A method for synthesizing deferasirox

Abstract

This invention provides a method for synthesizing deferasirox. The method involves reacting starting material A with hydrochloric acid-ethanol solution in solvent a to generate intermediate B; intermediate B reacts with salicylyl chloride and pyridine in solvent b to generate intermediate C; and intermediate C reacts with p-hydrazide benzoate in solvent c to generate deferasirox. This method is simple to operate, has mild reaction conditions, high yield, low cost, is environmentally friendly, and is suitable for large-scale industrial production of deferasirox.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug synthesis, specifically relating to a method for synthesizing derafloxacin. Background Technology

[0002] Deferasirox, chemically named 4-[3,5-di(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid, is an iron chelating agent developed by Novartis, a Swiss pharmaceutical company. It was the first oral iron chelator approved by the US FDA for routine use, approved for use in patients ≥2 years of age with chronic iron overload due to blood transfusions. In Europe, it is recommended as a first-line treatment for patients aged 6 years and older with thalassemia and iron overload. Clinical trials are currently underway in China. Phase II and III clinical trials and pharmacokinetic studies have shown that it has good safety and tolerability, and can significantly reduce iron load in the heart and liver, making it easily accepted by patients. It also possesses pharmacological properties such as antifungal activity (e.g., against Mucor molds that grow in iron-rich environments), anti-cell proliferation, antimalarial activity, anti-oxidative stress damage, and anti-cytotoxic apoptosis-inducing effects; it can be used to treat secondary hemochromatosis, porphyria cutanea tarda, and other diseases.

[0003] According to patent CN 116199637 A, a method for preparing derafloxacin is described as follows:

[0004] The method involves esterifying p-aminobenzoic acid with 2-trimethylsilylethanol to obtain compound INT-1; reacting compound INT-1 with sodium nitrite in an acidic aqueous solution to undergo diazotization, generating a diazonium salt intermediate, which is then reduced to obtain phenylhydrazine compound INT-2; reacting phenylhydrazine compound INT-2 with 2-[2-(benzyloxy)phenyl]-4H-benzo[e][1,3]oxazin-4-one in a solvent system to obtain compound INT-3; subjecting compound INT-3 to catalytic hydrogenation deprotection to obtain compound INT-4; and in the presence of tetrabutylammonium fluoride, subjecting compound INT-4 to deprotection to obtain derafloxacin.

[0005] This method reports the following drawbacks in the preparation of derafloxacin and its analogues: The entire preparation process has defects such as high raw material cost, many synthesis steps, complex process and difficult separation. (2) The entire preparation process requires high operator skills and generates a lot of waste, making it difficult to achieve industrial scale-up production requirements. Summary of the Invention

[0006] The present invention aims to provide a method for synthesizing avanafil that is simple to operate, has mild reaction conditions, high yield, low cost, and is environmentally friendly.

[0007] To achieve the above-mentioned objectives, the present invention provides a method for synthesizing delaros, the specific implementation of which is as follows: The present invention discloses a method for preparing derafloxacin, the synthetic route of which is as follows: .

[0008] The present invention discloses a method for preparing derafloxacin, characterized in that the synthetic route steps of the method are as follows: 1) Starting with 2-acetoxybenzyl nitrile as the starting material A and hydrochloric acid ethanol solution in the presence of solvent a, intermediate B is obtained: 2-acetoxybenzyl amino acid ethyl ester hydrochloride; 2) Intermediate B and salicyl chloride react in solvent b and under the condition of pyridine addition to give intermediate C: 2-(2-acetoxy)-4H-1,3-benzoxazine-4-one; 3) Intermediate C and p-hydrazinocarbamate react in solvent C to give derafloxacin.

[0009] The present invention discloses a method for synthesizing derafloxacin. In step 1), solvent a is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, xylene, ethylene glycol monomethyl ether, and ethylene glycol diethyl ether. The mass ratio of starting material A to solvent a is 1:3~3.5, and the molar ratio of starting material A to hydrochloric acid ethanol solution is 1:1.35~1.75. The system is reacted at room temperature with stirring. After the reaction is completed, the system is cooled to 0~10℃ and hydrochloric acid ethanol solution is added and the reaction is stirred for 11-15 hours.

