benzyl (1R,2R)-2-methylcyclopropane-1-carboxylate

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

Procedure: Add trimethylaluminum (2 M in toluene, 3.59 g, 45.5 mmol) to a 0° C. solution of 3-(4-methoxyphenyl)-4-methylisothiazol-5-ylamine (10.0 g, 45.5 mmol) in dichloromethane (455 mL). Stir 5 min and add benzyl (R,R)-2-methylcyclopropane-carboxylate (8.64 g, 45.5 mmol). Heat to 50° C. with nitrogen flow to remove solvent. The resulting oil is heated at 50° C. for 3 h. Quench with water and dilute with EtOAc (300 mL). Wash with 0.1 N HCl, dry (K2CO3), evaporate, and crystallize from hexane/EtOAc to afford (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 80.4%. ES-MS: m/e 303.0 (m+1). (The mother liquor may be used for further recrystallizations.) to remove solvent The resulting oil is heated at 50° C. for 3 h Quench with water dilute with EtOAc (300 mL) Wash with 0.1 N HCl dry (K2CO3) evaporate crystallize from hexane/EtOAc

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

Procedure: Add trimethylaluminum (2 M in toluene, 3.59 g, 45.5 mmol) to a 0° C. solution of 3-(4-methoxyphenyl)-4-methylisothiazol-5-ylamine (10.0 g, 45.5 mmol) in dichloromethane (455 mL). Stir 5 min and add benzyl (R,R)-2-methylcyclopropane-carboxylate (8.64 g, 45.5 mmol). Heat to 50° C. with nitrogen flow to remove solvent. The resulting oil is heated at 50° C. for 3 h. Quench with water and dilute with EtOAc (300 mL). Wash with 0.1 N HCl, dry (K2CO3), evaporate, and crystallize from hexane/EtOAc to afford (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 80.4%. ES-MS: m/e 303.0 (m+1). (The mother liquor may be used for further recrystallizations.) to remove solvent The resulting oil is heated at 50° C. for 3 h Quench with water dilute with EtOAc (300 mL) Wash with 0.1 N HCl dry (K2CO3) evaporate crystallize from hexane/EtOAc

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

Procedure: Mix 3-[4-(1,1-difluoroethyl)phenyl]isothiazol-5-ylamine (0.200 g, 0.833 mmol), benzyl (R,R)-2-methylcyclopropanecarboxylate (0.238 g, 1.250 mmol) and potassium t-butoxide (0.190 g, 1.667 mmol) for 1 h. Dilute with satd NaHCO3 and extract with EtOAc. Wash the organic phase with brine, dry (MgSO4) and evaporate. Chromatography on silica gel, eluting with 10% EtOAc in CHCl3, affords (R,R)—N-[3-[4-(1,1-difluoroethyl)phenyl]isothiazol-5-yl]-2-methylcyclopropane-carboxamide. Yield: 50.3%. ES-MS: m/e 323.3 (m+1). extract with EtOAc Wash the organic phase with brine dry (MgSO4) evaporate Chromatography on silica gel, eluting with 10% EtOAc in CHCl3

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

Procedure: Add benzyl (R,R)-2-methylcyclopropanecarboxylate (0.55 g, 2.89 mmol) to a 0° C. solution of 3-(3-fluoro-4-methoxyphenyl)isothiazol-5-ylamine (0.59 g, 2.63 mmol) and trimethylaluminum (2.0 M in toluene, 5.26 mmol) in dichloromethane (5 mL) and allow reaction to naturally warm to room temperature. Warm the reaction mixture to 40° C. and allow to stir overnight. Dilute the reaction mixture with EtOAc (100 mL) and 1 N HCl (40 mL) and water (100 mL), collect the organic phase, and evaporate. Chromatography over silica gel eluting with 25-50% EtOAc in hexane affords (R,R)—N-[3-(3-fluoro-4-methoxyphenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide. Yield: 55.9%. ES-MS: m/e 307.0 (m+1). reaction Warm the reaction mixture to 40° C. collect the organic phase evaporate

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

Procedure: Add benzyl (R,R)-2-methylcyclopropanecarboxylate (0.55 g, 2.89 mmol) to a 0° C. solution of 3-(3-fluoro-4-methoxyphenyl)isothiazol-5-ylamine (0.59 g, 2.63 mmol) and trimethylaluminum (2.0 M in toluene, 5.26 mmol) in dichloromethane (5 mL) and allow reaction to naturally warm to room temperature. Warm the reaction mixture to 40° C. and allow to stir overnight. Dilute the reaction mixture with EtOAc (100 mL) and 1 N HCl (40 mL) and water (100 mL), collect the organic phase, and evaporate. Chromatography over silica gel eluting with 25-50% EtOAc in hexane affords (R,R)—N-[3-(3-fluoro-4-methoxyphenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide. Yield: 55.9%. ES-MS: m/e 307.0 (m+1). reaction Warm the reaction mixture to 40° C. collect the organic phase evaporate

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

Procedure: To a stirred suspension of 3-(4-methoxyphenyl)isothiazol-5-ylamine (5.0 g, 24.3 mmol) in anhydrous dichloromethane (230 mL), cooled to 0-5° C., is added trimethylaluminum (2.0 M in toluene, 12.1 mL, 24.2 mmol) by syringe. The solution is stirred 5 min, and benzyl (R,R)-2-methylcyclopropanecarboxylate (4.6 g, 24.21 mmol) is added with the aid of anhydrous dichloromethane (10 mL). The mixture is then warmed to 40-45° C. with N2 flow (needle bleed valve) to slowly remove solvent. After 2 h, most of the dichloromethane has been removed, and the internal temperature rises to about 50° C. The solution is stirred further for 3 h, cooled, and quenched cautiously with dropwise addition of water followed by 0.1 N HCl under a good N2 stream. The resulting residue is then partitioned between ethyl acetate (400 mL) and 0.1 N HCl (400 mL). The organic layer is dried over potassium carbonate, filtered, and evaporated to a low volume. The resulting suspension is diluted with hexanes and the solid filtered to afford 5.9 g of crude product which is re-suspended in MTBE (100 mL), warmed to mild reflux for 1 h, and cooled to room temperature. After standing 1 h, the solid was filtered and dried (20 mm Hg, 40° C.) to afford (R,R)—N-[3-(4-methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide (5.2 g, 75%). 1H NMR (DMSO-d6) 7.86 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 3.78 (s, 3H), 1.62 (m, 1H), 1.34 (m, 1H), 1.10 (d, J=6.0 Hz, 3H), 1.09 (m, 1H), 0.80 (m, 1H); ES-MS m/e 289 (m+H). After 2 h most of the dichloromethane has been removed rises to about 50° C The solution is stirred further for 3 h cooled quenched cautiously with dropwise addition of water The resulting residue is then partitioned between ethyl acetate (400 mL) and 0.1 N HCl (400 mL) The organic layer is dried over potassium carbonate filtered evaporated to a low volume The resulting suspension is diluted with hexanes the solid filtered to afford 5.9 g of crude product which warmed to mild reflux for 1 h cooled to room temperature After standing 1 h the solid was filtered dried (20 mm Hg, 40° C.)

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

Procedure: To a stirred suspension of 3-(4-methoxyphenyl)isothiazol-5-ylamine (5.0 g, 24.3 mmol) in anhydrous dichloromethane (230 mL), cooled to 0-5° C., is added trimethylaluminum (2.0 M in toluene, 12.1 mL, 24.2 mmol) by syringe. The solution is stirred 5 min, and benzyl (R,R)-2-methylcyclopropanecarboxylate (4.6 g, 24.21 mmol) is added with the aid of anhydrous dichloromethane (10 mL). The mixture is then warmed to 40-45° C. with N2 flow (needle bleed valve) to slowly remove solvent. After 2 h, most of the dichloromethane has been removed, and the internal temperature rises to about 50° C. The solution is stirred further for 3 h, cooled, and quenched cautiously with dropwise addition of water followed by 0.1 N HCl under a good N2 stream. The resulting residue is then partitioned between ethyl acetate (400 mL) and 0.1 N HCl (400 mL). The organic layer is dried over potassium carbonate, filtered, and evaporated to a low volume. The resulting suspension is diluted with hexanes and the solid filtered to afford 5.9 g of crude product which is re-suspended in MTBE (100 mL), warmed to mild reflux for 1 h, and cooled to room temperature. After standing 1 h, the solid was filtered and dried (20 mm Hg, 40° C.) to afford (R,R)—N-[3-(4-methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide (5.2 g, 75%). 1H NMR (DMSO-d6) 7.86 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 3.78 (s, 3H), 1.62 (m, 1H), 1.34 (m, 1H), 1.10 (d, J=6.0 Hz, 3H), 1.09 (m, 1H), 0.80 (m, 1H); ES-MS m/e 289 (m+H). After 2 h most of the dichloromethane has been removed rises to about 50° C The solution is stirred further for 3 h cooled quenched cautiously with dropwise addition of water The resulting residue is then partitioned between ethyl acetate (400 mL) and 0.1 N HCl (400 mL) The organic layer is dried over potassium carbonate filtered evaporated to a low volume The resulting suspension is diluted with hexanes the solid filtered to afford 5.9 g of crude product which warmed to mild reflux for 1 h cooled to room temperature After standing 1 h the solid was filtered dried (20 mm Hg, 40° C.)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-methylcyclopropanecarboxylic acid (commercial product which is a cis-trans mixture, 75.0 g, 0.75 mol) and 1 N NaOH (900 mL, 0.90 mol) is warmed and stirred at 45° C. To the stirring solution is added benzyl bromide (131.0 mL, 1.10 mol) and methyltrialkyl(C8-C10)ammonium chloride (Adogen™ 464, 37.5 g). The mixture is stirred at 40-45° C. for 4 h, cooled to room temperature, and extracted with ethyl ether (800 mL). The organic layer is dried (MgSO4) and evaporated to a liquid. Chromatography over silica gel, eluting with hexanes gradually increasing to 5% ethyl acetate in hexanes, provides the racemic benzyl trans-2-methylcyclopropanecarboxylate as a liquid (132.2 g, 93%); 1H NMR (DMSO-d6) δ 7.40 (m, 5H), 5.05 (s, 2H), 1.43 (m, 1H), 1.30 (m, 1H), 1.06 (d, J=6.0 Hz, 3H), 1.02 (m, 2H), 0.74 (m, 1H). [Note: If NMR reveals the presence of a minor amount of cis isomer, it is removable by the chiral HPLC separation which may be carried out as described above.] is warmed The mixture is stirred at 40-45° C. for 4 h cooled to room temperature extracted with ethyl ether (800 mL) The organic layer is dried (MgSO4) evaporated to a liquid Chromatography over silica gel, eluting with hexanes gradually increasing to 5% ethyl acetate in hexanes

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

Procedure: A 2.0 M oxalyl chloride in dichloromethane solution is prepared by adding with stirring 98% oxalyl chloride (110.0 mL) to anhydrous dichloromethane (600.0 mL). The resulting solution of oxalyl chloride (1.20 mol) is added dropwise over 1 h to a stirring solution of 2-methylcyclopropanecarboxylic acid (commercially available product which is a cis-trans mixture, 120.0 g, 1.20 mol) in toluene (800.0 mL) containing DMF (0.6 mL, 7.8 mmol). The mixture is stirred 2 h at room temperature; then it is added dropwise to a solution of benzyl alcohol (114.0 mL, 1.10 mol), anhydrous THF (800.0 mL), and pyridine (194.0 mL, 2.41 mol) over 1.5 h. The mixture is stirred 1 h longer after addition, partitioned between ethyl acetate (2 L) and 10% aqueous potassium carbonate (2 L); and the organic phase is washed (10% aqueous potassium carbonate (2 L) and brine (2 L)), dried (MgSO4) and evaporated to a liquid. Chromatography over silica gel, eluting with 5% ethyl acetate in hexanes, provides the major product, racemic benzyl trans-2-methyl-cyclopropanecarboxylate as a clear, colorless liquid (193.8 g, 93%). by adding The mixture is stirred 1 h longer after addition partitioned between ethyl acetate (2 L) and 10% aqueous potassium carbonate (2 L) and the organic phase is washed (10% aqueous potassium carbonate (2 L) and brine (2 L)) dried (MgSO4) evaporated to a liquid Chromatography over silica gel, eluting with 5% ethyl acetate in hexanes

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

Procedure: A 2.0 M oxalyl chloride in dichloromethane solution is prepared by adding with stirring 98% oxalyl chloride (110.0 mL) to anhydrous dichloromethane (600.0 mL). The resulting solution of oxalyl chloride (1.20 mol) is added dropwise over 1 h to a stirring solution of 2-methylcyclopropanecarboxylic acid (commercially available product which is a cis-trans mixture, 120.0 g, 1.20 mol) in toluene (800.0 mL) containing DMF (0.6 mL, 7.8 mmol). The mixture is stirred 2 h at room temperature; then it is added dropwise to a solution of benzyl alcohol (114.0 mL, 1.10 mol), anhydrous THF (800.0 mL), and pyridine (194.0 mL, 2.41 mol) over 1.5 h. The mixture is stirred 1 h longer after addition, partitioned between ethyl acetate (2 L) and 10% aqueous potassium carbonate (2 L); and the organic phase is washed (10% aqueous potassium carbonate (2 L) and brine (2 L)), dried (MgSO4) and evaporated to a liquid. Chromatography over silica gel, eluting with 5% ethyl acetate in hexanes, provides the major product, racemic benzyl trans-2-methyl-cyclopropanecarboxylate as a clear, colorless liquid (193.8 g, 93%). by adding The mixture is stirred 1 h longer after addition partitioned between ethyl acetate (2 L) and 10% aqueous potassium carbonate (2 L) and the organic phase is washed (10% aqueous potassium carbonate (2 L) and brine (2 L)) dried (MgSO4) evaporated to a liquid Chromatography over silica gel, eluting with 5% ethyl acetate in hexanes