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WO2004011455A1 - Preparation de lansoprazole et composes connexes - Google Patents

Preparation de lansoprazole et composes connexes Download PDF

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Publication number
WO2004011455A1
WO2004011455A1 PCT/US2003/023588 US0323588W WO2004011455A1 WO 2004011455 A1 WO2004011455 A1 WO 2004011455A1 US 0323588 W US0323588 W US 0323588W WO 2004011455 A1 WO2004011455 A1 WO 2004011455A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
hydrogen
methyl
weak base
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Ceased
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PCT/US2003/023588
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English (en)
Inventor
Nina Finkelstein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Publication date
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Priority to EP03748985A priority Critical patent/EP1467987A1/fr
Priority to AU2003268034A priority patent/AU2003268034A1/en
Publication of WO2004011455A1 publication Critical patent/WO2004011455A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 relates to a process of preparing 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazole derivatives.
  • Substituted 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazole derivatives are well-known gastric proton pump inhibitors and these benzimidazole derivatives include lansoprazole (LNP) and LNP related compounds (for example, omeprazole, pantoprazole, and rabeprazole).
  • LNP lansoprazole
  • LNP related compounds for example, omeprazole, pantoprazole, and rabeprazole
  • lansoprazole has its chemical name as (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl] s lfmyl]-iH-benzimidazole), i.e., when R is hydrogen, Ri is hydrogen, R 2 is methyl, R 3 is trifluoro-ethoxy, R 4 is hydrogen of the following chemical formula (I) and lansopraozle can inhibit gastric acid secretion (due to its proton pump inhibiting activity) and is commonly used as an antiulcer agent.
  • U.S. Pat. No. 4,628,098 generically describes the lansoprazole compound.
  • Several known methods for preparing lansoprazole involve the use of a lansoprazole precursor having a thioester group.
  • the primary route for synthesis of lansoprazole consists of the oxidation of the corresponding sulfide (LNPS) having the chemical formula (II).
  • LNPS corresponding sulfide
  • II chemical formula
  • the thioether group of lansoprazole precursor is oxidized in the last step of preparation to form the lansoprazole.
  • m-chloroperbenzoic acid however, often results in a non-selective oxidation of the thioether group.
  • U.S. Pat. No. 5,578,732 and EP302720 further describe the process of lansoprazole preparation by an oxidation method using hydrogen peroxide (H 2 O 2 ) in the presence of vanadium pentoxide, sodium metavanadate, ammonium metavanadate or vanadium acetyl acetonate catalyst.
  • H 2 O 2 hydrogen peroxide
  • ES 2105953, WO 0121617, ES 2063705, U.S. Pat. No. 6,313,303, WO9947514, WO0168594, and US 2003/36554A1 all describe the use of other oxidation reagents and/or catalysts.
  • US 2003/46554A1 and ES2063705 describe the use of with tert-butylhydroperoxide (TBHP) and a vanadium catalyst, preferably, vanadium acetyl acetonate, for the oxidation of LNPS (II) and N-oxide LPNS (III). All of the disclosed methods could be improved by increasing their selectivity for the sulfinyl product.
  • TBHP tert-butylhydroperoxide
  • a vanadium catalyst preferably, vanadium acetyl acetonate
  • the present invention provides a process for preparing lansoprazole (LNP) (I) and related compounds by oxidation of corresponding sulfide (II) with tert- butyUiydroperoxide (TBHP), catalyzed by vanadium oxytrichloride.
  • the vanadium oxytrichloride is used in the presence of an alkanol.
  • the vanadium oxytrichloride in the alkanol is treated with a base.
  • the present invention provides a process for preparing a compound having formula (I):
  • R 1; R 2 , and R 4 are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower alkoxy; and R is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl, comprising the steps of: a) reacting a compound of formula (IT)
  • Lower alkanol such as C1-C 5 alkanol is preferred.
  • -Cs alkanol includes methanol, ethanol, isopropanol, propanol, sec-butanol, butanol and pentanol.
  • the reaction step is performed in the presence of a weak base.
  • the process relates to preparing a compound having formula (II) is (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl] sulfide]-'H- benzimidazole).
  • the compound having formula (I) is lansoprazole.
  • the compound having the formula (I) is omeprazole.
  • the compound having the formula (I) is pantoprazole.
  • the compound having the formula (I) is rabeprazole.
  • tert-butylhydroperoxide is used in an amount of from about 1 to about 3 mol. equivalents relative to the compound having the formula (II). More preferably, tert-butylhydroperoxide is used in an amount of from about 1.3 to about 2 mol. equivalents relative to the compound having the formula (II).
  • vanadium oxytrichloride is used in an amount of from about 0.01 to about 0.5 mol. equivalent relative to the compound having the formula (II). More preferably, vanadium oxytrichloride is used in an amount of from about 0.005 to about 0.3 mol. equivalent relative to the compound having the formula (II).
  • the oxidation is performed in the presence of a weak base which is an inorganic base or an organic base.
  • a weak base which is an inorganic base or an organic base.
  • the organic base is N,N-diethyl amine.
  • the reacting step is performed at a temperature of 5°C to about 15°C. More preferably, the reacting step is performed at a temperature of about 10°C.
  • the reacting step is performed for about 4 to about 24 hours. More preferably, the reacting step is performed for about 4 to about 15 hours. More preferably, the reacting step is performed for about 6 hours.
  • the isolating step is preformed by filtration. More preferably, the step of drying is carried out at about 40°C in vacuo at 10 mm ⁇ g overnight.
  • the present invention provides an oxidation which gives the lansoprazole product with a high yield and a low level of impurities.
  • the impurities include, but not limited to sulfones, N-oxides and N-oxide sulfones.
  • LNP refers to lansorpazole having the chemical name of 2-
  • LNPS refers to the sulfide-containing starting compound for lansoprazole preparation having the chemical name of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinil]thio]-lHbenzimidazole.
  • T ⁇ P refers to tert-butylhydroperoxide.
  • alkanol refers to an alkane with one or more hydrogen atoms substituted by the hydroxyl functional group.
  • exemplary alkanols are C1-C 5 which include methanol, ethanol, isopropanol, propanol, butanol, sec-butanol and pentanol.
  • Branched alkanol may be functionally equivalent as to primary alkanol.
  • IP A refers to isopropanol which is a representative primary alkanol.
  • Et2 ⁇ refers to N,N-diethyl amine.
  • Room temperature refers to the ambient temperature which is about 20°C to about 25°C.
  • % refers to % (wt/wt).
  • the present invention provides a process for preparing a compound having formula (I):
  • R 1? R 2 , and R- ⁇ are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower alkoxy; and R 3 is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl, comprising the steps of: a) reacting a compound of formula (II)
  • R 1 through R 4 are as in formula (I), with tert- butylhydroperoxide in the presence of a cataylst vanadium oxytrichloride, wherein the reaction is carried out in an organic solvent selected from the group consisting of Ci., C 2 _, C 3- , C - and Cs. alkanols, decane, nonane, toluene, and a mixture of the organic solvent and water; and b) isolating a compound having formula (I).
  • the reaction is performed in the presence of a weak base.
  • the present invention is to provide a process of preparing 2-[[[3- methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-iH-benzimidazole (lansoprazole).
  • lansoprazole i.e., compound of formula (I), wherein Ri is methyl; R 2 is 2-trifluoroethoxy; R is hydrogen and R 4 is hydrogen).
  • the compound is lansoprazole.
  • the present invention is to provide a process of preparing 5- methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-iH-benzimidazole (omeprazole) (i.e., compound of formula (I), wherein Ri is methyl; R 2 is methoxy; R 3 is methyl and R is methoxy).
  • omeprazole 5- methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-iH-benzimidazole
  • the present invention is to provide a process of 5- (difluoromethoxy)-2- [ [(3 ,4-dimethoxy-2-pyridinyl)methyl] sulfinyl] -1H- benzimidazole (pantoprazole) (i.e., compound of formula (I), wherein Ri is methoxy; R 2 is methoxy; R 3 is hydrogen and R-i is difluoromethoxy).
  • pantoprazole i.e., compound of formula (I), wherein Ri is methoxy; R 2 is methoxy; R 3 is hydrogen and R-i is difluoromethoxy.
  • the compound is pantoprazole.
  • the present invention is to provide a process of 5-methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridyl) methyl]sulfinyl]-iH-benzimidazole (rabeprazole) (i.e., compound of formula (I), wherein Ri is methyl; R 2 is MeOC ⁇ 2 C ⁇ C ⁇ 2 O, R 3 is hydrogen and R is hydrogen.
  • the compound is rabeprazole.
  • the present invention provides a method to prepare 2-(2-pyridylmethyl) sulfinyl-lH- benzimidazole compounds by selective oxidation with tert- butylhydroperoxide.
  • This oxidation method is generally applicable to benzimidazole derivatives including lansoprazole, omerparazole, pantoprazole, and rabeprazole.
  • LNP lansoprazole
  • 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methyl]sulfinyl-lHbenzimidazole) i.e., compound of formula (I), wherein R is hydrogen, Ri is hydrogen, R is methyl, R 3 is trifluoro-ethoxy, R 4 is hydrogen.
  • LNPS i.e., 2-[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinil]thio]-lHbenzimidazole
  • 2-[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinil]thio]-lHbenzimidazole is used as a starting material for preparation of LNP.
  • a process of preparing omerparazole by using the corresponding omerprazole sulfide as a precursor and selectively oxidize the thioether group of omperprazole precursor to form omerprazole.
  • pantoprazole by using the corresponding pantoprazole sulfide as a precursor and selectively oxidize the thioether group of pantoprazole precursor to form pantoprazole.
  • a process of preparaing rabeprazole by using the corresponding raberprazole sulfide as a precursor and selectively oxidize the thioether group of pantoprazole precursor to form raberprazole is achieved by vanadium catalyzed oxygenation.
  • the vanadium catalyzed oxidation of thioether with vanadium oxytrichloride and tertiary butyl hydroperoxide yields a high yield and a low level of impurities.
  • the vanadium oxytrichloride and tertiary butyl hydroperoxide catalyzed oxidation is performed in the presence of an alkanol.
  • the reaction is performed in the presence of an alkanol and a weak base.
  • the amount of the vanadium oxytrichloride used is generally about 0.01 to about 0.5 mole relative to one mole of the compound having the formula (II). More preferably, the vanadium oxytrichloride is used at about 0.005 to about 0.3 mole relative to one mole of the compound having the formula (II).
  • the method of this invention for selective oxidation is carried out with an aqueous solution of tertiary butyl hydroperoxide.
  • a solution of tertiary butyl hydroperoxide in organic solvent such as decane, nonane, toluene and a mixture of said organic solvent and water may also be used.
  • the concentration of teritary butyl hydroperoxide used is usually 10 to 70%, preferably 70%, but should not be limited only to these ranges.
  • the amount of oxidizing agent (i.e., tertiary butyl hydroperoxide) used is usually a slight excess relative to one molar equivalent of the compound having the formula (II).
  • the oxidizing agent used is about 1 to about 3 equivalents. More preferably, about 1.3 to about 2 equivalents.
  • the solvents used for the vanadium catalyzed oxidation of thioether with vanadium oxytrichloride include an alkanol.
  • a lower alkanol is preferred.
  • Exemplary alkanol includes C1-C 5 alkanols such as methanol, ethanol, isopropanol, propanol, sec-butanol, butanol and pentanol.
  • Primary alkanols and secondary alkanols can be used.
