GB2129793A - Thioether cyanoguanidines and their cyclisation to produce imidazoles - Google Patents
Thioether cyanoguanidines and their cyclisation to produce imidazoles Download PDFInfo
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- GB2129793A GB2129793A GB08326767A GB8326767A GB2129793A GB 2129793 A GB2129793 A GB 2129793A GB 08326767 A GB08326767 A GB 08326767A GB 8326767 A GB8326767 A GB 8326767A GB 2129793 A GB2129793 A GB 2129793A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/43—Y being a hetero atom
- C07C323/44—X or Y being nitrogen atoms
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Abstract
A new process is described for the production of 4-methyl-5-substituted- alkylthiomethyl-imidazoles, particularly Cimetidine of the formula <IMAGE> by the following series of reactions <IMAGE> 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
SPECIFICATION
A process for the production of imidazoles and new intermediates for use in the process
The invention relates to a new process for the preparation of 4-methyl-5-alkylthiomethylimidazoles.
In the British Patent Specification No. 1,533,380 a process is described, according to which compounds, e.g., of the following formula
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
wherein R1 is defined as hereinbefore.
The Spanish Patent Specification No. 463,839 describes the preparation of Cimetidine, N-cyano-N'-methyl N11-[2-[(4methyl-5-imidazolyj)methylthioj.ethyljguanidine by treating 4-methyl-5-hydroxymethylimidazole with thiourea followed by reaction with N-cyano-N'-methyl-N"-(2-hydroxethyl)guanidine.
The German published Specification No. 2,211,454 describes the preparation of, e.g., 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
to give, e.g., Cimetidine when R1 is CH3, R2 is CN, R3 is alkyl 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
wherein one of the substituents A and B is NOH and the other is O or NOH. Xis a suitable leaving group, e.g., halogen or OZ, wherein Z is a hydrogen atom, or, e.g., an acyl or a tosyl group, orX is NR3, where R is alkyl; the preferential starting materials being the easily available halogen compounds, e.g., 1-bromo-3-oximino-2butanone and 4-chloro-3-oximino-2-butanone. Compound I is treated, in a first step, with
preferably under cold conditions in the presence of a strong base, such as sodium ethoxide, to give
wherein Alk1 is an alkylene group and Alk2 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 Ill 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 wherein Y is HO or, preferentially, aralkyl, although other groups may also be suitable, to give an imidazole
N-oxide IV or V
Where Y is as herein before defined or H. When Y is H, the compounds may consist of a mixture of two tautometers, 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
which, in the preferred use of Alk1 = 02H4 and Alk2 = CH3, is Cimetidine. The deoxygenation may also take place before the reduction.
Compounds Ill 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 Zeitschriftfur 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 Vwas unforeseeable and quite suprising; a priori, it was be expected that the benzylic type 0-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., (CH3)3N±SO2, orformamidinosulphinic 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 )thio]ethyl]guanidine (lIla).
Sodium (11.0 g, 0.48 mol) was added to ethanol (250 ml), followed by N-cyano-N'-methy-N"-(2- mercaptoethyl) guanidine (it, 76.0 g, 0.48 mol).
To the above mixture was added, dropwise, at 20-25"C, a solution of 1-bromo-3-oximino-2-butanone (86.0 g, 0.524 mol) in anhydrous ethanol (250 ml). The reaction mixture was left at SOC 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.CgH15N502S; Found (Calc.): 041.97(42.00), H 5.90 (5.88), N 27.08(27.22), 5 12.66(12.46). The IR and 1 H-NMR spectra are in agreement with the given structure.
Example2 (first reaction step).
N-Cyano-N'-methyl-N"-[[2-(2-oximino-3-oxobutyl)thio]ethyljguanidine (Illb).
Sodium (5.75 g, 0.250 mol) was dissolved in ethanol (100 ml) and added to N-cyano-N'-methy-N"-(2mercaptoethyl)guanidine (it, 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 2500. The resulting solution was kept overnight 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%) and beige-coloured crystals. M.p. 133-1 34 C (dec).C9H15N502S; Found (Calc.) 042.15(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-[[(1-benzyl-3-oxido-4-methyl-imidazol-5-yl)methyl]thio]ethyl]guanidine (IV a).
