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EXAMPLE 200 2-Fluorobenzamidine hydrochloride salt (1:1) To a solution of lithium-bis(trimethylsilyl)amide (10 g, 59.8 mmol) in ether (200 ml) in a flame-dried flask, was added 2-fluorobenzonitrile (7.26 g, 59.8 mmol) dropwise over 45 min. at r.t. The mixture was stirred for a further 4 h. at r.t. then cooled to -10 C. and 6N HCl in ethanol (40 ml) added dropwise over 30 min. (exothermic). After allowing the reaction mixture to warm to r.t. overnight the precipitate was filtered and washed with ether then dried under high vacuum at 40 C. overnight. To remove LiCl the dried solid was re-suspended in ethanol (200 ml) and filtered, then the volume reduce volume to ca. 30 ml. The solution was filtered then triturated with ether, and stirred 30 min. at 4 C. Filtration of the precipitate, washing with ether and high vacuum drying overnight at 40 C., afforded the title compound (7.8 g, 44.7 mmol, 75% yield) as a white solid. MS: m/e=138 (M+).
With ammonia; ammonium chloride; In water; at 80℃; for 0.5h;
Reference Example 59 [2-(2-fluorophenyl)-1H-imidazol-4-yl]methanol A mixture of <strong>[57075-81-7]2-fluorobenzamidine hydrochloride</strong> (5 g), dihydroxyacetone dimer (5.16 g), ammonium chloride (7.66 g) and 25% aqueous ammonia (50 mL) was stirred at 80 C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound as colorless crystals (2.78 g, yield 51%). 1H-NMR (DMSO-d6) delta: 4.44 (2H, brs), 4.80-5.15 (1H, m), 6.84-7.10 (1H, m), 7.20-7.52 (3H, m), 7.90-8.05 (1H, m), 12.00 (1H, brs).
With sodium hydroxide; In dichloromethane; water; at 0 - 20℃; for 2h;
General procedure: To a stirred solution of <strong>[57075-81-7]2-fluorobenzenecarboximidamide</strong> (1.38 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 mL, 10.0 mmol) in CH2Cl2 (10 mL) was added a solution of NaOH (1.60 g, 40.0 mmol) in H2O (4.0 mL) dropwise at 0 C. The mixture was stirred at 0 C for 1.0 h and at room temperature for 1.0 h. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 9 (1.88 g, 87%) as a colorless oil. 1H NMR (300 MHz, CDCl3) d: 7.22-7.30 (2H, m), 7.44-7.52 (1H, m), 8.14-8.19 (1H, m).
With 1,10-Phenanthroline; copper diacetate; potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere; Schlenk technique;
General procedure: To a round-bottom flask (25 mL) equipped with a spherical condenser (40 cm length) were added amidine hydrochloride 1 (1.0 mmol), Cu(OAc)2 (0.2 equiv), K2CO3 (2.0 equiv), 1,10-phenanthroline (0.1 equiv) and anhyd DMF (2.0 mL). Then the mixture was well stirred at 130C under an inert atmosphere. After cooling off, the mixture was filtered through a pad of celite eluting with CH2Cl2 (3×6 mL). The volatiles were removed under reduced pressure and the residue was purified by a short flash silica gel column chromatography to give compound 2.
methyl (1‘S,4a’S,8a’S)-1‘-methyl-5‘-oxo-4a’-phenyloctahydro-1‘H-spiro[1,3-dioxolane-2,2’-naphthalene]-6’-carboxylate[ No CAS ]
[ 57075-81-7 ]
(6aS,7S,10aS)-2-(2-fluorophenyl)-7-methyl-10a-phenyl-5,6a,7,9,10,10a-hexahydro-6H-spiro[benzo[h]quinazoline-8,2’-[1,3]dioxolan]-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; at 90℃; for 72h;
To a solution of Example 13A (1.00 g, 2.79 mmol) in 1 M potassium t-butoxide (5.58 mL, 5.58 mmol) was added <strong>[57075-81-7]2-fluorobenzimidamide hydrochloride</strong> (0.877 g, 5.02 mmol). The reaction mixture was heated at 90 C. for 72 hours. The mixture was diluted with saturated aqueous sodium phosphate monobasic solution and extracted with ethyl acetate. The organic phase was concentrated to provide the titled compound which was used without additional purification. MS (APCI+) m/z 447 (M+H)+.
3,5-bis(2-fluorophenyl)-1H-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With iodine; caesium carbonate; In 1,2-dichloro-benzene; at 130℃; for 16h;
General procedure: To a stirred solution of amidine hydrochloride 1 (1.0 mmol) in o-dichlorobenzene (3.0 mL) was added Cs2CO3 (651 mg, 2.0 mmol) followed by iodine (508 mg, 2.0 mmol) at room temperature. The reaction mixture was stirred at 130 C for 16 h. After cooling to room temperature the reaction mixture was diluted with 10% aqueous Na2S2O3 (4.0 mL) and the product was extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filteredand evaporated in vacuum. The crude product was purified by flash column chromatography over silica gel using EtOAc/n-Hexane as the eluent to afford the desired product
A suspension of 346 2-fluoro-benzamidine hydrochloride (3 g, 17.18 mmol), 347 1,3-dihydroxy-propan-2-one (3.17 g, 35.22 mmol), and NH4Cl (4.2 g) in 348 NH4Cl (30 mL) was heated at 80 C. for 1 hr. The reaction mixture was extracted with EtOAc (50 mL×3), washed with brine, dried (Na2SO4) and evaporated in vacuo to give a solid that was purified by column chromatography on silica gel eluting with 2% methanol in 16 DCM to afford the 331 title compound as an off-white solid (2.2 g, 66.6%). 1HNMR (400 MHz, DMSO-d6, 100 C.) 4.50 (s, 2H), 7.01 (s, 1H), 7.25 (m, 2H), 7.38 (m, 1H), 7.99 (m, 1H). LCMS m/z=175 [M-Cl]+
With caesium carbonate; In acetonitrile; at 120℃; for 24h;
The reaction bottle by adding 1 b (4 mmol), two chlorofluorcarbons sodium acetate (4 mmol), cesium carbonate (8 mmol) and acetonitrile (10 ml), then in 120 C heating reaction 24 hours. After the reaction is finished using water quenching, and then the extraction of ethyl acetate, the combined organic phase after drying with anhydrous sodium sulfate, concentrated using petroleum ether and ethyl acetate mixed solvent of column chromatography to obtain the product 3 b, yield is 76%. White solid