SE459808B - CHEMICAL COMPOSITION THAT CAN BE USED AS INTERMEDIATE FOR THE PREPARATION OF 4-METHYL-5-ALKYLTYOMETHYLIMIDAZOLES - Google Patents

Description

Het-caz-Q where Q is a substitutable group and Het is a 4-methyl-5-imidazolyl group, with HSCH 2 CH 2 NH 2 to form Het-CH 2 SH 2 NH 2 2 which is then treated with 2.

NR 3 gave R 2 -C 2 NnR 1 to give cimetidine, if R 1 is cH 3, R 2 is cm 3, R 3 is alkyl or aryl and Z is S.

It is well known that the substituted imidazoles used in these and other known processes are difficult to obtain and the process according to the SE patent specification therefore proceeds in a completely different way, both in terms of starting materials1 * and_reactions. .

Thus, in the process according to the SE patent specification, a compound of the formula _CH -C-C-CH -X 3 H U 2 (I) A B is used as starting material, where one of the substituents A and B is NOH and the other is O or NOK. X is a suitable, substitutable group, e.g. a halogen atom or a group OZ, where Z is a hydrogen atom or e.g. an acyl or tosyl group, or X is NR 3, where R 6 is an alkyl group. Preferred starting materials are such readily available halogen compounds as e.g. 1-bromo-3-oximino-2-butanone and 4-chloro-3-oximino-2-butanone.

In a first reaction step, a compound of formula I is treated with a compound of the formula, NcN nsnlkïmu-cfáy g (III Nunlkz 459 808 in which Alk1 is an alkylene group and Alkz is an alkyl group having 1-4 C atoms, preferably in cooling with a strong base, eg sodium ethoxide, to form CN CH3-í-o-CH2-S-Alkl-NH-C4% 7N (III) 1 AB NHAlk2 in which A, B, Alkl and Alkz have the meanings given above.

The compounds of formula III are hitherto unknown compounds and thus constitute the invention.

In a next reaction step, a compound of formula III is cyclized by treatment with formaldehyde or a formaldehyde donor, e.g. paraformaldehyde, or mixtures thereof, or with formaldehyde and / or a formaldehyde donor mixed with ammonia or an ammonia donor, e.g. ammonium acetate, or with a reagent of the formula YN = CH2 in which Y is OH or preferably aralkyl, although other groups may also be suitable, to form an imidazole N-oxide of the following formula o + § ca <| 3 ¿çç9NCN N »'\ _, cnzscnzcnzuu c \\\\ (iv) Y NHCH3 or Y. å CH3 <* I NCN N: I: ï ca son cn NH-C45; (v) J 2 2 2 »o, Nncn3 in which Y has the same meaning as above or hydrogen. If Y is hydrogen, the compounds may consist of a mixture of two tautomers, namely an N-oxide and the corresponding N-hydroxy tautomer.

If Y differs from H or OH, the compound IV or V is selectively reduced to convert the Y group to veeë and finally deoxygenated to give the final product ßq C113 (1 If cuzsalkïnn-c 'H \ naAlkz NCN preferably cimetidine, where Alk1 = C2H4 and Alk2 = CH3.

The deoxygenation can also take place before the reduction. As previously mentioned, the compounds of formula III are hitherto unknown, and since they contain numerous reactive positions, it is both unexpected and surprising that they are added to imidazole N-oxides in good yields. It is in particular that the oyanoguanide group can withstand the treatment of the reagents necessary for the cyclization and, moreover, that according to the Journal of Chemistry, Ig (1970), 211-215, z-unsubstituted imidazole-N- oxides cannot be isolated under reaction conditions analogous to those used in the present process.

The present invention relates to a novel chemical compound of the formula III - / Non CrLB-cc-cuš-s-Alkj-Nn-c / (111) li ll 'A a \ Nunlkz Furthermore, the selective reduction of a compound of formula IV or V unpredictable and completely surprising. A priori, it would be expected that the benzylic C-S bond would be most easily reduced by known methods.

