HRP980116A2 - Process for the preparation of 2-//(2-pyridinyl) methyl) sulfinyl/-1h-benzimidazoles and novel compounds of use for such purpose - Google Patents

Description

The proposed invention relates to a process for the preparation of 2-[[(2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole derivatives of the general formula I

[image]

where

R2 represents H, OCH3, OCHF2 or CF3,

R3 represents H, CH3 or OCH3,

R 4 represents H, OCH 3 , OCH 2 CF 3 or halo, such as Cl, Br or F, and

R5 represents H, CH3 or OCH3,

and their salts.

Furthermore, the invention relates to new compounds used for this purpose.

The above-mentioned compounds of formula I are biologically active and/or can be used as intermediates in the synthesis of biologically active compounds.

Compounds 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (omeprazole), 2-[[[4-(2,2,2- trifluoroethoxy)-3-methyl-2-pyridinyl]methyl]-sulfonyl]-1H-benzimidazole (lansoprazole), 2-[[(2-pyridinyl)methyl]sulfonyl]-1H- benzimidazole (timoprazole) and 5-difluoromethoxy-2 -[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (pantoprazole), which are known as agents that inhibit gastric acid secretion, are examples of biologically active compounds of general formula I.

In principle, compounds of formula I are produced by oxidation of the corresponding thioethers to sulfinyl compounds using suitable oxidizing agents such as m-chloroperbenzoic acid. For example compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulfonyl]-1H-benzimidazole (omeprazole), and its preparation from 5-methoxy-2-[[(4 - methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole by oxidation with m-chloroperbenzoic acid is described in EP 0 005 129 B1. Also, the compound 2-[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl]methyl]-sulfonyl]-1H-benzimidazole (lansoprazole) and its preparation by oxidation of 2-[[[4 -(2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole with m-chloroperbenzoic acid is described in EP 0 174 726 B1.

However, it has been reported that the oxidation process is associated with certain difficulties, one of which is that the final product is unstable when released under acidic conditions. Another disadvantage, which has also been reported, is that the starting thioether is an oil under normal temperature and pressure conditions and is therefore difficult to purify. Furthermore, it has been reported that the oxidation of the thioether causes a change in the color of the final product.

To overcome these shortcomings, PCT/CA94/00452 (WO 95/12590) proposes a procedure for the preparation of omeprazole and lansoprazole, according to which oxidation is carried out on the amide analogue of thioether, which is a crystalline compound, after which the resulting corresponding sulfinyl compound is hydrolyzed in an alkaline environment. thereby yielding the corresponding carboxylic acid which can be decarboxylated to omeprazole or lansoprazole as the case may be.

OCT/SE91/00402 (WO 91/188959) refers to an improved method for the synthesis of omeprazole by oxidation of thioether with m-chloroperbenzoic acid with the aim of eliminating the disadvantages of previous known methods. For this purpose, the reaction with m-chloroperbenzoic acid is carried out in solution in methylene chloride at at a substantially constant pH of about 8.0 to 8.6; the reaction product is extracted with aqueous NaOH; the aqueous phase is separated from the organic phase; and alkyl formate is added to the aqueous phase, resulting in crystallization of omeprazole.

The proposed invention relates to a fundamentally different process for preparing compounds of formula I, according to which compounds of formula I are produced by reduction and not by oxidation, which avoids the above-mentioned disadvantages of the oxidation process.

The proposed invention therefore provides a new process for the preparation of 2-[[(2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole derivatives of the general formula I

[image]

where

R2 represents H, OCH3, OCHF2 or CF3,

R3 represents H, CH3 or OCH3,

R 4 represents H, OCH 3 , OCH 2 CF 3 or halo, such as Cl, Br or F, and

R5 represents H, CH3 or OCH3,

and their salts,

which process involves the reduction of a compound of general formula II or a salt thereof

[image]

wherein R2, R3, R4 and R5 are defined as above, in an alcoholic solvent, the reduction being carried out using thiobisamine as a reducing agent in the presence of a mineral acid, and optionally, converting the resulting compound from the free form into its salt, or vice versa.

Compounds of formula II, most of which are novel compounds, can be prepared, for example, as described in our published patent application (Danish Patent Application No. 0250/97), International Patent Application No. PCT/DK98 ) which refers to a new procedure for the synthesis of these compounds, which takes place in three stages via new cyclic intermediates and provides compounds with excellent utilization. The three stages can be performed in situ as a one-pot process.

The unsubstituted compound of formula II, i.e. the compound 2-[[(1-oxido-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole, is described in FR 2 567 123 A1, Example 13. The conversion of this compound to the corresponding compound is not described 2-[[(2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole.

It has been reported that the compound of formula II in which R3 and R5 represent CH3 and R2 and R4 represent OCH3, i.e. the compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-1-oxido-2- pyridinyl)methyl]sulfonyl]-1H-benzimidazole (omeprazole-N-oxide), found as a metabolite of omeprazole in rats, CA 124; - 306394, Yakubutsu Dotai, 11(1), 45-56 (Japan), 1996.

A compound of formula II in which R2 and R5 represent hydrogen, R3 is methyl and R4 is 2,2,2-trifluoroethoxy, i.e. the compound 2-[[[4-(2,2,2-trifluoroethoxy)-3-methyl-1 -oxido-2-pyridinyl]methyl]-sulfonyl]-1H-benzimidazole (lansoprazole-N-oxide), is described in ES 2 063 705 B1, and which was obtained as an impurity during the oxidation of the compound 2-[[[4-( 2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl]methyl]-sulfonyl]-1H-benzimidazole in 2-[[[4-(2,2,2- trifluoroethoxy)-3- methyl-2 -pyridinyl] methyl]-sulfonyl]-1H- benzimidazole (lansoprazole), using m-perbenzoic acid or hydrogen peroxide in the presence of vanadium compounds as an oxidizing agent. It was not mentioned that the N-oxide was isolated or converted to lansoprazole.

So far, ES 2 063 705 describes the N-oxide which has been converted into lansoprazole. However, this oxide is not lansoprazole-N-oxide, but the compound 2-[[[4-(2,2,2-trifluoroethoxy)-3-methyl-1-oxido-2-pyridinyl]methyl]-thio]-1H- benzimidazole and is not directly converted to lansoprazole. Conversely, it was reduced to the compound 2-[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl] methyl]thio]-1H-benzimidazole, which was oxidized to 2-[[ [4-(2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl]methyl]sulfonyl]-1H-benzimidazole, i.e. lansoprazole, therefore the last step corresponds to the oxidation described above in EP 0 174 726 B1.

By the process according to the invention, 2-[[(2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole derivatives of formula I can be obtained with high yield by reduction of the corresponding N-oxide using thiobisamine as a reducing agent under special reaction conditions.

Many reducing agents have been proposed for use in the reduction of pyridine-N-oxides to pyridines, see, for example, the review given in Houben-Weyl, "Methoden der organischen Chemie", Vol. E7b, Part 2, (1992), p. 543-547. However, to our knowledge, thiobisamines have so far not been proposed for use in the reduction of pyridine-N-oxides to pyridines.

Thiobisamines enable the selective reduction of the N-oxide group in compounds of formula II if the reduction is carried out in an alcoholic solvent in the presence of a mineral acid. Thus, the compounds of formula I can be obtained with almost quantitative yield.

A further advantage is that the reaction takes place under mild conditions. Also, the reaction takes place in an alcoholic solvent, such as in a methanol and/or ethanol solvent. Furthermore, the reaction is usually carried out at a temperature in the range of -10°C - 40°C, although in principle there is no reason to use temperatures outside this range, such as temperatures in the range of -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 sulfuric acid. Hydrochloric acid can be added as a solution of hydrochloric acid in water, eg as concentrated hydrochloric acid or as a solution of hydrochloric acid in a solvent, preferably an alcoholic solvent, such as a solution in methanol and/or ethanol. It is also possible to use a solution of bromodioxide, for example in the alcohol mentioned above. As can be estimated from the above, the alcoholic solvent does not have to be anhydrous, but can contain some water. However, an anhydrous alcohol solvent can of course also be used.

