Preparation method of triazolopyridine compound

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a method for preparing a triazolopyridine compound which has a PHD inhibiting effect and can be used for treating or preventing diseases caused by reduction of production of EPO and the like.

Description

TECHNICAL FIELD

[0001] The present disclosure belongs to the technical field of pharmaceutical chemistry, and relates to a method for preparing a triazolopyridine compound having a PHD inhibitory effect and being useful for treating or preventing a disease caused by a decrease in the production of EPO and the like, and more particularly, to a method for preparing an Vadadustat (2-({[7-hydroxy-5-(2-phenylethyl)-[1,2,4]triazolo[1,5-a]pyridin]-8-ylcarbonyl}amino)acetic acid). BACKGROUND

[0002] Renal anemia is mainly caused by a decrease in erythropoietin (EPO), and is also related to a deficiency of hematopoietic substances, inflammation, oxidative stress, accumulation of uremic toxins, and the like. Studies have found that the inhibition of the prolyl hydroxylase domain of HIF-PHI can stabilize hypoxia-inducible factor, promote the synthesis of red blood cells by increasing the production of endogenous erythropoietin, improving iron absorption, and reducing the level of hepcidin, and thus treat anemia.

[0003] Vadadustat is a new generation of hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) drug, and the drug has been marketed in Japan. The drug regulates the HIF target more reasonably and moderately, stimulates the production of endogenous EPO (erythropoietin) closer to the physiological concentration, has the advantages of good drug compliance, low risk of drug interaction, and convenient administration, and the like. The chemical name of Vadadustat (compound of formula I-1-a) is 2-({[7-hydroxy-5-(2-phenylethyl)-[1,2,4]triazolo[1,5-a]pyridin]-8-ylcarbonyl}amino)acetic acid, and its structural formula is as follows:

[0004]

[0005] The compound patent W02011007856 reports a preparation route of Vadadustat, in which the introduction of the key phenylethyl group involves a Pd(PPh3)2Cl2-catalyzed coupling reaction and a Pd / C-catalyzed deprotection reaction, and the economy of the synthetic route is not ideal. In addition, the synthesis route involves the treatment of heavy metal pollutants, and the overall process needs to be further improved in economy and greenness and the like.

[0006]

[0007] WO2018097254 reported another synthetic route of enasidenib, which introduced phenethyl group by using Cs2CO3 as base to promote alkylation reaction, followed by hydrolysis and decarboxylation to release phenethyl group. This route used non-metal catalyzed alkylation method, which reduced the cost and improved the economic efficiency of the route. However, this route used excessive Cs2CO3 as base, and the treatment of DMSO also generated additional wastewater. Such non-green production process caused great pressure on environmental protection, and needed to be further improved.

[0008]

[0009] In view of the key role of enasidenib, the present disclosure provides a synthetic route for preparing enasidenib. The purpose of the present disclosure is to overcome the defects of the prior art, and according to the synthesis concept of green chemistry, the route is simple to operate, the whole route is non-metal catalyzed, the yield is high, the hazardous waste discharge is less, and it is suitable for industrialized green production. SUMMARY

[0010] An aspect of the present disclosure aims to provide a method for synthesizing a triazolopyridine compound which is green, simple to operate, high in yield and purity, and suitable for industrial production of the compound. More specifically, an improved method for 2-({[7-hydroxy-5-(2-phenylethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-ylcarbonyl}amino)acetic acid is provided. The above method does not require the use of base as a catalyst, and simplifies the operation process, which is beneficial to the improvement of the quality of the drug and the industrialized production, and can promote the economic and technological development of the raw drug.

[0011] To achieve the above-mentioned purpose, the present disclosure provides the following technical solutions.

[0012] A method for preparing a compound of formula I, the method comprising:

[0013]

[0014] Step one, substituting a compound of formula II with a compound of formula III to obtain a compound of formula IV;

[0015] Step two, hydrolyzing the compound of formula IV under basic conditions, and then decarboxylating under acidic conditions to obtain a compound of formula V, preferably the hydrolysis and decarboxylation are carried out by one-pot method;

[0016] Step three, acylating the compound of formula V to obtain a compound of formula VI;

[0017] Step four, hydrolyzing the compound of formula VI, and then adjusting the acid to obtain a compound of formula I,

[0018] wherein X can be independently selected from Cl, Br and I, and is preferably Cl.

[0019] R1may be selected from C1-C6 alkyl, benzyl and the like carboxyl protecting groups;

[0020] Ar can be selected from the following structures (a) to (e), preferably structure (a),

[0021]

[0022] In some embodiments of the present disclosure, the above step one is carried out in a solvent under catalysis of a Lewis acid.

[0023] In some embodiments of the present disclosure, the molar ratio (mol / mol) of the compound of formula II to the compound of formula III in the above step one is 1:2.0-6.0, preferably 1:2.0-2.5.

[0024] In some embodiments of the present disclosure, the solvent used in the above step one is selected from one or more of N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMAc), acetonitrile (CH3CN), 1,4-dioxane, tetrahydrofuran, methyl isobutyl ketone (MIBK), preferably acetonitrile (CH3CN).

[0025] In some embodiments of the present disclosure, the mass ratio (w / w) of the above solvent to the above compound of formula II used in the above step one is 1:5.0-20.0, preferably 1:5.0-6.0.

[0026] In some embodiments of the present disclosure, the temperature in the above step one is 20-100℃, preferably 50-60℃.

[0027] In some embodiments of the present disclosure, the aqueous alkaline solution used in the above step two is formed by a base, and the base is selected from one or more of sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropylethylamine (DIPEA), preferably NaOH.

[0028] In some embodiments of the present disclosure, the mass ratio (w / w) of the above aqueous alkaline solution to the compound of formula IV used in the above step two is 1:2.0-6.0, preferably 1:2.0-2.5.

[0029] In some embodiments of the present disclosure, the molar concentration of the above aqueous alkaline solution used in the above step two is 2N-5N, preferably 4N.

[0030] In some embodiments of the present disclosure, the hydrolysis temperature in the above step two is 20-90℃, preferably 20-40℃.

[0031] In some embodiments of the present disclosure, the acidic aqueous solution used in the above step two is formed from an acid selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, preferably hydrochloric acid.

[0032] In some embodiments of the present disclosure, the mass ratio (w / w) of the above compound of formula IV to the above acidic aqueous solution in the above step two is 1:1-5, preferably 1:1-1.5.

[0033] In some embodiments of the present disclosure, the above acidic aqueous solution used in the above step two has a molar concentration of 4N-8N, preferably 6N.

[0034] In some embodiments of the present disclosure, the decarboxylation temperature in the above step two is 50-90°C, preferably 70°C.

[0035] In some embodiments of the present disclosure, the substance used in the above step three is a compound of formula V, glycine methyl ester or a salt thereof, an organic base, a condensing agent, the glycine methyl ester or a salt thereof is preferably glycine methyl ester hydrochloride, the organic base is preferably Et3N, and the condensing agent is preferably EDCI and HOBt; the feeding molar ratio (mol / mol) of the above compound of formula V, the above glycine methyl ester or a salt thereof, the above organic base, the above condensing agent is 1:1.0-5.0:1.0-5.0:1.0-5.0:0.2-0.8, preferably 1:1.0-1.5:1.0-1.5:1.0-1.5:0.2-0.3.

[0036] In some embodiments of the present disclosure, the solvent used in the above step three is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, 1,4-dioxane, preferably acetonitrile.

[0037] In some embodiments of the present disclosure, the mass ratio (w / w) of the above solvent to the above compound of formula V used in the above step three is 1:5-1:20, preferably 1:10.

[0038] In some embodiments of the present disclosure, the basic aqueous solution used in the above step four is formed from a base selected from one or more of NaOH, KOH, LiOH, DBU, DIPEA, preferably NaOH.

[0039] In some embodiments of the present disclosure, the basic aqueous solution used in the above step four has a molar concentration of 4N-6N, preferably 5N.

[0040] In some embodiments of the present disclosure, the mass ratio (w / w) of the compound of formula VI used in step four above to the aqueous alkaline solution is 1:2-1:4, preferably 1:3, and the mass ratio (w / w) of the compound of formula VI used in step four above to the ethanol is 1:4-1:6, preferably 1:5.

[0041] In some embodiments of the present disclosure, the temperature in step four above is 70-90°C, preferably 80°C.

[0042] In some embodiments of the present disclosure, in the preparation method of the compound of formula I, the compound of formula II is a compound of formula II-1 (methyl 5,7-dichloro-1,2,4-triazolo[1,5-a]pyridine-8-carboxylate); the compound of formula III is a compound of formula III-a (2,2-dimethyl-5-(phenylmethyl)-1,3-dioxane-4,6-dione potassium salt); the compound of formula IV is a compound of formula IV-1-a; the compound of formula V is a compound of formula V-1-a, the compound of formula VI is a compound of formula VI-1-a; and the compound of formula I is a compound of formula I-1-a (i.e., enasidenib),

[0043]

[0044] In the present disclosure, unless otherwise specified, the reagents used in the present disclosure are conventional reagents that can be purchased on the market, and the starting materials and reactants used can be prepared by existing technologies or existing literature.

[0045] Technical effects

[0046] The preparation method of the compound of formula I provided by the present disclosure uses different starting materials and reagents from those of the prior art, simplifies the operation procedure, and reduces the generation of hazardous waste, thereby laying a good foundation for the large-scale production of the preparation process. The above technical solution has the following advantages or beneficial effects:

[0047] (1) The preparation method of the present disclosure has a high yield, especially when the compound of formula I is a compound of formula I-1-a, i.e., enasidenib, the yield of each step in the preparation method is more than 85%, which greatly reduces the production cost and has a high atom utilization rate, in line with the concepts of economy and green chemistry.

[0048] (2) The reaction in step one of the present disclosure does not require an alkali as a catalyst, and the post-treatment only needs simple filtration and concentration, which is simple to operate, generates less hazardous waste, and is more environmentally friendly, making it suitable for industrial use.

[0049] (3) The five steps of the present disclosure can all obtain intermediates and target products through simple crystallization, which is simple and easy to operate, and is conducive to the industrialization of the process.

[0050] (4) The product prepared by the preparation method of the present disclosure has good purity, and the HPLC purity is all above 96%, and the optimal can reach above 99%, which is much higher than the prior art method.

[0051] (5) The post-treatment of the method of the present disclosure is simple and easy to scale up.

[0052] (6) The method of the present disclosure is environmentally friendly and has small environmental pressure.

[0053] (7) The method of the present disclosure has high yield, and the reagent solvent can be recycled as much as possible, and has low cost. DETAILED DESCRIPTION

[0054] The present disclosure will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present disclosure. The present disclosure has been described in detail herein, including specific embodiment modes, and it will be obvious to those skilled in the art to make various changes and improvements to the specific embodiment modes of the present disclosure without departing from the spirit and scope of the present disclosure.

[0055] Summary of experimental instruments:

[0056] The structure of the compound of the present disclosure is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The NMR chemical shift (δ) is given in units of millionths (ppm). The determination of NMR is carried out by using Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0057] The determination of liquid chromatography-mass spectrometry LC-MS is carried out by using Agilent 1260-6125B single quadrupole mass spectrometer, and the column is Welch Biomate column (C18, 2.7 μm, 4.6 x 50 mm) or waters H-Class SQD2, and the column is Welch Ultimate column (XB-C18, 1.8 μm, 2.1 x 50 mm) mass spectrometer (ion source is electrospray ionization).

[0058] The determination of ultra-performance liquid chromatography-mass spectrometry UPLC-MS is carried out by using Waters UPLC H-class SQD mass spectrometer (ion source is electrospray ionization).

[0059] The determination of HPLC uses Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0060] The thin layer chromatography silica gel plate uses Yantai Jiangyou Silica Gel Development Co., Ltd. GF254 silica gel plate or Rushan City Shangbang New Material Co., Ltd. GF254 silica gel plate, the TLC uses a specification of 0.15 mm to 0.20 mm, and the preparation type is 20*20 cm. The column chromatography generally uses 200-300 mesh silica gel as a carrier.

[0061] The starting materials in the embodiments of the present disclosure are known and can be purchased on the market, or can be synthesized by using or according to the methods known in the art.

[0062] Unless otherwise specified, all reactions of the present disclosure are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is Celsius or ℃. Unless otherwise specified, room temperature refers to 25±5℃.

[0063] Preparation of the compound of formula IV-1-a in Example 1

[0064]

[0065] The compound of formula II-1 (20.00 g, 81.3 mmol, 1.0 equiv) and the compound of formula III-a (44.27 g, 162.6 mmol, 2.0 equiv) were dissolved in CH3CN (100 g), and then warmed to 60℃ for 8 h. TLC showed that the reaction was complete after the raw material was reacted, the insoluble matter was removed by filtration, the filter cake was washed once with CH3CN (100 g), the filtrate was recovered, and was evaporated to dryness to obtain the compound of formula IV-1-a (36.07 g, 81.3 mmol, 100% yield) as a brownish red oil, which was directly used in the next step reaction without further purification.

[0066] MS (ESI) M / Z: 444.1 [M+H] + .

[0067] Preparation of the compound of formula IV-1-b in Example 2

[0068]

[0069] The compound of formula II-1 (2.00 g, 8.13 mmol, 1.0 equiv) and compound of formula III-b (3.25 g, 16.26 mmol, 2.0 equiv) were dissolved in CH3CN (20 g) and then warmed to 60 °C for 8 h, TLC showed that the starting material was consumed, after which the insoluble matter was removed by filtration, the filter cake was washed once with CH3CN (20 g), the filtrate was recovered and evaporated to dryness to obtain the compound of formula IV-1-b (3.31 g, 7.23 mmol, yield: 89%) as a brownish red oil.

[0070] 1 H NMR (500 MHz, Chloroform-d) d 8.51 (s, 1H), 7.57 (s, 1H), 7.23-7.08 (m, 4H), 3.85 (s, 3H), 3.56 (dd, J = 13.7, 0.9 Hz, 1H), 3.46 (dd, J = 13.9, 0.9 Hz, 1H), 2.31 (s, 3H).

[0071] MS (ESI) M / Z: 458.1 [M+H] + .

[0072] Example 3 Preparation of compound of formula IV-1-d

[0073]

[0074] The compound of formula II-1 (2.00 g, 8.13 mmol, 1.0 equiv) and compound of formula III-d (5.66 g, 16.26 mmol, 2.0 equiv) were dissolved in CH3CN (20 g) and then warmed to 60 °C for 8 h, TLC showed that the starting material was consumed, after which the insoluble matter was removed by filtration, the filter cake was washed once with CH3CN (20 g), the filtrate was recovered and evaporated to dryness to obtain the compound of formula IV-1-d (3.42 g, 6.58 mmol, yield: 81%) as a brownish red oil.

[0075] 1H NMR (500 MHz, Chloroform-d) δ 8.51 (s, 1H), 7.57 (s, 1H), 7.42-7.09 (m, 4H), 3.85 (s, 3H), 3.68 (dd, J = 13.6, 1.0 Hz, 1H), 3.53 (dd, J = 13.6, 1.0 Hz, 1H).

[0076] MS (ESI) M / Z: 520.1 [M+H] + .

[0077] Preparation of compound of formula IV-1-e

[0078]

[0079] The compound of formula II-1 (2.00 g, 8.13 mmol, 1.0 equiv) and compound of formula III-e (4.72 g, 16.26 mmol, 2.0 equiv) were dissolved in CH3CN (20 g), then warmed to 60 °C for 8 h, TLC showed that the starting material was consumed, the insoluble matter was removed by filtration, the filter cake was washed once with CH3CN (20 g), the filtrate was recovered and evaporated to dryness to obtain the compound of formula IV-1-e (2.85 g, 6.18 mmol, yield: 76%) as a brownish red oil.

[0080] 1 H NMR (500 MHz, Chloroform-d) δ 8.51 (s, 1H), 7.57 (s, 1H), 7.42-7.09 (m, 4H), 3.85 (s, 3H), 3.68 (dd, J = 13.6, 1.0 Hz, 1H), 3.53 (dd, J = 13.6, 1.0 Hz, 1H).

[0081] MS (ESI) M / Z: 520.1 [M+H] + .

[0082] Preparation of compound of formula IV-2-a

[0083]

[0084] Compound of formula II-2 (2.00 g, 5.97 mmol, 1.0 equiv) and compound of formula III-a (3.25 g, 11.94 mmol, 2.0 equiv) were dissolved in CH3CN (20 g) and then warmed to 60 °C for 8 h, TLC showed that the starting material was consumed, the insoluble was removed by filtration, the filter cake was washed once with CH3CN (20 g), the filtrate was recovered and evaporated to dryness to give compound of formula IV-2-a (1.72 g, 3.52 mmol, yield: 59%) as a brownish red oil.

[0085] 1 H NMR (500 MHz, Chloroform-d) δ 8.52 (s, 1H), 7.71 (s, 1H), 7.41-7.05 (m, 5H), 3.86 (s, 3H), 3.60 (dt, J = 12.5, 0.9 Hz, 1H), 3.54 (dt, J = 12.6, 1.0 Hz, 1H).

[0086] MS (ESI) M / Z: 488.1 [M+H] + .

[0087] Preparation of compound of formula IV-3-a

[0088]

[0089] Compound of formula II-3 (2.00 g, 7.72 mmol, 1.0 equiv) and compound of formula III-a (4.21 g, 15.44 mmol, 2.0 equiv) were dissolved in CH3CN (20 g) and then warmed to 60 °C for 8 h, TLC showed that the starting material was consumed, the insoluble was removed by filtration, the filter cake was washed once with CH3CN (20 g), the filtrate was recovered and evaporated to dryness to give compound of formula IV-3-a (3.18 g, 6.95 mmol, yield: 90%) as a brownish red oil.

[0090] 1 H NMR (500 MHz, Chloroform-d) δ 8.52 (s, 1H), 7.71 (s, 1H), 7.41-7.05 (m, 5H), 3.86 (s, 3H), 3.60 (dt, J = 12.5, 0.9 Hz, 1H), 3.54 (dt, J = 12.6, 1.0 Hz, 1H).

[0091] MS (ESI) M / Z: 458.1 [M+H] + .

[0092] Example 7 Preparation of compound of formula V-1-a

[0093]

[0094] I. Dissolve compound of formula IV-1-a (36.07 g, 81.3 mmol, 1.0 equiv) in ethanol (75 g), at room temperature, add 4N NaOH aqueous solution (75 g) dropwise into the reaction flask, the color of the reaction instantly turns dark, then raise the temperature to 30 °C and react for 3 h. II. Then, lower the reaction temperature to about 15 °C, slowly add 6N HCl (43 g) dropwise, after the addition is completed, raise the temperature of the reaction bath to 70 °C, after 4 h, gradually solid precipitates, turn off the heating, add EtOH (55 g) to the reaction solution while stirring, stir the resulting suspension at room temperature for 1-2 h, then filter, wash the filter cake with EtOH (300 g) twice, to obtain compound of formula V-1-a (20.85 g, 69.1 mmol, 85% yield for two steps) as a off-white solid.

[0095] 1 H NMR (400 MHz, DMSO-d6): δ 14.22 (br s, 1H), 8.65 (s, 1H), 7.32-7.18 (m, 6H), 3.47-3.41 (m, 2H), 3.47-3.43 (m, 2H), 3.12 (dd, 2H, J = 8.4 Hz, 6.0 Hz).

[0096] MS (ESI) M / Z: 302.0 [M+H] + .

