WO2007138468A2

WO2007138468A2 - Processes for the preparation of lansoprazole

Info

Publication number: WO2007138468A2
Application number: PCT/IB2007/001437
Authority: WO
Inventors: Mohammed Jaweed Mukarram Siddiqui; Dilip Ganesh Kulkarni; Praveen Raosaheb Supekar; Prakash Sakharam Shinde; Vikas Vitthalrao Deshmukh
Original assignee: Wockhardt Ltd
Priority date: 2006-06-01
Filing date: 2007-05-31
Publication date: 2007-12-06
Also published as: WO2007138468A3

Abstract

The invention relates to processes for the preparation of benzimidazole sulphinyl compounds. More particularly, it relates to the preparation of pure lansoprazole and pharmaceutical compositions that include the pure lansoprazole.

Description

PROCESSES FOR THE PREPARATION OF LANSOPRAZOLE

Field of the Invention

The field of the invention relates to processes for the preparation of benzimidazole sulphinyl compounds. More particularly, it relates to the preparation of pure lansoprazole and pharmaceutical compositions that include the pure lansoprazole.

Background of the Invention

Benzimidazole sulphinyl compounds of Formula I are known for gastric proton pump inhibitors. Several such agents for example, lansoprazole, wherein Ri and R₄ = H, R₂ = CH₃ and R₃ =OCH₂CF₃, pantoprazole R₁ =OCHF₂, R₂ and R₃= OCH₃ and R₄=H, omeprazole Ri and R₃=OCH₃, R₂ and R₄= CH₃ and its (S)-enantiomer esomeprazole, laminoprozole.and rabeprazole wherein Ri and R₄= H, R₂ = CH₃ and R₄= 0(CH)₂ O CH₃ are known in the art for treating ulcer diseases.

Formula I

Lansoprazole is known to have excellent gastric acid secretion inhibiting action and gastric mucous membrane protecting action. It is chemically, 2-[[[3-Methyl-4- (2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole having structure of Formula l-a.

Formula l-a

Several processes have been reported for the preparation of benzimidazole compounds for example, in U.S. Patent Nos. 4,255,431 ; 4,628,098; 4,758,579; 5,578,732; and 6,313,303. In general, these processes involve the oxidation of thioethers to corresponding sulfinyls by hydrogen peroxide, m-chloroperbenzoic acid, sodium hypochlorite, sodium bromite and peroxoborate in presence of acid anhydride.

U.S. Patent No. 4,689,333 discloses a process of making lansoprazole by reaction of 2-mercaptobenzimidazole with 2-chloromethyl 3-methyl-4-(2,2,2- trifluoroethoxy) pyridine derivative in presence of a base and solvent.

U.S. Patent No. 6,002,011 discloses a process of crystallizing benzimidazole compounds with aqueous alcohol. The process includes isolating the water alcohol solvate and desolvating by suspending the solvate in warm water.

U.S. Patent No. 6,423,846 discloses a process of crystallization in acetone water. The process includes further purification by column chromatography.

U.S. Patent Application No. 20040138466 discloses a process for the preparation of benzimidazole sulphinyl compounds by reacting a thioether with tert-butyl hydroperoxide (TBHP) in the presence of a vanadium catalyst. U.S. Patent Application No. 20040215021 discloses a purification process for benzimidazole compounds using organic solvents or mixture of organic solvents and water in the presence of a weak basic gas like ammonia and methylamine. European Patent No. 302,720 discloses a process wherein the benzimidazole compound is crystallized from water and ethanol.

PCT Patent Application No. 2002074766 discloses a process for making lansoprazole by reacting 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine or its salt with 2-mercaptobenzimidazole in the presence of a halogenating agent and oxidizing the obtained thioethers compound with hydrogen peroxide in presence of benzene seleseninic acid.

