EP0968205A1 - Verfahren zur herstellung von 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazolen und dabei verwendbare neue verbindungen - Google Patents

Verfahren zur herstellung von 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazolen und dabei verwendbare neue verbindungen

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Publication number
EP0968205A1
EP0968205A1 EP98902961A EP98902961A EP0968205A1 EP 0968205 A1 EP0968205 A1 EP 0968205A1 EP 98902961 A EP98902961 A EP 98902961A EP 98902961 A EP98902961 A EP 98902961A EP 0968205 A1 EP0968205 A1 EP 0968205A1
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EP
European Patent Office
Prior art keywords
compound
process according
general formula
carried out
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98902961A
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English (en)
French (fr)
Inventor
Finn Priess Clausen
Klaus Karl Mccluskey
Herbert Fritz Preikschat
Soren Bols Pedersen
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Sandoz AS
Original Assignee
GEA Farmaceutisk Fabrik AS
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Publication date
Application filed by GEA Farmaceutisk Fabrik AS filed Critical GEA Farmaceutisk Fabrik AS
Publication of EP0968205A1 publication Critical patent/EP0968205A1/de
Withdrawn legal-status Critical Current

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for the preparation of 2- [[ (2-pyridinyl) methyl] sulfinyl] -IH- benzimidazole derivatives of the general formula V
  • R represents H, OCH 3 , 0CHF 2 or CF 3 ,
  • R 3 represents H, CH 3 or 0CH 3 ,
  • R 4 represents H, 0CH 3 , OCH 2 CF 3 , halo or nitro
  • R 5 represents H, CH 3 or OCH 3 , and n is 0 or 1, and salts thereof.
  • the invention relates to novel compounds of use for such purpose .
  • the above mentioned compounds of formula V are biologically active and/or may be used as intermediates in the synthesis of biologically active compounds.
  • the compounds of formula V wherein n is 1 are novel compounds.
  • the present invention provides an elegant new synthesis for the preparation of these compounds, which proceeds in three steps via novel cyclic intermediates and provides the compounds in excellent yields. The three steps may even be carried out in situ as a one-pot process.
  • the compounds of formula V, wherein n is 1, are converted into the corresponding compounds of formula V, wherein n is 0, by reduction.
  • FR 2 567 123 Al includes no description of any other 2- [[ (l-oxido-2-pyridinyl) methyl] sulfinyl] -lH-benzimidazoles or their preparation. No conversion of the compound to the corresponding 2- [ [ (2-pyridinyl) methyl] sulfinyl] -IH-benzimidazole is described either.
  • N-oxide being isolated or converted into lansoprazole .
  • the present invention provides a new process for the preparation of 2- [[ (2-pyridinyl) methyl] sulfinyl] - IH-benzimidazole derivatives of the general formula V
  • R 2 represents H, OCH 3 , 0CHF 2 or CF 3 ,
  • R 3 represents H, CH 3 or OCH 3 ,
  • R 4 represents H, OCH 3 , OCH 2 CF 3 , halo or nitro
  • R 5 represents H, CH 3 or 0CH 3 , and n is 0 or 1, and salts thereof, which process comprises thhee sstteeppss ooff : ii)) ccyyccllii:zing a 2 , 3-diihhyyddrroo--22--tthhiiooxxoo--llHH--benzimida- zole-1-carboxamide of the g rre ⁇ neciraa ll f fo ⁇ rrmmunlla _a I T
  • R 1 represents branched or straight C 1 _ a - alkyl, C 3 . 8 -cycloalkyl , aryl, aralkyl having 1-8 C-atoms in the alkyl moiety, or a 5- or 6-membered heterocyclic group having one, two or three hetero atoms selected from nitrogen, sulfur and oxygen in the heterocyclic ring
  • R 2 have the same meanings as defined for formula V and is located in the 5- or 6-position of the benz- imidazole nucleus, by oxidation in a suitable solvent so as to form a 1, 2 , 4-thiadiazolo [4 , 5-a] benzimidazole-3 (2H) -one of the general formula II,
  • R 1 and R 2 are as defined above, and the R 2 group is located in the 6- or 7 -position of the condensed ring, ii) oxidizing the obtained compound of formula II so as to form a 1 , 2 , 4-thiadiazolo [4 , 5-a] benzimidazole- 3 (2H) -one-1-oxide of the general formula III,
  • R 1 and R 2 are as defined above, and the R 2 group is located in the 6- or 7 -position of the condensed ring, and iii) reacting the obtained compound of formula III with a pyridine-N-oxide of the general formula IV
  • R 3 , R 4 and R 5 are as defined above, in the presence of an alcoholate, so as to form a 2-[(2- pyridinylmethyl) sulfinyl] -IH-benzimidazole derivative of the general formula Va
