IE55946B1 - Thioethercyanoguanidines and their use as intermediates in producing imidazoles - Google Patents

Abstract

A new process is described for the production of 4-methyl-5-substituted- alkylthiomethyl-imidazoles, particularly Cimetidine of the formula by the following series of reactions wherein Alk<1> is alkylene preferably -CH2-CH2- and Alk<2> is C1-4 alkyl preferably CH3. The reactions for the selective reduction of Y and the deoxygenation may be effected in reverse order. The starting compound may have a second oxime group replacing the keto group or the oxime and keto groups shown may be transposed. The thioether cyanoguandines produced in the first reaction step are claimed as new compounds.

Description

Pries eop The invention relates to a new process for the production of 4-methy1-5-aIky1thiomethylimidazoles.

In the British Patent Specification No. 1,533,380 a process is described, according to which compounds, e.g., of the following formula Het-CH_-S-CH_CH'-ΝΗ-ΰζ ® _1 £ £ £ NHK are produced, wherein Het is a heterocyclic group, e.g., an imidazole group, E is S or NCN, and is H or lower alkyl, by letting a compound of the formula J 0 Het-CH2Z where Het is defined as hereinbefore, and Z is a leaving group react with a mercaptan of the formula HS-CH_CHo-NH-ci 2 NHR wherein R1 is defined as hereinbefore.

The Spanish Patent Specification No. 463,839 describes the preparation of Cimetidine, N-cyano-N’-methyl-N-[2-[(4-methyl5-imidazolyl)methylthio]-ethylIguanidine by treating 4-methyl5-hydroxymethylimidazole with thiourea followed by reaction with N-cyano-N1-methyl-N-(2-hydroxyethyl)guanidine.

The German published Specification No. 2,211,454 describes the preparation of, e.g.. Cimetidine by letting Het-CH2-Q wherein Q is zolyl group, a leaving group, and Het is a 4-methyl-5-imidareact with hsch2ch2nh2 to form Het-CH2SCH2CH2NH2 which is subsequently treated with r2 3z-c ^NHR1 3 R is CN, R is alkyl to give, e.g., Cimetidine when is CH^, or aryl and Z is S.

It is known that the starting materials, i.e. substituted imidazoles, for these and other known methods are not easy to obtain, and the present method consequently employs a totally different approach both with regard to starting materials and reaction pathway.

In the process according to the present invention, the starting material consists of a compound CH-C-CCH-X 3j| β 2 (I) A B wherein one of the substituents A and B is NOH and the other jo is 0 or NOH, X is a suitable leaving group, e.g., halogen or OZ, wherein Z is a hydrogen atom, or, e.g., an acyl or a tosyl group, or X is NR^, where R is alkyl; the preferential starting materials being the easily available halogen compounds, e.g., l-bromo-3-oximino-2-butanone and 4-chloro-3-oximino-2-butanone. ]5 Compound I is treated , in a first step, with ^NCN HSAlk NH-C 9 (ID \NHAlkZ preferably under cold conditions in the presence of a strong 1 base, such as sodium ethoxide, to give ^NCN CH-C-CCHoAlk NH-C o (III) 3|| || 2 ^NHAlk2 A B 7 wherein Alk is an alkylene group and Alk* is an alkyl group having 1-4 carbon atoms.

Compounds (III) are new and constitute a further aspect of the invention.

In a second step, the compound III is ring-closed by treat25 ment with formaldehyde or a formaldehyde donor, e.g. paraformaldehyde, or mixtures of formaldehyde and/or formaldehyde donor;, and ammonia or ammonia donors, e.g., ammonium acetate, or reagents with the formula YN = CH2 wherein Y in u removable «/roup such as 11 or HO or, preferentially, aralkyl, although other groups may also be suitable, to give an imidazole N-oxide IV or V ί Y NCN (IV) NHAlk2 Y I NCN (V) NHAlk Where Y is as hereinbefore defined or H. When Y is H, the compounds may consist of a mixture of two tautomers, e.g., an N-oxide and the corresponding N-hydroxy tautomer.

