A method for preparing triazolo[1,5-a]pyrazine-3-carboxylic acid and its application

Abstract

The present disclosure relates to a method for preparing triazolo[1,5-a]pyrazine-3-carboxylic acid and its applications. Specifically, a method for preparing triazolo[1,5-a]pyrazine-3-carboxylic acid is provided, which method comprises reacting a compound of formula F with a metal reagent, introducing carbon dioxide and an acidification step, wherein X is a halogen, such as chlorine or bromine. This process is simple to operate, has a high yield and the quality of the obtained samples is good, and it is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to a method for preparing triazolo[1,5-a]pyrazine-3-carboxylic acid and its application. Background Art

[0002] WO2019020070A describes a compound (S)-N5-(3,4-difluorophenyl)-6-methyl-N3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide with HBV inhibitory activity. Pharmacodynamic experiments show that this compound has an obvious inhibitory effect on the normal assembly of HBV capsid protein, and its pharmacokinetic absorption is good and the bioavailability is high. At the same time, this compound with a novel structure has no or little effect on the inhibition of the in vitro proliferation of HepG2 cells, showing good safety.

[0003]

[0004] Its preparation process is as follows:

[0005]

[0006] 6-Methyl-triazolo[1,5-a]pyrazine exists as a key intermediate for preparing the aforementioned HBV inhibitor. The quality of this intermediate is directly related to the quality and yield of the final product. However, when forming the triazolo[1,5-a]pyrazine structure through the Click reaction, 6-position methyl isomerization products are always generated. Especially when scaled up to the kilogram level, the Click reaction is not conducive to process scale-up production, and at the same time, it also restricts the quality and yield of the final product.

[0007]

[0008] In view of the fact that the methyl isomerization products will directly affect the yield of this step of the process and are related to the quality of the subsequent products, it is urgent to develop a new method for preparing (S)-N5-(3,4-difluorophenyl)-6-methyl-N3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide. Summary of the Invention

[0009] The present disclosure provides a method for preparing a compound of formula G of triazolo[1,5-a]pyrazine-3-carboxylic acid, including the steps of reacting a compound of formula F with a metal reagent and then reacting with carbon dioxide.

[0010]

[0011] Wherein X is a halogen, such as chlorine or bromine.

[0012] In some embodiments, the method for preparing the compound of formula G further includes an acidification step. In other embodiments, the acids used include, but are not limited to, hydrochloric acid or sulfuric acid.

[0013] In some embodiments, the metal (Grignard) reagent is selected from cyclohexylmagnesium chloride or isopropylmagnesium chloride. In some embodiments, the metal reagent needs to be used in excess, for example, the amount used is more than 3 times the molar amount of the compound of formula F. In some embodiments, the amount of the metal Grignard reagent used is 4 to 6 times the molar amount of the compound of formula F, including 4 times, 4.5 times, 5 times, 5.5 times, or 6 times or any value between any two numbers.

[0014] In some embodiments, the reaction temperature is selected from -20 to 10 °C, and can be -20 °C, -19 °C, -18 °C, -17 °C, -16 °C, -15 °C, -14 °C, -13 °C, -12 °C, -11 °C, -10 °C, -9 °C, -8 °C, -7 °C, -6 °C, -5 °C, -4 °C, -3 °C, -2 °C, -1 °C, -0 °C, 1 °C, 2 °C, 4 °C, 6 °C, 8 °C, 10 °C or any value between any two values, preferably -10 to -5 °C.

[0015] On the other hand, the method for preparing the compound of formula G further includes the step of converting the compound of formula E into the compound of formula F.

[0016] Wherein P is an amino protecting group and X is a halogen, such as chlorine or bromine.

[0017] In some embodiments, the amino protecting group is selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or benzyloxycarbonyl. In some embodiments, the amino protecting group is selected from tert-butoxycarbonyl or benzyloxycarbonyl.

[0018] In some embodiments, the step of converting the compound of formula E into the compound of formula F includes the following steps:

[0019]

[0020] The present disclosure also provides a method for preparing the compound of formula E, which includes the step of reacting the compound of formula C with a diphenylphosphine azide compound to form the compound of formula E.

[0021] Wherein P is an amino protecting group and X is a halogen, such as chlorine or bromine.

[0022] On the other hand, the compound of formula C in the present disclosure is a chiral molecule containing 1 chiral center and has 2 configurational isomers, such as

[0023]

[0024] In some embodiments, the method for preparing Compound E comprises the step of reacting a Compound of Formula C-1 with a diphenylphosphine azide compound.

[0025]

[0026] In some embodiments, the diphenylphosphine azide compound in the method described in the present disclosure is selected from diphenylphosphoryl azide.

[0027] In other embodiments, the reaction of the Compound of Formula C with the diphenylphosphine azide compound is carried out under basic conditions, and the base is selected from potassium carbonate, potassium phosphate, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the amount of the base used is 1 to 4 times the molar amount of the Compound of Formula C, being 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0 or any value between any two of these values.

[0028] In some embodiments, the solvent used for the reaction of the Compound of Formula C with the diphenylphosphine azide compound is selected from one or more of dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, xylene, dimethyl sulfoxide, preferably toluene.

[0029] In some embodiments, the reaction temperature is selected from 60 to 150 °C, being 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 110 °C, 120 °C, 130 °C, 140 °C, 150 °C or any value between any two of these values, preferably 80 to 120 °C.

[0030] In some embodiments, the molar ratio of the Compound of Formula C to the diphenylphosphine azide compound is 1:1.5 to 1:4, including but not limited to 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0 or any value between any two of these numbers.

[0031] In other embodiments, the Compound of Formula G is

[0032] The preparation method thereof comprises the step of converting a Compound of Formula F-1 into a Compound of Formula G-1.

[0033] Wherein X is a halogen, such as bromine or chlorine.

[0034] The present disclosure also provides a method for a compound of formula I or a pharmaceutically acceptable salt thereof,

[0035] The method includes the method steps for preparing the compound of formula G described above, and the step of reacting the compound of formula G with 1,1,1-trifluoropropan-2-amine to form the compound of formula I or a pharmaceutically acceptable salt thereof.

[0036]

[0037] In some embodiments, the method for a compound of formula I or a pharmaceutically acceptable salt thereof includes:

[0038]

[0039] wherein, P is an amino protecting group, and the amino protecting group is selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl, preferably tert-butoxycarbonyl or benzyloxycarbonyl; X is a halogen, such as chlorine or bromine.

[0040] In other embodiments, the method for a compound of formula I or a pharmaceutically acceptable salt thereof includes:

[0041]

[0042] wherein P is tert-butoxycarbonyl.

[0043] In other embodiments, the method for a compound of formula I or a pharmaceutically acceptable salt thereof includes:

[0044] Step a) Reacting the compound of formula E-1 with N-bromosuccinimide to form the compound of formula E-a1,

[0045] Step b) Removing the protecting group of the compound of formula E-a1 under acidic conditions to form the compound of formula E-b1,

[0046] Step c) Reacting the compound of formula E-b1 with methyl N-(3,4-difluorophenyl)carbamate to form the compound of formula F-1a,

[0047] Step d) After reacting the compound of formula F-1 with cyclohexylmagnesium chloride, reacting with carbon dioxide to form the compound of formula G-1,

[0048] Step e) Reacting the compound of formula G-1 with (R)-1,1,1-trifluoropropan-2-amine under the conditions of HATU / N,N-diisopropylethylamine to form the compound of formula I or a pharmaceutically acceptable salt thereof. Specific reaction conditions or operations can refer to the journal literature WO2019020070A, and the relevant content is incorporated herein for illustration.

[0049] The present disclosure also provides the following compounds:

[0050]

[0051] The method of the present disclosure further includes a post-treatment operation, such as one or more steps of filtration, extraction, concentration, column chromatography or chiral separation to obtain a pure target product.

[0052] The pharmaceutically acceptable salts of the present disclosure are the products formed by the salts of the compounds of formula I with acids, and the acids are selected from but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, malic acid or oxalic acid, etc.

