Method for obtaining (S)-chlorpheniramine through chiral resolution of chlorpheniramine
By recrystallizing the racemic chlorphenamine with (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid into a salt, and undergoing weak alkali hydrolysis, finally with Malay The acid reaction solves the problem of obtaining high purity (S)-chlorophenamine in the prior art, and achieves efficient and low-cost industrial production.
Patent Information
- Application Number
- CN202411623443.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-14
- Publication Date
- 2025-02-18
AI Technical Summary
There is a lack of efficient and low-cost method in the prior art to obtain high-purity (S)-chlorophenamine through chiral separation, especially in industrial production, where there are constraints and complicated operation problems.
After recrystallization, the racemic chlorphenamine salts with (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid is carried out, and then the weak alkali hydrolysis is performed, and finally the Maleic acid reaction forms maleic acid (S)-chlorophenin.
It achieves efficient and convenient access to high-purity (S)-chlorophenamine maleate, suitable for industrial production, has an optical purity of 98%, simplifies the operation process and reduces production costs.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a method for obtaining (S)-chlorpheniramine by chiral separation of chlorpheniramine. Background Art
[0002] Chlorpheniramine maleate, English name: Chlorpheniramine maleate, chemical name: 1-p-chlorophenyl-1-(2-pyridyl)-3-dimethylaminopropane, molecular formula: C 20 H 23 ClN2O4, molecular weight is 390.86, chemical structure is shown in formula I. Physical and chemical properties: white crystalline powder, melting point 131 ~ 135 ℃, easily soluble in water, ethanol, chloroform, slightly soluble in ether, odorless, bitter taste.
[0003]
[0004] Chlorpheniramine maleate, as a histamine H1 receptor antagonist, can counteract capillary dilation caused by allergic reactions (histamine), reduce capillary permeability, and relieve wheezing caused by bronchial smooth muscle contraction. It has a long-lasting antihistamine effect and also has a significant central inhibitory effect, which can increase the effects of anesthetics, analgesics, hypnotics and local anesthetics. It is mainly metabolized in the liver. It is suitable for skin allergies: urticaria, eczema, dermatitis, drug eruption, pruritus, neurodermatitis, insect bites, and solar dermatitis. It can also be used for allergic rhinitis, vasomotor rhinitis, drug and food allergies.
[0005] With the deepening of pharmaceutical research in the past 20 years, it has been shown that the different stereoselectivity of drug enantiomers makes their affinity with each receptor different, resulting in great differences in pharmacological effects. For example, the well-known DL-(+-) chloramphenicol has only half the efficacy of D(-) chloramphenicol; the drug activity of the L-isomer of propranolol is 100 times greater than that of the D-isomer. Using "chiral" technology, people can effectively remove the ineffective or toxic components in the drug and produce pure chiral drugs with a single directional structure, so that the drug ingredients are purer, and the efficacy is faster and the course of treatment is shorter when treating diseases. Therefore, the research on chiral drugs has become one of the new directions in international new drug research. Because although the dextrorotatory chlorpheniramine has the same mechanism of action as the racemic chlorpheniramine, its efficacy is stronger. Therefore, when dextrorotatory chlorpheniramine is used with other drugs to form a new compound preparation, better synergy can be obtained.
[0006] However, the existing literature reports rarely use the method of chlorpheniramine and chiral resolution reagent acid salt formation to obtain dextrorotatory chlorpheniramine. Therefore, it is necessary to provide a method for resolving the chiral drug of dextrorotatory chlorpheniramine maleate with higher resolution.
[0007] At present, there are few reports on the method of obtaining (S)-chlorpheniramine by splitting reagents efficiently and at low cost. Although patents IES950206A and IES950207A can finally obtain dextrorotatory chlorpheniramine by 3,5-dinitrobenzoic acid and chlorpheniramine salt formation, there are obvious limitations. First, it is necessary to add a large amount of seed crystals in advance, that is, to add 3,5-dinitrobenzoic acid and left-handed chlorpheniramine salt crystals to promote the precipitation of left-handed chlorpheniramine salt crystals, so that the (S)-chlorpheniramine in the mother liquor is enriched. If there is no seed crystal of the left-handed chlorpheniramine salt in advance, the left-handed chlorpheniramine salt crystals cannot be precipitated in large quantities, and the mother liquor cannot be enriched with (S)-chlorpheniramine, which shows that the seed crystals are a significant rate-limiting step and constraint factor of the method. Secondly, the operation method is also relatively cumbersome, and it is necessary to remove the salt crystals of left-handed chlorpheniramine first, and then add acid to the remaining mother liquor to continue the reaction. Summary of the invention
[0008] In view of this, the present invention provides a chiral separation method of chlorpheniramine. The chiral separation method has a good separation effect, can simply and conveniently obtain high-purity maleic acid (S)-chlorpheniramine, and is suitable for industrial production.
[0009] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:
[0010]
[0011] The invention provides a method for obtaining (S)-chlorpheniramine through chiral resolution of chlorpheniramine. The method is characterized in that racemic chlorpheniramine and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid are salified, and then crystals are precipitated through recrystallization, and crystallization is performed to obtain S-configuration chlorpheniramine and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid, and then the S-configuration chlorpheniramine in a free state is obtained through weak base hydrolysis, and then the chlorpheniramine is reacted with maleic acid to form a salt to obtain maleic acid (S)-chlorpheniramine.
[0012] Specific:
[0013] Step 1) In a solvent, racemic chlorpheniramine is reacted with a resolving agent acid to form a salt, and filtered to obtain a white solid;
[0014] Step 2) in a suitable solvent, at a certain temperature, the salt of chlorpheniramine and a resolving agent is recrystallized to obtain a solid salt of (S)-chlorpheniramine and a resolving agent;
[0015] Step 3) adding a weakly alkaline aqueous solution to the solid obtained in step 2 to dissociate, and extracting with an organic solvent to obtain a high-purity (S)-chlorpheniramine;
[0016] Step 4) in an organic solvent, (S)-chlorpheniramine and maleic acid are fully stirred and reacted, and (S)-chlorpheniramine maleate is obtained after suction filtration;
[0017] As an optimization method, the chiral separation method is characterized in that:
[0018] The resolution reagent acid in step 1) is (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid,
[0019] The solvent used in step 1) or 2) is selected from one or more of acetone, toluene, acetonitrile, tetrahydrofuran, isopropanol, 1,4-dioxane, chloroform, n-hexane, ethyl acetate, and ethanol.
[0020] The base used for the alkaline dissociation in step 3 is selected from one or more of ammonia water, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydroxide, and sodium hydroxide, preferably sodium carbonate, and the solvent is water. The mass molar ratio of the base to the compound of formula 3 is 2-6:1; preferably 4:1; and the reaction temperature is 0-100°C.
[0021] The solvent used in step 4 is selected from one or more of ethyl acetate, isopropanol, and anhydrous ethanol.
[0022] The principle of the invention is as follows: the chiral separation method forms a salt of racemic chlorpheniramine with (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid, and utilizes the difference in solubility of diastereoisomers in a solvent to separate (S)-chlorpheniramine and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinate, and then uses alkali to dissociate to obtain (S)-chlorpheniramine with high purity, and finally forms a salt with maleic acid to obtain (S)-chlorpheniramine maleate.
[0023] Beneficial Effects
[0024] The present invention screens a variety of resolution agents, wherein the resolution agent acid such as L-dibenzoyltartaric acid, S-(+) mandelic acid, N-acetyl-L-leucine, D-camphorsulfonic acid, D-(+)-p-methyldibenzoyltartaric acid, D-dibenzoyltartaric anhydride, D-(+)-di-p-methoxybenzoyltartaric acid is salified to form an oily substance, which cannot be recrystallized to obtain a resolution body. Only racemic chlorpheniramine is solid after salification with (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid, which can be recrystallized, and S-(S)-chlorpheniramine can be formed subsequently. The resolution agent acid used in the present invention is low in price, the raw materials are easily available, the process operation is convenient, and the obtained (S)-chlorpheniramine has an ee value of 98%, is suitable for large-scale industrial production, and has good industrial application prospects. DETAILED DESCRIPTION
[0025]
[0026] Example 1: Salt Formation of Chlorpheniramine and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic Acid
[0027] Weigh 25g of chlorpheniramine in a 5L beaker, add 700mL of methyl tert-butyl ether, and stir mechanically. Weigh 35.15g of (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid in a 500mL beaker, add 400mL of methyl tert-butyl ether, and dissolve the methyl tert-butyl ether solution of (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid by ultrasonic stirring, and then add the methyl tert-butyl ether of chlorpheniramine to produce a white insoluble solid. Then continue to add 2L of methyl tert-butyl ether. Stir for 10h, filter and dry to obtain 50.6457g of white chlorpheniramine and (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinate solid, with a yield of 84.20%.
[0028] Example 2 Recrystallization of S-configuration chlorpheniramine and (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid
[0029] 50 g of chlorpheniramine and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinate obtained in Example 1 (wherein free chlorpheniramine 20.78 g, (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid 29.22 g) were poured into an eggplant-shaped bottle, 150 mL of ethyl acetate and 50 mL of acetone were added, a reflux condenser was inserted, and the mixture was heated in an oil bath at 70 ° C for 0.5 h, cooled at room temperature for crystallization, and the crystallization time was 60 h. 12.72 g of a white solid was obtained by suction filtration, with a yield of 25.44% and an ee value of 77.2764%.
[0030] Example 3 Recrystallization of S-configuration chlorpheniramine and (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid
[0031] Weigh 0.5 g of chlorpheniramine and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinate obtained in Example 1 as a white solid (wherein free chlorpheniramine 0.2078 g, (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid 0.2922 g) into an eggplant-shaped bottle, add 1.0 mL of ethyl acetate and 0.5 mL of acetone, insert a reflux condenser, heat in an oil bath at 60 ° C for 0.5 h, cool and crystallize, cool and crystallize at room temperature for 12 h, and filter to obtain 0.105 g of a white solid, with a yield of 21% and an ee value of 70%.
[0032] Example 4 Recrystallization of S-configuration chlorpheniramine and (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid
[0033] 1 g of chlorpheniramine obtained in Example 1 and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinate white solid (wherein free chlorpheniramine 0.4156 g, (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid 0.5844 g) were poured into an eggplant-shaped bottle, 3 mL of ethyl acetate and 1 mL of acetone were added, a reflux condenser was inserted, and the mixture was heated in an oil bath at 60° C. for 0.5 h, cooled at room temperature for crystallization, and the crystallization time was 12 h. 0.302 g of a white solid was obtained by suction filtration, with a yield of 30.2% and an ee value of 70%.
[0034] Example 5 Recrystallization of S-configuration chlorpheniramine and (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid
[0035] 1 g of chlorpheniramine obtained in Example 1 and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinate white solid (wherein free chlorpheniramine 0.4156 g, (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid 0.5844 g) were poured into an eggplant-shaped bottle, 3 mL of ethyl acetate and 1 mL of acetone were added, a reflux condenser was inserted, and the mixture was heated in an oil bath at 60° C. for 0.5 h, cooled in an ice bath for crystallization, and the crystallization time was 12 h. 0.298 g of a white solid was obtained by suction filtration, with a yield of 29.8% and an ee value of 69%.
[0036] Example 6 Recrystallization of S-configuration chlorpheniramine and (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid
[0037] 1 g of chlorpheniramine obtained in Example 1 and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinate white solid (wherein free chlorpheniramine 0.4156 g, (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid 0.5844 g) were poured into an eggplant-shaped bottle, 3 mL of ethyl acetate and 1 mL of acetone were added, a reflux condenser was inserted, and the mixture was heated in an oil bath at 60° C. for 0.5 h, cooled at -5° C. for crystallization for 12 h, cooled in an ice bath for crystallization for 12 h, and filtered to obtain 0.296 g of a white solid, with a yield of 29.6% and an ee value of 70%.
[0038] Example 7 Recrystallization of S-configuration chlorpheniramine and (2R,3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid
[0039] Take 12.72g of chlorpheniramine and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinate white solid obtained in Example 2, add it to a single-mouth bottle, add a stirrer, add 38.2mL of ethyl acetate and 12.7mL of acetone, insert a reflux condenser, heat and stir at 60°C for 0.5h, cool and crystallize for 12h, and filter to obtain 5.0414g of white solid, with a yield of 39.64%, an ee value of 98.1%, [α] D 25 =+34.112 (c 0.21, CHCl3).
[0040] Table 1 is a summary of the recrystallization of S-configuration chlorpheniramine and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid obtained using different recrystallization conditions in Examples 2-7.
[0041]
[0042]
[0043]
[0044] Embodiment 8 Preparation of free state (S)-chlorpheniramine (weak alkalization)
[0045] Take a 500mL beaker 1, weigh 2.62g of (S)-chlorpheniramine and (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid salt obtained in Example 7, add a stirrer and 40mL of water to beaker 1, and start stirring. Weigh 1.68g of anhydrous sodium carbonate solid in a 50mL conical flask, add 10mL of water to the conical flask and dissolve it by ultrasonic stirring. Add the sodium carbonate solution dropwise to beaker 1, stir for 2h, then extract with dichloromethane (50mL×3), then dry with anhydrous sodium sulfate, and then spin dry the dichloromethane solution containing (S)-chlorpheniramine with a rotary evaporator to obtain 1.1418g of (S)-chlorpheniramine as a white oily liquid.
[0046] After recrystallization, add alkali to free (S)-(S)-chlorpheniramine 1 The H-NMR data have the following characteristics:
[0047] 1H NMR(300MHz,Chloroform-d)δ8.56(ddd,J=4.9,1.9,0.9Hz,1H),7.55(td,J=7.7,1.9Hz,1H),7 .27(q,J=8.6Hz,4H),7.18–7.03(m,2H),4.13(t,J=7.0Hz,1H),2.63–2.36(m,1H),2.19(s,9H).
[0048] Example 9 Preparation of (S)-Chlorpheniramine Maleate
[0049] Weigh 1.1323g of (S)-chlorpheniramine in a 50mL single-mouth bottle 1, add a stirrer and 8mL of ethyl acetate to the single-mouth bottle 1 for stirring. Weigh 0.4782g of maleic acid in a 50mL conical flask, add a stirrer and 8mL of ethyl acetate to the conical flask, stir for a while, add the ethyl acetate solution of maleic acid to the (S)-chlorpheniramine, then stir in a cold hydrazine at 0°C at a speed of 400rpm, and after stirring for 2h, filter and obtain 0.6576g of right (S)-chlorpheniramine maleate as a white solid, with a yield of 40.83%.
[0050] (S)-Chlorpheniramine is salified with maleic acid to obtain (S)-chlorpheniramine maleate. 1 The H-NMR data have the following characteristics:
[0051] 1 H NMR(300MHz,Chloroform-d)δ8.58(ddd,J=4.9,1.9,0.9Hz,1H),7.61(td,J=7.7,1.8Hz,1H),7.32–7.22(m,4H),7.21 –7.09(m,2H),6.29(s,2H),4.21–4.03(m,1H),3.33–2.91(m,2H),2.82(s,6H),2.79–2.71(m,1H),2.53–2.36(m,1H).
Claims
1. A method for obtaining (S)-chlorpheniramine by chiral resolution of chlorpheniramine, characterized in that, The specific steps are as follows: 1) In a solvent, racemic chlorpheniramine is reacted with a resolution agent acid to form a salt, and filtered to obtain a white solid; wherein the resolution agent acid is (2R, 3R)-2,3-bis(4-methylbenzoyl)oxysuccinic acid; 2) recrystallizing the salt of chlorpheniramine and a resolving agent in a solvent to obtain a solid salt of (S)-chlorpheniramine and a resolving agent; 3) adding a weakly alkaline aqueous solution to the solid obtained in step 2) to dissociate, and extracting with an organic solvent to obtain a high-purity (S)-chlorpheniramine; 4) In a solvent, (S)-chlorpheniramine and maleic acid are fully stirred for reaction, and (S)-chlorpheniramine maleate is obtained after suction filtration.
2. The chiral separation method according to claim 1, characterized in that: The solvent used in step 1) is selected from one or more of ethyl acetate, ethanol, tetrahydrofuran, toluene, methyl tert-butyl ether, acetonitrile, isopropanol, chloroform, and 1,4-dioxane; The solvent used in step 2) is selected from one or more of acetone, toluene, acetonitrile, tetrahydrofuran, isopropanol, 1,4-dioxane, chloroform, n-hexane, ethyl acetate, and ethanol; The base used in step 3) is selected from one or more of ammonia water, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydroxide, and sodium hydroxide; the mass molar ratio of the base to the compound of formula 3 is 2-6:1; the reaction temperature is 0-100°C; The solvent used in step 4 is selected from one or more of ethyl acetate, isopropanol, and anhydrous ethanol.