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EXAMPLE 10 4-Methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride 108 g of 4-methyl-5-hydroxymethylimidazole hydrochloride (=20 mole % excess) and 72 g of 2,2-dimethylthiazolidine are introduced into 1,350 ml of concentrated hydrochloric acid, whilst cooling to 20-30 C. The mixture is refluxed for 17 hours and then evaporated to dryness under reduced pressure. The residue obtained (235 g) is recrystallized from 400 ml of alcohol. 144 g of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride (corresponding to a yield of 98.1% of theory), of melting point 185-192.5 C., are obtained.
84.0%
EXAMPLE 8 4-Methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride 30 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 23 g of cysteamine in 450 ml of concentrated hydrochloric acid are refluxed for 17 hours. The solution is evaporated to dryness under reduced pressure. The residue (61 g) is recrystallized from 500 ml of alcohol. 41 g of 4-methyl-5-[(2-aminoethyl)-thiomethyl]imidazole dihydrochloride (corresponding to a yield of 84.0% of theory), of melting point 184-191 C., are obtained.
49%
EXAMPLE 4 Preparation of 4-methyl-5-(2-aminoethyl)-thio-methylimidazole dihydrochloride A mixture containing cysteamine hydrochloride (18.75 g, 0.165 mol),-4-hydroxymethyl-5-methylimidazole hydrochloride (25 g, 0.169 mol), concentrated hydrochloric acid (10 mL) and isopropanol (17 mL) is heated to 70-80 C. The solvent is removed under reduced pressure and the crude product is pulped with n-butanol. The precipitate is filtered and dried to give 19.7 g of the expected product (49%).
Five hundred and eighty two (582) g of this aqueous solution was concentrated and thrown into 1,000 g of 1-propanol. The precipitate consequently produced was separated by filtration and then dried, to afford 162 g of white crystals of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride.
One hundred (100) g of this aqueous solution was concentrated and thrown into 150 g of 1-propanol. The precipitate consequently produced was separated by filtration and then dried, to afford 19 g of white crystals of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride.
At the same time, 2,640 g of a liquid containing 74 g of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole hydrochloride, and other unaltered reactants and hydrochloric acid was obtained as the outer liquid. The inner liquis thus obtained was concentrated under a vacuum and thrown into 1-propanol. The crystals consequently precipitated were separated by filtration and dried, to produce 159 g of white crystals of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride
2
[ 23187-14-6 ]
[ 38603-72-4 ]
Yield
Reaction Conditions
Operation in experiment
Separately, the outer liquid obtained in the electrodialytic device 10 was withdrawn at a flow rate of 336.3 g/min. through a conduit 13 and supplied to a concentrator 14 and concentrated therein, to prepare a liquid containing 5.2% by weight of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride, 8.4% by weight of 4-methylimidazole hydrochloride, and the balance of unaltered reactants and hydrochloric acid. This liquid was returned at a flow rate of 141 g/min. through a conduit 15 to the reactor 6.
With sodium hydroxide; methylamine; In methanol; nitrogen;
Detection: UV (229 nm) EXAMPLE 3 4-Methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride 24.4 g (0.10 mole), N-cyano-2-imino-4-methyl-1,3-dithian 15.5 g (0.09 mole) and methanol 500 ml were placed in a reaction flask, 160 g of 5% methanolic solution of sodium hydroxide was added dropwise with stirring at a temperature in the range of 30 to 35 C. over a period of three hours while slowly flowing nitrogen gas, and stirring was continued at that temperature for an additional three hours. After making sure that the 1,3-dithian compound had been consumed almost completely, 78 g (1.0 mole) of 40% methanolic solution of methylamine was added, and the reaction was continued at 25 to 30 C. for 24 hours. Analysis of the reaction mixture thus obtained by liquid chromatography showed the formation of N-cyano-N'-methyl-N"[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine with a yield of 73%.
With ammonia; triethylamine; In tetrahydrofuran; methanol; chloroform; ethyl acetate; acetone;
EXAMPLE 63 A mixture of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (0.5 g.), triethylamine (1 ml.) and 2-[2-(2,2,2-trifluoroethyl)guanidino]-(4-isothiocyanatobutyl)thiazole (0.5 g.) in tetrahydrofuran (15 ml.) was allowed to stand at room temperature overnight. The solution then was filtered, and the filtrate evaporated to dryness. The residue was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:1 v/v/v as developing solvent. The appropriate band was isolated and further purified by preparative thin layer chromatography using methanol/chloroform/ammonia 15:85:1 v/v/v as developing solvent. The appropriate band after extraction and evaporation yielded a brown gum. This was treated in acetone with excess maleic acid to give 1-[4-(2-[2-(2,2,2-trifluoroethyl)-guanidino]thiazol-4-yl)butyl]-3-[2-([4-methylimidazol-5-yl]methylthio)ethyl]thiourea containing 2.25 equivalents of maleic acid.
N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In water;
b. i. Potassium carbonate (7.75 g.) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g.) in water (120 ml.). The solution was stirred at room temperature for 15 minutes and methyl isothiocyanate (5.15 g.) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5. The product (13.1 g.) was collected and recrystallized from water to give N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea, m.p. 150-152.
N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In water;
Potassium carbonate (7.75 g) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g) in water (120 ml). The solution was stored at room temperature for 15 minutes and methyl isothiocyanate (5.15 g) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5. The product was collected and recrystallized from water to give N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea, m.p.150-152.
With potassium carbonate; In water;
Potassium carbonate (7.75 g.) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g.) in water (120 ml.). The solution was stored at room temperature for 15 minutes and methyl isothiocyanate (5.15 g.) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5 C. The product was collected and recrystallized from water to give N-methyl-N'-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]thiourea, m.p. 150-152 C.
With potassium carbonate; In water;
(ii) Potassium carbonate (7.75 g.) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydro-chloride (14.6 g.) in water (120 ml.). The solution was stored at room temperature for 15 minutes and methyl isothiocyanate (5.15 g.) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5. The product (13.1 g.) was collected and recrystallized from water to give N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea, m.p. 150-152. (Found: C, 44.5; H, 6.7; N, 23.0; S, 26.2. C9 H16 N4 S2 requires: C, 44.2; H, 6.6; N, 22.9; S, 26.2).
ii. Potassium carbonate (7.75 g.) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g.) in water (120 ml.). The solution was stirred at room temperature for 15 minutes and methyl isothiocyanate (5.15 g.) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5. The product (13.1 g) was collected and re-crystallized from water to give N-methyl-N'-[2-((5-methyl-4-imidazolyl) methylthio)ethyl]thiourea, m.p. 150-152.
i. (a) A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g) and cysteamine hydrochloride (23.0 g.) in acetic acid (200 ml.) was heated under reflux for 10 hours. Following cooling to 15-20, the solid which crystallized was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride (45.5 g), m.p. 189-192.
i. a. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0g) and cysteamine hydrochloride (23.0g.) in acetic acid (200 ml.) was heated under reflux for 10 hours. Following cooling to 15-20, the solid which crystallized was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride (45.5g), m.p. 189-192.
In acetic acid;
EXAMPLE 6 A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g) and cysteamine hydrochloride (23.0 g) in acetic acid (200 ml) was heated under reflux for 10 hours. Following cooling to 15-20, the solid which crystallized was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride m.p. 189-192.
In acetic acid;
EXAMPLE 12 A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in acetic acid (200 ml.) was heated under reflux for 10 hours. Following cooling to 15-20 C., the solid which crystallized was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride, m.p. 189-192 C.
In concentrated aqueous hydrochloric acid;
b. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueous hydrochloric acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water afforded a residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (40.6 g.), m.p. 185-191.
In acetic acid;
i. a. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in acetic acid (200 ml.) was heated under reflux for 10 hours. Following cooling to 15-20, the solid which crystallized was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (45.5 g), m.p. 189-192.
In concentrated aqueous hydrochloric acid;
b. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueous hydrochloric acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water afforded a residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride (40.6 g.)m m.p. 185-191.
In acetic acid;
(i) a. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in acetic acid (200 ml.) ws heated under reflux for 10 hours. Following cooling to 15-20, the solid which crystallized was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (45.5 g.), m.p. 189-192.
N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea[ No CAS ]
[ 38603-72-4 ]
Yield
Reaction Conditions
Operation in experiment
In concentrated aqueous hydrochloric acid;
b. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g) in concentrated aqueous hydrochloric acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water afforded a residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride (40.6 g.), m.p. 185-191.
b. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g) in concentrated aqueous hydrochoric acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water afforded a residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (40.6 g.), m.p. 185-191.
With paraformaldehyde; In hydrogenchloride; ethanol;
EXAMPLE 1 42.0 Parts of 97.5% pure 4-methylimidazole, 56.8 parts of cysteamine hydrochloride and 18.0 parts of paraformaldehyde are dissolved in 207 parts of 37% strength aqueous hydrochloric acid, whilst cooling so that the temperature does not exceed 30 C. The mixture is heated in a closed glass-lined kettle for 5 hours at 110-120 C. and for a further 10 hours at 120 C. The hydrochloric acid is then distilled off under reduced pressure from a water-pump, at not more than 80 C., until the residue has almost been reduced to dryness, after which the latter is dissolved in 237 parts of boiling ethanol. The solution is cooled to 20 C. and the precipitate which forms is filtered off and dried. 81.9 Parts (constituting the 1st fraction) of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride, of melting point 179-180 C., are obtained. The filtrate is evaporated to about half its volume and is cooled to 20 C., and the precipitate is filtered off. After drying, a further 12.7 parts (constituting the 2nd fraction) of melting point 149-154 C. are obtained. Fractions 1 and 2 are combined and recrystallized from 315 parts of glacial acetic acid. After drying at 10 mm Hg and 90 C., 82.4 parts (67.5%) of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride of melting point 190-191 C. are obtained.
(b) 84 parts of 4-methyl-5-chloromethyl-imidazole hydrochloride, in the form of a fine powder, and 57 parts of cysteamine hydrochloride, also in the form of a fine powder, are mixed intimately and the mixture is heated in a solidstate reactor for 2 hours at 80 and then for 7 hours at 100; the progress of the reaction can be followed by NMR spectroscopy or from the evolution of hydrogen chloride. 120 parts (98%) of 4-methyl-5-[(2-amino-ethyl)-thiomethyl]-imidazole dihydrochloride are obtained; the substance melts at 186-189 C., after first sintering at about 181 C. A single recrystallization of the product from ethanol raises the melting point to 193-195 C.
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