Ketotifen impurity and method for synthesizing the same
Patent Information
- Application Number
- CN202410229877.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-02-29
- Publication Date
- 2026-09-22
- Estimated Expiration
- 2044-02-29
AI Technical Summary
[0029]本发明路线设计合理、可操作性强、成本低廉、收率高，通过该杂质的制备，为酮替芬的质量控制、安全性和有效性的评价提供了重要依据，具有十分重要的意义。
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Abstract
Description
Technical Field
[0001] This invention relates to the field of ketotifen fumarate technology, specifically to a ketotifen impurity and its synthesis method. Background Technology
[0002] Ketotifen fumarate, also known as mepiquatine, thiamethoxam, sardine, thiamethoxam, and ketotifen, is a potent anti-allergic drug with both tricyclic and piperidine structures. Its key characteristics include strong antagonism of histamine H1 receptors and inhibition of the release of allergic reaction mediators. It inhibits the release of various mediators from mast cells, basophils, and macrophages, including slow-reacting substances and other active substances. It antagonizes calcium ions, inhibits phosphodiesterase, and increases cAMP levels in mast cells. It inhibits neutrophil chemotaxis and inflammatory responses, with an effect 10 times stronger than chlorpheniramine and a longer duration of action, stronger than sodium cromoglycate. Ketotifen fumarate is effective against both type I and type III hypersensitivity reactions. Its chemical name is 4,9-dihydro-4-(1-methyl-4-piperidinyl)-10H-benzo[4,5]cyclohepta[1,2-b]thiophene-10-one fumarate.
[0003] Due to safety requirements, domestic and international regulatory authorities typically limit the content of unidentified or undetermined toxicity impurities in APIs (active pharmaceutical ingredients) to below 0.1%. If the content of relevant impurities in the API exceeds 0.1%, further investigation of these impurities is required to ensure that the obtained API meets pharmaceutical standards and is safe and effective.
[0004] Ketotifen fumarate, as an active pharmaceutical ingredient, may contain impurities from various sources. Some of these impurities are generated during the storage of the active pharmaceutical ingredient, some are generated by its own degradation, and some are generated from the preparation method, including but not limited to unreacted starting materials, synthetic byproducts, and degraded products. These impurities pose a risk to human safety in drug use.
[0005] This impurity is listed in the European Pharmacopoeia as an isomer of the API and is classified as a process impurity, theoretically unavoidable during preparation; however, no literature reports on the synthesis of this impurity have been found. Furthermore, the yield of this impurity prepared from crude API or by enrichment is extremely low. Therefore, finding an efficient and feasible route for the targeted synthesis of this impurity and successfully preparing it is of great significance for improving consistency evaluation, enhancing product quality, and ensuring safe drug use for humans. Summary of the Invention
[0006] The purpose of this invention is to provide a ketotifen impurity and a method for synthesizing it.
[0007] To achieve the above objectives, the present invention provides the following technical solution: a ketotifen impurity, with the following structural formula:
[0008]
[0009] A method for synthesizing a ketotifen impurity, comprising at least the following steps:
[0010] S1: Synthesis of intermediate 1: SM1 reacts with triphenylphosphine in an organic solvent under heating, and after post-treatment, the corresponding phosphorus reagent M1 is obtained;
[0011] S2: Synthesis of intermediate 2: M1 reacts with 3-thiophenecarboxaldehyde in an organic solvent with the addition of a base to undergo a Wittig reaction. After the reaction is completed by TLC monitoring, M2 is obtained after post-treatment.
[0012] S3: The synthesis of intermediate 3 involves the hydrolysis of M2 with sodium hydroxide to obtain the corresponding acid M3;
[0013] S4: Synthesis of intermediate 4: M3 was prepared in dichloromethane with the addition of a catalytic amount of N,N-dimethylaminoformamide. After chlorination with an acyl chloride reagent, the reaction solution was directly concentrated to dryness. DCN was added to the concentrate, dissolved, and then Lewis acid was added. After the reaction was completed, the concentrate was added to ice water, extracted, dried, concentrated, and then purified by silica gel column chromatography to obtain M4.
[0014] S5: Synthesis of intermediate 5: M4 is added to petroleum ether, and then an appropriate amount of bromine is added. After the reaction is complete, the solid is filtered to directly obtain M5.
[0015] S6: Synthesis of intermediate 6: M5 dibromo derivative is eliminated by alkali in methanol solution to obtain M6;
[0016] S7: The synthesis of intermediate 7 involves first preparing 4-chloro-N-methylpiperidine as a Grignard reagent in an organic solvent, then adding it to an organic solvent containing M6. After the reaction is complete, the reaction solution is added to water, and after extraction, drying, and concentration, M7 is obtained.
[0017] S8: Synthesis of the target impurity. M7 is heated to reflux in acid to undergo elimination and hydroxylation of bromine. After the reaction is completed, the product is diluted, neutralized with potassium carbonate, extracted, dried and concentrated, and finally purified by silica gel column chromatography to obtain the target product.
[0018] Further, this can be understood as follows: S1: Synthesis of the brominated phosphorus reagent; S2: Wittig reaction of intermediate 1 with starting material 2; S3: Hydrolysis of intermediate 2; S4: Intramolecular Friedel-Crafts cyclization of intermediate 3; S5: Bromine addition of intermediate 4; S6: Monobromine elimination of intermediate 5; S7: Grignard reaction of intermediate 6 with starting material 3; S8: Hydroxyl elimination and bromine hydroxylation of intermediate 7, thus completing the synthesis of the target impurity.
[0019] Furthermore, the organic solvent used in the synthesis of intermediate 1 of S1 is one or more of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, acetone, and dichloromethane, preferably ethyl acetate; the volume ratio of SM1 to the solvent is 1:1 to 10; the molar ratio of SM1 to triphenylphosphine is 1:0.9 to 1.5, preferably 1:1.0.
[0020] Further, the organic solvent used in the synthesis of intermediate 2 in step S2 is one or more of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, acetone, and dichloromethane, preferably N,N-dimethylformamide; the base used is sodium hydrogen, sodium methoxide, sodium ethoxide, potassium carbonate, sodium hydroxide, and triethylamine, preferably sodium methoxide; the volume ratio of intermediate 1 to solvent is 1:1 to 15; the molar ratio of intermediate 1 to 3-thiophenecarboxaldehyde is 1:1.0 to 2.0, preferably 1:1.5; the molar ratio of intermediate 1 to sodium methoxide is 1:1.0 to 2.0, preferably 1:1.2.
[0021] Further, the solvent used in the synthesis of intermediate 3 of S3 is one or more of water, methanol, ethanol, isopropanol, N,N-dimethylformamide, acetonitrile, and acetone, preferably water; the base used is sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide, preferably sodium hydroxide. The volume ratio of intermediate 2 to solvent is 1:1 to 10; the molar ratio of intermediate 2 to sodium hydroxide is 1:0.5 to 3.0, preferably 1:1.2.
[0022] Further, the solvent used in the synthesis of intermediate 4 of S4 is one or more of acetonitrile, dichloromethane, tetrahydrofuran, and N,N-dimethylformamide, preferably dichloromethane and N,N-dimethylformamide; the acyl chloride reagent is phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or thionyl chloride, preferably thionyl chloride. The volume ratio of intermediate 3 to solvent is 1:1 to 20; the molar ratio of intermediate 3 to thionyl chloride is 1:1.0 to 2.0, preferably 1:1.5;
[0023] The Lewis acid in S4 is tin tetrachloride, and the molar ratio of intermediate 3 to tin tetrachloride is 1:0.9 to 1.5, preferably 1:1.0.
[0024] Further, the solvent used in the synthesis of intermediate 5 of S5 is one or more of methyl tert-butyl ether, petroleum ether, diethyl ether, dichloromethane, and tetrahydrofuran, with petroleum ether being the preferred solvent. The volume ratio of intermediate 4 to bromine is 1:1 to 20; the molar ratio of intermediate 4 to bromine is 1:1.0 to 2.0, preferably 1:1.5.
[0025] Furthermore, the organic solvent used in the synthesis of intermediate 6 of S6 is THF, methanol, ethanol, isopropanol, or acetonitrile, with methanol being the preferred solvent; the base used is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, or sodium ethoxide, with potassium hydroxide being the preferred base. The volume ratio of intermediate 5 to solvent is 1:1 to 20; the molar ratio of intermediate 5 to potassium hydroxide is 1:1.0 to 5.0, preferably 1:3.0.
[0026] Further, the organic solvent used in S7 is one or more of toluene, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether, preferably tetrahydrofuran; the volume ratio of intermediate 6 to organic solvent is 1:1 to 30; the molar ratio of intermediate 6 to 4-chloro-N-methylpiperidine is 1:2.0 to 4.0, preferably 1:2.7.
