Production and preparation method of erlotinib intermediate
By optimizing the synthetic route of erlotinib intermediates and using composite catalysts for continuous cyclization in a fixed-bed reactor, the problems of lengthy reaction steps, harsh conditions, and safety hazards in existing technologies have been solved, enabling efficient and environmentally friendly large-scale production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ANHUI JIANFENG NORTH CAROLINA PHARM CO LTD
- Filing Date
- 2026-03-02
- Publication Date
- 2026-05-19
AI Technical Summary
Existing synthetic routes for erlotinib suffer from lengthy reaction steps, harsh conditions, insufficient safety, and unsatisfactory product purity. In particular, the nitration step is prone to explosion and frequent side reactions, making it difficult to meet the requirements for large-scale drug production.
A four-step reaction process of etherification, oxidation, nitration and continuous cyclization is adopted. Combined with a specific reaction solvent and buffer system, a composite catalyst is used to carry out continuous cyclization in a fixed bed reactor. The active components are loaded with magnetic microspheres and functionalized core-shell materials to achieve efficient recovery and reuse of the catalyst.
It significantly improves reaction efficiency and product purity, reduces separation and purification difficulty and waste treatment costs, and ensures the safety and stability of the production process, providing an efficient and environmentally friendly solution for the large-scale production of erlotinib intermediates.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, and more specifically, to a method for producing an intermediate of erlotinib. Background Technology
[0002] Erlotinib, marketed as Tarceva, is a highly potent epidermal growth factor receptor tyrosine kinase inhibitor. As a targeted anti-tumor drug, it is widely used in the treatment of non-small cell lung cancer. Its chemical structure features a quinazoline core ring with specific functional groups attached to the side chains. This structural characteristic dictates that the key to its synthetic route design lies in the construction method of the quinazoline ring. Currently, there are multiple synthetic routes for erlotinib, but they all face common challenges such as lengthy reaction steps, harsh conditions, insufficient safety, or unsatisfactory product purity, which restrict the efficiency and economy of large-scale production.
[0003] In known synthetic processes, a common route uses ethyl 3,4-dihydroxybenzoate or similar derivatives as starting materials, proceeding through multiple steps including nitration, reduction, cyclization, chlorination, and amination. However, the nitration step, as a critical initial reaction, has a decisive impact on the overall process yield and cost control due to its selectivity, conversion rate, and safety. Traditional nitration methods often employ a mixed acid system composed of concentrated nitric acid and concentrated sulfuric acid. This system carries a significant risk of exothermic reactions, especially in batch reactors. If stirring stops due to power outages or other abnormalities, explosions can easily occur due to localized overheating or uneven mixing, posing a significant safety hazard. Furthermore, the mixed acid system easily leads to the hydrolysis of sensitive functional groups during nitration, increasing side reactions. This not only reduces the yield and purity of the target product but also increases the difficulty of subsequent separation and purification, as well as the cost of waste treatment.
[0004] Another synthetic strategy involves using 4,5-bis(2-methoxyethoxy)-2-nitrobenzenenitrile as a key intermediate, constructing a quinazoline ring through reduction and cyclization steps. Although this route avoids the risk of mixed acid nitration to some extent, the subsequent cyclization reaction usually requires a formamidinium intermediate, making the steps relatively cumbersome and often dependent on expensive catalysts or high-temperature conditions. This results in poor atom economy and is detrimental to cost control and environmental friendliness. Particularly in the cyclization step, traditional batch reactors suffer from low mass and heat transfer efficiency, long reaction times, and numerous byproducts, making it difficult to meet the stringent requirements for large-scale pharmaceutical production in terms of purity and yield of the final product, 6,7-bis(2-methoxyethoxy)-4-quinazolinone. Therefore, this invention provides a method for producing an erlotinib intermediate to solve the aforementioned technical problems. Summary of the Invention
[0005] The purpose of this invention is to provide a method for the production of erlotinib intermediates. The raw materials are readily available. By optimizing the synthetic route and reaction conditions, the reaction efficiency and product purity are significantly improved, providing a new, efficient, environmentally friendly, and stable method for the large-scale production of key erlotinib intermediates.
[0006] This invention provides a method for producing an intermediate of erlotinib, using the following technical solution:
[0007] S1. 3,4-Dihydroxybenzaldehyde and 2-methoxyethyl p-toluenesulfonate were dispersed in a polar aprotic solvent, potassium carbonate and tert-butylammonium bromide were added, and the mixture was reacted at 70-80℃ and 300-350rpm for 8-10h under nitrogen protection. After cooling to room temperature, the mixture was diluted with ice water, extracted, washed, dried and concentrated under reduced pressure to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde.