Thiobisamine used in the process according to the invention is primarily a compound of general formula III

R'-(R'')-N-S-N-(R''')R''' III

in which R', R'', R''' and R'''', which may be the same or different, represent hydrogen C1-C8-alkyl or C3-C8-cycloalkyl, at least one of R' and R'' at least one of R''' and R'''' is different from hydrogen, or groups R'' and R'', or groups R''' and R'''' can be connected so that, together with the nitrogen atom on which are bound to form a five- or six-membered heterocyclic ring, which heterocyclic ring may, if necessary, contain one or two additional heteroatoms selected from oxygen, sulfur and nitrogen.

As examples of straight or branched C1-C8-alkyl groups, we can mention methyl, ethyl, propyl, including n-propyl and i-propyl, butyl including n-butyl, sec. butyl and tert. butyl, pentyl including n-pentyl, and tert. pentyl, hexyl, heptyl and octyl, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl can be mentioned as examples of C3-C8 alkyl groups.

Thiobisamines used as reducing agents in the process according to the invention can be symmetrical or asymmetrical, and they can be primary or secondary or mixed primary and secondary amines.

In the currently preferred embodiment, the reduction is carried out in a methanol and/or ethanol solvent in the presence of hydrogen chloride under mostly anhydrous conditions using thiobismorpholine or thiobispiperidine as a reducing agent.

Thiobisamine is usually used in at least an equimolar ratio to the compound of formula II, although the reaction can be carried out at lower ratios such as a ratio of approx. 0.8. There is no particular upper limit, but molar ratios above 5.0 are normally avoided for economic reasons. Typically, the molar ratio does not exceed 2.5, and in many cases it is in the range of 1.0 to 1.5.

The thiobisamines used as reducing agents in the process according to the invention can be produced, for example, by the process described by John L. Kice et al., J. Org. Chem. 1991, 56, 5235-5236. These are stable compounds that can be synthesized by a simple process using readily available starting materials, some of which are crystalline. Crystalline compounds are preferred for use due to ease of handling, although this does not mean that liquid thiobisamines cannot also be used as reducing agents in the process according to the invention. Thiobismorpholine and thiobispiperidine are examples of crystalline compounds and as such represent preferred reducing agents.

Other methods for the preparation of thiobisamine (diaminosulfan) are described, for example, in Houben-Weyl, "Methoden der organischen Chemie", Vol. E11, p. 15-21, (1985).

The invention will now be further illustrated by specific examples which, however, should not be considered as limiting the scope of the invention.

Examples

Preparation of initial materials

Example A.

N-cyclohexyl-2,3-dihydro-5-methoxy-2-thioxo-1H-benzimidazole-1-carboxamide (from 4-methoxy-2-nitroaniline)

N-cyclohexyl-N'-(4-methoxy-2-nitrophenyl)urea

4-Methoxy-2-nitroaniline (150 g, 892 mmol), cyclohexyl isocyanate (112 g, 892 mmol) and pyridine (45 ml) were dissolved in DMF (dimethylformamide) (1.5 L) and heated for 8 hours at 80°C. The resulting suspension was cooled to room temperature and ethanol (0.5 l) was added. After cooling in an ice bath, the precipitate was filtered off and washed with ethanol. Drying at 50°C gave 227 g (87%) of the title compound as a yellow product. Melting point 233-35°C.

N-cyclohexyl-N'-(2-amino-4-methoxyphenyl)urea

N-cyclohexyl-N'-(2-amino-4-methoxyphenyl)urea (50.0 g, 170 mmol) was suspended in ethanol (1.5 L) and 10% palladium on charcoal (5.0 Mr). The mixture is reduced overnight with hydrogen under 1 atm and at room temperature. The reaction mixture is heated to 70°C and the catalyst is filtered off. The filtrate is 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. Melting point 187-88°C.

N-cyclohexyl-2,3-dihydro-5-methoxy-2-thioxo-1H-benzimidazole-1-carboxamide

N-cyclohexyl-N'-(2-amino-4-methoxyphenyl)urea (104.4 g, 397 mmol) and carbon disulfide (66.4 g, 874 mmol) were heated in dry DMF (400 mL) 41 hour at 50°C. The obtained solution is cooled to room temperature and water (1250 ml) is added over 1.5 hours. Stirring was continued for 2 hours and the precipitate was filtered off, washed with water and dried at 60°C, yielding 118.6 g (98%) of the title compound as a white crystalline product. Melting point 188-90°C. Recrystallization from acetone raises the melting point to 198-210°C.

