WO2010134099A1 - One pot process for preparing omeprazole and related compounds - Google Patents

One pot process for preparing omeprazole and related compounds Download PDF

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WO2010134099A1
WO2010134099A1 PCT/IN2010/000344 IN2010000344W WO2010134099A1 WO 2010134099 A1 WO2010134099 A1 WO 2010134099A1 IN 2010000344 W IN2010000344 W IN 2010000344W WO 2010134099 A1 WO2010134099 A1 WO 2010134099A1
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formula
methoxy
omeprazole
process according
represents
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PCT/IN2010/000344
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French (fr)
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Shriprakash Dhar DWIVEDI
Viraj Sharadchandra Chitnis
Jitendra Verdia
Daya Ram Pal
Kalpesh Ashokkumar Shah
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Cadila Healthcare Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to one pot process for preparing 2- [(pyridinyl)methyl]sulfinyl-substituted benzimidazoles of Formula (I') or a pharmaceutically acceptable salt, hydrate, or solvate thereof. More particularly, the present invention relates to the process for preparation of omeprazole by in-situ oxidization of compound of general formula (II')

Description

ONE POT PROCESS FOR PREPARING OMEPRAZOLE AND RELATED COMPOUNDS

Field of the Invention

The present invention relates to one pot process for preparing 2- [(pyridinyl)methyl]sulfinyl-substituted benzimidazoles of Formula (F) or a pharmaceutically acceptable salt, hydrate, or solvate thereof. More particularly, the present invention relates to the process for preparation of omeprazole by in-situ oxidization of compound of general formula (H')

Figure imgf000002_0001

Background and Prior art The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field. There are a large number of patents and patent applications disclosing different substituted 2-(2-pyridinylmethylsulphinyl)-lH-benzimidazoles. This class of compounds has properties making the compounds useful as inhibitors of gastric acid secretion and generally known as proton pump inhibitors.

For example the compound (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl) methyl]sulfϊnyl]-lH-benzimidazole), with the generic name omeprazole, described in i.e. EP 5129. It is marketed under the brand name Prilosec® for treatment of duodenal ulcer, gastric ulcer and GERD; maintenance of healing of errosive esophagitis, and long term treatment of pathological hyperscretory conditions

Rabeprazole is another compound of the same class and chemically known by 2-[[[(4-(3-methoxypropoxy)-2-methyl-2-pyridinyl]methyl]sulfinyl- 1 H-benzimidazoles. It was reported in U.S. Pat. No. 5045552 and marketed in the United States under the brand name Aciphex® for healing of erosive or ulcerative GERD, maintenance of healing of GERD and treatment of symptomatic GERD. Pantoprazole is the active ingredient of a pharmaceutical product that is marketed in the United States by Wyeth-Ayerst Inc. under the brand name Protonix®. Pantoprazole is chemical Iy represented (5 -(difluoromethoxy)-2-[[(3 ,4-dimethoxy-2-pyridiny l)methyl] sulfinyl]-lH-benzimidazole. Pantoprazole useful for short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis and pathological hypersecretory conditions including Zollinger-Ellison syndrome.

Lansoprazole another compound represented by 2-[[[3-methyl-4(2,2,2,- triflouroethoxy)-2-pyridiyl]methyl]sulfinyl]-lH-benzimidazole and reported in U.S Patent No. 4628098. It is marketed under the brand name Prevacid® for short-term treatment of duodenal ulcer, H. Pylori eradication to prevent recurrence of duodenal ulcer and maintenance of healed duodenal ulcers.

These compounds as well as structurally related sulphoxides, have a stereogenic centre at the sulphur atom and thus exist as two optical isomers, i.e. enantiomers. If there is another stereogenic center in the molecule, these compounds can exist as pairs of enantiomers. Corresponding sulphides of such compounds, which already contain a stereogenic center, are not pro-chiral compounds, but chiral compounds. However, the sulphur atom in these compounds does not have asymmetry and therefore they are referred to as pro-chiral sulphides in respect of this invention.

The preparation of 2-[(pyridinyl]methyl]sulfinyl-susbstituted benzimidazoles of Formula (I) by oxidation of compound of Formula (II) is generally known and is discussed in U.S. patent Nos. 5045552, 4508905 and 4628098.

Figure imgf000003_0001

However, it has been reported that the sulfone compound of formula (III) is also generated because of over oxidation of thioether compound of formula (II).

Figure imgf000003_0002

(II1) Various methods employing various different oxidants to perform this oxidation are known. For example, Canadian Patent No. 1,263,119 describes the use of hydrogen peroxide over a vanadium catalyst (such as vanadium pentoxide, sodium vanadate and vanadium acteylacetonate). Canadian Patent No. 1,127,158 similarly describes the use of peracids, peresters, ozone, etc. European Patent Application, Publication No. 533,264 describes the use of magnesium monoperoxyphthalate as the oxidizing agent. PCT Publication No. WO91/18895 describes the use of m-chloroperoxy benzoic acid as the oxidizing agent. GB Pat. No. 2,069,492 generally describes this acid and other peroxy acids in the oxidation of substituted (phenylthiomethyl)pyridines.

According to example 32 of 505552, thioether is oxidized by using 0.96 equivalent (on a purity basis) of m-chloroperbenzoic acid, to produce sulfoxide at a yield of 80%, which is not an industrially satisfactory yield. Depending on the reaction conditions, disadvantageous^, the reaction does not ceased at the stage of sulfoxide production but further proceeds to a side reaction where a part of the produced sulfoxide is furthermore oxidized to sulfone as shown below. When sulfone is formed, there is a problem not only that the yield of the objective sulfoxide is reduced, but also that is difficult to separate and purify them, since there is a close resemblance in physicochemical property between the two. Additionally, the oxidation is conducted in dichloromethane (methylene chloride), but, from a viewpoint of environmental strategies and regulatory aspects, use of halogenated hydrocarbon solvents is preferably avoided. Moreover, m-chloroperbenzoic acid is expensive, it is extremely disadvantageous from a viewpoint of the production cost. US 5374730 relates to omeprazole and lansoprazole, in particular, two novel synthetic methods for their preparation. According to the process, amide analogues of the thioether compounds are oxidized to the corresponding sulfϊnyl compounds by using hydrogen peroxide as oxidizing agent.

