WO2010095144A2 - Procédé de préparation d'inhibiteurs de pompe à protons - Google Patents

Procédé de préparation d'inhibiteurs de pompe à protons Download PDF

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WO2010095144A2
WO2010095144A2 PCT/IN2010/000064 IN2010000064W WO2010095144A2 WO 2010095144 A2 WO2010095144 A2 WO 2010095144A2 IN 2010000064 W IN2010000064 W IN 2010000064W WO 2010095144 A2 WO2010095144 A2 WO 2010095144A2
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methyl
formula
compound
pyridinyl
trifluoroethoxy
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PCT/IN2010/000064
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WO2010095144A3 (fr
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Manne Satyanarayana Reddy
Sajja Eswaraiah
Mummadi Venkatesh
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Msn Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention related to novel and improved processes for the preparation of proton pump inhibitors such as Dexlansoprazole and its pharmaceutically acceptable salts thereof.
  • Dexlansoprazole is chemically known as 2-[(i?)-[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole represented as compound of formula- 1.
  • Dexlansoprazole is the R-enantiomer of lansoprazole and belongs to benzimidazole type proton pump inhibitors which work by undergoing a rearrangement to form a thiophilic species which then conveniently bind to gastric ⁇ K-ATPase, the enzyme involved in the final step of proton production in parietal cells and there by inhibit the enzyme subsequently inhibiting the secretion of the gastric acid. Therefore they are useful in the treatment of diseases which include peptic ulcer, heartburn, non- ulcer dispepsia, reflux esophagitis, and erosive esophagitis.
  • benzimidazole compounds capable of inhibiting the gastric ⁇ K ATPase enzyme have found substantial use as drugs in human medicine and are known under such names as lansoprazole (US Pt No: 4,628,098), omeprazole (US Pt No: 4,255,431 and US 5,693,818), pantoprazole (US Pt. No. 4,758,579) and rabeprazole (US Pt No: 5,045,552).
  • lansoprazole US Pt No: 4,628,098
  • omeprazole US Pt No: 4,255,431 and US 5,693,81
  • pantoprazole US Pt. No. 4,758,579
  • rabeprazole US Pt No: 5,045,552
  • These compounds are structurally related sulphoxides having stereogenic center at sulphur atom and thus exist as two optical isomers i.e. enantiomers.
  • the single enantiomer of pharmacologically active compounds has met an increased interest in the last few years because of improved pharmacokinetic and biological properties, but there is not yet any efficient asymmetric process described for the synthesis of the single enantiomer thereof.
  • US 5,948,789 disclose a process for enantioselective synthesis of single enantiomer of omeprazole and other structurally related compounds.
  • the example-22 of this patent particularly disclosed the preparation of dexlansoprazole by asymmetric oxidation.
  • the said process involves the oxidation of 2-[[[3-methyl-4-(2,2,2- trifiuoroethoxy)-2-pyridinyl]methyl]thio]- 1 H-benzimidazole using cumenehydroperoxide (in 1 molar ratio with respect of benzimidazole compound) in presence of diethyl tartrate, titanium isopropoxide, water and diisopropylethylamine in toluene medium for the period of 16 hours at room temperature provides the dexlanoprazole as an oil with 13% of sulfide, 8% of sulfone and 76% of sulfoxide by achiral HPLC.
  • the oil compound further purified using flash chromatography to provide the dexlansoprazole as oil with the optical purity of 99.6%ee.
  • the said patent involves flash chromatography for purification and the formation of sulfone is also high, hence this process is commercially not suitable.
  • the said process involves the usage of unprotected nitrogen group in oxidation reaction process which leads to the formation of unwanted impurities.
  • US 6,982,275 disclose a process for optically active sulfoxide derivatives by employing kagan oxidation conditions. But the process involves the use of excess mole ratio of oxidizing agent (i.e. cumene hydroperoxide) in 2.5 to 10 molar equivalents relative to the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH- benzimidazole and the reaction is carried out at low temperatures between -20 to 20 0 C.
  • oxidizing agent i.e. cumene hydroperoxide
  • the said application disclosed that the excess amount of oxidation agent used in the reaction helps to reduce the sulfone formation.
