Purification method of citric acid alverine intermediate

Abstract

The invention discloses a purification method of a citric acid alverine intermediate, and belongs to the technical field of medical intermediates. The purification method comprises the following steps: mixing alverine oily matter (the content is not less than 90%, the content of an EP pharmacopoeia impurity A is not higher than 3%, the content of an EP pharmacopoeia impurity B is not higher than 3%, the content of an EP pharmacopoeia impurity C is not higher than 1%, the content of an EP pharmacopoeia impurity D is not higher than 1%, and the content of an EP pharmacopoeia impurity E is not higher than 5%) with water, adding acid to adjust the pH value, and dissolving the alverine oily matter in water, washing the water layer by using an organic solvent which is insoluble in water, and removing an organic layer; adjusting the pH value of the water layer by adopting alkali, extracting the product by adopting an organic solvent, drying, filtering and evaporating the organic solvent under reduced pressure to dryness to obtain a pure product of the alverine intermediate. The purification method has the advantages of simple and feasible operation steps, reduction of the production cost of enterprises, reduction of the discharge of three wastes in the production process, and suitableness for industrial production.

Description

Technical Field

[0001] The present invention relates to a compound purification method in the technical field of pharmaceutical intermediates, in particular to a purification method for an alverine citrate intermediate (Formula I), which adopts an efficient, convenient and low-energy intermediate purification method which can significantly reduce impurities A, B, C, D and E in the European Pharmacopoeia 11.4 edition. Background Art

[0002] Alverine Citrate is a synthetic derivative of papaverine, independently developed by the British company Norgine, and is a highly selective calcium channel modulator. Alverine Citrate was first launched in the UK in 1996, and my country approved the import of the drug in 1996. It is widely used in the clinic to treat irritable bowel syndrome, intestinal spasm, abdominal pain and pain caused by diverticular disease, biliary spasm, spasmodic pain caused by urinary tract stones or infection, functional abdominal pain syndrome, etc.

[0003] Alverine (Formula I) is an important intermediate for the synthesis of alverine citrate. The raw material drug alverine citrate is obtained by salification with anhydrous citric acid. The European Pharmacopoeia has strict requirements on the quality profile of alverine citrate. The European Pharmacopoeia 11.4 clearly stipulates that the content of impurity C and impurity D shall not exceed 0.15% and the total impurity shall not exceed 0.5% (determined by gas chromatography). The specific structural formula is as follows:

[0004]

[0005] It can be inferred from the structure of the above impurities that impurity A, impurity B, and impurity C are all starting materials or intermediates in the route of "taking 3-phenylpropanol as starting material, obtaining alverine citrate through chlorination, amination, alkylation, salification and other steps" (impurity A and impurity C are intermediates, and impurity B is a starting material). Each intermediate of this route is a liquid oily substance, which cannot be purified by the mode of crystallization. If improper control is performed during the preparation process (especially post-treatment), one or more impurity contents may exceed the standard, thereby causing the quality of the alverine citrate bulk drug to be reduced or unable to meet the requirements of the European Pharmacopoeia for impurities. Therefore, before alverine (Formula I) and citric acid are salified, alverine (Formula I) should be purified to avoid the adverse effects of impurities on the quality of alverine citrate.

[0006] Document A: Synthesis of Alverine Citrate, "Chinese Journal of Pharmaceutical Industry", 2012, 43(3): 164-166. N-ethyl-3-phenylpropylamine and 3-phenylpropane bromide are used as starting materials, and the reaction is carried out under alkaline conditions with the catalyst of tetrabutylammonium iodide. After the reaction, the organic layer is separated and extracted with ethyl acetate. The organic layer is dried, filtered, and concentrated under reduced pressure to obtain a crude intermediate alverine (Formula I). ​​The crude intermediate alverine (Formula I) is distilled under reduced pressure at high temperature (200-220°C) to obtain pure alverine (Formula I) (purity 99.6%, determined by liquid chromatography, area normalization method).

[0007] Patent CN108658786B first dissolves the intermediate alverine crude product containing the impurity N-ethyl-3-phenylpropylamine (impurity C in European Pharmacopoeia 11.4) in an organic solvent with poor water miscibility, then extracts the organic layer with an aqueous solution of suitable pH, discards the water layer, and then dries, filters, and evaporates the solvent under reduced pressure on the organic layer. The residual amount of the impurity N-ethyl-3-phenylpropylamine in the intermediate alverine (Formula I) can be strictly controlled, thereby producing a relatively high-quality raw material drug alverine citrate.

[0008] Patent CN101838205A discloses a method for preparing alverine citrate, which uses 3-phenylpropanol as a starting material, obtains 3-phenylpropanol bromide through a bromination reaction, then reacts with an aqueous solution of ethylamine to obtain N-ethyl-3-phenylpropane, then reacts with 3-phenylpropanol bromide under alkaline conditions, and obtains alverine (Formula I) through high vacuum distillation, and finally salifies with citric acid to obtain alverine citrate.

[0009] In order to overcome the industrial energy-consuming methods such as distillation under high temperature and high vacuum, patent CN103508898B uses 3-phenylchloropropane as the starting material and reacts it with ethylamine hydrochloride under alkaline conditions in a "one-pot" reaction to produce alverine (Formula I), which is then post-treated and finally salified with citric acid to obtain alverine citrate.

[0010] Reference B: Benzimidazolin-2-ylidene N-heterocyclic carbine complexes of rutheniu m as a simple catalyst for the N-alkylation of amines using alcohols and diols, RSC Adv., 2015, 5, 4434–4442) Using ethylamine and 3-phenylpropanol as starting materials, the reaction was catalyzed by a self-made metal ruthenium (Ru) complex. After the reaction, alverine (Formula I) was obtained by separation by silica gel column chromatography.

[0011] The above-mentioned documents or patents involve the synthesis process of alverine citrate, and there is a probability of introducing the five impurities mentioned in the European Pharmacopoeia 11.4 Edition, but none of them studies the residue and removal of these five impurities that may seriously affect the quality of the raw material drug product; although document B uses a silica gel chromatographic column to separate alverine (Formula I), which guarantees its purity to a certain extent, it uses expensive methods such as homemade metal ruthenium (Ru) complexes for reaction catalysis and silica gel chromatographic columns, which is not only not suitable for industrial production, but also produces a large amount of solid waste, which does not comply with increasingly stringent environmental protection regulations; Document A and patent CN101838205A both obtain alverine (Formula I) through high vacuum and high temperature distillation purification. This method is inefficient and energy-intensive, and has high requirements for corresponding equipment, which greatly increases the difficulty of industrial promotion.

[0012] Therefore, a production method should be provided that is in line with the current energy-saving and environmental protection theme, is cheap and easy to operate, and is suitable for industrial promotion, which can effectively control the impurity residues of the raw material alverine citrate and ensure that it meets the requirements of existing pharmacopoeias (such as the European Pharmacopoeia 11.4 Edition). Summary of the invention

[0013] In order to overcome the above technical defects, the present invention provides a post-processing purification method, which can effectively reduce the related impurities of alverine specified in the European Pharmacopoeia 11.4.

[0014] The method for purifying an alverine citrate intermediate of the present invention comprises the following steps:

[0015] A. Mixing the alverine oil with water, adding acid to adjust the pH value to dissolve the alverine oil in water, washing the aqueous layer with a water-immiscible organic solvent, and discarding the organic layer;

[0016] B. The pH value of the aqueous layer is adjusted with alkali, the product is extracted with an organic solvent, and the organic solvent is dried, filtered and evaporated under reduced pressure to obtain the pure product of the alverine intermediate.

[0017] Furthermore, in the above technical scheme, the alverine oily substance described in step A comprises: an alverine content of not less than 90%, an EP Pharmacopoeia impurity A content of not more than 3%, an EP Pharmacopoeia impurity B content of not more than 3%, an EP Pharmacopoeia impurity C content of not more than 1%, an EP Pharmacopoeia impurity D content of not more than 1%, and an EP Pharmacopoeia impurity E content of not more than 5%.

[0018] Furthermore, in the above technical scheme, the alverine oily substance described in step A uses "3-phenylpropanol as a starting material, and undergoes chlorination, amination, alkylation, salification and other steps to obtain alverine citrate" or contains the alverine oily substance obtained by this route.

[0019] Furthermore, in the above technical solution, the acid in step A is selected from at least one of hydrochloric acid solution, sulfuric acid solution or acetic acid solution.

[0020] Further, in the above technical solution, the pH in step A is 3-8;

[0021] Furthermore, in the above technical solution, the organic solvent in step A is selected from at least one of n-hexane, cyclohexane, n-heptane, methyl tert-butyl ether or diethyl ether.

