6-fluoro-2,3-dihydrochromen-4-one

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

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

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

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

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

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

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

Procedure: 28.8 g of 2-trimethylsilyl-1,3-dithiane were dissolved in 290 ml of peroxide-free tetrahydrofuran and the solution was treated dropwise at -60° C. with 93 ml of a 1.6M solution of n-butyl lithium in hexane. The mixture was left to warm to 0° C. within 3 hours and subsequently again cooled to -60° C. A solution of 24.87 g of 6-fluoro-4-chromanone in 150 ml of tetrahydrofuran was subsequently slowly added dropwise and the mixture was left to warm slowly from -60° C. to room temperature while stirring overnight. The mixture was subsequently poured into 2.5 l of water and extracted with four portions of ethyl acetate. The organic extracts were washed with saturated sodium chloride solution and dried with sodium sulfate The concentrated extract was decolorized with active carbon in a mixture of ether and low-boiling petroleum ether (1:1) and crystallized from the same mixture in the cold. After two recrystallizations, the combined mother liquors were chromatographed on a silica gel 60 column [hexane/ethyl acetate (9:1)]. The product-containing fractions were concentrated and the residue was recrystallized. There was obtained 4-m-dithian-2-ylidene-6-fluoro-2,3-dihydro-4H-1-benzopyran of melting point 47°-49° C. The mixture was left subsequently again cooled to -60° C the mixture was left to warm slowly from -60° C. to room temperature extracted with four portions of ethyl acetate The organic extracts were washed with saturated sodium chloride solution dried with sodium sulfate The concentrated extract was decolorized with active carbon in a mixture of ether and low-boiling petroleum ether (1:1) crystallized from the same mixture in the cold After two recrystallizations the combined mother liquors were chromatographed on a silica gel 60 column [hexane/ethyl acetate (9:1)] The product-containing fractions were concentrated the residue was recrystallized

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

Procedure: 28.8 g of 2-trimethylsilyl-1,3-dithiane were dissolved in 290 ml of peroxide-free tetrahydrofuran and the solution was treated dropwise at -60° C. with 93 ml of a 1.6M solution of n-butyl lithium in hexane. The mixture was left to warm to 0° C. within 3 hours and subsequently again cooled to -60° C. A solution of 24.87 g of 6-fluoro-4-chromanone in 150 ml of tetrahydrofuran was subsequently slowly added dropwise and the mixture was left to warm slowly from -60° C. to room temperature while stirring overnight. The mixture was subsequently poured into 2.5 l of water and extracted with four portions of ethyl acetate. The organic extracts were washed with saturated sodium chloride solution and dried with sodium sulfate The concentrated extract was decolorized with active carbon in a mixture of ether and low-boiling petroleum ether (1:1) and crystallized from the same mixture in the cold. After two recrystallizations, the combined mother liquors were chromatographed on a silica gel 60 column [hexane/ethyl acetate (9:1)]. The product-containing fractions were concentrated and the residue was recrystallized. There was obtained 4-m-dithian-2-ylidene-6-fluoro-2,3-dihydro-4H-1-benzopyran of melting point 47°-49° C. The mixture was left subsequently again cooled to -60° C the mixture was left to warm slowly from -60° C. to room temperature extracted with four portions of ethyl acetate The organic extracts were washed with saturated sodium chloride solution dried with sodium sulfate The concentrated extract was decolorized with active carbon in a mixture of ether and low-boiling petroleum ether (1:1) crystallized from the same mixture in the cold After two recrystallizations the combined mother liquors were chromatographed on a silica gel 60 column [hexane/ethyl acetate (9:1)] The product-containing fractions were concentrated the residue was recrystallized

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

Procedure: 6-Fluorochroman-4-one (352 mg, 2.12 mmol) and 4-chlorothiophenol (320 mg, 2.2 mmol) were dissolved in 5 mL DCM. The reaction mixture was cooled to 0° C. and 2.4 mL of trifluoroacetic acid was added. After 5 min at 0° C., pyridine-borane complex (0.20 mL) was slowly added. The reaction mixture was stirred for 1 h at 0° C. Et2O (100 mL) and sat. NaHCO3 solution (100 mL) were added. The ether layer was dried over Na2SO4 and concentrated. The residue was dissolved in 10 mL DCM, mCPBA (77%, 1.01 g, 4.50 mmol) was added and the reaction mixture was stirred at room temperature overnight. 2 g of Na2SO3 in 20 mL of water was added and the reaction was stirred for 1 h then filtered. The layers were separated, then the organic layer was washed with 1N NaOH solution (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using hex./EtOAc as the eluent (gradient from 100/0 to 30/70 in 60 min, 0.37 g, 53%). 1H NMR (CDCl3 400 MHz) δ 7.67 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 6.92 (m, 2H), 6.77 (m, 1H), 4.24 (m, 2H), 4.10 (m, 1H), 2.36 (m, 1H), 2.18 (m, 1H). pyridine-borane complex (0.20 mL) was slowly added The ether layer was dried over Na2SO4 concentrated The residue was dissolved in 10 mL DCM the reaction mixture was stirred at room temperature overnight the reaction was stirred for 1 h then filtered The layers were separated the organic layer was washed with 1N NaOH solution (100 mL) dried over Na2SO4 concentrated The product was purified by column chromatography as the eluent (gradient from 100/0 to 30/70 in 60 min, 0.37 g, 53%)