Nor could it be foreseen that the deoxygenation of compounds IV and V could take place as indicated due to the number of other reactive positions open to attack by 459,808 known deoxygenating agents, and the use of these then also leads to unsatisfactory results. It was therefore surprising that it was found that complexes of trialkylamine and sulfur dioxide, such as e.g. (CH 3) 3 N + -SO; or formamidine sulfinic acid, gave the desired product in good yield, since the sulfur trioxide or sulfonic acid formed during the reaction could be assumed to give undesired side reactions, cf. Synthesis (1979), 36.

The following examples illustrate how the novel compounds of the invention are prepared and their use as an intermediate for the preparation of 4-methyl-5-alkyl-thiomethyl-imidazoles.

Example 1 N-cyano-N'-methyl-N "- ([2- (3-oximino-2-oxobutyl) thio] ethyl) guanidine (IIIa) Na 2 nm (11.0 g, 0.48 mol) was added to ethanol (250 ml) followed by N-cyano-N'-methyl-N "- (2-mercaptoethyl) -guanidine (II, 76.0 g, 0.48 mol). Then a solution of 1-bromo-3-oximino-2-butanone (86.0 g, 0.524.mol) in anhydrous ethanol (250 ml) was added dropwise at -25 ° C. The reaction mixture was allowed to stand at 5 ° C until the next day, when the precipitated sodium bromide was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in acetonitrile (800 ml) and stirred with silica gel for 30 minutes, after which the silica gel was filtered off and the filtrate was evaporated in vacuo. After trituration with ether, the title compound could be isolated (99.0 g, 80%). Stirring in water followed by filtration gave an analyte-pure product, m.p. 111-112 ° C. Calculated for C 9 H 15 N 5 O 2 S: C 42.00; H 5.88; N 27.22; S 12.46 Found: C 41.97; H 5.90; N 27.08; S 12.66 IR and 1 H NMR spectra were consistent with the indicated structure. 459 sus Example 2 ~ N-cyano-N'-methyl-N "- ([2- (2-Gemino-3-oxobutyl) tiq / ethyl) -guanidine (IIIb) Sodium (5.75 g 0.250 mol) was dissolved in ethanol (100 ml) and N-cyano-N'-methyl-N "- (2-mermaptoethyl) guanidine (II, 39.6 g, 0.250 mol) was added in ethanol (60 ml). The resulting solution was stirred under nitrogen for 1 hour, then added to a solution of 4-chloro-3-oximino-2-butanone (33.9 g, (80 ml) over 40 minutes at 25 ° C). day, 0.250 mol) in ethanol. The resulting solution was allowed to stand at 5 ° C until the next, after which the precipitate was filtered off and washed with ethanol. The product was stirred with water for 30 minutes, and the title compound was isolated as beige crystals (36.8 g, 57%), m.p. 133 DEG-134 DEG C. with decomposition.

Calculated fl for C 9 H 15 N 5 O 2 S: C 42.00; H 5.88; N 27.22; S 12.46 C 42.15; H 6.00; N 26.96; S 12.20 spectra, were consistent with the structure found by the IR: 1 H and 1 H NMR.

Example 3 N-cyano-N'-methyl-N "- (2- [11-benzyl-3-oxido-4-methylimidazol-5-yl) tiq] ethyl) -guanidine (IVa) Compound IIIa (67.5 g (0.262 mol) dissolved in methanol (1000 ml) was mixed with N-benzylmethyleneimine (62.0 g, 0.521 mol) in petroleum ether (1000 ml), and the mixture was refluxed for 72 hours, the methanol phase was isolated and extracted with petroleum ether, and the solvent was evaporated in vacuo at 40 DEG C. The semi-crystalline residue was stirred with ether, which caused further crystallization, and the crystals were filtered off.

The mother liquor was concentrated again and treated with ether to give a new crop of crystalline material. The combined product was dissolved in a 1: 4 mixture of methanol and chloroform and the solution was stirred with silica gel. The latter was filtered off. The filtrate was evaporated in vacuo, the residue was stirred with acetonitrile, and the resulting crystals were filtered off and washed with ether to give the title compound with decomposition.

