Title:

An improved process for preparation of crystalline lansoprazole.

Field of the invention:
An improved process for the preparation of substituted 2-(2-pyridylmethyl)-suliinyl-lH-benzimidazoles compounds.

Background of the invention:
The present invention relates to an improved process for preparation of proton pump inhibitors, and to such proton pump inhibitors prepared thereby, compositions containing the same and uses thereof.

Gastric proton pump inhibitors (PPIs) include substituted 2-(2-pyridylmethyl)-suliinyl-lH- benzimidazoles, such as lansoprazole (2- [ [ [3-methyl-4- (2, 2, 2-trifluoro-ethoxy)-2- pyridinyl] methyl] sulfinyl] IH-benzimidazole), omeprazole (5-methoxy-2- [ [ (4-methoxy-3, 5- dimethyl-2-pyirdyl) methyl] sulfinyl]-IH-benzimidazole), pantoprazole (5- (difluoromethoxy)- 2- [ [ (3, 4-dimethoxy-2-pyridinyl) methyl] sulfinyl] IH-benzimidazole) and rabeprazole (2- [ [ [4- (3-methoxy-propoxy) 3-methyl-2-pyridinyl] methyl] sulfinyl]-lH-benzimidazole).

Several proton-pump inhibitors, which are useful in the treatment of duodenal ulcers, are known. These include omeprazole that are described in EP5129, lansoprazole described in EP174726 and pantoprazole described in EP166287.

US Patent No. 4,628, 098 & 4,689,333 disclose a process for preparation of lansoprazole by oxidation of the sulphide precursor compound using peracids like m-chloro perbenzoic acid.

US6,002,011 claim the preparation of substantially solvent-free and stable crystal, describe the crystallization of Lansoprazole from the ethanol: water system, containing traces of ammonia. This patent discloses a re-slurry method in water, which permits to obtain more stable solvent free Lansoprazole. This patent fails to disclose the level of purity for Lansoprazole.

EP1615913A2 Claims the admixture of thioether with active chlorine containing oxidant, organic metal base and organic solvent at 5 deg C or below, then recovering sulfoxide compound wherein the oxidant is sodium hypochlorite, and the organic solvent as isobutyl acetate or acetonitrile (2 - 10 volumes), ethyl acetate, butyl acetate, methyl acetate, and dichloromethane.

US7060837 claims the purification of lansoprazole with an alcohol such as ethanol in presence of an amine compound (ammonium hydroxide) with the 1:1 mole:mole ratio with respect to lansoprazole.

US6919459 an improved process for the preparation of proton pump inhibitors of the benzimidazole-type such as rabeprazole, omeprazole, pantoprazole, lansoprazole and esomeprazole and particularly rabeprazole by reacting thio compound with m-chloroperoxybenzoic acid in a suitable solvent, extracting the reaction mixture with an aqueous alkaline solution and isolating the compound with less sulfone impurities.

The above all prior art process either uses expensive catalysts or hazardous oxidizing reagents, such as peracids, which are not suitable for commercial manufacture of the compound Lansoprazole.

After oxidation the usage of thioether compound leads to the excess of sulphone and sulphide impurities is a common problem encountered with the prior art processes.

Thus present invention provides an efficient, safe and industrially feasible method by the selective oxidation of a sulphide compound of formula II to a sulfinyl compound of formula I.

Summary of the invention:
The present invention relates to a process for preparation of substituted 2-(2-pyridylmethyl) sulphinyl-1H-benzimidazole of formula I comprising a) thio compound is reacted with an oxidizing agent sodium hypo chloride in presence of alcohol especially 2-butanol, b) extraction and then isolation of the compound formula II in a suitable halogenated hydrocarbon solvents selected from dichloromethane, chloroform and preferably chloroform c) further slurry made in a mixture of ketones and catalytic amount of amines, preferably methyl ethyl ketone and catalytic amount of triethyl amine d) drying the product.
The oxidizing agent used in the present invention is ecofriendly and particularly advantageous on industrial scale in terms of yield and purity.

Detailed description:

The present invention provides an efficient, safe and industrially feasible method for preparing substituted 2- (2-pyridylmethyl)-sulfinyl-lH-benzimidazole compound.

In particular, it is an aim of the present invention to provide an improved process for the preparation of a compound of formula I

comprising reacting a compound of formula II

with an oxidizing agent in C1-C6 alcohols and
b) Extraction and isolation of the compound of formula I in presence of a halogenated hydrocarbon solvents selected from dichloromethane, chloroform and preferably chloroform c) further slurry made in a mixture of ketones and catalytic amount of amines, preferably methyl ethyl ketone and catalytic amount of triethyl amine
d) drying of the product.

It is a further aim of the present invention relates to a process for preparation of lansoprazole, comprising a) thio compound is reacted with at least one oxidising agent sodium hypo chloride, in presence of a suitable solvent selected from C1-C6 alcohols, is selected from the group of methanol, ethanol, n-butanol, 2-butnaol, isopropyl alcohol, amyl alcohol, preferably 2-butanol and
b) extraction and isolation of the compound of formula I with a suitable halogenated hydrocarbon solvent preferably chloroform, and preferably chloroform c) further slurry made in a mixture of ketones and catalytic amount of amines, preferably methyl ethyl ketone and catalytic amount of triethyl amine
d) drying of the product.

It is a further aim of the invention relates to a process for preparation of substituted 2-(2-pyridylmethyl) sulphinyl-1H-benzimidazole compound especially lansoprazole formula I comprising
a) thio compound is reacted with at least one oxidising agent sodium hypo chloride, in presence of a suitable solvent selected from C1-C6 alcohols, is selected from the group of methanol, ethanol, n-butanol, 2-butnaol, isopropyl alcohol, amyl alcohol, preferably 2-butanol, wherein the oxidation is carried out at a temperature in the range of about 0 deg C to about 10 deg C, preferably about 0 deg C to about 5 deg C and
b) extraction is carried out at a temperature in the range of about 30 deg C to 60 deg C, preferably about 40 deg C to 50 deg C, and
isolating the compound of formula I with a suitable halogenated hydrocarbon solvents selected from dichloromethane, chloroform, isolation is carried out at a temperature in the range of about 0 deg C to about 10 deg C, preferably about 0 deg C to about 5 deg C and preferably chloroform
c) further slurry made in a mixture of ketones and catalytic amount of amines, preferably methyl ethyl ketone and catalytic amount of triethyl amine
d) drying the product of crystalline formula I of lansoprazole, at a temperature of about 30 deg C to 60 deg C, preferably about 40 deg C to 50 deg C.

The present invention is to provide a subsequent purification after isolation, which is carried out in presence of a solvent selected from the group of acetone, methylethylketone, methyl iso butyl ketone, methylene dichloride, tetrahydrofuran, toluene, water, acetonitrile or mixtures thereof, most preferably methylethylketone.

It is further aim of the present invention to provide an improved process for oxidation of (2-[[[3-methyl-4-(2, 2, 2-trifluoro-ethoxy)-2-pyridinyl] methyl]-thio] lH-benzimidazole to crystalline lansoprazole.

The present invention of substituted 2-(2- pyridylmethyl) sulfinyl-1 H-benzimidazole compound is lansoprazole, having purity at least 99.6%.

Example 1:
Preparation of 2-[[[3-methyl-4-(2, 2, 2-trifluoroethoxy)-2-pyridinyl]-methyl]-sulfinyl]-1H-benzimidazole

100 g of 2- [[[3- methyl –4-(2, 2, 2-trifluroethoxy) –pyridine-2-yl] Methyl] thio]-1H-benzimidazole and 200 ml of 2-Butanol taken into 2 L round bottom flask and the mixture was cooled to 0-5 °C, Sodium hypo chlorite (~4%) solution (700ml) was slowly added at the same temperature over a period of 1.5-2 hrs. The reaction mass maintained at 0-5 °C for about 1 - 2 hrs and reaction completion was confirmed by HPLC monitoring, further Sodium thiosulphate solution (2g in 3 ml water) was added to the reaction mass. Ammonium formate (80 g) was used to adjust the pH to 9.5-9.8 at 0-5 °C and stirred for 15-30 min at same temperature, 500 ml of De-Mineralized water was added to the reaction mixture and reaction mass temperature was raised to 25-30 °C and stirred for about 6-8 hrs, followed by filtration of the product. Obtained cake was washed with 125 ml of De-Mineralized water.
The wet cake was further mixed with 1 L of De-Mineralized water, stirred for some time and filtered off the product and washed with 250 ml of De-Mineralized water.
Wet cake was treated with sodium hydroxide solution (15.5 g in 1.4 L water) and heated to about 40°C and clear solution is obtained by stirring. Further treated with 10 g of activated carbon, 2.6 g of Hydrose, 1.5 g of Ethylenediaminotetraacetic acid (EDTA) and carbon bed washed with 100 ml of diluted sodium hydroxide solution. The above filtrate and chloroform (500 ml) taken into 2 L round bottom flask, heated to 40-45 °C and adjusted the pH to 7.0-7.5 with dilute acetic acid and separated the organic phase, extracted aqueous portion with 100 ml of chloroform.
Both organic layers were combined and cooled to 0-5 °C, maintained for about 1 hr at same temperature, filtered, washed with 600 ml of De-Mineralized water. Thus obtained wet cake was treated with a mixture of methylethylketone (75 ml) and triethylamine (2.7 ml) and heated to about 45 °C, stirred for 1 hr at same temperature, and cooled to 0-5 °C followed by filtration and washed with a mixture of methylethylketone (20 ml) and triethylamine (1 ml) and dried at 50-55 °C.
Yield of Lansoprazole: 71.0 g (68.0%).
Purity: 99.8%
Claims:

1. A process for the preparation a substituted 2-(2-pyridylmethyl) sulphinyl-1H-benzimidazoles compound of formula I

comprising the steps of
a) oxidizing a sulfide compound of formula II

with an oxidizing agent in presence of at least one C1-C6 alcohol.
b) extraction and isolation in halogenated hydrocarbon,

c) further slurry made in a mixture of ketones and catalytic amount of amines,

d) drying the resultant substituted 2-(2-pyridylmethyl) sulphinyl-1H-benzimidazole compound of formula I.

2. The process according to claim 1, wherein the said oxidation is carried out with an oxidizing agent like sodium hypohalite preferably sodium hypo chlorite.

3. The process according to claim 1, the said C1-C6 alcohol is selected from the group of methanol, ethanol, n-butanol, 2-butnaol, isopropyl alcohol, amyl alcohol, preferably 2-butanol.

4. The process according to claim 1, wherein step b) is carried out in presence of at least one halogenated hydrocarbon selected from chloroform, carbon tetrachloride, preferably chloroform.

5. The process according to claim 1, after isolation, subsequent purification is carried out in presence of a solvent selected from the group of acetone, methylethylketone, methyl iso butyl ketone, methylene dichloride, tetrahydrofuran, toluene, water, acetonitrile or mixtures thereof, most preferably methylethylketone.

6. The process according to claim 1, wherein said substituted 2-(2- pyridylmethyl) sulfinyl-1 H-benzimidazole compound is lansoprazole, having the purity at least 99.6%.

7. The process according to claim 5, the solvent further consists of one stabilizer, preferably triethylamine.

8. The process according to claim 1, after completing the oxidation reaction the reaction mass pH is adjusted to about 9.0 to 10.0 preferably 9.5 to 9.8 with at least one saturated aliphatic carboxylic acid salt selected from the group of sodium acetate, ammonium acetate, ammonium formate, and potassium butanoate, preferably ammonium formate.

9. The process according to claim 8, the ratio of ammonium formate ranges from about 1:1 to about 1:0.5, preferably about 1:0.8.

10. The compound of formula I as claimed in claim 1, having an X-ray diffraction

Angle
2-theta d-value Angstrom Intensity %
5.783 15.2703 100
11.482 7.70035 18.9
14.316 6.18184 26.7
16.988 5.21523 67.1
17.629 5.02696 63.3
18.757 4.72704 22.8
22.408 3.96443 39.3
23.013 3.86157 19.1
23.578 3.77028 15.1
25.043 3.55291 29.4
25.709 3.46242 26.3
26.017 3.42211 20.1
27.863 3.19946 19.5
31.332 2.85264 16.9

11. The process according to claim 2, wherein the said
a) oxidation is carried out at a temperature in the range of about 0 deg C to about 10 deg C, preferably about 0 deg C to about 5 deg C,
b) extraction is carried out at a temperature in the range of about 30 deg C to 60 deg C, preferably about 40 deg C to 50 deg C, and
c) isolation is carried out at a temperature in the range of about 0 deg C to about 10 deg C, preferably about 0 deg C to about 5 deg C.

Abstract:

The present invention provides a process for the preparation of substituted 2-(2-pyridylmethyl) sulphinyl-1H-benzimidazoles a compound comprising the steps of a) thio compound is oxidized with an oxidizing agent in presence of alcohol, b) extraction and followed by an isolation in halogenated hydrocarbon, c) further slurry made in a mixture of ketones and catalytic amount of amines,
d) drying of the product of formula I, where the said process being particularly advantageous in terms of commercial viability along with high purity.