Application background and overview of 3-aminotetrahydrofuran-3-carboxylic acid
3-Aminotetrahydrofuran-3-carboxylic acid is a carboxylic acid compound that can be used to synthesize pharmaceutical intermediates.
Application and preparation of 3-aminotetrahydrofuran-3-carboxylic acid
The synthesis route of 3-aminotetrahydrofuran-3-carboxylic acid is as follows:
Applications of 3-aminotetrahydrofuran-3-carboxylic acid
Alexandre V. Ivachtchenko and others designed and synthesized a series of new generation small molecule hepatitis C virus (HCV) NS5A inhibitors based on SAR, containing 2-pyrrolidin-2-yl-5-{4-[4-( The 2-pyrrolidin-2-yl-1,1-imidazol-5-yl)but-1,3-diynyl]phenyl}-1H-imidazole core can be used in the study of reported NS5A inhibitors. Among them, 3-aminotetrahydrofuran-3-carboxylic acid can be used to synthesize compounds 13c and 13d.
Sequence 1
Step 1
N-Moc-amino acids 22a-f are obtained by reacting the corresponding amino acids with methyl chloroformate under alkaline conditions.
Sequence 2
Step 1: Add the diethyl ether solution of methyllithium lithium bromide complex (1.5M) to 5.83g (30mmol) 1,4-bis(trimethylsilyl)butan-1 dissolved in 40mL diethyl ether, Solution of 3-diyne 15 in an argon atmosphere (aa) under vigorous stirring. The reaction mixture was stirred continuously at room temperature for 15 hours, then cooled in an ice bath and quenched with 40 mL of saturated NH4Cl solution. The organic layer was washed with brine, dried over Na2SO2, and the solvent was evaporated under vacuum in a rotary evaporator to obtain the product.
Step 2: (S)-2-[5-(4-iodophenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester 14a46 (8.8g, 20mmol), triethylamine (20mL), Pd (PPh) 4 (1.16g, 1mmol) and CuI (0.19g, 1mmol) were added to the solution dissolved in THF (70mL ) in a solution of liquid residue 16. The resulting mixture was stirred under aa at 40°C for 15 hours. The mixture was then filtered through Celite, rotary evaporated, and subjected to column chromatography on SiO2 (eluent = chloroform:acetone 15:1) to give 17a. The LC-MS molecular ion peak is 434 (M + H)+.
Step 3: Add potassium carbonate (K2CO3) (7.04g, 51mmol) to compound 17a (7.36g, 17mmol) in THF (120mL) and methanol (120 mL), and the reaction mixture was stirred under aa for 2 h. Then filter and rotary evaporate. Final product.
Step 4: (S)-2-(5-iodo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (19a) 10 (6.17 g, 17 mmol) in triethylamine (20 mL) was added to a mixture of Pd(PPh)4 (0.93 g, 0.8 mmol) and CuI (0.15 g, 0.8 mmol) dissolved in THF ( 60 mL) of the resulting solution of compound 18a. The resulting mixture was then stirred under aa at 40°C for 15 hours. After the reaction is completed, filter the mixture, wash the precipitate with a 3:1 solution of chloroform:methanol, rotary evaporate the filtrate, and boil the residue in 100 mL of methanol. The mixture was then cooled to room temperature and stirred in the refrigerator for 4 hours. The precipitate formed is then filtered out.� (Compound 20a), washed with cold methanol and diethyl ether, and dried in air.
The desired product, [2-((S)-2-{5-[4-(4-{2-[(S)-1-(tert-butoxycarbonyl))-pyrrolidin-2-yl ] -3H-tert-butyl ester obtained -imidazol-4-yl}-but-3,3-diynyl)-phenyl] -1H-imidazol-2-yl}-pyrrolidin-1-yl)-carboxylic acid Esters (20a). The LC-MS molecular ion peak is 597 (M + H)+. 1H NMR (DMSO-d6, MHz) δ12.67, 12.73 (2s, 0.2H) bromopyridine, 12.21, 12.28 (2s, 0.9H), 11.94, 12.01 (2s, 0.9H), 7.77 (m, 2H), 7.55 (m, 3.7H), 7.35 (m, 0.3H), 4.77 (m, 2H), 3.51 (m, 2H), 3.34 (m, 2H ), 2.18 (m, 2H), 1.95 (m, 3H), 1.84 (m, 3H), 1.39 (s, 7.5H), 1.14, 1.17 (2s, 10.5H).
Step 5: Add hydrochloric acid (HCl) (4M, 25mL) dropwise to a solution of compound 20a (5.78g, 9.7mmol) in dioxane (25mL). The resulting mixture was then stirred for 15 hours. The precipitate formed was filtered off, washed with diethyl ether, and dried under vacuum to obtain 5-[4-((S)-2-pyrrolidin-2-yl-3H-imidazol-4-yl)-butan-1,3-diyne phenyl]-2-[(S)-pyrrolidin-2-yl]-1H-imidazole tetrahydrochloride (21a). Yield 5.04g (96%). The LC-MS molecular ion peak is 397 (M + H)+. 1H NMR (DMSO-d6, MHz) δ10.38 (br s, 1H), 10.27 (br s, 1H), 9.86 (br s, 1H), 9.22 (br s, 1H), 8.18 (s, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.80 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 5.02 (m, 1H), 4.74 (m, 1H), 3.45 (m, 1H)), 3.37 (m, 1H), 3.29 (m, 2H), 2.47 (m, 2H), 2.35 (m, 1H), 2.17 (m, 2H), 2.09 (m, 1H), 2.00 (m, 2H).
Step 6: General/Typical Procedure: N-Moc-amino acid 22a f (0 sodium percarbonate, 283 mmol), 1-hydroxy-7-azabenzotriazole (40 mg, 0.295 mmol) and EDAC ( 53 mg, 0.277 mmol) in acetonitrile (1 mL) was stirred in the refrigerator for 1 h, then compound 21a (64 mg, 0.118 mmol) and DIPEA (61 mg, 0.472 mmol, 82 mL) were added, and the resulting mixture was continuously stirred in the refrigerator. Stir for 15 hours. The mixture was rotary evaporated, dissolved in dichloromethane, washed twice with 5% Na2 CO3 solution, and washed with Na2SO4dried, rotary evaporated again, and subjected to HPLC.
Compounds 13a-f were then readily converted into the corresponding salt compositions as described above and isolated into the dihydrochloride salts (13a-f·2HCl) by adding acetone. The synthesis of 13d refers to the above operation. 1H NMR (DMSO-d6, MHz) δ14.56 (br s, 1.8H), 8.18 (m, 2.7H), 7.99 (d, J = 8.0 Hz, 2H), 7.88 (br s, 1.3H), 7.77 (d, J = 8.0Hz, 2H), 5.71 (m, 0.03H), 5.44 (m, 0.06H), 5.18 (m, 0.96H), 5.04 (m, 0.94H), 4.16 (m, 2H), 3.77 (m, 8H), 3.59 (m, 8H), 2.34 (m, 3H
