Patent Application
20080051578
300 mg (1.45 mmol) 5-bromo-thiophene-2-carboxylic acid are combined in 9 ml THF with 0.44 ml (3.19 mmol) TEA and 461 mg (1.48 mmol) TBTU and then stirred for 30 min at ambient temperature. Then 286 mg (1.45 mmol) of 1,1-dimethyl-2-propargyl-amine-trifluoroacetate are added and stirred for 60 h at ambient temperature. Then the reaction mixture is mixed with water and turbined for 10 min. The precipitate formed is suction filtered and dried in the drying cupboard at 50° C.
Yield: 350 mg (89%)
Rf value: 0.82 (silica gel; dichloromethane/ethanol 95:5)
C10H10BrNOS (272.16)
Mass spectrum: (M+H)+=272/274 (bromine isotope)
1.00 g (6.45 mmol) 4-fluoro-3-methyl-1-nitro-benzene is combined in 20 ml DMF with 281 mg (6.45 mmol) 55% sodium hydride, dispersed in paraffin, stirred for 5 min at ambient temperature. Then 815 mg (8.06 mmol) morpholin-3-one were added and then stirred for 2 h at ambient temperature. Then the mixture is evaporated down i. vac., water is added to the residue and it is extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried on sodium sulphate, evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluant gradient:
cyclohexane/ethyl acetate=1:1→0:1).
Yield: 780 mg (51%)
Rf value: 0.52 (silica gel, ethyl acetate)
C11H12N2O4 (236.22)
Mass spectrum: (M+H)+=237
770 mg (3.26 mmol) 3-methyl-1-nitro-4-(3-oxo-morpholin-4-yl)-benzene are hydrogenated in a Parr apparatus in 50 ml of methanol together with 100 mg Raney nickel under a hydrogen atmosphere at 5 bars pressure at ambient temperature for 2 h. After filtration the mixture is evaporated down i. vac., the residue is combined in each case with ethanol and dichloromethane and evaporated down completely. The residue is further reacted without any further purification.
Yield: 650 mg (97%)
Rf value: 0.31 (silica gel; ethyl acetate+0.5% conc. ammonia solution)
C11H14N2O2 (206.24)
Mass spectrum: (M+H)+=207
1.00 g (4.85 mmol) 3-methyl-4(3-oxo-morpholin-4-yl)-aniline are dissolved in 7 ml conc. hydrochloric acid at 0° C. with stirring and cooling in the ice bath and slowly combined with a solution of 435 mg (6.30 mmol) potassium nitrite in 7 ml of water. After stirring for 30 min with cooling in the ice bath a solution of 567 mg (8.73 mmol) sodium azide in 10 ml of water is slowly added. After slow heating to ambient temperature the mixture is stirred for another 12 h at ambient temperature and extracted once with diethyl ether. Then it is adjusted to pH 10 with sodium carbonate solution and extracted again with diethyl ether. The combined organic phases are washed with water, sat. sodium carbonate solution and again with water, dried on magnesium sulphate and the solvent is distilled off using a distillation bridge. The residue is taken up in DMSO as stock solution.
Yield: 756 mg (67%)
Rt value: 3.69 min (A)
C11H12N4O2 (232.24)
Mass spectrum: (M+H)+=233
121 mg (0.52 mmol) 1-azido-3-methyl-4-(3-oxo-morpholin-4-yl)-benzene and 142 mg (0.52 mmol) 5-bromo-thiophene-2-carboxylic acid-(3-methyl-1-butyn-3-yl)-amide are dissolved in 3 ml DMSO and combined with solutions of 13 mg (52 μmol) copper(II)sulphate-pentahydrate and 52 mg (0.26 mmol) sodium ascorbate in 0.5 ml of water in each case. The reaction mixture is stirred for 24 h at ambient temperature, then filtered through aluminium oxide and rinsed with dichloromethane. Then it is evaporated down completely i. vac., mixed with water and freeze-dried.
Yield: 211 mg (80%)
Rt value: 4.18 min (B)
C21H22BrN5O3S (504.40)
Mass spectrum: (M+H)+=504/506 (bromine isotope)
The following compounds were prepared analogously:
1.37 g (6.62 mmol) 5-bromo-thiophene-2-carboxylic acid are stirred in 5 ml of thionyl chloride at 60° C. for 1 h. After evaporation i. vac. the residue is added dropwise in 5 ml dichloromethane to a mixture of 616 mg (6.66 mmol) aminoacetonitrile hydrochloride with 4.0 ml TEA in 30 ml dichloromethane at 0° C. with stirring and cooling in the ice bath. After stirring for 6 h at ambient temperature the mixture is evaporated down completely i. vac., the residue is combined with sat. sodium hydrogen carbonate solution and stirred for 10 min. Then it is extracted with ethyl acetate, the combined organic phases are washed with dil. hydrochloric acid and sat. sodium hydrogen carbonate solution and dried on sodium sulphate. After evaporation i. vac. the product is further reacted directly without any further purification.
Yield: 1.37 g (84%)
Rf value: 0.74 (silica gel; dichloromethane/methanol 9:1)
C7H5BrN2OS (245.10)
Mass spectrum: (M+H)+=245/247 (bromine isotopes)
100 mg (0.41 mmol) 5-bromo-thiophene-2-carboxylic acid-N-(cyano-methyl)-amide are combined with 10 ml of ethanolic hydrochloric acid at 0° C. and stirred for 5 h with cooling in the ice bath. Then at ambient temperature the mixture is evaporated down completely i. vac. The residue is further reacted directly without any further purification.
Yield: 133 mg (quant.)
1.18 g (5.01 mmol) 3-methyl-4-(3-oxo-morpholin-4-yl)-benzoic acid together with 1 drop of DMF are combined with 4.0 ml of thionyl chloride and stirred for 2 h at ambient temperature. After total evaporation i. vac. the residue is combined with 25 ml of ethanol and stirred for another 3 h at ambient temperature. The reaction mixture is combined with ethyl acetate and extracted with sat. sodium hydrogen carbonate solution. The aqueous phase is re-extracted with ethyl acetate. The combined organic phases are dried on sodium sulphate. After evaporation i. vac. the residue is further reacted without any further purification.
Yield: 1.40 g (quant.)
Rf value: 0.79 (silica gel; dichloromethane/ethanol 9:1)
C14H17NO4 (263.29)
Mass spectrum: (M+H)+=264
1.39 g (5.29 mmol) ethyl 3-methyl-4-(3-oxo-morpholin-4-yl)-benzoate in 10 ml of ethanol are combined with 2.5 ml 80% hydrazine hydrate versetzt and refluxed for 17 h. After evaporation i. vac. the residue is purified by chromatography on silica gel (eluant gradient: dichloromethane/methanol=95:5→90:10).
Yield: 1.04 g (79%)
Rf value: 0.32 (silica gel; dichloromethane/ethanol 9:1)
C12H15N3O3 (249.27)
Mass spectrum: (M+H)+=250
133 mg (0.41 mmol) 2-([5-bromo-thiophene-2-carbonyl)-amino]-acetimino-ethylester, together with 3 ml TEA in 6 ml acetonitrile, are combined with a mixture of 3-methyl-4-(3-oxo-morpholin-4-yl)-benzoic acid-hydrazide in 6 ml acetonitrile and 3 ml of 1,2-dichloroethane, with stirring, at ambient temperature, and the mixture is stirred for 2 h at ambient temperature and for 4.5 days at reflux temperature. Then the mixture is evaporated down i. vac., the residue is combined with DMF and filtered. After acidification with TFA it is purified on an RP column by preparative HPLC.
Yield: 56 mg (30%)
Rt value: 2.46 min (C)
C19H18BrN5O3S (476.35)
Mass spectrum: (M+H)+=476/478 (bromine isotopes)
The following compounds were prepared analogously:
12.0 g (124 mmol) 4-formyl-imidazole are placed together with 750 mg Raney nickel in 1000 ml of methanolic ammonia solution and shaken at 40° C. for 30 min. Then the mixture is hydrogenated in a Parr apparatus under a hydrogen atmosphere at 5 bars pressure at 40° C. for 14 h. Another 750 mg Raney nickel are then added and the mixture is again hydrogenated at 50° C. under a hydrogen atmosphere at 5 bars pressure for 14 h. The mixture is filtered, evaporated down i. vac., and in each case methanol, toluene and ethanol are added to the residue and it is again evaporated down completely i. vac. The residue is combined with ethereal hydrochloric acid in methanol and evaporated down completely i. vac. The residue is in each case combined with methanol and dichloromethane and evaporated down completely i. vac.
