A method for preparing high purity irinotecan hydrochloride

Abstract

The application discloses a preparation method of high-purity irinotecan hydrochloride. In the scheme, triethylamine is used as an acid-binding agent to react with SN38 to form an alcohol salt with stronger nucleophilicity. Then, in the presence of phase transfer catalysis assistance of polyethylene glycol (PEG-400) and a 2-methyltetrahydrofuran solvent system, the SN38 alcohol salt is caused to preferentially react with CDI to generate a high-activity acylimidazole intermediate. Finally, under the action of a solid-supported catalyst PS-DMAP, a 4-piperidyl piperidine side chain is introduced to the intermediate for nucleophilic attack, molecule coupling is completed by constructing a urethane bond, and finally, irinotecan hydrochloride is prepared through post-treatment. The method has mild preparation conditions, improves the operation safety, and improves the yield and purity of irinotecan hydrochloride.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, specifically relating to a method for preparing high-purity irinotecan hydrochloride. Background Technology

[0002] Irinotecan hydrochloride is a semi-synthetic camptothecin-based antitumor drug widely used in the clinical treatment of various malignant tumors, including colorectal cancer and lung cancer. As an inhibitor of topoisomerase I, it exerts its anticancer effect by blocking DNA replication and transcription, thereby inducing tumor cell apoptosis. With increasingly stringent clinical requirements for drug safety and efficacy, the preparation of high-purity irinotecan hydrochloride has become a key issue in pharmaceutical research and development and production. High purity not only signifies higher therapeutic efficacy but also directly relates to the control of drug toxicity and side effects and batch stability, making it a core element in ensuring patient safety.

[0003] Currently, the mainstream synthetic route of irinotecan hydrochloride mainly uses 7-ethyl-10-hydroxycamptothecin (SN38) as the key intermediate, which undergoes an acylation reaction with a side-chain precursor containing a piperidine structure (such as 4-piperidinylpiperidinecarboxyl chloride or its derivatives) to generate the free base of irinotecan, which is then salted with hydrochloric acid to obtain the final product.

[0004] Although acyl chlorides are often chosen as acylating agents due to their high reactivity, the use of acyl chlorides (such as 4-piperidinylpiperidincarbamoyl chloride) in the condensation reaction of irinotecan hydrochloride presents significant process drawbacks in actual production. First, the high reactivity of acyl chlorides is a double-edged sword; their reactions are violent and difficult to control, easily triggering hydrolysis or ring-opening side reactions of the active lactone ring in the SN-38 molecule, leading to a decrease in product purity. Second, acyl chlorides are typically extremely sensitive to water, undergoing violent hydrolysis upon contact with it. This not only consumes reagents and reduces reaction yield but also imposes extremely high equipment and cost requirements on the anhydrous operating conditions of the reaction system. Furthermore, acyl chlorides often have strong irritant and corrosive properties; their volatile vapors are highly irritating to the eyes, nose, throat, and skin of operators, posing significant safety hazards. The hydrogen chloride gas generated during the reaction requires a dedicated exhaust gas treatment system, increasing the burden of waste treatment. Simultaneously, traditional acyl chloride condensation processes often require large amounts of organic solvents, and efficient catalyst recovery is difficult, resulting in high production costs.

[0005] Therefore, developing a method for preparing irinotecan hydrochloride with mild reaction conditions, high safety, and effective suppression of side reactions is a technical challenge that urgently needs to be solved in this field. Summary of the Invention

[0006] Based on the above-mentioned prior art, the present invention provides a method for preparing high-purity irinotecan hydrochloride. This method prepares irinotecan under mild conditions, which not only improves the safety of operation, but also improves the yield and purity of irinotecan hydrochloride.

[0007] The technical solution adopted to achieve the above-mentioned objectives of this invention is as follows: A method for preparing high-purity irinotecan hydrochloride includes the following steps: S1. Mix 2-methyltetrahydrofuran and polyethylene glycol evenly to obtain a mixed solvent. Add [the following to the mixed solvent] 7-Ethyl-10-hydroxycamptothecin and triethylamine were stirred until the solid was completely dissolved, yielding a clear mixed solution; S2. At room temperature, 4-piperidinylpiperidine and N,N'-carbonyldiimidazole are added sequentially to the mixed solution, and then the mixture is stirred at room temperature for 0.5-1 h to obtain an intermediate solution. S3. Add polystyrene-supported DMAP to the intermediate solution, and then continue stirring at room temperature for 1-3 hours. S4. After the reaction is complete, filter the resulting mixed solution, add citric acid solution to the filtrate, stir evenly, let stand to separate the layers, take the organic phase and wash the organic phase with saturated brine, take the organic phase again and dry it with anhydrous sodium sulfate, concentrate the dried organic phase to dryness. S5. Dissolve the residue obtained in S4 in anhydrous ethanol, then add hydrochloric acid ethanol solution dropwise to adjust the pH to 1.5~2.0. Then, slowly add methyl tert-butyl ether dropwise while stirring. Precipitation begins to appear. After the precipitation is complete, filter, wash and dry the filter cake to obtain high-purity irinotecan hydrochloride.

[0008] Furthermore, the volume of the polyethylene glycol is 2%-5% of that of 2-methyltetrahydrofuran, and the volume-to-mass ratio of 2-methyltetrahydrofuran to 7-ethyl-10-hydroxycamptothecin is 10-20 mL / g.

[0009] Furthermore, the molar ratio of 7-ethyl-10-hydroxycamptothecin, 4-piperidinylpiperidine, and N,N'-carbonyldiimidazole is 1:1-2:1-2.

[0010] Furthermore, the polystyrene-supported DMAP contains 5-15% of the mass of 7-ethyl-10-hydroxycamptothecin.

[0011] Furthermore, the molar ratio of triethylamine to 7-ethyl-10-hydroxycamptothecin is 1-1.6:1.

[0012] Furthermore, in step S2, N,N'-carbonyldiimidazole is added in batches.

[0013] Furthermore, in step S4, the obtained filter cake is rinsed with 2-methyltetrahydrofuran, then washed with methanol, and finally dried for recycling.

[0014] Furthermore, in step S5, after the methyl tert-butyl ether is added dropwise, the resulting mixture is placed at 0~5°C and allowed to stand overnight to crystallize.

[0015] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows: 1. This invention uses 2-methyltetrahydrofuran as the main solvent and polyethylene glycol as the co-solvent. It utilizes 2-methyltetrahydrofuran as a green and stable main solvent to replace highly toxic dichloromethane or DMF. Combined with the unique solubilizing properties of polyethylene glycol, it effectively solves the problem of heterogeneous reaction caused by the poor solubility of SN38. While significantly improving the acylation efficiency, it inhibits the side reaction of lactone ring hydrolysis and achieves efficient recovery by taking advantage of the characteristics of the solvent system.

[0016] 2. This invention uses PS-DMAP as a catalyst and triethylamine as a base. PS-DMAP, as a supported nucleophilic catalyst, not only significantly accelerates the reaction rate but, more importantly, utilizes its insolubility to achieve complete catalyst separation and recycling via simple filtration after the reaction, eliminating DMAP residue at the source. Triethylamine not only maintains the catalyst's free base activity but, crucially, utilizes its organic salt solubility in water to completely remove byproducts via simple water washing in the post-treatment stage, avoiding the cumbersome problem of inorganic salt filtration at the process level. The combination of PS-DMAP and triethylamine ensures both high efficiency and mildness of the reaction while solving the pain points of difficult catalyst removal and cumbersome post-treatment in traditional processes, making it an ideal choice that balances high yield and high purity.

[0017] 3. This invention uses citric acid for post-treatment purification. Using citric acid for purification utilizes acid-base neutralization to convert residual triethylamine and imidazole in the system into highly water-soluble organic ammonium salts. These alkaline impurities can then be effectively removed by water washing or aqueous phase extraction, while avoiding the introduction of additional inorganic salts and reducing the burden of post-treatment. More importantly, citric acid, as a mild organic weak acid, not only controls the pH of the system within a suitable range to inhibit the base-catalyzed ring-opening of the lactone ring, but also utilizes its chelating effect to complex any trace metal ions that may be present in the system, thereby improving the purity of irinotecan hydrochloride. Detailed Implementation

[0018] To facilitate understanding and implementation of the present invention by those skilled in the art, the present invention will be further described in detail below with reference to embodiments. It should be understood that the embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0019] Example 1

[0020] 1. In a dry 500 mL three-necked flask, add 150 mL of 2-methyltetrahydrofuran, start stirring, add 4.5 mL of PEG-400, stir until homogeneous to obtain a mixed solvent, add 10.0 g of 7-ethyl-10-hydroxycamptothecin and 4.3 mL of triethylamine to the mixed solvent in sequence, stir until the solid is completely dissolved to obtain a clear mixed solution; 2. At room temperature, add 4.5 g of 4-piperidinylpiperidine to the mixed solution at once, followed by adding 4.36 g of N,N'-carbonyldiimidazole in batches. After the N,N'-carbonyldiimidazole is added, continue stirring the reaction at room temperature for 45 minutes to obtain an active acylimidazole intermediate solution. 3. Add 1.0 g of PS-DMAP solid to the intermediate solution, and then continue stirring at room temperature for 2 h. The reaction is terminated when the normalized concentration of 7-ethyl-10-hydroxycamptothecin is less than 1% as determined by HPLC.

[0021] 4. After the reaction is complete, filter the resulting mixed solution through a funnel while it is still hot. Rinse the filter cake with a small amount of 2-methyltetrahydrofuran (about 20 mL), then wash with methanol. After drying, it can be reused for the next batch. Combine the filtrates and transfer them to a separatory funnel. Add 100 mL of 0.05 g / mL citric acid solution, shake vigorously for 10 minutes, and then allow it to stand to separate the layers. Discard the lower aqueous phase. Take the organic phase and wash it with 100 mL of saturated saline to remove residual acid and PEG-400. Separate the organic phase (upper layer), place it in a drying conical flask, add an appropriate amount of anhydrous sodium sulfate, and dry for 15 minutes. Filter to remove the desiccant. Transfer the filtrate to a rotary evaporator and concentrate it to dryness under reduced pressure at 45 °C to obtain a pale yellow foamy solid.

[0022] 5. Add the pale yellow, foamy solid to 80 mL of anhydrous ethanol and dissolve it by gentle heating. Then, add hydrochloric acid ethanol solution dropwise to adjust the pH to 1.5-2.0. Subsequently, slowly add 200 mL of methyl tert-butyl ether dropwise while stirring. Precipitation begins to appear. After the addition of methyl tert-butyl ether is complete, place the mixture in a 0°C refrigerator and allow it to crystallize overnight. Filter the mixture, wash the filter cake with a cold ethanol / ether mixture, and finally dry it under vacuum at 40°C to constant weight to obtain 16.20 g of off-white solid irinotecan hydrochloride, with a yield of 87.8% and a purity of 99.9%.

[0023] Comparative Example 1 1. In a dry 500 mL three-necked flask, add 150 mL of 2-methyltetrahydrofuran, start stirring, and after stirring evenly, add 10.0 g of 7-ethyl-10-hydroxycamptothecin and 4.3 mL of triethylamine in sequence, and stir until the solid is completely dissolved to obtain a clear mixed solution. 2. At room temperature, add 4.5 g of 4-piperidinylpiperidine to the mixed solution at once, followed by adding 4.36 g of N,N'-carbonyldiimidazole in batches. After the N,N'-carbonyldiimidazole is added, continue stirring the reaction at room temperature for 45 minutes to obtain an active acylimidazole intermediate solution. 3. Add 1.0 g of PS-DMAP solid to the intermediate solution, and then continue stirring at room temperature for 2 h. The reaction is terminated when the normalized concentration of 7-ethyl-10-hydroxycamptothecin is less than 1% as determined by HPLC.

