A method for preparing triazolyl[1,5-a]pyrazine-3-carboxyl ester and its application

Abstract

The present disclosure relates to a method for preparing triazolyl [1,5-a] pyrazine-3-carboxylate and its application. Specifically, the present disclosure provides a method for preparing triazolyl [1,5-a] pyrazine-3-carboxylate (compound of formula f) or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 As defined in the description. The process is simple to operate, has a high yield and good sample quality, and is suitable for large-scale production of triazolo[1,5-a]pyrazine-3-carboxylate.

Description

Technical Field

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

[0002] 6-Methyl-4,5,6,7-tetrahydro-[1,2,3]triazolyl[1,5-a]pyrazine-3-carboxylic acid methyl ester (shown below) is a key intermediate in the preparation of HBV inhibitors. Its quality and yield are directly related to the feasibility of subsequent processes.

[0003]

[0004] For example, WO2018011163 reported the use of a click reaction to form a triazolo[1,5-a]pyrazine structure, and a series of reactions were performed to obtain 3-iodo-6-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolyl[1,5-a]pyrazine.

[0005]

[0006] However, when this method is applied to the preparation of (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 (the process is as follows, see WO2019020070 for details), when the click reaction forms a 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.

[0007]

[0008]

[0009] Considering that the methyl isotopic product will directly affect the yield of this step and is related to the quality of subsequent products, it is urgent to develop a new preparation method. Summary of the invention

[0010] The present disclosure provides a method for preparing a compound of formula f or a pharmaceutically acceptable salt thereof,

[0011] The method comprises the steps of reacting a compound of formula b with an azide to form a compound of formula c, wherein the azide is selected from azidotrimethylsilane, diphenylphosphoryl azide or sodium azide,

[0012] Where R 1Each independently selected from C 1-6 Alkyl; R 2 Selected from C 1-6 Alkyl; R 3 It is hydrogen or an amino-protecting group, and the amino-protecting group is preferably tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl.

[0013] In some embodiments, in the compound of formula c, R 1 Selected from hydrogen or C 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl or isopropyl.

[0014] In some embodiments, R 2 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclopentyl.

[0015] In some embodiments, R 3 is selected from hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl.

[0016] In some embodiments, the method for preparing a compound of formula f or a pharmaceutically acceptable salt thereof comprises the step of converting a compound of formula e into a compound of formula f,

[0017] Where R 2 , R 3 As defined above.

[0018] On the other hand, the compound of formula f disclosed herein is a chiral molecule containing one chiral center and has two configurational isomers.

[0019]

[0020] In some embodiments, the method comprises the step of converting a compound of formula eb to a compound of formula fb,

[0021] For specific reaction conditions or operations, please refer to WO2019020070A, and the relevant contents are introduced for illustration.

[0022] In some embodiments, the amount of the azide compound used in the method is 1 to 3 times the molar amount of the compound of formula b, including 1 times, 1.5 times, 2 times, 2.5 times, 3 times, or any value between any two values. In some embodiments, the amount of the azide compound used in the method is 1.5-2.5 times the molar amount of the compound of formula b. In some embodiments, the amount of the azide compound used in the method is 2 times the molar amount of the compound of formula b.

[0023] In some embodiments, the method comprises the steps of reacting a compound of formula b with an azide to form a compound of formula c, hydrolyzing the compound of formula c to form a compound of formula d, and converting the compound of formula d to a compound of formula e.

[0024]

[0025] Further, in some embodiments, the method further comprises the step of converting the compound of formula a into a compound of formula b.

[0026]

[0027] When R 3 When it is an amino protecting group, the method further comprises a step of removing the protecting group, as shown below:

[0028] P is an amino protecting group, and the amino protecting group includes tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl. The deprotection method adjusts the reaction conditions according to the type of protecting group. See the document ("Protective Groups in Organic Synthesis", 5Th Ed. TW Greene & P. ​​GMWuts), and the relevant content is introduced into the present disclosure for illustration. In some embodiments, P is a Boc protecting group, and the removal of the Boc protecting group is acidic conditions, such as hydrochloric acid / dioxane. In some embodiments, P is a Cbz protecting group, and the Cbz protecting group is removed by Pd / C catalytic hydrogenation.

[0029] The present disclosure also provides a compound of formula c Where R 1 , R 2 As defined above. In some embodiments, the compound of formula c is

[0030] The present disclosure also provides a compound of formula d Where R 2 As defined above. In some embodiments, the compound of formula d is

[0031] In another aspect, the present disclosure also provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof,

[0032] The method comprises the steps of the aforementioned method for preparing the compound of formula f and the step of converting the compound of formula f into the compound of formula I,

[0033]

[0034] In some embodiments, the method of preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the step of reacting a compound of formula f-2 with 1,1,1-trifluoropropan-2-amine to form a compound of formula h,

[0035] Where R 2 As defined above.

[0036] In some embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the steps of reacting a compound of formula f-2 with 1,1,1-trifluoropropan-2-amine to form a compound of formula h and converting the compound of formula h to a compound of formula I or a pharmaceutically acceptable salt thereof,

[0037]

[0038] Where R 2 As defined above.

[0039] In other embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the step of converting a compound of formula f-2 into a compound of formula g,

[0040] Where R 2 As defined above. For specific reaction conditions or operations, please refer to the journal document WO2019020070A, and the relevant content is introduced for illustration.

[0041] In some embodiments, the method of preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the step of reacting a compound of formula f-2 with methyl N-3,4-difluorophenylcarbamate to form a compound of formula g.

[0042] In some embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the steps of converting a compound of formula f-2 into a compound of formula g and reacting the compound of formula g with 1,1,1-trifluoropropan-2-amine to form a compound of formula I or a pharmaceutically acceptable salt thereof,

[0043]

[0044] Where R 2 As defined above. Specific reaction conditions or operations can be referred to WO2019020070A, and the relevant contents are introduced for illustration.

[0045] In some embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the steps of reacting a compound of formula b with an azide to form a compound of formula c, hydrolyzing the compound of formula c to form a compound of formula d, reacting the compound of formula d with an amine compound to form a compound of formula e, converting the compound of formula f into a compound of formula h, and converting the compound of formula h into a compound of formula I.

[0046]

[0047] For specific reaction conditions or operations, please refer to WO2019020070A, and the relevant contents are introduced for illustration.

[0048] In some embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the steps of reacting a compound of formula b with an azide to form a compound of formula c, hydrolyzing the compound of formula c to form a compound of formula d, reacting the compound of formula d with an amine compound to form a compound of formula e, converting the compound of formula f into a compound of formula g, and converting the compound of formula g into a compound of formula I.

[0049]

[0050] In some embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof further comprises the step of deprotecting a compound of formula f-1 to form a compound of formula f-2.

[0051] P is an amino protecting group, which includes tert-butyloxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl. The removal of the protecting group is described in the literature ("Protective Groups in Organic Synthesis", 5Th Ed. TW Greene & P. ​​GMWuts), and the relevant content is introduced into the present disclosure for illustration.

[0052] In some embodiments, the method of preparing a compound of Formula I or a pharmaceutically acceptable salt thereof comprises:

[0053]

[0054] Step b) reacting compound b-1 with azidotrimethylsilane to form compound c-1;

[0055] Step c) hydrolyzing compound c-1 under acidic conditions (such as acetic acid conditions) to form compound d-1;

[0056] Step d) converting compound d-1 into compound e-1;

[0057] Step e) Compound e-1 is reacted with Ph 3 Reaction under P / DIAD conditions to form compound f-1a;

[0058] Step f) deprotecting the amino protecting group of compound f-1a, such as removing Boc under acidic conditions, to form compound f-2a;

[0059] Step g) Compound f-2a reacts with methyl N-3,4-difluorophenylcarbamate to form compound g-1. Specific reaction conditions or operations may refer to WO2019020070A, and the relevant contents are introduced into the present disclosure for illustration.