US 6313303 Bl discloses the process for preparing Rabeprazole, Lansoprazole and other related compounds by oxidation thioether precursor compound with N- halosuccinamide, l,3-dihalo-5,5-dimethylhydantoin or dichloroisocyanurate in the presence of a base.

EP 0484265 Al discloses the process for the preparation of omeprazole (see example 32 and 33) by oxidation of 2-(((3,5-dimethyl-4-methoxy-2- pyridinyl)methyl)sulfinyl)-5-methoxy-lH-benzirnidazole in suitable organic solvent with 50% H2O2 in presence of catalyst like (P(WaO1O)4-X-H2O; ammonium Molybdate, having the formula (NHt)2MoO4; sodium tungstate, having the formula Na2WO4; phosphomolybdic acid, having the formula H3(P(Mθ3θio)4-XH2θ; and silicotungstic acid, having the formula H4(Si(W3OiO)4-XH2O at lower temperatures. Use of base in the oxidation process is essential. The process is suffering from tedious and costlier work up for the isolation of the product. The use of organic solvent like methylene dichloride and ethyl acetate and then washing with the same solvent at -15°C is very tedious workup procedure. EP 0484265 discloses in example-28 and 29, oxidation of omeprazole sulphide of general formula (II) in a mixture of ethyl acetate and 2-ethylhexanoic acid with 68% m-CPBA to obtain omeprazole. Similarly in example-31, oxidation of omeprazole sulphide of general formula (II) is disclosed in a mixture of ethyl acetate and acetic acid. The reference work reported in Shanxi Yike Daxue Xuebao, Vol. 34 (4), Pg.

330-332, (2002) discloses the condensation of 2-(chloromethyl)-3,5-dimethyl-4- methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in water/methanol solvent mixture in presence of sodium hydroxide. The omeprazole sulfide of general formula (II) is isolated and oxidized with m-CPBA in MDC to obtain omeprazole.

The Journal of Labelled compounds and Radiopharmaceuitcals, Vol. 23(1), Pg. 21-33, (1986) discloses the condensation of 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in water/ethanol solvent mixture in presence of sodium hydroxide. The 14C, 35S and 13C labelled forms of omeprazole were prepared by oxidation of omeprazole sulfide with m-CPBA in MDC.

Russian Patent 2215739 discloses the process for the condensation of 2- (chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2- mercapto-5-methoxy benzimidazole of formula (III) to obtain omeprazole sulphide of general formula (II). The reaction is performed in ethanol in presence of sodium hydroxide at 45°C to 500C at pH 8- 10.

WO 2004035565 Al discloses the process for the condensation of 2- (chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2- mercapto-5-methoxy benzimidazole of formula (III) to obtain omeprazole sulphide of general formula (II). The reaction is performed in water at 450C at pH 12.5 for 2 hours in presence of sodium hydroxide.

There is no report available in the prior for the one pot process for the preparation of omeprazole using 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) and 2-mercapto-5-methoxy benzimidazole of formula (HI) as the starting material. Hence, there is a need to provide a one-pot process for manufacturing of omeprazole of formula (I), which provides direct isolation of omeprazole by filtration with shorter reaction time and high yield and purity.

There are some patents related to the purity as well as residual alcohols in omeprazole. U.S. Patent No. 6,191,148 Bl claims 5-methoxy-2-[[4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole (omeprazole) of greater than

99.94% purity as determined by high-performance liquid chromatography and having less than 500 parts per million (p.p.m.) of residual ethanol relative to omeprazole.

U.S. Patent No. 6,147,103 and U.S. Patent No. 6,166,213 claims 5-methoxy-2- [[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]- 1 H-benzimidazole

(omeprazole) containing less than three parts per million (p.p.m) of residual aromatic hydrocarbon solvent and less than 20 p.p.m of residual methanol relative to omperazole.

Thus, there is a need to provide a process for the preparation of omeprazole with higher residual methanol greater than 20 ppm and well within the standards of ICH guidelines. Also, the purity of omeprazole is very essential and hence, the process of the present invention provides omeprazole with all the known and unknown individual impurities well within the phamacopial limits.

The polymorphism is an important criteria for omperazole. U.S. Patent No. 6,150,380 discloses two polymorphic forms of Omeprazole. Form A and Form B. Form A and Form B are characterized by XRD, Raman Spectra, single crystal, IR etc. analytical evidences. According, to the disclosure in US '380, the single crystal data and the molecular structure prepared according to EP 5129 and as disclosed in Acta Cryst. (1989), C45, 1921-1923 by Ohishi et al. is omeprazole Form-B. Eur. Patent No. 1,390,360 claims yet another crystalline Form of omeprazole i.e. omeprazole Form C characterized by X-ray powder diffraction pattern exhibiting the d-spacings, single crystal analysis and IR. Also claimed is the process for the preparation of omeprazole Form C by dissolving crude omeprazole in a solvent or a mixture of solvents in which omeprazole is freely soluble, and precipitating Omeprazole Form C with a solvent in which omeprazole is poorly soluble.

WO 2007008588 A2 discloses the process for the preparation of omeprazole Form-B free from Form-A after being kept under stability for 3 to 6 months at 2°C to 80C at 60% RH. Thus, there is still a need to provide a process for preparing omeprazole form-B substantially free from other crystalline forms and having purity of atleast 99.75% by HPLC and meeting the pharmacopial requirements for individual impurities. Objects of the Invention It is an object of the present invention to overcome or substantially ameliorate one or more of the disadvantages of the prior art or at least to provide a useful alternative.

It is another object of the invention to provide a one-pot process for preparing omeprazole of formula (I). It is another object of the present invention to provide a one-pot process for manufacturing of omeprazole by using 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) and 2-mercapto-5-methoxy benzimidazole of formula (III) as the starting material.