Calculated for C 17 H 22 N 6 OS: C 56.95; H 6.19; N 23.45; S 8.95 Found: C 56.56; H 6.17; N 23.23; S 8.78 IR, 1 H-NMR and 13 with the indicated structure.

C-NMR spectra were consistent with Example 4 N-cyano-N'-methyl-N "- (2 - [([1-benzyl-3-oxido-4-methyl-imidazol-5-yl] methyl) thio] ethyl) -guanidine (IVa) Compound IIIa (12.9 g, 50 mmol) in methanol (60 mL) was mixed with N-benzylmethyleneimine (9.0 g, 75 mmol) and acetic acid (0.6 g, 10. mol) and stirred at 25 ° C for 18 hours The solvent was evaporated in vacuo at 60 ° C. The residue was refluxed with acetone (100 ml) for 30 minutes, whereupon crystallization took place. At 13 ° C, the crystals were filtered off and dried, yielding the title compound in a yield of 15.2 g (85%), m.p. 183-184 ° C (dec.).

Example 5 N-Cyano-N'-methyl-N "- (2 - [(3-benzyl-3-oxido-5-methyl-imidazol-4-yl) thioethyl) -guanidine (Va) Compound IIIb (2, S7 g, 0.010 mol) in methanol (25 ml) was mixed with N-benzylmethyleneimine (2.38 g 0.020 mol) and heated under nitrogen to reflux for 17 hours The resulting solution was evaporated to dryness in vacuo and the residue crystallized from acetonitrile to give the title compound (2.87 9, 80%) m.p. 178-180 ° C with decomposition.

Calculated for c17n22N6os = c 56.95; H 6.59; N 23.45; s 3.95 Found: C 56.77; H 6.20; N 23.61; S 9.03 F ”IR and 1H ~ NHR spectra were consistent with the indicated structure. Example 6 N-Cyano-N'-methyl-N "- [2 - ([(1-oxido-5-methyl-yl) -methylthio) ethyl] -guanidine (IVb) imidazole-4-Compound IVa (35 .0 g (0.0976 mol) was suspended in liquid ammonia (700 ml) and sodium (7.2 g, 0.31 mol) was added followed by ammonium chloride (16.7 g, 0.3] mol). The nitrogen was removed by warming to room temperature, anhydrous ethanol (200 ml) was added and the reaction mixture was stirred for 30 minutes and then filtered, the filtrate was evaporated in vacuo and the residue was washed with ethyl acetate, the ethyl acetate phase was decanted off and the residue crystallized from the titanium. (15.3 161-162 ° C.

Calculated for C g 58%) with melting point] OH] 6N6OS: C44.74; H 6.01; N 31.32; S 11.95 Found: C 43.65; H 6.00; N 30.86; S 12.02 IR, 1 H-NMR and 13 C-NMR spectra were consistent with the indicated structure.

Example 7 N-Cyano-N'-methyl-N "- [2 - ([(1-oxido-4-yl) -methylthio) ethyl] -guanidine (Vb) -methylimidazole-5-Compound IVb (3.59 g .0 mmol) was dissolved in liquid ammonia (100 ml) and sodium (0.53 g, 23 mmol) was added in small portions followed by ammonium chloride (1.23 g 23 mmol) The ammonia was removed by heating to room temperature, propanol was added and the resulting suspension was stirred for 30 minutes, and filtered. The filtrate was seeded with crystals of Vb and cooled.

The separated crystalline material was filtered off and dried, yielding the title compound (2.0 g, 75%), m.p. 176-178 ° C with decomposition.

Recrystallization from dry methanol raised the melting point to 180 DEG-183 DEG C. with decomposition. Calculated for C 16 H 16 N 6 OS: C 44.75; H 6.01; N 31.32; S 11.95 Found: C 44.62; H 5.96; N 31.24; S 11.98 IR and 1 H NMR spectra were consistent with the indicated structure.