[0027] Furthermore, the solvent used in S8 is water, and the acid used is sulfuric acid, with a sulfuric acid concentration of 10% to 98%, preferably 50%; the reaction temperature is 50°C to 100°C, preferably 100°C.
[0028] Compared with the prior art, the beneficial effects of the present invention are:
[0029] The proposed method is rationally designed, highly operable, low in cost, and has a high yield. The preparation of this impurity provides an important basis for the quality control, safety, and efficacy evaluation of ketotifen, which is of great significance. Attached Figure Description
[0030] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some examples of structural verification and testing data of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0031] Figure 1 This is a schematic diagram of the synthetic route of the present invention;
[0032] Figure 2 The compounds of this invention 1 HNMR spectrum;
[0033] Figure 3 The compounds of this invention 13 CNMR plot;
[0034] Figure 4 This is the FTIR spectrum of the compound of the present invention. Detailed Implementation
[0035] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.
[0036] Example 1:
[0037] 46g of SM1 and 52g of triphenylphosphine were added to 200ml of ethyl acetate and reacted at 80℃ for 3h. The reaction solution was directly evaporated to dryness and then added to the solution. 98g of a semi-oil, semi-solid product was obtained.
[0038] Example 2:
[0039] 98g of crude M1 and 15g of SM2 were added to 500ml of N,N-dimethylformamide, cooled to 0℃, and 20g of sodium methoxide was added in batches. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 0.5h. The reaction solution was poured into 1L of water, the pH was adjusted to 5 with phosphoric acid, and the mixture was extracted with methyl tert-butyl ether (500ml*2). The organic phase was directly evaporated to dryness and then added to the solution. 98g of brown oil was obtained.
[0040] Example 3:
[0041] Add 98g of M2 to 300ml of water, add 20g of sodium hydroxide, and react at 90℃ overnight. Cool the reaction solution to room temperature, extract impurities with methyl tert-butyl ether, adjust the pH of the aqueous phase to 4 with hydrochloric acid, extract with ethyl acetate (500ml*2), and dry the organic phase by rotary evaporation. Add directly to the solution. 40g of brown oil is obtained.
[0042] Example 4:
[0043] 40 g of M3 was added to 300 ml of dichloromethane and cooled to 0 °C. 1 ml of N,N-dimethylformamide was added, followed by the dropwise addition of 31 g of thionyl chloride. The reaction mixture was allowed to react for 2 h after the addition was complete. The reaction solution was directly evaporated to dryness, and then 300 ml of dichloromethane was added. The mixture was cooled to 0 °C, and then 45 g of tin tetrachloride was added dropwise. The reaction mixture was allowed to react for 10 min after the addition was complete. The reaction solution was poured into ice water and extracted with dichloromethane (200 ml * 2). The organic phase was dried, evaporated to dryness, stirred, and passed through a column (petroleum ether:ethyl acetate = 10:1). 7 g of a light brown solid was obtained.
[0044] Example 5:
[0045] Add 7g of M4 to 100ml of petroleum ether, then add 2.5ml of bromine. React at room temperature for 2 hours. Filter, and add the solid directly downstream.
[0046] Example 6:
[0047] Add 3.7g M5 to 100ml methanol, add 1.7g potassium hydroxide, and heat under reflux for 4 hours. Directly evaporate the reaction solution to dryness, add 100ml water and 100ml dichloromethane, dry the organic phase, and evaporate to dryness. Pulverize the crude product with petroleum ether:ethyl acetate = 10:1, and air-dry the solid. 2g solid.
[0048] Example 7:
[0049] Add 5g of magnesium shavings to 400g of tetrahydrofuran, heat to 65℃, add 5g of 4-chloro-N-methylpiperidine, then add 2ml of methyl Grignard reagent, followed by dropwise addition of 20g of 4-chloro-N-methylpiperidine. React at 65℃ for 2 hours after the addition is complete. Cool the reaction solution to room temperature; the solution becomes turbid and a solid precipitates. Transfer the reaction solution and weigh it to obtain 300g of Grignard reagent.
[0050] Add 10g of M6 to 500ml of tetrahydrofuran, add 150g of a homemade Grignard reagent, and react for 10 minutes. Pour the reaction solution into 200ml of water, extract with ethyl acetate (500ml*2), and add the organic phase directly after rotary evaporation. 10g of a light brown semi-oil, semi-solid product is obtained.
