Field of the invention:
The present invention relates to a process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-p5^ridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of
formula-1 represented by the following formula:
OCH3
OCH,
The present invention also provides process for the preparation of bis(5-methoxy-2-[(S)-[(4-methoxy-3J5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-l-yl) magnesium dihydraté represented by following formula-2.
OCH
OCH-
2+
Mgz: 2H20
Formula-2 Background of the invention:
Esomeprazole i,e. S-isomer of Omeprazole is chemically known as (S)-5-methoxy-2-[[(4-methoxy-3?5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole. It is a proton-pump inhibitor developed as an oral treatment for peptic ulcer, gastroesophageal reflux disease (GERD), duodenal ulcer and esophagitis.
Esomeprazole magnesium is available in the market under the brand name NEXIUM as delayed release capsules for oral administration. Each delayed-release capsule contains 20 mg or 40 mg of Esomeprazole (present as 22.3 mg or 44.5 mg Esomeprazole magnesium trihydrate) in the form of enteric-coated pellets. Esomeprazole sodium is available under a brand name Nexium I. V. as a sterile, freeze-dried, white to off-white, porous cake or powder in a 5 mL vial, intended for intravenous administration. NEXIUM I.V. for Injection contains Esomeprazole sodium 21.3 mg or 42.5 mg, equivalent to Esomeprazole 20 mg or 40 mg.
US pat. No 6,369,085 discloses crystalline forms of Esomeprazole magnesium i,e.

Esomeprazole magnesium dihydrate Form-A, Esomeprazole magnesium dihydrate Form-B and Esomeprazole magnesium trihydrate and Esomeprazole potassium. And characterizes them by powder X-ray Diffraction (P-XRD).
US pat Application No 2008/0249134 discloses crystalline Esomeprazole sodium 5 Form-B, US pat. No 8,658,799 discloses crystalline Esomeprazole sodium Form-C, E & H and US pat No 8,063,074 discloses crystalline Esomeprazole sodium Form-J, K, L5 M and N. And characterizes them by powder X-ray Diffraction (P-XRD).
US pat. No 5,948,789 discloses process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-benzimidazole sodium. The
10 disclosed process involves the reaction of 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio)-lH-benzo[d]imidazole with diethyl tartrate, titaniumsiopropoxide in presence of diisopropylethylamine in ethylacetate followed by treatment with cumene hydrogen peroxide afforded Esomeprazole, which is further treated with sodium hydroxide to give (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-benzimidazole
15 sodium along with the formation of sulphoxide impurity which is difficult to remove from the product and also results in the formation of fínal product with low yield and low purity. There is additional purification required to remove the samé which results in increasing the production cost and provides lower yields.
Hence, there is a need in the art to develop an improved, economically viable and
20 . effícient, simple process for the preparation of (S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1 and bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-yl) magnesium dihydrate represented by following formula-(2) with high yield and purity.
25 Brief description of the invention:
The first aspect of the present invention is to provide process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3?5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1.
The second aspect of the present invention is to provide process for the preparation of 30 bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-lH-
benzimidazole-1-yl) magnesium dihydrate compound of formula-2.
The third aspect of the present invention is to provide process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimefo^ calcium compound of formula-6. 5 The forth aspect of the present invention is to provide process for the preparation of
(S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH-benzimidazole sodium compound of formula-1.
The fifth aspect of the present invention is to provide process for the preparation of bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-lH-10 benzimidazole-1-yl) magnesium dihydrate compound of formula-2.
Brief description of the drawings:
Figure-1: Illustrates the PXRD pattern of crystalline (S)-5-methoxy-2[[(4-methoxy-3,5-
dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1.
15 Figure-2: Illustrates the PXRD pattern of crystalline bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-
dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-l-yl) magnesium dihydrate
compound of formula-2.
Figure-3: Illustrates the PXRD pattern of crystalline (S)-5-methoxy-2[[(4-methoxy-3,5-
dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6.
20
Detailed description of the invention:
The term "suitable solvent" used in the present invention includes, but not limited to
"ester solvents" šuch as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and
the like; "ether solvents" šuch as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl
25 ether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents" šuch as toluéne, hexane, heptane, pet ether, benzéne, xyléne, cyclohexane and the like; "polar aprotic solvents" šuch as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone and the like; "ketóne solvents" šuch as acetóne, methyl ethyl ketóne, methyl isobutyl ketóne and the like; "alcoholic solvents" šuch as methanol, ethanol, n-propanol,
isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chloro solvents" šuch as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; "nitrile solvents" šuch as acetonitrile, butyronitrile, isobutyronitrile and the like; "protic solvent" šuch as acetic acid; "polar solvent" šuch as water or mixtures thereof.
The term "base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" šuch as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" šuch as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" šuch as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydrides" šuch as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal alkoxides" šuch as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases šuch as triethyl amine, methyl amine, ethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), Tetra-n-butylammonium fluoride (TBAF), l,5-Diazabicyclo(4.3.0)non-5-ene (DBN), lithium dioisoporpylamide (LDA), n-
15 butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
The term "acid" used in the present invention refers to inorganic acid selected from
20 hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid and the like; organic acid šuch as formic acid, acetic acid, trifluoro acetic acid, methane sulfonic acid, ethane sulfonic acid, benzéne sulfonic acid, trifluoromethane sulfonic acid, p-toluene sulfonic acid, tartaric acid, mandelic acid, malic acid, maleic acid, succinic acid, malonic acid,"Oxalic acid, dibenzoyl tararic acid, lactic acid, cinnamic acid and the like.
The first aspect of the present invention provides a process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1, comprising of: a) Reacting 5-methoxy-lH-benzo[d]imidazole-2-thiol compound of formula-4 with 2-
(chloromethyl)-4-methoxy-335-dimethyl pyridine hydrochloride compound of formula-3 in presence of a base in a suitable solvent to provide 5'methoxy-2-((4-methoxy-3,5-dimethylpjaidin-2-yl)methylthio)-lH-benzo[d]imidazole compound of formula-5,
b) reacting compound of formula-5 with D-(-)-diethyl tartrate and titanium isopropoxide in presence of a base in a suitable solvent followed by oxidizing in presence of a suitable oxidizing agent, which on further treating with sodium hydroxide in a suitable solvent to provide (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-benzimidazole sodium compound of formula-1,
c) treating compound of formula-1 with calcium chloride dihydrate in a suitable solvent to provide (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6,
d) reacting compound of formula-6 with a suitable acid in a suitable solvent followed by treating with sodium hydroxide in a suitable solvent to provide (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1,
e) purifying compound of formula-1 from a suitable solvent to provide high pure (S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium.
Wherein
in step-a), b) and c) a suitable solvent is selected from ester solvents, ether solvents, chloro
solvents, hydrocarbon solvents, ketóne solvents and alcohol solvents or mixture thereof;
in step-d) a suitable solvent is selected from ketóne solvents šuch as acetóne, methyl ethyl
ketóne, methyl isobutyl ketóne and the like; a suitable acid is selected from inorganic acid or
organic acid;
in step-e) a suitable solvent is selected from methyl isobutyl ketóne and acetóne.
The preferred embodiment of the present invention provides a process for the
preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-
benzimidazole sodium compound of formula-1, comprising of:
a) Reacting 5-methoxy-lH-benzo[d]imidazole-2-thiol compound of formula-4 with 2-(chloromethyl)-4-methoxy-355-dimethylpyridine hydrochloride compound of formula-3 in presence of sodium hydroxide in toluéne provides 5-methoxy-2-((4-methoxy-3,5-
dimethylpyridin-2-yl)methylthio)-lH-benzo[d]imidazole compound of formuIa-5,
b) reacting compound of formula-5 with D-(-)-diethyl tartrate and titanium isopropoxide in presence of diisopropylethylamine in toluéne followed by oxidizing in presence of cumene hydrogen peroxide, which on further treating with sodium hydroxide in methanol and dichloromethane provides (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1,
c) treating compound of formula-1 with calcium chloride dihydrate in acetóne and water provides (S)-5-methoxy-2[[(4-methoxy-3,5-dTO
benzimidazole calcium compound of formula-6,
d) reacting compound of formula-6 with acetic acid in dichloromethane and water followed by treating with sodium hydroxide in methanol provides (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1,
e) purifying the obtained compound of formula-1 using methyl isobutyl ketóne and followed by slurring in acetóne provides high pure (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1.
US5948789 patent discloses process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3í5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium. The said 20 process involves reaction of 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio)-lH-benzo[d]imidazole with diethyl tatrate, titaniumisopropoxide in presence of diisopropylethylamine in ethylacetate followed by treatment with cumene hydrogen peroxide afforded Esomeprazole, which is further treated with sodium hydroxide to give (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-benzimidazole sodium along with the formation of sulphoxide impurity. The said impurity is difficult to remove and requires number of purifications which causes increase in the production cost and decrease in the yield. The present inventors found that whenever Esomeprazole Sodium is converted to Esomeprazole Calcium salt then the sulfoxide impurity is reduced to minimum levels thereby increases the yield and purity of the final product.
solvent is selected from ester solvents, ether solvents, chloro solvents, hydrocarbon solvents,
ketóne solvents and alcohol solvents or mixture thereof;
in step-e) a suitable solvent is selected from methanol, acetóne or mixture thereof
The preferred embodiment of the present invention provides a process for the preparation of bis(5-methoxy-2-[(S)-[(4-methoxy-355-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-1-yl) magnesium dihydrate compound of formula-2, comprising of:
a) Reacting 5-methoxy-lH-benzo[d]imidazole-2-thiol compound of formula-4 with 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride compound of formula-3 in presence of sodium hydroxide in toluéne provides 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)-lH-benzo[d]imidazole compound of formula-5,
b) reacting compound of formula-5 with D-(-)-diethyl tartrate and titanium isopropoxide in presence of diisopropylethylamine in toluéne foliowed by oxidizing in presence of cumene hydrogen peroxide, which on further treating with sodium hydroxide in methanol and dichloromethane provides (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-benzimidazole sodium compound of formula-1,
c) treating compound of formula-1 with calcium chloride dihydrate in acetóne and water provides (S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6,
d) reacting compound of formula-6 with acetic acid in dichloromethane and water foliowed by treating with sodium hydroxide in methanol, which on further treating with magnesium chloride hexahydrate in methanol provides bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-l-yl) magnesium dihydrate compound of formula-2,
e) crystallizing the obtained compound of formula-2 using methanol and acetóne provides pure bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfmyl]-lH-benzimidazole-1-yl) magnesium dihydrate compound of formula-2,
f) optionally slurring the compound of formula-2 in water to provide high pure compound of formula-2.
The third aspect of the present invention provides process for the preparation of (S)-
5-methoxy-2[[(4-methoxy-3J5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-benzimidazole calcium compound of formula-6, comprising of treating the compound of formula-1 with calcium chloride dihydrate in a suitable solvent to provide (S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6. 5 Wherein, the suitable solvents used are samé as defmed in the first aspect of the
present invention.
The preferred embodiment of the present invention provides a process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6, comprising of treating the compound of
10 formula-1 with calcium chloride dihydrate in acetóne and water provides (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium
compound of formula-6.
The forth aspect of the present invention provides a novel process for the preparation of (S)-5-methoxy-2[[(4-methoxy-335-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-
15 benzimidazole sodium compound of formula-1, comprising of reacting compound of formula-6 with a suitable acid in a suitable solvent to provide (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH-benzimidazole sodium compound of formula-1. Optionally purifying the compound frorn a suitable solvent to provide high pure (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole
20 ■ sodium compound of formula-1.
Wherein, the suitable solvent and suitable acid used are samé as defíned in step-d) and e) of the first aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3J5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-
25 benzimidazole sodium compound of formula-1, comprising of reacting compound of formula-6 with acetic acid in dichloromethane and water followed by treating with sodium hydroxide in methanol provides (S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH-benzimidazole sodium compound of formula-1. Purifying the obtained compound of formula-1 using methyl isobutyl ketóne and followed by slurring in acetóne
30 provides pure (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH-
benzimidazole sodium compound of formula-1.
