A method for preparing a mupirocin derivative

Abstract

This invention relates to mupirocin compounds, specifically to a method for preparing mupirocin derivatives. The method includes the following steps: 1) benzyloxyheptenol reacts with triethyl orthoacetate via a Claisen rearrangement to generate trans-ethyl olefin ester; 2) the trans-ethyl olefin ester undergoes oxidation to remove debenzylic protection, producing an alcohol compound; 3) the alcohol compound undergoes halogenation to generate a key branched iodide; 4) mupirocin reacts with excess trimethyl orthoformate under acidic catalysis for alcohol protection, followed by ester hydrolysis under alkaline conditions to obtain polyol-protected mupirocin acid; 5) the polyol-protected mupirocin acid reacts with the iodide via a nucleophilic substitution reaction to generate a polyalkyl mupirocin ester; 6) the polyalkyl mupirocin ester undergoes alkaline hydrolysis, followed by acid-base adjustment and deprotection to obtain the crude product, which is then neutralized to acid and purified by slurrying with an inorganic base to obtain the target compound. This invention avoids harsh reaction conditions, has readily available raw materials, high yield, simple operation and purification, and can be used for large-scale production of high-quality target compounds.

Description

Technical Field

[0001] This invention relates to mupirocin-like compounds, specifically to a method for preparing a mupirocin derivative. Background Technology

[0002] Mupirocin is a topical antibiotic produced by the culture medium of *Pseudomonas fluorescens*, specifically *Pseudomonas A*. Its antibacterial action primarily occurs through reversible binding to isoleucine transfer RNA synthase, preventing isoleucine infiltration and halting the synthesis of isoleucine-containing proteins within the cell, thus achieving bactericidal or bacteriostatic effects. The structural formula of mupirocin is...

[0003] The structural formula of the mupirocin derivative involved in this invention patent is as follows:

[0004] Patent EP0068690 (priority date 1981-06-20) first disclosed the antibacterial and mycoplasma-resistant activities of this compound, and further revealed the following method for synthesizing the compound, which involves using light to perform cis-trans conversion of the alkene bond to obtain a single trans configuration.

[0005] This route suffers from technical flaws. It fails to disclose the source and process of the sodium salt after mupirocin hydrolysis, and the reaction conditions are extremely harsh and specific, resulting in an overall yield of less than 0.01%, which is highly unfavorable for large-scale production. Furthermore, mupirocin is primarily obtained through bio-fermentation. Similar structures in room-temperature acid-base systems can cause ring-switching of the three-membered ring, forming multiple chiral inversion isomers. Moreover, the docking of the two fragments mentioned above directly employs high-temperature conditions, essentially an active construction of racemic isomers. Additionally, ring-opening is easily achieved under neutral hydrogenation conditions, making it extremely difficult to obtain large quantities of high-purity mupirocin derivatives under typical chemical reaction conditions.

[0006] J.Chem. Soc., Perkin Trans. 1, 1982, 2827-2833 The disclosed synthetic route is as follows:

[0007] This process involves synthesizing a racemic isomer of cis-trans isomers from the sodium salt of Pseudomonas acid C and its chlorinated derivative, followed by separation and final neutralization to obtain the target product. It suffers from the same drawbacks as the aforementioned patent: the product is not singular, separation of the target analyte is difficult, and racemization is unavoidable.

[0008] Therefore, obtaining large quantities of high-purity mupirocin derivatives has become an urgent technical challenge. Summary of the Invention

[0009] Purpose of the Invention: The purpose of this invention is to provide a novel, efficient, low-cost, scalable, single-configuration, and high-quality method for preparing mupirocin degradation derivatives. This invention avoids harsh reaction conditions, features readily available raw materials, mild reaction conditions, high yield, simple operation and purification, and allows for large-scale production of high-quality target compounds. A single operation can meet market demand for standards of this mupirocin derivative (the diffractometer possesses the triple properties of active pharmaceutical ingredient activity, mupirocin metabolite diffractometer standard, and essential impurity for EP).

[0010] Technical solution A method for preparing a mupirocin derivative, characterized by comprising the following steps:

[0011] Synthesis of S1, compound STD-RM70923MN-2: Benzyloxyheptenol (STD-RM70923MN-1) was dissolved in triethyl orthoformate. A catalytic amount of organic acid was added at room temperature, and the reaction was heated. After the reaction was complete, TLC was used to detect the reaction. The triethyl orthoformate was then concentrated and recovered. The concentrate was poured into water, extracted with petroleum ether, washed, dried, and concentrated to obtain the compound STD-RM70923MN-2. Synthesis of S2 and compound STD-RM70923MN-3: Compound STD-RM70923MN-2 was dissolved in a heterogeneous mixture of dichloromethane and water. The oxidative removal reagent 2,3-dichloro-5,6-dicyanobenzoquinone was added at 20-25℃. After the reaction was completed, water was added and the mixture was extracted with dichloromethane, washed, dried, concentrated, and purified by dry column chromatography to obtain compound STD-RM70923MN-3. Synthesis of S3 and compound STD-RM70923MN-4: Compound STD-RM70923MN-3 was dissolved in toluene, then triphenylphosphine and imidazole were added, nitrogen gas was substituted, and then elemental iodine was added. The mixture was kept at 20-25°C and monitored by TLC until the reactants were completely removed. The solvent was then removed by concentration and column purification to obtain compound STD-RM70923MN-4. Synthesis of S4, compound STD-RM70923MN-5: Mupirocin (RM7092MD) was added to the protecting group reagent trimethyl orthoformate, and p-toluenesulfonic acid was added with stirring. The reaction was carried out at 20-25°C for 1.5 h, the solvent was removed by concentration, and sodium hydroxide aqueous solution (1M) was added to the mixture after rotary evaporation. The reaction was carried out at 65°C with stirring for 4.5 h. LC-MS was monitored until the reactants were completely reacted. The pH of the reaction solution was adjusted to 7-7.5 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, washed, dried, and rotary evaporated to obtain the crude compound STD-RM70923MN-5.

[0012] Synthesis of S5 and compound STD-RM70923MN-6: Compound STD-RM70923MN-5 was dissolved in an organic solvent. After dissolution, an inorganic base was added and the mixture was stirred for 10 minutes. Then, compound STD-RM70923MN-4 was added and the mixture was stirred at 20-25°C. LCMS monitoring showed that the reaction proceeded completely. Water was added, and the mixture was extracted with ethyl acetate, washed, dried, and then evaporated to dryness to obtain crude compound STD-RM70923MN-6.

[0013] Synthesis of S6 and compound STD-RM70923MN The crude compound, STD-RM70923MN-6, was dissolved in an alcohol solvent (300 ml). The mixture was cooled to 0-5℃, and an aqueous solution of calcium chloride / lithium hydroxide was added. The reaction was stirred at 20-25℃ and monitored by LCMS until completion. The reaction solution was extracted with petroleum ether / ethyl acetate, washed, dried, and evaporated to dryness to obtain an oily substance. The oily substance was redissolved in methanol / water, and the pH was adjusted to 3-3.5 with concentrated hydrochloric acid at 0-5℃. The temperature was then naturally raised to 20-25℃ and reacted for 40 min. After cooling to 0-5℃, the pH was adjusted to 8.5-9.0 with sodium hydroxide (1M), and the temperature was naturally raised to 20-25℃ and reacted overnight. After the reaction was complete, the temperature was lowered to 0-5℃, and the pH was adjusted to 6 with hydrochloric acid. Finally, the pH was adjusted to 7-7.5 with an inorganic base, and the mixture was lyophilized to obtain the crude product containing inorganic salts. The insoluble inorganic salts were removed by repeated slurrying with acetonitrile / water, and the compound STD-RM70923MN was obtained by area normalization until the content no longer changed.

[0014] The method is characterized in that, in step S1, the reaction temperature is 120-150℃, preferably 125-135℃, the molar ratio of benzyloxyheptenol (STD-RM70923MN-1) to the catalyst organic acid is 1%-10%, preferably 2%-5%, and the organic acid is formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc., preferably acetic acid.

[0015] The method is characterized in that, in step S2, the molar ratio of compound STD-RM70923MN-2 to 2,3-dichloro-5,6-dicyanobenzoquinone is 1:1 to 1:1.5, preferably 1:1 to 1.2.

[0016] The method is characterized in that, in step S3, the molar ratio of STD-RM70923MN-2 to triphenylphosphine, imidazole, and iodine is 1:1.5:1.5:1.5-1:1:3:3:3, preferably 1:2:2:2~1:3:3:3; The method is characterized in that, in step S4, the molar ratio of mupirocin to p-toluenesulfonic acid is 1:0.01-1:0.1, preferably 1:0.01~0.02; and the alkaline hydrolysis temperature is 60-70℃, preferably 60-65℃. The method is characterized in that the solvent selected in step S5 is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, or acetonitrile, preferably N,N-dimethylformamide; the molar ratio of compound STD-RM70923MN-5: compound STD-RM70923MN-4: inorganic base is 1:1.2~1.7:2~3, preferably 1:1.3~1.5:2.2~2.7; the inorganic base is sodium carbonate and potassium carbonate, preferably potassium carbonate; The method is characterized in that the alcohol solvent used in step S6 is ethanol, isopropanol and tert-butanol, preferably isopropanol; the molar ratio of compound STD-RM70923MN-6: lithium hydroxide: calcium chloride is 1:2.5~5:8~15, preferably 1:3.0~3.5:12~14.

[0017] Key points of this invention: This invention relates to mupirocin derivatives, which suffer from the following problems: the three-membered ring structure of mupirocin or its derivatives is extremely unstable. Specifically, under acidic or basic conditions, ring-opening rearrangement reactions readily occur, such as ring-closing reactions forming multiple chiral inverted isomers, and racemic isomers are easily generated. Simultaneously, ring-opening is also easily achieved under neutral hydrogenation conditions, making it very difficult to obtain large quantities of high-purity mupirocin derivatives under typical chemical reaction conditions. Furthermore, as described in patent EP0068690, when using photo-induced reactions to control the cis-trans conversion of alkene bonds to obtain a single trans configuration, the actual yield is low. While acceptable for impurity synthesis, it is unsuitable for synthesizing large quantities of products and cannot meet the needs of industrial production.

[0018] For the reasons mentioned above, the inventors discovered that steps S4-S5 are key steps in this invention. Through extensive experimentation, they found that trimethyl orthoformate is the most suitable protecting agent in step S4. The inventors also found that only trimethyl orthoformate provides a stable intermediate under certain pH conditions, while other protecting agents are prone to deprotection or rearrangement reactions, resulting in isomers. Furthermore, step S5 employs the Williamson reaction, which converts the cis-trans configuration of the alkene to a single trans configuration. This reaction is not photoreactive, thus resulting in a high yield of the single configuration. This invention constructs STD-RM70923MN-4, which is an iodine-containing alkene compound. The compounds STD-RM70923MN-4 and STD-RM70923MN-5 synthesized through steps S1-S3 reacted under mild conditions, ensuring the stability of the product configuration. However, other leaving groups, due to insufficient reactivity, required heating for the reaction, resulting in racemization of the product.

[0019] Beneficial effects: 1. This invention provides a novel, efficient, and simple method for preparing mupirocin derivatives, avoiding harsh reaction conditions. It features readily available raw materials, short steps, a total yield of over 40% based on starting mupirocin, simple purification, single chirality, high quality, and the ability to be mass-produced. A single operation in a short time can meet the large market demand for standards or reference products of this degradation derivative, making it suitable for industrial production.

[0020] 2. This degradation derivative possesses the triple attributes of antibacterial activity, being an API degradation derivative, and a required impurity for EP registration. It is a scarce and expensive impurity in the market. This invention solves the bottleneck technology in the synthesis of this derivative, finding a better alternative to imported or domestically produced solutions. The derivative standards or reference standards prepared by this method are of great significance for studying the metabolic pathway of mupirocin and for quality control in the production of the active pharmaceutical ingredient. Attached Figure Description

[0021] Figure 1 The 1H NMR data are for the mupirocin derivative STD-RM70923MN. Detailed Implementation

[0022] Example 1 (Synthesis of benzyloxyheptenol STD-RM70923MN-1)

[0023] At room temperature, potassium tert-butoxide (54.0 g, 0.481 mol) was added to a tetrahydrofuran (300 mL) solution of 1,5-pentanediol (50.0 g, 0.481 mol). After the addition was complete, the mixture was heated to 65 °C and stirred for 4 hours. After cooling to room temperature, a tetrahydrofuran (100 mL) solution of p-methoxybenzyl chloride (53.0 g, 0.338 mol) and tetrabutylammonium iodide (17.0 g, 460 mmol) were added dropwise. The mixture was then heated to 65 °C and stirred for approximately 8 hours. After TLC monitoring, column chromatography yielded a yellow oily substance, Int-2 (70.0 g, 65%).