[0053] The present disclosure also provides a pharmaceutical composition, which contains an effective therapeutic amount of the compound of formula I or its pharmaceutically acceptable salt prepared by the foregoing method, and one or more pharmaceutically acceptable excipients.

[0054] The present disclosure also provides a method for preparing a pharmaceutical composition, which includes the step of mixing the compound of formula I or its pharmaceutically acceptable salt prepared by the foregoing method with one or more pharmaceutically acceptable excipients.

[0055] The present disclosure also provides the use of the compound of formula I or its pharmaceutically acceptable salt prepared by the foregoing method, or the foregoing pharmaceutical composition in the preparation of a drug for treating viral infectious diseases, the virus is preferably hepatitis B virus, influenza virus, herpes virus and human immunodeficiency virus, and the diseases are preferably hepatitis B, influenza, herpes and acquired immunodeficiency syndrome.

[0056] The terms used in the present invention, unless otherwise stated, have the following meanings:

[0057] "To form" and "to be transformed into" in the present disclosure do not specifically refer to the transformation reaction between two substrates as a single-step reaction, and can be a single-step or multi-step reaction between two substrates.

[0058] "Amino protecting group" is a suitable group known in the art for protecting amino groups, see the hydroxyl protecting groups in the literature (《Protective Groups in Organic Synthesis》, 5 Th Ed.T.W.Greene&P.G.M.Wuts). As examples, it includes but is not limited to carbamate protecting groups, such as tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz).

[0059] As used herein, "effective amount" or "effective therapeutic amount" includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical disorder. An effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the disorder to be treated, the overall health of the patient, the method and route of administration and dosage, and the severity of side effects. The effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0060] As used herein, "excipient" includes, but is not limited to, any adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, or emulsifying agent that has been approved by the US Food and Drug Administration for use in humans or domestic animals.

[0061] The structure of the compound was determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, and the solvents used were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0062] The HPLC measurements were performed using an Agilent 1200 high-pressure liquid chromatograph (Evo C18 4.6*250mm, 5um column or Xtimate C18 2.1*30mm column).

[0063] Chiral HPLC analysis was performed using a Chiralpak IF 150*4.6mm, 5um column or a Lux Amylose-2 150*4.6mm, 5um column.

[0064] The thin-layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin-layer chromatography (TLC) were 0.15mm - 0.2mm, and the specifications of the silica gel plates used for separating and purifying products by thin-layer chromatography were 0.4mm - 0.5mm.

[0065] The rapid column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0066] The advantages of the technical solutions in the present disclosure are embodied in the following aspects:

[0067] As is well known, alkenyl and aryl halides are very prone to undergo oxidative addition with Pd to form palladium-carbon-containing complexes, and then carbon monoxide inserts between the palladium-carbon bonds to achieve carbonylation. However, carbon monoxide is a highly toxic pollutant to the blood and the nervous system. It binds to hemoglobin in the blood, not only reducing the ability of blood cells to carry oxygen, but also inhibiting and delaying the dissociation and release of oxyhemoglobin, leading to necrosis of body tissues due to hypoxia, and in severe cases, it may endanger human life. Therefore, the use of carbon monoxide will inevitably bring more uncertainties to the entire process or its scale-up. The technical solution in this disclosure avoids the use of carbon monoxide in the process, and the overall process is more feasible, safe, and environmentally friendly.

[0068] On the other hand, although the metal palladium catalyst can achieve carbonylation efficiently to a certain extent, the cost of the metal palladium catalyst is high, resulting in a relatively high overall process cost. The technical solution in this disclosure uses Grignard reagents to greatly reduce the overall process cost and avoid the use of heavy metals, making the process more environmentally friendly. Detailed implementation manners

[0069] The following will illustrate the present disclosure in detail with specific examples, so that those skilled in the art can understand the content of the present disclosure more comprehensively. The specific examples are only used to illustrate the technical solutions of the present disclosure and do not limit the present invention in any way.

[0070] Example 1

[0071]

[0072] Step 1)

[0073] In a 30 L reaction kettle, (S)-2-aminopropanol (3788.0 g, 50.4 mol, 3.0 eq), acetonitrile (10 L, 5 V), and anhydrous sodium carbonate (3563.0 g, 33.6 mol, 2.0 eq) were successively added. Stirring was started, and the temperature was lowered to 0 - 5 °C. A solution of 3-bromopropyne (2000.0 g, 16.8 mol, 1.0 eq) in acetonitrile (10 L) was added. Stirring reaction was carried out until 3-bromopropyne was basically completely reacted. Filtration was carried out, and the filtrate was concentrated under reduced pressure. Water (8 L) was added, and extraction was carried out with toluene / 2-methyltetrahydrofuran. After drying and concentration, the target product (1.166 kg) was obtained, with a yield of 61.3%.

[0074] Step 2)

[0075] In a 20 L reactor, add the product of the previous step (1100.0 g, 9.7 mol, 1.0 eq), toluene (11 L) and DBU (1479.9 g, 9.7 mol). Heat to 50 °C, add DPPA (diphenylphosphoryl azide, 2675.2 g, 9.7 mol, 1.0 eq) to the reactor, heat to 100 - 120 °C and stir until the reaction is complete. Quench the reaction with purified water (5.5 L, 5V), extract with toluene, and retain the aqueous phase for later use.

[0076] Step 3)

[0077] Add methanol (11 L) and triethylamine (1969.0 g) to the aqueous phase obtained in the above step, cool to 10 - 15 °C, and add Boc 2 O (di-tert-butyl dicarbonate, 4240.5 g, 19.4 mol, 2.0 eq), stir until the reaction is complete, concentrate under reduced pressure to dryness, add water for dilution, extract with toluene, combine the organic phases, dry, and concentrate to obtain 1.4 kg of the target product, HPLC ≥ 99%.

[0078] Step 4)

[0079] Add the product of the previous step (1.4 kg) to the reactor, add DMF (7 L), heat to 40 - 50 °C, add NBS (0.2266 kg, 1.3 eq), stir and react for 30 - 40 min, quench the reaction with 10% aqueous sodium sulfite solution, extract with tetrahydrofuran (7 L) and MTBE (21 L, 15V), wash with saturated brine, dry, and concentrate to obtain the target product.

[0080] 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 4.96 - 4.92 (m, 1H), 4.78 - 4.70 (m, 1H), 4.54 - 4.29 (m, 3H), 1.47 (s, 9H), 1.05 (d, 3H).

[0081] Step 5)

[0082] Dissolve the product of the previous step in ethyl acetate (10.5 L) and ethanol (2.8 L), add 4M hydrochloric acid dioxane solution (10.5 L), stir and react at 40 °C, cool to room temperature, filter, wash with ethyl acetate, and dry to obtain 0.868 kg, with a yield of 62.3% and HPLC of 85%.

[0083] 1 H NMR (400 MHz, DMSO-d 6)δ 10.50 (s, 2H), 4.89 (dd, 1H), 4.59 - 4.55 (m, 1H), 4.44 - 4.41 (m, 1H), 4.40 - 4.33 (m, 1H), 3.94 - 3.89 (m, 1H), 1.49 (d, 3H).

[0084] Example 2

[0085]

[0086] In a 25 mL reaction flask, successively add compound 3 (0.8 g, 1.0 eq), anhydrous THF (8 mL). Under nitrogen protection, cool the temperature to -10 - 10 °C. After dropping 8 mL of 1.3 M cyclohexylmagnesium chloride solution, slowly introduce dry carbon dioxide, control the reaction temperature according to Table 1, and introduce carbon dioxide for 1 - 2 h.

[0087] Monitor the reaction by HPLC until it is completed. Dropwise add 4 M hydrochloric acid to quench the reaction, separate the layers, extract with ethyl acetate, extract twice with saturated sodium bicarbonate aqueous solution, collect the aqueous layer, adjust the pH to 1 - 2 with concentrated hydrochloric acid, then add methyl tert-butyl ether, and a large amount of white solid precipitates. Filter the white solid, dry it, and calculate the yield.

