A process for the preparation of a cefbiprozil sodium bicyclo-ester side chain

Abstract

This invention discloses a method for preparing the bicyclic ester side chain of cefoperazone sodium. The steps are as follows: First, 2-hydroxy-4-aminobutyric acid is used as a raw material, and intramolecular cyclization is performed under certain conditions to obtain intermediate 1, which is further oxidized to intermediate 2; 3-bromo-4-hydroxybutyronitrile is hydrolyzed with concentrated sulfuric acid to obtain intermediate 3, which is then reacted with Ms2O to obtain intermediate 4, followed by cyclization and reduction reactions to obtain intermediate 5; intermediate 2 and intermediate 5 undergo a coupling reaction to obtain intermediate 6, which is then added dropwise to undergo an amidation reaction to obtain intermediate 7; 4-(hydroxymethyl)-5-methyl-1,3-dioxo-2-one undergoes an esterification reaction with 4-nitrophenyl carbochloride to obtain intermediate 8; intermediate 7 and intermediate 8 undergo a condensation reaction to obtain the target product. The preparation method of this invention has low preparation cost, mild reaction conditions, safe operation, and the materials used are inexpensive and readily available, which is beneficial for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for preparing a cefoperazone sodium bicyclic ester side chain. Background Technology

[0002] Cefbiro ester sodium is a novel cephalosporin antibiotic jointly developed by Basellia Pharma and Johnson & Johnson. It is a water-soluble prodrug of cefbiro and has an antibacterial spectrum including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA), showing broad application prospects and considered a member of the "fifth generation" of cephalosporin antibiotics. In 2013, it received marketing authorization in 11 European countries for the treatment of hospital-acquired and community-acquired pneumonia infections. To meet the growing market demand and clinical research needs of cefbiro ester sodium, researchers have been continuously optimizing and developing new manufacturing processes.

[0003] Currently, there are many methods for preparing cefbiroform sodium, among which the following route is more suitable for industrial production: Part A and part B first undergo an amidation reaction to generate a 7-functionalized intermediate. The quaternary phosphine salt formed from this intermediate undergoes a Wittig reaction with the carbonyl functional group of part C, ultimately forming a salt to give cefoperazone sodium.

[0004] This route involves three key starting materials: part A, part B, and part C. However, current research only covers the preparation of the side-chain acid, part B, with few reports on the preparation of the bicyclic ester side chain, part C. Therefore, research on the preparation of the bicyclic ester side chain of cefbilobromide sodium is of great significance. Summary of the Invention

[0005] The present invention aims to overcome the above-mentioned problems in the prior art and provides a method for preparing the bicyclic ester side chain of cefoperazone sodium. The materials used in the method of the present invention are inexpensive and readily available, and the preparation cost is low, the reaction conditions are mild, and the operation is safe, which is conducive to industrial production.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing the bicyclic ester side chain of cefoperazone sodium, the preparation route is as follows: The cefoperazone sodium bicyclic ester has a side chain of (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl(R)-2,3-dioxo-[1,3'-bipyrrolidine]-1'-carboxylate, with the molecular structure shown in Formula I.

[0007] Preferably, the intramolecular cyclization reaction in step (1) is carried out under organic solvent and alkaline conditions. The organic solvent is one or more of 5,5-dimethyl-1,3-cyclohexanedione, NMP, DMF, and 1,4-dioxane. The alkaline conditions are obtained by adding one or more of 6-methyldisilazane, triethylamine, and imidazole. The reaction temperature for intramolecular cyclization is 100–180 °C.

[0008] Preferably, in step (2), the oxidant is one or more of Dysmart oxidant, Jones oxidant, TEMPO-NaClO, and chromic acid; the amount of oxidant added is 5-20% of the mass of intermediate 1; the reaction between intermediate 1 and the oxidant is carried out in an organic solvent, wherein the organic solvent is one or more of dichloromethane, toluene, and tetrahydrofuran.

[0009] Preferably, in step (3), the mass of concentrated sulfuric acid is 3 to 5 times that of 3-bromo-4-hydroxybutyronitrile; after adding 3-bromo-4-hydroxybutyronitrile to concentrated sulfuric acid, the temperature is lowered to -5 to 10°C and the mixture is stirred to react; then anhydrous methanol is added dropwise and filtered to obtain intermediate 3, the mass of the added anhydrous methanol being 15 to 20 times that of 3-bromo-4-hydroxybutyronitrile.