Example B.

N-cyclohexyl-2,3-dihydro-2-thioxo-1H-benzimidazole-1-carboxamide

The title compound was synthesized from 2-mercaptobenzimidazole and cyclohexylisocyanate mainly by the procedure described by E. Dyer et al., J. Heterocyclic Chem. 6 (1969) 23-28.

Example C.

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-1-oxido-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (omeprazole-N-oxide)

A. 2-cyclohexyl-7-methoxy-1,2,4-thiadiazolo[4,5-a]benzimidazol-3-(2H)-one

N-Cyclohexyl-2,3-dihydro-5-methoxy-2-thioxo-1H-benzimidazole-1-carboxamide (91.6 g, 300 mmol) (Example A) was suspended in chloroform (1.1 L) at room temperature. temperature. Bromine (47.9 g, 300 mmol) in chloroform (150 ml) was added over 70 minutes at room temperature. Add thiethylamine (60.6 g, 600 mmol). The resulting solution is cooled to room temperature for 1 hour and then washed with water (2 x 1 l). The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo to an oily crystalline suspension. Add ethanol (1.0 L). When cooled to 0°C the precipitate was filtered off, washed with ethanol and dried in vacuo at 35°C to give 87.0 g (96%) of the title compound as a white product. Melting point 181-4°C.

Calculated for C15H17N3O2S:

C: 59.4%; H: 5.7%; N: 13.9%; S: 10.6%

Found C: 59.2%; H: 5.8% N: 13.6%; S: 10.6%

B. 2-cyclohexyl-7-methoxy-1,2,4-thiadiazolo[4,5-a]benzimidazol-3-(2H)-one-1-oxide

2-Cyclohexyl-7-methoxy-1,2,4-thiadiazolo[4,5-a]benzimidazol-3-(2H)-one (24.3 g, 80 mmol) (Example C-A) was suspended in chloroform (160 ml) and cool in an ice bath. At 5°C, 99% m-CPBA (m-chloroperbenzoic acid) (13.8 g, 80 mmol) was added in small portions over 45 minutes. Then the ice bath is replaced with a n-propanol/ice bath. Stirring was continued for a further 20 minutes and then cold t-butylmethylether (480 ml) was added over 15 minutes.

When cooled to -9°C, the precipitate is filtered off and washed with t-butylmethylether. After drying in vacuum at room temperature, 20.6 g (81%) of the title compound is obtained as a white product. melting point 155-60°C.

Calculated for C15H17N3O2S:

C: 56.4%; H: 5.4%; N: 13.2%; S: 10.0%

Found C: 55.9%; H: 5.4% N: 12.8%; S: 9.8%

C. 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-1-oxido-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (omeprazole-N-oxide)

2-Cyclohexyl-7-methoxy-1,2,4-thiadiazolo[4,5-a]benzimidazol-3-(2H)-one-1-oxide (19.2 g, 60 mmol) (Example C-B) was suspended in dry tetrahydrofuran (200 ml) and cooled in an ice bath. Potassium t-butylate (20.2 g, 180 mmol) is added in portions over 30 minutes. Stir for another 5 minutes and then add 4-methoxy-2,3,5-trimethylpyridine-N-oxide (8.0 g, 48 mmol). The dark green reaction mixture was stirred for 20 minutes, after which acetic acid (7.2 g, 120 mmol) was added. The suspension is evaporated to approx. 100 ml and the resulting residue is dissolved in 1-butanol-toluene (1:4) (100 ml) - water (250 ml). When the pH is adjusted to 12 with 1N sodium hydroxide, the phases separate. The aqueous phase is slowly neutralized to pH 7.5 with acetic acid, which precipitates the title compound. When cooled to 0°C, the precipitate is filtered off, washed with water and dried, thereby obtaining 12.8 g of crude omeprazole-N-oxide. The crude product was stirred for 20 minutes at room temperature with methanol (150 ml) and then cooled to -20°C. The precipitate was filtered off and dried at 60°C, yielding 11.1 g (64%) of imeprazole-N-oxide as a white product. Melting point 177-8°C.

Example D.

