Title of Invention	"A METHOD OF PREPARING OMEPRAZOLE"
Abstract	A method of preparing omeprazole characterized in that 5-rnethoxy-2(4-metnoxy -3,5-dimethyl-2-pyridinyl)-methylthio) IH-benzimidazole (compound I) is reacted with peroxyacetic acid in an amount) of 0.8 to 2.0 molar equivalent, with respect to compound I, in a two-phase medium of water and chlorinated organic solvent selected from the group consisting of dichloromethane, chloroform, and diehloroeth-ane, at an alkaline pH of from 7.1 to 9.5, at the tempera¬ture of the reaction mixture between 0 and 25°c, followed, after the reaction. be separation of the aqueous and organic phases and isolation of omeprazole from the organic phase.

Title of Invention

"A METHOD OF PREPARING OMEPRAZOLE"

Abstract

A method of preparing omeprazole characterized in that 5-rnethoxy-2(4-metnoxy -3,5-dimethyl-2-pyridinyl)-methylthio) IH-benzimidazole (compound I) is reacted with peroxyacetic acid in an amount) of 0.8 to 2.0 molar equivalent, with respect to compound I, in a two-phase medium of water and chlorinated organic solvent selected from the group consisting of dichloromethane, chloroform, and diehloroeth-ane, at an alkaline pH of from 7.1 to 9.5, at the tempera¬ture of the reaction mixture between 0 and 25°c, followed, after the reaction. be separation of the aqueous and organic phases and isolation of omeprazole from the organic phase.

Full Text	The present application relates to a method of preparing omeprazole. Omeprazole is the generic name of a pharmaceutical substance 5-methoxy-2[[(4-niethoxy-3,5-diinethyl-2-p3rridinyl)-methyl]su]finyl]-lH-benziniidazole. Background Art According to Swedish patent SE 4231, omeprazole is prepared by oxidation of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)--methylthio]-1H benzimidazole, (referred to as compound I below) with m-chloroperoxybenzoic acid. In the PCT application published under WO 91/18895 there is described an improved method of preparing omeprazole again by oxidation of compound I with m-chloroperoxybenzoic acid, but in an alkaline medium. Also other patents describe the preparation of omeprazole by oxidation of compound I with different oxidizing agents. European patent EP 484 265 describes the preparation of omeprazole by oxidation of compound I with hydrogen peroxide in the presence of molybdenum salts as catalysts. European patent EP 302 720 claims the preparation of omeprazole by oxidation of compound I with hydrogen peroxide using vanadium catalysts. British patent GB 2 239 453 describes the preparation of omeprazole by photochemical oxidation of compound I. Other methods of preparing omeprazole consist in oxidation of compound I with magnesium peroxy phthalate as described in European patent EP 533 264 and in oxidation with iodosobenzene or iodosotoiuene described in Spanish patent ES 539 793. Spanish patent ES 543 816 describes the preparation of omeprazole by oxidation of compound I with powdered m-chloroperoxybenzoic acid. Said preparing methods suffer from the drawbacks that the obtained omeprazole is contaminated with the starting substance and that various by¬products are formed during the reactions, including especially 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfonyl]-1H-benzimidazole as a product of subsequent oxidation of omeprazole. Summary of the Invention The above mentioned disadvantages are overcome by a method of preparing omeprazole according to the present invention, which comprises reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole (compound I) with peroxyacetic acid in a two-phase medium of water and a chlorinated organic solvent, at an alkaline pH, followed by separation of the aqueous and organic phases after the reaction and isolation of omeprazole from the organic phase. Therefore the present invention provides for a method of preparing omeprazole characterized in that 5-methoxy-2[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-lH-benzimidazole (compound I) is reacted with peroxyacetic acid in an amount of 0.8 to 2.0 molar equivalent, with respect to compound I, in a two-phase medium of water and chlorinated organic solvent selected from the group consisting of dichloromethane, chloroform, and dichloroethane, at an alkaline pH of from 7.1 to 9.5, at the temperature of the reaction mixture between 0 and 25°C, followed, after the reaction, by separation of the aqueous and organic phases and isolation of omeprazole from the organic phase. Peroxyacetic acid is employed in an amount of 0,8 to 2,0 molar equivalents with respect to compound I, preferably in an amount of 0,9 to 1,1 molar equivalents. The reaction mixture is maintained at a pH of from 7,1 to 9,5 during the reaction. Most preferably, however, the reaction is carried out at a pH ranging from 8,0 to 8,5. The temperature of the reaction mixture is maintained between 0 °C and 25 °C, during the reaction, most preferably between 1 °C and 5 °C. Useful chlorinated organic solvents include dichloromethane, chloroform, or dichloroethane, most preferably dichloromethane. After the reaction is complete, the organic and aqueous phases are separated, and omeprazole is isolated from the organic phase. An advantage of the method according to the present invention is that omeprazole is isolated from the organic phase after the reaction is finished, and acetic acid formed from peroxyacetic acid during the reaction remains in the aqueous phase. The main advantage of the method according to this invention consists in high purity of the obtained omeprazole which contains only very small amounts of the starting substance and of the hardly removable sulfonic impurity 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfonyl]-1H-benzimidazole. The following specific examples are intended as being illustrative of the invention without limiting it in any way. Examples Example 1 3,29 g (0,01 mole) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole is dissolved in 50 ml of dichloromethane and the pH is adjusted to 8,0 to 8,5 by adding an aqueous solution of sodium carbonate. Then, 3,46 g (0,01 mole) of peroxyacetic acid is added dropwise at a temperature of the reaction mixture of from 0 °C to 5 °C, and the pH is maintained between 8,0 and 8,5 by adding an aqueous solution of sodium carbonate. The reaction mixture is stirred for 120 minutes. Afterwards, the dichloromethane layer is separated and washed with water and brine, dried with sodium sulfate and concentrated in a vacuum evaporator to dryness. 3,27 g (94,8 %) of omeprazole are obtained. Example 2 3,29 g (0,01 mole) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-imethylthio]-1 H-benzimidazole is dissolved in 50 ml of chloroform and the pH is adjusted to 7,1 to 7,5 by adding an aqueous solution of sodium carbonate. Then. 2,76 g (0,008 mole) of peroxyacetic acid is added dropwise at a temperature of the reaction mixture of from 20 °C to 25 °C, and the pH is maintained between 7,1 and 7,6 by adding an aqueous solution of sodium carbonate. The reaction mixture is stirred for 120 minutes. Afterwards, the chloroform layer is separated and washed with water and brine, dried with sodium sulfate and concentrated in a vacuum evaporator to dryness. 2,58 g (74,8 %) of omeprazole are obtained. Example 3 3,29 g (0,01 mole) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1 H-benzimidazole is dissolved in 50 ml of dichloroethane and the pH is adjusted to 9,0 to 9,5 by adding an aqueous solution of sodium carbonate. Then, 6,92 g (0,02 mole) of peroxyacetic acid is added dropwise at a temperature of the reaction mixture of from 5 °C to 10 °C, and the pH is maintained between 9,0 to 9,5 by adding an aqueous solution of sodium carbonate. The reaction mixture is stirred for 120 minutes. Afterwards, the dichloroethane layer is separated and washed with water and brine, dried with sodium sulfate and concentrated in a vacuum evaporator to dryness. 2,76 g (80,1 %) of omeprazole are obtained. Example 4 3,29 g (0,01 mole) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1 H-benzimidazole is dissolved in 50 ml of dichloromethane and the pH is adjusted to 8,0 to 8,5 by adding an aqueous solution of sodium carbonate. Then, 3,81 g (0,011 mole) of peroxyacetic acid is added dropwise at a temperature of the reaction mixture of from 10 °C to 15 °C, and the pH is maintained between 8,0 to 8,5 by adding an aqueous solution of sodium carbonate. The reaction mixture is stirred for 120 minutes. Afterwards, the dichloromethane layer is separated and washed with water and brine, dried with sodium sulfate and concentrated in a vacuum evaporator to dryness. 3,15 g (90,2 %) of omeprazole are obtained. Industrial Application Omeprazole is employed in pharmaceutical industry as a pharmaceutical substance in human medicine. A method of preparing omeprazole characterized in that 5-methoxy-2[(4-niethoxy-3,5-dirnethyl-2-pyridinyl)-rnethylthio]-lH-benzirnidazole (compound I) is reacted with peroxyacetic acid in an amount of 0.8 to 2.0 molar equivalent, with respect to compound I, in a two-phase medium of water and chlorinated organic solvent selected from the group consisting of dichloromethane, chloroform, and dichloroethane, at an alkaline pH of from 7.1 to 9.5, at the temperature of the reaction mixture between 0 and 25°C, followed, after the reaction, by separation of the aqueous and organic phases and isolation of omeprazole from the organic phase. A method as claimed in claim 1, wherein peroxyacetic acid is employed preferably in an amount of 0.9 to 1.1 molar equivalents, with respect to compound I. A method as claimed in claims 1 and 2, wherein the reaction mixture is maintained at an alkaline pH preferably of from 8.0 to 8.5 during the reaction. A method as claimed in claims 1 to 3, wherein the temperature of the reaction mixture is maintained preferably between 1 and 5°C. A method as claimed in claims 1 to 4, wherein the chlorinated organic solvent employed is preferably dichloromethane. 6. A method of preparing omeprazole substantially as hereinbefore described with reference to the foregoing examples.

Full Text

The present application relates to a method of preparing omeprazole. Omeprazole is the generic name of a pharmaceutical substance 5-methoxy-2[[(4-niethoxy-3,5-diinethyl-2-p3rridinyl)-methyl]su]finyl]-lH-benziniidazole.
Background Art
According to Swedish patent SE 4231, omeprazole is prepared by oxidation of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)--methylthio]-1H benzimidazole, (referred to as compound I below) with m-chloroperoxybenzoic
acid.
In the PCT application published under WO 91/18895 there is described an improved method of preparing omeprazole again by oxidation of compound I with m-chloroperoxybenzoic acid, but in an alkaline medium.
Also other patents describe the preparation of omeprazole by oxidation of compound I with different oxidizing agents.
European patent EP 484 265 describes the preparation of omeprazole by oxidation of compound I with hydrogen peroxide in the presence of molybdenum salts as catalysts. European patent EP 302 720 claims the preparation of omeprazole by oxidation of compound I with hydrogen peroxide using vanadium catalysts. British patent GB 2 239 453 describes the preparation of omeprazole by photochemical oxidation of compound I.
Other methods of preparing omeprazole consist in oxidation of compound I with magnesium peroxy phthalate as described in European patent EP 533 264 and in oxidation with iodosobenzene or iodosotoiuene described in Spanish patent ES 539 793. Spanish patent ES 543 816 describes the preparation of omeprazole by oxidation of compound I with powdered m-chloroperoxybenzoic acid.
Said preparing methods suffer from the drawbacks that the obtained omeprazole is contaminated with the starting substance and that various by¬products are formed during the reactions, including especially 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfonyl]-1H-benzimidazole as a product of subsequent oxidation of omeprazole.
Summary of the Invention
The above mentioned disadvantages are overcome by a method of preparing omeprazole according to the present invention, which comprises reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole (compound I) with peroxyacetic acid in a two-phase medium of water and a chlorinated organic solvent, at an alkaline pH, followed by separation of the aqueous and organic phases after the reaction and isolation of omeprazole from the organic phase.
Therefore the present invention provides for a method of preparing omeprazole characterized in that 5-methoxy-2[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-lH-benzimidazole (compound I) is reacted with peroxyacetic acid in an amount of 0.8 to 2.0 molar equivalent, with respect to compound I, in a two-phase medium of water and chlorinated organic solvent selected from the group consisting of dichloromethane, chloroform, and dichloroethane, at an alkaline pH of from 7.1 to 9.5, at the temperature of the reaction mixture between 0 and 25°C, followed, after the reaction, by separation of the aqueous and organic phases and isolation of omeprazole from the organic phase.
Peroxyacetic acid is employed in an amount of 0,8 to 2,0 molar equivalents with respect to compound I, preferably in an amount of 0,9 to 1,1 molar
equivalents.
The reaction mixture is maintained at a pH of from 7,1 to 9,5 during the reaction. Most preferably, however, the reaction is carried out at a pH ranging from 8,0 to 8,5.
The temperature of the reaction mixture is maintained between 0 °C and 25 °C, during the reaction, most preferably between 1 °C and 5 °C.
Useful chlorinated organic solvents include dichloromethane, chloroform, or dichloroethane, most preferably dichloromethane.
After the reaction is complete, the organic and aqueous phases are separated, and omeprazole is isolated from the organic phase.
An advantage of the method according to the present invention is that omeprazole is isolated from the organic phase after the reaction is finished, and acetic acid formed from peroxyacetic acid during the reaction remains in the aqueous phase.
The main advantage of the method according to this invention consists in high purity of the obtained omeprazole which contains only very small amounts of the starting substance and of the hardly removable sulfonic impurity 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfonyl]-1H-benzimidazole.
The following specific examples are intended as being illustrative of the invention without limiting it in any way.
Examples
Example 1
3,29 g (0,01 mole) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole is dissolved in 50 ml of dichloromethane and the pH is adjusted to 8,0 to 8,5 by adding an aqueous solution of sodium carbonate. Then, 3,46 g (0,01 mole) of peroxyacetic acid is added dropwise at a temperature of the reaction mixture of from 0 °C to 5 °C, and the pH is maintained between 8,0 and 8,5 by adding an aqueous solution of sodium carbonate. The reaction mixture is stirred for 120 minutes. Afterwards, the dichloromethane layer is separated and
washed with water and brine, dried with sodium sulfate and concentrated in a vacuum evaporator to dryness. 3,27 g (94,8 %) of omeprazole are obtained.
Example 2
3,29 g (0,01 mole) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-imethylthio]-1 H-benzimidazole is dissolved in 50 ml of chloroform and the pH is adjusted to 7,1 to 7,5 by adding an aqueous solution of sodium carbonate. Then. 2,76 g (0,008 mole) of peroxyacetic acid is added dropwise at a temperature of the reaction mixture of from 20 °C to 25 °C, and the pH is maintained between 7,1 and 7,6 by adding an aqueous solution of sodium carbonate. The reaction mixture is stirred for 120 minutes. Afterwards, the chloroform layer is separated and washed with water and brine, dried with sodium sulfate and concentrated in a vacuum evaporator to dryness. 2,58 g (74,8 %) of omeprazole are obtained.
Example 3
3,29 g (0,01 mole) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1 H-benzimidazole is dissolved in 50 ml of dichloroethane and the pH is adjusted to 9,0 to 9,5 by adding an aqueous solution of sodium carbonate. Then, 6,92 g (0,02 mole) of peroxyacetic acid is added dropwise at a temperature of the reaction mixture of from 5 °C to 10 °C, and the pH is maintained between 9,0 to 9,5 by adding an aqueous solution of sodium carbonate. The reaction mixture is stirred for 120 minutes. Afterwards, the dichloroethane layer is separated and washed with water and brine, dried with sodium sulfate and concentrated in a vacuum evaporator to dryness. 2,76 g (80,1 %) of omeprazole are obtained.
Example 4
3,29 g (0,01 mole) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1 H-benzimidazole is dissolved in 50 ml of dichloromethane and the pH is adjusted to 8,0 to 8,5 by adding an aqueous solution of sodium carbonate. Then, 3,81 g (0,011 mole) of peroxyacetic acid is added dropwise at a temperature of the reaction mixture of from 10 °C to 15 °C, and the pH is
maintained between 8,0 to 8,5 by adding an aqueous solution of sodium carbonate. The reaction mixture is stirred for 120 minutes. Afterwards, the dichloromethane layer is separated and washed with water and brine, dried with sodium sulfate and concentrated in a vacuum evaporator to dryness. 3,15 g (90,2 %) of omeprazole are obtained.
Industrial Application
Omeprazole is employed in pharmaceutical industry as a pharmaceutical substance in human medicine.

