Method for preparing triazolo [1, 5-a] pyrazine-3-carboxylic acid and application thereof

Abstract

The invention relates to a method for preparing triazolo [1, 5-a] pyrazine-3-carboxylic acid and application of the triazolo [1, 5-a] pyrazine-3-carboxylic acid. Specifically, provided is a process for the preparation of triazolo [1, 5-a] pyrazine-3-carboxylic acid comprising the steps of reacting a compound of formula F with a metal reagent, introducing carbon dioxide and acidifying wherein X is a halogen, such as chlorine or bromine. The process is simple and convenient to operate, high in yield, high in sample quality and suitable for large-scale production.

Description

Technical Field

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

[0002] WO2019020070A describes a compound having HBV inhibitory activity ( S )- N 5-(3,4-difluorophenyl)-6-methyl- N 3-(( R )-1,1,1-trifluoropropan-2-yl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide. The efficacy experiment showed that the compound had a significant inhibitory effect on the normal assembly of HBV capsid protein, and its pharmacokinetic absorption was good and its bioavailability was high. At the same time, the new structure compound had no effect or little effect on the proliferation inhibition of HepG2 cells in vitro, showing good safety. .

[0003] The preparation process is as follows: .

[0004] 6-Methyl-triazolo[1,5-a]pyrazine is a key intermediate in the preparation of the aforementioned HBV inhibitors. The quality of the intermediate is directly related to the quality and yield of the final product. However, when the Click reaction forms the triazolo[1,5-a]pyrazine structure, a 6-methyl isotopic product is always produced. Especially when the Click reaction is scaled up to the kilogram level, the Click reaction is not conducive to process scale-up production, and also restricts the quality and yield of the final product. .

[0005] Since the methyl isotope product will directly affect the process yield of this step and the quality of subsequent products, it is urgent to develop new ( S )- N 5-(3,4-difluorophenyl)-6-methyl- N 3-(( R A method for preparing 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

[0006] The present disclosure provides a method for preparing a triazolo[1,5-a]pyrazine-3-carboxylic acid 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 X is a halogen, such as chlorine or bromine.

[0007] In some embodiments, the method for preparing the compound of formula G further comprises the step of acidification. In other embodiments, the acid used includes but is not limited to hydrochloric acid or sulfuric acid.

[0008] 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 F, including 4 times, 4.5 times, 5 times, 5.5 times or 6 times or any value between two numbers.

[0009] In some embodiments, the reaction temperature is selected from -20~10°C, which 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~-5°C.

[0010] In another aspect, the method for preparing the compound of formula G further comprises the step of converting the compound of formula E into the compound of formula F, , wherein P is an amino protecting group and X is a halogen, such as chlorine or bromine.

[0011] 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.

[0012] In some embodiments, the step of converting the compound of formula E to the compound of formula F comprises the following steps: .

[0013] The present disclosure also provides a method for preparing a compound of formula E, which comprises the step of reacting a compound of formula C with a diphenylphosphine azide compound to form a compound of formula E, , wherein P is an amino protecting group and X is a halogen, such as chlorine or bromine.

[0014] On the other hand, the compound of formula C disclosed herein is a chiral molecule containing 1 chiral center and has 2 configurational isomers, such as .

[0015] 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, .

[0016] In some embodiments, the diphenylphosphine azide compound in the methods of the present disclosure is selected from diphenylphosphoryl azide.

[0017] In other embodiments, the reaction of the compound of formula C with the diphenylphosphine azide is carried out under alkaline conditions, and the base is selected from potassium carbonate, potassium phosphate, triethylamine or 1,8-diazabicycloundec-7-ene. In some embodiments, the amount of the base is 1 to 4 times the molar amount of the compound of formula C, which is 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 values.

[0018] 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, and dimethyl sulfoxide, preferably toluene.

[0019] In some embodiments, the reaction temperature is selected from 60-150°C, 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 values, preferably 80-120°C.

[0020] 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 two numbers.

[0021] In other embodiments, the compound of formula G is , the preparation method thereof comprises the step of converting the compound of formula F-1 into the compound of formula G-1, , wherein X is a halogen, such as bromine or chlorine.

[0022] The present disclosure also provides a method for treating a compound of formula I or a pharmaceutically acceptable salt thereof. , the method comprising the steps of preparing the compound of formula G as described above, and reacting the compound of formula G with 1,1,1-trifluoropropane-2-amine to form a compound of formula I or a pharmaceutically acceptable salt thereof, .

[0023] In some embodiments, the method of the compound of Formula I or a pharmaceutically acceptable salt thereof comprises: , 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.