Example 8 Direct conversion of IIIb to Vb Compound IIIb (2.57 g 10.0 mmol), ammonium acetate (1.15 g, .0 mmol) and paraformaldehyde (0.33 g, 11.0 mmol) in 2N acetic acid (20 ml) is stirred for 2 hours at 5 ° C. aPLc (low pressure liquid chromatography) indicated a yield of 72% of Vb. The solvent was removed in vacuo and the residue was adjusted to pH 8 with 3N potassium hydroxide. The solvent was removed in vacuo and the residue was dissolved in a mixture of chloroform and methanol (4: 1), followed by stirring with silica gel and filtration. The filtrate was evaporated in vacuo and the residue was crystallized from methanol to give 1.20 g of the monohydrate of Vb. The mother liquor gave a further yield of Vb, H 2 O (0.51 g) by chromatography on silica gel. The total yield of Vb, H 2 O was 60%.

Calculated for C10HIGNGOS, H2 O: C 41.94; H 6.34; N 29.35; s 11.20; H 2 O 6.29 Punnet "= c 41.70; H 6.19; N 29.42; s 11.25; H 2 O 6.33 Recrystallization from dry ethanol increased the melting point to 181-183 ° C with decomposition.

The compound was identical to an authentic sample (IR and TH-NMR spectroscopy).

Example 9 Direct conversion of Iixb to vb Compound IIIb (5.15 g 20.0 mmol), ammonium dihydrogen phosphate (2.30 g 20.0 mmol), ammonium hydrogen phosphate (1.32 g, 10.0 mmol) and paraformaldehyde (0, 72 g (24 mmol) in water (40 ml) were stirred for 2 hours at 65 ° C, whereupon an HPLC analysis indicated a content of 57% of compound Vb. The reaction mixture was adjusted to pH 8 with ammonia water and the solvent was removed in vacuo. The residue was chromatographed on silica gel with chloroform-methanol (3: 1) as eluant. The main fraction from here kris- Gn & iLncunáuI'ur mnhnnul øuh nav l.?ä u lila! of vb »flfi ßß 0 - 3 10 459 808 Example 10 Direct conversion of IIIb to vb The solvent was removed in vacuo for 10 hours at room temperature of ammonium acetate (1.61, 21.0 mmol) in vacuo, the solvent was removed in vacuo and the residue was chromatographed on silica gel with chloroform-methanol (3: 1) as eluent. methanol to give Vb, HO (1.71 g, 41%), which on IR and 1H NHR spectroscopy could be shown to be identical to an authentic sample Example 11 Direct conversion of IIIa to Ivb Compound IIIa (2.57 g 0 mmolL, ammonium acetate (J, J5 g, 11.0 mmol) and paraformaldehyde (0.33 g, acid (20 ml) were stirred for 2 h at es ° C, indicating a content of 40% Ivb. Des in vacuo and the residue adjusted hydroxide 11 mmol) in 2N acetic acid on an HPLC analysis The solvent was removed at pH 8 with 3N potassium, then evaporation in vacuo took place again. The residue was chromatographed on silica gel with claw roform -methanol- (3í1) as eluent.

The main fraction was crystallized from methanol to give 0.68 g (25%) of Ivb.

Example 12 N-cyano-N'-methyl-N "- (2 - [(4-methylimidazol-5-yl) methyl) thioethyl) -guanidine (Cimetidine) Compound IVb (3.00 g 11.2 mmol) and trimethylamine sulfur dioxide ((cH3) 3n + -s_š, 2.7 9.22 mmol) in methano des in an autoclave at 130 ° C for 5 hours the reaction mixture in vacuo and potassium carbonate (2.0 g 14.5 l (60 ml After cooling, water was recovered (6 ml) (mmol) was added, whereby an almost quantitative yield of crude cimetidine could be isolated (2.83 g, melting point 13e413s ° c) to 142-143 ° c.