[0088] Table 1

[0089] Sequence Reagent Reaction temperature Yield 1 Magnesium chloride 25-30℃ 25.4％ 2 Magnesium chloride 10-15℃ 45.3％ 4 Magnesium chloride -10～-5℃ 55.1％ 5 Magnesium chloride -30～-20℃ <![CDATA[57% a >

[0090] Note: a The reaction time is about 1 time longer than that at the reaction temperature of -15 - -5 °C.

[0091] Example 3

[0092]

[0093] Step 1)

[0094] In a 50 L reaction kettle, successively add compound 1 (6000 g, 23.0 mol, 1 eq), N,N-dimethylformamide (60 L, 10 V), compound 2 (5625 g, 22.5 mol, 0.98 eq), triethylamine (4660 g, 46.0 mol, 2.0 eq), stir evenly, slowly raise the temperature to 50 - 60 °C and stir for reaction. Monitor the reaction by HPLC until compound 2 is basically completely reacted. Add water to quench the reaction, stir for 1 h, filter, collect the filter cake, wash it, and filter and place it in a vacuum drying oven at 55 °C for drying for 15 - 20 h to obtain 7.92 g, with a yield of 90.2%.

[0095] Step 2)

[0096] In a 250 L reactor, compound 3 (7900 g, 21.22 mol, 1.0 eq) and anhydrous THF (79 L, 10 V) were added successively. Under nitrogen protection, the temperature was lowered to -10 - 10 °C. After dropping 73.5 L of 1.3 M cyclohexylmagnesium chloride solution, dry carbon dioxide was slowly introduced while maintaining the reaction solution temperature < -5 °C, and carbon dioxide was introduced for 1 - 2 h.

[0097] 4 M hydrochloric acid was dropped in, controlling the reaction solution temperature < 10 °C to quench the reaction. It was stirred and left to stand for liquid separation. The organic phase was collected. The aqueous phase was extracted once with ethyl acetate (24 L, 3 V). The organic phases were combined and extracted twice with saturated aqueous sodium bicarbonate (24 L, 3 V). The aqueous layers collected were combined. The aqueous phase was washed once with methyl tert-butyl ether (24 L, 3 V). Concentrated hydrochloric acid was slowly dropped into the aqueous phase to adjust the pH to 1 - 2. Then methyl tert-butyl ether (32 L, 4 V) was added, and a large amount of white solid precipitated out. It was filtered, washed, and vacuum dried at 50 °C to obtain 3.58 kg of white solid with a yield of 50.2%.

[0098] Step 3)

[0099] In a 50 L reactor, compound 4 (3000 g, 8.89 mol, 1 eq) was added to DMF (12.0 L, 4 V). HATU (4.057 kg, 10.67 mol), (R)-1,1,1-trifluoropropan-2-amine (1.4 kg, 9.34 mol), and DIPEA (2.53 kg, 19.56 mol) were added successively. After addition, the temperature was maintained at 20 - 25 °C and stirred until the reaction was basically complete. Water (180 L, 60 V) was added to quench the reaction. It was filtered and washed to obtain a crude filter cake.

[0100] It was dissolved in isopropyl acetate (15 L) and washed successively with 10% aqueous citric acid (15 L), saturated aqueous sodium bicarbonate (15 L), saturated sodium chloride (30 L), and again with purified water (15 L). The organic phase was slowly added dropwise to n-heptane (225 L), and a large amount of white solid precipitated out. It was filtered, and the filter cake was washed with n-heptane (3.0 L) and dried under reduced pressure to obtain 3.27 kg with a yield of 86.0% and an HPLC purity of 99.1%.

[0101] 1 HNMR (400 MHz, CD 3 OD) δ ppm 1.20 (d, 3H) 1.45 (d, 3H) 4.48 (dd, 1H) 4.59 (d, 1H) 4.72 (d, 1H) 4.88 - 4.94 (m, 1H) 5.02 - 5.11 (m, 1H) 5.41 (d, 1H) 7.10 - 7.22 (m, 2H) 7.41 - 7.53 (m, 1H) 8.76 (d, 1H).

