The way to get omeprazole

 

(57) Abstract:

The invention relates to a new process for the preparation of omeprazole, which is effective as an inhibitor of the secretion of gastric acid and is useful as an antiulcer agent. Describes how to obtain omeprazole, which includes phase oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole in an organic solvent, oxidant, and possibly in the presence of a base, in this case the oxidation is performed in the presence of a complex of titanium. The technical result - the creation of a new, more convenient and effective method of making racemic omeprazole. 9 C.p. f-crystals.

This invention relates to a new method of obtaining 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole, known by the international nonproprietary name omeprazole. In addition, this invention also relates to the manufacture of its pharmaceutical drug and its use in medicine,

The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole with international non-proprietary name omeprazole is a proton pump inhibitor, then eats the sense omeprazole can be used to treat diseases associated with the secretion of gastric acid in mammals and especially in humans.

Omeprazole and its therapeutically acceptable salts described in EP 5 129. This patent also discloses a method of obtaining omeprazole and other structurally similar substituted benzimidazole.

U.S. patent 5,386,032 describes an improved method for the synthesis of omeprazole. This method describes the stage of oxidation and procedure of omeprazole. Oxidation step uses m-chloroperoxybenzoic acid in the solvent system comprising an organic solvent and the aqueous phase with constant pH. The processing procedure includes a step of extraction and precipitation of omeprazole by adding alkylphosphate to the aqueous phase.

Another alternative method of manufacturing omeprazole described in U.S. patent 5,391,752. This method uses monoperoxyphthalate magnesium as the oxidant.

Omeprazole is a sulfoxide and a chiral compound in which the sulfur atom is a stereogenic center. Thus, omeprazole is a racemic mixture of the two individual enantiomers, R and S enantiomers of omeprazole. Enantioselective method for the synthesis otdelaetsya chiral complex of titanium.

In light of the above still had the need for a new convenient and more efficient way of making racemic omeprazole.

The objective of the invention is to create a new way of receiving omeprazole. In this invention, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] thio] -1H-benzimidazole oxidizes to omeprazole in an organic solvent, oxidant in the presence of a complex of titanium and possibly in the presence of a base. This invention also differs in that omeprazole is precipitated from the reaction mixture. Omeprazole, substantially free from titanium salts, which can then be easily filtered from the reaction mixture, thus avoiding substantial time stages, such as handling procedure, including extraction. This deposition of omeprazole from the reaction mixture unexpectedly, since the corresponding single enantiomers of omeprazole does not fall out from the reaction mixture under the same reaction conditions.

This deposition of omeprazole from the reaction mixture advantageously, this invention is the first method described to obtain omeprazole, not including the extraction step. Deposition of omeprazole gives many further mainly the ako, although both these reactions take place in solution phase, both of which are suppressed by the deposition of omeprazole from the reaction mixture. Deposition of omeprazole also suppresses other possible side reactions such as thermal decomposition omeprazole.

The complex of titanium, suitable for catalysis of the method according to this invention, are derived from ligands and compounds of titanium (IV) alkoxide preferably titanium (IV), and optionally in the presence of additional water. Especially preferred alkoxide of titanium (IV) is titanium (IV) isopropoxide or proposed. The number of complex titanium used in this invention, is not essential. The amount of less than about 0.50 equivalent (with respect to sulfide), preferred and especially preferred is an amount of 0.05-0.30 equivalent. However, less than 0.05 equivalent could also be used, and a lower limit of 0.05 equivalent is given only for technological reasons.

The ligand used in this invention to obtain a complex of titanium, can be either achiral or chiral, the latter being preferred. Convenient ligands are alcohols, such as diols, preferably vicinal diols. the sustained fashion dialami are esters of tartaric acid, for example ethyl ether.

The complex titanium may also be prepared by the interaction of tetrachloride titanium with a suitable ligand in the presence of a base.

This invention is also characterized by the use of achiral ligand or mixture of stereoisomers, such as a mixture of enantiomers, chiral ligand. All mixtures, including racemic mixtures, are within the scope of this invention.

In this invention preferably uses a racemic mixture of chiral ligands for the preparation of a complex of titanium.

The oxidizing agents can be used in different, and are selected so as to satisfy the conditions of the reaction and used equipment. Examples of such oxidizing agents include, but are not limited to, peroxyacids, such as m-chloroperoxybenzoic acid, and peroxides, such as cumene hydroperoxide, tert-butyl hydroperoxide and hydrogen peroxide. One advantage of this invention is that less strong and less corrosive-capable of oxidizing agent can be used for the preparation of omeprazole compared to the previous practice. The amount of oxidizing agent used according to this invention, tx2">

According to the invention are preferably used as the oxidizing cumene hydroperoxide or tert-butyl hydroperoxide.

According to one aspect of the invention, the oxidation is performed in the presence of a base, for example 0.05 to 1.0 equivalent, preferably 0.15 to 0.3 equivalent. The oxidation can also be performed in the absence of base.

The base may be inorganic or organic. Organic bases are preferred, and especially preferred bases are amines, preferably triethylamine or N,N-diisopropylethylamine. The amount of base added to the reaction mixture, is not significant.

The oxidation is preferably performed in an organic solvent at room temperature or higher, for example between 10-60oC. Suitable organic solvents are toluene, ethyl acetate, etc., Toluene is the preferred solvent.

The order in which the reagents, i.e., a compound of titanium, ligand, base, solvent, water and 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] thio] -1H-benzimidazole, is loaded into the reaction vessel, is not essential and can be adapted to the used oxidant.

Preparation of the complex of titanium can be performed at room temperature or at elevated temperature and/or for a long time of preparation and in the presence or absence of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole.

According to one aspect of the present invention the complex of titanium is prepared in the presence of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole.

The advantage of the method according to this invention is that omeprazole is precipitated from the reaction mixture without the simultaneous deposition of titanium salts. Because of this deposition omeprazole can be easily separated from the reaction mixture by filtration or centrifugation, and thus it is possible to avoid substantial time of processing.

The method according to this invention may also be used to obtain not only omeprazole, but also other substituted sulfinyl heterocyclic compounds known from the prior art, such as connections with the international nonproprietary name: lansoprazole, pantoprazole, leminoprazole and rabeprazole.

The following example further illustrates from

Example 1.

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] thio] -1H-benzimidazole (15,4 g, to 46.7 mmol) was dissolved in toluene (70 ml). The solution was heated to 50oWith and added water (0,030 ml). To the mixture was added diethyl ether (D, L) tartaric acid (2,02 g, 9,78 mmol) in toluene (8 ml) and isopropyl titanium (IV) (1,33 g, and 4.68 mmol). The mixture was cooled to 30oWith and added diisopropylethylamine (0,962 g, 7,44 mmol), and then cumene hydroperoxide (8,21 g, 53,9 mmol). The mixture was stirred at 30oC for 5 h, and the precipitated product was filtered and washed with toluene (12 ml).

Yield: 13.1 g (81%).

Example 2.

The complex titanium are simply contacting compounds of titanium (IV) and ligand, thus obtaining a complex of titanium is also possible in the presence of primary product 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio] -lH-benzimidazole. I.e. you can take the source components to obtain a complex of titanium (i.e., a compound of titanium (IV) and the ligand), to bring them into contact and add the resulting complex of titanium to the core product, or all three components enter into the reaction flask independently from each other. However, as described in example 1 to a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-Pirna namely, the titanium alkoxide (IV) (isopropoxide titanium (IV) and the ligand, representing diethyl ether (D, L) tartaric acid, i.e. a racemic mixture of chiral ligands. Next, the mixture was added to the base (diisopropylethylamine) and an oxidant (cumene hydroperoxide). The base and the oxidizing agent does not particularly limited.

1. The way to get omeprazole, which includes phase oxidation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] thio] -1H-benzimidazole in an organic solvent, oxidant, and possibly in the presence of a base, characterized in that the oxidation is performed in the presence of a complex of titanium.

2. The method according to p. 1, characterized in that the oxidation is performed in the presence of a base.

3. The method according to p. 1 or 2, characterized in that the complex titanium prepared from compounds of titanium (IV) and enantiomeric mixtures of chiral ligands.

4. The method according to p. 3, wherein the enantiomeric mixture is a racemic mixture.

5. The method according to p. 1, wherein the omeprazole is precipitated from the reaction mixture.

6. The method according to p. 1, characterized in that the stage of extraction is missing.

7. The method according to any of paragraphs. 1-6, characterized in that idea"ptx2">

8. The method according to any of paragraphs. 1-7, characterized in that the oxidant is a cumene hydroperoxide or tert-butylhydroperoxide.

9. The method according to any of paragraphs. 1-8, characterized in that the organic solvent is a toluene.

10. The method according to any of paragraphs. 1-9, characterized in that the base is a triethylamine or N, N-diisopropylethylamine.

 

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