WO2007017244A2 - A PROCESS FOR THE PURIFICATION OF SUBSTITUTED 2-(2-PYRIDYLMETHYL)SULFINYL-lH-BENZIMIDAZOLE COMPOUNDS BY PRECIPITATION IN THE PRESENCE OF A QUATERNARY AMMONIUM SALT - Google Patents
A PROCESS FOR THE PURIFICATION OF SUBSTITUTED 2-(2-PYRIDYLMETHYL)SULFINYL-lH-BENZIMIDAZOLE COMPOUNDS BY PRECIPITATION IN THE PRESENCE OF A QUATERNARY AMMONIUM SALT Download PDFInfo
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- WO2007017244A2 WO2007017244A2 PCT/EP2006/007832 EP2006007832W WO2007017244A2 WO 2007017244 A2 WO2007017244 A2 WO 2007017244A2 EP 2006007832 W EP2006007832 W EP 2006007832W WO 2007017244 A2 WO2007017244 A2 WO 2007017244A2
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- C07D401/00—Heterocyclic 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
- C07D401/02—Heterocyclic 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
- C07D401/12—Heterocyclic 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
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Definitions
- the present invention relates to a new process for the preparation of substituted 2-(2- pyridylmethyl)sulfinyl-1 H-benzimidazole compounds such as lansoprazole, rabeprazole, panteprazole, omeprazole, esomeprazole and salts thereof from a suitable solvent or a mixture of solvents in the presence of a tetra alkyl ammonium compound.
- substituted 2-(2- pyridylmethyl)sulfinyl-1 H-benzimidazole compounds such as lansoprazole, rabeprazole, panteprazole, omeprazole, esomeprazole and salts thereof from a suitable solvent or a mixture of solvents in the presence of a tetra alkyl ammonium compound.
- R1 represents a hydrogen atom, a methoxy group or a difluoromethoxy group
- R2 represents a methyl group or a methoxy group
- R3 represents a 3-methoxypropoxy group, a methoxy group or a 2,2,2-trifluoroethoxy group
- R4 represents a hydrogen atom or a methyl group
- benzimidazole compounds include: omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
- pantoprazole (5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinylJ-
- Substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compounds of formula (I) are usually prepared form corresponding sulfide intermediates by the oxidation of thioether group using different oxidizing agents, e.g. m-chloroperbenzoic acid.
- the preparation of said benzimidazole compounds disclosed in the prior art processes is generally accompanied by the formation of small quantities of the corresponding sulfone derivatives and N-oxide derivatives as impurities.
- unreacted sulfides are present as impurities in final product. Said impurities are very difficult to remove due to their very similar physico-chemical properties.
- US 6,180,652 describes a process for the purification of lansoprazole by preparing acetone complex of the lansoprazole salt, which permits separation of lansprazole from its sulfone derivative.
- WO 2003/008406 describes a process for the preparation of proton pump inhibitors of the benzimidazole-type such as rabeprazole, omeprazole, pantoprazole, lansoprazole and esomeprazole, comprising (a) oxidation of the corresponding sulfide compound followed by extraction of the reaction mixture with an aqueous alkaline solution with a pH ranging from 9.50 to 12.00, removing the water layer, (b) extracting the organic layer with an aqueous alkaline solution having a pH of 13.0 or higher and removing the organic layer, (c) isolating the desired compound from the water layer.
- This is suffering with multiple operations and extractions, hence it limiting to use on commercial scale.
- WO 2004/018454 describes a method for preparing a substantially pure lansoprazole that is free of sulfone and sulfide derivatives and also describes preparing lansoprazole containing less than 0.1% (wt/wt) of water.
- the process disclosed in this patent uses large amounts of amines i.e. weak bases. The use of amines requires an additional acidification step prior to the isolation of lansoprazole. In addition, amines may be rather toxic or tetratogenic, and their use should therefore be avoided.
- WO 2004/072061 provides a stable lansoprazole and a method for stabilizing acid sensitive compounds like lansoprazole by use of a weakly basic material
- the said application also describes a method for the preparation of a stable lansoprazole.
- the said application also describes a method for stabilizing lansoprazole by drying the obtained lansoprazole in the presence of a weakly basic material like an ammonium compound and an amine.
- Lansoprazole and other substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compounds tend to lose crystalline stability and undergo molecular reorientation when contaminated with traces of a solvents, particularly water, in their crystal structure.
- a first object of the present invention is related to a process for the preparation of substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compounds of formula (I) comprising the steps of: (a) providing a slurry of a substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound in a solvent or mixture of solvents comprising a quaternary amine compound,
- the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound is preferably selected from the group consisting of lansoprazole, rabeprazole, pantoprazole, omeprazole, esomeprazole, and is more preferably lansoprazole.
- the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound may be obtained by any process for the preparation thereof known from the prior art.
- the basic process for the preparation of lansoprazole may be outlined as follows.
- the resulting 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2- pyridinil)methyl)]thio]-1H-benzimidazole (formula V) is then oxidized with m- chloroperbenzoic acid to yield the raw 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2- pyridinil)methyl)]sulfinyl]-1H-benzimidazole (formula II).
- the solvent used in step (a) of the process of the present invention is for example an organic solvent or a mixture of organic solvents or is a mixture of one or more organic solvents and water.
- Suitable organic solvents include: (i) polar solvents, for example CVC ⁇ alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, sec-butanol or tert- butanol; (ii) non-polar aprotic solvents, for example aromatic hydrocarbons such as toluene, xylene, e.g. o-xylene, m-xylene, p-xylene and mixtures of different isomers; and (iii) mixtures of two or more of the above-mentioned organic solvents.
- polar solvents for example CVC ⁇ alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, sec-butanol or tert- butanol
- non-polar aprotic solvents for example
- an organic solvent used in step (a) is selected from the group consisting of ethanol, methanol, n-propanol, isopropanol, xylene, toluene and mixtures of two or more of said solvents, more preferably an organic solvent used in step (a) is selected from the group consisting of ethanol, xylene and mixtures thereof.
- the quaternary amine compound of step (a) is a quaternary ammonium hydroxide.
- a quaternary ammonium hydroxide is selected from the group consisting of tetra-Ci-Ce-alkyl ammonium hydroxides; phenyl tri-C t -Ce-alkyl ammonium hydroxides, in particular phenyl trimethyl ammonium hydroxide; and benzyl tri-CrC 6 -alkyl ammonium hydroxides, in particular benzyl trimethyl ammonium hydroxide.
- tetra-d-C ⁇ -alkyl ammonium hydroxide is selected from the group consisting of tetra methyl ammonium hydroxide, tetra ethyl ammonium hydroxide, tetra n-butyl ammonium hydroxide and tetra isobutyl ammonium hydroxide.
- the quaternary ammonium hydroxide is a tetra CrC 4 -alkyl ammonium hydroxide, in particular tetra n-butyl ammonium hydroxide.
- step (a) from about 0.05 to about 0.5 moles, more preferably from about 0.1 to about 0.3 moles, of a quaternary amine compound per mole of the substituted 2-(2- pyridylmethyl)sulfinyl-1H-benzimidazole compound are used in step (a).
- a preferred process according to step (a) comprises the following sub-steps:
- a more preferred process according to step (a) comprises the following sub-steps: (aT) adding the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound to a mixture of xylene and ethanol, and
- a most preferred process according to step (a) comprises the following sub-steps:
- step (b) isolation may involve any conventional methods known from the state of the art, preferably crystallization.
- the crystallization of the compounds of formula (I) may be performed according to methods known in the art.
- a preferred process according to step (b) comprises the following sub-steps: (b1) heating the reaction mixture obtained from step (a), (b2) adding water,
- the reaction mixture is preferably heated to about 40-55 0 C, more preferably to about 45-50 0 C, for about 25 minutes to 2 hours, preferably for about 30 minutes.
- sub-step (b2) water is added in order to obtain a maximum precipitation of the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound.
- sub-step (b3) the reaction mixture is cooled to about -10 0 C to 15°C, preferably to 0-10 0 C 1 under stirring for about 30 minutes to 3 hours, preferably for 1-2 hours.
- An organic solvent or a mixture of solvents used in step (b4) may be one of the solvents or a mixture of solvents mentioned before.
- a preferred solvent in step (b4) is a mixture of xylene and ethanol.
- step (b) comprises the following sub-steps:
- step (b1 " ) heating the reaction mixture obtained from step (a) to about 40-55 0 C, preferably for about 25 minutes to 2 hours,
- a most preferred process according to step (b) comprises the following sub-steps:
- step (b1 " ) heating the reaction mixture obtained from step (a) to about 45-50 0 C, preferably for about 30 minutes, (b2 " ' ) adding from about 15 to 20 % (v/v) of water,
- Crystallization of the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compounds of the present invention by using the method of the present invention is an easy and eco- friendly process for commercially scalable batches and also permits a good separation of said substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound from impurities, especially sulfone and/or sulfide derivatives.
- a drying (step (c)) of the substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compound obtained from step (b) is performed under reduced pressure at, for example, 25-85°C, more preferably at 35-65°C, most preferably at 40-50°C.
- the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound obtained from step (c) contains less than 0.5% (wt/wt) water and in particular less than 0.1% (wt/wt) of water.
- the obtained pure compound after drying (step (c)) may be further purified by the recrystallization from the mixture of an organic solvent and water.
- Suitable organic water miscible solvents include: tetrahydrofuran, methanol, acetone, etc.
- recrystallization of the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound is performed from a mixture of tetrahydrofuran and water.
- substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compounds obtained according to the process of the present invention contain less than about 0.2% (w/w) corresponding sulfone derivative impurities or less than about 0.2% (w/w) corresponding sulfide derivative impurities. More preferably said substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compounds contain less than about 0.2% (w/w) corresponding sulfone derivative impurities and corresponding sulfide derivative impurities together.
- the present relates to a process for the preparation of lansoprazole comprising the steps of: (a * ) condensing 2-mercapto benzimidazole with 2-chloromethyl-3-methyl-4-(2,2,2- trifluoroethoxy)pyridine hydrochloride in an alcoholic solvent in the presence of a base to obtain 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2-pyridinil)methyl)]thio]-1H- benzimidazole, (b')oxidizing obtained 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2-pyridinil)methyl)]thio]-
- step (d “ ) adding about 0.1 to about 0.3 moles of tetra n-butyl ammonium hydroxide per mol of lansoprazole, (e " ) heating the reaction mixture obtained from step (d) to about 45-50 0 C for 30 minutes, (f ' ) adding of water, preferably from about 10 to 30% (v/v) of water,
- the present invention is related to a process as described above, wherein in a further step the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound of formula (I) as obtained after step (c), is formulated into a pharmaceutically acceptable dosage form, in particular wherein said dosage form is a tablet, pill, capsule or injectable.
- Another object of the present invention is related to a process as described above, wherein in a further step lansoprazole as obtained after step (e") or step (i " ) is formulated into a pharmaceutically acceptable dosage form, in particular wherein said dosage form is a tablet, pill, capsule or injectable.
- the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound of formula (I) 1 preferably lansoprazole, obtained by the process of the present invention may be used for the preparation of a variety of pharmaceutical compositions and dosage forms that are of therapeutic uses in treating patients.
- compositions of the present invention contain in addition to the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound of formula (I) one or more pharmaceutically acceptable excipients or carriers.
- the possible excipients include binders, e.g. povidone, gelatin, sucrose, starch mucilage, pregelatinised starch, sorbitol, hydroxypropylmethyl cellulose (HPMC) etc.; disintegrating agents, e.g. microcrystalline cellulose, sodium carboxymethyl cellulose, alginic acid, sodium starch glycollate, corn starch etc.; fillers, e.g.
- the amount of active substance contained in said pharmaceutical compositions of the present invention is generally from 2-40%, preferably from 5-30%, and most preferably 5-20%.
- Dosage forms include solid dosage forms, e.g. tablets, powders, capsules, liquid syrups, suspensions.
- An especially preferred dosage form of the present invention is a tablet.
- Example 1 illustrates the present invention, which are not to be limited in scope by the specific embodiments described herein: Example 1
- the impurities are detected by HPLC using UV detector.
- the method used for the detection of impurities is as follows,
- Eluent B Prepare a filtered and degassed mixture of acetonitrile, water, and triethylamine ( 80:20:5 ). Adjust with phosphoric acid to a PH of 6.0.
- Eluent C Prepare a filtered and degassed mixture of acetonitrile, water, and triethylamine ( 80:20:5 ). Adjust with phosphoric acid to a PH of 10.0.
- Table 1 Amount of impurities present in lansoprazole before and after purification
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Abstract
A process for the preparation of substituted 2-(2-pyridylmethyl) sulfinyl-1H- benzimidazoles compounds from a suitable solvent or a mixture of solvents in the presence of a quaternary ammonium compound.
Description
A process for the preparation of substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compounds
The present invention relates to a new process for the preparation of substituted 2-(2- pyridylmethyl)sulfinyl-1 H-benzimidazole compounds such as lansoprazole, rabeprazole, panteprazole, omeprazole, esomeprazole and salts thereof from a suitable solvent or a mixture of solvents in the presence of a tetra alkyl ammonium compound.
Several substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compounds of formula (I)
wherein R1 represents a hydrogen atom, a methoxy group or a difluoromethoxy group, R2 represents a methyl group or a methoxy group, R3 represents a 3-methoxypropoxy group, a methoxy group or a 2,2,2-trifluoroethoxy group, and R4 represents a hydrogen atom or a methyl group, are known reversible proton (acid) pump inhibitors.
These benzimidazole compounds include: omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
1 H-benzimidazole), - lansoprazole (2-[[[3-methyl-4-(2,212-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-
1 H-benzimidazole), pantoprazole (5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinylJ-
1 H-benzimidazole, and rabeprazole (2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1 H- benzimidazole, as disclosed, for example, in EP 0005129, EP 0066287, EP 0174726, and EP 0268956.
Lansoprazole, represented by Formula (II), is, for example, disclosed by EP 0174726.
(H)
Substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compounds of formula (I) are usually prepared form corresponding sulfide intermediates by the oxidation of thioether group using different oxidizing agents, e.g. m-chloroperbenzoic acid. The preparation of said benzimidazole compounds disclosed in the prior art processes is generally accompanied by the formation of small quantities of the corresponding sulfone derivatives and N-oxide derivatives as impurities. Furthermore, also unreacted sulfides are present as impurities in final product. Said impurities are very difficult to remove due to their very similar physico-chemical properties.
US 6,180,652 describes a process for the purification of lansoprazole by preparing acetone complex of the lansoprazole salt, which permits separation of lansprazole from its sulfone derivative.
WO 2003/008406 describes a process for the preparation of proton pump inhibitors of the benzimidazole-type such as rabeprazole, omeprazole, pantoprazole, lansoprazole and esomeprazole, comprising (a) oxidation of the corresponding sulfide compound followed by extraction of the reaction mixture with an aqueous alkaline solution with a pH ranging from 9.50 to 12.00, removing the water layer, (b) extracting the organic layer with an aqueous alkaline solution having a pH of 13.0 or higher and removing the organic layer, (c) isolating the desired compound from the water layer. This is suffering with multiple operations and extractions, hence it limiting to use on commercial scale.
WO 2004/018454 describes a method for preparing a substantially pure lansoprazole that is free of sulfone and sulfide derivatives and also describes preparing lansoprazole containing less than 0.1% (wt/wt) of water. The process disclosed in this patent uses large amounts of
amines i.e. weak bases. The use of amines requires an additional acidification step prior to the isolation of lansoprazole. In addition, amines may be rather toxic or tetratogenic, and their use should therefore be avoided.
WO 2004/072061 provides a stable lansoprazole and a method for stabilizing acid sensitive compounds like lansoprazole by use of a weakly basic material, the said application also describes a method for the preparation of a stable lansoprazole. The said application also describes a method for stabilizing lansoprazole by drying the obtained lansoprazole in the presence of a weakly basic material like an ammonium compound and an amine.
Lansoprazole and other substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compounds tend to lose crystalline stability and undergo molecular reorientation when contaminated with traces of a solvents, particularly water, in their crystal structure.
Therefore, there is a need for developing a simple, industrial applicable process for the preparation of pure substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compounds and related compounds wherein the product is free of impurities, such as for example sulfone derivatives, N-oxide derivatives and sulphide derivatives, and wherein the product has a reduced water content as well.
Surprisingly, it now has been found that pure substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compounds may be obtained by crystallizing the raw product from a solvent comprising a quaternary amine compound. Said new process does not involve any additional process steps like layer separation, acidification and heating to reflux temperature.
A first object of the present invention is related to a process for the preparation of substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compounds of formula (I) comprising the steps of: (a) providing a slurry of a substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound in a solvent or mixture of solvents comprising a quaternary amine compound,
(b) isolating the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound, and
(c) drying the obtained substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound.
The substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound is preferably selected from the group consisting of lansoprazole, rabeprazole, pantoprazole, omeprazole, esomeprazole, and is more preferably lansoprazole.
The substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound may be obtained by any process for the preparation thereof known from the prior art.
The basic process for the preparation of lansoprazole may be outlined as follows.
LANSOPRAZOLE
2-mercapto benzimidazole (Formula III) is reacted in a first step with 2-chloromethyl-3- methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride (Formula IV) in an alcoholic solvent in the presence of a base. The resulting 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2- pyridinil)methyl)]thio]-1H-benzimidazole (formula V) is then oxidized with m- chloroperbenzoic acid to yield the raw 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2- pyridinil)methyl)]sulfinyl]-1H-benzimidazole (formula II).
The solvent used in step (a) of the process of the present invention is for example an organic solvent or a mixture of organic solvents or is a mixture of one or more organic solvents and water.
Suitable organic solvents include: (i) polar solvents, for example CVC^alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, sec-butanol or tert- butanol; (ii) non-polar aprotic solvents, for example aromatic hydrocarbons such as toluene, xylene, e.g. o-xylene, m-xylene, p-xylene and mixtures of different isomers; and (iii) mixtures of two or more of the above-mentioned organic solvents.
Preferably, an organic solvent used in step (a) is selected from the group consisting of ethanol, methanol, n-propanol, isopropanol, xylene, toluene and mixtures of two or more of said solvents, more preferably an organic solvent used in step (a) is selected from the group consisting of ethanol, xylene and mixtures thereof.
Preferably, the quaternary amine compound of step (a) is a quaternary ammonium hydroxide. Preferably, a quaternary ammonium hydroxide is selected from the group consisting of tetra-Ci-Ce-alkyl ammonium hydroxides; phenyl tri-Ct-Ce-alkyl ammonium hydroxides, in particular phenyl trimethyl ammonium hydroxide; and benzyl tri-CrC6-alkyl ammonium hydroxides, in particular benzyl trimethyl ammonium hydroxide. Preferably, tetra-d-Cβ-alkyl ammonium hydroxide is selected from the group consisting of tetra methyl ammonium hydroxide, tetra ethyl ammonium hydroxide, tetra n-butyl ammonium hydroxide and tetra isobutyl ammonium hydroxide. Most preferably, the quaternary ammonium hydroxide is a tetra CrC4-alkyl ammonium hydroxide, in particular tetra n-butyl ammonium hydroxide.
Preferably, from about 0.05 to about 0.5 moles, more preferably from about 0.1 to about 0.3 moles, of a quaternary amine compound per mole of the substituted 2-(2- pyridylmethyl)sulfinyl-1H-benzimidazole compound are used in step (a).
A preferred process according to step (a) comprises the following sub-steps:
(a1) adding the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound to the afore-mentioned solvent or solvent mixtures, and
(a2) adding the afore-mentioned quaternary ammonium hydroxide, preferably in solution, most preferably as methanol or water solution thereof.
A more preferred process according to step (a) comprises the following sub-steps: (aT) adding the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound to a mixture of xylene and ethanol, and
(a2") adding tetra-Ct-Cβ-alkyl ammonium hydroxide, preferably in solution, most preferably as methanol or water solution thereof.
A most preferred process according to step (a) comprises the following sub-steps:
(aT') adding the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound to a mixture of xylene and ethanol, and
(a2") adding from about 0.1 to about 0.3 moles of tetra n-butyl ammonium hydroxide per mole of the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound, preferably as methanol or water solution thereof.
In step (b), isolation may involve any conventional methods known from the state of the art, preferably crystallization. In general, the crystallization of the compounds of formula (I) may be performed according to methods known in the art. A preferred process according to step (b) comprises the following sub-steps: (b1) heating the reaction mixture obtained from step (a), (b2) adding water,
(b3) cooling the reaction mixture to ambient temperature or below under stirring, and (b4) filtrating the obtained precipitate and washing with an organic solvent or mixture of organic solvents.
In sub-step (b1) the reaction mixture is preferably heated to about 40-550C, more preferably to about 45-500C, for about 25 minutes to 2 hours, preferably for about 30 minutes.
In sub-step (b2) water is added in order to obtain a maximum precipitation of the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound. Preferably from about 10 to 30 % (v/v), more preferably from about 15 to 20 % (v/v), of water is added.
In sub-step (b3) the reaction mixture is cooled to about -100C to 15°C, preferably to 0-100C1 under stirring for about 30 minutes to 3 hours, preferably for 1-2 hours.
An organic solvent or a mixture of solvents used in step (b4) may be one of the solvents or a mixture of solvents mentioned before. A preferred solvent in step (b4) is a mixture of xylene and ethanol.
A more preferred process according to step (b) comprises the following sub-steps:
(b1") heating the reaction mixture obtained from step (a) to about 40-550C, preferably for about 25 minutes to 2 hours,
(b2") adding from about 10 to 30 % (v/v) of water,
(b3*) cooling the reaction mixture to about -100C to 15°C under stirring, preferably for about 30 minutes to 3 hours, and
(b4*) filtrating the obtained precipitate and washing with an organic solvent or a mixture of organic solvents.
A most preferred process according to step (b) comprises the following sub-steps:
(b1") heating the reaction mixture obtained from step (a) to about 45-500C, preferably for about 30 minutes, (b2" ') adding from about 15 to 20 % (v/v) of water,
(b3") cooling the reaction mixture to 0-100C under stirring, preferably for about 1-2 hours, and (b4") filtrating the obtained precipitate and washing with a mixture of xylene and ethanol.
Crystallization of the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compounds of the present invention by using the method of the present invention is an easy and eco- friendly process for commercially scalable batches and also permits a good separation of said substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound from impurities, especially sulfone and/or sulfide derivatives.
Preferably, a drying (step (c)) of the substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compound obtained from step (b) is performed under reduced pressure at, for example, 25-85°C, more preferably at 35-65°C, most preferably at 40-50°C.
Preferably, the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound obtained from step (c) contains less than 0.5% (wt/wt) water and in particular less than 0.1% (wt/wt) of water.
Optionally the obtained pure compound after drying (step (c)) may be further purified by the recrystallization from the mixture of an organic solvent and water. Suitable organic water miscible solvents include: tetrahydrofuran, methanol, acetone, etc. Preferably, recrystallization of the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound is performed from a mixture of tetrahydrofuran and water.
Preferably, substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compounds obtained according to the process of the present invention contain less than about 0.2% (w/w) corresponding sulfone derivative impurities or less than about 0.2% (w/w) corresponding sulfide derivative impurities. More preferably said substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compounds contain less than about 0.2% (w/w) corresponding sulfone derivative impurities and corresponding sulfide derivative impurities together.
A preferred embodiment of the present invention relates to a process for the preparation of lansoprazole comprising the steps of:
(aT) adding lansoprazole to a mixture of xylene and ethanol,
(a2') adding from about 0.1 to about 0.3 moles of tetra n-butyl ammonium hydroxide per mol of lansoprazole,
(bV) heating the obtained reaction mixture to about 45-500C for 30 minutes, (b2') adding of water, preferably from about 10 to 30% (v/v) of water, more preferably from about 15 to 20% (v/v) of water,
(b3x) cooling the reaction mixture to 0-100C under stirring for about 1-2 hours, (b4") filtrating the obtained precipitate and washing with pre cooled mixture of xylene and ethanol, and (c") drying the obtained lansoprazole under reduced pressure at 40-500C.
In another embodiment the present relates to a process for the preparation of lansoprazole comprising the steps of:
(a*) condensing 2-mercapto benzimidazole with 2-chloromethyl-3-methyl-4-(2,2,2- trifluoroethoxy)pyridine hydrochloride in an alcoholic solvent in the presence of a base to obtain 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2-pyridinil)methyl)]thio]-1H- benzimidazole, (b')oxidizing obtained 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2-pyridinil)methyl)]thio]-
1 H-benzimidazole with m-chloroperbenzoic acid to obtain crude lansoprazole,
(c') providing a slurry of lansoprazole in a solvent or a mixture of solvents comprising a quaternary amine compound, and
(d") isolating lansoprazole, and (e')drying the obtained lansoprazole.
In another embodiment the present relates a process for the preparation of lansoprazole comprising the steps of:
(a") condensing 2-mercapto benzimidazole with 2-chloromethyl-3-methyl-4-(2,2,2- trifluoroethoxy)pyridine hydrochloride in an alcoholic solvent in the presence of a base to obtain 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2-pyridinil)methyl)]thio]-1H- benzimidazole,
(b") oxid izing obtained 2-[[3-methyl-4-(((2,2,2-tri-fluoroethoxy)-2-pyridinil)methyl)]thio]-
1 H-benzimidazole with m-chloroperbenzoic acid to obtain crude lansoprazole, (c") adding lansoprazole to a mixture of xylene and ethanol,
(d") adding about 0.1 to about 0.3 moles of tetra n-butyl ammonium hydroxide per mol of lansoprazole, (e") heating the reaction mixture obtained from step (d) to about 45-500C for 30 minutes, (f ') adding of water, preferably from about 10 to 30% (v/v) of water,
(g") cooling the reaction mixture to 0-100C under stirring for about 1-2 hours,
(h") filt rating the obtained precipitate and washing with pre cooled mixture of xylene and ethanol, and
(i") drying the obtained lansoprazole under reduced pressure at 40-500C.
In another embodiment the present invention is related to a process as described above, wherein in a further step the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound of formula (I) as obtained after step (c), is formulated into a pharmaceutically
acceptable dosage form, in particular wherein said dosage form is a tablet, pill, capsule or injectable.
Another object of the present invention is related to a process as described above, wherein in a further step lansoprazole as obtained after step (e") or step (i") is formulated into a pharmaceutically acceptable dosage form, in particular wherein said dosage form is a tablet, pill, capsule or injectable.
The substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound of formula (I)1 preferably lansoprazole, obtained by the process of the present invention may be used for the preparation of a variety of pharmaceutical compositions and dosage forms that are of therapeutic uses in treating patients.
Pharmaceutical compositions of the present invention contain in addition to the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound of formula (I) one or more pharmaceutically acceptable excipients or carriers. The possible excipients include binders, e.g. povidone, gelatin, sucrose, starch mucilage, pregelatinised starch, sorbitol, hydroxypropylmethyl cellulose (HPMC) etc.; disintegrating agents, e.g. microcrystalline cellulose, sodium carboxymethyl cellulose, alginic acid, sodium starch glycollate, corn starch etc.; fillers, e.g. dextrose, mannitol, sodium chloride, sorbitol, xylitol, calcium carbonate, magnesium carbonate, calcium phosphate, aluminum hydroxide; lubricants, e.g. polyethylene glycol, liquid paraffin, sodium lauryl sulphate, colloidal silicon dioxide, stearic acid, zinc stearate etc.; glidants, e.g. silica derivatives; and also flavouring agents and sweetening agents. The amount of active substance contained in said pharmaceutical compositions of the present invention is generally from 2-40%, preferably from 5-30%, and most preferably 5-20%.
Dosage forms include solid dosage forms, e.g. tablets, powders, capsules, liquid syrups, suspensions. An especially preferred dosage form of the present invention is a tablet.
The following examples illustrate the present invention, which are not to be limited in scope by the specific embodiments described herein:
Example 1
Preparation of 2-[[3-methyl-4-(((2l2,2-trifluoroethoxy)-2-pyridinil)methyl)]thio]-1 H- benzimidazole (V)
54.4 g (0.36 mol) of 2-mercapto benzimidazole (III) was added to the solution of 30.4 g (0.76 mol) of sodium hydroxide in 500 ml of methanol and stirred for 30-40 minutes at 25- 35°C. A solution of 100 g (0.36 mol) of 2-chloromethyl-3-methyl-4-(2,2,2- trifluoroethoxy)pyridine hydrochloride (IV) in 500 ml of methanol was slowly added to the reaction solution at 20-250C for about 35-45 minutes. The reaction contents were stirred at 25-35°C till to the completion of the reaction. 1000 ml of water was added slowly to the reaction mixture for about 30 minutes at 15-200C and stirred for 1-2 hours. The separated solid was filtered and washed with water (2x100 ml). The obtained compound was dried at 40-45°C under reduced pressure to give 2-[[3-methyl-4-(((2,2,2-trifluoroethoxy)-2- pyridinil)methyl)]thio]-1 H benzimidazole (V)
Example 2
Preparation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinil]methyl]sulfinyl]-1 H- benzimidazole (lansoprazole crude)
100 g (0.269 mol) of 2-[[3-methyl-4-(((2,212-trifluoroethoxy)-2-pyridinil)methyl)] thio]-1 H- benzimidazole (V) obtained from example 1 was dissolved in 1500 ml mixture of 1540 ml of xylene and 660 ml of ethanol at 25-35°C. A solution of 93 g of meta-chloroperbenzoic acid ( 50-65% purity) dissolved in 500 ml of the mixture of 1540 ml of xylene and 660 ml of ethanol was added to the reaction mass for about 1 hour at -35 to -300C. The contents were stirred for about 30 minutes to 1 hour at -35 to -30°C. A solution of 23 g (0.161 mol) of potassium carbonate dissolved in 250 ml of water was added to the reaction mass and stirred for 35-45 minutes at 35-400C. The contents were cooled to 0-50C and stirred for 1-2 hours. The separated solid was filtered and washed (2x 100 ml) with pre cooled mixture of 1540 ml of xylene and 660 ml of ethanol. The obtained compound was dried at 35-45°C to give 82.5 g lansoprazole.
Example 3
Process for the purification of lansoprazole
50 g (0.135 mole) of crude lansoprazole obtained from example 2 was added to the mixture of 87.5 ml of xylene and 37.5 ml of ethanol at 25-35°C. 8.8 ml (0.0135 mole) of tetra n-butyl ammonium hydroxide (40% w/v in methanol or water) was added and stirred the contents at 45-5O0C for about 30 minutes. 25 ml of water was added and reaction mass was cooled to 0-50C for 1-2 hours. The separated solid was filtered and washed with pre cooled 25 ml mixture of 17.5 ml of xylene and 7.5 ml of ethanol. The obtained compound was dried at 40-50°C under reduced pressure to give 42.5 g of pure lansoprazole.