[0060] In some embodiments, the method of preparing a compound of Formula I or a pharmaceutically acceptable salt thereof comprises:

[0061]

[0062] Step b) reacting compound b-1 with azidotrimethylsilane to form compound c-1;

[0063] Step c) hydrolyzing compound c-1 under acidic conditions (such as acetic acid conditions) to form compound d-1;

[0064] Step d) converting compound d-1 into compound e-1;

[0065] Step e) Compound e-1 is reacted under Ph3P / DIAD conditions to form compound f-1a;

[0066] Step f) deprotecting the amino protecting group of compound f-1a, such as removing Boc under acidic conditions, to form compound f-2a;

[0067] Step g) Compound f-2a is converted into a compound of formula I. For specific reaction conditions or operations, reference may be made to WO2019020070A, and the relevant contents are introduced into the present disclosure for illustration.

[0068] On the other hand, the conversion of the "ester" compound of the present disclosure into an "amide" compound further comprises the step of hydrolyzing the ester group to a carboxylic acid. In some embodiments, the reaction conditions for the hydrolysis of the ester group are acidic or LiOH.

[0069] In some embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the steps of hydrolyzing a compound of formula g (e.g., under LiOH conditions) to form a compound of formula k, and reacting the compound of formula k with 1,1,1-trifluoropropane-2-amine to form a compound of formula I,

[0070]

[0071] In some embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the steps of hydrolyzing compound g-1 (e.g., under LiOH conditions) to form compound k-1, reacting compound k-1 with 1,1,1-trifluoropropane-2-amine to form a compound of formula I,

[0072]

[0073] 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.

[0074] On the other hand, the present disclosure also provides the use of the compound of formula I or its pharmaceutically acceptable salt or the pharmaceutical composition prepared by the aforementioned method in the preparation of a drug 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.

[0075] The method disclosed herein may further include post-processing operations, such as one or more steps of filtration, extraction, concentration, column chromatography or hand-type separation to obtain a pure target product.

[0076] On the other hand, the click reaction described in the present disclosure needs to be carried out under anhydrous and oxygen-free conditions. The treatment method of the solvent used can be referred to "Solvent Handbook" (4th edition) - edited by Cheng Nenglin.

[0077] The pharmaceutically acceptable salt disclosed herein is the product of the salt formation between 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.

[0078] The salt disclosed herein is a product of a corresponding compound and an acid, wherein the acid is selected from but not limited to hydrochloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid or oxalic acid.

[0079] Unless otherwise stated, the terms used in this invention have the following meanings:

[0080] The term "to form" and "to convert" in the present disclosure does not specifically mean that the conversion reaction between two substrates is a single step, and can be a single step or multi-step reaction between two substrates. If the intermediate contains an amino protecting group, the intermediate is subjected to a step of deamination of the protecting agent, and then reacts with the corresponding substrate to obtain the corresponding target product.

[0081] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclopentyl, etc.

[0082] DIAD: diisopropyl azodicarboxylate.

[0083] Ph 3 P: triphenylphosphine.

[0084] LiOH: lithium hydroxide.

[0085] "Amino protecting group" is a suitable group for protecting amino group known in the art, see the literature ("Protective Groups in Organic Synthesis", 5Th Ed.TW Greene & P.GMWuts) 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).

[0086] As used herein, an "effective therapeutic amount" includes an amount sufficient to improve or prevent the symptoms or conditions 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.

[0087] 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.

[0088] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer and the solvent used was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0089] 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).

[0090] Chiral HPLC analysis was performed using a Chiralpak IF 150*4.6mm, 5um column or a Lux Amylose-2150*4.6mm, 5um column.

[0091] 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 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0092] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage). DETAILED DESCRIPTION

[0093] 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.

[0094] Example 1

[0095]

[0096] Step 1:

[0097] In a 10L reactor, add propiolic aldehyde diethyl acetal (compound 1, 1000.0g, 7.80mol, 1eq) and tetrahydrofuran (5L, 5V) in sequence, protect with nitrogen, cool to ≤-40°C, add n-butyl lithium (3260.0L, 1.5eq) dropwise, maintain the temperature range and stir for 1-3h after the addition is complete, add isopropyl chloroformate (1148.0g, 9.36mol, 1.2eq) tetrahydrofuran (5.0L) solution dropwise, add dropwise, after the addition is complete, slowly warm to room temperature (15-25°C) and stir for 10-16h.

[0098] 1.5 L of 30% saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, and the mixture was concentrated under reduced pressure. 5 L of water was added, the mixture was separated, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and distilled under reduced pressure. The product fraction came out at 120°C-135°C, with a vacuum degree of 350 Pa, to obtain 1100.0 g of intermediate 2 with a yield of 65.8%.

[0099] 1 H NMR (400 MHz, CDCl 3 )δ5.36(s,1H),5.13-5.07(m,1H),3.79-3.72(m,2H),3.66-3.58(m,2H),1.29(d,6H),1.25(t,6H).

[0100] Step 2:

[0101] In a 10L reactor, intermediate 2 (1000.0 g, 4.67 mol, 1 eq) and trimethylsilyl azide (1080.0 g, 9.34 mol, 2 eq) were added. The temperature was raised to 95°C-105°C under nitrogen protection and the reaction was carried out for 20 h. The intermediate 2 was controlled to be ≤3.0% by HPLC. Saturated aqueous sodium bicarbonate solution was added, and ethyl acetate was added for extraction. The mixture was washed with saturated aqueous sodium chloride solution and concentrated (40-45°C) to obtain 1100.0 g of clear liquid intermediate 3 with a yield of 91.6%.

[0102] 1 H NMR (400 MHz, CDCl 3 )δ13.83(s,1H),6.02(s,1H),5.21-5.18(m,1H),3.64-3.44(m,4H),1.22(d,6H),1.05(dd,6H).

[0103] Step 3:

[0104] The clarified liquid was poured into a 20 L reactor, and acetonitrile (5.5 L), acetic acid (1.1 L), and purified water (1.1 L) were added in sequence. The temperature was slowly raised to 40°C-50°C and stirred for 20 hours. The intermediate 3 was <3.0% as detected by HPLC. The mixture was concentrated under reduced pressure to obtain 783.0 g of a transparent oily intermediate 4 with a yield of 100%.

[0105] Step 4:

[0106] In a 20L reactor, add intermediate 4 (780.0g, 4.26mol, 1eq), methanol (7.8L, 10V), then add S-aminopropanol (319.6g, 4.26mol, 1eq), heat to 40-50°C and stir for 1-3h, cool to 0-10°C, add sodium borohydride (161.1g, 4.26mol), maintain the temperature and stir for 0.5-1h, control intermediate 4 <0.2% in HPLC, add Boc anhydride (1207.3g, 6.39mol, 1.3eq), slowly heat to room temperature 20-25°C and stir for 2-3h, add 30% saturated ammonium chloride dropwise, and concentrate under reduced pressure. Add ethyl acetate for extraction, wash with saturated sodium chloride, and concentrate under reduced pressure at 40-50°C to obtain intermediate 51457.7g, with a yield of 100%.

[0107] 1 H NMR (400 MHz, CDCl 3)δ5.35-5.25(m,1H),4.78-4.47(m,1H),4.25-4.17(m,2H),3.83-3.71(m,1H),3.65-3.61(m,2H),1.45(s,9H),1.40(d,3H),1.15(d,6H).

[0108] Step 5-6:

[0109] In a 30L reactor, intermediate 5 (1450.0 g, 4.23 mol, 1 eq), tetrahydrofuran (14.5 L, 10 V), triphenylphosphine (1661.0 g, 6.34 mol) were added in sequence, and the mixture was cooled to 0-5°C under nitrogen protection and stirred. DIAD (1280.6 g, 6.34 mol, 1.5 eq) was added dropwise. After the addition was completed, the temperature was maintained and stirred for 2-6 h. 4M hydrochloric acid / ethanol (2.2 L, 4 eq) was added dropwise to the reaction solution, and the temperature was slowly raised to room temperature (20-25°C) and stirred for 16 h. The temperature was raised to 40-50°C and concentrated under reduced pressure. Purified water was added to the reactor, filtered, the filter cake was washed with purified water, and the aqueous phase was collected.

[0110] The aqueous phase was put into a 20L reactor, ethyl acetate (2.9L) was added to wash the aqueous phase twice, the organic layer was separated, saturated sodium carbonate solution was slowly added to the aqueous layer, the temperature was controlled to <15°C, and the pH was adjusted to 8-9; ethyl acetate (4.35L) was added for extraction, the organic layers were combined, washed with saturated sodium chloride (5.8L), and washed again with purified water (5.8L), the ethyl acetate organic layer was separated by layers, anhydrous sodium sulfate was added to dry, filtered, and concentrated under reduced pressure at 40-50°C until no liquid was evaporated.

[0111] Add methyl tert-butyl ether (14.5 L) and transfer to a 20 L reactor, heat to 40-50 ° C, stir to dissolve, cool to 0-10 ° C, slowly add 4M hydrochloric acid / ethyl acetate (1.7 L, 1.05 eq) dropwise to precipitate a large amount of white solid, slowly heat to room temperature and stir for 1-2 hours, filter, wash the filter cake with methyl tert-butyl ether, slurry the filter cake with ethyl acetate at room temperature for 1 h, filter, and dry under reduced pressure at 45 ° C to obtain 554.9 g of the target product, with a two-step yield of 50.5%.

[0112] Step 7:

[0113] In a 1L reaction bottle, add intermediate 7 (200g, 769mmol, 1eq), ethyl acetate (2.0L), SM-01 (210g, 845.9mmol, 1.1eq), DIPEA (296g, 2.3mol, 3eq) in sequence, stir evenly, slowly heat to 60°C and stir for 2h, detect intermediate 7≤0.5% by HPLC control, add 10% citric acid aqueous solution, separate the liquids, wash with saturated sodium bicarbonate aqueous solution, wash with saturated sodium chloride aqueous solution, collect the EA layer, concentrate under reduced pressure at 40-50°C until no liquid drops.

[0114] It was dissolved in isopropyl acetate (800 mL) and then slowly added dropwise to n-heptane (12 L). A large amount of solid precipitated, which was filtered and dried to obtain 278 g of intermediate 9 with a yield of 95%.

[0115] Step 8:

[0116] In a 10L reactor, add intermediate 9 (275g, 4.67mol), THF (1375mL), purified water (1375mL), lithium hydroxide monohydrate (90.6g, 2.16mol, 3eq) in sequence, stir at room temperature 20-25°C for 2h, control in HPLC, intermediate 9≤0.5%, stop the reaction. Add n-heptane (2.75L) and stir for 30min, let stand for stratification and collect the aqueous phase, stir again with n-heptane (1.37L) at room temperature, let stand for stratification and collect the aqueous phase, wash the aqueous layer once with EA (1.37L), collect the aqueous layer, slowly cool down to <15°C, slowly add 6M hydrochloric acid, pH value is about 3-5, stir to precipitate solid, filter, wash with purified water, and vacuum dry at 55°C for 20h to obtain 183g of white solid, yield 75%.

[0117] Step 9:

[0118] In a 2L three-necked flask, add intermediate 10 (180 g, 0.53 mol, 1 eq) into DMF (720 mL, 4 V) and control the temperature to <20°C under stirring. Add HATU (241.8 g, 0.636 mol), 1,1,1-trifluoroisopropylamine hydrochloride (83.8 g, 0.56 mol) and DIPEA (153.5 g, 1.18 mol). After the addition is completed, maintain the temperature at 20-25°C and stir for 2 h. Control the intermediate 10 ≤ 0.2% by HPLC and stop the reaction. The reaction solution was slowly added dropwise to purified water (10.8 L), a large amount of white solid was generated, filtered, washed with purified water (900 mL), the filter cake was dissolved with isopropyl acetate (900 mL), washed once with 10% citric acid aqueous solution (720 mL), saturated sodium bicarbonate aqueous solution (720 mL), and saturated sodium chloride (720 mL), and then washed twice with purified water (720 mL). The organic phase was collected and slowly added dropwise to n-heptane (13.5 L, 75 V), a large amount of white solid precipitated, filtered, and dried under reduced pressure at 55 ° C for 20 h to obtain 210 g, with a yield of 94% and a HPLC purity of 99.05%.

[0119] ESI[M+1] + =433.2

[0120] 1 H NMR (400MHz, CD 3 OD)δppm 1.20(d,J=7.03Hz,3H)1.45(d,J=7.03Hz,3H)4.48(dd,J=13.18,4.39Hz,1H)4.59(d,J=13.30Hz,1H)4.72(d,J=18.32Hz,1H)4.8 2-4.87(m,1H)5.01-5.13(m,1H)5.41(d,J=18.32Hz,1H)7.07-7.22(m,2H)7.47(dd,J=12.30,6.78Hz,1H)8.77(d,J=9.03Hz,1H).

[0121] Comparative Example 1

[0122]

[0123] Compound 2b was prepared by the known method "Journal of Medicine Chemistry, 2014, 57(9), 3687-3706".

[0124] 1) In a 500 ml reaction bottle, add compound 2a (27 g, 138.28 mmol), 2b (30 g, 204.68 mmol) and 300 ml of 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%, according to LC-MS detection, Rt=2.542 min, m / z=306.2.

[0125] 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 reaction 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.

[0126] 3) Add the product from the previous step to dimethylformamide and add NaN 3 (10 g, 153.82 mmol), heated to 80 °C until the reaction was almost complete, cooled to room temperature, and Pd(OH) was added 2 , heated to 80°C to react until the reaction is basically complete, added water to quench the reaction, 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%, LC-MS detection, Rt = 1.640 min, m / z = 331.2. 5.9 g of the methyl isotopic product, with a yield of 22%, LC-MS detection, Rt = 1.636 min, m / z = 331.2.

Claims

1. A method for preparing a compound of formula f or a pharmaceutically acceptable salt thereof, , comprising the steps of reacting a compound of formula b with an azide to form a compound of formula c, hydrolyzing the compound of formula c to form a compound of formula d, reacting the compound of formula d with an amine compound to form a compound of formula e, and reacting the compound of formula e under Ph3P / DIAD conditions to form a compound of formula f, wherein the azide is selected from azidotrimethylsilane, diphenylphosphoryl azide or sodium azide, , where R 1 Each independently selected from C 1-6 Alkyl; R 2 Selected from C 1-6 Alkyl; R 3 is a hydrogen or amino protecting group.

2. The method according to claim 1, further comprising the step of converting the compound of formula a into the compound of formula b, .

3. The method according to claim 1, wherein the amount of the azide compound used is 1 to 3 times the molar amount of the compound of formula b.

4. Compound of formula c , where R 1 Each independently selected from C 1-6 Alkyl; R 2 Selected from C 1-6 alkyl.

5. Compound of formula d , where R 2 Selected from C 1-6 alkyl.

6. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, , comprising the steps of the method according to any one of claims 1 to 3 and the step of converting the compound of formula f into a compound of formula I, , where R 2 Selected from C 1-6 Alkyl; R 3 is a hydrogen or amino protecting group.

7. The method according to claim 6, comprising the step of reacting the compound of formula f-2 with 1,1,1-trifluoropropane-2-amine to form the compound of formula h, , where R 2 Selected from C 1-6 alkyl.

8. The method according to claim 6 or 7, comprising the steps of reacting the compound of formula f-2 with 1,1,1-trifluoropropane-2-amine to form the compound of formula h and converting the compound of formula h into the compound of formula I or a pharmaceutically acceptable salt thereof, , where R 2 Selected from C 1-6 alkyl.

9. The method according to claim 6, comprising the step of converting the compound of formula f-2 into the compound of formula g, , where R 2 Selected from C 1-6 alkyl.

10. The method according to claim 9, which comprises the steps of converting the compound of formula f-2 into the compound of formula g and reacting the compound of formula g with 1,1,1-trifluoropropane-2-amine to form the compound of formula I or a pharmaceutically acceptable salt thereof, , where R 2 Selected from C 1-6 alkyl.

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