2-fluoro-5-iodobenzoyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500 mL flask, 2-fluoro-5-iodobenzoyl chloride (6.06 g, 21.3 mmol) and 1-bromo-4-methoxy-2-(trifluoromethoxy)benzene (5.77 g, 21.3 mmol) were dissolved in 1,2-dichloroethane (50.7 mL, 21.3 mmol) and the solution was cooled to 0 to 5° C. Aluminum chloride (2.84 g, 21.3 mmol) was added portionwise to the solution. The red solution was warmed to rt. After 2 h, LCMS showed mainly (5-bromo-2-methoxy-4-(trifluoromethoxy)phenyl)(2-fluoro-5-iodophenyl)methanone. The whole was refluxed for 1 h. LCMS showed complete consumption of (5-bromo-2-methoxy-4-(trifluoromethoxy)phenyl)(2-fluoro-5-iodophenyl)methanone. The reaction was cooled to rt. Ice (5-10 chips) and concentrated HCl (2 mL) was added until pH ˜1. The whole was stirred at rt for 30 min. The resulting slurry was extracted with ether (3×80 mL). The organic layer was washed with water, dried over MgSO4, filtered, and concentrated to afford a semi-black solid that was carried on to the next step. The crude was added to a mixture of ethanol (85 mL, 21.3 mmol), methanol (30.4 mL, 21.3 mmol), and sodium methoxide (2.30 g, 42.6 mmol) at rt. After refluxing for 1 h, LCMS showed mainly the cyclized xanthenone product. The whole was cooled to rt and concentrated. Water (80 mL) and EtOAc (120 mL) was added. The product was extracted with EtOAc (2×80 mL). The organic layer was separated, combined, dried over MgSO4, filtered, and concentrated. Trituration with hexanes gave 2-bromo-7-iodo-3-(trifluoromethoxy)-9H-xanthen-9-one (2.94 g, 6.06 mmol, 29% yield) as a gray solid. LCMS (ESI) calcd for C14H5BrF3IO3: [M]+=484. Found [M+H]+=485. The red solution was warmed to rt The whole was refluxed for 1 h consumption of (5-bromo-2-methoxy-4-(trifluoromethoxy)phenyl)(2-fluoro-5-iodophenyl)methanone The reaction was cooled to rt Ice (5-10 chips) and concentrated HCl (2 mL) was added until pH ˜1 The resulting slurry was extracted with ether (3×80 mL) The organic layer was washed with water dried over MgSO4 filtered concentrated to afford a semi-black solid After refluxing for 1 h The whole was cooled to rt concentrated Water (80 mL) and EtOAc (120 mL) was added The product was extracted with EtOAc (2×80 mL) The organic layer was separated dried over MgSO4 filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a vial, (S)-tert-butyl 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate (0.500 g, 1.3 mmol) was taken up in CH2Cl2. The solution was cooled to 0 deg. C and Triethylamine (0.24 ml, 1.7 mmol) and 2-fluoro-5-iodobenzoyl chloride (0.42 g, 1.5 mmol) were added. The tube was sealed and the reaction stirred for 2 h. The reaction mixture was poured into EtOAc/1N NaOH. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting off-white foam (S)-tert-butyl 1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate was used without further purification. MS m/z=622 [M+H]+. Calc'd for C25H28F4IN3O3: 621. The solution was cooled to 0 deg. C The tube was sealed The organic layer was dried over anhydrous sodium sulfate concentrated in vacuo The resulting off-white foam (S)-tert-butyl 1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate was used without further purification

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a vial, (R)-2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)benzenamine (.517 g, 1.4 mmol) was taken up in THF. Triethylamine (0.29 ml, 2.1 mmol) and 2-fluoro-5-iodobenzoyl chloride (0.43 g, 1.5 mmol) were added. The vial was sealed and the reaction stirred for 48 h. The reaction mixture was poured into EtOAc/1N NaOH. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was treated with hexanes and passed through a Redi-Sep® pre-packed silica gel column (40 g) eluting with 0-10% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)—N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamide as a white foam. The vial was sealed The organic layer was dried over anhydrous sodium sulfate concentrated in vacuo The crude material was treated with hexanes eluting with 0-10% EtOAc/hexane The product-containing fractions were concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add a 2.0 M solution of dimethylamine in tetrahydrofuran (5 mL, 10.1 mmol) to a solution of 2-fluoro-5-iodobenzoylchloride (1.3 g, 4.6 mmol) in dichloromethane (20 mL) and stir at room temperature for 0.5 h. Sequentially wash the reaction mixture with a 1 N hydrochloric acid (50 mL), a 1 N sodium hydroxide (50 mL), and an aqueous saturated solution of sodium chloride (50 