[0024] Oxaloyl chloride (68.0 g, 0.535 mol) was dissolved in dichloromethane, purged with nitrogen, and cooled to -78 °C. A dichloromethane solution of dimethyl sulfoxide (62.7 g, 0.803 mol) was then added dropwise, and the mixture was stirred for 30 minutes. Next, a dichloromethane solution of Int-2 (70.0 g, 0.268 mol) was added dropwise, and the mixture was stirred for 1.5 hours. Finally, triethylamine (135 g, 1.37 mol) was added dropwise, and the mixture was heated to 0 °C and stirred for 30 minutes. After the reaction was complete as shown by TLC, the reaction mixture was poured into water, extracted with dichloromethane, washed, dried, and purified by column chromatography to obtain a pale yellow oily substance, Int-3 (40.0 g, 67%).

[0025] Int-3 (80.0 g, 0.360 mol) was dissolved in 2-methyltetrahydrofuran (300 ml), cooled to 0 °C, and then vinyl magnesium bromide (540 ml, 0.540 mol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was poured into a saturated ammonium chloride solution, washed with 2-methyltetrahydrofuran, dried, concentrated, and column chromatography was performed to obtain a yellow oily compound, benzyloxyheptenol (Int-4, also known as STD-RM70923MN-1) (74.0 g, 78%). Example 2: Synthesis of mupirocin derivative STD-RM70923MN

[0026] Step 1: Benzyloxyheptenol (120 g, 0.45 mol) was dissolved in triethyl orthoformate, and then glacial acetic acid (5.50 g, 9.17 mmol) was added. The reaction was stirred at 135 °C for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was poured into water, and then extracted twice with petroleum ether. The organic phases were separated and combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column purification yielded a yellow oily substance STD-RM70923MN-2 (80.0 g, 55%).

[0027] ESI-MS (m / z): 320.2; 1 HNMR (400 MHz, CDCl3) d 7.25(d, 2H, J =12), 6.88 (d, 2H, J =12), 5.55-5.35 (m, 2H), 4.42 (s, 2H), 4.12 (dd, 2H, J =8.0& J =8.0), 3.80 (s, 3H), 3.42(t, 2H),2.40-2.20 (m, 4H), 2.00(dd, 2H, J =8.0& J =8.0), 1.65-1.50(m,2H), 1.45-1.35(m,2H), 1.25(t, 3H) Step Two: Compound STD-RM70923MN-2 (80.0 g, 0.25 mol) was dissolved in a heterogeneous mixture of dichloromethane and water (800 ml / 80 ml). The oxidative removal reagent 2,3-dichloro-5,6-dicyanobenzoquinone (57.0 g, 0.25 mol) was added at 20-25 °C. After the reaction was complete as detected by TLC, the mixture was extracted with water and dichloromethane (200 ml * 2), washed, dried, concentrated, and purified by dry column chromatography to obtain the yellow oily compound STD-RM70923MN-3 (48.0 g, 96%). Step 3: STD-RM70923MN-3 (80.0 g, 0.40 mol) was dissolved in toluene (1.6 L), followed by the addition of triphenylphosphine (96.0 g, 0.37 mol) and imidazole (24.5 g, 0.36 mol). Nitrogen gas was then added, followed by the addition of elemental iodine (61.0 g, 0.24 mol). The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The combined organic phases were separated, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column chromatography yielded a pale yellow oily substance, STD-RM70923MN-4 (56.0 g, 45%). Step Four: Mupirocin (38.0 g, 76 mmol) was added to a 1000 ml single-necked flask, followed by trimethyl orthoformate (380 ml). After dissolving, p-toluenesulfonic acid (380 mg, 2.21 mmol) was added with stirring. The reaction was allowed to proceed at room temperature for 1.5 h. The trimethyl orthoformate was then evaporated to dryness, and 1 M sodium hydroxide aqueous solution (380 ml) was added. The reaction was continued at 65 °C with stirring for 4.5 h. After the reaction was completed by LCMS monitoring, the pH of the complete reaction solution was adjusted to 7-7.5 with concentrated hydrochloric acid. The mixture was extracted three times with ethyl acetate (200 ml * 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (250 ml), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 38.0 g of crude, pale yellow oily STD-RM70923MN-5, which was used directly in the next step. Step 5: Crude mupirocin (30.0 g, 71.0 mmol) was added to a 1000 ml single-necked flask and dissolved in NN-dimethylformamide (300 ml). Potassium carbonate (24.6 g, 178 mmol) was added to the reaction mixture, and the mixture was stirred for 10 min. Iodide (30.0 g, 96.8 mmol) was then added, and the mixture was stirred overnight at room temperature. LC-MS showed that the starting material had reacted completely. The reaction mixture was extracted twice with ethyl acetate (300 ml * 2) by adding 500 ml of water. The combined organic phases were washed twice with saturated sodium chloride solution (300 ml * 2). The washed organic phases were dried over anhydrous sodium sulfate and evaporated to dryness to obtain 45.0 g of crude product STD-RM70923MN-6, a pale yellow oil.