Summary of the Invention In one general aspect there is provided a process for the preparation of a compound of Formula I,

Formula I

wherein Ri is H, OCH₃ or OCHF₂; R₂ is CH₃ or OCH₃; R₃ is OCH₃ , OCH₂CF₃ or O(CH₂)₃OCH₃; and R₄ is H or CH₃. The process includes the steps of: a) oxidizing a thioether of Formula Il in presence of oxygen scavenger with a suitable oxidizing agent in one or more organic solvents,

FORMULA Il

wherein Ri, R₂, R₃, and R₄ are as defined above; and b) isolating the compound of Formula I from reaction mass.

Embodiments of the process may include one or more of the following features. For example, the oxidation may be carried out in the presence of one or more suitable oxidizing agents. Suitable oxidizing agents may include one or more of m-chloroperbezoic acid, peracids, sodium hypohalides, magnesium monoperoxyphalate, hydrogen peroxide, benzeneseleseninic acid or Vanadium catalyst. The process may include carrying out the oxidation reaction in the presence of an oxygen scavenger. The oxygen scavenger may include one or more of dimethylsulphoxide, N-methylmorpholine or sulphur containing heterocycles.

Suitable organic solvents may include one or more of lower alkanols, halogenated hydrocarbons or mixtures thereof. The lower alkanol may include one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol, and iso- butanol. The halogenated hydrocarbon may include one or more of dichloromethane, dibromomethane, chloroform and ethylene dichloride.

In another general aspect there is provided a process for the preparation of lansoprazole of Formula l-a.

Formula l-a

The process includes the steps of: a) reacting a compound of Formula III,

Formula III with a compound of Formula IV,

Formula IV in the presence of aqueous acetone and a base to get lansoprazole sulphide of Formula I l-a; and

Formula I l-a b) oxidizing the sulphide of Formula ll-a to obtain the lansoprazole.

Embodiments of the process may include one or more of the following features. The base may be, for example one or more of inorganic bases or organic bases. The inorganic base may include one or more of alkali metal and alkaline earth metal hydroxides, hydrides, carbonates, bicarbonates and alkoxides and their solution in water. The organic base may include one or more of ammonia, primary, secondary or tertiary amines.

In another general aspect there is provided a process for the purification of compound of Formula I,

Formula I

wherein Ri is H, OCH₃ or OCHF₂; R2 is CH₃ or OCH₃; R3 is OCH₃ , OCH₂CF₃ or O(CH₂)₃OCH₃; and R₄ is H or CH₃, the process comprising: a) dissolving the compound of Formula I in aqueous alkali to get a solution; b) purging carbon dioxide into the solution; and c) isolating the compound of Formula I.

Embodiments of the process may include one or more of the following features. The aqueous alkali may include one or more of sodium hydroxide, potassium hydroxide, water, and mixtures thereof.

In one general aspect there is provided a pure lansoprazole. In another general aspect there is provided a process for preparing lansoprazole containing less than about 100 ppm residual solvent. The process includes dissolving lansoprazole in aqueous alkali to get a solution; purging carbon dioxide into the solution; and isolating the lansoprazole containing less than about 100 ppm residual solvent.

The process may include further drying of the product obtained.

The process may produce the pure lansoprazole having purity more than 99.2% as determined by HPLC. In particular, it may produce the lansoprazole having purity more than 99.2% and residual solvent less than 50 ppm.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of pure lansoprazole having less than 50 ppm residual solvent; and one or more pharmaceutically acceptable carriers, excipients or diluents.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description of the Invention

The inventors have identified that sulphone is formed as an impurity during the synthesis of benzimidazole compounds. The sulphone impurity is formed during the oxidation step. It was also noticed that the known processes for the oxidation involve the use of expensive and/or toxic catalyst, which are not selective.

Invariably, the known reagents for oxidation result in over oxidation of the benzimidazole sulphinyl compound to sulphone impurity, removal of which is extremely difficult from the finished product. In addition, the sulphone impurity rapidly imparts color to the product during storage and handling. The inventors have now developed a controlled oxidative process, which employs the use of oxygen scavengers to prevent the further oxidation of desired benzimidazole sulphinyl compounds to sulphone impurities.