The fifth aspect of the present invention provides an improved process for the preparation of bís(5-methoxy-2-[(S)-[(4-methoxy-355-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-1-yl) magnesium dihydrate compound of formula-2, comprising of reacting compound of formula-6 with a suitable acid in a suitable solvent followed by treating with sodium hydroxide in a suitable solvent, which on further reacting with magnesium chloride hexahydrate to provide bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridiny l)methylsulfmyl]-1 H-benzimidazole-1 -y 1) magnesium dihydrate compound of formula-2. Crystallizing the compound of formula-2 from solvent or mixture of solvents to provide pure bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfínyl]-l H-benzimidazole- 1-yl) magnesium dihydrate. Optionally slurring the compound of formula-2 in water to provide high pure compound of formula-2.
Wherein in the suitable solvent and suitable acid are samé as defíned in step-d) and e) of the second aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methylsulfmyl]-1 H-benzimidazole-1-yl) magnesium dihydrate compound of formula-2, comprising of reacting compound of formula-6 with acetic acid in dichloromethane and water followed by treating with sodium hydroxide in methanol, which on further treating with magnesium chloride hexahydrate in methanol provides bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole-1 -yl)magnesium dihydrate compound of formula-2. Crystallizing the compound of formula-2 using methanol and acetóne provides pure bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfmyl]-lH-
benzimidazole-1-yl) magnesium dihydrate compound of formula-2. Optionally slurring the compound of formula-2 in water to provide high pure compound of formula-2.
The compounds of the formula-3 and formula-4 can be prepared by the process known in art.
The compound of formula-1 & formula-2 of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage mičronization
using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, balí mills
and roller mills. Milling or mičronization may be performed before drying or after drying of
the product.
P-XRD Method of Analysis:
PXRD analysis of compounds of formulae-1 & 2 was carried out using SIEMENS/D-5000
X-Ray diffractometer úsing Cu, Ka radiation of wavelength 1.54 A° and continuous scan
speedof0.0457min.
HPLC Method of Analysis:
Compounds of formulae-1 & 2 and its related substances were analyzed by HPLC with the
following chromatographic conditions:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector.
Column: Develosil ODS-UG 250 x 4.6 mm, 5|im or equivalent;
Wavelength: 276 nm;
Column temperature: 20°C;
Injection volume: 5 \iľ9
Elution: Gradient;
Diluent: Methanol.
Buffer: Weigh accurately about 1.36gr of Potassium dihydrogen phosphate and 3.48 gr of Di
potassium hydrogen phosphate in 1000 mL of Milli-Q-water. Filter this solution through
0.22(im Nylon membráne filter paper.
Mobile Phase-A : Buffer: Acetonitrile (95:05) v/v
Mobile Phase-B: Acetonitrile: Buffer (70:30) v/v
The process of the present invention can be represented schematically as follows:
OCH
OCH,
+
.HCl FormuIa-3
OCH,
Formula-4
OCH,
Formula-5
Diefhyl tartrate
Titanium isopropoxide
DIPEA
Cumine hydrogen per oxide
Toluéne
Dichloromethane
MeOH
OCH3 NaOH
OCH,
Formula-1
OCH
Calcium chloride dihydrate Acetóne
OCH,
Dichloromethane Acetic acid H20, MeOH NaOH
i^CT
Na+ Formula-1
OCH
Dichloromethane Acetic acid Water, Metganol NaOH, MeOH MgCl2.6H20 _ Acetóne
OCH,
Mg2t 2H20
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl
thio)-lH-benzo[d]imidazole(Formula-5)
2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride compound of formula-3 (100 gm) was added to a mixture of 5-methoxy-lH-benzo[d]imidazole-2-thiol compound of formula-4 (81 gm) and toluéne (100 ml) at 25-30°C. Aqueous Sodium hydroxide solution (40.5 gm in 200 ml of water) was added to the reaction mixture at 25-30°C. The reaction mixture was seeded with 5-methoxy-2-((4-methoxy-355-dimethylpyridin-2-yl)methylthio)-lH-benzo[d]imidazole compound of formula-5 (0.5 gm) at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 4 hrs at the samé temperature. Cooled the reaction mixture to 25-30°C. Toluéne (150 ml) was added to the reaction mixture at 25-30°C and stirred for 4 hrs at the samé temperature. Filtered the precipitated solid and washed with water. To the obtained compound water was added at 25-30°C and stirred for 45 minutes at the samé temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 146.83 gm