Compound Illa (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 (1,011), and the mixture was refluxed for 72 h. The methanol phase was isolated, extracted with petroleum ether, and the solvent was evaporated, in vacuo, art4000. 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). C17H22N6OS; Found (Calc.) C56.56 (56.95), H 6.17 (6.19), N 23.23 (23.45) S 8.78 (8.95). The IR, 1H-NMR and 13C-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-methylimidazol-5-yl)methyl]thio]ethylXguanidine (IV a).
N-Cyano-N'-methyl-N"-[[2-3-oximino-3-oxobutyl)thio]ethyl]guanidine (Illa) (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 25for 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 1000 the crystals were filtered off and dried to give the tital compound (15.2 g, 85%). M.p. 183-184"C (dec.).
Example 5 (second reaction step) N-Cyano-N '-methyl-N"-[2-[[( 1 -benzyl-3-oxide-5-methyli midazol-4-yl)methyl]thio]ethyl]guan idine (Va).
Compound IlIb (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). C17H22N60S; 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-N'-methyl-N"-[2[[(1-oxido-5-methylimidazol-4-yl)methyl]thio]ethyl]guanidine (lVb).
Compound IVa (35.0 g, 0.976 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. C10H16N60S; Found (Calc.) C43.65 (44.75), H 6.00 (6.01), N 30.86 (31.32), 5.12.02 (11.95).The IR 1H-NMR and 13C-NMR spectra are in agreement with the given structure.
Example 7 (removal step) N-Cyano-N '-methyl-N"-[2-[[(1 -oxidoA-methylimidazol-5-yl)methyl]thiojethyliguanidine (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 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). C10H16N6OS; Found (Calc.) C 44.62 (44.75), H 5.96 (6.01), N 31.24 (31.32), S 11.98(11.95). The IR and 1H-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 hat 6500. 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 crystallised from methanol to give 1.20 g of Vb, H20. The mother liquor yielded a further crop of Vb, H20 (0.51 g) by chromatography on silica gel.Total yield of crystalline Vb, H2O was 60%. C10H16N6OS, H2O; 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 - Illb 636 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 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, H2O.
Example 10 (second reaction step - Ilib < 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, H2O (1.71 g, 41%), identical by IR and 1H-NMR with an authentic sample.
Example 11 (second reaction step - Illa < IVb) Compound IVb.
Compound Illa (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 (deoxidation step) N-Cyano-N '-methyl-N"-[2-[[4-methylimidazol-5-yl )methyl]thio]ethyl]guanidine (Cimetidine).
Compound IVb (3.00 g, 11.2 mmol) and trimethylaminesuiphur dioxide ((CH3) 3N±SO2, 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 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 (call.) 47.60 (47.60), H 6.42 (6.39), N 32.94 (33.31), S 12.81 (12.71). The IR and 1HNMR spectra are identical to those of an authentic sample.
Example 13 (deoxidation step)
Cimetidine.
Compound IVb (121 mg, 0.45 mmol) was dissolved in dimethylformamide (4.8 ml), formamidinosulfinic acid ((H2N)2C-SO2,49 mg, 0.45 mmol) was added, and the mixture was heated to 10000 for 1 h, after which it was shown to contain 48% Cimetidine by HALO.
Example 14 (deoxidation step)
Cimetidine.
Compound IVb (2.00 g, 7.5 mmol) was dissolved in 2-ethoxyethanol (40 ml), trimethylammonium sulfinate (2.709,21.9 mmol) was added, and the mixture was heated to reflux four 15 min. Subsequently, analysis by
HPLC revealed the presence of 72% Cimetidine, of which 1.30 g, 69%, could be isolated.
Example 15 (deoxidation step)
Cimetidine.
Compound Vb was deoxygenated analogously to the method described in Example 12 to give Cimetidine.
Example 16 (deoxidation of V before removal of the benzyl group).
