WO2010146428A1

WO2010146428A1 - An improved process for the preparation of rabeprazole

Info

Publication number: WO2010146428A1
Application number: PCT/IB2010/001371
Authority: WO
Inventors: Buchi Reddy Reguri; Nagamani Nagabushanam; Alagudurai Anandan; Venkateshwar Goud Thirumani
Original assignee: Orchid Chemicals And Pharmaceuticals Ltd.
Priority date: 2009-06-15
Filing date: 2010-06-08
Publication date: 2010-12-23

Abstract

The present invention provides a purification process for Rabeprazole compound of formula (I) or its sodium salt. Formula (I)

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF RABEPRAZOLE

Field of the Invention

The present invention provides an improved process for the preparation of

Rabeprazole of formula (I) or its salts.

Formula (I)

Background of the Invention

Rabeprazole sodium is chemically designated as 2-[[[4-(3-methoxypropoxy)- 3-methyl-2-pyridinyl]-methyl]sulfmyl]-lH-benzimidazole sodium salt. Rabeprazole is an antiulcer drug in the class of proton pump inhibitors. It was developed by Eisai Co. and is marketed under the brand name ACIPΗEX® which is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of Rabeprazole sodium.

US 5,045,552 patent discloses the preparation of Rabeprazole by oxidizing the Rabeprazole sulfide using m-chloroperbenzoic acid as shown in scheme-I. The crude Rabeprazole was dissolved in sodium hydroxide and the resulting solution was azeotropically distilled together with ethanol thrice to remove the water. Finally ether was added to get the crystals of Rabeprazole sodium.

Scheme I

le sulfide

NaOH

Ethanol ether

Rabeprazole Sodium

US 6,313,303 discloses the preparation of sulfoxides by oxidizing thio ether with a peroxoborate salt in the presence of an acid anhydride or a metal catalyst; and the preparation of sulfoxides by oxidizing thio ether with an N- halosuccinimide, l,3-dihalo-5,5-dimethyl-hydantoin or dichloroisocyanuric acid salt in the presence of a base.

IN 192030 discloses the purification process of Rabeprazole, in which sulfone enriched Rabeprazole is treated with an amino alcohol e.g. ethanolamine in the presence of an organic solvent, further the reaction mixture washed with water to remove the sulfone impurities. US 7,439,367 (IN218648, 058/MUM/2003, 193/MUM/2003) discloses the preparation of Rabeprazole by oxidizing its corresponding sulfide compound, where aqueous hypohalite solution is used as an oxidizing agent. The said oxidation is carried out at a controlled temperature and pH. During said oxidation the pH of the reaction mixture is maintained in the range of 9 to 12. This process utilizes catalyst such as pyridine, di-isopropyl ethyl amine and N,N-dimethyl amino pyridine.

US 7,060,837 discloses the purification of lansoprazole using ammonia, ammonium hydroxide, diethylamine, triethylamine and methylamine in the presence of solvent. The said patent utilizes acid for the isolation of lanzoprazole in pure form.

US 2008/0161579 (IN190/MUM/2005) discloses a process for the preparation of Rabeprazole sodium comprising oxidation of Rabeprazole sulfide with sodium hypohalite in water or a mixture of water and water miscible solvent using alkali metal hydroxide and catalyst. It also discloses a process for the preparation of Rabeprazole sulfide.

WO 2008/045777 (1856/CHE/2006) discloses the preparation of

Rabeprazole by oxidizing the corresponding sulfide compound using about 0.8 to 1.25 equivalents of an oxidizing agent in the presence of less than or about 2.25 equivalents of a base where aqueous sodium hypohalite used as an oxidizing agent.

WO 2006/024890 discloses a process for the preparation of Rabeprazole in which the Rabeprazole obtained was treated with the triethylamine in hexane. The use of n-hexane in the final stage is not suitable for manufacturing point of view as it is difficult to remove residual hexane solvent. There are several disadvantages associated with such known processes; all the methods reported in these prior arts leads to the formation of many impurities which ultimately affects the purity of the final product.

With our research and intense investigation to overcome the aforementioned problem, we have developed an efficient and improved process for the preparation of pure Rabeprazole.

Objectives of the Invention

The main objective of the present invention is to provide a simple and economical process to produce Rabeprazole.

Another objective of the present invention is to provide an efficient and robust process for the purification of Rabeprazole.

Summary of the Invention

Accordingly, the present invention provides a process for the preparation of compound of formula (I), or its salts.

Formula (I)

the said process comprising the steps of : i) oxidizing the Rabeprazole sulfide of formula (II);

Formula (II)

ii) obtaining the crude Rabeprazole; and iii) treating the crude Rabeprazole with diethylamine in the presence of solvent to obtain the pure Rabeprazole.

Accordingly the present invention provides a purification process for preparing pure Rabeprazole, which comprises treating crude Rabeprazole with diethyl amine in a solvent.

Description of the Invention

In an embodiment of the present invention, the oxidation of crude

Rabeprazole is done by any conventional manner, for example treating the compound of formula (II) with oxidizing agent such as N-chloro succinimide, sodium hypochlorite and in the presence of sodium hydroxide. The oxidation is preferably carried out using the organic solvent selected from ethanol, isopropanol, butanol, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, acetone, ethyl acetate, butyl acetate or mixtures thereof. The percentage of sodium hypochlorite used for oxidation of Rabeprazole sulfide is in the range of 6% to 20%. The sodium hypochlorite was added to the reaction mass either portion wise or in a single lot and about 1.3 to 2 equivalents of an oxidizing agent and about 2 to 14 equivalents of sodium hydroxide solution was preferably employed for oxidation. Though the use of sodium hypochlorite with sodium hydroxide for the oxidation of Rabeprazole sulfide as reported in the prior art provides Rabeprazole containing sulfone impurity less than 0.1%, it associated with the problem that the final Rabeprazole contains higher level of unknown impurities, which ultimately affects the quality of the product. The conventional oxidation of compound of formula (II) particularly the use of sodium hypochlorite/sodium hydroxide yields Rabeprazole with more impurities, particularly at 2.12 RRT (393 mass), 3.51 RRT (491 mass), 4.47 RRT (457 mass), 4.85 RRT (684 mass) and 4.54 RRT (893 mass). The mass (molecular or formula weight) number of the impurities were identified using LCMS. Particularly, the obtained product contains unknown impurities of higher molecular weight in the range of 0.1-1.0 % at relative retention time (RRT) of 2.12, 3.51, 4.47, 4.85, and 4.54 RRT as measured by high performance liquid chromatography (HPLC) method provided below.

The purity of the product obtained is determined by high performance liquid chromatography method under the conditions mentioned below.

Column: Prontosil Kromabond 100-5-C18 (250 x 4.6 mm), 5μ,

Mobile phase A: 1.36g KH₂PO4 to 1 litre water, 0.5ml OfEt₃N, Mobile phase B: Methanol: ACN (95:5),

Diluent: Mobile phase A and ACN (70:30),

Flow Rate: 1.0 mL/min,

Detection: UV at 280 nm,

Injection Volume: 20 μL, Run Time: 60 min.

Column oven temperature: 3O⁰C. Surprisingly the applicant identified a method in which, crude Rabeprazole was treated with diethylamine and optionally addition of TBAB (tetrabutylammmonium bromide) as catalyst, where the impurity level reduced. Though the reported amines like triethyl amine, ethanolamine, and ammonia are effectively used to minimize sulfone impurity, those are failed or unsatisfactory to remove the impurities at 2.12 RRT, 3.51 RRT, 4.47 RRT, 4.85 RRT and 4.54 RRT.

In an embodiment of the present invention, the crude Rabeprazole (purity by HPLC is 90% - 98.99%) obtained is taken in an organic solvent and treated with diethylamine to obtain the pure Rabeprazole base (purity by HPLC is 99.1% - 99.9%). The obtained Rabeprazole contains less than 0.05 % of higher molecular weight impurities, particularly at 2.12 RRT, 3.51 RRT, 4.47 RRT, 4.85 RRT and 4.54 RRT. The treatment of Rabeprazole with amine may optionally contain phase transfer catalyst such as TBAB (tetrabutylammmonium bromide).

In another embodiment of the present invention, the organic solvent used in

(step-iii) purification, is selected from ethylacetate, methylisobutylketone, toluene acetonitrile isopropylalcohol and dichloromethane, preferably ethyl acetate. The obtained rabeprazole may optionally re-crystallized using mixture of toluene: acetonitrile.

The foregoing technique has been found to be attractive from commercial and technological perspective, and affords compounds of formula (I) with high purity. Rabeprazole sulfide compound of formula (II) or Rabeprazole sodium can be prepared using the methods reported in the prior arts or by following the process provided in Reference example.

The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.

Example 1:

Preparation of 2-{4-(3-Methoxypropoxy)-3-methylpyridine-2-yl} methy lsulfinyl-lH-benzimidazole (Rabeprazole) :

To a RB flask IPA (30 mL) was charged followed by Rabeprazole sulfide (10 g) at 25-30° C. To this NaOH (2.0 equivalent) solution was added followed by the lot wise addition of 6%-12% NaOCl solution (>1.3 equivalent) at 0-5°C. The reaction was monitored by HPLC. After completion of the reaction, reaction mass was poured into aqueous sodium thiosulphate pentahydrate solution (35-60%). The reaction solution subjected to carbon treatment and filtered. To the obtained filtrate, 2V MDC is charged, and then pH was adjusted to 8-8.8 using formic acid. Layers were separated and MDC distilled out under vacuum and stripped out with ethyl acetate. To the residue ethyl acetate was charged and cooled to 0-5° C. The solid obtained was filtered and washed with ethyl acetate. The crude Rabeprazole (Purity by HPLC: <99.0%) obtained was taken in ethyl acetate and treated with 1.0 equivalent of diethylamine at 50-55° C. To the clear solution Rabeprazole is seeded and the reaction mass cooled to 0-5° C. The solid obtained was filtered, washed with ethyl acetate to yield the pure Rabeprazole (Purity by HPLC: >99.7%) which was dried under vacuum at 50-55° C. Example 2:

Preparation of 2-{4-(3-Methoxypropoxy)-3-methylpyridine-2-yl} methylsulfinyl-lH-benzimidazole (crude Rabeprazole):

To aqueous NaOH (4.3 equivalent; 10% solution) solution, were added Rabeprazole sulfide (10 g) and IPA (30 mL) at 25-30° C. To this mixture of 6%- 12% NaOCl solution (>1.3 equivalent) and sodium hydroxide solution (4.3 equivalent) was added in lot wise at 0-5 °C. The reaction was monitored by HPLC. After the completion of reaction, sodium thiosulphate solution (35-60%) was charged into reaction mixture at 0-5°C and pH was adjusted to 8-8.5 using acetic acid at 15-20°C, again cooled to 0-5°C and maintained for 2-3 hours after seeding. The obtained solid was filtered and washed with water and dried under vacuum at 45-50°C (Moisture content NMT 1.0%).

Purification of Rabeprazole freebase

The crude Rabeprazole (Purity by HPLC: <99.0%) obtained was taken in ethyl acetate and treated with 0.45 equivalent of diethylamine and optionally addition of TBAB (Tetrabutylammonium bromide), heated to 50-55° C. Carbon was added over it and filtered at through the hyflo bed at 50-55⁰C. Reaction mass gradually cooled to 0-5 °C and solid obtained was filtered and washed with ethylacetate under nitrogen atmosphere. Finally material was dried under vacuum at 50-55°C till LOD is less than 0.5%. Comparative Table:

ND = Not Detectable

The above table indicates the treatment of crude Rabeprazole with diethyl amine reduces the impurity at 2.12 RRT (393 mass impurity), 3.51 RRT (491 mass impurity), 4.47 RRT (457 mass impurity), 4.85 RRT (684 mass impurity) and 4.54 RRT (893 mass impurity). In view of pharmacopeia requirement, the final compound is required to have unknown impurity less than 0.1%, the prior art process of using triethylamine or other amine found to be unsatisfactory to remove all impurities, where as the use of diethyl amine yields pure Rabeprazole, which meets the pharmacopeia requirement. The use of TEA for the purification results Rabeprazole with 98.51% only. Reference Example 1:

2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthio]-lH benzimidazole (Rabeprazole sulfide):

To IPA (1000 mL), 2-mercaptobenzimidazole, sodium carbonate followed by 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride were added at 25-30° C. The reaction mixture temperature raised to 50-55° C, and stirred till completion of reaction. After the completion of reaction, the IPA was distilled, and to residue water was charged under stirring. The product obtained was filtered and washed with water dried under vacuum at 50-55° C till LOD reaches less than 0.5%.

Reference Example 2:

2-{4-(3-Methoxypropoxy)-3-methylpyridine-2-yl} methylsulfinyl-lH- benzimidazole Sodium (Rabeprazole Sodium):

To mixture of IPA (250 mL) and aqueous sodium hydroxide (1.2 equivalents) solution Rabeprazole was added under stirring. The clear solution subjected to carbon treatment. IPA was distilled out under vacuum at 50°, and stripped out by adding methyl tert-butyl ether (MTBE). To the residue MTBE was charged under stirring. The product obtained was filtered and washed with MTBE to afford amorphous Rabeprazole sodium which was dried under vacuum at 45-50° C. The obtained rabeprazole sodium having particle size less than about 120 microns, preferably less than about 90 microns.

Claims

We claim:

1. An improved purification process for the preparation of compound of formula (I), or its salts

Formula (I) the said process comprising the steps of : i) oxidizing the Rabeprazole sulfide of formula (II);

Formula (II) ii) obtaining the crude Rabeprazole; iii) treating the crude Rabeprazole with diethylamine in the presence of solvent to obtain the pure Rabeprazole; and iv) converting Rabeprazole to its sodium salt.

2. The process according to claim 1, wherein the oxidation is carried out using an oxidizing agent selected form N-chloro succinimide or sodium hypochlorite and in the presence of base selected from sodium hydroxide.

3. A process for purification of Rabeprazole which comprises treating crude Rabeprazole with diethyl amine.

4. A process as claimed in claim 3, wherein the purification is carried out in the presence of solvent.

5. A process as claimed in claim 4 or claim 1, wherein the solvent used is selected from ethyl acetate, methylisobutylketone, toluene, acetonitrile, isopropylalcohol and dichloromethane, preferably ethylacetate.

6. A process as claimed in claim 3, wherein the crude Rabeprazole has purity in the range of 90 % to 98.99 % by HPLC.

7. A process as claimed in 3, wherein the Rabeprazole is obtained with a purity of greater than 99.1% by HPLC, preferably greater than 99.3%.