Summary of Invention:

According to the first aspect of the present invention, there is provided one pot process for preparing omeprazole of formula (I)

Figure imgf000007_0001
which comprises of: (a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in organic solvent in presence of base to obtain 5-methoxy-2-((4-methoxy-3,5- dimethylpyridin-2-yl)methyl -thio)-lH-benzo[d]midazole of formula (II);

Figure imgf000007_0002

(b) in-situ oxidizing 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)- lH-benzo[d] imidazole of formula (II) with an oxidizing agent in presence of catalyst in organic solvent to obtain omeprazole of formula (I). According to the another aspect of the present invention, there is provided one pot process for preparing omeprazole of formula (I)

Figure imgf000008_0001
which comprises of: (a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in C1-C4 alkyl acetate solvent in presence of base to obtain 5-methoxy-2-((4-methoxy-3,5- dimethylpyridin-2-yl) methylthio)-lH-benzo[d]imidazole of formula (II);

Figure imgf000008_0002

(b) in-situ oxidizing 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)- lH-benzo[d] imidazole of formula (II) with an oxidizing agent in presence of catalyst in C1-C4 alkyl acetate solvent to obtain omeprazole of formula (I);

According to the second aspect of the present invention, there is provided one- pot process for preparing 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of Formula (I') or its pharmaceutically acceptable salt, hydrate, or solvate thereof

Figure imgf000008_0003
wherein Ri is selected from the group consisting of hydrogen or substituted or unsubstituted Q-C-^alkoxy; R2 and R4 are independently selected from the group consisting of hydrogen, Ci-C4alkyl or Ci-C4alkoxy; R3 is selected from the group consisting of substituted or unsubstituted Ci-C4alkoxy; which comprises of:

(a) reacting 2-chloromethyl-substituted pyridine hydrochloride of formula (FV") with 2-mercapto-5-substituted benzimidazole of formula (IH') in Ci-C4 alkyl acetate solvent in presence of base to obtain 5-methoxy-2-((4-methoxy-3,5- dimethylpyridin-2-yl) methylthio)-lH-benzo[d] imidazole of formula (H');

Figure imgf000009_0001

(b) in-situ oxidizing thioether compound of formula (H') with suitable oxidizing agent formed by the reaction product of hydrogen peroxide and a catalyst in Ci-C4 alkyl acetate solvent; and wherein Rj, R2, R3 and R4 is same as described above,

(c) isolating 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

According to another aspect of the present invention, there is provided one pot process for preparation of a crystalline omeprazole form-B, characterized by having atleast one of the following properties:

(a) a powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure I; and/or

(b) a powder x-ray diffraction (PXRD) having characteristic peaks at about 9.6, 8.9, 8.0, 7.8, 7.0, 5.9, 5.6, 5.2, 5.0, and 4.4 d-values ±0.04 (A)

(c) a melting point in the range of about 156°C to about 159°C; and/or

(d) differential scanning calorimetric (DSC) theromgram substantially in accordance with Figure II and having endothermic peak at about 158.30C; and/or

(e) an Infrared (IR) absorption spectrum in potassium bromide comprising peaks at about 545, 821, 1011, 1017, 1202, 1407, 1587, 3006, 3061 ± 5 cm 1

(f) an Infrared (IR) spectrum substantially in accordance with Figure IH. Brief Description of Drawings The above and other objects and features of the present invention will become apparent from the following description of the invention taken in conjunction with the following accompaying drawings, which respectively show:

FIG. 1: X-ray diffraction pattern of omeprazole Form-B as obtained in example 1. FIG. 2: Differential Scanning Calorimetry analysis of omeprazole Form-B as obtained in example 1. FIG. 3: Infrared spectra analysis of omeprazole Form-B as obtained in example 1. Detailed Description of the Invention:

The present invention provides an one pot process for preparing omeprazole of formula (I)

Figure imgf000010_0001
which comprises of:

(a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in organic solvent in presence of base to obtain 5-methoxy-2-((4-methoxy-3,5- dimethylpyridin-2-yl)methyl -thio)-lH-benzo[d]midazole of formula (II);

Figure imgf000010_0002

(b) in-situ oxidizing 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)- lH-benzo[d] imidazole of formula (II) with an oxidizing agent in presence of catalyst in organic solvent to obtain omeprazole of formula (I). Further the present invention provides an one pot process for preparing omeprazole of formula (I)

Figure imgf000010_0003
which comprises of:

(a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in Ci-C4 alkyl acetate solvent in presence of base to obtain 5-methoxy-2-((4-methoxy-3,5- dimethylpyridin-2-yl) methylthio)-l H-benzo[d] imidazole of formula (II);

Figure imgf000011_0001

(b) in-situ oxidizing 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)- lH-benzo[d] imidazole of formula (H) with an oxidizing agent in presence of catalyst in C1-C4 alkyl acetate solvent to obtain omeprazole of formula (I). Preferably, the one pot process for preparing omeprazole of formula (I)

Figure imgf000011_0002
which comprises of:

(a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in C1-C4 alkyl acetate solvent in presence of base to obtain 5-methoxy-2-((4-methoxy-3,5- dimethylpyridin-2-yl) methylthio)-lH-benzo[d]imidazole of formula (II);

Figure imgf000011_0003

(b) in-situ oxidizing 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)- lH-benzo[d]imidazole of formula (II) with an oxidizing agent in presence of catalyst in C1-C4 alkyl acetate solvent in absence of base at about -1O0C to 5O0C;

(c) isolating omeprazole of formula (I);

(d) optionally, purifying said omeprazole by treating with base in a suitable organic solvent;

(e) treating with weak acid; and

(f) isolating omeprazole of formula ( 1 ).

According to an embodiment of the present invention, C1-C4 alkyl acetate solvent can be selected from ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate and the like, preferably ethyl acetate. The condensation can be carried out in presence of base selected from alkali metal or alkaline earth metal hydroxide, alkoxide, carbonates, bicarbonates, hydrides or ammonia and the like.

According to an embodiment of the present invention, the base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or ammonia, preferably sodium hydroxide.

According to an embodiment of the present invention, oxidizing agent can be selected from m-chlorperbenozic acid, hydrogen peroxide, N-chlorosuccinimide, N- bromosuccinimide, vanadium acetlacetonate and the like. The preferred oxidizing agent is 49% solution of hydrogen peroxide.

Suitable catalyst can be selected from (P(W3OiO)4 X-H2O; ammonium

Molybdate, having the formula -(NHj)2MoO4; sodium Molybdate, having the formula

Na2MoO4, sodium tungstate, having the formula Na2 WO4; phosphomolybdic acid, having the formula H3(P(Mo3OiO)4-XH2O; and silicotungstic acid, having the formula

H4(Si(W3OiO)4-XH2O, preferably sodium Molybdate, having the formula Na2MoO4.

According to the present invention, hydrogen peroxide in presence of suitable catalyst itself generates the oxidizing agent. The reaction is preferably carried out in absence of base in an organic solvent for the oxidation of thioether linkage in order to obtain highly pure 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of formula (II).

According to another embodiment of the present invention, in-situ oxidation of thioether compound of formula (II) is carried out Ci-C4 alkyl acetate solvent inactive to compound of formula (II), or Formula (I). Preferably oxidation is carried out in ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate and the like, preferably ethyl acetate.

Suitable catalyst can be selected from (P(W3OiO)4-X-H2O; ammonium

Molybdate, having the formula (NHU)2MoO4; sodium Molybdate, having the formula

Na2MoO4, sodium tungstate, having the formula Na2WO4; phosphomolybdic acid, having the formula H3(P(Mo3OiO)4-XH2O; and silicotungstic acid, having the formula H4(Si(W3OiO)4-XH2O, preferably sodium Molybdate, having the formula Na2MoO4.

The substantially pure compound of formula (I) is further isolated by well know techniques used in the art such as filtration, concentration followed by drying.

The said solution of compound of formula (II) is oxidized with 50% hydrogen peroxide in presence of sodium molybdate catalyst. The reaction is preferably carried out at temperature of -10 to 50° C. More preferably, the reaction is carried out at about 0° to 5°C. The complete reaction time is about 10 minutes to about 3 hours to obtain omeprazole crude.

Upon completion of the reaction, the product is isolated by filtration and washed with suitable organic solvent or mixture thereof with water. Suitable organic solvent can be selected from alcoholic solvent like methanol, ethanol, isopropanol, propanol, ethyl acetate, butyl acetate, isopropyl acetate etc, preferably mixture of methanol and water followed by ethyl acetate to obtain optimum result in terms of better purity and better yield. Optionally, the isolated omeprazole is purified by treating with base selected from alkali metal or alkaline earth metal hydroxides like sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium hydroxide and the like, alkali metal or alkaline earth metal carbonates or bicarbonates like sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate and the like, preferably sodium hydroxide.

The reaction of omeprazole with base can be carried out in suitable organic solvent selected from alcohols like methanol, ethanol, isopropanol, n-propanol, n- butanol, isobutanol; hydrocarbons like toluene, xylene, ethylbenzene; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran; esters like ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate; dimethylformamide, dimethyl sulfoxide or mixture thereof with water, preferably methanol or mixture thereof with water.

The pure omeprazole is isolated by treating the reaction mixture with weak acid like acetic acid.

Thus obtain omeprazole is crystalline Form-B which is characterized by a powder x-ray diffraction (PXRD) having characteristic peaks at about 9.7, 8.0, 7.9, 7.1, 5.9, 5.6, 5.3, 5.1, and 4.5 d-values ±0.04 (A).

Further, crystalline omeprazole Form-B is characterized by differential scanning calorimetry analysis having endothermic peak at about 158.3°C.

A crystalline omeprazole Form-B is also characterized by IR having characteristic peaks at about 545, 821, 1011, 1017, 1202, 1407, 1587, 3006, 3061 ± 5 cm"1. A crystalline omeprazole form-B prepared by the process of the present invention is having particle size distribution Dio less than about 10 μm, D50 less than about 20 μm and D90 less than about 50 μm.

The purity by high-performance liquid chromatography and residual solvent by gas chromatography can be performed by using the known methods as disclosed in U.S. Patents No. 6,191,148, 6,166,213 and 6,147,103 are incorporated herein as reference.

The HPLC purity of omeprazole form-B obtained in the following examples were determined by following HPLC (high performance liquid chromatography) conditions listed below: column: - Zorbax SB C8 (150x4.6 mm, 5 μ) flow rate : - 1.0 mIVmin wavelength : - 280 nm oven temp: - 25°C Buffer : - 1.4 g Na2HPO4 -» 1000 mL with water, pH 7.8 with OPA (orthophosphoric acid)

Mobile Phase : - Buffer : Acetonitrile:::76:24 Diluent: - Mobile Phase

According to the another preferred embodiment, there is provided one-pot process for preparing 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of Formula (I) or its pharmaceutically acceptable salt, hydrate, or solvate thereof

Figure imgf000014_0001
wherein Ri is selected from the group consisting of hydrogen or substituted or unsubstituted C1.C4a.koxy; R2 and R» are independently selected from the group consisting of hydrogen, Ci-C4alkyl or Ci-C4alkoxy; R3 is selected from the group consisting of substituted or unsubstituted Q-C4alkoxy; which comprises of:

(a) reacting 2-chloromethyl-3,4,5-substituted pyridine hydrochloride of formula (IV) with 2-mercapto-5 -substituted benzimidazole of formula (IIP) in C1-C4 alkyl acetate solvent in presence of base to obtain thioether compound of formula (H')

Figure imgf000015_0001

(b) in-situ oxidizing thioether compound of formula (H');

Figure imgf000015_0002
wherein Ri, R2, R3 and R4 is same as described above, with suitable oxidizing agent formed by the reaction product of hydrogen peroxide and a catalyst in absence of base in Ci-C4 alkyl acetate solvent at about -100C to 500C; and (c) isolating 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles of Formula (I') or its pharmaceutically acceptable salt, hydrate, or solvate thereof In the case where Ri represents substituted alkoxy substantially as hereinbefore described, suitable substituents is selected from the group consisting of hydrogen or substituted or unsubstituted Q-C4 alkoxy, especially methoxy.