Yield: 21.2 g (quant.)
Rt value: 0.49 min (D)
C4H7N3*2 HCl (170.04/97.12)
Mass spectrum: (M+H)+=98
Prepared analogously to Example 1 a from 5-chloro-thiophene-2-carboxylic acid and 4-(amino-methyl)-1H-imidazole dihydrochloride with TBTU and TEA in DMF.
Yield: 43%
Rt value: 1.81 min (D)
C9H8ClN3OS (241.70)
Mass spectrum: (M+H)+=241/243 (chlorine isotopes)
Prepared analogously to Example 1b from 4-fluoro-2-methyl-1-nitro-benzene and 4-([5-chloro-thiophene-2-carbonyl]-amino-methyl)-1H-imidazole with sodium hydride in THF.
Yield: 52%
Rf value: 0.40 (silica gel; ethyl acetate+0.5% conc. ammonia solution)
C16H13ClN4O3S (376.82)
Mass spectrum: (M+H)+=376/378 (chlorine isotopes)
Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid-N-({1-[3-methyl-4-nitro-phenyl]-1H-imidazol-4-yl}-methyl)-amide and hydrogen with Raney nickel in methanol.
Yield: 90%
Rf value: 0.74 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C16H15ClN4OS (346.84)
Mass spectrum: (M+H)+=347/349 (chlorine isotopes)
225 mg (0.65 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-amino-3-methyl-phenyl]-1H-imidazol-4-yl}-methyl)-amide in 5 ml THF are added dropwise at ambient temperature to a solution of 93.1 μl (0.65 mmol) of 90% 5-chlorovaleric acid chloride with 137 μl (0.97 mmol) TEA in 25 ml THF and stirred for 16 h at ambient temperature. After filtration through a fibreglass filter the mixture is evaporated down completely i. vac. and the residue is further reacted directly without any further purification.
Yield: quant. (contaminated)
C21H22Cl2N4O2S (465.40)
370 mg (0.60 mmol) of the product obtained in Example 7e in 60 ml THF are combined with 67 mg (0.60 mmol) potassium-tert.-butoxide and stirred at ambient temperature. After 30 min another 50 mg (45 mmol) potassium-tert.-butoxide are added and the mixture is stirred for 2 h at ambient temperature. Then it is filtered through a fibreglass filter, washed with dichloromethane and the filtrate is evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant gradient: ethyl acetate/(ethanol/conc. ammonia solution 98:2)=10:0→8:2).
Yield: 100 mg (39%)
Rf value: 0.36 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C21H21ClN4O2S (428.94)
Mass spectrum: (M+H)+=429/431 (chlorine isotopes)
The following compound was prepared analogously:
1.39 g (10.0 mmol) 2-(2-chloro-ethoxy)-acetic acid are heated to 60° C. for 1 h with 1 drop of DMF in 8.0 ml of thionyl chloride and then evaporated down completely i. vac. The residue is added in 5 ml THF to a mixture of 1.18 g (10.0 mmol) 4-amino-benzonitrile and 4.5 ml (32.5 mmol) TEA in 20 ml THF at 0° C. and rinsed with 5 ml THF. Then the mixture is stirred for 16 h at ambient temperature. After evaporation i. vac. the residue is combined with ethyl acetate, washed with 2N hydrochloric acid and sat. sodium hydrogen carbonate solution and dried on sodium sulphate. After evaporation i. vac. the residue is purified by chromatography on silica gel (eluant gradient: petroleum ether/ethyl acetate=6:1→3:1).
Yield: 1.82 g (76%)
Rf value: 0.43 (silica gel, petroleum ether/ethyl acetate 1:1)
C11H11ClN2O2 (238.67)
Mass spectrum: (M−H)−=237/239 (chlorine isotopes)
1.75 g (7.35 mmol) 2-(2-chloro-ethoxy)-N-(4-cyano-phenyl)-acetamide in 50 ml acetonitrile are combined with 4.07 g (12.5 mmol) caesium carbonate and stirred for 16 h at ambient temperature. Then the mixture is evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=1:2).
Yield: 1.39 g (94%)
Rf value: 0.17 (silica gel, petroleum ether/ethyl acetate 1:1)
C11H10N2O2 (202.21)
Mass spectrum: M+=202
1.39 g (6.89 mmol) 4-(3-oxo-morpholin-4-yl)-benzonitrile in 50 ml of ethanol are combined with 3 ml 50% aqueous hydroxylamine solution and refluxed for 1 h with stirring. Then the mixture is evaporated down i. vac. and further reacted without any further purification.
Yield: 1.62 g (quant.)
Rf value: 0.42 (silica gel, dichloromethane/methanol 9:1)
C11H13N3O3 (235.24)
Mass spectrum: (M+H)+=236
60.0 mg (0.26 mmol) N-hydroxy-(3-oxo-morpholin-4-yl)-benzamidine together with 53.6 mg (0.31 mmol) N-Boc-glycine and 41.3 mg (0.31 mmol) HOBt in 2 ml DMF and 1 ml dichloromethane at 0° C. are combined with 47.9 μl (0.31 mmol) DIC and stirred for 20 min at 0° C. and for 3 h at ambient temperature. Then the mixture is heated to 120° C. for 7 h with stirring. Then 2 ml TFA are added to the mixture at 0° C. and it is heated to 40° C. for 1 h with stirring. The mixture is evaporated down i. vac. and the concentrated solution is combined with 5 ml TEA. To this mixture is added dropwise at 0° C. a solution which may be obtained by refluxing 5-chloro-thiophene-2-carboxylic acid in 2 ml of thionyl chloride with 1 drop of DMF, subsequently evaporating it down completely i. vac. and taking up in 1 ml DMF, and the resulting mixture is rinsed with 1 ml DMF. This mixture is stirred for 16 h at ambient temperature, then poured into 0.5n hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium hydrogen carbonate solution and sat. sodium chloride solution, dried on sodium sulphate and evaporated down i. vac. The residue is taken up in DMF, acidified with TFA and purified by preparative HPLC on an RP column. Yield: 25 mg (23%)
Rt value: 2.83 min (C)
C18H15ClN4O4S (418.86)
Mass spectrum: (M−H)−=417/419 (chlorine isotopes)
Prepared analogously to Example 7c from 2,4-difluoro-1-nitro-benzene and 5-chloro-thiophene-2-carboxylic acid-N-({1H-imidazol-4-yl}-methyl)-amide with sodium hydride in THF with DMF.
Yield: 75%
C15H10ClFN4O3S (380.78)
Mass spectrum: (M+H)+=381/383 (chlorine isotopes)
Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid-N-({1-[2-fluoro-4-nitro-phenyl]-1H-imidazol-4-yl}-methyl)-amide with hydrogen at 5 bars pressure and Raney nickel in methanol.
Yield: 54%
C15H12ClFN4OS (350.80)
Mass spectrum: (M+H)+=351/353 (chlorine isotopes)
13.86 g (100 mmol) 2-(2-chloro-ethoxy)-acetic acid are combined with 15 ml (207 mmol) thionyl chloride at ambient temperature and 3 drops of DMF are added. The mixture is stirred for 16 h at 60° C. Then it is evaporated down i. vac., the residue is distilled i. vac. and the overflow is collected at 75-78° C.
Yield: 12.90 g (82%)
C4H6Cl2O2 (157.00)
Mass spectrum: (M+H)+=157/159/161 (chlorine isotopes)
351 mg (1.00 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({1-[3-fluoro-aniline-4-yl)-phenyl]-1H-imidazol-4-yl}-methyl)-amide in 10 ml acetonitrile and 5 ml DMF are combined with 208 μl (1.50 mmol) TEA and after the addition of 157 mg (1.00 mmol) 2-(2-chloro-ethoxy)-acetic acid chloride stirred for 16 h at ambient temperature. Then 489 mg (1.50 mmol) caesium carbonate are added and the mixture is stirred for 24 h at ambient temperature. After filtering through a fibreglass filter and washing with DMF the mixture is evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluting gradient: ethyl acetate/(ethanol+0.5% conc. ammonia solution)=5:0→4:1).
Yield: 260 mg (60%)
C19H16ClFN4O3S (434.87)
Mass spectrum: (M+H)+=435/437 (chlorine isotopes)
The following compounds were prepared analogously:
Prepared analogously to Example 7a from 4-formyl-2-methyl-1H-imidazole, methanolic ammonia and hydrogen with Raney nickel.