[0008] S2. Dissolve the product obtained in S1 in a mixed solvent of tert-butanol and acetonitrile. Prepare a buffer solution composed of sodium chlorite and sodium dihydrogen phosphate dissolved in water. Slowly add the buffer solution to the reaction system at 20-25℃ and stir for 6-8 hours. Quench the reaction with saturated sodium sulfite solution, distill under reduced pressure, adjust the pH to 2-3, and obtain the intermediate acid by extraction, drying and concentration.
[0009] S3. Dissolve the intermediate acid obtained in S2 in glacial acetic acid, heat to 60-70℃, add concentrated nitric acid in batches at 350-400 rpm for 1 hour, keep the reaction at this temperature for 3-4 hours, cool to room temperature, slowly pour the reaction solution into ice water, and precipitate a yellow solid. After filtration, washing, and recrystallization, 2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid is obtained.
[0010] S4. The product obtained in S3 and formamide are dissolved in γ-valerol to form material stream A. Formic acid and triethylamine are dissolved in γ-valerol to form material stream B. The two material streams are preheated to 90-110℃ and continuously fed into a fixed-bed reactor packed with composite catalyst at a volume ratio of A:B=1:(0.7-0.8). The reactor is held at 130-140℃ and 1.0-2.0MPa for 2-3 hours. The reaction effluent is separated from the composite catalyst by a magnetic field and cooled to 5-10℃ at a programmed rate of 5°C / h to crystallize, yielding 6,7-bis(2-methoxyethoxy)-4-quinazolinone.
[0011] The specific reaction route is as follows:
[0012]
[0013] Preferably, the preparation step of the composite catalyst in step S4 is as follows:
[0014] A1. Dissolve ferric chloride and ferrous chloride in deionized water, heat to 60-80℃ under nitrogen protection, add 25-28wt% ammonia water dropwise at 400-500rpm and 2-5mL / min to adjust the pH to 10-11, react at a constant temperature for 1-1.5h, then separate, wash, and re-disperse in anhydrous ethanol by ultrasonication, add ammonia water and tetraethyl orthosilicate, continue the reaction for 12-24h, then separate, wash, and vacuum dry to obtain magnetic microspheres;
[0015] A2. Magnetic microspheres are dispersed in N,N-dimethylformamide, zirconium tetrachloride, 2-aminoterephthalic acid and acetic acid are added, and the mixture is reacted at 120-125℃ for 20-24h. After magnetic separation, washing and vacuum drying, the core-shell material is obtained.
[0016] A3. Disperse the core-shell material in methanol, add sodium chloropalladium aqueous solution, stir and adsorb at room temperature for 10-12 h, slowly add sodium borohydride while stirring, continue the reaction for 1.5-2 h, and then separate, wash and vacuum dry to obtain the composite catalyst.
[0017] Preferably, in step S1, the components by weight are 10-15 parts of 3,4-dihydroxybenzaldehyde, 34-38 parts of 2-methoxyethyl p-toluenesulfonate, 50-60 parts of polar aprotic solvent, 8-10 parts of potassium carbonate, and 0.2-0.4 parts of tert-butylammonium bromide.
[0018] Preferably, the polar aprotic solvent in step S1 is at least one of N,N-dimethylformamide and N,N-dimethylacetamide.
[0019] Preferably, in step S2, the ingredients are 40-50 parts by weight of tert-butanol, 20-25 parts of acetonitrile, 3-4 parts of sodium chlorite, 8-10 parts of sodium dihydrogen phosphate, and 20-30 parts of water.
[0020] Preferably, step S3 comprises 40-50 parts by weight of glacial acetic acid and 6-8 parts by weight of concentrated nitric acid.
[0021] Preferably, in step S4, the weight parts and proportions of the components of material stream A and material stream B are as follows: material stream A contains 18-22 parts of formamide and 30-35 parts of γ-valerolactone; material stream B contains 5-8 parts of formic acid, 10-12 parts of triethylamine and 20-25 parts of γ-valerolactone; and the volume ratio of material stream A to material stream B is 1:(0.7-0.8).
[0022] Preferably, in step A1, the components by weight are 5-6 parts ferric chloride, 2-3 parts ferrous chloride, 75-80 parts deionized water, 40-45 parts anhydrous ethanol, 1-3 parts ammonia water, and 2-5 parts tetraethyl orthosilicate.
[0023] Preferably, step A2 comprises, by weight, 1-3 parts magnetic microspheres, 20-25 parts N,N-dimethylformamide, 0.8-1.2 parts zirconium tetrachloride, 0.6-0.8 parts 2-aminoterephthalic acid, and 1.5-2.0 parts acetic acid.
[0024] Preferably, step A3 comprises, by weight, 1-3 parts core-shell material, 20-25 parts methanol, 10-15 parts 1.2-1.5%wt sodium chloropalladium aqueous solution and 0.03-0.05 parts sodium borohydride.
[0025] In summary, the present invention has the following beneficial effects:
[0026] 1. This invention optimizes the synthetic route of erlotinib intermediates, constructing the core structure of the target product through four steps: etherification, oxidation, nitration, and continuous cyclization, using readily available starting materials. The reaction steps are synergistically matched to form a complete and efficient synthetic process. This process effectively solves the problems of lengthy synthetic steps, harsh reaction conditions, frequent side reactions, and difficulty in product separation and purification in existing technologies through precise design of the reaction path and rational control of the reaction system. By selecting specific reaction solvents and introducing buffer systems, the reaction selectivity is significantly improved, byproduct generation is reduced, and the subsequent separation and purification load and waste treatment costs are greatly reduced. At the same time, the overall process is simple to operate and controllable, avoiding the safety hazards present in traditional processes, ensuring the stability and safety of the production process, laying a solid foundation for the large-scale production of intermediates, and possessing both good economic efficiency and practicality.
[0027] 2. This invention prepares a composite catalyst with a specific structure and combines it with a fixed-bed reactor to achieve continuous cyclization reactions, forming a synergistic system between the catalyst and the reactor. This composite catalyst uses magnetic microspheres as the core and functionalized core-shell materials as supports to load the active components. Utilizing magnetic separation properties, it achieves efficient catalyst recovery and reuse, effectively solving problems in existing technologies such as difficulty in catalyst separation, low reuse rates, and the potential for resource waste and environmental pollution. Simultaneously, the synergistic effect of the catalyst components significantly enhances the catalytic activity and selectivity of the cyclization reaction, ensuring high purity and high yield of the target product. Detailed Implementation
[0028] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.
[0029] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the experimental materials used, unless otherwise specified, were all purchased from conventional biochemical reagent stores. All quantitative experiments in the following examples were performed in triplicate, and the data are the average of the three replicates or the average ± standard deviation.
[0030] Example 1
[0031] This embodiment provides a method for producing an intermediate of erlotinib, using the following technical solution:
[0032] S1. Disperse 10 parts of 3,4-dihydroxybenzaldehyde and 34 parts of 2-methoxyethyl p-toluenesulfonate in 50 parts of N,N-dimethylformamide, add 8 parts of potassium carbonate and 0.2 parts of tert-butylammonium bromide, react at 70°C and 300 rpm for 10 h under nitrogen protection, cool to room temperature, dilute with ice water, extract, wash, dry and concentrate under reduced pressure to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde;
[0033] S2. Dissolve the product obtained in S1 in a mixed solvent of 40 parts tert-butanol and 20 parts acetonitrile. Separately prepare a buffer solution consisting of 3 parts sodium chlorite, 8 parts sodium dihydrogen phosphate dissolved in 20 parts water. Slowly add the buffer solution to the reaction system at 20°C and stir at 300 rpm for 8 hours. Quench the reaction with saturated sodium sulfite solution, distill under reduced pressure, adjust the pH to 2, and obtain the intermediate acid by extraction, drying and concentration.
[0034] S3. Dissolve the intermediate acid obtained in S2 in 40 parts of glacial acetic acid, heat to 60℃, add 6 parts of concentrated nitric acid in batches at 350 rpm for 1 h, keep the reaction at this temperature for 4 h, cool to room temperature, slowly pour the reaction solution into ice water, and precipitate a yellow solid. After filtration, washing, and recrystallization, 2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid is obtained.
[0035] S4. The product obtained in S3 and 18 parts of formamide were dissolved in 30 parts of γ-valerol to form material stream A. 5 parts of formic acid and 10 parts of triethylamine were dissolved in 20 parts of γ-valerol to form material stream B. The two material streams were preheated to 90°C and continuously fed into a fixed-bed reactor packed with a composite catalyst at a volume ratio of A:B=1:0.7. The reactor was held at 130°C and 1.0 MPa for 3 hours. The reaction effluent was separated from the composite catalyst by a magnetic field and cooled to 10°C at a programmed rate of 5°C / h to crystallize, yielding 6,7-bis(2-methoxyethoxy)-4-quinazolinone.
[0036] The preparation step of the composite catalyst in step S4 is as follows:
[0037] A1. Dissolve 5 parts of ferric chloride and 2 parts of ferrous chloride in 75 parts of deionized water. Under nitrogen protection, heat to 60℃ and adjust the pH to 10 by adding 25wt% ammonia water dropwise at 400rpm and 2mL / min. After reacting at a constant temperature for 1.5h, separate and wash, then re-disperse in 40 parts of anhydrous ethanol by ultrasonication. Add 1 part of ammonia water and 2 parts of tetraethyl orthosilicate and continue reacting for 24h. After separation, washing and vacuum drying, obtain magnetic microspheres.
