FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"Process for preparation of Pyridinylmethylsulphinyl benzimidazoie compounds
and pyridine intermediates" 2. APPLICANT(S):
(a) NAME: IPCA LABORATORIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:

Field of the invention:
The present invention relates to process for preparation of pyridinylmethylsulphinyl benzimidazole compounds and pyridine intermediates useful for preparation of the same, especially Rabeprazole. The invention, further relates to a process for preparation of stable Rabeprazole sodium of high purity in a reproducible & consistent manner..
Background of the invention:
Sulphoxide compounds, particularly, Pyridinylmethylsulphinyl benzimidazoles compounds of general formula IA are known to have H+/K+-ATPase-inhibitory action and therefore have considerable importance in the therapy of diseases associated with an increased secretion of gastric acid or used as anti-ulcerative agent. Many sulphoxide compounds of closely related structure are known, for example, from EP0005129, EP166287, EP174726 and EP268956.

R
R2 .1
R1 N

R6 R3 0
|j N R7

R8
N H
R9
Formula IA wherein R, Rl, R2, R3, R6 to R9 are the same or different and selected from hydrogen, hydroxyl, halogen, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxyalkoxy, halogen, phenylalkyl and phenylalkoxy.
Examples of pharmaceutically active compounds of this class are 5-methoxy-2- [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methylsulphinyl]-lH-benzimidazole (also named as Omeprazole), (S)-5-methoxy-2- [ (4-methoxy-3, 5-dimethyl-2- pyridinyl) methylsulphinyl]-lH-benzimidazole (common name: Esomeprazole), 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridinyl) methylsulphinyl]-lH-benzimidazole (Common name: Pantoprazole), 2- [3-methyl-4- (2, 2,2- trifluoroethoxy)-2-pyridinyl) methylsulphinyl]-lH-benzimidazole (Common name: Lansoprazole), 2- { [4- (3- methoxypropoxy)-3-methylpyridin-2-yl] methylsulphinyl}-lH-benzimidazole (Rabeprazole) and 5-methoxy-


2- ((4-methoxy-3, 5-dimethyl-2-pyridylmethyl) sulphinyl)-l H-imidazo (4,5-b) pyridine (Tenatoprazole).
The above mentioned sulphoxide compounds are also referred to as proton pump inhibitors or abbreviated as PPI owing to their mechanism of action.
4-Chloro-substituted pyridine compounds of formula I are important intermediates for preparation of the above pharmaceutically valuable sulphoxide compounds. In the formula, Rl, R2, R3 are independently a hydrogen, or an alkyl group, which may be optionally substituted with a group selected from OH, acetoxy, halo, or tosyl group or an alkoxy group, and R4 stands for alkyl group which may be substituted with a leaving group or hydroxyl residue. The chlorine atom at 4th position of puridine ring is substitutable easily with a suitable alkoxy group, for example a methoxypropoxy group in the case of Rabeprazole, or a methoxy group for Omeprazole, before condensing it with the suitably substituted benzimidazole residue during the preparation of said PPIs. Therefore it is important to get this intermediate in high purity and yield.
Formula I Formula II
In the literature, various processes are reported for preparation of 4-chloro-substituted pyridine compounds of formula I. For example, EPO167943 discloses chlorination of 2, 3 dimethyl-4-nitro pyridine-1-oxide with acetyl chloride in order to prepare 4-chloro-2, 3-dimethyl pyridine-1-oxide. The reported yields are in the range of 77%, and essentially requires column chromatography to isolate pure product. Owing to the handling & economy of the process, acetylchloride is not a right choice as a chlorination agent, because this reagent should be freshly prepared and being acid chloride.
A direct chlorination of 4-H-pyridine-N-oxide was reported in WO02/102779, by treatment with chlorine gas, but the reported yields were only 47%. Other direct chlorination processes were reported in GB958877, by treatment of 4-H-pyridine-N-oxide


with Chlorine gas and SO2; KR9106983 by treatment of 4-H-pyridine-N-oxide with POCl3. However, in these processes the pyridine N-oxide is reduced during the chlorination and to be reoxidised in order to substitute it with alkoxy groups at the 4th position for further use in subsequent steps.
Hazardous chemicals like diphosgene or triphosgene in presence of amine were reported for chlorination of 4-H-pyridine-N-oxide, for example in Synthetic communications 2004, 34(6), 1097-1103, and were not found to have industrial applicability due to safety issues associated with use and handling of phosgenes.
Yet another process was disclosed for chlorination using a much cheaper & readily available reagent -concentrated hydrochloric acid for substitution of 4-nitro-pyridine-N-oxide, in the publications - J. Med. Chem 1976, Vol 19(10), pages 1209-14; J. Pharm. Soc. Jpn., 68, 126(1948); and Chem-Abstract, 47, 8074(1953). But the process is accomplished at very high temperatures, for example, above 160 degrees, and obtained the chloro-pyridine in only moderate yields.
An improved version of this process was reported recently in US2004/0063957, which discloses uses of a phase transfer catalyst, an acid and an alkali metal halide combination for chlorination of 4-nitro-pyridine-N-oxide, to accomplish better conversion to chloroderivative. However the process requires various catalysts combination such as phase-transfer catalyst and metal halide composition, expanding the raw material base.
Thus, the search for a process for the preparation of 4-chloro-substituted pyridine compounds of formula I resulting in a satisfactory yield / purity using industrially viable reagents under milder conditions remains undoubtedly of interest. This forms the object of the present invention.
The 4-chloro-substituted pyridine compounds of formula 1 prepared according to the present invention is useful for the production PPIs, such as rabeprazole, and therefore has considerable importance in the synthesis of those PPIs.
The synthesis of Rabeprazole was first disclosed in US 5045552. The synthetic route consists of preparing 2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl} methylthio}-H-benzmidazole followed by oxidation in presence of suitable oxidizing agent, for example, m-chloroperbenzoic acid to afford rabeprazole base. The base is then converted to the


marketed salt-Rabeprazole sodium by reacting with aq. Sodium hydroxide solution in ethanol, followed by subsequent precipitation using diethylether.
Similar processes were reported in US4727150, US5045552, EP0773940, EP1277752, US 6313303, WO2004/063188, WO 01/68594, EP302720, WO03/097606, US 2003/0036554, WO2004/111029, US2004/0192929, US6919459, US2006/0205791, WO2006/049486, WO2004063188, WO2006024890, WOO 104109 & WO2007/026188 with improvisations in the oxidation catalyst, conditions of oxidation etc.. All of these publications discuss on the isolation of Rabeprazole sodium salt from various solvents, mainly of a combination of alcohols and non-polar solvents like ether/hydrocarbons and all of them uses sodium hydroxide as the reagent for obtaining sodium salt. A critical issue with this process for Rabeprazole sodium salt because of its highly unstable & hydroscopic nature. Even under optimized conditions the isolation of rabeparzole sodium is very difficult in a repeatable manner as it either picks up moisture or unacceptable colour or shows varying solubility. Therefore there is still a need for a rugged process for preparing Rabeprazole sodium in a consistent & reproducible manner with acceptable colour, solubility and impurity level. In attending these technical insufficiencies, the present inventors have discovered a simple and mild process for preparation of the 4-chloro-substituted pyridine compounds of formula I and its application to preparation of Rabeprazole & its sodium salt in a reproducible manner.
Summary of the invention:
Thus the present invention provides a process for preparation of 4-chloro-substituted pyridine compounds of formula I, wherein Rl, R2, R3 are independently a hydrogen, or an alkyl group, which may be optionally substituted with a group selected from OH, acetoxy, halo, or tosyl group or an alkoxy group, and R4 stands for alkyl group which may be substituted with a leaving group or hydroxyl residue, which process comprises reaction of 4-nitro-substituted pyridine compounds of formula II, where Rl, R2, R3, R4 has the same meaning as defined above, with either gaseous hydrochloric acid or a solution of anhydrous hydrochloric acid in an organic solvent. The reaction yields 4-chloro-substituted pyridine compounds of formula I in almost quantitative yields under industrially acceptable milder reaction conditions.


In another aspect the invention provides a process for preparation of substituted benzimidazole compounds of Formula IA, specifically 5-methoxy-2-[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methylsulphinyl]-lH-benzimidazole (also named as Omeprazole), (S)-5-methoxy-2- [ (4-methoxy-3, 5-dimethyl-2- pyridinyl) methylsulphinyl]-lH-benzimidazole (common name: Esomeprazole), 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridinyl) methylsulphinyl]-lH-benzimidazole (Common name: Pantoprazole), 2- [3-methyl-4- (2, 2,2- trifluoroethoxy)-2-pyridinyl) methylsulphinyl]-lH-benzimidazole (Common name: Lansoprazole), 2- { [4- (3- methoxypropoxy)-3-methylpyridin-2-yl] methylsulphinyl}-lH-benzimidazole (Rabeprazole) and 5-methoxy-2- ((4-methoxy-3, 5-dimethyl-2-pyridylmethyl) sulphinyl)-l H-imidazo (4,5-b) pyridine (Tenatoprazole), which process involves obtaining 4-chloro-substituted pyridine compounds of formula I by the substitution of 4-nitro-substituted pyridine compounds of formula II with HC1 in gaseous form or as a solution in anhydrous solvents in suitable anhydrous solvent medium. The invention is illustrated with the preparation of rabeprazole.
In another aspect the present invention provides a process for obtaining the sodium salt of Rabeprazole, said process comprises treating the Rabeprazole base with sodium salt, for example, sodium alkoxide in an anhydrous reaction medium. The process is characterized by quantitative isolation of Rabeprazole sodium salt, in water free organic solvent.
In a preferred embodiment, the process comprising obtaining Rabeprazole, wherein the process involves an intermediate stage of preparing 4-chloro-substituted pyridine compounds of formula I by the substitution of 4-nitro-substituted pyridine compounds of formula II with HC1 in gaseous form or as a solution in anhydrous solvents in a suitable solvent medium, transforming it to rabeprazole through a series of reactions, followed by treating rabeprazole in presence of a sodium alkoxide in an anhydrous medium to obtain Rabeprazole sodium reproducibly & consistently.
The details of one or more embodiments in the practice of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.


Detailed Description of the Invention:
Unless specified otherwise, all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art, to which this
invention belongs. Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the present invention, the
preferred methods and materials are described. To describe the invention, certain terms
are defined herein specifically as follows.
Unless stated to the contrary, any of the words "including," "includes," "comprising," and
"comprises" mean "including without limitation" and shall not be construed to limit any
general statement that it follows to the specific or similar items or matters immediately
following it. Embodiments of the invention are not mutually exclusive, but may be
implemented in various combinations. The described embodiments of the invention and
the disclosed examples are given for the purpose of illustration rather than limitation of
the invention as set forth the appended claims.
The term "obtaining" is used to indicate formation or isolation or recovery of the
compound being obtained, which include in situ conversion of the said compound into a
target product.
The term "isolating" is used to indicate separation or collection or recovery of the
compound being isolated in a reasonably pure form.
The term "treating" means adding or combining or mixing the stated reagent or materials
to the thing being treated.
The term "anhydrous medium" means solvent medium which is free of water. The term
does not exclude solvents containing insignificant amounts of moisture.
"Rabeprazole" is chemically 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]

Formula IV
methylsulphinyl}-lH-benzimidazole . It has the structural formula IV:

"Rabeprazole sodium" is a sodium salt of 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl] methylsulphinyl}-lH-benzimidazole. It has the following formula V. It should be noted that both the species exists in tautuomeric isomeric form with regard to the benzimidazole nitrogen atoms at 5 & 6 positions.

Formula V
Accordingly the present invention provides a process for preparation of 4-chloro-substituted pyridine compounds of formula I , wherein Rl, R2, R3 are independently a hydrogen, or an alkyl group, which may be optionally substituted with a group selected from hydroxy, acetoxy, halo, or tosyl group or an alkoxy group, and R4 stands for alkyl group which may be substituted with a leaving group or hydroxyl residue, wherein the process comprises reaction of 4-nitro-substituted pyridine compounds of formula II, where Rl, R2, R3, R4 has the same meaning as defined above, with either gaseous hydrochloric acid or a solution of anhydrous hydrochloric acid in a suitable organic solvent.
The process is capable of providing of 4-chloro-substituted pyridine compounds of formula I in almost quantitative yields under a milder reaction conditions. In the process, the hydrochloric acid is used in gaseous form or as a pre-formed solution of hydrochloric acid in an organic solvent obtained by passing HC1 gas in said solvent, which is suitable as reagent for substitution of nitro-group. The organic solvents may be selected from any anhydrous inert solvent, preferably the solvent is any alcohols or polar aprotic solvent like dimethyl formamide. In the case of introducing HC1 in gaseous form into the reaction, 4-nitro-substituted pyridine compounds of formula II, is preferably dissolved/suspended in one or more suitable solvent, and passed HC1 into the mixture under anhydrous condition. In the case of HC1 solution, preferably a preformed solution of HC1 obtained by passing HC1 gas into one or more of the suitable solvent and the obtained solution is contacted with 4-nitro-substituted pyridine compounds of formula II.


As the solvent used herein, all the inert solvents can be used so far as they exercise no adverse influence on the reaction. Examples of the solvent usable include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; ketones such as acetone, methyl ethyl ketone, ethyl isobutyl ketone and the like; mixtures of alcohols with aromatic hydrocarbons such as benzene, o-dichlorobenzene, chlorobenzene, toluene, xylene and the like, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like. Among these solvents, particularly preferred are alcohols or amides, preferably the alcohol is isopropanol, and amide is dimethyl formamide.
The reaction is carried out usually at a temperature from 0 °C to reflux temperature and ideally not higher than 100 °C, and preferably at a temperature of 60-90 °C. The reaction time is usually from about 4 hours to about 8 hours.
It is recommended to use the hydrochloric acid in excess, usually in an amount of at least 10% concentration, and preferably from about 10% to 17% concentration in the reaction.
The chloro-compound of formula (I) obtained by the above-mentioned reaction can easily be isolated by the conventional separating means. As said separating means, mention can be made of, for example, distillation of solvent and followed by crystallization, neutralization followed by extraction method using a solvent, , and can be if necessary purified by distillation under suitable temperature & pressure or recrystallization from suitable solvent.
The invention provides a process for preparation of substituted benzimidazole compounds, for example, omeprazole, patoprazole or rabeprazole, which involves use of 4-chloro-substituted pyridine compounds of formula I obtained by the afore-mentioned process, comprising the steps of substituting chlorine of 4-chloro-substituted pyridine with suitable alkoxide or alcohol; acetylating 2-methyl group followed by hydrolysis, and conversion into a leaving group; condensation with a suitably substituted benzimidazole compound of Formula III, oxidizing the obtained sulphide intermediate; and converting to


suitable metal salts. The process is further elaborated for the preparation of Rabeprazole in the following examples and the process as illustrated produces Rabeprazole sodium substantially free of corresponding sulphone impurity, preferably less than 0.05%.
R6
R7 ' N
[i [ —-SH R8 , N R9
R6-R9 = H for Rabeprazole Formula III
The present inventors had discovered that the prior art processes for obtaining
Rabeprazole sodium present substantial difficulties in producing sodium salt in a
consistent & reproducible manner. The problem has been found associated with the
nature of the Rabeprazole sodium salt, which is highly hygroscopic, unstable, or
variations in solubility pattern or color etc.. The inventors of the present invention had
found that the use of sodium hydroxide, as reported in prior art, does not provide a
reliable, consistent methodology to prepare Rabeprazole sodium in a stable manner. The
inventors had recognized that even small changes in manufacturing parameters during
sodium salt formation/isolation might have led to changes in the color, solubility and
stability. The inventors, on exploring various process alternatives, for a reliable process
solution have found that the use of sodium salt such as sodium alkoxide in a suitable
anhydrous solvent medium permits reliable preparation & isolation of sodium salt.
The metal alkoxides suitable for this application may be selected from sodium methoxide,
ethoxide, isopropoxide, n-propoxide, tert-butoxide, n-butoxide etc.. Owing to the
economy of the process, it is preferred to use sodium methoxide in the process.
The especially important solvent or solvent combinations as anhydrous medium include alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; ketones such as acetone, methyl ethyl ketone, ethyl isobutyl ketone and the like; or their mixtures thereof. Among these solvents, particularly preferred are alcohols, preferably the alcohol is isopropanol.


In the present invention, it is recommended to carry out the salt forming step at a temperature below 50 degrees, preferably below ambient temperature, and preferably between a temperature of 0-25 degree C. The complete transformation of base to salt is usually achieved in from about 2 hours to about 5 hours.
After complete transformation of rabeprazole base into sodium salt, it is isolated by a conventional procedure or by the process of the present invention. A suitably preferred isolation process involves optional removal of the organic solvent from the reaction mass, followed by making a solution of rabeprazole sodium in a second solvent selected from chlorinated hydrocarbons, and precipitating by contacting said solution with an anhydrous non-polar solvent.
The especially preferred chlorinated solvents for preparing the solution of Rabeprazole sodium includes dichloromethane or dichloroethane. The especially important precipitation solvent or solvent combinations for Rabeprazole includes the C5-C10 hydrocarbon solvents (aromatic or aliphatic) or its mixtures with esters like ethyl acetate; and ethers such as methylcellosolve, tert. butyl methyl ether, cyclopentylmethyl ether, diisopropyl ether etc.. Among this tert.butyl methyl ether is most preferred.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples:
Example 1. Preparation of 4-Chloro-2,3-lutidine -N-oxide (I)
260 g (1.55 mol) of 4-Nitro-2,3-lutidine-N-oxide was added in 1300 g (4.8 mol) of 13.6 % of HCI in isopropyl alcohol. The reaction mixture was heated to 85 °C and stirred for 5 hrs. The mixture was cooled to 5 °C and maintain 0-5 °C for an hr. The precipitated solid was filtered and washed with isopropyl alcohol. The obtained solid was dissolved in 420 ml of water and adjusted pH to 8 by using 50% sodium hydroxide. The obtained product was extracted with methylene dichloride. The organic phases were combined and dried


over sodium sulfate. The solvent was removed under vacuum to obtain 238 gm (yield 98%) 4-Chloro-2,3-lutidine -N-oxide

Formula (I)
Example 2. Preparation of Pyridine -4-(3-methoxy propoxy)-2,3-dimethyl-N-oxide (Formula-VI):
128 g (1.42 mol) 3-methoxy -1-propanol was dissolved in 250 ml of dimethyl sulfoxide to obtain a solution. 76.1 g (1.9 mol) of sodium hydroxide was added to this solution at room temperature. The obtained mixture was stirred at 60 °C for 2 hrs and 150 g (0.954 mol) of 4-chloro- 2,3-lutidine-N-oxide was added. The reaction mixture was stirred at 75 °C for 5 hrs. After the completion of reaction, mixture cooled to 20°C & quenched in 2 liter of water under stirring. Reaction mixture was extracted with chloroform (500 ml X 3). The organic phases were combined & dried over sodium sulfate and chloroform was concentrated under reduced pressure to obtained 195 g ( 95 %) of title compound as brown oil.

O Formula VI
Example 3. Preparation of 2-Hydroxymethyl -4-(3-methoxy propoxy)-3-methyl pyridine :
145 g (1.42 mol) of the acetic anhydride was added over 30 minutes to 150 g (0.71 mol) of 4-(3-methoxy propoxy)-2,3-dimethyl pyridine-N-oxide at 0 °C. The solution was


heated to 90 C and stirred for 6 hrs. After the completion of reaction , it was distilled under reduced pressure to remove acetic anhydride. The obtained residue containing 2-acetoxymethyl-4-(3-methoxy propoxy)-3-methyl pyridine was added in 34.2 g (0.85 mol) of sodium hydroxide & 450 ml of ethanol at room temperature. The reaction mixture was stirred at 55 °C for 2 hrs. After completion of reaction, removed ethanol by distillation under reduced pressure. The obtained residue was diluted with 1500 ml of water & extracted with methylene dichloride (500 ml X 2 & 100 ml X 1). The combined organic layer was dried over sodium sulfate. The methylene dichloride layer was concentrated to obtain 98 g (79 %) of 2-hydroxymethyl -4-(3-methoxy propoxy)-3-methyl pyridine as brown oil.

Example 4. Preparation of 2-Chloromethyl -4-(3-methoxy propoxy)-3-methylpyridine (Formula VIII)
Formula VIII
70 g of the 2-hydroxymethyl-4-(3-methoxy propoxy)-3-methyl pyridine obtained in example 3 was dissolved in 135 ml of methylene dichloride to obtain a solution. 73.1 g (0.61 mol) of thionyl chloride was drop wise added to this solution at 0 °C. The obtained mixture was stirred at room temperature for 2 hrs. After the completion of reaction, the reaction mixture was distilled to remove the methylene dichloride & thionyl chloride under vacuum. The obtained residue was cooled to 5 °C and neutralized using saturated sodium bicarbonate solution to pH-7.5 and extracted with methylene dichloride. The methylene dichloride layer dried over sodium sulfate & filtered. The obtained filtrate concentrated to obtain 76 g (99 %) of 2-chloromethyl-4-(3-methoxy propoxy)-3-methyl pyridine as a brown oil.


Example 5. Preparation of 2-[4-(3-methoxy propoxy-3-methylpyridine-2-yl methylthio)-lH-benzimidazole. (Formula-IX)
11 g (0.27mol) of sodium hydroxide was added in 350 ml of ethanol at room temperature. The mixture was stirred at 55 °C for 30 minutes and cooled. 30 g (0.2mol) of 2-mercapto benzimidazole and 50 g (0.21 mol) of 2-chloromethyl-4-(3-methoxy propoxy) -3-methylpyridine was added in above mixture. The obtained reaction mixture was stirred at 55 °C for 2 hrs. After completion of the reaction, the reaction mixture was distilled to remove ethanol. 500 ml of ethyl acetate was added in residue. The ethyl acetate layer was extracted with 5 % sodium hydroxide aqueous solution. The ethyl acetate layer was dried over sodium sulfate & distilled out ethyl acetate under reduced pressure. The obtained residue was dissolved in methylene dichloride & filtered the suspended particles. Distilled out the methylene dichloride, residue dissolved in 500 ml of ethyl acetate and cooled the mixture to 0 °C .The precipitated solid was filtered, wash with ethyl acetate and dried the product under vacuum to obtain 50.4 g (67.8 %) crude title compound as a off white crystalline solid. The obtained crude compound was further purified in ethyl acetate to obtain pure 2-[4-(3-methoxy propoxy-3-methylpyridine-2-yl) methyl thio]-lH-benzimidazole.

Formula(IX)
Example 6. Preparation of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-
pyridinyl)]methyl]sulfinyl]-l H-benzimidazole: (Rabeprazole base)
50 g of 2-[4-(3-methoxy propoxy-3-methylpyridine-2-yl) methyl thio]- 1 H-benzimidazole was taken in 100 ml acetonitrile. To this mixture 185.2 g (0.95mol) sodium hypochlorite was added drop wise between 0-5 °C in a nitrogen atmosphere and the obtained mixture was stirred at 0-5°C for 30 minutes. After completion of reaction, the pH of reaction


mixture was adjusted to 9.0 by using 5 % acetic acid. The mixture was extracted with methylene dichloride, and the extract was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried under vacuum. The obtained residue was dissolved in 20 ml of methylene dichloride followed by t-butyl methyl ether to get the clear solution. Stirred the mass for one hour at room temperature to get the precipitate. Filtered the precipitated product and washed with 100 ml of t-butyl methyl ether. Dried the product at 60°C under vacuum to obtain title compound 41 g (78.25%) as a off white solid.

Rabeprazole base
Example 7. Preparation of Sodium salt of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl)]methyl]sulfinyl]-lH-benzimidazole : (Rabeprazole sodium)
1.73 g (0.075 mol) of sodium metal was dissolved in 120 ml of methanol at room temperature under nitrogen atmosphere. 27 g (0.075 mol) of 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridinyl)]methyl]sulfinyl]-lH-benzimidazole was added to the solution at room temperature. The obtained mixture was stirred for 15 minutes to get clear solution . The clear reaction mass was stirred at 30°C for one hour. 2.7 g of activated charcoal was added & stirred for one hour (30±2 °C). Filtered the reaction mixture, the clear filtrate was concentrated under reduced pressure to obtain 29 g of crude title compound. The above crude solid was crystallized from a mixture of 87 ml methylene dichloride and 290 ml of t-butyl methyl ether in a nitrogen atmosphere to obtain 27 g (94%) of title compound.
Na+


We claim,
1. A process for preparation of Pyridinylmethylsulphinyl benzimidazole compounds of Formula IA,
R2R1 R1 R3| N 0 S N-NH R6 R9 R7 R8
Formula IA
CI N02
R4
N
Y O
Formula II
R1
R2 R3
R2 R3
R7 R1 N R4
R8 1 0Formula 1
wherein, R, Rl, R2, R3, R6 to R9 are the same or different and independently selected from hydrogen, halogen, hydroxyl, alkyl, alkylthio, alkoxy group optionally substituted by fluorine, alkoxyalkoxy, halogen, phenylalkyl and phenylalkoxy, comprising an intermediate step of obtaining 4-chloro-substituted pyridine compounds of formula I (where R4 stands for alkyl group which may be substituted with a leaving group or an acetoxy or hydroxyl group) by the substitution of 4-nitro-substituted pyridine compounds of formula II with hydrochloric acid in anhydrous solvent medium.
2. A process as claimed in claim 1, wherein the hydrochloric acid is in gaseous form or as a solution in organic solvent.
3. A process as claimed in claim 1 to 2, wherein the anhydrous solvent medium is alcohol; ether; ketones; mixtures of alcohols with aromatic hydrocarbons; or aprotic polar solvents.
4. A process as claimed in claim 1 to 3, wherein the solvent is methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, acetone, methyl ethyl ketone, ethyl isobutyl ketone, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide; and mixtures of alcohols with benzene or o-dichlorobenzene or chlorobenzene, toluene, or xylene.


5. The process as claimed in claim 1 to 4, wherein the compound IA is selected from Omeprazole, Esomeprazole, Rabeprazole, Pantoprazole, Tenatoprazole, Lansoprazole and their pharmaceutically acceptable salts thereof.
6. The process as claimed in claim 5, wherein the compound IA is Rabeprazole or its sodium salt.
7. A process for preparation of compounds of Formula IA as claimed in claim 1, comprising the steps:
i) substitution of 4-nitro-substituted pyridine compounds of formula II with hydrochloric
acid in anhydrous solvent medium to obtain 4-chloro-substituted pyridine of Formula I;
ii) substituting chlorine of 4-chloro-substituted pyridine with a suitable alkoxide or
alcohol in presence of alkali;
iii) acetylating the resulting intermediate, followed by hydrolysis, and conversion into a
leaving group;
iv) reacting the intermediate product of step (iii) with a suitably substituted benzimidazole
compound of Formula III (where R6-R9 are as defined in claim 1);
v) oxidizing the condensation intermediate of step (iv) to obtain the compound of
Formula IA; and optionally,
v) converting compound of Formula IA to suitable metal salts.
8. A process as claimed in claim 7, wherein the benzimidazole compound of Formula IA
is Omeprazole, Esomeprazole, Rabeprazole, Pantoprazole, Tenatoprazole, Lansoprazole
and their pharmaceutically acceptable salts thereof.
9. The process as claimed in claim 8, wherein the benzimidazole compound is
Rabeprazole or its sodium salt.
10. A process as claimed claim 6 or 9, wherein the process for rabeprazole sodium
comprises treatment of Rabeprazole with a sodium alkoxide in anhydrous solvent
medium.


11. A process as claimed in claim 10, wherein the sodium alkoxide is sodium methoxide, sodium butoxide or sodium propoxide.
12. A process for preparation of Rabeprazole sodium comprising reacting Rabeprazole base with a sodium alkoxide in anhydrous solvent medium.
13. A process as claimed in claim 10 to 12, wherein the anhydrous solvent medium is ether, alcohol, ketones or their mixtures thereof.
14. A process as claimed in claim 13, wherein the solvent is methanol, ethanol, propanol, isopropyl alcohol, butanol; dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, acetone, methyl ethyl ketone, ethyl isobutyl ketone or their mixtures thereof.
15 A process for preparation of Rabeprazole sodium comprising at least the following steps:
a) obtaining 4-chloro-substituted pyridine compounds of formula 1, wherein Rl to R4 are as defined above, by the substitution of 4-nitro-substituted pyridine compounds of formula II (Rl to R4 are as defined above) with hydrochloric acid in anhydrous solvent medium;
b) reacting Rabeprazole free base with sodium alkoxide in a suitable solvent; and
c) recovering rabeprazole sodium from the step (b) reaction mixture.

16. A process for preparation of rabeprazole sodium as claimed in claim 15, wherein the hydrochloric acid is in gaseous form or as a solution in organic solvent; and sodium alkoxide is sodium methoxide, sodium butoxide or sodium propoxide.
17. A process for preparation of 4-chloro-substituted pyridine compounds of formula I, Rl, R2, R3 are independently a hydrogen, or an alkyl group, which may be optionally substituted with a group selected from OH, acetoxy, halo, or tosyl group or an alkoxy group, and R4 stands for alkyl group which may be substituted with a leaving group or hydroxyl residue, which process comprises substitution of 4-nitro-substituted pyridine compounds of formula II with hydrochloric acid in anhydrous solvent medium.


18. A process as claimed in claim 17, wherein the hydrochloric acid is in gaseous form or as a solution in organic solvent.
19. A process as claimed in claim 17 or 18, wherein the solvent is methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, acetone, methyl ethyl ketone, ethyl isobutyl ketone, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide; and mixtures of alcohols with benzene or o-dichlorobenzene or chlorobenzene, toluene, or xylene.




Abstract:
Process for preparing 4-chloro-substituted pyridine intermediates of formula I, useful for preparation of pyridinylmethylsulphinyl benzimidazole compounds, ©specially Rabeprazole is disclosed herein. The invention, further describes process for preparation of stable Rabeprazole sodium of high purity in a reproducible & consistent manner.