction temperature (°C) Yield (%) 1-2 Potassium carbonate 40 78％ 1-3 Potassium carbonate 50 90％ 1-4 Potassium carbonate 60 97％ 1-5 Potassium carbonate 75 85％ 1-6 potassium hydroxide 60 92％ 1-7 potassium hydroxide 70 86％

[0074] [Preparation of 4-(2,2,2-trifluoro-1-ethoxyethyl)phenol]

[0075] Example 2-1

[0076] Intermediate A (2 g, 5.6 mmol, 1.0 eq) was dissolved in EtOH (20 mL, 10 V) and added to a 100 mL round-bottom flask. Potassium hydroxide (1.5 eq) was added, and the mixture was heated to 65 °C and reacted for 1 h. TLC monitoring (PE:EA = 1:1) showed Rf(DP) = 0.5. After the starting material disappeared, the reaction solution was concentrated to dryness, diluted with 20 mL of ethyl acetate, washed twice with 50 mL of water, and once with 50 mL of saturated sodium chloride solution. The organic phase after washing with brine was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and then eluted by column chromatography using a PE:EA = 1:3 system to obtain 1.1 g of colorless liquid product.

[0077] The same tests were performed as for Examples 1-1, and the results were as follows: 1 ¹H NMR (400MHz, Chloroform-d) δ 7.31 (d, J = 8.2 Hz, 2H), 6.90–6.82 (m, 2H), 4.99 (s, 1H), 4.54 (q, J = 6.7 Hz, 1H), 3.55 (q, J = 7.0 Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H). 1.1 g of 4-(2,2,2-trifluoro-1-ethoxyethyl)phenol was synthesized in 89% yield.

[0078] Except for changing the corresponding conditions as shown in the table below, the experiments of Examples 2-2 to 2-7 were carried out in the same manner as in Example 2-1, and the yields are shown in the table below.

[0079] Example alkaline substances Reaction temperature (°C) Yield (%) 2-2 Potassium carbonate 40 27％ 2-3 Potassium carbonate 50 46％ 2-4 Potassium carbonate 60 54％ 2-5 potassium hydroxide 50 64％ 2-6 potassium hydroxide 65 89％ 2-7 potassium hydroxide 70 84％

[0080] Comparative Example 1: The phenolic hydroxyl group on phenol has no protecting group.

[0081]

[0082] Except for replacing intermediate A and using raw material SM1 as shown in the figure above, the reaction was carried out in the same manner as in Example 1-1. After the reaction was completed, the solvent was evaporated, and no product spot was observed.

[0083] The reason for not obtaining the product is speculated to be that the substrate SM1 has poor stability and is prone to N2 removal, making it unable to form a stable carbene intermediate, thus preventing the acquisition of the trifluoromethyl-modified product.

[0084] Comparative Example 2: The phenolic hydroxyl protecting group on phenol is TMS.

[0085]

[0086] In Comparative Example 2 and the following Comparative Examples, the phenolic hydroxyl protecting group on the phenol can be introduced by conventional methods for introducing the phenolic hydroxyl protecting group.

[0087] Add the starting material SM1 (1 g, 3.65 mmol, 1.0 eq) from the above diagram to a 100 mL round-bottom flask, dissolved in MeOH (20 mL, 10 V), and add K2CO3 (1.2 g, 2.4 eq). Heat to 65 °C and reflux for 1-2 h. TLC monitoring (PE:EA = 1:1), Rf(DP) = 0.5. After the starting material disappears, concentrate the reaction solution to dryness, dilute with 20 mL of ethyl acetate, wash twice with 50 mL of water, and once with 50 mL of saturated sodium chloride solution. Dry the organic phase after washing with brine with anhydrous sodium sulfate and concentrate under reduced pressure to obtain 1.0 g of crude product. Dissolve the crude product in 10 mL of methanol, add 12 M HCl, and stir at room temperature for 2 h. After the reaction is complete, evaporate the solvent to dryness, and then elute by column chromatography with a PE:EA = 1:3 system to obtain TM (80 mg, 0.365 mmol) as a colorless liquid product. The two-step yield is 10%.

[0088] Comparative Example 3: The phenolic hydroxyl protecting group on the phenol is MOM.

[0089]

[0090] Add the starting material SM1 (1 g, 4.0 mmol, 1.0 eq) shown in the above figure to a 100 mL round-bottom flask, dissolved in MeOH (20 mL, 10 V), and add K2CO3 (1.3 g, 2.4 eq). Heat to 65 °C and reflux for 1-2 h. TLC monitoring (PE:EA = 1:1) showed no obvious new spot. After the starting material disappeared, the reaction solution was concentrated to dryness, diluted with 20 mL of ethyl acetate, washed twice with 50 mL of water, and once with 50 mL of saturated sodium chloride solution. The organic phase after washing with brine was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.1 g of crude product. The crude product was dissolved in 10 mL of methanol, and 12 M HCl was added. The mixture was refluxed and stirred for 12 h. After the reaction was complete, the solvent was evaporated to dryness; no product spot was observed.