[0010] Preferably, in step (4), the amount of Ms2O added is 0.6 to 1.0 times the equivalent of intermediate 3; the reaction between intermediate 3 and Ms2O is carried out under organic solvent and alkaline conditions; the organic solvent is one or more of tetrahydrofuran, dichloromethane, acetonitrile, and 1,4-dioxane; the alkaline conditions are obtained by adding one or more of triethylamine, DIEA, potassium carbonate, and sodium carbonate.

[0011] Preferably, in step (5), the cyclization reaction is carried out under THF and alkaline conditions. The alkaline conditions are obtained by adding one or more of triethylamine, DIEA, potassium carbonate, and sodium carbonate. During reduction, the amount of 1 mol / L BH3-THF added is 9 to 12 times the mass of intermediate 4.

[0012] Preferably, in step (6), the molar ratio of intermediate 2 to intermediate 5 is 1.1 to 1.5:1.0; the ligand is one or more of 1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, D-glucosamine hydrochloride, and Xant-phos; the amount of ligand added is 5 to 20% of the mass of intermediate 5; the coupling reaction of intermediate 2 and intermediate 5 with the ligand is carried out under catalytic and alkaline conditions, wherein the catalyst is one or two of CuI and CuCl; the alkaline conditions are obtained by adding one or more of cesium carbonate, potassium carbonate, and potassium tert-butoxide.

[0013] Preferably, in step (7), the molar ratio of intermediate 6 to allyl chlorocarbonate is 1.0:1.1 to 1.5; the amidation reaction of intermediate 6 with allyl chlorocarbonate is carried out under organic solvent and alkaline conditions, wherein the organic solvent is one or two of dichloromethane and tetrahydrofuran, and the alkaline conditions are obtained by adding one or more of potassium carbonate, sodium carbonate, pyridine, triethylamine, and DBU.

[0014] Preferably, in step (8), the molar ratio of 4-(hydroxymethyl)-5-methyl-1,3-dioxo-2-one to 4-nitrophenyl carbochloride is 1.0:1.1 to 1.5; the esterification reaction of 4-(hydroxymethyl)-5-methyl-1,3-dioxo-2-one and 4-nitrophenyl carbochloride is carried out under organic solvent and alkaline conditions, wherein the organic solvent is one or more of chloroform, dichloromethane, and tetrahydrofuran, and the alkaline conditions are obtained by adding one or two of pyridine and triethylamine.

[0015] Preferably, in step (9), the molar ratio of intermediate 7 to intermediate 8 is 1.0:1.1 to 1.3; the reducing agent is one or more of Bu3SnH, Et3SiH, and Ph3SiH, and the amount of reducing agent added is 3 to 10% of the mass of intermediate 7; the condensation reaction of intermediate 7, intermediate 8 and reducing agent is carried out under the conditions of a catalyst and an organic solvent, wherein the organic solvent is one or more of dichloromethane, tetrahydrofuran, and acetonitrile, and the catalyst is one or more of bis(triphenylphosphine)palladium chloride, tetra(triphenylphosphine)palladium, DPPF, and palladium dichloride.

[0016] Therefore, the present invention has the following beneficial effects: (1) This invention utilizes a novel, previously undisclosed preparation route to complete the preparation of the bicyclic ester side chain of cefoperazone; (2) The preparation method of the present invention is simple, has a high yield, mild reaction conditions, and safe operation, and has great implementation value and social and economic benefits. Detailed Implementation

[0017] The present invention will be further described below with reference to specific embodiments.

[0018] In this invention, unless otherwise specified, all equipment and raw materials are available from the market or commonly used in the industry. Unless otherwise specified, the methods in the following embodiments are conventional methods in the art.

