Preparation method of trifluoromethyl heterocyclic compound

Abstract

The invention discloses a preparation method of a trifluoromethyl heterocyclic compound. The method comprises the following steps: carrying out reduction reaction on a compound # imgabs0 # as shown in a formula III and a reducing agent in an organic solvent to generate a compound # imgabs1 # as shown in a formula IV; wherein X is selected from O, S or N-R, R is an amino protecting group, and n is selected from 1, 2, 3 or 4; and when X is N-R, the preparation method further comprises the step of removing an amino protecting group R from the compound as shown in the formula IV to obtain a compound # imgabs2. The preparation method disclosed by the invention is relatively safe, does not involve the use of highly toxic reagents, and is relatively low in cost, relatively mild in reaction conditions, relatively high in target product yield and easy to industrialize.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly to a method for preparing trifluoromethyl heterocyclic compounds. Background Art

[0002] Due to the characteristics of trifluoromethyl (CF3) such as strong electron-withdrawing property, lipophilicity, and stable C-F bonds, introducing it into organic compounds can significantly change the acidity, dipole moment, polarity, lipophilicity, and chemical and metabolic stability of the compounds. Therefore, compounds containing trifluoromethyl have been widely used in the fields of medicine, pesticides, and materials, and are commonly used molecular building blocks in the new drug R & D process. In addition, heterocycles are widely used in medicinal chemistry and materials science. Incorporating heterocyclic groups into molecules can form interactions with targets or serve as linking groups to make the molecules form geometric conformations favorable for activity. Among many heterocyclic structures, nitrogen-containing heterocycles are the most widely used. Research shows that between 2013 and 2023, the FDA approved 321 new small molecule drugs, of which 82% contain at least one nitrogen heterocycle, and this proportion has shown an astonishing increase compared to 59% in the past few decades. Therefore, in recent years, nitrogen-containing heterocycles containing trifluoromethyl have been increasingly used as important molecular building blocks in new drug R & D.

[0003] Currently, such trifluoromethyl-containing heterocyclic compounds, especially nitrogen-containing heterocyclic compounds substituted with trifluoromethyl, are usually prepared by the conversion of corresponding carboxylic acids (as shown in the following formula).

[0004]

[0005] Specifically, under the catalysis of anhydrous hydrogen fluoride, sulfur tetrafluoride can convert carboxyl groups into trifluoromethyl groups (Smith, W.C., etc., J. Am. Chem. Soc., 1959, 3165 - 3166), or carboxyl groups can be converted into trifluoromethyl groups by trifluoromethylation reagents under transition metal catalysis (Tan, X., etc., J. Am. Chem. Soc., 2017, 139, 12430 - 12433. Kautzky, J.A., etc., J. Am. Chem. Soc., 2018, 140, 6522 - 6526). However, the above methods either require the use of highly toxic hydrogen fluoride and sulfur tetrafluoride, or require the use of expensive trifluoromethylation reagents and harsh reaction conditions, which are not conducive to the large-scale preparation of trifluoromethyl-containing heterocyclic compounds and also hinder the application of such compounds in new drug R & D. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a preparation method of trifluoromethyl heterocyclic compounds in view of the disadvantages and deficiencies of the prior art. This preparation method is relatively safe, does not involve the use of highly toxic reagents, has a relatively low cost, mild reaction conditions, a high yield of the target product, and is easy to industrialize.

[0007] To solve the above technical problems, the present invention adopts the following technical solutions:

[0008] A preparation method of trifluoromethyl heterocyclic compounds, wherein the preparation method includes reacting a compound represented by Formula III

[0009] with a reducing agent in an organic solvent to generate a compound represented by Formula IV ; wherein, X is selected from O, S or N-R, R is an amino protecting group, n is selected from 1, 2, 3 or 4; and when X is N-R, the preparation method further includes removing the amino protecting group R from the compound represented by Formula IV to obtain a compound .

[0010] When it is an oxygen-containing or sulfur-containing heterocyclic compound, no protecting group is required for protection, while when it is a nitrogen-containing heterocyclic compound, a protecting group needs to be used for protection, and finally the protecting group is removed to obtain the target product.

[0011] In some embodiments, the reducing agent is selected from one or a combination of more of hydrogen, triethylsilane / boron trifluoride, lithium aluminum hydride, sodium borohydride, tributyltin hydride. Triethylsilane / boron trifluoride refers to the combination of the two, wherein triethylsilane is used as the reducing agent, and boron trifluoride can promote the reduction. In a conventional reduction reaction, triethylsilane can be used alone as the reducing agent, while in the aforementioned reduction reaction of the present invention, the cooperation of the two must be used to utilize the promoting effect of boron trifluoride on the reduction of triethylsilane.

[0012] Furthermore, the reducing agent is preferably triethylsilane / boron trifluoride, lithium aluminum hydride.

[0013] Furthermore, the molar ratio of triethylsilane to boron trifluoride in triethylsilane / boron trifluoride is 1:0.1 - 1:1.

[0014] In some embodiments, the organic solvent is selected from one or a combination of more of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, and diethyl ether.

[0015] In some embodiments, the molar ratio of the compound represented by Formula III to the reducing agent is 1:1 - 5.

[0016] In some embodiments, R is selected from one or more combinations of benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), o-methylbenzenesulfonyl (Ns), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), and trifluoroacetyl (Tfa).

[0017] Preferably, it is benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), trityl (Trt), trifluoroacetyl (Tfa).

[0018] In some embodiments, R is benzyloxycarbonyl, and the deprotection of the amino protecting group R is achieved by hydrogen reduction, acidolytic cleavage, or reduction with sodium metal-ammonia solution in the presence of a metal catalyst.

[0019] Furthermore, the metal catalyst can be palladium on carbon, palladium chloride, palladium hydroxide, ruthenium on carbon, platinum oxide, or Raney nickel, and the acid used for acidolytic cleavage can be hydrogen chloride, hydrogen bromide, trimethylsilyl iodide, trimethylsilyl chloride, trifluoromethanesulfonic acid, or trifluoroacetic acid.

[0020] In some embodiments, R is fluorenylmethoxycarbonyl, and the deprotection of the amino protecting group R is achieved by hydrolysis under basic conditions.

