3-fluorobenzene-1,2-diol

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: A mixture of 3-fluorobenzene-1,2-diol (5.12 g) and (R*, R*)-(±)-1,4-bis (phenylmethoxy)-2,3-butanediol, bis (4-methylbenzenesulphonate) (24.4 g) was stirred with dimethylformamide (DMF) (160 ml) under a nitrogen stream for 45 min. Anhydrous cesium carbonate (13.0 g) was added and the mixture was heated to 150° under reflux for 18 hours. The dark brown mixture was cooled to 30° and diluted with di-isopropyl ether (370 ml) and water (30 ml). The layers were separated and the aqueous layer was re-extracted with di-isopropyl ether (150 ml and then 100 ml). The extracts were sequentially washed within 1M hydrochloric acid (300 ml), 30% aqueous sodium chloride (100 ml) and were combined and evaporated in vacuo to a dark brown oil (12.6 g) which was dissolved in a light petroleum-dichloromethane (3:1) (40 ml) and chromatographed over Sorbsil (Trade Mark) (126 g) using light petroleum-dichloromethane mixtures of gradually increasing polarity. Combination of appropriate fractions and evaporation of the solvents gave the title compound as a yellow oil (7.0 g), NMR (CDCl3) 2.6-2.8 (10H, m, Ph), 3.18-3.38 (3H, m, 6-H, 7-H, 8-H), 5.32-5.58 (4H, m, CH2Ph), 5.64 (2H, m, 2-H, 3-H), 6.06-6.32 (4H, m, CH2O). the mixture was heated to 150° under reflux for 18 hours The dark brown mixture was cooled to 30° The layers were separated the aqueous layer was re-extracted with di-isopropyl ether (150 ml The extracts were sequentially washed within 1M hydrochloric acid (300 ml), 30% aqueous sodium chloride (100 ml) evaporated in vacuo to a dark brown oil (12.6 g) which was dissolved in a light petroleum-dichloromethane (3:1) (40 ml) chromatographed over Sorbsil (Trade Mark) (126 g) of gradually increasing polarity Combination of appropriate fractions and evaporation of the solvents

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

Procedure: A mixture of 3-fluorobenzene-1,2-diol (5.12 g) and (R*, R*)-(±)-1,4-bis (phenylmethoxy)-2,3-butanediol, bis (4-methylbenzenesulphonate) (24.4 g) was stirred with dimethylformamide (DMF) (160 ml) under a nitrogen stream for 45 min. Anhydrous cesium carbonate (13.0 g) was added and the mixture was heated to 150° under reflux for 18 hours. The dark brown mixture was cooled to 30° and diluted with di-isopropyl ether (370 ml) and water (30 ml). The layers were separated and the aqueous layer was re-extracted with di-isopropyl ether (150 ml and then 100 ml). The extracts were sequentially washed within 1M hydrochloric acid (300 ml), 30% aqueous sodium chloride (100 ml) and were combined and evaporated in vacuo to a dark brown oil (12.6 g) which was dissolved in a light petroleum-dichloromethane (3:1) (40 ml) and chromatographed over Sorbsil (Trade Mark) (126 g) using light petroleum-dichloromethane mixtures of gradually increasing polarity. Combination of appropriate fractions and evaporation of the solvents gave the title compound as a yellow oil (7.0 g), NMR (CDCl3) 2.6-2.8 (10H, m, Ph), 3.18-3.38 (3H, m, 6-H, 7-H, 8-H), 5.32-5.58 (4H, m, CH2Ph), 5.64 (2H, m, 2-H, 3-H), 6.06-6.32 (4H, m, CH2O). the mixture was heated to 150° under reflux for 18 hours The dark brown mixture was cooled to 30° The layers were separated the aqueous layer was re-extracted with di-isopropyl ether (150 ml The extracts were sequentially washed within 1M hydrochloric acid (300 ml), 30% aqueous sodium chloride (100 ml) evaporated in vacuo to a dark brown oil (12.6 g) which was dissolved in a light petroleum-dichloromethane (3:1) (40 ml) chromatographed over Sorbsil (Trade Mark) (126 g) of gradually increasing polarity Combination of appropriate fractions and evaporation of the solvents