The compound IV or V is subsequently selectively reduced, if Y is other than H or OH, to reduce the Y group to H and finally deoxygenated to give the desired product Ν' H ^NCN \nhair2 2 which, in the preferred use of Alk = C2H4 ant* Alk = CH^, is Cimetidine. The deoxygenation may also take place before the reduction.

Compounds III were previously unknown, and since they contain a multitude of reactive sites, it is both unexpected and surprising that they can be transformed to imidazole N-oxides in good yields. It is particularly surprising that the N-cyano20 guanidine moiety could sustain the treatment with the reagents necessary for the ring-closure, and furthermore, according to Zeitschrift fur Chemie, 10 (1970),211-215, 2-unsubstituted imidazole N-oxides cannot be isolated under reaction conditions analogous to those used in the present invention.

The selective reduction of IV and V was unforeseeable and quite surprising; a priori, it was to be expected that the benzylic type OS bond would be the one most easily reduced by known methods.

Neither was it foreseeable that the deoxygenation of compounds IV and V could be undertaken, due to the number of other reactive sites which are open for attack by known deoxygenation reagents, and the use of these also led to unsatisfactory results. Surprisingly, it was found that trialkylamine-sulphur dioxide com10 plexes, e.g., (CH^^Niso^, or formamidinosulphinic acid gave the desired product in good yield; the resulting sulphur trioxide or sulphonic acid would have been expected to give unwarranted side reactions, cf. Synthesis,(1979), 36.

The following examples are illustrative of the present invention .

Example 1 (first reaction step) N-Cyano-N’-methyl-N-[(2-(3-oximino-2-oxobutyl)thioJethyl] guanidine (Ilia).

Sodium (13.0 g, 0.48 mol) was added to ethanol (250 ml), fol5 lowed by I-cyano-N’-methyl-N-(2-mercaptoethyl)guanidine (II, 76.0 g, 0.48 mol).

To the above mixture was added, dropwise, at 20-25°C, a solution of l-bromo-3-oximino-2-butanone (86.0 g, 0.524 mol) in anhydrous ethanol (250 ml). The reaction mixture was left at °C over night, the precipitated sodium bromide was removed by filtration and the filtrate was evaporated to dryness, in vacuo. The residue was dissolved in acetonitrile (800 ml) and stirred with silica for 30 min., the silica was subsequently removed by filtration, and the filtrate was evaporated, in vacuo. After tri15 turation with ether, the title compound could be isolated (99.0 g, 80%). By stirring with water and filtering, an analytically pure sample was obtained. M.p. lll-112°CnC9H15N5°2Si Found (Calc.): C 41.97 (42.00), H 5.90 (5.88), N 27.08 (27.22), S 12.66 (12.46). The IR and 1H~NMR spectra are in agreement with the given structure.

Example 2 (first reaction step) N-Cyano-N’-methyl-N-[[2-(2-oximino-3-oxobutyl)thio]ethyl] guanidine (Illb).

Sodium (5.75 g, 0-250 mol) was dissolved in ethanol (100 ml), and added to N-cyano-N’-methyl-N-(2-mercaptoethyl)guanidine (II, 39.6 g, 0·250 mol) in ethanol (60 ml). The resulting solution was stirred, under nitrogen, for 1 h, and subsequently added to a solution of 4-chloro-3-oximino-2-butanone (33.9 g, 0.250 mol) in ethanol (8C ml) during a period of 40 min. at 25°C. The resulting solution was kept over night at 5°C, and the precipitate isolated by filtration followed by washing with ethanol. This product was stirred with water for 30 min., and reisolated to give the title compound (36.3 g, 57%) as beige-coloured crystals. M.p.133-134°C (dec). C9H15N5O2S; Found (Calc.) C 42.15 (42.00), H 6.00 (5.88), N 26.96 (27.22), S 12.20 (12.46). The IR and 1H-NMR spectra are in agreement with the given structure.

