Title of Invention	A PROCESS FOR THE PREPARATION OF 2-(HYDROXYMETHYL)-4-(3-METHOXYPROPOXY)-3-METHYLPYRIDINE HYDROCHLORIDE
Abstract	A simple and cost effective process for the preparation of 2-(hydroxymethyl)-4- (3- methoxypropoxy)-3-methylpyridine hydrochloride which comprises, condensing 4"' chloro-2,3-dimethylpyridine-N-oxide with 3-methoxypropanol by means of base in a suitable solvent to prepare 4-(3-methoxypropoxy)-2,3-dimethylpyridine-N-oxide. Thereafter,' treating 4-(3-methoxypropoxy)-2,3-dimethylpyridine-N-oxide with acetic anhydride at 90 C to prepare 2-(acetoxymethyl)-4-(3-methoxypropoxy)-3- methylpyridine, which on subsequent hydrolysis with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine and then treating with hydrochloric acid to give 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3- methylpyridine hydrochloride.

Title of Invention

A PROCESS FOR THE PREPARATION OF 2-(HYDROXYMETHYL)-4-(3-METHOXYPROPOXY)-3-METHYLPYRIDINE HYDROCHLORIDE

Abstract

A simple and cost effective process for the preparation of 2-(hydroxymethyl)-4- (3- methoxypropoxy)-3-methylpyridine hydrochloride which comprises, condensing 4"' chloro-2,3-dimethylpyridine-N-oxide with 3-methoxypropanol by means of base in a suitable solvent to prepare 4-(3-methoxypropoxy)-2,3-dimethylpyridine-N-oxide. Thereafter,' treating 4-(3-methoxypropoxy)-2,3-dimethylpyridine-N-oxide with acetic anhydride at 90 C to prepare 2-(acetoxymethyl)-4-(3-methoxypropoxy)-3- methylpyridine, which on subsequent hydrolysis with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine and then treating with hydrochloric acid to give 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3- methylpyridine hydrochloride.

Full Text	FIELD OF THE INVENTION The present invention relates to an industrially advantageous process for the preparation of novel intermediate 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride of Formula I, which is further used in the preparation of highly pure Rabeprazole Sodium of Formula II, BACKGROUND OF THE INVENTION There are a large number of patents and patent applications disclosing differently substituted 2-(2-pyridinylmethylsulphinyl)-lH-benzimidazoles. This class of compounds has properties making them useful as inhibitors of gastric acid secretion. For example, the compound (±)-Sodium-2-[[[4-(3-methoxypropoxy)-3-methyl-2- pyridyl]methyl]sulfinyl]-lH-benzimidazole with the generic name Rabeprazole sodium of Formula II, described in US Patent 5,045,552, is useful as an antiulcer agent. US Patent 5,045,552 teaches the preparation of Rabeprazole sodium which comprises the condensation of 4-chloro-2,3-dimethylpyridine-iV-oxide (III) with 3-methoxypropanol (IV) by means of base in dimethylsulfoxide yielding 4-(3-methoxypropoxy)-2,3-dimethylpyridine-7V-oxide (V), which is treated with acetic anhydride at 90°C to yield 2-(acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (VI). The hydrolysis of (VI) with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (VII) which by treatment with thionyl chloride in methylene chloride is converted into 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine (VIII). The condensation of (VIII) with 2-mercaptobenzimidazole (IX) by means of sodium hydroxide in ethanol gives 2-[4-(3-methoxypropoxy)-3-methylpyridin-2-yl methylthijbenzimidazole (X) which is oxidized with w-chloroperbenzoic acid in ether-^ethylene chloride to afford the title compound. Finally, the compound was treated with aqueous sodium hydroxide to prepare the required salt as shown in Scheme -1. This process of preparing Rabeprazole sodium has numerous disadvantages, like during the preparation of 4-(3-Methoxypropoxy)-2,3-dimethyl pyridine-N-oxide of formula V by the condensation reaction of 4-chloro-2,3-dimethylpyridine-JV-oxide of formula III with 3-methoxypropanol of formula IV, the required product of formula V is contaminated with impurities in unacceptable amounts, which are carried forward along with the required product, because of structurally related nature. The removal of the impurities by usual purification processes is very difficult and it leads to extensive and expensive purification techniques. US 5,045,552 used the chromatographic technique to prepare compound of formula V of required purity. The use of chromatographic technique is cumbersome, tedious and not practicable on an industrial scale. This requires capital investment for creating technical infrastructure and make the process highly unattractive from economic and handling point of view and is not suitable to operate on an industrial scale. In the light of the above drawbacks in the prior art process, there still remains the need however to provide an efficient, cost effective and industrially viable process for the preparation of Rabeprazole, which is convenient to operate on an industrial scale. It is an object of the present invention to provide a simple and commercially attractive process for the preparation of Rabeprazole in high yield and high purity which is very convenient to operate on industrial scale. SUMMARY OF THE INVENTION The present invention relates to a simple and cost effective process for the preparation of 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methyIpyridine hydrochloride of formula I, condensing 4-chloro-2,3-dimethylpyridine-N-oxide of formula III in presence of a base as described, in any suitable solvent, to prepare 4-(3-methoxypropoxy)-253-dimethylpyridine-N-oxide of formula V, treating compound of formula V with acetic anhydride at 90°C to prepare 2- (acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine which on hydrolysis with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3 -methoxypropoxy)-3 -methylpyridine of formula VII, treating compound of formula VII with any suitable acid such as HC1 results in a highly pure compound of formula I. Further the compound of formula I is used advantageously to prepare highly pure Rabeprazole sodium of formula II. DETAILED DESCRIPTION OF INVENTION The instant invention provides an alternative, simplified and industrially viable process for the preparation a intermediate of formula I, which is further used in the preparation of highly pure rabeprazole of formula II, while avoiding the use of chromatographic technique. In our hands we have found that Rabeprazole prepared by the method reported in US patent 5,045,552 was not of required quality. It was contaminated with impurities in considerable amounts. The identified impurities, 2-[[[4-(3-methoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-lH-benzimidazole of formula XII and 2-[[[4-(3-thiomethyl)-3 -methyl-2-pyridinyl] -methyl] sulfinyl]-lH-benzimidazole of formula XIII and some other unidentified impurities were present in unacceptable amounts. The impurities of formula XII and XIII were prepared and characterized. To prepare the product of required quality, it requires extensive and expensive purification processes which leads to low yields. During our extensive experimentation studies with an intension to overcome the difficulties of producing rabeprazole in high yields and high purity. We have unexpectedly found that the source of generation of these impurities is from the Stage I i.e. the condensation of 4-chloro-2,3-dimethylpyridine N-oxide (III) with 3-methoxy propanol (IV), by means of base in dimethylsulfoxide. It is observed that during this condensation reaction to prepare 4-(3-methoxypropoxy)-2,3-dimethylpyridine-N-oxide of formula V, some impurities, namely 4-methoxy-2,3-lutidine-N-oxide of formula XIV and 4-thiomethyl-2,3-lutidine-N-oxide of formula XV, are also formed, which in the subsequent steps leads to the formation of impurities of formula XII and XIII and contaminate the Rabeprazole. It has also been observed that condensation reaction of III and IV by means of sodium hydride behaves differently in different solvents. The object of the present invention is to prevent the formation of the impurities of formula XII and XIII so that no extra purification is required to prepare pure Rabeprazole in high yield. A further object of the present invention is to prepare pure Rabeprazole free from impurities of formula XII and XIII. This object is achieved by preparing pure and novel intermediate of formula I, which is free from the impurities of formula XIV and XV and was preferably used in the preparation of highly pure Rabeprazole sodium. The compound of formula V is prepared by the condensation of compound of formula III and compound of formula IV in the presence of base, in suitable solvent such as toluene, dimethylsulfoxide, xylene. The base can be selected from sodium hydroxide, potassium hydroxide, sodium hydride and the like and preferably sodium hydride is used in solvent dimethylsulfoxide. The crude compound of formula V as such is treated with acetic anhydride, which on subsequent hydrolysis give the corresponding 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methyl pyridine along with impurities. The resultant hydroxymethyl compound is distilled under reduced pressure and it is subjected to the formation of acid salt by means of treatment with acids such as inorganic or organic acids. Preferably acid can be selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and the like. Most preferably hydrochloric acid is used. Specifically, the hydrochloric acid gas is passed in a solution of corresponding 2-hydroxymethyl compound of formula VII in a mixture of acetone-methanol. The precipitated highly pure hydrochloride salt of 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine of formula I is collected in high yield having purity greater than 99% by high performance liquid chromatography. is free from the impurities of formula XIV and XV, which leads to the formation of impurities XIV and XV and other unidentified impurities in the rabeprazole of formula II The acid salt of corresponding 2-hydroxymethanol can be prepared in any solvent such as acetone, methyl isobutyl ketone, methanol, ethanol, isopropanol and the like or mixture thereof. However varying ratios of solvents can be used depending upon the choice of solvent medium without affecting the quality and quantity of the novel intermediate. In the present invention, preferably acetone and methanol are used in the ratio of about 100:0 to 75:25 with respect to acetone and methanol. Preferably, the intermediate is further used for the preparation of Rabeprazole which comprises the step of chlorination of 2-hydroxymethyl group of compound of formuala I, which on subsequent condensation with 2-mercaptobenzimidazole results in corresponding sulfide compound; the resulting corresponding sulfide compound was oxidized by the methods known in the art for the preparation of Rabeprazole base. The oxidizing agent can be selected from m-chloroperbenezoic acid, sodium hypochlorite, peracetic acid and preferably sodium hypochlorite is used. The pure Rabeprazole base is isolated from the reaction mass by repeating pH adjustment and extractions. The Rabeprazole base is optionally recrystallized prior to the formation of sodium salt. Sodium salt of Rabeprazole is prepared by conventional methods using sodium metal carrier such as sodium hydroxide. The major advantages realized in the instant invention as compared to prior art are increased product purity and high productivity. The involvement of expensive, tedious and cumbersome techniques like column chromatography is avoided. Removal of impurities is carried out by simple and easy technique, which is cost-effective and industrially viable. Apart from these, Rabeprazole sodium obtained, is having high purity greater than 99.5% by high performance liquid chromatography. The present invention thus fulfills the need for a process, which is convenient to operate on an industrial scale. In the meaning of the present invention the term pure Rabeprazole refer to Rabeprazole sodium having a purity of 99.5% or more by HPLC. Further details of the present invention are to be found in the following examples without limiting it: EXAMPLE-I: PREPARATION OF 2-HYDROXYMETHYL-4-(3-METHOXYPROPOXY)-3-METHYLPYRIDINE HYDROCHLORIDE STEP -1 Preparation Of 4-(3-Methoxypropoxy)-2-dimethyl pyridine-N-oxide Sodium hydride (23.04 g, Assay 50% w/w. 1.5 m.) was suspended in DMSO (100 ml) under nitrogen atmosphere. To this a solution of 3-methoxy-l-propanol (34.6 g, 1.2 m..) in DMSO (50 ml) was added slowly in 1 h maintaining the temperature between 60-70°C. The reaction mass was stirred for 1 h at 60-65°C and thereafter cooled to 40°C. 4-Chloro-2,3-dimethyl-N-oxide (50 g) was added at a temperature range of 40-45°C and the reaction mass was stirred for 4-5 h at 40-45°C. After completion of reaction, 800 ml DM water was added to the reaction mass and the layers were separated. The aqueous layer was then extracted with methylene dichloride. The methylene dichloride layer was concentrated and the title compound was isolated as oily mass (50 g). STEP -2 Preparation Of 2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methyIpyridine Acetic anhydride (50 ml) was added to a solution of 4-(3-Methoxypropoxy)-2,3-dimethyl pyridine-N-oxide (20 g) in acetic acid (20 ml). The reaction mixture was heated at 100- 125°C for 4 h. Thereafter the acetic acid and acetic anhydride were distilled completely and oily mass was obtained, which was dissolved in methanol (20 ml). To this solution was added 20% w/v sodium hydroxide solution to adjust the pH between 12-13. The reaction mixture was heated at 50-55°C for 4-5 h. Thereafter methanol was distilled, DM water was added and the product was extracted in methylene dichloride. Methylene dichloride was distilled at 40-60°C at atmospheric pressure and the residue was distilled under reduced pressure ( STEP-3 Preparation Of 2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride 2-Hydroxymethyl-4-(3 -methoxypropoxy)-3 -methyl pyridine (5 g) was dissolved in acetone (25 ml) and cooled the solution to 10°C. Dry HCl gas was passed to obtain pH 1. The white solid was crystallized out, the reaction mixture was stirred for further 30 min at 10-15°C to complete the crystallization. The product was filtered and dried to obtain 4.68 g of the title compound having purity 99.3% by HPLC EXAMPLE-II: PREPARATION OF 2-HYDROXYMETHYL-4-(3-METHOXYPROPOXY)-3-METHYLPYRIDINE HYDROCHLORIDE 2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methyl pyridine (100 g) was dissolved in acetone (450 ml) and cooled the solution to 3°C. Dry HCl gas was passed to obtain pH 1. The white solid was crystallized out, the reaction mixture was stirred for further 30 min at 10-15°C to complete the crystallization. The product was filtered and dried to obtain pure title compound having purity 99.15% by HPLC, yield= 88%. *H NMR in CDC13 5(ppm); 1.97-2.01 (m, 2H), 2.01(s, 3H), 3.20 (s, 3H), 3.40(t,2H), 4.34-4.39 (t,2H), 4.87 (s, 2H), 7.29-7.39(d, 1H), 8.85 (d, 1H). EXAMPLE-IH: PREPARATION OF (±)-SODIUM-2-[[[4-(3-METHOXYPROPOXY)-3-METHYL-2-PYRIDINYL]METHYL]SULFINYL]-lH-BENZIMIDAZOLE (RABEPRAZOLE SODIUM) STEP -1 Preparation Of 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]thio]lH-benzimidazole 2-Hydroxymethyl-4-(3-methoxypropoxy)-3 -methyl pyridine hydrochloride (100 g) was suspended in toluene (500 ml) and thionyl chloride (57.69 g) was added slowly maintaining the temperature 5-10°C. The solution was stirred for 1 h and 2-chloromethyl-4-(3-methoxypropoxy)-3-methyl pyridine hydrochloride was extracted in DM water (250 ml). The aqueous solution was added to 2-mercapto-benzimidazole solution (prepared from 2-mercapto-benzimidazole (72.73 g) and sodium hydroxide (72.73 g) in 750 ml of DM water). The solution was stirred for 4 h, the compound which precipitated out was filtered and dried to obtain 128 g of the title compound. Step 2 Preparation Of (±)-2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]- methyl]sulfinyl]-lH-benzimidazole (Rabeprazole) 2-[[[4-(3-Methoxy-propoxy-3-metiiyl-2-pyridyl]methyl]thio]-lH-benzimidazole (50 g) was dissolved in methylene chloride (650 ml) and cooled to 0-5°C. To this sodium hypochlorite solution (1.05 m. eq.) was added and stirred. After the completion of the reaction and pH was adjusted to 10-10.5 by adding ammonium salt. The layers were separated and methylene chloride layer was distilled. The obtained oily product was crystallized from acetonitrile to obtain 37.5 g as off-white powder. HPLC Purity: 99.53% Step-3 Preparation of (±)-Sodium-2-[[[4-(3-methoxypropoxy)-3~methyI-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole (Rabeprazole Sodium) Sodium hydroxide (5.62 g) was dissolved in DM water (200 ml) and cooled to 4-5°C. Rabeprazole (50 g) was added to the above solution and mixture was stirred to obtain a clear solution. The solution was treated with 2 g of carbon enoanticromos for 3- min at 5-10°C. Carbon was removed by filtration and residue washed with DM water (2x25 ml). The contents were lyophilized using standard method. Rabeprazole sodium (52 g) was obtained as a white powder. HPLC Purity: 99.6% and Assay: 99.5%. WE CLAIM 1) A simple and cost effective process for the preparation of 2-(hydroxymethyl)-4- (3-methoxypropoxy)-3-methylpyridine hydrochloride of formula I, treating compound of formula V with acetic anhydride at 90°C to prepare 2- (acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine, which on subsequent hydrolysis with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine of formula VII treating the compound of formula VII with hydrochloric acid, to prepare the highly pure compound of formula I. 2) The process according to claim 1, wherein base can be selected from sodium hydroxide, potassium hydroxide and sodium hydride. 3) The process according to claim 1, wherein the compound of formula I is obtained in high purity i.e. greater than 99%. 4) The process accordingly to claim 1, wherein the compound of formula I, is converted into Rabeprazole sodium of formula II by the process comprising, chlorinating compound of formula I, with thionyl chloride and subsequently treated with 2-mercaptobenzimidazole to prepare rabeprazole base and converting rabeprazole base to rabeprazole sodium using sodium hydroxide by conventional methods. WE CLAIM 1) A simple and cost effective process for the preparation of 2-(hydroxymethyl)-4- (3-methoxypropoxy)-3-methylpyridine hydrochloride of formula I, treating compound of formula V with acetic anhydride at 90°C to prepare 2- (acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine, which on subsequent hydrolysis with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine of formula VII treating the compound of formula VII with hydrochloric acid, to prepare the highly pure compound of formula I. 2) The process according to claim 1, wherein base can be selected from sodium hydroxide, potassium hydroxide and sodium hydride. 3) The process according to claim 1, wherein the compound of formula I is obtained in high purity i.e. greater than 99%. 4) The process accordingly to claim 1, wherein the compound of formula I, is converted into Rabeprazole sodium of formula II by the process comprising, chlorinating compound of formula I, with thionyl chloride and subsequently treated with 2-mercaptobenzimidazole to prepare rabeprazole base and converting rabeprazole base to rabeprazole sodium using sodium hydroxide by conventional methods.

Full Text

FIELD OF THE INVENTION
The present invention relates to an industrially advantageous process for the preparation of novel intermediate 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride of Formula I,

which is further used in the preparation of highly pure Rabeprazole Sodium of Formula II,
BACKGROUND OF THE INVENTION
There are a large number of patents and patent applications disclosing differently
substituted 2-(2-pyridinylmethylsulphinyl)-lH-benzimidazoles. This class of compounds
has properties making them useful as inhibitors of gastric acid secretion. For example,
the compound (±)-Sodium-2-[[[4-(3-methoxypropoxy)-3-methyl-2-
pyridyl]methyl]sulfinyl]-lH-benzimidazole with the generic name Rabeprazole sodium of Formula II, described in US Patent 5,045,552, is useful as an antiulcer agent.

US Patent 5,045,552 teaches the preparation of Rabeprazole sodium which comprises the condensation of 4-chloro-2,3-dimethylpyridine-iV-oxide (III) with 3-methoxypropanol (IV) by means of base in dimethylsulfoxide yielding 4-(3-methoxypropoxy)-2,3-dimethylpyridine-7V-oxide (V), which is treated with acetic anhydride at 90°C to yield 2-(acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (VI). The hydrolysis of (VI) with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (VII) which by treatment with thionyl chloride in methylene chloride is converted into 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine (VIII). The condensation of (VIII) with 2-mercaptobenzimidazole (IX) by means of sodium hydroxide in ethanol gives 2-[4-(3-methoxypropoxy)-3-methylpyridin-2-yl methylthijbenzimidazole (X) which is oxidized with w-chloroperbenzoic acid in ether-^ethylene chloride to afford the title compound. Finally, the compound was treated with aqueous sodium hydroxide to prepare the required salt as shown in Scheme -1.

This process of preparing Rabeprazole sodium has numerous disadvantages, like during the preparation of 4-(3-Methoxypropoxy)-2,3-dimethyl pyridine-N-oxide of formula V by the condensation reaction of 4-chloro-2,3-dimethylpyridine-JV-oxide of formula III with 3-methoxypropanol of formula IV, the required product of formula V is contaminated with impurities in unacceptable amounts, which are carried forward along with the required product, because of structurally related nature.
The removal of the impurities by usual purification processes is very difficult and it leads to extensive and expensive purification techniques. US 5,045,552 used the chromatographic technique to prepare compound of formula V of required purity. The use of chromatographic technique is cumbersome, tedious and not practicable on an industrial scale. This requires capital investment for creating technical infrastructure and make the process highly unattractive from economic and handling point of view and is not suitable to operate on an industrial scale.
In the light of the above drawbacks in the prior art process, there still remains the need however to provide an efficient, cost effective and industrially viable process for the preparation of Rabeprazole, which is convenient to operate on an industrial scale.

It is an object of the present invention to provide a simple and commercially attractive process for the preparation of Rabeprazole in high yield and high purity which is very convenient to operate on industrial scale.
SUMMARY OF THE INVENTION
The present invention relates to a simple and cost effective process for the preparation of 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methyIpyridine hydrochloride of formula I,

condensing 4-chloro-2,3-dimethylpyridine-N-oxide of formula III

in presence of a base as described, in any suitable solvent, to prepare 4-(3-methoxypropoxy)-253-dimethylpyridine-N-oxide of formula V,

treating compound of formula V with acetic anhydride at 90°C to prepare 2-
(acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine which on hydrolysis with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3 -methoxypropoxy)-3 -methylpyridine of formula VII,

treating compound of formula VII with any suitable acid such as HC1 results in a highly pure compound of formula I.
Further the compound of formula I is used advantageously to prepare highly pure Rabeprazole sodium of formula II.
DETAILED DESCRIPTION OF INVENTION
The instant invention provides an alternative, simplified and industrially viable process for the preparation a intermediate of formula I,

which is further used in the preparation of highly pure rabeprazole of formula II,

while avoiding the use of chromatographic technique.
In our hands we have found that Rabeprazole prepared by the method reported in US patent 5,045,552 was not of required quality. It was contaminated with impurities in considerable amounts. The identified impurities, 2-[[[4-(3-methoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-lH-benzimidazole of formula XII and 2-[[[4-(3-thiomethyl)-3 -methyl-2-pyridinyl] -methyl] sulfinyl]-lH-benzimidazole of formula XIII and some other unidentified impurities were present in unacceptable amounts.

The impurities of formula XII and XIII were prepared and characterized. To prepare the product of required quality, it requires extensive and expensive purification processes which leads to low yields.
During our extensive experimentation studies with an intension to overcome the difficulties of producing rabeprazole in high yields and high purity. We have unexpectedly found that the source of generation of these impurities is from the Stage I i.e. the condensation of 4-chloro-2,3-dimethylpyridine N-oxide (III) with 3-methoxy

propanol (IV), by means of base in dimethylsulfoxide. It is observed that during this condensation reaction to prepare 4-(3-methoxypropoxy)-2,3-dimethylpyridine-N-oxide of formula V, some impurities, namely 4-methoxy-2,3-lutidine-N-oxide of formula XIV and 4-thiomethyl-2,3-lutidine-N-oxide of formula XV,

are also formed, which in the subsequent steps leads to the formation of impurities of formula XII and XIII and contaminate the Rabeprazole. It has also been observed that condensation reaction of III and IV by means of sodium hydride behaves differently in different solvents.
The object of the present invention is to prevent the formation of the impurities of formula XII and XIII so that no extra purification is required to prepare pure Rabeprazole in high yield.
A further object of the present invention is to prepare pure Rabeprazole free from impurities of formula XII and XIII. This object is achieved by preparing pure and novel intermediate of formula I, which is free from the impurities of formula XIV and XV and was preferably used in the preparation of highly pure Rabeprazole sodium.

The compound of formula V is prepared by the condensation of compound of formula III and compound of formula IV in the presence of base, in suitable solvent such as toluene, dimethylsulfoxide, xylene. The base can be selected from sodium hydroxide, potassium hydroxide, sodium hydride and the like and preferably sodium hydride is used in solvent dimethylsulfoxide.
The crude compound of formula V as such is treated with acetic anhydride, which on subsequent hydrolysis give the corresponding 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methyl pyridine along with impurities.
The resultant hydroxymethyl compound is distilled under reduced pressure and it is subjected to the formation of acid salt by means of treatment with acids such as inorganic or organic acids. Preferably acid can be selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and the like. Most preferably hydrochloric acid is used. Specifically, the hydrochloric acid gas is passed in a solution of corresponding 2-hydroxymethyl compound of formula VII in a mixture of acetone-methanol.
The precipitated highly pure hydrochloride salt of 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine of formula I is collected in high yield having purity greater than 99% by high performance liquid chromatography.

is free from the impurities of formula XIV and XV, which leads to the formation of impurities XIV and XV and other unidentified impurities in the rabeprazole of formula II
The acid salt of corresponding 2-hydroxymethanol can be prepared in any solvent such as acetone, methyl isobutyl ketone, methanol, ethanol, isopropanol and the like or mixture thereof. However varying ratios of solvents can be used depending upon the choice of solvent medium without affecting the quality and quantity of the novel intermediate.
In the present invention, preferably acetone and methanol are used in the ratio of about 100:0 to 75:25 with respect to acetone and methanol.
Preferably, the intermediate is further used for the preparation of Rabeprazole which comprises the step of chlorination of 2-hydroxymethyl group of compound of formuala I, which on subsequent condensation with 2-mercaptobenzimidazole results in corresponding sulfide compound; the resulting corresponding sulfide compound was oxidized by the methods known in the art for the preparation of Rabeprazole base. The oxidizing agent can be selected from m-chloroperbenezoic acid, sodium hypochlorite, peracetic acid and preferably sodium hypochlorite is used. The pure Rabeprazole base is isolated from the reaction mass by repeating pH adjustment and extractions. The Rabeprazole base is optionally recrystallized prior to the formation of sodium salt. Sodium salt of Rabeprazole is prepared by conventional methods using sodium metal carrier such as sodium hydroxide.
The major advantages realized in the instant invention as compared to prior art are increased product purity and high productivity. The involvement of expensive, tedious and cumbersome techniques like column chromatography is avoided. Removal of impurities is carried out by simple and easy technique, which is cost-effective and industrially viable. Apart from these, Rabeprazole sodium obtained, is having high purity greater than 99.5% by high performance liquid chromatography.

The present invention thus fulfills the need for a process, which is convenient to operate on an industrial scale.
In the meaning of the present invention the term pure Rabeprazole refer to Rabeprazole sodium having a purity of 99.5% or more by HPLC.
Further details of the present invention are to be found in the following examples without limiting it:
EXAMPLE-I:
PREPARATION OF 2-HYDROXYMETHYL-4-(3-METHOXYPROPOXY)-3-METHYLPYRIDINE HYDROCHLORIDE
STEP -1
Preparation Of 4-(3-Methoxypropoxy)-2-dimethyl pyridine-N-oxide
Sodium hydride (23.04 g, Assay 50% w/w. 1.5 m.) was suspended in DMSO (100 ml) under nitrogen atmosphere. To this a solution of 3-methoxy-l-propanol (34.6 g, 1.2 m..) in DMSO (50 ml) was added slowly in 1 h maintaining the temperature between 60-70°C. The reaction mass was stirred for 1 h at 60-65°C and thereafter cooled to 40°C. 4-Chloro-2,3-dimethyl-N-oxide (50 g) was added at a temperature range of 40-45°C and the reaction mass was stirred for 4-5 h at 40-45°C. After completion of reaction, 800 ml DM water was added to the reaction mass and the layers were separated. The aqueous layer was then extracted with methylene dichloride. The methylene dichloride layer was concentrated and the title compound was isolated as oily mass (50 g).
STEP -2
Preparation Of 2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methyIpyridine
Acetic anhydride (50 ml) was added to a solution of 4-(3-Methoxypropoxy)-2,3-dimethyl pyridine-N-oxide (20 g) in acetic acid (20 ml). The reaction mixture was heated at 100-

125°C for 4 h. Thereafter the acetic acid and acetic anhydride were distilled completely and oily mass was obtained, which was dissolved in methanol (20 ml). To this solution was added 20% w/v sodium hydroxide solution to adjust the pH between 12-13. The reaction mixture was heated at 50-55°C for 4-5 h. Thereafter methanol was distilled, DM water was added and the product was extracted in methylene dichloride. Methylene dichloride was distilled at 40-60°C at atmospheric pressure and the residue was distilled under reduced pressure ( STEP-3
Preparation Of 2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine
hydrochloride
2-Hydroxymethyl-4-(3 -methoxypropoxy)-3 -methyl pyridine (5 g) was dissolved in acetone (25 ml) and cooled the solution to 10°C. Dry HCl gas was passed to obtain pH 1. The white solid was crystallized out, the reaction mixture was stirred for further 30 min at 10-15°C to complete the crystallization. The product was filtered and dried to obtain 4.68 g of the title compound having purity 99.3% by HPLC
EXAMPLE-II:
PREPARATION OF 2-HYDROXYMETHYL-4-(3-METHOXYPROPOXY)-3-METHYLPYRIDINE HYDROCHLORIDE
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methyl pyridine (100 g) was dissolved in acetone (450 ml) and cooled the solution to 3°C. Dry HCl gas was passed to obtain pH 1. The white solid was crystallized out, the reaction mixture was stirred for further 30 min at 10-15°C to complete the crystallization. The product was filtered and dried to obtain pure title compound having purity 99.15% by HPLC, yield= 88%.
*H NMR in CDC13 5(ppm); 1.97-2.01 (m, 2H), 2.01(s, 3H), 3.20 (s, 3H),
3.40(t,2H), 4.34-4.39 (t,2H), 4.87 (s, 2H), 7.29-7.39(d, 1H), 8.85 (d, 1H).

EXAMPLE-IH:
PREPARATION OF (±)-SODIUM-2-[[[4-(3-METHOXYPROPOXY)-3-METHYL-2-PYRIDINYL]METHYL]SULFINYL]-lH-BENZIMIDAZOLE (RABEPRAZOLE SODIUM)
STEP -1
Preparation Of 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]thio]lH-benzimidazole
2-Hydroxymethyl-4-(3-methoxypropoxy)-3 -methyl pyridine hydrochloride (100 g) was suspended in toluene (500 ml) and thionyl chloride (57.69 g) was added slowly maintaining the temperature 5-10°C. The solution was stirred for 1 h and 2-chloromethyl-4-(3-methoxypropoxy)-3-methyl pyridine hydrochloride was extracted in DM water (250 ml). The aqueous solution was added to 2-mercapto-benzimidazole solution (prepared from 2-mercapto-benzimidazole (72.73 g) and sodium hydroxide (72.73 g) in 750 ml of DM water). The solution was stirred for 4 h, the compound which precipitated out was filtered and dried to obtain 128 g of the title compound.
Step 2
Preparation Of (±)-2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]-
methyl]sulfinyl]-lH-benzimidazole (Rabeprazole)
2-[[[4-(3-Methoxy-propoxy-3-metiiyl-2-pyridyl]methyl]thio]-lH-benzimidazole (50 g) was dissolved in methylene chloride (650 ml) and cooled to 0-5°C. To this sodium hypochlorite solution (1.05 m. eq.) was added and stirred. After the completion of the reaction and pH was adjusted to 10-10.5 by adding ammonium salt. The layers were separated and methylene chloride layer was distilled. The obtained oily product was crystallized from acetonitrile to obtain 37.5 g as off-white powder. HPLC Purity: 99.53%

Step-3
Preparation of (±)-Sodium-2-[[[4-(3-methoxypropoxy)-3~methyI-2-
pyridinyl]methyl]sulfinyl]-lH-benzimidazole (Rabeprazole Sodium)
Sodium hydroxide (5.62 g) was dissolved in DM water (200 ml) and cooled to 4-5°C. Rabeprazole (50 g) was added to the above solution and mixture was stirred to obtain a clear solution. The solution was treated with 2 g of carbon enoanticromos for 3- min at 5-10°C. Carbon was removed by filtration and residue washed with DM water (2x25 ml). The contents were lyophilized using standard method. Rabeprazole sodium (52 g) was obtained as a white powder. HPLC Purity: 99.6% and Assay: 99.5%.

WE CLAIM
1) A simple and cost effective process for the preparation of 2-(hydroxymethyl)-4- (3-methoxypropoxy)-3-methylpyridine hydrochloride of formula I,

treating compound of formula V with acetic anhydride at 90°C to prepare 2-
(acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine, which on subsequent hydrolysis with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine of formula VII

treating the compound of formula VII with hydrochloric acid, to prepare the highly pure compound of formula I.
2) The process according to claim 1, wherein base can be selected from sodium
hydroxide, potassium hydroxide and sodium hydride.
3) The process according to claim 1, wherein the compound of formula I is obtained in
high purity i.e. greater than 99%.
4) The process accordingly to claim 1, wherein the compound of formula I, is converted
into Rabeprazole sodium of formula II

by the process comprising,
chlorinating compound of formula I, with thionyl chloride and subsequently treated with 2-mercaptobenzimidazole to prepare rabeprazole base and
converting rabeprazole base to rabeprazole sodium using sodium hydroxide by conventional methods.

WE CLAIM
1) A simple and cost effective process for the preparation of 2-(hydroxymethyl)-4- (3-methoxypropoxy)-3-methylpyridine hydrochloride of formula I,

treating compound of formula V with acetic anhydride at 90°C to prepare 2-
(acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine, which on subsequent hydrolysis with sodium hydroxide in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine of formula VII

treating the compound of formula VII with hydrochloric acid, to prepare the highly pure compound of formula I.
2) The process according to claim 1, wherein base can be selected from sodium
hydroxide, potassium hydroxide and sodium hydride.
3) The process according to claim 1, wherein the compound of formula I is obtained in
high purity i.e. greater than 99%.
4) The process accordingly to claim 1, wherein the compound of formula I, is converted
into Rabeprazole sodium of formula II

by the process comprising,
chlorinating compound of formula I, with thionyl chloride and subsequently treated with 2-mercaptobenzimidazole to prepare rabeprazole base and
converting rabeprazole base to rabeprazole sodium using sodium hydroxide by conventional methods.

Documents:

793-che-2004-abstract.pdf

793-che-2004-claims duplicate.pdf

793-che-2004-claims original.pdf

793-che-2004-correspondnece-others.pdf

793-che-2004-correspondnece-po.pdf

793-che-2004-description(complete) duplicate.pdf

793-che-2004-description(complete) original.pdf

793-che-2004-form 1.pdf

793-che-2004-others.pdf

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Patent Number

205213

Indian Patent Application Number

793/CHE/2004

PG Journal Number

26/2007

Publication Date

29-Jun-2007

Grant Date

22-Mar-2007

Date of Filing

09-Aug-2004

Name of Patentee

M/S. AUROBINDO PHARMA LIMITED

Applicant Address

PLOT NO.2,MAITRIVIHAR COMPLEX,,AMEERPET,HYDERABAD-500 038,,ANDHRA PRADESH

Inventors:

#	Inventor's Name	Inventor's Address
1	RAMESH DANDALA	PLOT NO.2,MAITRIVIHAR COMPLEX,,AMEERPET,HYDERABAD-500 038,,ANDHRA PRADESH
2	UTTAM KUMAR RAY.	PLOT NO.2,MAITRIVIHAR COMPLEX,,AMEERPET,HYDERABAD-500 038,,ANDHRA PRADESH,,
3	MEENAKSHISUNDERAM SIVAKUMARAN.	PLOT NO.2,MAITRIVIHAR COMPLEX,,AMEERPET,HYDERABAD-500 038,,ANDHRA PRADESH,,

PCT International Classification Number

C 07 D 211/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA