2-methylpropanethioamide

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

Procedure: The thioisobutyramide resulting from Example 24A was dissolved in 70 mls THF and added slowly to a solution of (34.1 g, 0.27 mols) 1,3-dichloracetone in 40 mls THF. A 10 ml rinse of THF was used to completely transfer the thioamide. The reaction was carried out in a 250 ml flask with mechanical stirring under nitrogen atmosphere. The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath. The bath was kept in place for 1 hour after which it was removed and the reaction stirred for 18 hours. Next this stirred chloromethyl-thiazole solution was added to 376 mls (4.37 mols) 40% aqueous methylamine solution at 15° C. in a 1 liter flask. The temperature was maintained below 25° C. during addition. After half an hour the bath was removed and the reaction stirred for 3 hours at ambient temperature. The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls. The residue was then basilled with 50 g 10% NaOH to pH 12 and extracted into methylene chloride (2×160 mls). The combined organics were then washed with 1×150 g of 20% ammonium chloride followed by 1×90 g of 20% ammonium chloride. The combined aqueous washes were then back extracted with 150 mls methylene chloride. The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water. This acidic product solution was then washed with 135 mls methylene chloride. Next the acidic product solution was cooled, then neutralized with 100 g 20% NaOH solution. The product was extracted from this mixture with methylene chloride (2×135 mls). The solvent was removed under vacuum to afford the desired product as an amber oil. (yield approx. 28 grams) A 10 ml rinse of THF The reaction was carried out in a 250 ml flask The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath after which it was removed the reaction stirred for 18 hours The temperature was maintained below 25° C. during addition After half an hour the bath was removed the reaction stirred for 3 hours at ambient temperature The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls extracted into methylene chloride (2×160 mls) The combined organics were then washed with 1×150 g of 20% ammonium chloride The combined aqueous washes were then back extracted with 150 mls methylene chloride The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water This acidic product solution was then washed with 135 mls methylene chloride Next the acidic product solution was cooled The product was extracted from this mixture with methylene chloride (2×135 mls) The solvent was removed under vacuum

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

Procedure: Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-4-fluorophenyl}carbamate (20 g, 57.3 mmol), NBS (10.2 g, 57.3 mmol) and 2-methylpropanethioamide (7.4 g, 63 mmol) the title compound of Step C was obtained (11 g, 44.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.90-9.98 (br, 1H), 8.61 (d, J=5.3 Hz, 1H), 7.65-7.72 (m, 1H), 7.49-7.54 (m, 1H), 7.21-7.30 (m, 1H), 7.10 (d, J=5.3 Hz, 1H), 5.90-6.05 (m, 1H), 5.20-5.40 (m, 2H), 4.58-4.63 (m, 2H), 1.47 (s, 9H).

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

Procedure: To a solution of methyl 5-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (21 g, 60.8 mmol) in dry THF (250 mL) at −10° C., LIHMDS (1M in THF, 213 mmol, 213 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of pyrimidine chloride (9.3 g, 73 mmol) in THF (50 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (200 mL) at 0° C. The reaction mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flush column on silica gel, rinsing with DCM. This solution was concentrated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-4-fluorophenyl)-2,6-difluorobenzenesulfonamide (13 g, 50.5%). N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-4-fluorophenyl)-2,6-difluorobenzenesulfonamide (13 g) was diluted in DMA (150 mL). NBS (5.5 g, 30.7 mmol) was added and the reaction mixture was stirred at rt for 1 h. Then 2-methylpropanethioamide (4.8 g, 33.8 mmol) was added at 0° C. The mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound of Step C (7.5 g, 22% yield over 2 steps). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (d, J=5.5 Hz, 1H), 7.48-7.56 (m, 1H), 7.40-7.48 (br, 1H), 7.26-7.38 (m, 2H), 7.07-7.14 (m, 1H), 6.92-7.04 (m, 2H), 6.51 (d, J=5.5 Hz, 1H), 3.80-3.88 (m, 4H), 3.58-3.65 (m, 4H), m/z (ES+): 468 [M+H]+. The mixture was stirred at rt for 2 h extracted with EtOAc (500 mL×3) The combined organic layers were washed with water and brine successively dried over Na2SO4 filtered concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1)