[0038] A2. Disperse 1 part of magnetic microspheres in 20 parts of N,N-dimethylformamide, add 0.8 parts of zirconium tetrachloride, 0.6 parts of 2-aminoterephthalic acid and 1.5 parts of acetic acid, react at 120℃ for 24 h, and then obtain the core-shell material by magnetic separation, washing and vacuum drying.
[0039] A3. Disperse 1 part of core-shell material in 20 parts of methanol, add 10 parts of 1.5% wt sodium chloropalladium aqueous solution, stir and adsorb at room temperature for 12 h, slowly add 0.03 parts of sodium borohydride while stirring, continue to react for 2 h, and then obtain the composite catalyst by separation, washing and vacuum drying.
[0040] Example 2
[0041] This embodiment provides a method for producing an intermediate of erlotinib, using the following technical solution:
[0042] S1. 12 parts of 3,4-dihydroxybenzaldehyde and 35 parts of 2-methoxyethyl p-toluenesulfonate were dispersed in 52 parts of N,N-dimethylformamide, 9 parts of potassium carbonate and 0.3 parts of tert-butylammonium bromide were added, and the mixture was reacted at 72°C and 320 rpm for 9.8 h under nitrogen protection. After cooling to room temperature, the mixture was diluted with ice water, extracted, washed, dried and concentrated under reduced pressure to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde.
[0043] S2. Dissolve the product obtained in S1 in a mixed solvent of 42 parts tert-butanol and 22 parts acetonitrile. Separately prepare a buffer solution consisting of 3.2 parts sodium chlorite and 9 parts sodium dihydrogen phosphate dissolved in 22 parts water. Slowly add the buffer solution to the reaction system at 22°C and stir the reaction for 7.8 hours. Quench the reaction with saturated sodium sulfite solution, distill under reduced pressure, adjust the pH to 2.2, and obtain the intermediate acid by extraction, drying and concentration.
[0044] S3. Dissolve the intermediate acid obtained in S2 in 42 parts of glacial acetic acid, heat to 62℃, add 7 parts of concentrated nitric acid in batches at 360 rpm for 1 h, keep the reaction at this temperature for 3.8 h, cool to room temperature, slowly pour the reaction solution into ice water, and precipitate a yellow solid. After filtration, washing, and recrystallization, 2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid is obtained.
[0045] S4. The product obtained in S3 and 20 parts of formamide were dissolved in 31 parts of γ-valerol to form material stream A. 6 parts of formic acid and 11 parts of triethylamine were dissolved in 21 parts of γ-valerol to form material stream B. The two material streams were preheated to 92°C and continuously fed into a fixed-bed reactor packed with a composite catalyst at a volume ratio of A:B=1:0.72. The reactor was held at 132°C and 1.2MPa for 2.8h. The effluent was separated from the composite catalyst by a magnetic field and cooled to 8°C at a programmed rate of 5°C / h to crystallize, yielding 6,7-bis(2-methoxyethoxy)-4-quinazolinone.
[0046] The preparation step of the composite catalyst in step S4 is as follows:
[0047] A1. Dissolve 5.2 parts of ferric chloride and 2.3 parts of ferrous chloride in 76 parts of deionized water. Under nitrogen protection, heat to 65℃ and adjust the pH to 10.5 by adding 26wt% ammonia water dropwise at 420rpm and 3mL / min. After reacting at a constant temperature for 1.4h, separate and wash, then re-disperse in 41 parts of anhydrous ethanol by ultrasonication. Add 2 parts of ammonia water and 3 parts of tetraethyl orthosilicate and continue reacting for 20h. After separation, washing and vacuum drying, obtain magnetic microspheres.
[0048] A2. Two parts of magnetic microspheres were dispersed in 22 parts of N,N-dimethylformamide, and 0.9 parts of zirconium tetrachloride, 0.7 parts of 2-aminoterephthalic acid and 1.8 parts of acetic acid were added. After reacting at 121℃ for 23 h, the core-shell material was obtained by magnetic separation, washing and vacuum drying.
[0049] A3. Two parts of core-shell material were dispersed in 21 parts of methanol, and 12 parts of 1.4% wt sodium chloropalladium aqueous solution were added. The mixture was stirred and adsorbed at room temperature for 11 h. Then, 0.04 parts of sodium borohydride were slowly added while stirring, and the reaction was continued for 1.9 h. After separation, washing, and vacuum drying, the composite catalyst was obtained.