Example 4
Process for the purification of lansoprazole
5O g (0.135 mole) of crude lansoprazole obtained from example 2 was added to the mixture of 87.5 ml of xylene and 37.5 ml of ethanol at 25-35°C. 26.4 ml (0.0405 mole) of tetra n- butyl ammonium hydroxide (40% w/v in methanol or water) was added and stirred the contents at 45-50°C for about 30 minutes. 25 ml of water was added and reaction mass was cooled to 0-5°C for 1-2 hours. The separated solid was filtered and washed with pre cooled 25 ml mixture of 17.5 ml of xylene and 7.5 ml of ethanol. The obtained compound was dried at 40-500C under reduced pressure to give 38.6 g of pure lansoprazole.
Example 5
Process for the purification of lansoprazole
50 g (0.135 mole) of crude lansoprazole obtained from example 2 was added to the mixture of 87.5 ml of xylene and 37.5 ml of ethanol at 25-35°C. 10 ml (0.0274 mole) of tetra methyl ammonium hydroxide (25% w/v in water) was added and stirred the contents at 45-500C for about 30 minutes. 25 ml of water was added and reaction mass was cooled to 0-50C for 1- 2 hours. The separated solid was filtered and washed with pre cooled 25 ml mixture of 17.5 ml of xylene and 7.5 ml of ethanol. The obtained compound was dried at 40-50°C under reduced pressure to give 38.6 g of pure lansoprazole.
Example 6
Process for the purification of lansoprazole (from tetrahydrofuran and water)
50 g (0.135 mole) of crude lansoprazole was dissolved in 250 ml of tetrahydrofuran at 45- 500C and un-dissolved particles was removed by filtration. 500 ml of water was slowly added to the reaction solution for about 45 minutes under stirring. The contents was further stirred for about 2 hours at 0-50C. The separated solid was filtered and washed with 100 ml of pre cooled 20% v/v aqueous tetrahydrofuran solution. The obtained compound was dried at 35-60°C under reduced pressure to give 40 g of pure lansoprazole.
Example 7
Detection of the impurities in lansoprazole
The impurities are detected by HPLC using UV detector. The method used for the detection of impurities is as follows,
Acetonitrile Chromatography grade
Eluent B Prepare a filtered and degassed mixture of acetonitrile, water, and triethylamine ( 80:20:5 ). Adjust with phosphoric acid to a PH of 6.0.
Eluent A Water : Eluent B :: 80:20 v/v
Eluent C Prepare a filtered and degassed mixture of acetonitrile, water, and triethylamine ( 80:20:5 ). Adjust with phosphoric acid to a PH of 10.0.
Diluent Water : Eluent C::80:20 v/v
Filter Nylon 66, 0.45 μm and 0.22 μm of Gelman
HPLC system Agilent, 1100 series pH meter Metrohm
Chromatographic Conditions
Column 150 mm x 4.6 mm i.d., C18, 5 μm. e.g. YMC pack ODS-A
System Gradient
Temperature 25°C
Flow rate 1.0 ml/minute
Injection volume 20 μl
Detection 285 nm
Gradient program Time % Eluent A % Eluent B
00 70 30
03 70 30
20 30 70
25 30 70
28 70 30
35 70 30
RRT (Calculation: By Area percent method)
Table 1 : Amount of impurities present in lansoprazole before and after purification
*<DL=under the detection limit
Claims
1. A process for the preparation of a substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compound of formula (I)
(I)
wherein R1 represents a hydrogen atom, a methoxy group or a difluoromethoxy group, R2 represents a methyl group or a methoxy group, R3 represents a 3-methoxypropoxy group, a methoxy group or a 2,2,2-trifluoroethoxy group, and R4 represents a hydrogen atom or a methyl group, comprising the steps of:
(a) providing a slurry of substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound in a solvent or a mixture of solvents comprising a quaternary amine compound,
(b) isolating the substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound, and
(c) drying the obtained substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazole compound.
2. A process according to claim 1 , wherein said substituted 2-(2-pyridylmethyl)sulfinyl-1H- benzimidazole compound is selected from the group consisting of omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.
3. A process according to claim 1 or claim 2, wherein said substituted 2-(2- pyridylmethy!)sulfinyl-1 H-benzimidazole compound is lansoprazole.
4. A process according to any one of claims 1 to 3, wherein said quaternary amine compound is selected from the group consisting of tetra-CVCβ-alkyl ammonium hydroxides, phenyl tri-d-Ce-alkyl ammonium hydroxides and benzyl tri-Ci-C6-alkyl ammonium hydroxides.
5. A process according to any one of claims 1 to 4, wherein said quaternary amine compound is tetra-CrC6-alkyl ammonium hydroxide.
6. A process according to any one of claim 4 or claim 5, wherein said tetrad -C6-alkyl ammonium hydroxide is selected from the group consisting of tetra methyl ammonium hydroxide, tetra ethyl ammonium hydroxide, tetra n-butyl ammonium hydroxide and tetra isobutyl ammonium hydroxide.
8. A process to any one of claims 1 to 7, wherein from 0.05 to 0.5 moles of said quaternary amine compound per mole of said substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compound are used in step (a).