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

Procedure: To a solution of 2-propen-1-yl [3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate (15.4 g, 42 mmol) in DCM (150 mL), NBS (7.6 g, 42 mmol) was added and the solution was allowed to stir at rt for 30 min. The reaction mixture was then concentrated in vacuo and the resulting oil was diluted with DMSO (150 mL) and 2-methylpropanethioamide (6.6 g 63.8 mmol) was added at once. The reaction was complete after stirring 1 h at rt. The reaction mixture was diluted with EtOAc and organic layer was washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound of Step F (12.1 g, 63.8% yield) which was used directly in the next step. The reaction mixture was then concentrated in vacuo was added at once after stirring 1 h at rt was washed with water and brine successively dried over Na2SO4 filtered concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1)

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

Procedure: To a solution of N-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1.0 g, 2.3 mmol) in DMF (10 mL) was added NBS (0.49 g, 2.8 mmol). After stirring for 45 min at rt, 2-methylpropanethioamide (0.35 g, 3.4 mmol), was added and the reaction was stirred at rt. After 4 h, the reaction mixture was partitioned between ether and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over anhydrous NaSCO4, filtered, and concentrated to generate 0.49 g (41% yield) as a yellow powder. MS (ESI) 525 (M+H). the reaction was stirred at rt After 4 h the reaction mixture was partitioned between ether and saturated aqueous NaHCO3 The organic layer was washed with brine dried over anhydrous NaSCO4 filtered concentrated

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

Procedure: In a 250 mL flask was placed N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (4 g, 9.05 mmol) and DMF (60 mL) was added. NBS (1.62 g, 9.10 mmol) was added and, after stirring at rt for 40 min, 2-methylpropanethioamide (1.4 g, 13.6 mmol), prepared by a procedure analogous to Intermediate 1, was added. After 4 h at rt, the reaction mixture was poured into 800 mL of EtOAc and washed 4 times with 250 mL of H2O, washed once with 200 mL of brine, and dried over NaSO4. Silica gel was added and the volatiles were removed under reduced pressure. Column chromatography with 10% to 60% EtOAc:Hexane gave 2.15 g (45%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.06 (d, J=5.3 Hz, 1H), 8.12-8.30 (m, 1H), 7.93-8.06 (m, 2H), 7.84 (t, J=7.9 Hz, 1H), 7.75 (t, J=9.2 Hz, 2H), 7.37 (d, J=5.3 Hz, 1H), 3.77-3.93 (m, 1H), and 1.89 (d, J=6.8 Hz, 6H). MS (ESI): 524 [M]+. In a 250 mL flask was placed was added After 4 h at rt washed 4 times with 250 mL of H2O washed once with 200 mL of brine dried over NaSO4 Silica gel was added the volatiles were removed under reduced pressure

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

Procedure: Following a procedure analogous to the procedure described in Intermediate 6, using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate (10.0 g, 30.14 mmol), and 2-methylpropanethioamide (3.73 g, 36.17 mmol), prepared by a procedure analogous to Intermediate 1, 5.74 g of the title compound was obtained. MS (ESI): 415 [M+H]+.

