Preparation method and application of trifluoromethyl alcohol compound

Abstract

The invention discloses a preparation method and application of a trifluoromethyl alcohol compound, and relates to the technical field of chemical engineering. The preparation method comprises the following steps: mixing trifluoromethyl propylene oxide, an electrophilic reagent, a nickel-based catalyst, a reducing agent and a nitrogen-containing ligand in an organic solvent, and reacting to obtain the trifluoromethyl alcohol compound. According to the preparation method, under the catalysis of the nickel-based catalyst, high-selectivity ring opening of the trifluoromethyl epoxypropane is achieved, the trifluoromethyl epoxypropane and the electrophilic reagent are successfully subjected to a reduction coupling reaction, the trifluoromethyl alcohol compound is synthesized, the preparation steps are simple and convenient, the reaction can be carried out under mild conditions, and the method is suitable for industrial production. And the yield of the trifluoromethyl alcohol compound can be improved by adjusting the raw materials.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical engineering, and particularly relates to a preparation method and application of a trifluoromethyl alcohol compound. Background Art

[0002] In recent years, trifluoromethyl-containing compounds have attracted much attention due to their wide applications in medicinal chemistry, pesticide science, and materials science. The trifluoromethyl group (–CF3) has unique physical and chemical properties, such as high electronegativity, high lipid solubility, and good metabolic stability, which enable it to significantly affect the biological activity and physical properties of compounds. In drug design, the trifluoromethyl group is often introduced to improve the membrane permeability and metabolic stability of candidate molecules, thereby enhancing the drug efficacy or prolonging the drug half-life. Among them, trifluoromethyl alcohol compounds are not only common structural skeletons of bioactive inhibitors, but also the presence of a trifluoromethyl group on the same carbon atom connected to the hydroxyl group provides convenient conditions for introducing trifluoromethyl into the synthesis of other compounds, and can be used to synthesize ketones, esters, amines, halides, etc. Currently, the preparation methods of α-trifluoromethyl alcohol generally include the reaction of aldehydes with trifluoromethyl reagents, the reduction of trifluoromethyl ketones, or the preparation of trifluoromethyl alcohol by transition metal-catalyzed hydrogenation. However, these methods have cumbersome synthesis steps and are not conducive to industrial production. The efficient introduction of trifluoromethyl compounds remains a challenging topic, especially how to achieve the efficient preparation of trifluoromethyl alcohol compounds under mild and green conditions. Although transition metal-catalyzed cross-coupling reactions or photocatalytic methods provide important means for constructing new compounds, these methods are often used to construct aryl and alkyl products, while transition metals are prone to inactivation during the catalytic coupling reaction for preparing trifluoromethyl compounds, and side reactions are also likely to occur, resulting in low yields and making it difficult to efficiently and simply prepare trifluoromethyl alcohol compounds. Summary of the Invention

[0003] The present invention aims to at least solve the above technical problems existing in the prior art. To this end, the object of the present invention is to provide a preparation method of a trifluoromethyl alcohol compound, which can efficiently prepare a trifluoromethyl alcohol compound through the highly selective ring-opening of trifluoromethyl epoxide by nickel catalysis and the reduction coupling reaction with an electrophilic reagent under mild conditions.

[0004] The second aspect of the present invention lies in providing an application of the preparation method of a trifluoromethyl alcohol compound To achieve the above object, the technical solutions adopted by the present invention are as follows: The first aspect of the present invention provides a preparation method of a trifluoromethyl alcohol compound, comprising the following steps: Mix trifluoromethyl epoxide, an electrophilic reagent, a nickel-based catalyst, a reducing agent, and a nitrogen-containing ligand in an organic solvent, and react to obtain a trifluoromethyl alcohol compound.