It was also noticed that the sulphone impurity could be kept under control during reaction by using a combination of solvents for example, lower alkanols and halogenated hydrocarbons. However, the use of such solvents for the preparation of lansoprazole sulphide of Formula ll-a results in a product having moisture content more than the required limit, which requires rigorous drying to get moisture content of the product in limit. The recovery of solvent is also insufficient. The drying of the lansoprazole sulphide to get the desired moisture results in increased impurity content.

The inventors have now developed an efficient process for the preparation of lansoprazole sulphide of Formula ll-a wherein the process does not require extensive drying of the intermediate and provide very efficient recovery of the solvent.

It was also noticed that the sulphone impurity increases rapidly when the pH of the reaction mass is alkaline, whereas pH below 4 leads to N-oxide impurity formation thus resulting in degradation of the product. The inventors have developed an efficient and simple process for the oxidation of thioethers wherein the oxidation is carried out in the presence of buffer so that the pH of the reaction mass can be maintained in the range of about 4 to about 7.

The inventors have also noticed that the known processes of producing benzimidazole sulphinyl compounds yield a product where the level of solvents and water are high which do not suit the requirement of a formulator. Reducing the level of water and solvents is very time consuming and costly. Prolonged drying deteriorates the quality of the final product and the use of column chromatography is not feasible at commercial scale.

The inventors have developed a process to desolvate the benzimidazole compound that employs the use of carbon dioxide to produce the bezimidazoles which are solvent and water free.

The inventors have developed processes for the preparation of anti-ulcerative agents for example, lansoprazole, pantoprazole, omeprazole, esomeprazole, laminoprazole and rabeprazole having a compound of Formula I,

Formula I

wherein R₁ is H, OCH₃ or OCHF₂; R2 is CH₃ or OCH₃; R₃ is OCH₃ , OCH₂CF₃ or O(CH₂)₃OCH₃; and R₄ is H or CH₃.

The thioethers of Formula Il and ll-a can be prepared by, methods known in the literature. In particular, these may be prepared by the methods described in U.S. Patent No. 4,628,098 and U.S. Patent No. 6,423,846. The thioether may be suspended in a suitable organic solvent and the mass may be oxidized using one or more oxidizing agents while maintaining the pH of the reaction mass in range of about 4 to about 7 using a buffer optionally in the presence of an oxygen scavenger.

Suitable solvents include one or more of lower alkanol, halogenated hydrocarbon, ketone or ester. The lower alkanol may include one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol, and isobutanol. The halogenated hydrocarbon may include one or more of dichloromethane, dibromomethane, chloroform, ethylene dichloride, and the like.

The oxidizing agent may include one or more of m-chloroperbezoic acid, peracids, sodium hypohalides, magnesium monoperoxyphalate, hydrogen peroxide, benzeneseleseninic acid or Vanadium catalyst. The oxygen scavenger may include one or more of dimethylsulphoxide, N-methylmorpholine or sulphur containing heterocycles

The buffering effect can be obtained by using a mixture of sodium acetate and acetic acid. After completion of the reaction, the pH of the reaction mass can be raised and the organic phase can be separated. The organic layer so obtained can be extracted with an aqueous alkali from which the product can be isolated by acidification.

The compounds of Formula III and IV may be prepared by the methods known in the literature. In particular, these may be prepared by the methods described in U.S. Patent No. 4,628,098 and German Patent No. 4,230,923. The compound of Formula III may be reacted with a compound of Formula IV in aqueous acetone in the presence of a base. The base may include one or more of inorganic bases or organic bases. Inorganic bases may include alkali metal and alkaline earth metal hydroxides, hydrides, carbonates, bicarbonates and alkoxides. Organic bases may include ammonia, primary, secondary or tertiary amines.

The compound of Formula Il and ll-a may be subjected to oxidation using oxidizing agent to get benzimidazole sulphinyl compounds of Formula I.

The benzimidazole sulphinyl of Formula I may be dissolved in aqueous alkali such as sodium hydroxide, potassium hydroxide, and the like. The pH of the reaction mixture may be adjusted to about 8 and carbon dioxide may be purged into the solution. The separated benzimidazole compound of Formula I may be isolated.

The isolation may include filtration, filtration under vacuum, centrifugation, and decantation.

The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

The pure lansoprazole has a purity of more than 99.2%. More particularly, the lansoprazole has a purity of more than 99.2% and less than 100 ppm residual solvent, for example less than 50 ppm residual solvent.

The compound of formula I is purified by any process know in art, which may optionally include crystallization and chromatographic purification.

The present invention is illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1 : Preparation of lansoprazole

Lansoprazole thioether (980 gm) was dissolved in a mixture of dichloromethane (9.0 Lit) and isopropyl alcohol (4.5 Lit). The reaction mixture was cooled to -10° to 5⁰C and to it was added percacetic acid (1.35 Lit, 22.5%) in 4-6 hours. The pH of the reaction mixture was maintained in the range of 4-7 during the reaction with sodium acetate and acetic acid. After completion of the reaction, a solution of sodium thiosulphate (10%, q.s.) was added and pH was adjusted to 8-9 with sodium hydroxide solution. The organic layer was separated and extracted with sodium hydroxide solution. The product was precipitated by adjusting the pH of the alkaline layer to 8-9 with acetic acid, filtered and dried to get lansoprazole.

Example 2: Preparation of lansoprazole

Lansoprazole thioether (980 gm) was dissolved in a mixture of dichlo^'romethane (9.0 Lit) and isopropyl alcohol (4.5 Lit). To this mass, sodium acetate (95 gm) and dimethylsulphoxide (1.0 Lit) were added. The reaction mixture was cooled to -10° to 5°C and percacetic acid 1.35 Lit, 22.5%) was added to it in 4-6 hours. The pH of the reaction mixture was maintained to 4-7 during the reaction with acetic acid. After completion of the reaction, excess of peracetic acid was quenched by 10% sodium thiosulphate and pH was increased to 8-9 with caustic lye solution. The organic layer was separated and extracted with alkaline sodium hydroxide solution. The product was precipitated by adjusting the pH of alkaline layer to 8-9 with acetic acid and the separated product was filtered and dried to get lansoprazole.

Example 3: Preparation of lansoprazole sulphide

A saturated solution of potassium carbonate (800 gm) in water (1.0 Lit) was added drop-wise to a mixture of 2-chloromethyl-3-methyl-4-(2,2,2-trifluroethoxy) pyridine hydrochloride (1.0 Kg) and 2-mercaptobenzimidazole (560 gm) in aqueous acetone (9 Lit, 10%). The reaction mixture was heated for 4-5 hours at 40 - 60⁰C and acetone (about 5 Lit) was distilled off under reduced pressure from the reaction mass. Water (8.0 Lit) was added to the resultant mass and the separated product was filtered, washed with water and dried to get the title compound. Yield: 1.3 Kg HPLC Purity: 99.8% Moisture content: 4.8%

Example 4: Purification of lansoprazole

Lansoprazole (750 gm) was dissolved in 10% aqueous ethyl alcohol (6 Lit, 1:9) by portion wise addition of solid sodium carbonate (20 gm). The reaction mixture was heated to 60-70⁰C to get a clear solution. The solution was filtered hot and the filtrate was cooled to 5°C gradually to crystallize out the product. The solid was filtered.

The wet cake so obtained was suspended in water (8 Lit) and dissolved by addition of aqueous sodium hydroxide solution (1 Lit, 8%). The reaction mixture was charcolized and filtered. Carbon dioxide gas was bubbled slowly through the filtrate to attain the pH of about 8.5. The precipitated solid was filtered, washed and dried to obtain the lansoprazole in high purity. Yield: 520 gm Assay by HPLC: 99.2%

Residual solvent: Not detected (less than 50 ppm)

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We Claim:

1. A process for the preparation of a compound of Formula I₁

Formula I wherein Ri is H, OCH₃ or OCHF₂; R2 is CH₃ or OCH₃; R₃ is OCH₃ , OCH₂CF₃ or O(CH₂)₃OCH₃; and R₄ is H or CH₃ , the process comprising:

a) oxidizing a thioether of Formula Il in presence of oxygen scavenger with a suitable oxidizing agent in one or more organic solvents,

FORMULA Il

wherein R₁, R₂, R₃, and R₄ are as defined above; and b) isolating the compound of Formula I from reaction mass.

2. The process of claim 1 , wherein the oxidizing agent comprises one or more of m-chloroperbezoic acid, peracids, sodium hypohalides, magnesium monoperoxyphalate, hydrogen peroxide, benzeneseleseninic acid, and Vanadium catalyst.

3. The process of claim 1 , wherein the solvent comprises one or more of lower alkanol, halogenated hydrocarbon or mixtures thereof.

4. The process of claim 3, wherein the lower alkanol comprises one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol and isobutanol.

5. The process of claim 3, wherein the halogenated solvent comprises one or more of dichloromethane, dibromomethane, chloroform and ethylene dichloride.

6. The process of claim 1 , wherein the oxygen scavenger comprises one or more of dimethylsulphoxide, N-methylmorpholine, and sulphur containing heterocycles.

7. The process of claim 1 , wherein the oxidation is carried out at a pH in the range of about 4 to about 7.

8. The process of claim 7, wherein the pH is maintained by using a buffering agent.

9. The process of claim 8, wherein the buffering agent is a combination of sodium acetate and acetic acid.

10. A process for the preparation of lansoprazole of Formula l-a, the process comprising:

Formula l-a a) reacting a compound of Formula III,

Formula

with a compound of Formula IV,

Formula IV

in the presence of aqueous acetone and a base to get lansoprazole sulphide of Formula ll-a; and

Formula ll-a b) oxidizing the sulphide of Formula ll-a to obtain the lansoprazole.

11. The process of claim 10, wherein the aqueous acetone contains from about 5% to about 30% water by volume.

12. The process of claim 10, wherein the base comprises one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and diclyclohexyl amine.

13. The process of claim 10, wherein the lansoprazole sulfide has a moisture content of about 5% w/w or less.

14. A process for the purification of a compound of Formula I,

Formula I wherein Ri is H, OCH₃ or OCHF₂; R₂ is CH₃ or OCH₃; R3 is OCH₃ , OCH₂CF₃ or O(CH₂)₃OCH₃; and R₄ is H or CH₃, the process comprising: a) dissolving the compound of Formula I in aqueous alkali to get a solution; b) purging carbon dioxide into the solution; and c) isolating the compound of Formula I.

15. The process of claim 14, wherein the aqueous alkali comprises one or more of sodium hydroxide, potassium hydroxide, water and mixtures thereof.

16. The process of claims 1 or 14, wherein the compound of formula I is selected from the group consisting of lansoprazole, pantoprazole, omeprazole, laminoprazole, rabeprazole, pharmaceutically acceptable salts, or enantiomers thereof.

17. Pure lansoprazole having purity more than 99.2% by HPLC.

18. Pure lansoprazole of claim 17, wherein the lansoprazole has a moisture content less than 0.1% w/w.

19. Pure lansoprazole of claim 17, wherein the lansoprazole has less than about 100 ppm residual solvent.

20. Pure lansoprazole of claim 19, wherein the lansoprazole has less than about 50 ppm residual solvent.

21. A process for the preparation of lansoprazole containing less than about 100 ppm residual solvent, the process comprising: a) dissolving lansoprazole in aqueous alkali to get a solution; b) purging carbon dioxide into the solution; and c) isolating the lansoprazole containing less than about 100 ppm residual solvent.

22. The process of claim 21 , wherein the lansoprazole prepared has less than about 50 ppm residual solvent.

23. A pharmaceutical composition comprising a therapeutically effective amount of the pure lansoprazole having less than about 50 ppm residual solvent; and one or more pharmaceutically acceptable carriers, excipients or diluents.