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

Definitions

• the present invention relates to a process for the preparation of 2- [[ (2 -pyridinyl) methyl] sulfinyl] -1H- benzimidazole derivatives of the general formula I
• R 2 represents H, OCH 3 , OCHF 2 or CF 3
• R 3 represents H, CH 3 or OCH 3
• R 4 represents H, 0CH 3 , OCH 2 CF 3 or halo, such as Cl , Br or F, and
• R 5 represents H, CH 3 or OCH 3 , and salts thereof.
• the invention relates to novel compounds of use for such purpose .
• the above mentioned compounds of formula I are biologically active and/or may be of use as inter- mediates in the synthesis of biologically active compounds .
• compounds of formula I has been prepared by oxidation of the corresponding thioether into the sulfinyl compound using suitable oxidation agents such as m-chloroperbenzoic acid.
• suitable oxidation agents such as m-chloroperbenzoic acid.
• PCT- /CA94/00452 suggests a process for the preparation of omeprazole and lansoprazole, wherein the oxidation is carried out on an amide analogue of the thioether, which is a crystalline compound, after which the resulting corresponding sulfinyl compound is hydrolysed in an alkaline medium to give the corresponding carboxylic acid salt which can be decarboxylated to omeprazole or lansoprazole, as the case may be.
• PCT/SE91/00402 (WO 91/18895) is directed to an improved method for the synthesis of omeprazole by oxidation of the thioether with m-chloroperbenzoic acid aiming at eliminating the drawbacks of previously known methods.
• the reaction with m-chloro- perbenzoic acid is carried out in a methylene chloride solution at a substantially constant pH of about 8.0 to 8.6; the reaction is extracted with aqueous NaOH; the aqueous phase is separated from the organic phase; and an alkyl formate is added to the aqueous phase, result - ing in crystallization of omeprazole.
• the present invention is directed to a basically different process for the preparation of the compounds of formula I whereby the compounds of formula I are prepared by reduction rather than by oxidation, the above mentioned disadvantages by the oxidation process thereby being eliminated.
• the present invention provides a new process for the preparation of 2- [[ (2-pyridinyl) methyl] sulfinyl] -IH-benzimidazole derivatives of the general formula I
• R 2 represents H, 0CH 3 , OCHF 2 or CF 3
• R 3 represents H, CH 3 or OCH 3
• R 4 represents H, 0CH 3 , OCH 2 CF 3 or halo, such as Cl, Br or F, and
• R 5 represents H, CH 3 or OCH 3 , and salts thereof, which process comprises reducing a compound of the general formula II or a salt thereof
• R 2 , R 3 , R 4 and R s are as defined above, in an alcoholic solvent, the reduction being carried out using a thiobisamine as reducing agent in the presence of a mineral acid, and, if desired, converting a compound obtained in free form into a salt thereof, or vice versa.
• the compounds of formula II may e.g. be prepared as described in our copending patent application (Danish patent application No. 0250/97, International patent application No. PCT/DK98/ ) being directed to a new synthesis for the preparation of these compounds which proceeds in three steps via novel cyclic intermediates and provides the compounds in excellent yield. The three steps may even be carried out in situ as a one-pot process .
• the unsubstituted compound of formula II i.e. the compound 2- [[ (l-oxido-2-pyridinyl) methyl] sulfinyl] -IH- benzimidazole, is described in FR 2 567 123 Al , Example 13. No conversion of the compound to the corresponding 2- [ [ (2 -pyridinyl) ethyl] sulfinyl] -IH-benzimidazole is described.
• the compound of formula II wherein R 3 and R 5 represent CH 3 , and R 2 and R 4 represent 0CH 3 i.e. the compound, 5-methoxy-2- [ [ (4-methoxy-3 , 5-dimethyl-l- oxido- 2 -pyridinyl ) methyl ] sulf inyl ] - IH-benzimidazole