[0050] Example 3
[0051] This embodiment provides a method for producing an intermediate of erlotinib, using the following technical solution:
[0052] S1. 13 parts of 3,4-dihydroxybenzaldehyde and 35 parts of 2-methoxyethyl p-toluenesulfonate were dispersed in 55 parts of N,N-dimethylacetamide, 9 parts of potassium carbonate and 0.4 parts of tert-butylammonium bromide were added, and the mixture was reacted at 76°C and 340 rpm for 9.5 h under nitrogen protection. After cooling to room temperature, the mixture was diluted with ice water, extracted, washed, dried and concentrated under reduced pressure to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde.
[0053] S2. Dissolve the product obtained in S1 in a mixed solvent of 44 parts tert-butanol and 23 parts acetonitrile. Separately prepare a buffer solution consisting of 3.5 parts sodium chlorite and 9.4 parts sodium dihydrogen phosphate dissolved in 27 parts water. Slowly add the buffer solution to the reaction system at 23°C and stir the reaction for 7.2 hours. Quench the reaction with saturated sodium sulfite solution, distill under reduced pressure, adjust the pH to 2.5, and obtain the intermediate acid by extraction, drying and concentration.
[0054] S3. Dissolve the intermediate acid obtained in S2 in 46 parts of glacial acetic acid, heat to 65°C, add 7.5 parts of concentrated nitric acid in batches at 380 rpm for 1 h, keep the reaction at this temperature for 3.4 h, cool to room temperature, slowly pour the reaction solution into ice water, and precipitate a yellow solid. After filtration, washing, and recrystallization, 2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid is obtained.
[0055] S4. The product obtained in S3 and 21 parts of formamide were dissolved in 33 parts of γ-valerol to form material stream A. 6 parts of formic acid and 11 parts of triethylamine were dissolved in 24 parts of γ-valerol to form material stream B. The two material streams were preheated to 104°C and continuously fed into a fixed-bed reactor packed with a composite catalyst at a volume ratio of A:B=1:0.75. The reactor was held at 137°C and 1.6MPa for 2.6 hours. The effluent was separated from the composite catalyst by a magnetic field and cooled to 6°C at a programmed rate of 5°C / h to crystallize, yielding 6,7-bis(2-methoxyethoxy)-4-quinazolinone.
[0056] The preparation step of the composite catalyst in step S4 is as follows:
[0057] A1. Dissolve 5.7 parts of ferric chloride and 2.8 parts of ferrous chloride in 77 parts of deionized water. Under nitrogen protection, heat to 75℃ and adjust the pH to 10 by adding 27wt% ammonia water dropwise at 420rpm and 4mL / min. After reacting at a constant temperature for 1.2h, separate and wash, then re-disperse in 44 parts of anhydrous ethanol by ultrasonication. Add 2.5 parts of ammonia water and 4 parts of tetraethyl orthosilicate, and continue to react for 15h. After separation, washing, and vacuum drying, obtain magnetic microspheres.
[0058] A2. 2.7 parts of magnetic microspheres were dispersed in 23 parts of N,N-dimethylformamide, and 1.1 parts of zirconium tetrachloride, 0.7 parts of 2-aminoterephthalic acid and 1.9 parts of acetic acid were added. After reacting at 123℃ for 20h, the core-shell material was obtained by magnetic separation, washing and vacuum drying.
[0059] A3. Disperse 2.5 parts of core-shell material in 20 parts of methanol, add 13 parts of 1.3% wt sodium chloropalladium aqueous solution, stir and adsorb at room temperature for 10.5 h, slowly add 0.04 parts of sodium borohydride while stirring, continue the reaction for 1.7 h, and then obtain the composite catalyst by separation, washing and vacuum drying.
[0060] Example 4
[0061] This embodiment provides a method for producing an intermediate of erlotinib, using the following technical solution:
[0062] S1. 15 parts of 3,4-dihydroxybenzaldehyde and 38 parts of 2-methoxyethyl p-toluenesulfonate were dispersed in 60 parts of N,N-dimethylacetamide, 10 parts of potassium carbonate and 0.4 parts of tert-butylammonium bromide were added, and the mixture was reacted at 80°C and 350 rpm for 8 hours under nitrogen protection. After cooling to room temperature, the mixture was diluted with ice water, extracted, washed, dried and concentrated under reduced pressure to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde.
[0063] S2. Dissolve the product obtained in S1 in a mixed solvent of 50 parts tert-butanol and 25 parts acetonitrile. Separately prepare a buffer solution consisting of 4 parts sodium chlorite, 10 parts sodium dihydrogen phosphate dissolved in 30 parts water. Slowly add the buffer solution to the reaction system at 25°C and stir for 6 hours. Quench the reaction with saturated sodium sulfite solution, distill under reduced pressure, adjust the pH to 3, and obtain the intermediate acid by extraction, drying and concentration.
