(2,2,3,3-tetramethylcyclopropyl)methanol

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.97 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.08 g of 2,5-dimethyl-4-nitrophenol, 0.83 g of (2,2,3,3-tetramethylcyclopropyl)methanol, 2.04 g of triphenylphosphine and 100 mL of toluene at 0° C., and the mixture was stirred at 90° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.15 g of 2,5-dimethyl-4-nitro-1-[(2,2,3,3-tetramethylcyclopropyl) methoxy]benzene. After cooling the mixture was extracted with ethyl acetate the organic layer was washed with water and saturated salt water dried over anhydrous magnesium sulfate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.97 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.08 g of 2,5-dimethyl-4-nitrophenol, 0.83 g of (2,2,3,3-tetramethylcyclopropyl)methanol, 2.04 g of triphenylphosphine and 100 mL of toluene at 0° C., and the mixture was stirred at 90° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.15 g of 2,5-dimethyl-4-nitro-1-[(2,2,3,3-tetramethylcyclopropyl) methoxy]benzene. After cooling the mixture was extracted with ethyl acetate the organic layer was washed with water and saturated salt water dried over anhydrous magnesium sulfate

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

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

Procedure: To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (48 mg, 0.37 mmol) in dry DMSO (5 mL) was added potassium t-butoxide (124 mg, 1.11 mmol) at room temperature. After stirring for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (50 mg, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs. The mixture was cooled to 0° C., quenched by hydrochloride acid (1N, 30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (40 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by prep HPLC (20%-50% MeCN in 0.1% formic acid) to afford the title compound as a white solid (7 mg, 10%). LCMS (ESI) Method A: RT=5.28 min, m/z: 268.1 [M-109]+; 1H-NMR (500 MHz, DMSO-d6): δ 8.13 (br s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.21-7.10 (m, 1H), 4.18 (d, J=7.0 Hz, 2H), 3.02 (s, 3H), 1.10 (s, 6H), 1.03 (s, 6H), 0.74 (t, J=7.5 Hz, 1H). the reaction mixture was stirred at room temperature for 16 hrs quenched by hydrochloride acid (1N, 30 mL) extracted with ethyl acetate (50 mL) The organic layer was washed with water (40 mL×2) dried over anhydrous sodium sulfate filtered concentrated in vacuo The crude product was purified by prep HPLC (20%-50% MeCN in 0.1% formic acid)

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

Procedure: To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (80 mg, 0.62 mmol) in dry DMF (10 mL) at 0° C. was added NaH (25 mg, 0.62 mmol). After being stirred for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (54 mg, 0.21 mmol) was added. After being stirred at room temperature for 18 h, the mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 ml×2). The combined organic layers was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 5-chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethylcyclopropyl)-methoxy)benzamide (20 mg, 25% yield) as a white solid. LCMS (ESI) Method A: RT=5.11 min, m/z: 268 [M-109]+. 1H NMR (500 MHz, DMSO-d6): δ 7.35 (d, J=9.0 Hz 1H), 7.03 (d, J=7.0 Hz, 1H), 6.04 (brs, 1H), 3.99 (d, J=7.5 Hz, 2H), 2.80 (s, 3H), 1.06 (s, 6H), 0.99 (s, 6H), 0.65 (t, J=7.5 Hz, 1H); 13C NMR (125 MHz, MeOH-d4): δ 159.4 (d, J=3.5 Hz), 133.9 (d, J=2.1 Hz), 114.1, 104.2, 103.9, 71.4, 41.7, 32.5, 24.2, 23.7, 17.4. After being stirred at room temperature for 18 h The organic layer was separated the aqueous layer was extracted with EtOAc (20 ml×2) The combined organic layers was dried over Na2SO4 concentrated The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min)

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

Procedure: To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (80 mg, 0.62 mmol) in dry DMF (10 mL) at 0° C. was added NaH (25 mg, 0.62 mmol). After being stirred for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (54 mg, 0.21 mmol) was added. After being stirred at room temperature for 18 h, the mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 ml×2). The combined organic layers was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 5-chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethylcyclopropyl)-methoxy)benzamide (20 mg, 25% yield) as a white solid. LCMS (ESI) Method A: RT=5.11 min, m/z: 268 [M−109]+. 1H NMR (500 MHz, DMSO-d6): δ 7.35 (d, J=9.0 Hz 1H), 7.03 (d, J=7.0 Hz, 1H), 6.04 (brs, 1H), 3.99 (d, J=7.5 Hz, 2H), 2.80 (s, 3H), 1.06 (s, 6H), 0.99 (s, 6H), 0.65 (t, J=7.5 Hz, 1H); 13C NMR (125 MHz, MeOH-d4): δ 159.4 (d, J=3.5 Hz), 133.9 (d, J=2.1 Hz), 114.1, 104.2, 103.9, 71.4, 41.7, 32.5, 24.2, 23.7, 17.4. After being stirred at room temperature for 18 h The organic layer was separated the aqueous layer was extracted with EtOAc (20 ml×2) The combined organic layers was dried over Na2SO4 concentrated The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min)

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

Procedure: A solution of 20 g of 2,2,3,3-tetramethylcyclopropylmethanol and 41.9 g of 3-bromo-4-fluorobenzyl bromide in 100 ml of a 1:1 mixture of toluene/dimethylformamide is added dropwise at 0°-10° C. to 8.2 g of sodium hydride (50% dispersion in mineral oil) in 200 ml of a 1:1 mixture of toluene/dimethylformamide. When the reaction has subsided, the batch is stirred for 16 hours at room temperature and, after the dropwise addition of a saturated solution of ammonium chloride, extracted with toluene. The combined toluene extracts are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The crude product is chromatographed through a column of silica gel (elution with a 5:1 mixture of hexane/ether), affording the title compound in the form of a clear oil with a refractive index of nD24 =1.5128. extracted with toluene The combined toluene extracts are washed with saturated sodium chloride solution dried over MgSO4 concentrated by rotary evaporation The crude product is chromatographed through a column of silica gel ( elution with a 5:1 mixture of hexane/ether),

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

Procedure: A solution of 20 g of 2,2,3,3-tetramethylcyclopropylmethanol and 41.9 g of 3-bromo-4-fluorobenzyl bromide in 100 ml of a 1:1 mixture of toluene/dimethylformamide is added dropwise at 0°-10° C. to 8.2 g of sodium hydride (50% dispersion in mineral oil) in 200 ml of a 1:1 mixture of toluene/dimethylformamide. When the reaction has subsided, the batch is stirred for 16 hours at room temperature and, after the dropwise addition of a saturated solution of ammonium chloride, extracted with toluene. The combined toluene extracts are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The crude product is chromatographed through a column of silica gel (elution with a 5:1 mixture of hexane/ether), affording the title compound in the form of a clear oil with a refractive index of nD24 =1.5128. extracted with toluene The combined toluene extracts are washed with saturated sodium chloride solution dried over MgSO4 concentrated by rotary evaporation The crude product is chromatographed through a column of silica gel ( elution with a 5:1 mixture of hexane/ether),

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

Procedure: A solution of 1.9 g of 2,2,3,3-tetramethylcyclopropylmethanol and 4.2 g of 3-phenoxy-4-fluorobenzyl bromide in 20 ml of a 1:1 mixture of toluene/dimethylformamide is added dropwise at 0°-5° C. to 0.9 g of sodium hydride (50% dispersion in mineral oil) in 60 ml of a 1:1 mixture of toluene/dimethylformamide. When the reaction has subsided, the batch is stirred for 16 hours at room temperature and, after the dropwise addition of a saturated solution of ammonium chloride, extracted with toluene. The combined toluene extracts are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The crude product is chromatographed through a column of 300 g of silica gel (elution with a 95:5 mixture of hexane/ether), affording the title compound of formula ##STR9## in the form of a clear oil with a refractive index of nD24 =1.5300 (compound 1). extracted with toluene The combined toluene extracts are washed with saturated sodium chloride solution dried over MgSO4 concentrated by rotary evaporation The crude product is chromatographed through a column of 300 g of silica gel ( elution with a 95:5 mixture of hexane/ether),

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

Procedure: To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (48 mg, 0.37 mmol) in dry DMSO (5 mL) was added potassium t-butoxide (124 mg, 1.11 mmol) at room temperature. After stirring for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (50 mg, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs. The mixture was cooled to 0° C., quenched by hydrochloride acid (1N, 30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (40 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by prep HPLC (20%-50% MeCN in 0.1% formic acid) to afford the title compound as a white solid (7 mg, 10%). LCMS (ESI) Method A: RT=5.28 min, m/z: 268.1 [M−109]+; 1H-NMR (500 MHz, DMSO-d6): δ 8.13 (br s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.21-7.10 (m, 1H), 4.18 (d, J=7.0 Hz, 2H), 3.02 (s, 3H), 1.10 (s, 6H), 1.03 (s, 6H), 0.74 (t, J=7.5 Hz, 1H). the reaction mixture was stirred at room temperature for 16 hrs quenched by hydrochloride acid (1N, 30 mL) extracted with ethyl acetate (50 mL) The organic layer was washed with water (40 mL×2) dried over anhydrous sodium sulfate filtered concentrated in vacuo The crude product was purified by prep HPLC (20%-50% MeCN in 0.1% formic acid)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.97 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.08 g of 2,5-dimethyl-4-nitrophenol, 0.83 g of (2,2,3,3-tetramethylcyclopropyl)methanol, 2.04 g of triphenylphosphine and 100 mL of toluene at 0° C., and the mixture was stirred at 90° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.15 g of 2,5-dimethyl-4-nitro-1-[(2,2,3,3-tetramethylcyclopropyl) methoxy]benzene. After cooling the mixture was extracted with ethyl acetate the organic layer was washed with water and saturated salt water dried over anhydrous magnesium sulfate