In the case where R3 represents substituted alkoxy substantially as hereinbefore described, suitable substituents one or more alkoxy substituents, such as C1-C3 alkoxy, especially methoxy.

In the preferred embodiment, Ri is selected from hydrogen atom, methoxy group or difluoromethoxy group; represents methyl group or methoxy group; R2 represents methyl group or methoxy group; R3 represents methoxy group, or 2,2,2- trifluoroethoxy group; and R4 represents hydrogen atom or methyl group. A preferred compound prepared according to a process of the present invention is lansoprazole, wherein in formula (I) R4 represents methyl, R3 represents trifluoroethoxy, R2 represents hydrogen and Ri represents hydrogen.

A further preferred compound prepared according to a process of the present invention is omeprazole, wherein in formula (I) R4 represents methyl, R3 represents methoxy, R2 represents methyl and Ri represents methoxy.

A further preferred compound prepared according to a process of the present invention is pantoprazole, wherein in formula (I) R4 represents methoxy, R3 represents methoxy, R2 represents hydrogen and Ri represents difluoromethoxy. A further preferred compound prepared according to a process of the present invention is rabeprazole, wherein in formula (I) R4 represents methyl, R3 represents - OCH2CH2CH2OMe, R2 represents hydrogen and Ri represents hydrogen.

According to the important embodiment of the present invention, there is provided one pot process for the preparation of crystalline omeprazole Form-B of formula (I) comprises of:

(a) reacting 2-chloromethyl-3,4,5-substituted pyridine hydrochloride of formula (IV) with 2-mercapto-5 -substituted benzimidazole of formula (HI) in presence of sodium hydroxide in ethyl acetate to obtain 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin- 2-yl)methylthio)- 1 H-benzo[d] imidazole of formula (II);

(b) in-situ oxidizing 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)- lH-benzo[d] imidazole of formula (II) with 50% hydrogen peroxide in presence of sodium molybdate catalyst in ethyl acetate at 00C to 5°C to obtain omeprazole;

(c) purifying crude omeprazole using aqueous sodium hydroxide followed by treatment with acetic acid; and

(d) drying omeprazole wet-cake at 400C to 450C to isolate omeprazole of formula (I).

According to the embodiment, the one pot process for the preparation of crystalline omeprazole Form-B of formula (I) having total reaction time of less than 35 hours is in the batch sizes of greater than 30 Kg cyrstalline omeprazole Form-B.

According to the embodiment, the one pot one pot process for the preparation of crystalline omeprazole Form-B of formula (I) having total reaction time of less than 35 hours is in the batch sizes of greater than 50 Kg cyrstalline omeprazole Form-B.

According to the present invention, one pot process for the preparation crystalline omeprazole Form B of formula (I) can be illustrated by below mentioned scheme- 1, which should not be considered as limiting the scope of the invention.

Figure imgf000017_0001

Oxidation

Figure imgf000017_0002

Scheme- 1 S Examples

While the present invention is described with respect to particular examples and preferred embodiments, it is understood that the present invention is not limited to these examples and embodiments. The present invention, therefore, includes variations form0 the particular examples embodiments described herein, as will be applicant to one of skill in the art.

Exam pie- 1:

Preparation of 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-5 pyridinyl)methyl]sulfinyl]-lH-benzimidazole (Omeprazole) (I)

2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV) (100.0 g) and 2-mercapto-5-methoxy benzimidazole (III) (81.0 g) were taken in RBF. Ethyl Acetate (400 mL) was added to RBF at 25°C to 350C. Sodium hydroxide (50.0 g) solution in water (200 mL) was added to the reaction mass within 30 mins. The reaction0 mass was stirred for 1 hr and heated to 500C to 55°C for 1 hr. After completion of the reaction on TLC, reaction mass was cooled to 250C to 300C. Water (200 mL) was added and stirred to separate the organic and aqueous layers. Aqueous layer was extracted with ethyl acetate (150 mL) and separated. The combined ethyl acetate layer was charcaolised (5.0 g) and stirred for 30 mins. The reaction mass was filtered through hyflow bed and washed with ethyl acetate (50 mL). The pH of the organic layer was adjusted to about 6.0 to 6.5 with acetic acid (0.5 mL) and cooled to 5°C to 100C.

Sodium molybdate (1.33 g) solution in water (13.2 mL) was added to the reaction mass and stirred for 15 mins. 50% hydrogen peroxide (37.0 g) was added into the reaction mass within 1.5 hrs at 5°C to 12°C. The reaction mass was stirred for 5 hrs.

After completion of the reaction on TLC, the reaction mass is treated with sodium thiosulphate (11.0 g) solution in water (11.0 mL). Sodium hydroxide (6.0 g) solution in water (6 mL) was added into the reaction mass to adjust the pH of about 7.0 to 7.5. The reaction mass was further cooled to 00C to 5°C and stirred for 60 mins. The product was filtered and washed with mixture of methanol (50 mL) and water (50 mL) followed by washing with chilled ethyl acetate (75 mL).

Crude omeprazole (120.0 g) wet-cake as obtained above and methanol (160 mL) were taken in another RBF at 25°C to 35°C. Sodium hydroxide (15.8 g) solution in water (176 mL) was added into the reaction mass. Charcaol (2.6 g) was added and stirred for 30 mins. The reaction mass was filtered on hyflow bed and washed with mixture of methanol (10 mL) and water (10 mL). The filtrate was treated with sodium hydrosulphite (2.0 g). The reaction mass was slowly treated with acetic acid (22.5 mL) to adjust the pH of about 7.5 to 7.9. The product was filtered and washed with water

(244 mL) and dried at 400C to 45°C to obtain 100.0 g crystalline omeprazole Form B. Yield 68% based on input 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV).

