A method for preparing lebrikizumab

Abstract

The application belongs to the technical field of organic synthesis and particularly relates to a preparation method of riboprine. The method comprises the following steps: starting from a key intermediate (1S, 5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one, hydrolysis is performed to form an open ring compound, then a protecting group of a hydroxyl group is introduced under alkaline conditions; then, reduction is performed on a carboxyl group to form a hydroxyl compound, an intermediate compound is generated by introducing a leaving group and then reacting with 2, 4-dimethyl-5-hydroxypyrimidine, the protecting group is removed to expose the hydroxyl group, oxidation is performed to form a carboxyl compound, and finally, acid-amine condensation reaction is performed on 2-amino-5-fluoropyridine to generate riboprine. The preparation method provided by the present application is simple in operation, high in yield and suitable for industrial production of riboprine.

Description

A method for preparing Leboresen Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing leboresen. Background Technology

[0002] Lemborexant, chemically named (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide, is a dual orexin receptor antagonist (DORA) that competitively blocks OX1R / OX2R receptors, inhibiting excessive arousal signals and reshaping the natural sleep rhythm. Its chemical structural formula is:

[0003] .

[0004] The preparation of leboresen is reported in patents WO2013123240A1 and CN110847756A as follows:

[0005] .

[0006] After ring-opening reduction of the intermediate (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one, a lipase is used for selective substitution to introduce an acetyl group to protect the hydroxyl group. Then, a p-toluenesulfonyl group is introduced onto the other hydroxyl group, followed by 2,4-dimethyl-5-hydroxypyrimidine. Subsequently, deprotection, oxidation, and condensation yield leboresen. The main disadvantage of this route is that it uses an enzyme-catalyzed reaction, which is costly, and the residues after enzyme catalysis are extremely difficult to remove.

[0007] .

[0008] Starting from the key intermediate (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one, after oxidation, followed by 5-fluoro-2-aminopyridine and reduction, an easily leaving group is introduced, or 2,4-dimethyl-5-hydroxypyrimidine is introduced via photoelectrophoresis to obtain Leborrheic API. However, whether the above route can selectively introduce 5-fluoro-2-aminopyridine in the second step remains debatable, and the presence of the amide group during carboxyl reduction can significantly interfere with the reaction, leading to increased impurities.

[0009] In conclusion, it is essential to develop an economical, efficient, and environmentally friendly method for synthesizing Leboresen. Summary of the Invention

[0010] To address the above problems, this invention provides a method for preparing leboresen that is low-cost, environmentally friendly, highly selective, and has a high yield, specifically including the following steps:

[0011] S1 and compound SMA undergo hydrolysis and then react with RX in a first substitution reaction to generate compound M1; the reaction process is as follows:

[0012] ;

[0013] S2. Compound M1 is esterified and then reduced to generate compound M2; the reaction process is as follows:

[0014] ;

[0015] S3. Compound M2 undergoes a second substitution reaction with R'-X to generate compound M3, which then undergoes a third substitution reaction with SMB to generate M4; or, M2 undergoes a photo-spreading reaction with SMB to generate compound M4; the reaction process is as follows:

[0016] ;

[0017] or

[0018] ;

[0019] S4. The protecting group R of compound M4 is removed under the action of a deprotecting agent to obtain compound M5; the reaction process is as follows:

[0020] ;

[0021] S5. Oxidize compound M5 to obtain compound M6; the reaction process is as follows:

[0022] ;

[0023] S6. Compound M6 is reacted with SMC via an amide condensation reaction to obtain Leboresen; the reaction process is as follows:

[0024] .

[0025] In a specific embodiment, in step S1, the alkali added during hydrolysis is one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide; the molar ratio of compound SMA to the alkali is 1:2~5. In RX, R is any one of benzyl, allyl, triphenylmethyl, p-methoxybenzyl, 2-methoxyethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and methoxymethyl, and X is any one of F, Cl, Br, and I. During the first substitution reaction, the reaction temperature is 50~80℃, and the reaction time is 0.2~18h; the solvent used in the reaction system is at least one of toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, N,N-methylformamide, dichloromethane, and ethyl acetate.