  • R 2 , R 3 , R 4 and R 5 are as defined above, and, if desired, converting a compound obtained in free form into a salt thereof, or vice versa, a compound of any of the formulae I, II, III and Va, if desired, being converted into a different compound of said formula before the reaction in the next step is carried out, and furthermore, if desired, iv) reducing the obtained compound of formula Va or a salt thereof into a compound of the general formula Vb,
  • R 2 , R 3 , R 4 and R 5 are as defined above, and, if desired, converting a compound obtained in free form into a salt thereof, or vice versa.
  • the synthesis of addition products of the unsub- stituted benzimidazolinethione and isocyanates and the cyclization of the addition products by treatment with bromine/triethylamine, sulfurylchloride or thionyl- chloride has been described in Tetrahedron, Vol. 39, No. 13, pp. 2311 - 2314, (1983), D. Martin and F. Tittelbach, "Synthesen von Benzimidazolo [1, 2-d] (1,2,4)- thiadiazolinen” .
  • the compounds of formula II wherein R 2 is other than hydrogen appear to be novel compounds and as such represent a particular aspect of the invention.
  • the compounds of formula I wherein R 2 is other than hydrogen appear to be novel compounds and as such represent a particular aspect of the invention.
  • the oxidation of sulphenamides into sulphinamides has been described in e.g. Houben-Weyl , " Methoden der Organischen Chemie", Vol. Ell, p. 655, (1985) and Patai, "The Chemistry of Sulphinic Acids", p. 259 and pp. 609-10 (1990).
  • the compounds of formula III appear not only to be novel, but also to represent a novel cyclic structure.
  • R 2 ; R J R 4 and R 5 are as defined above, are formed.
  • R 1 represents branched or straight preferably such as methyl, ethyl, propyl , incl . n-propyl and i-propyl, butyl, incl. n-butyl, sec. -butyl and tert. -butyl, pentyl, incl. n-pentyl and tert . -pentyl , hexyl , heptyl and octyl, C 3 .
  • R 1 group is not particularly critical as long as it allows the desired reactions to take place.
  • a presently preferred R 1 group is cyclohexyl being easily obtainable through the commercially available cyclohexyliso- cyanate .
  • the oxidative cyclisation in step i) is carried out in a suitable solvent, such as a halogenated hydrocarbon solvent, preferably chloroform, methylene chloride, 1 , 1 , 1-trichloroethane or a mixture thereof.
  • a suitable solvent such as a halogenated hydrocarbon solvent, preferably chloroform, methylene chloride, 1 , 1 , 1-trichloroethane or a mixture thereof.
  • any solvent allowing the desired reaction to take place may be used.
  • the cyclisation is carried out using an oxidation agent, such as an oxidation agent selected from bromine, chlorine and sulfuryl chloride.
  • an oxidation agent selected from bromine, chlorine and sulfuryl chloride.
  • a base such as a trialkylamine base and preferably triethylamine, may be added.
  • the cyclisation is carried out using bromine as oxidation agent followed by addition of triethylamine.
  • the oxidative cyclisation will be carried out at a temperature from -20°C - 70°C, and preferably from 0°C - 40°C.
  • step ii) the compound of formula II is oxidized into a compound of formula III using a suitable oxidation agent.
  • a suitable oxidation agent such as oxidation agents selected from peracids, alkylhydroperoxides, benzoylperoxides, hydrogenperoxide, tetraalkylammonium meta-periodates and perborates, can be mentioned.
  • the peracids are preferably optionally substituted perben- zoic acids, such as m-chloroperbenzoic acid.
  • the oxidation in step ii) is carried out at a temperature from -70°C - 70°C, and preferably from -20°C - 30°C.
  • the oxidation in step ii) is carried out in a suitable solvent, such as a halogenated hydrocarbon solvent, preferably chloroform, methylene chloride, 1,1,1- trichloroethane or a mixture thereof.
  • a suitable solvent such as a halogenated hydrocarbon solvent, preferably chloroform, methylene chloride, 1,1,1- trichloroethane or a mixture thereof.
  • any solvent allowing the desired reaction to take place may be used.
  • the reaction of the compound of formula III with the pyridine-N-oxide of formula IV in step iii) is carried out in the presence of an alcoholate, such as an alkali or alkaline earth metal alcoholate of an aliphatic or alicyclic alcohol.
  • an alcoholate such as an alkali or alkaline earth metal alcoholate of an aliphatic or alicyclic alcohol.
  • Lithium, sodium and potassium are specific examples of the alkali metals and calcium and magnesium are specific examples of the alkaline earth metals which may be of use in the preparation of the alcoholate.
  • Methanol , ethanol, n- propanol , i-propanol, n-butanol, i-butanol and t- butanol are specific examples of the aliphatic alcohols, and benzyl alcohol of the alicyclic alcohols which may be of use in the preparation of the alcoholate.
  • a presently preferred alcoholate is an alkali metal alcoholate, particularly potassium t- butoxide.
  • the reaction in step iii) is carried out at a temperature from -70°C - 50°C and preferably from -30°C - 30°C.
  • suitable solvents for the reaction in step iii) are solvents of alkyl- or cycloalkylether type, such as tetrahydrofuran and dioxane, although any solvent allowing the reaction to take place may be used.
  • all three steps i) , ii) and iii) or the steps i) and ii) , respectively ii) and iii) may be carried out in situ as a one-pot process.
  • a compound of formula Va or a salt thereof as obtained by the above steps i) , ii) and iii) may be reduced into a compound of formula Vb using a suitable reducing agent, a compound of any of the formulae I, II, III and Va, if desired, being converted into a different compound of said formula before the reaction in the next step is carried out.
  • reducing agents which may be of use for the reduction of a compound of formula Va into a compound of formula Vb
  • thiobisamines diaminosul- fanes
  • dialkoxysulfanes dialkoxysulfanes
  • catalytical reduction agents such as RaNi/H 2 and Ru-catalysts/H 2
  • the reduction is carried out using a thiobisamine and particularly thiobismorpholine or thiobispiperidine as reducing agent in the presence of an alcohol and an acid.
  • the thiobisamines allow for selective reduction of the N-oxide group in the compounds of formula Va, whereby the compounds of formula Vb may be obtained in almost quantitative yield.
  • the reaction takes place under mild conditions.
  • the reduction can be carried out in an alcoholic solvent, such as in a meth- anolic and/or ethanolic solvent.
  • the reaction will usually be carried out at a temperature in the range from -10°C - 40°C, although, in principle, there is no hindrance to using temperatures outside this range, such as temperatures in the ranges from -50°C - -10°C and from 40°C - 70°C.
  • the thiobisamine is used in at least an equimolar ratio to the compound of formula Va, although the reaction may proceed at lower ratios such as at ratios of about 0.8.
  • the reaction may proceed at lower ratios such as at ratios of about 0.8.
  • molar ratios above 5.0 will normally be avoided.
  • the molar ratio will not exceed 2.5 and in most cases the molar ratio will be in the range from 1.0 to 1.5.
  • the reduction is carried out in the presence of a mineral acid, preferably hydrochloric acid and/or sulphuric acid.
  • the hydrochloric acid may be added as a solution of hydrogen chloride in water, e.g.
  • a solvent preferably an alcoholic solvent, such as a solution in methanol and/or ethanol .
  • a solution of hydrogen bromide e.g. in an alcohol as mentioned above, may be used.
  • the reduction is carried out in a methanolic and/or ethanolic solvent in the presence of hydrogen chloride under substantially anhydrous conditions.
  • Example A N-Cyclohexyl -2 , 3-dihydro-5-methoxy-2- thioxo-lH-benzimidazole-1-carboxamide (from 4-methoxy- 2-nitroaniline) . N-Cyclohexyl-N' - (4-methoxy-2-nitrophenyl) urea.
  • N-Cyclohexyl-N' - (2-amino-4-methoxyphenyl) urea N-Cyclohexyl-N' - (4-methoxy-2-nitrophenyl) urea .
  • N-Cyclohexyl-N' - (4-methoxy-2-nitrophenyl) urea 50.0 g, 170 mmol) was suspended in ethanol (1.5 L) and 10% Palladium on Carbon (5.0 g) was added. The mixture was reduced with hydrogen at 1 atm. and room temperature overnight. Then the reaction mixture was heated to 70°C and the catalyst filtered off. The filtrate was evaporated to 400 mL and cooled to -20°C. The precipitate was filtered off, washed with ethanol and dried at 50°C to give 39.8 g (89 %) of the title compound as a white crystalline product. Mp . 187-88°C.
  • N-Cyclohexyl-N' - (2 -amino-4 -methoxyphenyl ) urea (104.4 g, 397 mmol) and carbondisulfide (66.4 g, 874 mmol) were heated in dry DMF (400 mL) for 41 h at 50°C. The resulting solution was cooled to room temperature and added to water (1250 mL) over 1_ h. After further stirring for 2 h the precipitate was filtered off, washed with water and dried at 60°C to give 118.6 g (98 %) of the title compound as a white crystalline product. Mp. 188-90°C. Recrystallisation from acetone raised the melting point to 198-201°C.
  • Example B N-Cyclohexyl-2 , 3-dihydro-2 -thioxo-lH- benzimidazole-1-carboxamide .
  • N-Cyclohexyl-2 , 3 -dihydro-5-methoxy-2 - thioxo-lH- benzimidazole-1-carboxamide (91.6 g, 300 mmol) (Ex. A) was suspended in chloroform (1.1 L) at room temperature. Bromine (47.9 g, 300 mmol) in chloroform (150 mL) was added over 70 min. at room temperature. Triethylamine (60.6 g, 600 mmol) was added. The formed solution was allowed to cool to room temperature over 1 h and then washed with water (2x1 L) . The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuum into a fat crystalline suspension.
  • N-Cyclohexyl -2, 3 -dihydro-5-methoxy-2 -thioxo-lH- benzimidazole-1-carboxamide (9.16 g, 30 mmol) (Ex. A) was suspended in chloroform (100 mL) at room temperature. Bromine (4.80 g, 30 mmol) in chloroform (50 mL) was added over a period of 1 h at room temperature.
  • Triethylamine (6.06 g, 60 mmol) was added. The formed solution was cooled to room temperature and washed with water (2x150 mL) . The organic phase was dried over anhydrous sodium sulfate and filtered. The above solution was cooled on an ice bath. 98 % m-CPBA (5.02 g, 29 mmol) was added in portions over 25 min. After further stirring for 40 min. chloroform was distilled off in vacuum. Remaining chloroform was removed by evaporation in vacuum with toluene to give a fat crystalline suspension.
  • Example 4 was repeated, but using 1, 1 ' -thiobis- piperidine (synthesized from sodium thiosulfate penta- hydrate, bromine and piperidine as described by J. L. Kice et al, J. Org . Chem. 56 (1991) 5235-6) as the reducing agent. Yield 91%. Mp . 154-5°C (dec). Calc. for C 17 H 19 N 3 0 3 S : C:59.1%; H:5.6%; N:12.2%; S:9.3%. Found: C:59.1%; H:5.6%; N:12.2%; S:9.5%.
  • Petroleum benzine (bp. 80-100°C) was added. The formed precipitate was filtered off, washed with petroleum benzine and dried in vacuum at 35°C to give 24.3 g (89 %) of the title compound as an off-white product. Mp . 202-6°C.
  • acetic acid (4.8 g, 80 mmol) was added.
  • the reaction mixture was evaporated in vacuum to a fat suspension (about 50 mL) and then 1-butanol-toluene (1:3) (80 mL) and water (150 mL) were added.
  • the pH was adjusted to 12 with UN sodium hydroxide.
  • the water phase was washed with further 1-butanol-toluene (1:3) (80 mL) and then adjusted to pH 7.7 by slowly addition of acetic acid.
  • the resulting suspension was cooled on an ice bath.
  • the precipitate was filtered off and washed with water. Drying at 50°C gave 7.0 g of the crude title compound.
  • the formed suspension was extracted with 1-butanol-toluene (1:1) (120 mL) at 30 °C.
  • the organic phase was dried over anhydrous sodium sulfate and then evaporated in vacuum to about 35 L. Cooling to 5°C, filtration, washing with 1- butanol and drying at 50 °C gave 2.41 g (77 %) of the title compound as a white crystalline product. Mp . 164- 5°C (dec.) .
  • the title compound was prepared in 3 steps from N- cyclohexyl-2 , 3-dihydro-5-methoxy-2-thioxo-lH-benzimida- zole-1-carboxamide and 4-chloro-2 , 3 , 5-trimethyl-pyri- dine-N-oxide in 40 % yield essentially following the procedure described for omeprazole-N-oxide (Ex. 2) . Mp . 188-9°C (dec.) .
  • the reaction mixture was poured into water (40 mL) , and pH was adjusted to 7.0 with acetic acid (1.35 mL) . Then chloroform (50 mL) was added. After separ- ation of the water phase, the chloroform phase was washed with water (2 x 50 mL) and dried over magnesium sulf te. After removal of the magnesium sulfate by filtering, hexane in excess (50 mL) was added. The reaction mixture was left for crystallisation for 1 h, after which the crystals were removed by filtering, washed with hexane (25 mL) and dried.
  • the NMR data correspond to those of an authentic sample .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP98902961A 1997-03-07 1998-02-16 Verfahren zur herstellung von 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazolen und dabei verwendbare neue verbindungen Withdrawn EP0968205A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK25097 1997-03-07
DK25097 1997-03-07
PCT/DK1998/000059 WO1998040378A1 (en) 1997-03-07 1998-02-16 Process for the preparation of 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazoles and novel compounds of use for such purpose