[0064] S3. Dissolve the intermediate acid obtained in S2 in 50 parts of glacial acetic acid, heat to 70℃, add 8 parts of concentrated nitric acid in batches at 400 rpm for 1 h, keep the reaction at this temperature for 3 h, cool to room temperature, slowly pour the reaction solution into ice water, and precipitate a yellow solid. After filtration, washing, and recrystallization, 2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid is obtained.
[0065] S4. The product obtained in S3 and 22 parts of formamide were dissolved in 35 parts of γ-valerol to form material stream A. 8 parts of formic acid and 12 parts of triethylamine were dissolved in 25 parts of γ-valerol to form material stream B. The two material streams were preheated to 110°C and continuously fed into a fixed-bed reactor packed with a composite catalyst at a volume ratio of A:B=1:0.8. The reactor was held at 140°C and 2.0 MPa for 2 hours. The effluent was separated from the composite catalyst by a magnetic field and cooled to 5°C at a programmed rate of 5°C / h to crystallize, yielding 6,7-bis(2-methoxyethoxy)-4-quinazolinone.
[0066] The preparation step of the composite catalyst in step S4 is as follows:
[0067] A1. Dissolve 6 parts of ferric chloride and 3 parts of ferrous chloride in 80 parts of deionized water. Under nitrogen protection, heat to 80℃ and adjust the pH to 11 by adding 28wt% ammonia water dropwise at 500rpm and 5mL / min. After reacting at a constant temperature for 1h, separate and wash, then re-disperse in 45 parts of anhydrous ethanol by ultrasonication. Add 3 parts of ammonia water and 5 parts of tetraethyl orthosilicate and continue reacting for 12h. After separation, washing and vacuum drying, obtain magnetic microspheres.
[0068] A2. Three parts of magnetic microspheres were dispersed in 25 parts of N,N-dimethylformamide, and 1.2 parts of zirconium tetrachloride, 0.8 parts of 2-aminoterephthalic acid and 2.0 parts of acetic acid were added. After reacting at 125°C for 20 h, the core-shell material was obtained by magnetic separation, washing and vacuum drying.
[0069] A3. Disperse 3 parts of core-shell material in 25 parts of methanol, add 15 parts of 1.2% wt sodium chloropalladium aqueous solution, stir and adsorb at room temperature for 10 h, slowly add 0.05 parts of sodium borohydride while stirring, continue to react for 1.5 h, and then obtain the composite catalyst by separation, washing and vacuum drying.
[0070] Example 5
[0071] This embodiment provides a method for producing an intermediate of erlotinib, using the following technical solution:
[0072] S1. 15 parts of 3,4-dihydroxybenzaldehyde and 38 parts of 2-methoxyethyl p-toluenesulfonate were dispersed in 60 parts of N,N-dimethylformamide, 9 parts of potassium carbonate and 0.3 parts of tert-butylammonium bromide were added, and the mixture was reacted at 80°C and 350 rpm for 8 hours under nitrogen protection. After cooling to room temperature, the mixture was diluted with ice water, extracted, washed, dried and concentrated under reduced pressure to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde.
[0073] S2. Dissolve the product obtained in S1 in a mixed solvent of 50 parts tert-butanol and 20 parts acetonitrile. Separately prepare a buffer solution consisting of 4 parts sodium chlorite, 10 parts sodium dihydrogen phosphate dissolved in 30 parts water. Slowly add the buffer solution to the reaction system at 25°C and stir for 6 hours. Quench the reaction with saturated sodium sulfite solution, distill under reduced pressure, adjust the pH to 3, and obtain the intermediate acid by extraction, drying and concentration.
[0074] S3. Dissolve the intermediate acid obtained in S2 in 50 parts of glacial acetic acid, heat to 70℃, add 8 parts of concentrated nitric acid in batches at 400 rpm for 1 h, keep the reaction at this temperature for 3.5 h, cool to room temperature, slowly pour the reaction solution into ice water, and precipitate a yellow solid. After filtration, washing, and recrystallization, 2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid is obtained.
[0075] S4. The product obtained in S3 and 22 parts of formamide were dissolved in 35 parts of γ-valerol to form material stream A. 8 parts of formic acid and 12 parts of triethylamine were dissolved in 25 parts of γ-valerol to form material stream B. The two material streams were preheated to 110°C and continuously fed into a fixed-bed reactor packed with a composite catalyst at a volume ratio of A:B=1:0.8. The reactor was held at 140°C and 2.0 MPa for 2 hours. The effluent was separated from the composite catalyst by a magnetic field and cooled to 5°C at a programmed rate of 5°C / h to crystallize, yielding 6,7-bis(2-methoxyethoxy)-4-quinazolinone.
