MXPA99006369A - New process - Google Patents
New processInfo
- Publication number
- MXPA99006369A MXPA99006369A MXPA/A/1999/006369A MX9906369A MXPA99006369A MX PA99006369 A MXPA99006369 A MX PA99006369A MX 9906369 A MX9906369 A MX 9906369A MX PA99006369 A MXPA99006369 A MX PA99006369A
- Authority
- MX
- Mexico
- Prior art keywords
- omeprazole
- process according
- methoxy
- prepared
- titanium
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 34
- SUBDBMMJDZJVOS-UHFFFAOYSA-N Esomeprazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229960000381 omeprazole Drugs 0.000 claims abstract description 37
- RTAQQCXQSZGOHL-UHFFFAOYSA-N titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910052719 titanium Inorganic materials 0.000 claims abstract description 15
- 239000010936 titanium Substances 0.000 claims abstract description 15
- 239000007800 oxidant agent Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- XURCIPRUUASYLR-UHFFFAOYSA-N 6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfanyl]-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(OC)=C1C XURCIPRUUASYLR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000001590 oxidative Effects 0.000 claims abstract 2
- 230000027455 binding Effects 0.000 claims description 12
- 239000003446 ligand Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 238000007254 oxidation reaction Methods 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 230000003647 oxidation Effects 0.000 claims description 9
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tBuOOH Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
- 150000003609 titanium compounds Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000002194 synthesizing Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000001556 precipitation Methods 0.000 description 7
- -1 titanium (IV) compound Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 5
- 150000002009 diols Chemical class 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 210000004211 Gastric Acid Anatomy 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N Titanium isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 150000003608 titanium Chemical class 0.000 description 2
- PSIREIZGKQBEEO-UHFFFAOYSA-N 2-(1H-benzimidazol-2-ylsulfinylmethyl)-N-methyl-N-(2-methylpropyl)aniline Chemical compound CC(C)CN(C)C1=CC=CC=C1CS(=O)C1=NC2=CC=CC=C2N1 PSIREIZGKQBEEO-UHFFFAOYSA-N 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N Dexlansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 229950007395 Leminoprazole Drugs 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J Titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 231100000078 corrosive Toxicity 0.000 description 1
- 231100001010 corrosive Toxicity 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- XTTBFCWRLDKOQU-UHFFFAOYSA-N propan-1-ol;titanium Chemical compound [Ti].CCCO.CCCO.CCCO.CCCO XTTBFCWRLDKOQU-UHFFFAOYSA-N 0.000 description 1
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical group CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 230000003482 proton pump inhibitor Effects 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
Abstract
The present invention relates to a novel process for the synthesis of 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2- pyridinyl)methyl]sulfinyl]-1H- benzimidazole, known under the generic name omeprazole. Moreover, the present invention also relates to manufacture of a pharmaceutical preparation thereof and its use in medicine. The novel process for the preparation of omeprazole, comprises the step of oxidizing 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2- pyridinyl) methyl]thio]-1H- benzimidazole in an organic solvent with an oxidizing agent in the presence of a titanium complex and optionally in the presence of a base.
Description
NOVEDOUS PROCESS FOR THE SYNTHESIS OF 5-METOXY-2 - [[(4-METOXY-3, 5-DIMETHYL-2-PYRIDINYL) METHYL] SULFINYL] -1H-BENZYMIDAZOLE, PRODUCT OBTAINED FROM IT AND PHARMACEUTICAL FORMULATION COMPRISING
SAID PRODUCT
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-iri inyl) ethyl] sulfinyl] -IH-benzimidazole, known under the name generic of omeprazole. On the other hand, the present invention also relates to the manufacture of a pharmaceutical preparation thereof and its use in medicine.
BACKGROUND OF THE INVENTION AND PREVIOUS TECHNIQUE
The compound 5-methoxy-2- [[(-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lH-benzimidazole, which has the generic name of omeprazole, is a proton pump inhibitor, that is, effective to inhibit the secretion of gastric acid, and is useful as an antiulcer agent. In a more general sense, oiaeprazole can be used for the treatment of conditions related to gastric acid in mammals and especially in man. Omeprazole and therapeutically acceptable salts thereof are described in EP 5 129.