[0010] The present invention discloses a method for synthesizing derafloxacin. In step 2), solvent b is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, acetonitrile, petroleum ether, and ethyl acetate; the molar ratio of intermediate B to salicylyl chloride is 1:1.5~1.6; the mass ratio of intermediate B to solvent b is 1:2.5~3; the molar ratio of intermediate B to pyridine is 1:0.5~0.8; the system is heated to 50~60℃ under stirring; and the reaction time for adding pyridine is 11~13h.

[0011] The method for synthesizing delarosx according to the present invention, in step 3), uses one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, tert-amyl alcohol, ethanol, methanol, tert-butanol, isopropanol, ethyl acetate, and toluene; the mass ratio of intermediate C to solvent C is 1:2.5~2.8; the molar ratio of intermediate C to p-hydrazide benzoate is 1:1.25~1.45; the reaction temperature of the system under stirring is 75~85℃, the reflux reaction time is 3~5h; the crystallization temperature of the system is 0~10℃; the crystallization time is 2~3h, followed by filtration and drying; wherein, the delarosx purification process involves anhydrous ethanol and purified water in a mass ratio of 1:1.85~2.1:0.7~1.2, and the mixture is stirred at 0~10℃ for 3~5h.

[0012] The present invention discloses a method for synthesizing derafloxacin. In step 1), solvent a is dichloromethane; the mass ratio of starting material A to solvent a is 1:3.5, and the molar ratio of starting material A to hydrochloric acid ethanol solution is 1:1.45; the system is reacted at room temperature under stirring. After the reaction is completed, the system is cooled to 0~10℃, hydrochloric acid ethanol solution is added, and the system is stirred for 11-15 hours.

[0013] The present invention discloses a method for synthesizing derafloxacin, wherein in step 2), solvent b is 2-methyltetrahydrofuran; the molar ratio of intermediate B to salicylyl chloride is 1:1.5; the mass ratio of intermediate B to solvent b is 1:3; the molar ratio of intermediate B to pyridine is 1:0.65; the system is heated to 50-60°C under stirring; and the reaction time for adding pyridine is 11-13 h.

[0014] The method for synthesizing delarosus according to the present invention includes the following steps: Step 3) uses 2-methyltetrahydrofuran as the solvent; the mass ratio of intermediate C to solvent C is 1:2.8; the molar ratio of intermediate C to p-hydrazine benzoate is 1:1.35; the reaction temperature of the system under stirring is 75~85℃, the reflux reaction time is 3~5h; the crystallization temperature of the system is 0~10℃; the crystallization time is 2~3h, followed by filtration and drying; wherein, the delarosus purification process involves anhydrous ethanol and purified water in a mass ratio of 1:2.5:1.1, and the mixture is stirred at 0~10℃ for 3~5h.

[0015] Analysis of the beneficial effects of this invention: The method of this invention is simple to operate, has mild reaction conditions, high yield, low cost, is environmentally friendly, and is suitable for large-scale industrial production of larosi. Detailed Implementation

[0016] The following examples are only for further illustration of the present invention and do not limit the scope of the present invention in any way.

[0017] Example 1 Step 1: Starting material A (50 g, 0.31 mmol) and dichloromethane were added to a 175 g three-necked reaction flask and stirred until dissolved. The mixture was kept at 0°C with ice and salt incubation and stirring until the system temperature dropped to 0-5°C. Then, 37.14 g of hydrochloric acid-ethanol solution (0.45 mmol) was added. After the addition was complete, the mixture was kept at 0°C with ice and salt incubation and stirring for 11-15 h. The reaction was monitored by TLC until completion. The mixture was washed with 50 g of anhydrous ethanol. Intermediate B was obtained in a quantity of 32.86 g, with a yield of 98.53%.

[0018] Step 2: Intermediate B (30 g, 0.12 mmol), salicyl chloride (29.16 g, 0.19 mmol), and 90 g of 2-methyltetrahydrofuran were added to a 500 mL three-necked flask. The mixture was heated to 50–60 °C with stirring. Pyridine was added dropwise over 11–13 h. The reaction was monitored by TLC until complete. The mixture was washed twice with water and twice with 2 mol / L brine. The organic phase was concentrated by separation until no fraction was distilled off, yielding 25.11 g of solid, with a yield of 102.99%.

