Separation method of chlorpheniramine maleate intermediate impurities

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a separation method of chlorpheniramine maleate intermediate impurities. The method comprises the following steps: 1, taking 200g of column chromatography silica gel, adding 400g of petroleum ether, uniformly stirring until no bubble exists, adding into a 52cm / 3.1 cm column, and adding petroleum ether until the silica gel surface does not descend any more; step 2, adding 10g of p-chlorobenzylpyridine mother liquor, starting to add a developing solvent after all the materials enter the silica gel, starting to perform column chromatography separation, and collecting corresponding impurity components through TLC (Thin Layer Chromatography) control; step 3, after the separation in the step 2 is completed, concentrating under reduced pressure until a material is separated out, stopping concentrating, cooling to 5-10 DEG C, filtering, filtering and draining; step 4, drying the product filtered in the step 3 at 50 DEG C to obtain 0.6 g of white crystalline solid impurity 4-chlorphenyl-2-pyridyl ketone; according to the method, high-purity impurities can be prepared through a column chromatography separation method, and the quality control and medication safety of chlorpheniramine maleate are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and specifically relates to a method for separating impurities of a chlorpheniramine maleate intermediate. Background Art

[0002] Chlorpheniramine maleate belongs to H1 receptor antagonists, which can competitively block the histamine H1 receptor on allergic reaction target cells, so that histamine cannot bind to the H1 receptor, thereby inhibiting the allergic reaction caused by it; however, chlorpheniramine does not affect the metabolism of histamine, nor does it affect the release of histamine in the body. Through long-term clinical practice, it is considered that chlorpheniramine has a strong antihistamine effect, small dosage, and small side effects; the antihistamine effect of chlorpheniramine maleate is stronger than that of diphenhydramine and promethazine, but its anticholinergic and central inhibitory effects are weaker, and adverse reactions such as drowsiness are mild, so it can be suitable for children and patients who need to work during the day to take.

[0003] Impurities are very important for the quality control of drugs. The existence of impurities may directly affect the quality and safety of drugs. The current mainstream industrial synthesis route of chlorpheniramine maleate uses chlorobenzylpyridine as a key intermediate, and it is easy to produce oxidative impurity 4-chlorophenyl-2-pyridylmethanone during the synthesis process and storage process. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for separating impurities of a chlorpheniramine maleate intermediate to solve the problems raised in the above background art.

[0005] To achieve the above purpose, the present invention provides the following technical solution: A method for separating impurities of a chlorpheniramine maleate intermediate, including the following steps; Step 1: Take 200 g of column chromatography silica gel, add 400 g of petroleum ether and stir evenly until there are no bubbles, add it to a column of 52 cm × 3.1 cm, and add petroleum ether to make it solid until the silica gel surface no longer drops; Step 2: Add 10 g of chlorobenzylpyridine mother liquor. After all the materials enter the silica gel, start adding the developing agent and start column chromatography separation. Control the TLC to collect the corresponding impurity components; Step 3: After the separation in Step 2 is completed, concentrate under reduced pressure until materials precipitate, stop concentration, cool down to 5 - 10 °C, and then perform filtration treatment and filter until dry; Step 4: Dry the product filtered in Step 3 at 50 °C to obtain 0.6 g of white crystalline solid impurity 4-chlorophenyl-2-pyridylmethanone; Step 5: Take samples for analysis.

[0006] Preferably, the developing agent is composed of petroleum ether and ethyl acetate, and the mass ratio of petroleum ether to ethyl acetate is 10:1.

[0007] Preferably, an appropriate amount of petroleum ether is added for washing during the filtration process.

[0008] Preferably, the product with a purity of 100% and a melting point of 63.7 - 64.5 °C in Step 5 is a qualified product.

[0009] Compared with the prior art, the beneficial effects of the present invention are as follows: First, the present invention uses column chromatography separation method to obtain high-purity impurities.

[0010] Second, the obtained 4-chlorophenyl-2-pyridylmethanone impurity can effectively fill the gap in the control of impurities in the pharmacopoeia. Using it as an impurity reference substance for the raw material drug of chlorpheniramine maleate is of great significance for improving the quality control and drug safety of chlorpheniramine maleate.

[0011] Third, it has guiding significance for the control of synthesis process parameters and effectively improves the yield and quality of chlorpheniramine maleate. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 It is the synthesis process of chlorobenzylpyridine.

[0013] Figure 2 It is the process of impurity generation.

[0014] Figure 3 It is the GC spectrum of 4-chlorophenyl-2-pyridylmethanone.

[0015] Figure 4 It is the 1H NMR spectrum of 4-chlorophenyl-2-pyridylmethanone.

[0016] Figure 5 It is the 13C NMR spectrum of 4-chlorophenyl-2-pyridylmethanone.

[0017] Figure 6 It is the high-resolution mass spectrum of 4-chlorophenyl-2-pyridylmethanone. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0018] In order to deepen the understanding and recognition of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described and introduced with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments, and no formal restrictions are imposed on this embodiment. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the scope of protection of the present invention. Embodiment

[0019] Please refer to Figures 1-6 , the present invention provides a technical solution: a method for separating impurities of chlorpheniramine maleate intermediate, including the following steps; Step 1: Take 200 g of column chromatography silica gel, add 400 g of petroleum ether, stir evenly until there are no bubbles, add it to a column of 52 cm × 3.1 cm, and add petroleum ether to pack it firmly until the silica gel surface no longer drops; Step 2: Add 10 g of p-chlorobenzylpyridine mother liquor. After all the materials enter the silica gel, start adding the developing agent and start column chromatography separation. Use TLC to control the collection of the corresponding impurity components; Step 3: After the separation in Step 2 is completed, concentrate under reduced pressure until materials precipitate, stop concentration, cool down to 5 - 10 °C, then perform filtration, and filter until dry; Step 4: Dry the product filtered in Step 3 at 50 °C to obtain 0.6 g of white crystalline solid impurity 4-chlorophenyl-2-pyridylmethanone; Step 5: Take a sample for analysis.

[0020] The developing agent is composed of petroleum ether and ethyl acetate, and the mass ratio of petroleum ether to ethyl acetate is 10:1.

[0021] Add an appropriate amount of petroleum ether for washing during the filtration process.

[0022] In Step 5, a product with a purity of 100% and a melting point of 63.7 - 64.5 °C is a qualified product. Example

[0023] Please refer to Figures 1-6 , the present invention provides a technical solution: A method for separating impurities of chlorpheniramine maleate intermediate, including the following steps; Step 1: Take 200 g of column chromatography silica gel, add 400 g of petroleum ether, stir evenly until there are no bubbles, add it to a column of 52 cm × 3.1 cm, and add petroleum ether to pack it firmly until the silica gel surface no longer drops; Step 2: Add 10 g of p-chlorobenzylpyridine mother liquor. After all the materials enter the silica gel, start adding the developing agent and start column chromatography separation. Use TLC to control the collection of the corresponding impurity components; Step 3: After the separation in Step 2 is completed, concentrate under reduced pressure until materials precipitate, stop concentration, cool down to 5 - 10 °C, then perform filtration, and filter until dry; Step 4: Dry the product filtered in Step 3 at 50 °C to obtain 0.6 g of white crystalline solid impurity 4-chlorophenyl-2-pyridylmethanone; Step 5: Take a sample for analysis.

[0024] The developing agent is composed of petroleum ether and ethyl acetate, and the mass ratio of petroleum ether to ethyl acetate is 5:1.

[0025] Add an appropriate amount of petroleum ether for washing during the filtration process.

[0026] The product with a purity of 100% and a melting point of 63.7 - 64.5 °C in Step Five is a qualified product.

[0027] Although the embodiments of the present invention have been shown and described, it should be emphasized that the above description is only an introduction and description of the usage mode of the embodiments of the present invention, and does not impose any formal limitation on the present invention. For those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principle and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for separating impurities of chlorpheniramine maleate intermediate, characterized in that: It includes the following steps; Step 1: Take 200 g of column chromatography silica gel, add 400 g of petroleum ether, stir evenly until there are no bubbles, add it to a column of 52 cm × 3.1 cm, add petroleum ether to make it compact until the silica gel surface no longer drops; Step 2: Add 10 g of 4-chlorobenzylpyridine mother liquor. After all the materials enter the silica gel, start adding the developing agent and start column chromatography separation. Control the collection of corresponding impurity components by TLC; Step 3: After the separation in Step 2 is completed, concentrate under reduced pressure until materials precipitate, stop concentration, cool down to 5 - 10 °C, and then carry out filtration treatment and filter until dry; Step 4: Dry the product filtered in Step 3 at 50 °C to obtain 0.6 g of white crystalline solid impurity 4-chlorophenyl-2-pyridylmethanone; Step 5: Take samples for analysis.

2. The separation method of a chlorpheniramine maleate intermediate impurity according to claim 1, wherein: The developing agent is composed of petroleum ether and ethyl acetate, and the mass ratio of petroleum ether to ethyl acetate is 10:

1.

3. The separation method of an impurity of chlorpheniramine maleate intermediate according to claim 1, wherein: An appropriate amount of petroleum ether is added for washing during the filtration process.

4. The separation method of an impurity of chlorpheniramine maleate intermediate according to claim 1, characterized in that: In Step 5, a product with a purity of 100% and a melting point of 63.7 - 64.5 °C is a qualified product.

Images