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

Procedure: 51.2 g of 3-fluorocatechol and 36.8 g of glyoxylic acid were dissolved at 20° C. in 160 ml of water and 34.8 g of sodium hydroxide in solution in 400 ml of water were added to this solution cooled to 0° C. The mixture was heated for 4 hours at 46° C., then cooled to 0° C. and the pH was brought to 4.6 by the addition of concentrated hydrochloric acid. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) and the aqueous phase was acidified with concentrated hydrochloric acid until a pH of 1.8 was obtained. Extraction was carried out with ethyl acetate and after evaporation of the solvent, 47.7 g of the desired product were obtained (mixture of isomers, 2,3-bis-hydroxy-4-fluoro; 3,4-bis-hydroxy-5-fluoro; 2-fluoro-3,4-bis-hydroxy) which was used as is in Step A of Example 16. The mixture was heated for 4 hours at 46° C. cooled to 0° C. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) was obtained Extraction after evaporation of the solvent

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

Procedure: 51.2 g of 3-fluorocatechol and 36.8 g of glyoxylic acid were dissolved at 20° C. in 160 ml of water and 34.8 g of sodium hydroxide in solution in 400 ml of water were added to this solution cooled to 0° C. The mixture was heated for 4 hours at 46° C., then cooled to 0° C. and the pH was brought to 4.6 by the addition of concentrated hydrochloric acid. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) and the aqueous phase was acidified with concentrated hydrochloric acid until a pH of 1.8 was obtained. Extraction was carried out with ethyl acetate and after evaporation of the solvent, 47.7 g of the desired product were obtained (mixture of isomers, 2,3-bis-hydroxy-4-fluoro; 3,4-bis-hydroxy-5-fluoro; 2-fluoro-3,4-bis-hydroxy) which was used as is in Step A of Example 16. The mixture was heated for 4 hours at 46° C. cooled to 0° C. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) was obtained Extraction after evaporation of the solvent

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

Procedure: 51.2 g of 3-fluorocatechol and 36.8 g of glyoxylic acid were dissolved at 20° C. in 160 ml of water and 34.8 g of sodium hydroxide in solution in 400 ml of water were added to this solution cooled to 0° C. The mixture was heated for 4 hours at 46° C., then cooled to 0° C. and the pH was brought to 4.6 by the addition of concentrated hydrochloric acid. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) and the aqueous phase was acidified with concentrated hydrochloric acid until a pH of 1.8 was obtained. Extraction was carried out with ethyl acetate and after evaporation of the solvent, 47.7 g of the desired product were obtained (mixture of isomers, 2,3-bis-hydroxy-4-fluoro; 3,4-bis-hydroxy-5-fluoro; 2-fluoro-3,4-bis-hydroxy) which was used as is in Step A of Example 16. The mixture was heated for 4 hours at 46° C. cooled to 0° C. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) was obtained Extraction after evaporation of the solvent

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

Procedure: 51.2 g of 3-fluorocatechol and 36.8 g of glyoxylic acid were dissolved at 20° C. in 160 ml of water and 34.8 g of sodium hydroxide in solution in 400 ml of water were added to this solution cooled to 0° C. The mixture was heated for 4 hours at 46° C., then cooled to 0° C. and the pH was brought to 4.6 by the addition of concentrated hydrochloric acid. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) and the aqueous phase was acidified with concentrated hydrochloric acid until a pH of 1.8 was obtained. Extraction was carried out with ethyl acetate and after evaporation of the solvent, 47.7 g of the desired product were obtained (mixture of isomers, 2,3-bis-hydroxy-4-fluoro; 3,4-bis-hydroxy-5-fluoro; 2-fluoro-3,4-bis-hydroxy) which was used as is in Step A of Example 16. The mixture was heated for 4 hours at 46° C. cooled to 0° C. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) was obtained Extraction after evaporation of the solvent