Example-2: Preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyI-2-pyridinyI)-methyl]sulfinyl]-lH-benzimidazole sodium (Formula-1)
D(-) diethyl tartrate (14 gm) was added to the mixture of 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)-lH-benzo[d]imidazole compound of formula-5 (100 gm) and toluéne (500 ml). Heated the reaction mixture to 65-70°C. Titanium isopropoxide (11 gm) was added to the reaction mixture at 65-70°C and stirred for 45 minutes at the samé temperature. Cooled the reaction mixture to 25-30°C. Diisopropylethylamine (8 gm) was added to the reaction mixture at 25-30°C under nitrogen atmosphere and stirred for 45 minutes at the samé temperature under nitrogen atmosphere. Cooled the reaction mixture to 0-5°C. Cumene hydrogen peroxide (60 gm) was slowly added to the reaction mixture at 0-5°C under nitrogen atmosphere and stirred for 10 hrs at the samé temperature under nitrogen atmosphere. Methanolic sodium hydroxide solution [sodium hydroxide (21.8 gm) and methanol (150 ml) heated for 20 min at 45-50°C] was slowly added to the reaction mixture at 25-30°C. Dimethyl sulfoxide (2 ml) was added to the reaction mixture at 25-30°C and stirred for 2 hrs at the samé temperature. Distilled off the solvent completely from the reaction
mixture under reduced pressure. Cooled the reaction mixture to 25-30°C. Water was added to the obtained compound at 25-30°C and stirred for 45 minutes at the samé temperature. Carbon (2.5 gm) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the samé temperature. Filtered the reaction mixture through high ílový and washed with water. The fíltrate was washed with toluéne at 25-30°C. Dichloromethane (200 ml) was added to the reaction mixture. The reaction mixture was neutralized by using acetic acid at 25-30°C and stirred for 15 minutes at the samé temperature. Both the organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with aqueous sodium bicarbonate solution. Methanolic sodium hydroxide solution [sodium hydroxide (14.6 gm) and methanol (100 ml) heated for 20 min at 45-50°C] was added to the organic layer at 25-30°C and stirred for 2 hrs at the samé temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and co-distilled with cyclohexane followed by ethyl acetate. Ethyl acetate was added to the obtained compound at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 45 minutes at the samé temperature. Further cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the samé temperature under nitrogen atmosphere. Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the samé temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 108 gm; Purity by HPLC: 90.14%, Sulfone impurity (Impurity-D): 9.08%. Example-3: Preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyI)-methyl]sulfinyl]-lH-benzimidazoIe calcium (Formula-6)
(S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1 (250 gm) was added to acetóne (1500 ml). Water (500 ml) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the samé temperature. Aqueous calcium chloride solution (110 gm in 1000 ml of water) was slowly added to the reaction mixture at 25-30°C and stirred for 90 minutes at the samé temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 200 gm; Purity by HPLC: 99.88%, Sulfone impurity (Impurity-D): 0.09%. ExampIe-4: Preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyI]-lH-benzimidazole sodium (Formula-1)
(S)-5-methoxy-2[[(4-methoxy-3J5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6 (100 gm) was added to dichloromethane (250 ml). Water (100 ml) was added to the reaction mixture. Cooled the reaction mixture to 25-30°C. The reaction mixture was neutralized by using acetic acid. Both the organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water Sodium hydroxide solution (9 gm in 100 ml of methanol) was added to the organic layer at 25-30°C and stirred for 60 minutes at the samé temperature. Carbon (3 gm) was added to the reaction mixture at 25-30°C and stirred for 15 minutes. Filtered the reaction mixture through high flow and washed with methanol. Distilled off the solvent completely fŕom the reaction mixture and co-distilled with methyl isobutyl ketóne. Methyl isobutyl ketóne (250 ml) was added to the obtained compound. Heated the reaction mixture at 50-55°C and stirred for 45 minutes at the samé temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the samé temperature. Filtered the precipitated solid and washed with methyl isobutyl ketóne. Acetóne (150 ml) was added to the obtained compound and stirred for 45 minutes. Filtered the solid, washed with acetóne and dried to get the title compound.
Yield: 80 gm, Purity by HPLC: 99.91%, Sulfone impurity (Impurity-D): 0.02%. Example-5: Preparation of bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2pyridinyl) methyl]sulfinyl]-lH-benzimidazole-l-yl) magnesium dihydrate (Formula-2) Water (100 ml) was added to the mixture of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-benzimidazole calcium compound of formula-6 (100 gm) and dichloromethane (250 ml). The reaction mixture was neutralized by using acetic acid. Both the organic and aqueous layers were separated. The organic layer was washed with water. Sodium hydroxide solution (9 gm in 100 ml of methanol) was added to the organic layer at 25-30°C and stirred for 60 minutes at the samé temperature. Distilled off the solvent completely ftom the reaction mixture under reduced pressure. Methanol (500 ml) was added to the obtained compound at 25-30°C and stirred for 20 minutes at the samé temperature. Magnesium chloride hexahydrate (18.5 gm) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the samé temperature. Carbon (3 gm) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the samé temperature. Filtered the reaction mixture through high flow and washed with methanol. Distilled off the solvent completely from the fíltrate under reduced pressure. Methanol (25 ml) was added to the obtained compound. Cooled the reaction mixture to 25-30°C. Acetóne (150 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 2 hrs at the samé temperature. Cooled the reaction mixture to 10-15°C and stirred for 45 minutes at the samé temperature. Filtered the precipitated solid and washed with acetóne. The obtained compound was added to water (150 ml) at 10-15°C and stirred for 45 minutes at the samé temperature. Filtered the solid, washed with water and dried to get the title compound.
Yield: 80 gm; Purity by HPLC: 99.58%, Sulfone impurity (Impurity-D): 0.04%. ExampIe-6: Preparation of bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2pyridinyl) methyl]sulfinyl]-lH-benzimidazole-l-yl) magnesium dihydrate (Formula-2) Water (300 ml) was added to the mixture of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6 (150 gm) and dichloromethane (375 ml). Cooled the reaction mixture to 25-30°C. The reaction mixture was neutralized by using acetic acid. Both the organic and aqueous layers were separated. The organic layer was washed with water. Sodium hydroxide solution (13.35 gm in 150 ml of methanol) was added to the organic layer at 25-30°C and stirred for 60 minutes at the samé temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Methanol (225 ml) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the samé temperature. Magnesium chloride hexahydrate (27.75 gm) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the samé temperature. Carbon (4.5 gm) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the samé temperature. Filtered the reaction mixture through high flow and washed with methanol. Methanol (75 ml) was added to the obtained compound. Acetóne (900 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 2 hrs at the samé temperature. Cooled the reaction mixture to 10-15°C and stirred for 45 minutes at the samé temperature. Filtered the precipitated solid and washed with acetóne. The obtained compound was added to water (150 ml) at 10-15°C and stirred for 45 minutes at the samé temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 80 gm; Purity by HPLC: 99.57%, Sulfone impurity (Impurity-D): 0.04%.
We Claim:
1. A process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3)5-dimethyl-2-pyridinyl)-
methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-15 comprising of:
a) Reacting 5-methoxy-lH-benzo[d]imidazole-2-thiol compound of formula-4 with 2-
(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride compound of
formula-3 in presence of a base in a suitable solvent to provide 5-methoxy-2-((4-
methoxy-3,5-dimethylpyridin-2-yl)methylthio)-lH-benzo[d]imidazole compound of
formula-5,
OCH3
N^^^OCH3
-<»xj
S N H
Formula-5
b) reacting compound of formula-5 with D-(-)-diethyl tartrate and titanium isopropoxide
in presence of a base in a suitable solvent followed by oxidizing in presence of a
suitable oxidizing agent, which on further treating with sodium hydroxide in a
suitable solvent to provide.(S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-
methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1,
OCH3
c) treating compound of formula-1 with calcium chloride dihydrate in a suitable solvent to provide (S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfínyl]-
lH-benzimidazole calcium compound of formula-6,
OCH3
N^/^/OCH3
Ca+ Formula-6
d) reacting compound of formula-6 with a suitable acid in a suitable solvent followed by
treating with sodium hydroxide in a suitable solvent to provide (S)-5-methoxy-2[[(4-
methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-benzimidazole sodium
compound of formula-l, e) purifying the compound of formula-l from a suitable solvent to provide high pure (S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-l.
2. The process according to claim 1, wherein
in step-a), b) and c) a suitable solveňt is selected from ester solvents, ether solvents,
chloro solvents, hydrocarbon solvents, ketóne solvents and alcohol solvents or mixture
thereof;
in step-d) a suitable solvent is selected from ketóne solvents šuch as acetóne, methyl
ethyl ketóne, methyl isobutyl ketóne and the like; a suitable acid is selected from
inorganic acid or organic acid;
in step-e) a suitable solvent is selected from methyl isobutyl ketóne and acetóne.
3. Aprocess for the preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-l, comprising of:
a) Reacting 5-methoxy-lH-benzo[d]imidazole-2-thiol compound of formula-4 with 2-(chloromethyl)-4-methoxy-3s5-dimethylpyridine hydrochloride compound of formula-3 in presence of sodium hydroxide in toluéne provides 5-methoxy-2-((4-methoxy-355-dimethylpyridin-2-yl)methylthio)-lH-benzo[d]imidazole compound of formula-5,
b) reacting compound of formula-5 with D-(-)-diethyl tartrate and titanium isopropoxide in presence of diisopropylethylamine in toluéne followed by oxidizing in presence of cumene hydrogen peroxide, which on further treating with sodium hydroxide in methanol and dichloromethane provides (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH-benzimidazole sodium compound of formula-l,
c) treating compound of formula-l with calcium chloride dihydrate in acetóne and water provides (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]- lH-benzimidazole calcium compound of formula-6,
d) reacting compound of formula-6 with acetic acid in dichloromethane and water followed by treating with sodium hydroxide in methanol provides (S)-5-methoxy-2[[(4-methoxy-3?5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1,
e) purifying the compound of formula-1 using methyl isobutyl ketóne and followed by slurring in acetóne provides pure (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1.
4. A process for the preparation of bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-l-yl) magnesium dihydrate compound of formula-2, comprising of:
a) Reacting 5-methoxy-lH-benzo[d]imidazole-2-thiol compound of formula-4 with 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride compound of formula-3 in presence of a base in a suitable solvent to provide 5-methoxy-2-((4-methoxy-355-dimethylpyridin-2-yl)methylthio)-lH-benzo[d]imidazole compound of formula-55
b) reacting compound of formula-5 with D-(-)-diethyl tartrate and titanium isopropoxide in presence of a base in a suitable solvent followed by oxidizing in presence of a suitable oxidizing agent, which on further treating with sodium hydroxide in a suitable solvent to provide (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH-benzimidazole sodium compound of formula-1,
c) treating compound of formula-1 with calcium chloride dihydrate in a suitable solvent to provide (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6,
d) reacting compound of formula-6 with a suitable acid in a suitable solvent followed by treating with sodium hydroxide in a suitable solvent, which on further reacting with magnesium chloride hexahydrate in a suitable solvent to provide bis(5-methoxy-2-[(S)-[(4-methoxy-355-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-l-yl) magnesium dihydrate compound of formula-2,
e) crystallizing the obtained compound of formula-2 from a solvent or mixture of solvents to provide pure bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-l~yl) magnesium dihydrate compound of formula-2,
f) optionally slurring the compound of formula-2 in water to provide high pure compound of formula-2.
