Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
  • C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides

Definitions

• the present invention relates to a process for the oxidation of a thioether group to a sulfoxide group. More specifically, it refers to a process for the oxidation of a thioether group of a compound of formula (I) to a sulfoxide group, to obtain the sulfinyl derivative of formula (II).
• R ,, R,, R_, R 5 , R 6 and R 8 independently of each other, represent hydrogen, an alkyl group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms;
• R- represents hydrogen, an alkyl group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, or a fluorinated alkoxy group of 1 to 6 carbon atoms;
• R : represents an alkyl group of 1 to 6 carbon atoms, a halogenated alkyl group of 1 to 6 carbon atoms, or a group - (CH 2 ) n -0R 9 , where n is an integer between 1 and 6, both inclusive, and R q represents hydrogen or an alkyl group of 1 to 6 carbon atoms.
• EP-302720 describes a process in which the oxidation of the thioether group of compounds 2- (2- pyridylmethylthio) benzimidazoles is carried out with hydrogen peroxide and as a catalyst vanadium pentoxide, sodium metavanadate, ammonium metavanadate or vanadium acetylacetonate ( IV).
• O98 / 40378 describes a process in which the oxidation of the thioether group of compounds 2- (2- pyridylmethylthio) benzimidazoles is carried out with peroxy-type compounds such as peracids, alkylhydroperoxides, benzoylperoxides, hydrogen peroxide, metape ⁇ odates and tetraalkylamine perborates etc. , and as a catalyst vanadium compounds are used.
• peroxy-type compounds such as peracids, alkylhydroperoxides, benzoylperoxides, hydrogen peroxide, metape ⁇ odates and tetraalkylamine perborates etc.
• Patent application O99 / 02521 describes a method of oxidation of the thioether to sulfoxide based on the use of a peroxoborate salt in the presence of an anhydride acid or a metal catalyst, or with an N-halosuccm measure, 1, 3-d ⁇ halo- 5, 5-d ⁇ met ⁇ lh ⁇ danto ⁇ na or an anhydrous dichloroisoc acid salt in the presence of a base
• Patent ES-2105953 describes conditions for the oxidation of thioether to sulfoxide based on the use of hydrogen peroxide in sodium bicarbonate medium and catalyzed by phosphotungstic acid H 3 (P ( 3 O ] 0 ).) XH 2 0.
• Patent ES-2060541 describes a process of oxidation of sulphide to sulfoxide with potassium peroxymethyl sulfate, with or without the presence of a ketone, or with hydrogen peroxide, in the presence of Mo and V acetylacetonate catalysts.
• US-5374730 describes a step of oxidation of sulphide to sulfoxide with hydrogen peroxide and catalyzed by vanadium acetylacetonate.
• Patent ES-2036948 describes a method of synthesis of lansoprazole, in which the last stage consists in the oxidation of the thioether precursor of lansoprazole to sulfoxide, with m-chloroperbenzoic acid or magnesium monoperoxyphthalate in the presence of a quaternary ammonium salt, or hydrogen peroxide, with W or molybdenum catalyst. It follows from the state of the art that the most developed and frequently used process for oxidation is that which uses vanadium catalysts.
• the present invention relates to a process for the oxidation of a thioether group to a sulfoxide group, and in particular to the oxidation of a thioether group of a compound of formula (I) as defined above to a sulfyl derivative of formula (II).
• halogenated alkyl group of 1 to 6 carbon atoms means an alkyl group of 1 to 6 carbon atoms containing one or more halogen atoms, preferably fluorine or chlorine, in place of one or more hydrogen atoms.
• fluorinated alkoxy group of 1 to 6 carbon atoms means an alkoxy group of 1 to 6 carbon atoms containing one or more fluorine atoms replacing one or more hydrogen atoms, for example, 2, 2, 2-t ⁇ fluoroethoxy or difluoromethoxy.
• the process consists in the oxidation of the thioether with sodium percarbonate in the presence of a molybdenum salt as a catalyst, which is preferably ammonium molybdate.
• a molybdenum salt as a catalyst, which is preferably ammonium molybdate.
• This new procedure has proven to be more effective than the various procedures described in the art.
• sodium percarbonate stands out as an oxidizing agent that is easy to handle, relatively stable and easy to store.
• the process of the present invention has a number of advantages over the above procedures, such as the following: - the reagents used are commercially available, molybdenum catalysts are less toxic than vanadium,
• the pH of the reaction mixture being slightly basic, is suitable for the stability of compounds such as lansoprazole in solution,
• a first purification of the sample can be performed by performing a fractional precipitation at controlled pH.
• the oxidation is carried out with a molar ratio of sodium percarbonate in relation to the thioether of formula (I) between 0.5 and 1.4, more preferably between 0.6 and 1, two.
• the amount of catalyst (molybdenum salt) preferably used is between 0.3% and 7%, more preferably between 0.5% and 5%, by weight, based on the thioether of formula (I).
• the solvent used for the oxidation reaction is a low molecular weight alcohol, preferably methanol.
• the reaction temperature is between -
• the compounds of formula (II) are lansoprazole, omeprazole, rabeprazole, pantoprazole and 2- [[[[4- (3-hydroxypropoxy) -3-methyl-2-pyridinyl] methyl] sulfinyl] -lH -benzimidazole, which can be obtained from the corresponding precursor thioethers by oxidation of the thioether group to sulfoxide according to the procedure provided by this invention.
• said compounds of formula (II) are obtained by oxidation of the thioether group present in the corresponding precursor thioethers of formula (I), to sulfoxide, in methanol (solvent), with sodium percarbonate, in a molar ratio with respect to the starting thioether between 0.6 and 1.2, in the presence of ammonium molybdate ( catalyst), with a proportion of ammonium molybdate with respect to the starting thioether between 0.5% and 5% by weight with respect to said thioether, and at a reaction temperature between -5 ° C and 20 ° C.
• 2- [[[4- (3-H ⁇ drox ⁇ propox ⁇ ) -3-methyl-2- pyridyl] methyl] sulfmil] -IH-benzimidazole can be used as a material to synthesize rabeprazole by transforming the hydroxyl group into a methoxy group.
• EXAMPLE 1 Obtaining lansoprazole Dissolve 10 g of 2 - [[[3-methyl-4- (2, 2, 2-t ⁇ fluoroethoxy) -2 -pi idmil] methyl] uncle] - lf ⁇ -benzimidazole in 50 ml of methanol and 0.3 g of ammonium molybdate are added. The solution is cooled to 10 ° C, gradually added 3.35 g of sodium percarbonate and kept under stirring at the same temperature for 15 hours. After the reaction, 250 ml of water are added and the pH of the mixture is adjusted to 10 with 10% acetic acid. It is kept under stirring for 1 hour and the solid obtained is filtered, which is washed with water and dried in a vacuum oven at 40 ° C. 9.4 g of lansoprazole are obtained (yield: 90%).

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
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• 2000
  • 2000-03-13 ES ES200000595A patent/ES2163372B1/es not_active Expired - Fee Related
• 2001
  • 2001-03-08 ES ES01909846T patent/ES2227145T3/es not_active Expired - Lifetime
  • 2001-03-08 HU HU0301885A patent/HUP0301885A2/hu unknown
  • 2001-03-08 PT PT01909846T patent/PT1270555E/pt unknown
  • 2001-03-08 US US10/204,506 patent/US6603009B2/en not_active Expired - Fee Related
  • 2001-03-08 MX MXPA02008961A patent/MXPA02008961A/es active IP Right Grant
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  • 2001-03-08 JP JP2001567691A patent/JP5041646B2/ja not_active Expired - Fee Related
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  • 2001-03-08 DE DE60105139T patent/DE60105139T2/de not_active Expired - Lifetime
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• 2002
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