GB2239453A - Omeprazole - Google Patents

Abstract

Omeprazole is prepared by irradiating a solution containing a compound of the formula: <IMAGE> and sensitising agent having a light absorption spectrum showing a main light absorption band covering wavelengths emitted by the light source.

Description

PREPARATION OF OMEPRAZOLE The invention relates to the preparation of omeprazole and more particularly to a process for preparing omeprazole and also includes such omeprazole prepared by said process.

Omeprazole is the accepted designation of the compound 5-methOxy-2-(((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfi- nyl)-lH-benzimidazole of formula I

This compound is known e.g. from EP-5129. It is also known from EP-5129 as well as from analogue processes disclosed in EP-240158 or JP-61-178919 to prepare omeprazole from a compound of formula II

by an oxidation process using as an oxidant a compound selected from various possible oxidation agents, for instance m-chloro-perbenzoic acid (thus, the compound of formula II also is a known compound). This process for preparing omeprazole has the drawback of not being highly selective in respect of the product obtained, so that the work-up process is costly to perform.

The aim of the present invention is to overcome this drawback and to provide a process using a simple reaction procedure for preparing omeprazole with a high specificity.

According to the invention, there is provided a process of preparing omeprazole, comprising the steps of providing a reactor vessel for performing photochemical reactions, adapted to contain a solution and to allow irradiation of said solution by light from a light source; selecting a solvent transparent to the light from the light source; selecting a sensitising agent having a light absorption spectrum showing a main light absorption band encompassing light wavelengths emitted by said light source; providing in said reactor vessel a solution containing the compound of formula II in said solvent in a concentration ranging from 1 g/l to saturation and providing in said reactor vessel said sensitising agent in a quantity ranging from 0,05 g to 0,5 g per litre of said solution in said reactor vessel;; irradiating said solution in said reactor vessel with said light during a predetermined time; and subjecting said irradiated solution to a separation process for separating from the solution the omeprazole thus formed.

Preferably, the light source is selected from doped or undoped mercury or sodium vapour arc light sources and tungsten light sources optionally filled with inert or halogen gas.

Preferably, the solvent is selected from the group consisting of water, C1-C4-alcohols, esters, ethers, hydrocarbons comprising aliphatic, alicyclic and aromatic hydrocarbons, acetonitrile, amides and derivatives thereof, and mixtures thereof.

Preferably, the sensitising agent is selected from the group consisting of xanthene dyes, porphyrines, phthalocyanines and metallic complexes thereof, acridine dyes, and phenothiazine dyes.

Preferably, the solution is saturated with air or oxygen.

The invention is also directed to the omeprazole formed as a product of the above defined process.

An advantage of the present invention is to provide a process for preparing omeprazole with a high specificity, and to provide a product of this process which substantially does not contain any of such by-products which result from the oxidation of the compound of formula II by other undesirable oxidations processes.

In a first exemplary embodiment of the invention, there has been provided a DEMA 13/11 circulating flow immersion type Pyrex photochemical reactor equipped with a Philips HPK 125 mercury arc.

Before entering the reactor, the light has been filtered by means of a circulated and refrigerated aqueous solution containing 25 % by weight of potassium dichromate and 0.1 t by weight of 2,7-dimethyl-3,6-diazacyclohepta-2,6-diene perchlorate [cf. S.L. urov, Handbook of Photochemistry, Dekker, New York, 1973).

As a sensitising agent in relationship with the above described light filter, there was used rose bengal or a polysulfonated aluminium phthalocyanine chloride of formula III

which is commercially available under the designation "Tinolux" from Ciba-Geigy AG (Easel, Switzerland). The concentration of the sensitising agent in the solution was selected so as to yield a substantially total absorption of light, typically an absorption by a factor greater that about 2, within the spectral domain of the main absorption band (550-700 nm) of the sensitising agent under the given irradiation conditions.

To this purpose, the solution contained 0.25 g/l of the compound of formula II and typically 0,076 to 0.13 g/l of "Tinolux" in methanol. The photochemical reactor was then loaded with 140 ml of this first exemplary solution and then irradiated during up to 250 hours.

In another exemplary embodiment of the invention, the solution contained 6.9 g/l of the compound of formula II and 0.076 g/l of "Tinolux" in methanol. The photochemical reactor was then loaded with 150 ml of this second exemplary solution and then irradiated during up to 225 hours.

In still another exemplary embodiment of the invention, the solvent used comprised a mixture of 275 ml of acetonitrile and 725 ml of 0.025 M phosphate buffered aqueous solu tion (pH 7.6). The photochemical reactor was then loaded with 150 ml of this second exemplary solution and then irradiated during up to 25 hours.

In still another exemplary embodiment of the invention, the solvent used was pure acetonitrile. The photochemical reactor was then loaded with 150 ml of this second exemplary solution and then irradiated during up to 17 hours.

In still another exemplary embodiment of the invention, the sensitising agent used was 4,5,6,7-tetrachloro-2',4' ,5' ,- 7'-tetraiodofluoresceine (rose bengal). This sensitising agent is more active than "Tinolox" but showed a rather unsatisfactory light stability under the experimental conditions used. Nevertheless, under appropriate experimental conditions rose bengal is usable as the sensitising agent, as it can be stabilised in photolysis solution of high pH value (e.g. pH > 9). However, this implies that in conjunction with rose bengal a solvent must be used which is a mixture of organic solvents and water buffer solutions. Incidentally, one could also use methylene blue as a sensitising agent, as the latter is more stable under these conditions.

The omeprazole resulting from the photochemical oxidation of the compound of formula II was then separated from the solution by the following method. Methanol was evaporated at room temperature under reduced pressure. The residue was dissolved in 100 ml aqueous NaOH (3,4 g/l) and there were added 100 ml methylene chloride. Complete phase separation afforded an aqueous solution of omeprazole and sensitising agent which was then acidified to pH 7 and evaporated under reduced pressure. Finally, omeprazole was extracted from the residue by means of acetonitrile at 30 to 40"C. The separation of the sensitising agent can be avoided if the sensitised photochemical oxidation is carried out in a heterogeneous phase mixture, e.g. using "Tinolux" and acetonitrile because the former is not soluble in the latter.

The chemical yield was in each case determined by HPLC analysis, using a 25 cm Nucleosil 5 C8 column and, as the eluting agent for detection at 280 nm, 275 ml of acetonitrile diluted to 1 litre in 0,025 M phosphate buffer (pH 7,6), with reference to a standardisation curve of the HPLC response vs.

the omeprazole concentration. The photolysis reactions were carried out to a reaction yield of up to 15 %, calculated with respect to the starting quantity of the compound of formula II.

In further exemplary embodiments of the invention, there was noted that although the solution of the compound of formula II and "Tinolux" in methanol could be used as such, best results were obtained when an air saturated solution was used which contained the products in the proportions indicated above.

Claims (8)

1. A process for preparing omeprazole, comprising the steps of providing a reactor vessel for performing photochemical reactions, adapted to contain a solution and to allow irradiation of said solution by light from a light source; selecting a solvent transparent to the light from the light source; selecting a sensitising agent having a light absorption spectrum showing a main light absorption band encompassing light wavelengths emitted by said light source; providing in said reactor vessel a solution containing a compound of formula II

in said solvent in a concentration ranging from 1 g/l to saturation and providing in said reactor vessel said sensitising agent in a quantity ranging from 0,05 g to 0,5 g per litre of said solution in said reactor vessel; irradiating said solution in said reactor vessel with said light during a predetermined time; and subjecting said irradiated solution to a separation process for separating from the solution the omeprazole thus formed.

2. A process for preparing omeprazole as set forth in claim 1, in which the light source is selected from doped or undoped mercury or sodium vapour arc light sources and tungsten light sources optionally filled with inert or halogen gas.

3. A process for preparing omeprazole as set forth in claim 1, in which the solvent is selected from the group consisting of water, C1-C4-alcohols, esters, ethers, hydrocarbons comprising aliphatic, alicyclic and aromatic hydrocarbons, acetonitrile, amides and derivatives thereof, and mixtures thereof.

4. A process for preparing omeprazole as set forth in claim 1, in which the sensitising agent is selected from the group consisting of xanthene dyes, porphyrines, phthalocyanines and metallic complexes thereof, acridine dyes, and phenothiazine dyes.

5. A process for preparing omeprazole as set forth in claim 1, in which the solution is saturated with air or oxygen.

6. Omeprazole prepared by a process comprising the steps of providing a reactor vessel for performing photochemical reactions, adapted to contain a solution and to allow irradiation of said solution by light from a light source; selecting a solvent transparent to the light from the light source; selecting a sensitising agent having a light absorption spectrum showing a main light absorption band encompassing light wavelengths emitted by said light source; providing in said reactor vessel a solution containing a compound of formula II

in said solvent in a concentration ranging from 1 g/l to saturation and providing in said reactor vessel said sensitising agent in a quantity ranging from 0,05 g to 0,5 g per litre of said solution in said reactor vessel; irradiating said solution in said reactor vessel with said light during a predetermined time; and subjecting said irradiated solution to a separation process for separating from the solution the omeprazole thus formed.

7. A process for preparing omeprazole, substantially as described herein with reference to the foregoing examples.

8. Omeprazole when prepared by the process of any of claims 2 to 6.