ethyl 2-(3,5-dimethylphenoxy)acetate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Referring to FIG. 42, a mixture of PPh3 (0.8 g, 3.0 mmol) and imidazole (0.3 g, 4.5 mmol) in DCM (20 mL) was stirred for 30 min at 0° C. Then a solution of Br2 (0.7 g, 4.5 mmol) in DCM (5 mL) was added. The mixture was kept at 0° C. for 10 min and compound 1 (0.3 g, 1.5 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min (monitored by TLC and UPLC analysis). The mixture was washed with diluted HCl solution (20 mL×2), saturated aqueous NaHSO3 (20 mL) and brine (20 mL), respectively. The organic layer was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1 to 30:1) to afford the title compound 2 (0.2 g, 40% yield); 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=8.4 Hz, 2H), 7.10 (d. J=8.4 Hz, 2H), 4.51 (s, 2H), 2.86-2.81 (m, 2H), 2.68-2.65 (m, 2H), 2.07-2.06 (m, 1H). The mixture was kept at 0° C. for 10 min The reaction mixture was stirred at 0° C. for 10 min (monitored by TLC and UPLC analysis) The mixture was washed with diluted HCl solution (20 mL×2), saturated aqueous NaHSO3 (20 mL) and brine (20 mL) The organic layer was concentrated under reduced pressure the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1 to 30:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Referring to FIG. 42, a mixture of PPh3 (0.8 g, 3.0 mmol) and imidazole (0.3 g, 4.5 mmol) in DCM (20 mL) was stirred for 30 min at 0° C. Then a solution of Br2 (0.7 g, 4.5 mmol) in DCM (5 mL) was added. The mixture was kept at 0° C. for 10 min and compound 1 (0.3 g, 1.5 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min (monitored by TLC and UPLC analysis). The mixture was washed with diluted HCl solution (20 mL×2), saturated aqueous NaHSO3 (20 mL) and brine (20 mL), respectively. The organic layer was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1 to 30:1) to afford the title compound 2 (0.2 g, 40% yield); 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=8.4 Hz, 2H), 7.10 (d. J=8.4 Hz, 2H), 4.51 (s, 2H), 2.86-2.81 (m, 2H), 2.68-2.65 (m, 2H), 2.07-2.06 (m, 1H). The mixture was kept at 0° C. for 10 min The reaction mixture was stirred at 0° C. for 10 min (monitored by TLC and UPLC analysis) The mixture was washed with diluted HCl solution (20 mL×2), saturated aqueous NaHSO3 (20 mL) and brine (20 mL) The organic layer was concentrated under reduced pressure the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1 to 30:1)

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

Procedure: Referring to FIG. 42, a mixture of pent-4-ynoic acid (1.10 g. 11.2 mmol), 4-(hydroxymethyl)phenol (1.40 g, 11.2 mmol) and DCC (3.5 g, 16.8 mmol) in THF (30 mL) was stirred at room temperature overnight. Ethyl acetate was added to dilute the mixture and the white solid was filtered off. The filtrate was collected and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=3:1 to 2:1) to afford compound 1 (0.91 g, 40% yield); 1H NMR (300 MHz, DMSO-d6): δ 7.35 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 5.23 (t, J=6.0 Hz, 1H), 4.49 (d, J=5.7 Hz, 2H), 2.90-2.89 (m, 1H), 2.81-2.76 (m, 2H), 2.55-2.50 (m, 2H). to dilute the mixture the white solid was filtered off The filtrate was collected concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=3:1 to 2:1)

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

Procedure: Referring to FIG. 37, to a solution of ethyl 2-(3,5-dimethylphenoxy)acetate (19 g, obtained from the previous step) in methanol (150 mL) was added NaOH solution (6 N, 50 mL). The reaction mixture was stirred at room temperature for 4 h and then adjusted to pH=1˜2 with 2 N HCl solution. The resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a solid, which was washed with ethyl acetate/hexane (1:15, 40 mL) to give product (14 g, 95% yield over two steps); 1H NMR (CDCl3, 300 MHz): δ 6.69 (s, 1H), 6.58 (s, 2H), 4.68 (s, 2H). 2.31 (s, 6H). The resulting mixture was extracted with ethyl acetate (150 mL×2) The combined extracts were washed with brine dried over anhydrous Na2SO4 concentrated under reduced pressure to give a solid, which was washed with ethyl acetate/hexane (1:15, 40 mL) to give product (14 g, 95% yield over two steps)

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

Procedure: Referring to FIG. 37, to a solution of 3,5-dimethylphenol (10 g, 82 mmol) in CH3CN (150 mL) were added ethyl 2-bromoacetate (14.9 g, 90 mmol) and K2CO3 (16.9 g, 123 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was poured into water (200 mL) and the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g); 1H NMR (CDCl3, 300 MHz): δ 6.13 (s, 1H), 6.11 (s, 2H), 4.59 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.77 (s, 6H), 1.31 (1, J=7.2 Hz, 3H). the resulting mixture was extracted with ethyl acetate (150 mL×2) The combined extracts were washed with brine dried over anhydrous Na2SO4 concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g)