Yield: quant.
C5H9N3 (111.15)
Mass spectrum: (M+H)+=112
32.0 g (0.20 mmol) 5-chloro-thiophene-2-carboxylic acid are 150 ml dichloromethane refluxed for 16 h with stirring with 100 ml of thionyl chloride and 250 μl DMF. The reaction mixture is evaporated down i. vac., the residue in each case is mixed 5 times with toluene and twice with dichloromethane and evaporated down completely. The residue is further reacted directly without any further purification.
Yield: quant.
C5H2Cl2OS (181.04)
5.00 g (45.0 mmol) 4-(amino-methyl)-1H-imidazol are combined together with 15.7 ml TEA in 180 ml THF and 20 ml DMF with 8.14 g (45.0 mmol) 5-chloro-thiophene-2-carboxylic acid chloride in 50 ml THF with stirring at ambient temperature. After stirring for 19 h the mixture is filtered, washed with THF and the filtrate is evaporated down i. vac. The residue is triturated with water and after suction filtering dried in the drying cupboard. The dried precipitate is triturated with diethyl ether, suction filtered, washed with diethyl ether and dried again.
Yield: 5.90 g (51%)
C10H10ClN3OS (255.73)
Mass spectrum: (M+H)+=256/258 (chlorine isotopes)
Prepared analogously to Example 1b from 4-fluoro-2-methyl-1-nitro-benzene and 4-([5-chloro-thiophene-2-carbonyl]-amino-methyl)-2-methyl-1H-imidazole with sodium hydride in THF with DMF.
Yield: 52%
Rf value: 0.50 (silica gel; ethyl acetate/ethanol=95:5+0.5% conc. ammonia solution)
C17H15ClN4O3S (390.85)
Mass spectrum: (M+H)+=390/392 (chlorine isotopes)
Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid-N-({1-[3-methyl-4-nitro-phenyl]-2-methyl-1H-imidazol-4-yl}-methyl)-amide and hydrogen with Raney nickel in ethanol with ethyl acetate.
Yield: 93%
Rf value: 0.50 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C17H17ClN4OS (360.86)
Mass spectrum: (M+H)+=360/362 (chlorine isotopes)
430 mg (1.13 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-amino-3-methyl-phenyl]-2-methyl-1H-imidazol-4-yl}-methyl)-amide are combined with 385 μl (2.05 mmol) DIPEA in 15 ml THF with 2-(2-chloro-ethoxy)-acetic acid chloride in 10 ml THF and stirred for 3 h at ambient temperature. Then 815 mg (2.50 mmol) caesium carbonate are added and the mixture is stirred for 17 h at ambient temperature and 2 h at reflux temperature. Then at ambient temperature 4 ml of 1n sodium hydroxide solution are added and the mixture is stirred for 1.25 h. The mixture is poured onto ice and adjusted to pH 7 with 1n hydrochloric acid. The mixture is evaporated down i. vac. and the aqueous residue is extracted with ethyl acetate. The combined organic phases are washed with semisat. and sat. sodium chloride solution, dried on magnesium sulphate and evaporated down i. vac. Ethanol and diethyl ether are added to the residue, it is triturated and the precipitate formed is suction filtered. After washing with diethyl ether the precipitate is dried in the drying pistol.
Yield: 290 mg (58%)
Rf value: 0.38 (silica gel; ethyl acetate/ethanol=85:15+0.5% conc. ammonia solution)
C21H21ClN4O3S (444.94)
Mass spectrum: (M+H)+=445/447 (chlorine isotopes)
The following compounds were prepared analogously:
Prepared analogously to Example 7a from 4-formyl-5-methyl-1H-imidazole, methanolic ammonia and hydrogen with Raney nickel.
Yield: quant.
C5H9N3 (111.15)
Mass spectrum: (M−H)−=110
Prepared analogously to Example 1a from 5-chloro-thiophene-2-carboxylic acid and 4-(amino-methyl)-1H-imidazole with TBTU and TEA in THF with DMF.
Yield: 4.30 g (34%)
Rf value: 0.65 (silica gel; dichloromethane/methanol=8:2+0.5% conc. ammonia solution)
C10H10ClN3OS (255.73)
Mass spectrum: (M+H)+=256/258 (chlorine isotopes)
Prepared analogously to Example 1b from 4-fluoro-2-methyl-1-nitro-benzene and 4-([5-chloro-thiophene-2-carbonyl]-amino-methyl)-5-methyl-1H-imidazole with sodium hydride in THF with DMF.
Yield: 46%
Rf value: 0.55 (silica gel; ethyl acetate/ethanol=95:5+0.5% conc. ammonia solution)
C17H15ClN4O3S (390.85)
Mass spectrum: (M+H)+=390/392 (chlorine isotopes)
Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid-N-({1-[3-methyl-4-nitro-phenyl]-5-methyl-1H-imidazol-4-yl}-methyl)-amide and hydrogen with Raney nickel in ethanol with ethyl acetate.
Yield: 99% (slightly contaminated)
Rf value: 0.63 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C17H17ClN4OS (360.86)
Mass spectrum: (M+H)+=360/362 (chlorine isotopes)
Prepared analogously to Example 12f from 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-amino-3-methyl-phenyl]-5-methyl-1H-imidazol-4-yl}-methyl)-amide and 2-(2-chloro-ethoxy)-acetic acid chloride with DIPEA and caesium carbonate in THF.
Yield: 19%
Rf value: 0.35 (silica gel; ethyl acetate/ethanol=85:15+0.5% conc. ammonia solution)
C21H21ClN4O3S (444.94)
Mass spectrum: (M+H)+=445/447 (chlorine isotopes)
Prepared analogously to Example 10d from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline and 2-(2-chloroethoxy)-acetyl chloride with TEA and caesium carbonate in acetonitrile.
Yield: 33%
Rf value: 0.60 (silica gel; cyclohexane/ethyl acetate=1:1)
C16H22BNO4 (303.16)
Mass spectrum: (M+H)+=304
400 mg (1.32 mmol) 4-(4-{4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl}-phenyl)-3-oxo-morpholine are combined together with 317 mg (1.32 mmol) 2,4-dibromo-1-methyl-1H-imidazole and 424 mg (4.0 mmol) sodium carbonate in 5 ml dioxane under a nitrogen atmosphere with 50 mg (43 μmol) tetrakis-(triphenylphosphine)-palladium(0) and heated to 85° C. for 5 h. The reaction mixture is combined with sat. sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried on magnesium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: ethyl acetate).
Yield: 220 mg (50%)
Rf value: 0.23 (silica gel; ethyl acetate)
C14H14BrN3O2 (336.18)
Mass spectrum: (M+H)+=336/338 (bromine isotopes)
220 mg (0.65 mmol) 4-bromo-1-methyl-2-(4-{3-oxo-morpholin-4-yl}-phenyl)-1H-imidazole are combined together with 94 mg (0.80 mmol) zinc cyamide in 2.0 ml NMP, which has been deoxygenated by piping in nitrogen, with 46 mg (40 μmol) tetrakis-(triphenylphosphine)-palladium(0) and the mixture is heated to 140° C. with stirring under a nitrogen atmosphere for 1.5 h. Then 5 ml NMP are added, the mixture is stirred for 2 h at 160° C., and another 100 mg (87 μmol) tetrakis-(triphenylphosphine)-palladium(0) are added and the mixture is stirred for 1.5 h at 160° C. Then another 60 mg (52 μmol) tetrakis-(triphenylphosphine)-palladium(0) are added and the mixture is stirred for another 15 min at 160° C. After cooling it is poured into water, made alkaline with sat. sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic phases are washed with water and dil. sodium chloride solution, dried on magnesium sulphate and evaporated down i. vac. The residue is purified by preparative HPLC (eluting gradient: acetonitrile/(water/acetic acid 19:1)=5:95→95:5).
Yield: 40 mg (22%, slightly contaminated)
Rf value: 0.20 (silica gel; ethyl acetate)
C15H14N4O2 (282.30)
Mass spectrum: (M+H)+=283
40 mg (0.14 mmol) 4-cyano-1-methyl-2-(4-{3-oxo-morpholin-4-yl}-phenyl)-1H-imidazole are stirred together with 50 mg Raney nickel in 10 ml of methanolic ammonia solution at ambient temperature and with hydrogen at 5 bars pressure for 7.5 h. Then the mixture is filtered and the filtrate is evaporated down completely i. vac. The residue is further reacted without purification.
Yield: 40 mg (quant.)
Rf value: 0.20 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C15H18N4O2 (286.33)
Mass spectrum: (M+H)+=287
Prepared analogously to Example 1a from 5-chloro-thiophene-2-carboxylic acid and 4-aminomethyl-1-methyl-2-(4-{3-oxo-morpholin-4-yl}-phenyl)-1H-imidazole with TBTU and NMM in DMF.
Yield: 33%
Rf value: 0.35 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C20H19ClN4O3S (430.91)
Mass spectrum: (M+H)+=431/433 (chlorine isotopes)
Prepared analogously to Example 1b from 4-fluoro-1-nitro-benzene and 4-([5-chloro-thiophene-2-carbonyl]-amino-methyl)-1H-imidazole with sodium hydride in THF with DMF.
Yield: 65%
Rf value: 0.60 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C15H11ClN4O3S (362.79)
Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-nitro-phenyl]-1H-imidazol-4-yl}-methyl)-amide and hydrogen with Raney nickel in methanol with THF.
Yield: 97%
Rf value: 0.40 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C15H13ClN4OS (332.81)
Mass spectrum: (M+H)+=333/335 (chlorine isotopes)
333 mg (1.00 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-amino-phenyl]-1H-imidazol-4-yl}-methyl)-amide in 2 ml DMF are combined with a solution of 90 μl (1.00 mmol) 95% 2-chloro-ethyl-isocyanate in 1 ml DMF and stirred for 6 h at ambient temperature. Then another 30 μl (0.33 mmol) 95% 2-chloro-ethyl-isocyanate are added and the mixture is stirred for 17 h at ambient temperature. Then at ambient temperature 112 mg (1.00 mmol) potassium-tert.-butoxide are added, the mixture is stirred for 4 h at ambient temperature, another 11 mg (0.1 mmol) potassium-tert.-butoxide are added and the mixture is stirred for another 2 h. The mixture is poured into water, suction filtered and washed with water. The filter cake is dried at 60° C. in the circulating air dryer.
Yield: 350 mg (87%)
Rf value: 0.25 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C18H16ClN5O2S (401.87)
Mass spectrum: (M+H)+=402/404 (chlorine isotopes)
The following compound was prepared analogously:
109 μl (1.10 mmol) 4-chloro-butyric acid in 2 ml DMF are combined with 132 μl (1.20 mmol) NMM and 353 mg (1.10 mmol) TBTU and stirred for 5 min at ambient temperature. Then 333 mg (1.00 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-amino-phenyl]-1H-imidazol-4-yl}-methyl)-amide are added and the mixture is stirred for 16 h at ambient temperature. Then 96 mg (2.0 mmol) 50% sodium hydride are added batchwise and the mixture is stirred for 45 min at ambient temperature and for 45 min at 70° C., another 48 mg (1.0 mmol) 50% sodium hydride are added and the mixture is stirred for another 1.5 h at 70° C. Then it is poured into ice water, suction filtered and washed with water. After drying the filter cake is purified by chromatography on silica gel (eluting gradient: dichloromethane/(methanol/conc. ammonia 19:1)=20:0→19:1).
Yield: 250 mg (62%)
Rf value: 0.30 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C19H17ClN4O2S (400.88)
Mass spectrum: (M+H)+=401/403 (chlorine isotopes)
700 mg (2.10 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-amino-phenyl]-1H-imidazol-4-yl}-methyl)-amide are refluxed together with 292 μl (2.4 mmol) trichloromethyl chloroformate in 20 ml of toluene under a nitrogen atmosphere for 1 h, another 25 ml of toluene are added and the mixture is refluxed for 3 h, and again 0.3 ml (2.4 mmol) trichloromethyl chloroformate are added and the mixture is refluxed for a further 3 h. Then it is evaporated down i. vac. and evaporated twice with toluene. The residue is further reacted directly without any further purification.
The product obtained in 22a is suspended in 25 ml of toluene with 148 μl (2.20 mmol) 2-chloroethanol and heated to 80° C. under a nitrogen atmosphere for 2 h. Then it is poured into ice water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried on magnesium sulphate and evaporated down completely i. vac.
Yield: 500 mg (52%)
Rf value: 0.70 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C18H16Cl2N4O3S (439.32)
Mass spectrum: (M+H)+=439/441/443 (chlorine isotopes)
500 mg (1.14 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-(2-chloro-ethoxy-carbonyl-amino)-phenyl]-1H-imidazol-4-yl}-methyl)-amide are combined in 3 ml DMSO with 168 mg (1.50 mmol) potassium-tert.-butoxide and stirred for 40 min at ambient temperature. The mixture is poured into water, suction filtered and washed with water. The filter cake is dried on clay, stirred into acetone, suction filtered, washed with acetone and diethyl ether and dried in the drying pistol at 50° C.
Yield: 250 mg (55%)
Rf value: 0.45 (silica gel; ethyl acetate/ethanol=9:1+0.5% conc. ammonia solution)
C18H15ClN4O3S (402.86)
Mass spectrum: (M+H)+=403/405 (chlorine isotopes)
5.00 g (35.2 mmol) 4-hydroxymethyl-2-methoxymethyl-1H-imidazole and 4.96 g (35.2 mmol) 4-fluoro-1-nitro-benzene are stirred together with 9.72 g (70.3 mmol) potassium carbonate in 50 ml DMF for 5.5 h at 80° C. Then the mixture is stirred for 2.5 d at ambient temperature. The precipitate formed is separated off and the filtrate is evaporated down i. vac. The residue is taken up in a mixture of dichloromethane and ethanol 1:1 and slowly evaporated down i. vac. The suspension formed is cooled in the ice bath and the precipitate is suction filtered, washed twice with ethanol and dried in the circulating air dryer at 55° C.
Yield: 5.35 g (58%)
Rf value: 0.46 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C12H13N3O4 (263.25)
Mass spectrum: (M+H)+=264
5.30 g (20.1 mmol) 4-hydroxymethyl-2-methoxymethyl-1-[4-nitro-phenyl]-1H-imidazole are combined in 50 ml dichloromethane with 2.0 ml (27.6 mmol) thionyl chloride and stirred for 5 min at ambient temperature. Then the mixture is evaporated down completely i. vac. and evaporated with toluene. The residue is taken up in 100 ml conc. ammonia solution, stirred in a bomb tube at 100° C. for 45 min and left to cool to ambient temperature for 16 h. The reaction mixture is combined with sodium hydroxide solution and extracted with dichloromethane. The combined organic phases are dried on magnesium sulphate and evaporated down i. vac., the residue is purified by preparative HPLC (C-18 StableBond, eluting gradient (water+0.15% formic acid)/acetonitrile=95:5→5:95).
Yield: 620 mg (12%)
Rf value: 0.43 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C12H14N4O3 (262.27)
Mass spectrum: (M+H)+=263
Prepared analogously to Example 1a from 4-chloro-thiophene-2-carboxylic acid and 4-aminomethyl-2-methoxymethyl-1-[4-nitro-phenyl]-1H-imidazole with TBTU and TEA in DMF.
Yield: 37%
Rf value: 0.65 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C17H15ClN4O4S (406.84)
Mass spectrum: (M+H)+=407/409 (chlorine isotopes)
Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid-N-({2-methoxymethyl-1-[4-nitro-phenyl]-1H-imidazol-4-yl}-methyl)-amide and hydrogen with Raney nickel in methanol.
Yield: 98%
Rf value: 0.49 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C17H17ClN4O4S (376.86)
Mass spectrum: (M+H)+=377/379 (chlorine isotopes)
Prepared analogously to Example 12f from 5-chloro-thiophene-2-carboxylic acid-N-({2-methoxymethyl-1-[4-amino-phenyl]-1H-imidazol-4-yl}-methyl)-amide and 2-(2-chloro-ethoxy)-acetic acid chloride with DIPEA and caesium carbonate in THF.
Yield: 17%
Rf value: 0.76 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C21H21ClN4O4S (460.94)
Mass spectrum: (M+H)+=461/463 (chlorine isotopes)
Prepared analogously to Example 7e from 5-chloro-thiophene-2-carboxylic acid-N-({2-methoxymethyl-1-[4-amino-phenyl]-1H-imidazol-4-yl}-methyl)-amide and chloroacetic acid chloride with TEA in THF.
Yield: quant.