  • isopropanol is used.
  • These solvents may be used singly or in combination. It is convenient to conduct this reaction in the presence of a weak base.
  • the weak base is exemplified by alkali metal carboante (e.g., potassium carbonate and sodium carbonate), and organic amines (e.g., diethyl amine and triethyl amine).
  • alkali metal carboante e.g., potassium carbonate and sodium carbonate
  • organic amines e.g., diethyl amine and triethyl amine.
  • the amount of weak base used is in an amount of about from about 4 to about 5 mol. equivalent relative to the compound having the formula (II). More preferably, the weak base is from about 3 mol. equivalent relative to the compound having the formula (11).
  • the reaction temperature for vanadium catalyzed oxidation of thioether with vanadium oxytrichloride is usually the temperature below the room temperature.
  • the temperature is about 5°C to about 15°C. More preferably, the temperature is about 10°C.
  • the reaction time is about 4 to about 24 hours.
  • the reaction time is about 4 to about 15 hours. More preferably, the reaction time is about 6 hours.
  • sodium sulfite is used to neutralize the oxidation reaction.
  • Other compounds e.g., sodium bisulfite
  • sodium bisulfite that can neutralize the oxidizing agent may be used as well.
  • the compound of the formula (I) produced by the oxidation reaction described above may be separated out by conventional methods such as filtration, after the addition of sodium sulfite.
  • the filtrate may be washed.
  • the filtrate may then be dried to obtain the compound of formula (I). Drying may be optimized. Preferably, drying is performed by exposing filtrate at about 40°C in vacuo at 10 mm Hg for overnight.
  • the obtained compound of formula (I) may further be purifed by crystallization or chromatography.
  • Crystallization in an organic solvent may be used and exemplary crystallizing organic solvents include aqueous ethanol and acetone.
  • the obtained compound of formula (I) is of good yield and high purity.
  • the obtained 2-(2-pyridylmethylsulfinyl) benzimidazole is routinely obtained in a good yield (about 85% or more) and with low production of by-products such as 2-(2-pyridylmethylsulfonyl) benzimidazole N- oxide.
  • the invention will be better understood from the following experimental details. These examples are provided to illustrate specific embodiments of the present invention but they are not intended to be limiting in any way.
  • reaction mixture was then stirred at 10°C for 6 hours. Then an aqueous solution of sodium sulfite (5%, 25 mL) was added dropwise to the reaction mixture. The mixture was further stirred at room temperature for 1 hour. The suspension was filtered and washed with water. The filtrate was dried at 40°C in vacuo at 10 mm Hg overnight to give crude L ⁇ P (5 grams, assay 86.28%, yield was 86%).
  • Example 3 0.1 ⁇ solution of NOCl 3 in IPA was used.
  • a suspension of L ⁇ PS 5.0 grams, 14.16 mmoL
  • IPA 25 mL
  • 0.01 mol. eq. of NOCl 3 i.e., 0.01 x 14.16 mmoL
  • Et 2 ⁇ H 1.3 mL of 0.1 N solution VOCl 3 in IPA treated with 88 microliter (0.03 eq x 14.16 mmoL) of Et 2 NH].
  • a 70% aqueous TBHP (2.9 mL, 21.24 mmoL) was subsequently added and the resultant mixture was held at 10°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de lansoprazole (LNP) (I) et de composés connexes dont le rendement est élevé et le niveau d'impuretés faible par oxydation de sulfure correspondant (composé de formule (II)) avec du tert-butyl hydroperoxyde (TBHP), que l'on catalyse à l'aide de l'oxytrichlorure de vanadium catalytique dans un solvant organique choisi dans le groupe constitué de C1-C5 alkanol, de décane, de nonane, de toluène et d'un mélange du solvant organique et de l'eau, de préférence en présence d'une base.
PCT/US2003/023588 2002-07-26 2003-07-28 Preparation de lansoprazole et composes connexes Ceased WO2004011455A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP03748985A EP1467987A1 (fr) 2002-07-26 2003-07-28 Preparation de lansoprazole et composes connexes
AU2003268034A AU2003268034A1 (en) 2002-07-26 2003-07-28 Preparation of lansoprazole and related compounds