• ES 2 063 705 does describe an N-oxide which is converted into lansoprazol .
• this N- oxide is not lansoprazole-N-oxide, but the compound 2-
• the 2- [ [ (2 -pyridinyl ) methyl] sulfinyl] -IH-benzimidazole derivatives of the formula I can be obtained in high yield by reduction of the corresponding N-oxides using thiobisamines as reducing agent under particular reaction conditions.
• Many reducing agents have been suggested for use in the reduction of pyridine-N-oxides into pyridines, cf . e.g. the survey given in Houben-Weyl , "Methoden der Organischen Chemie", Vol. E7b, Part 2, (1992), pp. 543 - 557.
• thiobisamines have not hitherto been suggested for use in the reduction of pyridine-N-oxides into pyridines.
• the thiobisamines allow for selective reduction of the N-oxide group in the compounds of formula II when the reduction is carried out in an alcoholic solvent in the presence of a mineral acid.
• the compounds of formula I may be obtained in an almost quantitative yield.
• the reaction takes place under mild conditions.
• the reduction is carried out in an alcoholic solvent, such as in a methanolic 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 reduction is carried out in the presence of a mineral acid, such as hydrochloric acid and/or sulphuric acid.
• a mineral acid such as hydrochloric acid and/or sulphuric acid.
• the hydrochloric acid may be added as a solution of hydrogen chloride in water, e.g. as concentrated hydrochloric acid or as a solution of hydrogen chloride in 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 alcoholic solvent does not need to be anhydrous, but may include some water. However, it will also be appreciated that an anhydrous alcoholic solvent may be used.
• the thiobisamine used in the process according to the invention is preferably a compound of the general formula III
• R', R" , R" ' and R" which may be the same or different, represent hydrogen, alkyl or C 3 -C 8 cycloalkyl, at least one of R' and R" and at least one of R" ' and R"" being other than hydrogen, or the groups R' and R" , respectively the groups R" ' and R" " , may be joined so as to form a 5- or 6-membered heterocyclic ring together with the nitrogen atom to which they are bound, which heterocyclic ring may optionally contain one or two additional hetero atoms selected from oxygen, sulphur and nitrogen.
• C.-C 8 alkyl groups linear and branched alkyl groups like 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 may be mentioned, and as examples of the C 3 -C 8 alkyl groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl may be mentioned.
• the thiobisamines used as reducing agents in the process according to the invention may be symmetrical or asymmetrical, and they may be primary or secondary or mixed primary and secondary amines .
• the reduction is carried out in a methanolic and/or ethanolic solvent in the presence of hydrogen chloride under substantially anhydrous conditions using thiobismorpholine or thiobispiperidine as reducing agent .
• the thiobisamine is used in at least an equimolar ratio to the compound of formula II, 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 thiobisdiamines used as reducing agents by the process according to the invention may e.g. be prepared by the process described by John L. Kice et al . , J. Org. Chem. 1991, 56, 5235-5236. They are stable compounds which can be synthesized by a simple process using easily available starting materials and several of them are crystalline. The crystalline compounds are preferred for ease of handling, although it does not mean that liquid thiobisamines cannot be used as reducing agents by the process according to the invention. Thiobismorpholine and thiobispiperidine are examples of the crystalline compounds and as such represent preferred reducing agents. Other methods for the preparation of thiobisamines (diaminosulfanes) have e.g. been described in Houben- Weyl, "Methoden der organischen Chemie", Vol. Ell, pp. 15-21, (1985) .