[0028] Step Six: Add STD-RM70923MN-6 (45.0 g, 70.0 mmol) to a 1000 ml single-necked flask and dissolve in isopropanol (900 ml). Cool to 0°C, dissolve calcium chloride (99.0 g, 900 mmol) in water (300 ml) in a vigorous exothermic reaction, cool to room temperature, add lithium hydroxide monohydrate (10.2 g, 220 mmol) to the calcium chloride solution, sonicate to homogenize the suspension, cool this solution to 0°C, and add it dropwise to the reaction mixture at 0°C. Monitor the reaction for completion using LC-MS. Extract the reaction mixture with 200 ml of petroleum ether, collect the petroleum ether phase, add 250 ml of water, extract again, and collect the aqueous layer. Add 60 g of sodium chloride solid to the aqueous phase until saturated. Extract twice with ethyl acetate (150 ml * 2). Combine the organic phases, wash with saturated sodium chloride solution (200 ml), dry with anhydrous sodium sulfate, evaporate to dryness, and dissolve in methanol / water (380 / 380 ml). Maintain at 0-5℃, adjust the pH to 3 with concentrated HCl until the solution becomes cloudy, then allow to naturally warm to room temperature for 40 min. Cool to 0-5℃, adjust the pH to 9 with 1M sodium hydroxide, and stir overnight at room temperature. Monitor the reaction completion by LCMS. Cool to 0-5℃, adjust the pH to 6 with HCl, and adjust the pH to 7.5 with saturated sodium bicarbonate, then freeze-dry. Repeat the slurry with acetonitrile / water (120 ml / 12) at least five times to remove insoluble inorganic salts. Analyze the concentration using the area normalization method until no further change occurs to obtain a white solid compound STD-RM70923MN (20.0 g, 57%). ESI-MS (m / z): 498.3; 1 HNMR (400 MHz, D 2 O ) d5.71 (s, 1H), 5.45-5.35 (m, 2H), 4.05(t, 2H),3.90-3.70 (m, 4H), 3.55-3.40 (m, 2H), 3.00-2.90(m, 1H), 2.81 (dd, 1H, J =4.0& J =4.0), 2.55(d,1H, J =16.0), 2.26(dd, 1H, J =8.0& J =8.0), 2.12(s, 4H), 2.04(s, 3H),2.02-1.88(m, 3H), 1.75-1.65(m, 1H), 1.62-1.50(m, 3H), 1.40-1.30(m, 3H), 1.11(d, 3H, J =8.0), 0.86(d, 3H, J = 8.0)。