Example 3 (second reaction step) N-Cyano-N’-methyl-N-[2-I[ {1-benzyl-3-oxido-4-methy1imidazol5-yl)methyl]thio]ethyl]guanidine (IVa).

Compound Ilia (67.5 g, 0.262 mol) in methanol (1.0 1) was mixed 5 with N-benzylmethyleneimine (62.0 g, 0.521 mol) in petroleum ether (1*01 1), and the mixture was refluxed for 72 h. The metha nol phase was isolated, extracted with petroleum ether, and the solvent was evaporated, in vacuo, at 40°C. The semicrystalline residue was stirred with ether which caused further crystalli10 zation, and the crystals were filtered off. The mother liquor was again concentrated and once more treated with ether which afforded a new crop of crystalline material. The combined product was dissolved in a 1:4 mixture of methanol and chloroform, the solution was stirred with silica, and the silica was fil15 tered off. The filtrate was concentrated, in vacuo, the residue stirred with acetonitrile, and the resulting crystals were filtered off and washed with ether to give the title compound (66.0 g, 70%). M.p. 186-187°C (dec). C17H22N6OS; Found (Calc.) C 56.56 (56.95), H 6.17 (6.19), N 23.23 (23.45) S 8.78 (8.95). 13 The IR, H-NMR and C-NMR spectra are in agreement with the given structure.

Example 4 (second reaction step) N-Cyano-N1-methyl-N-[2-[( (1-benzyl-3-oxido-4-methyl imidazol5-yl)methyl]thioJethyl]guanidine (IV a).

N-Cyano-N'-methyl-N-[[2-(3-oximino-2-oxobutyl)-thio]ethyl] * guanidine (111 a) (12.9 g, 50 mmol)in methanol (60 ml) was mixed with N-benzyl methylene-imine (9.0 g, 75 mmol) and acetic acid (0.6 g, 10 mmol) and stirred at 25°C for 18 h. The solvent was evaporated in vacuo, at 60°C. The resulting residue was heated to reflux with acetone (100 ml) for 30 min. whereby crystallization occurred. After cooling to l0°C the crystals were filtered off and dried to give the title compound (15.2 g, 85%). M.p.183-134°C (dec.).

Example 5 (second reaction step) N-Cyano-N’-methyl-N-[2-([(l-benzyl-3-oxido-5-methylimidazol4-yl)methyl]thio]ethyl]guanidine (Va).

Compound III b (2.57 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 h. The resulting solution was evaporated to dryness in vacuo, and the residue was crystallized from acetonitrile to give the title compound (2.87 g, 80%, m.p. 178°- * 180°C (dec). C1?H22N6OS; Found (Calc.) C 56.77 (56.96), H 6.20 (6.19), N 23.61 (23.45), S 9.03 (8.95). The IR and 1H-NMR spectra are in agreement with the structure given.

Example 6 (removal step) N-Cyano-N1-methyl-N-[2[[(1-oxido-5-methylimidazol-4-yl)methyl] thioJethyllguanidine (IVb).

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, 0.31 mol). The ammonia was subsequently removed by heating to room temperature, anhydrous alcohol (200 ml) was added, and the reaction mixture was stirred for 30 min. and filtered. The filtrate was concentrated, in vacuo, the residue was washed with ethyl acetate, the ethyl acetate phase was decanted off, and the resulting residue crystallized from methanol to give the title compound (15.3 g, 58%). M.p. 161-162°C. ClnH,cN,OS; Found (Calc.) C 43.65 (44.75), H 6.00 ll) 10 Ο i (6.01), N 30.86 (31.32), S 12.02 (11.95). The IR XH-NMR and ' 13C-NMR spectra are in agreement with the given structure.

Example 7_ (removal step) N-Cyano-N’-methyl-N-[2-[[(1-oxido-4-methylimidazol-5-yl)methylJ thioJethyllguanidine (Vb).

Compound Va (3.59, 10.0 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, the formed suspension was stirred for 30 min and filtered. The filtrate was seeded with crystals of Vb and cooled. The precipitated crystalline material was filtered off and dried to give the title compound (2.0 g, 75%). M.p. 176-178°C (dec). i Recrystallization from dry methanol raised the m.p. to 180-183 C (dec). C,nH,,N,OS; Found (Calc.) C 44.62 (44.75), H 5.96 (6.01), I U 16 6 i N 31.24 (31.32), S 11.98 (11.95). The IR and H-NMR spectra are In agreement with the given StructureExample 8 (second reaction step - IHb —> Vb direct) Compound Vb.

Compound IHb (2.57 g, 10.0 mmol), ammonium acetate (1.15 g, .0 mmol) and paraformaldehyde (0.33 g, 11.0 mmol) in 2 N acetic acid (20 ml) were stirred for 2 h at 65°C. HPLC indicated a yield of 72% of the title compound. The solvent was removed in vacuo, and the residue adjusted to pH 8 with 3 N potassium hydroxide. The solvent was removed in vacuo, and the residue was dissolved in chloroform-methanol (4:1) followed by stirring with silica and filtration. The filtrate was evaporated, in vacuo, and the residue was crystallized from methanol to give 1.20 g of Vb, h2O. The mother liquor yielded a further crop of Vb, H2O (0.51g) by chromatography on silica gel. Total yield of crystalline Vb, H2O was 60%. C1QH16N6OS, H20; Found (Calc.) C 41.70 (41.94), H 6.19 (6.34), N 29.42 (29.35), S 11.25 (11.20), H2O 6.33 (6.29). Recrystallization from dry ethanol raised the m.p. to 181-183°C (dec).

The compound was identical with an authentic sample (IR and 1H-NMR spectroscopy).

Example 9 (second reaction step - IHb -) Vb direct) Compound Vb.

Compound IHb (5.15 g, 20.0 mmol), ammonium dihydrogenphosphate (2.30 g, 20.0 mmol), ammonium hydrogenphosphate (1.32 g, 10.0 mmol) and paraformaldehyde (0.72 g, 24 mmol) in water (40 ml) were stirred for 2 h at 65°C, after which time, HPLC analysis showed a content of 57% of compound Vb. The reaction mixture was adjusted to pH 8 with aqueous ammonia and the solvent was removed, in vacuo. The residue was chromatographed on silica gel with chloroformmethanol (3:1) as eluent. The main fraction from this was crystallized from methanol to give 2.73 g (48%) of Vb, H20.

Example 10 (second reaction step - Illb--> Vb direct) Compound Vb.

Compound Illb (3.86 g, 15.0 mmol), ammonium acetate (1.61 g, 21.0 mmol) and paraformaldehyde (0.63 g, 21.0 mmol) in acetic acid (40 ml) was stirred for 10 h at room temperature, the solvent was removed, in vacuo, and the residue chromatographed on silica with chloroform-methanol (3:1) as eluent. The main fraction was crystallized from methanol to give Vb, HjO (1.71 g, 41%), identical by IR and 1H-NMR with an authentic sample.

Example IJ (second reaction step - Ilia —> IVb) ]5 Compound IVb.

Compound Ilia (2.57 g, 10.,0 mmol), ammonium acetate (1,15 g, 11.0 mmol) and paraformaldehyde (0.33 g, 11.0 mmol) in 2 N acetic acid (20 ml) were stirred for 2 h at 65° C, after which time, HPLC analysis showed a content of 40% of IVb. The solvent was re20 moved, in vacuo, and the residue was adjusted to pH 8 with 3 N potassium hydroxide, followed by renewed evaporation, in vacuo.

The residue from this was chromatographed on silica gel with ι chloroform-methanol (3:1) as eluent. The main fraction was crystallized from methanol to give 0*68 g (25%) of IVbo Example 12 (deoxydation step) N-Cyano-N’-methyl-N*'-(2- ((4-methylimidazol-5-yl)methyl ] thio J ethylIguanidine (Cimetidine)e Compound IVb (3.00 g, 11.2 mmol) and trimethylamine-sulphur dioxide ((CH3)3N+-SO~, 2.7 g, 22 mmol) in methanol (60 ml) was heated to 13O‘°C for 5 h in an autoclave. After cooling, the reaction mixture was concentrated, in vacuo. Water (6 ml), and potassium carbonate (2.0 g, 14.5 mmol) was added, which permitted the isolation of an almost quantitative yield of crude Cimetidine (2.83 g, m.p. 136-138°C). After recryetallization, the m.p. was raised to 142“143°C. C10H16NgS; Found (Calc., C 47.60 (47.60), 6.42 (6.39), N 32.94 (33.31), S 12.81 (12.71). The IR and 3HNMR spectra are identical to those of an authentic sample.

Example 13 (deoxydation step) Cimetidine.

Compound IVb (121 mg, 0.45 mmol) was dissolved in dimethylformamide (4.8 ml), formamidinosulfinic acid ((H2N)^C-SO*, 49 mg, 0.45 mmol) was added, and the mixture was heated to 100°C for 1 h, after which it was shown to contain 48% Cimetidine by HPLC.

Example 14 (deoxydation step) Cimetidine.

Compound IVb (2.00 g, 7.5 mmol) was dissolved in 2-ethoxyethanol (40 ml), trimethylammonium sulfinate (2.70 g, 21.9 mmol) was added, and the mixture was heated to reflux for 15 min. Subsequently, analysis by HPLC revealed the presence of 72% Cimetidine, of which 1.30 g, 69%, could be isolated.

Example 15 (deoxydation step) Cimetidine.

Compound Vb was deoxygenated analogously to the method described in Example 11 to give Cimetidine. 2 Example 16 (deoxydation of V before removal of the benzyl group) N-Cyano-N'-muthyl-N-[2-([(1-benzyl-5-methyl imidazol-4-yl) methyl]thio]ethyl]guanidine (A).

N-Cyano-N'-methyl-N“-[2-[[(1-benzyl-3-oxldo-5~methyl-imidazol 5 -4-yl)methyl]thio]ethyl]guanidine (Va) (7.2 g, 20 mmol) was heated to reflux with 1.7M trimethylamine-sulphur dioxide in ethanol (24 ml) for 16 h. After cooling toO°C, the crystals were filtered off and dried to give the title compound (6.2 g, 91%). M.p.178-179°C. CL7H22N6S; Found (Calc.) C 59.53 (59.62), H 6.55 (6.48), N 24.43 (24.54), S 9.41 (9.36). The lH-NMR and 1^C-NMR spectra are in agreement with the given structure.

Example 17 (deoxydation of IVa before removal of the benzyl group) N-Cyano-N'-methyl-N-[2-[[(1-benzyl-4~methyl imidazol-5-yl) methyl]thio]ethyl]guanidine (B) Method L N-Cyano-N1-methyl-N“-[2-[[(1-benzyl-3-oxido-4-methyi“imidazol -5-yl)methyllthio]ethyl]guanidine (IV a) (17.9 g, 50 mmol) me heated to reflux with 1.7M trimethylamine-sulphur dioxide in ethanol (60 ml) for 5 h. After cooling to 0°C, the crystals were filtered off and dried to give the title compound (14.9 g, 87%).

M.p. 173-175°C.

