CA1199030A - Production of imidazoles - Google Patents
Production of imidazolesInfo
- Publication number
- CA1199030A CA1199030A CA000438623A CA438623A CA1199030A CA 1199030 A CA1199030 A CA 1199030A CA 000438623 A CA000438623 A CA 000438623A CA 438623 A CA438623 A CA 438623A CA 1199030 A CA1199030 A CA 1199030A
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- Prior art keywords
- compound
- methyl
- give
- formula
- alk1
- Prior art date
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Classifications
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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
-
- 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
Abstract
ABSTRACT
PRODUCTION OF IMIDAZOLES
A new process is described for the production of 4-methyl-5-imidazoles, particularly Cimetidine of the for-mula by the following series of reactions wherein Alk1 preferably is -CH2-CH2- and Alk2 preferably CH3.
The process is unexpectedly carried out in extremely good yields.
PRODUCTION OF IMIDAZOLES
A new process is described for the production of 4-methyl-5-imidazoles, particularly Cimetidine of the for-mula by the following series of reactions wherein Alk1 preferably is -CH2-CH2- and Alk2 preferably CH3.
The process is unexpectedly carried out in extremely good yields.
Description
:;' 1 ?9U3~
! ~
~he ~res~nt -invention relates to ~ proces~ For tile pro~u(tic)n o~
4~ ethyl-5-alkylthiomethylimidazoles.
In British Patent Specification No. 1,533,380 a process is descri~ed, according to which compounds, e.g., of the following formula Het-Cll2-S~c~~l2cll2~Nl~l C NHR
i are produced, wherein Elet is a heterocyclic group, e.g., an j imidazole group, E is S or NCN, and R is H or lower alkyl, by letting a compound of the formula Het-CE12Z
where Het is defined as hereinbefore, and Z is a leaving group i react with a mercaptan of the formula Hs~cEl2cH2-NH-c~ NHRl wherein Rlis defined as hereinbefore~
Spanish Patent Specification No. 463,839 describes 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)guanidiile.
German published Specification No. 2,211,454 describes the preparation of, e.g., Cimetidine by letting Het-cH2-Q
wherein ~ is a leaving group, and Het is a 4-methyl-5-imida-zolyl group, react with IlSCH2CE12Nii2 to form llet-CH2SCE12CE12NE12 wllich is subsequently treated with R3Z C ~NR21 to give, e.g., Cimetidine when R is C113, R is CN, R is alkyl or aryl and Z is S.
~ L9903~ 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 (I) B
Wherein one of the substituents A and B is NOH and the other is O or NGH. 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 NR3, 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 1 ~NCN
HSAlk NH-C 2 (II~
\ NHAlk preferably under cold conditions in the presence of a strong base, such as sodium ethoxide, to give ~NCN
3 2Alk 2 (III) ~ \ NHAlk A B
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 III is ring-closed by treat-ment with formaldehyde or a formaldehyde donor, e.g. para-formaldehyde, or mixtures of formaldehyde and/or formalde-hyde donors and ammonia or ammonia donors, e.g., ammonium acetate, or reagents with the formula YN = CH2 ~1~9~
wherein Y is HO or, preferentially, aralkyl, although other groups may also be suitable~ to give an imidazole N-oxide IV or V
- o N CH2scH2cH2NH-c95 (IV) N ~ CH3 ~N ~ CH ScH2cH2NH-c~NHcH (V) _O
~hereY isas hereinbeforedefined or H. When Y is H, the com-pounds 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 </ ~ ~NCN
NH H SAlk -NH-C 2 which, in the preferred use of Alk1 = C2H4 and Alk2 = CH3, 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 sur-prising 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 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 C-S bond would be the one most easily reduced by known methods.
Neither was it foreseeable that the deoxyyenation of compounds IV and V could be undertaken, due to the number of other reactive sites which are open for attack by known deoxygenation rea~ents, and the use of these also led to unsatisfactory results. Sur-prisingly, it was found that trialkylamine~sulphurdioxide com-plexes, e.g., (CH3)3N-S02, or formamidinosulphinicacid gave the desired product in good yield; the resulting sulphurtrioxide or sulphonicacid would have been expected to give unwarranted side reactions, cf. Synthesis,(1979),36.
The following examples are illustrative of the present in-vention.
Example 1 l~irst reaction step) N-Cyano-N'-methyl-N"-[[2-(3-oximino-2-oxobutyl)thio]ethyl]
guanidine (IIIa).
Sodium (11.0 g, 0.48 mol~ was added to ethanol (250 ml), fol-lowed 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 solu-tion of l-bromo-3-oximino-2-butanone (86.0 g, 0.524 mol) in anhydrous ethanol (250 ml). The reaction mixture was left at 5C over night, the precipitated sodium bromide was removed by ~iltration 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 tri-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. 111-112 C. CgH15N5O2S;
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]ethil]
guanidine (IIIb).
Sodium (5.75 g, 0-250 mol) was dissolved in ethanol (100 ml) and added to N-cyano-NI-methyl-N''-(2-mercaptoethyl)guanidine (II, 39.6 g, 0-250 mol) in ethanol (60 ml). The resulting solution was stirredF under nitrogen, for 1 h, and subsequently added to a solution of 4-chloro-3-o~imino-2-butanone ~33.9 g, 0.250 mol) in ethanol (80 ml) during a period of 40 min. at 25C. The resulting solution was kept over night at 5C, 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). CgH15N5O2S; 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.
3q~ 6 Example 3 (second reaction step) N-Cyano-N'-methyl-N"-[2-[[(1-benzyl-3-oxido-4-methylimidazol-5-yl)methyl]thio]ethyl]guanidlne (IVa).
Compound IIIa (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 metha-nol phase was isolated, extracted with petroleum ether, and the solvent was evaporated, in vacuo, at 40C. The semicrystalline residue was stirred with ether which caused fuxther crystalli-zation, and the crystals were filtered o~f. The mother liquor was again concentrated and once more treated with ether which afforded a new crop of crystalline material. The combined pro-duct was dissolved in a 1:4 mixture of methanol and chloroform, the solution was stirred with silica, and the silica was fil tered off. The filtrate was concentrated, in vacuo, the residue stirred with acetonitrile, and the resulting cr~stals 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 B.7~ (8.95).
The IR, lH-NMR and 13C-NMR spectra are in agreement with the gi~en structure.
Example 4 (second reaction step) N-Cyano-N'-methyl-N"-~2-~[~1-benzyl-3-oxido-4-methyl imida~ol-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 mmol~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 25Cfor 13 h. The solvent was evaporated in vacuo, at 60C-The resulting residue was heated to reflux with acetone ~100 ml) for 30 min. whereby crystallization occured. After cooling to 10C the crystals were filtered off and dried to give the title compound !15.2 g, 85%). M.p.1~3-1~4QC (dec.).
~9~ 7 Exam~le 5 (second reaction step3 N-Cyano-N'-methyl-N"-[2-[[(1-ben~yl-3-oxido-5-methylimidazol-4-yl)methyl]thio]ethyl]guanidine (Va).
Compound III b (2.57g, 0.010 mol)in methanol (25 ml) was mixed with N-benzylmethyleneimine (2.38 g, 0.020 mol3 and heated under nitrogen to reflux for 17 h. The resulting solution was evapo-rat~d 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 5G.77 (56i96), 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[[(1-oxido-5-methylimidazol-4-yl)methyl]
thio]ethyl]~uanidine (IVb).
Compound IVa (35.0 g, 0.0976 mol) was suspended in li~uid ammo-nia (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 subse-quently removed by heating to room temperature, anhydrous alco-hol (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. CloH16N6OS; Found (Calc.) C 43.65 ~44O75)~ H 6.00 (6.01), N 30.86 (31.32),S 12.02 (11.95). The IR H-NMR and C-NMR spectra are in agreement with the given structure.
(removal step3 N-Cyano-N'-methyl-N"-[2-[[(1-oxido-4-methylimidazol-5-yl3methyl]
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 por-tion~, ~ollowed by ammonium chloride (1.23 g 23 mmol)~ The ammonia ~as removed by heating to room temperature, propanol was added, the formed suspension was stirred for 30 min and filtered. The fil~rate was seeded with crystals of Vb and cooled.
The precipitated crystallin~ material was filtered off and dried to gi~e the title compound (2.0 g, 75~). M.p. 176-178C (dec)~
Recrystalli~ation from dry methanol raised the m.p. to 180-183C
ldec). C1oH16N6OS; Found (Calc.) C 44.62 (44.75), H 5.96 (6.01), N 31.24 (31.32), ~ 98 (11.95). The IR and H-NMR spectra are in agreement with ~he given structure.
Example 8 (second reaction step - IIIb > Vb direct) Compound Vb.
Compound IIIb (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 65C. 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 hydro-~ide. The solvent was removed in vacuo, and the residue was dis-solved 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~. C10H16N6OS, H2~; Found (Calc.) C 41.70 (41.94), H 6-19 (6.3~), N 29.42 (29.35), S 11.25 (11.20), H2O 6.33 (6.29). Recry-stallization from dry ethanol raised the m.p. to 181-183C (dec).
The compound was identical with an authentic sample (IR and H-~MR
spec-troscop~
Example 9 (second reaction step - IIIb ` Vb direct) Compound V~.
Compound IIIb (5.15 g, 20.0 mmol~, ammonium dihydrogenphosphate t2~30 g, 20.0 mmol), ammonium hydrogenphosphate (1.32 g, lO.0 mmol) and paraformaldehyde (0.72 g, 24 mmolj in water (40 ml) were stirred for 2 h at 65C, 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 crystal-lized from methanol to give 2.73 g (48~) of Vb, H2O.
Example10 (second reaction step - IIIb ~ Vb direct) Compound Vb.
Compound IIIb (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 rcom 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, H2O (1.71 g, 41~), identical by IR and 1H-NMR with an authentic sample.
Example 11 (second reaction step - IIIa ~ IVb) Compound IVb.
Compound IIIa (2.57 g, lO.0 nmol), 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 re-moved, in vacuo, and the residue was adjusted to pH 8 with 3 N
potassiun 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 cry-stallized from methanol to give 0.68 g (25%) of IVb.
Example 12 (deoxydation step) N-Cyano-N'-methyl-N"-[2-[[4-methylimidazol-5-yl)methvl]thio]
ethyl]guanidine (Cimetidine~.
Compound IVb (3.00 g, 11.2 mmol) and trimethylamine-sulphur dioxide ((CH3)3N~SO2, 2.7 g, 22 mmol) in methanol (60 ml) was heated to 130C for 5 h in an autoclave. After cooling, the reaction mixture was concentrated, in vacuo. Water (6 ml), and ~ ~ 10 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. CloH16N6lS; Found (Calc.) C 47.60 (47.60), Il 6.42 (6.39), N 32.94 (33.31), S 12.81 (12.71). The I~ and lHNMR 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 (~.8 ml), formamidinosulfinic acid ((H2N)2C-SO2, 49 mg, 0.45 mmol) was added, and the mixture was heated to 100C for 1 h, after which it was shown to contain 48~ Cimetidine ~y HPLC.
~xample 14 (deoxydation step) Cin~eLidine.
Compound IVb (2.00 9, 7.5 mmol) was dissolved in '-ethox,ethanol (40 ml), trime~hylammonium sulfinate (2.70 ~, 21.9 mmol) was added~ and the mixture was ~leated to reflux for 15 min. Su~se-quently, analysis by }IPLC revealed the presence of 72~ Cimeti-dine, of which 1.30 g, 69%, could be isolated.
Example 15 (deoxydation step~
Cimetidine.
Compound Vb was deoxyc;enated analogously to the method described in Example 11to qive Cimetidine.
l~lLg'90~ 0 11 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~ l7,2 g, 20 mmol) was heated to reflux with 1.7M trimethylamine-~ulphur d1oxide 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.C~7~l22N6S; Found (Calc.) C 59.53 (59.~2), H 6.55 (6.48), N 24.43 (24.54), S 9.41 (9.36). The 'H-NM~ and 3C-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 I.
N-Cyano-N'-methyl-N"-[2-~[(1-benzyl-3-oxido-4-methyl-imidazol -5-yl)methyl~thio]ethyl]guanidine (IV a) ~17.9 g, 50 mmol) wa~
heated to reflux with 1.7M trimethylamine-sulphur dioxlde in ethanol (60 ml) for 5 h. After cooling to 0C,the crystals were filtered off and dried to give the title compound (14.9 g, 87~).
M.p. 173-175 C.
C17~22N6S; 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.
0~
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 wers filtered off and dried to give the title compound (3.05 g, ~9~).
M.p. 172-175C.
Example 19 (removal of the benzyl group) N-Cyano-N'-methyl-N"-[2-[[(4-methyl imidazol-5-yl)methylj -thio~ethyl]guanidine (Cimetidine).
Compound B (274 g, 0.80 mol) was suspended in liquid ammonia (1200 mll. 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. 138-141C.
HPLC indicated a purity of 97%.
! ~
~he ~res~nt -invention relates to ~ proces~ For tile pro~u(tic)n o~
4~ ethyl-5-alkylthiomethylimidazoles.
In British Patent Specification No. 1,533,380 a process is descri~ed, according to which compounds, e.g., of the following formula Het-Cll2-S~c~~l2cll2~Nl~l C NHR
i are produced, wherein Elet is a heterocyclic group, e.g., an j imidazole group, E is S or NCN, and R is H or lower alkyl, by letting a compound of the formula Het-CE12Z
where Het is defined as hereinbefore, and Z is a leaving group i react with a mercaptan of the formula Hs~cEl2cH2-NH-c~ NHRl wherein Rlis defined as hereinbefore~
Spanish Patent Specification No. 463,839 describes 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)guanidiile.
German published Specification No. 2,211,454 describes the preparation of, e.g., Cimetidine by letting Het-cH2-Q
wherein ~ is a leaving group, and Het is a 4-methyl-5-imida-zolyl group, react with IlSCH2CE12Nii2 to form llet-CH2SCE12CE12NE12 wllich is subsequently treated with R3Z C ~NR21 to give, e.g., Cimetidine when R is C113, R is CN, R is alkyl or aryl and Z is S.
~ L9903~ 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 (I) B
Wherein one of the substituents A and B is NOH and the other is O or NGH. 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 NR3, 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 1 ~NCN
HSAlk NH-C 2 (II~
\ NHAlk preferably under cold conditions in the presence of a strong base, such as sodium ethoxide, to give ~NCN
3 2Alk 2 (III) ~ \ NHAlk A B
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 III is ring-closed by treat-ment with formaldehyde or a formaldehyde donor, e.g. para-formaldehyde, or mixtures of formaldehyde and/or formalde-hyde donors and ammonia or ammonia donors, e.g., ammonium acetate, or reagents with the formula YN = CH2 ~1~9~
wherein Y is HO or, preferentially, aralkyl, although other groups may also be suitable~ to give an imidazole N-oxide IV or V
- o N CH2scH2cH2NH-c95 (IV) N ~ CH3 ~N ~ CH ScH2cH2NH-c~NHcH (V) _O
~hereY isas hereinbeforedefined or H. When Y is H, the com-pounds 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 </ ~ ~NCN
NH H SAlk -NH-C 2 which, in the preferred use of Alk1 = C2H4 and Alk2 = CH3, 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 sur-prising 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 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 C-S bond would be the one most easily reduced by known methods.
Neither was it foreseeable that the deoxyyenation of compounds IV and V could be undertaken, due to the number of other reactive sites which are open for attack by known deoxygenation rea~ents, and the use of these also led to unsatisfactory results. Sur-prisingly, it was found that trialkylamine~sulphurdioxide com-plexes, e.g., (CH3)3N-S02, or formamidinosulphinicacid gave the desired product in good yield; the resulting sulphurtrioxide or sulphonicacid would have been expected to give unwarranted side reactions, cf. Synthesis,(1979),36.
The following examples are illustrative of the present in-vention.
Example 1 l~irst reaction step) N-Cyano-N'-methyl-N"-[[2-(3-oximino-2-oxobutyl)thio]ethyl]
guanidine (IIIa).
Sodium (11.0 g, 0.48 mol~ was added to ethanol (250 ml), fol-lowed 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 solu-tion of l-bromo-3-oximino-2-butanone (86.0 g, 0.524 mol) in anhydrous ethanol (250 ml). The reaction mixture was left at 5C over night, the precipitated sodium bromide was removed by ~iltration 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 tri-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. 111-112 C. CgH15N5O2S;
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]ethil]
guanidine (IIIb).
Sodium (5.75 g, 0-250 mol) was dissolved in ethanol (100 ml) and added to N-cyano-NI-methyl-N''-(2-mercaptoethyl)guanidine (II, 39.6 g, 0-250 mol) in ethanol (60 ml). The resulting solution was stirredF under nitrogen, for 1 h, and subsequently added to a solution of 4-chloro-3-o~imino-2-butanone ~33.9 g, 0.250 mol) in ethanol (80 ml) during a period of 40 min. at 25C. The resulting solution was kept over night at 5C, 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). CgH15N5O2S; 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.
3q~ 6 Example 3 (second reaction step) N-Cyano-N'-methyl-N"-[2-[[(1-benzyl-3-oxido-4-methylimidazol-5-yl)methyl]thio]ethyl]guanidlne (IVa).
Compound IIIa (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 metha-nol phase was isolated, extracted with petroleum ether, and the solvent was evaporated, in vacuo, at 40C. The semicrystalline residue was stirred with ether which caused fuxther crystalli-zation, and the crystals were filtered o~f. The mother liquor was again concentrated and once more treated with ether which afforded a new crop of crystalline material. The combined pro-duct was dissolved in a 1:4 mixture of methanol and chloroform, the solution was stirred with silica, and the silica was fil tered off. The filtrate was concentrated, in vacuo, the residue stirred with acetonitrile, and the resulting cr~stals 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 B.7~ (8.95).
The IR, lH-NMR and 13C-NMR spectra are in agreement with the gi~en structure.
Example 4 (second reaction step) N-Cyano-N'-methyl-N"-~2-~[~1-benzyl-3-oxido-4-methyl imida~ol-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 mmol~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 25Cfor 13 h. The solvent was evaporated in vacuo, at 60C-The resulting residue was heated to reflux with acetone ~100 ml) for 30 min. whereby crystallization occured. After cooling to 10C the crystals were filtered off and dried to give the title compound !15.2 g, 85%). M.p.1~3-1~4QC (dec.).
~9~ 7 Exam~le 5 (second reaction step3 N-Cyano-N'-methyl-N"-[2-[[(1-ben~yl-3-oxido-5-methylimidazol-4-yl)methyl]thio]ethyl]guanidine (Va).
Compound III b (2.57g, 0.010 mol)in methanol (25 ml) was mixed with N-benzylmethyleneimine (2.38 g, 0.020 mol3 and heated under nitrogen to reflux for 17 h. The resulting solution was evapo-rat~d 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 5G.77 (56i96), 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[[(1-oxido-5-methylimidazol-4-yl)methyl]
thio]ethyl]~uanidine (IVb).
Compound IVa (35.0 g, 0.0976 mol) was suspended in li~uid ammo-nia (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 subse-quently removed by heating to room temperature, anhydrous alco-hol (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. CloH16N6OS; Found (Calc.) C 43.65 ~44O75)~ H 6.00 (6.01), N 30.86 (31.32),S 12.02 (11.95). The IR H-NMR and C-NMR spectra are in agreement with the given structure.
(removal step3 N-Cyano-N'-methyl-N"-[2-[[(1-oxido-4-methylimidazol-5-yl3methyl]
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 por-tion~, ~ollowed by ammonium chloride (1.23 g 23 mmol)~ The ammonia ~as removed by heating to room temperature, propanol was added, the formed suspension was stirred for 30 min and filtered. The fil~rate was seeded with crystals of Vb and cooled.
The precipitated crystallin~ material was filtered off and dried to gi~e the title compound (2.0 g, 75~). M.p. 176-178C (dec)~
Recrystalli~ation from dry methanol raised the m.p. to 180-183C
ldec). C1oH16N6OS; Found (Calc.) C 44.62 (44.75), H 5.96 (6.01), N 31.24 (31.32), ~ 98 (11.95). The IR and H-NMR spectra are in agreement with ~he given structure.
Example 8 (second reaction step - IIIb > Vb direct) Compound Vb.
Compound IIIb (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 65C. 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 hydro-~ide. The solvent was removed in vacuo, and the residue was dis-solved 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~. C10H16N6OS, H2~; Found (Calc.) C 41.70 (41.94), H 6-19 (6.3~), N 29.42 (29.35), S 11.25 (11.20), H2O 6.33 (6.29). Recry-stallization from dry ethanol raised the m.p. to 181-183C (dec).
The compound was identical with an authentic sample (IR and H-~MR
spec-troscop~
Example 9 (second reaction step - IIIb ` Vb direct) Compound V~.
Compound IIIb (5.15 g, 20.0 mmol~, ammonium dihydrogenphosphate t2~30 g, 20.0 mmol), ammonium hydrogenphosphate (1.32 g, lO.0 mmol) and paraformaldehyde (0.72 g, 24 mmolj in water (40 ml) were stirred for 2 h at 65C, 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 crystal-lized from methanol to give 2.73 g (48~) of Vb, H2O.
Example10 (second reaction step - IIIb ~ Vb direct) Compound Vb.
Compound IIIb (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 rcom 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, H2O (1.71 g, 41~), identical by IR and 1H-NMR with an authentic sample.
Example 11 (second reaction step - IIIa ~ IVb) Compound IVb.
Compound IIIa (2.57 g, lO.0 nmol), 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 re-moved, in vacuo, and the residue was adjusted to pH 8 with 3 N
potassiun 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 cry-stallized from methanol to give 0.68 g (25%) of IVb.
Example 12 (deoxydation step) N-Cyano-N'-methyl-N"-[2-[[4-methylimidazol-5-yl)methvl]thio]
ethyl]guanidine (Cimetidine~.
Compound IVb (3.00 g, 11.2 mmol) and trimethylamine-sulphur dioxide ((CH3)3N~SO2, 2.7 g, 22 mmol) in methanol (60 ml) was heated to 130C for 5 h in an autoclave. After cooling, the reaction mixture was concentrated, in vacuo. Water (6 ml), and ~ ~ 10 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. CloH16N6lS; Found (Calc.) C 47.60 (47.60), Il 6.42 (6.39), N 32.94 (33.31), S 12.81 (12.71). The I~ and lHNMR 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 (~.8 ml), formamidinosulfinic acid ((H2N)2C-SO2, 49 mg, 0.45 mmol) was added, and the mixture was heated to 100C for 1 h, after which it was shown to contain 48~ Cimetidine ~y HPLC.
~xample 14 (deoxydation step) Cin~eLidine.
Compound IVb (2.00 9, 7.5 mmol) was dissolved in '-ethox,ethanol (40 ml), trime~hylammonium sulfinate (2.70 ~, 21.9 mmol) was added~ and the mixture was ~leated to reflux for 15 min. Su~se-quently, analysis by }IPLC revealed the presence of 72~ Cimeti-dine, of which 1.30 g, 69%, could be isolated.
Example 15 (deoxydation step~
Cimetidine.
Compound Vb was deoxyc;enated analogously to the method described in Example 11to qive Cimetidine.
l~lLg'90~ 0 11 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~ l7,2 g, 20 mmol) was heated to reflux with 1.7M trimethylamine-~ulphur d1oxide 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.C~7~l22N6S; Found (Calc.) C 59.53 (59.~2), H 6.55 (6.48), N 24.43 (24.54), S 9.41 (9.36). The 'H-NM~ and 3C-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 I.
N-Cyano-N'-methyl-N"-[2-~[(1-benzyl-3-oxido-4-methyl-imidazol -5-yl)methyl~thio]ethyl]guanidine (IV a) ~17.9 g, 50 mmol) wa~
heated to reflux with 1.7M trimethylamine-sulphur dioxlde in ethanol (60 ml) for 5 h. After cooling to 0C,the crystals were filtered off and dried to give the title compound (14.9 g, 87~).
M.p. 173-175 C.
C17~22N6S; 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.
0~
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 wers filtered off and dried to give the title compound (3.05 g, ~9~).
M.p. 172-175C.
Example 19 (removal of the benzyl group) N-Cyano-N'-methyl-N"-[2-[[(4-methyl imidazol-5-yl)methylj -thio~ethyl]guanidine (Cimetidine).
Compound B (274 g, 0.80 mol) was suspended in liquid ammonia (1200 mll. 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. 138-141C.
HPLC indicated a purity of 97%.
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a 4-methyl-5-alkylthioimida-zole 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 X is a leaving group and one of the substituents A and B is NOH the other being O or NOH, with a compound of the formula :
wherein Alk1 and Alk2 are as above go give a compound of the formula which is subsequently ring-closed by treatment with formalde-hyde or a formaldehyde donor, or mixtures of formaldehyde and/or formaldehyde donors,and ammonia or an ammonia donor, or rea-gents with the formula:
YN = CH2 wherein Y is H or a removable group to form which, when Y is other than H or OH, is selectively reduced to give the mono N-oxide the final compound being deoxygenated to give the desired product.
wherein X is a leaving group and one of the substituents A and B is NOH the other being O or NOH, with a compound of the formula :
wherein Alk1 and Alk2 are as above go give a compound of the formula which is subsequently ring-closed by treatment with formalde-hyde or a formaldehyde donor, or mixtures of formaldehyde and/or formaldehyde donors,and ammonia or an ammonia donor, or rea-gents with the formula:
YN = CH2 wherein Y is H or a removable group to form which, when Y is other than H or OH, is selectively reduced to give the mono N-oxide the final compound being deoxygenated to give the desired product.
2. A process as claimed in claim 1, in which X is halogen, acyloxy or tosyloxy, or NR3 wherein R is alkyl.
3. The process of claim 1, wherein Alk1 is CH2CH2 and Alk2 is CH3.
4. A process as claimed in claim 1, 2 or 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 claim 1, 2 or 3, in which the deoxidising agent used in the final step comprises a trialkylamine-sulphur dioxide complex or formamidino-sulphinic acid.
6. A process as claimed in claim 1, in which Alk1 is alkylene of 1 to 4 carbon atoms.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB28782/82 | 1982-10-08 | ||
| GB8228782 | 1982-10-08 |
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| CA1199030A true CA1199030A (en) | 1986-01-07 |
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| CA000438623A Expired CA1199030A (en) | 1982-10-08 | 1983-10-07 | Production of imidazoles |
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| JP (3) | JPS5988472A (en) |
| AU (1) | AU560031B2 (en) |
| BE (1) | BE897952A (en) |
| CA (1) | CA1199030A (en) |
| CH (2) | CH659650A5 (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) |
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| 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 |
| JPH0623181B2 (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 |
| 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 |
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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 |
-
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 DK DK451883A patent/DK159309C/en not_active IP Right Cessation
- 1983-09-30 NL NL8303351A patent/NL191181C/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 FR FR8315903A patent/FR2534256B1/fr not_active Expired
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- 1983-10-06 JP JP58186070A patent/JPS5988472A/en active Granted
- 1983-10-07 AU AU19956/83A patent/AU560031B2/en not_active Ceased
- 1983-10-07 PT PT77468A patent/PT77468B/en unknown
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1985
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1986
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