HPLC purity: 99.87%

Individual Impurities are as under:

Im purity- A at RRT 0.44 : 0.01% Impurity-B at RRT 0.46 : Not detected

Impuriry-C at RRT 0.80 : 0.02%

Impurity-D at RRT 0.90 : Not detected

Impurity-E at RRT 3.26 : Not detected

Unk Impurity: 0.03% Total Impurities : 0.13%

Impurity-A: 5-methoxy- 1 H-benzimidazole-2-thiol

Impurity-B: 2-[(R,S)]-[(3,5-dimethylpyridine-2-yl)methyl]sulphinyl]-5-methoxy-lH- benzimidazole Impurity-C: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphanyl]- lH-benzimidazole [Omeprazole Sulfide]

Impurity-D: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]suIphonyl]- lH-benzimidazole [Omeprazole Sulfone] Impurity-E: 4-methoxy-2-[[(R,S)-(5-methoxy- 1 H-benzimidazole-2-yl)- sulphinyl]methyl)-3,5-dimethylpyridine- 1 -oxide [Omeprazole N-Oxide]

Advantages of Invention:

1) The present invention provides one pot process for the preparation of Omeprazole Form-B.

2) The present invention provides one pot for the preparation of Omeprazole Form-B having total reaction time of less than about 35 hours and purity of atleast 99.70% but not more than 99.90% by area percentage of HPLC.

3) The present invention provides an improved process for the purification of crude omeprazole to obtain polymorphic Form-B.

4) The present invention provides a simple, cost effective and large scale applicable process for the preparation of omeprazole Form-B in batch size of 30 Kg, preferably 50 Kg.

5) The present invention is very simple with shorter reaction time for large-scale production cycle.