C17H22N6S; Found (calc.) C 59.81 (59.62), H 6.44 (6.48), N 24.83 (24.54), S 9.42 (9.36). The *H-NMR and ^C-NMR spectra are in agreement with the given structure <, 3 Example 18 (Deoxidation of IVa before removal of the benzyl group) (B) Method II.

Compound IV a (3.58 g, 10 mmol) was dissolved in methanol (50 ml) and 5% Palladiisn on carbon (0.36 g) was added. The mixture was stirred in an atmosphere of hydrogen (1 atm) for 3 days at room temperature.

The catalyst was filtered off. The filtrate was evaporated to dryness, acetone (60 ml) was added to the residue and the mixture heated under reflux. After cooling to reran tenperature the crystals were filtered off and dried to give the title canpound (B) (3.05g, 89%).

M.p. 172-175°C.

Example 19 (removal of the benzyl group) , / N-CyanO'N‘-methy1-N-[2- [ [(4-methyl imidazol-5-yl,methyl 1 -thio]ethylJguanidine (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 ln i*ater (400 ml). Excess of ammonia was allowed to evaporate. The resulting suspension was filtered. The precipitate was dried to give the title compound (185 g, 92%,, M.pe 138-141°CU HPLC indicated a purity of 97%.

Claims (10)

CLAIMS : Ί e A process for the production of 4-methyl-5-alkyl thiomethyl imidazole of the formula CH 3 NCN NHAlk 2 N^*-CH-SAlk 1 -NH-C * H 2 '

1 2 5 wherein Alk is an alkylene group, and Alk is an alkyl group having 1-4 carbon atoms, comprising’ the reaction of compounds of the formula: CH->C-CCH n X 3 b C9 2 A B wherein X is a leaving group and one of the substituents 10 A and B is NOH the other being 0 or NOH,with a compound of the formula: hsaiiJnh ^WCN \ 2 NHAlK wherein Alk and Alk arc as hereinbefore defined to give : ^NCN \ 2 NHAlk CH 3 C-CCH o SAlk 1 NH-C 3 II Λ 2 A B 15 which is subsequently ring-closed by treatment with formaldehyde or a formaldehyde donor, or mixtures of formaldehyde ani/or formaldehyde donors and ammonia or an ammonia donor, or reagents with the formula: YN - CH^ wherein Y is H or a group removable to form NHAlk 2 or γ ι I vn 3 ch-sauJnh-c^” 01 NHAlk which, if Y is 11 or Oil, is deoxygenated to give the 10 desired product, and if Y is other than H or OH is subjected to separate reduction and deoxygenation reactions to reduce the Y group to H and to remove oxygen respectively to give the desired product.

2. Λ process as claimed in Claim 1, in which X is halogen, 15 acyloxy or tosyloxy, or NR^ wherein R is alkyl.

3. The process of Claim 1 or Claim 2, wherein Alk^ is CH 2 CH 2 and Alk is CH 3 ·

4. A process as claimed in any preceding claim, in which the deoxidising agent used in the deoxygenation reaction 20 comprises a trialkylamine-sulphur dioxide complex or formamidinosulphinic acid.

5. A process as claimed in Claim 1 substantially as herein described with reference to the Examples for the preparation of cimetidine.

6. Cimetidine when prepared by the process of Claim 3 or 5 Claim 5. »

7. A compound having the formula: .NCN 1 # CH-,C-C-CH«SAlk NH-C ί J II II 2 X. 2 A B NHAlk wherein one of the substituents A and B is NOH and the 1 2 other is 0 or NOH, Alk is an alkylene group and Alk 10 is an alkyl group having from 1 to 4 carbon atoms.

8. A compound as claimed in Claim 7, in which Alk 1 is C2H4 and Alk 2 is CH3.

9. A compound having the formula given and defined in Claim 7, substantially as hereinbefore described and 15 exemplified.

10. 4-Ethyl-5-alkylthiomethylimida2ole of the formula given and defined in Claim 1, whenever prepared by a process claimed in a preceding claim.