9. A process to any one of claims 1 to 8, wherein from 0.1 to 0.3 moles of said quaternary amine compound per mole of said substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compound are used in step (a).
10. A process according to any one of claims 1 to 9, wherein said solvent used in step (a) is selected from the group consisting of ethanol, methanol, n-propanol, isopropanol, xylene, toluene, water and mixtures thereof.
11. A process according to any one of claims 1 to 10, wherein said solvent used in step (a) is selected from the group consisting of ethanol, methanol, xylene, water and mixtures thereof.
12. A process according to any one of claims 1 to 11 , wherein step (b) comprises the sub- steps of:
(b1) heating the reaction mixture obtained from step (a), (b2) adding water, (b3) cooling the reaction mixture to ambient temperature or below under stirring, and (b4) filtrating the obtained precipitate and washing with an organic solvent or mixture of organic solvents.
13. A process according to claim 12, wherein in sub-step (b1) the reaction mixture is heated to 40-550C.
14. A process according to claim 12, wherein in sub-step (b2) from 10 to 30 % (v/v) of water is added.
15. A process according to claim 12, wherein in sub-step (b3) the reaction mixture is cooled to -10°C to 15°C.
16. A process for the preparation of lansoprazole according to the claim 3 comprising the steps of:
(a) adding lansoprazole to a mixture of xylene and ethanol,
(b) adding from 0.1 to 0.3 moles of tetra n-butyl ammonium hydroxide per mole of lansoprazole,
(c) heating the obtained reaction mixture to 45-500C for 30 minutes, (d) adding from 10 to 30% (v/v) of water,
(e) cooling the reaction mixture to 0-100C under stirring for 1-2 hours,
(f) filtrating the obtained precipitate and washing with pre cooled mixture of xylene and ethanol, and
(g) drying the obtained lansoprazole under reduced pressure at 40-500C.
17. A process according to any one of claims 1 to 16, wherein said substituted 2-(2- pyridylmethyl)sulfinyl-1 H-benzimidazole compound contains less than about 0.2% (w/w) corresponding sulfone derivative impurities.
18. A process according to any one of claims 1 to 16, wherein said substituted 2-(2- pyridylmethyl)sulfinyl-1 H-benzimidazole compound contains less than about 0.2% (w/w) corresponding sulfide derivative impurities.
19. A process according to any one of claims 1 to 18, wherein said substituted 2-(2- pyridylmethyl)sulfinyl-1H-benzimidazole compound contains less than about 0.2% (w/w) corresponding sulfone and sulfide derivative impurities together.
20. A process according to any one of claims 1 to 15, wherein in a further step the substituted 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole compound of formula (I) as obtained after step (c), is formulated into a pharmaceutically acceptable dosage form, in particular wherein said dosage form is a tablet, pill, capsule or injectable.
21. A process according to claim 16, wherein in a further step lansoprazole as obtained after step (g), is formulated into a pharmaceutically acceptable dosage form, in particular wherein said dosage form is a tablet, pill, capsule or injectable.
22. A pharmaceutical composition comprising a substituted 2-(2-pyridylmethyl)sulfinyl-1 H- benzimidazole compound obtained by the process according to any one of claims 1 to
16 and one or more pharmaceutically acceptable excipients or carriers.
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Cited By (5)
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CN102180866A (en) * | 2011-05-23 | 2011-09-14 | 中山大学 | New crystal form of lansoprazole and preparation method and application thereof |
CN102558148A (en) * | 2010-12-15 | 2012-07-11 | 山东方明药业股份有限公司 | Synthesis process of lansoprazole important intermediate |
CN103012369A (en) * | 2011-05-23 | 2013-04-03 | 中山大学 | Lansoprazole N crystal form and preparation method and application thereof |
EP3187494A1 (en) | 2015-12-30 | 2017-07-05 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for the preparation of pantoprazole sodium sesquihydrate |
AU2017307431B2 (en) * | 2016-08-04 | 2022-03-31 | Plumettaz Holding S.A. | Apparatus and method for jetting a cable into a duct |
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CN1473822A (en) * | 2003-08-05 | 2004-02-11 | 西安翠宝首饰集团公司 | Extracting process of flavone and poly saccharide in duckweed |
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JPS6067481A (en) * | 1983-09-22 | 1985-04-17 | Showa Denko Kk | Purification of dibenzylidenesorbitol |
WO2004072061A1 (en) * | 2003-02-05 | 2004-08-26 | Teva Pharmaceutical Industries Ltd. | Method of stabilizing lansoprazole |
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Cited By (5)
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CN102558148A (en) * | 2010-12-15 | 2012-07-11 | 山东方明药业股份有限公司 | Synthesis process of lansoprazole important intermediate |
CN102180866A (en) * | 2011-05-23 | 2011-09-14 | 中山大学 | New crystal form of lansoprazole and preparation method and application thereof |
CN103012369A (en) * | 2011-05-23 | 2013-04-03 | 中山大学 | Lansoprazole N crystal form and preparation method and application thereof |
EP3187494A1 (en) | 2015-12-30 | 2017-07-05 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for the preparation of pantoprazole sodium sesquihydrate |
AU2017307431B2 (en) * | 2016-08-04 | 2022-03-31 | Plumettaz Holding S.A. | Apparatus and method for jetting a cable into a duct |
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