[0019] General Implementation Examples: A method for preparing the bicyclic ester side chain of cefoperazone sodium, the preparation route is as follows: The molecular structure of the cefoperazone sodium bicyclic ester side chain is shown in Formula I. Specifically, the preparation method includes the following steps: (1) Using 2-hydroxy-4-aminobutyric acid as a raw material, an intramolecular cyclization reaction is carried out under organic solvent and alkaline conditions to obtain intermediate 1; the organic solvent is one or more of 5,5-dimethyl-1,3-cyclohexanedione, NMP, DMF, and 1,4-dioxane; the alkaline conditions are obtained by adding one or more of 6-methyldisilazane, triethylamine, and imidazole; the reaction temperature for intramolecular cyclization is 100-180℃; (2) Intermediate 1 is oxidized in an organic solvent under the action of an oxidant to generate intermediate 2; the oxidant is one or more of Dysmart oxidant, Jones oxidant, TEMPO-NaClO, and chromic acid; the amount of oxidant added is 5 to 20% of the mass of intermediate 1; the organic solvent is one or more of dichloromethane, toluene, and tetrahydrofuran. (3) 3-Bromo-4-hydroxybutyronitrile was slowly added to a certain amount of concentrated sulfuric acid, cooled to -5 to 10°C and stirred to react. After adding a certain amount of anhydrous methanol, the mixture was filtered to obtain intermediate 3. The mass of concentrated sulfuric acid was 3 to 5 times that of 3-bromo-4-hydroxybutyronitrile. The mass of anhydrous methanol was 15 to 20 times that of 3-bromo-4-hydroxybutyronitrile. (4) Intermediate 3 reacts with Ms2O under organic solvent and alkaline conditions to obtain intermediate 4; the amount of Ms2O added is 0.6-1.0 times the equivalent of intermediate 3; the organic solvent is one or more of tetrahydrofuran, dichloromethane, acetonitrile, and 1,4-dioxane; the alkaline conditions are obtained by adding one or more of triethylamine, DIEA, potassium carbonate, and sodium carbonate; (5) Intermediate 4 is first cyclized under THF and alkaline conditions. The alkaline conditions are obtained by adding one or more of triethylamine, DIEA, potassium carbonate, and sodium carbonate. Then, it is reduced under 1 mol / L BH3-THF conditions to obtain intermediate 5. The amount of 1 mol / L BH3-THF added during reduction is 9 to 12 times the mass of intermediate 4. (6) Intermediate 2 and intermediate 5 undergo a coupling reaction under ligand, catalyst, and alkaline conditions to obtain intermediate 6; the molar ratio of intermediate 2 to intermediate 5 is 1.1 to 1.5:1.0; the ligand is one or more of 1,10-o-phenanthroline, 4,7-dimethoxy-1,10-o-diazaphenanthroline, D-glucosamine hydrochloride, and Xant-phos; the amount of ligand added is 5 to 20% of the mass of intermediate 5; the catalyst is one or two of CuI and CuCl; the alkaline conditions are obtained by adding one or more of cesium carbonate, potassium carbonate, and potassium tert-butoxide. (7) Intermediate 6 is subjected to an amidation reaction at room temperature by adding allyl chlorocarbonate dropwise under organic solvent and alkaline conditions to obtain intermediate 7; the molar ratio of intermediate 6 to allyl chlorocarbonate is 1.0:1.1-1.5; the organic solvent is one or two of dichloromethane and tetrahydrofuran, and the alkaline conditions are obtained by adding one or more of potassium carbonate, sodium carbonate, pyridine, triethylamine, and DBU; (8) 4-(hydroxymethyl)-5-methyl-1,3-dioxo-2-one undergoes esterification reaction by dropwise addition of 4-nitrophenyl carbide under organic solvent and alkaline conditions to obtain intermediate 8; the molar ratio of 4-(hydroxymethyl)-5-methyl-1,3-dioxo-2-one to 4-nitrophenyl carbide is 1.0:1.1-1.5; the organic solvent is one or more of chloroform, dichloromethane, and tetrahydrofuran, and the alkaline conditions are obtained by adding one or two of pyridine and triethylamine; (9) The cefoperazone sodium bicyclic ester side chain is obtained by condensation reaction of intermediates 7 and 8 in an organic solvent with a catalyst and a reducing agent; the molar ratio of intermediates 7 and 8 is 1.0:1.1-1.3; the reducing agent is one or more of Bu3SnH, Et3SiH, and Ph3SiH, and the amount of reducing agent added is 3-10% of the mass of intermediate 7; the organic solvent is one or more of dichloromethane, tetrahydrofuran, and acetonitrile; and the catalyst is one or more of bis(triphenylphosphine)palladium chloride, tetra(triphenylphosphine)palladium, DPPF, and palladium dichloride.

