A process for the preparation of high purity digoxin

Abstract

This invention relates to the field of diclofenac preparation technology and discloses a method for preparing high-purity diclofenac, comprising the following steps: synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine; synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester; synthesis of D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester; and synthesis of diclofenac. The key intermediates in the synthesis process of this invention can be obtained by precipitation or recrystallization, without the need for purification using chromatography columns or HPLC, offering advantages such as convenient operation and low cost, and ultimately producing high-purity diclofenac.

Description

Technical Field

[0001] This invention relates to the field of diclofenac preparation technology, and more specifically to a method for preparing high-purity diclofenac. Background Technology

[0002] Chronic kidney disease-associated pruritus (CKD-aP) is a refractory, generalized pruritus that occurs frequently and intensely in patients with chronic kidney disease (CKD) undergoing hemodialysis. Currently used medications include gatapentine (a second-line drug), antihistamines, pregabalin, and corticosteroids, but these do not adequately relieve symptoms. Diclave is a peripherally selective κ-opioid receptor (KOR) agonist that exerts its antipruritic effect by stimulating κ-opioid receptors on peripheral nerves and immune cells. This drug is used to treat pruritus in hemodialysis patients with end-stage renal disease (ESRD). Diclave is the first and only drug approved for the treatment of CKD-aP in adult hemodialysis patients, and has the potential to fundamentally change the treatment paradigm for CKD-aP in dialysis-receiving adults. Diclave acetate injection was first approved for marketing in the United States on August 23, 2021, and its structural formula is as follows:

[0003] There are relatively few reported synthetic routes for diclofenac, and the main ones are as follows: Route 1: Patent CN101627049B, uses solid-phase peptide synthesis and purification with preparative liquid-phase separation, which is costly and not suitable for large-scale production.

[0004] Route 2: Patent CN106459150B / US20170183307A1. Dickfarin is a pentapeptide compound involving the condensation reaction of five carboxyl and amino groups. This route has many synthetic steps, involving multiple selective protection and deprotection of protecting groups, making it suitable for scale-up production. However, the hydrogenation deprotection step is a hazardous process under key national regulation, requiring special high-pressure equipment and workshops, which is not a very user-friendly process in our production. Another issue is the high price of the starting material methyl 4-N-BOC-piperidine-4-carboxylate, and the long reaction steps, resulting in a high cost of dickfarin based on the yield. The dickfarin synthetic route in patent CN106459150B is as follows: Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for preparing high-purity diclave. On the one hand, it avoids the use of solid-phase peptide synthesis to produce diclave, because after synthesizing the pentapeptide protectant, purification is performed using preparative HPLC after resin removal and complete deprotection. This purification requires a large-scale preparative HPLC apparatus, resulting in high costs and a long processing time. On the other hand, it utilizes liquid-phase peptide synthesis, avoiding the palladium-on-carbon hydrogenation deprotection step. High-pressure palladium-on-carbon hydrogenation is a hazardous process under strict national regulation, requiring specialized equipment and workshops, and the use of precious metal catalysts such as palladium on carbon significantly increases costs. While researching methods for manufacturing high-purity diclofenac, the inventors of this invention unexpectedly discovered that intermediate compounds 1, 3, 5, 7, and 8 could be purified using recrystallization with different solvents, and that by obtaining high-purity intermediates, high-purity diclofenac (compound 9) could be advantageously manufactured industrially. This invention involves recrystallization purification of diclofenac and its intermediates, thereby obtaining high-purity diclofenac intermediates and the finished diclofenac product.

[0006] To achieve the above objectives, the technical solution of the present invention is: a method for preparing high-purity diclofenac sodium, comprising the following steps: (1) Synthesis of BOC-D-phenylalanine-D-phenylalanine methyl ester: Using compound R-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid as raw material, it is mixed in an aprotic solvent and condensed with D-phenylalanine methyl ester hydrochloride under the action of a condensing agent to obtain BOC-D-phenylalanine-D-phenylalanine methyl ester; (2) Synthesis of BOC-D-phenylalanine-D-phenylalanine: Using BOC-D-phenylalanine-D-phenylalanine methyl ester as raw material, it is mixed in a protic solvent and hydrolyzed under the action of alkali to obtain BOC-D-phenylalanine-D-phenylalanine. (3) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester: Using compound BOC-D-phenylalanine-D-phenylalanine as raw material, it is mixed in an aprotic solvent and condensed with D-leucine methyl ester hydrochloride under the action of a condensing agent to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester; (4) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine: Using compound BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester as raw material, it is mixed in a protic solvent and hydrolyzed under the action of alkali to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine. (5) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester: Using compound BOC-D-phenylalanine-D-phenylalanine-D-leucine as raw material, it is mixed in an aprotic solvent and condensed with N'-BOC-D-lysine methyl ester hydrochloride under the action of a condensing agent to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester; (6) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine: Using compound BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester as raw material, the mixture was mixed in a protic solvent and hydrolyzed under the action of alkali to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine; (7) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester: Using compound BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine as raw material, it is mixed in an aprotic solvent and condensed with 4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester hemioxalate under the action of a condensing agent to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester; (8) Synthesis of D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester: Using BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester as raw material, it was mixed in a protic solvent and subjected to a reaction to remove the BOC protecting group under the action of acid to obtain D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester; (9) Synthesis of diclofenac: D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester was used as a raw material, mixed in a protic solvent, and hydrolyzed under the action of alkali to obtain diclofenac.

[0007] Further; the molar ratio of R-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid to D-phenylalanine methyl ester hydrochloride in step (1) is 1:(1~2); the molar ratio of R-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid to condensing agent is 1:(1~2).

[0008] Further; the molar ratio of BOC-D-phenylalanine-D-phenylalanine methyl ester and base in step (2) is 1:(1-5).

[0009] Further; the molar ratio of BOC-D-phenylalanine-D-phenylalanine to D-leucine methyl ester hydrochloride in step (3) is 1:(1~2); the molar ratio of BOC-D-phenylalanine-D-phenylalanine to condensing agent is 1:(1~2).

[0010] Further; the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester to the base in step (4) is 1:(1-5).

[0011] Further; the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine to N'-BOC-D-lysine methyl ester hydrochloride in step (5) is 1:(1~2); the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine to the condensing agent is 1:(1~2).

[0012] Further; the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester to the base in step (6) is 1:(1-5).

[0013] Further; in step (7), the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine to 4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester hemioxalate is 1:(1-2); the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine to the condensing agent is 1:(1-2).

[0014] Further; in step (8), the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester to acid is 1:(2-20); the acid is HCl or trifluoroacetic acid; the reaction temperature for removing the BOC protecting group is 0℃-30℃, and the reaction time is 1h-72h; in step (9), the molar ratio of D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester to base is 1:(1-5).

[0015] Further; the aprotic solvent is selected from one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, carbon tetrachloride, toluene, and chloroform; the condensing agent is selected from compound A, a composition of compound A and an organic base, a composition of compound A and compound B, or a composition of compound A, compound B, and an organic base; wherein, compound A is selected from EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), DCC (cyclohexylcarbodiimide), DIC (N,N-diisopropylcarbodiimide), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), HBTU (O-benzotriazole-tetramethylurea hexafluorophosphate), TATU ( 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea tetrafluoroborate, TBTU (O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate), PyAOP ((3H-1,2,3-triazolo[4,5-b]pyridin-3-oxy)tri-1-pyrrolidinyl hexafluorophosphate) or PyBOP (1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate); compound B is selected from HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzotriazole), Oxyma (1-hydroxyphenyl-4,5-diphenylimidazolium), HOSu (N-hydroxysuccinimide) or HONb (N-hydroxy-5-norbornene-2,3-dicarboximide); the organic base is selected from 2 4,6-Trimethylpyridine, DIPEA (diisopropylethylamine), triethylamine, pyridine, triethylamine or N-methylmorpholine; the condensing agent is preferably a combination of EDCI, HOBt and DIPEA, wherein the molar ratio of EDCI, HOBt and DIPEA is 1:(1-2):(2-3); the condensation reaction temperature is 0℃-30℃, and the condensation reaction time is 1h-72h; The protic solvent is selected from one or more of methanol, ethanol, isopropanol, and water; the base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, and sodium carbonate; the hydrolysis reaction temperature is 0℃~30℃, and the hydrolysis reaction time is 1h~72h.

[0016] The synthetic route for high-purity diclofenac in this invention is as follows:

[0017] The beneficial effects of this invention are as follows: First, this invention adopts a liquid-phase synthesis method, avoiding the high-pressure hydrogenation deprotection process used in existing technologies. This results in low synthesis costs, ease of large-scale production, and minimal environmental pollution, making it highly promising for industrial applications. Second, the key intermediates in the synthesis process of this invention can be obtained through precipitation or recrystallization, eliminating the need for purification using chromatography columns or HPLC. This method offers advantages such as convenient operation and low cost, and ultimately, high-purity diclofenac can be prepared. Finally, the materials used in the process of this invention are all conventional and inexpensive, offering advantages such as readily available materials and low equipment requirements. Detailed Implementation

[0018] Example:

[0019] A method for preparing high-purity diclofenac includes the following steps: (1) Synthesis of BOC-D-phenylalanine-D-phenylalanine methyl ester: Add R-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid (20 g, 75.4 mmol), 1-hydroxybenzotriazole (12.20 g, 90 mmol), and dichloromethane (200 mL) to a three-necked flask. Cool to 0-5 °C, then add diisopropylethylamine (29.2 g, 226 mmol). After dissolving, add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.25 g, 90 mmol). Maintain the reaction temperature at 0-5 °C for 3 minutes. After 1 hour, D-phenylalanine methyl ester hydrochloride (17.80 g, 82 mmol) was added, and the reaction was maintained at 0-5℃. After the reaction was detected by TLC, 100 mL of water was added for washing. The organic phase was washed once with 1N hydrochloric acid, 5% sodium bicarbonate solution, and saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure and then purified by recrystallization with 100 mL of isopropanol. The product BOC-D-phenylalanine-D-phenylalanine methyl ester (compound 1) was obtained by filtration, with a yield of 92.28% and a purity of 98.13%.

[0020] (2) Synthesis of BOC-D-phenylalanine-D-phenylalanine BOC-D-phenylalanine-D-phenylalanine methyl ester (29.50 g, 69.2 mmol) and methanol (300 mL) were added to a three-necked flask. Then, a solution of sodium hydroxide (7.2 g, 180 mmol) and water (244 mL) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC, the pH of the organic phase was adjusted to 5 with 10% citric acid. The mixture was stirred to induce crystallization. The crystals were filtered, and the filter cake was dried to obtain 20.01 g of product BOC-D-phenylalanine-D-phenylalanine (compound 2), with a yield of 70.14% and a purity of 99.18%.

[0021] (3) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester Add BOC-D-phenylalanine (13.10 g, 31.76 mmol), 1-hydroxybenzotriazole (6.10 g, 45 mmol), and dichloromethane (100 mL) to a three-necked flask. Cool to 0-5 °C, then add diisopropylethylamine (12.31 g, 95.24 mmol). After dissolving, add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.70 g, 45 mmol). Incubate at 0-5 °C for 3 hours, then add D-leucine. Methyl ester hydrochloride (6.06 g, 33.36 mmol) was reacted at 0-5 °C. After the reaction was detected by TLC, 100 mL of water was added for washing. The organic phase was washed once each with 1 N hydrochloric acid, 5% sodium bicarbonate solution, and saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure and then purified by recrystallization with 60 mL of isopropanol. The product BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester (compound 3) was obtained by filtration, with a yield of 86.88% and a purity of 99.56%.

[0022] (4) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester (16.59 g, 30.7 mmol) and methanol (166 mL) were added to a three-necked flask. Then, a solution of sodium hydroxide (3.20 g, 80 mmol) and water (100 mL) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC, the pH of the organic phase was adjusted to 5 with 10% citric acid. The mixture was stirred to induce crystallization, filtered, and the filter cake was dried to obtain 15.37 g of product BOC-D-phenylalanine-D-phenylalanine-D-leucine (compound 4), with a yield of 95.12% and a purity of 99.86%.

[0023] (5) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester Add BOC-D-phenylalanine-D-phenylalanine-D-leucine (8.88 g, 16.9 mmol), 1-hydroxybenzotriazole (3.04 g, 22.5 mmol), and dichloromethane (100 mL) to a three-necked flask. Cool to 0–5 °C, then add diisopropylethylamine (6.55 g, 50.7 mmol). After dissolving, add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.31 g, 22.5 mmol). Incubate at 0–5 °C for 3 hours, then add N'-BOC-D-lysine. 6.32 g of methyl lysine hydrochloride (21.3 mmol) was reacted at 0-5 °C. After the reaction was completed by TLC, 100 mL of water was added for washing. The organic phase was washed once each with 1 N hydrochloric acid, 5% sodium bicarbonate solution, and saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered. The filtrate was evaporated under reduced pressure and then purified by recrystallization with 30 mL of ethanol. The product was filtered to obtain 8.85 g of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester (compound 5), with a yield of 68.22% and a purity of 99.82%.

[0024] (6) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine 13 g (16.9 mmol) of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester and 130 mL of methanol were added to a three-necked flask. Then, a solution of sodium hydroxide (1.76 g, 44 mmol) and water (60 mL) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC, the pH of the organic phase was adjusted to 5 with 10% citric acid. The mixture was stirred to induce crystallization, filtered, and the filter cake was dried to obtain 12.45 g of the product BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine (compound 6), with a yield of 97.55% and a purity of 99.86%.

[0025] (7) Synthesis of ethyl BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylate Add BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine (6.40 g, 8.49 mmol), 1-hydroxybenzotriazole (1.59 g, 11.8 mmol), and dichloromethane (100 mL) to a three-necked flask. Cool to 0–5 °C, then add diisopropylethylamine (3.23 g, 25 mmol). After dissolving, add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.26 g, 11.8 mmol). Incubate at 0–5 °C for 3 hours, then add 4-(Trt-amino)piperidine-4-carboxylic acid. Ethyl hemioxalate (5.47 g, 11.9 mmol) was reacted at 0-5 °C. After the reaction was completed by TLC, 100 mL of water was added for washing. The organic phase was washed once each with 1 N hydrochloric acid, 5% sodium bicarbonate solution, and saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered. The filtrate was evaporated under reduced pressure and then purified by recrystallization with 30 mL of ethanol. The product was filtered to obtain 8.54 g of ethyl BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylate (compound 7), with a yield of 87.45% and a purity of 99.20%.

[0026] (8) Synthesis of D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester (8) Acetyl chloride (22.0 g, 280 mmol) was added dropwise to a three-necked flask containing isopropanol (70 mL) at a temperature of 0-5 °C. After the addition was complete, the mixture was stirred at 0-5 °C for 1 h. Then, ethyl BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylate (20.7 g, 18 mmol) was weighed and added to the three-necked flask. Toluene (70 mL) was then added, and the mixture was stirred at room temperature. After the reaction was completed by TLC, the mixture was cooled to 0-5 °C for 2 h to crystallize. The crystals were filtered, and the filter cake was evaporated under reduced pressure and then purified by recrystallization with 30 mL of ethanol. The product D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylate (compound 8) was obtained by filtration, with a yield of 73.37% and a purity of 99.65%.

[0027] (9) Synthesis of diclofenac Ethyl D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylate (10.13 g, 12.4 mmol) and methanol (100 mL) were added to a three-necked flask. Then, a solution of sodium hydroxide (2.0 g, 50 mmol) and water (50 mL) was added dropwise. The mixture was kept at 0-10 °C with stirring. After the reaction was completed by TLC, acetic acid (3.0 g, 50 mmol) was added to adjust the pH to 5. The solid was evaporated to dryness and purified by recrystallization with 25 mL of ethanol. The solid was filtered, and the filter cake was dried to give 6.28 g of diclofenac (compound 9), with a yield of 74.53% and a purity of 99.55%.

[0028] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications may be made without departing from the technical solutions described in the claims.

Claims

1. A method for preparing high-purity diclofenac sodium, characterized in that, Includes the following steps: (1) Synthesis of BOC-D-phenylalanine-D-phenylalanine methyl ester: Using compound R-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid as raw material, it is mixed in an aprotic solvent and condensed with D-phenylalanine methyl ester hydrochloride under the action of a condensing agent to obtain BOC-D-phenylalanine-D-phenylalanine methyl ester; (2) Synthesis of BOC-D-phenylalanine-D-phenylalanine: Using BOC-D-phenylalanine-D-phenylalanine methyl ester as raw material, it is mixed in a protic solvent and hydrolyzed under the action of alkali to obtain BOC-D-phenylalanine-D-phenylalanine. (3) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester: Using compound BOC-D-phenylalanine-D-phenylalanine as raw material, it is mixed in an aprotic solvent and condensed with D-leucine methyl ester hydrochloride under the action of a condensing agent to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester; (4) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine: Using compound BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester as raw material, it is mixed in a protic solvent and hydrolyzed under the action of alkali to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine. (5) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester: Using compound BOC-D-phenylalanine-D-phenylalanine-D-leucine as raw material, it is mixed in an aprotic solvent and condensed with N'-BOC-D-lysine methyl ester hydrochloride under the action of a condensing agent to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester; (6) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine: Using compound BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester as raw material, the mixture was mixed in a protic solvent and hydrolyzed under the action of alkali to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine; (7) Synthesis of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester: Using compound BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine as raw material, it is mixed in an aprotic solvent and condensed with 4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester hemioxalate under the action of a condensing agent to obtain BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester; (8) Synthesis of D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester: Using BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester as raw material, it was mixed in a protic solvent and subjected to a reaction to remove the BOC protecting group under the action of acid to obtain D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester; (9) Synthesis of diclofenac: D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester was used as a raw material, mixed in a protic solvent, and hydrolyzed under the action of alkali to obtain diclofenac.

2. The method for preparing high-purity diclofenac according to claim 1, characterized in that: The molar ratio of R-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid to D-phenylalanine methyl ester hydrochloride in step (1) is 1:(1-2); the molar ratio of R-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid to the condensing agent is 1:(1-2).

3. The method for preparing high-purity diclofenac according to claim 1, characterized in that: The molar ratio of BOC-D-phenylalanine-D-phenylalanine methyl ester and base in step (2) is 1:(1-5).

4. The method for preparing high-purity diclofenac according to claim 1, characterized in that: In step (3), the molar ratio of BOC-D-phenylalanine-D-phenylalanine to D-leucine methyl ester hydrochloride is 1:(1-2); the molar ratio of BOC-D-phenylalanine-D-phenylalanine to the condensing agent is 1:(1-2).

5. The method for preparing high-purity diclofenac according to claim 1, characterized in that: The molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine methyl ester to the base in step (4) is 1:(1-5).

6. The method for preparing high-purity diclofenac according to claim 1, characterized in that: In step (5), the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine to N'-BOC-D-lysine methyl ester hydrochloride is 1:(1-2); the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine to the condensing agent is 1:(1-2).

7. The method for preparing high-purity diclofenac according to claim 1, characterized in that: The molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine methyl ester to the base in step (6) is 1:(1-5).

8. The method for preparing high-purity diclofenac according to claim 1, characterized in that: In step (7), the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine to 4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester hemioxalate is 1:(1-2); the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine to the condensing agent is 1:(1-2).

9. The method for preparing high-purity diclofenac according to claim 1, characterized in that: In step (8), the molar ratio of BOC-D-phenylalanine-D-phenylalanine-D-leucine-N'-BOC-D-lysine-4-(Trt-amino)piperidine-4-carboxylic acid ethyl ester to acid is 1:(2-20); the acid is HCl or trifluoroacetic acid; the reaction temperature for removing the BOC protecting group is 0℃-30℃, and the reaction time is 1h-72h; in step (9), the molar ratio of D-phenylalanine-D-phenylalanine-D-leucine-D-lysine-4-aminopiperidine-4-carboxylic acid ethyl ester to base is 1:(1-5).

10. The method for preparing high-purity diclofenac according to claim 1, characterized in that: The aprotic solvent is selected from one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, carbon tetrachloride, toluene, and chloroform; the condensing agent is selected from compound A, a composition of compound A and an organic base, a composition of compound A and compound B, or a composition of compound A, compound B, and an organic base; wherein, compound A is selected from EDCI, DCC, DIC, HATU, HBTU, TATU, TBTU, PyAOP, or PyBOP; compound B is selected from HOAt, HOBt, Oxyma, HOSu, or HONb; the organic base is selected from 2,4,6-trimethylpyridine, DIPEA, triethylamine, pyridine, triethylamine, or N-methylmorpholine; the condensation reaction temperature is 0℃~30℃, and the condensation reaction time is 1h~72h; The protic solvent is selected from one or more of methanol, ethanol, isopropanol, and water; the base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, and sodium carbonate; the hydrolysis reaction temperature is 0℃~30℃, and the hydrolysis reaction time is 1h~72h.

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