* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
REFERENCE EXAMPLE a-3 Preparation of 2-imino-1,3-dimethylimidazol-4-ine hydrochloride STR733 16.9 g (150 mmol) of <strong>[60-27-5]creatinine</strong> was dissolved in 100 ml of N,N-dimethylformamide. Then, 27.6 g (194 mmol) of methyl iodide was added thereto, and the mixture was heated to 50 C. and stirred at that temperature for 2 hours and further at room temperature overnight. To the reaction mixture, 500 ml of ethyl acetate was added, and crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and dried to obtain 26.2 g of 2-imino-1,3-dimethylimidazolidin-4-one hydroiodide as white crystals.
1-methyl-3-n-propyl-2-iminoimidazolidin-4-one[ No CAS ]
1-methyl-3-n-propyl-2-iminoimidazolidin-4-one hydroiodide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; ethyl acetate;
REFERENCE EXAMPLE d-2 Preparation of 1-methyl-3-n-propyl-2-iminoimidazolidin-4-one hydroiodide STR745 9.04 g (80 mmol) of <strong>[60-27-5]creatinine</strong> was suspended in 50 ml of dimethylformamide, and 17.0 g (100 mmol) of n-propyl iodide was added thereto. Then, the mixture was heated and stirred within a range of from 70 C. to 80 C. until <strong>[60-27-5]creatinine</strong> was completely dissolved. The mixture was left to cool, and 500 ml of ethyl acetate was added thereto. Precipitated crystals were collected by filtration to obtain 10.6 g of 1-methyl-3-n-propyl-2-iminoimidazolidin-4-one hydroiodide. Melting point: 159-161 C. The 1-methyl-3-n-propyl-2-iminoimidazolidin-4-one hydroiodide was neutralized in accordance with the following method to obtain 1-methyl-3-n-propyl-2-iminoimidazolidin-4-one.
(ii) N-[[3-(2-Aminoethyl)-1H-indol-5-yl]methyl]methanesulphonamide, compound with <strong>[60-27-5]creatinine</strong>, sulphuric acid and water (1:1:1:1) A solution of N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]methanesulphonamide (0.95 g) in ethanolic methylamine (33%; 40 ml) was kept at room temperature for 2.5 h. The solvent was evaporated in vacuo and the residue was re-evaporated with ethanol (2*50 ml). The residue was dissolved in hot ethanol (100 ml) and an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (1:1; 2M; 1.25 ml) was added, followed by ethanol (50 ml). Filtration of the cooled solution gave the title compound (0.6 g) as a cream solid m.p. 215-8. Analysis Found: C, 38.5; H, 5.4; N, 16.8; C12 H17 N3 O2 S.C4 H7 N3 O.H2 SO4.H2 O requires: C, 38.7; H, 5.7; N, 16.95%.
phenylmethyl [2-[5-[[(methylsulphonyl)amino]methyl]-1H-indol-3-yl]ethyl]carbamate[ No CAS ]
[ 81880-66-2 ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; In ethanol; water;
(ii) N-[[3-(2-Aminoethyl)-1H-indol-5-yl]methyl]methanesulphonamide, compound with <strong>[60-27-5]creatinine</strong>, sulphuric acid and water (1:1:1:1) A solution of phenylmethyl [2-[5-[[(methylsulphonyl)amino]methyl]-1H-indol-3-yl]ethyl]carbamate (0.22 g) in ethanol (20 ml) was hydrogenated at room temperature and pressure over palladium oxide on charcoal (10%; pre-reduced, 0.2 g) until uptake of hydrogen ceased (12 minutes; 8 ml). The catalyst was filtered off and the filtrate was evaporated in vacuo to leave a pale yellow oil. The oil was dissolved in hot ethanol (12 ml) and water (0.1 ml) and an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (2M; 1:1; 0.26 ml) was added. Filtration of the cooled mixture gave the title compound (0.175 g) as a white solid m.p. 215-8.
N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]trifluoromethanesulphonamide[ No CAS ]
N-[[3-(2-Aminoethyl)-1H-indol-5-yl]methyl]trifluoromethanesulphonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; hydrazine hydrate; In ethanol; water;
(ii) N-[[3-(2-Aminoethyl)-1H-indol-5-yl]methyl]trifluoromethanesulphonamide, compound with <strong>[60-27-5]creatinine</strong>, sulphuric acid and water (1:1:1:1) A solution of N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]trifluoromethanesulphonamide (0.59 g) in ethanol (90 ml) was treated with hydrazine hydrate (0.35 ml) and heated at reflux for 6 h. After cooling, the solution was evaporated to dryness, and the resulting white solid was partitioned between sodium carbonate solution (2N; 100 ml) and ethyl acetate (4*100 ml). The combined organic extract was dried (magnesium sulphate) and evaporated to dryness, affording an orange foam (0.45 g) which was purified by chromatography on a silica column (Merck Kieselgel 60; 15 g) eluted with methanol-ammonium hydroxide (66:1), affording pure title base as a pale yellow oil (0.28 g). This was dissolved in a hot mixture of ethanol (24 ml) and water (3 ml), and an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (1:1; 2M; 0.45 ml) was added. Filtration of the cooled solution gave the title compound (0.37 g) as white solid, m.p. 244-6 (dec). Analysis Found: C, 34.5; H, 4.5; N, 15.9%; C12 H14 F3 N3 O2 S.C4 H7 N3 O.H2 SO4.H2 O requires: C, 34.9; H, 4.6; N, 15.3%.
N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]-N-methyltrifluoromethanesulphonamide[ No CAS ]
N-[[3-(2-Aminoethyl)-1H-indol-5-yl]methyl]-N-methyltrifluoromethanesulphonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; hydrazine hydrate; In ethanol; water;
(ii) N-[[3-(2-Aminoethyl)-1H-indol-5-yl]methyl]-N-methyltrifluoromethanesulphonamide, compound with <strong>[60-27-5]creatinine</strong>, sulphuric acid and water (1:1:1:1) A solution of N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]-N-methyltrifluoromethanesulphonamide (0.39 g) in ethanol (55 ml) was treated with hydrazine hydrate (0.70 ml) and heated at reflux for 1.5 h. After cooling, the mixture was evaporated to dryness, giving a white solid. This was partitioned between sodium carbonate solution (2N, 50 ml) and ethyl acetate (4*50 ml), and the combined organic extract was dried (magnesium sulphate) and evaporated to dryness, affording a yellow gum (0.33 g). This was dissolved in a hot mixture of ethanol (40 ml) and water (5 ml) and treated with an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (2M; 1:1; 0.44 ml). On cooling the title compound crystallized as a white solid (0.37 g) m.p. 237-9 (d). Analysis Found: C, 36.65; H, 4.8; N, 14.7. C13 H16 F3 N3 O2 S.C4 H7 N3 O.H2 SO4.H2 O requires: C, 36.2; H, 4.8; N, 14.9%.
N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]ethanesulphonamide[ No CAS ]
N-[[3-(2-Aminoethyl)-1H-indol-5-yl]methyl]ethanesulphonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; hydrazine hydrate; In ethanol; water;
(ii)a N-[[3-(2-Aminoethyl)-1H-indol-5-yl]methyl]ethanesulphonamide, compound with <strong>[60-27-5]creatinine</strong>, sulphuric acid and water (1:1:1:1) A solution of N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]ethanesulphonamide (0.70 g) in ethanol (100 ml) was treated with hydrazine hydrate (1.4 ml) and heated at reflux for 1 h. After cooling, the resulting solution was evaporated to dryness, and the resulting white solid was partitioned between sodium carbonate solution (2N; 80 ml) and ethyl acetate (3*80 ml). The organic extract was dried (magnesium sulphate) and evaporated to dryness, giving a yellow oil (0.49 g). This was dissolved in a hot mixture of ethanol (56 ml) and water (7 ml), and treated with an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (2M; 1:1; 0.85 ml). On cooling the title compound crystallized as a white solid (0.66 g) m.p. 206-8 (d). Analysis Found: C, 40.1; H, 5.9; N, 16.4; C13 H19 N3 O2 S.C4 H7 N3 O.H2 SO4.H2 O requires: C, 40.0; H, 5.9; N, 16.5%.