[0021] Furthermore, the base can be piperidine, ammonia water, sodium hydroxide, ethanolamine, cyclohexylamine, morpholine, pyrrolidone, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.

[0022] In some embodiments, R is trityl, and the deprotection of the amino protecting group R is achieved by acidolytic cleavage.

[0023] Furthermore, the acid used for acidolytic cleavage can be hydrogen chloride, hydrogen bromide, acetic acid, or trifluoroacetic acid.

[0024] In some embodiments, R is trifluoroacetyl, and the deprotection of the amino protecting group R is achieved by acidolytic cleavage or hydrolysis under basic conditions.

[0025] Furthermore, the acid used for acidolytic cleavage can be hydrogen chloride, hydrogen bromide, acetic acid, or trifluoroacetic acid, and the base used for base hydrolysis can be piperidine, ammonia water, sodium hydroxide, ethanolamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.

[0026] In some embodiments, the time of the reduction reaction is 1 - 10 h.

[0027] In some embodiments, the temperature of the reduction reaction is -10 to 50 °C.

[0028] In some embodiments, the preparation method further comprises subjecting the compound represented by Formula II to a trifluoromethylation reaction with a trifluoromethylation reagent to form a compound represented by Formula III ; the trifluoromethylation reagent is selected from one or two of (trifluoromethyl)trimethylsilane and bromotrifluoromethane. The compound represented by Formula II is difficult to undergo trifluoromethylation reaction. Through extensive research, the inventors of the present application found that when one or two of (trifluoromethyl)trimethylsilane and bromotrifluoromethane are used as the trifluoromethylation reagent, the trifluoromethylation reaction can proceed smoothly to form the target compound represented by Formula III. However, when other conventional trifluoromethylation reagents are used, the reaction cannot proceed smoothly, and the compound represented by Formula II may undergo ring opening, and the target product cannot be obtained. In the present invention, the intermediate III is prepared by subjecting the compound (heterocyclic ketone) represented by Formula II to a trifluoromethylation reaction, and then the target product is prepared by reducing it. This reaction route is completely different from the prior art.

[0029] In some embodiments, the molar ratio of the compound represented by Formula II to the trifluoromethylation reagent is 1:1 - 5.

[0030] In some embodiments, when the trifluoromethylation reagent contains (trifluoromethyl)trimethylsilane, an activator and a leaving group promoter are further added during the trifluoromethylation reaction. The activator is selected from one or more combinations of KF, CsF, sodium fluoride, pyridine hydrogen fluoride, and triethylamine trihydrofluoride, and the leaving group promoter is selected from one or more combinations of tetrabutylammonium fluoride, hydrochloric acid, and hydrofluoric acid.

[0031] Preferably, the molar ratio of (trifluoromethyl)trimethylsilane, activator, and leaving group promoter is 1:0.7 - 3:0.7 - 3.

[0032] In some embodiments, when the trifluoromethylation reagent contains bromotrifluoromethane, an activator is further added during the trifluoromethylation reaction. The activator is selected from one or more combinations of zinc powder and indium.

[0033] Preferably, bromotrifluoromethane makes the pressure of the reaction system 0.2 - 0.5 MPa.

[0034] In some embodiments, the temperature of the trifluoromethylation reaction is -10 to 50 °C.

[0035] In some embodiments, the time of the trifluoromethylation reaction is 1 - 10 h.

[0036] In some embodiments, the preparation method further comprises subjecting the compound represented by Formula I It undergoes an oxidation reaction with an oxidant to form the compound shown in Formula II The compound shown in Formula II can be commercially available or can be prepared by the oxidation reaction of heterocyclic alcohol, and the latter can further save costs

[0037] In some embodiments, the oxidant is selected from one or a combination of ruthenium tetroxide, manganese dioxide, potassium monopersulfate triple salt, sodium hypochlorite, trichloroisocyanuric acid, pyridine sulfur trioxide, lead tetraacetate, sodium periodate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, Dess-Martin periodinane, peroxybenzoic acid, and pyridinium dichromate

[0038] Furthermore, the oxidant is preferably manganese dioxide, trichloroisocyanuric acid, pyridine sulfur trioxide, Dess-Martin periodinane

[0039] In some embodiments, the molar ratio of the compound shown in Formula I to the oxidant is 1:1 - 5

[0040] In some embodiments, the temperature of the oxidation reaction is -10 to 50 °C

[0041] In some embodiments, the time of the oxidation reaction is 1 - 10 h

[0042] The present invention also provides an intermediate suitable for preparing the compound shown in Formula IV The intermediate has the structure shown in Formula III below

[0043]

[0044] Wherein, X is selected from O, S or N-R, R is an amino protecting group, and n is selected from 1, 2, 3 or 4

[0045] Compared with the prior art, the present invention has the following technical advantages

[0046] The prior art usually introduces a trifluoromethyl group into a heterocyclic substrate molecule by converting a carboxyl group into a trifluoromethyl group, while the present invention introduces a trifluoromethyl group onto a heterocyclic ketone substrate, selects a specific trifluoromethylation reagent, and then reduces the intermediate containing a hydroxyl group and a trifluoromethyl group to obtain the target product trifluoromethyl heterocyclic compound, and this reaction route is completely new

[0047] The preparation method of the present invention does not involve the use of highly toxic hydrogen fluoride and sulfur tetrafluoride, nor does it involve the use of expensive trifluoromethylation reagents. There are no harsh conditions that are not conducive to scale-up reactions during the process, the requirements for the reaction system are low, the production process cost is low, the yield of the target product is high, and the environmental friendliness of the process is significantly improved Brief Description of the Drawings

[0048] Figure 1 The 1 H-NMR spectrum of compound 3 prepared in Example 1;

[0049] Figure 2 The 1 H-NMR spectrum of compound 7 prepared in Example 7;

[0050] Figure 3 The 1 H-NMR spectrum of compound 11 prepared in Example 8;

[0051] Figure 4 The 1 H-NMR spectrum of compound 15 prepared in Example 9;

[0052] Figure 5 The 1 H-NMR spectrum of compound 20 prepared in Example 10;

[0053] Figure 6 The 1 H-NMR spectrum of compound 34 prepared in Example 13;

[0054] Figure 7 The 1 H-NMR spectrum of compound 40 prepared in Example 13;

[0055] Figure 8 The 1 H-NMR spectrum of compound 46 prepared in Example 15. Detailed implementation manners

[0056] In the present invention, heterocyclic alcohol I is used as the starting material, and after oxidation, heterocyclic ketone II is prepared. Then, a trifluoromethylation reaction is carried out to prepare intermediate III, and then reduction is carried out to prepare the corresponding trifluoromethyl-containing heterocyclic compound IV, where X is O or S.