REF .: 30692 This patent also describes a process for the preparation of structurally related omeprazole and other substituted benzimidazoles. US 5,386,032 describes an improved process for the synthesis of omeprazole. This process describes the oxidation step and a working procedure for omeprazole. The oxidation step uses m-chloroperoxybenzoic acid in a solvent system consisting of an organic solvent and an aqueous phase of constant pH. The working procedure includes a step of extraction and precipitation of omeprazole by the addition of an alkyl format to the aqueous phase. Another alternative process for the manufacture of omeprazole is described in US 5,391,752. This process uses magnesium monoperoxyphthalate as an oxidizing agent. Omeprazole is a sulfoxide and a chiral compound, with the sulfur atom being the stereogenic center. Thus, omeprazole is a racemic mixture of its two individual enantiomers, the R and S enantiomers of omeprazole. An enantioselective process for the synthesis of the individual enantiomers of omeprazole is described in WO 96/02535. Asymmetric oxidation uses a chiral titanium complex to induce chirality. In view of those described above, there is still a need for a convenient and more efficient new process for the manufacture of racemic omeprazole.
BRIEF DESCRIPTION OF THE INVENTION
The object of the present invention is to provide a novel process for the preparation of omeprazole. In the present invention, 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1H-benzimidazole is oxidized to omeprazole in an organic solvent with an oxidizing agent in presence of a titanium complex, and optionally in the presence of a base. The present invention is further characterized in that omeprazole precipitates from the reaction mixture. The omeprazole, substantially free of titanium salts, can thereafter be easily separated by filtration of the reaction mixture and thereby avoid time-consuming steps, such as working procedures that include extraction. This precipitation of omeprazole from the reaction mixture is unexpected, since the corresponding individual enantiomers of omeprazole do not precipitate from the reaction mixture if the same reaction conditions are used. This precipitation of omeprazole from the reaction mixture is advantageous and the present invention is the first described process for the preparation of omeprazole that does not involve an extraction step. The precipitation of omeprazole results in a number of additional benefits. Omeprazole is sensitive to acid and over-oxidation, ie the oxidation of sulfoxide to sulfone. However, since both reactions are carried out in the solution phase, both are suppressed by the fact that omeprazole precipitates from the reaction mixture. This precipitation of omeprazole also suppresses other potential side reactions, such as thermal decomposition of omeprazole. The titanium complex suitable for catalyzing the process of the present invention is prepared from a ligand and a titanium (IV) compound, preferably an alkoxide. of titanium (IV), and optionally in the presence of additional water. An especially preferred titanium (IV) alkoxide is isopropoxide or titanium (IV) propoxide. The amount of the titanium complex used in the present invention is not critical. An amount of less than about 0.50 equivalents, in proportion to the sulfide, is preferred and an especially preferred amount is 0.05-0.30 equivalents. However, less than 0.05 equivalents could also be used and the lower limit of 0.05 equivalents is given only for management reasons. The ligand used in the present invention to produce the titanium complex can be either an achiral ligand or a chiral ligand, of which the latter is preferred. Useful ligands are alcohols, such as diols, and preferably vicinal diols. The diol can be a branched or unbranched alkyldiol, or an aromatic diol. Preferred diols are esters of tartaric acid, such as ethyl esters. The titanium complex can also be prepared by reacting titanium tetrachloride with a suitable ligand in the presence of a base. The present invention is further characterized in that an achiral ligand or a mixture of stereoisomers, such as a mixture of enantiomers, of a chiral ligand is used. All mixtures, including a racemic mixture are within the scope of the present invention.
In a preferred aspect of the present invention, a racemic mixture of chiral ligands is used to prepare the titanium complex. The oxidizing agent used is not crucial, and can be selected to suit the reaction conditions and equipment used. Examples of such oxidizing agents include, but are not limited to, peroxyacids, such as m-chloroperoxybenzoic acid, and peroxides such as eumenal hydroperoxide, tert-butyl hydroperoxide, and hydrogen peroxide. An advantage of the present invention is that a less reactive and less corrosive oxidizing agent can be used to prepare omeprazole compared to those used in the prior art. The amount of oxidizing agent used according to the present invention is preferably about one equivalent, such as from 0.9 to 1.05 equivalents, in proportion to the sulfide. According to a preferred aspect of the invention, eumeno hydroperoxide or tert-butyl hydroperoxide are used as the oxidizing agent. According to one aspect of the invention, the oxidation is carried out in the presence of a base, such as 0.05-1.0 equivalents, preferably 0.15-0.3 equivalents. Optionally, oxidation can be performed in the absence of a base. The base can be an inorganic or an organic base. Organic bases are preferred and especially suitable bases are amines, preferably triethylamine or N, N-diisopropyl-ethylamine. The amount of base added to the reaction mixture is not crucial. The oxidation is preferably carried out in an organic solvent around room temperature or above, for example between 10-60 ° C. Suitable organic solvents are for example toluene, ethyl acetate, and the like. Toluene is the preferred solvent. The order in which the reactants, ie the titanium compound, the ligand, the base, the solvent, water, and the 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) ) methyl] io] -lH-benzimidazole are loaded in the reaction flask is not crucial, and must be adapted to suit the equipment used. However, it is preferred that all reagents are charged into the reaction vessel before the oxidizing agent is added. The preparation of the titanium complex can be carried out at room temperature, or at an elevated temperature and / or during a prolonged preparation time and in the presence or absence of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl) -2-pyridinyl) methyl] thio] -lH-benzimidazole. According to one aspect of the present invention, the titanium complex is prepared in the presence of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio} -IH-benzimidazole. An advantage of the process according to the present invention is that the omeprazole precipitates from the reaction mixture without the simultaneous precipitation of the titanium salts. Due to this precipitation, omeprazole can be easily separated from the reaction mixture by filtration or centrifugation, and thereby avoiding any time-consuming working procedure. The process of the present invention can also be used to produce not only omeprazole, but also other substituted sulfinyl heterocyclic compounds known in the art, such as compounds with the generic names lansoprazole, pantoprazole, leminoprazole and rabeprazole. The following example which will further illustrate the invention, but is not intended to limit the scope of the invention defined in the foregoing or as claimed in the following.