[0026] In a specific embodiment, in step S2, during the reduction reaction, the reducing agent is selected from one or more of sodium borohydride, lithium aluminum hydride, red aluminum, a complex of borane, and triethylsilane; the temperature of the reduction reaction is -10~40℃; the reaction time is 0.2~18h; and the solvent used in the reaction system is at least one of tetrahydrofuran, toluene, acetonitrile, and dichloromethane.

[0027] In a specific embodiment, in step S3, R' in R'-X is one of benzenesulfonyl, methanesulfonyl, or nitrobenzenesulfonyl; X is any one of F, Cl, Br, or I; the molar ratio of compound M3 to compound SMB is 1:0.9~2.5. During the second substitution reaction, the reaction temperature is 5~10℃, the reaction time is 0.2~18h, and the solvent is a mixture of acetonitrile and toluene; during the third substitution reaction, the reaction temperature is 50-55℃, the reaction time is 0.2~18h, and the solvent is N-methylpyrrolidone; the base used in the second and third substitution reactions is at least one of triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, or sodium tert-butoxide.

[0028] In a specific embodiment, in step S3, the compound M2 and SMB undergo a photo-extending reaction, specifically including: the photo-extending reaction temperature is 15~25℃; the reaction time is 0.5~24h; the molar ratio of compound M2 to compound SMB is 1:0.8~3; and the solvent of the reaction system is at least one selected from dichloromethane, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, diethyl ether, chloroform, N,N-dimethylformamide, and dimethyl sulfoxide.

[0029] In a specific embodiment, in step S4, the removing agent includes a palladium-based reagent and a protic acid, specifically including palladium on carbon, palladium hydroxide on carbon, tetra(triphenylphosphine)palladium, trifluoroacetic acid, and hydrochloric acid; the molar ratio of the palladium-based reagent to compound M4 is 0.1~0.2:1, and the molar ratio of the protic acid to compound M4 is 1~4:1.

[0030] In a specific embodiment, step S5, the oxidation reaction specifically includes: oxidizing compound M5 with sodium hypochlorite / 2,2,6,6-tetramethylpiperidine, and then oxidizing it with sodium chlorite to obtain compound M6; the oxidation reaction temperature is 20~30℃; the reaction time is 2~24h; the molar ratio of compound M5 to sodium hypochlorite is 1:0.1~1; the molar ratio of compound M5 to sodium chlorite is 1:1~2.

[0031] In a specific embodiment, in step S6, the catalyst used in the amide condensation reaction is any one of 1-propylphosphoric anhydride, 1-butylphosphoric anhydride, diisopropylcarbodiimide, dicyclohexylcarbodiimide, O-benzotriazole-tetramethylurea hexafluorophosphate, and 2-(7-azabenzotriazole)-N,N,N',N'tetramethylurea hexafluorophosphate.

[0032] In a specific embodiment, compound M6 can be first reacted with an acyl chloride reagent to prepare an acyl chloride, and then reacted with SMC via an amide condensation reaction to prepare leboresen; the acyl chloride reagent is any one of phosphorus oxychloride, thionyl chloride, or oxalyl chloride. Alternatively, compound M6 can be first reacted with titanium tetrachloride to prepare a titanium salt, and then reacted with an amide condensation reaction to prepare leboresen.

[0033] Compared with the prior art, the beneficial effects of the technical solution of the present invention are as follows:

[0034] This invention uses compound SMA as the starting material. After hydrolysis, a hydroxyl protecting group is introduced. Then, the carboxyl group is reduced and a leaving group is introduced. The mixture then reacts with SMB, and the hydroxyl protecting group is removed. Following oxidation and amidation, leboresen is obtained. The above process features a rationally designed route, uses readily available and widely applicable raw materials, operates under mild and controllable conditions, is simple to operate, does not involve selectivity, produces a single product with high yield, has a fast reaction time, and uses environmentally friendly and easily treatable chemical reagents, making it easily scalable for industrialization. Attached Figure Description

[0035] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0036] Figure 1 shows the 1H NMR spectrum of Leber Resen obtained in Example 1 of this invention;

[0037] Figure 2 shows the carbon NMR spectrum of Leber Resen obtained in Example 1 of this invention. Detailed Implementation

[0038] To facilitate understanding of the present invention, the present invention will be described more fully and in detail below with reference to the accompanying drawings and preferred embodiments, but the scope of protection of the present invention is not limited to the following specific embodiments.

[0039] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the scope of the invention.

[0040] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be purchased from the market or prepared by existing methods.

[0041] To address the technical problems existing in the preparation process of leboresen in the prior art, the present invention provides a method for preparing leboresen, comprising the following steps:

[0042] S1. Compound SMA undergoes hydrolysis and then a substitution reaction with RX to generate compound M1. First, compound SMA is dissolved in a solvent. A base is added at a molar ratio of SMA to base of 1:2-5 to initiate the hydrolysis reaction. After hydrolysis, RX is added, and a substitution reaction is carried out at 50-80℃ for 0.2-18 hours to obtain M1. The base added during hydrolysis is one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide. In the RX, R is any one of benzyl, allyl, triphenylmethyl, p-methoxybenzyl, 2-methoxyethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and methoxymethyl, and X is any one of F, Cl, Br, and I. The solvent used in the reaction system is at least one of toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, N,N-methylformamide, dichloromethane, and ethyl acetate. The reaction process is as follows:

[0043] .

[0044] S2. Compound M1 is esterified and then reduced to generate compound M2. First, compound M1 reacts with a haloalkane to form an ester, which is then extracted and concentrated to obtain M12. M12 is dissolved in a solvent system, and a reducing agent is added under nitrogen protection. The reaction is carried out at a temperature of -10 to 40°C for 0.2 to 18 hours. After the reaction is complete, water is added to quench the reaction, and compound M2 is obtained after separation and purification. The reducing agent is selected from one or more of sodium borohydride, lithium aluminum hydride, red aluminum, borane complexes, and triethylsilane. The solvent used in the reaction system is at least one of tetrahydrofuran, toluene, acetonitrile, and dichloromethane. The reaction process is as follows:

[0045] .

[0046] S3. Compound M2 undergoes a second substitution reaction with R'-X to generate compound M3, which then undergoes a third substitution reaction with SMB to generate M4; alternatively, M2 undergoes a photocatalytic reaction with SMB to generate compound M4. Compound M2 and R'-X are added to a base, and a substitution reaction is carried out under inert gas protection, at a reaction temperature of 5-10℃, a reaction time of 0.2-18h, and in a mixed solvent of acetonitrile and toluene. The mixture is then separated and concentrated to obtain M3. Compound M3 is then mixed with SMB at a molar ratio of 1:0.9-2.5 and subjected to a substitution reaction under alkaline conditions, specifically at a reaction temperature of 50-55℃, a reaction time of 0.2-18h, and in an N-methylpyrrolidone solvent. The base used is at least one selected from triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide; R' in R'-X is one of benzenesulfonyl, methanesulfonyl, and nitrobenzenesulfonyl; X is any one of F, Cl, Br, and I. The reaction process is as follows:

[0047] .

[0048] Alternatively, M2 and SMB are subjected to a photo-extending reaction to generate compound M4. The photo-extending reaction temperature is 15-25°C; the reaction time is 0.5-24 h; the molar ratio of compound M2 to compound SMB is 1:0.8-3; and the solvent of the reaction system is at least one selected from dichloromethane, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, diethyl ether, chloroform, N,N-dimethylformamide, and dimethyl sulfoxide. The reaction process is as follows:

[0049] .