  • WO 2005/116011 discloses a process for the preparation of S-omeprazole
  • R-omeprazole which involves the protection of sulfide, followed by oxidation with m-chloroperbenzoic acid and subsequent deprotection to provide the product.
  • prazoles have been generically described in the patent, none of them have been exemplified in this application. It is known to any person skilled in the art that until and unless one reaction is performed on a specific molecule it is difficult to really ascertain whether it behaves in the similar manner as omeprazole and gives the similar results. In most of the cases it has been observed that different molecules behave in a different manner in similar reaction conditions. Therefore there is a demand and a need for an enantioselective process that can be used in the large scale for manufacture of the enantiomers of pharmacologically active compounds.
  • the present invention was devised based on the above teachings and in order to overcome the disadvantages of prior art.
  • the process involves the use of Kagan oxidation conditions but the oxidizing agent cumene hydroperoxide was replaced with m-chloroperbenzoic acid, and the reaction was carried out in presence of a base which improved the reaction yields and enantiomeric purity substantially.
  • the route for the preparation of dexlansoprazole in the present invention involves the protection of lansoprazole sulphide with D (+)-camphor sulphonyl chloride followed by stereo selective oxidation using kagan oxidation conditions using meta chloroperbenzoic acid to provide camphor sulphonyl protected sulfoxide derivative which on deprotection provides stereo specifically dexlansoprazole with high enantiomeric excess and yield.
  • D (+)-camphor sulphonyl chloride D (+)-camphor sulphonyl chloride
  • meta chloroperbenzoic acid to provide camphor sulphonyl protected sulfoxide derivative which on deprotection provides stereo specifically dexlansoprazole with high enantiomeric excess and yield.
  • WO 2008/18091 particularly disclosed a process for the preparation of omeprazole salts, by the asymmetric oxidation of 5-methyoxy-2-[(4-methoxy-3,5- dimethyl-2-pyridinyl)-methyl]thio]-lH-benzimidazole with a oxidizing agent in presence of chiral transition metal complex without using organic solvent and a base.
  • the present invention provides an efficient process for the preparation of dexlansoprazole using kagan conditions with the optimum amount of oxidation agent at ambient temperature, which provides high yields, purity with low levels of sulfones.
  • the first aspect of the present invention is to provide a novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]- lH-benzimidazole compound of formula-2 with D(+) camphorsulfonyl chloride in presence of an alkali metal base in a suitable solvent to provide N-camphor sulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH- benzimidazole compound of formula-3, which is optionally purified using a suitable solvent, b) oxidizing the N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy
  • the second aspect of the present invention is to provide a novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]- lH-benzimidazole compound of formula-2 with D(+) camphorsulfonyl chloride in presence of an alkali metal base in a suitable solvent provides N-camphor sulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH- benzimidazole compound of formula-3, which is optionally purified using a suitable solvent, b) oxidizing the N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridiny
  • the third aspect of the present invention is to provide a crystalline camphor sulphonyl protected sulfide intermediate i.e., N-camphorsulfonyl-2-[[[3-methyl-4- (2,2,2 -trifluoroethoxy)-2-pyridiny l]methy l]sulphanyl]- 1 H-benzimidazole compound of formula-3.
  • a crystalline camphor sulphonyl protected sulfide intermediate i.e., N-camphorsulfonyl-2-[[[3-methyl-4- (2,2,2 -trifluoroethoxy)-2-pyridiny l]methy l]sulphanyl]- 1 H-benzimidazole compound of formula-3.
  • the fourth aspect of the present invention is to provide a crystalline camphor sulphonyl protected sulfoxide intermediate, i.e. N-camphorsulfonyl-2-[(R)-[[3-rnethyl-4- (2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulf ⁇ nyl]-lH-benzimidazole compound of formula-4.
  • the fifth aspect of the present invention is to provide an improved process for the preparation of dexlansoprazole compound of formula- 1, which comprise of oxidizing 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-2 with an oxidizing agent in presence of a chiral titanium complex and a base, characterized in that the oxidizing agent used in the ratio of 1.1 to 1.4 with respect to the compound of formula-2.