[0005] The present invention uses 3,3,3-trifluoropropylene oxide and an electrophilic reagent as reaction substrates, and through the catalytic ring-opening of 3,3,3-trifluoropropylene oxide with high selectivity by a nickel-based catalyst, a successful reductive coupling reaction occurs with the electrophilic reagent under the action of a nitrogen-containing ligand and a reducing agent, and an α-trifluoromethyl alcohol compound is successfully synthesized. The reaction can be carried out under mild conditions and has a good yield.

[0006] In some embodiments of the present invention, the electrophilic reagent includes aryl iodides and / or heteroaryl iodides.

[0007] In some examples of the present invention, the aryl iodide includes a monocyclic aryl iodide or a polycyclic aryl iodide; the monocyclic aryl iodide has a structure shown in the following formula (Ⅰ): Formula (Ⅰ); wherein, R represents a substituent on the aromatic ring, selected from hydrogen, fluorine, chlorine, bromine, ether group, thioether, trifluoromethyl, cyano, keto group, ester group, amine group, phenyl, hydroxyl, borate group, aldehyde group, alkenyl or sulfonamide group.

[0008] It can be understood that the number of substituents can be 0 to 5, such as 1, 2, 3 or 4, etc., and are independently selected from hydrogen, fluorine, chlorine, bromine, ether group, thioether, trifluoromethyl, cyano, keto group, ester group, amine group, phenyl, hydroxyl, borate group, aldehyde group, alkenyl, sulfonamide group.

[0009] In some specific examples of the present invention, in the polycyclic aryl iodide, the polycyclic aryl is selected from a substituted or unsubstituted naphthalene ring, phenanthrene ring, anthracene ring or fluorene ring.

[0010] In some examples of the present invention, in the heteroaryl iodide, the heteroaryl is selected from a substituted or unsubstituted benzofuran, acetal, benzothiophene, pyridine, quinoline, indole, pyrimidine, dibenzofuran, dibenzothiophene or carbazole.

[0011] The electrophilic reagent of the present invention can be an aryl iodide, and the aryl iodide can be substituted with an electron-donating group or an electron-withdrawing group, and it is also applicable to a heteroaryl iodide as an electrophilic reagent. It can be seen that the preparation method of the present invention is applicable to a variety of electrophilic reagents and has universality.

[0012] In some embodiments of the present invention, the nickel-based catalyst includes nickel bromide.

[0013] Specifically, in the present invention, the nickel-based catalyst can be nickel bromide, a complex of nickel bromide and an organic substance, or hydrated nickel bromide. Among them, the complex of nickel bromide and an organic substance can be a complex of nickel bromide and ethylene glycol dimethyl ether (NiBr2·DME), and the hydrated nickel bromide can be nickel bromide trihydrate (NiBr2·3H2O). When different nickel-based catalysts are selected, the catalytic effect on the reaction is different, and there are differences in the product yield.

[0014] In some embodiments of the present invention, the reducing agent includes manganese or a manganese-containing compound.

[0015] In the present invention, the reducing agent affects the progress of the reaction, and a suitable reducing agent is beneficial to improving the yield of the trifluoromethyl alcohol compound. Compared with other transition metals such as zinc, manganese has a better effect on the reaction of the present invention.

[0016] In some embodiments of the present invention, the nitrogen-containing ligand includes bipyridine or its derivatives.

[0017] By defining the nitrogen-containing ligand in the present invention, it is beneficial to promote the progress of the reaction and improve the yield of the reaction. For example, in some embodiments of the present invention, the nitrogen-containing ligand includes at least one of 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, and 4,4'-bis(trifluoromethyl)-2,2'-bipyridine.

[0018] In some embodiments of the present invention, the organic solvent includes at least one of N,N-dimethylacetamide (DMA) and N-methylpyrrolidone (NMP).

[0019] In some embodiments of the present invention, the temperature of the reaction is 25-40 °C.

[0020] In some embodiments of the present invention, the temperature of the reaction is 30-35 °C.

[0021] In some embodiments of the present invention, the reaction time is 10-30 h.