[0022] Furthermore, in the above technical scheme, the mass ratio of the alverine oil to water in step A is 1:1-50; the mass ratio of the alverine oil to the water-insoluble organic solvent is 1:0.3-10, wherein the preferred ratio is 1:0.5-5, and the more preferred ratio is 1:1-4 times.

[0023] Furthermore, in the above technical solution, step A is repeated 1-30 times, wherein the preferred ratio is 1-10 times, and the more preferred ratio is 1-5 times.

[0024] Furthermore, in the above scheme, when the ratio of the alverine oil to the water-insoluble organic solvent in step A is 0.3-0.5 times, the washing times are 3-10 times; when the ratio of the alverine oil to the water-insoluble organic solvent in step A is 1-4 times, the washing times are 1-3 times.

[0025] Furthermore, in the above technical solution, the base in step B is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

[0026] Furthermore, in the above technical solution, the pH in step B is 5.5-14.

[0027] Furthermore, in the above technical solution, the organic solvent in step B is selected from at least one of ethyl acetate, dichloromethane, chloroform, toluene, xylene, n-butanol, C7-C12 fatty alkanes or fatty olefins.

[0028] Advantageous Effects of the Invention

[0029] 1. The present invention is the first to provide a clear, simple, easy and reliable solution to the residual and control problems of all impurities mentioned in the EP Pharmacopoeia of alverine citrate intermediates, which can ensure that the alverine citrate raw materials produced subsequently have high quality and meet the requirements of the EP Pharmacopoeia.

[0030] 2. Compared with other purification methods, the present invention can reduce the residual amounts of the five impurities specified in the EP Pharmacopoeia in the intermediate alverine only by liquid-liquid extraction. The method is simple and easy to operate, produces less waste, and is suitable for large-scale industrial promotion.

[0031] 3. This method does not require high-temperature distillation and can be operated using only conventional equipment, which consumes less energy and is consistent with the current environmental protection concept of energy conservation and emission reduction. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the GC spectrum of the alverine oily product before purification in Example 2;

[0033] Figure 2 This is the GC spectrum of the alverine oily product after purification in Example 2.

[0034] Figure 1 and Figure 2 Middle: a is the normal spectrum, b is the impurity magnification, and c is the list of peak positions and area values ​​corresponding to the spectrum. DETAILED DESCRIPTION

[0035] Example 1 Preparation of Alverine Oil

[0036] (1) Preparation of 3-phenylchloropropane

[0037] Add 30g of 3-phenylpropanol and 0.6g of DMF to a 250mL three-necked round-bottom flask, cool to 15°C, slowly add 27.52g of thionyl chloride, and control the internal temperature below 30°C. After the addition is complete, heat to 80-85°C and react for 1-3h. After the reaction is complete, cool down. In another reaction bottle, weigh 100g of saturated sodium bicarbonate + 200g of water, cool in an ice water bath, add the reaction solution, and control the internal temperature below 30°C. After the addition is complete, transfer to room temperature and stir for 0.5h, separate the layers, separate the water layer, and the organic layer is a light yellow oily 3-phenylchloropropane, which does not need further purification.

[0038] (2) Preparation of N-ethylamphetamine

[0039] Add the above-mentioned whole batch of 3-phenylchloropropane oil to the autoclave. Add 25.87 g of 70% ethylamine aqueous solution, 25 mL of water and 50 mL of ethanol. Seal and react at 100 ° C for 5 hours. After the reaction is completed, cool to room temperature, add 26.78 g of liquid caustic soda and 90 g of water, stir and separate, and obtain a light yellow to orange N-ethylamphetamine organic layer without further purification.

[0040] (3) Preparation of Alverine

[0041] The above-mentioned whole batch of N-ethylamphetamine organic layer is added to the autoclave. Weigh into light yellow oily 3-phenylchloropropane 23.3g, sodium bicarbonate 12.66g, 90mL water and 18mL ethanol. Closed 140 ℃ reaction 10h. The reaction is cooled to room temperature after completion. Standing stratification, the organic layer is distilled under reduced pressure at 50-70 ℃ to no distillate, and a light yellow or brown oily substance (alverine oily substance) of about 45g is obtained. The alverine oily substance is subjected to gas chromatography detection (GC), and the area normalization method is calculated, and the alverine content is 93.54%, the EP Pharmacopoeia impurity A content is 1.15%, the EP Pharmacopoeia impurity B content is 1.35%, the EP Pharmacopoeia impurity C content is 0.28%, the EP Pharmacopoeia impurity D content is 0.30%, and the EP Pharmacopoeia impurity E content is 2.54%.

[0042] The alverine oily substance obtained above (alverine content is 93.54%, EP Pharmacopoeia impurity A content is 1.15%, EP Pharmacopoeia impurity B content is 1.35%, EP Pharmacopoeia impurity C content is 0.28%, EP Pharmacopoeia impurity D content is 0.30%, EP Pharmacopoeia impurity E content is 2.54%) is subjected to post-treatment under different conditions respectively, and the purity and impurity content of the obtained alverine are as follows:

[0043] Experiment 1 Post-treatment conditions: Add 30 g of water to 15 g of alverine oil, add 1N hydrochloric acid dropwise to adjust the pH of the water layer to 5 under stirring at room temperature, wash the water layer 3 times with n-heptane, 5 g each time, and discard the n-heptane layer. Adjust the pH of the water layer to 7 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, discard the water layer, and distill the organic layer under reduced pressure until there is no distillate, to obtain 14 g of alverine oil, with a content of 99.76%.

[0044] Experiment 2 Post-treatment conditions: Add 30 g of water to 15 g of alverine oil, stir at room temperature, add 1N hydrochloric acid to adjust the pH of the water layer to 5, wash the water layer 3 times with n-heptane, 10 g each time, and discard the n-heptane layer. Adjust the pH of the water layer to 7 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, discard the water layer, and distill the organic layer under reduced pressure until there is no distillate, to obtain 14 g of alverine oil, with a content of 99.54%.

[0045] Experiment 3 Post-treatment conditions: Add 30 g of water to 15 g of alverine oil, add 1N hydrochloric acid dropwise to adjust the pH of the water layer to 5 under stirring at room temperature, wash the water layer 3 times with n-heptane, 15 g each time, and discard the n-heptane layer. Adjust the pH of the water layer to 7 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, discard the water layer, and distill the organic layer under reduced pressure until there is no distillate, to obtain 14 g of alverine oil, with a content of 99.60%.

[0046]

[0047] Example 2

[0048] Add the whole batch of N-ethylamphetamine organic layer to the autoclave. Weigh in 23.3g of light yellow oily 3-phenylchloropropane, 12.66g of sodium bicarbonate, 90mL of water and 18mL of ethanol. Seal and react at 140℃ for 10h. After the reaction is finished, cool to room temperature. Let stand and separate, distill the organic layer under reduced pressure at 50-70℃ until there is no distillate, and obtain about 42g of light yellow or brown oily substance (alverine oily substance).

[0049] The obtained alverine oil was subjected to gas chromatography detection (GC, Figure 1 ), calculated by area normalization method, the content of alverine is 92.10%, the content of EP Pharmacopoeia impurity A (13.3min) is 1.65%, the content of EP Pharmacopoeia impurity B (13.6min) is 2.28%, the content of EP Pharmacopoeia impurity C (15.2min) is 0.06%, the content of EP Pharmacopoeia impurity D (25.5min) is 0.21%, and the content of EP Pharmacopoeia impurity E (38.5min) is 3.14%.

[0050] The alverine oily substance obtained above was post-treated. 100g of water was added to the alverine oily substance (92.10%). Under stirring at room temperature, 1N hydrochloric acid was added dropwise to adjust the pH value of the water layer to 4. The water layer was washed twice with n-heptane, 14g each time, and then washed once with 14g of methyl tert-butyl ether. The n-heptane layer and the methyl tert-butyl ether layer were discarded. The water layer was adjusted to pH=8 with a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, the water layer was discarded, and the organic layer was distilled under reduced pressure until there was no distillate, to obtain 38g of alverine oily substance, which was detected by gas chromatography (GC, Figure 2 ), calculated by area normalization method, the purity is 99.71%, and the impurities after post-treatment are shown in the following table:

[0051]

[0052]

[0053] Example 3

[0054] Add the whole batch of N-ethylamphetamine organic layer to the autoclave. Weigh in 23.3g of light yellow oily 3-phenylchloropropane, 12.66g of sodium bicarbonate, 90mL of water and 18mL of ethanol. Seal and react at 140℃ for 10h. After the reaction is completed, cool to room temperature. Let stand and separate, and distill the organic layer under reduced pressure at 50℃-70℃ until there is no distillate, to obtain about 44g of light yellow or brown oily substance (alverine oily substance).