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

Procedure: 3-fluorocatechol 1.0 g was dissolved in 15% borontrifluoride acetonitrile solution. To the solution was added 7-aminocephalosporanic acid at 5° C. After the stirring for 40 hours at room temperature, the reaction mixture was concentrated to dryness and dissolved in water with the addition of sodium bicarbonate pH 7.0). The solution was washed with ethyl acetate and acidified with 6N-hydrochloric acid to pH The resulting crude crystals were collected by filtration and washed with water to give a mixture of the title compounds (1.74 g). The isolation and purification by high performance liquid chromatography (eluent; 3% acetonitrile in potassium phosphate buffer pH 6.0, column; ODS) gave the fractions of A and B as the order of elution. Each fraction was concentrated to dryness and the resulting solids were slurried in N,N-dimethylacetamide and filtered, respectively. Each DMAc solutions of title compounds A and B were submitted to the next step (Exp. 9 and Exp. 10) without further purification. the reaction mixture was concentrated to dryness dissolved in water with the addition of sodium bicarbonate pH 7.0) The solution was washed with ethyl acetate were collected by filtration washed with water to give The isolation and purification by high performance liquid chromatography (eluent; 3% acetonitrile in potassium phosphate buffer pH 6.0, column; ODS) gave the fractions of A and B as the order of elution Each fraction was concentrated to dryness filtered Each DMAc solutions of title compounds A and B were submitted to the next step (Exp. 9 and Exp. 10) without further purification

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

Procedure: 51.2 g of 3-fluorocatechol and 36.8 g of glyoxylic acid were dissolved at 20° C. in 160 ml of water and 34.8 g of sodium hydroxide in solution in 400 ml of water were added to this solution cooled to 0° C. The mixture was heated for 4 hours at 46° C., then cooled to 0° C. and the pH was brought to 4.6 by the addition of concentrated hydrochloric acid. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) and the aqueous phase was acidified with concentrated hydrochloric acid until a pH of 1.8 was obtained. Extraction was carried out with ethyl acetate and after evaporation of the solvent, 47.7 g of the desired product were obtained (mixture of isomers, 2,3-bis-hydroxy-4-fluoro; 3,4-bis-hydroxy-5-fluoro; 2-fluoro-3,4-bis-hydroxy) which was used as is in Step A of Example 16. The mixture was heated for 4 hours at 46° C. cooled to 0° C. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) was obtained Extraction after evaporation of the solvent

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

Procedure: A mixture of 3-fluorobenzene-1,2-diol (145 g, 1132 mmol), potassium carbonate (313 g, 2264 mmol) and iodomethane (177 mL, 2830 mmol) in N,N-Dimethylformamide (DMF) (300 mL) was stirred at RT for 48 h. LCMS showed the complete consuption of starting material. The mixture was diluted with ethyl acetate (EA), filtered, washed with water, dried and evaporated in vacuo. The crude material was purified by normal phase automatic silica gel column chromatography (Combiflash RF, 220 g column), eluting with EA/Hexane (10%-80%) to afford 1-fluoro-2,3-dimethoxybenzene (149 g, 954 mmol, 84% yield) as a colorless oil. LCMS (M+H)+: 157.0. filtered washed with water dried evaporated in vacuo The crude material was purified by normal phase automatic silica gel column chromatography (Combiflash RF, 220 g column) eluting with EA/Hexane (10%-80%)

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 ml flask were added 38.4 (0.3 mol) of 3-fluorocatechol [H], 12 g (0.3 mol) of sodium hydroxide and 100 ml of ethanol. After cooling to around 10° C., 100 ml of an ethanol solution of 76.3 g (0.7 mol) of bromoethane was slowly added. After the termination of the addition, they were reacted under a reflux temperature for 5 hours. After the termination of the reaction, dichloromethane was added, followed by extraction. The extraction liquid was washed with water and dried, and the solvent was removed by distillation to obtain 45.5 g of 1,2-diethoxy-3-fluorobenzene [G1] as an oily product. The process yield was 81%. After the termination of the addition, they were reacted under a reflux temperature for 5 hours was added followed by extraction The extraction liquid was washed with water dried the solvent was removed by distillation