[0050] S4. The protecting group R of compound M4 is removed under the action of a removing agent to obtain compound M5. Specifically, this involves adding the removing agent to compound M4 in an alcohol-water solvent system, and stirring the reaction under an inert gas atmosphere at a temperature of 40-80°C for 10-20 hours. The reaction solution is then filtered, concentrated, extracted, and concentrated again to obtain compound M5. The removing agent includes palladium-based reagents and protic acids, specifically palladium on carbon, palladium hydroxide on carbon, tetra(triphenylphosphine)palladium, trifluoroacetic acid, and hydrochloric acid. The molar ratio of the palladium-based reagent to compound M4 is 0.1-0.2:1, and the molar ratio of the protic acid to compound M4 is 1-4:1. The reaction process is as follows:

[0051] .

[0052] S5. The compound M5 is oxidized to obtain compound M6. Specifically, this involves mixing compound M5, a solvent, and an aqueous solution of disodium hydrogen phosphate, oxidizing the mixture with sodium chlorate / 2,2,6,6-tetramethylpiperidine, and then oxidizing it with sodium chlorite. The molar ratio of compound M5 to sodium hypochlorite is 1:0.1~1; the molar ratio of compound M5 to sodium chlorite is 1:1~2. The specific reaction temperature is 20~30℃, and the reaction time is 2~24h. After HPLC analysis confirms the completion of the reaction, the aqueous phase is separated by alkaline extraction. The pH is adjusted by adding acid, and the organic phase is extracted and separated by toluene. Acetonitrile is then added for concentration, followed by the addition of water and acetonitrile. A solid is precipitated by dropwise addition to acetone, washed, and dried to obtain compound M6. The reaction process is as follows:

[0053] .

[0054] S6. The compound M6 is reacted with SMC via an amide condensation reaction to obtain leboresen. There are three specific methods: using condensing agents such as 1-propylphosphonic anhydride, 1-butylphosphonic anhydride, diisopropylcarbodiimide, dicyclohexylcarbodiimide, O-benzotriazole-tetramethylurea hexafluorophosphate, or 2-(7-azabenzotriazole)-N,N,N',N'tetramethylurea hexafluorophosphate to directly condense compound M6 and SMC to generate leboresen. Alternatively, compound M6 can be first prepared into an acyl chloride, and then reacted with SMC to obtain leboresen, wherein the acyl chloride reagent is phosphorus oxychloride, sulfoxide, or oxalyl chloride; or M6 can be reacted with titanium tetrachloride to generate a titanium salt, and then reacted with SMC to prepare leboresen. The reaction process is as follows:

[0055] .

[0056] The following is a further explanation using specific embodiments.

[0057] Example 1

[0058] The synthesis route is as follows:

[0059] .

[0060] The preparation process is as follows:

[0061] S1. In a reaction flask, (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one (15.0 g), acetonitrile 120 ml, and sodium hydroxide (3.43 g) were added in one step. After the addition was complete, the temperature was raised to 50℃ and the reaction was carried out for 2.0 h. Then, sodium hydroxide (5.93 g) was added. Benzyl bromine was added dropwise while maintaining the temperature at 50-60℃. After the reaction was complete, the temperature was lowered to room temperature and filtered to obtain 24.8 g of white solid. DCM and 3N hydrochloric acid were added to the solid to adjust the pH to 2-3. The mixture was separated, and the lower organic phase was collected and concentrated to obtain [(1S,2R)-2-[(benzyloxy)methyl]-1-(3-fluorophenyl)cyclopropyl]acetic acid (i.e., compound LM1), with a yield of 98.4%.

