DESCRIPTION
The present invention provides a process for the preparation of chloro derivative of pantoprazole of Formula II or pharmaceutical acceptable salt thereof.

Formula II
wherein –Cl group may be present at C4, C6, or C7 position

Pantopraozole is chemically known as 5-(difluoromethoxy)-2-((3,4-dimethoxypyridin-2-yl) methylsulfinyl)-1H-benzo[d] imidazole and represented as formula I.

Formula I
This compound is available under the trade name Protenix® and is indicated for the treatment of erosive esophagitis and pathological hypersecretory conditions, including Zollinger-Ellison syndrome. Protenix®, active ingredient is pantoprazole sodium, is available as delayed-release oral suspension and delayed-release tablets.

US 4,758,579 discloses pantoprazole and salts thereof. US ‘579 also discloses use of pantoprazole or its salt for the inhibition of gastric acid secretion for the treatment of gastric ulcer.

US 7,683,177 discloses chloro derivatives of pantoprazole, 5-(difluoromethoxy)-2-[((3,4-dimethoxypyridin-2-yl)-chloromethyl] sulfinyl)-1H-benzo[d] imidazole and 5-(difluoromethoxy)-2-[((3,4-dimethoxypyridin-2-yl)-chlorohydroxymethyl] sulfinyl)-1H-benzo[d] imidazole, obtained from the process of pantoprazole.

IN 2526/MUM/2007 discloses isolated chloro derivative of pantoprazole of formula II, for example,
1) 6-chloro-5-(difluoromethoxy)-2-((3,4-dimethoxypyridin-2-yl) methylsulfinyl)- 1H-benzo[d] imidazole,
2) 7-Chloro-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole;
3)4-Chloro-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole; and salts thereof.

The present inventors while developing the process of making pantoprazole have identified the compond of Formula-II present as an impurity in the pantaprazole and developed a process of making of compound of Formula-II.

The present inventors provides a simple process for the preparation of chloro derivative of pantoprazole of formula II in a relatively pure state, which can be used as reference marker (reference standard). A reference standard is used to quantify the amount of reference compound present in the finish product.

In one of the aspect of the present invention relates to a process for preparing chloro derivative of pantoprazole of formula II or its salt, which comprises:
i) condensation of compound of formula IV

Formula IV
with 2-(chloromethyl)-3,4-dimethoxypyridine in the presence of base to provide compound of formula III; and

Formula III

ii) oxidation of compound of formula III with oxidizing agent in the presence of base to provide chloro derivative of pantoprazole of formula II or its salt.

Formula II

wherein –Cl group may be present at C4, C6, or C7 position

The condensation reaction is performed in the presence of base to provide thio compound. Suitable base used for the condensation reaction includes but are not limited to inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; orgnaic base such as triethyl amine, pryridine and the like.

The condensation reaction may be performed in presence of solvent. Solvent is selected from water; alcohol such as methanol, ethanol, isopropyl alcohol, and the like; or mixtures thereof. The suitable temperature for the condensation reaction may range from about 20 to about 60 °C.

After completion of the reaction, the reaction mixture cooled to 25 °C and neutralized with acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid and the like.

The obtained Formula III (thio compound) may be directly used in the further reaction or it may be isolated. The isolation of solid involves concentration of the solvent completely from the resultant reaction mass followed by making slurry in presence of solvent, solvent is selected from water; alcohol such as methanol, ethanol, isopropyl alcohol and the like or combination thereof.

Step ii) involves oxidation of formula III using oxidizing agent to provide chloro derivative of pantoprazole of formula II or its salt.

Suitable oxidizing agent is selected from sodium hypochlorite, sodium hypobromite, sodium metaperiodate, hydrogen peroxide, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, and the like. Oxidation usually performs in presence of solvent and base. Suitable solvent is selected from water; chlorinated solvent such as dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; alcohol such as methanol, ethanol, isopropyl alcohol and the like; esters such as ethyl acetate, isobutyl acetate, and the like. Suitable base includes but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium methoxide, potassium t-butaoxide and the like.

Optionally, the obtained chloro derivative of pantoprazole of formula II may be converted to its pharamaceutically acceptable salt by the treatment with an acid. Acid may be selected from inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; organic acid such as formic acid, acetic acid, methane sulfonic acid, p-toluene sulfonic acid, and the like.