[0022] In some embodiments of the present invention, the reaction time is 11-20 h.

[0023] In some specific embodiments of the present invention, the reaction time is 11-13 h.

[0024] The reaction conditions of the present invention are mild, and the efficient synthesis of the trifluoromethyl alcohol compound can be achieved through a relatively low reaction temperature.

[0025] In some embodiments of the present invention, the reaction is carried out in an inert atmosphere. For example, the reaction is carried out in a nitrogen atmosphere.

[0026] In some embodiments of the present invention, the molar ratio of the electrophilic reagent to the trifluoromethyl propylene oxide is 1:(2-4).

[0027] In some embodiments of the present invention, the molar ratio of the electrophilic reagent to the trifluoromethyl propylene oxide is 1:(1.5-3.5).

[0028] In some specific embodiments of the present invention, the molar ratio of the electrophilic reagent to the trifluoromethyl epoxypropane is 1:(1.8~3.2).

[0029] In some embodiments of the present invention, the molar ratio of the electrophilic reagent to the reducing agent is 1:(1.5~4).

[0030] In some embodiments of the present invention, the molar ratio of the electrophilic reagent to the reducing agent is 1:(2~3.5).

[0031] In some specific embodiments of the present invention, the molar ratio of the electrophilic reagent to the reducing agent is 1:(2.8~3.2).

[0032] In some embodiments of the present invention, the molar volume ratio of the electrophilic reagent to the organic solvent is 1 mmol:(7~11) mL.

[0033] In some embodiments of the present invention, the molar volume ratio of the electrophilic reagent to the organic solvent is 1 mmol:(7~10) mL.

[0034] In some specific embodiments of the present invention, the molar volume ratio of the electrophilic reagent to the organic solvent is 1 mmol:(7~8) mL.

[0035] In some embodiments of the present invention, the addition amount of the nitrogen-containing ligand is 10~15% of the molar amount of the electrophilic reagent.

[0036] In some embodiments of the present invention, the addition amount of the nitrogen-containing ligand is 11~13% of the molar amount of the electrophilic reagent In some embodiments of the present invention, the addition amount of the nickel-based catalyst is 8~12% of the molar amount of the electrophilic reagent.

[0037] In some embodiments of the present invention, the addition amount of the nickel-based catalyst is 9~11% of the molar amount of the electrophilic reagent.

[0038] In some embodiments of the present invention, post-treatment is further included after the reaction; the post-treatment includes the following steps: after the reaction is completed, water is added to quench the reaction, and after extraction, drying, filtration, and column chromatography separation, the trifluoromethyl alcohol compound is obtained.

[0039] In some embodiments of the present invention, the extractant for the extraction includes ethyl acetate; the number of extractions is 2~3 times.

[0040] In some embodiments of the present invention, the column chromatography separation is silica gel column chromatography, and gradient elution with petroleum ether / ethyl acetate is used.

[0041] In some embodiments of the present invention, the method for preparing the trifluoromethyl alcohol compound comprises the following steps: Mix trifluoromethyl epoxypropane, an electrophilic reagent, a nickel-based catalyst, a reducing agent, and a nitrogen-containing ligand in an organic solvent. After reacting for 10 - 30 h, quench the reaction with water, and then obtain the trifluoromethyl alcohol compound through extraction, drying, filtration, and column chromatography separation.

[0042] The second aspect of the present invention provides the application of the preparation method described in the first aspect of the present invention in the preparation of drugs or fluorescent probes.

[0043] In some embodiments of the present invention, the fluorescent probe is a fluorescence molecular imaging probe, such as pTP-TFE.

[0044] The trifluoromethyl alcohol compound synthesized by the preparation method of the present invention Compared with the prior art, the present invention has at least the following beneficial technical effects: (1) The present invention provides a method for preparing a trifluoromethyl alcohol compound. Under the catalysis of a nickel-based catalyst, high-selectivity ring opening of trifluoromethyl epoxypropane is achieved, and a successful reductive coupling reaction with an electrophilic reagent is carried out to synthesize the trifluoromethyl alcohol compound. Moreover, the preparation steps are simple, the reaction can be carried out under mild conditions, and a good product yield can be achieved.

[0045] (2) The preparation method of the present invention is applicable to a variety of electrophilic reagents, including aryl iodides substituted with electron-donating groups or electron-withdrawing groups, and the reaction has high generality.

[0046] (3) By further selecting specific nickel-based catalysts, reducing agents, nitrogen-containing ligands, or organic solvents, the present invention can better promote the smooth progress of the reaction, ensure that oxidative addition only occurs between carbon-iodine bonds, thereby improving the yield of the product trifluoromethyl alcohol compound.

[0047] (4) The trifluoromethyl alcohol compound obtained by the preparation method of the present invention can be transformed or modified through a simple one-step reaction to obtain new drug compounds or intermediates, or a fluorescence molecular imaging probe can be obtained through specific treatment (such as NBS treatment). Therefore, the preparation method of the trifluoromethyl alcohol compound of the present invention can also be used for the preparation of drugs or fluorescent probes, providing new strategies for the preparation of drugs or fluorescent probes and simplifying the preparation steps. Description of the Drawings

[0048] Figure 1 It is a schematic diagram of the reaction process involved in Example 13 of the present invention.

[0049] Figure 2 It is a schematic diagram of the reaction process involved in Example 16 of the present invention. Detailed Embodiments

[0050] The content of the present invention will be further described in detail through specific embodiments below. Unless otherwise specified, the raw materials, reagents or devices used in the examples and comparative examples can be obtained from conventional commercial channels or can be obtained by existing technical methods. Unless otherwise specified, the test or measurement methods are conventional methods in the art.

[0051] The 3,3,3-trifluoropropylene oxide used in the following examples of the present invention was purchased from Bide Pharmatech; the electrophilic reagent, nickel-based catalyst, reducing agent, nitrogen-containing ligand and organic solvent were all obtained commercially.

[0052] The following will be described in detail in combination with specific examples.

[0053] Example 1 This example provides a method for preparing a trifluoromethyl alcohol compound, which includes the following steps: Mix 3,3,3-trifluoropropylene oxide (0.6 mmol), electrophilic reagent (0.2 mmol), nickel-based catalyst (0.02 mmol), reducing agent (0.4 mmol) and nitrogen-containing ligand (0.024 mmol) in an organic solvent (2.0 mL), and then react in a nitrogen atmosphere at 35 °C for 12 h; after the reaction is completed, add 5 mL of water to quench the reaction, and then extract with ethyl acetate, using 2 mL of ethyl acetate for each extraction, and extract three times repeatedly. Combine the extracted organic phases, then wash the organic phase with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a filtrate. Separate by silica gel column chromatography, and use a petroleum ether / ethyl acetate gradient elution to obtain the trifluoromethyl alcohol compound; Among them, the electrophilic reagent is an aryl iodide represented by the following formula (1): Formula (1), Me is methyl; The nickel-based catalyst is NiBr2·DME (a complex of NiBr2 and ethylene glycol dimethyl ether), the reducing agent is manganese powder, the nitrogen-containing ligand is 2,2'-bipyridine, and the organic solvent is DMA (N,N-dimethylacetamide); The trifluoromethyl alcohol compound obtained in this example has the structure shown in No. 2 of Table 4: .

[0054] Examples 2 to 4 This example provides a method for preparing a trifluoromethyl alcohol compound, which is different from Example 1 in that the nickel-based catalyst is different. For the specific nickel-based catalyst, see Table 1; the rest is the same as in Example 1.

[0055] Table 1 Nickel-based catalysts of Examples 1 to 4

[0056] Examples 5 to 7 This example provides a method for preparing a trifluoromethyl alcohol compound, which is different from Example 4 in that the nitrogen-containing ligand is different. For the specific nitrogen-containing ligand, see Table 2; the rest is the same as in Example 4.

[0057] Table 2 Nitrogen-containing ligands of Examples 4 to 7

[0058] Example 8 This example provides a method for preparing a trifluoromethyl alcohol compound, which is different from Example 4 in that the amount of the reducing agent is 0.6 mmol; the rest is the same as in Example 4.

[0059] Example 9 This example provides a method for preparing a trifluoromethyl alcohol compound, which is different from Example 8 in that the reducing agent is zinc powder; the rest is the same as in Example 8.

[0060] Example 10 This example provides a method for preparing a trifluoromethyl alcohol compound, which is different from Example 8 in that the organic solvent is DMF (N,N-dimethylformamide); the rest is the same as in Example 8.

[0061] Example 11 This example provides a method for preparing a trifluoromethyl alcohol compound, which is different from Example 8 in that the organic solvent is NMP (N-methylpyrrolidone); the rest is the same as in Example 8.

[0062] Example 12 This example provides a method for preparing a trifluoromethyl alcohol compound, which is different from Example 8 in that the reaction is carried out in a nitrogen atmosphere at 30 °C for 12 h, and the amount of the organic solvent DMA is 1.5 mL; the rest is the same as in Example 8.

[0063] Calculate the yields of the trifluoromethyl alcohol compounds obtained in Examples 1 to 12. The calculation formula is: yield = actual product mass / theoretical product mass × 100%. The results are shown in Table 3 below.

[0064] Table 3 Yields of Examples 1 to 12

[0065] In Table 3, N.R. indicates that no reaction occurred.

[0066] It should be understood that in Examples 2 to 12, the reaction conditions were adjusted, and the electrophilic reagent was not replaced. The trifluoromethyl alcohol compounds obtained when the reaction proceeded smoothly also have the structure shown in No. 2 of Table 4.

[0067] As can be seen from Table 3, in the preparation method of the present invention, the selection of the catalyst, nitrogen-containing ligand, reducing agent, organic solvent and the adjustment of the reaction conditions all affect the synthesis of trifluoromethyl alcohol compounds. For nickel-based catalysts, even though they are all nickel halides, when nickel chloride is selected, the trifluoromethyl alcohol compound cannot be synthesized smoothly. When the nickel-based catalysts all contain nickel bromide, the reactions can proceed smoothly, but the yields are NiBr2·DME < NiBr2 < NiBr2·3H2O. It can be seen that when the catalyst NiBr2·3H2O is selected, it has a higher catalytic efficiency. Among different nitrogen-containing ligands, 2,2'-bipyridine ligands can promote the reaction. Although α,α,α-terpyridine is also a chiral nitrogen-containing ligand, it has no effect on the reaction. For the reducing agent, even though they are all transition metals with reducibility, when Zn is selected, the reaction cannot be promoted, which also shows the importance of the selection of the reducing agent for the smooth progress of the reaction of the present invention. In addition, organic solvents are generally considered only as solvents for dissolving reaction raw materials and reaction environments. However, through research in the present invention, it is found that different organic solvents also affect the smooth progress of the reaction, and selecting a suitable organic solvent is beneficial to improving the yield of the trifluoromethyl alcohol compound product.

[0068] In Example 8, when the amount of the reducing agent was increased compared with Example 4, the yield increased. At the same time, in Example 12, when the reaction temperature was further reduced to 30 °C compared with Example 8 and the amount of the organic solvent was reduced to increase the concentration of the reaction system, the yield also increased further. This also shows that in the present invention, the synthesis of trifluoromethyl alcohol compounds only requires mild reaction conditions and has a good yield.