[0024] 4. After the reaction is complete, filter the resulting mixed solution through a funnel while it is still hot. Rinse the filter cake with a small amount of 2-methyltetrahydrofuran (about 20 mL), then wash with methanol. After drying, it can be reused for the next batch. Combine the filtrates and transfer them to a separatory funnel. Add 100 mL of 0.05 g / mL citric acid solution, shake vigorously for 10 minutes, and then allow it to stand for separation. Discard the lower aqueous phase. Take the organic phase and wash it with 100 mL of saturated saline to remove residual acid and PEG-400. Separate the organic phase (upper layer), place it in a drying conical flask, add an appropriate amount of anhydrous sodium sulfate, and dry for 15 minutes. Filter to remove the desiccant. Transfer the filtrate to a rotary evaporator and concentrate it to dryness under reduced pressure at 45 °C to obtain a pale yellow foamy solid.

[0025] 5. Add the pale yellow, foamy solid to 80 mL of anhydrous ethanol and dissolve it by gentle heating. Then, add hydrochloric acid ethanol solution dropwise to adjust the pH to 1.5-2.0. Subsequently, slowly add 200 mL of methyl tert-butyl ether dropwise while stirring. Precipitation begins to appear. After the addition of methyl tert-butyl ether is complete, place the mixture in a 0°C refrigerator and allow it to stand overnight to crystallize. Filter the mixture, wash the filter cake with a cold ethanol / ether mixture, and finally dry it under vacuum at 40°C to constant weight to obtain 12.88 g of pale yellow solid irinotecan hydrochloride, with a yield of 72.6% and a purity of 92.3%.

[0026] Comparative Example 2 1. In a dry 500 mL three-necked flask, add 150 mL of 2-methyltetrahydrofuran, start stirring, add 4.5 mL of PEG-400, stir until homogeneous to obtain a mixed solvent, add 10.0 g of 7-ethyl-10-hydroxycamptothecin and 4.27 g of potassium carbonate to the mixed solvent in sequence, stir until the solid is completely dissolved to obtain a clear mixed solution; 2. At room temperature, add 4.5 g of 4-piperidinylpiperidine to the mixed solution at once, followed by adding 4.36 g of N,N'-carbonyldiimidazole in batches. After the N,N'-carbonyldiimidazole is added, continue stirring the reaction at room temperature for 45 minutes to obtain an active acylimidazole intermediate solution. 3. Add 1.0 g of PS-DMAP solid to the intermediate solution, and then continue stirring at room temperature for 2 h. The reaction is terminated when the normalized concentration of 7-ethyl-10-hydroxycamptothecin is less than 1% as determined by HPLC.

[0027] 4. After the reaction is complete, filter the resulting mixed solution while hot through a funnel. Rinse the filter cake with a small amount of 2-methyltetrahydrofuran (about 20 mL), then wash with methanol. After drying, it can be reused for the next batch. Combine the filtrates and transfer them to a separatory funnel. Add 100 mL of 0.05 g / mL citric acid solution, shake vigorously for 10 minutes, and then allow to stand for separation. Discard the lower aqueous phase. Take the organic phase and wash it with 100 mL of saturated saline to remove residual acid and PEG-400. Separate the organic phase (upper layer), place it in a drying conical flask, add an appropriate amount of anhydrous sodium sulfate, and dry for 15 minutes. Filter to remove the desiccant. Transfer the filtrate to a rotary evaporator and concentrate it to dryness under reduced pressure at 45°C to obtain a pale yellow foamy solid.

[0028] 5. Add the pale yellow, foamy solid to 80 mL of anhydrous ethanol and dissolve it by gentle heating. Then, add hydrochloric acid ethanol solution dropwise to adjust the pH to 1.5-2.0. Subsequently, slowly add 200 mL of methyl tert-butyl ether dropwise while stirring. Precipitation begins to appear. After the addition of methyl tert-butyl ether is complete, place the mixture in a 0°C refrigerator and allow it to crystallize overnight. Filter the mixture, wash the filter cake with a cold ethanol / ether mixture, and finally dry it under vacuum at 40°C to constant weight to obtain 10.97 g of pale yellow solid irinotecan hydrochloride, with a yield of 63.5% and a purity of 90.1%.