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

Procedure: 6-Fluorochroman-4-one (352 mg, 2.12 mmol) and 4-chlorothiophenol (320 mg, 2.2 mmol) were dissolved in 5 mL DCM. The reaction mixture was cooled to 0° C. and 2.4 mL of trifluoroacetic acid was added. After 5 min at 0° C., pyridine-borane complex (0.20 mL) was slowly added. The reaction mixture was stirred for 1 h at 0° C. Et2O (100 mL) and sat. NaHCO3 solution (100 mL) were added. The ether layer was dried over Na2SO4 and concentrated. The residue was dissolved in 10 mL DCM, mCPBA (77%, 1.01 g, 4.50 mmol) was added and the reaction mixture was stirred at room temperature overnight. 2 g of Na2SO3 in 20 mL of water was added and the reaction was stirred for 1 h then filtered. The layers were separated, then the organic layer was washed with 1N NaOH solution (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using hex./EtOAc as the eluent (gradient from 100/0 to 30/70 in 60 min, 0.37 g, 53%). 1H NMR (CDCl3 400 MHz) δ 7.67 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 6.92 (m, 2H), 6.77 (m, 1H), 4.24 (m, 2H), 4.10 (m, 1H), 2.36 (m, 1H), 2.18 (m, 1H). pyridine-borane complex (0.20 mL) was slowly added The ether layer was dried over Na2SO4 concentrated The residue was dissolved in 10 mL DCM the reaction mixture was stirred at room temperature overnight the reaction was stirred for 1 h then filtered The layers were separated the organic layer was washed with 1N NaOH solution (100 mL) dried over Na2SO4 concentrated The product was purified by column chromatography as the eluent (gradient from 100/0 to 30/70 in 60 min, 0.37 g, 53%)

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

Procedure: 6-Fluoro-chroman-4-one (539 mg, 3.24 mmol) was dissolved in Sulfuric acid (6.0 mL) and Sodium azide (258 mg, 3.97 mmol) was added at room temperature. The reaction was stirred for 30 h, then poured into water. The solids were collected by filtration, washing with 50 mL water. After drying, 7-Fluoro-3,4-dihydro-2H-b enzo[f][1,4]oxazepin-5-one was isolated as a white solid (395 mg, 67%). 1H-NMR (CDCl3): 7.65 (m, 1H), 7.15 (m, 1H), 7.01 (m, 1H), 6.74 (s, 1H), The solids were collected by filtration washing with 50 mL water After drying

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

Procedure: Later developments in the overall method of production then finally gave a process for producing sorbinil which involved the following steps, viz., (1) p-fluorophenol was first converted to β-(p-fluorophenoxy)propionitrile by treatment with acrylonitrile in the presence of Triton B; (2) the nitrile intermediate was then converted to β-(p-fluorophenoxy)propionic acid by means of hydrochloric acid; (3) β-(p-fluorophenoxy)propionic acid was then condensed in the presence of concentrated sulfuric acid at 50° C. to afford 6-fluoro-4-chromanone; (4) the latter compound was thereafter condensed with potassium cyanide and ammonium carbonate in ethanol under standard Bucherer-Berg conditions to give the racemic precursor of sorbinil, which is called dl-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione; (5) the latter racemic spiro-hydantoin was then hydrolyzed with aqueous sodium hydroxide to the corresponding spiro-amino acid, which is called 4-amino-6-fluorochroman-4-carboxylic acid; (6) the latter acid, which can not be conveniently isolated in the process, was then treated in situ with sodium or potassium cyanate (after first adjusting the pH of the aqueous solution) in order to convert the amino acid to the corresponding hydantoic acid, which is called 6-fluoro-4-ureidochroman-4-carboxylic acid; (7) the latter hydantoic acid was then resolved according to the method described by B. W. Cue, Jr. et al. U.S. Pat. No. 4,435,578 by treatment with l-(-)-ephedrine in aqueous methanol to form the l-(-)-ephedrine salt of (4S)-6-fluoro-4-ureidochroman-4-carboxylic acid; and (8) the latter crystalline salt was thereafter converted to sorbinil by heating the diastereoisomer in glacial acetic acid to effect conversion to the desired (4S)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione.