A process for the preparation of 2-hydroxyethyl-3-pentyloxy-4-pyrone

Abstract

The application provides a new preparation method of 2-hydroxyethyl-3-pentyloxy-4-pyrone (a compound of formula I) which is a synthesis raw material of a key intermediate of maraviroc, and has the advantages that: a new process is used, 2-bromoethyl-3-pentyloxy-4-pyrone (a compound of formula I-1) is activated, complete reaction is realized, 2-hydroxyethyl-3-pentyloxy-4-pyrone is obtained, the reaction speed is improved, the occurrence of side reactions is reduced, a large amount of calcium salt solid waste is reduced, the reaction yield is increased from 50% to more than 80%; and the application also provides a method for preparing a key intermediate (a compound of formula III) of maraviroc by using the compound of formula I, and the total yield can reach more than 30%, which is an industrialized amplification implementation feasible process.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing 2-hydroxyethyl-3-pentoxy-4-pyranone. Background Technology

[0002] Baloxavir Marboxil, also known as Marboxil, is a novel anti-influenza drug developed by Shionogi Pharmaceutical Co., Ltd. of Japan, marketed under the brand name Xofluza. Xofluza is an innovative Cap-dependent endonuclease inhibitor and one of the few drugs in the world capable of inhibiting influenza virus replication. It targets a key step in influenza virus replication, inhibiting the acquisition of the 5' end of the host mRNA from host cells by the virus, thereby suppressing the transcription of the influenza virus's own mRNA. In February 2018, the drug was approved in Japan for the treatment of influenza A and B in adults and pediatric patients. In October 2018, it was approved by the FDA for the treatment of uncomplicated acute influenza in patients aged 12 years and older with symptoms lasting no more than 48 hours.

[0003] Marloxavir is a prodrug that hydrolyzes in the body into the active substance balloxavir, which exerts its antiviral activity against influenza viruses. The oxazinidine triazine ring fragment is a key intermediate in the synthesis of mabaloxavir, and its chemical name is (12AR)-3,4,12,12A-tetrahydro-7-pentoxy-1H-[1,4]oxazino[3,4-C]pyrido[2,1-F][1,2,4]triazin-6,8-dione (compound of formula III).

[0004] Compounds of Formula III can be prepared from compounds of Formula II-1: Patent WO2019070059 discloses a method for synthesizing compound II-1: compound I-1 is hydrolyzed and oxidized to obtain the target compound. For the first step of the hydrolysis reaction, the original research company used acetonitrile-water as a solvent and added calcium carbonate to compound I-1 for reflux hydrolysis. However, the reaction was very slow, with 10% of the starting material remaining after 24 hours, and a large number of ring-opening impurities were generated, resulting in a reaction yield of less than 50%. With the global market availability of mabaloxavir and the increasing use of anti-influenza drugs, the demand for mabaloxavir is growing. Therefore, there is a need to develop industrial synthetic routes for key intermediates of mabaloxavir with high yield, high purity, and low cost. Summary of the Invention

[0005] This invention provides a novel method for preparing 2-hydroxyethyl-3-pentoxy-4-pyranone (compound of formula I), a key intermediate for the synthesis of baloxavir. The invention achieves complete reaction by activating 2-bromoethyl-3-pentoxy-4-pyranone (compound of formula I-1) to obtain 2-hydroxyethyl-3-pentoxy-4-pyranone. This method increases the reaction rate while reducing side reactions and minimizing the amount of calcium salt waste, increasing the reaction yield from 50% to over 80%. Furthermore, this invention also provides a method for preparing the key intermediate for baloxavir (compound of formula III) from compound of formula I, with an overall yield exceeding 30%, making it a feasible process for industrial-scale implementation.

[0006] The first aspect of this invention provides a method for preparing 2-hydroxyethyl-3-pentoxy-4-pyranone (compound of formula I), the method comprising the following steps: (1) An alkali metal acetate salt is added to an organic solvent system containing compound I-1, and the reaction yields a mixed system A containing compound I-2; and (2) Add alkali to the mixture A and react to obtain compound I.

[0007] In another preferred embodiment, in step (1), the alkali metal acetate is selected from the group consisting of sodium acetate, potassium acetate, lithium acetate, or combinations thereof, preferably sodium acetate and potassium acetate.

[0008] In another preferred embodiment, in step (1), the organic solvent is selected from C1-C6 alcohol solvents, preferably methanol, ethanol, isopropanol, or combinations thereof, more preferably ethanol.

[0009] In another preferred embodiment, in step (1), the reaction temperature is 40~80℃, preferably 50-65℃.

[0010] In another preferred embodiment, in step (2), the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium ethoxide, or combinations thereof, preferably sodium hydroxide.

[0011] In another preferred embodiment, in step (2), the reaction temperature is -10~30℃, preferably -5~10℃.

[0012] In another preferred embodiment, step (2) further includes one or more post-processing steps selected from the group consisting of: acid neutralization, removal of organic solvent from the reaction solution, extraction, separation, and concentration.

[0013] In another preferred embodiment, in step (2), the extraction solvent is selected from the group consisting of ethyl acetate, methyl ether, isopropyl ether, tetrahydrofuran, toluene, or combinations thereof, preferably ethyl acetate.

[0014] In a second aspect, the present invention provides a method for preparing a baloxavir intermediate compound of formula II, the method comprising the following steps: (a) Compound I reacts with an oxidizing agent to give compound II-1; (b) Compound II-1 reacts with dimethyl sulfate under alkaline conditions to give compound II-2; (c) Compound II-2 reacts with tert-butyl hydrazine carbamate in a system containing pyridinium p-toluenesulfonate to give compound II; and Prior to step (a), the method of the first aspect of the present invention is used to prepare compound I.

[0015] In another preferred embodiment, step (a) includes the step of reacting compound I in a reaction system containing sodium bicarbonate, sodium bromide, 2,2,6,6-tetramethylpiperidine oxide and trichloroisocyanuric acid at 0-10°C.

[0016] In a third aspect, the present invention provides a method for preparing a compound of formula III, specifically comprising the following steps: (A) Compound II and Compound III-1 react in the presence of a condensing agent to give Compound III-2, wherein the condensing agent is selected from one or more of 1,8-diazabicyclo[5.4.0]-7-undecene, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; (B) An organic acid is added to a reaction system containing compound III-2, and the reaction yields compound III-3, wherein the organic acid is selected from one or more of methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid; (C) Compound III-3 and Compound III-4 are condensed under acid-binding conditions, and after the reaction is completed, the mixture is further purified to obtain isomer-pure Compound III-5, wherein the acid-binding agent is selected from one or more of triethylamine, diisopropylethylamine, and pyridine. (D) Compound III-5 undergoes defuranoyl group removal under the action of 1,8-diazabicyclo[5.4.0]-7-undecene to yield compound III; and Prior to step (A), the method of the second aspect of the present invention is used to prepare compound II.

[0017] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0018] For the hydrolysis reaction of 2-bromoethyl-3-pentoxy-4-pyranone (compound I-1), the original research company used acetonitrile-water as a solvent and added calcium carbonate for reflux hydrolysis. This process was slow, had low conversion rate, and produced many byproducts. Therefore, the inventors attempted to optimize this step. Extensive and in-depth research revealed that hydrolysis using other alkaline aqueous systems (including sodium carbonate aqueous solution, sodium hydroxide aqueous solution, sodium bicarbonate aqueous solution, etc.) is difficult to carry out below 30°C and requires heating. However, while heating produces hydrolysis products, the high temperature causes ring-opening of the raw material, generating ring-opening byproducts, increasing the burden of post-processing, and affecting product yield and purity. The inventors' research found that activating benzyl bromide increases its reactivity, allowing the hydrolysis reaction to proceed at low temperatures, effectively reducing byproduct generation, shortening reaction time, and improving the yield of this step.

[0019] the term Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0020] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0021] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0022] As used in this article, the terms "room temperature" or "normal temperature" refer to a temperature between 4 and 40 degrees Celsius. o C, preferably, 25±5 o C.

[0023] In this invention, in the reaction system of each reaction step, each substance (except the solvent) can participate in the reaction independently in any suitable ratio, such as 1:(0.1-10), 1:(0.2-5), 1:(0.5-2), 1:(0.8-1.5) or 1:(1.0-1.2).

[0024] Preparation method of 2-hydroxyethyl-3-pentoxy-4-pyranone (compound of formula I) This invention provides a method for preparing 2-hydroxyethyl-3-pentoxy-4-pyranone (compound of formula I), the method comprising the following steps: (1) An alkali metal acetate salt is added to an organic solvent system containing compound I-1, and the reaction yields a mixed system A containing compound I-2; and (2) Add alkali to the mixture A and react to obtain compound I.

[0025] In another preferred embodiment, in step (1), the alkali metal acetate is selected from the group consisting of sodium acetate, potassium acetate, lithium acetate, or combinations thereof, preferably sodium acetate and potassium acetate.

[0026] In another preferred embodiment, in step (1), the organic solvent is selected from C1-C6 alcohol solvents, preferably methanol, ethanol, isopropanol, or combinations thereof, more preferably ethanol.

[0027] In another preferred embodiment, in step (1), the reaction temperature is 40~80℃.

[0028] In another preferred embodiment, in step (2), the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium ethoxide, or combinations thereof, preferably sodium hydroxide.

[0029] In another preferred embodiment, in step (2), the reaction temperature is -10~30℃.

[0030] In another preferred embodiment, step (2) further includes one or more post-processing steps selected from the group consisting of: acid neutralization, removal of organic solvent from the reaction solution, extraction, separation, and concentration.

[0031] In another preferred embodiment, in step (2), the extraction solvent is selected from the group consisting of ethyl acetate, methyl ether, isopropyl ether, tetrahydrofuran, toluene, or combinations thereof, preferably ethyl acetate.

[0032] In another preferred embodiment, the method further includes the step of: (a) Compound I reacts with an oxidizing agent to give compound II-1; In another preferred embodiment, step (a) includes the step of reacting compound I in a reaction system containing sodium bicarbonate, sodium bromide, 2,2,6,6-tetramethylpiperidine oxide and trichloroisocyanuric acid at 0-10°C.

[0033] Preparation method of compound II This invention further provides a method for preparing the baloxavir intermediate compound of formula II, the method comprising the following steps: (a) Compound I reacts with an oxidizing agent to give compound II-1; (b) Compound II-1 reacts with dimethyl sulfate under alkaline conditions to give compound II-2; (c) Compound II-2 was reacted with tert-butyl hydrazine carboxylate in a system containing p-toluenesulfonic acid pyridinium to give compound II.

[0034] Preferably, before step (a), the method of preparing compound I according to the present invention is further included.

[0035] In another preferred embodiment, step (a) includes the step of reacting compound I in a reaction system containing sodium bicarbonate, sodium bromide, 2,2,6,6-tetramethylpiperidine oxide and trichloroisocyanuric acid at 0-10°C.

[0036] Preparation method of compound III This invention also includes a method for preparing a compound of formula III, specifically comprising the following steps: (A) Compound II and Compound III-1 react in the presence of a condensing agent to give Compound III-2, wherein the condensing agent is selected from one or more of 1,8-diazabicyclo[5.4.0]-7-undecene, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; (B) An organic acid is added to a reaction system containing compound III-2, and the reaction yields compound III-3, wherein the organic acid is selected from one or more of methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid; (C) Compound III-3 and Compound III-4 are condensed under acid-binding conditions, and after the reaction is completed, the mixture is further purified to obtain isomer-pure Compound III-5, wherein the acid-binding agent is selected from one or more of triethylamine, diisopropylethylamine, and pyridine. (D) Compound III-5 was de-furanoyl grouped by 1,8-diazabicyclo[5.4.0]-7-undecene to obtain compound III.

[0037] Preferably, prior to step (A), the method further includes a step of preparing a compound of formula II according to the present invention.

[0038] Preferably, the purity of the isomer of compound III obtained in this invention is not less than 99.0%.

[0039] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0040] Example 1 Preparation of Formula I compounds In 27.5 g (0.10 mol) of I-1, 120 mL of 95% ethanol and 11.5 g (0.14 mol) of sodium acetate were added sequentially. The mixture was heated to 55-60 °C and reacted for 7 hours. The reaction was observed on a TLC plate, indicating that the starting materials had reacted almost completely. Then, the mixture was cooled to -5-5 °C, and 4.8 g (0.12 mol) of an aqueous solution of sodium hydroxide (dissolved in 30 mL of water) was added dropwise over 10-20 minutes. After the addition was complete, the mixture was reacted at -5-5 °C for another 1.5 hours. After the reaction was complete, 5 mL of acetic acid was added, and the reaction solution was concentrated to remove the ethanol. The aqueous phase was then extracted twice with 40 mL of ethyl acetate. The organic phases were combined and washed once with 20 mL of water. Finally, the mixture was concentrated under reduced pressure to remove the ethyl acetate, yielding 18.2 g of an oily substance, which was compound I with a purity of 96.4% and a yield of 85.8%.

[0041] Example 2 Preparation of compound II-1 Weigh 21.2 g (0.10 mol) of compound I, 30.03 g (0.30 mol) of sodium bicarbonate, 3.32 g (0.02 mol) of sodium bromide, and 0.31 g (0.002 mol) of 2,2,6,6-tetramethylpiperidine oxide (TEMPO). Then add 220 mL of acetone and 80 mL of water, cool to 0-10 °C, and add dropwise 22.27 g (0.096 mol) of trichloroisocyanuric acid (TCCA) in acetone (dissolved in 80 mL of acetone). The addition is completed in about 30 minutes. After the addition is completed, the reaction is carried out at 0-10 °C for 1.5 h. The reaction is then checked on a TLC plate, and the starting materials have basically reacted completely. Add 14 mL of methanol to the reaction solution and stir for 0.5 h. Then add 10.96 g of sodium bisulfite and stir for another 0.5 h. Filter the solution and concentrate the filtrate under reduced pressure at 35 °C until no obvious distillate flows out. Adjust the pH to about 9 with sodium hydroxide, and a solid precipitates out. Add 80 mL of ethyl acetate, filter the solution, separate the filtrate, collect the aqueous phase, wash the aqueous phase twice with 55 mL + 27 mL of ethyl acetate, combine the aqueous phases, cool to 0-10 °C, adjust the pH to 2-3 with concentrated hydrochloric acid, and filter to obtain 21.09 g of yellow solid, which is compound II-1, with a purity of 97.6% and a yield of 91.0%.

[0042] Example 3 Preparation of compound II-2 At room temperature, 800 mL of acetone was added to compound II-1 (91.75 g, 0.41 mol), followed by potassium carbonate (36.51 g, 0.26 mol). The mixture was stirred, and dimethyl sulfate (58.91 g, 0.47 mmol) was added dropwise. The reaction was continued at room temperature until the starting material was completely eliminated. The pH was adjusted to 3-4 with hydrochloric acid, the mixture was concentrated to remove acetone, and then extracted once with ethyl acetate. The aqueous phase was separated and extracted again with ethyl acetate. The organic phases were combined and concentrated to obtain an oily substance, which was used directly in the next reaction step.

[0043] Example 4 Preparation of Compounds of Formula II At room temperature, 300 mL of N,N-dimethylacetamide was added to the concentrate II-2 prepared in Example 3, followed by the addition of pyridinium p-toluenesulfonate (265.42 g, 1.06 mol). The reaction mixture was heated to 60 °C. Then, a solution of tert-butyl hydrazinoate (69.80 g, 0.53 mmol) in N,N-dimethylacetamide (200 mL) was slowly added to the reaction mixture. After the addition was complete, the mixture was stirred at this temperature for 1 hour, then cooled to room temperature. Water and ethyl acetate were added, and the mixture was extracted. After separation, the organic phase was concentrated. 100 mL of ethanol and 600 mL of water were added to the concentrate, and the mixture was stirred for 1 hour. The mixture was filtered and dried under vacuum to give 124.2 g of compound II with a purity of 95.4% and a yield of 86.3%.

[0044] Example 5 Preparation of compound III-2 Compound II (10.3 g, 0.07 mol) and 1,8-diazabicyclo[5.4.0]-7-undecene (8.9 g, 0.058 mol) were added to 40 mL of THF at room temperature. Compound III-1 (18.93 g, 0.053 mol) was added to the solution and stirred until dissolved. The reaction system was heated to 60 °C and stirred until the substrate was completely converted. The system was cooled to room temperature, and water and acetic acid were added to adjust the pH to 5-6. The mixture was then extracted with ethyl acetate, and the organic phases were combined and concentrated to obtain an oil. Methyl tert-butyl ether was added to the oil, and the mixture was stirred. A solid precipitated out and was filtered to give 22.0 g of pale yellow to off-white solid compound III-2 with a purity of 92.1% and a yield of 87.4%.

[0045] Example 6 Preparation of compounds of formula III-3 Compound III-2 (19.19 g, 0.041 mol) was added to a mixture of 170 mL acetonitrile and 30 mL water, and stirred. The reaction mixture was then heated to 60 °C, and methanesulfonic acid (11.70 g, 0.12 mol) was slowly added dropwise. The mixture was kept at this temperature and stirred for 3–5 hours until the reaction was complete. The system was cooled to room temperature, and the pH was adjusted to 6–7 with a 30% sodium hydroxide aqueous solution. The acetonitrile in the reaction mixture was concentrated, and the residue was stirred in water. The resulting yellow precipitate was collected by filtration and dried to give 10.2 g of compound III-3 as yellow crystals, with a purity of 94.1% and a yield of 85.7%.

[0046] Example 7 Preparation of Compounds of Formula III-5 Compound III-3 (9.4 g, 0.03 mol), 80 mL of N,N-dimethylformamide, and triethylamine (8.0 g, 0.08 mol) were added to the reaction flask. Compound III-4 (5.38 g, 0.04 mol) was added dropwise while maintaining the internal temperature below 15 °C. After the addition was complete, the mixture was stirred at room temperature for 2–3 hours until the reaction was complete. 80 mL of dichloromethane was added, the mixture was cooled, water was added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated. 50 mL of ethyl acetate was added to the concentrate, and the mixture was stirred at 60–65 °C for 0.5 hours. The temperature was further lowered to 0–5 °C, and the mixture was stirred for 0.5 hours. The mixture was filtered, and the filter cake was purified again with 30 mL of ethyl acetate. The filtered cake was then dried under vacuum to obtain 5.8 g of compound III-5 with a purity of 99.3% and a yield of 47.1%.

[0047] Example 8 Preparation of Compounds of Formula III Compound III-5 (14.56 g, 0.036 mol) was added to 120 mL of ethyl acetate and stirred until dissolved. Then, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (5.3 g, 0.035 mol) was added. The reaction mixture was heated to 30 °C and stirred for 1 hour. The mixture was then cooled to 0–5 °C and stirred for 0.5 h. After filtration and drying, 10.76 g of white solid, namely compound III, was obtained with a purity of 99.1% and a yield of 97.3%.

[0048] Comparative Example 1 Compound I-1 (2.75 g, 0.01 mol) was dissolved in a mixed solution of acetonitrile (55 mL) and water (55 mL), and then calcium carbonate (2.00 g, 0.02 mol) was added. The mixture was stirred under reflux for 24 h. After the reaction was completed, the mixture was cooled to room temperature and extracted twice with ethyl acetate (50 mL * 2). The organic phases were combined, washed once with saturated brine (20 mL), and then concentrated under reduced pressure to remove ethyl acetate, yielding 1.04 g of an oily substance, which was compound I, with a yield of 48.9%.

[0049] Comparative Example 2 Compound I-1 (2.75 g, 0.01 mol) was dissolved in a mixed solution of acetonitrile (55 mL) and water (55 mL), and then sodium bicarbonate (3.36 g, 0.04 mol) was added. The mixture was stirred at room temperature for 24 h, and HPLC showed that the reaction solution contained 82.7% of the starting material. After reacting for another 12 h, ethyl acetate (50 mL * 2) was added for extraction twice. The organic phases were combined, washed once with saturated brine (20 mL), and then concentrated under reduced pressure to remove ethyl acetate, yielding 0.33 g of an oily substance, which was compound I, with a yield of 15.7%.