[0097] Example 8 Preparation of compound of formula VI-1-a

[0098]

[0099] Into a reaction flask was placed compound of formula V-1-a (5.00 g, 16.6 mmol, 1.0 equiv), HOBt (672 mg, 5.0 mmol, 0.3 equiv) Et3N (2.01 g, 19.9 mmol, 1.2 equiv) and glycine methyl ester hydrochloride (2.50 g, 19.9 mmol, 1.2 equiv), CH3CN / H2O (20 g, 3 / 1, w / w) was added at room temperature, followed by EDCI (3.81 g, 19.9 mmol, 1.2 equiv), stirred at room temperature for 1 h. After TLC showed the starting material was consumed, purified water (25 g) was added at room temperature, a large amount of solid precipitated, stirred at room temperature for 2 h, filtered, the filter cake was washed with EtOH (50 g) twice to give compound of formula VI-1-a (5.42 g, 14.5 mmol, 88% yield, 96.3% HPLC purity) as off-white solid.

[0100] 1 H NMR (400 MHz, DMSO-d6): δ 9.29 (t, 1H, J = 5.6 Hz), 8.65 (s, 1H), 7.33-7.22 (m, 6H), 4.14 (d, 2H, J = 5.6 Hz), 3.70 (s, 3H), 3.46 (t, 2H, J = 7.2 Hz), 3.13 (t, 2H, J = 8.4 Hz).

[0101] MS (ESI) M / Z: 302.0 [M+H] + .

[0102] Example 9 Preparation of compound of formula I-1-a

[0103]

[0104] The compound of formula VI-1-a (3.00 g, 8.1 mmol, 1.0 equiv) was added to a reaction flask, ethanol (15 g) was added, the solid did not dissolve, then 5N NaOH aqueous solution (9.0 g) was added, part of the solid dissolved, then the temperature was raised to 80 °C for reaction, after 3 h a large amount of solid precipitated, the stirring was continued for 1 h. The reaction solution was filtered, the filter cake was washed once with a mixed solution of EtOH and water (15 g, 1:1, w / w) to give a white solid. The solid was directly transferred to a reaction flask without further drying, purified water (15 g) was added, then a mixed solution of purified water (13.5 g), acetone (22 g) and concentrated hydrochloric acid (0.62 g) was added dropwise to the suspension, after the dropwise addition was completed, a large amount of solid precipitated, purified water 12 g was continuously added dropwise to the suspension, the reaction was raised to 48 °C for stirring for 2 h, then filtered, the filter cake was washed with a mixed solution of acetone (9 g) and purified water (9 g) to give the compound of formula I-1-a, enasidenib, as a white powdery solid (2.40 g, 7.05 mmol, yield 88%, HPLC purity 99.8%).

[0105] 1 H NMR (400 MHz, DMSO-d6): δ 10.83 (brs, 1H), 8.08 (s, 1H), 7.23-7.10 (m, 5H), 6.26 (s, 1H), 3.67 (s, 2H), 3.30 (brs, 1H), 3.14-3.05 (m, 2H), 7.23-7.10 (m, 5H), 3.00-2.96 (m, 2H).

[0106] MS (ESI) M / Z: 339.1 [M-H] - .

Claims

1. A preparation method of formula V, comprising: Step 1, subjecting the compound of formula II to a substitution reaction with the compound of formula III to obtain the compound of formula IV; Step 2, hydrolyzing the compound of formula IV under alkaline conditions, and then decarboxylating under acidic conditions to produce the compound of formula V; wherein X is independently selected from Cl, Br and I, preferably Cl; R1 is selected from C1-C6 alkyl, benzyl and other carboxyl protecting groups; Ar is selected from the following structures (a) to (e), preferably structure (a), The compound of formula II is preferably a compound of formula II-1; the compound of formula III is preferably a compound of formula III-a; the compound of formula IV is preferably a compound of formula IV-1-a; the compound of formula V is preferably a compound of formula V-1-a, 2. A method for preparing a compound of formula I, comprising: Wherein, step 1 and step 2 adopt the preparation method as claimed in claim 1, and, Step 3, subjecting the compound of formula V to amidation reaction to obtain the compound of formula VI; Step 4: hydrolyze the compound of formula VI and then adjust the acid to obtain the compound of formula I. Wherein, the definitions of X, R1, and Ar are the same as those in claim 1.

3. The preparation method according to claim 1 or 2, characterized in that The step 1 is carried out in a solvent under Lewis acid catalysis; the temperature in the step 1 is 20 to 100° C., preferably 50 to 60° C.; the molar ratio (mol / mol) of the compound of formula II to the compound of formula III in the step 1 is 1:2.0 to 6.0, preferably 1:2.0 to 2.5; the solvent used in the step 1 is selected from one or more of N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMAc), acetonitrile, 1,4-dioxane, tetrahydrofuran, and methyl isobutyl ketone (MIBK), preferably acetonitrile; the mass ratio (w / w) of the solvent used in the step 1 to the compound of formula II is 1:5.0 to 20.0, preferably 1:5.0 to 6.

0.

4. The preparation method according to any one of claims 1 to 3, characterized in that The alkaline aqueous solution used in step 2 is formed by a base, and the base is selected from one or more of sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), and diisopropylethylamine (DIPEA), preferably NaOH; the mass ratio (w / w) of the alkaline aqueous solution used in step 2 to the compound of formula IV is 1:2.0-6.0, preferably 1:2.0-2.5; the molar concentration of the alkaline aqueous solution used in step 2 is 2N-5N, preferably 4N; the hydrolysis temperature in step 2 is 20-90°C, preferably 20-40°C; and the decarboxylation temperature in step 2 is 50-90°C, preferably 70°C.

5. The preparation method according to any one of claims 1 to 4, characterized in that The acidic aqueous solution used in the step 2 is formed by an acid, and the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, and acetic acid, preferably hydrochloric acid; the mass ratio (w / w) of the compound of formula IV in the step 2 to the acidic aqueous solution is 1:1 to 5, preferably 1:1 to 1.5; the molar concentration of the acidic aqueous solution used in the step 2 is 4N to 8N, preferably 6N.

6. The preparation method according to any one of claims 2 to 5, characterized in that The substances used in the step three are a compound of formula V, glycine methyl ester or a salt thereof, an organic base, and a condensing agent. The glycine methyl ester or a salt thereof is preferably glycine methyl ester hydrochloride, the organic base is preferably Et3N, and the condensing agent is preferably EDCI and HOBt; the molar ratio (mol / mol) of the compound of formula V, the glycine methyl ester or a salt thereof, the organic base, and the condensing agent is 1:1.0~5.0:1.0~5.0:1.0~5.0:0.2~0.8, preferably 1:1.0~1.5:1.0~1.5:1.0~1.5:0.2~0.

3.

7. The preparation method according to any one of claims 2 to 6, characterized in that The solvent used in step 3 is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, and 1,4-dioxane, preferably acetonitrile; the mass ratio (w / w) of the solvent used in step 3 to the compound of formula V is 1:5 to 1:20, preferably 1:

10.

8. The preparation method according to any one of claims 2 to 7, characterized in that The alkaline aqueous solution used in step 4 is formed by a base, and the base is selected from one or more of NaOH, KOH, LiOH, DBU, and DIPEA, preferably NaOH; the molar concentration of the alkaline aqueous solution used in step 4 is 4N to 6N, preferably 5N; the mass ratio (w / w) of the compound of formula VI used in step 4 to the alkaline aqueous solution is 1:2 to 1:4, preferably 1:3, and the mass ratio (w / w) of the compound of formula VI used in step 4 to the ethanol is 1:4 to 1:6, preferably 1:5; the temperature in step 4 is 70 to 90°C, preferably 80°C.

9. The preparation method according to any one of claims 2 to 8, characterized in that The compound of formula VI is a compound of formula VI-1-a; the compound of formula I is a compound of formula I-1-a, 10. Compounds of formula IV: in, Ar is selected from the following structures (a) to (e), X is independently selected from Cl, Br and I; R1 is selected from C1-C6 alkyl, benzyl and other carboxyl protecting groups.

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