[0029] Comparative Example 3 1. In a dry 500 mL three-necked flask, add 150 mL of 2-methyltetrahydrofuran, start stirring, add 4.5 mL of PEG-400, stir until homogeneous to obtain a mixed solvent, add 10.0 g of 7-ethyl-10-hydroxycamptothecin and 4.3 mL of triethylamine to the mixed solvent in sequence, stir until the solid is completely dissolved to obtain a clear mixed solution; 2. At room temperature, 4.93 g of 4-piperidinylpiperidine was added to the mixed solution at once, followed by 4.96 g of N,N'-carbonyldiimidazole in batches. After the N,N'-carbonyldiimidazole was added, the reaction was stirred at room temperature for 45 minutes to obtain an active acylimidazole intermediate solution. 3. Add 1.0 g of PS-DMAP solid to the intermediate solution, and then continue stirring at room temperature for 2 h. The reaction is terminated when the normalized concentration of 7-ethyl-10-hydroxycamptothecin is less than 1% as determined by HPLC.

[0030] 4. After the reaction is complete, filter the resulting mixed solution through a funnel while it is still hot. Rinse the filter cake with a small amount of 2-methyltetrahydrofuran (about 20 mL), then wash with methanol. After drying, it can be reused for the next batch. Combine the filtrates and transfer them to a separatory funnel. Add 100 mL of 5% hydrochloric acid solution, shake vigorously for 10 minutes, and then allow it to stand to separate the layers. Discard the lower aqueous phase. Take the organic phase and wash it with 100 mL of saturated saline solution to remove residual acid and PEG-400. Separate the organic phase (upper layer), place it in a drying conical flask, add an appropriate amount of anhydrous sodium sulfate, and dry for 15 minutes. Filter to remove the desiccant. Transfer the filtrate to a rotary evaporator and concentrate it to dryness under reduced pressure at 45°C to obtain a pale yellow foamy solid.

[0031] 5. Add the pale yellow, foamy solid to 80 mL of anhydrous ethanol and dissolve it by gentle heating. Then, add hydrochloric acid ethanol solution dropwise to adjust the pH to 1.5-2.0. Subsequently, slowly add 200 mL of methyl tert-butyl ether dropwise while stirring. Precipitation begins to appear. After the addition of methyl tert-butyl ether is complete, place the mixture in a 0°C refrigerator and allow it to crystallize overnight. Filter the mixture, wash the filter cake with a cold ethanol / ether mixture, and finally dry it under vacuum at 40°C to constant weight to obtain 14.61 g of off-white solid irinotecan hydrochloride, with a yield of 79.6% and a purity of 95.4%.

[0032] Example 2

[0033] 1. In a dry 500 mL three-necked flask, add 150 mL of 2-methyltetrahydrofuran, start stirring, add 4.5 mL of PEG-400, stir until homogeneous to obtain a mixed solvent, add 10.0 g of 7-ethyl-10-hydroxycamptothecin and 4.3 mL of triethylamine to the mixed solvent in sequence, stir until the solid is completely dissolved to obtain a clear mixed solution; 2. At room temperature, 4.93 g of 4-piperidinylpiperidine was added to the mixed solution at once, followed by 4.96 g of N,N'-carbonyldiimidazole in batches. After the N,N'-carbonyldiimidazole was added, the reaction was stirred at room temperature for 45 minutes to obtain an active acylimidazole intermediate solution. 3. Add 1.0 g of PS-DMAP solid to the intermediate solution, and then continue stirring at room temperature for 2 h. The reaction is terminated when the normalized concentration of 7-ethyl-10-hydroxycamptothecin is less than 1% as determined by HPLC.

[0034] 4. After the reaction is complete, filter the resulting mixed solution through a funnel while it is still hot. Rinse the filter cake with a small amount of 2-methyltetrahydrofuran (about 20 mL), then wash with methanol. After drying, it can be reused for the next batch. Combine the filtrates and transfer them to a separatory funnel. Add 100 mL of 0.05 g / mL citric acid solution, shake vigorously for 10 minutes, and allow to stand for separation. Discard the lower aqueous phase. Add another 50 mL of 0.05 g / mL citric acid solution to the separatory funnel, shake vigorously again for 10 minutes, allow to stand for separation, and discard the lower aqueous phase. Combine the two organic phases and wash the organic phase with 100 mL of saturated saline to remove residual acid and PEG-400. Separate the organic phase (upper layer), place it in a drying conical flask, add an appropriate amount of anhydrous sodium sulfate, and dry for 15 minutes. Filter to remove the desiccant. Transfer the filtrate to a rotary evaporator and concentrate under reduced pressure at 45 °C to dryness to obtain a pale yellow foamy solid.

