2,3-DICHLORO-6-FLUOROBENZALDEHYDE

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

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

Procedure: A solution of 1.3M s-butyl lithium in cyclohexane (244 mL, 317 mmol) is added to a dry-ice/acetone cooled solution of TMEDA (34 g, 293 mmol) in THF (250 mL), maintaining the internal reaction temperature <-70° C. The resulting reaction mixture is cooled and maintained at ≤-90° C. with an ether/liquid nitrogen bath while a solution of 1,2-dichloro-4-fluorobenzene (40 g, 244 mmol) in THF (100 mL) is added dropwise. The resulting reaction mixture is stirred with dry-ice/acetone cooling for 1h, then is cannulated into an ether/liquid nitrogen cooled and mechanically stirred solution of DMF (89.1 g, 1.22 mol) in THF (125 mL). The resulting mixture is warmed to -45° C. and partitioned between dilute aqueous HCl and ether. The organic solution is washed with aqueous NaHCO3, dried (MgSO4), and concentrated to afford 44.38 g of 2-fluoro-5,6-dichlorobenzaldehyde as an oil. maintaining the internal reaction temperature <-70° C The resulting reaction mixture is cooled is added dropwise The resulting reaction mixture cooled partitioned between dilute aqueous HCl and ether The organic solution is washed with aqueous NaHCO3 dried (MgSO4) concentrated

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

Procedure: Butyl lithium (48 ml of 1.6M in hexane, 52.3 mmoles) was added with stirring over 1.5 hours under nitrogen to a solution of 1,2-dichloro-4-fluorobenzene (7.85 g, 47.6 mmoles) in dry tetrahydrofuran (120 ml) at -68°. The solution wa stirred at -68° for 2 hours and then N-methyl-N-phenylformamide (6.48 ml) in dry tetrahydrofuran (15 ml) was added over 1.5 hours. After a further 1.5 hours at -68°, the reaction mixture was poured into 10% aqueous sulphuric acid and ether. The ethereal layer was separated, washed with brine, dried (Na2SO4) and evaporated to give the desired aldehyde (8 g). M+ 196/194/192, nmr (CDCl3)δ10.5 (s,H). After a further 1.5 hours at -68° The ethereal layer was separated washed with brine dried (Na2SO4) evaporated

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

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

Procedure: Butyl-[1-(2,3-dichloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,3-dichloro-6-fluorobenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 191a): brown oil; 1H-NMR (CDCl3): 0.96 (3H, t, CH3), 1.39 (2H, sextet, CH2), 1.73 (2H, quintet, CH2), 3.71 (2H, q, CH2), 7.02 (1H, dd, ArH), 7.44 (1H, dd, ArH), 8.44 (1H, s, CH═N).

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

Procedure: Butyl-[1-(2,3-dichloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,3-dichloro-6-fluorobenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 191a): brown oil; 1H-NMR (CDCl3): 0.96 (3H, t, CH3), 1.39 (2H, sextet, CH2), 1.73 (2H, quintet, CH2), 3.71 (2H, q, CH2), 7.02 (1H, dd, ArH), 7.44 (1H, dd, ArH), 8.44 (1H, s, CH═N).

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

Procedure: A solution of 1.3M s-butyl lithium in cyclohexane (244 mL, 317 mmol) is added to a dry-ice/acetone cooled solution of TMEDA (34 g, 293 mmol) in THF (250 mL), maintaining the internal reaction temperature <-70° C. The resulting reaction mixture is cooled and maintained at ≤-90° C. with an ether/liquid nitrogen bath while a solution of 1,2-dichloro-4-fluorobenzene (40 g, 244 mmol) in THF (100 mL) is added dropwise. The resulting reaction mixture is stirred with dry-ice/acetone cooling for 1h, then is cannulated into an ether/liquid nitrogen cooled and mechanically stirred solution of DMF (89.1 g, 1.22 mol) in THF (125 mL). The resulting mixture is warmed to -45° C. and partitioned between dilute aqueous HCl and ether. The organic solution is washed with aqueous NaHCO3, dried (MgSO4), and concentrated to afford 44.38 g of 2-fluoro-5,6-dichlorobenzaldehyde as an oil. maintaining the internal reaction temperature <-70° C The resulting reaction mixture is cooled is added dropwise The resulting reaction mixture cooled partitioned between dilute aqueous HCl and ether The organic solution is washed with aqueous NaHCO3 dried (MgSO4) concentrated

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

Procedure: A solution of 1.3M s-butyl lithium in cyclohexane (244 mL, 317 mmol) is added to a dry-ice/acetone cooled solution of TMEDA (34 g, 293 mmol) in THF (250 mL), maintaining the internal reaction temperature <-70° C. The resulting reaction mixture is cooled and maintained at ≤-90° C. with an ether/liquid nitrogen bath while a solution of 1,2-dichloro-4-fluorobenzene (40 g, 244 mmol) in THF (100 mL) is added dropwise. The resulting reaction mixture is stirred with dry-ice/acetone cooling for 1h, then is cannulated into an ether/liquid nitrogen cooled and mechanically stirred solution of DMF (89.1 g, 1.22 mol) in THF (125 mL). The resulting mixture is warmed to -45° C. and partitioned between dilute aqueous HCl and ether. The organic solution is washed with aqueous NaHCO3, dried (MgSO4), and concentrated to afford 44.38 g of 2-fluoro-5,6-dichlorobenzaldehyde as an oil. maintaining the internal reaction temperature <-70° C The resulting reaction mixture is cooled is added dropwise The resulting reaction mixture cooled partitioned between dilute aqueous HCl and ether The organic solution is washed with aqueous NaHCO3 dried (MgSO4) concentrated

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

Procedure: Butyl lithium (48 ml of 1.6M in hexane, 52.3 mmoles) was added with stirring over 1.5 hours under nitrogen to a solution of 1,2-dichloro-4-fluorobenzene (7.85 g, 47.6 mmoles) in dry tetrahydrofuran (120 ml) at -68°. The solution wa stirred at -68° for 2 hours and then N-methyl-N-phenylformamide (6.48 ml) in dry tetrahydrofuran (15 ml) was added over 1.5 hours. After a further 1.5 hours at -68°, the reaction mixture was poured into 10% aqueous sulphuric acid and ether. The ethereal layer was separated, washed with brine, dried (Na2SO4) and evaporated to give the desired aldehyde (8 g). M+ 196/194/192, nmr (CDCl3)δ10.5 (s,H). After a further 1.5 hours at -68° The ethereal layer was separated washed with brine dried (Na2SO4) evaporated

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

Procedure: Butyl lithium (48 ml of 1.6M in hexane, 52.3 mmoles) was added with stirring over 1.5 hours under nitrogen to a solution of 1,2-dichloro-4-fluorobenzene (7.85 g, 47.6 mmoles) in dry tetrahydrofuran (120 ml) at -68°. The solution wa stirred at -68° for 2 hours and then N-methyl-N-phenylformamide (6.48 ml) in dry tetrahydrofuran (15 ml) was added over 1.5 hours. After a further 1.5 hours at -68°, the reaction mixture was poured into 10% aqueous sulphuric acid and ether. The ethereal layer was separated, washed with brine, dried (Na2SO4) and evaporated to give the desired aldehyde (8 g). M+ 196/194/192, nmr (CDCl3)δ10.5 (s,H). After a further 1.5 hours at -68° The ethereal layer was separated washed with brine dried (Na2SO4) evaporated

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

Procedure: Butyl-[1-(2,3-dichloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,3-dichloro-6-fluorobenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 191a): brown oil; 1H-NMR (CDCl3): 0.96 (3H, t, CH3), 1.39 (2H, sextet, CH2), 1.73 (2H, quintet, CH2), 3.71 (2H, q, CH2), 7.02 (1H, dd, ArH), 7.44 (1H, dd, ArH), 8.44 (1H, s, CH═N).

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

Procedure: Methanol (400 ml), 22.1 g (0.1 mole) of 1-benzyl-3-hydroxy-5-oxo-1,2,3,6-tetrahydropyridine hydrate, 19.3 g (0.1 mole) of 2,3-dichloro-6-fluorobenzaldehyde, 29.1 g (0.1 mole) of 2-(2,3-dichlorophenoxy)ethyl acetoacetate and 16 g (0.21 mole) of ammonium acetate were combined and heated to reflux. Solid began to precipitate after one-half hour, but refluxing was continued for 4 hours. The mixture was cooled to room temperature and filtered. The solid was washed with methanol, then dried in vacuo to obtain 34 grams (52.3%) of 4-(2,3-Dichloro-6-fluorophenyl)-1,4,5,6,7,8-hexahydro-2-methyl-7-phenyl-methyl-5-oxo-1,7-naphthyridine-3-carboxylic acid 2-(2,3-dichlorophenoxy)ethyl ester, m.p. 204°-6° C. heated to reflux to precipitate after one-half hour refluxing filtered The solid was washed with methanol dried in vacuo