[0024] In other embodiments, the method of the compound of formula I or a pharmaceutically acceptable salt thereof comprises: , Wherein P is tert-butoxycarbonyl.

[0025] In other embodiments, the method of the compound of formula I or a pharmaceutically acceptable salt thereof 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 a compound of formula E-b1 with methyl N-3,4-difluorophenylcarbamate to form a compound of formula F-1, Step d) reacting the compound of formula F-1 with cyclohexylmagnesium chloride and then reacting with carbon dioxide to form a compound of formula G-1, Step e) Compound G-1 is reacted with ( R )-1,1,1-trifluoropropan-2-amine is reacted to form a compound of formula I or a pharmaceutically acceptable salt thereof. For specific reaction conditions or operations, reference may be made to the journal document WO2019020070A, and the relevant contents are introduced into the present disclosure for illustration.

[0026] The present disclosure also provides the following compounds: .

[0027] The method of the present disclosure may also include post-processing operations, such as one or more steps of filtration, extraction, concentration, column chromatography or chiral separation to obtain a pure target product.

[0028] The pharmaceutically acceptable salts disclosed herein are salt products of the compound of formula I and an acid, wherein the acid is selected from, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, malic acid or oxalic acid.

[0029] The present disclosure also provides a pharmaceutical composition, which contains an effective therapeutic amount of the compound of formula I or a pharmaceutically acceptable salt thereof prepared by the aforementioned method, and one or more pharmaceutically acceptable excipients.

[0030] The present disclosure also provides a method for preparing a pharmaceutical composition, which comprises the step of mixing the compound of formula I or a pharmaceutically acceptable salt thereof prepared by the aforementioned method with one or more pharmaceutically acceptable excipients.

[0031] The present disclosure also provides the use of the compound of formula I or its pharmaceutically acceptable salt prepared by the aforementioned method, or the aforementioned pharmaceutical composition in the preparation of a medicament for treating viral infectious diseases, wherein the virus is preferably hepatitis B virus, influenza virus, herpes virus and HIV, and the disease is preferably hepatitis B, influenza, herpes and AIDS.

[0032] Unless otherwise stated, the terms used in this invention have the following meanings: The terms “to form” and “to convert” in the present disclosure do not specifically mean that the conversion reaction between two substrates is a single step, but may be a single step or multi-step reaction between two substrates.

[0033] "Amino protecting group" is a suitable group for amino protection known in the art, see the literature (Protective Groups in Organic Synthesis, 5 Th Ed. TW Greene & P. ​​GM Wuts) in the hydroxyl protecting group. As examples, include but are not limited to carbamate protecting groups, such as tert-butyloxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz).

[0034] As used herein, an "effective amount" or "therapeutically effective amount" includes an amount sufficient to improve or prevent the symptoms or symptoms of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0035] The "excipients" described in the present disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals.

[0036] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, and the solvent used was deuterated dimethyl sulfoxide (DMSO- d 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0037] HPLC determination can be performed using an Agilent 1200 high pressure liquid chromatograph (Evo C18 4.6*250mm, 5um, chromatographic column or Xtimate C18 2.1*30mm chromatographic column).

[0038] Chiral HPLC analysis was performed using a Chiralpak IF 150*4.6mm, 5um column or a Lux Amylose-2150*4.6mm, 5um column.

[0039] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0040] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0041] The advantages of the technical solution in this disclosure are reflected in the following aspects: As is known to all, alkenyl and aryl halides are very easy to react with Pd to form palladium-carbon complexes, and then carbon monoxide is inserted between the palladium-carbon bonds to achieve carbonylation reaction. However, carbon monoxide is a pollutant that is highly toxic to the blood and 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 analysis and release of oxyhemoglobin, causing body tissues to necrotize due to lack of oxygen, and in severe cases, it may endanger human life. For this reason, the use of carbon monoxide will inevitably bring more uncertainties to the entire process or its amplification. The technical solution in the present disclosure avoids the use of carbon monoxide in the process, and the overall process is more feasible, safe and environmentally friendly.

[0042] On the other hand, although metal palladium catalysts can achieve carbonylation efficiently to a certain extent, the metal palladium catalysts are expensive, resulting in high overall process costs. The technical solution disclosed in the present invention uses Grignard reagents to greatly reduce the overall process costs, and avoids the use of heavy metals, making the process more environmentally friendly. DETAILED DESCRIPTION

[0043] The present disclosure will be described in detail below in conjunction with specific embodiments so that those skilled in the art can have a more comprehensive understanding of the present disclosure. The specific embodiments are only used to illustrate the technical solutions of the present disclosure and do not limit the present disclosure in any way.

[0044] Example 1

[0045] Step 1) In a 30L reactor, (S)-2-aminopropanol (3788.0g, 50.4mol, 3.0eq), acetonitrile (10L, 5V) and anhydrous sodium carbonate (3563.0g, 33.6mol, 2.0eq) were added in sequence, stirring was started, the temperature was lowered to 0-5°C, 3-bromopropyne (2000.0g, 16.8mol, 1.0eq) acetonitrile solution (10L) was added, stirring was carried out until the reaction of 3-bromopropyne was basically completed, filtered, concentrated under reduced pressure, water (8L) was added, extracted with toluene / 2-methyltetrahydrofuran, dried, and concentrated to obtain the target product (1.166kg) with a yield of 61.3%.

[0046] Step 2) In a 20L reactor, add the product from the previous step (1100.0g, 9.7mol, 1.0eq), toluene (11L) and DBU (1479.9g, 9.7mol), heat to 50°C, add DPPA (diphenylphosphoryl azide, 2675.2g, 9.7mol, 1.0eq) to the reactor, heat to 100-120°C and stir until the reaction is complete, add purified water (5.5L, 5V) to quench the reaction, extract with toluene, and retain the aqueous phase for later use.

[0047] Step 3) Add methanol (11L) and triethylamine (1969.0g) to the aqueous phase obtained in the above step, cool to 10-15°C, add Boc2O (di-tert-butyl dicarbonate, 4240.5g, 19.4mol, 2.0eq), stir until the reaction is complete, concentrate to dryness under reduced pressure, add water to dilute, extract with toluene, combine the organic phases, dry, and concentrate to obtain 1.4kg of the target product, HPLC ≥99%.

[0048] Step 4) Add the product of the previous step (1.4 kg) and DMF (7 L) into the reactor, heat to 40-50 ° C, add NBS (0.2266 kg, 1.3 eq), stir and react for 30-40 min, add 10% sodium sulfite aqueous solution to quench the reaction, extract with tetrahydrofuran (7 L) and MTBE (21 L, 15 V), wash with saturated brine, dry and concentrate to obtain the target product.

[0049] 1H 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). Step 5) The product of the previous step was dissolved in ethyl acetate (10.5 L) and ethanol (2.8 L), and a 4M hydrochloric acid dioxane solution (10.5 L) was added. The mixture was stirred at 40°C for reaction, cooled to room temperature, filtered, washed with ethyl acetate, and dried to obtain 0.868 kg, with a yield of 62.3%, and an HPLC value of 85%.

[0050] 1 H NMR (400 MHz, DMSO-d6) 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). Example 2

[0051]

[0052] In a 25 mL reaction bottle, compound 3 (0.8 g, 1.0 eq) and anhydrous THF (8 ml) were added in sequence. Under nitrogen protection, the temperature was lowered to -10-10°C. After 8 ml of 1.3 M cyclohexylmagnesium chloride solution was added dropwise, dry carbon dioxide was slowly introduced. The reaction temperature was controlled according to Table 1, and carbon dioxide was introduced for 1-2 h.

[0053] When the reaction was completed during HPLC control, 4M hydrochloric acid was added dropwise to quench the reaction. The mixture was separated and extracted with ethyl acetate. The mixture was extracted twice with saturated aqueous sodium bicarbonate solution. The aqueous layer was collected and the pH value was adjusted to 1-2 with concentrated hydrochloric acid. Methyl tert-butyl ether was added to precipitate a large amount of white solid. The white solid was filtered and dried to calculate the yield.

[0054]

[0055] Note: a The reaction time is about 1 times longer than the reaction temperature of -15~-5℃.

[0056] Example 3

[0057] Step 1) In a 50L reactor, compound 1 (6000g, 23.0mol, 1eq), N,N-dimethylformamide (60L, 10V), compound 2 (5625g, 22.5mol, 0.98eq), and triethylamine (4660g, 46.0mol, 2.0eq) were added in sequence, stirred evenly, and the temperature was slowly raised to 50-60°C with stirring for reaction. The reaction of compound 2 was basically completed by HPLC control. Water was added to quench the reaction, stirred for 1h, filtered, and the filter cake was collected, washed, filtered, and dried in a vacuum drying oven at 55°C for 15-20h to obtain 7.92g, with a yield of 90.2%.