[0035] 5. Add the pale yellow, foamy solid to 80 mL of anhydrous ethanol and dissolve it by gentle heating. Then, add hydrochloric acid ethanol solution dropwise to adjust the pH to 1.5-2.0. Subsequently, slowly add 200 mL of methyl tert-butyl ether dropwise while stirring. Precipitation begins to appear. After the addition of methyl tert-butyl ether is complete, place the mixture in a 0°C refrigerator and allow it to crystallize overnight. Filter the mixture, wash the filter cake with a cold ethanol / ether mixture, and finally dry it under vacuum at 40°C to constant weight to obtain 14.61 g of off-white solid irinotecan hydrochloride, with a yield of 88.2% and a purity of 99.9%.

Claims

1. A method for preparing high-purity irinotecan hydrochloride, characterized in that... Includes the following steps: S1. Mix 2-methyltetrahydrofuran and polyethylene glycol evenly to obtain a mixed solvent. Add [the following to the mixed solvent] 7-Ethyl-10-hydroxycamptothecin and triethylamine were stirred until the solid was completely dissolved, yielding a clear mixed solution; S2. At room temperature, 4-piperidinylpiperidine and N,N'-carbonyldiimidazole are added sequentially to the mixed solution, and then the mixture is stirred at room temperature for 0.5-1 h to obtain an intermediate solution. S3. Add polystyrene-supported 4-dimethylaminopyridine to the intermediate solution, and then continue stirring at room temperature for 1-3 hours. S4. After the reaction is complete, filter the resulting mixed solution, add citric acid solution to the filtrate, stir evenly, let stand to separate the layers, take the organic phase and wash the organic phase with saturated brine, take the organic phase again and dry it with anhydrous sodium sulfate, concentrate the dried organic phase to dryness. S5. Dissolve the residue obtained in S4 in anhydrous ethanol, then add hydrochloric acid ethanol solution dropwise to adjust the pH to 1.5-2.

0. Then, slowly add methyl tert-butyl ether dropwise while stirring. Precipitation begins to appear. After the precipitation is complete, filter, wash and dry the filter cake to obtain high-purity irinotecan hydrochloride.

2. The method for preparing high-purity irinotecan hydrochloride according to claim 1, characterized in that: The volume of the polyethylene glycol is 2%-5% of that of 2-methyltetrahydrofuran, and the volume-to-mass ratio of 2-methyltetrahydrofuran to 7-ethyl-10-hydroxycamptothecin is 10-20 mL / g.

3. The method for preparing high-purity irinotecan hydrochloride according to claim 1, characterized in that: The molar ratio of 7-ethyl-10-hydroxycamptothecin, 4-piperidinylpiperidine, and N,N'-carbonyldiimidazole is 1:1-2:1-2.

4. The method for preparing high-purity irinotecan hydrochloride according to claim 1, characterized in that: The polystyrene-supported DMAP contains 5-15% of the mass of 7-ethyl-10-hydroxycamptothecin.

5. The method for preparing high-purity irinotecan hydrochloride according to claim 1, characterized in that: The molar ratio of triethylamine to 7-ethyl-10-hydroxycamptothecin is 1-1.6:

1.

6. The method for preparing high-purity irinotecan hydrochloride according to claim 1, characterized in that: In step S2, N,N'-carbonyldiimidazole is added in batches.

7. The method for preparing high-purity irinotecan hydrochloride according to claim 1, characterized in that: In step S4, the obtained filter cake is rinsed with 2-methyltetrahydrofuran, then washed with methanol, and finally dried for recycling.

8. The method for preparing high-purity irinotecan hydrochloride according to claim 1, characterized in that: In step S5, after the methyl tert-butyl ether is added dropwise, the resulting mixture is left to stand at 0-5°C overnight to crystallize.