[0050] Comparative Example 3 Compound I-1 (2.75 g, 0.01 mol) was dissolved in a mixed solution of acetonitrile (55 mL) and water (55 mL), and then sodium bicarbonate (3.36 g, 0.04 mol) was added. The mixture was stirred under reflux for 24 h. TLC showed that many impurities were generated. The mixture was then cooled to room temperature and extracted twice with ethyl acetate (50 mL * 2). The organic phases were combined and washed once with saturated brine (20 mL). The mixture was then concentrated under reduced pressure to remove ethyl acetate, yielding 0.85 g of an oily substance, which was compound I, with a yield of 40.1%.

[0051] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing compound I, 2-hydroxyethyl-3-pentoxy-4-pyranone, the method comprising the following steps: (1) An alkali metal acetate salt is added to an organic solvent system containing compound I-1, and the reaction yields a mixed system A containing compound I-2; and (2) Adding a base to mixture A results in the reaction of compound I; The alkali metal salt of acetate is sodium acetate. The alkali is sodium hydroxide; The organic solvent is ethanol; In step (1), the reaction temperature is 55-60℃; In step (2), the reaction temperature is -5~5℃.

2. The method as described in claim 1, characterized in that, The ethanol is 95% ethanol.

3. The method as described in claim 1, characterized in that, In step (2), after the reaction is completed, one or more post-processing steps selected from the group below are also included to obtain compound I: acid neutralization, removal of organic solvent from the reaction solution, extraction, separation, and concentration.

4. The method as described in claim 3, characterized in that, The solvent used for extraction is selected from the group consisting of ethyl acetate, methyl ether, isopropyl ether, tetrahydrofuran, toluene, or combinations thereof.

5. The method as described in claim 1, characterized in that, The method includes the following steps: 120 mL of 95% ethanol and 11.5 g of sodium acetate are added sequentially to 27.5 g of I-1, and the mixture is heated to 55–60 °C and reacted for 7 hours; then the temperature is lowered to -5–5 °C, and an aqueous solution of 4.8 g of sodium hydroxide dissolved in 30 mL of water is added dropwise over 10–20 minutes. After the addition is complete, the mixture is reacted at -5–5 °C for another 1.5 hours; after the reaction is complete, 5 mL of acetic acid is added, and the reaction solution is concentrated to remove the ethanol; then 40 mL of ethyl acetate is added to extract the aqueous phase twice, the organic phases are combined, and the mixture is washed once with 20 mL of water; finally, the mixture is concentrated under reduced pressure to remove the ethyl acetate, yielding an oily substance, which is compound I.

6. A method for preparing a baloxavir intermediate compound of formula II, the method comprising the following steps: (a) Compound I reacts with an oxidizing agent to give compound II-1; (b) Compound II-1 reacts with dimethyl sulfate under alkaline conditions to give compound II-2; (c) Compound II-2 reacts with tert-butyl hydrazine carbamate in a system containing pyridinium p-toluenesulfonate to give compound II; and Prior to step (a), the method of claim 1 is used to prepare compound I. Furthermore, step (a) includes the step of reacting compound I in a reaction system containing sodium bicarbonate, sodium bromide, 2,2,6,6-tetramethylpiperidine oxide, and trichloroisocyanuric acid at 0-10°C.

7. A method for preparing a compound of formula III, specifically comprising the following steps: (A) Compound II and Compound III-1 react in the presence of a condensing agent to give Compound III-2, wherein the condensing agent is selected from one or more of 1,8-diazabicyclo[5.4.0]-7-undecene, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; (B) An organic acid is added to a reaction system containing compound III-2, and the reaction yields compound III-3, wherein the organic acid is selected from one or more of methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid; (C) Compound III-3 and Compound III-4 are condensed under acid-binding conditions, and after the reaction is completed, the mixture is further purified to obtain isomer-pure Compound III-5, wherein the acid-binding agent is selected from one or more of triethylamine, diisopropylethylamine, and pyridine. (D) Compound III-5 is de-furanoylated by 1,8-diazabicyclo[5.4.0]-7-undecene to yield compound III; and Prior to step (A), the method of claim 6 is used to prepare compound II.

Images