2-methoxyethyl trifluoromethanesulfonate

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

Procedure: A solution of 2-methoxyethyl triflate (prepared on a 6 mmole scale from 2-methoxyethanol and trifluoromethanesulphonic anhydride by the method published in Synthesis 1982 85) in DCM (20 ml) was added dropwise to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 1.5 g, 4 mmol) in DCM (5 ml) and the mixture was stirred for 40 hours at ambient temperature. The volatiles were removed by evaporation to give a solid (2.4 g) which was purified by flash chromatography on silica gel eluting with DCM/MeOH (100:0 increasing in polarity to 95:5) to yield the title compound (660 mg, 88%) as a solid NMR (CDCl3) 1.31 (s, 3H), 1.49 (s, 3H), 2.02 (s, 3H), 2.43 (m, 2H), 3.31 (m, 2H), 6.87 (s, 1H); m/z 183. The volatiles were removed by evaporation

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

Procedure: To a of −30° C. cooled solution of 7.40 g (17.6 mmol) (7R,8R,9R)-10-acetyl-7-hydroxy-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine in dichloromethane (25 ml) and N-methyl-pyrrolidinone (25 ml) is added 4.00 g (19.3 mmol) methoxyethyl triflate and 1.40 g (35.2 mmol) sodium hydride and it is stirred for further 2 h at this temperature. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1) to give 7.50 g (15.63 mmol/89%) of the title compound as a yellow amorphous solid. 1H-NMR (200 MHz,[D6] DMSO): δ=1.19 (s, 9H), 2.15 (s, 3H), 2.38 (s, 3H), 3.27 (s, 3H), 3.45-3.57 (m, 2H), 3.83-3.93 (m, 2H), 4.60 (d, 1H), 5.31 (t, 1H), 5.79 (d, 1H), 6.94 (s, 1H), 7,20 (s, 5H), 7.74 (s, 1H), 8.43 (d, 1H). The reaction is quenched by adding of saturated aqueous ammonium chloride solution Subsequently the mixture is extracted twice with dichloromethane The combined organic layers are washed with brine dried over sodium sulphate evaporated in vacuo The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1)

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

Procedure: To a of −30° C. cooled solution of 7.40 g (17.6 mmol) (7R,8R,9R)-10-acetyl-7-hydroxy-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in dichloromethane (25 ml) and N-methyl-pyrrolidinone (25 ml) is added 4.00 g (19.3 mmol) methoxyethyl triflate and 1.40 g (35.2 mmol) sodium hydride and it is stirred for further 2 h at this temperature. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1) to give 7.50 g (15.63 mmol/89%) of the title compound as a yellow amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=1.19(s, 9H), 2.15(s, 3H), 2.38(s, 3H), 3.27(s, 3H), 3.45–3.57(m, 2H), 3.83–3.93(m, 2H), 4.60(d, 1H), 5.31(t, 1H), 5.79(d, 1H), 6.94 (s, 1H), 7.20(s, 5H); 7.74(s, 1H), 8.43(d, 1H). The reaction is quenched by adding of saturated aqueous ammonium chloride solution Subsequently the mixture is extracted twice with dichloromethane The combined organic layers are washed with brine dried over sodium sulphate evaporated in vacuo The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1)

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

Procedure: To a of −30° C. cooled solution of 7.40 g (17.6 mmol) (7R,8R,9R)-10-acetyl-7-hydroxy-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in dichloromethane (25 ml) and N-methyl-pyrrolidinone (25 ml) is added 4.00 g (19.3 mmol) methoxyethyl triflate and 1.40 g (35.2 mmol) sodium hydride and it is stirred for further 2 h at this temperature. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1) to give 7.50 g (15.63 mmol/89%) of the title compound as a yellow amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=1.19(s, 9H), 2.15(s, 3H), 2.38(s, 3H), 3.27(s, 3H), 3.45–3.57(m, 2H), 3.83–3.93(m, 2H), 4.60(d, 1H), 5.31(t, 1H), 5.79(d, 1H), 6.94 (s, 1H), 7.20(s, 5H); 7.74(s, 1H), 8.43(d, 1H). The reaction is quenched by adding of saturated aqueous ammonium chloride solution Subsequently the mixture is extracted twice with dichloromethane The combined organic layers are washed with brine dried over sodium sulphate evaporated in vacuo The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1)