[0091] Possible reasons for not obtaining the product are that a stable carbene intermediate could not be formed during the reaction to insert into the alcohol, or that the ether in the product structure was destroyed during the deprotection process.

[0092] Comparative Example 4: The phenolic hydroxyl protecting group on phenol is an acetyl group.

[0093]

[0094] Add the starting material SM1 (890 mg, 3.65 mmol, 1.0 eq) from the above diagram, dissolved in MeOH (20 mL, 10V), to a 100 mL round-bottom flask. Add K2CO3 (1.2 g, 2.4 eq), heat to 65 °C, and reflux for 1-2 h. Monitor by TLC (PE:EA = 1:1), Rf(DP) = 0.5. After the starting material disappears, concentrate the reaction solution to dryness, dilute with 20 mL of ethyl acetate, wash twice with 50 mL of water, and once with 50 mL of saturated sodium chloride solution. Dry the organic phase after washing with brine with anhydrous sodium sulfate and concentrate under reduced pressure to obtain 1.0 g of crude product. Dissolve the crude product in 10 mL of methanol, add NaOH (365 mg, 2.5 eq), and stir at room temperature for 2 h. After the reaction was complete, the solvent was evaporated and then eluted by column chromatography with a PE:EA = 1:3 system to obtain TM (200 mg, 0.9 mmol) colorless liquid product. The two-step yield was 25%.

[0095] Comparative Example 5: The phenolic hydroxyl protecting group on phenol is benzyl.

[0096]

[0097] Add the starting material SM1 (1.06 g, 3.65 mmol, 1.0 eq) dissolved in MeOH (20 mL, 10 V) to a 100 mL round-bottom flask, then add K2CO3 (1.2 g, 2.4 eq), heat to 65 °C, and reflux for 1-2 h. TLC monitoring (PE:EA = 1:1) showed Rf(DP) = 0.5. After the starting material disappeared, concentrate the reaction solution to dryness, dilute with 20 mL of ethyl acetate, wash twice with 50 mL of water, and once with 50 mL of saturated sodium chloride solution. Dry the organic phase after washing with brine with anhydrous sodium sulfate and concentrate under reduced pressure to obtain 1.3 g of crude product. Dissolve the crude product in 10 mL of methanol, add 130 mg of 10% Pd / C palladium on carbon, and stir at room temperature for 12 h. After the reaction is complete, evaporate the solvent, and elute by column chromatography with a PE:EA = 1:3 system to obtain TM (40 mg, 0.18 mmol) as a colorless liquid product. The two-step yield is 5%.

[0098] The above experimental results show that the synthetic route of the present invention using intermediate A can obtain good yields. In contrast, when the phenolic hydroxyl protecting group on phenol is another group, no product can be obtained or the yield is extremely low.

[0099] In summary, the preparation method of 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol of the present invention has the following excellent effects: (1) the starting materials are inexpensive and readily available. (2) the reaction conditions are simple and mild, especially the reaction can be carried out in a short time under relatively low temperature conditions. (3) the yield is high, and the target product can be obtained after simple purification. Therefore, the preparation method provided by the present invention is suitable for process scale-up and industrial production, and has good industrial value.

Claims

1. A method for preparing 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol, characterized in that, It includes: Step (1): Using trifluoro-1-(4-hydroxyphenyl)ethyl ketone as a raw material, intermediate A is prepared. as well as, Step (2): The intermediate A obtained in step (1) is dissolved or dispersed in alkanol B, and reacted in the presence of an alkaline substance to obtain 4-(2,2,2-trifluoro-1-alkoxyethyl)phenol. The reaction temperature is 60~80℃, and the reaction time is within 3 hours. In step (2), the alkanol B is selected from one or more of methanol, ethanol, propanol, and butanol. The alkaline substance has a chemical equivalent of 1.2 to 4.0 stoichiometric amounts relative to the added intermediate A, and the alkaline substance is sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide.

2. The preparation method according to claim 1, characterized in that, In step (2), the reaction temperature is 60~75℃.

3. The preparation method according to claim 1, characterized in that, In step (2), the reaction time is 30 minutes to 2 hours.

4. The preparation method according to any one of claims 1 to 3, characterized in that, It is a method for preparing 4-(2,2,2-trifluoro-1-methoxyethyl)phenol.

5. A method for preparing an intermediate with insertional reaction activity, characterized in that, The p-toluenesulfonate of 4-[3-(trifluoromethyl)-3H-bisacryl-3-yl]phenol is heated at 60-75°C in the presence of an alkaline substance, wherein the alkaline substance is sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide.

6. The preparation method according to claim 5, characterized in that, The heating time is 30 minutes to 2 hours, and 1.2 to 4.0 stoichiometric amounts of basic substances are added relative to the p-toluenesulfonate of 4-[3-(trifluoromethyl)-3H-bisacrylidine-3-yl]phenol.

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