CN114989074B - Preparation method of sodium picosulfate - Google Patents
Preparation method of sodium picosulfate Download PDFInfo
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- CN114989074B CN114989074B CN202210710242.4A CN202210710242A CN114989074B CN 114989074 B CN114989074 B CN 114989074B CN 202210710242 A CN202210710242 A CN 202210710242A CN 114989074 B CN114989074 B CN 114989074B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/10—Energy storage using batteries
Abstract
The invention provides a preparation method of sodium picosulfate, and belongs to the field of pharmaceutical chemistry. The preparation method of the sodium picosulfate comprises the following steps: mixing a compound with a structure shown in a formula II, pyridine sulfur trioxide with a structure shown in a formula III and an organic solvent, and performing sulfonation reaction to obtain a sulfonation product; mixing the sulfonated product with sodium hydroxide solution, and neutralizing to obtain a neutralized product; mixing the neutralization product with a poor solvent, and crystallizing to obtain a solid product; and mixing the solid product with a desalting solvent, desalting, and sequentially concentrating, pulping, filtering and drying the obtained product to obtain the sodium picosulfate. The method has the advantages of easily obtained raw materials, simple process operation, no need of extraction and simple post-treatment process, and the prepared sodium picosulfate product has higher purity (more than 99 percent) and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a preparation method of sodium picosulfate.
Background
Sodium picosulfate, also known as sodium picosulfate, is a laxative developed by DeAngeli corporation of italy. The active ingredient diphenol substances are generated after the enzyme produced by colonic flora is hydrolyzed, so that intestinal mucosa can be directly stimulated, intestinal peristalsis is promoted, the absorption of water in intestinal tracts is inhibited, and the function of guide and release is shown. The sodium picosulfate is suitable for constipation, postoperative auxiliary defecation, defecation promotion after administration of contrast agent, preoperative intestinal canal content removal, preoperative treatment for large intestine examination (endoscope), intestinal canal content removal, etc. The chemical name of sodium picosulfate is: sodium 4,4- (pyridin-2-ylmethylene) bisphenyl disulfate having the structural formula:
at present, the reported preparation method of the sodium picosulfate mainly comprises the following steps:
the method comprises the following steps: (patent CN105884678A or US 3558643) condensing 2-pyridine formaldehyde and phenol or phenol derivatives in an acidic environment, reducing Raney nickel, sulfonating by chlorosulfonic acid, pouring the reaction liquid into water, neutralizing, extracting, washing, concentrating under reduced pressure, removing water to obtain solid, and desalting and purifying to obtain sodium picosulfate, wherein the specific reaction formula is as follows:
the second method is as follows: after hydrolysis of bisacodyl, patent CN103086957A is prepared by sulfonating an obtained product by chlorosulfonic acid, pouring a reaction solution into water, neutralizing, extracting, washing, concentrating under reduced pressure, removing water to obtain a solid, and purifying by desalting to obtain sodium picosulfate, wherein the specific reaction formula is as follows:
and a third method: patent US 2827465[ p ] 1958-03-18 discloses the following method:
the reaction conditions of the hydrolysis and the demethylation of the hydrobromic acid cyano are severe, and the method is not applicable to industrialization and hardly has application.
In the method for preparing the sodium picolinate, the 4, 4-dihydroxyphenyl- (2-pyridine) -methane is prepared firstly, then the sodium picolinate is obtained through sulfonation reaction and sodium hydroxide post-treatment, and the steps of extraction, reduced pressure concentration, water removal and the like are needed in the post-treatment process, so that the operation is complex.
Disclosure of Invention
The invention aims to provide a preparation method of sodium picosulfate, which has simple post-treatment process, does not need extraction and reduced pressure concentration for water removal and is beneficial to industrial mass production.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of sodium picosulfate, which comprises the following steps:
mixing a compound with a structure shown in a formula II, pyridine sulfur trioxide with a structure shown in a formula III and an organic solvent, and performing sulfonation reaction to obtain a sulfonation product;
mixing the sulfonated product with sodium hydroxide solution, and neutralizing to obtain a neutralized product;
mixing the neutralization product with a poor solvent, and crystallizing to obtain a solid product;
mixing the solid product with a desalting solvent for desalting, and sequentially concentrating, pulping, filtering and drying the obtained product to obtain sodium picosulfate;
preferably, the molar ratio of the compound with the structure shown in the formula II to the pyridine sulfur trioxide with the structure shown in the formula III is 1 (2-4).
Preferably, the temperature of the sulfonation reaction is 0-40 ℃ and the time is 1-24 h.
Preferably, the molar ratio of sodium hydroxide in the sodium hydroxide solution to the compound having the structure represented by formula II is (4-8): 1.
Preferably, the poor solvent is ethanol or isopropanol; the ratio of the volume of the poor solvent to the mass of the compound of the structure shown in the formula II is 1L (100-300 g).
Preferably, the crystallization temperature is 0-30 ℃.
Preferably, the desalting solvent is methanol.
Preferably, the temperature of the concentration is 20-80 ℃.
Preferably, the beating solvent used for beating is isopropanol or ethanol; the ratio of the volume of the beating solvent to the mass of the compound with the structure shown in the formula II is 1L (100-200 g).
The invention provides a preparation method of sodium picosulfate, which comprises the following steps: mixing a compound with a structure shown in a formula II, pyridine sulfur trioxide with a structure shown in a formula III and an organic solvent, and performing sulfonation reaction to obtain a sulfonation product; mixing the sulfonated product with sodium hydroxide solution, and neutralizing to obtain a neutralized product; mixing the neutralization product with a poor solvent, and crystallizing to obtain a solid product; and mixing the solid product with a desalting solvent, desalting, and sequentially concentrating, pulping, filtering and drying the obtained product to obtain the sodium picosulfate. The method has the advantages of easily obtained raw materials, simple process operation, no need of extraction and decompression concentration steps, simple post-treatment process, and high purity (more than 99 percent) of the prepared sodium picosulfate product, and is suitable for industrial production.
Detailed Description
The invention provides a preparation method of sodium picosulfate, which comprises the following steps:
mixing a compound with a structure shown in a formula II, pyridine sulfur trioxide with a structure shown in a formula III and an organic solvent, and performing sulfonation reaction to obtain a sulfonation product;
mixing the sulfonated product with sodium hydroxide solution, and neutralizing to obtain a neutralized product;
mixing the neutralization product with a poor solvent, and crystallizing to obtain a solid product;
mixing the solid product with a desalting solvent for desalting, and sequentially concentrating, pulping, filtering and drying the obtained product to obtain sodium picosulfate;
in the present invention, the preparation materials are commercially available as known to those skilled in the art unless otherwise specified.
According to the invention, a compound with a structure shown in a formula II, pyridine sulfur trioxide with a structure shown in a formula III and an organic solvent are mixed for sulfonation reaction to obtain a sulfonation product.
In the present invention, the compound having the structure represented by formula II is preferably commercially available.
In the present invention, the molar ratio of the compound of the structure represented by formula II to pyridine sulfur trioxide of the structure represented by formula III is preferably 1 (2 to 4), more preferably 1 (3 to 4).
In the present invention, the organic solvent is preferably pyridine or N, N dimethylformamide; the invention does not limit the dosage of the organic solvent in particular, and the dosage is adjusted according to actual requirements to ensure that the reaction is carried out smoothly.
In the present invention, the mixing process of the compound having the structure shown in formula II, the pyridine sulfur trioxide having the structure shown in formula III and the organic solvent is preferably to dissolve the compound having the structure shown in formula II in the organic solvent, stirring and dissolving, and adding the pyridine sulfur trioxide having the structure shown in formula III into the obtained solution.
In the present invention, the temperature of the sulfonation reaction is preferably 0 to 40 ℃, more preferably 20 to 30 ℃; the time is preferably 1 to 24 hours, more preferably 3 to 5 hours.
In the invention, the sulfonation reaction comprises the following steps:
after the sulfonated product is obtained, the sulfonated product is mixed with sodium hydroxide solution, and neutralization is carried out to obtain a neutralization product.
In the present invention, the molar ratio of sodium hydroxide in the sodium hydroxide solution to the compound having the structure represented by formula II is preferably (4 to 8): 1, more preferably (5 to 6): 1. In the present invention, the sodium hydroxide solution is preferably obtained by dissolving sodium hydroxide in pure water; the preparation process and concentration of the sodium hydroxide solution are not particularly limited, and the sodium hydroxide solution can meet the molar quantity.
The sodium hydroxide solution is preferably added dropwise to the sulphonated product; the rate of the dropping is not particularly limited in the present invention, and the dropping may be performed according to a process well known in the art.
In the invention, the temperature of the neutralization is preferably less than or equal to 30 ℃, the time is preferably 30min, and the neutralization is preferably carried out under stirring conditions; the stirring rate is not particularly limited in the present invention, and the reaction is ensured to proceed smoothly according to a process well known in the art.
After the neutralization product is obtained, the neutralization product is mixed with a poor solvent, and crystallization is carried out to obtain a solid product. In the present invention, the poor solvent is preferably ethanol or isopropanol; the ratio of the volume of the poor solvent to the mass of the compound of the structure represented by formula II is preferably 1L (100 to 300 g), more preferably 1L:100g.
The process of mixing the neutralization product with the poor solvent is not particularly limited in the present invention, and the materials may be uniformly mixed according to a process well known in the art.
In the present invention, the crystallization temperature is preferably 0 to 30 ℃, more preferably 25 ℃; the time is preferably 1h.
After completion of the crystallization, the present invention preferably filters the resulting product to obtain a solid product. The filtering process is not particularly limited and may be performed according to a process well known in the art.
After a solid product is obtained, the solid product is mixed with a desalting solvent for desalting, and the obtained product is concentrated, pulped, filtered and dried in sequence to obtain sodium picosulfate. In the present invention, the desalting solvent is preferably methanol. The invention has no special limit to the dosage of the desalting solvent, and can ensure the sufficient desalting. The process of mixing the solid product with the desalting solvent is not particularly limited in the present invention, and may be carried out according to a process well known in the art. In the present invention, the time for desalting is preferably 30min; the desalting is preferably carried out under stirring conditions, and the stirring rate is not particularly limited in the present invention, and may be carried out according to a process well known in the art.
After the completion of the desalting, the present invention concentrates the obtained product to obtain a residue. In the present invention, the temperature of the concentration is preferably 20 to 80 ℃, more preferably 50 to 75 ℃.
After obtaining a residue, mixing the residue with a beating solvent for beating; the beating solvent used in beating is preferably isopropanol or ethanol; the ratio of the volume of the beating solvent to the mass of the compound of the structure shown in the formula II is preferably 1L (100-200 g); the beating time is preferably 1h.
The process of filtering and drying is not particularly limited in the present invention, and may be performed according to a process well known in the art.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following examples, the compound of formula (II) is derived from beijing melt in pharmaceutical technologies limited.
Example 1
At room temperature, adding a compound (100 g,0.36 mol) of formula (II) and N, N-dimethylformamide (250 mL) into a 500mL three-necked flask, stirring and dissolving, adding pyridine sulfur trioxide (172.2 g,1.08 mol), controlling the temperature to be 25+/-5 ℃, carrying out sulfonation reaction for 3h, dissolving sodium hydroxide (86.5 g,2.16 mol) into purified water (100 mL), dripping the obtained solution into a reaction system, controlling the temperature to be not more than 30 ℃, stirring and reacting for 30min after the addition, transferring the obtained neutralization product into a cooling 5L reaction flask, adding ethanol (1.0L) and stirring, crystallizing for 1h at 25 ℃, filtering, adding the obtained solid into methanol (2L), stirring for 30min to remove salt, concentrating the obtained product at 55+/-5 ℃, adding ethanol (1L) into the obtained residue, pulping for 1h, filtering the obtained product, drying the obtained filtered solid material to obtain 162g of sodium sulfate, obtaining the yield of 93%, and purity of 99.5% by HPLC.
Example 2
At room temperature, adding a compound (100 g,0.36 mol) of formula (II) and N, N-dimethylformamide (250 mL) into a 500mL three-necked flask, stirring and dissolving, adding pyridine sulfur trioxide (172.2 g,1.08 mol), controlling the temperature to be 25+/-5 ℃, carrying out sulfonation reaction for 3h, dissolving sodium hydroxide (72 g,1.8 mol) into purified water (100 mL), dripping the obtained solution into a reaction system, controlling the temperature to be not more than 30 ℃, stirring and reacting for 30min after the addition, transferring the obtained neutralization product into a cooling 5L reaction flask, adding isopropanol (1.0L), stirring at 25 ℃, crystallizing for 1h, filtering, adding the obtained solid into methanol (2L), stirring for 30min for desalting, concentrating the obtained product at 55+/-5 ℃, adding isopropanol (1L) into the obtained residue, pulping for 1h, filtering the obtained product, drying the obtained solid material to obtain 144g of sodium sulfate, obtaining 144g, yield of 83%, purity of 99.5% by HPLC.
Example 3
At room temperature, adding a compound (100 g,0.36 mol) of formula (II) and N, N-dimethylformamide (250 mL) into a 500mL three-necked flask, stirring and dissolving, adding pyridine sulfur trioxide (172.2 g,1.08 mol), controlling the temperature to be 25+/-5 ℃, carrying out sulfonation reaction for 5h, adding sodium hydroxide (86.5 g,2.16 mol) into purified water (100 mL), dripping the obtained solution into a reaction system, controlling the temperature to be not more than 30 ℃, stirring and reacting for 30min after the addition, transferring the obtained neutralization product into a cooling 5L reaction flask, adding isopropanol (1.0L), stirring at 25 ℃, crystallizing for 1h, filtering, adding the obtained solid into methanol (2L), stirring for 30min for desalting, concentrating the obtained product at 75+/-5 ℃, adding ethanol (1L) into the obtained residue, pulping for 1h, filtering the obtained product, drying the obtained solid material, obtaining 166g of sodium sulfate with the yield of 96%, and the purity of HPLC (high performance liquid chromatography).
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (1)
1. A method for preparing sodium picosulfate, which is characterized by comprising the following steps:
adding 0.36mol of a compound shown in a formula II and 250mL of N, N-dimethylformamide into a 500mL three-port bottle at room temperature, stirring and dissolving, adding 1.08mol of a compound shown in a formula III, namely pyridine sulfur trioxide, controlling the temperature to be 25+/-5 ℃, carrying out sulfonation reaction for 5 hours, dissolving 2.16mol of sodium hydroxide into 100mL of purified water, dripping the obtained solution into a reaction system, controlling the temperature to be not more than 30 ℃, stirring and reacting for 30 minutes after the addition, transferring the obtained neutralization product into a cooling 5L reaction bottle, adding 1.0L of isopropanol and stirring, crystallizing for 1 hour at 25 ℃, filtering, adding the obtained solid into 2L of methanol, stirring for 30 minutes for desalting, concentrating the obtained product at 75+/-5 ℃, adding 1L of ethanol into the obtained residue, pulping for 1 hour, filtering the obtained solid material, and drying to obtain sodium picogram;
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175317A (en) * | 2015-10-23 | 2015-12-23 | 青岛辰达生物科技有限公司 | Method for preparing sodium picosulfate |
| CN105254556A (en) * | 2015-11-17 | 2016-01-20 | 重庆莱美药业股份有限公司 | Method for preparing high-purity sodium picosulfate |
| CN113354574A (en) * | 2021-04-13 | 2021-09-07 | 上海高准医药有限公司 | Synthetic method of sodium picosulfate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175317A (en) * | 2015-10-23 | 2015-12-23 | 青岛辰达生物科技有限公司 | Method for preparing sodium picosulfate |
| CN105254556A (en) * | 2015-11-17 | 2016-01-20 | 重庆莱美药业股份有限公司 | Method for preparing high-purity sodium picosulfate |
| CN113354574A (en) * | 2021-04-13 | 2021-09-07 | 上海高准医药有限公司 | Synthetic method of sodium picosulfate |
Non-Patent Citations (1)
| Title |
|---|
| 匹可硫酸钠的合成工艺研究;陈年根等;《广州化工》;第50卷(第5期);第95-96页 * |
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