  • the sixth aspect of the present invention is to provide one pot process for the preparation of dexlansoprazole compound of formula- 1, which comprises of reacting the 2-mercaptobenzimidazole with 2-(chloromethyl)-3-methyl(4-(2,2,2,-trifluoroethoxy) pyridine hydrochloride in presence of a suitable base in a suitable polar solvent then extracting the obtained compound of formula-2 in a suitable solvent followed by oxidizing it with a suitable oxidizing agent in presence of a chiral titanium complex and a base to provide the compound of formula- 1.
  • the further aspects of the present invention is to provide an improved process for the preparation of anhydrous, sesquihydrate crystalline forms and amorphous form of dexlansoprazole compound of formula- 1 and also provide a solvated form of dexlansoprazole.
  • Figure-1 Illustrates the powder X-Ray diffractogram of crystalline N-camphorsulfonyl- 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-3.
  • Figure-2 Illustrates the powder X-Ray diffractogram of crystalline N-camphor sulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH- benzimidazole compound of formula-4.
  • Figure-3 Illustrates the powder X-Ray diffractogram of IPA solvated dexlansoprazole.
  • the present invention provides novel and improved processes for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts thereof.
  • the first aspect of the present invention provides a novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]- lH-benzimidazole compound of formula-2
  • the suitable alkali metal base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like or mixtures thereof; preferably potassium carbonate and the solvent is selected from chloro solvents such as methylenechloride, ethylene dichloride, carbon tetra chloride, chloroform and the like or mixtures thereof, preferably methylenechloride.
  • the suitable solvent for the purification of compound of formula-3 is selected from alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like or mixtures thereof; preferably methanol.
  • the oxidizing reagent is selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; preferably m-chloro perbenzoic acid;
  • the base is selected from organic bases such as tertiary butylamine, triethyl amine, N,N-diisopropyl-ethylamine, n-methyl glucamine, thiophene alkyl amine and the like or mixtures thereof; preferably N 5 N- diisopropyl ethylamine and the solvent is selected from hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane and the like or mixtures there of; preferably toluene.
  • the alkali metal base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like or mixtures thereof; preferably sodium hydroxide and the solvent is selected from alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like or mixtures thereof; preferably methanol
  • the solvent used for purification is selected from keto solvents such as acetone, methyl ethyl ketone and the like; and polar solvents like water or mixture there of, preferably acetone/water mixture.
  • the second aspect of the present invention provides a novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]- lH-benzimidazole compound of formula-2 with D (+) camphorsulfonyl chloride in presence of an alkali metal base in a suitable solvent, to provide N-camphor sulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH- benzimidazole compound of formula-3, which
  • the oxidizing reagent is selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; preferably m-chloro perbenzoic acid ;
  • the base is selected from organic bases such as tertiary butylamine, triethyl amine, N,N-diisopropyl-ethylamine, n-methyl glucamine, thiophene alkyl amine and the like; preferably N,N-diisopropyl ethylamine and the solvent is selected from hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane and the like; preferably toluene.
  • step c) and d) used are similar to the bases and solvent described in step c) and d) of first aspect of the invention.
  • L-(-)-camphorsulfonyl chloride is used in place of D(+)-camphorsulfonyl chloride in the above processes provides S-Lansoprazole.
  • the third aspect of the present invention provides a crystalline camphorsulfonyl protected sulfide intermediate, i.e. N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-3, which is characterized by its strong powder X-ray diffractogram peaks at about 7.05, 8.29, 8.95, 9.66, 10.45, 13.33, 14.04, 14.95, 16.66, 18.81, 23.89, 24.76, 26.86, 31.35 ⁇ 0.2 degrees two theta (represented in Figure-1).
  • the novel crystalline form of compound of formula-3 of the present invention is used to prepare highly pure dexlansoprazole or its intermediates and pharmaceutically acceptable salt thereof.
  • the fourth aspect of the present invention provides a crystalline camphor sulphonyl protected sulfoxide intermediate, i.e.
  • N-camphorsulfonyl-2-[(R)-[[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4 which is characterized by its strong powder X-ray diffractogram peaks at about 5.83, 6.27, 8.01, 8.26, 9.00,10.20, 12.63, 13.86, 16.54, 17.33, 18.28, 18.75, 19.84, 21.38, 23.58, 28.02 ⁇ 0.2 degrees two theta (represented in Figure-2).
