ethyl 2,3-dibromopropanoate

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a hot (about 80° C.) solution of N,N′-dibenzylethylenediamine (216 g, 0.9 mol) and triethylamine (300 uL, 2.16 mol) in toluene (650 mL) was added rapidly dropwise ethyl 2,3-dibromopropionate (240 g, 0.93 mol) in toluene (650 mL). After the addition, the reaction mixture was stirred at 80° C. for about three hours. A temperature below about 95° C. was maintained. The heavy precipitate was filtered off and then solvent and excess TEA removed. t-butyl methyl ether (about 300 mL) was added. The reaction was stirred well, and any precipitate that was formed was filtered. The reaction was concentrated to a pale yellow oil (about 287 g, about 94%) After the addition A temperature below about 95° C. was maintained The heavy precipitate was filtered off solvent and excess TEA removed t-butyl methyl ether (about 300 mL) was added The reaction was stirred well any precipitate that was formed was filtered The reaction was concentrated to a pale yellow oil (about 287 g, about 94%)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of ethyl 2,3-dibromopropionate (142.7 g, 0.549 mol) in dry toluene (2000 mL) was added N,N′-dibenzylethylene diamine (132 g, 0.549 mol), followed by triethylamine (110.8 g, 1.098 mol), under N2 at 40° C. (a dense white precipitate formed immediately, thus good stirring was necessary). The mixture was heated at 80° C. overnight, cooled and filtered. The filtrate was then washed with H2O, dried over MgSO4, and concentrated under reduced pressure. The residue oil was taken on to the next step without further purification (GC-MS shows one peak at 6.79) or purified by column chromatography (EtOAc/hexane 1:4). Weight of crude product: 169.6 g (91%). formed immediately cooled filtered The filtrate was then washed with H2O dried over MgSO4 concentrated under reduced pressure The residue oil was taken on to the next step without further purification (GC-MS shows one peak at 6.79) purified by column chromatography (EtOAc/hexane 1:4)

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

Procedure: 26 g (100 mmol) of ethyl 2,3-dibromopropionate and 36.4 g (264 mmol) of anhydrous potassium carbonate are added to 40 g (181 mmol) of catechol dissolved in 200 ml of anhydrous acetone. The operation is repeated 4 times within one hour; the reaction mixture is then heated to boiling. After 18 hours at reflux under argon, the mixture is cooled and then filtered over Celite. After concentration of the filtrate in vacuo, the residue is hydrolysed and then the aqueous phase is extracted with ether. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. The title ester is obtained pure by distillation under reduced pressure (15 mm Hg; b.p.=155° C.). within one hour the reaction mixture is then heated to boiling After 18 hours at reflux under argon the mixture is cooled filtered over Celite the aqueous phase is extracted with ether The organic phase is dried over magnesium sulphate concentrated in vacuo

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

Procedure: 3-Amino-4-hydroxy-benzonitrile (180 mg, 1.34 mmol) was dissolved in acetone (1.4 mL). To the solution was added K2CO3 (555 mg, 4.02 mmol) and ethyl 2,3-dibromopropanoate (380 mg, 1.46 mmol). The mixture was heated to reflux for 16 h. After cooling to room temperature the reaction mixture was filtered and concentrated in vacuo to give an oil. The oil was dissolved in methanol and was purified by silica gel chromatography (0-10% dichloromethane/hexanes) to afford methyl 6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (148 mg, 0.68 mmol). The methyl ester was isolated as methanol was used for loading the compound on silica resulting in transesterification. 1H NMR (400.0 MHz, DMSO-d6) δ 6.98 (dd, J=2.0, 8.2 Hz, 1H), 6.93-6.90 (m, 2H), 6.34 (s, 1H), 5.13 (t, J=3.3 Hz, 1H), 3.66 (s, 3H), 3.50-3.41 (m, 2H). The mixture was heated to reflux for 16 h was filtered concentrated in vacuo to give an oil was purified by silica gel chromatography (0-10% dichloromethane/hexanes)

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

Procedure: To a solution of 2-amino-5-methylphenol (10 g, 81.3 mmol) in acetone (150 mL) was added K2CO3 (24.5 g, 243.9 mmol) and ethyl 2,3-dibromopropanoate (23.3 g, 89.4 mmol). The mixture was heated at reflux for 16 h. The filtrate was concentrated in vacuo to give an oil. Purification by silica gel chromatography (hexane/ethyl acetate gradient) provided ethyl 7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (8.5 g, 47.3% yield). 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J=0.8 Hz, 1H), 6.60 (dd, J=1.2, 8.0 Hz, 1H), 6.19 (d, J=8.0 Hz, 1H), 4.78 (t, J=3.6 Hz, 1H), 4.29-4.21 (m, 2H), 3.59-3.52 (m, 2H), 2.23 (s, 3H), 1.28 (t, J=7 Hz, 3H). The mixture was heated at reflux for 16 h The filtrate was concentrated in vacuo to give an oil Purification by silica gel chromatography (hexane/ethyl acetate gradient)

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

Procedure: A warm solution of 2-aminoethanethiol (10.0 g, 0.130 mol) and triethylamine (36 mL, 0.260 mol) in chloroform is added over 5 minutes to a solution of ethyl 2,3-dibromopropionate (33.9 g, 0.130 mol) in a chloroform/toluene (1:1.6) solution. The reaction mixture is stirred at room temperature for 2.5 hours, filtered and concentrated in vacuo to obtain an orange liquid. The liquid is vacuum distilled to give the title product as a colorless liquid, bp 121°-124° C. at 3 mm Hg. filtered concentrated in vacuo to obtain an orange liquid distilled

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

Procedure: 7B was treated with ethyl 2,3-dibromopropionate to form the ethyl ester of 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid, and this was converted to 7, mp: 83°-85° C., by the procedures described in the other examples.

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

Procedure: 7B was treated with ethyl 2,3-dibromopropionate to form the ethyl ester of 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid, and this was converted to 7, mp: 83°-85° C., by the procedures described in the other examples.

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

Procedure: 43.0 g of 2-amino-4-chlorophenol was dissolved in 500 ml of anhydrous acetone containing 42.0 g of anhydrous potassium carbonate. That mixture was heated to reflux temperature and 23.0 g of ethyl 2,3-dibromopropionate was added dropwise. In three additional portions each, additional ester and carbonate were added to the refluxing mixture until a total of 124 g of carbonate and 85.8 g of ester had been added. The mixture was refluxed for 21 hours. Solids were filtered from the mixture and washed with acetone. The filtrate was stripped of solvent and the residue was taken up in water. The water solution was extracted with ether. The ether extract was dried (MgSO4) and the solvent was stripped. The residue was eluted through a silica gel column using Solvent No. 3, the solvent was stripped and the residue was recrystallized from ethanol, then from ether to give ethyl 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (3A), as white crystals, mp; 85.5°-86.5° C. That mixture was heated was added dropwise had been added The mixture was refluxed for 21 hours Solids were filtered from the mixture washed with acetone The water solution was extracted with ether The ether extract was dried (MgSO4) The residue was eluted through a silica gel column the residue was recrystallized from ethanol

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

Procedure: 43.0 g of 2-amino-4-chlorophenol was dissolved in 500 ml of anhydrous acetone containing 42.0 g of anhydrous potassium carbonate. That mixture was heated to reflux temperature and 23.0 g of ethyl 2,3-dibromopropionate was added dropwise. In three additional portions each, additional ester and carbonate were added to the refluxing mixture until a total of 124 g of carbonate and 85.8 g of ester had been added. The mixture was refluxed for 21 hours. Solids were filtered from the mixture and washed with acetone. The filtrate was stripped of solvent and the residue was taken up in water. The water solution was extracted with ether. The ether extract was dried (MgSO4) and the solvent was stripped. The residue was eluted through a silica gel column using Solvent No. 3, the solvent was stripped and the residue was recrystallized from ethanol, then from ether to give ethyl 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (3A), as white crystals, mp; 85.5°-86.5° C. That mixture was heated was added dropwise had been added The mixture was refluxed for 21 hours Solids were filtered from the mixture washed with acetone The water solution was extracted with ether The ether extract was dried (MgSO4) The residue was eluted through a silica gel column the residue was recrystallized from ethanol

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 150 ml of dimethylformamide was dissolved 8.42 g (46.2 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 12.8 g (92.4 mmol) of potassium carbonate and 18.0 ml (69.3 mmol) of ethyl 2,3-dibromopropionate were added to the solution, followed by stirring at 80° C. for 6 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 3.16 g (24%) of Compound 42. The compound was recrystallized from ethanol for purification. were added to the solution After evaporation of the solvent to partition between chloroform and water the chloroform layer was concentrated to dryness under reduced pressure eluted with chloroform

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 150 ml of dimethylformamide was dissolved 8.42 g (46.2 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 12.8 g (92.4 mmol) of potassium carbonate and 18.0 ml (69.3 mmol) of ethyl 2,3-dibromopropionate were added to the solution, followed by stirring at 80° C. for 6 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 3.16 g (24%) of Compound 42. The compound was recrystallized from ethanol for purification. were added to the solution After evaporation of the solvent to partition between chloroform and water the chloroform layer was concentrated to dryness under reduced pressure eluted with chloroform