• 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 4-Methoxy-2-nitroaniline (150 g, 892 mmol) , cyclo- hexylisocyanate (112 g, 892 mmol) og pyridine (45 mL) were dissolved in DMF (dimethylformamide) (1.5 L) and heated to 80 °C for 8 h. The formed suspension was cooled to room temperature and ethanol (0.5 L) was added. After cooling on an ice bath, the precipitate was filtered off and washed with ethanol. Drying at 50°C afforded 227 g (87 %) of the title compound as a yellow product. Mp. 233-35°C.
• 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.
• Example C 5-Methoxy-2- [ ⁇ (4-methoxy-3 , 5 -dimethyl - l-oxido-2-pyridinyl) methyl] sulfinyl] IH-benzimidazole (Omeprazole-N-oxide) .
• N-Cyclohexyl-2 , 3-dihydro-5-methoxy-2 - thioxo-lH- benzimidazole-1-carboxamide 91.6 g, 300 mmol
• Example 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
• Example C-B was suspended in dry tetrahydrofuran (200 mL) and cooled on an ice bath. Potassium-t-butylate (20.2 g, 180 mmol) was added in portions over 30 min. After further stirring for 5 min., 4-methoxy-2 , 3 , 5-trimethyl- pyridine-N-oxide (8.0 g, 48 mmol) was added. The dark green reaction mixture was stirred for 20 min., whereupon acetic acid (7.2 g, 120 mmol) was added. The suspension was evaporated in vacuum to about 100 mL, and the formed residue was dissolved in 1-butanol- toluene (1:4) (100 mL) - water (250 mL) .
• Example D 2 -Cyclohexyl-1 , 2 , 4-thiadiazolo [4 , 5- a] benzimidazole-3 (2H) -one-1-oxide (2 steps in situ).
• N-Cyclohexyl-2 , 3 -dihydro- 2 -thioxo- IH-benzimidazole- 1-carboxamide (68.8 g, 250 mmol) (Ex. B) was suspended in chloroform (1.0 L) at room temperature. Bromine (40.0 g, 250 mmol) was added over 30 min. at 23-30°C. Triethylamine (50.5 g, 500 mmol) was added. The formed solution was cooled to room temperature and stirred for 1 h and then washed with water (2x500 mL) . The organic phase was dried over anhydrous sodium sulfate .
• Example E 2 -[[ [3 -methyl-4- (2 , 2 , 2-trifluoroethoxy) -l-oxido-2-pyridinyll methyl] sulfinyl] -lH-benzimida- zole (Lansoprazole-N-oxide) .
• Omeprazole sodium salt Preparation of Omeprazole sodium salt.
• Omeprazole (3.45 g, 10.0 mmol) was suspended in methanol (15 mL) .
• Sodium methoxide (540 mg, 10.0 mmol) was added, whereby a new precipitate was formed.
• t-butylmethylether 50 mL
• the precipitate was filtered off, washed with t-butylmethylether and dried to give 3.7 g of omeprazole sodium salt as a white product .
• Example 1 was repeated, but using 1 , 1' -thiobis- piperidine (synthesized from sodium thiosulfate pen- tahydrate, 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% .
• the reaction mixture was evaporated in vacuum to about 35 mL and then water (100 mL) and t-butylmethylether (50 mL) were added.
• the pH was adjusted to 12 with IN sodium hydroxide. After stirring at pH 12.0 for 5 min. , the phases were separated.
• the water phase was washed with t-butylmethylether (50 mL) and then acetic acid was added slowly until pH 8.0.
• 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 mL. 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.) .

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=8091443

Family Applications (1)

Country Status (6)

Families Citing this family (11)

Family Cites Families (1)

• 1998
  • 1998-02-16 EP EP98902960A patent/EP0968204A1/de not_active Ceased
  • 1998-02-16 WO PCT/DK1998/000058 patent/WO1998040377A1/en not_active Application Discontinuation
  • 1998-02-16 AU AU59821/98A patent/AU5982198A/en not_active Abandoned
  • 1998-03-02 ZA ZA981733A patent/ZA981733B/xx unknown
  • 1998-03-06 HR HR0251/97A patent/HRP980116A2/hr not_active Application Discontinuation
• 1999
  • 1999-08-31 NO NO994209A patent/NO994209D0/no not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events