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

Procedure: 500 mg (1.32 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.58 ml (1.58 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) were reacted with 556 mg (purity 74%, 1.98 mmol, 1.5 eq.) of 2-methoxyethyl trifluoromethanesulphonate according to General Method 7B. Yield: 455 mg (purity 80%, 63% of theory)

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

Procedure: 312 mg (0.75 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 0.90 ml (0.90 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 312 mg (1.50 mmol, 1.5 eq.) of 2-methoxyethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 201 mg (purity 91%, 51% of theory)

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

Procedure: 500 mg (1.32 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.58 ml (1.58 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) were reacted with 556 mg (purity 74%, 1.98 mmol, 1.5 eq.) of 2-methoxyethyl trifluoromethanesulphonate according to General Method 7B. Yield: 455 mg (purity 80%, 63% of theory)

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

Procedure: 312 mg (0.75 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 0.90 ml (0.90 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 312 mg (1.50 mmol, 1.5 eq.) of 2-methoxyethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 201 mg (purity 91%, 51% of theory)

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

Procedure: A solution of 2-methoxyethyl triflate (prepared on a 6 mmole scale from 2-methoxyethanol and trifluoromethanesulphonic anhydride by the method published in Synthesis 1982 85) in DCM (20 ml) was added dropwise to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 1.5 g, 4 mmol) in DCM (5 ml) and the mixture was stirred for 40 hours at ambient temperature. The volatiles were removed by evaporation to give a solid (2.4 g) which was purified by flash chromatography on silica gel eluting with DCM/MeOH (100:0 increasing in polarity to 95:5) to yield the title compound (660 mg, 88%) as a solid NMR (CDCl3) 1.31 (s, 3H), 1.49 (s, 3H), 2.02 (s, 3H), 2.43 (m, 2H), 3.31 (m, 2H), 6.87 (s, 1H); m/z 183. The volatiles were removed by evaporation

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

Procedure: To a of −30° C. cooled solution of 7.40 g (17.6 mmol) (7R,8R,9R)-10-acetyl-7-hydroxy-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine in dichloromethane (25 ml) and N-methyl-pyrrolidinone (25 ml) is added 4.00 g (19.3 mmol) methoxyethyl triflate and 1.40 g (35.2 mmol) sodium hydride and it is stirred for further 2 h at this temperature. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1) to give 7.50 g (15.63 mmol/89%) of the title compound as a yellow amorphous solid. 1H-NMR (200 MHz,[D6] DMSO): δ=1.19 (s, 9H), 2.15 (s, 3H), 2.38 (s, 3H), 3.27 (s, 3H), 3.45-3.57 (m, 2H), 3.83-3.93 (m, 2H), 4.60 (d, 1H), 5.31 (t, 1H), 5.79 (d, 1H), 6.94 (s, 1H), 7,20 (s, 5H), 7.74 (s, 1H), 8.43 (d, 1H). The reaction is quenched by adding of saturated aqueous ammonium chloride solution Subsequently the mixture is extracted twice with dichloromethane The combined organic layers are washed with brine dried over sodium sulphate evaporated in vacuo The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1)

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

Procedure: To a of −30° C. cooled solution of 7.40 g (17.6 mmol) (7R,8R,9R)-10-acetyl-7-hydroxy-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in dichloromethane (25 ml) and N-methyl-pyrrolidinone (25 ml) is added 4.00 g (19.3 mmol) methoxyethyl triflate and 1.40 g (35.2 mmol) sodium hydride and it is stirred for further 2 h at this temperature. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1) to give 7.50 g (15.63 mmol/89%) of the title compound as a yellow amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=1.19(s, 9H), 2.15(s, 3H), 2.38(s, 3H), 3.27(s, 3H), 3.45–3.57(m, 2H), 3.83–3.93(m, 2H), 4.60(d, 1H), 5.31(t, 1H), 5.79(d, 1H), 6.94 (s, 1H), 7.20(s, 5H); 7.74(s, 1H), 8.43(d, 1H). The reaction is quenched by adding of saturated aqueous ammonium chloride solution Subsequently the mixture is extracted twice with dichloromethane The combined organic layers are washed with brine dried over sodium sulphate evaporated in vacuo The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1)

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

Procedure: 500 mg (1.32 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.58 ml (1.58 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) were reacted with 556 mg (purity 74%, 1.98 mmol, 1.5 eq.) of 2-methoxyethyl trifluoromethanesulphonate according to General Method 7B. Yield: 455 mg (purity 80%, 63% of theory)