NZ205652A

NZ205652A - Preparation of 4-methyl-5-alkylthiomethylimidazoles

Info

Publication number: NZ205652A
Application number: NZ205652A
Authority: NZ
Inventors: B Alhede; N Gelting; H Preikschat; F P Clausen
Original assignee: Gea Farmaceutisk Fabrik As
Priority date: 1982-10-08
Filing date: 1983-09-20
Publication date: 1987-05-29
Also published as: JPS62161766A; AU560031B2; DK159309B; JPS5988472A; SE449746B; BE897952A; NO162018C; FI833648A0; DE3336225A1; IE55946B1; GB8326767D0; PT77468A; PT77468B; CH660483A5; JPS62161767A; SE8500176D0; NL8303351A; SE8305508D0; NL191181B; NL191181C

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £05652 c 205652. Priority Date(s): .... &J. £ Complete Specification Filed: Class: ?.?.?. 29 MAY 1987"' Publication Date: .. P.O. Journal, No: ...... .ZO NEW ZEALAND No.: Date: PATENTS ACT. I "53 HO DRAWINGS COMI'LETF. SPEC!FfCATiON PRODUCTION OF IMIDAZOLES T^We. A/S GEA FARMACEUTISK FABRIK (GEA LTD. PHARMACEUTICAL MANUFACTURING COMPANY) a Danish Company of 89 Holger Danskesvej, DK-2000, Copenhagen F, Denmark hereby declare the invention for whicli we pray that a patent may be granted to us, and the method by which i.t is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) 205652 A process for the production of imidazoles „ \ The invention relates to a new process for the production of 4-methy1-5-aIky1thiomethy1imidazo1es. In the British Patent Specification No. 1,533,380 a process is described, according to which compounds, e.g., of the following formula Het-CH2-S-CH2CH2-NH-Ci J^l are produced, wherein Het is a heterocyclic group, e.g., an imidazole group, E is S or NCN, and R1 is H or lower alkyl, by letting a compound of the formula Het-CH2Z where Het is defined as hereinbefore, and Z is a leaving group react with a mercaptan of the formula hs-ch2ch2-nh-c^ jj^l wherein R^is defined as hereinbefore. The | preparation of Cimetidine, N-cyano-N,-methyl-N"-[2-[(4-methyl- 5-imidazolyl)methylthio]-ethyl]guanidine by treating 4-methyi-5-hydroxymethylimidazole with thiourea followed by reaction with N-cyano-N'-methyl-N"-(2-hydroxyethyl)guanidine» is also known. A similar known process involves the j preparation of, e.g., Cimetidine by letting Het-CH2-Q wherein Q is a leaving group, and Het is a 4-methyl-5-imida-zolyl group, react with hsch2ch2nh2 to form Het-CH2 SCH2 CH2NH2 which is subsequently treated with 3 ^nr2i R C^NHR 12 3 to give, e.g., Cimetidine when R is CH3, R is CN, R is alkyl or aryl and Z is S. 205652 2 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 3ji || 2 (I) A B Wherein one of the substituents A and B is NOH and the other 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. Compound I is treated , in a first step, with ! ^NCN HSAlk NH-C , (II) \ NHAlk preferably under cold conditions in the presence of a strong "" base, such as sodium ethoxide, to give ! ^NCN CH,C-CCH0Alk NH-C _ (III) 3|l || 2 ^ NHAlk2 A B 1 0 ' wherein Alk is an alkylene group and Alk is an alkyl group having 1-4 carbon atoms. Compounds (III) are new and constitute the subject matter of New Zealand Patent Specification No. 218,113 to which the reader's attention is directed. In a second step, the compound III is ring-closed by treatment with formaldehyde or a formaldehyde donor, e.g. paraformaldehyde, or mixtures of formaldehyde and/or formaldehyde donors and ammonia or ammonia donors, e.g., ammonium acetate, or reagents with the formula YN = CH2 3 2056&2- wherein Y is HO or, preferentially, aralkyl, although other groups may also be suitable, to give an imidazole N-oxide IV or V 0 +. CH3 ~ — — — „^NCN CH0SCH0CH0NH-C-" (IV) £ 2 2 2 ^NHCHj Y N^ CH- CH0SCHnCH^NH-C^"NCN (V) """*3 I 2 2 2 ^NHCH- -O 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 / YCH3 \ /VCH2SAlk1-NH-C^NCN - £ * \NHAlk 1 2 j which, in the preferred use of Alk = C2H4 an(^ = C"H3' is Cimetidine. The deoxygenation may also take place before the reduction. The compounds of formula III which are described and claimed in New Zealand Patent Specification No. 2-/8/(3 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-cyano-guanidine moiety could sustain the treatment with the reagents necessary for the ring-closure, and furthermore, according to Zeitschrift fur Ch^foie, 1_0 (1970) , 211-215, 2-unsubstituted imidazole N-oxides cannot be isolated under reaction conditions analogous to those used in the present invention. 4 20 5 6 5? The selective reduction of IV and V was unforeseeable and quite surprising; a priori, it was to be expected that the benzylic type C-S 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 complexes, e.g., (CH-jJ^N-SO^/ or formamidinosulphinicacid 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 . o 2 0 5 6 5 ?5 Example 1 (first reaction step) N-Cyano-N'-methyl-N"-[[2-(3-oximino-2-oxobutyl)thio]ethyl] guanidine (Ilia). Sodium (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). 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 5°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 trituration 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. 111-112°C. C^H^N^C^S; 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]ethylJ 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 (80 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 (36.8 g, 57%) as beige-colored crystals. M.p. 133-134°C (dec). C9H15N502S; 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. 205652 Example 3 (second reaction step) N-Cyano-N'-methyl-N"-[2-[[(l-benzyl-3-oxido-4-methylimidazol-5-yl)methyl]thio]ethyl]guanidine (IVa). Compound IIla (67.5 g, 0.262 mol) in methanol (1.0 1) was mixed with N-benzylmethyleneimine (62.0 g, 0.521 mol) in petroleum ether (1,0 1), and the mixture was refluxed for 72 h. The methanol 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 crystallization, 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 filtered 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). C^H^NgOS; Found (Calc.) C 56.56 (56.95), H 6.17 (6.19), N 23.23 (23.45) S 8.78 (8.95). 1 13 The IR, H-NMR and C-NMR spectra are in agreement with the given structure. Example 4 (second reaction step) N-Cyano-N'-methyl-N"-[2-[[(1-benzyl-3-oxido-4-methyl imidazol-5-yl)methyl]thio]ethyl]guanidine (IV a). N-Cyano-N'-methyl-N"-[[2-(3-oximino-2-oxobutyl)~thio]ethyl] • guanidine (III a) (12.9 g, 50 inmol) in methanol (60 ml) was mixed with N-benzyl methylene-imine (9.0 g, 75 mmol) and acetic acid (o.6 g, 10 mmol) and stirred at 25°Cfor 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 occured. After cooling to 10°C the crystals were filtered off and dried to give the title compound (15.2 g, 85%). M.p.183-184°C (dec.). 205652 Example 5 (second reaction step) N-Cyano-N'-methyl-N"-[2-[[(l-benzyl-3-oxido-5-methylimidazol-4-yl)methyl]thio]ethyl]guanidine (Va). Compound XII 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). C17H22N6OS; 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 *H-NMR spectra are in agreement with the structure given. Example 6 (removal step) N-Cyano-N'-methyl-N"-[2[[(l-oxido-5-methylimidazol-4-yl)methyl] thiolethyl]guanidine (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. C10H16N6OS; Found (Calc.) C 43.65 (44.75), H 6.00 (6.01), N 30.86 (31.32), S 12.02 (11.95). The IR LH-NMR and ' ^■3C-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)methyl] thio]ethyl]guanidine (Vb). Compound IVb (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 2 0 5' r>?° 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). Recrystallization from dry methanol raised the m.p. to 180-183°C (dec). C,nH1cN,OS; Found (Calc.) C 44.62 (44.75), H 5.96 (6.01), 1U 1 D b 1 N 31.24 (31.32), S 11.98 (11.95). The IR and H-NMR spectra are in agreement with the given structure. Example 8 (second reaction step - Illb > Vb direct) Compound Vb. Compound Illb (2.57 g, 10.0 mmol), ammonium acetate (1.15 g, 15.0 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, H20 (0.51g) by chromatography on silica gel. Total yield of crystalline Vb, H20 was 60%. Cl0H16NgOS, H20; Found (Calc.) C 41.70 (41.94), H 6.19 (6.34), N 29.42 (29.35), S 11.25 (11.20), H20 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 ^H-NMR spectroscopy). Example 9 (second reaction step - Illb > Vb direct) Compound Vb. Compound Illb (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 2056 5 2 to pH 8 with aqueous ammonia and the solvent was removed, in vacuo. The residue was chromatographed on silica gel with chloroform-methanol (3:1) as eluent. The main fraction from this was crystallized from methanol to give 2.73 g (48%) of Vb, ^0. 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 m2 was stirred for 10 h at room temperature, the solvent was removed, in vacuo, and the residue chromatographed on silica with chloro-form-methanol (3:1) as eluent. The main fraction was crystallized from methanol to give Vb, 1^0 (1.71 g, 41%), identical by IR and ''h-NMR with an authentic sample. Example 11 (second reaction step - Ilia —=? IVb) 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 removed, 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 chloroform-methanol (3:1) as eluent. The main fraction was crystallized from methanol to give 0.68 g (25%) of IVb. Example 12 (deoxydation step) N-Cyano-N'-methyl-N"-[2-[[4-methylimidazol-5-yl)methyl]thio J ethyl]guanidine (Cimetidine). 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 130'°C for 5 h in an autoclave. After cooling, the reaction mixture was concentrated, in vacuo. Water (6 ml), and 2056 52 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 recrystallization, the m.p. was raised to 142-143°C. C10H16N6S; Found (Calc.) C 47.60 (47.60), H 6.42 (6.39), N 32.94 (33.31), S 12.81 (12.71). The IR and ^"HNMR spectra are identical to those of an authentic sample. Example 13 (deoxydation step) Cimetidine. Compound IVb (121 mg, 0.45 mmol) was dissolved in dimethylfor-mamide (4.8 ml), formamidinosulfinic acid ((H2N)^C-SO^, 49 mg, 0.45 nvmol) 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-ethoxyet'nanol (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 aive Cimetidine. 2056 5? Example 16 (deoxydation of V before removal of the benzyl group) N-Cyano-N'-methyl-N"-[2-[[(1-benzyl-5-methyl imidazol-4-yl) methyl]thiol ethyl]guanidine (A). N-Cyano-N'-methyl-N"-[2—£[(1-benzyl-3-oxido-5~methyl-imidazol -4-yl)methyl]thio]ethyl]guanidine (V) (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.C17H22N6S; Found (Calc.) C 59.53 (59.62), H 6.55 (6.48), N 24.43 (24.54), S 9.41 (9.36). The 'H-NMR and 1 3 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-benzy1-4-methyl imidazol-5-yl) methyl]thio]ethyl]guanidine (B) Method I. N-Cyano-N'-methyl-N"-[2-I[(1-benzyl-3-oxido-4-methyl-imidazol -5-yl)methyl Jthio]ethyl]guanidine (IV a) (17.9 g, 50 mmol) was 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.) C59.81 (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. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 205 6 5'*; Example 18 (B) Method II. Compound IV a (3.58 g, 10 mmol) was dissolved in methanol (50 ml) and added 5% Palladium on carbon (0.36 g). 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, to the residue was added acetone (60 ml) and heated to reflux. After cooling to room temperature the crystals were filtered off and dried to give the title compound (3.05 g, 89%). M.p. 172-175°C. Example 19 (removal of the benzyl group) . / N-Cyano-N'-methyl-N"-[2-[[(4-methyl imidazol-5-yl)methylj -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 in water (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.p. 138-141°C. HPLC indicated a purity of 97%. 13 2Q565& WHAT WE CLAIM IS:

1. A process for the production of 4-methy1-5-alkylthioxmida-zoles of the formula O.CH - NCN "CH0SAlk -NH-C ^ H N 2 K NHAlk 1 2 wherein Alk is an alkylene group, and Alk is an alkyl group having 1—4 carbon atoms, comprising (a) the reaction of compounds of the formula ; CH,C-CCH-X 3 II 0 2 A B wherein X is a leaving group and one of the substituents A and B is NOH the other being 0 or NOH,with a compound of the formula I 1 HSAlk NH~C \ 2 NHAlk 1 2 wherein Alk and Alk are as hereinbefore defined to give : « 1 JMCN CH^C—CCH-SAlk NH-C 3U 3 2 X 2 A B NHAlk which is (b) \subsequently ring-closed by treatment with formalde- -<■ V. SftBW®7' *cf<* / 20S6S2 14 © o. hyde or a formaldehyde donor, or mixtures of formaldehyde and/or formaldehyde donors,and ammonia or an ammonia donor, or reagents with the formula: \ YN = CH2 wherein Y is H or a removable group to form which, if Y is other than H or OH, is (c) selectively reduced to give the mono N-oxide 0 0 o +. m rn ^NHAlk H or H n /-itt o the final compound being (d) deoxygenated to give the desired r^.; product. 4 r t O 15 20^652

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

3. The process of Claim 1 or Claim 2fwherein Alk1 is CH2CH2 and Alk2 is CH3.

4. A process as claimed in Claim 1, Claim 2 or Claim 3, in which reaction step (a) \ carried out under cold conditions in the presence of sodium ethoxide.

5. A process as claimed in any preceding claim, in which the deoxidising agent used in the final step comprises a triaIky1amine-sulphur dioxide complex or formamidinosulphinic acid.

6. A process substantially as herein described with reference to the Examples for the preparation of cimetidine.

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

8. a process for the production of & 4-methyl-5-alkyl-thioimidazole of the formula group having 1-4 carbon atoms substantially as herein described with reference to the Examples. 1 7 wherexn Alk is an alkylene group, and Alk is an alkyl 1 dated thi agents for the applicants DAY OF£e.brut* 19%~f </div>