[0057]

[0058] When X is a nitrogen atom, it needs to be protected to prepare intermediate V, then oxidation is carried out to prepare intermediate VI, then a trifluoromethylation reaction is carried out to prepare intermediate VII, then a reduction reaction is carried out to prepare intermediate VIII, and finally the protecting group is removed to obtain the target compound. The specific reaction formula is as follows:

[0059]

[0060] In the starting material heterocyclic alcohol I of the present invention, X can be an oxygen atom, a nitrogen atom, or a sulfur atom, and the heterocycle can be a four-membered ring, a five-membered ring, or a six-membered ring, that is, n can be 1, 2, or 3. Further, in the raw material heterocyclic alcohol I, X is preferably a nitrogen atom and an oxygen atom, and specifically can be compounds with the following structural formulas:

[0061]

[0062] The following further describes the present invention in conjunction with embodiments, but these embodiments are not intended to limit the protection scope of the present invention.

[0063] The technical features of the following described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the following embodiments are described. However, as long as the combinations of these technical features do not conflict, they should all be considered as the scope described in this specification.

[0064] The following described embodiments only represent several implementation manners of the present invention. The description is relatively specific and detailed, but it cannot be understood as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several deformations and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent should be subject to the appended claims.

[0065] Example 1

[0066] In this example, compound 4 is prepared, and the reaction formula is as follows:

[0067]

[0068] The preparation steps are as follows:

[0069] Dissolve 50 g of compound 1 in 300 mL of dichloromethane (DCM), then add 315 g of Dess-Martin periodinane (DMP) portionwise at room temperature, continue stirring for 2 h, then filter the system, collect the filtrate, concentrate it, and perform silica gel column purification to obtain compound 2 with a yield of 75%.

[0070] Dissolve 30 g of compound 2 in 200 mL of tetrahydrofuran (THF), then add 24 g of potassium fluoride (KF), stir for 10 min, then cool the system in an ice-water bath, and then add 71 g of (trifluoromethyl)trimethylsilane (TMSCF3) portionwise. After the addition is complete, restore the system to room temperature and continue stirring and reacting for 3 h. Then add 108 g of tetrabutylammonium fluoride (TBAF) and continue stirring and reacting for 1 h. Then concentrate the system and perform silica gel column purification to obtain compound 3 with a yield of 65% for this step.

[0071] 1H-NMR (400 MHz, CD3OD): δ 5.08 (d, J = 5.9 Hz, 2H), 4.75 (d, J = 5.9 Hz, 2H).

[0072] The NMR spectrum of Compound 3 is as follows Figure 1 shown below.

[0073] Dissolve 35 g of Compound 3 in 500 mL of THF, then cool the system in an ice-water bath, add 14 g of lithium aluminum hydride portionwise, then heat the system to 60 °C and react for 5 h. Then cool the system in an ice-water bath, gradually add 6 M aqueous sodium hydroxide solution dropwise to quench the reaction. Then add 1 L of ethyl acetate and 1 L of water, stir for 30 min, then let it stand, separate and collect the ethyl acetate layer, add anhydrous sodium sulfate for drying, and then remove the solvent. The residue is subjected to fractional distillation to obtain Compound 4, and the yield of this step is 50%. 1 H-NMR (400 MHz, CD3OD): δ 4.93 (dd, J = 7.0, 5.9 Hz, 2H), 4.76 (dd, J = 7.0, 6.0 Hz, 2H), 3.36–3.17 (m, 1H).

[0074] Example 2

[0075] This example is basically the same as Example 1, except that: the process for preparing Compound 2 from Compound 1 is different.

[0076] Specifically as follows:

[0077]

[0078] Dissolve 20 g of Compound 1 in 150 mL of dichloromethane (DCM), then add 47 g of activated manganese dioxide portionwise at room temperature. Stir the system at room temperature for 48 h, then filter the system, collect the filtrate, concentrate it and perform silica gel column purification to obtain Compound 2, with a yield of 60%.

[0079] Example 3

[0080] This example is basically the same as Example 1, except that: the process for preparing Compound 2 from Compound 1 is different.

[0081] Specifically as follows:

[0082]

[0083] Dissolve 20 g of Compound 1 in 150 mL of dichloromethane (DCM). Then add 2.1 g of 2,2,6,6 - tetramethylpiperidine 1 - oxide (TEMPO) at room temperature, followed by adding 34 g of sodium bicarbonate. After the system is stirred for 10 min, add 44 g of trichloroisocyanuric acid (TCCA) in batches. The system is continuously stirred at room temperature for 1 h, filtered and the filtrate is collected. Then cool the filtrate in an ice - water bath, add 200 mL of water and stir. Let the system stand still, separate and collect the dichloromethane phase, add anhydrous sodium sulfate for drying, and then remove the solvent. Purify the residue by silica gel column chromatography to obtain Compound 2 with a yield of 80%.

[0084] Example 4

[0085] This example is basically the same as Example 1, with the only difference being that the process for preparing Compound 2 from Compound 1 is different.

[0086] Specifically as follows:

[0087]

[0088] Dissolve 20 g of Compound 1 in 150 mL of dichloromethane (DCM). Then add 86 g of pyridine sulfur trioxide (Py.SO3) in batches at room temperature. Stir the system at room temperature for 48 h, then concentrate the system and directly perform silica gel column purification to obtain Compound 2 with a yield of 50%.

[0089] Example 5

[0090] This example is basically the same as Example 1, with the only difference being that the process for preparing Compound 3 from Compound 2 is different.

[0091] Specifically as follows:

[0092]

[0093] Add 200 mL of pyridine (Py) to a 1 L Hastelloy reactor, then add 20 g of Compound 2. Subsequently, add 17.6 g of zinc powder at room temperature. After stirring for 10 min, introduce bromotrifluoromethane, maintain the system pressure at 0.3 - 0.4 MPa and react for 5 h. After the reaction is completed, add 10 mL of water, stir and filter the system. Collect the filtrate, concentrate it and perform silica gel column purification to obtain Compound 3 with a yield of 50% for this step.

[0094] Example 6

[0095] This example is basically the same as Example 1, with the only difference being that the process for preparing Compound 4 from Compound 3 is different.

[0096] Specifically as follows:

[0097]

[0098] Dissolve 30 g of Compound 3 in 200 mL of dichloromethane. Then cool the system in an ice-water bath, add 6 g of 47% boron trifluoride diethyl etherate and stir for 10 min. Next, add 36.8 g of triethylsilane. Restore the system to room temperature and continue stirring for 5 h. Then add 200 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand still, separate and collect the dichloromethane phase, add anhydrous sodium sulfate for drying, and then remove the solvent. Subject the residue to rectification to obtain Compound 4, and the yield of this step is 65%.

[0099] Example 7

[0100] In this example, Compound 8 was prepared, and the reaction formula is as follows:

[0101]

[0102] The preparation steps are as follows:

[0103] Dissolve 100 g of Compound 5 in 500 mL of dichloromethane (DCM). Then add 18 g of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) at room temperature, and then add 95 g of sodium bicarbonate. After stirring the system for 10 min, add 185 g of trichloroisocyanuric acid (TCCA) in batches. Continue to stir the system at room temperature for 2 h, filter and collect the filtrate. Then cool the filtrate in an ice-water bath, add 500 mL of water and stir. Let the system stand still, separate and collect the dichloromethane phase, add anhydrous sodium sulfate for drying, and then remove the solvent. Subject the residue to silica gel column purification to obtain Compound 6, and the yield is 65%.

[0104] Dissolve 60 g of Compound 6 in 300 mL of tetrahydrofuran (THF). Cool the system in an ice-water bath, and then add 119 g of (trifluoromethyl)trimethylsilane (TMSCF3) in batches. After the addition, restore the system to room temperature and continue stirring for 3 h. Then add 182 g of tetrabutylammonium fluoride (TBAF) and continue stirring for 1 h. Then concentrate the system and perform silica gel column purification to obtain Compound 7, and the yield of this step is 60%.

[0105] 1 H NMR (400 MHz, CD3OD) δ 3.84–4.06 (m, 3H), 3.75 (d, J = 7.9 Hz, 1H), 2.28–2.41 (m, 1H), 1.93–2.06 (m, 1H).

[0106] The NMR spectrum of Compound 7 is as Figure 2 shown.

[0107] Dissolve 60 g of Compound 7 in 500 mL of dichloromethane. Then cool the system in an ice-water bath, add 11 g of 47% boron trifluoride diethyl etherate and stir for 10 min. Then add 49 g of triethylsilane. Restore the system to room temperature and continue stirring for 5 h. Then add 500 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand still, separate and collect the dichloromethane phase. Add anhydrous sodium sulfate for drying. Subsequently, remove the solvent and rectify the residue to obtain Compound 8, and the yield of this step is 55%.

[0108] 1 1H-NMR(400MHz,CD3OD):δ3.83(d,J = 8.3Hz,2H),3.71(m,2H),2.62 - 3.31(m,1H),2.15(m,2H).

[0109] Example 8

[0110] In this example, Compound 12 was prepared, and the reaction formula is as follows:

[0111]

[0112] The preparation steps are as follows:

[0113] Dissolve 100 g of Compound 9 in 500 mL of dichloromethane (DCM). Then add 15.3 g of 2,2,6,6-tetramethylpiperidine 1-oxide (TEMPO) at room temperature, and then add 82 g of sodium bicarbonate. After stirring the system for 10 min, add 159 g of trichloroisocyanuric acid (TCCA) in batches. Continue to stir the system at room temperature for 1 h, filter and collect the filtrate. Then cool the filtrate in an ice-water bath, add 500 mL of water and stir. Let the system stand still, separate and collect the dichloromethane phase. Add anhydrous sodium sulfate for drying. Subsequently, remove the solvent and purify the residue by silica gel column to obtain Compound 10, and the yield is 70%.

[0114] Dissolve 60 g of Compound 10 in 300 mL of tetrahydrofuran (THF). Cool the system in an ice-water bath. Then add 93.6 g of (trifluoromethyl)trimethylsilane (TMSCF3) in batches. After adding, restore the system to room temperature and continue stirring for 2 h. Then add 156 g of tetrabutylammonium fluoride (TBAF) and continue stirring for 1 h. Then concentrate the system and purify it by silica gel column to obtain Compound 11, and the yield of this step is 65%.

[0115] 1 1H NMR(400MHz,CD3OD)δ3.92–4.03(m,2H),3.75–3.89(m,2H),2.01–2.12(m,2H),1.76–1.90(m,2H).

[0116] The NMR spectrum of Compound 11 is as follows Figure 3 as shown

[0117] Dissolve 60 g of Compound 11 in 500 mL of dichloromethane. Then cool the system in an ice - water bath, add 10 g of 47% boron trifluoride etherate and stir for 10 min. Then add 45 g of triethylsilane. Let the system return to room temperature and continue stirring for 5 h. After that, add 500 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand, separate and collect the dichloromethane phase. Add anhydrous sodium sulfate for drying, then remove the solvent, and rectify the residue to obtain Compound 12, with a yield of 60% for this step.

[0118] 1 1H - NMR(400 MHz, CD3OD): δ 3.8–4.0(m, 2H), 3.4–3.6(m, 2H), 2.1–2.2(m, 1H), 1.72–1.88(m, 2H), 1.42–1.51(m, 2H).

[0119] Example 9

[0120] In this example, Compound 16 is prepared, and the reaction formula is as follows:

[0121]

[0122] The preparation steps are as follows:

[0123] Dissolve 100 g of Compound 13 in 500 mL of dichloromethane (DCM). Then add 15.3 g of 2,2,6,6 - tetramethylpiperidine - 1 - oxide (TEMPO) at room temperature, and then add 82 g of sodium bicarbonate. After stirring the system for 10 min, add 159 g of trichloroisocyanuric acid (TCCA) in batches. Let the system continue to stir at room temperature for 1 h, filter and collect the filtrate. Then cool the filtrate in an ice - water bath, add 500 mL of water and stir. Let the system stand, separate and collect the dichloromethane phase. Add anhydrous sodium sulfate for drying, then remove the solvent, and purify the residue by silica gel column chromatography to obtain Compound 14, with a yield of 60%.

[0124] Dissolve 60 g of Compound 14 in 300 mL of tetrahydrofuran (THF). Cool the system in an ice - water bath, and then add 93.6 g of (trifluoromethyl)trimethylsilane (TMSCF3) in batches. After adding, let the system return to room temperature and continue stirring for 2 h. Then add 156 g of tetrabutylammonium fluoride (TBAF) and continue stirring for 1 h. Then concentrate the system and purify it by silica gel column chromatography to obtain Compound 15, with a yield of 55% for this step.

[0125] 11H NMR (400 MHz, CD3OD) δ 3.99 (d, J = 11.4 Hz, 1H), 3.70–3.91 (m, 2H), 3.61 (d, J = 11.5 Hz, 1H), 2.05–2.18 (m, 1H), 1.90–2.01 (m, 1H), 1.59–1.86 (m, 2H).

[0126] The NMR spectrum of Compound 15 is as Figure 4 shown below.

[0127] Dissolve 60 g of Compound 15 in 500 mL of dichloromethane. Then cool the system in an ice-water bath, add 10 g of 47% boron trifluoride diethyl etherate and stir for 10 min. Then add 45 g of triethylsilane. Let the system return to room temperature and continue stirring for 5 h. Then add 500 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand still, separate the layers, collect the dichloromethane phase, dry it with anhydrous sodium sulfate, then remove the solvent, and rectify the residue to obtain Compound 16. The yield of this step is 50%.

[0128] 1 1H-NMR (400 MHz, CD3OD): δ 4.05 (dd, J = 11.2, 6.8 Hz, 1H), 3.55–3.65 (m, 3H), 2.12–2.33 (m, 1H), 1.9–2.1 (m, 1H), 1.41–1.82 (m, 3H).

[0129] Example 10

[0130] In this example, Compound 22 was prepared, and the reaction formula is as follows:

[0131]

[0132] The preparation steps are as follows:

[0133] Place 50 g of Compound 17 in 200 ml of trifluoroacetic anhydride and stir at room temperature for 5 h. Then use a mechanical pump to dry the system to obtain Compound 18 with a yield of 95%.

[0134] Dissolve 100 g of Compound 18 in 1 L of dichloromethane (DCM). Then add 276 g of Dess-Martin periodinane (DMP) portionwise at room temperature and continue stirring for 3 h. Then filter the system, collect the filtrate, concentrate it, and purify it by silica gel column chromatography to obtain Compound 19. The yield of this step is 70%.

[0135] Dissolve 60 g of Compound 19 in 300 mL of tetrahydrofuran (THF), then cool the system in an ice-water bath, and then add 56 g of (trifluoromethyl)trimethylsilane (TMSCF3) in batches. After the addition is complete, restore the system to room temperature and continue stirring the reaction for 3 h. Then add 94 g of tetrabutylammonium fluoride (TBAF) and continue stirring the reaction for 1 h. Then concentrate the system and perform silica gel column purification to obtain Compound 20, and the yield of this step is 60%.

[0136] 1 1H NMR (400 MHz, CD3OD) δ 4.69–4.55 (m, 1H), 4.42–4.53 (m, 1H), 4.26–4.37 (m, 1H), 4.12–4.21 (m, 1H).

[0137] The NMR spectrum of Compound 20 is as Figure 5 shown.

[0138] Dissolve 50 g of Compound 20 in 500 mL of dichloromethane, then cool the system in an ice-water bath, add 3 g of 47% boron trifluoride diethyl etherate and stir for 10 min, then add 45 g of triethylsilane. Restore the system to room temperature and continue stirring for 5 h. Then add 500 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand, separate and collect the dichloromethane phase, add anhydrous sodium sulfate for drying, and then remove the solvent. Distill the residue to obtain Compound 21, and the yield of this step is 50%.

[0139] Place 23 g of Compound 21 in 80 mL of 4 M hydrogen chloride methanol solution and stir at room temperature for 3 h. Then dry the system by suction to obtain the hydrochloride salt of Compound 22, and the yield of this step is 90%. 1 1H-NMR (400 MHz, CD3OD): δ 4.34–4.49 (m, 2H), 4.12–4.26 (m, 2H), 3.74–3.93 (m, 1H).

[0140] Example 11

[0141] In this example, Compound 22 was prepared, and the reaction formula is as follows:

[0142]

[0143] The preparation steps are as follows:

[0144] Place 50 g of Compound 17 in 300 ml of DCM, cool the system in an ice-water bath, and then add 123 g of benzyloxycarbonyl chloride (Cbz-Cl). React the system at room temperature for 3 h, and then use a mechanical pump to dry the system to obtain Compound 23 with a yield of 85%.

[0145] Dissolve 120 g of Compound 23 in 1.5 L of dichloromethane (DCM). Then, add 258 g of Dess-Martin periodinane (DMP) portionwise at room temperature and continue stirring for 2 h. After that, filter the system, collect the filtrate, concentrate it, and perform silica gel column purification to obtain Compound 24 with a yield of 60% for this step.

[0146] Dissolve 71 g of Compound 24 in 400 mL of tetrahydrofuran (THF). Then, cool the system in an ice-water bath and add 52 g of (trifluoromethyl)trimethylsilane (TMSCF3) portionwise. After addition, restore the system to room temperature and continue stirring for 2 h. Then, add 90.5 g of tetrabutylammonium fluoride (TBAF) and continue stirring for 1 h. After that, concentrate the system and perform silica gel column purification to obtain Compound 25 with a yield of 55% for this step.

[0147] Dissolve 50 g of Compound 25 in 500 mL of dichloromethane. Then, cool the system in an ice-water bath, add 5.2 g of 47% boron trifluoride diethyl etherate and stir for 10 min. Then, add 22 g of triethylsilane. Restore the system to room temperature and continue stirring for 5 h. Then, add 500 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand, separate the dichloromethane phase, add anhydrous sodium sulfate for drying, and then remove the solvent. Distill the residue to obtain Compound 26 with a yield of 55% for this step.

[0148] Place 25 g of Compound 26 in 250 mL of methanol and stir. Then, add 2.5 g of 10% Pd / C. Hydrogenate the system at a pressure of 0.2 MPa for 5 h. After the reaction is completed, filter the system, collect the filtrate, remove the solvent, and perform silica gel column purification to obtain Compound 22 with a yield of 90% for this step.