C19H18Cl2N4O3S (453.34)
Mass spectrum: (M+H)+=453/455/457 (chlorine isotopes)
750 mg (1.65 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({2-methoxymethyl-1-[4-(2-chloro-acetamino)-phenyl]-1H-imidazol-4-yl}-methyl)-amide are combined in 20 ml DMF with 264 μl (3.31 mmol) N-methyl-aminoethanol and 809 mg (2.48 mmol) caesium carbonate and stirred for 3 d at ambient temperature. Then the mixture is filtered and the filtrate is evaporated down completely i. vac. The residue is stirred in 100 ml ice water with 5 ml dil. sodium hydroxide solution, the precipitate formed is filtered off, washed twice with a little water and dried in the drying pistol.
Yield: 690 mg (contaminated) (68%)
C22H26ClN5O4S (491.99)
Mass spectrum: (M+H)+=492/494 (chlorine isotopes)
680 mg (1.11 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({2-methoxymethyl-1-[4-(2-{N-[2-hydroxy-ethyl]-N-methyl-amino}-acetamino)-phenyl]-1H-imidazol-4-yl}-methyl)-amide are combined in 10 ml DMF with 367 μl (2.64 mmol) TEA with 95.1 μl (1.11 mmol) methanesulphonic acid chloride and stirred for 10 min at ambient temperature. Then another 47.5 μl (0.55 mmol) methanesulphonic acid chloride are added, the mixture is stirred for 15 min at ambient temperature and finally 1.08 g (3.30 mmol) caesium carbonate are added. After stirring at ambient temperature for 16 h another 1.61 g (4.95 mmol) caesium carbonate are added and the mixture is again stirred for 1 h at ambient temperature. After filtering through a fibreglass filter the filtrate is evaporated down completely i. vac. and the residue is purified by preparative HPLC (C-18 StableBond, eluting gradients: (water+0.15% formic acid)/acetonitrile=1. 95:5→5:95; 2. 95:5→10:90).
Yield: 70 mg (12%)
Rt value: 1.94 min (D)
C22H24ClN5O3S (473.98)
Mass spectrum: (M+H)+=474/476 (chlorine isotopes)
Prepared analogously to Example 24b from 5-chloro-thiophene-2-carboxylic acid-N-({2-methoxymethyl-1-[4-(2-chloro-acetamino)-phenyl]-1H-imidazol-4-yl}-methyl)-amide and aminoethanol with caesium carbonate in DMF.
Yield: 78%
C21H24ClN5O4S (477.97)
Mass spectrum: (M+H)+=478/480 (chlorine isotopes)
1.30 g (2.50 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({2-methoxymethyl-1-[4-(2-{N-[2-hydroxy-ethyl]-amino}-acetamino)-phenyl]-1H-imidazol-4-yl}-methyl)-amide are combined in 75 ml THF with 601 mg (2.75 mmol) di-tert.-butyl pyrocarbonate and stirred for 16 h at ambient temperature. After evaporation of the mixture i. vac. the residue is purified by preparative HPLC (C-18 StableBond, eluting gradient (water+0.15% formic acid)/acetonitrile=95:5→5:95). The product fractions are neutralised with ammonia and evaporated down i. vac. The aqueous residue is extracted with dichloromethane, the combined organic phases dried on magnesium sulphate and evaporated down completely.
Yield: 900 mg (62%)
C26H32ClN5O6S (578.08)
Mass spectrum: (M+H)+=578/580 (chlorine isotopes)
Prepared analogously to Example 24c from 5-chloro-thiophene-2-carboxylic acid-N-({2-methoxymethyl-1-[4-(2-{N-Boc-N-[2-hydroxy-ethyl]-amino}-acetamino)-phenyl]-1H-imidazol-4-yl}-methyl)-amide with methanesulphonic acid chloride and TEA and subsequently caesium chloride in DMF.
Yield: 56%
C26H30ClN5O5S (560.07)
Mass spectrum: (M+H)+=560/562 (chlorine isotopes)
470 mg (0.84 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({2-methoxymethyl-1-[4-(4-Boc-2-oxo-piperazin-1-yl)-phenyl]-1H-imidazol-4-yl}-methyl)-amide are combined in 20 ml dichloromethane with 2.0 ml (26.0 mmol) TFA and stirred for 16 h at ambient temperature. Then the mixture is evaporated down i. vac. and the residue is purified by preparative HPLC (C-18 StableBond, eluting gradient (water+0.15% formic acid)/acetonitrile=95:5→10:90). The product fractions are freeze-dried and subsequently treated with 1n sodium hydroxide solution, extracted with dichloromethane/methanol 9:1 and evaporated down completely i. vac. The residue is dissolved in a little acetonitrile, mixed with a little water and freeze-dried.
Yield: 240 mg (62%)
Rt value: 1.94 min (D)
C21H22ClN5O3S (459.95)
Mass spectrum: (M+H)+=460/462 (chlorine isotopes)
20.4 g (144 mmol) 4-hydroxymethyl-2-methoxymethyl-1H-imidazole are combined in 250 ml dichloromethane with 117.4 g (1.15 mol) manganese(IV)oxide (85%) and stirred for 16 h at ambient temperature. After suction filtering and washing of the filter cake with a mixture of dichloromethane and methanol (4:1) the filtrate is filtered again, washed with dichloromethane/methanol 2:1 and methanol and evaporated down i. vac.
Yield: 18.57 g (132.5 mmol, 92%)
C6H8N2O2 (111.15)
Mass spectrum: (M+H)+=141
Prepared analogously to Example 7a from 4-formyl-2-methoxymethyl-1H-imidazole with methanolic ammonia solution, hydrogen and Raney nickel.
Yield: 38%
C6H11N3O*2 HCl (141.18/214.09)
Prepared analogously to Example 25b from 4-aminomethyl-2-methoxymethyl-1H-imidazole with di-tert.-butyl pyrocarbonate and TEA in DMF.
Yield: 41%
C11H19N3O3 (241.29)
Mass spectrum: (M+H)+=242
5.00 g (20.7 mmol) 4-N-Boc-aminomethyl-2-methoxymethyl-1H-imidazole in 75 ml DMF are combined with 21.8 ml (21.8 mmol) 1n lithium hexamethyldisilazide solution in THF with stirring and cooling in the ice bath so as to keep the temperature below 15° C. Then the mixture is stirred for 20 min at 15° C. and then 3.22 g (22.8 mmol) 4-fluoro-1-nitro-benzene in 15 ml DMF are added and the mixture is stirred for another 45 min with cooling in the ice bath. Then the ice bath is removed and the mixture is stirred for another 3 h at ambient temperature. The mixture is evaporated down i. vac. and purified by chromatography on silica gel (eluting gradient: dichloromethane/(ethanol/conc. ammonia solution=19:1)=1:0→17:3).
Yield: 7.15 g (18.7 mmol, 90%)
Rt value: 2.73 min (D)
C17H22N4O5 (362.38)
Mass spectrum: (M+H)+=363
7.00 g (19.3 mmol) 4-N-Boc-aminomethyl-2-methoxymethyl-1-(4-nitro-phenyl)-1H-imidazole are hydrogenated in a Parr apparatus in 250 ml of methanol together with 1.00 g palladium charcoal under a hydrogen atmosphere at 5 bars pressure at ambient temperature for 1 h. After filtration the mixture is evaporated down i. vac., the residue in each case is combined with toluene and evaporated down completely. The residue is further reacted without any further purification.
Yield: 6.23 g (97%)
Rf value: 0.53 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C17H24N4O3 (332.40)
Mass spectrum: (M+H)+=333
Prepared analogously to Example 10d from 4-N-Boc-aminomethyl-2-methoxymethyl-1-(4-amino-phenyl)-1H-imidazole with 2-(2-chloro-ethoxy)-acetic acid chloride, TEA and caesium carbonate in THF.
Yield: 83%
Rf value: 0.55 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C21H28N4O5 (416.47)
Mass spectrum: (M+H)+=417
Prepared analogously to Example 25d from 4-N-Boc-aminomethyl-2-methoxymethyl-1-(4-(3-oxo-morpholin-4-yl)-phenyl)-1H-imidazole with TFA in dichloromethane.
Yield: 50%
Rf value: 0.39 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C16H20N4O3 (316.36)
Mass spectrum: (M+H)+=317
Prepared analogously to Example 12c from 4-aminomethyl-2-methoxymethyl-1-(4-(3-oxo-morpholin-4-yl)-phenyl)-1H-imidazole with 4-chloro-benzoic acid chloride and TEA in DMF.