A method of preparing omeprazole characterized in that 5-methoxy-2[(4-niethoxy-3,5-dirnethyl-2-pyridinyl)-rnethylthio]-lH-benzirnidazole (compound I) is reacted with peroxyacetic acid in an amount of 0.8 to 2.0 molar equivalent, with respect to compound I, in a two-phase medium of water and chlorinated organic solvent selected from the group consisting of dichloromethane, chloroform, and dichloroethane, at an alkaline pH of from 7.1 to 9.5, at the temperature of the reaction mixture between 0 and 25°C, followed, after the reaction, by separation of the aqueous and organic phases and isolation of omeprazole from the organic phase.
A method as claimed in claim 1, wherein peroxyacetic acid is employed preferably in an amount of 0.9 to 1.1 molar equivalents, with respect to compound I.
A method as claimed in claims 1 and 2, wherein the reaction mixture is maintained at an alkaline pH preferably of from 8.0 to 8.5 during the reaction.
A method as claimed in claims 1 to 3, wherein the temperature of the reaction mixture is maintained preferably between 1 and 5°C.
A method as claimed in claims 1 to 4, wherein the chlorinated organic solvent employed is preferably dichloromethane.
6. A method of preparing omeprazole substantially as hereinbefore described with reference to the foregoing examples.

Documents:

3039-del-1997-abstract.pdf

3039-del-1997-claims.pdf

3039-del-1997-complete specification (granted).pdf

3039-del-1997-correspondence-others.pdf

3039-del-1997-correspondence-po.pdf

3039-del-1997-description (complete).pdf

3039-del-1997-form-1.pdf

3039-del-1997-form-2.pdf

3039-del-1997-form-3.pdf

3039-del-1997-form-4.pdf

3039-del-1997-gpa.pdf

3039-del-1997-pct-210.pdf

3039-del-1997-petition-others.pdf

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Patent Number

233538

Indian Patent Application Number

3039/DEL/1997

PG Journal Number

14/2009

Publication Date

27-Mar-2009

Grant Date

30-Mar-2009

Date of Filing

23-Oct-1997

Name of Patentee

SLOVAKOFARMA,A.S.

Applicant Address

ZELEZNICNA 12,920 27 HLOHOVEC,SLOVAKIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	VLADIMIR OREMUS	VYSOKA 4,811 06 BRATISLAVA,SLOVAKIA.
2	KATARINA HELEYOVA	PRIBINOVA 14,010 01 ZILINA,SLOVAKIA.
3	ONDREJ GATTNAR	KALETOVA 6,841 02 BRATISLAVA SLOVAKIA.
4	LADISLAV JEZEK	KOMENSKEHO 12,900 01 MODRA,SLOVAKIA.
5	VENDEL SMAHOVSKY	NOVOMESKEHO 18,902 01 PEZINOK,SLOVAKIA.
6	PAVOL ZLATOIDSKY	FLORIANSKE NAM 2,811 01 BRATISLAVA, SLOVAKIA.
7	IVAN VARGA	VETERNA 12 920 01 HLOHOVEC, SLOVAKIA.
8	VALDEMAR STALMACH	URSINYHO 1, 831 02 BRATISLAVA,SLOVAKIA.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA