Preparation method of oxcarbazepine intermediate
The synthesis of oxcarzepine intermediates by adding bromine in stages to the aprotic organic solution and controlling the temperature in one pot method, the problems of complex synthesis process and low purity in the prior art were solved, and industrial production with high purity and high yield were achieved.
Patent Information
- Application Number
- CN202510687950.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-27
- Publication Date
- 2025-08-19
AI Technical Summary
In the prior art, the synthesis process of the oxcarzepine intermediate is complex, with low yield and low purity, which is not suitable for industrial large-scale production, and the use of benzoyl peroxide will reduce the purity of the product.
Acyl chloride iminodibenzyl is dissolved in an aprotic organic solution, bromine is added in stages, and the reaction temperature is controlled. The oxcarzepine intermediate is synthesized by one-pot method to avoid purification and solvent replacement, and simplify operation.
It improves the purity and yield of the oxcarzepine intermediate, reduces the synthesis cost, and is suitable for large-scale industrial applications.
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of drug synthesis, in particular to a method for preparing an oxcarbazepine intermediate. Background Art
[0002] Oxcarbazepine, chemically known as 10,11-dihydro-10-oxo-5 H -dibenzo[ b,f ]Azaphene-5-carboxamide, molecular formula C 15 H 12 N2O2, CAS No. 28721-07-5. As a derivative of carbamazepine, it works by inhibiting abnormal neuronal discharges by blocking voltage-dependent sodium channels, thereby exerting its anti-epileptic effect. Compared to carbamazepine, it has the advantages of less liver enzyme induction, fewer drug interactions, and better tolerability.
[0003] In the process of synthesizing oxcarbazepine, 10,11-dibromo-10,11-dihydro-5 H -dibenzo[ b,f ] Azocyclopentane-5-carbonyl chloride is a key intermediate that affects the quality and yield of oxcarbazepine. H -dibenzo[ b,f ]Azolene-5-carbonyl chloride, molecular formula C 15 H 10 Br2ClNO, CAS No. 40421-03-2. In the prior art, the journal "Synthesis of Oxcarbazepine" (China Pharmaceutical Industry Journal, 2006, 37 (7)) discloses the use of 10,11-dibromo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl chloride by benzyl substitution, elimination and addition to prepare 10,11-dibromo-10,11-dihydro-5 H -dibenzo[ b,f ] Azocyclopentene-5-carbonyl chloride. The specific steps are as follows: (1) Mix imidodibenzyl chloride with chlorobenzene and benzoyl peroxide, heat to 140-150°C, add bromine dropwise, keep warm for reaction, purify, and obtain imidostilbene carboxylic acid chloride; (2) Dissolve imidostilbene carboxylic acid chloride in chloroform solution, slowly add bromine and chloroform mixture dropwise in a water bath with the temperature controlled below 30°C, react for 6 hours after the addition is complete, and purify to obtain the product. The specific process is as follows: .
[0004] The above process uses a two-step method to synthesize the oxcarbazepine intermediate. First, during the synthesis process, the iminostilbenecarbonyl chloride needs to be purified, and then the purified iminostilbenecarbonyl chloride is redissolved in chloroform solution for subsequent reactions. The purification operation not only leads to a decrease in yield, but also increases the complexity of the synthesis operation, increases time and economic costs, and is not conducive to industrial large-scale production. Secondly, the above synthesis process is simplified, and the purified iminostilbenecarbonyl chloride needs to be redissolved in chloroform for subsequent reactions. The redissolution treatment after changing the solvent is not conducive to industrial application. Finally, in the two-step synthesis process, benzoyl peroxide is also used to activate the benzylic free radical to increase the bromination reaction rate, but the addition of benzoyl peroxide will reduce the purity of the final product, the oxcarbazepine intermediate. The oxcarbazepine intermediate synthesized using the two-step method is brown crystals, and its yield is only 71.2%.