[0019] Step 3: Intermediate C (20 g, 0.07 mol) and p-hydrazide benzoate (17.82 g, 0.09 mmol) were added to a 500 mL three-necked reaction flask. 56 g of 2-methyltetrahydrofuran was added to the system. After addition, the temperature was raised to 75-85 °C, and the reaction was monitored by TLC until completion. The mixture was stirred and cooled to room temperature. Dilute hydrochloric acid was added dropwise until the pH reached 1-3. The mixture was washed with water, separated, and the concentrated organic phase was cooled to 0-10 °C for 2-3 hours to crystallize. The crystals were then filtered, dried, and 26.15 g of crude product was obtained. Refining steps: Add 10g of crude product, 25g of ethanol and 11g of purified water to a 50ml reaction flask, place at 0~10℃ and stir for 3~5 hours, filter, dry to obtain 9.78g of finished product, yield 97.80%.

[0020] Example 2 Step 1: Add starting material A (50g, 0.31mmol) and toluene to a 175g three-necked reaction flask and stir. A small amount of material remains undissolved. Maintain the mixture at 0°C with ice and salt, stirring until the system temperature drops to 0-5°C. Add 37.14g of hydrochloric acid-ethanol solution (0.45mmol). After the addition is complete, maintain the mixture at 0°C with ice and salt, stirring for 11-15 hours. Monitor the reaction by TLC until completion. Elute with 50g of anhydrous ethanol. Intermediate B was obtained in a quantity of 28.36g, yield 85.04%.

[0021] Step 2: Intermediate B (20 g, 0.08 mmol), salicyl chloride (19.44 g, 0.12 mmol), and 60 g of tetrahydrofuran were added to a 500 mL three-necked reaction flask. The mixture was heated to 50–60 °C with stirring. Pyridine was added dropwise over 11–13 h. The reaction was monitored by TLC until completion. The mixture was washed twice with water and twice with 2 mol / L brine. The organic phase was concentrated by separation until no fraction was distilled off, yielding 16.28 g of solid, with a yield of 100.16%.

[0022] Step 3: Intermediate C (10 g, 0.03 mol) and p-hydrazide benzoate (8.5 g, 0.05 mmol) were added to a 100 mL three-necked flask. 28 g of methyltetrahydrofuran was added to the system. After addition, the temperature was raised to 75-85 °C, and the reaction was monitored by TLC until completion. The mixture was stirred and cooled to room temperature. Dilute hydrochloric acid was added dropwise until the pH reached 1-3. The mixture was washed with water, separated, and the concentrated organic phase was cooled to 0-10 °C for 2-3 hours to crystallize. The crystals were then filtered, dried, and 14.35 g of crude product was obtained. Refining steps: Add 10g of crude product, 25g of ethanol and 11g of purified water to a 50ml reaction flask, place at 0~10℃ and stir for 3~5 hours, filter, dry to obtain 9.67g of finished product, yield 96.70%.

[0023] Example 3 Step 1: Starting material A (50 g, 0.31 mmol) and tetrahydrofuran were added to a 175 g three-necked reaction flask and stirred until dissolved. The mixture was kept at 0°C with ice and salt incubation and stirring until the system temperature dropped to 0-5°C. Then, 37.14 g of hydrochloric acid-ethanol solution (0.45 mmol) was added. After the addition was complete, the mixture was kept at 0°C with ice and salt incubation and stirring for 11-15 h. The reaction was monitored by TLC until completion. The mixture was washed with 50 g of anhydrous ethanol. Intermediate B was obtained in a quantity of 31.16 g, with a yield of 93.43%.

[0024] Step 2: Intermediate B (30 g, 0.12 mmol), salicyl chloride (29.16 g, 0.19 mmol), and 90 g of tetrahydrofuran were added to a 500 mL three-necked reaction flask. The mixture was heated to 50–60 °C with stirring. Pyridine was added dropwise over 11–13 h. The reaction was monitored by TLC until completion. The mixture was washed twice with water and twice with 2 mol / L brine. The organic phase was concentrated by separation until no fraction was distilled off, yielding 23.78 g of solid, with a yield of 97.53%.

[0025] Step 3: Intermediate C (20 g, 0.07 mol) and p-hydrazide benzoate (17.82 g, 0.09 mmol) were added to a 500 mL three-necked flask. 56 g of tetrahydrofuran was added to the system. After addition, the temperature was raised to 75-85 °C, and the reaction was monitored by TLC until completion. The mixture was stirred and cooled to room temperature. Dilute hydrochloric acid was added dropwise until the pH reached 1-3. The mixture was washed with water, separated, and the concentrated organic phase was cooled to 0-10 °C for 2-3 hours to crystallize. The crystals were then filtered, dried, and 26.35 g of crude product was obtained. Purification steps: Add 10g of crude product, 25g of ethanol and 11g of purified water to a 50ml reaction flask, place at 0~10℃ and stir for 3~5h, filter, dry to obtain 9.77g of finished product, yield 97.70%.

Claims

1. A method for preparing deferasirox, characterized by, The synthetic route of this method is as follows: 。 2. The method for preparing derafloxacin according to claim 1, characterized in that, The synthesis route steps of this method are as follows: 1) Starting with 2-acetoxybenzyl nitrile as the starting material A and hydrochloric acid ethanol solution in the presence of solvent a, intermediate B is obtained: 2-acetoxybenzyl amino acid ethyl ester hydrochloride; 2) Intermediate B and salicyl chloride react in solvent b and under the condition of pyridine addition to give intermediate C: 2-(2-acetoxy)-4H-1,3-benzoxazine-4-one; 3) Intermediate C and p-hydrazinocarbamate react in solvent C to give derafloxacin.

3. The method of claim 2, wherein, The solvent a used in step 1) is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, xylene, ethylene glycol monomethyl ether, and ethylene glycol diethyl ether; the mass ratio of starting material A to solvent a is 1:3~3.5, and the molar ratio of starting material A to hydrochloric acid ethanol solution is 1:1.35~1.75; the system is reacted at room temperature with stirring, and after the reaction is completed, the system is cooled to 0~10℃ and hydrochloric acid ethanol solution is added and stirred for 11-15h. 4.The method of claim 2, wherein Step 2) The solvent b used is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, acetonitrile, petroleum ether, and ethyl acetate; the molar ratio of intermediate B to salicylyl chloride is 1:1.5~1.6; the mass ratio of intermediate B to solvent b is 1:2.5~3; the molar ratio of intermediate B to pyridine is 1:0.5~0.8; the system is heated to 50~60℃ under stirring; the reaction time for adding pyridine is 11~13h. 5.The method of claim 2, wherein Step 3) The solvent used is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, tert-amyl alcohol, ethanol, methanol, tert-butanol, isopropanol, ethyl acetate, and toluene; the mass ratio of intermediate C to solvent C is 1:2.5~2.8; the molar ratio of intermediate C to p-hydrazide benzoate is 1:1.25~1.45; the reaction temperature of the system under stirring is 75~85℃, and the reflux reaction time is 3~5h; the crystallization temperature of the system is 0~10℃; the crystallization time is 2~3h, filtered, and dried; wherein, the derarosixidation is purified by anhydrous ethanol and purified water in a mass ratio of 1:1.85~2.1:0.7~1.2, and the mixture is stirred at 0~10℃ for 3~5h. 6.The method of claim 3, wherein The solvent a used in step 1) is dichloromethane; the mass ratio of starting material A to solvent a is 1:3.5, and the molar ratio of starting material A to hydrochloric acid ethanol solution is 1:1.45; the system is reacted at room temperature under stirring. After the reaction is completed, the system is cooled to 0~10℃ and hydrochloric acid ethanol solution is added and stirred for 11-15h.

7. The method for synthesizing delaros according to claim 4, characterized in that, Step 2) The solvent b used is 2-methyltetrahydrofuran; the molar ratio of intermediate B to salicyl chloride is 1:1.5; the mass ratio of intermediate B to solvent b is 1:3; the molar ratio of intermediate B to pyridine is 1:0.65; the system is heated to 50~60℃ under stirring; the reaction time for adding pyridine is 11~13h.

8. The method for synthesizing delaros according to claim 5, characterized in that, Step 3) The solvent used is 2-methyltetrahydrofuran; the mass ratio of intermediate C to solvent C is 1:2.8; the molar ratio of intermediate C to p-hydrazine benzoate is 1:1.35; the reaction temperature of the system under stirring is 75~85℃, the reflux reaction time is 3~5h; the crystallization temperature of the system is 0~10℃; the crystallization time is 2~3h, filtered, and dried; wherein, the derarosixidation is purified by anhydrous ethanol and purified water in a mass ratio of 1:2.5:1.1, and the mixture is stirred at 0~10℃ for 3~5h.

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