Claims

1. A method for preparing a mupirocin derivative, characterized in that... To achieve this, follow these steps: Includes the following steps: Synthesis of S1, compound STD-RM70923MN-2: Benzyloxyheptenol STD-RM70923MN-1 was dissolved in triethyl orthoformate. An organic acid was added at room temperature and the reaction was heated. After the reaction was completed, the reaction was detected by TLC. The triethyl orthoformate was recovered by concentration. The concentrate was poured into water, extracted with petroleum ether, washed, dried and concentrated to obtain compound STD-RM70923MN-2. Synthesis of S2 and compound STD-RM70923MN-3: Compound STD-RM70923MN-2 was dissolved in a heterogeneous mixture of dichloromethane and water. The oxidative removal reagent 2,3-dichloro-5,6-dicyanobenzoquinone was added at 20-25°C. After the reaction was complete, water was added, followed by dichloromethane extraction, washing, drying, concentration, and column purification to obtain compound STD-RM70923MN-3. Synthesis of S3 and compound STD-RM70923MN-4: Compound STD-RM70923MN-3 was dissolved in toluene, then triphenylphosphine and imidazole were added, nitrogen was replaced, and then iodine was added. The mixture was monitored by TLC at 20-25°C until the raw material was completely removed. The solvent was then removed by concentration and column purification to obtain compound STD-RM70923MN-4. Synthesis of S4, compound STD-RM70923MN-5: Mupirocin RM7092MD was added to trimethyl orthoformate, and p-toluenesulfonic acid was added with stirring. After the addition was complete, the mixture was reacted at 20-25℃ for 1.5 h. The solvent was removed by concentration, and 1M sodium hydroxide aqueous solution was added to the mixture after rotary evaporation. After the addition was complete, the mixture was stirred at 65℃ for 4.5 h. The reaction was monitored by LCMS until the reactants were completely reacted. The pH of the reaction solution was adjusted to 7-7.5 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, washed, dried, and rotary evaporated to obtain the crude compound STD-RM70923MN-5. Synthesis of S5 and compound STD-RM70923MN-6: Compound STD-RM70923MN-5 was dissolved in an organic solvent. After the solution was clear, an inorganic base was added and the mixture was stirred for 10 minutes. Then, compound STD-RM70923MN-4 was added and the mixture was stirred at 20-25℃. LCMS monitoring showed that the reaction of the starting material was complete. Water was added, and the mixture was extracted with ethyl acetate, washed, dried, and then evaporated to dryness to obtain crude compound STD-RM70923MN-6. Synthesis of S6 and compound STD-RM70923MN The crude compound STD-RM70923MN-6 was dissolved in 300 ml of an alcohol solvent. The temperature was lowered to 0-5℃, and an aqueous solution of calcium chloride / lithium hydroxide was added. The reaction was stirred at 20-25℃ and monitored by LCMS until completion. The reaction solution was extracted with petroleum ether / ethyl acetate, washed, dried, and evaporated to obtain an oily substance. The oily substance was redissolved in methanol / water, and the pH was adjusted to 3-3.5 with concentrated hydrochloric acid at 0-5℃. The temperature was then naturally raised to 20-25℃ for 40 min, lowered to 0-5℃, and the pH was adjusted to 8.5-9.0 with 1M sodium hydroxide. The temperature was then naturally raised to 20-25℃ and reacted overnight. After the reaction was complete, the temperature was lowered to 0-5℃, and the pH was adjusted to 6 with hydrochloric acid. Finally, the pH was adjusted to 7-7.5 with an inorganic base, and the product was lyophilized to obtain a crude product containing inorganic salts. The insoluble inorganic salts were removed by repeated slurrying with acetonitrile / water. The content of the inorganic salts was determined by area normalization until it no longer changed, yielding the compound STD-RM70923MN.

2. The method according to claim 1, characterized in that, In step S1, the reaction temperature is 120-150℃, and the molar ratio of benzyloxyheptenol STD-RM70923MN-1 to the catalyst organic acid is 1%-10%; the organic acid is formic acid, acetic acid, propionic acid or trifluoroacetic acid.

3. The method according to claim 1, characterized in that, In step S2, the molar ratio of compound STD-RM70923MN-2 to 2,3-dichloro-5,6-dicyanobenzoquinone is 1:1 to 1:1.

5.

4. The method according to claim 1, characterized in that, In step S3, the molar ratio of STD-RM70923MN-2 to triphenylphosphine, imidazole, and iodine is 1:1.5:1.5:1.5-1:1:3:3:

3.

5. The method according to claim 1, characterized in that, In step S4, the molar ratio of mupirocin to p-toluenesulfonic acid is 1:0.01-1:0.1; the alkaline hydrolysis temperature is 60-70℃.

6. The method according to claim 1, characterized in that... The solvent selected in step S5 is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, or acetonitrile; the molar ratio of compound STD-RM70923MN-5 to compound STD-RM70923MN-4 to inorganic base is 1:1.2~1.7:2~3:2.2~2.7; the inorganic base is sodium carbonate or potassium carbonate.

7. The method according to claim 1, characterized in that... The alcohol solvent used in step S6 is ethanol, isopropanol, or tert-butanol; the molar ratio of compound STD-RM70923MN-6, lithium hydroxide, and calcium chloride is 1:2.5~5:8~15.

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