Yield: 66%
Rf value: 0.64 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C23H23ClN4O4 (454.91)
Mass spectrum: (M+H)+=455/457 (chlorine isotopes)
Prepared analogously to Example 12c from 4-aminomethyl-2-methoxymethyl-1-(4-(3-oxo-morpholin-4-yl)-phenyl)-1H-imidazole with 4-chloro-phenyl-isocyanate and TEA in DMF.
Yield: 74%
Rf value: 0.38 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C23H24ClN5O4 (469.92)
Mass spectrum: (M+H)+=470/472 (chlorine isotopes)
15.0 g (156 mmol) 4-formyl-1H-imidazole in 100 ml of pyridine are combined with 12.5 g (180 mmol) hydroxylamine-hydrochloride at 60° C. with stirring and the mixture is stirred at 60° C. for 1.25 h. Then the mixture is heated to 80° C. and 28.0 ml (297 mmol) acetic anydride are added such that the temperature remains between 80 and 120° C. After removal of the heating bath stirring is continued for a further 1.5 h during the cooling and the mixture is then evaporated down i. vac. The residue is mixed with ice and neutralised with 10n sodium hydroxide solution. The mixture is extracted with ethyl acetate and the combined organic phases are washed with semisat. and sat. sodium chloride solution, dried on magnesium sulphate and evaporated down i. vac. The residue is taken up twice in toluene and in dichloromethane and in each case evaporated down completely. Then the residue is triturated in diethyl ether, filtered and washed with a little diethyl ether and dried.
Yield: 12.22 g (127.3 mmol, 82%)
C4H3N3 (93.09)
Mass spectrum: (M+H)+=94
1.42 g (15.3 mmol) 4-cyano-1H-imidazole are combined with 11.2 ml (33.6 mmol) 3n ethereal methyl-magnesium-bromide solution with 25 ml THF in 75 ml THF at 10° C. with cooling in the ice bath and after removal of the ice bath the mixture is stirred for another 2.5 h at ambient temperature. After the addition of another 3.5 ml (10.5 mmol) 3n ethereal methyl-magnesium bromide solution and stirring for 15 min at ambient temperature, 45 ml of 1m sulphuric acid are added and the mixture is stirred for 30 min. After the addition of 20 ml of 10n sodium hydroxide solution the organic phase is separated off, the aqueous phase is saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases are dried on magnesium sulphate and evaporated down i. vac.
Yield: 48%
C5H6N2O (110.11)
Mass spectrum: (M+H)+=111
Prepared analogously to Example 7a from 4-acetyl-1H-imidazole with methanolic ammonia solution, hydrogen and Raney nickel.
Yield: 88%
C5H9N3 (111.15)
Mass spectrum: (M+H)+=242
Prepared analogously to Example 12c from 4-(1-amino-ethyl)-1H-imidazole and 5-chloro-thiophene-2-carboxylic acid chloride with TEA in DMF.
Yield: 35%
Rf value: 0.19 (silica gel; dichloromethane/methanol=9:1+0.5% acetic acid)
C10H10ClN3OS (255.73)
Mass spectrum: (M+H)+=256/258 (chlorine isotopes)
Prepared analogously to Example 32d from 5-chloro-thiophene-2-carboxylic acid-N-(1-{1H-imidazol-4-yl}-ethyl)-amide and 4-fluoro-1-nitro-benzene with 1n lithium hexamethyldisilazide solution in THF in DMF.
Yield: 53%
Rf value: 0.68 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C16H13ClN4O3S (376.82)
Mass spectrum: (M+H)+=377/379 (chlorine isotopes)
Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid-N-(1-{1-[4-nitro-phenyl]-1H-imidazol-4-yl}-ethyl)-amide with hydrogen and Raney nickel in methanol.
Yield: 77%
Rf value: 0.54 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C16H15ClN4OS (346.84)
Mass spectrum: (M+H)+=347/349 (chlorine isotopes)
Prepared analogously to Example 10d from 5-chloro-thiophene-2-carboxylic acid-N-(1-{1-[4-amino-phenyl]-1H-imidazol-4-yl}-ethyl)-amide and 2-(2-chloro-ethoxy)-acetic acid chloride with TEA and caesium carbonate in DMF.
Yield: 55%
Rt value: 2.69 min (E)
C20H19ClN4O3S (430.91)
Mass spectrum: (M+H)+=431/433 (chlorine isotopes)
The following compounds were prepared analogously:
5.50 g (50.9 mmol) 3-amino-4-cyano-1H-pyrazole are stirred together with 7.54 g (53.4 mmol) 4-fluoro-1-nitro-benzene and 8.44 g (61.1 mmol) potassium carbonate in 50 ml DMSO for 64 h at ambient temperature. Then the mixture is poured into 1800 ml of water and stirred for 20 min. Then it is suction filtered, the filter cake is dried, stirred in ethyl acetate, filtered off and dried again.
Yield: 9.00 g (39.3 mmol, 77%)
C10H7N5O2 (229.20)
Mass spectrum: (M−H)−=228
4.00 g (17.5 mmol) 3-amino-4-cyano-1-(4-nitro-phenyl)-1H-pyrazole are stirred with 2.48 ml (26.2 mmol) acetic anhydride in 65 ml acetic acid for 5 h at 110° C. Then the mixture is poured into 1 l ice water and stirred. Then it is suction filtered, washed with water and dried.
Yield: 4.22 g (15.6 mmol, 89%)
C12H9N5O3 (271.23)
Mass spectrum: (M+H)+=272
Prepared analogously to Example 1c from 3-N-acetyl-amino-4-cyano-1-(4-nitro-phenyl)-1H-pyrazole with hydrogen and Raney nickel in methanolic ammonia solution.
Yield: 73%
C12H15N5O (245.28)
Rf value: 0.54 (RP-8; 5%-ige sodium chloride solution/methanol=2:3)
Prepared analogously to Example 1a from 3-N-acetyl-amino-4-aminomethyl-1-(4-amino-phenyl)-1H-pyrazole and 5-chloro-thiophene-2-carboxylic acid with TBTU and NMM in DMF.
Yield: 87%
Rt value: 2.71 min (E)
C17H16ClN5O2S (389.86)
Mass spectrum: (M+H)+=390/392 (chlorine isotopes)
Prepared analogously to Example 10d from 5-chloro-thiophene-2-carboxylic acid-N-({3-[N′-acetyl-amino]-1-[4-amino-phenyl]-1H-pyrazol-4-yl}-methyl )-amide and 2-(2-chloro-ethoxy)-acetic acid chloride with TEA and caesium carbonate in DMF.
Yield: 48%
Rt value: 3.10 min (E)
C21H20ClN5O4S (473.93)
Mass spectrum: (M+H)+=474/476 (chlorine isotopes)
47.6 g (250 mmol) 2-benzyloxy-carbonyl-amino-acetonitrile in 450 ml of ethanol are combined with 150 ml 5m ethanolic hydrochloric acid at −8° C. with cooling, while keeping the temperature below −5° C. The mixture is stirred for 1.5 h at −10° C. and for 2 h at ambient temperature. After evaporation i. vac. the residue is triturated with diethyl ether, filtered off and dried i. vac.
Yield: 36.60 g (134.2 mmol, 54%)
C12H16N2O3*HCl (236.29/272.73)
Mass spectrum: (M+H)+=237
36.6 g (134 mmol) 2-benzyloxy-carbonyl-amino-acetimido-ethylester are stirred with 12.09 g (134 mmol) dihydroxyacetone dimer in 75 ml ammonia in a bomb tube for 4 h at 70° C. After cooling to ambient temperature, stirring for 16 h and elimination of the ammonia the residue is mixed with ethanol and evaporated down i. vac. The residue is combined with a dichloromethane-ethanol mixture (8:2), filtered and washed with a dichloromethane-ethanol mixture (8:2). The filtrate is evaporated down i. vac. and the residue is purified by chromatography on aluminium oxide (eluting gradient: dichloromethane/(ethanol+conc. ammonia solution 19:1)=1:0→4:1).
Yield: 18.10 g (69.3 mmol, 52%)
C13H15N3O3 (261.28)
Mass spectrum: (M+H)+=262
Prepared analogously to Example 32e from 2-benzyloxy-carbonyl-aminomethyl-4-hydroxymethyl-1H-imidazole with hydrogen and 10% palladium charcoal in methanol.
Yield: 94%
C5H9N3O (127.15)
Mass spectrum: (M+H)+=128
Prepared analogously to Example 25b from 2-aminomethyl-4-hydroxymethyl-1H-imidazole with di-tert.-butyl pyrocarbonate in DMF.