N-Cyano-N '-methy-N8-[2-[[(1 -benzyl-5-methylimidazol-4-yl)methyl]thio]ethyljguanidine (A).
N-Cyano-N'-methyl-N"-[2-[[(1 -benzyl-3-oxido-5-methylimidazol-4-yl)methyljthio]ethyljguanidine (Va) (7.29, 20 mmol) was heated under 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 1H-NMR and 13C-NMR spectra are in agreement with the given structure.
Example 17(deoxidation 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 I.
N-Cyano-N'-methyl-N"-[2-[[(1-benzyl-3-oxido-4-methylimidazol-5-yl)methyl]thio]ethyl]guanidine (IV a) (17.99,50 mmol) was heated under reflux with 1.7 M trimethylamine-sulphur dioxide in ethanol (60 ml) for 5h. 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 13C-NMR spectra are in agreement with the given structure.
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% Palladium on carbon (0.369) 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 was heated under reflux. After cooling to room temperature the crystals were filtered off and dried to give the title compound (B) (3.05 g, 89%). M.p.172-175 C.
Example 19 (removal of the benzyl group)
N-Cyano-N'-methyl-N"-[2-[[(4-methyl imidazole-5-yl)methyl]thio]ethyl]guanidine (Cimetidine).
Compound B (2749,0.80 mol) was suspended in liquid ammonia (1200 ml). Sodium (40.0 1.74 mol) was added, followed by ammonia chloride (93.1 g, 1.74 mol) dissolved in water (400 ml). Excess 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 HPLC indicated a purity of 97%.
Claims (9)
1. A process for the production of 4-methyl-5-alkylthioimidazole of the formula
wherein Alk1 is an alkylene group, and Alk2 is an alkyl group having 1-4 carbon atoms, comprising the reaction of compounds of the formula:
wherein Xis a leaving group and one of the substituents A and B is NOH the other being 0 or NOH, with a compound oftheformula:
wherein Alk1 and Alk2 are as hereinbefore defined to give:
which is subsequently ring-closed by treatment with formaldehyde or a formaldehyde donor, or mixtures of formaldehyde and/orformaldehyde 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 H or OH, is deoxygenated to give the 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. A process as claimed in Claim 1, in which Xis halogen, acyloxy or tosyloxy, or NR3 wherein R is alkyl.
3. The process of Claim 1 or Claim 2, wherein Alk1 is CH2CH2 and Alk2 is CH3.
4. A process as claimed in Claim 1, Claim 2 or Claim 3, in which the first reaction step is 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 deoxygenation reaction comprises a trialkylamine-sulphur dioxide complex orformamidinosulphonic 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. Acompound havingtheformula:
wherein one of the substituents A and B is NOH and the other is O or NOH, Alk1 is an alkylene group and Alk2 is an alkyl group having from 1 to 4 carbon atoms.
9. A compound as claimed in Claim 8, in which Alk1 is 02H4 and Alk2 is CH3.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB8228782 | 1982-10-08 |
Publications (3)
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GB8326767D0 GB8326767D0 (en) | 1983-11-09 |
GB2129793A true GB2129793A (en) | 1984-05-23 |
GB2129793B GB2129793B (en) | 1986-03-12 |
Family
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GB08326767A Expired GB2129793B (en) | 1982-10-08 | 1983-10-06 | Thioether cyanoguanidines and their cyclisation to produce imidazoles |
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JP (3) | JPS5988472A (en) |
AU (1) | AU560031B2 (en) |
BE (1) | BE897952A (en) |
CA (1) | CA1199030A (en) |
CH (2) | CH660483A5 (en) |
DE (1) | DE3336225A1 (en) |
DK (1) | DK159309C (en) |
FI (1) | FI79301C (en) |
FR (1) | FR2534256B1 (en) |
GB (1) | GB2129793B (en) |