Publications (1)

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EP0968205A1 true EP0968205A1 (de) 2000-01-05

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Country Status (6)

Country Link
EP (1) EP0968205A1 (de)
AU (1) AU5982298A (de)
HR (1) HRP980115A2 (de)
NO (1) NO994340L (de)
WO (1) WO1998040378A1 (de)
ZA (1) ZA981732B (de)

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SE510643C2 (sv) * 1997-06-27 1999-06-14 Astra Ab Termodynamiskt stabil omeprazol natrium form B
US6166213A (en) * 1998-08-11 2000-12-26 Merck & Co., Inc. Omeprazole process and compositions thereof
US6191148B1 (en) 1998-08-11 2001-02-20 Merck & Co., Inc. Omerazole process and compositions thereof
WO2002030886A2 (en) * 2000-10-12 2002-04-18 Matthews Barry R Heterocyclic angiogenesis inhibitors
WO2004056804A2 (en) 2002-12-19 2004-07-08 Teva Pharmaceutical Industries Ltd. Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates
EP1615913A2 (de) 2003-06-10 2006-01-18 Teva Pharmaceutical Industries Limited Verfahren zur herstellung von (pyridinyl)methyl]sulfinyl-substituierte benzimidazoles und neue chlorierte derivate von pantoprazole
SE0400410D0 (sv) 2004-02-20 2004-02-20 Astrazeneca Ab New compounds
EP1921075B1 (de) * 2006-10-30 2010-03-03 Dipharma Francis S.r.l. Verfahren zur Herstellung von Pyridinmethylsulphinylverbindungen
EP2022789A1 (de) * 2007-08-06 2009-02-11 Farmaprojects, S.A. Verfahren zur Herstellung eines Magensäuresekretionshemmers
CN102964336B (zh) * 2012-11-29 2014-08-06 寿光富康制药有限公司 质子泵抑制剂的精制方法及其n-氧化物的还原方法
CN103044401A (zh) * 2012-12-21 2013-04-17 北京华禧联合科技发展有限公司 苯并咪唑类化合物的制备方法
CN103951651B (zh) * 2014-03-24 2018-11-30 翰宇药业（武汉）有限公司 雷贝拉唑相关物d的合成方法
CN105111187B (zh) * 2015-08-07 2017-08-25 齐鲁天和惠世制药有限公司 一种泮托拉唑钠氮氧化杂质的制备方法

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DD231787A1 (de) * 1984-08-10 1986-01-08 Akad Wissenschaften Ddr Verfahren zur herstellung von omega-substituierten bzw. omega, omega-disubstituierten 2-methylthio-benzimidazolderivaten
ES2026761A6 (es) * 1990-10-31 1992-05-01 Genesis Para La Investigacion Procedimiento de obtencion del omeprazol.

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Title
See references of WO9840378A1 *

Also Published As

Publication number Publication date
AU5982298A (en) 1998-09-29
NO994340D0 (no) 1999-09-07
ZA981732B (en) 1998-09-07
NO994340L (no) 1999-09-07
HRP980115A2 (en) 1999-02-28
WO1998040378A1 (en) 1998-09-17

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