WO2007066202A1

WO2007066202A1 - Process for the preparation of 2-(2-pyridylmethyl)-sulfinyl-1h-benzimidazoles

Info

Publication number: WO2007066202A1
Application number: PCT/IB2006/003482
Authority: WO
Inventors: Reguri Buchi Reddy; Gudaparthi Om Prakash; Gutta Madhusudhan
Original assignee: Inogent Laboratories Private Limited
Priority date: 2005-12-06
Filing date: 2006-11-23
Publication date: 2007-06-14

Abstract

The present invention relates to an improved process for the preparation of substituted. 2-(2-pyridylmethyl)-sulfinyl-1H-benzimidazoles or its derivatives, which are useful for a medicament such as an inhibitor of gastric acid secretion or an anti-ulcer agent or an intermediate to produce medicaments in good yield and high purity. More particularly, the present invention relates to a process for preparing a sulfoxide compound of the formula (I) in good yield and relatively high purity and pharmaceutically acceptable salt, hydrate and solvate thereof. (I) wherein R1 and R3 are selected from the group consisting of hydrogen, methyl or C1-4 alkoxy, R2 is selected from the group consisting of substituted or unsubstituted C1-4 alkoxy, R4 is selected from the group consisting of hydrogen or substituted or unsubstituted C1-4 alkoxy. Comprising the step of oxidizing a sulfide compound of formula (II) with Peroxyacetic acid or its derivatives necessarily at the pH 5-7 using aqueous sodium carbonate solution. (II) wherein R1 R2 R3 & R4 are as defined above.

Description

PROCESS FOR THE PREPARATION OF 2- (2-PYRIDYLMETHYL) -SULFINYL-lH-BENZIMIDASOLES

Field of the Invention

The present invention relates to an improved process for the preparation of substituted 2-(2-pyridylmethyl)-sulfinyl-lH-benzimidazoles or its derivatives, which are useful for a medicament such as an inhibitor of gastric acid secretion or an anti-ulcer agent or an intermediate to produce medicaments in good yield and high purity. More particularly, the present invention relates to a process for preparing a sulfoxide compound of the formula (I) in good yield with relatively high purity and pharmaceutically acceptable salt, hydrate and solvate thereof.

I

wherein Rj and R₃ are selected from the group consisting of hydrogen, methyl or C₁ -₄ alkoxy, R₂ is selected from the group consisting of substituted or unsubstituted C_1-4 alkoxy, R₄ is selected from the group consisting of hydrogen or substituted or unsubstituted C,-₄ alkoxy.

Comprising the step of oxidizing a sulfide compound of formula (II) with Peroxyacetic acid or its derivatives necessarily at the pH 5-7 using aqueous sodium carbonate solution.

II

wherein Ri R₂ R₃ & R₄ are as defined above.

- i Background of the Invention

A number of compounds of industrial interest, in particular Pharmaceuticals for human or veterinary use, contain a sulfinyl or sulfonyi group. Their synthesis usually comprises an oxidation step wherein a thioether intermediate (-S-) is transformed into a sulfinyl (-SO-) compound. Different oxidizing agents are available for this oxidation, such as those described by S. Uemura in "Comprehensive Organic Synthesis", chapter 6.2, edited B. M. Trost and J. Fleming, Pergamon Press (1991). Nevertheless, only some of these oxidizing agents are suitable for industrial application, due to the facts that they are not easily available on the market, environmentally unsafe and their poor chemical selectivity. Among those suitable for industrial use, hydrogen peroxide and sodium hypochlorite arc usually preferred, as they are commercially available in large amounts and at low cost, Moreover, the oxidation of organic compounds with hydrogen peroxide is very often carried out in the presence of catalysts based on transition metals, such as tungsten, titanium, vanadium and molybdenum. The removal of these catalysts from the reaction product is recognizably troublesome, as it requires additional purification steps with consequent increase in production costs and decrease in yield.

In general, the oxidizing power of sodium hypochlorite is not sufficient to obtain sulfonyi derivatives. Moreover, in most cases the oxidation of thioethers with sodium hypochlorite is not sufficiently selective and leads to undesired byproducts.