N-Methyl-N-[[3-[2-[(1-methyl-3-phenylpropyl)amino]ethyl]-1H-indol-5-yl]methyl]methanesulphonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; In ethanol; water; ethyl acetate; Petroleum ether;
EXAMPLE 13 N-Methyl-N-[[3-[2-[(1-methyl-3-phenylpropyl)amino]ethyl]-1H-indol-5-yl]methyl]methanesulphonamide, compound with <strong>[60-27-5]creatinine</strong>, sulphuric acid and water (1:1:1:1) A solution of N-[[3-(2-aminoethyl)-1H-indol-5-yl]methyl]-N-methylmethanesulphonamide (0.4 g) and benzyl acetone (2 ml) in ethanol (70 ml) was hydrogenated at room temperature and pressure over palladium oxide on carbon (10%; 50% aq paste; 0.1 g; pre-reduced) until hydrogen uptake ceased. The catalyst was filtered off and the filtrate evaporated to give a yellow oil which was dissolved in ethyl acetate (10 ml) and added dropwise to vigorously stirred petroleum ether (b.p. 60-80, 80 ml). The solvent was decanted off and the precipitated oil washed with petroleum ether (100 ml). The washed oil (0.27 g) was dissolved in a hot mixture of ethanol (32 ml) and water (4 ml) and an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (2M; 1:1; 0.3 ml) was added. On cooling and scratching the title compound crystallized as a white solid (0.23 g) m.p. 142-150. Analysis Found: C, 50.0; H, 6.4; N, 12.8; C23 H31 N3 O2 S.C4 H7 N3 O.H2 SO4.H2 O requires: C, 50.4; H, 6.7; N, 13.05%.
ethyl N-(3-Cyanomethyl-1H-indol-5-yl)carbamate[ No CAS ]
[ 67-63-0 ]
ethyl N-[3-(2-Aminoethyl)-1H-indol-5-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; ammonia; In ethanol; water; ethyl acetate;
(ii) Ethyl [3-(aminoethyl)-1H-indol-5-yl]carbamate, compound with <strong>[60-27-5]creatinine</strong>, sulphuric acid and water (2:2:2:1) Ethyl [3-(cyanomethyl)-1H-indol-5-yl]carbamate (1.5 g) was catalytically hydrogenated over 5% rhodium-on-alumina (0.5 g) in a mixture of ethanol (50 ml) and ammonia (0.6 ml) for 40 h at 40 then at 50 for a further 8 h. The mixture was filtered through hyflo and evaporated to dryness to afford a brown oil. This oil was purified by column chromatography on silica (25 g) using ethyl acetate/2-propanol/water/ammonia (25:15:4:1) as eluant to give a brown oil (0.58 g) which was dissolved in ethanol and treated with an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (1:1, 2M, 1 ml) to give an off-white solid which was recrystallized from aqueous acetone to give the title compound as a colourless solid (0.65 g) m.p. 184.5-187.5. Analysis. Found: C,43.4; H,5.9; N,17.65. C13 H17 N3 O2.C4 H7 N3 O.H2 SO4.O.5H2 O requires: C,43.7; H,5.8; N,18.0%.
With sulfuric acid; In ethanol; water; methylamine;
Example 7 N-[3-[2-(Methylamino)ethyl]-1H-indol-5yl]formamide, compound with <strong>[60-27-5]creatinine</strong>, sulphuric acid and water (10:12:11:20) A solution of N-[3-(cyanomethyl)-1H-indol-5-yl]formamide (0.3 g) in absolute ethanol (30 ml) containing methylamine, (33% in ethanol, 2 ml) was hydrogenated at room temperature and pressure over palladium oxide on charcoal (10%, 0.5 g) for 24 h until hydrogen uptake ceased (90 ml). The catalyst was filtered off, washed with absolute ethanol, and the filtrate was evaporated in vacuo yielding a brown oil. The amine was dissolved in a hot mixture of ethanol and water (8:1, 18 ml) and an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (1:1, 2M, 0.6 ml) was added. Filtration of the cooled mixture gave the title compound as an off-white solid (0.35 g) m.p. 205-207. Analysis. Found: C,40.6: H,5.5: N,.18.8. C12 H15 N3 O.1.2C4 H7 N3 O.1.1H2 SO4.2H2 O requires: C,40.7; H,5.8; N.18.6%.
ethyl [3-(2-aminoethyl)-1H-indol-5-yl]methylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid;palladium on charcoal; In hydrogenchloride; ethanol; water;
(ii) Ethyl [3-(2-aminoethyl)-1H-indol-5-yl]methylcarbamate, compound with <strong>[60-27-5]creatinine</strong>, sulphuric acid, and water (1:1:1:2) A solution of ethyl [3-(cyanomethyl)-1H-indol-5-yl]methylcarbamate (0.2 g) in absolute ethanol (30 ml) containing concentrated hydrochloric acid (8 drops) was hydrogenated at room temperature and pressure over palladium on charcoal (10%, 0.4 g) until hydrogen uptake ceased (8 h, 23 ml). The catalyst was filtered off, washed with absolute ethanol, and the filtrate evaporated in vacuo yielding a brown oil. The amine was dissolved in a hot solution of ethanol and water (8:1, 18 ml) and treated with an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (1:1, 2M, 0.38 ml). Filtration of the cooled mixture gave the title compound as a white solid m.p. 210-212 (dec.) (0.15 g). Analysis. Found: C,42.7; H,5.9; N,16.7. C14 H19 N3 O2.C4 H7 N3 O.H2 SO4.2H2 O requires: C,42.5; H,6.3; N,16.5%.
N-[3-(2-Aminoethyl)-1H-indol-5-yl]trifluoroacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; ammonia; In ethanol;
(ii) N-[3-(Cyanomethyl)-1H-indol-5-yl]trifluoroacetamide (1.3 g) in ethanol (50 ml) and ammonia (0.6 ml) was hydrogenated at room temperature and pressure over rhodium-on-alumina (0.5 g) for 48 h. The mixture was filtered through hyflo and evaporated to dryness under reduced pressure to afford a brown oil. The brown oil was purified by column chromatography (Kieselgel 60, 25 g) using a mixture of ethyl acetate, 2-propanol, water and ammonia (25:15:4:1) as eluent. The resulting solid was dissolved in hot ethanol and treated with an aqueous solution of <strong>[60-27-5]creatinine</strong> and sulphuric acid (2M, 1:1, 1 ml) and the resulting solid was recrystallized from aqueous acetone to give the title compound as a pinkish solid m.p. 186-215 (dec). Analysis. Found: C,37.2; H,5.05; N,16.2. C12 H12 F3 N3 O.C4 H7 N3 O.H2 SO4 2H2 O requires: C,37.1; H,4.9; N,16.2%.
EXAMPLE VI 1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-p-chlorophenylurea To a stirring suspension of <strong>[60-27-5]creatinine</strong> (11.88 g, 0.105 mole) in 100 ml dry DMF, p-chlorophenylisocyanate (15.36 g, 0.100 mole) is added dropwise with cooling. The mixture is stirred for 16 hours and then poured into about 500 ml of iced-water to yield the crystalline product which is filtered off, washed with water and recrystallized twice from acetone-methanol, once from tetrahydrofuran (THF) and then from DMF-methanol.