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

Procedure: Referring to FIG. 37, to a solution of 3,5-dimethylphenol (10 g, 82 mmol) in CH3CN (150 mL) were added ethyl 2-bromoacetate (14.9 g, 90 mmol) and K2CO3 (16.9 g, 123 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was poured into water (200 mL) and the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g); 1H NMR (CDCl3, 300 MHz): δ 6.13 (s, 1H), 6.11 (s, 2H), 4.59 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.77 (s, 6H), 1.31 (1, J=7.2 Hz, 3H). the resulting mixture was extracted with ethyl acetate (150 mL×2) The combined extracts were washed with brine dried over anhydrous Na2SO4 concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Referring to FIG. 42, a mixture of PPh3 (0.8 g, 3.0 mmol) and imidazole (0.3 g, 4.5 mmol) in DCM (20 mL) was stirred for 30 min at 0° C. Then a solution of Br2 (0.7 g, 4.5 mmol) in DCM (5 mL) was added. The mixture was kept at 0° C. for 10 min and compound 1 (0.3 g, 1.5 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min (monitored by TLC and UPLC analysis). The mixture was washed with diluted HCl solution (20 mL×2), saturated aqueous NaHSO3 (20 mL) and brine (20 mL), respectively. The organic layer was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1 to 30:1) to afford the title compound 2 (0.2 g, 40% yield); 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 4.51 (s, 2H), 2.86-2.81 (m, 2H), 2.68-2.65 (m, 2H), 2.07-2.06 (m, 1H). The mixture was kept at 0° C. for 10 min The reaction mixture was stirred at 0° C. for 10 min (monitored by TLC and UPLC analysis) The mixture was washed with diluted HCl solution (20 mL×2), saturated aqueous NaHSO3 (20 mL) and brine (20 mL) The organic layer was concentrated under reduced pressure the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1 to 30:1)

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

Procedure: Referring to FIG. 42, a mixture of pent-4-ynoic acid (1.10 g, 11.2 mmol), 4-(hydroxymethyl)phenol (1.40 g, 11.2 mmol) and DCC (3.5 g, 16.8 mmol) in THF (30 mL) was stirred at room temperature overnight. Ethyl acetate was added to dilute the mixture and the white solid was filtered off. The filtrate was collected and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=3:1 to 2:1) to afford compound 1 (0.91 g, 40% yield); 1H NMR (300 MHz, DMSO-d6): δ 7.35 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 5.23 (t, J=6.0 Hz, 1H), 4.49 (d, J=5.7 Hz, 2H), 2.90-2.89 (m, 1H), 2.81-2.76 (m, 2H), 2.55-2.50 (m, 2H). to dilute the mixture the white solid was filtered off The filtrate was collected concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=3:1 to 2:1)

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

Procedure: Referring to FIG. 42, a mixture of pent-4-ynoic acid (1.10 g, 11.2 mmol), 4-(hydroxymethyl)phenol (1.40 g, 11.2 mmol) and DCC (3.5 g, 16.8 mmol) in THF (30 mL) was stirred at room temperature overnight. Ethyl acetate was added to dilute the mixture and the white solid was filtered off. The filtrate was collected and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=3:1 to 2:1) to afford compound 1 (0.91 g, 40% yield); 1H NMR (300 MHz, DMSO-d6): δ 7.35 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 5.23 (t, J=6.0 Hz, 1H), 4.49 (d, J=5.7 Hz, 2H), 2.90-2.89 (m, 1H), 2.81-2.76 (m, 2H), 2.55-2.50 (m, 2H). to dilute the mixture the white solid was filtered off The filtrate was collected concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=3:1 to 2:1)

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

Procedure: Referring to FIG. 37, to a solution of ethyl 2-(3,5-dimethylphenoxy)acetate (19 g, obtained from the previous step) in methanol (150 mL) was added NaOH solution (6 N, 50 mL). The reaction mixture was stirred at room temperature for 4 h and then adjusted to pH=1˜2 with 2 N HCl solution. The resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a solid, which was washed with ethyl acetate/hexane (1:15, 40 mL) to give product (14 g, 95% yield over two steps); 1H NMR (CDCl3, 300 MHz): δ 6.69 (s, 1H), 6.58 (s, 2H), 4.68 (s, 2H), 2.31 (s, 6H). The resulting mixture was extracted with ethyl acetate (150 mL×2) The combined extracts were washed with brine dried over anhydrous Na2SO4 concentrated under reduced pressure to give a solid, which was washed with ethyl acetate/hexane (1:15, 40 mL) to give product (14 g, 95% yield over two steps)

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

Procedure: Referring to FIG. 37, to a solution of 3,5-dimethylphenol (10 g, 82 mmol) in CH3CN (150 mL) were added ethyl 2-bromoacetate (14.9 g, 90 mmol) and K2CO3 (16.9 g, 123 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was poured into water (200 mL) and the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g); 1H NMR (CDCl3, 300 MHz): δ 6.13 (s, 1H), 6.11 (s, 2H), 4.59 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.77 (s, 6H), 1.31 (t, J=7.2 Hz, 3H). the resulting mixture was extracted with ethyl acetate (150 mL×2) The combined extracts were washed with brine dried over anhydrous Na2SO4 concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g)

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

Procedure: Referring to FIG. 37, to a solution of 3,5-dimethylphenol (10 g, 82 mmol) in CH3CN (150 mL) were added ethyl 2-bromoacetate (14.9 g, 90 mmol) and K2CO3 (16.9 g, 123 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was poured into water (200 mL) and the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g); 1H NMR (CDCl3, 300 MHz): δ 6.13 (s, 1H), 6.11 (s, 2H), 4.59 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.77 (s, 6H), 1.31 (t, J=7.2 Hz, 3H). the resulting mixture was extracted with ethyl acetate (150 mL×2) The combined extracts were washed with brine dried over anhydrous Na2SO4 concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g)