Sodium Iodide → (2S)-tert-butyl 2-(5-(6-iodothieno[3,2-b]thiophen-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Temperature

110 °C

A mixture of 0.715 mmol), (S)-2-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-1-[2-(trimethylsilyl)ethoxymethyl]-1H-imidazol-5-ylboronic acid (3.37), 3,6-dibromothieno[3,2-b]thiophene (3.38) (213 mg, (294 mg, 0.715 mmol), Na2CO3 (303 mg, 2.86 mmol) and Pd(PPh3)4 (83 mg, 0.072 mmol) in DMF (10 mL) and water (1 mL) was stirred under aa at 85° C. for 48 h. After the reaction was completed, the mixture was diluted with water, extracted with DCM, washed with water, dried over Na2SO4, rotovapped and subjected to HPLC to obtain 74 mg (18%) of (2S)-tert-butyl 2-(5-(6-bromothieno[3,2-b]thiophen-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3.39). The LC-MS molecular ion peaks were at 584, 586 (M+H)+. A mixture of compound 3.39 (74 mg, 0.13 mmol), dry sodium iodide (NaI) (95 mg, 0.63 mmol), CuI (8 mg, 0.042 mmol) and N,N′-dimethylethelenediamine (7.5 mg, 0.085 mmol, 9.1 μL) in dioxane (1.5 mL) was stirred under aa at 110° C. for 5 days. After the reaction was completed, the mixture was diluted with water, extracted with DCM, washed with water, dried over Na2SO4, rotovapped and subjected to column chromatography on silica gel (chloroform/acetone 20:1) to obtain 28 mg (35%) of (2S)-tert-butyl 2-(5-(6-iodothieno[3,2-b]thiophen-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3.40). The LC-MS molecular ion peak was at 632 (M+H)+. Potassium carbonate (K2CO3) (35 mg, 0.25 mmol) was added to the solution of compound 3.41 (30 mg, 0.084 mmol) in THF (3 mL) and methanol (3 mL), and the reaction mixture was stirred under an argon atmosphere for 2 h, then filtered and rotovapped. Triethylamine (0.8 mL), compound 3.40 (28 mg, 0.044 mmol), Pd(PPh)4 (9 mg, 0.008 mmol) and CuI (3 mg, 0.016 mmol) were added to the solution of the obtained compound in THF (3.2 mL). The resulting mixture was then stirred under aa at 40° C. for 15 h. After the reaction was completed, the mixture was rotovapped, dissolved in DCM, filtered, washed with a sat. NH4Cl solution, rotovapped again and subjected to column chromatography on silica gel (hexane/EtOAc 1:1) to obtain 29 mg (83%) of (S)-tert-butyl 2-{5-[(6-{2-[(S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-1-[2-(trimethylsilyl)ethoxymethyl]-1H-imidazol-5-yl}thieno[3,2-b]thiophen-3-yl)buta-1,3-diynyl]-1H-imidazol-2-yl}pyrrolidine-1-carboxylate (3.42). The LC-MS molecular ion peak was at 789 (M+H)+. Hydrochloric acid (HCl) in dioxane (4 M, 1.5 mL) was added to the solution of compound 3.42 (29 mg, 0.037 mmol) in dioxane (1 mL) and methanol (0.5 mL). The resulting mixture was then stirred for 12 h (LC-MS check, molecular ion peak at 789 (M+H)+) and rotovapped. The mixture of resulted 2-((S)-pyrrolidin-2-yl)-5-{6-([2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl]buta-1,3-diynyl)thieno[3,2-b]thiophen-3-yl}-1H-imidazole tetrahydrochloride, N-Moc-L-valine (14.2 mg, 0.081 mmol) and HATU (35 mg, 0.092 mmol) in DMF (1.5 mL) was stirred in a fridge for 0.5 h, then DIPEA (24 mg, 0.185 mmol, 0.032 mL) was added, and the resulting mixture was continuously stirred in a fridge for 2 h. The mixture was diluted with 20 mL of DCM, washed twice with a 5% Na2CO3 solution, dried over Na2SO4, rotovapped and subjected to HPLC to obtain 7.4 mg (26%) of methyl (S)-1-[(S)-2-(5-{6-[(2-{(S)-1-[(S)-2-(methoxy carbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)buta-1,3-diynyl]thieno[3,2-b]thiophen-3-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxo-butan-2-ylcarbamate dihydrochloride (1.10). The LC-MS molecular ion peak was at 773 (M+H)+.

1. extractionextracted with DCM
2. washwashed with water
3. dry with materialdried over Na2SO4

ORD record

ord-3f3b538e61b945b18f7f0b55711b8621

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09428491B2