Calculated for C Upon recrystallization, the melting point was increased; 6N6s = c 47, so; H 6.39; N 33.31; s 12.11: C 47.60; H 6.42; N 32.94; S 12.81 spectra are identical to those for an authentic found IR and 1NMR sample. Example 13 Cimetidine Compound IVb (121 mg, 0.45 mmol) was dissolved in dimethylformamide (4.8 mL), formamidine sulfinic acid ((H2N) E-C'SO6, 49 mg, 0.45 mmol was added ) and the mixture was heated to 100 ° C for one hour, after which it could be shown by HPLC to contain 48% cimetidine.

Example 14 Cimetidine Compound IVb (2.00 g 7.5 mmol) was dissolved in 2-ethoxyethanol (40 ml), trimethylammonium sulfinate was added (2.70 g, 21.9 mmol) and the mixture was heated under reflux for 15 minutes. . Analysis by HPLC then indicated the presence of 72% cimetidine, of which 1.30 g (69%) could be isolated.

Example 15 Cimetidine In the manner described in Example 11, the compound Vb could be deogygenated to cimetidine.

Example 16 Deoxidation of Compound V to remove the benzyl group N-cyano-N'-methyl-N "- (2 - [([1-benzyl-5-methylimidazol-4-yl] -methyl) thioethyl) -guanidine ( A) Compound Va (7.2 g 20 mmol) was refluxed for 16 hours with 1.7 M trimethylamine sulfur dioxide in ethanol (24 ml).

After cooling to 0 ° C, separated crystals were filtered off and dried to give the title compound (6.2 g, 91%), m.p. 178-179 ° C.

Calculated for C 17 H 22 N 6 S: C 59.62; H 6.48; N 24.54; S 9.36 Found: C 59.53; H 6.55; N 24.43; S 9.41 1 13 H = NMR and C 1 NMR spectra correspond to the indicated structure. Example 17 Deoxidation of Compound Iva to remove the benzyl group N-cyano-N'-methyl-N "- [2 - ([(1-benzyl-4-methylimidazol-5-yl) -methyl] thio) ethyl ] -guanidine (B) Method I.c Compound IVa (7.9.9, SO mmol) was refluxed for 5 hours with 1.7 M trimethylamine sulfur dioxide in ethanol (60 ml).

After cooling to 0 ° C, separated crystals were filtered off and dried to give the title compound (14.9 g, 173-175 ° C).

Calculated for C 87%) with mp 17H 22 N 6 S: C 59.62; H 6.48; N 24.54; S 9.36 Found: C 59.81; H 6.44; N 24.83; S 9.42 1 H-NMR and 13 C-NMR spectra correspond to the indicated structure.

Example 18 (B) Method II Compound IVa (3.58 g, 10 mmol) was dissolved in methanol (50 ml) and carbon monoxide was added (a, 3s 91. was stirred at room temperature for 3 days for one week. Then the catalyst was filtered off. dryness; The mixture is a re-gas atmosphere.

The filtrate was evaporated to the residue, acetone (60 ml) was added and refluxing was carried out. room temperature was filtered off, desiccator was dried to compound B (3.05 g 89%) m After cooling to red crystals and at the melting point 172-17 ° C Example 19 N-cyano-N'-methyl + N "- [2 ([(4-methylimidazole + 5-yl) (methyl] + thio) -ethyl] guanidine (cimetidine) Compound B (274 g, 0.80 mol) was suspended in liquid ammonia (1200 ml. Sodium (40.0 g, 1.74 mol) was added followed by ammonium chloride (93.1 g, 1.74 mol) dissolved in water (400 ml), excess ammonia was evaporated, the resulting suspension was filtered and the precipitate was dried to give the title compound (185 g, 92%), m.p. 138 DEG-141 DEG. FPLC indicated a purity of 97%.

Claims (3)

13 459 808 PATENT CLAIMS 1. l. Association, k ä n n e t e c k n a d a v that it 'has the formula NcN çH3-c-c-cu2-s-A1k knee-c / I! II 1 * - B Nfmlkz where one of the substituents A and B is NOH and the other O or NOH, Alk1 is an alkylene and Alkz is an alkyl group having 1 to 4 carbon atoms. A compound as claimed in claim 1, characterized in that Aikl is czn4 and A113 is cn 3.