[0069] Example 13 The difference between the preparation method of the trifluoromethyl alcohol compound provided in this example and that of Example 12 is that different electrophilic reagents are set for comparison; the rest is the same as Example 12; the involved reaction is as Figure 1 shown, where Ar represents the aryl or heteroaryl group in the electrophilic reagent; Taking the electrophilic reagent as monocyclic aryl iodide as an example, the involved reaction process is as follows:

[0070] The different electrophilic reagents only differ in the R group. The structural formulas of the obtained trifluoromethyl alcohol compounds are shown in Table 4 below. The yields of the obtained trifluoromethyl alcohol compounds are shown in Table 4; among them, the trifluoromethyl alcohol compound with the serial number 2 is the trifluoromethyl alcohol compound obtained in Example 12.

[0071] Table 4 Trifluoromethyl alcohol compounds obtained from different electrophilic reagents in Example 13 and their yields

[0072] In Table 4, Me represents methyl, Ph represents phenyl, Boc represents tert-butoxycarbonyl, and Bpin represents pinacol borate ester.

[0073] The structural analysis of some of the products in Table 4 is as shown in Table 5 below: Table 5 Structural analysis of some of the products in Example 13

[0074] As can be seen from Table 4, aryl iodides with electron-donating groups or electron-withdrawing substituents show good reaction effects, providing the desired reductive coupling products (trifluoromethyl alcohol compounds) in moderate to excellent yields. Various functional groups such as ethers (2 - 3), thioethers (4), trifluoromethyl (6), cyano (7), ketones (8), esters (9), amines (10), etc. are all well-compatible, with yields ranging from moderate to high. Ortho-substituted iodobenzenes with relatively large steric hindrance (11, 15) can also proceed with the reaction smoothly, but the yields are lower compared to others. Iodobenzene without substitution (12), para-methyl substitution (13), and meta-methyl substitution (14) also have good yields. In addition, groups suitable for nickel-catalyzed reactions, such as fluorine (16), chlorine (17), or bromine (18), do not interfere with the efficient formation of the desired trifluoromethyl alcohol compounds, indicating that oxidative addition only occurs between the carbon-iodine bonds in this reaction. For polysubstituted iodobenzenes, such as disubstituted (19 - 20) and trisubstituted (21) iodobenzenes, the target products can still be obtained under standard conditions with good yields. Polycyclic aryl iodides such as naphthalene (22 - 23) and phenanthrene (24) are also suitable substrates in the preparation method of the present invention. Iodofluorene (25 - 26) also shows good reactivity in this reaction, giving the corresponding target products in good yields. At the same time, when the aryl iodide is connected with free hydroxyl groups (27), borate ester groups (28), aldehydes (29), alkenyl groups (30), or sulfonamides (31), it still does not affect the progress of the reaction, which also fully demonstrates the universality of the preparation method of the present invention for preparing trifluoromethyl alcohol compounds.

[0075] In addition, considering the widespread presence of heterocycles in drugs, the present invention further conducted research and found that heteroaryl iodides can also be successfully coupled in the reaction of the present invention. For example, iodobenzenes of benzofuran (32) and acetal (33) can obtain trifluoromethyl alcohol compounds in good yields. Thiophene (34) and benzothiophene (35) can also well tolerate the reaction of the present invention to obtain the desired products. Different nitrogen-containing heterocycles, such as 4-substituted pyridine (36), quinoline (37), indole (38), pyrimidine (39 - 40), can also be incorporated in good yields to obtain trifluoromethyl alcohol compounds. Dibenzofuran (41), dibenzothiophene (42), and carbazole (43) can also be successfully reacted to transform into the corresponding trifluoromethyl alcohol products.

[0076] Example 14 The difference between the preparation method of the trifluoromethyl alcohol compound provided in this example and that of Example 12 lies in the different electrophilic reagents; the electrophilic reagent in this example is also aryl iodide or heteroaryl iodide, specifically including derivatives of naproxen, menthol, ibuprofen, probenecid, fenofibrate, indomethacin, as well as empagliflozin intermediate and argeloxine intermediate; the rest is the same as in Example 12.

[0077] The structures and yields of the trifluoromethyl alcohol compounds obtained in this example are shown in Table 6.