5. The process according to claim 4, wherein
in step-a), b) and c) the suitable solvent is samé as defíned in the fírst aspect of the
present invention.
in step-d) a suitable acid is selected from inorganic acid or organic acid, and a suitable
solvent is selected from ester solvents, ether solvents, chloro solvents, hydrocarbon
solvents, ketóne solvents and alcohol solvents or mixture thereof;
in step-e) a suitable solvent is selected from methanol, acetóne or mixture thereof.
6. A process for the preparation of bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-l-yl) magnesium dihydrate compound of formula-2, comprising of:
a) Reacting 5-methoxy-lH-benzo[d]imidazole-2-thiol compound of formula-4 with 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride compound of formula-3 in presence of sodium hydroxide in toluéne provides 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)-lH-benzo[d]imidazole compound of formula-5,
b) reacting compound of formula-5 with D-(-)-diethyl tartrate and titanium isopropoxide in presence of diisopropylethylamine in toluéne followed by oxidizing in presence of cumene hydrogen peroxide, which on further treating with sodium hydroxide in methanol and dichloromethane provides (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1, c) treating compound of formula-1 with calcium chloride dihydraté in acetóne and water provides (S)-5-methoxy-2[[(4-methoxy-3J5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6,
d) reacting compound of formula-6 with acetic acid in dichloromethane and water followed by treating with sodium hydroxide in methanol., which on further treating with magnesium chloride hexahydrate in methanol provides bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfmyl] -1 H-benzimidazole-1-y 1) magnesium dihydrate compound of formula-2,
e) crystallizing the obtained compound of formula-2 using methanol and acetóne provides pure bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-l H-benzimidazole- 1-yl) magnesium dihydrate compound of formula-25
f) optionally slurring the compound of formula-2 in water to provide high pure compound of formula-2.
7. A process for the preparation of (S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfmyl]-l H-benzimidazole calcium compound of formula-6, comprising of treating compound of formula-1 with calcium chloride dihydrate in a suitable solvent selected from ketóne solvent preferably acetóne and a suitable polar solvent preferably water to provide (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-l H-benzimidazole calcium compound of formula-6.
8. A process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinyl] -1 H-benzimidazole sodium compound of formula-1, comprising of reacting (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH-benzimidazole calcium compound of formula-6 with a suitable acid in a suitable solvent followed by treating with sodium hydroxide in a suitable solvent to provide (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-l H-benzimidazole sodium compound of formula-1, purifying the compound of formula-1 from a suitable solvent to provide high pure (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1.
9. A process for the preparation of (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-15 comprising of reacting (S)-5-methoxy-2[[(4-methoxy-3?5-dimethyl-2-pyridinyl)-methyl]sulfínyl]-lH-benzimidazole calcium compound of formula-6 with acetic acid in dichloromethane and water followed by treating with sodium hydroxide in methanol provides (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1, purifying the compound of formula-1 using methyl isobutyl ketóne and followed by slurring in acetóne provides pure (S)-5-methoxy-2[[(4-methoxy-355-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium compound of formula-1.
10. A process for the preparation of bis(5-methoxy-2-[(S)-[(4-methoxy-355-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-l-yl) magnesium dihy draté compound of formula-2, comprising of
a) Reacting (S)-5-methoxy-2[[(4-methoxy-3J5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole calcium compound of formula-6 with a suitable acid preferably acetic acid in a suitable solvent selected from chloro solvent preferably dichloromathane and a suitable polar solvent preferably water followed by treating with sodium hydroxide in a suitable solvent selected from alcohol solvent preferably methanol, which on further reacting with magnesium chloride hexahydrate in a suitable solvent selected from alcohol solvent preferably methanol provides bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfmyl]-lH-benzimidazole-l-yl)magnesium dihydrate compound of formula-2,
b) crystallizing the obtained compound of formula-2 from solvent or mixture of solvents preferably methanol and acetóne to provide pure bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole-l-yl)magnesium.
dihydrate compound of formula-2, c) optionally slurring the compound of formula-2 in water to provide high pure compound of formula-2.