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With PyBOP; triethylamine In tetrahydrofuran at 20℃; for 18h;
1
In a 250 mL round bottom flask was placed 3.0 g of 4-trifluoronicotinic acid (15.7 mmol, 1 eq) in 100 mL of THF. To this was added 5.3 mL (3.8 g, 37.7 mmol, 2.4 eq) of triethylamine and 9.8 g (18.8 mmol, 1.2 eq) of [PYBOP.] This was allowed to stir for 10 min at room temperature where 2.7 g of [MELDRUM'S] acid (18.8 mmol, 1.2 eq) was added and the reaction allowed stirring at room temperature overnight. (18 h) At this point, 30 mL of 1 M HCI (aq) was added and the reaction turned immediately from orange to purple. This was then heated at for 18 h gradually turning from purple to yellow. The reaction was then basified with saturated [NAHCO3] and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried, filtered, and evaporated. The residue was purified via BIOTAGE (35% EtOAc/Hex) to provide methyl [4-TRIFLUOROMETHYLNICOTINATE] 1.84 g (62%) of the desired product as a colorless oil. TLC Rf= 0.57 (50% EtOAc: Hex).
62%
Stage #1: 4-(trifluoromethyl)nicotinic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In tetrahydrofuran at 20℃; for 0.166667h;
Stage #2: cycl-isopropylidene malonate In tetrahydrofuran at 20℃;
Stage #3: With hydrogenchloride In tetrahydrofuran; water for 18h; Heating / reflux;
Preparation of 2-chloro-1-f4-(trifluoromethyl)-3-nvridinyllethanone hvdrochloride; Step 1 :; In a 250 mL round bottom flask was placed 3.0 g of 4-trifluoronicotinic acid (15.7 mmol, 1 eq) in 100 mL of THF. To this was added 5.3 mL (3.8 g, 37.7 mmol, 2.4 eq) of triethylamine and 9.8 g (18. 8 mmol, 1.2 eq) of PyBOP. This was allowed to stir for 10 min at room temperature where 2.7 g of Meldrum's acid (18.8 mmol, 1.2 eq) was added and the reaction allowed stirring at room temperature overnight. (18 h) At this point, 30 mL of 1 M HCI (aq) was added and the reaction turned immediately from orange to purple. This was then heated at for 18 h gradually turning from purple to yellow. The reaction was then basified with saturated NaHCO3 and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried, filtered, and evaporated. The residue was purified via BIOTAGE (35% EtOAc/Hex) to provide methyl 4-trifluoromethylnicotinate 1.84 g (62%) of the desired product as a colorless oil. TLC Rf= 0.57 (50% EtOAc: Hex).
2-chloro-1-[4-(trifluoromethyl)-3-pyridinyl]ethanone hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
Stage #1: C8H6F3NO With hydrogenchloride; N-chloro-succinimide In acetic acid for 18h;
Stage #2: With hydrogenchloride In diethyl ether; acetic acid
A-3.2
In a 100 mL flask was placed 1.84 G (9.7 MMOL, 1 eq) of methyl 4- TRIFLUOROMETHYLNICOTINATE in 25 mL of 1 M HCI in CH3COOH. To this was then added 1.3 G of NCS (9.7 MMOL, 1 eq) and the reaction allowed to stir overnight (18 h). The mixture was then transferred to a 500 mL Erlenmeyer flask and to this was added 300 mL of 2 M HCI in ET20 WITH stirring. This resulted in a white precipitate which was then filtered to provide 1.2 G (49%) of the desired 2-chloro-1- [4- (trifluoromethyl)-3-pyridinyl] ethanone hydrochloride as a white SOLID. H-NMR (DMSO-D6) å 9.21 (s, 1H), 9.02 (d, 1H), 7.94 (d, 1H), 5.19 (s, 2H).
49%
With hydrogenchloride; N-chloro-succinimide; acetic acid In water for 18h;
2
In a 100 mL flask was placed 1.84 g (9.7 mmol, 1 eq) of methyl 4- [TRIFLUOROMETHYLNICOTINATE] in 25 mL of 1 M HCI in CH3COOH. To this was then added 1.3 g of NCS (9.7 mmol, 1 eq) and the reaction allowed stirring overnight [(18H).] The mixture was then transferred to a 500 mL Erlenmeyer flask and to this was added 300 mL of 2 [M] HCI in [ET20] with stirring. This resulted in a white precipitate which was then filtered to provide 1.2 g (49%) of the desired 2-chloro-1- [4- (trifluoromethyl)-3- pyridinyl] ethanone hydrochloride as a white [SOLID. 1H-NMR (DMSO-D6) 6] 9.21 (s, 1H), 9.02 (d, [1H),] 7.94 (d, 1H), 5.19 (s, 2H).