[0078] Table 6 Structures and Yields of Trifluoromethyl Alcohol Compounds Obtained in Example 14

[0079] In Table 6, Me represents methyl, and the serial numbers 44 - 51 correspond to empagliflozin intermediate, argeloxine intermediate, and derivatives of naproxen, menthol, ibuprofen, probenecid, fenofibrate, and indomethacin in sequence.

[0080] The structural analysis of some products in Table 6 is as follows in Table 7: Table 7 Structural Analysis of Some Products in Example 14

[0081] As can be seen from Table 6, the preparation method of the trifluoromethyl alcohol compound provided by the present invention is also effective for medicinally relevant compound aryl iodides (such as empagliflozin intermediate and aleglitazar intermediate). Both the empagliflozin intermediate and the aleglitazar intermediate can smoothly undergo reductive coupling reactions with a yield of not less than 67%. In addition, the preparation method of the present invention is also applicable to the structural diversification of some drugs. For example, derivatives of naproxen, menthol, ibuprofen, probenecid, fenofibrate, and indomethacin can also smoothly react to obtain the corresponding trifluoromethyl alcohol compounds. These trifluoromethyl alcohol compounds can all be further used for the expansion of chemical space, providing a convenient way for the rapid construction of high-value compounds. The results in Table 5 also further illustrate the synthetic practicability of the preparation method of the present invention. Due to the mild reaction conditions and good functional group compatibility of the reaction of the present invention, electrophilic reagents derived from natural products, bioactive molecules, drugs, etc. can also be efficiently converted into the corresponding trifluoromethyl alcohol compounds.

[0082] Example 15 This example provides a preparation method of a trifluoromethyl alcohol compound, which is different from Example 12 in that the specific conditions are as follows: Trifluoromethyl epoxypropane (3 mmol), electrophilic reagent (1 mmol), nickel-based catalyst (0.1 mmol), reducing agent (3 mmol), and nitrogen-containing ligand (0.12 mmol) are mixed in an organic solvent (7.5 mL), and then reacted in a nitrogen atmosphere at 30 °C for 12 h; After the reaction is completed, water with twice the volume of the organic solvent is added to quench the reaction, and the volume of ethyl acetate used in the extraction process is the same as that of the organic solvent; The rest is the same as in Example 12.

[0083] The yield of the trifluoromethyl alcohol compound in Example 15 was 64%.

[0084] Example 16 This example demonstrates the further transformation or modification of some trifluoromethyl alcohol compounds in Table 4, specifically as follows: The trifluoromethyl alcohol compound with the serial number 2 in Table 4 is converted into trifluoromethyl ketone (52), oxazoline containing N and O heterocyclic skeletons (53), isoxoic acid derivative (54), trifluoromethyl alkyl bromide (55), and polyfluoroalkane (56) through a one-step reaction; The reaction process involved is as Figure 2 shown; Using the compound shown by formula 57 in the following reaction formula as an electrophilic reagent, the intermediate (58) of the FAAH inhibitor can be synthesized under the preparation conditions of Example 12, and then the FAAH inhibitor (59) can be obtained through transformation. The reaction process is as follows:

[0085] The transformation of the trifluoromethyl alcohol compound with the serial number 34 in Table 4 can obtain the intermediate of pTP-TFE (yield 66%) through the treatment with NBS (N-bromosuccinimide). Then, pTP-TFE can be synthesized using this intermediate. The reaction process is as follows:

[0086] pTP-TFE is a selective fluorescent molecular imaging probe and a potential tool for the detection of early Alzheimer's disease. The preparation method of the present invention can provide a simplified synthesis step for the synthesis of this fluorescent probe.

[0087] Comparative Example 1 This comparative example provides a preparation method of a trifluoromethyl alcohol compound, which is different from Example 12 in that: nickel-based catalyst (NiBr2·3H2O) is not added; the rest is the same as Example 12.