[0051] Example 8:
[0052] 100g of concentrated sulfuric acid was slowly added to 100ml of water, then cooled to room temperature. 10g of M7 was added, and the reaction was carried out at 100℃ for 4 hours. The reaction solution was cooled to room temperature, 500ml of water was added, and the pH was adjusted to 8 with potassium carbonate. Extraction was performed with ethyl acetate (300ml x 2). The organic phase was dried, evaporated to dryness, stirred, and passed through a column (petroleum ether:ethyl acetate = 2:1, triethylamine column alkalization). The crude product was washed once with petroleum ether slurry. 4g of off-white solid was obtained.
[0053] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.
Claims
1. A method for synthesizing a ketotifen impurity, characterized in that: At least the following steps are included: S1: Synthesis of intermediate 1: SM1 reacts with triphenylphosphine in an organic solvent under heating, and after post-treatment, the corresponding phosphorus reagent M1 is obtained; S2: Synthesis of intermediate 2: M1 reacts with 3-thiophenecarboxaldehyde in an organic solvent with the addition of a base to undergo a Wittig reaction. After the reaction is completed by TLC monitoring, M2 is obtained after post-treatment. S3: The synthesis of intermediate 3 involves the hydrolysis of M2 with sodium hydroxide to obtain the corresponding acid M3; S4: Synthesis of intermediate 4: M3 is prepared by adding a catalytic amount of N,N-dimethylaminoformamide to dichloromethane, followed by chlorination with an acyl chloride reagent, and then directly concentrating the reaction solution to dryness. Dichloromethane was added to the concentrate to dissolve it, and then Lewis acid was added. After the reaction was complete, the concentrate was added to ice water, and then extracted, dried, concentrated, and purified by silica gel column chromatography to obtain M4. S5: Synthesis of intermediate 5: M4 is added to petroleum ether, and then an appropriate amount of bromine is added. After the reaction is complete, the solid is filtered to directly obtain M5. S6: Synthesis of intermediate 6: M5 dibromo derivative is eliminated by alkali in methanol solution to obtain M6; S7: The synthesis of intermediate 7 involves first preparing 4-chloro-N-methylpiperidine as a Grignard reagent in an organic solvent, then adding it to an organic solvent containing M6. After the reaction is complete, the reaction solution is added to water, and after extraction, drying, and concentration, M7 is obtained. S8: Synthesis of the target impurity. M7 is heated to reflux in acid. After the reaction is completed, it is diluted, neutralized with potassium carbonate, extracted, dried and concentrated, and finally purified by silica gel column chromatography to obtain the target product. 。 2. The method for synthesizing a ketotifen impurity according to claim 1, characterized in that: The organic solvent used in the synthesis of intermediate 1 of S1 is ethyl acetate, and the molar ratio of SM1 to triphenylphosphine is 1:0.9 to 1.
5.
3. The method for synthesizing a ketotifen impurity according to claim 1, characterized in that: The organic solvent used in the synthesis of intermediate 2 of S2 is N,N-dimethylaminocarboxamide, and the base used is sodium methoxide. The molar ratio of intermediate 1 to 3-thiophenecarboxaldehyde is 1:1.0~2.0, and the molar ratio of intermediate 1 to sodium methoxide is 1:1.0~2.
0.
4. The method for synthesizing a ketotifen impurity according to claim 1, characterized in that: The acyl chloride reagent used in the synthesis of intermediate 4 of S4 is thionyl chloride, and the molar ratio of intermediate 3 to thionyl chloride is 1:1.0~2.
0. The Lewis acid in S4 is tin tetrachloride, and the molar ratio of intermediate 3 to tin tetrachloride is 1:0.9~1.
5.
5. The method for synthesizing a ketotifen impurity according to claim 1, characterized in that: The base used in the synthesis of intermediate 6 of S6 is potassium hydroxide, and the molar ratio of intermediate 5 to potassium hydroxide is 1:1.0~5.
0.
6. The method for synthesizing a ketotifen impurity according to claim 1, characterized in that: The organic solvent used in the synthesis of intermediate 7 of S7 is tetrahydrofuran, and the molar ratio of intermediate 6 to 4-chloro-N-methylpiperidine is 1:2.0~4.
0.
7. The method for synthesizing a ketotifen impurity according to claim 1, characterized in that: The acid used in S8 is sulfuric acid, and the concentration of the sulfuric acid is 10% to 98%. The reaction temperature is 50℃~100℃.