4-(bromomethyl)-3-fluorobenzonitrile

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

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

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

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

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

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

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

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-2-(4-Chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (3.444 kg), potassium carbonate (2.774 kg), tetrabutylammonium bromide (0.484 kg), and 4-(bromomethyl)-3-fluorobenzonitrile (2.092 kg) were charged to a reactor. Ethyl acetate (17.2 L) and water (3.44 L) were then charged and the batch was heated to 50° C. until complete by HPLC (<1 relative AP starting material). The reaction is usually complete in about 15 hours. The batch was cooled to 15-20° C. and water (6.88 L) was charged and the bottom aqueous phase was separated. A solution of sodium phosphate monobasic (0.2 M in water, 20.66 L) was charged and the bottom aqueous phase was separated and the pH was tested to ensure that it was <6.5. (Note: If the pH is >6.5, an additional 20.66 L of 0.2 M sodium phosphate monobasic solution may be charged and the extraction and pH measurement repeated.) The solvent was then exchanged by a constant volume vacuum distillation. The reactor was placed under vacuum (270 mmHg) and the jacket was heated to 75-80° C. Once distillation of ethyl acetate started, isopropanol (41.34 L) was added at the same rate of distillate collection, and the overall batch volume was maintained at a constant level. Once all of the isopropanol was added, the vacuum was released and water (13.76 L) was charged. The batch temperature was maintained at approximately 50° C. during the water addition. The batch was then cooled to 15-20° C. and filtered. The wet cake was washed with 50% (v/v) aqueous isopropanol (4×21.6 kg) and then dried under vacuum at 50° C. to give the title compound as an off-white solid (3.648 kg, 78% yield.) 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42-1.55 (m, 1H) 1.80-1.93 (m, 1 H) 2.00-2.15 (m, 2 H) 4.44 (dd, J=7.91, 1.13 Hz, 1 H) 4.68 (d, J=17.71 Hz, 1 H) 4.99 (d, J=17.71 Hz, 1 H) 7.26 (s, 1 H) 7.50 (s, 1 H) 7.63-7.73 (m, 4 H) 7.78-7.87 (m, 3 H). 13C NMR (75 MHz, DMSO-d6) ppm 22.58-22.97 (m, 1 C) 29.96 (d, J=29.09 Hz, 1 C) 41.46 (d, J=5.49 Hz, 1 C), 57.86, 110.97, 111.45 (d, J=10.43 Hz, 1 C), 117.58, 119.11 (d, J=25.80 Hz, 1 C), 124.89, 128.53, 128.56, 129.21, 131.17, 131.98, 137.44, 138.32, 158.99 (d, J=247.54 Hz, 2 C), 170.25. 19F NMR, (CDCl3, 282 MHz) δ: −116.5, −65.9. IR (KBr): 3443, 3342, 3210, 2955, 2245, 1699, 1577, 1476, 1163 cm−1. Anal. Calcd. for C19H16ClF4N3O3S Calc. C, 47.75; H, 3.37; N, 8.79; S, 6.71; F, 15.90; C, 7.41. Found: C, 47.95; H, 3.31; N, 8.67; S, 6.72; F, 15.59; Cl, 7.49. The batch was cooled to 15-20° C. the bottom aqueous phase was separated A solution of sodium phosphate monobasic (0.2 M in water, 20.66 L) was charged the bottom aqueous phase was separated (Note: If the pH is >6.5, an additional 20.66 L of 0.2 M sodium phosphate monobasic solution may be charged the extraction ) The solvent was then exchanged by a constant volume vacuum distillation the jacket was heated to 75-80° C Once distillation of ethyl acetate isopropanol (41.34 L) was added at the same rate of distillate collection the overall batch volume was maintained at a constant level Once all of the isopropanol was added water (13.76 L) was charged The batch temperature was maintained at approximately 50° C. during the water addition The batch was then cooled to 15-20° C. filtered The wet cake was washed with 50% (v/v) aqueous isopropanol (4×21.6 kg) dried under vacuum at 50° C.

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

Procedure: To a solution of (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (6.88 g, 20.0 mmol) and 4-(bromomethyl)-3-fluorobenzonitrile (6.43 g, 30 mmol) in DMF (35 mL) was added anhydrous Cs2CO3 (19.56 g, 60 mmol). The resulting mixture was stirred at room temperature for 45 min. and then diluted with EtOAc (200 mL), washed with water (100 mL×4) and dried over Na2SO4. The product was purified by Biotage (40+M column, 3% to 80% EtOAc in hexanes, 651 mL). The title compound was obtained as a white solid (6.50 g, 68.1% yield). 1H NMR (DMSO-d6, 400 MHz) δ 7.80-7.88 (m, 3H), 7.70-7.75 (m, 2H), 7.67 (d, 2H, J=8), 7.60 (s, 1H), 7.26 (s, 1H), 4.99 (d, 1H, J=16), 4.68 (d, 1H, J=16), 4.14 (t, 1H, J=8), 1.99-2.17 (m, 2H), 1.80-1.94 (m, 1H), 1.40-1.56 (m, 1H). LC/MS M+H 478.14, 94%. washed with water (100 mL×4) dried over Na2SO4 The product was purified by Biotage (40+M column, 3% to 80% EtOAc in hexanes, 651 mL)

Conditions: temp:72.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,2-Dichloroethane (151 kg) was charged to a suitable vessel along with 4-cyano-2-fluorotoluene (24 kg) and AIBN (2 kg). The mixture was heated to 70˜74° C. Once the batch temperature reached 70° C., N-bromosuccinimide (47.4 kg) was added in portions at the rate of 12 kg/h, maintaining the temperature at 70˜74° C. (it is important to control addition rate to avoid exothermic reaction). The mixture was sampled via GC detection after 24 kg of N-bromosuccinimide was added, and the reaction was heated at 70-74° C. until complete reaction was observed. The mixture was cooled to 0-5° C. and allowed to stand for 2 additional hours. The mixture was filtered, and the cake was washed with MTBE (24 kg). The filtrate was washed with water (3×65 kg). The organic layer was dried with sodium sulfate (10.3 kg) for 6 hours, filtered and the cake was washed with MTBE (24 kg). The solution was evaporated under reduced pressure, ethanol (12 kg) was added and the mixture was heated to 40-45° C., then cooled slowly to 0-5° C. while stirring to crystallize. The mixture was filtered and the cake was washed with cold ethanol (5 kg). The crude solid was recrystallized from petroleum ether, filtered and washed with petroleum ether (10 kg), giving the title compound 4-(bromomethyl)-3-fluorobenzonitrile as an off white solid (21 kg, 55% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.46-4.50 (m, 2H) 7.36 (dd, J=8.85, 1.32 Hz, 1H) 7.44 (dd, J7.91, 1.32 Hz, 1 H) 7.52 (dd, J7.91, 7.16 Hz, 1 H). 13C NMR (75 MHz, CDCl3) δ ppm 23.65 (d, J=4.60 Hz, 1 C) 113.76 (d, J=9.77 Hz, 1 C) 117.09 (d, J=2.87 Hz, 1 C) 119.44 (d, J=24.71 Hz, 1 C) 128.44 (d, J=4.02 Hz, 1 C) 130.66-130.81 (s, 1 C) 130.81-131.06 (s, 1 C) 132.18 (d, J=3.45 Hz, 1 C) 159.86 (d, J=254.03 Hz, 1C). IR: (KBr) 3088, 3077, 3040, 2982, 2250, 1571, 1508, 1439, 1248 cm−1. Anal. Calcd for C8H5BrFN: Calc. C, 44.89; H, 2.35; N, 6.54; F, 8.88. Found: C, 44.94; H, 2.73; N, 6.56; F, 8.73. The mixture was heated to 70˜74° C reached 70° C. maintaining the temperature at 70˜74° C. (it is important to control addition rate to avoid exothermic reaction) was added The mixture was cooled to 0-5° C. The mixture was filtered the cake was washed with MTBE (24 kg) The filtrate was washed with water (3×65 kg) The organic layer was dried with sodium sulfate (10.3 kg) for 6 hours filtered the cake was washed with MTBE (24 kg) The solution was evaporated under reduced pressure, ethanol (12 kg) was added the mixture was heated to 40-45° C. cooled slowly to 0-5° C. to crystallize The mixture was filtered the cake was washed with cold ethanol (5 kg) The crude solid was recrystallized from petroleum ether filtered washed with petroleum ether (10 kg)

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

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

Procedure: To a suspension of sodium hydride (2.62 g) in dimethylformamide (100 ml) at 0° C. was slowly added a solution of [(diphenylmethylidene)amino]acetonitrile (13.20 g) in 40 ml of dimethylformamide. The reaction temperature varied between 2 and 8° C. during the addition. The color went from yellow to brown with gas evolution. The reaction mixture was stirred at 0° C. for 10 more minutes then 4-(bromomethyl)-3-fluorobenzonitrile from step 1 (12.72 g) was added very quickly in 60 ml of dimethylformamide. The temperature rose to 27° C. and the cold bath was removed. The reaction was stirred for 4 h. The flask content was poured into sodium dihydrogen phosphate solution (300 ml) and icy water (1.4 L). The mixture turned yellow and a big lump formed along with very small amounts of fine powder. The fine solid was filtered and the lump kept in the Erlenmeyer. The lump was dissolved in ether (500 ml) and put in a separating funnel along with water (200 ml). The phases were separated and the organic layer was washed with brine (100 ml) and dried over magnesium sulfate. The organic phase is concentrated under reduced pressure to give 4-{2-cyano-2-[(diphenylmethylene)amino]ethyl}-3-fluorobenzonitrile an orange solid that was used as such in the next step. The reaction temperature varied between 2 and 8° C. during the addition rose to 27° C. the cold bath was removed The reaction was stirred for 4 h The flask content was poured into sodium dihydrogen phosphate solution (300 ml) and icy water (1.4 L) a big lump formed along with very small amounts of fine powder The fine solid was filtered The lump was dissolved in ether (500 ml) put in a separating funnel along with water (200 ml) The phases were separated the organic layer was washed with brine (100 ml) dried over magnesium sulfate The organic phase is concentrated under reduced pressure