Yield: 97%
C10H17N3O3 (227.26)
Mass spectrum: (M+H)+=363
Prepared analogously to Example 32a from 2-N-Boc-aminomethyl-4-hydroxymethyl-1H-imidazole and manganese(IV)oxide in dichloromethane.
Yield: 81%
C10H15N3O3 (225.25)
Mass spectrum: (M+H)+=226
Prepared analogously to Example 7a from 2-N-Boc-aminomethyl-4-formyl-1H-imidazole and Raney nickel in methanolic ammonia solution with hydrogen.
Yield: 94%
C10H18N4O2 (226.28)
Prepared analogously to Example 12a from 2-N-Boc-aminomethyl-4-aminomethyl-1H-imidazole with 5-chloro-thiophene-2-carboxylic acid chloride and TEA in dichloromethane.
Yield: 70%
C15H19ClN4O3S (370.86)
Mass spectrum: (M+H)+=371/373 (chlorine isotopes)
Prepared analogously to Example 32d from 5-chloro-thiophene-2-carboxylic acid-N-({2-[N′-Boc-aminomethyl]-1H-imidazol-4-yl}-methyl)-amide with 5-fluoro-2-nitro-toluene with 1n lithium hexamethyldisilazide in hexane in DMF.
Yield: 27%
C22H24ClN5O5S (505.98)
Mass spectrum: (M+H)+=506/508 (chlorine isotopes)
Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid-N-({2-[N′-Boc-aminomethyl]-1-[3-methyl-4-nitro-phenyl]-1H-imidazol-4-yl}-methyl)-amide with hydrogen and Raney nickel in ethanol.
Yield: 75%
C22H26ClN5O3S (475.99)
Mass spectrum: (M+H)+=476/478 (chlorine isotopes)
Prepared analogously to Example 10d from 5-chloro-thiophene-2-carboxylic acid-N-({2-[N′-Boc-aminomethyl]-1-[3-methyl-4-amino-phenyl]-1H-imidazol-4-yl}-methyl)-amide and 2-(2-chloro-ethoxy)-acetic acid chloride with TEA and caesium chloride in DMF.
Yield: 70%
Rt value: 3.08 min (E)
C26H30ClN5O5S (560.07)
Mass spectrum: (M+H)+=560/562 (chlorine isotopes)
Prepared analogously to Example 25d from 5-chloro-thiophene-2-carboxylic acid-N-({2-[N′-Boc-aminomethyl]-1-[3-methyl-4-(3-oxo-morpholin-4-yl)-phenyl]-1H-imidazol-4-yl}-methyl)-amide with TFA in dichloromethane.
Yield: quant.
Rt value: 2.59 min (E)
C21H22ClN5O3S (459.95)
Mass spectrum: (M+H)+=460/462 (chlorine isotopes)
Prepared analogously to Example 12c from 5-chloro-thiophene-2-carboxylic acid-N-({2-aminomethyl-1-[3-methyl-4-(3-oxo-morpholin-4-yl)-phenyl]-1H-imidazol-4-yl}-methyl)-amide and acetyl chloride with TEA in dichloromethane.
Yield: 55%
Rf value: 0.21 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C23H24ClN5O4S (501.99)
Mass spectrum: (M+H)+=502/504 (chlorine isotopes)
60 mg (0.13 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({2-aminomethyl-1-[3-methyl-4-(3-oxo-morpholin-4-yl)-phenyl]-1H-imidazol-4-yl}-methyl)-amide and 21.6 μl (0.29 mmol) 37% aqueous formaldehyde solution are stirred in 500 μl formic acid for 2 h at 80° C. After evaporation i. vac. the residue is purified by preparative HPLC (gradient: (water+0.1% formic acid)/(acetonitrile+0.1% formic acid)=95:5→5:95).
Yield: 35 mg (55%)
Rf value: 0.24 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C23H26ClN5O3S (488.00)
Mass spectrum: (M+H)+=488/490 (chlorine isotopes)
Prepared analogously to Example 10d from 5-chloro-thiophene-2-carboxylic acid-N-({2-aminomethyl-1-[3-methyl-4-(3-oxo-morpholin-4-yl)-phenyl]-1H-imidazol-4-yl}-methyl)-amide and 2-(2-chloro-ethoxy)-acetic acid chloride with TEA and caesium carbonate in DMF.
Yield: 51%
Rf value: 0.29 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C25H26ClN5O5S (544.02)
Mass spectrum: (M+H)+=544/546 (chlorine isotopes)
The following compounds were prepared analogously:
8.00 g (45.4 mmol) 4-methyl-1-phenyl-1H-pyrazolidin-3-one are added to 80 ml conc. sulphuric acid at −5° C. with stirring and stirred for another 5 min. Then 3.8 ml (54.5 mmol) 65% nitric acid are added with cooling such that the temperature remains between −15 and −10° C. The reaction mixture is stirred for 1 h between −20 and −5° C., then poured into ice water and suction filtered. The filter cake is washed with water, dried at 55° C. and further reacted without any further purification.
Yield: 8.00 g (approx. 40%), approx. 50%
C10H9N3O3 (219.20)
Rf value: 0.70 (silica gel; cyclohexane/ethyl acetate=1:1)
7.50 g (17.1 mmol) of the product obtained in 44a are combined with 11.8 g (85.5 mmol) potassium carbonate in 200 ml acetone with 8.6 ml (137 mmol) iodomethane in 50 ml acetone. The mixture is stirred for 10 min at ambient temperature and for 1.5 h at reflux temperature. After cooling 20 ml of water are added, the mixture is filtered and the filtrate is evaporated down i. vac. The residue is stirred with water and extracted with dichloromethane. The combined organic phases are dried on magnesium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: cyclohexane/ethyl acetate=9:1→7:3)
Yield: 2.30 g (9.86 mmol, 58%)
C11H11N3O3 (233.22)
Rf value: 0.60 (silica gel; cyclohexane/ethyl acetate=7:3)
1.50 g (6.43 mmol) 3-methoxy-4-methyl-1-(4-nitro-phenyl)-1H-pyrazole with 1.30 g (7.30 mmol) N-bromo-succinimide and 53 mg (0.32 mmol) 2,2′-azobis(isobutyronitrile) in 50 ml tetrachloromethane are irradiated for 3.5 h at 85° C. with a UV lamp. After cooling to ambient temperature the mixture is filtered off, the filter cake is treated with tetrachloromethane, suction filtered again and washed with tetrachloromethane. The filtrate is evaporated down i. vac. and further reacted directly without any further purification.
Yield: 1.60 g (approx. 48%), approx. 60%
C11H10BrN3O3 (312.12)
1.20 g of the product obtained in 44c are stirred with 20 ml benzylamine in a microwave oven for 20 min at 120° C. After evaporation i. vac. the residue is purified by chromatography (Stable-Bond C18, 8 μm, eluting gradient: (water+0.15% formic acid)/acetonitrile=16:4→1:19). After evaporation of the product-containing fractions the residue is adjusted to ˜pH 9.5 with sat. sodium hydrogen carbonate solution and conc. ammonia solution and extracted with ethyl acetate. The combined organic phases are washed with semisat. and sat. sodium chloride solution, dried on magnesium sulphate and evaporated down i. vac.
Yield: 480 mg (approx. 34%), approx. 55%
C18H18N4O3 (338.36)
Mass spectrum: (M+H)+=339
Prepared analogously to Example 32e from the product obtained in 44d with hydrogen and 10% palladium charcoal in methanol.
Yield: 74%
C11H14N4O (218.26)
Mass spectrum: (M−NH2)+=202
Prepared analogously to Example 1a from 4-aminomethyl-1-[4-amino-phenyl]-3-methoxy-1H-pyrazole and 5-chloro-thiophene-2-carboxylic acid with TBTU and NMM in DMF.
Yield: 86%
Rt value: 3.19 min (E)
C16H15ClN4O2S (362.84)
Mass spectrum: (M+H)+=363/365 (chlorine isotopes)
Prepared analogously to Example 12f from 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-amino-phenyl]-3-methoxy-1H-pyrazol-4-yl}-methyl)-amide and 2-(2-chloro-ethoxy)-acetic acid chloride with DIPEA and caesium carbonate in acetonitrile.
Yield: 44%
Rt value: 3.70 min (E)
C20H19ClN4O4S (446.91)
Mass spectrum: (M+H)+=447/449 (chlorine isotopes)
Prepared analogously to Example 35a from 4-cyano-1H-imidazole and 5-fluoro-2-nitro-toluene with potassium carbonate in DMSO.
