Resolution refining method of clemastine fumarate
By using racemic clomastine fumarate as the starting material, free disassembly, refining and free salting steps are adopted to solve the problems of complex operation and high cost of existing preparation methods, and achieve high efficiency and low cost Fumarate Synthesis of chloromastin acid, suitable for industrial production.
Patent Information
- Application Number
- CN202411639124.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-18
- Publication Date
- 2025-02-11
AI Technical Summary
The existing preparation method of clomastine fumarate is complex in operation, has many steps, is costly, and is difficult to improve chiral splitting efficiency, yield and quality.
Using racemic clomastin fumarate as the starting material, the synthesis of the target product is achieved through the steps of free disassembly, refining, and free salting, including the use of sodium hydroxide to adjust the pH value, ethyl acetate extraction, water washing, and water-free Steps such as drying sodium sulfate and distillation of the organic phase under reduced pressure.
The synthesis route is simplified, the reaction conditions are mild, the operation is convenient, the yield is high, the cost is low, and the environmental pollution is small. It is suitable for factory-based large-scale production, and the chiral splitting efficiency, yield and quality of chlormastin fumarate is improved.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of medicines, and in particular relates to a method for splitting and refining rimastine fumarate. Background Art
[0002] The English name of clemastine fumarate is Clemastine fumarate, and its chemical name is (R-(R*,R*))-1-methyl-2-(2-(1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-pyrrolidine (E)-2-butenedioate, and its molecular formula is C 21 H 26 ClNOC4H4O4, molecular weight is 459.97, CAS registration number is 14976-57-9, structural formula is Figure 2 .
[0003] Clemastine fumarate is a potent, long-acting, fast-acting, highly selective histamine H1 receptor antagonist that simultaneously blocks H1 receptors and antagonizes cytotoxicity. It is mainly used clinically for allergic diseases such as allergic skin diseases and allergic rhinitis. It has no inhibitory effect on the cholinergic receptors of the central nervous system, and has no sedative or drowsiness effects. It is mostly used for allergic rhinitis, anti-allergic asthma, urticaria, eczema, dermatitis and pruritus.
[0004] At present, the preparation method of clemastine fumarate mainly uses chiral N-methyl-2-(2-hydroxyethyl)pyrrolidine as a starting material. The method is complicated to operate, has many steps, and is costly. The steps of the method are as follows: Summary of the invention
[0005] The purpose of the present invention is to overcome the shortcomings of the prior art, provide a method for splitting and refining clemastine fumarate, improve the chiral splitting efficiency of clemastine fumarate, and improve the yield and quality.
[0006] The present invention is realized by the following technical scheme: a method for splitting and refining clemastine fumarate, which comprises the following steps.
[0007] S1. Free separation: Add water and racemic clemastine fumarate to the reaction kettle, adjust the pH value to 10-14 with sodium hydroxide aqueous solution, extract with ethyl acetate, wash with water, wash with brine, dry with anhydrous sodium sulfate, and evaporate the organic phase under reduced pressure to remove the solvent. Add ethanol to the residue, stir at room temperature, add L-di-p-toluoyltartaric acid dissolved in ethanol dropwise, stir for 1-4 hours, cool to 0-10°C, keep warm and stir for 1-4 hours, filter and dry to obtain the crude clemastine fumarate intermediate.
[0008] S2. Refining: Add ethanol and crude clemastine fumarate intermediate into the reaction kettle, heat to 40-80°C with stirring, keep stirring for 1-4 hours, slowly cool down, crystallize, filter and dry to obtain the finished clemastine fumarate intermediate.
[0009] S3. Free salt formation: Add water and the finished intermediate of clemastine fumarate to the reactor, adjust the pH value to 10-14 with sodium hydroxide aqueous solution, extract with ethyl acetate, wash with water, wash with brine, dry with anhydrous sodium sulfate, and evaporate the organic phase under reduced pressure to remove the solvent. Add ethanol to the residue, heat to 40-80°C, add fumaric acid, stir for 1-4 hours, slowly cool, crystallize, filter and dry to obtain clemastine fumarate. See the synthetic route. Figure 1 .