[0020] Example 1 (Preparation of Intermediate 1: 3-Hydroxy-2-pyrrolidone): 40.00 g of 2-hydroxy-4-aminobutyric acid and 207.46 g of 5,5-dimethyl-1,3-cyclohexanedione were added to a 500 mL three-necked flask, followed by 65.04 g of 6-methyldisilazane. The mixture was heated to 180 °C and reacted for 3 h. After filtration and drying under reduced pressure, 31.64 g of intermediate 1 was obtained, with a yield of 93.25% and a purity of 98.64%. ESI-MS (m / z): 102.05 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ2.11 (m, 2H, CH2), 2.96 (m, 2H, CH2), 4.48 (m, 1H, CH), 5.37 (br, 1H, OH), 5.53 (br, 1H, NH).

[0021] Example 2 (Preparation of Intermediate 2: Pyrrolidine-2,3-dione): 30.00 g of intermediate 1 prepared in Example 1 and 118.20 g of acetone were added to a 250 mL three-necked flask, followed by 6.00 g of chromic acid. The mixture was stirred at 20 °C for 0.5 h, filtered, and dried under reduced pressure to obtain 28.01 g of intermediate 2, with a yield of 95.34% and a purity of 99.02%. ESI-MS (m / z): 100.03 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ1.90 (m, 2H, CH2), 2.96 (m, 2H, CH2), 5.53 (br, 1H, NH).

[0022] Example 3 (Preparation of Intermediate 3: 3-Bromo-4-hydroxybutyramide): 200.00 g of concentrated sulfuric acid was added to a 1000 mL three-necked flask, and the mixture was cooled to 5 °C in an ice bath. 40.00 g of 3-bromo-4-hydroxybutyronitrile was slowly added, and the mixture was stirred and kept at this temperature for 3 h. After the reaction was complete, 475.08 g of anhydrous methanol was added dropwise, and stirring was continued for 0.5 h. The mixture was filtered, and the filter cake was washed twice with 63.34 g * 2 g of anhydrous methanol. After drying under reduced pressure, 39.37 g of intermediate 3 was obtained, with a yield of 88.69% and a purity of 97.21%. ESI-MS (m / z): 181.97 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ 1.90 (m, 2H, CH2), 4.00 (br, 2H, NH2), 4.13 (m, 2H, CH2), 4.43 (m, 1H, CH) 5.37 (br, 1H, OH).

[0023] Example 4 (Intermediate 4: Preparation of 4-amino-2-bromo-4-oxobutylmethanesulfonate): 38.00 g of intermediate 3 prepared in Example 3 and 235.94 g of tetrahydrofuran were added to a 500 mL three-necked flask, followed by 42.25 g of triethylamine. The mixture was stirred at 20 °C for 0.5 h, and then 28.70 g of Ms₂O was slowly added dropwise. After the addition was complete, the mixture was stirred for another 1 h. The mixture was filtered, washed with 67.64 g * 2 tetrahydrofuran, and dried under reduced pressure to obtain 35.06 g of intermediate 4, with a yield of 64.57% and a purity of 96.89%. ESI-MS (m / z): 261.10 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ 1.90 (m, 2H, CH2), 3.04 (s, 3H, CH3), 4.00 (br, 2H, NH2), 4.13 (m, 2H, CH2), 4.43 (m, 1H, CH).

[0024] Example 5 (Preparation of intermediate 5: 3-bromopyrrolidine): Add 33.00 g of intermediate 4 prepared in Example 4 and 148.50 g of THF to a 250 mL three-necked flask, then add 25.67 g of triethylamine. Stir at 65 °C for 3 h, filter, and transfer the filter cake to a 500 mL three-necked flask. Add 300 g of 1 mol / L BH3-THF solution, stir at 45 °C for 2 h, filter, transfer the filter cake to a 250 mL three-necked flask, slurry with 150 g of 5% NaHCO3 solution, filter, wash the filter cake with 66.00 g * 2 of water, and dry under reduced pressure to obtain 16.51 g of intermediate 5, yield 86.72%, purity 96.90%. ESI-MS (m / z): 149.98 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ 1.90 (m, 2H, CH2), 2.96 (m, 2H, CH2), 3.56 (m, 2H, CH2), 4.43 (m, 1H, CH), 5.53 (br, 1H, NH).

[0025] Example 6 (Preparation of Intermediate 6: (R)-[1,3'-bipyrrolidine]-2,3-dione): 11.89 g of intermediate 2 prepared in Example 2 and 15.00 g of intermediate 5 prepared in Example 5 were added to a 250 mL three-necked flask. Then, 116.91 g of toluene, 0.75 g of CuI, 1.50 g of 1,10-o-phenanthroline, and 65.16 g of cesium carbonate were added. The mixture was refluxed for 6 h, filtered, washed with 26.70 g * 2 g of anhydrous methanol, and dried under reduced pressure to obtain 13.60 g of intermediate 6, with a yield of 80.85% and a purity of 98.77%. ESI-MS (m / z): 169.09 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ1.86 (m, 2H, CH2), 1.90 (m, 2H, CH2), 2.92 (m, 2H, CH2), 2.96 (m, 2H, CH2), 3.40 (m, 2H, CH2), 4.37 (m, 1H, CH), 5.53 (br, 1H, NH).

[0026] Example 7 (Intermediate 7: Preparation of allyl(R)-2,3-dioxo-[1,3'-bipyrrolidine]-1'-carboxylate): 12.00 g of intermediate 6 prepared in Example 6 and 106.44 g of tetrahydrofuran were added to a 250 mL three-necked flask, followed by 19.72 g of potassium carbonate. The mixture was stirred for 0.5 h, and then 10.32 g of allyl chlorocarbonate was slowly added dropwise at 20 °C. After the addition was complete, the mixture was stirred and kept at this temperature for another 2 h. The mixture was filtered, washed twice with 21.36 g x 2 tetrahydrofuran, and dried under reduced pressure to obtain 12.28 g of intermediate 7, with a yield of 68.23% and a purity of 94.69%. ESI-MS (m / z): 253.11 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ1.86 (m, 2H, CH2), 1.90 (m, 2H, CH2), 2.96 (m, 2H, CH2), 3.40 (m, 4H, C H2), 4.37 (m, 1H, CH), 4.56 (d, J=6.2Hz, 2H, CH2), 5.20 (d, J=2.1Hz, 2H, CH2), 6.01 (m, 1H, CH).

[0027] Example 8 (Intermediate 8: Preparation of 5-methyl-2-oxo-1,3-dioxo-4-yl)methyl(4-nitrophenyl)carbonate): 15.00 g of 4-(hydroxymethyl)-5-methyl-1,3-dioxo-2-one and 159.00 g of dichloromethane were added to a 250 mL three-necked flask, followed by 18.24 g of pyridine. The mixture was stirred for 0.5 h, and then 27.89 g of 4-nitrophenyl carbide was slowly added dropwise at 20 °C. After the addition was complete, the mixture was stirred and kept at this temperature for another 2 h. The mixture was filtered, washed twice with 39.75 g * 2 dichloromethane, and dried under reduced pressure to obtain 28.17 g of intermediate 8, with a yield of 82.78% and a purity of 95.44%. ESI-MS (m / z): 296.03 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ2.04 (s, 3H, CH3), 5.05 (s, 2H, CH2), 6.88 (m, 2H, Ar), 7.40 (m, 2H, Ar).

[0028] Example 9 (Preparation of the bicyclic ester side chain of cefoperazone sodium): 12.00 g of intermediate 7 prepared in Example 7 and 15.44 g of intermediate 8 prepared in Example 8 were added to a 250 mL three-necked flask, followed by 69.89 g of dichloromethane, 0.60 g of bis(triphenylphosphine)palladium chloride, and 5.53 g of triethylsilane. The mixture was stirred at 25 °C for 4 h. After filtration, the sample was washed twice with 17.47 g * 2 dichloromethanes and dried under reduced pressure to obtain 13.38 g of the target compound, cefoperazone sodium bicyclic ester side chain, with a yield of 86.75% and a purity of 98.21%. ESI-MS (m / z): 325.10 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ1.86 (m, 2H, CH2), 1.90 (m, 2H, CH2), 2.04 (s, 3H, CH3), 2.96 (m, 2H, CH2), 3.40 (m, 4H, CH2), 4.37 (m, 1H, CH), 5.05 (s, 2H, CH2).

[0029] The embodiments of the present invention are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the invention, but all such modifications and substitutions fall within the protection scope of the present invention.

Claims

1. A process for the preparation of the sodium salt of the bicyclic ester side chain of Cefbiproxil, characterized in that, The preparation route is as follows: The molecular structure of the cefoperazone sodium bicyclic ester side chain is shown in Formula I.

2. The preparation method according to claim 1, characterized in that, The intramolecular cyclization reaction in step (1) is carried out under organic solvent and alkaline conditions. The organic solvent is one or more of 5,5-dimethyl-1,3-cyclohexanedione, NMP, DMF, and 1,4-dioxane. The alkaline conditions are obtained by adding one or more of 6-methyldisilazane, triethylamine, and imidazole. The reaction temperature for intramolecular cyclization is 100–180 °C.

3. The preparation method according to claim 1, characterized in that, In step (2), the oxidant is one or more of Des Martin oxidant, Jones oxidant, TEMPO-NaClO, and chromic acid; the amount of oxidant added is 5 to 20% of the mass of intermediate 1; the reaction between intermediate 1 and the oxidant is carried out in an organic solvent, wherein the organic solvent is one or more of dichloromethane, toluene, and tetrahydrofuran.

4. The preparation method according to claim 1, characterized in that, In step (3), the mass of concentrated sulfuric acid is 3 to 5 times that of 3-bromo-4-hydroxybutyronitrile; after adding 3-bromo-4-hydroxybutyronitrile to concentrated sulfuric acid, the temperature is lowered to -5 to 10°C and the mixture is stirred to react; then anhydrous methanol is added dropwise and filtered to obtain intermediate 3, with the mass of the added anhydrous methanol being 15 to 20 times that of 3-bromo-4-hydroxybutyronitrile.

5. The preparation method according to claim 1, characterized in that, In step (4), the amount of Ms2O added is 0.6 to 1.0 times the equivalent of intermediate 3; the reaction between intermediate 3 and Ms2O is carried out under organic solvent and alkaline conditions; the organic solvent is one or more of tetrahydrofuran, dichloromethane, acetonitrile, and 1,4-dioxane; the alkaline conditions are obtained by adding one or more of triethylamine, DIEA, potassium carbonate, and sodium carbonate.

6. The preparation method according to claim 1, characterized in that, In step (5), the ring-closing reaction is carried out under THF and alkaline conditions. The alkaline conditions are obtained by adding one or more of triethylamine, DIEA, potassium carbonate, and sodium carbonate. During reduction, the amount of 1 mol / L BH3-THF added is 9 to 12 times the mass of intermediate 4.

7. The preparation method according to claim 1, characterized in that, In step (6), the molar ratio of intermediate 2 to intermediate 5 is 1.1 to 1.5:1.0; the ligand is one or more of 1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, D-glucosamine hydrochloride, and Xant-phos; the amount of ligand added is 5 to 20% of the mass of intermediate 5; the coupling reaction of intermediate 2 and intermediate 5 with the ligand is carried out under catalytic and alkaline conditions, wherein the catalyst is one or two of CuI and CuCl; the alkaline conditions are obtained by adding one or more of cesium carbonate, potassium carbonate, and potassium tert-butoxide.

8. The preparation method according to claim 1, characterized in that, In step (7), the molar ratio of intermediate 6 to allyl chlorocarbonate is 1.0:1.1 to 1.5; the amidation reaction of intermediate 6 with allyl chlorocarbonate is carried out under organic solvent and alkaline conditions, wherein the organic solvent is one or two of dichloromethane and tetrahydrofuran, and the alkaline conditions are obtained by adding one or more of potassium carbonate, sodium carbonate, pyridine, triethylamine, and DBU.

9. The preparation method according to claim 1, characterized in that, In step (8), the molar ratio of 4-(hydroxymethyl)-5-methyl-1,3-dioxo-2-one and 4-nitrophenyl carbochloride is 1.0:1.1 to 1.5; the esterification reaction of 4-(hydroxymethyl)-5-methyl-1,3-dioxo-2-one and 4-nitrophenyl carbochloride is carried out under organic solvent and alkaline conditions, wherein the organic solvent is one or more of chloroform, dichloromethane, and tetrahydrofuran, and the alkaline conditions are obtained by adding one or two of pyridine and triethylamine.

10. The preparation method according to claim 1, characterized in that, In step (9), the molar ratio of intermediate 7 to intermediate 8 is 1.0:1.1 to 1.3; the reducing agent is one or more of Bu3SnH, Et3SiH, and Ph3SiH, and the amount of reducing agent added is 3 to 10% of the mass of intermediate 7; the condensation reaction of intermediate 7, intermediate 8 and reducing agent is carried out under the conditions of catalyst and organic solvent, wherein the organic solvent is one or more of dichloromethane, tetrahydrofuran, and acetonitrile, and the catalyst is one or more of bis(triphenylphosphine)palladium chloride, tetra(triphenylphosphine)palladium, DPPF, and palladium dichloride.

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