2-cyclohexyl-1,2,4-thiadiazolo[4,5-a]benzimidazol-3-(2H)-one-1-oxide (2 steps in situ)

N-Cyclohexyl-2,3-dihydro-2-thioxo-1H-benzimidazole-1-carboxamide (68.8 g, 250 mmol) (Example B) was suspended in chloroform (1.0 L) at room temperature (Example B ) is suspended in chloroform (1.0 l) at room temperature. Bromine (40.0 g, 250 mmol) was added over 30 minutes at a temperature of 23-30°C. Triethylamine (50.5 g, 500 mmol) was added. The resulting solution is cooled to room temperature, stirred for 1 hour and then washed with water (2x500 ml). The organic phase is dried over anhydrous sodium sulfate.

The above solution is cooled in an ice bath. 98% m-CPBA (43.3 g, 250 mmol) dissolved in chloroform was added over 30 minutes at 3-8°C. It is stirred for another 30 minutes and then the chloroform is distilled off in a vacuum (bath at 40°C) enough to obtain a fatty suspension (approx. 250 ml). Add t-butylmethylether (1 L). After cooling in an ice bath, the precipitate is filtered off and washed with t-butyl methyl ether. Drying at 30°C in vacuum gives 61.2 g (85% in two steps) of the title compound as a white product. Melting point 155-7°C.

Calculated for C14H15N3O2S:

C: 58.1%; H: 5.2%; N: 14.5%; S: 11.1%

Found C: 58.6%; H: 5.4% N: 14.4%; S: 11.2%

Example E.

2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-1-oxido-2-pyridinyl]methyl]-sulfonyl]-1H-benzimidazole (lasoprazole-N-oxide)

2-Cyclohexyl-1,2,4-thiadiazolo[4,5-a]benzimidazol-3-(2H)-one-1-oxide (28.9 g, 100 mmol) (Example D) was dissolved in dry tetrahydrofuran ( 300 ml) and cool in an ice bath. Potassium t-butylate (28.0 g, 250 mmol) is added in portions over 40 minutes. It was stirred for another 10 minutes and then 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine-N-oxide (13.3 g, 60 mmol) was added. The reaction mixture was stirred for 15 minutes and then acetic acid (9.0 g, 150 mmol) was added. The mixture is evaporated under vacuum and the obtained residue is dissolved in 1-butanol - toluene (3:2) (250 ml) - water (250 ml) and enough acetic acid is added to obtain a pH of 7.0. The phases are separated and the organic phase is washed. The resulting fatty suspension was taken up in methanol (200 ml) and cooled in an ice bath. The precipitate is filtered off and washed with methanol and then with water. Drying at 50°C yields 7.9 g of crude lansoprazole-N-oxide. The product is briefly heated under reflux in chloroform (100 ml) and then cooled to room temperature. The crystals were filtered off, washed with chloroform and dried to give 5.3 g (23%) of lansoprazole N-oxide as a white crystalline product. Melting point 183-3.5°C (dec.).

Calculated for C16H14 F3N3O3S:

C: 49.9%; H: 3.7%; N: 10.9%; S: 8.3%

Found C: 50.3%; H: 3.8% N: 10.8%; S: 8.5%

Example F.

2-[[(4-methoxy-3,5-dimethyl-1-oxido-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole

2-Cyclohexyl-1,2,4-thiadiazolo[4,5-a]benzimidazol-3-(2H)-one-1-oxide (11.6 g, 40 mmol) (Example D) was suspended in dry tetrahydrofuran ( 150 ml) and cool in an ice bath. Potassium t-butylate (13.4 g, 120 mmol) is added in portions over 25 minutes. Stir for 5 minutes and then add 4-methoxy-2,3,5-trimethylpyridine-N-oxide (5.4 g, 24 mmol). The dark green solution was stirred for 30 minutes and then acetic acid (4.8 g, 80 mmol) was added. The reaction mixture was evaporated in vacuo to give an oily suspension (approx. 50 ml) and then 1-butanol - toluene (1:3) (80 ml) and water (150 ml) were added. Adjust the pH to 12 with 11N sodium hydroxide. The aqueous phase is then washed with 1-butanol - toluene (1:3) (80 ml) and then acetic acid is added slowly to adjust the pH to 7.7. The resulting suspension is cooled in an ice bath. The precipitate is filtered off and washed with water. Drying at 50°C gave 7.0 g of the crude title compound. The product is briefly stirred with methanol (0 ml) at room temperature and then cooled to -20°C. the product was filtered off, washed with methanol and dried at 50°C to give 6.3 g (59%) of the title compound as a white powder. Melting point 183-4°C (dec.).

Calculated for C16H17N3O3S:

C: 58.0%; H: 5.2%; N: 12.7%; S: 9.7%

Found C: 57.9%; H: 5.4% N: 12.8%; S: 9.8%

Examples illustrating the process according to the invention

Example 1.

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (omeprazole)

Powdered omeprazole N-oxide (3.61 g, 10.0 mmol) (Example C) and 4,4'-thiobismorpholine (2.65 g, 13.0 mmol) (synthesized from sodium thiosulfate pentahydrate, bromine, and morpholine, as described by J.L. Kice et al., J. Org. Chem. 56 (1991) 5235-6), suspended in methanol (70 ml) and cooled in an ice bath. Add 2.83 N hydrogen chloride in ethanol (7.4 ml 21.0 mmol). It is stirred for 20 minutes, resulting in a clear yellowish solution. 1N sodium hydroxide solution (20 ml) was added and the resulting solution was evaporated under vacuum at approx. 25 ml. Water (100 ml) and t-butyl methyl ether (50 ml) were added to the residue. The pH was adjusted to 12 with 1N sodium hydroxide. It is mixed for 20 minutes at pH 12, the phases are separated and acetic acid is slowly added to the aqueous phase until pH 7.8 is obtained. After mixing at room temperature, the precipitate is filtered off, washed with water and dried at 50°C. 3.24 g (94%) of omeprazole was obtained as a beige colored powder. Melting point 153-4°C (exp.). The FTIR spectra of the product and the authentic sample were identical.

Calculated for C17H19N3O3S:

C: 59.1%; H: 5.6%; N: 12.2%; S: 9.3%

Found C: 59.1%; H: 5.6% N: 12.1%; S: 9.6%

Example 2.

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (omeprazole)

Example 1 was repeated, but using 1,1'-thiobispiperidine (synthesized from sodium thiosulfate pentahydrate, bromine, and piperidine, as described by J.L. Kice et al., J. Org. Chem. 56 (1991) 5235-6) as the reducing agent. resources. Utilization 91%. Melting point 154-5°C (dec.).

Calculated for C17H19N3O3S:

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%

Example 3.

2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]-sulfonyl]-1H-benzimidazole (lasoprazole)

Lansoprazole N-oxide (3.85 g, 10.0 g, 14.0 mmol) (synthesized from sodium thiosulfate pentahydrate, bromine, and morpholine, as described by J. L. Koce et al., J. Org. Chem. 56 (1991 ) 5235-6), suspended in methanol (80 ml) at room temperature. 2.85 N hydrogen chloride in ethanol ((.4 ml, 24 mmol) is added over 3 minutes. Stir for 90 minutes, the resulting solution is evaporated in vacuo to approx. 25 ml and water (100 ml) is slowly added. With 1N pH is adjusted to 7.5 with sodium hydroxide. The precipitate, which is separated after stirring at room temperature, is filtered off and washed with water. Drying at 40°C gives 3.57 g (97%) of lansoprazole with a purity of 94%. Melting point 169 -70°C (diss.). Analytical pure lansoprazole is obtained by recrystallization from acetone as a white crystalline product. Melting point 176-7°C (diss.). The FTIR spectra of the product and the authentic sample were identical.

Calculated for C16H14 F3N3O2S:

C: 52.0%; H: 3.8%; N: 11.4%; S: 8.7%

Found C: 52.2%; H: 4.0% N: 11.1%; S: 8.8%

Example 4

2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole

2-[[(4-methoxy-3,5-dimethyl-1-oxido-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (3.31 g, 10.0 mmol) (Example F) and 4.4 '-thiobismorpholine (2.86 g, 14.0 mmol) (synthesized from sodium thiosulfate pentahydrate, bromine and morpholine, as described by J. L. Kice et. al., Org. Chem. 56 (1991) 5235-6), suspended in methanol (75 ml) and cooled in an ice bath. Add 2.83 N hydrogen chloride in ethanol (7.4 ml, 21 mmol). The reaction is monitored by HPLC. After stirring for 1.5 hours and another 2.5 hours, more thiobismorpholine (0.82 g, and 0.41 g) and 2.83 N hydrogen chloride in ethanol (2.8 ml and 1.4 ml) were added. It is stirred for another 30 minutes and 1N sodium hydroxide (33 ml) is added. The reaction mixture is evaporated in vacuo at approx. 35 ml and then water (100 ml) and t-butylmethylether (50 ml) were added. Adjust the pH to 12 with 1N sodium hydroxide. After stirring for 5 minutes at pH 12.0, the phases are separated. The aqueous phase was washed with t-butylmethylether (50 ml) and then acetic acid was added slowly until pH 8.0. The resulting suspension is extracted with 1-butanol - toluene (1:1) (120 ml) at 30°C. The organic phase is dried over anhydrous sodium sulfate and then evaporated in vacuo at approx. 35 ml. Cool to 5°C, filter, wash with 1-butanol and dry at 50°C to give 2.41 g (77%) of the title compound as a white crystalline product. Melting point 164-5°C (dec.).

Calculated for C16H17 N3O2S:

C: 60.9%; H: 5.4%; N: 13.3%; S: 10.2%

Found C: 61.1%; H: 5.6% N: 13.3%; S: 10.0%

A second yield of 0.21 g (7%) of the title compound (purity 96%) could be obtained from the mother plant.

In the preceding, the invention was described by means of examples of preferred embodiments. However, it is understood that various modifications may be made by those skilled in the art without departing from the spirit and purpose of the invention.

Claims (9)

1. Process for the preparation of 2-[[(2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole derivatives of general formula I [image] where R2 represents H, OCH3, OCHF2 or CF3, R3 represents H, CH3 or OCH3, R 4 represents H, OCH 3 , OCH 2 CF 3 or halo, such as Cl, Br or F, and R5 represents H, CH3 or OCH3, and their salts characterized in that the compound of general formula II or its salt is reduced [image] wherein R2, R3, R4 and R5 are defined as above, in an alcoholic solvent, the reduction being carried out using thiobisamine as a reducing agent in the presence of a mineral acid, and optionally, converting the resulting compound from the free form into its salt, or vice versa. 2. The method according to claim 1, characterized in that thiobisamine is a compound of the general formula III R'-(R")-N-S-N-(R"')R"" in which R', R", R"' and R"", which may be the same or different, represent hydrogen, C1-C8-alkyl or C3-C8-cycloalkyl, at least one of R' and R", or the group R ”' and R””2 can be connected so that, together with the nitrogen atom to which they are attached, they form a five- or six-membered heterocyclic ring, which heterocyclic ring can optionally contain one or two additional heteroatoms selected from oxygen, sulfur and nitrogen. 3. The method according to claim 1, characterized in that the thiobisamine is thiobismorpholine or thiobispiperidine. 4. The method according to one or more previous claims, characterized in that thiobisamine is used in a molar ratio to the compound of formula (II) of 0.8 - 5.0, especially in a molar ratio of 1.0 - 2.5, and preferably in molar ratio of 1.0 - 1.5. 5. The process according to one or more of the preceding claims, characterized in that the reduction takes place in a methanol and/or ethanol solvent. 6. The process according to one or more of the preceding claims, characterized in that the reduction takes place in the presence of hydrochloric acid and/or sulfuric acid. 7. The method according to one or more of the preceding claims, characterized in that the reduction takes place in the temperature range of -50°C - 70°C, preferably in the range of -10°C - 40°C. 8. Compound of general formula (II) [image] characterized in that R 2 , R 3 , R 4 and R 5 are as defined above, or a salt thereof, provided that all of R 2 , R 3 , R 4 and R 5 are not hydrogen, but if R 3 is methyl and R 4 is 2,2,2- trifluoroethoxy, then both R2 and R5 are not hydrogen, and if both R3 and R5 represent CH3, then both R2 and R4 carry OCH3. 9. A compound according to claim 9, characterized in that R 2 represents OCHF 2 , R 3 and R 4 represent OCH 3 , and R 5 is H.