[0010] Furthermore, the racemic clemastine fumarate described in step S1 is adjusted to a pH value of 10-14 with a 5%-20% sodium hydroxide solution, extracted, washed with water, dried, and concentrated to obtain racemic clemastine, which is dissolved with ethanol, wherein the mass ratio of racemic clemastine to ethanol is 1:5-30, and L-di-p-toluoyltartaric acid ethanol solution is added dropwise at 10-40° C., wherein the molar ratio of racemic clemastine to L-di-p-toluoyltartaric acid solution is 1:0.2-1.6, and the mixture is stirred at this temperature for 1-4 hours, cooled to 0-10° C., stirred at this temperature for 1-4 hours, filtered, and dried to obtain a crude clemastine fumarate intermediate.
[0011] Furthermore, the crude clemastine fumarate intermediate in step S2 is dissolved in ethanol at 40-80° C., the mass ratio of the crude clemastine fumarate intermediate to ethanol is 1:5-30, the mixture is stirred at this temperature for 1-4 hours, the temperature is slowly lowered, crystallization is carried out, and the mixture is filtered and dried to obtain a finished clemastine fumarate intermediate.
[0012] Furthermore, the finished clemastine fumarate intermediate product in step S3 is adjusted to a pH value of 10-14 with a 5%-20% sodium hydroxide solution, extracted, washed, dried, and concentrated to obtain clemastine, ethanol is added to clemastine, the mass ratio of clemastine to ethanol is 1:5-20, fumaric acid is added at a temperature of 40-80°C, the molar ratio of clemastine to fumaric acid is 1:0.8-1.3, the mixture is kept warm for 1-4h, the temperature is slowly lowered, crystallized, filtered, and dried to obtain clemastine fumarate.
[0013] The invention has the following advantages: racemic clemastine fumarate is used as a starting material, and the synthesis of the target product clemastine fumarate is achieved through free splitting, refining and free salt formation; the method of the invention has the advantages of simple synthesis route, mild reaction conditions, convenient operation, high yield, low cost and low environmental pollution, and is suitable for large-scale factory production. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1This is a separation and purification route for clemastine fumarate.
[0015] Figure 2 It is the structural formula of clemastine fumarate.
[0016] Figure 3 The purity of clemastine fumarate.
[0017] Figure 4 It is the isomeric purity of clemastine fumarate. DETAILED DESCRIPTION
[0018] The present invention is further described below in conjunction with the accompanying drawings and embodiments, but the protection scope of the present invention is not limited to the following description.
[0019] The present invention uses racemic clemastine fumarate as the starting material, and synthesizes the target product clemastine fumarate by free splitting, refining, and free salt formation. The synthetic route is shown in Figure 1 .
[0020] Embodiment: A method for resolving and refining clemastine fumarate comprises the following steps.
[0021] S1. Free splitting: Add 5L of water and 1.0kg of racemic clemastine fumarate to the reactor, adjust the pH value to 10-14 with 5L of 20% sodium hydroxide aqueous solution, extract three times with 5L*3 ethyl acetate, wash once with 5L of water, wash once with 5L of brine, dry with 1.0kg of anhydrous sodium sulfate, filter, and evaporate the organic phase under reduced pressure at 60°C to obtain about 750g of light yellow oil. Add 10L of ethanol to the light yellow oil, stir at room temperature, drop 420g of L-di-p-toluoyltartaric acid dissolved in 5L of ethanol, stir for 2h, cool to 0-10°C, keep warm and stir for 2h, filter and dry to obtain 300g of crude clemastine fumarate intermediate, with a yield of 25.7%.
[0022] S2. Refining: Add 7.5L ethanol and 300g crude clemastine fumarate intermediate to the reactor, heat to 80°C with stirring, keep stirring for 1h, slowly cool to 60°C to precipitate solid, keep warm for 2h, reduce to room temperature and keep warm for 1h, reduce to 0-10°C and keep warm for 1h, filter and dry to obtain 270g finished clemastine fumarate intermediate with a yield of 90%.
[0023] S3. Free salt formation: Add 1.5L water and 270g of clemastine fumarate intermediate finished product to the reactor, adjust the pH value to 10-14 with 1.5L of 20% sodium hydroxide aqueous solution, extract three times with 1.5L*3 ethyl acetate, wash once with 1.5L water, wash once with 1.5L brine, dry with 270g anhydrous sodium sulfate, filter, and evaporate the organic phase under reduced pressure at 60°C to obtain about 155g of colorless oil. Add 1.5L ethanol to the colorless oil, heat to 70°C, add 57.7g of fumaric acid, keep at 70°C and stir for 1h, slowly cool to 60°C to precipitate solid, keep for 2h, cool to room temperature for 1h, cool to 0-10°C for 1h, filter and dry to obtain 158g of clemastine fumarate, with a yield of 68.3%.