[0076] The preparation step of the composite catalyst in step S4 is as follows:
[0077] A1. Dissolve 6 parts of ferric chloride and 2.5 parts of ferrous chloride in 80 parts of deionized water. Under nitrogen protection, heat to 80℃ and adjust the pH to 11 by adding 28wt% ammonia water dropwise at 400rpm and 3mL / min. After reacting at a constant temperature for 1.2h, separate and wash, then re-disperse in 45 parts of anhydrous ethanol by ultrasonication. Add 3 parts of ammonia water and 5 parts of tetraethyl orthosilicate and continue reacting for 14h. After separation, washing and vacuum drying, obtain magnetic microspheres.
[0078] A2. 13 parts of magnetic microspheres were dispersed in 25 parts of N,N-dimethylformamide, and 1.2 parts of zirconium tetrachloride, 0.8 parts of 2-aminoterephthalic acid and 1.8 parts of acetic acid were added. After reacting at 125℃ for 24 h, the core-shell material was obtained by magnetic separation, washing and vacuum drying.
[0079] A3. Disperse 3 parts of core-shell material in 25 parts of methanol, add 12 parts of 1.2% wt sodium chloropalladium aqueous solution, stir and adsorb at room temperature for 12 h, slowly add 0.04 parts of sodium borohydride while stirring, continue the reaction for 1.6 h, and then obtain the composite catalyst by separation, washing and vacuum drying.
[0080] Comparative Example 1
[0081] A method for producing an intermediate of erlotinib differs from Example 4 in that a composite catalyst is not added in step S4, i.e., no composite catalyst is loaded in the fixed-bed reactor, and material streams A and B pass directly through the reaction pipeline under high temperature and high pressure conditions, while other conditions are the same as in Example 4.
[0082] Comparative Example 2
[0083] A method for producing an intermediate of erlotinib differs from Example 4 in that step A2 is omitted in the preparation of the composite catalyst. That is, after obtaining magnetic microspheres in step A1, the palladium loading reaction in step A3 is carried out directly to obtain a catalyst without zirconium-based core-shell material structure. Other conditions are the same as in Example 4.
[0084] Comparative Example 3
[0085] A method for producing an erlotinib intermediate differs from Example 4 in that step A3 is not performed in the preparation of the composite catalyst. That is, the core-shell material is prepared only through steps A1 and A2 and directly used in the fixed-bed reaction in step S4. The adsorption and reduction loading of palladium metal are not performed. Other conditions are the same as in Example 4.
[0086] Comparative Example 4
[0087] A method for producing an erlotinib intermediate differs from Example 4 in that step S4 does not employ a fixed-bed continuous flow reaction process. Instead, material streams A and B are fed into a conventional stirred tank reactor at once and subjected to a batch reaction under the same temperature and pressure. Other conditions are the same as in Example 4.
[0088] Performance testing
[0089] The production methods of the erlotinib intermediates in Examples 1-5 and Comparative Examples 1-4 were tested for performance, and the test results are shown in Table 1.
[0090] Table 1
[0091] Test Project Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 S4 step reaction yield % 94.28 95.43 96.77 97.13 97.54 15.49 78.59 49.07 85.61 Product purity % 98.82 99.23 99.51 99.78 99.82 85.54 94.20 92.07 96.80 Catalyst reuse times 7 8 8 9 9 / 3 1 5
[0092] The preparation methods for erlotinib intermediates in Examples 1-5 exhibit excellent reaction efficiency, product quality, and catalytic stability. This is attributed to the synergistic adaptation of each reaction step in the process and the optimized design of the composite catalyst system. The composite catalyst, through the stable support of the magnetic microsphere carrier, the dispersion of active sites in the zirconium-based core-shell structure, and the efficient catalysis of the palladium active component, combined with the precise process control from etherification, oxidation, nitration to continuous cyclization, effectively promotes the directional progress of the reaction, reduces the generation of by-products, and improves the recyclability of the catalyst, ensuring the high efficiency and stability of the production process. The performance data of the comparative examples are significantly lower than those of the examples, mainly because they all disrupt the synergy of the reaction system or the integrity of the catalytic system.
[0093] The above description is merely an example and illustration of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described, or use similar methods to replace them, as long as they do not deviate from the invention or exceed the scope defined in the claims, all of which should fall within the protection scope of the present invention.
Claims
1. A method for producing an intermediate of erlotinib, characterized in that, Includes the following steps: S1. 3,4-Dihydroxybenzaldehyde and 2-methoxyethyl p-toluenesulfonate were dispersed in a polar aprotic solvent, potassium carbonate and tert-butylammonium bromide were added, and the reaction was carried out under nitrogen protection. After cooling, the mixture was diluted, extracted, washed, dried and concentrated to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde. S2. Dissolve the product obtained in S1 in a mixed solvent of tert-butanol and acetonitrile, and slowly add a buffer solution composed of sodium chlorite and sodium dihydrogen phosphate to react. After the reaction is completed, add a saturated sodium sulfite solution to quench the reaction. After vacuum distillation, pH adjustment, extraction, drying and concentration, the intermediate acid is obtained. S3. Dissolve the intermediate acid obtained in S2 in glacial acetic acid, heat it up and add concentrated nitric acid in batches to keep it warm for the reaction. After cooling, pour the reaction solution into ice water to precipitate the solid. After filtration, washing and recrystallization, 2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid is obtained. S4. The product obtained in S3 and formamide are dissolved in γ-valerol to form material stream A. Formic acid and triethylamine are dissolved in γ-valerol to form material stream B. The two material streams are preheated and continuously fed into a fixed-bed reactor filled with a composite catalyst for reaction. The reaction effluent is separated from the composite catalyst by a magnetic field and then subjected to programmed cooling and crystallization to obtain 6,7-bis(2-methoxyethoxy)-4-quinazolinone.
2. The method for producing the erlotinib intermediate according to claim 1, characterized in that, The preparation steps of the composite catalyst in step S4 are as follows: A1. Ferric chloride and ferrous chloride were dissolved in deionized water, and ammonia was added dropwise to adjust the pH to alkaline. After the reaction, the mixture was separated, washed, and then dispersed in anhydrous ethanol. Ammonia and tetraethyl orthosilicate were added to react, and after separation, washing, and drying, magnetic microspheres were obtained. A2. Magnetic microspheres were dispersed in N,N-dimethylformamide, and zirconium tetrachloride, 2-aminoterephthalic acid and acetic acid were added and reacted. The core-shell material was obtained by magnetic separation, washing and drying. A3. The core-shell material was dispersed in methanol, and after adsorption by sodium chloropalladium aqueous solution, sodium borohydride was added for reduction. After separation, washing and drying, the composite catalyst was obtained.
3. The method for producing the erlotinib intermediate according to claim 1, characterized in that, In step S1, the components by weight are 10-15 parts of 3,4-dihydroxybenzaldehyde, 34-38 parts of 2-methoxyethyl p-toluenesulfonate, 50-60 parts of polar aprotic solvent, 8-10 parts of potassium carbonate, and 0.2-0.4 parts of tert-butylammonium bromide.
4. The method for producing the erlotinib intermediate according to claim 1, characterized in that, In step S1, the polar aprotic solvent is at least one of N,N-dimethylformamide and N,N-dimethylacetamide.
5. The method for producing the erlotinib intermediate according to claim 1, characterized in that, In step S2, the ingredients are 40-50 parts by weight of tert-butanol, 20-25 parts of acetonitrile, 3-4 parts of sodium chlorite, 8-10 parts of sodium dihydrogen phosphate, and 20-30 parts of water.
6. The method for producing the erlotinib intermediate according to claim 1, characterized in that, In step S3, the components are 40-50 parts by weight of glacial acetic acid and 6-8 parts by weight of concentrated nitric acid.
7. The method for producing the erlotinib intermediate according to claim 1, characterized in that, In step S4, the weight parts and proportions of the components of material stream A and material stream B are as follows: material stream A contains 18-22 parts of formamide and 30-35 parts of γ-valerolactone; material stream B contains 5-8 parts of formic acid, 10-12 parts of triethylamine and 20-25 parts of γ-valerolactone; the volume ratio of material stream A to material stream B is 1:(0.7-0.8).
8. The method for producing the erlotinib intermediate according to claim 2, characterized in that, In step A1, the ingredients by weight are 5-6 parts ferric chloride, 2-3 parts ferrous chloride, 75-80 parts deionized water, 40-45 parts anhydrous ethanol, 1-3 parts ammonia water, and 2-5 parts tetraethyl orthosilicate.
9. The method for producing the erlotinib intermediate according to claim 2, characterized in that, In step A2, the ingredients are 1-3 parts by weight of magnetic microspheres, 20-25 parts of N,N-dimethylformamide, 0.8-1.2 parts of zirconium tetrachloride, 0.6-0.8 parts of 2-aminoterephthalic acid, and 1.5-2.0 parts of acetic acid.
10. The method for producing the erlotinib intermediate according to claim 2, characterized in that, In step A3, the ingredients are 1-3 parts by weight of core-shell material, 20-25 parts by weight of methanol, 10-15 parts by weight of 1.2-1.5% wt sodium chloropalladium aqueous solution, and 0.03-0.05 parts by weight of sodium borohydride.