A known medicament that contains a sulfinyl group is modafmil, i.e. 2- [(diphenylmcthyl)sulfmyl]acetamide. According to various synthetic methods^, intermediate 2- [(diphenylmethyl)thio] acetic acid or 2-[(diphenylmethyl) thio]acetamide is oxidized with hydrogen peroxide to give 2-[(diphenylmethyl) sulfmyl]acetic acid, or 2-[(diphenylmethyl)sulfmyl]acetamide, respectively. This oxidation, usually performed with 110 volumes hydrogen peroxide. involves safety problems. Similar problems also occur in the synthesis of other biologically active sulfinyl compounds, such as sulindac, i.e. (Z)-5-fluoro-2- metfayl- l-[[4-(methyl^ulflnyI)phenyl]niethytene]-lH-indcne-3-acetic acid, and the so-called "prazoles", i.e. [[(pyridyl)methyl]sulfmyl]benzimidazole derivatives, which are known anti-secretory agents. Benzimidazole derivatives of general formula (I) are produced from their corresponding sulphides by oxidation with an oxidising agent exemplified by m-chloroperbenzoic acid, petacetic acid, trifluoroperacetic acid, permaleic acid, sodium bromite, sodiumhypochlorite, hydrogen peroxide or other reagents as described in a number of patents.

The reported prior art synthesis of these substituted 2- (2-pyridyImethyi)- sulfmyl-lH- benzϊmidazoles generally involves an oxidation process of a sulfide compound to the corresponding sulfinyl compound as indicated in the following scheme 1.

Scheme 1

Oxidizing agents previously disclosed in the art for the oxidation of the sulfide compound include iodosobenzene (Spanish Patent No. 539,793 (1985)), iodosomethylbenzene (Spanish Patent No. 540,147 (1985)), m-chloroperbenzoic acid (US Patent No. 4,628,098 (1986) and 4,255,431 (1981)), peroxyacetic acid (WO 98/09962 (1998)), sodium hypochlorite (EP 268,956 (198S))^, sodium periodate (Spanish Patent No. 550,070 (1985)) and the like. However, m-chloroperbenzoic acid is usually used in view of its activity and easiness of weighing. In European patent application 030272O₅ production of 2- (2- pyridylmethylsulfinyl)-benzimidazole compounds is described. In this patent, production of compound (I) with the oxidation of its corresponding sulphide with hydrogen peroxide in the presence vanadium compounds in good yield and with low production of by product is laid open.

All these prior art processes either use expensive catalysts or oxidising agents like meta chloroperbenzoic acid. Moreover, their usage results in over- oxidation of the thioether compound leading to corresponding sulphone analogues.

The processes to date described for the preparation of benzimidazole derivatives still suffer from some drawbacks and there is need for a safer, cost- effective and more efficient synthetic process, which at the same time provides a sufficiently pure material to meet regulatory requirements while the by-products formed are easily removed without damaging the environment.

It has now been found that the oxidation of a thioether group to a sulfinyl (sulfoxide) or sulfonyl (.sulfone) group can be advantageously carried out using peroxyacetic acid as the oxidizing agent. In particular, it has been found that peroxyacetic acid in combination with sodium carbonate while maintaining the pH between 5-7 produces benzimidazole derivatives such as Pantoprazole, Lansoprazole and Rabeprazole with relatively higher purity and remarkably reduced process impurities. Moreover, peroxyacetic acid and its reduced byproduct, acetic acid is low polluting and can be advantageously used on a large scale.

It has been surprisingly found that the usage of mixture of chlorinated solvent and alcohol in the oxidation process is drastically reducing the process impurities like sulphone and N-oxide. Objective of the Invention

The main objective of the present invention is to provide an improved process for the preparation of substituted 2-(2-pyridylmethyl)-sulfinyl-lH- benzirnidazoles the formula (I) or its pharmaceutically acceptable salts.

Yet another objective of the present invention is to develop a simple and commercially viable process for the preparation of substituted 2-(2- pyridylmethyl)-siulfinyl-lH-benzimidazoles derivatives of the formula (I) using the compound of formula (IT).

Yet another objective of the present invention to provide an improved process for oxidation of (2- [[[3-methyl-4- (2, 2, 2-trifluoro-ethoxy)-2-pyridinyl] methyl] thio] IH- benzimidazole to the corresponding (2- ([[3-methyl-4- (2, 2,2- trifluoro-ethoxy)-2- pyridinyl] methylj-sulfinyl] IH-benzimidazole (lansoprazole), preferably using an inexpensive and readily available reagent.

Still another objective of the present invention is to provide an improved process for oxidation of ((5-(difruoromethoxy)-2-[[(3, 4-dimethoxy-2-pyridinyl) methyl] thio] IH-benzimidazole, to the corresponding ((5-(difluoromethoxy)-2-[ [(3_?4-dimethoxy-2-pyridmyl)methyl]-sulfmyl]lH-ben2imidazole (pantoprazole), preferably using an inexpensive and readily available reagent.

Yet another objective of the present invention is to provide an improved process for oxidation of (2- [[[4- (3-methoxy-propoxy) 3-methyl-2-pyridmyl] methyl]-thio]-lH- benzimidazole, to the corresponding (2- [[[4- (3-methoxy- propoxy) 3-methyl-2- pyridinyl] methyl]-sulfinyl]-lH-benzimidazole (rabeprazole), preferably using an inexpensive and readily available reagent.

Yet another objective of the present invention is to use Peroxyacetic acid or its derivatives at a pH around 5-7 using alkaline Sodium Carbonate solution to produce benzimidazole derivatives with higher purity and remarkably reduced process impurities.

Yet another objective of the invention is to carryout the process of oxidation in a single or bi phase reaction medium using organic solvents selected from alcohols such as methanol, ethanol, isopropylalcohol (EPA) and the like or chlorinated solvents like chloroform, dichloromethane (DCM) and the like or ethers such as Isopropylether, diethylether and cyclic ethers such as tetrahydrofαran, dioxane, or water and the like or mixtures thereof.

Summary of the Invention

Accordingly, the present invention provides a process for the preparation of substituted 2-(2-pyridylmethyl)-sulfmyI-lH-benzimidazoles derivatives of the formula (D in good yield with relatively high purity and pharmaceutically acceptable salt, hydrate and solvate thereof.

I

wherein R₁ and R₃ are selected from the group consisting of hydrogen, methyl or Cr₄ alkoxy. R₂ is selected from the group consisting of substituted or unsubstituted C_w alkoxy, R₄ is selected from the group consisting of hydrogen or substituted or unsubstituted C ₁-₄ alkoxy

Comprising the step of oxidizing a sulfide compound of formula (DL) with Peroxyacetic acid or its derivatives in presence of solvent, necessarily at the pH 5-7 using aqueous sodium carbonate solution.

π

wherein R] R₂ R₃ & R₄ are as defined above. Detailed Description of the Invention

The present invention provides an efficient and industrially feasible process for preparing various substituted 2-(2-pyridylmethyl)-sulfmyl-lH- benzimidazoles derivatives in good yield with relatively high purity and pharmaceutically acceptable salt, hydrate and solvate thereof.

In an embodiment of the present invention the peroxyacetic acid or its derivatives used is selected from peroxyacetic acid (PAA), substituted peroxyaceticacids such as fluoroperoxyacetic acid, and the like or mixture thereof.

In another embodiment of the present invention, oxidation of sulfide (II) is carried out with Peroxyacetic acid or its derivatives at a pH around 5-7 using aqueous sodium carbonate solution during oxidation process.

In another embodiment of the present invention, the purpose of using peroxyacetic acid along with aqueous sodium carbonate is to eliminate or minimize the impurities such as sulphone and N-oxide that are formed in the final product.

In another embodiment of the present invention, is to carryout the process of oxidation in a single or bi phase reaction medium using organic solvents selected from alcohols such as methanol, ethanol, isopropylalcohol (IPA) and the like, or chlorinated solvents like chloroform, dichloromethane (DCM) and the like or ethers such as Isopropylether, diethylether and cyclic ethers such as tetrahydrofuran, dioxane, or water and the like or mixtures thereof.

In still another embodiment of the present invention the corresponding starting material of formula (II) is prepared from the methods available in the prior art. The following examples aτe provided by way of illustration only and should not be limited to construe the scope of the invention.

Example :1

Preparation of 2-[(3,4-Dimethoxy-2-pyridyl)methylsulfinyl]-5-difluoro methoxy-lH-ben-rimidazole (Pantopmole)

To a solution of 2-[(3,4-dimethoxy-2-pyridyl)metliyltliio]-5_"difluoromethoxy- lH-benzimidazole (20.0 gm, 0.054 moles) in water (88 mL), dichloromethane (120 mL), and methanol (32 mL) and sodium carbonate (5.8 gm, 0.054 moles), of a solution of peracetic acid (13.3%; 20 mL) are added at -10 to -15⁰C. The mixture is stirred at the stated temperature for 30 minutes. The reaction mixture was quenched with sodium metabisulfUe solution and then treated with sodium hydroxide solution. The organic layer was separated and pH was adjusted to 13- 13.5 with sodium hydroxide solution. The pH of aqueous layer obtained, was adjusted to 8 - 8.5 with acetic acid, The aqueous layer was back extracted with dichloromethane and concentrated. The residue was precipitated from dichloromethane/diisopropylether, to yield the title compound (15,6gm).

Example 2:

Preparation of 2-[[[3-Methyl-4-(2,2,2-trifluoro ethoxy)pyrid-2- yllmethyl]sulfinyI]-lH-benzimidazole (Lansoprazole)

A suspension of 2-[[[3-Methyl-4-(2,2,2-trifluoro ethoxy)pyrid-2- yl]methyl]sulfinyl]-lH-benzimidazole (100 gm, 0.293 moles) sodium carbonate (15.2 gm, 0.143 moles) in isopropyl alcohol (200 mL) and DMSO (22.8 gm, 0.293 moles) was treated with a solution of peracetic acid (38.6 gm, 0.50 moles) in isopropyl alcohol (70 mL) at 0-5⁰C in 90 minutes. The reaction mass is maintained at same temperature for 3 hours under stirring. After completion of reaction, it was treated with aqueous solution of sodium thiosulfate and stirred for 30 minutes and basified with aqueous sodium hydroxide solution (pH 8.5 to 9.0). Stirred for 15 minutes at temperature below 0 to 5⁰C. Precipitated compound was filtered and dried to give title compound (65 gm) Example 3:

Preparation of 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]niethyl] sulfinyl]-lH-benzimidazole (Rabeprazol€)

A suspension of 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]tliio]- lH-benzimidazoIe (100 gm, 0.291 moles) Sodium carbonate (30.89 gm, 0.29 moles) and Dimethyl sulphoxide (22.73 gm, 0.291 moles) in chloroform (500 mL) was treated with a solution of peracetic acid (33.2 gm, 0.43 moles) in chloroform at -10⁰C. The reaction mixture was stirred at same temperature for 30 minutes. After completion of reaction, lhe reaction was quenched with sodium thiosulphite and then pH was adjusted to 8.5 - 9.0 with aqueous sodium hydroxide solution and stirred for 15 minutes at 0-5⁰C and organic layer separated. Then the organic layer was back extracted with sodium hydroxide solution at pH 13-14. The pH of aqueous layer thus obtained re-adjusted to 8.0- 8.5 by using acetic acid at 5-1O⁰C. The precipitate obtained was filtered to give title compound (50 gm).

Claims

We claim:

1. A process for the preparation of substituted 2-(2-pyridylmethyl)-sulfmyl-lB- benzimidazoles or its derivatives of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof

I

wherein Ri and R₃ are selected from the group consisting of hydrogen, methyl or C_r4 alkoxy, R₂ is selected from the group consisting of substituted or unsubstituted C ₁₄ alkoxy, R₄ is selected from the group consisting of hydrogen or substituted or unsubstituted C₁ -₄ alkoxy.

which the process comprises oxidizing a sulfide compound of formula (II)

II

wherein R] R₂ R₃ & R₄ are as defined above.

with peroxyacetic acid or its derivatives in a two-phase water and organic solvent or in solvents medium,, said oxidation is carried out at a controlled temperature and pH so as to prepare a compound of formula (I), and optionally converting a sulfmyl compound of formula (1) to a pharmaceutically acceptable salt, hydrate or solvate thereof ; characterised in that an alkali is present in the reaction mixture at least during said oxidation, whereby the pH of the reaction mixture is in the range of 5 to 7, subsequent separation of water and organic phases after the reaction and isolation of formula(I) from organic phase.

2. A process according to claim 1, wherein the oxidation is carried out with peroxyacetic acid or its derivatives such as halogenated peroxyacetic acids preferably triflouro peroxyacetic acid and the like or mixture thereof,

3. A process according to claim I₅ wherein the oxidation step is carried out at the pH range of 5 to 7, preferably at 5.5 to 6.5.

4. A process according to claim 1 , wherein the alkali used during oxidation is selected from carbonates and bicarbonates of alkaline or alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium or mixtures thereof, preferably sodium carbonate.

5. A process according to claim 1, wherein the solvent is selected from alcohols such as methanol, ethanol, isopropylalcohol (IPA) and the like, or chlorinated solvents like chloroform, dichloromethane (DCM) and the like or ethers such as isopropylether, diethylether or cyclic ethers such as tetrahydrofuran, dioxane, or water or mixture of two or more of these solvents thereof, preferably mixture of water, methanol and dichloromethane,

6. A process according to claim 1 , which is carried out at a temperature in the range of -30 to 50⁰C, preferably in -20 to 1O⁰C.

Dated this eighteenth (18^th) day of October 2005 for Inogent Laboratories Private Limited.

Dr. R. Buchi Reddy

Head Process R&D & Custom Manufacturing

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