[0005] Therefore, using imidodibenzyl chloride as raw material, the reaction conditions were optimized to improve the yield of oxcarbazepine key intermediate 10,11-dibromo-10,11-dihydro-5- H -dibenzo[ b,f ]The yield and purity of azocyclopentyl-5-carbonyl chloride are particularly important to make it more in line with pharmaceutical standards. Summary of the Invention
[0006] In response to the above-mentioned prior art, the present invention aims to provide a method for preparing an oxcarbazepine intermediate. The present invention dissolves iminodibenzyl chloride in an aprotic organic solvent to obtain a reaction solution, and then adds bromine to the reaction solution in two steps to react and produce the oxcarbazepine intermediate. During the synthesis process, the temperature of each bromine addition reaction is controlled in stages, thereby improving the purity and yield of the oxcarbazepine intermediate product, reducing bromine volatilization, and lowering synthesis costs. The present invention utilizes a one-pot process to produce the oxcarbazepine intermediate, eliminating the need to purify p-iminostilbenecarbonyl chloride or replace the solvent for redissolution. This method simplifies the operation, reduces production costs, and is suitable for large-scale industrial applications.
[0007] To achieve the above object, the present invention adopts the following technical solutions: The present invention provides a method for preparing an oxcarbazepine intermediate, comprising the following steps: (1) Heat the acyl chloride iminodibenzyl solution to 90-110°C and then add bromine dropwise. Perform the first reaction under heat preservation. After the reaction is completed, heat it to 130-140°C for the second reaction to obtain a mixed solution. (2) After cooling the mixed solution to 20-30°C, bromine is added and the mixture is reacted for the third time under heat preservation. After the reaction is completed, the mixture is heated to 60-80°C for the fourth reaction to obtain a mother liquor; (3) The mother liquor is purified to obtain the oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5-oxcarbazepine H -dibenzo[ b,f ]Azolene-5-carbonyl chloride.
[0008] Preferably, in step (1), the imidodibenzyl chloride solution is prepared by mixing imidodibenzyl chloride and an organic solvent, and the concentration of the imidodibenzyl chloride solution is 0.8-1.2 mol / L.
[0009] Furthermore, the organic solvent is at least one of chlorobenzene, N,N-dimethylformamide (DMF), and N,N-dimethylacetamide (DMA).
[0010] Preferably, the molar ratio of bromine to imidodibenzyl chloride in the imidodibenzyl chloride solution added in step (1) is (1-1.5):1.
[0011] Preferably, in step (1), the dropping rate of bromine is 0.8-1.2 mL / min.
[0012] Preferably, in step (1), the reaction time of the first reaction is 2-4 h; and the reaction time of the second reaction is 4-6 h.
[0013] Preferably, the molar ratio of bromine added in step (2) to the imidodibenzyl chloride solution is 1:(0.9-1.2).
[0014] Preferably, in step (2), the dropping speed of bromine is 0.8-1.2 mL / min.
[0015] Preferably, in step (2), the reaction time of the third reaction is 5-7 h, and the reaction time of the fourth reaction is 1-3 h.
[0016] Preferably, in step (3), the specific operation of the purification treatment is: decompressing the mother liquor and then recrystallizing it using chloroform.
[0017] Beneficial effects of the present invention: 1. In the present invention, imidodibenzyl chloride is used as a raw material, which is dissolved in an organic solvent to obtain a reaction solution, bromine is added to the reaction solution in stages to react, and after purification, the oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5- H -dibenzo[ b,f The present invention can realize the one-step efficient preparation of oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5-nitropropene by controlling the dripping speed of bromine and the reaction temperature gradient. H -dibenzo[b, f ] Azocyclopentyl-5-carbonyl chloride can also improve the purity and yield of the obtained oxcarbazepine intermediate. Specifically, the purity of the oxcarbazepine intermediate obtained by the present invention is 99.5%, and the yield is 77.5%.
[0018] 2. The present invention adopts a one-pot method to synthesize the oxcarbazepine intermediate, which does not require purification of the iminostilbenecarbonyl chloride or replacement of the solvent for redissolution. The operation is simple, production costs are saved, and it is suitable for large-scale industrial application. DETAILED DESCRIPTION
[0019] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present application belongs.
[0020] In the prior art, oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5-oxazoline is synthesized by a two-step method using imidodibenzyl chloride as a reaction raw material. H -dibenzo[ b,f However, the two-step synthesis process for preparing oxcarbazepine intermediates is cumbersome, with low product yield and purity, making it unsuitable for large-scale industrial application.
[0021] Based on this, the present invention provides a one-pot method for synthesizing an oxcarbazepine intermediate. The specific steps are: adding chlorobenzene to imidodibenzyl chloride to obtain a reaction solution, adding bromine to the reaction solution in two stages, and reacting and purifying to obtain the oxcarbazepine intermediate. The present invention controls the reaction temperature in stages at each stage of adding bromine. Specifically, First, imidodibenzyl chloride and chlorobenzene are mixed as the reaction raw materials. After heating the reaction raw materials, bromine is added dropwise for a first reaction. The temperature is then raised and a second reaction is carried out to obtain a mixed solution. During the first addition of bromine, the bromine is added dropwise at the lowest possible temperature (90-110°C). This ensures the reaction proceeds while minimizing bromine volatilization, thereby reducing bromine usage and synthesis costs. Furthermore, controlling the temperature gradient during this reaction stage can avoid the use of benzoyl peroxide, thereby preventing the introduction of impurities and improving product purity.
[0022] On the other hand, after the mixed solution is cooled, bromine is added dropwise for a second time for a third reaction, and then the temperature is raised for a fourth reaction. During the second addition of bromine, the reaction temperature is also controlled in stages, that is, after the third reaction is carried out at 20-30°C, the temperature is raised to 60-80°C for the fourth reaction. By controlling the temperature gradient in this way, different chemical reactions can be carried out at different temperatures, thereby increasing yield and reducing reaction solvent consumption.
[0023] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.
[0024] The experimental materials used in the examples of the present invention are all conventional experimental materials in the art and can be purchased through commercial channels.
[0025] Example 1: (1) 3.88 mol of imidodibenzyl chloride was mixed with 2 L of chlorobenzene to prepare an imidodibenzyl chloride solution with a concentration of 1.94 mol / L. After the imidodibenzyl chloride solution was deheated to 100°C, 5.04 mol of bromine was added dropwise at a rate of 1 L / min. After the addition was complete, the mixture was kept warm for 2 h. After the reaction was complete, the mixture was heated to 140°C and reacted for 4 h until no white mist escaped, thereby obtaining a mixed solution. (2) The mixed solution was allowed to cool to 30°C, and 3.88 mol of bromine was added dropwise to the cooled mixed solution at a rate of 1 L / min. The mixture was kept warm for 5 h. After the reaction was completed, the temperature was raised to 60°C and the mixture was reacted for 1 h to obtain the mother liquor. (3) The mother liquor was decompressed to remove chlorobenzene, and a viscous substance was obtained. 200 mL of toluene was added to the viscous substance, and the mixture was beaten for 15 minutes, and then allowed to stand for 1 hour. The filtered solid was recrystallized with chloroform and dried to obtain 1249 g of a white solid, which was the oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5-oxazoline. H -dibenzo[ b,f ]Azolene-5-carbonyl chloride.
[0026] The hydrogen spectrum data of the above-mentioned oxcarbazepine intermediate are: 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.81 – 7.59(m, 4H), 7.54 (dt, J = 25.9, 7.7 Hz, 2H), 7.47 – 7.34 (m, 2H), 6.58 (d, J= 19.2Hz, 1H), 6.07 (d, J = 4.3 Hz, 1H). Melting point 166-168°C.
[0027] The oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5-oxcarbazepine prepared in this example H -dibenzo[ b,f ]The yield of azocyclopentane-5-carbonyl chloride was 77.5% and the purity was 99.5%.
[0028] Comparative Example 1: (1) 3.88 mol of imidodibenzyl chloride was mixed with 2 L of chlorobenzene to obtain an imidodibenzyl chloride solution. The imidodibenzyl chloride solution was heated to 100°C, and 5.04 mol of bromine was added dropwise at a rate of 1 L / min. After the addition was complete, the mixture was reacted under heat preservation for 6 h to obtain a mixed solution. (2) The mixed solution was allowed to cool to 30°C, and 3.88 mol of bromine was added dropwise to the cooled mixed solution at a rate of 1 L / min. The mixture was kept warm for 5 h. After the reaction was completed, the temperature was raised to 60°C and the reaction was continued for 1 h to obtain the mother liquor. (3) The mother liquor was purified in the same manner as in Example 1 to obtain the oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5-oxcarbazepine. H -dibenzo[ b,f ]Azolene-5-carbonyl chloride.
