A method for resolving a clemastine fumarate intermediate

Abstract

The application provides a resolution method of clemastine fumarate intermediate, comprising the following steps: 1) reacting racemic N-methyl-2-(2-chloroethyl)pyrrolidine with a chiral resolving agent in a first organic solvent to obtain a diastereomeric salt solution; 2) purifying the material after the reaction in step 1) by cooling and crystallization, and filtering to obtain R-N-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt; 3) dissolving the R-N-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt obtained in step 2) in a second organic solvent-water two-phase system, adjusting the pH value to 9-13, then separating the organic phase, and concentrating to obtain R-N-methyl-2-(2-chloroethyl)pyrrolidine; wherein the chiral resolving agent is at least one selected from L-di(3,5-dinitrobenzoyl) tartaric acid and L-di-p-chlorobenzoyl tartaric acid. By using a specific chiral resolving agent, the resolution efficiency of racemic N-methyl-2-(2-chloroethyl)pyrrolidine is significantly improved, and combined with cooling and crystallization and two-phase acid adjustment replacement, the operation is simple, and the cost is controllable.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a method for resolving chlormastine fumarate intermediates. Background Technology

[0002] Clemastine Fumarate, also known by the trade name Snoping, has the chemical structural formula C. 21 H 26 ClNO·C4H4O4, chemical name is (R-(R) * ,R * 1-Methyl-2-(2-(1-(4-chlorophenyl)-1-phenethoxy)ethyl)-pyrrolidine(E)-2-butenediazone. Chlormastine fumarate is a second-generation H1 receptor antagonist that exerts its anti-allergic effect by selectively blocking histamine H1 receptors. Clinically, it is widely used to treat histamine-mediated allergic diseases such as allergic rhinitis, urticaria, and allergic dermatitis, and is recognized as one of the best antihistamines.

[0003] The chlormastine fumarate molecule contains two chiral centers, theoretically resulting in four stereoisomers (RR, RS, SR, SS). Among them, the (RR)-configuration of chlormastine exhibits significantly superior antihistamine activity compared to the other isomers and is the target product required by the pharmacopoeia. According to the Chinese Pharmacopoeia, chlormastine fumarate raw material must meet specific optical purity requirements, with a specific rotation of 15°–18° dextrorotatory.

[0004] In existing technologies, the preparation processes of chlormastine fumarate mainly fall into the following two routes: Route 1: Final Product Resolution Method. This route uses racemic N-methyl-2-(2-chloroethyl)pyrrolidine as a starting material, and synthesizes the target product through sequential chlorination, etherification, and salt formation reactions, ultimately obtaining racemic chlormastine fumarate (containing four stereoisomers). This is then resolved using a resolving agent to obtain chlormastine fumarate raw material that meets pharmacopoeia requirements (see CN201911136117.1, CN202010194711.2, etc.). A significant drawback of this method is that the target product (R-(R...)... * ,R * Chlomastine fumarate constitutes only 25% of the racemic mixture, with approximately 75% being ineffective or low-activity isomers, resulting in poor atom economy. Furthermore, since the final product contains four stereoisomers, resolution is difficult, typically requiring multiple resolutions and purifications using two or more resolving agents, leading to an overall yield of only about 8%, high production costs, cumbersome operating procedures, and significant waste of subsequent materials.

[0005] Route 2: Intermediate Resolution-Chlorination Method. This route first resolves the racemic N-methyl-2-(2-hydroxyethyl)pyrrolidine to obtain chiral (R)-N-methyl-2-(2-hydroxyethyl)pyrrolidine. Then, using this as a starting material, the target product is synthesized through chlorination, etherification, and salt formation reactions (see CN201310330986.4, etc.). Although this method only requires the resolution of an intermediate containing a single chiral center, making the resolution relatively easy, it has a fatal flaw: the chiral center in the (R)-N-methyl-2-(2-hydroxyethyl)pyrrolidine molecule is located on the carbon atom adjacent to the hydroxyl group. This structure is highly susceptible to racemization or configuration inversion under acidic conditions (e.g., CN201310330986.4). The subsequent chlorination process usually uses strong acidic chlorination reagents such as thionyl chloride or phosphorus oxychloride. Under these conditions, the (R)- intermediate obtained by resolution is very prone to racemization or configuration inversion, which leads to a decrease in the optical purity of the final product, making purification difficult and quality control challenging. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention discloses a method for resolving chlormastine fumarate intermediates, which solves the technical problems of low yield, complex operation, and high product quality risk in the preparation of chlormastine fumarate.

[0007] To achieve the above technical objectives, this invention proposes a method for resolving clomastine fumarate intermediates, the method comprising the following steps: (1) Racemic N-methyl-2-(2-chloroethyl)pyrrolidine was reacted with a chiral resolving agent in a first organic solvent to obtain a diastereomer salt solution; (2) The material after the reaction in step (1) is cooled and purified by crystallization, and the solid and liquid are separated to obtain RN-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt; (3) Dissolve the RN-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt obtained in step (2) in the second organic solvent-water two-phase system, adjust the pH value to 9~13, then separate the organic phase and concentrate it to obtain RN-methyl-2-(2-chloroethyl)pyrrolidine; The chiral resolving agent is selected from at least one of L-bis(3,5-dinitrobenzoyl)tartaric acid and L-dichlorobenzoyltartaric acid.

[0008] Through extensive experiments, the research team of this invention discovered that the use of a specific resolving agent can effectively improve the resolution efficiency of N-methyl-2-(2-hydroxyethyl)pyrrolidine. The resolving agent in the above-mentioned technical solution introduces electron-withdrawing nitro or chlorine groups into the benzene ring, thereby enhancing acidity and intermolecular hydrogen bonding, and can specifically improve the resolution efficiency of racemic N-methyl-2-(2-chloroethyl)pyrrolidine.

[0009] Furthermore, the above technical solution uses racemic N-methyl-2-(2-chloroethyl)pyrrolidine as raw material, and obtains high-purity RN-methyl-2-(2-chloroethyl)pyrrolidine product through salt formation with a chiral resolving agent, crystallization, and acid adjustment and displacement operations. The overall method is simple to operate, has a high yield, and low cost. When the RN-methyl-2-(2-chloroethyl)pyrrolidine obtained by this invention is used in the preparation of chlormastine fumarate, high-purity chlormastine fumarate salt can be stably obtained through etherification and salt formation reactions.

[0010] In a further example of the invention, the dosage of the resolving agent was explored and optimized. Optionally, the molar ratio of the chiral resolving agent to the racemic N-methyl-2-(2-chloroethyl)pyrrolidine is (0.5~0.95):1. A suitable dosage of the resolving agent can significantly reduce costs and impurity content, thereby improving product purity. In an optional example of the invention, the molar ratio of the chiral resolving agent to the racemic N-methyl-2-(2-chloroethyl)pyrrolidine is (0.6~0.9):1, preferably (0.6~0.8):1.

[0011] In a further example of the present invention, the controlled temperature of step (1) is 50~90℃, preferably 60~65℃, and in specific experiments, it can be monitored until the reaction is complete.

[0012] This invention does not restrict the order in which the chiral resolving agent and the racemic N-methyl-2-(2-chloroethyl)pyrrolidine are added to the first solvent. Optionally, the racemic N-methyl-2-(2-chloroethyl)pyrrolidine and the chiral resolving agent are dissolved separately in the first solvent to obtain a racemic solution and a resolving agent solution, and then the resolving agent solution is added dropwise to the racemic solution. This avoids excessively high local concentrations of the resolving agent, prevents non-selective salt formation, improves the selectivity of diastereomeric salt formation, and promotes homogeneous salt formation, which is beneficial for regular crystal growth, reduces impurity encapsulation, and optimizes crystal growth. Optionally, mechanical stirring can be used to promote the dissolution of the reactants in the first solvent. Optionally, stirring for 0.2 to 2.0 h, preferably 0.5 to 1.0 h, is also included after the dropwise addition.

[0013] In a further example of the invention, the type and amount of the first organic solvent were explored and optimized.

[0014] Optionally, the first organic solvent is selected from at least one of ethanol, methanol, acetonitrile, and tetrahydrofuran.

[0015] Optionally, the mass-to-volume ratio of the first organic solvent to the racemic N-methyl-2-(2-chloroethyl)pyrrolidine is (6~12) ml:1 g. An appropriate amount of the first solvent provides a reaction environment that promotes mass transfer and reduces process costs. In an optional example of the invention, the mass ratio of the first organic solvent to the racemic N-methyl-2-(2-chloroethyl)pyrrolidine is (6~10) ml:1 g.

[0016] In a further example of the present invention, the cooling crystallization operation was explored and optimized. Optionally, the cooling crystallization operation includes: cooling the material after the reaction in step (1) to 45~50°C, adding seed crystals and holding for 0.5~2h, followed by gradient cooling crystallization. In an optional example of the present invention, gradient cooling crystallization includes: cooling to 40~45°C and holding for 0.5~2h, then cooling to 20~40°C and holding for 0.5~2h, and finally cooling to 0~20°C and holding for 0.5~2h, and then filtering to obtain RN-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt. The seed crystal is RN-methyl-2-(2-chloroethyl)pyrrolidine crystal, and its dosage is 0.5%~2% of the feed mass of RN-methyl-2-(2-chloroethyl)pyrrolidine, preferably 0.5%~1%. The preparation method of the seed crystal can be: the crystallization product obtained normally without the addition of a seed crystal inducer is purified by repeating the "dissolution-cooling crystallization" operation 2-3 times to obtain the seed crystal.

[0017] It should be noted that the present invention does not limit the specific operation of solid-liquid separation in step (2). Any method that can separate the crystals after crystallization from the mother liquor is acceptable, such as filtration, vacuum filtration, etc. Those skilled in the art can choose according to their needs.

[0018] In a further example of the present invention, in step (3), the pH is adjusted to 9-11 at 0-10°C, thereby promoting the dissolution and recovery of RN-methyl-2-(2-chloroethyl)pyrrolidine through a second organic solvent-water two-phase system, combined with low temperature (0-10°C) and specific pH adjustment, simplifying the operation, and high-purity target product can be obtained by separation. Optionally, the pH of the system can be adjusted using a sodium hydroxide, potassium hydroxide, or sodium carbonate solution with a mass concentration of 2%-20%.

[0019] In an optional example of the present invention, in step (3), the pH is adjusted to 10-11 at 0-10°C.

[0020] It should be noted that the solid phase RN-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt obtained by solid-liquid separation in step (2) does not need to be dried and can be used in the operation of step (3), which further reduces the operation difficulty of the present invention.

[0021] In a further example of the present invention, the composition and amount of the second organic solvent-water two-phase system were explored and optimized.

[0022] Optionally, the second organic solvent is selected from at least one of dichloromethane, ethyl acetate, 1,4-dioxane, and toluene.

[0023] Optionally, in the second organic solvent-water two-phase system, the mass ratio of the second organic solvent to water is 1:(1~8), thereby controlling the alkaline free reaction environment to prevent racemization, improve product quality, and promote complete solvent formation while avoiding emulsification. In an optional example of the present invention, the mass ratio of the second organic solvent to water is 1:(2~6).

[0024] Optionally, the mass-to-volume ratio of the second organic solvent to N-methyl-2-(2-chloroethyl)pyrrolidine is (6~20) ml:1 g, preferably (8~12) ml:1 g.

[0025] In a further example of the present invention, step (3) further includes extracting the aqueous phase after separation with an extractant, and combining the extracted extractant phase into the organic phase, thereby improving the yield of the target product. Optionally, the extractant is selected from at least one of dichloromethane, ethyl acetate, 1,4-dioxane, and toluene. Optionally, the type of extractant may be the same as or different from the type of the second organic solvent, preferably the same, to simplify subsequent operations. It should be noted that the present invention does not limit the specific amount of the extractant, and those skilled in the art can set it according to specific operating conditions.

[0026] In a further example of the invention, step (3) further includes washing the organic phase with water to improve product purity. Optionally, the washing operation includes sequential washing with deionized water and washing with a saturated sodium chloride solution.

[0027] In a further example of the present invention, step (3) further includes drying the washed organic phase; optionally, the drying operation includes adding a desiccant to the organic phase; the desiccant is selected from at least one of anhydrous sodium sulfate, anhydrous magnesium sulfate or molecular sieve.

[0028] This invention significantly improves the resolution efficiency of racemic N-methyl-2-(2-chloroethyl)pyrrolidine by using a chiral resolving agent containing specific electron-withdrawing groups (nitro or chlorine) to enhance acidity and intermolecular hydrogen bonding. Combined with cooling crystallization and two-phase acid-adjusting substitution, it achieves simple, cost-effective, and large-scale production. Compared with existing technologies, this invention avoids the complexity of resolving the four isomers of the final product and also avoids the risk of racemization of the (R)-hydroxy intermediate under acidic conditions in the intermediate resolution-chlorination method. The obtained RN-methyl-2-(2-chloroethyl)pyrrolidine can be stably used to prepare high-purity chlormastine fumarate through etherification and salt formation reactions. Attached Figure Description

[0029] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0030] Figure 1 The liquid chromatogram of RN-methyl-2-(2-chloroethyl)pyrrolidine prepared in Example 1 is shown.

[0031] Figure 2 The liquid chromatogram of chlormastine fumarate prepared in Example 1 is shown.

[0032] Figure 3 The 1H NMR spectrum of chlormastine fumarate prepared in Example 1 is shown.

[0033] Figure 4 The liquid chromatography chromatogram of RN-methyl-2-(2-chloroethyl)pyrrolidine prepared in Example 2 is shown.

[0034] Figure 5 The liquid chromatogram of RN-methyl-2-(2-chloroethyl)pyrrolidine prepared in Example 3 is shown. Detailed Implementation

[0035] To facilitate understanding of the present invention, a more comprehensive description will be provided below, along with preferred embodiments. However, it should be understood that these embodiments are merely for more detailed explanation and should not be construed as limiting the invention in any way, i.e., not intended to limit the scope of protection of the invention.

[0036] Furthermore, it should be noted that although the various steps of the preparation method of the present invention are described in a specific order in the description of the present invention, these orders are not restrictive. Without departing from the basic principles of the present invention, those skilled in the art can perform the steps in different orders.

[0037] Furthermore, the terms "first," "second," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined with "first," "second," etc., may explicitly or implicitly include one or more of that feature. In the description of this invention, unless otherwise stated, "multiple" or "at least one" means two or more.

[0038] All numerical designations, such as pH, temperature, and time, including ranges, are approximate values. It should be understood that, while not always explicitly stated, all numerical designations are preceded by the term "approximately." It should also be understood that, while not always explicitly stated, the reagents described herein are merely examples, and their equivalents are known in the art.

[0039] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1–5” is disclosed, the described range should be interpreted as including ranges “1–4”, “1–3”, “1–2”, “1–2 and 4–5”, “1–3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0040] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as commonly understood by those skilled in the art to which this invention pertains. Unless otherwise specified, the experimental reagents used in the following embodiments are conventional biochemical reagents; and the experimental methods described are conventional methods.

[0041] The chiral resolving agent L-di(3,5-dinitrobenzoyl) tartaric acid used in this embodiment of the invention is named L-(-)-Di(3,5-dinitrobenzoyl) tartrate. Its L-tartaric acid skeleton is esterified with 3,5-dinitrobenzoyl groups at both ends, with the nitro group located at the meta position of the benzene ring. The chiral resolving agent (2) L-di-p-chlorobenzoyl tartaric acid is named (2R,3R)-2,3-bis(4-chlorobenzoyloxy)butanedioic acid. In its structure, the two hydroxyl groups of the L-tartaric acid skeleton are esterified with p-chlorobenzoyl (4-chlorobenzoyl). Both of these resolving agents can be commercially available or prepared in-house.

[0042] Example 1

[0043] A method for resolving chlormastine fumarate intermediates, specifically: (1) Add 400 mL of ethanol and 100 g (0.677 mol) racemic N-methyl-2-(2-chloroethyl)pyrrolidine to a 1 L four-necked flask, stir mechanically and heat to 60~65 °C; control the temperature at 60~65 °C, add 300 mL of the dissolved ethanol solution (207.5 g L-bis(3,5-dinitrobenzoyl)tartaric acid 0.407 mol), and stir for 0.5 h after the addition is complete.

[0044] (2) Cool the reaction solution to 45~50℃, add 1.0g of RN-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt as a seed crystal to induce crystallization, and keep for 1h; cool to 40~45℃ and keep for 1h; cool to 20~40℃ and keep for 1h; cool to 20-25℃ and keep for 1h; filter to obtain a white crystalline granular solid, and proceed directly to the next step without drying.

[0045] (3) Add the solid obtained in the previous step to a 2L four-necked flask, add 300mL of dichloromethane and 600mL of water, and stir until dissolved; cool to 0-10℃, adjust pH to 9-10 with 10% sodium hydroxide, and stir for 10min; separate the liquid and extract the aqueous phase twice with 150mL of dichloromethane, and combine the dichloromethane phases; then wash twice with 300mL of water and 300mL of saturated sodium chloride; finally, dry with anhydrous sodium sulfate, concentrate, and obtain 38g of colorless liquid, yield 38%, liquid phase purity 99.88%, and dextrorotatory 62.5%. The liquid chromatography detection results of RN-methyl-2-(2-chloroethyl)pyrrolidine prepared in this example are shown in the figure. Figure 1 .

[0046] Furthermore, in this embodiment, the obtained RN-methyl-2-(2-chloroethyl)pyrrolidine is used in the preparation of chlormastine fumarate, specifically: The first step, the etherification reaction, involved adding 30g of RN-methyl-2-(2-chloroethyl)pyrrolidine, 33.7g of 1-(4-chlorophenyl)-1-phenylethanol, and 200mL of toluene to a 1L four-necked flask. 14g of sodium amino acid was added in portions, and the mixture was stirred and heated to 90-95°C. The reaction was monitored for completeness. The reaction was quenched with water, and the organic phase was concentrated. The fumaric acid (33.64g) and ethanol (200mL) system formed a salt, yielding 40.6g of a white solid with a yield of 61%.

[0047] The second step involves crystallization: Take 30g of the white solid obtained in the previous step, add 150mL of water and 100mL of dichloromethane, adjust the pH to 2-3 with 5% hydrochloric acid, and separate the liquids; wash the organic phase with water, concentrate 18g of the solution, add 100mL of ethanol and 13g of L-di-p-methylbenzoyl tartaric acid, and cool to crystallize to obtain 42g of white solid.

[0048] Step 3: Fumaric acid replacement: Take 35g of the solid obtained in step 2, add 200mL of water and 150mL of dichloromethane, adjust the pH to 2-3 with 5% hydrochloric acid, and separate the liquid. Wash the organic phase with water, concentrate 11g, add 60mL of ethanol and 3.8g of fumaric acid, and cool to crystallize to obtain 10.5g of white solid with an optical rotation of 16.5. HPLC analysis (T=2.5min, fumaric acid; T=4.4min, chlormastine peak; no single impurities detected) and HPLC detection results are shown in [see attached table]. Figure 2 1H NMR results ( Figure 3 It meets the requirements and is generally in line with the pharmacopoeia requirements.

[0049] Comparative Example 1 The following resolving agents, reported in the prior art (CN201911136117.1): malic acid and L-di-p-toluyl tartaric acid, were selected and subjected to the same resolution process as in Example 1 to resolve racemic methyl-2-(2-chloroethyl)pyrrolidine. The results showed that neither malic acid nor L-di-p-toluyl tartaric acid could precipitate a solid. This may be because methyl-2-(2-chloroethyl)pyrrolidine differs from the methyl-2-(2-hydroxyethyl)pyrrolidine reported in the literature, leading to significant differences in salt formation and crystallization.

[0050] Comparative Example 2 A method for resolving chlormastine fumarate intermediates, specifically: (1) Add 600 mL of ethanol and 100 g (0.677 mol) of racemic N-methyl-2-(2-chloroethyl)pyrrolidine to a 2 L four-necked flask, and heat to 60~65 °C with mechanical stirring; control the temperature at 60~65 °C, and add 600 mL of the dissolved ethanol solution (413 g L-bis(3,5-dinitrobenzoyl)tartaric acid 0.812 mol) dropwise. After the addition is complete, stir for 15 min, and the solid precipitates directly at 50-60 °C; cool down to 40~45 °C and keep for 1 h; cool down to 20~40 °C and keep for 1 h; cool down to 20-25 °C and keep for 1 h; filter to obtain a white crystalline granular solid, which is directly proceeded to the next step without drying.

[0051] (2) Add the solid obtained in the previous step to a 2L four-necked flask, add 400mL of dichloromethane and 1200mL of water, stir to dissolve; cool to 0-10℃, adjust pH to 9-10 with 10% sodium hydroxide, stir for 10min; separate the liquid and extract the aqueous phase twice with 150mL of dichloromethane, combine the dichloromethane phases; then wash twice with 300mL of water and 300mL of saturated sodium chloride; finally, dry with anhydrous sodium sulfate, concentrate, and obtain 67g of colorless liquid with a yield of 67%, dextrorotatory 3.2, basically no separation effect, and the purity of the liquid phase does not need to be tested.

[0052] Example 2

[0053] A method for resolving chlormastine fumarate intermediates, specifically: (1) Add 400 mL of acetonitrile and 100 g (0.677 mol) racemic N-methyl-2-(2-chloroethyl)pyrrolidine to a 1 L four-necked flask, stir mechanically and heat to 50~60 °C; control the temperature at 60~70 °C, add 300 mL of the dissolved acetonitrile solution (272 g L-dichlorobenzoyl tartaric acid 0.644 mol), and stir for 1.0 h after the addition is complete.

[0054] (2) Cool the reaction solution to 50~55℃, add 0.8g of RN-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt as seed crystal to induce crystallization, and keep for 1h; cool to 40~45℃ and keep for 1h; cool to 30~40℃ and keep for 1h; cool to 10-20℃ and keep for 1h; filter to obtain white crystalline granular solid, and proceed directly to the next step without drying.

[0055] (3) Add the solid obtained in the previous step to a 2L four-necked flask, add 300mL of ethyl acetate and 900mL of water, and stir until dissolved; cool to 0~10℃, adjust the pH to 10~11 with 10% potassium hydroxide, and stir for 10min; separate the liquid and extract the aqueous phase twice with 100mL of ethyl acetate, and combine the ethyl acetate phases; then wash twice with 300mL of water and 300mL of saturated sodium chloride; finally, dry with anhydrous sodium sulfate, concentrate, and obtain 52.5g of colorless liquid, with a yield of 52.5%. Figure 4 Liquid phase purity 99.47%, dextrorotatory 50.2%.

[0056] Example 3

[0057] (1) Add 400 mL of methanol and 100 g (0.677 mol) racemic N-methyl-2-(2-chloroethyl)pyrrolidine to a 2 L four-necked flask, stir mechanically and heat to 50~60 °C; control the temperature at 60~65 °C, add 400 mL of the dissolved methanol solution (276 g L-bis(3,5-dinitrobenzoyl)tartaric acid 0.542 mol), and stir for 0.5 h after the addition is complete.

[0058] (2) Cool the reaction solution to 45~50℃, add 0.5g of RN-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt as seed crystal to induce crystallization, and keep for 1h; cool to 40~45℃ and keep for 1h; cool to 30~40℃ and keep for 1h; cool to 10~20℃ and keep for 1h; filter to obtain white crystalline granular solid, and proceed directly to the next step without drying.

[0059] (3) Add the solid obtained in the previous step to a 2L four-necked flask, add 300mL of dichloromethane and 800mL of water, and stir until dissolved; cool to 0~10℃, adjust pH to 9~10 with 5% sodium carbonate, and stir for 15min; separate the liquid and extract the aqueous phase twice with 100mL of dichloromethane, and combine the dichloromethane phases; then wash twice with 300mL of water and 300mL of saturated sodium chloride; finally, dry with anhydrous sodium sulfate, concentrate, and obtain 43g of colorless liquid, with a yield of 43%. Figure 5 Liquid phase purity 99.86%, dextrorotatory 53.5%.

[0060] It should be noted that the above description is a further detailed explanation of the present invention in conjunction with specific embodiments, and it should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, several simple improvements can be made without departing from the concept of the present invention, and all such improvements should be considered to fall within the scope of protection of the present invention.

Claims

1. A method for resolving chlormastine fumarate intermediates, characterized in that, Includes the following steps: (1) Racemic N-methyl-2-(2-chloroethyl)pyrrolidine was reacted with a chiral resolving agent in a first organic solvent to obtain a diastereomer salt solution; (2) The material after the reaction in step (1) is cooled and purified by crystallization, and the solid and liquid are separated to obtain RN-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt; (3) Dissolve the RN-methyl-2-(2-chloroethyl)pyrrolidine resolving agent salt obtained in step (2) in the second organic solvent-water two-phase system, adjust the pH value to 9~13, then separate the organic phase and concentrate it to obtain RN-methyl-2-(2-chloroethyl)pyrrolidine; The chiral resolving agent is selected from at least one of L-bis(3,5-dinitrobenzoyl)tartaric acid and L-dichlorobenzoyltartaric acid.

2. The method for resolving the chlormastine fumarate intermediate according to claim 1, characterized in that, The molar ratio of the chiral resolving agent to the racemic N-methyl-2-(2-chloroethyl)pyrrolidine is (0.5~0.95):1, preferably (0.6~0.9):1, and more preferably (0.6~0.8):

1.

3. The method for resolving the chlormastine fumarate intermediate according to claim 1, characterized in that, The controlled temperature in step (1) is 50~90℃, preferably 60~65℃.

4. The method for resolving the chlormastine fumarate intermediate according to claim 1, characterized in that, The first organic solvent is selected from at least one of ethanol, methanol, acetonitrile, and tetrahydrofuran; And / or, the mass-to-volume ratio of the first organic solvent to the racemic N-methyl-2-(2-chloroethyl)pyrrolidine is (6~12) ml:1 g, preferably (6~10) ml:1 g.

5. The method for resolving the chlormastine fumarate intermediate according to claim 1, characterized in that, The cooling crystallization operation includes: cooling the material after the reaction in step (1) to 45~50℃, adding seed crystals and maintaining for 0.5~2h, and then performing gradient cooling crystallization.

6. The method for resolving the chlormastine fumarate intermediate according to claim 1, characterized in that, In step (3), the pH is adjusted to 9-11 under conditions of 0-10℃, preferably to 10-11.

7. The method for resolving the chlormastine fumarate intermediate according to claim 1, characterized in that, The second organic solvent is selected from at least one of dichloromethane, ethyl acetate, 1,4-dioxane, and toluene; And / or, in the second organic solvent-water two-phase system, the mass ratio of the second organic solvent to water is 1:(1~8), preferably 1:(2~6); And / or, the mass-to-volume ratio of the second organic solvent to N-methyl-2-(2-chloroethyl)pyrrolidine is (6~20) ml:1 g, preferably (8~12) ml:1 g.

8. The method for resolving the chlormastine fumarate intermediate according to claim 1, characterized in that, Step (3) further includes extracting the aqueous phase after separation with an extractant and combining the extracted extractant phase into the organic phase; Preferably, the extractant is selected from at least one of dichloromethane, ethyl acetate, and 1,4-dioxane.

9. The method for resolving the chlormastine fumarate intermediate according to claim 1, characterized in that, Step (3) further includes washing the organic phase with water; Preferably, the water washing operation includes sequential washing with deionized water and washing with saturated sodium chloride solution.

10. The method for resolving the chlormastine fumarate intermediate according to claim 9, characterized in that, Step (3) also includes drying the organic phase after water washing; Preferably, the drying operation includes adding a desiccant to the organic phase; the desiccant is selected from at least one of anhydrous sodium sulfate, anhydrous magnesium sulfate, or molecular sieves.

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