  • the novel crystalline form of compound of formula-4 of the present invention is used to prepare highly pure dexlansoprazole or its pharmaceutically acceptable salts thereof
  • the fifth aspect of the present invention provides an improved process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of asymmetrically oxidizing the 2-[[[3-methyl-4-
  • Formula-2 with an optimum amount of oxidizing agent in presence of a chiral transition metal complex, an organic solvent and a base, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar equivalents relative to the 2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]-lH-benzimidazole compound of formula-2, optionally converting the obtained compound of formula- 1 into its pharmaceutically acceptable salts.
  • the oxidation is carried out in the presence of a suitable oxidizing agent selected from cumene hydroperoxide, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; preferably the oxidizing agent used in the process is cumene hydroperoxide.
  • a suitable oxidizing agent selected from cumene hydroperoxide, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; preferably the oxidizing agent used in the process is cumene hydroperoxide.
  • the asymmetric oxidation of sulfide derivative is carried out using either one equivalent (US 5948789) or more equivalents of oxidizing agent (US 6982275) with respect to sulfide, in presence of a base, organic solvent, chiral metal ligand to provide the corresponding s
  • the reaction is incomplete and the sulphide compound used as starting material remains unreacted and contaminates with the sulfoxide product. If excess amount of oxidizing agent used leads to the increase in cost of over all production as well as the sulfone impurity formation due to over oxidation. Whereas the present invention utilizes the optimum amount of oxidizing agent for the said reaction avoids the prior art problems. According to the present invention, the asymmetric oxidation is carried out in the presence of a chiral transition metal complex, which is prepared from a transition metal catalyst and a chiral ligand.
  • the transition metal is selected from the group comprising titanium, vanadium, molybdenum and tungsten, preferably titanium and vanadium compound.
  • Preferred transition metal compound is titanium (IV) isopropoxide, titanium (IV)propoxide, titanium(IV)ethoxide, titanium(IV)methoxide, vanadium oxy tripropoxide or vanadium oxy triisopropoxide and the like.
  • the chiral ligand used is selected from chiral diols which are esters of tartaric acid particularly (+)-diethyl L-tartarate or (-)- diethyl D-tartarate, (+)-dimethyl L- tartarate or (-)- dimethyl D-tartarate and the like.
  • the asymmetric oxidation of the present invention is carried out in presence of catalytic amount of water.
  • the oxidation reaction of the present invention is carried out at a temperature in the range of 20 to 30°C, preferably between 21-28°C more preferably between 21-25°C, for a period of about 1-6 hours, preferably between 1-3 hours.
  • the base used in the oxidation reaction is selected from a group comprising of but not limited to tertiary butylamine, triethyl amine, N,N-diisopropyl-ethylamine, n-methyl glucamine, thiophene alkyl amine and the like preferably N,N-diisopropylethylamine.
  • the asymmetric oxidation in the present invention is carried out in a suitable solvent and the solvent is selected from hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane and the like; preferably toluene.
  • hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane and the like; preferably toluene.
  • the dexlansoprazole obtained after the asymmetric oxidation may be further converted into its pharmaceutically acceptable salts by the conventional methods.
  • the starting material 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH- benzimidazole compound of formula-2 can be prepared as per the process known in the art.
  • the sixth aspect of the present invention provides one pot process for the preparation of compound of formula- 1, which comprises of reacting the 2- mercaptobenzimidazole with 2-(chloromethyl)-3-methyl(4-(2,2,2,-trifluoroethoxy) pyridine hydrochloride in presence of a suitable alkali metal hydroxides base like sodium hydroxide or potassium hydroxide, preferably sodium hydroxide in a suitable polar solvent such as water followed by extracting the obtained compound of formula-2 in a suitable solvent selected from chloro solvents like methylenechloride, ethylene dichloride, carbon tetra chloride, chloroform or hydrocarbon solvent like toluene, heptane, cyclohexane and hexane, preferably methylene chloride and then treating it with an optimum amount of oxidizing agent in presence of a chiral transition metal complex and a base and catalytic amount of water, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar
  • the further aspect of the present invention provides a process for the preparation of amorphous dexlansoprazole compound of formula- 1, which comprises of the following steps, a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture and filtering the solid, g) adding suitable chloro solvents like methylene chloride or chloroform to the obtained solid, h) separating water from the organic layer, i) distilling off the solvent from the organic layer under reduced pressure, j) adding a suitable ketone solvent selected from acetone or methyl isobut
  • the process for the preparation of amorphous dexlansoprazole compound of formula- 1 comprises of the following steps; a) dissolving dexlansoprazole in acetone at room temperature, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture for 30 minutes at 25-30 0 C and filtering the solid, g) adding methylene chloride to the obtained solid, h) separating water from the organic layer, i) distilling off methylene chloride from the organic layer under reduced pressure, j) adding acetone to the obtained solid and co-distilled off the solvent from the reaction mixture under reduced pressure to get the amorphous dexlansoprazole.