In an embodiment of the present invention provides oxidation of the compound of formula III using sodium hypochlorite, which is an inexpensive. The oxidation reaction may be performed at a temperature of about 5°C or below for a suficient period of time until the oxidation reaction is satisfactorily complete.

After completion of the reaction, the reaction mass is quenched by admixing with aqueous solution of sodium thiosulphate. If the reaction mixture is in two different phases, then they may be separated. Generally, the obtained aqueous layer will be basic. Therefore, the obtained aqueous layer is subjected to pH adjustment to 9 to 9.5 with acid, for example, hydrochloric acid and the like.

The reaction mixture is extracted with water immiscible organic solvent such as dichloromethane, chloroform, ethyl acetate, toluene and the like. Optionally, obtained organic layer may be washed with solvent and dried using conventional methods. The solution may be allowed to stand at room temperature 25ºC or below room temperature to induce crystallization directly from the solution or the solution can be concentrated and the residue subjected to chromatography to further purify the compound followed by crystallization to provide isolated pure compound.

In an embodiment of the present invention provides a process for the preparation of 6-chloro-5-(difluoromethoxy)-2-((3,4-dimethoxypyridin-2-yl)methylsulfinyl)-1H-benzo[d] imidazole of formula IIA or salt thereof,

Formula IIA
which include steps of:
i) condensation of 6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole-2-thiol of formula IVA with 2-(chloromethyl)-3,4-dimethoxypyridine

Formula IVA
in the presence of base, for example, sodium hydroxide, to provide 2-((3,4-dimethoxypyridin-2-yl)methylthio)-6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole of formula IIIA; and

Formula IIIA
ii) oxidation of 2-((3,4-dimethoxypyridin-2-yl)methylthio)-6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole of formula IIIA with oxidizing agent, for example, sodium hypochlorite, in the presence of base to provide chloro derivative of pantoprazole of formula IIA.

In another aspect, the present invention relates to a process for the preparation of compound of formula IV, which is useful as an intermediate in the preparation of chloro derivative of pantoprazole of formula II and pantoprazole.

Formula IV
wherein –Cl group may be present at C4, C6 or C7 position
a) reaction of chloro substituted 4-nitro phenol with sodiumchlorodifluoroacetate to provide nitro compound of formula A;

Formula A
wherein –Cl group may be present at C2 or C3 position
b) hydrogenation of the compound of formula A in presence of catalyst to provide 3-chloro-4-(difluoromethoxy) aniline of formula B or its salt;

Formula B
wherein –Cl group may be present at C2 or C3 position
c) acylation of the compound of formula B or its salt with acetic anhydride in presence of base to provide compound of formula C;

Formula C
wherein –Cl group may be present at C2 or C3 position
d) nitration of the compound of formula C with niric acid in the presence of acetic anhydride to provide nitro compound of formula D;

Formula D
wherein –Cl group may be present at C3, C4 or C6 position
e) hydrogenation of the compound of formula D in presence of raney nickel to provide amino compound of formula E or its salt; and

Formula E
wherein –Cl group may be present at C3, C4 or C6 position
f) reaction of the compound of formula E or its salt with carbon disulfide in the presence of base to provide compound of formula IV.

The overall process is schematically presented in the following scheme:

wherein –Cl group may be present as described above.

The step a) involves reaction of chloro substituted 4-nitrophenol with sodiumchlorodifluoroacetate in presence of base and solvent to provide compound of formula A.

The base used for conducting the reaction includes but are not limited to potassium carbonate, potassium bicarbonate, potassium t-butoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, and the like. The solvent is selected from polar solvent, for example, water, dichloromethane, dimethyl formamide , dimethyl sulfoxide (DMSO), alcohol such as methanol, ethanol, isopropyl alcohol and the like;

The reaction may be performed at a temperature of about 90 to about 110 °C or at a reflux temperature of the solvent. Generally, the suitable temperature depends on solvent used for the reaction.

The obtained reaction mixture may be used directly for further reaction or it may be subjected to isolation involves concentration of solvent till to certain amount and subjected to cooling to induce crystallization or concentration of solvent completely followed by providing slurry in a solvent, for example, chlorinated solvent such as dichloromethane.

The step b) involves hydrogenation reaction of the compound of formula A by the treatment with hydrogen gas in presence of catalyst for a sufficient period of time to complete the reaction in presence of catalyst to provide compound of formula B or its salt.

The catalyst used for the hydrogenation includes palladium on support, platinum (IV) oxide, raney nickel, sodium sulfide, hydrogen sulfide and base, and the like. In an embodiment, the catalyst is palladium on support for hydrogenation of nitro group. The concentration of palladium on the support, such as carbon, that can be used for the hydrogenation reaction may range from about 1 % to about 30%, or about 5% to 10%, or about 10% by weight.

The hydrogenation reaction may be performed in the presence of solvent. The solvent includes but not limited to alcohol, such as, methanol, ethanol, isopropyl alcohol and the like. Optionally, the reaction may involve the use of acid, the acid includes inorganic acid and organic acid, such as but not limited to: inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; organic acid includes acetic acid, formic acid, methane sulfonic acid, trifluoroacetic acid and the like.

After the completion of the reaction, the reaction mixture may be filtered to remove the catalyst and then the filtrate is concentrated completely.

The obtained compound of formula B or its salt may be utilized directly in further reaction stages.

The step c) involves the acylation of compound of formula B or its salt with acetic anhydride in presence of base to provide compound of formula C;

The reaction of acylation may be performed in presence of solvent such as dichloromethane, dichloroethane, chloroform, chlorobenzene, and the like. Suitable base includes but are not limited to triehtyl amine, methyl amine, pyridine and the like;

The acylation reaciton involves addition of base and acetic anhydride to a solution of compound of formula B or its salt in a solvent at a temperature about 5°C or below. After completion of addition, the reaction mass may be heated to about 35°C to about 50 °C and maintained for suifficient time to complete the reaction.

If there are two phases found after the completion of the reaction, they may be separated. The resultant organic layer optionally washed with brine solution, dried over sodium sulphate and concentrated completely to provide compound of formula C.

The step d) involves nitration of the compound of formula C with niric acid in the presence of acetic anhydride to provide compound of formula D.

The reaction may be performed at a temperature of about 0°C or below, for example, at a temperature of about -5 to about -10 °C, for a period of 30 minutes to 2 hours or more until the completion of the nitration reaction. The obtained reaction mixture may be charged to crushed ice to afford the compound of formula D, which may be used directly for further reaction.

The step e) involves hydrogenation of the compound of formula D in presence of catalyst to provide compound of formula E or its salt; and

The hydrogenation reaction may be performed by the treatment of the compound of formula D with hydrogen gas in presence of catalyst such as raney nickel and the like. The reaction may be carried out in presence of solvent such as alcohol. The obtained reaction mixture may be filtered and washed with alcohol. Optionally, the obtained compound of formula E may be converted into its salt by the treatment with acid such as inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like; organic acid includes but are not limited to acetic acid, formic acid and the like.

f) reaction of compound of formula E or its salt with carbon disulfide in the presence of base to provide compound of formula IV.

The reaction may be carried out in presence of solvent selected from water, alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol and the like or combination thereof. The suitable base used for the reaction is selected from inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like; organic base such as methyl amine, triethyl amine, pyridine and the like.

The reaction may be performed at a temperature of about 70 to about 100°C or at a reflux temperature of the solvent used. The temperature may be maintained for a period of time, for example, about 10 hour or more until the reaction completion.

After completion of the reaction, the reaction mixture may be cooled to below 5 °C and subjected to isolation of the solid by neutralization with acid, for example, hydrochloric acid. The resultant solid of formula IV optionally purified using conventional techniques such as crystallization and column chromatography.

In an embodiment, the present invention provides a process for preparing 6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole-2-thiol of formula IVA, which is useful as an intermediate in the preparation of chloro derivative of pantoprazole and pantoprazole. The process include steps of:
a) reaction of 2-chloro-4-nitro phenol with sodiumchlorodifluoroacetate to provide 2-chloro-1-(difluoromethoxy)-4-nitrobenzene;
b) hydrogenation of 2-chloro-1-(difluoromethoxy)-4-nitrobenzene in presence of catalyst, such as 10% Pd/C to provide 3-chloro-4-(difluoromethoxy) aniline or its salt;
c) acylation of 3-chloro-4-(difluoromethoxy) aniline or its salt with acetic anhydride in presence of triehtylamine to provide N-(3-chloro-4-(difluoromethoxy)phenyl)acetamide;
d) nitration of N-(3-chloro-4-(difluoromethoxy)phenyl)acetamide with niric acid in the presence of acetic anhydride to provide N-(5-chloro-4-(difluoromethoxy)-2-nitrophenyl)acetamide;
e) hydrogenation of N-(5-chloro-4-(difluoromethoxy)-2-nitrophenyl)acetamide in presence of catalyst such as raney nickel to provide N-(2-amino-5-chloro-4-(difluoromethoxy)phenyl)acetamide or its salt; and
f) reaction of N-(2-amino-5-chloro-4-(difluoromethoxy)phenyl)acetamide or its salt with carbon disulfide in the presence of base to provide 6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole-2-thiol.

The resultant chloro derivative of pantoprazole may be converted into pantoprazole by using conventional prior art techniques.

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

Examples
Example-1: Preparation of 2-chloro-1-(difluoromethoxy)-4-nitrobenzene:
2-Chloro-4-nitrophenol (20 g) was dissolved in dimethyl formamide (15 ml). Sodium Chloro difluoro acetate (26.35 g) solution in dimethyl formamide (15 ml) was then added followed by anhydrous potassium carbonate (19.14 g). The reaction mixture was heated at 100 °C for 2 hours, cooled to RT and filtered. The residue was washed with dimethyl formamide (30 ml) and the filtrate was concentrated. The residue was dissolved in dichloromethane, filtered and concentrated to afford the title compound.
Yield: 21 g
1H NMR (400 MHz, CDCl3): 6.67 (1H,t,J=72 Hz), 7.40 (1H,d,J=8.8 Hz), 8.16 (1H,dd,J1=8.8 Hz,J2=2.8 Hz), 8.35 (1H,d,J=2.8 Hz).
IR (KBr): 3691, 3112, 3052, 2936, 1673, 1607, 1590, 1538, 1531, 1520, 1486, 1385,
1352, 1274, 1252, 1233, 1151, 1095, 898 cm-1.

Example-2: Preparation of 3-chloro-4-(difluoromethoxy) aniline hydrochloride:
2-Chloro-1-(difluoromethoxy)-4-nitrobenzene (21 g) was dissolved in ethanol (100 ml). Pd/C (10% wet; 2 g) was added to the obtained solution followed by of Conc.HCl (25 ml). The reaction mixture was hydrogenated at 50 psi for 45 minutes, filtered over Celite and then washed with ethanol (25 ml). The filtrate was concentrated to obtained title compound.
Yield: 21 g
1H NMR (400 MHz, CD3OD): 6.93(1H,t,J=72.4 Hz), 7.37(1H,dd,J1=9.2 Hz,J2=2.4 Hz),7.45(1H,d,J=9.2 Hz),7.55(1H,d,J=2.8 Hz).
IR (KBr):2892, 2596,1647,1616,1515,1493,1386,1353,1247,1190,1153,1118,1058,898 cm-1
Mass: (m/e): 194.1 (M+1)

Example-3: Preparation of N-(3-chloro-4-(difluoromethoxy)phenyl)acetamide:
3-chloro-4-(difluoromethoxy) aniline hydrochloride (21 g) was dissolved in dichloromethane (150 ml) and cooled to 0 °C. Triethylamine (22 g) was added slowly to the reaction solution followed by acetic anhydride (13.3 g). The reaction mixture was stirred for 1 hour at a temperature of 40 °C and diluted with dichloromethane (100 ml) and water (100 ml). The layers were separated and the organic layer was washed with brine. The organic layer was dried over sodium sulphate and concentrated to afford the title compound.
Yield: 20.10 g
1H NMR (400 MHz, DMSO): 2.02(3H,s),7.11(1H,t,J=73.2 Hz),7.27(1H,d,J=8.4 Hz), 7.44(1H,dd,J1=8.8 Hz,J2=2.4 Hz), 7.88(1H,d,J=2 Hz),10.14(1H,bs).
Mass: (m/e): 236.0 (M+1)

Example-4: Preparation of N-(5-chloro-4-(difluoromethoxy)-2-nitrophenyl)acetamide:
N-(3-chloro-4-(difluoromethoxy)phenyl)acetamide (9 g) was taken in acetic anhydride (45 ml) and cooled to –10 °C. Concentrated nitric acid (15 ml) was added drop-wise and stirred for 2 h. The reaction mixture was poured in to crushed ice and the yellow color solid was filtered and dried to obtain the title compound.
Yield: 8.7 g
1H NMR (400 MHz, DMSO): 2.06(3H,s),7.36(1H,t,J=72.8 Hz),7.89(1H,s), 7.97(1H,s), 10.33(1H,bs).
IR (KBr):3367,3094,2187,1701,1585,1512,1455,1394,1345,1249,1141,1098,1061,992,
905 cm-1
Mass: (m/e): 279.0 (M-1)

Example-5: Preparation of N-(2-amino-5-chloro-4-(difluoromethoxy)phenyl)acetamide hydrochloride:
N-(5-chloro-4-(difluoromethoxy)-2-nitrophenyl)acetamide (8 g) was dissolved in methanol (100 ml). Raney nickel (1 g) was added to the reaction mixture and then hydrogenated at 50 psi for 1 hour. The reaction mixture was filtered over celite and washed with methanol (25 ml). The pH of the reaction solution was adjusted to 1 with hydrochloric acid and precipitated product was filtered washed and dried to get title product.
Yield: 10 g
Mass: (m/e): 249.0 (M-1)

Example-6: Preparation of 6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole-2-thiol:
N-(2-amino-5-chloro-4-(difluoromethoxy)phenyl)acetamide hydrochloride (10 g) was dissolved in ethanol (100 ml). Carbon disulfide (12.82 g) was added followed by potassium hydroxide (4.48 g) in water (50 ml). The reaction mixture was heated at 80-90 °C for 15 hours. The reaction mixture was cooled to 0 °C and neutralized with hydrochloric acid. The resultant suspension was filtered and the crude material (5 g) was purified by column chromatography using 4% Methanol in dichloriomethane to obtain the title compound.
Yield: 0.85 g.
1H NMR (400 MHz, DMSO): 7.06(1H,s),7.19(1H,t,J=73.2 Hz), 7.25(1H,s),12.71(1H,bs), 12.76(1H,bs)
IR (KBr):3119, 2945, 1618, 1520, 1480, 1333, 1182, 1114, 1049, 985 cm-1
Mass: (m/e): 249.1 (M-1)

Example-7: Preparation of 6-chloro-5-(difluoromethoxy)-2-((3,4-dimethoxypyridin-2-yl)methylthio)- 1H-benzo[d]imidazole:
The solution of 6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole-2-thiol (0.85 g) in methanol and the solution of NaOH (0.27 g) in water (10 ml) were added to the solution of 2-(Chloromethyl)-3,4-dimethoxypyridine (0.63 g) in water (20 ml). The resultant reaction mixture was heated to a temperature of about 50°C for 4 hours, cooled to 0°C, neutralized with hydrochloric acid and then concentrated. The residue was taken into water (20 ml), stirred and filtered to obtain off white powder of the title compound.
Yield: 1.10 g
1H NMR (400 MHz, CD3OD): 3.86(3H,s), 3.94(3H,s), 4.59(2H,s),6.79(1H,t,J=73.6 Hz), 7.05(1H,d,J=6Hz),7.40(1H,s), 7.59(1H,s), 8.12(1H,d,J=5.6Hz).
IR(KBr):3534, 3019, 2938,1587,1485,1425,1333,1300,1281,1228,1174,1104,1071,1045, 998, 975, 926 cm-1
Mass: (m/e): 402.1 (M+1)

Example-8: Preparation of 6-chloro-5-(difluoromethoxy)-2-((3,4-dimethoxypyridin-2-yl)methylsulfinyl)-1H-benzo[d]imidazole sodium:
2-((3,4-dimethoxypyridin-2-yl)methylthio)-6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole (0.9 g) was suspended in dichloromethane (6 ml) and water (1 ml), cooled to a temperature of –10 °C. A mixture of NaOH (0.5 g) and NaOCl (7.5 ml) was added drop wise in to the reaction mixture maintaining the temperature at –10 °C and stirred for 2 hours. The reaction was quenched with sodium thiosulphate solution, diluted with water (20 ml) and then extracted with dichloromethane. The pH of the aqueous layer was adjusted to 9.5 using hydrochloric acid. The aqueous layer was extracted with dichloromethane and concentrated. The title compound was dissolved in dichloromethane and passed through alumina column. The collected organic layer was concentrated and the residue was suspended in n-hexane (20 ml) , stirred for 1h and filtered and dried.
Yield: 0.3 g
The 1H NMR data was found to be identical with that of the impurity isolated by prep. HPLC from pantoprazole.
1H NMR (400 MHz, CD3OD): 3.84(3H,S), 3.93(3H,S), 4.72(2H,S),6.86(1H,t,J=74 Hz), 7.05(1H, m),7.56(1H,S), 7.78(1H,S), 8.04(1H,d,J=6Hz).
IR(KBr):3106, 2947, 2844, 1712, 1582, 1488, 1466, 1429, 1387, 1333, 1304, 1280, 1238, 1168, 1118, 1068, 1044, 968, 872 cm-1
Mass: (m/e): 418.1 (M+1).

We claim:

1 A process for the preparation of chloro derivative of pantoprazole of formula II or its salt,

Formula II
wherein –Cl group may be present at C4, C6, or C7 position
which comprises:
i) condensation of compound of formula IV

Formula IV
with 2-(chloromethyl)-3,4-dimethoxypyridine in the presence of base to provide compound of formula III; and

Formula III
ii) oxidation of compound of formula III with oxidizing agent in the presence of base to provide chloro derivative of pantoprazole of formula II or its salt.
2. The process according to claim 1, wherein said base in step i) and ii) is selected from inorganic bases or organic base.
3. The process according to claim 1, wherein said oxidizing agent in step ii) is selected from sodium hypochlorite, sodium hypobromite, sodium metaperiodate, hydrogen peroxide, peracetic acid, trifluoroperacetic acid and m-chloroperbenzoic acid .
4. A process for the preparation of 6-chloro-5-(difluoromethoxy)-2-((3,4-dimethoxypyridin-2-yl)methylsulfinyl)-1H-benzo[d] imidazole of formula IIA or salt thereof,

Formula IIA
which comprises:
i) condensation of 6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole-2-thiol of formula IVA with 2-(chloromethyl)-3,4-dimethoxypyridine

Formula IVA
in the presence of base to provide 2-((3,4-dimethoxypyridin-2-yl)methylthio)-6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole of formula IIIA; and

Formula IIIA
ii) oxidation of 2-((3,4-dimethoxypyridin-2-yl)methylthio)-6-chloro-5-(difluoromethoxy)-1H-benzo[d]imidazole of formula IIIA with oxidizing agent in the presence of base to provide chloro derivative of pantoprazole of formula IIA.
5. The process according to claim 4, wherein said oxidizing agent is sodium hypochlorite.
6. A process for the preparation of compound of formula IV

Formula IV
wherein –Cl group may be present at C4, C6 or C7 position
a) reaction of chloro substituted 4-nitro phenol with sodiumchlorodifluoroacetate to provide nitro compound of formula A;

Formula A
wherein –Cl group may be present at C2 or C3 position
b) hydrogenation of the compound of formula A in presence of catalyst to provide 3-chloro-4-(difluoromethoxy) aniline of formula B or its salt;

Formula B
wherein –Cl group may be present at C2 or C3 position
c) acylation of the compound of formula B or its salt with acetic anhydride in presence of base to provide compound of formula C;

Formula C
wherein –Cl group may be present at C2 or C3 position
d) nitration of the compound of formula C with niric acid in the presence of acetic anhydride to provide nitro compound of formula D;

Formula D
wherein –Cl group may be present at C3, C4 or C6 position
e) hydrogenation of the compound of formula D in presence of raney nickel to provide amino compound of formula E or its salt; and

Formula E
wherein –Cl group may be present at C3, C4 or C6 position
f) reaction of the compound of formula E or its salt with carbon disulfide in the presence of base to provide compound of formula IV.
7. The processs according to claim 6, wherein said catalyst for hydrogenation is selected from palladium on support, platinum (IV) oxide, raney nickel, sodium sulfide, hydrogen sulfide and base, and the like.
8. The process according to the claim 6, wherein said salt is formed by the treatment with an acid.
9. The process according to the claim 8, wherein said acid is selected from organic acid or inorganic acid.
10. The compound obtained according to the process of claim 1, may be used as reference marker.