[0062] S2. 22.5 g of [(1S,2R)-2-[(benzyloxy)methyl]-1-(3-fluorophenyl)cyclopropyl]acetic acid, 110 ml of N,N-dimethylformamide, iodomethane (16.60 g), and sodium carbonate (16.54 g) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 2 h. After the reaction was complete, 150 ml of purified water and 90 ml of toluene were added. The aqueous phase was discarded after separation, and the organic phase was concentrated to dryness under reduced pressure to obtain 24.53 g of methyl [(1S,2R)-2-[(benzyloxy)methyl]-1-(3-fluorophenyl)cyclopropyl]acetic acid (i.e., compound LM1-3), a yellow oil. The yield was 100%, and it was used directly in the next step. Compound (LM1-3) 24.53 g and tetrahydrofuran (125 ml) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was placed at 5-10℃. Lithium aluminum hydride tetrahydrofuran solution was added dropwise. After the addition was complete, the mixture was stirred for 30 min. After the reaction was complete, 50 ml of water was added to quench the reaction. The solid was filtered off, and the mixture was separated. The organic layer was washed once with saturated brine. After the organic phase was concentrated, 22.36 g of pale yellow oily [(1S,2R)-2-[(benzyloxy)methyl]-1-(3-fluorophenyl)cyclopropyl]methanol (i.e. compound LM2) was obtained.

[0063] S3. 22.36 g of compound (LM2), triethylamine (15.78 g), 1-methylimidazole (0.32 g), and tetrahydrofuran (110 ml) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was placed in an environment of 0-10℃. p-Toluenesulfonyl chloride (37.18 g) was added dropwise. The reaction was allowed to proceed for 18 h. After the reaction was complete, sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was separated, the aqueous phase was discarded, and the organic phase was concentrated under reduced pressure until no liquid flowed out, yielding 34.36 g of yellow liquid 4-methylbenzenesulfonic acid-[(1S,2R)-2-[(benzyloxy)methyl]-1-(3-fluorophenyl)cyclopropyl]methyl ester (i.e., compound LM3), which was directly used for the next step of the reaction. The yield was 100%. 34.36 g of compound LM3, tetrahydrofuran (140 ml), potassium tert-butoxide (10.50 g), and 2,4-dimethylpyrimidin-5-ol were added sequentially to the reaction flask. The mixture was stirred at 50 °C for 3 h. After the reaction was complete, purified water was added to quench the reaction. The mixture was washed with saturated brine, and the aqueous phase was separated. The organic phase was concentrated under reduced pressure until no liquid flowed out, yielding 30.61 g of colorless liquid 5-({[(1S,2R)-2-[(benzyloxy)methyl]-1-(3-fluorophenyl)cyclopropyl]methyl}oxy)-2,4-dimethylpyrimidin (i.e., compound LM4), which was directly used for the next step of the reaction. The yield was 100%.

[0064] S4. 30.61 g of compound (LM4), methanol (150 ml), purified water (20 ml), and palladium on carbon (6.12 g) were added sequentially to the reaction flask. Under hydrogen protection, the mixture was stirred at 60°C for 18 h. After the reaction was complete, the mixture was filtered, the reaction solution was concentrated, and toluene (50 ml) was added for extraction. The organic phase was concentrated until no liquid flowed out, yielding 23.58 g of colorless liquid [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methanol (i.e., compound LM5), which was directly used for the next step of feeding, with a yield of 100%.

[0065] S5. In a reaction flask, 23.58 g of compound (M5), TEMPO (1.22 g), toluene (120 ml), and a mixture of disodium hydrogen phosphate aqueous solution (4.00 g disodium hydrogen phosphate and 25 ml water) were added sequentially and cooled to room temperature. 12% sodium hypochlorite aqueous solution (4.62 g) and sodium chlorite aqueous solution (30.85 g) were added and stirred. After confirming the reaction was complete by HPLC analysis, 16.32 ml of 25% sodium hydroxide aqueous solution was added. The mixture was stirred at 50°C, separated, and the organic phase was discarded, retaining the aqueous phase. 3M hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. Toluene (50 ml) was added, and the mixture was separated again. The aqueous phase was discarded, and the obtained organic phase was concentrated under reduced pressure to remove the solvent. Acetonitrile (50 ml) was added, and the solvent was removed by concentrated under reduced pressure. Water (1000 ml) and acetonitrile (300 ml) were added, and the mixture was placed at 15°C. Acetone (100 ml) was slowly added dropwise. The solid was slowly precipitated (ml), washed with acetonitrile, and dried at an external temperature of 50°C to obtain 24.67 g of (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl)2-(3-fluorophenyl)cyclopropanecarboxylic acid (i.e., compound M6).