  • Further aspect of the present invention provides a process for the preparation of anhydrous crystalline form of dexlansoprazole compound of formula- 1, which comprises of the following steps, a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof, b) adding the obtained solution to a suitable hydrocarbon solvent selected from toluene, heptane, cyclohexane, hexane or mixtures thereof at a suitable temperature ranges from 0°C to reflux temperature of the solvent, c) stirring the reaction mixture at a suitable temperature, d) filtering the solid, washing with suitable hydrocarbon solvent as defined above, e) drying the solid to get the anhydrous form of dexlansoprazole.
  • a suitable hydrocarbon solvent selected from toluene, heptane, cyclohexane, hexane or mixtures thereof at a suitable temperature ranges from 0°C to reflux
  • step b) of the present aspect of the invention can be done in either ways i.e., adding a suitable hydrocarbon solvent to a solution of dexlansoprazole or adding a solution of dexlansoprazole in suitable solvent to the hydrocarbon solvent at a suitable temperature.
  • the anhydrous crystalline form of dexlansoprazole compound of formula- 1 comprises of the following steps; a) Dissolving the amorphous dexlansoprazole in acetone, b) adding the obtained solution to heptane at 35-45°C, c) stirring the reaction mixture for an hour at 35-45°C, d) filtering the solid, washing with heptane, e) drying the solid to get the anhydrous crystalline form of dexlansoprazole.
  • Another aspect of the present invention provides a process for the preparation of crystalline sesquihydrate of dexlansoprazole compound of formula- 1, which comprises of the following steps, a) dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture and filtering the solid, g) drying the solid to get the sesquihydrate of dexlansoprazole.
  • the process for the preparation of crystalline sesquihydrate of dexlansoprazole compound of formula- 1 comprises of the following steps; a) dissolving the dexlansoprazole in acetone at room temperature, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture for 30 minutes and filtering the solid, g) drying the solid at less than 40°C to get the crystalline sesquihydrate of dexlansoprazole.
  • the present invention also provides crystalline IPA solvated dexlansoprazole, which is characterized by its strong powder X-ray diffractogram peaks at about 5.87, 9.19, 9.98, 11.00, 13.39, 14.95, 15.69, 17.66, 19.70, 20.96, 24.90, 25.45 ⁇ 0.2 degrees two theta and the same has been represented in Figure-3.
  • the novel IPA solvated form of dexlansoprazole of the present invention can used to prepare highly pure dexlansoprazole in amorphous and other available crystalline forms.
  • the dexlansoprazole which is used for the preparation of crystalline and amorphous form of the present invention may be in crude dexlansoprazole obtained directly from the reaction mixture or crystalline material or amorphous material or a mixture of crystalline and amorphous material prepared by the conventional methods.
  • the present invention further provides a process for the preparation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-2, which comprises of reacting the 2-mercaptobenzimidazole with 2-(chloromethyl)-3-methyl(4-(2,2,2,-trifluoroethoxy)pyridine hydrochloride in presence of a suitable alkali metal hydroxides base such as sodium hydroxide in a suitable polar solvent such as water to provide the compound of formula-2, which is optionally purified from suitable hydrocarbon solvents such as toluene to provide the highly pure compound of formula-2.
  • a suitable alkali metal hydroxides base such as sodium hydroxide
  • a suitable polar solvent such as water
  • the anhydrous crystalline dexlansoprazole particles prepared by the present invention having the mean particle size D[4,3] in the range from 2 to 35 microns and having D(0.9) in the range of 2 to 80 microns.
