ethyl 4-hydroxy-3-iodobenzoate

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

Procedure: Dissolve ethyl 4-hydroxy-3-iodo-benzoate (45 g, 154.1 mmoles) in DMSO (125 mL). Add CuCN (15.17 g, 169.5 mmoles). Stir the mixture at 100° C. overnight. After cooling, pour the mixture into ice/water. Filter the solid obtained, wash with water and dry under reduced pressure. Dissolve the solid in EtOAc. Filter through Celite®. Dry over MgSO4 and remove the solvent to obtain 22.36 g of ethyl 3-cyano-4-hydroxy-benzoate (76% yield). MS(ES): m/z=190.0 [M-H]. After cooling Filter the solid obtained wash with water dry under reduced pressure Dissolve the solid in EtOAc Filter through Celite® Dry over MgSO4 remove the solvent

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve ethyl 4-hydroxy-benzoate (102.2 g, 0.61 mol) in AcOH (200 mL) at 65° C. Add dropwise a solution of ICl (100 g, 0.61 moles) in AcOH (500 mL). After the addition, stir the mixture at 65° C. for 6 hours. Pour the mixture into ice/water, filter and wash the solid with water. Dissolve the solid in CH2Cl2, dry it over MgSO4, filter and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with CH2Cl2 to obtain 131.3 g of ethyl 4-hydroxy-3-iodo-benzoate (74% yield). After the addition filter wash the solid with water Dissolve the solid in CH2Cl2 dry it over MgSO4 filter concentrate under reduced pressure Subject residue to silica gel chromatography eluting with CH2Cl2

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Charge a 10 L double jacket reactor, equipped with a mechanical stirrer, a reflux condenser and set under N2 with 4-hydroxy-3-iodo-benzoic acid ethyl ester (1312 g, 4.49 mol), dimethylsulfoxide (3277 mL) and CuCN (442.3 g). Heat the mixture to 105° C. and hold at this temperature for 2.5 h. Cool the brown solution down to 20° C. Add water at 48° C. water (6.5 L) Filter the mixture at 20° C., then wash the cake with water (2 L). Suspend the cake in EtOAc (5 L) and stir during 1 h at 20° C. Filter the suspension on Hyflo Super Cel® (250 g) and rinse with EtOAc (3 L). Decant the filtrates, then evaporate the organic layer to dryness. Take the residue up in n-heptane (10 L). Distill off 2 L of n-heptane, then add CH2Cl2 (400 mL). Cool the mixture cooled to 27° C., filter and rinse the cake with n-heptane (2 L). Dry 48 h at 55° C. under pressure to give 4-hydroxy-3-cyano-benzoic acid ethyl ester. (777.7 g, 4.067 mol). 1H NMR (250 MHz, DMSOd): 1.32 (t, j=7.1 Hz, 3H), 4.3 (q, j=7.1 Hz, 2H), 7.13(d, j=8.8 Hz, 1H), 8.07(dxd, j=8.8 Hz, 2.2 Hz, 1H), 8.16 (d, j=2.2 Hz), 12.11(s (broad), 1H). Charge a 10 L double jacket reactor equipped with a mechanical stirrer, a reflux condenser Cool the brown solution down to 20° C Add water at 48° C. water (6.5 L) Filter the mixture at 20° C. wash the cake with water (2 L) Filter the suspension on Hyflo Super Cel® (250 g) rinse with EtOAc (3 L) Decant the filtrates evaporate the organic layer to dryness Distill off 2 L of n-heptane Cool the mixture cooled to 27° C. filter rinse the cake with n-heptane (2 L) Dry 48 h at 55° C. under pressure

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Charge a 10 L double jacket reactor, equipped with a mechanical stirrer, a reflux condenser and set under N2 with 4-hydroxy-3-iodo-benzoic acid ethyl ester (1312 g, 4.49 mol), dimethylsulfoxide (3277 mL) and CuCN (442.3 g). Heat the mixture to 105° C. and hold at this temperature for 2.5 h. Cool the brown solution down to 20° C. Add water at 48° C. water (6.5 L) Filter the mixture at 20° C., then wash the cake with water (2 L). Suspend the cake in EtOAc (5 L) and stir during 1 h at 20° C. Filter the suspension on Hyflo Super Cel® (250 g) and rinse with EtOAc (3 L). Decant the filtrates, then evaporate the organic layer to dryness. Take the residue up in n-heptane (10 L). Distill off 2 L of n-heptane, then add CH2Cl2 (400 mL). Cool the mixture cooled to 27° C., filter and rinse the cake with n-heptane (2 L). Dry 48 h at 55° C. under pressure to give 4-hydroxy-3-cyano-benzoic acid ethyl ester. (777.7 g, 4.067 mol). 1H NMR (250 MHz, DMSOd): 1.32 (t, j=7.1 Hz, 3H), 4.3 (q, j=7.1 Hz, 2H), 7.13(d, j=8.8 Hz, 1H), 8.07(dxd, j=8.8 Hz, 2.2 Hz, 1H), 8.16 (d, j=2.2 Hz), 12.11(s (broad), 1H). Charge a 10 L double jacket reactor equipped with a mechanical stirrer, a reflux condenser Cool the brown solution down to 20° C Add water at 48° C. water (6.5 L) Filter the mixture at 20° C. wash the cake with water (2 L) Filter the suspension on Hyflo Super Cel® (250 g) rinse with EtOAc (3 L) Decant the filtrates evaporate the organic layer to dryness Distill off 2 L of n-heptane Cool the mixture cooled to 27° C. filter rinse the cake with n-heptane (2 L) Dry 48 h at 55° C. under pressure

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Charge a 10 L double jacketed reactor with a mechanical stirrer and a reflux condenser with 4-hydroxy benzoic acid ethyl ester (967 g, 8.81 mol) and acetic acid (5.8 L). Heat the mixture to 65° C. and add a solution of ICl (1010 g) in acetic acid (1 L) in ½ h. Stir the resulting mixture at 60-62° C. for 16 h. Cool the black solution to 20° C. and transfer on water (5 L) and ice (7.5 kg). Stir the resulting suspension over 1 h at 20° C., filter and wash the cake with water (2 L) and cyclohexane (6 L). Dry the solid under vacuum at 55° C. till constant weight to give 4-hydroxy-3-iodo-benzoic acid ethyl ester (1372.8 g, 4.70 mol). 11H NMR (250 MHz, CDCl3): 1.38 (t, J=7.1 Hz, 3H), 4.35 (quartet, J=7.1 Hz, 2H), 5.8 (s, 1 H), 7.01 (d, J=8.5 Hz, 1H), 7.95 (dd, J=8.5 Hz, 2.0 Hz, 1H), 8.37 (d, J=2 Hz, 1 H). Cool the black solution to 20° C. Stir the resulting suspension over 1 h at 20° C. filter wash the cake with water (2 L) and cyclohexane (6 L) Dry the solid under vacuum at 55° C. till constant weight

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

Procedure: To the resultant ester (3.10 g, 10.61 mmol) and potassium carbonate (2.87 g, 20.75 mmol) in 40 ml acetonitrile, add iodoethane (1.3 ml, 16.25 mmol) at RT while stirring vigorously. Heat the resulting white suspension under reflux for 1.5 h. Evaporate acetonitrile and replace with EtOAc. Wash the organic layer first with water, then with saturated aq. sodium chloride. Dry over anhydrous sodium sulfate, filter and concentrate to give the title compound as a yellow oil. Heat the resulting white suspension under reflux for 1.5 h Wash the organic layer first with water Dry over anhydrous sodium sulfate filter concentrate

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

Procedure: To the resultant ester (3.10 g, 10.61 mmol) and potassium carbonate (2.87 g, 20.75 mmol) in 40 ml acetonitrile, add iodoethane (1.3 ml, 16.25 mmol) at RT while stirring vigorously. Heat the resulting white suspension under reflux for 1.5 h. Evaporate acetonitrile and replace with EtOAc. Wash the organic layer first with water, then with saturated aq. sodium chloride. Dry over anhydrous sodium sulfate, filter and concentrate to give the title compound as a yellow oil. Heat the resulting white suspension under reflux for 1.5 h Wash the organic layer first with water Dry over anhydrous sodium sulfate filter concentrate

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

Procedure: Dissolve ethyl 4-hydroxy-3-iodo-benzoate (45 g, 154.1 mmoles) in DMSO (125 mL). Add CuCN (15.17 g, 169.5 mmoles). Stir the mixture at 100° C. overnight. After cooling, pour the mixture into ice/water. Filter the solid obtained, wash with water and dry under reduced pressure. Dissolve the solid in EtOAc. Filter through Celite®. Dry over MgSO4 and remove the solvent to obtain 22.36 g of ethyl 3-cyano-4-hydroxy-benzoate (76% yield). MS(ES): m/z=190.0 [M-H]. After cooling Filter the solid obtained wash with water dry under reduced pressure Dissolve the solid in EtOAc Filter through Celite® Dry over MgSO4 remove the solvent

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve ethyl 4-hydroxy-benzoate (102.2 g, 0.61 mol) in AcOH (200 mL) at 65° C. Add dropwise a solution of ICl (100 g, 0.61 moles) in AcOH (500 mL). After the addition, stir the mixture at 65° C. for 6 hours. Pour the mixture into ice/water, filter and wash the solid with water. Dissolve the solid in CH2Cl2, dry it over MgSO4, filter and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with CH2Cl2 to obtain 131.3 g of ethyl 4-hydroxy-3-iodo-benzoate (74% yield). After the addition filter wash the solid with water Dissolve the solid in CH2Cl2 dry it over MgSO4 filter concentrate under reduced pressure Subject residue to silica gel chromatography eluting with CH2Cl2

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve ethyl 4-hydroxy-benzoate (102.2 g, 0.61 mol) in AcOH (200 mL) at 65° C. Add dropwise a solution of ICl (100 g, 0.61 moles) in AcOH (500 mL). After the addition, stir the mixture at 65° C. for 6 hours. Pour the mixture into ice/water, filter and wash the solid with water. Dissolve the solid in CH2Cl2, dry it over MgSO4, filter and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with CH2Cl2 to obtain 131.3 g of ethyl 4-hydroxy-3-iodo-benzoate (74% yield). After the addition filter wash the solid with water Dissolve the solid in CH2Cl2 dry it over MgSO4 filter concentrate under reduced pressure Subject residue to silica gel chromatography eluting with CH2Cl2

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

Procedure: To a suspension of NaH (0.82 g, 20.5 mmol) in THF (40 ml), a solution of ethyl 4-hydroxy-3-iodo-benzoate (5.0 g, 17.1 mmol) in THF (40 ml), then 15-crown-5 (4.0 ml, 25.6 mmol) and finally a solution of 4-phenylbut-2-enyl bromide (5.41 g, 25.6 mmol) in THF (50 ml) were added subsequently at 0° C. The reaction mixture was kept under stirring at room temperature for 10 minutes and then warmed to 50° C. for 6 h. After equilibration at room temperature, 3 N HCl was added (30 ml) and the mixture poured into a separatory funnel. The organic layer was separated and the aqueous layer extracted with ethyl acetate (3×30 ml). The collected organic layers were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent was eliminated with a rotary evaporator. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=95/5) affording 5.94 g of the title compound (82% yield). warmed to 50° C. for 6 h the mixture poured into a separatory funnel The organic layer was separated the aqueous layer extracted with ethyl acetate (3×30 ml) The collected organic layers were washed with saturated aqueous sodium chloride dried over sodium sulfate The solvent was eliminated with a rotary evaporator The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=95/5)

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

Procedure: To a suspension of NaH (0.82 g, 20.5 mmol) in THF (40 ml), a solution of ethyl 4-hydroxy-3-iodo-benzoate (5.0 g, 17.1 mmol) in THF (40 ml), then 15-crown-5 (4.0 ml, 25.6 mmol) and finally a solution of 4-phenylbut-2-enyl bromide (5.41 g, 25.6 mmol) in THF (50 ml) were added subsequently at 0° C. The reaction mixture was kept under stirring at room temperature for 10 minutes and then warmed to 50° C. for 6 h. After equilibration at room temperature, 3 N HCl was added (30 ml) and the mixture poured into a separatory funnel. The organic layer was separated and the aqueous layer extracted with ethyl acetate (3×30 ml). The collected organic layers were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent was eliminated with a rotary evaporator. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=95/5) affording 5.94 g of the title compound (82% yield). warmed to 50° C. for 6 h the mixture poured into a separatory funnel The organic layer was separated the aqueous layer extracted with ethyl acetate (3×30 ml) The collected organic layers were washed with saturated aqueous sodium chloride dried over sodium sulfate The solvent was eliminated with a rotary evaporator The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=95/5)