NZ218113A

NZ218113A - Guanidine derivatives

Info

Publication number: NZ218113A
Application number: NZ21811383A
Authority: NZ
Inventors: B Alhede; N Getting; H Prelkschat; F P Clausen
Original assignee: Gea Farmaceutisk Fabrik As
Priority date: 1982-10-08
Filing date: 1983-09-20
Publication date: 1987-05-29

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £18113 *•<' i IS:tt+n+^_. v. . _ © o Priority Date(s): lO $3- Complete Specification Filed: Class: C?.7.9/.<'rflttll, ..&?.7.$/J.f/.4.& q ... „n\.2 9MAY 1987. Publication Date* ■•»••»•■>»•••«• P.O. Journal, No: ...... 2181 1 3 Under the provisions of Regulation 23 (I) the Cay»pl<rte Specification has been ante-dated «/% 2. O 19_2JL T M Cf - NEW ZEALAND PATENTS ACT, 1953 Divided oat of: No.: 205652 Date: 20 September 1983 COMPLETE SPECIFICATION NOVEL INTEFMEDIA1ES FOR USE IN THE PPODUCTICN CF IMIDAZOLES 300CTI986|I r o /•■ M t, •> sj K/ we, A/S GEA EARMACEUTISK FABRIK (GEA LTD. PHARMACEUTICAL MANUFACTURING COMPANY) a Danish company of 89 Holger Danskesvej, DK-2000, Copenhagen F, Denmark, hereby declare the invention for which X / we pray thit a patent may be granted to Q£te/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - 2181 2 This invention relates to compounds of the formula 1 ^ncn CH C-£-CH-SAlk 'NH-< a b nhalk wherein one of A and B is NOH and the other is 0 or NOH, Alk* is an alkylene-group and Alk^ is an alkyl group having from 1 to 4 carbon atoms. The compounds of the present invention are useful as intermediates in the production of 4-methyl-5-alkyl thiomethylimidazoles. The readers attention is directed to New Zealand Patent Specification No. 205652 which describes and claims a process for the production of 4-methyl-5-alkylthioimidazoles of the formula /vch3 ^N^*CH-,SAlk -NH-C ^ H \ 2 " NHAlk wherein A1k^ is an alkylene group, and Alk^ is an alkyl group having 1 to 4 carbon atoms. In the British Patent Specification No. 1,533,380 a process is described, according to which compounds, eg., of the following formula Het-CH2-S-CH2CH2-NH-C< ^ are produced, wherein Het is a heterocyclic group, eg., an imidazole group, E is S or NCN, and R1 is H or lower alkyl, by letting a compound of the formula 2181 1 3 Het-CH2Z where Het is defined as hereinbefore, and Z is a leaving group react with a mercaptan of the formula HS-CH2CH2-HH-CS»™1 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-methyl-5-hydroxymethylimidazole with thiourea followed by reaction with N-cyano-N'-methyl -N"-(2-hydroxyethyl )guanidine is known. Similarly, the preparation of, eg., Cimetidine by letting Het-CH2-Q „ wherein Q is a leaving group, and Het is a 4-methyl-5-imidazolyl group, react with HSCH2CH2NH2 to form Het-CH2SCH2CH2NH2 which is subsequently treated with 3 ^NR2 R Z NHR to give, eg., Cimetidine when is CH3, is CN, R^ is alkyl or aryl and Z is S is also known. , j.j.-Ml.-vVM ' ' —,'L . Is' Jl © O 218113 It is known that the starting materials, ie. substituted imidazoles, for these and other known methods are not easy to obtain, and the method of New Zealand Patent Specification No. 205652 consequently employs a totally different approach both with regard to starting materials and reaction pathway. In the process according to the New Zealand Patent Specification No. 205652, the starting material consists of a compound CH-C-CCH-X 31| g 2 (I J 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, eg., halogen or 0Z, wherein Z is a hydrogen atom, or, eg., an acyl or a tosyl group, or X is Nl^ Where R is alkyl; the preferential starting materials being the easily available halogen compounds, eg., 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 the compounds of the present invention, having the formula: ^NCN CH-C-CCH_SAlk NH-C - (III) || || 2 \ NHAlk2 A B wherein A and B are as defined above, Alk1 is an alkylene group and Alk2 is an alkyl group having 1-4 carbon atoms. ' L..,^. C~. . w '^V-; BX 218113 © Preferred compounds according to the present invention are those in which Alk1 is C2H4 and Alk2 is CH3. In a second step of the process according to New Zealand Patent Specification No. 205652, the compound III is ring-closed by treatment with formaldehyde or a formaldehyde donor, eg. paraformaldehyde, or mixtures of formaldehyde and/or formaldehyde donors and ammonia or ammonia donors, eg., ammonium acetate, or reagents with the formula YN = CH2 wherein Y is HO or, preferentially, aralkyl, although other groups may also be suitable, to give an imidazole N-oxide IV or V "0 N^j. CH3 i X N-^ CH_ SCH_ CH_ NH-C **'' ( * 2 2 Y NCN NHCH. (IV) o a CH. CH SCH CH,NH-C^ 1 2 2 2 ^NHCH- _0 (V) Where Y is as hereinbefore defined or H. When Y is H, the compounds may consist of a mixture of two tautomers, eg., 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 deoxyge- ; fc. %S>:'.; m 218113 nated to give the desired product of the process / YCH3 \ II , \ m/VcH0 SAlk -NH-C , „ ^ \ NHAlk which,.in the preferred use of Alk1 = C2H4 and Alk^ = CH3, is Cimetidine. The deoxygenation may also take place before the reduc-> tion. The compounds of formula III which are the subject of the present invention 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 Chemie, _10 (1970), 211-215, 2-unsubstituted imidazole N-oxides cannot be isolated under reaction conditions analogous to those used in the process according to New Zealand Patent Specification No. 205652. 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 218113 7 that tri alkyl ami ne-sulphur dioxide complexes, eg., (CH3) 3N+S02', 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 prepartion of the compounds of the present invention and of their use as intermediates in the process according to New Zealand Patent Specification No. 205652. 3 2 18113 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, 8 0%) . By stirring with water and filtering, an analytically pure sample was obtained. M.p. 111-112°C. CgH^NgC^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 ''h-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 (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). CgHi5N502S; 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. 21811 Example 3 (second reaction step) N-Cyano-N'-methyl-N"-[2-[ [ (l-benzyl-3-oxido-4-methylimidazol-5-yl)methyl]thio]ethylJguanidine (IVa). Compound Ilia (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^H22NgOS; Found (Calc.) C 56.56 (56.95), H 6.17 (6.19), N 23.23 (23.45) S 8.78 (8.95). The IR, ^"H-NMR and "^C-UMR 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 nunol)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.1d3-1S4°C (dec.). 218113 N-Cyano-N'-methyl-N"-[2-[[(l-benzyl-3-oxido-5-methylimidazol-4-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). C17H22NgOS; 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] thio3 ethyl]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. C10H16NgOS; Found (Calc.) C 43.65 (44.75), H 6.00 (6.01), N 30.86 (31.32), S 12.02 (11.95). The IR 1H-NMR and ' C-NMR spectra are in agreement with the given structure. Example 7 (removal step) N-Cyano-N1-methyl-N"-[2-[[(1-oxido-4-methylimidazol-5-yl)methyll 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 10 I Example 5 (second reaction step) u 2 18113 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). CinH1cNc0S; Found (Calc.) C 44.62 (44.75), H 5-96 (6.01), 1 u 1 b o 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-methano 1 (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%. C1()H15N6OS, 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 1 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 , u 218113 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, H20. Example 1 0 (second reaction step - Illb 2 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 chloro-form-methanol (3:1) as eluent. The main fraction was crystallized from methanol to give Vb, H20 (1.71 g, 41%), identical by IR and 1H-NMR with an authentic sample. Example 11 (second reaction step - Ilia —IVb) Compound IVb. Compound Ilia (2.57 9» 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'-methy1-N"-[2-[[4-methylimi dazol-5-yl)methyl]thio] ethyl]guanidine (Cimetidine) . Compound IVb (3.00 g, 11.2 mmol) and trimethylamine-sulphur dioxide ((CH^)2N+~S02, 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 13 2 18113 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. c10Hi5N6S? 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 d'imethylfor-mamide (4.8 ml), formamidinosulfinic acid ((I^N) ^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-ethoxyetnanol (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. 2181 1 3 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]thio]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 to 0°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. H-Cyano-N' -methyl-N"- [,2-[ [ (1 -benzyl*-3-oxido-4-methyl-imidazol -5-yl) methyl] thio]eth£L]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.) C 59.81 (59.62), H 6.44 (6.48), N 24.83 (24.54), S 9.42 (9.36). The 'H-NMR arid ^C-NMR spectra are in agreement with the given structure. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 2 18113 (B) Method II. Compound IV a (3.58 g, 10 irunol) 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 refiux. 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) , j 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.T~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%. • , i IS t Examole 18 16 2 18113 WHAT WE CLAIM IS:

1. A compound having the formula: 1 ^NQJ CH,C-C-CH0SAlk NH-C,: A S 2 NHAlk viierein one of the substituents A and B is NOH and the other is O or 1 . 2 NOH, Alk is an alkylene group and Alk is an alkyl group having frcm 1 to 4 carbon atoms. 1 2

2. A compound as claimed in Claim 1, in which Alk is C2H4 and Alk is CH^.

3. A compound as claimed in claim 1 substantial ly as herein described. DATED THIS SOU. DAY OF Ot/ob&r 19g£> A. J. PARK & SON PEP, (/tt-t/JcJ AGENTS FOR THE APPLICANTS A/'S 0&=< fo-rvviO.cex^'H fek- Peitofifc (C<e CK Urd • PhcxrrrGLOeMsKcoJL 300CTI986t, </div>