Applications Claiming Priority (2)

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US39868602P 2002-07-26 2002-07-26
US60/398,686 2002-07-26

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WO2004011455A1 true WO2004011455A1 (fr) 2004-02-05

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AU (1) AU2003268034A1 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1681056A1 (fr) * 2005-01-14 2006-07-19 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation du lansoprazole
EP2030973A1 (fr) * 2007-08-31 2009-03-04 KRKA, tovarna zdravil, d.d., Novo mesto Procédé pour la préparation de 2-sulfinyl-1H-benzimidazoles
CN103288799A (zh) * 2013-03-05 2013-09-11 宁夏康亚药业有限公司 兰索拉唑的合成方法及由该方法合成的兰索拉唑

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2063705A1 (es) * 1993-06-14 1995-01-01 S A L V A T Lab Sa Intermedio para la sintesis de lansoprazol y su procedimiento de obtencion.
US5578732A (en) * 1987-08-04 1996-11-26 Takeda Chemical Industries, Ltd. Production of 2-(2-pyridylmethylsulfinyl) benzimidazole compounds by selective oxidation in the presence of a vanadium catalyst
WO2002062786A1 (fr) * 2001-02-02 2002-08-15 Teva Pharmaceutical Industries Ltd. Procedes de production de 2-(2-pyridylmethyl) sulfinyl-1h-benzimidazoles substitues

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578732A (en) * 1987-08-04 1996-11-26 Takeda Chemical Industries, Ltd. Production of 2-(2-pyridylmethylsulfinyl) benzimidazole compounds by selective oxidation in the presence of a vanadium catalyst
ES2063705A1 (es) * 1993-06-14 1995-01-01 S A L V A T Lab Sa Intermedio para la sintesis de lansoprazol y su procedimiento de obtencion.
WO2002062786A1 (fr) * 2001-02-02 2002-08-15 Teva Pharmaceutical Industries Ltd. Procedes de production de 2-(2-pyridylmethyl) sulfinyl-1h-benzimidazoles substitues
US20030036554A1 (en) * 2001-02-02 2003-02-20 Ilya Avrutov Processes for the production fo substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1681056A1 (fr) * 2005-01-14 2006-07-19 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation du lansoprazole
WO2006074952A1 (fr) * 2005-01-14 2006-07-20 Krka, Tovarna Zdravil, D.D., Novo Mesto Procede de preparation de lansoprazole
US7662968B2 (en) 2005-01-14 2010-02-16 KRKA tovarna zdravil, d.d.. Process for preparing lansoprazole
EP2308492A1 (fr) 2005-01-14 2011-04-13 KRKA, tovarna zdravil, d.d., Novo mesto Procédé de préparation du lansoprazole
EA015043B1 (ru) * 2005-01-14 2011-04-29 Крка, Товарна Здравил, Д.Д., Ново Место Способ получения лансопразола
CN101137371B (zh) * 2005-01-14 2011-05-25 克卡制药新梅斯托股份公司 制备兰索拉唑的方法
EP2030973A1 (fr) * 2007-08-31 2009-03-04 KRKA, tovarna zdravil, d.d., Novo mesto Procédé pour la préparation de 2-sulfinyl-1H-benzimidazoles
WO2009027533A1 (fr) * 2007-08-31 2009-03-05 Krka, Tovarna Zdravil, D.D., Novo Mesto Procede de preparation de 2-sulfinyl-1h-benzimidazoles
EA018796B1 (ru) * 2007-08-31 2013-10-30 Крка, Товарна Здравил, Д. Д., Ново Место Способ получения 2-(2-пиридинилметилсульфинил)-1н-бензимидазолов
CN103288799A (zh) * 2013-03-05 2013-09-11 宁夏康亚药业有限公司 兰索拉唑的合成方法及由该方法合成的兰索拉唑
CN103288799B (zh) * 2013-03-05 2015-05-20 宁夏康亚药业有限公司 兰索拉唑的合成方法及由该方法合成的兰索拉唑

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EP1467987A1 (fr) 2004-10-20

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