[0088] Comparative Example 2 This comparative example provides a preparation method of a trifluoromethyl alcohol compound, which is different from Example 12 in that: nitrogen-containing ligand (2,2'-bipyridine) is not added; the rest is the same as Example 12.

[0089] Comparative Example 3 This comparative example provides a preparation method of a trifluoromethyl alcohol compound, which is different from Example 12 in that: reducing agent (manganese powder) is not added; the rest is the same as Example 12.

[0090] In Comparative Examples 1 to 3, the catalyst, nitrogen-containing ligand or reducing agent is missing. It is found through detection that the reaction cannot proceed smoothly.

[0091] As can be seen from the above examples and comparative examples, the preparation method provided by the present invention can efficiently catalyze the selective ring-opening of 1,2-epoxy-3,3,3-trifluoropropane under mild conditions by using a specific catalyst, and perform a reductive coupling reaction with aryl iodide to construct α-trifluoromethyl alcohol compounds. The preparation method of the present invention has mild reaction conditions and a high product yield. The yield can reach more than 80% through the adjustment of reaction conditions, and it has good regioselectivity and substrate adaptability, good functional group compatibility, and is applicable to electrophilic reagents of various heterocycles or bioactive molecules. In addition, the trifluoromethyl alcohol compounds obtained by the present invention can also be converted into other compounds through a simple one-step reaction. For example, the trifluoromethyl alcohol compound numbered 1 in Table 4 can be converted into trifluoromethyl ketone and trichloroacetimidate ester, and can also be processed or modified to obtain trifluoromethyl alkyl bromide and isoxoic acid derivatives. The trifluoromethyl alcohol compound numbered 33 in Table 4 can be treated with NBS (N-bromosuccinimide) to obtain an intermediate of the selective fluorescence molecular imaging probe pTP-TFE. It can be seen that the preparation method of the present invention can not only efficiently prepare trifluoromethyl alcohol compounds under mild conditions, but also obtain new drugs or fluorescence probes through further transformation or modification, and has strong practicability.

[0092] The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above examples. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A method for preparing a trifluoromethyl alcohol compound, characterized in that: The following steps are involved: The trifluoromethyl propylene oxide, an electrophilic reagent, a nickel-based catalyst, a reducing agent and a nitrogen-containing ligand are mixed in an organic solvent and reacted to obtain the trifluoromethyl alcohol compound.

2. The preparation method according to claim 1, characterized in that: The electrophilic reagent includes an aryl iodide and / or a heteroaryl iodide.

3. The preparation method according to claim 1, characterized in that: The nickel-based catalyst includes nickel bromide.

4. The preparation method according to claim 1, characterized in that: The reducing agent includes manganese or a manganese-containing compound.

5. The preparation method according to claim 1, characterized in that: The nitrogen-containing ligand includes bipyridine or a derivative thereof.

6. The preparation method according to claim 1, characterized in that: The organic solvent includes at least one of N,N-dimethylacetamide and N-methylpyrrolidone.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The reaction temperature is 25-40°C; And / or, the reaction time is 10 to 30 hours; And / or, the reaction is carried out under an inert atmosphere.

8. The preparation method according to any one of claims 1 to 6, characterized in that: The molar ratio of the electrophilic reagent to the trifluoromethylpropylene oxide is 1:(2-4); and / or, the molar ratio of the electrophilic reagent to the reducing agent is 1:(1.5-4); And / or, the molar volume ratio of the electrophilic reagent to the organic solvent is 1 mmol: (7-11) mL.

9. The preparation method according to any one of claims 1 to 6, characterized in that: The amount of the nitrogen-containing ligand added is 10 to 15% of the molar amount of the electrophilic reagent; And / or, the amount of the nickel-based catalyst added is 8-12% of the molar amount of the electrophilic reagent.

10. Use of the preparation method according to any one of claims 1 to 9 in the preparation of drugs or fluorescent probes.

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