IE (1) | IE55946B1 (en) |
NL (1) | NL191181C (en) |
NO (1) | NO162018C (en) |
NZ (1) | NZ205652A (en) |
PT (1) | PT77468B (en) |
SE (2) | SE449746B (en) |
ZA (1) | ZA837237B (en) |
ZW (1) | ZW21383A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0279643A2 (en) * | 1987-02-17 | 1988-08-24 | Mitsui Petrochemical Industries, Ltd. | Cyanoguanidine derivatives, the preparation thereof and their use for the synthesis of Cimetidine |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8618846D0 (en) * | 1986-08-01 | 1986-09-10 | Smithkline Beckman Corp | Chemical process |
JPH0623179B2 (en) * | 1986-09-01 | 1994-03-30 | 三井石油化学工業株式会社 | Cyanoguanidine derivative and method for producing the same |
JPH0629234B2 (en) * | 1986-12-26 | 1994-04-20 | 三井石油化学工業株式会社 | α-acyloxyketone derivative |
JPH0623180B2 (en) * | 1987-02-17 | 1994-03-30 | 三井石油化学工業株式会社 | Cyanoguanidine derivative and method for producing the same |
JPS63208566A (en) * | 1987-02-23 | 1988-08-30 | Mitsui Petrochem Ind Ltd | Production of guanidine derivative |
JPS63208565A (en) * | 1987-02-23 | 1988-08-30 | Mitsui Petrochem Ind Ltd | Production of guanidine derivative |
JP3006356U (en) * | 1994-04-12 | 1995-01-24 | 株式会社フコク | Torsional vibration absorber |
CN115745893A (en) * | 2022-11-16 | 2023-03-07 | 西安近代化学研究所 | Method for synthesizing 2-cyano-5-aryl-1H-imidazole compound |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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GB1338169A (en) * | 1971-03-09 | 1973-11-21 | Smith Kline French Lab | Ureas thioureas and guanidines |
GB1533380A (en) * | 1974-09-02 | 1978-11-22 | Smith Kline French Lab | Process for the preparation of heterocyclic substituted thioureas and h-cyanoguanidines |
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1983
- 1983-09-19 IE IE2198/83A patent/IE55946B1/en unknown
- 1983-09-20 NZ NZ205652A patent/NZ205652A/en unknown
- 1983-09-28 ZA ZA837237A patent/ZA837237B/en unknown
- 1983-09-30 NL NL8303351A patent/NL191181C/en not_active IP Right Cessation
- 1983-09-30 DK DK451883A patent/DK159309C/en not_active IP Right Cessation
- 1983-10-05 ZW ZW213/83A patent/ZW21383A1/en unknown
- 1983-10-05 DE DE19833336225 patent/DE3336225A1/en active Granted
- 1983-10-06 SE SE8305508A patent/SE449746B/en not_active IP Right Cessation
- 1983-10-06 JP JP58186070A patent/JPS5988472A/en active Granted
- 1983-10-06 FR FR8315903A patent/FR2534256B1/fr not_active Expired
- 1983-10-06 GB GB08326767A patent/GB2129793B/en not_active Expired
- 1983-10-07 FI FI833648A patent/FI79301C/en not_active IP Right Cessation
- 1983-10-07 CA CA000438623A patent/CA1199030A/en not_active Expired
- 1983-10-07 PT PT77468A patent/PT77468B/en unknown
- 1983-10-07 BE BE0/211673A patent/BE897952A/en not_active IP Right Cessation
- 1983-10-07 AU AU19956/83A patent/AU560031B2/en not_active Ceased
- 1983-10-07 NO NO833664A patent/NO162018C/en unknown
- 1983-12-15 CH CH2014/86A patent/CH660483A5/en not_active IP Right Cessation
- 1983-12-15 CH CH6694/83A patent/CH659650A5/en not_active IP Right Cessation
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1985
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1986
- 1986-11-14 JP JP61272756A patent/JPS62161767A/en active Pending
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0279643A2 (en) * | 1987-02-17 | 1988-08-24 | Mitsui Petrochemical Industries, Ltd. | Cyanoguanidine derivatives, the preparation thereof and their use for the synthesis of Cimetidine |
EP0279643A3 (en) * | 1987-02-17 | 1989-05-31 | Mitsui Petrochemical Industries, Ltd. | Cyanoguanidine derivative and process for preparation thereof |
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