[0058] Step 2) In a 250L reactor, compound 3 (7900g, 21.22mol, 1.0eq) and anhydrous THF (79L, 10V) were added in sequence. Under nitrogen protection, the temperature was lowered to -10-10°C. After 73.5L of 1.3M cyclohexylmagnesium chloride solution was added dropwise, dry carbon dioxide was slowly passed through to maintain the reaction liquid temperature <-5°C. Carbon dioxide was passed through for 1-2h.

[0059] 4M hydrochloric acid was added dropwise, and the reaction solution temperature was controlled to be less than 10°C to quench. The mixture was stirred and allowed to stand for stratification. The organic phase was collected. The aqueous phase was extracted once with ethyl acetate (24L, 3V). The organic phases were combined and extracted twice with saturated aqueous sodium bicarbonate solution (24L, 3V). The aqueous layers were combined and collected. The aqueous phase was washed once with methyl tert-butyl ether (24L, 3V). Concentrated hydrochloric acid was slowly added dropwise to the aqueous phase, and the pH was adjusted to 1-2. Methyl tert-butyl ether (32L, 4V) was then added. A large amount of white solid was precipitated. The mixture was filtered, washed, and dried in vacuo at 50°C to obtain a white solid, 3.58 kg, with a yield of 50.2%.

[0060] Step 3) In a 50L reactor, compound 4 (3000g, 8.89mol, 1eq) was added to DMF (12.0L, 4V), followed by HATU (4.057kg, 10.67mol), (R)-1,1,1-trifluoropropane-2-amine (1.4kg, 9.34mol), and DIPEA (2.53kg, 19.56mol). After the addition was completed, the temperature was maintained at 20-25°C and stirred until the reaction was basically completed. Water (180L, 60V) was added to quench the reaction, and the mixture was filtered and washed to obtain a crude filter cake.

[0061] Dissolve it with isopropyl acetate (15 L), wash it with 10% citric acid aqueous solution (15 L), saturated sodium bicarbonate aqueous solution (15 L), saturated sodium chloride (30 L), and then wash it with purified water (15 L). Slowly add the organic phase dropwise into n-heptane (225 L). A large amount of white solid precipitates. Filter it, wash the filter cake with n-heptane (3.0 L), and dry it under reduced pressure to obtain 3.27 kg, with a yield of 86.0% and a HPLC purity of 99.1%.

[0062] 1 HNMR (400 MHz, CD3OD) δppm 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).

[0063] Comparative Example 1:

[0064] Using the known method Journal of Medicine Chemistry , 2014, 57(9), 3687-3706" Preparation of compound 2b 1) In a 500 ml reaction bottle, add compound 2a (27 g, 138.28 mmol), 2b (30 g, 204.68 mmol) and 300 ml acetonitrile, heat under reflux to react until the reaction is almost complete, concentrate, and purify by column chromatography (eluent dichloromethane / ethyl acetate) to obtain 25 g of the title product, with a yield of 40%. LC-MS detection, Rt=2.542 min, m / z=306.2.

[0065] 2) The product of the previous step was dissolved in dichloromethane solvent, pyridine (13.2 ml, 163.72 mmol) was added, and the mixture was cooled in an ice bath. Dichlorothionyl (8.9 ml, 122.80 mmol) was added dropwise, and the mixture was stirred for 2-4 h. Water was added to quench the reaction, and 500 ml of dichloromethane was added. The mixture was washed with sodium bicarbonate and saturated brine, dried, and concentrated to obtain a crude product, which was directly used in the next step. LC-MS detection showed Rt = 2.142 min, m / z = 324.2.

[0066] 3) The product of the previous step was added to dimethylformamide, NaN3 (10 g, 153.82 mmol) was added, and the mixture was heated to 80°C for reaction until the reaction was basically complete, cooled to room temperature, Pd(OH)2 was added, and the mixture was heated to 80°C for reaction until the reaction was basically complete, and water was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried, and concentrated to obtain a crude product, which was purified by column chromatography (eluent: dichloromethane / ethyl acetate) to obtain 5.5 g of the title product, with a yield of 21%. The LC-MS detection showed that Rt=1.640 min, m / z=331.2. The methyl isotopic product showed 5.9 g, with a yield of 22%. The LC-MS detection showed that 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 n-butyl lithium or 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 with 1,1,1-trifluoropropan-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-butyloxycarbonyl, 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-1, step d) reacting the compound of formula F-1 with cyclohexylmagnesium chloride and then with carbon dioxide to form a compound of formula G-1, and step e) reacting the compound of formula G-1 with (R)-1,1,1-trifluoropropane-2-amine under HATU / N, N-diisopropylethylamine conditions to form a compound of formula I or a pharmaceutically acceptable salt thereof.

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