mL). Dry (sodium sulfate), filter, and concentrate to give the title compound as a white solid (1.3 g, 98%). Sequentially wash the reaction mixture with a 1 N hydrochloric acid (50 mL) Dry (sodium sulfate) filter concentrate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add slowly 2-fluoro-5-iodobenzoyl chloride (4.0 g, 14.1 mmol) to a 7 N solution of ammonia in methanol (20 mL, 141 mmol) cooled to 0° C. Stir at 0° C. for 45 min then warm to room temperature and stir 5 h. Add an additional amount of the 7 N solution of ammonia in methanol (20 mL) to the reaction mixture and stir for 15 h. Concentrate, dilute with ethyl acetate (300 mL) and wash twice with water (30 mL) and twice with an aqueous saturated solution of sodium chloride (30 mL). Dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 60:40 to 40:60 hexanes:ethyl acetate, to give the title compound as a white solid (3.45 g, 92%). then warm to room temperature stir 5 h stir for 15 h Concentrate dilute with ethyl acetate (300 mL) wash twice with water (30 mL) and twice with an aqueous saturated solution of sodium chloride (30 mL) Dry (sodium sulfate) filter concentrate Purify by silica gel chromatography eluting with 60:40 to 40:60 hexanes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add slowly 2-fluoro-5-iodobenzoyl chloride (4.0 g, 14.1 mmol) to a 7 N solution of ammonia in methanol (20 mL, 141 mmol) cooled to 0° C. Stir at 0° C. for 45 min then warm to room temperature and stir 5 h. Add an additional amount of the 7 N solution of ammonia in methanol (20 mL) to the reaction mixture and stir for 15 h. Concentrate, dilute with ethyl acetate (300 mL) and wash twice with water (30 mL) and twice with an aqueous saturated solution of sodium chloride (30 mL). Dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 60:40 to 40:60 hexanes:ethyl acetate, to give the title compound as a white solid (3.45 g, 92%). then warm to room temperature stir 5 h stir for 15 h Concentrate dilute with ethyl acetate (300 mL) wash twice with water (30 mL) and twice with an aqueous saturated solution of sodium chloride (30 mL) Dry (sodium sulfate) filter concentrate Purify by silica gel chromatography eluting with 60:40 to 40:60 hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add methylamine hydrochloride (0.57 g, 8.4 mmol) and triethylamine (2.17 mL, 15.5 mmol) to a solution of 2-fluoro-5-iodobenzoyl chloride (2.0 g, 7.0 mmol) in dichloromethane (100 mL) at 0° C. Warm to room temperature and stir 20 h. Concentrate and purify by silica gel chromatography, eluting with a gradient of 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (1.7 g, 87%). Concentrate purify by silica gel chromatography eluting with a gradient of 75:25 to 60:40 hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, magnesium was added to 1-bromo-3,4,5-trimethoxybenzene as a starting material, as shown in Reaction 6, and then 2-fluoro-5-iodobenzoyl chloride was added thereto to obtain a Compound 21 derivative [(2-fluoro-5-iodophenyl)(3,4,5-trimethoxyphenyl)methanone]. Using NaOMe, the fluoro group of thus obtained compound was substituted with a methoxy group to obtain (2-methoxy-5-iodophenyl)(3,4,5-trimethoxyphenyl)methanone. Thus obtained (2-methoxy-5-iodophenyl)(3,4,5-trimethoxyphenyl)methanone (320 mg, 0.75 mmol) was dissolved in tetrahydrofuran (50 ml), and 2-(tributylstannyl)thiazole (475 mg, 1.27 mmol) and Pd(PPh3)2Cl2 (26 mg, 0.04 mmol) were slowly added thereto at room temperature. The mixture was heat refluxed for 8 hours. After completion of the reaction, the reaction mixture was extracted with water and EtOAc. The organic layer was washed with brine, and dried over anhydrous MgSO4. The solid substance was filtered off, and the filtrate was vacuum concentrated. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=1/2) to obtain Compound 583 (140 mg, 49%). as shown in Reaction 6

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 2-fluoro-5-iodobenzoic acid (Aldrich, 5.27 g, 19.8 mmol) in CH2Cl2 (35.0 mL) was added oxalyl chloride (14.9 mL, 29.7 mmol, 1M solution in CH2Cl2) followed by 2 drops of DMF via syringe. Gas evolution was initiated and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with sat. aq. NH4Cl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give crude 2-fluoro-5-iodobenzoyl chloride which was used directly in the next step. The reaction mixture was then quenched with sat. aq. NH4Cl solution extracted with EtOAc (3×) The combined organic extracts were dried over Na2SO4 filtered concentrated in vacuo