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

Procedure: The thioisobutyramide resulting from Example 73A was dissolved in 70 mls THF and added slowly to a solution of (34.1 g, 27 mols) 1,3-dichloracetone in 40 mls THF. A 10 ml rinse of THF was used to completely transfer the thioamide. The reaction was carried out in a 250 ml flask with mechanical stirring under nitrogen atmosphere. The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath. The bath was kept in place for 1 hour after which it was removed and the reaction stirred for 18 hours. Next this stirred chloromethyl-thiazole solution was added to 376 mls (4.37 mols) 40% aqueous methylamine solution at 15° C. in a 1 liter flask. The temperature was maintained below 25° C. during addition. After half an hour the bath was removed and the reaction stirred for 3 hours at ambient temperature. The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls. The residue was then basified with 50 g 10% NaOH to pH 12 and extracted into methylene chloride (2×160 mls). The combined organics were then washed with 1×150 g of 20% ammonium chloride followed by 1×90 g of 20% ammonium chloride. The combined aqueous washes were then back extracted with 150 mls methylene chloride. The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water. This acidic product solution was then washed with 135 mls methylene chloride. Next the acidic product solution was cooled, then neutralized with 100 g 20% NaOH solution. The product was extracted from this mixture with methylene chloride (2×135 mls). The solvent was removed under vacuum to afford the desired product as an amber oil. (yield approx. 28 grams) A 10 ml rinse of THF The reaction was carried out in a 250 ml flask The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath after which it was removed the reaction stirred for 18 hours The temperature was maintained below 25° C. during addition After half an hour the bath was removed the reaction stirred for 3 hours at ambient temperature The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls extracted into methylene chloride (2×160 mls) The combined organics were then washed with 1×150 g of 20% ammonium chloride The combined aqueous washes were then back extracted with 150 mls methylene chloride The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water This acidic product solution was then washed with 135 mls methylene chloride Next the acidic product solution was cooled The product was extracted from this mixture with methylene chloride (2×135 mls) The solvent was removed under vacuum

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

Procedure: Using the procedure of Example 1J but replacing thioformamide with 2-methylpropane-thioamide provided, after silica gel chromatography using 9:1 ethyl acetate:hexane, the desired compound, Rf 0.8, (5% methanol in chloroform) in 83% yield. provided

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

Procedure: The thioisobutyramide resulting from Example 73A was dissolved in 70 mls THF and added slowly to a solution of (34.1 g, 0.27 mols) 1,3-dichloracetone in 40 mls THF. A 10 ml rinse of THF was used to completely transfer the thioamide. The reaction was carried out in a 250 ml flask with mechanical stirring under nitrogen atmosphere. The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath. The bath was kept in place for 1 hour after which it was removed and the reaction stirred for 18 hours. Next this stirred chloromethyl-thiazole solution was added to 376 mls (4.37 mols) 40% aqueous methylamine solution at 15° C. in a 1 liter flask. The temperature was maintained below 25° C. during addition. After half an hour the bath was removed and the reaction stirred for 3 hours at ambient temperature. The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls. The residue was then basified with 50 g 10% NaOH to pH 12 and extracted into methylene chloride (2×160 mls). The combined organics were then washed with 1×150 g of 20% ammonium chloride followed by 1×90 g of 20% ammonium chloride. The combined aqueous washes were then back extracted with 150 mls methylene chloride. The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water. This acidic product solution was then washed with 135 mls methylene chloride. Next the acidic product solution was cooled, then neutralized with 100 g 20% NaOH solution. The product was extracted from this mixture with methylene chloride (2×135 mls). The solvent was removed under vacuum to afford the desired product as an amber oil. (yield approx. 28 grams) A 10 ml rinse of THF The reaction was carried out in a 250 ml flask The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath after which it was removed the reaction stirred for 18 hours The temperature was maintained below 25° C. during addition After half an hour the bath was removed the reaction stirred for 3 hours at ambient temperature The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls extracted into methylene chloride (2×160 mls) The combined organics were then washed with 1×150 g of 20% ammonium chloride The combined aqueous washes were then back extracted with 150 mls methylene chloride The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water This acidic product solution was then washed with 135 mls methylene chloride Next the acidic product solution was cooled The product was extracted from this mixture with methylene chloride (2×135 mls) The solvent was removed under vacuum

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

Procedure: The thioisobutyramide resulting from Example 73A was dissolved in 70 mls THF and added slowly to a solution of (34.1 g, 0.27 mols) 1,3-dichloracetone in 40 mls THF. A 10 ml rinse of THF was used to completely transfer the thioamide. The reaction was carried out in a 250 ml flask with mechanical stirring under nitrogen atmosphere. The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath. The bath was kept in place for 1 hour after which it was removed and the reaction stirred for 18 hours. Next this stirred chloromethyl-thiazole solution was added to 376 mls (4.37 mols) 40% aqueous methylamine solution at 15° C. in a 1 liter flask. The temperature was maintained below 25° C. during addition. After half an hour the bath was removed and the reaction stirred for 3 hours at ambient temperature. The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls. The residue was then basified with 50 g 10% NaOH to pH 12 and extracted into methylene chloride (2×160 mls). The combined organics were then washed with 1×150 g of 20% ammonium chloride followed by 1×90 g of 20% ammonium chloride. The combined aqueous washes were then back extracted with 150 mls methylene chloride. The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water. This acidic product solution was then washed with 135 mls methylene chloride. Next the acidic product solution was cooled, then neutralized with 100 g 20% NaOH solution. The product was extracted from this mixture with methylene chloride (2×135 mls). The solvent was removed under vacuum to afford the desired product as an amber oil. (yield approx. 28 grams) A 10 ml rinse of THF The reaction was carried out in a 250 ml flask The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath after which it was removed the reaction stirred for 18 hours The temperature was maintained below 25° C. during addition After half an hour the bath was removed the reaction stirred for 3 hours at ambient temperature The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls extracted into methylene chloride (2×160 mls) The combined organics were then washed with 1×150 g of 20% ammonium chloride The combined aqueous washes were then back extracted with 150 mls methylene chloride The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water This acidic product solution was then washed with 135 mls methylene chloride Next the acidic product solution was cooled The product was extracted from this mixture with methylene chloride (2×135 mls) The solvent was removed under vacuum

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

Procedure: The thioisobutyramide resulting from Example 73A was dissolved in 70 mls THF and added slowly to a solution of (34.1 g, 0.27 mols) 1,3-dichloracetone in 40 mls THF. A 10 ml rinse of THF was used to completely transfer the thioamide. The reaction was carried out in a 250 ml flask with mechanical stirring under nitrogen atmosphere. The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath. The bath was kept in place for 1 hour after which it was removed and the reaction stirred for 18 hours. Next this stirred chloromethyl-thiazole solution was added to 376 mls (4.37 mols) 40% aqueous methylamine solution at 15° C. in a 1 liter flask. The temperature was maintained below 25° C. during addition. After half an hour the bath was removed and the reaction stirred for 3 hours at ambient temperature. The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls. The residue was then basified with 50 g 10% NaOH to pH 12 and extracted into methylene chloride (2×160 mls). The combined organics were then washed with 1×150 g of 20% ammonium chloride followed by 1×90 g of 20% ammonium chloride. The combined aqueous washes were then back extracted with 150 mls methylene chloride. The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water. This acidic product solution was then washed with 135 mls methylene chloride. Next the acidic product solution was cooled, then neutralized with 100 g 20% NaOH solution. The product was extracted from this mixture with methylene chloride (2×135 mls). The solvent was removed under vacuum to afford the desired product as an amber oil. (yield approx. 28 grams) A 10 ml rinse of THF The reaction was carried out in a 250 ml flask The reaction temperature was maintained below 25° C. during addition with a 15°±5° C. bath after which it was removed the reaction stirred for 18 hours The temperature was maintained below 25° C. during addition After half an hour the bath was removed the reaction stirred for 3 hours at ambient temperature The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls extracted into methylene chloride (2×160 mls) The combined organics were then washed with 1×150 g of 20% ammonium chloride The combined aqueous washes were then back extracted with 150 mls methylene chloride The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water This acidic product solution was then washed with 135 mls methylene chloride Next the acidic product solution was cooled The product was extracted from this mixture with methylene chloride (2×135 mls) The solvent was removed under vacuum