[0066] S6. 24.67 g of compound (M6), pyridine (12.33 g), and toluene (120 ml) were added to the reaction flask. Phosphorus oxychloride (14.31 g) was slowly added dropwise at room temperature and stirred for 30 min. 2-Amino-5-fluoropyridine was dissolved in toluene (50 ml) and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was washed with saturated sodium bicarbonate solution and separated. The aqueous phase was discarded, and the organic phase was concentrated. Isopropanol was added and heated to 65 °C. Heptane was added and the mixture was cooled to room temperature to precipitate. The white solid was filtered off, and the filter cake was dried under reduced pressure at 50-60 °C to obtain 29.88 g of a white solid compound (i.e., Leberesen), with a yield of 94%. 1H NMR (400MHz, MeOD) δ 8.20 (d, J = 3.0 Hz, 1H), 8.11 (s, 1H), 7.95 (dd, J = 9.2, 4.1Hz, 1H), 7.53 – 7.44 (m, 1H), 7.43 – 7.34 (m, 3H), 7.07 – 6.99 (m, 1H), 4.69(d, J = 10.0 Hz, 1H), 4.47 (d, J = 10.0 Hz, 1H), 2.53 (dd, J = 7.9, 6.2 Hz,1H), 2.49 (s, 3H), 2.20 (s, 3H), 1.92 – 1.85 (m, 1H), 1.59 (dd, J = 8.1, 5.0Hz, 1H).

[0067] 13C NMR (101 MHz, MeOD) δ 169.41 (s), 163.97 (s), 161.54 (s), 158.51(s), 157.24 (s), 149.54 (s), 148.26 (d, J = 2.2 Hz), 144.92 (d, J = 7.5 Hz), 138.45 (s), 135.02 (d, J = 25.5 Hz), 129.89 (d, J = 8.4 Hz), 124.52 (d, J =19.7 Hz), 124.32 (d, J = 2.8 Hz), 115.51 (d, J = 22.2 Hz), 114.61 (d, J = 4.3Hz), 113.68 (d, J = 21.2 Hz), 71.13 (s), 34.48 (s), 27.46 (s), 22.76 (s), 18.00 (s), 17.00 (s).

[0068] Example 2

[0069] The compound Leberezen was prepared by replacing benzyl bromo in step 1 of Example 1 with propenyl bromo, while adhering to the same reaction conditions and steps as in Example 1. The reaction process is as follows:

[0070] .

[0071] As can be seen from the above preparation process, the leboresen preparation method of the present invention has a reasonable reaction process design, the raw materials used in the preparation process are generally readily available, the conditions are mild and controllable, the yield is high, the cost is low, and it is suitable for the industrial production of leboresen.

[0072] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. However, it should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.

Claims

1. A method for preparing leboresen, characterized in that, Includes the following steps: S1 and compound SMA undergo hydrolysis and then react with RX in a first substitution reaction to generate compound M1; wherein in RX, R is any one of benzyl, allyl, triphenylmethyl, p-methoxybenzyl, 2-methoxyethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and methoxymethyl, and X is any one of F, Cl, Br, and I; the reaction process is as follows: S2. Compound M1 is esterified with a haloalkane under the action of a base, followed by reduction to generate compound M2; the reaction process is as follows: S3. Compound M2 undergoes a second substitution reaction with R'-X to generate compound M3, and then undergoes a third substitution reaction with SMB to generate M4; in R'-X, R' is one of benzenesulfonyl, methanesulfonyl, or nitrobenzenesulfonyl; X is any one of F, Cl, Br, or I; or, M2 undergoes a photo-extending reaction with SMB to generate compound M4; the reaction process is as follows: ;or S4. The protecting group R of compound M4 is removed under the action of a deprotecting agent to obtain compound M5; the reaction process is as follows: S5. Oxidize compound M5 to obtain compound M6; the reaction process is as follows: S6. Compound M6 is reacted with SMC via an amide condensation reaction to obtain Leboresen; the reaction process is as follows: 。 2. The method for preparing leboresen according to claim 1, characterized in that, In step S1, the alkali added during the hydrolysis process is one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide; the molar ratio of the compound SMA to the alkali is 1:2~5.

3. The method for preparing leboresen according to claim 1, characterized in that, In step S1, during the first substitution reaction, the reaction temperature is 50~80℃ and the reaction time is 0.2~18h; the solvent used in the reaction system is at least one of toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, N,N-methylformamide, dichloromethane and ethyl acetate.

4. The method for preparing leboresen according to claim 1, characterized in that, In step S2, during the reduction reaction, the reducing agent is selected from one or more of sodium borohydride, lithium aluminum hydride, red aluminum, a complex of borane, and triethylsilane; the temperature of the reduction reaction is -10~40℃; the reaction time is 0.2~18h; and the solvent used in the reaction system is at least one of tetrahydrofuran, toluene, acetonitrile, and dichloromethane.

5. The method for preparing leboresen according to claim 1, characterized in that, In step S3, the molar ratio of compound M3 to compound SMB is 1:0.9~2.

5.

6. The method for preparing leboresen according to claim 1, characterized in that, In step S3, during the second substitution reaction, the reaction temperature is 5-10℃, the reaction time is 0.2-18h, and the solvent is a mixture of acetonitrile and toluene; during the third substitution reaction, the reaction temperature is 50-55℃, the reaction time is 0.2-18h, and the solvent is N-methylpyrrolidone; the base used in the second and third substitution reactions is at least one of triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide.

7. The method for preparing leboresen according to claim 1, characterized in that, In step S3, the compound M2 undergoes a photo-extending reaction with SMB, specifically including: the photo-extending reaction temperature is 15~25℃; the reaction time is 0.5~24h; the molar ratio of compound M2 to compound SMB is 1:0.8~3; and the solvent of the reaction system is at least one selected from dichloromethane, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, diethyl ether, chloroform, N,N-dimethylformamide, and dimethyl sulfoxide.

8. The method for preparing leboresen according to claim 1, characterized in that, In step S4, the removing agent includes a palladium-based reagent and a protic acid, specifically palladium on carbon, palladium hydroxide on carbon, tetra(triphenylphosphine)palladium, trifluoroacetic acid, and hydrochloric acid; the molar ratio of the palladium-based reagent to compound M4 is 0.1~0.2:1, and the molar ratio of the protic acid to compound M4 is 1~4:

1.

9. The method for preparing leboresen according to claim 1, characterized in that, In step S5, the oxidation reaction specifically includes: oxidizing compound M5 with sodium hypochlorite / 2,2,6,6-tetramethylpiperidine, and then oxidizing it with sodium chlorite to obtain compound M6; the oxidation reaction temperature is 20~30℃; the reaction time is 2~24h; the molar ratio of compound M5 to sodium hypochlorite is 1:0.1~1; the molar ratio of compound M5 to sodium chlorite is 1:1~2.

10. The method for preparing leboresen according to claim 1, characterized in that, In step S6, the catalyst used in the amide condensation reaction is any one of 1-propylphosphoric anhydride, 1-butylphosphoric anhydride, diisopropylcarbodiimide, dicyclohexylcarbodiimide, O-benzotriazole-tetramethylurea hexafluorophosphate, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

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