[0029] In this comparative example, the oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5- H -dibenzo[ b,f ]The yield of azocyclopentane-5-carbonyl chloride was 61.2% and the purity was 80.5%.
[0030] Comparative Example 2: (1) 3.88 mol of imidodibenzyl chloride was mixed with 2 L of chlorobenzene to obtain an imidodibenzyl chloride solution; the imidodibenzyl chloride solution was heated to 100°C, and 5.04 mol of bromine was added dropwise at a rate of 1 L / min. After the addition was complete, the mixture was kept warm for 2 h. After the reaction was complete, the mixture was heated to 140°C and reacted for 4 h until no white mist escaped, thereby obtaining a mixed solution; (2) The mixed solution was allowed to cool to 30°C, and 3.88 mol of bromine was added dropwise to the cooled mixed solution at a rate of 1 L / min. The mixture was reacted for 6 h at this temperature to obtain a mother solution. (3) The mother liquor was purified to obtain the oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5-oxcarbazepine H -dibenzo[ b,f ]Azolene-5-carbonyl chloride.
[0031] In this comparative example, the oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5 H -dibenzo[ b,f ]The yield of azocyclopentane-5-carbonyl chloride was 56.1% and the purity was 99.1%.
[0032] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application. Various modifications and variations are possible for those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present application shall be included within the scope of protection of the present application.
Claims
1. A method for preparing an oxcarbazepine intermediate, characterized in that: The following steps are involved: (1) Heat the acyl chloride iminodibenzyl solution to 90-110°C and then add bromine dropwise. Perform the first reaction under heat preservation. After the reaction is completed, heat it to 130-140°C for the second reaction to obtain a mixed solution. (2) After cooling the mixed solution to 20-30°C, bromine is added and the mixture is reacted for the third time under heat preservation. After the reaction is completed, the mixture is heated to 60-80°C for the fourth reaction to obtain a mother liquor; (3) The mother liquor is purified to obtain the oxcarbazepine intermediate 10,11-dibromo-10,11-dihydro-5-oxcarbazepine H -dibenzo[ b,f ]Azolene-5-carbonyl chloride.
2. The method for preparing an oxcarbazepine intermediate according to claim 1, wherein: The imidodibenzyl chloride solution is prepared by mixing imidodibenzyl chloride and an organic solvent. The concentration of the imidodibenzyl chloride solution is 0.8-1.2 mol / L.
3. The method for preparing an oxcarbazepine intermediate according to claim 2, wherein: The organic solvent is at least one of chlorobenzene, N,N-dimethylformamide and N,N-dimethylacetamide.
4. The method for preparing an oxcarbazepine intermediate according to claim 1, wherein The molar ratio of bromine and imidodibenzyl chloride in the imidodibenzyl chloride solution added in step (1) is (1-1.5):
1.
5. The method for preparing an oxcarbazepine intermediate according to claim 1, wherein: In step (1), the dropwise addition rate of bromine is 0.8-1.2 mL / min.
6. The method for preparing an oxcarbazepine intermediate according to claim 1, wherein: In step (1), the reaction time of the first reaction is 2-4 h; the reaction time of the second reaction is 4-6 h.
7. The method for preparing an oxcarbazepine intermediate according to claim 1, wherein: The Bohr ratio of bromine to imidodibenzyl chloride in the imidodibenzyl chloride solution added in step (2) is 1:(0.9-1.2).
8. The method for preparing an oxcarbazepine intermediate according to claim 1, wherein: In step (2), the addition rate of bromine is 0.8-1.2 mL / min.
9. The method for preparing an oxcarbazepine intermediate according to claim 1, wherein: In step (2), the reaction time of the third reaction is 5-7 h, and the reaction time of the fourth reaction is 1-3 h.
10. The method for preparing an oxcarbazepine intermediate according to claim 1, wherein: The specific operation of the purification treatment is: the mother liquor is subjected to decompression treatment and then recrystallized using chloroform.