[0102] Comparative Example 1:

[0103]

[0104] The 2b compound was prepared by a well-known method “Journal of Medicine Chemistry, 2014, 57(9), 3687 - 3706”.

[0105] 1) In a 500 ml reaction flask, add compound 2a (27 g, 138.28 mmol), 2b (30 g, 204.68 mmol) and 300 ml of acetonitrile, heat under reflux until the reaction is basically complete, concentrate, and purify by column chromatography (eluent dichloromethane / ethyl acetate) to obtain 25 g of the title product, with a yield of 40%. Detection by LC-MS, Rt = 2.542 min, m / z = 306.2.

[0106] 2) Dissolve the product of the previous step in dichloromethane solvent, add pyridine (13.2 ml, 163.72 mmol), cool in an ice bath, dropwise add thionyl chloride (8.9 ml, 122.80 mmol), stir and react for 2 - 4 h, quench the reaction with water, add 500 ml of dichloromethane, wash with sodium bicarbonate, wash with saturated brine, dry, concentrate to obtain a crude product, which is directly used in the next step. Detection by LC-MS, Rt = 2.142 min, m / z = 324.2.

[0107] 3) Add the product of the previous step to dimethylformamide, add NaN 3 (10 g, 153.82 mmol), heat to 80 °C until the reaction is basically complete, cool to room temperature, add Pd(OH) 2 , heat to 80 °C until the reaction is basically complete, quench the reaction with water, extract with ethyl acetate, wash with saturated brine, dry, concentrate to obtain a crude product, and purify by column chromatography (eluent dichloromethane / ethyl acetate) to obtain 5.5 g of the title product, with a yield of 21%. Detection by LC-MS, Rt = 1.640 min, m / z = 331.2. 5.9 g of the methyl isomer product, with a yield of 22%. Detection by LC-MS, Rt = 1.636 min, m / z = 331.2.

Claims

1. A method for preparing a compound of formula G, comprising the steps of reacting a compound of formula F with a metal reagent and then reacting with carbon dioxide, wherein the metal reagent is a magnesium metal Grignard reagent, Wherein X is a halogen.

2. The method according to claim 1, characterized in that The magnesium metal Grignard reagent is selected from cyclohexylmagnesium chloride or isopropylmagnesium chloride; and the solvent used in the reaction is selected from tetrahydrofuran.

3. The method according to claim 1 or 2, characterized in that: The method further comprises the step of converting the compound of formula E into a compound of formula F, , wherein P is an amino protecting group selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl; and X is a halogen.

4. The method according to claim 1, characterized in that The compound of formula G is , comprising the step of converting a compound of formula F-1 into a compound of formula G-1, , wherein X is a halogen.

5. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, , comprising the steps of the method of claim 1, and the step of reacting a compound of formula G-1 with 1,1,1-trifluoropropane-2-amine to form a compound of formula I or a pharmaceutically acceptable salt thereof, .

6. The method according to claim 5, characterized in that The method comprises the following steps: , wherein P is an amino protecting group, and the amino protecting group is selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl; and X is a halogen.

7. The method according to claim 5 or 6, characterized in that: The method comprises the following steps: , wherein P is tert-butoxycarbonyl.

8. The method according to claim 7, characterized in that The method comprises: step a) reacting a compound of formula E-1 with N-bromosuccinimide to form a compound of formula E-a1; step b) removing the protecting group of the compound of formula E-a1 under acidic conditions to form a compound of formula E-b1; step c) reacting the compound of formula E-b1 with methyl N-3,4-difluorophenylcarbamate to form a compound of formula F-1a; step d) reacting the compound of formula F-1a with cyclohexylmagnesium chloride and then with carbon dioxide to form a compound of formula G-1; step e) reacting the compound of formula G-1 with ( R )-1,1,1-trifluoropropan-2-amine to form a compound of Formula I or a pharmaceutically acceptable salt thereof.

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