methyl 5-chloro-2-ethylbenzoate

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 2-bromo-5-chlorobenzoate (1.0 g, 4 mmol), lithium chloride (490 mg, 11.58 mmol), tetraethyltin (0.81 mL, 4.1 mmol) and bis(triphenylphosphine)-palladium(II)chloride (100 mg, 0.13 mmol) were combined in DMF (20 mL) and heated at 100° C. for 5 h. Solvent was removed at reduced pressure and the residue was diluted with water and EtOAc. The organic layer was separated, washed with water, dried over sodium sulfate and concentrated. Column chromatography on silica gel (0 to 10% EtOAc/hexane) provided the title compound (435 mg, 55%). Solvent was removed at reduced pressure the residue was diluted with water and EtOAc The organic layer was separated washed with water dried over sodium sulfate concentrated

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

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 5-chloro-2-ethylbenzoate (1.08 g, 5.4 mmol) in concentrated sulphuric acid (7.0 ml) was cooled to −5° C. in an acetone/ice bath. A mixture of 70% nitric acid (0.45 ml, 7.1 mmol) and concentrated sulphuric acid (0.5 ml) was added dropwise to the reaction mixture at −5° C. over 15 minutes. The resulting pale yellow reaction mixture was stirred at −5° C. for 1 hour before being poured onto ice (100 ml) and extracted with CH2Cl2 (3×20 ml). The combined organic phases were washed with deionized water (20 ml), brine (20 ml), dried over Na2SO4, filtered and concentrated in-vacuo. The resulting oil was added to a solution containing methanol (25 ml) and thionyl chloride (0.75 ml) at 0° C. Following addition, the mixture was heated under gentle reflux for 6 hours, before cooling to room temperature and concentrating in-vacuo to give the title compound (1.2 g) as an orange oil which was used without further purification in the next step. was added dropwise to the reaction mixture at −5° C. over 15 minutes before being poured onto ice (100 ml) extracted with CH2Cl2 (3×20 ml) The combined organic phases were washed with deionized water (20 ml), brine (20 ml) dried over Na2SO4 filtered concentrated in-vacuo The resulting oil was added to a solution containing methanol (25 ml) and thionyl chloride (0.75 ml) at 0° C addition the mixture was heated under gentle reflux for 6 hours before cooling to room temperature concentrating in-vacuo

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

Procedure: To a solution of methyl 5-chloro-2-ethynylbenzoate (1.13 g, 5.8 mmol) in TBME (50 ml) was added Pd/C (10%) (50% water, 0.61 g, 0.29 mmol). The reaction mixture was stirred under a hydrogen atmosphere for 130 minutes. The mixture was filtered through Celite and the filter cake was washed with TBME. The filtrate was concentrated in-vacuo to give the title compound (1.08 g, 74%) as a pale brown oil. LC-MS 79%, m/z=198.9/200.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.85 (s, 1H) 7.40 (d, J=8.20 Hz, 1H) 7.22 (d, J=8.20 Hz, 1H) 3.91 (s, 3H) 2.95 (q, J=7.46 Hz, 2H) 1.22 (t, J=7.49 Hz, 3H). The mixture was filtered through Celite the filter cake was washed with TBME The filtrate was concentrated in-vacuo

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 5-chloro-2-ethylbenzoate (5.12 g, 25.8 mmol) in concentrated H2SO4 (31 ml, 587 mmol) was cooled to −5° C. in an acetone/ice bath. A mixture of concentrated nitric acid (2.15 ml, 33.5 mmol) and concentrated H2SO4 (2.0 ml, 37.5 mmol) was added dropwise to the reaction mixture at −5° C. over 15 minutes. The pale yellow reaction mixture was stirred at −5° C. for 1 hour before being poured onto ice (500 ml) and this was extracted with EtOAc (3×100 ml). The combined organic phases were washed with deionized water (100 ml) and then brine (100 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. LCMS and NMR showed ˜30% hydrolysis of the ester. The crude material was dissolved in methanol (30 ml) and cooled to 0° C. under nitrogen where SOCl2 (2.25 ml, 30.93 mmol) was added slowly. The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure to give 6.18 g (98%) of the title compound containing material as an orange oil which was a 1:1 mixture of 3-nitro:6-nitro isomers along with some ethyl ester. The material was suitable for use in the next step without any further purification. was added dropwise to the reaction mixture at −5° C. over 15 minutes before being poured onto ice (500 ml) this was extracted with EtOAc (3×100 ml) The combined organic phases were washed with deionized water (100 ml) The organic phase was dried over MgSO4 filtered concentrated under reduced pressure ˜30% hydrolysis of the ester was added slowly The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure

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

Procedure: To a solution of methyl 5-chloro-2-ethynylbenzoate (5.34 g, 27 mmol) in ethyl acetate (135 ml) was added Pd/C (10%) (50% water, 2.92 g, 1.37 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The mixture was filtered through Celite. The filter cake washed with EtOAc (50 ml) and the filtrate was concentrated under reduced pressure to give 5.12 g (94%) of the title compound as a brown oil which was suitable for use without any further purification. LC-MS 56%, m/z=198.9/200.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.84 (d, J=2.3 Hz, 1H), 7.39 (dd, J=8.3, 2.3 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 2.94 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H). The mixture was filtered through Celite The filter cake washed with EtOAc (50 ml) the filtrate was concentrated under reduced pressure

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 5-chloro-2-ethylbenzoate (5.12 g, 25.8 mmol) in concentrated H2SO4 (31 ml, 587 mmol) was cooled to −5° C. in an acetone/ice bath. A mixture of concentrated nitric acid (2.15 ml, 33.5 mmol) and concentrated H2SO4 (2.0 ml, 37.5 mmol) was added dropwise to the reaction mixture at −5° C. over 15 minutes. The pale yellow reaction mixture was stirred at −5° C. for 1 hour before being poured onto ice (500 ml) and this was extracted with EtOAc (3×100 ml). The combined organic phases were washed with deionized water (100 ml) and then brine (100 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. LCMS and NMR showed ˜30% hydrolysis of the ester. The crude material was dissolved in methanol (30 ml) and cooled to 0° C. under nitrogen where SOCl2 (2.25 ml, 30.93 mmol) was added slowly. The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure to give 6.18 g (98%) of the title compound containing material as an orange oil which was a 1:1 mixture of 3-nitro:6-nitro isomers along with some ethyl ester. The material was suitable for use in the next step without any further purification. was added dropwise to the reaction mixture at −5° C. over 15 minutes before being poured onto ice (500 ml) this was extracted with EtOAc (3×100 ml) The combined organic phases were washed with deionized water (100 ml) The organic phase was dried over MgSO4 filtered concentrated under reduced pressure ˜30% hydrolysis of the ester was added slowly The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure

Conditions: temp:-2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 5-chloro-2-ethylbenzoate (5.12 g, 25.77 mmol) in concentrated H2SO4 (31 ml, 587 mmol) was cooled to −5° C. in an acetone/ice bath in air. A mixture of concentrated nitric acid (2.15 ml, 33.51 mmol) and concentrated H2SO4 (2 ml, 37.52 mmol) was added dropwise to the reaction mixture at −5 to 0° C. over 15 minutes. The pale yellow reaction mixture was stirred at −5 to 0° C. for 1 hour before being poured onto ice (500 ml) and this was extracted with EtOAc (3×100 ml). The combined organic phases was washed with deionized water (100 ml) and then brine (100 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. LCMS and NMR showed ˜30% hydrolysis of the ester. The crude material was dissolved in Methanol (30 ml) and cooled to 0° C. under nitrogen where SOCl2 (2.25 ml, 30.93 mmol) was added slowly. The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure to give 6.18 g (98.4%) of methyl 5-chloro-2-ethyl-3-nitrobenzoate as an orange oil. Product contained 1:1 mixture of 3-nitro:6-nitro isomers along with some ethyl ester which was suitable for use without any further purification. was added dropwise to the reaction mixture at −5 to 0° C. over 15 minutes before being poured onto ice (500 ml) this was extracted with EtOAc (3×100 ml) The combined organic phases was washed with deionized water (100 ml) The organic phase was dried over MgSO4 filtered concentrated under reduced pressure ˜30% hydrolysis of the ester was added slowly The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure

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

Procedure: To a solution of methyl 5-chloro-2-ethynylbenzoate (5.34 g, 27.44 mmol) in Ethyl acetate (135 ml) was added Pd/C (10%) (50% water, 2.92 g, 1.37 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. LCMS indicated the reaction had gone to completion and the mixture was filtered through Celite. The filter cake washed with EtOAc (50 ml) and the filtrate was concentrated under reduced pressure to give 5.12 g (93.9%) of methyl 5-chloro-2-ethylbenzoate as a brown oil which was suitable for use without any further purification. LC-MS 56%, 2.21 min (3 minute LC-MS method), m/z=198.9/200.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.84 (d, J=2.3 Hz, 1H), 7.39 (dd, J=8.3, 2.3 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 2.94 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H). the mixture was filtered through Celite The filter cake washed with EtOAc (50 ml) the filtrate was concentrated under reduced pressure

Conditions: temp:-2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 5-chloro-2-ethylbenzoate (5.12 g, 25.77 mmol) in concentrated H2SO4 (31 ml, 587 mmol) was cooled to −5° C. in an acetone/ice bath in air. A mixture of concentrated nitric acid (2.15 ml, 33.51 mmol) and concentrated H2SO4 (2 ml, 37.52 mmol) was added dropwise to the reaction mixture at −5 to 0° C. over 15 minutes. The pale yellow reaction mixture was stirred at −5 to 0° C. for 1 hour before being poured onto ice (500 ml) and this was extracted with EtOAc (3×100 ml). The combined organic phases was washed with deionized water (100 ml) and then brine (100 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. LCMS and NMR showed ˜30% hydrolysis of the ester. The crude material was dissolved in Methanol (30 ml) and cooled to 0° C. under nitrogen where SOCl2 (2.25 ml, 30.93 mmol) was added slowly. The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure to give 6.18 g (98.4%) of methyl 5-chloro-2-ethyl-3-nitrobenzoate as an orange oil. Product contained 1:1 mixture of 3-nitro:6-nitro isomers along with some ethyl ester which was suitable for use without any further purification. was added dropwise to the reaction mixture at −5 to 0° C. over 15 minutes before being poured onto ice (500 ml) this was extracted with EtOAc (3×100 ml) The combined organic phases was washed with deionized water (100 ml) The organic phase was dried over MgSO4 filtered concentrated under reduced pressure ˜30% hydrolysis of the ester was added slowly The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure

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

Procedure: To a solution of methyl 5-chloro-2-ethynylbenzoate (5.34 g, 27.44 mmol) in Ethyl acetate (135 ml) was added Pd/C (10%) (50% water, 2.92 g, 1.37 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. LCMS indicated the reaction had gone to completion and the mixture was filtered through Celite. The filter cake washed with EtOAc (50 ml) and the filtrate was concentrated under reduced pressure to give 5.12 g (93.9%) of methyl 5-chloro-2-ethylbenzoate as a brown oil which was suitable for use without any further purification. LC-MS 56%, 2.21 min (3 minute LC-MS method), m/z=198.9/200.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.84 (d, J=2.3 Hz, 1H), 7.39 (dd, J=8.3, 2.3 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 2.94 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H). the mixture was filtered through Celite The filter cake washed with EtOAc (50 ml) the filtrate was concentrated under reduced pressure