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Preparation method of sodium picosulfate

A technology of sodium picosulfate and acidic conditions, which is applied in the field of preparation of sodium picosulfate, and can solve problems such as difficulty in purification, slow reaction speed, and reduced oxidation of concentrated sulfuric acid

Active Publication Date: 2021-09-14
HAINAN MEDICAL COLLEGE
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  • Summary
  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And phenol and pyridine-2-carboxaldehyde are all easy to oxidize, adopt concentrated sulfuric acid as catalyst yield is not high, add chloroform or ethyl acetate as solvent and can reduce the oxidizability of concentrated sulfuric acid, but reaction speed is slow
Improve the reaction conditions and purification method for the preparation of intermediate 4,4'-(pyridin-2-ylmethylene)-bisphenol, and use hydrochloric acid-acetic acid system to solve the problem of many impurities in the traditional process of sodium picosulfate intermediate and difficult to purify
[0014] The problems that the last step sodium picosulfate prepares include: (1) owing to adopting sodium hydroxide to form a salt, and excessive chlorosulfonic acid decomposition can produce a large amount of inorganic salts, easily exceed standard as chloride, vitriol, need to adopt repeatedly to remove The step of salt is loaded down with trivial details; (2) because sodium picosulfate is easily soluble in water, aftertreatment needs to adopt the method for distilling and removing water, and in the process of distillation, sodium picosulfate is easy to oxidize and produces document and Pharmacopoeia do not list The oxidized impurities are produced, and the structure is shown in the figure below:
[0016] (3) Since the isomer impurity 2,4'-(pyridin-2-yl methylene)-bisphenol in the intermediate 4,4'-(2-pyridyl methylene)-bisphenol is relatively large, it cannot Controlled within a certain range, the derived impurities produced by it are difficult to remove due to their polarity being close to that of sodium picosulfate

Method used

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  • Preparation method of sodium picosulfate
  • Preparation method of sodium picosulfate
  • Preparation method of sodium picosulfate

Examples

Experimental program
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Effect test

Embodiment 1

[0041] 1. Synthesis of 4,4'-(2-pyridinemethylene)-bisphenol

[0042] Phenol (79.1g, 0.84mol), pyridine-2-carbaldehyde (42.9g, 0.4mol), 79ml of hydrochloric acid, and 100ml of glacial acetic acid were successively added to a 1L three-necked flask, heated to 40-50°C and stirred for 10 hours, then concentrated under reduced pressure to Dry, cool down to 0-10°C, slowly add 30% sodium hydroxide solution dropwise, adjust pH = 7-7.5, add 500ml absolute ethanol dropwise, a large amount of solid precipitates, filter, wash with purified water, methanol and ethyl acetate Esters (volume ratio: 1:8) were recrystallized in a mixed solvent to obtain 72.4 g of a white solid, yield: 65.3%, isomer impurity 2,4'-(pyridin-2-ylmethylene)-bisphenol 0.21 %.

[0043] 2. Synthesis of sodium picosulfate

[0044]400ml of pyridine, 2.8g of morpholine, 7ml of N-methylpyrrolidone, 4,4'-(2-pyridylmethylene)-bisphenol (69.3g, 0.25mol), sulfamic acid ( 68.9g, 0.71mol), heated to 40-50°C and stirred for 12 ...

Embodiment 2

[0046] 1. Synthesis of 4,4'-(2-pyridinemethylene)-bisphenol

[0047] Phenol (103.5g, 1.1mol), pyridine-2-carboxaldehyde (53.6g, 0.5mol), 100ml hydrochloric acid, and 130ml glacial acetic acid were successively added to a 500ml three-necked flask, heated to 40-50°C and stirred for 8 hours, then concentrated under reduced pressure to Dry, cool down to 0-10°C, slowly add 30% sodium hydroxide solution dropwise, adjust pH=6-7, add 650ml absolute ethanol dropwise, precipitate a large amount of solid, filter, wash, use methanol and ethyl acetate Recrystallize according to the mixed solvent with a volume ratio of 1:8 to obtain 87.6g of white solid, yield: 63.2%, isomer impurity 2,4'-(pyridin-2-ylmethylene)-bisphenol 0.17% .

[0048] 2. Synthesis of sodium picosulfate

[0049] 700ml of pyridine, 5.6g of morpholine, 20ml of N-methylpyrrolidone, 4,4'-(2-pyridylmethylene)-bisphenol (138.7g, 0.5mol), sulfamic acid ( 140.8g, 1.45mol), heated to 40-50°C and stirred for 12 hours. Add 3.5L...

Embodiment 3

[0051] 1. Synthesis of 4,4'-(2-pyridinemethylene)-bisphenol

[0052] Add phenol (210.8g, 2.24mol), pyridine-2-carbaldehyde (107.1g, 1.0mol), 200ml hydrochloric acid, and 250ml glacial acetic acid to a 1000ml three-necked flask in sequence, heat up to 40-50°C and stir for 8 hours, then concentrate under reduced pressure to Dry, cool down to 0-10°C, slowly add 30% sodium hydroxide solution dropwise, adjust pH=6-7, add dropwise 1300ml of absolute ethanol-ethyl acetate mixed solution, precipitate a large amount of solid, filter, wash, Recrystallization was carried out using ethanol and ethyl acetate in a mixed solvent with a volume ratio of 1:8 to obtain 178.8 g of a white solid, yield: 64.5%, isomer impurity 2,4′-(pyridin-2-ylmethylene )-bisphenol 0.19%.

[0053] 2. Synthesis of sodium picosulfate

[0054] 1380ml of pyridine, 10.8g of morpholine, 45ml of N-methylpyrrolidone, 4,4'-(2-pyridylmethylene)-bisphenol (277.3g, 1.0mol), sulfamic acid ( 279.6g, 2.88mol), heated to 40-50...

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Abstract

The invention belongs to the technical field of medicines, relates to a preparation method of sodium picosulfate, and particularly relates to a synthesis method which comprises the following steps: under an acidic condition, carrying out condensation on pyridine-2-formaldehyde and phenol to obtain an intermediate 4, 4 '-(2-pyridylmethylene)-bisphenol, adding a catalyst, carrying out sulfonation reaction, and carrying out post-treatment and refining to obtain sodium picosulfate. The method is relatively simple in process operation, and the obtained sample is high in purity.

Description

technical field [0001] The invention relates to the technical field of sodium picosulfate, in particular to a preparation method of sodium picosulfate. Background technique [0002] The chemical name of sodium picosulfate (Sodium picosulfate) is 4,4'-(pyridin-2-ylmethylene) bisphenyl bissulfate sodium salt monohydrate, which was developed by DeAngeli Company in Italy. In May 1980, the drug was approved for marketing under the trade name of Laxoberon, and it has been widely used in Italy, Germany, Japan, Australia and other countries. In July 2012, the US FDA approved sodium picosulfate-magnesium oxide-citric acid Oral powder is on the market (trade name: Prepopik). The drug has good clinical effects, few side effects, and high safety factor. As a constipation drug taken once a day, sodium picosulfate has greater clinical advantages and market prospects compared with domestic marketed drugs for treating constipation. broad. [0003] The earliest reported patent for the pre...

Claims

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Application Information

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IPC IPC(8): C07D213/30
CPCC07D213/30
Inventor 陈年根
Owner HAINAN MEDICAL COLLEGE
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