[0055] The obtained alverine oil was subjected to gas chromatography (GC) detection and calculated by area normalization method. The content of alverine was 92.01%, the content of EP Pharmacopoeia impurity A was 1.70%, the content of EP Pharmacopoeia impurity B was 2.29%, the content of EP Pharmacopoeia impurity C was 0.18%, the content of EP Pharmacopoeia impurity D was 0.19%, and the content of EP Pharmacopoeia impurity E was 2.78%.

[0056] The alverine oily substance obtained above was post-treated. 100g of water was added to the alverine oily substance (92.01%). Under stirring at room temperature, 1N hydrochloric acid was added dropwise to adjust the pH value of the water layer to 5. 36g of methyl tert-butyl ether and 36g of n-heptane were used to wash the water layer once, and the methyl tert-butyl ether layer and the n-heptane layer were discarded. The water layer was adjusted to pH=8 with a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the water layer was discarded. The organic layer was distilled under reduced pressure until there was no distillate, and 39g of alverine oily substance was obtained. Gas chromatography (GC) was performed, and the purity was calculated by area normalization method. It was 99.85%. The impurity situation after post-treatment is shown in the following table:

[0057]

[0058] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.

Claims

1. A method for purifying an alverine citrate intermediate, characterized in that: The following steps are involved: A. Mixing the alverine oil with water, adding acid to adjust the pH value to dissolve the alverine oil in water, washing the aqueous layer with a water-immiscible organic solvent, and discarding the organic layer; B. The pH value of the aqueous layer is adjusted with alkali, the product is extracted with an organic solvent, and the organic solvent is dried, filtered and evaporated under reduced pressure to obtain the pure product of the alverine intermediate.

2. The method for purifying the alverine citrate intermediate according to claim 1, characterized in that: The alverine oily substance described in step A, wherein: the alverine content is not less than 90%, the EP Pharmacopoeia impurity A content is not higher than 3%, the EP Pharmacopoeia impurity B content is not higher than 3%, the EP Pharmacopoeia impurity C content is not higher than 1%, the EP Pharmacopoeia impurity D content is not higher than 1%, and the EP Pharmacopoeia impurity E content is not higher than 5%.

3. The method for purifying the alverine citrate intermediate according to claim 1, characterized in that: The alverine oily substance described in step A uses "3-phenylpropanol as a starting material, and undergoes chlorination, amination, alkylation, salification and other steps to obtain alverine citrate" route or the alverine oily substance obtained by this route.

4. The method for purifying the alverine citrate intermediate according to claim 1, characterized in that: The acid in step A is selected from at least one of hydrochloric acid solution, sulfuric acid solution or acetic acid solution.

5. The method for purifying the alverine citrate intermediate according to claim 1, characterized in that: The pH in step A is 3-8; the pH in step B is 5.5-14.

6. The method for purifying the alverine citrate intermediate according to claim 1, characterized in that: The organic solvent in step A is selected from at least one of n-hexane, cyclohexane, n-heptane, methyl tert-butyl ether or diethyl ether; the organic solvent in step B is selected from at least one of ethyl acetate, dichloromethane, chloroform, toluene, xylene, n-butanol, C7-C12 aliphatic alkane or aliphatic olefin.

7. The method for purifying the alverine citrate intermediate according to claim 1, characterized in that: In step A, the mass ratio of the alverine oil to water is 1:1-50; the mass ratio of the alverine oil to the water-insoluble organic solvent is 1:0.3-10, wherein the preferred ratio is 1:0.5-5, and the more preferred ratio is 1:1-4 times.

8. The method for purifying the alverine citrate intermediate according to claim 1, characterized in that: Step A is repeated 1-30 times, wherein the preferred ratio is 1-10 times, and the more preferred ratio is 1-5 times.

9. The method for purifying the alverine citrate intermediate according to claim 1, characterized in that: When the ratio of the alverine oil to the water-insoluble organic solvent in step A is 0.3-0.5 times, the washing times are 3-10 times; when the ratio of the alverine oil to the water-insoluble organic solvent in step A is 1-4 times, the washing times are 1-3 times.

10. The method for purifying the alverine citrate intermediate according to claim 1, characterized in that: The base in step B is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

Images