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Step i :To a solution of 53a (10.0 g, 48.3 mmol) in acetic acid (150 ml.) at RT is added iron (10.8 g, 193 mmol) and the reaction mixture is stirred at 700C for 2 h. The cooled reaction mixture is filtered and the filtate concentrated under vacuum. The residue diluted with EtOAc (300 mL) is washed with water (100 ml_), brine (100 ml_), dried over MgSO4, filtered and concentrated under vacuum to give 53b as a yellow solid (8.8 g, 100percent yield). This material is used in the next step without further purification.
72%
at 100℃;
Step i :Zn dust (7.89 g, 121 mmol) is added to a solution of 17a (5.0 g, 24 mmol) in AcOH (100 mL). The reaction mixture is then heated to 1000C and is stirred overnight. The reaction is cooled to RT and the mixture is filtered (EtOAc washing), the solvent is evaporated and the residue purified by CombiFlash.(R). Companion to afford aniline 17b (3.06 g, 72percent yield) as a yellow solid.
72%
at 100℃;
Zn dust (7.89 g, 121 mmol) is added to a solution of 17a (5.0 g, 24 mmol) in AcOH (100 ml_). The reaction mixture is then heated to 1000C and is stirred overnight. The reaction is cooled to RT and the mixture is filtered (EtOAc washing), the solvent is evaporated and the residue purified by CombiFlash.(R). Companion to afford aniline 17b (3.06 g, 72percent yield) as a yellow solid.
72%
at 100℃;
Zn dust (7 89 g, 121 mmol) is added to a solution of 17a (5 0 g, 24 mmol) in AcOH (10O mL) The reaction mixture is then heated to 10O0C and is stirred overnight The reaction is cooled to RT and the mixture is filtered (EtOAc washing), the solvent is evaporated and the residue purified by CombiFlash.(R). Companion to afford aniline 17b (3 06 g, 72percent yield) as a yellow solid
72%
at 100℃;
Zn dust (7.89 g, 121 mmol) is added to a solution of 17a (5.0 g, 24 mmol) in AcOH (100 mL). The reaction mixture is then heated to 1000C and is stirred overnight. The reaction is cooled to RT and the mixture is filtered (EtOAc washing), the solvent is <n="91"/>evaporated and the residue purified by CombiFlash.(R). Companion (30percent EtOAc/hexanes) to afford aniline 17b (3.06 g, 72percent yield) as a yellow solid.
With iron; acetic acid; at 70℃; for 2h;Product distribution / selectivity;
Step i :To a solution of 53a (10.0 g, 48.3 mmol) in acetic acid (150 ml.) at RT is added iron (10.8 g, 193 mmol) and the reaction mixture is stirred at 700C for 2 h. The cooled reaction mixture is filtered and the filtate concentrated under vacuum. The residue diluted with EtOAc (300 mL) is washed with water (100 ml_), brine (100 ml_), dried over MgSO4, filtered and concentrated under vacuum to give 53b as a yellow solid (8.8 g, 100% yield). This material is used in the next step without further purification.
72%
With acetic acid; zinc; at 100℃;Product distribution / selectivity;
Step i :Zn dust (7.89 g, 121 mmol) is added to a solution of 17a (5.0 g, 24 mmol) in AcOH (100 mL). The reaction mixture is then heated to 1000C and is stirred overnight. The reaction is cooled to RT and the mixture is filtered (EtOAc washing), the solvent is evaporated and the residue purified by CombiFlash Companion to afford aniline 17b (3.06 g, 72% yield) as a yellow solid.
72%
With acetic acid; zinc; at 100℃;
Zn dust (7.89 g, 121 mmol) is added to a solution of 17a (5.0 g, 24 mmol) in AcOH (100 ml_). The reaction mixture is then heated to 1000C and is stirred overnight. The reaction is cooled to RT and the mixture is filtered (EtOAc washing), the solvent is evaporated and the residue purified by CombiFlash Companion to afford aniline 17b (3.06 g, 72% yield) as a yellow solid.
72%
With acetic acid; zinc; at 100℃;
Zn dust (7 89 g, 121 mmol) is added to a solution of 17a (5 0 g, 24 mmol) in AcOH (10O mL) The reaction mixture is then heated to 10O0C and is stirred overnight The reaction is cooled to RT and the mixture is filtered (EtOAc washing), the solvent is evaporated and the residue purified by CombiFlash Companion to afford aniline 17b (3 06 g, 72% yield) as a yellow solid
72%
With acetic acid; zinc; at 100℃;
Zn dust (7.89 g, 121 mmol) is added to a solution of 17a (5.0 g, 24 mmol) in AcOH (100 mL). The reaction mixture is then heated to 1000C and is stirred overnight. The reaction is cooled to RT and the mixture is filtered (EtOAc washing), the solvent is <n="91"/>evaporated and the residue purified by CombiFlash Companion (30% EtOAc/hexanes) to afford aniline 17b (3.06 g, 72% yield) as a yellow solid.
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 5h;
Step 2:To a solution of aniline 53b (8.8 g, 49.7 mmol) and diethylphosphonoacetic acid (8.8 mL, 54.6 mmol) in DCM (300 mL) is added HATU (22.7 g, 59.6 mmol) followed by DIPEA (21.6 mL, 124 mmol). The reaction mixture is stirred at RT for 3 h. After that period, the transformation is incomplete, therefore, more diethylphosphonoacetic acid (4.0 mL, 24.9 mmol), HATU (9.4 g, 24.9 mmol) and DIPEA (4.3 mL, 24.9 mmol) are added. The mixture is stirred for another 2 h. The mixture is diluted with DCM (300 mL), washed with aqueous 0.2N HCI (3 x 100 mL), aqueous 0.2N NaOH (3 x100 mL), water (100 mL) and brine (100 mL). The organic phase is dried over <n="115"/>MgSO4, filtered and concentrated under vacuum. The residue is dried under vacuum overnight to give the desired product 53c as a pale orange solid (16.0 g, 60% yield). This material is used in the next step without further purification.
Step 2:A solution of NaNO2 (640 mg, 9.3 mmol) in water (3 mL) is slowly added to a solution of aniline 17b (1.5 g, 8.5 mmol) dissolved in AcOH (12 mL) and 2 M HCI (25 mL) at O0C. The resulting mixture is stirred at this temperature for 1 h. Solid CuCI (2.6 g, 26 mmol) is added portionwise (over 2 min) and the reaction is allowed to come to RT, <n="78"/>is then stirred for 30 min and then is warmed to 6O0C for 40 min. The mixture is poured into water (100 mL) and extracted with EtOAc (2 x 100 ml_). The organic layer is dried with MgSO4, filtered and evaporated to dryness. The product is purified by CombiFlash Companion to afford aryl chloride 17c (1.11 g, 99% yield) as a pale yellow solid.
99%
A solution of NaNO2 (640 mg, 9.3 mmol) in water (3 ml.) is slowly added to a solution of aniline 17b (1.5 g, 8.5 mmol) dissolved in AcOH (12 mL) and 2 M HCI (25 mL) at O0C. The resulting mixture is stirred at this temperature for about 1 h. Solid CuCI (2.6 g, 26 mmol) is added portionwise (over about 2 min) and the reaction is allowed to come to RT, is then stirred for about 30 min and then is warmed to 6O0C for about 40 min. The mixture is poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer is dried with MgSO4, filtered and evaporated to dryness. The product is purified by CombiFlash Companion to afford aryl chloride 17c (1.11 g, 99% yield) as a pale yellow solid.
99%
A solution of NaNO2 (640 mg, 9 3 mmol) in water (3 mL) is slowly added to a solution of aniline 17b (1 5 g, 8 5 mmol) dissolved in AcOH (12 mL) and 2 M HCI (25 mL) at O0C The resulting mixture is stirred at this temperature for 1 h Solid CuCI (2 6 g, 26 mmol) is added portionwise (over 2 mm) and the reaction is allowed to come to RT, is then stirred for 30 mm and then is warmed to 6O0C for 40 mm The mixture is poured into water (100 mL) and extracted with EtOAc (2 x 100 mL) The organic layer is dried with MgSO4, filtered and evaporated to dryness The product is purified by CombiFlash Companion to afford aryl chloride 17c (1 1 1 g, 99% yield) as a pale yellow solid
99%
A solution of NaNO2 (640 mg, 9.3 mmol) in water (3 ml_) is slowly added to a solution of aniline 17b (1.5 g, 8.5 mmol) dissolved in AcOH (12 mL) and 2 M HCI (25 m L) at O0C. The resulting mixture is stirred at this temperature for 1 h. Solid CuCI (2.6 g, 26 mmol) is added portionwise (over 2 min) and the reaction is allowed to come to RT, is then stirred for 30 min and then is warmed to 6O0C for 40 min. The mixture is poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer is dried with MgSO4, filtered and evaporated to dryness. The product is purified by CombiFlash Companion (40% EtOAc/hexanes) to afford aryl chloride 17c (1.11 g, 99% yield) as a pale yellow solid.
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