In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
EXAMPLE I 1-m-Chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea To a suspension of <strong>[60-27-5]creatinine</strong> (5.66 g, 0.05 mole) in 150 ml. of dry dimethylformamide (DMF) is added 7.68 g (0.05 mole) of m-chlorophenylisocyanate. The mixture is stirred for 2 hours and heated on a steam bath for 30 minutes. During this time the solution becomes clear (yellow). The solution is filtered and the filtrate cooled. Ice and ice-water are added to the filtrate. A light yellow solid precipitates and is filtered off. After recrystallizations from acetone-methanol and tetrahydrofuran-ether, the pure product, 1-m-chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea, is obtained, mp 180-180.5C. Analysis: Calcd. for C11 H11 ClN 4 O2: C, 49.54; H, 4.16%. Found: C, 49.45; H, 4.19%.
1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-p-tolylurea[ No CAS ]
[ 58030-64-1 ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide;
EXAMPLE VII 1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-p-tolylurea To a stirring suspension of <strong>[60-27-5]creatinine</strong> (11.88 g, 0.105 mole) in 100 ml dry DMF, p-tolylisocyante (13.31 g - 0.100 mole) is added dropwise over a period of about 15 minutes with cooling. After stirring for 3.5 hrs., the mixture is poured into about 500 ml iced-water to give white crystals of product which are filtered off and washed with water. Recrystallization of the product from acetone-methanol and then from THF-methanol affords the product, 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-p-tolyl urea. The crystalline particles are reduced in to finer size by adding a solution of the thus-obtained product in minimal DMF to about 1.1 liters of vigorously stirring water, filtering off and drying the resultant fine crystals in vacuo for 24 hours; m.p. 198-200C dec.
1-(1-Methyl-4-oxoimidazolidene)-3-(2,6-xylyl) urea[ No CAS ]
[ 58030-67-4 ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
EXAMPLE X 1-(1-Methyl-4-oxoimidazolidinylidene)-3-(2,6-xylyl) urea A suspension of 5.66 g (0.05 mole) of <strong>[60-27-5]creatinine</strong> and 7.36 g (0.05 mole) of 2,6-xylylisocyanate in 200 ml of dry THF is heated under reflux overnight (about 15 hours). The hot solution is filtered and the filtrate diluted with ether to about 400 ml total volume, giving the crude product. Recrystallization from methanol affords pure 1-(1-Methyl-4-oxoimidazolidene)-3-(2,6-xylyl) urea, m.p. <190C dec. Analysis: Calcd. for C13 H16 N4 O2 (260.30): C, 59.98; H, 6.20%. Found: C, 60.17; H, 6.24%.
In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;
1-(methyl-4-oxo-2-imidazolidinylidene)-3-m-nitrophenyl urea. To a stirred slurry of 12.45 g (0.11 mole) of <strong>[60-27-5]creatinine</strong> in 100 ml of dry DMF is added 16.41 g (0.1 mole) of m-nitrophenyl isocyanate (previously recrystallized from benzenepentane). After 9 hours, ice water is gradually added until crystallization occurres. A large excess of ice water precipitates the product as gummy crystals which then crystallize. The crude product is allowed to air dry for several days. Recrystallization from THF-H2 O followed by THF gives pure product, 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-m-nitrophenyl urea; m.p. 182-188C sl. dec.
EXAMPLE XIV 1-(3-Chloro-2,6-dimethylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea. To a stirring suspension of 7.92 g (0.07 mole) of <strong>[60-27-5]creatinine</strong> in 50 ml of dry DMF is added 9.08 g (0.05 mole) of 3-chloro-2,6-dimethylphenyl isocyanate. After stirring for four hours, the reaction mixture is filtered through a diatomaceous earth pad to remove unreacted <strong>[60-27-5]creatinine</strong>. Addition of a large excess of ice water precipitates a gummy semisolid mass which eventually crystallizes. After blowing the product to dry it for about eighteen hours, it is recrystallized from acetone-ether. Finally the product is taken up in dichloromethane and the resulting solution is filtered through diatomaceous earth. Concentration and dilution with ether gives pure product, 1-(3-chloro-2,6-dimethylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea; m.p. 140-141.5C.
EXAMPLE II Procedure 2 described above is exemplified by the preparation of 1-(3-pyridinyl)-3-tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea 11. To a solution of 2.13 g (17.8 mM) of 3-pyridinylisocyanate 10 in 30 ml of dimethylformamide was added 2.0 g (17.8 mM) of <strong>[60-27-5]creatinine</strong> 7. The mixture was stirred at 90-95 C. for 3 hrs. and then cooled to form a precipitate. The solid was collected, washed with ether, and then chromatographed over silica gel using 5% methanol in chloroform as the eluent. The fractions containing the product were combined, treated with charcoal, filtered, and the filtrate diluted with ether to precipitate 1.1 g of 1-(3-pyridinyl)-3-(tetra hydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea 11 as pale yellow crystals, m.p. 200-201 C. (dec.).
EXAMPLE XV 1-(Tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene)-3-(2-thienyl) urea To 9.4 g (83 mM) of <strong>[60-27-5]creatinine</strong> in 100 ml of anhydrous DMF was added with stirring of solution of 9.2 g (75 mM) 2-thienyl isocyanate in 60 ml of toluene. After the addition was completed, the mixture was stirred at 55 C. for 1 hr., cooled, and the solvents removed in vacuo. The residue was recrystallized first from ethanol and then ethyl acetate (treated with charcoal) to give 5.3 g of the above urea as an off-white solid, m.p. 191-192 C. (dec.). Anal. calcd. for C9 H10 N4 O2 S: C, 45.37; H, 4.23; N, 23.51. Found: C, 45.46; H, 4.40; N, 23.59.
In water; N,N-dimethyl-formamide; acetone; toluene;
EXAMPLE XX 1-(5-Bromo-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea To a stirred suspension of 3.0 g (26 mM) of <strong>[60-27-5]creatinine</strong> in 30 ml of anhydrous DMF was added a solution of 5.0 g (26.5 mM) of 5-bromo-2-thienyl isocyanate in 15 ml of toluene. The resulting mixture was heated at 75 C. for 3 hrs., cooled, and poured into 200 ml of water. The precipitate was collected, washed with ethanol and ether, and air-dried. The solid was dissolved in 250 ml hot acetone, treated with charcoal, filtered, and the filtrate diluted with water (250 ml). The resulting precipitate was collected, washed with acetone and then ether. Air-drying gave 2.3 g of the above urea as a buff powder, m.p. 192-193 C. (dec.). Anal. calcd. for C9 H9 BrN4 O2 S: C, 34.08; H, 2.86; N, 17.66. Found: C, 33.94; H, 3.04; N, 17.30.
EXAMPLE I 1-(6-methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene)urea To a stirred suspension of 50 g (0.44 moles) of <strong>[60-27-5]creatinine</strong> 7 in 600 mls. of anhydrous tetrahydrofuran (THF) was added 49.2 g (0.49 moles) of triethylamine and then dropwise 69.2 g (0.44 moles) of phenyl chloroformate over 1/2 hour. The mixture was then refluxed for 17 hrs. (hours), cooled and filtered to separate and solid material. The filtrate was concentrated and the residue triturated with 500 ml of ether-hexane (1:1). The solid which formed was chromatographed over silica gel using chloroform as the eluent. The fractions containing the product were combined and concentrated. The residue was again triturated with 500 ml of ether-hexane (1:1) to give 21.2 g of the phenyl ester of tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene carbamic acid, 8, m.p. 129-132 C. STR7 A pure sample of the carbamate 8 was obtained by recrystallization from acetonitrile and a final chromatography over silica gel using chloroformethyl acetate as the eluent.
In ethyl acetate; N,N-dimethyl-formamide; toluene;
EXAMPLE XXII 1-(2-Furanyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea To a stirred mixture of 6.9 g (60 mM) of <strong>[60-27-5]creatinine</strong> in 100 ml of anhydrous DMF was added a solution of 6.5 g (60 mM) of 2-furanyl isocyanate in 75 ml of toluene. After stirring the mixture 1 hr. at 25 C. and then 1 hr. at 55 C., the solvents were removed in vacuo and the residue taken up in ethyl acetate and washed with water. The solvent was removed and the residue chromatographed over silica gel using ether-ethyl acetate (4:1) as the eluant. The fractions containing the product were combined and concentrated to leave 1.1 g of the above urea as an off-white solid, m.p. 173-175 C. (dec.) Anal. calcd. for C9 H10 N4 O3: C, 48.65; H, 4.53; N, 25.21. Found: C, 48.54; H, 4.72; N, 24.92.
EXAMPLE XVI 1-(Tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene)-3-(3-thienyl) urea To a stirred suspension of 2.6 (23 mM) of <strong>[60-27-5]creatinine</strong> in 50 ml of anhydrous DMF was added a solution of 3.0 g (23 mM) of 3-thienyl isocyanate in 25 ml of toluene. The resulting mixture was heated at 75 C. for 4.5 hrs., cooled and added to 150 ml of water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.4 g of the above urea as a cream colored solid, m.p. 194-195 C. Anal. calcd. for C9 H10 N4 O2 S: C, 45.37; H, 4.23; N, 23.51. Found: C, 44.96; H, 4.39; N, 23.67.
In water; ethyl acetate; N,N-dimethyl-formamide; toluene;
EXAMPLE XVII 1-(4-Chloro-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea To 3.0 g (26.5 mM) of <strong>[60-27-5]creatinine</strong> in 50 ml of anhydrous DMF was added with stirring a solution of 4-chloro-2-thienyl isocyanate in 25 ml of toluene. After stirring at 65 C. for 5 hrs., the mixture was cooled, added to 200 ml of water and filtered to separate a precipitate, which was recrystallized from ethanol and then ethyl acetate to give 1.0 g of the above urea as a light tan solid, m.p. 203-204 C. (dec.) containing 1/8 mole of ethyl acetate of recrystallization. Anal. calcd. for C9 H9 N4 C102 S.1/8 C4 H8 O2: C, 40.22; H, 3.55; N, 19.75. Found: C, 40.10; H, 3.84; N, 20.02.
EXAMPLE XVIII 1-(5-Methyl-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea To 1.44 g (12.8 mM) of <strong>[60-27-5]creatinine</strong> in 25 ml of anhydrous DMF was added with stirring 1.78 g (12.8 mM) of 5-methyl-2-thienyl isocyanate in 12 ml of toluene. After 6 hrs. at 60 C., the mixture was cooled, poured into 100 ml of water and filtered. The collected solid was recrystallized twice from ethyl acetate to give 2.4 g of the above urea as a yellow-orange solid, m.p. 207-209 C. Anal calcd. for C10 H12 N4 O2 S: C, 47.61; H, 4.79; N, 22.21. Found: C, 47.57; H, 4.76; N, 22.31.
EXAMPLE XIX 1-(3-Methyl-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea To a stirred suspension of 3.0 g (26.0 mM) of <strong>[60-27-5]creatinine</strong> in 50 ml of anhydrous DMF was added dropwise a solution of 3.7 g (26 mM) of 3-methyl-2-thienyl isocyanate in 35 ml of toluene. After stirring at 90 C. for 6 hrs., the reaction mixture was cooled and poured into 100 ml of water. The separated solid was collected, washed with water and recrystallized from ethyl acetate to give 1.2 g of the above urea as a grey-white solid, m.p. 201-202 C. Anal. calcd. for C10 H12 N4 O2 S: C, 47.61; H, 4.79; N, 22.21. Found: C, 47.76; H, 4.83; N, 22.25.
EXAMPLE XXI 1-(5-Methoxy-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea To a stirred suspension of 3.0 g (26 mM) of <strong>[60-27-5]creatinine</strong> in 25 ml of anhydrous DMF was added a solution of 4.1 g (26 mM) of 5-methoxy-2-thienyl isocyanate in 20 ml of toluene. The resulting mixture was heated at 65 C. for 4.5 hrs., cooled, and poured into 200 ml of water. The mixture was extracted with ethyl acetate, and the combined extracts dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate and then ethanol. Final purification was accomplished by chromatography over silica gel (ethyl acetate as eluant), decolorizing the product with charcoal, concentration and recrystallization from acetone-hexane to give 0.23 g of the above urea as a light brown solid, m.p. 180-182 C. (dec.). Anal. calcd. for C10 H12 N4 O3 S: C, 44.78; H, 4.51; N, 20.88. Found: C, 44.71; H, 4.67; N, 20.88.
EXAMPLE XXIII 1-(3-Furanyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea To a stirred mixture of 18.3 g (162 mM) of <strong>[60-27-5]creatinine</strong> in 120 ml of anhydrous DMF was added a solution of 17.2 g (162 mM) of 3-furanyl isocyanate in 80 ml of toluene. After stirring the mixture for 3 hrs. at 65 C., the mixture was partially concentrated under vacuum and the residue poured into 1200 ml of water. The resulting precipitate was collected, washed with water and recrystallized from ethyl acetate. The solid was then chromatographed over silica gel using ethyl acetate as the eluant and the fractions containing the product were concentrated and the residue recrystallized from toluene to give 0.5 g of the above urea as a tan solid, m.p. 179-181 C. (dec.). Anal. calcd. for C9 H10 N4 O3: C, 48.65; H, 4.53; N, 25.21. Found: C, 48.85; H, 4.68; N, 25.17.
EXAMPLE XXV 1-(2-Chloro-4-thienyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea To a stirred suspension of 2.5 g (22.5 mM) of <strong>[60-27-5]creatinine</strong> in 30 ml of anhydrous DMF was added a solution of 2.87 g (18 mM) of 2-chloro-4-thienyl isocyanate in 20 mls toluene. The resulting mixture was heated at 80 C. for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 50 ml toluene. The precipitate was collected and recrystallized from ethyl acetate to give 1.5 g of the above urea as a tan solid, m.p. 198-200 C. Anal. calcd. for C9 H9 N4 Cl O2 S: C, 39.64; H, 3.33; N, 20.54. Found: C, 39.55; H, 3.33; N, 20.70.
EXAMPLE XXVI 1-(5-Chloro-2-thienyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea To a stirred suspension of 2.5 g (22.5 mM) of <strong>[60-27-5]creatinine</strong> in 30 ml of anhydrous DMF was added a solution of 2.87 g (18 mM) of 5-chloro-2-thienyl isocyanate in 15 ml of toluene. The resulting mixture was heated at 80 C. for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 50 ml of toluene. The precipitate was collected and recrystallized from ethyl acetate to give 1.5 g of the above urea as a tan solid, m.p. 204-205 C. Anal. calcd. for C9 H9 N4 Cl O2 S: C, 39.64; H, 3.33; N, 20.54. Found: C, 39.56; H, 3.45; N, 20.31.
N-(1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-1H-indole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20 - 30℃;Inert atmosphere;
General procedure: Compounds (4a-u) synthesized from N-substituted-4-indole carboxylic acids (3a-o) and derivatives (4p-u) from heterocyclic carboxylic acids using standard amidation reaction. To a 100 ml single neck RB flask, (N-substituted-4-indole carboxylic acids (3a-u)) (1 eq/1mol), creatinine (1.5 eq/1.5 mol), HATU (1 eq/1 mol) and DMF(8-12 V) were added under nitrogen atmosphere and stirred for 5mins at 20-30 C. Upon a clear solution formed, DIPEA (2 eq or 2 mol) was added and the reaction mass stirred again for 12-16 h at 20-30 C. After 12-16 h, TLC/LCMS confirmed the completion of the reaction. Ice-cold water (20 volumes) was added slowly to the reaction mixture under stirring condition. The product was extracted with dichloromethane(2×10 volumes). The combined dichloromethane extract washed with(10 volumes) water and the organic layer separated then dried over anhydrous sodium sulfate. Further, the volatiles was distilled off under reduced pressure to get the crude product. The crude material further purified using column chromatography with silica as the stationary phase and MDC: MeOH as the mobile phase to get pure products (4a-u) with 60-88% yield.