Claims

Claims:
1. One pot process for preparing omeprazole of formula (I)
Figure imgf000020_0001
which comprises of: (a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in organic solvent in presence of base to obtain 5-methoxy-2-((4-methoxy-3,5- dimethylpyridin-2-yl)methyl-thio)- 1 H-benzo[d]midazole of formula (II);
Figure imgf000020_0002
(b) in-situ oxidizing 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)- lH-benzo[d]imidazole of formula (II) with an oxidizing agent in presence of catalyst in organic solvent to obtain omeprazole of formula (I).
2. A process according to claim 1, wherein organic solvent is ethyl acetate.
3. One pot process for preparing omeprazole of formula (I)
Figure imgf000020_0003
which comprises of:
(a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in C1-C4 alkyl acetate solvent in presence of base to obtain 5-methoxy-2-((4-methoxy-3,5- dimethylpyridin-2-yl) methylthio)-lH-benzo[d]imidazole of formula (II);
Figure imgf000021_0001
(b) in-situ oxidizing 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)- lH-benzo[d] imidazole of formula (II) with an oxidizing agent in presence of catalyst in Ci-C4 alkyl acetate solvent to obtain omeprazole of formula (I).
4. One pot process for preparing omeprazole of formula (I)
Figure imgf000021_0002
which comprises of:
(a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of formula (IV) with 2-mercapto-5-methoxy benzimidazole of formula (III) in Ci-C4 alkyl acetate solvent in presence of base to obtain 5-methoxy-2-((4-methoxy-3,5- dimethylpyridin-2-yl) methylthio)-lH-benzo[d] imidazole of formula (II);
Figure imgf000021_0003
(b) in-situ oxidizing 5-methoxy-2-((4-methoxy-3,5-dimethyIpyridin-2-yl)methylthio)- lH-benzo[d] imidazole of formula (II) with an oxidizing agent in presence of catalyst in Ci-C4 alkyl acetate solvent in absence of base at about -100C to 500C;
(c) isolating omeprazole of formula (I);
(d) optionally, purifying said omeprazole by treating with base in a suitable organic solvent;
(e) treating with weak acid; and
(f) isolating omeprazole of formula (1).
5. A process according to claims 2-3, wherein Ci-C4 alkyl acetate solvent can be selected from ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate and the like, preferably ethyl acetate.
6. A process according to any one of claims 1-3, wherein base is selected from alkali metal or alkaline earth metal hydroxide, alkoxide, carbonates, bicarbonates, hydrides or ammonia and the like.
7. A process according to claim 6, wherein base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or ammonia.
8. A process to claims 1-3, wherein oxidizing agent is selected from m- chloroperbenzoic acid, hydrogen peroxide, N-chlorosuccinimide, N- bromosuccinimide, vanadium acetlacetonate and the like.
9. A process according to claims 1-3, wherein catalyst is selected from (P(W3O io)4.X.H20; ammonium Molybdate, having the formula (NFLt)2MoO4; sodium Molybdate, having the formula Na2MoO4, sodium tungstate, having the formula Na2WO4; phosphomolybdic acid, having the formula H3(P(Mθ3θio)4.XH20; and silicotungstic acid, having the formula
H4(Si(WsOiO)4-XH2O, preferably sodium Molybdate, having the formula Na2MoO4
10. A process according to claim 3 (d), wherein suitable organic solvent is selected from alcohols like methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; hydrocarbons like toluene, xylene, ethylbenzene; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran; esters like ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate; dimethylformamide, dimethyl sulfoxide or mixture thereof with water.
11. A process according to claim 10, wherein suitable solvent is methanol or mixture thereof with water.
12. A process according to claim 3 (d), wherein base can be selected from alkali metal or alkaline earth metal hydroxides like sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium hydroxide and the like, alkali metal or alkaline earth metal carbonates or bicarbonates like sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate and the like, preferably sodium hydroxide.
13. A process according to claim 3 (f), wherein weak acid is acetic acid.
14. A process according to any preceding claims, wherein isolated omeprazole is crystalline Form-B characterized by having atleast one of the following properties: (a) a powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure I; and/or
(b) a powder x-ray diffraction (PXRD) having characteristic peaks at about 9.6, 8.9, 8.0, 7.8, 7.0, 5.9, 5.6, 5.2, 5.0, and 4.4 d-values ±0.04 (A) (c) a melting point in the range of about 156°C to about 159°C; and/or
(d) differential scanning calorimetric (DSC) theromgram substantially in accordance with Figure II and having endothermic peak at about 158.3°C; and/or
(e) an Infrared (IR) absorption spectrum in potassium bromide comprising peaks at about 545, 821, 1011, 1017, 1202, 1407, 1587, 3006, 3061 ± 5 cm"1 (f) an Infrared (IR) spectrum substantially in accordance with Figure III.
15. Crystalline omeprazole form-B according to claim 14, having purity of atleast
99.70% but not more than 99.90% by area percentage of HPLC and having individual impurities as below: impurity-A not more than about 0.05%, impurity-B not in detectable amount, impurity-C not more than 0.05%, impurity-D not in detectable amount, impurity-E not in detectable amount, impurity 8-methoxy- 1,3 -dimethyl- 12-thixopyrido-
[r,2':3,4]imdazo[l,2'-a]- benzimidazol-2(12H)-one and impurity 9-methoxy-l,3- dimethyl- 12-thioxopyrido [ 1 ',2':3,4]imidazo[ 1 ,2-a]benzimidazole-2[ 12H]-one not in detectable amount by area percentage of HPLC.
16. A process according to any preceding claim, wherein crystalline omeprazole form-
B prepared by the process of the present invention is having particle size distribution Di0 less than about 10 μm, D50 less than about 20 μm and D90 less than about 50 μm.
17. A process according to any preceding claim, wherein crystalline omeprazole Form- B is prepared in the batch sizes of greater than 30 Kg.
18. A process according to claim 17, wherein crystalline omeprazole Form-B is prepared in the batch sizes of greater than 50 Kg.
19. A process for preparing 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of formula (I') or a pharmaceutically acceptable salt, hydrate, or solvate thereof,
Figure imgf000023_0001
wherein Rt is selected from the group consisting of hydrogen or substituted or unsubstituted Q.Qalkoxy; R2 and R4 are independently selected from the group consisting of hydrogen, Cι-C4alkyl or Ci-C4alkoxy; R3 is selected from the group consisting of substituted or unsubstituted Q-C4alkoxy; which comprises of:
(a) reacting 2-chloromethyl-3,4,5-substituted pyridine hydrochloride of formula (IV) with 2-mercapto-5-substituted benzimidazole of formula (HI') in Ci-C4 alkyl acetate solvent in presence of base to obtain thioether compound of formula (H')
Figure imgf000024_0001
(b) in-situ oxidizing thioether compound of formula (H');
Figure imgf000024_0002
wherein Ri, R2, R3 and R4 is same as described above, with suitable oxidizing agent formed by the reaction product of hydrogen peroxide and a catalyst in absence of base in Ci-C4 alkyl acetate solvent at about -100C to 500C; and (c) isolating 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles of Formula (V) or its pharmaceutically acceptable salts, hydrates or solvate thereof.
20. A process according to claim 19, wherein Ri represents substituted alkoxy substantially as hereinbefore described, suitable substituents is selected from the group consisting of hydrogen or substituted or unsubstituted Ci-C4 alkoxy, especially methoxy.
21. A process according to claim 19, wherein R3 represents substituted alkoxy substantially as hereinbefore described, suitable substituents one or more alkoxy substituents, such as C1-C3 alkoxy, especially methoxy.
22. A process according to claim 19, wherein Ri is selected from hydrogen atom, methoxy group or difluoromethoxy group; represents methyl group or methoxy group; R2 represents methyl group or methoxy group; R3 represents methoxy group, or 2,2,2-trifluoroethoxy group; and R4 represents hydrogen atom or methyl group.
23. A process according to claim 19, wherein compound prepared according to a process of the present invention is lansoprazole, wherein in formula (I) R4 represents methyl, R3 represents trifluoroethoxy, R2 represents hydrogen and Ri represents hydrogen.
24. A process according to claim 19, wherein compound prepared according to a process of the present invention is omeprazole, wherein in formula (I) R4 represents methyl, R3 represents methoxy, R2 represents methyl and Ri represents methoxy.
25. A process according to claim 19, wherein compound prepared according to a process of the present invention is pantoprazole, wherein in formula (I) R4 represents methoxy, R3 represents methoxy, R2 represents hydrogen and Ri represents difluoromethoxy.
26. A process according to claim 19, wherein compound prepared according to a process of the present invention is rabeprazole, wherein in formula (I) R4 represents methyl, R3 represents -OCH2CHaCH2OMe, R2 represents hydrogen and Ri represents hydrogen.
27. A process of preparing crystalline omeprazole Form-B substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompaying drawings and/or examples.
PCT/IN2010/000344 2009-05-21 2010-05-21 One pot process for preparing omeprazole and related compounds WO2010134099A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603621A (en) * 2012-02-07 2012-07-25 成都苑东药业有限公司 Novel chiral sulfoxide compound and method for preparing esomeprazole by using novel chiral sulfoxide compound
CN102993181A (en) * 2012-12-26 2013-03-27 寿光富康制药有限公司 Preparation method of esomeprazole and preparation method of esomeprazole salt

Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2069492A (en) 1980-02-20 1981-08-26 Wyeth John & Brother Ltd Novel sulphur compounds
CA1127158A (en) 1978-04-14 1982-07-06 Ulf K. Junggren 2-pyridylmethylsulfinyl-benzimidazole compounds
US4628098A (en) 1984-08-16 1986-12-09 Takeda Chemical Industries, Ltd. 2-[2-pyridylmethylthio-(sulfinyl)]benzimidazoles
CA1263119A (en) 1987-08-04 1989-11-21 Masayasu Kato Production of 2-(2- pyridylmethylsulfinyl)benzimidazole compounds
US5045552A (en) 1986-11-13 1991-09-03 Eisai Co., Ltd. Pyridine derivatives having anti-ulcerative activity
WO1991018895A1 (en) 1990-06-07 1991-12-12 Aktiebolaget Astra Improved method for synthesis
EP0484265A1 (en) 1990-10-31 1992-05-06 Centro Genesis Para La Investigacion, S.L. A process for the preparation of omeprazol
EP0533264A1 (en) 1991-09-20 1993-03-24 Merck & Co., Inc. Process for the preparation of anti-ulcer agents
US5374730A (en) 1993-11-04 1994-12-20 Torcan Chemical Ltd. Preparation of omeprazole and lansoprazole
US6147103A (en) 1998-08-11 2000-11-14 Merck & Co., Inc. Omeprazole process and compositions thereof
US6150380A (en) 1998-11-10 2000-11-21 Astra Aktiebolag Crystalline form of omeprazole
US6191148B1 (en) 1998-08-11 2001-02-20 Merck & Co., Inc. Omerazole process and compositions thereof
US6313303B1 (en) 1997-07-11 2001-11-06 Eisai Co., Ltd. Process for the preparation of pyridine derivatives
US20030036554A1 (en) * 2001-02-02 2003-02-20 Ilya Avrutov Processes for the production fo substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles
RU2215739C1 (en) 2002-04-03 2003-11-10 Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" Method for preparing 5-methoxy-2-(4-methoxy-3,5-dimethyl-2- pyridylmethylthio)-benzimidazole
EP1390360A1 (en) 2001-04-25 2004-02-25 Lek Pharmaceutical and Chemical Co. D.D. Crystalline form of omeprazole
WO2004035565A1 (en) 2002-10-18 2004-04-29 Astrazeneca Ab Method for the synthesis of a benzimidazole compound
WO2007008588A2 (en) 2005-07-07 2007-01-18 Dr. Reddy's Laboratories Ltd. Omeprazole form b
WO2007086077A2 (en) * 2006-01-24 2007-08-02 Unichem Laboratories Limited A novel one pot process for preparation of pantoprazole sodium sesquihydrate
WO2009010937A1 (en) * 2007-07-17 2009-01-22 Ranbaxy Laboratories Limited Process for the preparation op pantoprazole sodium and pantoprazole sodium sesquihydrate

Patent Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1127158A (en) 1978-04-14 1982-07-06 Ulf K. Junggren 2-pyridylmethylsulfinyl-benzimidazole compounds
US4508905A (en) 1978-04-14 1985-04-02 Aktiebolaget Hassle Substituted 2-(-benzimidazolyl)pyridines
GB2069492A (en) 1980-02-20 1981-08-26 Wyeth John & Brother Ltd Novel sulphur compounds
US4628098A (en) 1984-08-16 1986-12-09 Takeda Chemical Industries, Ltd. 2-[2-pyridylmethylthio-(sulfinyl)]benzimidazoles
US5045552A (en) 1986-11-13 1991-09-03 Eisai Co., Ltd. Pyridine derivatives having anti-ulcerative activity
CA1263119A (en) 1987-08-04 1989-11-21 Masayasu Kato Production of 2-(2- pyridylmethylsulfinyl)benzimidazole compounds
WO1991018895A1 (en) 1990-06-07 1991-12-12 Aktiebolaget Astra Improved method for synthesis
EP0484265A1 (en) 1990-10-31 1992-05-06 Centro Genesis Para La Investigacion, S.L. A process for the preparation of omeprazol
EP0533264A1 (en) 1991-09-20 1993-03-24 Merck & Co., Inc. Process for the preparation of anti-ulcer agents
US5374730A (en) 1993-11-04 1994-12-20 Torcan Chemical Ltd. Preparation of omeprazole and lansoprazole
US6313303B1 (en) 1997-07-11 2001-11-06 Eisai Co., Ltd. Process for the preparation of pyridine derivatives
US6147103A (en) 1998-08-11 2000-11-14 Merck & Co., Inc. Omeprazole process and compositions thereof
US6166213A (en) 1998-08-11 2000-12-26 Merck & Co., Inc. Omeprazole process and compositions thereof
US6191148B1 (en) 1998-08-11 2001-02-20 Merck & Co., Inc. Omerazole process and compositions thereof
US6150380A (en) 1998-11-10 2000-11-21 Astra Aktiebolag Crystalline form of omeprazole
US20030036554A1 (en) * 2001-02-02 2003-02-20 Ilya Avrutov Processes for the production fo substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles
EP1390360A1 (en) 2001-04-25 2004-02-25 Lek Pharmaceutical and Chemical Co. D.D. Crystalline form of omeprazole
RU2215739C1 (en) 2002-04-03 2003-11-10 Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" Method for preparing 5-methoxy-2-(4-methoxy-3,5-dimethyl-2- pyridylmethylthio)-benzimidazole
WO2004035565A1 (en) 2002-10-18 2004-04-29 Astrazeneca Ab Method for the synthesis of a benzimidazole compound
WO2007008588A2 (en) 2005-07-07 2007-01-18 Dr. Reddy's Laboratories Ltd. Omeprazole form b
WO2007086077A2 (en) * 2006-01-24 2007-08-02 Unichem Laboratories Limited A novel one pot process for preparation of pantoprazole sodium sesquihydrate
WO2009010937A1 (en) * 2007-07-17 2009-01-22 Ranbaxy Laboratories Limited Process for the preparation op pantoprazole sodium and pantoprazole sodium sesquihydrate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SHANXI YIKE DAXUE XUEBAO, vol. 34, no. 4, 2002, pages 330 - 332
THE JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUITCALS, vol. 23, no. 1, 1986, pages 21 - 33

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603621A (en) * 2012-02-07 2012-07-25 成都苑东药业有限公司 Novel chiral sulfoxide compound and method for preparing esomeprazole by using novel chiral sulfoxide compound
CN102993181A (en) * 2012-12-26 2013-03-27 寿光富康制药有限公司 Preparation method of esomeprazole and preparation method of esomeprazole salt
CN102993181B (en) 2012-12-26 2014-07-23 山东大学 Preparation method of esomeprazole and preparation method of esomeprazole salt

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