EXAMPLE
-Methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -lH-benzimidazole (15.4 g, 46.7 mmol) was dissolved in toluene. { 70 ml). The solution was heated to 50 ° C and water (0.030 ml) was added to the resulting mixture, diethyl (D, L) -tartrate (2.02 g, 9.78 mmol) in toluene (8 ml) and titanium isopropoxide (IV) was added. (1.33 g, 4.68 mmol) The mixture was cooled to 30 ° C and diisopropylethylamine (0.962 g, 7.44 mmol) was added followed by eumeno hydroperoxide (8.21 g, 53.9 mmol) The mixture was stirred at 30 ° C by 5 hours, and the precipitated product was separated by filtration and washed with toluene (12 ml) Yield: 13.1 g (81%).
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (13)
1. A process for the preparation of omeprazole, comprising the step of oxidizing 5-methoxy-2- [t (4-methoxy-3,5-dimethy1-2-pyridinyl) ethyl] thio] -1H-benzimidazole in an organic solvent with an oxidizing agent and optionally in the presence of a base, characterized in that the oxidation is carried out in the presence of a titanium complex.
2. A process according to claim 1, characterized in that the oxidation is carried out in the presence of a base.
3. A process according to claim 1 or 2, characterized in that the titanium complex is prepared from a titanium compound (IV) and an enantiomeric mixture of chiral ligands.
4. A process according to claim 3, characterized in that the enantiomeric mixture is a racemic mixture.
5. A process according to claim 1, characterized in that the titanium complex is prepared from a titanium compound (IV) and an achiral ligand.
6. A process according to claim 1, characterized in that the omeprazole precipitates from the reaction mixture.
7. A process according to claim 1, characterized in that an extraction stage is not used.
8. A process according to any of claims 1-7, characterized in that the titanium complex is prepared in the presence of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -lH-benzimidazole.
9. A process according to any of claims 1-8, characterized in that the oxidizing agent is eumeno hydroperoxide or tert-butyl hydroperoxide.
10. A process according to any of claims 1-9, characterized in that the organic solvent is toluene.
11. A process according to any of claims 1-10, characterized in that the base is triethylamine or N, N-diisopropylethylamine.
12. A pharmaceutical formulation comprising omeprazole and a pharmaceutically acceptable carrier or diluent, characterized in that the omeprazole is prepared according to any of claims 1-11.
13. Omeprazole characterized in that it is prepared by a process according to any of claims 1-11.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9704183-4 | 1997-11-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99006369A true MXPA99006369A (en) | 2000-07-01 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU750743B2 (en) | New process | |
| UA47409C2 (en) | Process for synthesis of substituted sulphoxides (variants) and sulphoxide | |
| US7452998B2 (en) | Process for preparing optically pure active compounds | |
| EP1802584A1 (en) | Processes for the preparation of substituted sulfoxides | |
| IL168554A (en) | Process for preparing s-pantoprazole | |
| ZA200503911B (en) | Process for preparing (s)-pantoprazole | |
| WO2009066321A2 (en) | Process for optically active sulfoxide compounds | |
| MXPA99006369A (en) | New process | |
| US20070225500A1 (en) | Process for the Preparation of Pyridin-2-Ylmethylsulphinyl-1H-Benzimidazol Compounds | |
| CZ249699A3 (en) | Novel treatment process | |
| KR20070031945A (en) | Process for the preparation of pyridin-2-ylmethylsulphinyl-1h-benzimidazol compounds |