Yield: 42%
Rf value: 0.50 (silica gel; cyclohexane/ethyl acetate=1:1)
C11H8N4O2 (228.21)
Mass spectrum: (M−H)−=227
7.30 g (30.4 mmol) 4-cyano-1-(3-methyl-4-nitro-phenyl)-1H-imidazole in 200 ml tetrachloromethane and 20 ml NMP are combined with 6.50 g (36.5 mmol) N-bromo-succinimide and 150 mg (0.91 mmol) azobis(isobutyronitrile) under a nitrogen atmosphere and stirred for 6.5 h at 60° C. 500 mg (2.8 mmol) N-bromo-succinimide and 150 mg (0.91 mmol) azobis(isobutyronitrile) are added and the mixture is stirred for 50 min at 60° C. and for 14 h at ambient temperature. 500 mg (2.8 mmol) N-bromo-succinimide and 150 mg (0.91 mmol) azobis(isobutyronitrile) are added and the mixture is stirred for 7 h at 65° C. Water is added to the mixture and it is evaporated down i. vac. The residue is stirred into water, filtered, the filter cake is washed with water and dried at 55° C. under a nitrogen atmosphere. Then it is purified by chromatography on silica gel (eluting gradient: cyclohexane/ethyl acetate=8:2→6:4)
Yield: 4.70 g (14.4 mmol, 47%)
C11H7BrN4O2 (307.10)
Rf value: 0.80 (silica gel; cyclohexane/ethyl acetate=1:1)
750 mg (2.39 mmol) 2-bromo-4-cyano-1-(3-methyl-4-nitro-phenyl)-1H-imidazole are stirred under a nitrogen atmosphere with 666 μl (5.98 mmol) N-methyl-piperidine in 2 ml NMP for 16 h at 85° C. Then 100 μl (0.90 mmol) N-methyl-piperidine are added and the mixture is heated to 85° C. for 3 h. After cooling to ambient temperature the mixture is combined with 2 ml DMF and purified by preparative HPLC (Symmetry Prep C18, 7μm, gradient: (water+0.15% formic acid)/acetonitrile=16:4→1:19).
Yield: 300 mg (0.92 mmol, 38%)
C16H18N6O2 (326.35)
Prepared analogously to Example 18d from 4-cyano-1-(3-methyl-4-nitro-phenyl)-2-(4-methyl-piperidin-1-yl)-1H-imidazole with Raney nickel and hydrogen in methanolic ammonia solution.
Yield: 89%
C16H24N6 (300.40)
Mass spectrum: (M+H)+=301
Prepared analogously to Example 1a from 4-aminomethyl-1-[4-amino-3-methyl-phenyl]-2-(4-methyl-piperazin-1-yl)-1H-imidazole and 5-chloro-thiophene-2-carboxylic acid with TBTU and NMM in DMF.
Yield: 42%
Rt value: 2.23 min (E)
C21H25ClN6OS (444.98)
Mass spectrum: (M+H)+=445/447 (chlorine isotopes)
Prepared analogously to Example 12f from 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-amino-3-methyl-phenyl]-2-(4-methyl-piperazin-1-yl)-1H-pyrazol-4-yl}-methyl)-amide and 2-(2-chloro-ethoxy)-acetic acid chloride with DIPEA and caesium carbonate in DMF.
Yield: 34%
Rt value: 2.43 min (E)
C25H29ClN6O3S*2HCl (529.06/601.98)
Mass spectrum: (M+H)+=529/531 (chlorine isotopes)
The following compounds were prepared analogously:
85 mg (0.185 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({2-aminomethyl-1-[3-methyl-4-(3-oxo-morpholin-4-yl)-phenyl]-1H-imidazol-4-yl}-methyl)-amide in 4 ml DMF are combined with 16.6 μl (0.194 mmol) 2-chloro-ethylisocyanate and the mixture is stirred for 2 h at ambient temperature. Then 181 mg (0.55 mmol) caesium carbonate are added, the mixture is heated to 70° C. for 1.5 h and stirred for 2.5 d at ambient temperature. After filtration it is purified by preparative HPLC (C18 StableBond, 7 μm, gradient: (water+0.1% formic acid)/(acetonitrile+0.1% formic acid)=19:1→1:19).
Yield: 5 mg (9 μmol, 5%)
Rt value: 2.58 min (E)
C24H25 ClN6O4S (529.01)
Mass spectrum: (M+H)+=529/531 (chlorine isotopes)
Hydrogen chloride is piped into a mixture of 5.50 g (51.3 mmol) 4-cyano-1-methyl-1H-imidazole in 150 ml of ethanol at −0° C., with cooling, for 1.5 h, while the temperature is kept below 10° C. Then the mixture is stirred for 2.5 h at below 10° C. Then the mixture is poured into 500 ml diethyl ether, filtered, washed with diethyl ether and dried i. vac.
Yield: 10.57 g (46.7 mmol, 91%)
C7H10N2O2*HCl (154.17/190.63)
Mass spectrum: (M+H)+=154
Prepared analogously to Example 36b from 1-methyl-1H-imidazol-4-carbimido-ethylester and dihydroxyacetone dimer in liquid ammonia.
Yield: 59%
C8H10N4O (178.19)
Mass spectrum: (M+H)+=179
Prepared analogously to Example 32a from 4-hydroxymethyl-2-(1-methyl-1H-imidazol-4-yl)-1H-imidazole and manganese(IV)oxide in dichloromethane.
Yield: 96%
Rf value: 0.51 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C8H8N4O (176.18)
Mass spectrum: (M+H)+=177
Prepared analogously to Example 7a from 4-formyl-2-(1-methyl-1H-imidazol-4-yl)-1H-imidazole and Raney nickel in methanolic ammonia solution with hydrogen.
Yield: quant.
C8H11N5 (177.21)
Prepared analogously to Example 12a from 4-aminomethyl-2-(1-methyl-1H-imidazol-4-yl)-1H-imidazole with 5-chloro-thiophene-2-carboxylic acid chloride and TEA in DMF.
Yield: 46%
Rf value: 0.38 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C13H12ClN5OS (321.79)
Mass spectrum: (M+H)+=322/324 (chlorine isotopes)
Prepared analogously to Example 32d from 5-chloro-thiophene-2-carboxylic acid-N-({2-[1-methyl-1H-imidazol-4-yl]-1H-imidazol-4-yl}-methyl)-amide and 4-fluoro-1-nitro-benzene with 1n lithium hexamethyldisilazide in THF in DMF.
Yield: 50%
Rf value: 0.50 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C19H15ClN6O3S (442.88)
Mass spectrum: (M+H)+=443/445 (chlorine isotopes)
Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid-N-({2-[1-methyl-1H-imidazol-4-yl]-1-[4-nitro-phenyl]-1H-imidazol-4-yl}-methyl)-amide with hydrogen and Raney nickel in methanol.
Yield: 89%
Rf value: 0.29 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C19H17ClN6OS (412.90)
Mass spectrum: (M+H)+=413/415 (chlorine isotopes)
Prepared analogously to Example 10d from 5-chloro-thiophene-2-carboxylic acid-N-({2-[1-methyl-1H-imidazol-4-yl]-1-[4-amino-phenyl]-1H-imidazol-4-yl}-methyl)-amide and 2-(2-chloro-ethoxy)-acetic acid chloride with TEA and caesium chloride in DMF.
Yield: 70%
Rf value: 0.31 (silica gel; dichloromethane/methanol=9:1+0.5% conc. ammonia solution)
C23H21ClN6O3S (496.97)
Mass spectrum: (M+H)+=497/499 (chlorine isotopes)
The following compounds were prepared analogously:
150 mg (0.33 mmol) 5-chloro-thiophene-2-carboxylic acid-N-({2-aminomethyl-1-[3-methyl-4-(3-oxo-morpholin-4-yl)-phenyl]-1H-imidazol-4-yl}-methyl)-amide in 5 ml dichloromethane are combined with 53 μl (0.66 mmol) pyridine and 31 μl (0.40 mmol) methylsulphonyl chloride. The mixture is stirred for 16 h at ambient temperature. Then 20 ml dichloromethane are added, the organic phase is washed with water and dried on magnesium sulphate. After evaporation i. vac. the residue is triturated with diethyl ether, filtered off and dried.
Yield: 140 mg (80%)
Rf value: 0.40 (silica gel; dichloromethane/methanol=9:1)
C22H24ClN5O5S2 (538.04)
Mass spectrum: (M+H)+=538/540 (chlorine isotopes)