49%
Stage #1: C8H6F3NO With hydrogenchloride; N-chloro-succinimide In acetic acid
Stage #2: With hydrogenchloride In diethyl ether; acetic acid
Step 2 :; In a 100 mL flask was placed 1.84 g (9.7 mmol, 1 eq) of methyl 4- trifluoromethylnicotinate in 25 mL of 1 M HCI in CH3COOH. To this was then added 1.3 g of NCS (9.7 mmol, 1 eq) and the reaction allowed stirring overnight (18h). The mixture was then transferred to a 500 mL Erlenmeyer flask and to this was added 300 mL of 2 M HCI in Et2O with stirring. This resulted in a white precipitate which was then filtered to provide 1.2 g (49%) of the desired 2-chloro-1- [4- (trifluoromethyl)-3- pyridinyl] ethanone hydrochloride as a white solid. 1H-NMR (DMSO-d6) 6 9.21 (s, 1H), 9.02 (d, 1H), 7.94 (d, 1H), 5.19 (s, 2H).
49%
Stage #1: C8H6F3NO With hydrogenchloride; N-chloro-succinimide In acetic acid
Stage #2: With hydrogenchloride In diethyl ether; acetic acid
5.2
Step 2. In a 100 mL flask was placed 1.84 g (9.7 mmol, 1 eq) of methyl 4-trifluoromethylnicotinate in 25 mL of 1 M HCl in CH3COOH. To this was then added 1.3 g of NCS (9.7 mmol, 1 eq) and the reaction allowed to stir overnight (18h).The mixture was then transferred to a 500 mL Erlenmeyer flask and to this was added 300 mL of 2 M HCl in Et2O with stirring. This resulted in a white precipitate which was then filtered to provide 1.2 g (49%) of the desired 2-chloro-l-[4-(trifluoromethyl)-3-pyridinyl]ethanone hydrochloride as a white solid. 1H-NMR (DMSO-J6) D 9.21 (s, IH), 9.02 (d, IH), 7.94 (d, IH), 5.19 (s, 2H).
Stage #1: 4-(trifluoromethyl)nicotinic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In tetrahydrofuran at 20℃; for 0.166667h;
Stage #2: cycl-isopropylidene malonate In tetrahydrofuran at 20℃; for 18h;
Stage #3: With hydrogenchloride; sodium hydrogencarbonate more than 3 stages;
A-3.1
In a 250 mL round bottom flask was placed 3.0 g of 4-trifluoronicotinic acid (15.7 mmol, 1 eq) in 100 mL of THF. To this was added 5.3 mL (3.8 g, 37.7 mmol, 2.4 eq) of triethylamine and 9.8 G (18.8 mmol, 1.2 eq) of PYBOP. This was allowed to stir for 10 min at room temperature where 2.7 g of Meldrum's acid (18.8 MMOL, 1.2 eq) was added and the reaction allowed to stir at room temperature overnight (18 h). At this point, 30 mL of 1 M HCI (aq) was added and the reaction turned immediately from orange to purple. This was then heated at for 18 h gradually turning from purple to yellow. The reaction was then basified with saturated NAHC03 AND extracted with EtOAc (3 x 200 mL). The combined organics were dried, filtered, and evaporated. The residue was purified via BIOTAGE (35% EtOAc/Hex) to provide methyl 4-TRIFLUOROMETHYINICOTINATE 1.84 G (62%) of the desired product as a colorless oil. TLC Rf= 0.57 (50% EtOAc: Hex).
62%
Stage #1: 4-(trifluoromethyl)nicotinic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In tetrahydrofuran at 20℃; for 0.166667h;
Stage #2: cycl-isopropylidene malonate In tetrahydrofuran at 20℃; for 18h;
Stage #3: With hydrogenchloride; water In tetrahydrofuran for 18h; Heating / reflux;
5.1
Step 1.In a 250 mL round bottom flask was placed 3.O g of 4-trifluoronicotinic acid (15.7 mmol, 1 eq) in 100 mL of THF. To this was added 5.3 mL (3.8 g, 37.7 mmol, 2.4 eq) of triethylamine and 9.8 g (18.8 mmol, 1.2 eq) of PyBOP. This was allowed to stir for 10 min at room temperature where 2.7 g of Meldrum's acid (18.8 mmol, 1.2 eq) was added and the reaction allowed to stir at room temperature overnight (18 h).At this point, 30 mL of IM HCl (aq) was added and the reaction turned immediately from orange to purple. This was then heated at for 18 h gradually turning from purple to yellow. The reaction was then basified with saturated NaHCO3 and extracted with EtOAc (3 x 200 mL). The combined organics were dried, filtered, and evaporated. The residue was purified via BIOTAGE (35% EtO Ac/Hex) to provide methyl 4-trifluoromethylnicotinate 1.84 g (62%) of the desired product as a colorless oil. TLC Rf = 0.57 (50%EtOAc:Hex).
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