  • the crystalline sesquihydrate dexlansoprazole particles prepared by the present invention having the mean particle size D[4,3] in the range from 1 to 50 microns and having D(0.9) in the range of 2 to 120 microns.
  • Dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts thereof can be milled or micronized by the conventional methods to obtain the required particle size.
  • the anhydrous and sesquihydrate crystalline dexlansoprazole as prepared by the present invention is characterized by its powder X-ray diffractogram values, which are similar to the PXRD values of anhydrous and sesquihydrate crystalline dexlansoprazole disclosed in US 6462058 respectively.
  • the term "highly pure” refers to the compound with purity greater than 99.50% by HPLC, preferably > 99.70 % by HPLC and more preferably > 99.95% by HPLC.
  • Dexlansoprazole prepared as per any aspect of the present invention can be micronized or milled to get the desired particle size.
  • the particle size distribution (P.S.D) of dexlansoprazole can be measured using Malvern Mastersizer 2000 instrument.
  • dexlansoprazole were analyzed by HPLC using the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and Column: YMC-PAK ODS-A Flow rate: 1.0 ml/min; wavelength: 285 nm;
  • XRD analysis of Dexlansoprazole intermediates was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A 0 and continuous scan speed of 0.0457min.
  • the present invention is schematically represented by the following scheme:
  • Example-1 Preparation of N-camphorsulfonyl 2-[[[3-methyl-4-(2,2,2-trifIuoro ethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole of formuIa-3:
  • Example-3 Preparation of N-camphorsulfonyI-2-[(R)-[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinyl] methyI]suIfinyl]-LH-benzimidazole of formula-4: To 5 g of N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole obtained in example-2, added 25 ml of toluene, D-(+)-diethyl tartrate (1.39g) and heated the reaction mixture to 65°C.
  • Example-5 Purification of N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifl ⁇ ioro ethoxy)-2-pyridinyl] methyI]sulf ⁇ nyl]-lH-benzimidazoIe of formula-4: 5.0 g of N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole obtained as per example-3 or example-4 was dissolved in 15 ml of acetone. Added 30 ml of water to the reaction mixture and stirred for 20 minutes. Filtered the precipitated solid and washed with water. Yield: 4.0 grams; M.R: 120-130 0 C.
  • ExampIe-7 Purification of dexlansoprazole To 1 g of dexlansoprazole compound obtained in example-5 added 20 ml of acetone, stirred for 10 minutes at 25°C. Filtered the reaction mixture and the filtrate is saturated with water (100 ml). Filtered the compound obtained and washed with water then dried to get the title compound.
  • Example-8 Preparation of crystalline IPA solvated dexlansoprazole.
  • Example-9 Preparation of lansoprazole sulphide protected with L-(-)-camphor sulfonyl chloride.
  • Example-10 Purification of lansoprazole sulphide protected with L-(-)-camphor sulfonyl chloride. Take the obtained compound in example-9, added methanol (880 ml) and stirred for 45 minutes. Filtered the solid and washed with methanol. Dried the compound to get the title compound. Yield: 95 grams
  • Example-16 Preparation of amorphous dexlansoprazole: 1% aqueous ammonia (100 ml) was added to a solution of dexlanosprazole
  • Example-18 Preparation of crystalline sesquihydrate of dexlansoprazole:
  • aqueous ammonia 100 ml was added to a solution of dexlanosprazole (75 grams) obtained as per example- 14 in acetone (200 ml) and the reaction mixture was subjected to carbon treatment. The reaction mixture was filtered through hyflow and the bed was washed with acetone. Aqueous ammonia (500 ml) solution was added to the filtrate and stirred for 45 minutes at room temperature. The solid obtained was filtered and washed with aqueous ammonia. The solid was dried at below 40°C under reduced pressure until the water content to reach below 6-8% w/w to get the title compound.
  • Example-20 One pot process for dexlansoprazole:

Abstract

La présente invention porte sur des procédés nouveaux et améliorés permettant la préparation d'inhibiteurs de pompe à protons tels que le 2-[(R)-[[3-méthyl-4-(2,2,2-trifluoroéthoxy)-2-pyridinyl]méthyl]sulfinyl]-1H-benzimidazole et sur leurs sels pharmaceutiquement acceptables.