[0149] Example 12

[0150] Compound 22 is prepared in this example, and the reaction formula is as follows:

[0151]

[0152] The preparation steps are as follows:

[0153] Place 50 g of Compound 17 in 300 ml of DCM. Cool the system in an ice-water bath and then add 177 g of 9-fluorenylmethyl chloroformate (Fmoc-Cl). React the system at room temperature for 5 h. Then, use a mechanical pump to dry the system to obtain Compound 27 with a yield of 95%.

[0154] Dissolve 190 g of Compound 27 in 2 L of dichloromethane (DCM). Then, add 286 g of Dess-Martin periodinane (DMP) portionwise at room temperature. Continue stirring for 2 h. Then, filter the system, collect the filtrate, concentrate it, and perform silica gel column purification to obtain Compound 28. The yield of this step is 70%.

[0155] Dissolve 130 g of Compound 28 in 800 mL of tetrahydrofuran (THF). Then, cool the system in an ice-water bath. Next, add 66.2 g of (trifluoromethyl)trimethylsilane (TMSCF3) portionwise. After addition, restore the system to room temperature and continue stirring for 2 h. Then, add 116 g of tetrabutylammonium fluoride (TBAF) and continue stirring for 1 h. Then, concentrate the system and perform silica gel column purification to obtain Compound 29. The yield of this step is 60%.

[0156] Dissolve 90 g of Compound 29 in 500 mL of dichloromethane. Then, cool the system in an ice-water bath. Add 7.3 g of 47% boron trifluoride diethyl etherate and stir for 10 min. Then, add 29 g of triethylsilane. Restore the system to room temperature and continue stirring for 5 h. Then, add 500 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand, separate the dichloromethane phase, add anhydrous sodium sulfate for drying, and then remove the solvent. Distill the residue to obtain Compound 30. The yield of this step is 60%.

[0157] Place 50 g of Compound 30 in 250 mL of methanol and stir. Then, add 250 mL of 25% ammonia water. React the system at room temperature for 12 h. After the reaction is complete, concentrate the system and perform silica gel column purification to obtain Compound 22. The yield of this step is 85%.

[0158] Example 13

[0159] In this example, Compound 36 is prepared, and the reaction formula is as follows:

[0160]

[0161] The preparation steps are as follows:

[0162] Place 50 g of Compound 31 in 200 ml of trifluoroacetic anhydride and stir at room temperature for 6 h. Then, use a mechanical pump to dry the system to obtain Compound 32 with a yield of 90%.

[0163] Dissolve 90 g of Compound 32 in 1 L of dichloromethane (DCM). Then, add 219 g of Dess-Martin periodinane (DMP) portionwise at room temperature. Continue stirring for 2 h. Then, filter the system, collect the filtrate, concentrate it, and perform silica gel column purification to obtain Compound 33. The yield of this step is 65%.

[0164] Dissolve 50 g of Compound 33 in 300 mL of tetrahydrofuran (THF), then cool the system in an ice-water bath. Subsequently, add 41.2 g of (trifluoromethyl)trimethylsilane (TMSCF3) portionwise. After the addition is complete, restore the system to room temperature and continue stirring the reaction for 3 h. Then add 72.2 g of tetrabutylammonium fluoride (TBAF) and continue stirring the reaction for 1 h. Then concentrate the system and perform silica gel column purification to obtain Compound 34, with a yield of 60% for this step.

[0165] 1 H NMR (400 MHz, CD3OD) δ 3.89 (d, J = 9.5 Hz, 1H), 3.76–3.85 (m, 1H), 3.56–3.71 (m, 2H), 2.27–2.40 (m, 1H), 2.12–2.25 (m, 1H).

[0166] The NMR spectrum of Compound 34 is as Figure 6 shown.

[0167] Dissolve 40 g of Compound 34 in 500 mL of dichloromethane, then cool the system in an ice-water bath. Add 2.3 g of 47% boron trifluoride diethyl etherate and stir for 10 min. Then add 19.4 g of triethylsilane. Restore the system to room temperature and continue stirring for 5 h. Then add 500 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand, separate and collect the dichloromethane phase, add anhydrous sodium sulfate for drying, and then remove the solvent. Distill the residue to obtain Compound 35, with a yield of 50% for this step.

[0168] Place 18 g of Compound 35 in 90 mL of 4 M hydrogen chloride in methanol solution and stir at room temperature for 3 h. Then dry the system by suction to obtain the hydrochloride salt of Compound 36, with a yield of 95% for this step. 1 H-NMR (400 MHz, CD3OD): δ 3.12–3.20 (m, 1H), 2.95–3.12 (m, 1H), 2.70–2.85 (m, 2H), 2.431–2.50 (m, 1H), 1.77–1.92 (m, 1H), 1.45–1.52 (m, 1H).

[0169] Example 14

[0170] In this example, Compound 42 is prepared, and the reaction formula is as follows:

[0171]

[0172] The preparation steps are as follows:

[0173] Place 50 g of Compound 37 in 200 ml of trifluoroacetic anhydride and stir at room temperature for 6 h. Then use a mechanical pump to dry the system to obtain Compound 38, with a yield of 95%.

[0174] Dissolve 90 g of Compound 38 in 1 L of dichloromethane (DCM), then add 203 g of Dess-Martin periodinane (DMP) portionwise at room temperature, continue stirring for 2 h, then filter the system, collect the filtrate, concentrate it, and perform silica gel column purification to obtain Compound 39 with a yield of 60% for this step.

[0175] Dissolve 50 g of Compound 39 in 300 mL of tetrahydrofuran (THF), then cool the system in an ice-water bath, and then add 38.3 g of (trifluoromethyl)trimethylsilane (TMSCF3) portionwise. After addition, warm the system to room temperature and continue stirring for 3 h. Then add 67 g of tetrabutylammonium fluoride (TBAF) and continue stirring for 1 h. Then concentrate the system, perform silica gel column purification to obtain Compound 40 with a yield of 65% for this step.

[0176] 1 H NMR (400 MHz, CD3OD) δ 4.25–4.41 (m, 2H), 3.12–3.32 (m, 2H), 2.06–2.32 (m, 2H), 1.70–1.95 (m, 2H).

[0177] The NMR spectrum of Compound 40 is as Figure 7 shown.

[0178] Dissolve 40 g of Compound 40 in 500 mL of dichloromethane, then cool the system in an ice-water bath, add 4.4 g of 47% boron trifluoride diethyl etherate and stir for 10 min, then add 17.5 g of triethylsilane. Warm the system to room temperature and continue stirring for 5 h. Then add 500 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand, separate and collect the dichloromethane phase, add anhydrous sodium sulfate for drying, then remove the solvent, and perform rectification on the residue to obtain Compound 41 with a yield of 55% for this step.

[0179] Place 18 g of Compound 41 in 90 mL of 4 M hydrogen chloride in methanol solution and stir at room temperature for 3 h, then dry the system by suction to obtain the hydrochloride salt of Compound 42 with a yield of 95% for this step. 1 H-NMR (400 MHz, CD3OD): δ 3.15–3.32 (m, 2H), 2.66–2.87 (m, 2H), 1.91–2.08 (m, 1H), 1.78–1.89 (m, 2H), 1.55–1.68 (m, 2H).

[0180] Example 15

[0181] In this example, Compound 48 is prepared, and the reaction formula is as follows:

[0182]

[0183] The preparation steps are as follows:

[0184] Place 50 g of Compound 43 in 200 ml of trifluoroacetic anhydride and stir at room temperature for 6 h. Then, use a mechanical pump to dry the system to obtain Compound 44 with a yield of 92%.

[0185] Dissolve 90 g of Compound 44 in 1 L of dichloromethane (DCM). Then, add 203 g of Dess-Martin periodinane (DMP) portionwise at room temperature and continue stirring for 2 h. Then, filter the system, collect the filtrate, concentrate it, and perform silica gel column purification to obtain Compound 45 with a yield of 65% for this step.

[0186] Dissolve 50 g of Compound 45 in 300 mL of tetrahydrofuran (THF). Then, cool the system in an ice-water bath and add 38.3 g of (trifluoromethyl)trimethylsilane (TMSCF3) portionwise. After addition, restore the system to room temperature and continue stirring for 3 h. Then, add 67 g of tetrabutylammonium fluoride (TBAF) and continue stirring for 1 h. Then, concentrate the system and perform silica gel column purification to obtain Compound 46 with a yield of 65% for this step.

[0187] 1 H NMR (400 MHz, CD3OD) δ 4.35–4.53 (m, 1H), 4.07 (d, J = 12.4 Hz, 1H), 3.62 (d, J = 12.6 Hz, 1H), 2.83–2.97 (m, 1H), 2.01–2.17 (m, 1H), 1.62–1.86 (m, 3H).

[0188] Dissolve 40 g of Compound 46 in 500 mL of dichloromethane. Then, cool the system in an ice-water bath, add 4.4 g of 47% boron trifluoride diethyl etherate and stir for 10 min. Then, add 17.5 g of triethylsilane. Restore the system to room temperature and continue stirring for 5 h. Then, add 500 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand, separate the dichloromethane phase, add anhydrous sodium sulfate for drying, and then remove the solvent. Distill the residue to obtain Compound 47 with a yield of 55% for this step.

[0189] Place 18 g of Compound 47 in 90 mL of 4 M hydrogen chloride in methanol solution and stir at room temperature for 3 h. Then, dry the system to obtain the hydrochloride salt of Compound 48 with a yield of 95% for this step. 1 H-NMR (400 MHz, CD3OD): δ 3.15–3.28 (m, 2H), 2.63–2.87 (m, 2H), 2.09–2.25 (m, 1H), 1.77–1.95 (m, 1H), 1.33–1.65 (m, 3H).

[0190] Comparative Example 1

[0191]

[0192] Dissolve 10 g of Compound 17 in 100 mL of dichloromethane (DCM), then add 64 g of Dess-Martin periodinane (DMP) portionwise at room temperature, continue stirring for 3 h, then filter the system, collect the filtrate, concentrate it, and perform silica gel column purification to obtain Compound 49, with a yield of 30% for this step.

[0193] Dissolve 10 g of Compound 49 in 50 mL of tetrahydrofuran (THF), then cool the system in an ice-water bath, and then add 22 g of (trifluoromethyl)trimethylsilane (TMSCF3) portionwise. After addition, restore the system to room temperature and continue stirring for 3 h. Then add 36.7 g of tetrabutylammonium fluoride (TBAF) and continue stirring for 1 h. Then concentrate the system and perform silica gel column purification to obtain Compound 50, with a yield of only 6% for this step.

[0194] Dissolve 1 g of Compound 50 in 10 mL of dichloromethane, then cool the system in an ice-water bath, add 0.1 g of 47% boron trifluoride diethyl etherate and stir for 10 min, then add 1.5 g of triethylsilane. Restore the system to room temperature and continue stirring for 5 h. Then add 10 mL of saturated sodium bicarbonate solution and stir for 10 min. Let the system stand, separate the dichloromethane layer, add anhydrous sodium sulfate for drying, then remove the solvent, and perform rectification on the residue to obtain Compound 22, with a yield of only 25% for this step.

[0195] It can be seen that for oxygen-containing heterocyclic compounds, protection can be not carried out, that is, the reaction route of the present invention can be carried out. However, for nitrogen-containing heterocyclic compounds, N needs to be protected. When not protected, not only the yield will be significantly reduced during the oxidation reaction, but also the heterocyclic reaction substrate will ring-open during the subsequent trifluoromethylation reaction, resulting in a very low yield of the target product.

[0196] Comparative Example 2

[0197] Basically the same as Example 6, the only difference is that: in the process of preparing Compound 4 from Compound 3, boron trifluoride diethyl etherate is not added, and as a result, no reaction occurs in this step, and the yield is 0%. It can be seen that in the reaction system of the present invention, when using triethylsilane as a reducing agent, boron trifluoride must be added simultaneously to obtain the target product.

[0198] Comparative Example 3

[0199] Basically the same as Example 1, the only difference is that: in the process of preparing Compound 3 from Compound 2, KF is not added, and as a result, Compound 3 cannot be obtained in this step. It shows that during this step of the reaction, TMSCF3 requires KF as an activator.

[0200] Comparative Example 4

[0201] Basically the same as Example 1, except that: in the process of preparing Compound 3 from Compound 2, TBAF was not added, and as a result, Compound 3 could not be obtained in this step. It shows that in this step of the reaction, TMSCF3 requires TBAF as a leaving agent. Without adding TBAF, the product cannot be obtained, and the reaction will theoretically stay in the intermediate state, causing a significant reduction in the yield.

[0202] Comparative Example 5

[0203] Basically the same as Example 1, except that: in the process of preparing Compound 3 from Compound 2, KF / TMSCF3 / TBAF was not added, but methyl fluorosulfonyldifluoroacetate with an equimolar amount of TMSCF3 was added, and as a result, Compound 3 could not be obtained in this step.

[0204] Comparative Example 6

[0205] Basically the same as Example 1, except that: in the process of preparing Compound 3 from Compound 2, KF / TMSCF3 / TBAF was not added, but sodium trifluoroacetate with an equimolar amount of TMSCF3 was added, and as a result, Compound 3 could not be obtained in this step.

[0206] The descriptions of the above examples are only used to help understand the method and its core idea of the present invention. It should be noted that for those of ordinary skill in the art of this technology, without departing from the principle of the present invention, several improvements and modifications can still be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing a trifluoromethyl heterocyclic compound, characterized in that: The preparation method includes reacting a compound represented by Formula III with a reducing agent in an organic solvent to generate a compound represented by Formula IV ; wherein, X is selected from O, S or N-R, R is an amino protecting group, n is selected from 1, 2, 3 or 4; and when X is N-R, the preparation method further includes removing the amino protecting group R from the compound represented by Formula IV to obtain a compound .

2. The preparation method of the trifluoromethyl heterocyclic compound according to claim 1, characterized in that: The reducing agent is selected from one or a combination of more than one of hydrogen, triethylsilane / boron trifluoride, lithium aluminum hydride, sodium borohydride, and tributyltin hydride; and / or, the organic solvent is selected from one or a combination of more than one of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, and diethyl ether.

3. The preparation method of the trifluoromethyl heterocyclic compound according to claim 1, characterized in that: The molar ratio of the compound shown in Formula III to the reducing agent is 1:1 - 5.

4. The preparation method of the trifluoromethyl heterocyclic compound according to claim 1, wherein: R is selected from one or a combination of more than one of benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, o-methylphenylsulfonyl, triphenylmethyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, and trifluoroacetyl.

5. The preparation method of the trifluoromethyl heterocyclic compound according to claim 4, characterized in that: When R is benzyloxycarbonyl, the deprotection of the amino protecting group R is achieved by hydrogen reduction, acidolysis cleavage, or reduction with sodium metal-ammonia solution in the presence of a metal catalyst; or, when R is 9-fluorenylmethoxycarbonyl, the deprotection of the amino protecting group R is achieved by hydrolysis under basic conditions; or, when R is triphenylmethyl, the deprotection of the amino protecting group R is achieved by acidolysis cleavage; or, when R is trifluoroacetyl, the deprotection of the amino protecting group R is achieved by acidolysis cleavage or hydrolysis under basic conditions.

6. The preparation method of the trifluoromethyl heterocyclic compound according to claim 1, wherein: The time of the reduction reaction is 1 - 10 h; and / or, the temperature of the reduction reaction is -10 to 50 °C.

7. The method for preparing the trifluoromethyl heterocyclic compound according to claim 1, wherein: The preparation method further includes reacting a compound represented by Formula II with a trifluoromethylating reagent to form a compound represented by Formula III ; the trifluoromethylating reagent is selected from one or two of (trifluoromethyl)trimethylsilane and bromotrifluoromethane.

8. The preparation method of the trifluoromethyl heterocyclic compound according to claim 7, characterized in that: The compound shown in Formula II The molar ratio with the trifluoromethylating reagent is 1:1 - 5.

9. The preparation method of the trifluoromethyl heterocyclic compound according to claim 7, wherein: When the trifluoromethylation reagent contains (trifluoromethyl)trimethylsilane, an activator and a leaving group promoter are also added during the trifluoromethylation reaction. The activator is selected from one or a combination of more than one of KF, CsF, sodium fluoride, pyridine hydrogen fluoride, and triethylamine trihydrofluoride. The leaving group promoter is selected from one or a combination of more than one of tetrabutylammonium fluoride, hydrochloric acid, and hydrofluoric acid; preferably, the molar ratio of (trifluoromethyl)trimethylsilane, activator, and leaving group promoter is 1:0.7 - 3:0.7 - 3.

10. The preparation method of the trifluoromethyl heterocyclic compound according to claim 7, characterized in that: When the trifluoromethylation reagent contains bromotrifluoromethane, an activator is also added during the trifluoromethylation reaction. The activator is selected from one or a combination of more than one of zinc powder and indium.

11. The preparation method of the trifluoromethyl heterocyclic compound according to claim 7, wherein: The temperature of the trifluoromethylation reaction is -10 to 50 °C; and / or, the time of the trifluoromethylation reaction is 1 - 10 h.

12. The preparation method of the trifluoromethyl heterocyclic compound according to claim 7, characterized in that: The preparation method further includes subjecting the compound represented by Formula I to an oxidation reaction with an oxidizing agent to form the compound represented by Formula II .

13. The method for preparing the trifluoromethyl heterocyclic compound according to claim 12, wherein: The oxidizing agent is selected from one or a combination of more than one of ruthenium tetroxide, manganese dioxide, potassium monopersulfate triple salt, sodium hypochlorite, trichloroisocyanuric acid, sulfur trioxide pyridine, lead tetraacetate, sodium periodate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, Dess-Martin periodinane, peroxybenzoic acid, and pyridinium dichromate.

14. The preparation method of the trifluoromethyl heterocyclic compound according to claim 12, characterized in that: The molar ratio of the compound shown in Formula I to the oxidizing agent is 1:1 - 5; and / or, the temperature of the oxidation reaction is -10 to 50 °C; and / or, the time of the oxidation reaction is 1 - 10 h.

15. An intermediate suitable for preparing the compound shown in Formula IV , characterized in that: The intermediate has the structure shown in Formula III below: Wherein, X is selected from O, S, or N-R, R is an amino protecting group, and n is selected from 1, 2, 3, or 4.

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