[0024] In summary, the preparation method of clemastine fumarate with high chiral purity of the present invention uses racemic clemastine fumarate as the starting material, and realizes the synthesis of the target product clemastine fumarate through free splitting, refining, and free salt formation. The clemastine fumarate raw material prepared by the process method has high chiral purity, and the product quality meets the requirements of injection drugs stipulated in the pharmacopoeia. The process is simple and easy to control, and the operability is strong, and industrial production can be realized.
Claims
1. A method for resolving and refining clemastine fumarate, characterized in that: It includes the following steps: S1. Free separation: Add water and racemic clemastine fumarate to the reactor, adjust the pH value to 10-14 with sodium hydroxide aqueous solution, extract with ethyl acetate, wash with water, wash with brine, dry with anhydrous sodium sulfate, and evaporate the organic phase under reduced pressure to remove the solvent. Add ethanol to the residue, stir at room temperature, add L-di-p-toluoyltartaric acid dissolved in ethanol dropwise, stir for 1-4 hours, cool to 0-10°C, keep warm and stir for 1-4 hours, filter and dry to obtain the crude clemastine fumarate intermediate; S2. Refining: Add ethanol and crude clemastine fumarate intermediate to the reactor, heat to 40-80°C with stirring, keep stirring for 1-4h, slowly cool, crystallize, filter and dry to obtain the finished clemastine fumarate intermediate; S3. Free salt formation: Add water and the finished intermediate of clemastine fumarate to the reactor, adjust the pH value to 10-14 with sodium hydroxide aqueous solution, extract with ethyl acetate, wash with water, wash with brine, dry with anhydrous sodium sulfate, and evaporate the organic phase under reduced pressure to remove the solvent. Add ethanol to the residue, heat to 40-80°C, add fumaric acid, keep warm and stir for 1-4h, slowly cool, crystallize, filter and dry to obtain clemastine fumarate; The splitting and refining route is shown in Figure 1.
2. The synthetic method of clemastine fumarate as claimed in claim 1, characterized in that, The racemic clemastine fumarate described in step S1 is adjusted to a pH value of 10 to 14 with a 5% to 20% sodium hydroxide solution, extracted, washed with water, dried, and concentrated to obtain racemic clemastine, which is dissolved with ethanol, wherein the mass ratio of racemic clemastine to ethanol is 1:5 to 30, and L-di-p-toluoyltartaric acid ethanol solution is added dropwise at 10 to 40° C., wherein the mass ratio of racemic clemastine to L-di-p-toluoyltartaric acid solution is 1:0.2 to 1.6, and the mixture is stirred at this temperature for 1 to 4 hours, cooled to 0 to 10° C., stirred at this temperature for 1 to 4 hours, filtered, and dried to obtain a crude clemastine fumarate intermediate.
3. The synthetic method of clemastine fumarate as claimed in claim 1, characterized in that, The crude clemastine fumarate intermediate in step S2 is dissolved in ethanol at 40-80° C., the mass ratio of the crude clemastine fumarate intermediate to ethanol is 1:5-30, the mixture is stirred at this temperature for 1-4 hours, the temperature is slowly lowered, crystallization is performed, and the mixture is filtered and dried to obtain a finished clemastine fumarate intermediate.
4. The synthetic method of clemastine fumarate as claimed in claim 1, characterized in that, The finished clemastine fumarate intermediate product in step S3 is adjusted to a pH value of 10 to 14 with a 5% to 20% sodium hydroxide solution, extracted, washed, dried, and concentrated to obtain clemastine, ethanol is added to clemastine, the mass ratio of clemastine to ethanol is 1:5 to 20, fumaric acid is added at a temperature of 40 to 80° C., the mass ratio of clemastine to fumaric acid is 1:0.8 to 1.3, the mixture is kept warm for 1 to 4 hours, the temperature is slowly lowered, crystallized, filtered, and dried to obtain clemastine fumarate.