Process of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] sulfinyl-1 H-benzimidazole

a technology of methyl sulfinyl and h-benzimidazole, which is applied in the direction of carbonyl group formation/introduction, digestive system, organic active ingredients, etc., can solve the problems of risk of contamination of the final product with heavy metals, the ph of the aqueous phase over the reaction mixture has to be carefully monitored

Inactive Publication Date: 2002-01-17
HAFNER MILAC NATASA +1
View PDF0 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] 3-chlorobenzoic acid formed in oxidation is, due to the instability of omeprazole in acidic medium, the cause of omeprazole decomposition and therefore it is absolutely necessary that the acid formed and the final product are in contact for as short a period of time as possible. In hitherto known processes this problem has been solved by filtration or a simultaneous removal of 3-chlorobenzoic acid formed in oxidation by extraction into the alkaline aqueous phase, whereas the omeprazole formed remained in the organic phase. The isolation of the final product from a two-phase system, alkaline aqueous phase--organic phase, requires several steps (extraction of 3-chlorobenzoic acid from the organic phase into the alkaline aqueous phase, extraction of omeprazole with NaOH into the aqueous phase under pH control and temperature control, separation of the organic and aqueous phases, crystallization of omeprazole under pH control and filtration of the final product), which means a more sophisticated technological process.
[0011] The object of the invention is thus an improved process of the synthesis of omeprazole, wherein the effect of the acidic medium on omeprazole decomposition is reduced in such a way that as a solvent in the oxidation of 5-methoxy-2-[[(4-methoxy3,5-dimethyl-2-pyridyl)methyl]th-io]benzimidazole with 3-chloroperoxybenzoic acid ethyl acetate is used wherein the final product--omeprazole--is poorly soluble since omeprazole formed during the reaction is crystallized and the acid formed remains in the ethyl acetate solution. Hence, for the final isolation of the product only one step is necessary, i.e. the filtration of the product. Therefore the present invention is, with regard to technological feasibility, essentially more simple, more economical and faster.

Problems solved by technology

A disadvantage of the said process is also the fact that the pH of the aqueous phase over the reaction mixture has to be carefully monitored during the whole process.
At a greater amount of the catalyst there is also a risk of contamination of the final product with heavy metals.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Process of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] sulfinyl-1 H-benzimidazole
  • Process of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] sulfinyl-1 H-benzimidazole

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0014] 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio] benzimidazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0.degree. C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5.degree. C. After completed addition it was left to crystallize for another half an hour at a temperature below 5.degree. C. The product formed was filtered off, washed with ethyl acetate and dried in vacuo. Crude omeprazole (8.3 g; 79.1 %) was obtained.

[0015] Crude omeprazole (5 g) was dissolved in water (20 ml) and 40% aqueous methylamine (4 ml). The clear solution was diluted with acetone (30 ml) and the pH was adjusted to 7 to 8 with 1N HC1. To the suspension formed, water (70 ml) was added. The crystals separated were filtered off, washed with water and dried in vacuo. Pure omeprazole (4.6 g; 92%) was obtained.

example 2

[0016] 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-benzim-idazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0.degree. C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5.degree. C. After the completed addition it was stirred for half an hour, the cooling was removed, a 4% sodium carbonate solution (40 ml) was added and it was stirred for another half an hour. The product was filtered off and washed with water. After drying in vacuo crude omeprazole (8.0 g; 76.2%) was obtained and it was purified according to the process disclosed in Example 1.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
reaction timeaaaaaaaaaa
Login to view more

Abstract

An improved process of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H-benzimidazole (omeprazole) by oxidation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole with 3-chloroperoxybenzoic acid in ethyl acetate wherein omeprazole is poorly soluble, at a temperature between -10° C. and 5° C. is disclosed. The second step is a purification of the crude product by dissolution and reprecipitation of the final product.

Description

[0001] The present invention relates to an improved process of synthesis of 5-methoxy-2-[(4-methoxy 3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H-benz-imidazole (omeprazole) of the formula 1[0002] wherein 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio-]-benzimidazole is reacted with 3-chloroperoxybenzoic acid in ethyl acetate, wherein the final product--omeprazole--is poorly soluble.[0003] Omeprazole is the first medicament from the group of formulations for controlling the secretion of gastric acid, from the group of proton pump inhibitors. Namely, it inhibits the enzyme H / K-ATPase (a proton pump) in a parietal cell and thus also inhibits the last phase of acid secretion.TECHNICAL PROBLEM[0004] There is a constant need to prepare omeprazole of high purity in a simple and readily feasible way. In the literature processes of synthesis up to a crude omeprazole are disclosed; said omeprazole, however, contains by-products and hence it is not suitable for pharmaceutical use.PRI...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/00A61P1/00C07B41/06C07D213/00C07D235/00C07D401/12
CPCC07B41/06C07D401/12A61P1/00A61P1/04
Inventor HAFNER MILAC, NATASAJEREB, DARJA
Owner HAFNER MILAC NATASA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap