METHOD OF OMEPRAZOLE PREPARATION

Abstract: The invention solves a method of preparation of omeprazole by a reaction of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole with peroxyacetic acid in a two-phase water and chlorinated organic solvent medium, in alkaline pH, subsequent separation of water and organic phases after the reaction and isolation of omeprazole from organic phase.

Description: Method of omeprazole preparation Technical field The invention solves a method of preparation of a pharmaceutical substance 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H- benzimidazole, which is known under its generic name omeprazole. Description of the related art According to the Swedish patent SE 4231 , omeprazole is prepared by oxidation of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)— methylthio]-1 H ben- zimidazole. (further referred to as the compound I) with m-chloroperoxybenzoic acid. In the PCT application published under WO 91/18895 is described an improved method of preparation of omeprazole by oxidation of the compound I again with m-chloroperoxybenzoic acid, but in an alkaline medium. Also other patents provide for preparation of omeprazole by oxidation of the compound I with different oxidizing agents. In the European patent EP 484 265 preparation of omeprazole by oxidation of the compound I with hydrogen peroxide in the presence of molybdenum salts as catalysts is described. The European patent EP 302 720 has patented preparation of omeprazole by oxidation of the compound I with hydrogen peroxide using vanadium catalysts. The British patent GB 2 239 453 describes preparation of omeprazole by photo- che ic oxidation of the compound I. Other way of omeprazole preparation is oxidation of the compound I by magnesium peroxyphatalate provided for in the European patent EP 533 264, and oxidation by iodosobenzene or iodosotoluene described in the Spanish patent ES 539 793. The Spanish patent ES 543 816 describes preparation of omeprazole by oxidation of the compound I with powder m-chloroperoxybenzoic acid. Disadvantages of these preparation methods are that prepared omeprazole is contaminated by starting substance and there are many side products produced during the reactions, including especially 5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyl)-methyl]sulphonyI]-1 H-benzimidazole as a product of following omeprazole oxidation. Summary of the invention The mentioned disadvantages are removed by a method of preparation of omeprazole according to the present invention, which comprises the reaction of 5- methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1 H-benzimidazole (the compound I) with peroxyacetic acid in a two-phase water and chlorinated organic solvent medium, in alkaline pH, subsequent separation of water and organic phases after the reaction and isolation of omeprazole from organic phase. The peroxyacetic acid is used in amount of 0,8 to 2,0 molar equivalents to the compound I, advantageously in the amount of 0,9 to 1 ,1 molar equivalent. The pH of reaction mixture during the reaction is maintained from 7,1 to 9,5. The best is, however, to work with the pH ranging from 8,0 to 8,5. The temperature of reaction mixture is maintained during the reaction from 0°C to 25°C, the best range from 1°C to 5°C. As chlorinated organic solvent can be used dichloromethane , chloroform, or dichloroethane, using of dichloromethane is preferable. When the reaction is over, organic and water phases are separated, and omeprazole is isolated from the organic phase. The advantage of this procedure according the present invention is that omeprazole is isolated from the organic phase after the reaction is finished, and the acetic acid formed from the peroxyacetic acid during the reaction remains in the water phase. The primary advantage of this invention procedure is that prepared omeprazole is of high purity and contains only very small amount of initial substance and hardly removable sulphonic impurity caused by 5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyhdinyl)-methyl]sulphonyl]-1 H-benzimidazole. The following text provides for several examples of the invention practical application, not being limited just to them. Examples of carrying out the invention: Example No. 1 3,29 g (0,01 mol) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)- methylthio]-1 H-benzimidazole is dissolved in 50 ml of dichloromethane and pH is adjusted to 8,0 - 8,5 by adding water solution of sodium carbonate. Then, 3,46 g (0,01 mol) of peroxyacetic acid is added in drops at temperature of the reaction compound from 0°C to 5°C, and pH is maintained by adding water solution of sodium carbonate between 8,0 to 8,5.The reaction mixture is stirred for 120 minutes. Afterwards , the dichloromethane layer is separated and scrubbed with water and brine, dried with sodium sulphate and densified on a vacuum evaporator till it is dry. The yield is 3,27 g (94,8 %) of omeprazole. Example No. 2 3,29 g (0,01 mol) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)- methylthio]-1 H-benzimidazole is dissolved in 50 ml of chloroform and pH is adjusted to 7,1 - 7,6 by adding water solution of sodium carbonate. Then, 2,76 g (0,008 mol) of peroxyacetic acid is added in drops at temperature of the reaction mixture from 20°C to 25°C, and pH is maintained by adding water solution of sodium carbonate between 7,1 to 7,6.The reaction mixture is stirred for 120 minutes. Afterwards , the chloroform layer is separated and scrubbed with water and brine, dried with sodium sulphate and densified on a vacuum evaporator till it is dry. The yield is 2,58 g (74,8 %) of omeprazole. Example No. 3 3,29 g (0,01 mol) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)- methylthio]-1 H-benzimidazole is dissolved in 50 ml of dichloroethane and pH is adjusted to 9,0 - 9,5 by adding water solution of sodium carbonate. Then, 6,92 g (0,02 mol) of peroxyacetic acid is added in drops at temperature of the reaction mixture from 5°C to 10°C, and pH is maintained by adding water solution of sodium carbonate between 9,0 to 9,5.The reaction mixture is stirred for 120 minutes. Afterwards , the dichloroethane layer is separated and scrubbed with water and brine, dried with sodium sulphate and densified on a vacuum evaporator till it is dry. The yield is 2,76 g (80,1 %) of omeprazole. Example No. 4 3,29 g (0,01 mol) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)- methylthio]-1 H-benzimidazole is dissolved in 50 ml of dichloromethane and pH is adjusted to 8,0 - 8,5 by water solution of sodium carbonate. Then, 3,81 g (0,011 mol) of peroxyacetic acid is added in drops at temperature of the reaction mixture from 10°C to 15°C, and pH is maintained by adding water solution of sodium carbonate between 8,0 to 8,5.The reaction mixture is stirred for 120 minutes. Afterwards , the dichloromethane layer is separated and scrubbed with water and brine, dried with sodium sulphate and densified on a vacuum evaporator till it is dry. The yield is 3,15 g (90,2 %) of omeprazole. industrial utilisation Omeprazole is used in pharmaceutical industry as a pharmaceutical substance in human medicine.

Claims: CLAIMS 1. The method of omeprazole preparation characterised by reaction of 5-methoxy- 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1 H-benzimidazole with peroxyacetic acid in a two-phase water and chlorinated organic solvent medium, in alkaline pH, subsequent separation of water and organic phases after the reaction and isolation of omeprazole from organic phase. 2. The method according to claim 1 , characterised by using of 0,8 to 2,0 molar equivalents, preferably 0,9 to 1 ,1 molar equivalent of peroxyacetic acid to 5- methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1 H-benzimidazole. 3. The method according to claims 1 and 2, characterised by maintaining the alkaline pH of the reaction mixture in the range from 7,1 to 9,5 with the advantage of pH from 8,0 to 8,5. 4. The method according to claims 1 to 3, characterised by maintaining the temperature of reaction mixture in the range from 0°C to 25°C with advantage of temperature from 1 °C to 5 β C. 5. The method according to claims 1 to 4, characterised by using dichloromethane, chloroform or dichloroethane as chlorinated organic solvent with advantage of dichloromethane.

Inventors: GATTNAR ONDREJ, HELEYOVA KATARINA, JEZEK LADISLAV, OREMUS VLADIMIR, SMAHOVSKY VENDEL, STALMACH VALDEMAR, VARGA IVAN, ZLATOIDSKY PAVOL, GATTNAR, ONDREJ, HELEYOVA, KATARINA, JEZEK, LADISLAV, OREMUS, VLADIMIR, SALMACH, VALDEMAR, SMAHOVSKY, VENDEL, VARGA, IVAN, ZLATOIDSKY, PAVOL
Applicants: GATTNAR ONDREJ, HELEYOVA KATARINA, JEZEK LADISLAV, OREMUS VLADIMIR, SALMACH VALDEMAR, SLOVAKOFARMA AS, SMAHOVSKY VENDEL, VARGA IVAN, ZLATOIDSKY PAVOL, GATTNAR, ONDREJ, HELEYOVA, KATARINA, JEZEK, LADISLAV, OREMUS, VLADIMIR, SALMACH, VALDEMAR, SLOVAKOFARMA, A.S., SMAHOVSKY, VENDEL, VARGA, IVAN, ZLATOIDSKY, PAVOL
Application year: 1997
Main classification: C07D401
IPC codes: C07D401