ethyl 7-hydroxy-3,4-dihydro-2H-chromene-2-carboxylate

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

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

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

Procedure: In a similar manner 4-(5-fluorobenzothiazol-2-ylmethoxy)-4'-hydroxydiphenyl, m.p. 210°-211° C. was prepared from 2-chloromethyl-5-fluorobenzothiazole and 4,4-dihydroxydiphenyl, 3-(5-fluorobenzothiazol-2-ylmethylthio)benzyl alcohol was prepared from 3-mercaptobenzyl alcohol and 2-chloromethyl-5-fluorobenzothiazole and 2-ethoxycarbonyl-7-(5-fluorobenzothiazol-2-ylmethoxy)chroman, m.p. 109°-112° C. was prepared from 2-chloromethyl-5-fluorobenzothiazole and 2-ethoxycarbonyl-7-hydroxychroman.

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

Procedure: A solution of ethyl 7-hydroxychroman-2-carboxylate (5.0 g, 22.5 mmol) in THF is treated with N-chlorosuccinimide (NCS) (3.6 g, 27 mmol), stirred for 40 hr and concentrated in vacuo. The resultant residue is purified chromatographically (silica gel/20% EtOAc in hexanes as eluent) to give the title product, 3.0 g (52% yield), identified by NMR and mass spectral analyses. concentrated in vacuo The resultant residue is purified chromatographically (silica gel/20% EtOAc in hexanes as eluent)

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

Procedure: A mixture of ethyl 7-hydroxy-chroman-2-carboxylate (6.1 g, 27.5 mmol), potassium carbonate (7.6 g, 55 mmol), potassium iodide (1.8 g, 11 mmol) and benzyl chloride (3.4 mL, 30 mmol) in acetone is heated at reflux for 16 hr under nitrogen, cooled, concentrated, diluted with water and extracted with EtOAc. The combined extracts are dried over MgSO4 and concentrated to afford the title compound as a straw-colored oil 8.58 g (100% yield), identified by NMR and mass spectral analyses. is heated at reflux for 16 hr under nitrogen cooled concentrated diluted with water extracted with EtOAc The combined extracts are dried over MgSO4 concentrated

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

Procedure: A solution of ethyl 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (19.0 g, 0.081 mol) in acetic acid is hydrogenated over 10% Pd/C (4.5 g) at 50 psi H2 for 16 hr at ambient temperatures. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to give a residue. The residue is dissolved in EtOAc, washed with saturated NaHCO3, dried over Na2SO4 and concentrated in vacuo to give a solid residue. Crystallization of the solid from CCl4 affords the title compound as an off-white solid, 17.2 g (96% yield), mp 78-80° C., identified by NMR and mass spectral analyses. The catalyst is removed by filtration the filtrate is concentrated in vacuo to give a residue washed with saturated NaHCO3 dried over Na2SO4 concentrated in vacuo to give a solid residue Crystallization of the solid from CCl4

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

Procedure: To a 5 L acetone solution of ethyl 7-hydroxy-chromane-2-carboxylate (630.1 g, 2.84 mol) was added potassium carbonate powder (785 g, 5.68 mol) and benzyl bromide (405 ml, 3.41 mol). The resulting suspension was heated to reflux for 16 hr. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give solid material, which was re-dissolved in AcOEt, washed with water to remove residual salt, dried over MgSO4, filtered, concentrated to a small volume. Addition of hexanes caused precipitation of the title compound, which was collected by suction-filtration. The filtrate was triturated from dichloromethane-hexanes to give more precipitates. Finally the filtrate was concentrated and chromatographed on silica gel eluting with 20 to 80% dichloromethane/hexanes. Combination of all crops yielded the title compound 760.2 g as off-white solid (86%). The resulting suspension was heated to reflux for 16 hr The reaction mixture was filtered through a pad of celite The filtrate was concentrated to give solid material, which washed with water to remove residual salt dried over MgSO4 filtered concentrated to a small volume Addition of hexanes precipitation of the title compound, which was collected by suction-filtration The filtrate was triturated from dichloromethane-hexanes to give more precipitates Finally the filtrate was concentrated chromatographed on silica gel eluting with 20 to 80% dichloromethane/hexanes

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

Procedure: To a 60 ml dichloromethane solution of ethyl 7-hydroxychromane-2-carboxylate (1.32 g, 5.9 mmol), 2-bromoethanol (0.84 ml, 11.9 mmol), and triphenylphosphine (3.12 g, 11.9 mmol) was added diisopropyl azodicarboxylate (2.34 ml, 11.9 mmol) dropwise upon cooling in an ice-water bath. After stirring at rt overnight, the solvent was removed under reduced pressure, and the residue was chromatographed on silica gel eluting with 10% AcOEt/hexanes to give the title compound 1.27 g (65%). upon cooling in an ice-water bath the solvent was removed under reduced pressure the residue was chromatographed on silica gel eluting with 10% AcOEt/hexanes

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

Procedure: To a 60 ml dichloromethane solution of ethyl 7-hydroxychromane-2-carboxylate (1.32 g, 5.9 mmol), 2-bromoethanol (0.84 ml, 11.9 mmol), and triphenylphosphine (3.12 g, 11.9 mmol) was added diisopropyl azodicarboxylate (2.34 ml, 11.9 mmol) dropwise upon cooling in an ice-water bath. After stirring at rt overnight, the solvent was removed under reduced pressure, and the residue was chromatographed on silica gel eluting with 10% AcOEt/hexanes to give the title compound 1.27 g (65%). upon cooling in an ice-water bath the solvent was removed under reduced pressure the residue was chromatographed on silica gel eluting with 10% AcOEt/hexanes

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

Procedure: To a 200 ml acetone solution of ethyl 7-hydroxychromane-2-carboxylate (9.18 g, 41.3 mmol) was added benzyl 3-bromopropyl ether (14.2 g, 62.0 mmol), powdered potassium carbonate (11.4 g, 82.5 mmol), and tetrabutylammonium iodide (1.53 g, 4 mmol). The resulting suspension was heated to reflux overnight. Acetone was removed under reduced pressure, diluted with AcOEt and sat. NH4Claq. The organic layer was separated. The aqueous layer was extracted with AcOEt twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on slica gel eluting with 10% AcOEt/hexanes to give the title compound 10.1 g (66%). The resulting suspension was heated to reflux overnight Acetone was removed under reduced pressure diluted with AcOEt and sat. NH4Claq The organic layer was separated The aqueous layer was extracted with AcOEt twice The combined organic layers were dried over anhydrous Na2SO4 filtered concentrated chromatographed on slica gel eluting with 10% AcOEt/hexanes

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

Procedure: To a 200 ml acetone solution of ethyl 7-hydroxychromane-2-carboxylate (9.18 g, 41.3 mmol) was added benzyl 3-bromopropyl ether (14.2 g, 62.0 mmol), powdered potassium carbonate (11.4 g, 82.5 mmol), and tetrabutylammonium iodide (1.53 g, 4 mmol). The resulting suspension was heated to reflux overnight. Acetone was removed under reduced pressure, diluted with AcOEt and sat. NH4Claq. The organic layer was separated. The aqueous layer was extracted with AcOEt twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on slica gel eluting with 10% AcOEt/hexanes to give the title compound 10.1 g (66%). The resulting suspension was heated to reflux overnight Acetone was removed under reduced pressure diluted with AcOEt and sat. NH4Claq The organic layer was separated The aqueous layer was extracted with AcOEt twice The combined organic layers were dried over anhydrous Na2SO4 filtered concentrated chromatographed on slica gel eluting with 10% AcOEt/hexanes

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 50 ml round-bottom flask were added ethyl 7-hydroxychromane-2-carboxylate (100 mg, 0.45 mmol), 4-(3-bromopropoxy)-3-propylphenyl phenyl ether (U.S. Pat. No. 6,008,237) (188 mg, 0.54 mmol), cesium carbonate (176 mg, 0.54 mmol), and DMF 3 ml. The resulting suspension was stirred at 70° C. for 5 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Eluting with 10% AcOEt/hexanes gave the title compound as a pale yellow oil 167 mg (76%). The solvent was removed under reduced pressure The residue was diluted with AcOEt and water The organic layer was separated The aqueous layer was extracted twice with AcOEt The combined organic layers were dried over anhydrous Na2SO4 filtered concentrated chromatographed on silica gel Eluting with 10% AcOEt/hexanes