PCT/IN2010/000064 2009-02-04 2010-02-04 Procédé de préparation d'inhibiteurs de pompe à protons WO2010095144A2 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012104805A1 (fr) 2011-02-01 2012-08-09 Ranbaxy Laboratories Limited Procédé de préparation de dexlansoprazole
CN102659763A (zh) * 2012-04-27 2012-09-12 南京优科生物医药研究有限公司 一种右旋兰索拉唑合成与纯化的方法
WO2012176140A1 (fr) * 2011-06-21 2012-12-27 Ranbaxy Laboratories Limited Procédé pour la préparation de dexlansoprazole
WO2013179194A1 (fr) 2012-05-31 2013-12-05 Ranbaxy Laboratories Limited Procédé de préparation de dexlansoprazole cristallin
CN113582973A (zh) * 2021-09-28 2021-11-02 丽珠医药集团股份有限公司 一种硫醚的制备方法
CN114853678A (zh) * 2022-03-31 2022-08-05 山东科源制药股份有限公司 一种兰索拉唑原料药中间体h-苯并咪唑的合成方法

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US6982275B2 (en) * 2000-04-28 2006-01-03 Takeda Pharmaceutical Company Limited Process for producing optically active sulfoxide derivative
US7285668B2 (en) * 2000-12-01 2007-10-23 Takeda Pharmaceutical Company Limited Process for the crystallization of (R)- or (S)-lansoprazole
WO2007138468A2 (fr) * 2006-06-01 2007-12-06 Wockhardt Ltd Procédés de préparation de lansoprazole
WO2009088857A1 (fr) * 2007-12-31 2009-07-16 Takeda Pharmaceutical Company Limited Formes solvatées de cristaux de (r) -2- [ [ [3-méthyl-4- (2, 2, 2-trifluoroéthoxy) -2-pyridinyl] méthyl] sulfinyl] -1h-benzimidazole
WO2009117489A1 (fr) * 2008-03-18 2009-09-24 Dr. Reddy's Laboratories Ltd. Procédé de préparation du dexlansoprazole et autres formes polymorphes

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US6982275B2 (en) * 2000-04-28 2006-01-03 Takeda Pharmaceutical Company Limited Process for producing optically active sulfoxide derivative
US7285668B2 (en) * 2000-12-01 2007-10-23 Takeda Pharmaceutical Company Limited Process for the crystallization of (R)- or (S)-lansoprazole
WO2005116011A1 (fr) * 2004-05-28 2005-12-08 Hetero Drugs Limited Nouveau procede de synthese stereoselective de sulfoxydes de benzimidazole
WO2007138468A2 (fr) * 2006-06-01 2007-12-06 Wockhardt Ltd Procédés de préparation de lansoprazole
WO2009088857A1 (fr) * 2007-12-31 2009-07-16 Takeda Pharmaceutical Company Limited Formes solvatées de cristaux de (r) -2- [ [ [3-méthyl-4- (2, 2, 2-trifluoroéthoxy) -2-pyridinyl] méthyl] sulfinyl] -1h-benzimidazole
WO2009117489A1 (fr) * 2008-03-18 2009-09-24 Dr. Reddy's Laboratories Ltd. Procédé de préparation du dexlansoprazole et autres formes polymorphes

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012104805A1 (fr) 2011-02-01 2012-08-09 Ranbaxy Laboratories Limited Procédé de préparation de dexlansoprazole
WO2012176140A1 (fr) * 2011-06-21 2012-12-27 Ranbaxy Laboratories Limited Procédé pour la préparation de dexlansoprazole
CN102659763A (zh) * 2012-04-27 2012-09-12 南京优科生物医药研究有限公司 一种右旋兰索拉唑合成与纯化的方法
WO2013179194A1 (fr) 2012-05-31 2013-12-05 Ranbaxy Laboratories Limited Procédé de préparation de dexlansoprazole cristallin
CN113582973A (zh) * 2021-09-28 2021-11-02 丽珠医药集团股份有限公司 一种硫醚的制备方法
CN113582973B (zh) * 2021-09-28 2022-05-10 丽珠医药集团股份有限公司 一种硫醚的制备方法
CN114853678A (zh) * 2022-03-31 2022-08-05 山东科源制药股份有限公司 一种兰索拉唑原料药中间体h-苯并咪唑的合成方法

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