1H-Imidazole-4-carboxylicacid,5-(1,1-dimethylethyl)-(9CI) synthesis

Yield:51721-21-2 26% ，714273-89-9 26% ，714273-88-8 2%

Reaction Conditions:

in water at 150; for 3.5 h;

Steps:

3.h 5-tert-Butyl-3H-imidazole-4-carboxylic acid ethyl ester

A solution of 2-chloro-4,4-dimethyl-3-oxo-pentanoic acid ethyl ester (25.0 g, 0.12 mol) in formamide (47.5 ml) and water (2.5 ml) was shaken, then dispensed into 15×8 ml vials. All vials were sealed and then heated at 150° for 3.5 h. The vials were allowed to cool to room temperature, then water (20 ml) was added and the mixture was exhaustively extracted with chloroform. The chloroform was removed to give a concentrated formamide solution (22.2 g) which was added to a flash silica column (6 cm diameter, 12 cm height) packed in 1% MeOH/1% Et₃N in chloroform. Elution of the column with 2.5 L of this mixture followed by 1 L of 2% MeOH/1% Et₃N in chloroform gave, in the early fractions, a product suspected of being 5-tert-butyl-oxazole-4-carboxylic acid ethyl ester (6.3 g, 26%).HPLC (214 nm) t_R=8.77 min.¹H NMR (400 MHz, CDCl₃) δ 1.41 (t, J=7.2 Hz, 3H); 1.43 (s, 9H); 4.40 (q, J=7.2 Hz, 2H); 7.81 (s, 1H).¹³C NMR (100 MHz, CDCl₃) δ 14.1, 28.8, 32.5, 61.3, 136.9, 149.9, 156.4, 158.3.ESMS m/z 198.3 [M+H]⁺, 239.3 [M+CH₄CN].LC/MS t_R=7.97 (198.1 [M+H]⁺) min.Recovered from later fractions was 5-tert-butyl-3H-imidazole-4-carboxylic acid ethyl ester (6.20 g, 26%). (Durant et al., “Aminoalkylimidazoles and Process for their Production.” Patent No. GB 1341375 (Great Britain, 1973)).HPLC (214 nm) t_R=5.41 (93.7%) min.¹H NMR (400 MHz, CDCl₃) δ 1.38 (t, J=7.0 Hz, 3H); 1.47 (s, 9H); 4.36 (q, J=7.2 Hz, 2H); 7.54 (s, 1H).¹³C NMR (100 MHz, CDCl₃) δ 13.7, 28.8, 32.0, 59.8, 124.2, 133.3, 149.2, 162.6.ESMS m/z 197.3 [M+H]⁺, 238.3 [M+CH₄CN].Further elution of the column with 1 L of 5% MeOh/1% Et₃N gave a compound suspected of being 5-tert-butyl-3H-imidazole-4-carboxylic acid (0.50 g, 2%).HPLC (245 nm) t_R=4.68 (83.1%) min.¹H NMR (400 MHz, CD₃OD) δ 1.36 (s, 9H); 7.69 (s, 1H).¹H NMR (400 MHz, CDCl₃) δ 1.37 (s, 9H); 7.74 (s, 1H).¹H NMR (400 MHz, CD₃SO) δ 1.28 (s, 9H); 7.68 (s, 1H).ESMS m/z 169.2 [M+H]⁺, 210.4 [M+CH₄CN].

References:

US2008/221122,2008,A1 Location in patent:Page/Page column 27