2,2,5-trimethyl-1,3-dioxane-4,6-dione

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,2,5-trimethyl-1,3-dioxan-4,6-dione II (17.4 g, 110 mmol), 4-acetoxy-azetidinone I (28.7 g, 100 mmol) and K2CO3 (15.2 g, 110 mmol) were mixed in dry acetonitrile (150 mL, KF=5.6 mg/mL), and the mixture was aged at 45-50° for 14 hours. Upon completion, the reaction mixture was cooled to room temperature and water (150 mL) was added. The organic layer was separated and the aqueous layer was back extracted with acetonitrile (100 mL). Combined organic extracts were washed with brine (100 mL) and concentrated to ca. 50 mL in volume. The mixture was then diluted with heptane (200 mL) and concentrated to 50 mL. Additional heptane (150 mL) was added and the mixture was aged at room temperature for crystallization. The resulting product was collected by filtration, washed with heptane (50 mL) and dried under vacuum at 40-50 for 15 hours to give an off-white crystalline solid (30.9 g, 80.2 mmol). A second crop was obtained by concentrating the combined filtrate and washed to ca. 50 mL in and aging at room temperature to give a white, fluffy solid (2.07 g, 5.4 mmol). Combined yield was 85.6%. Melting Range (° C.) 78-83 d. The organic layer was separated the aqueous layer was back extracted with acetonitrile (100 mL) Combined organic extracts were washed with brine (100 mL) concentrated to ca. 50 mL in volume The mixture was then diluted with heptane (200 mL) concentrated to 50 mL Additional heptane (150 mL) was added the mixture was aged at room temperature for crystallization The resulting product was collected by filtration washed with heptane (50 mL) dried under vacuum at 40-50 for 15 hours

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL 3-necked round bottomed flask equipped with a stir bar, thermowell and a condenser connected to a nitrogen line was added 10.0 g (0.0632 mole) of 2,2,5-trimethyl-1,3-dioxane-4,6-dione, 7.7 g (0.0632 mol) of allyl bromide, 21 g (0.152 mol) of potassium carbonate and 200 mL of acetone. The mixture was refluxed with stirring overnight at which time it was allowed to cool, diluted with 200 mL of ethyl ether and filtered through a bed of Celite/activated charcoal. The filtrate was washed with water and brine and dried overnight over anhydrous sodium sulfate. The suspension was filtered and the filtrate evaporated on a rotary evaporator to yield 11 g of 2,2-dimethyl-5-allyl-1,3-dioxane-4,6-dione compound as shown in Formula (IV)) as a clear, colorless oil. To a 500 mL 3-necked round bottomed flask equipped with a stir bar thermowell and a condenser connected to a nitrogen line The mixture was refluxed to cool filtered through a bed of Celite/activated charcoal The filtrate was washed with water and brine dried overnight over anhydrous sodium sulfate The suspension was filtered the filtrate evaporated on a rotary evaporator

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL 3-necked round bottomed flask equipped with a stir bar, thermowell, and a condenser connected to a nitrogen line was added 10.0 g (0.0632 mole) of 2,2,5-trimethyl-1,3-dioxane-4,6-dione, 10.6 g (0.0632 mol) of p-(chloromethyl)styrene, 35 g (0.2528 mol) of potassium carbonate and 200 mL of acetone. Approximately 1 g of phenothiazine was added as a stabilizer. The mixture was refluxed with stirring overnight at which time it was allowed to cool, diluted with 200 mL of ethyl acetate and filtered through a bed of Celite. The filtrate was washed with water and brine and dried overnight over anhydrous sodium sulfate. The suspension was filtered and the filtrate evaporated on a rotary evaporator to a light brown oil which spontaneously crystallized. The crystals were collected and washed with 35-65 petroleum ether to yield 3.5 g of 2,2-dimethyl-5-(4-vinylbenzyl)-1,3-dioxane-4,6-dione as shown by formula (III). To a 500 mL 3-necked round bottomed flask equipped with a stir bar thermowell, and a condenser connected to a nitrogen line The mixture was refluxed to cool filtered through a bed of Celite The filtrate was washed with water and brine dried overnight over anhydrous sodium sulfate The suspension was filtered the filtrate evaporated on a rotary evaporator to a light brown oil which spontaneously crystallized The crystals were collected washed with 35-65 petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL 3-necked round bottomed flask equipped with a stir bar, thermowell, and a condenser connected to a nitrogen line was added 10.0 g (0.0632 mole) of 2,2,5-trimethyl-1,3-dioxane-4,6-dione, 10.6 g (0.0632 mol) of p-(chloromethyl)styrene, 35 g (0.2528 mol) of potassium carbonate and 200 mL of acetone. Approximately 1 g of phenothiazine was added as a stabilizer. The mixture was refluxed with stirring overnight at which time it was allowed to cool, diluted with 200 mL of ethyl acetate and filtered through a bed of Celite. The filtrate was washed with water and brine and dried overnight over anhydrous sodium sulfate. The suspension was filtered and the filtrate evaporated on a rotary evaporator to a light brown oil which spontaneously crystallized. The crystals were collected and washed with 35-65 petroleum ether to yield 3.5 g of 2,2-dimethyl-5-(4-vinylbenzyl)-1,3-dioxane-4,6-dione as shown by formula (III). To a 500 mL 3-necked round bottomed flask equipped with a stir bar thermowell, and a condenser connected to a nitrogen line The mixture was refluxed to cool filtered through a bed of Celite The filtrate was washed with water and brine dried overnight over anhydrous sodium sulfate The suspension was filtered the filtrate evaporated on a rotary evaporator to a light brown oil which spontaneously crystallized The crystals were collected washed with 35-65 petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Anthranilic acid (1.00 g, 7.29 mmol) was added to a solution of 2,2,5-trimethyl-1,3-dioxane-4,6-dione (1.27 g, 8.02 mmol) in toluene (10 mL). The reaction flask was fitted with a Dean-Stark apparatus and the suspension was heated to reflux for 3 h. The suspension was cooled, filtered, washed with toluene and dried. 2-[(2-Carboxy-1-oxopropyl)amino]benzoic acid (1.46 g, 85%) was obtained as a colourless solid; δH (500 MHz, DMSO-d6) 1.31 (d, J=7.2 Hz, 3H, CH3), 3.52 (q, J=7.2 Hz, 1H, CH), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.59 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.98 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.46 (d, J5,6=8.0 Hz, 1H, H6), 11.36 (s, 1H, NH), 12.87 (br s, 1H, CO2H), 13.52 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 13.6, 48.4, 116.7, 120.0, 122.9, 131.1, 134.1, 140.5, 168.2, 169.4, 171.6. νmax 1172, 1251, 1587, 1679, 2553, 2941, 2990, 3332 cm−1. The reaction flask was fitted with a Dean-Stark apparatus the suspension was heated to reflux for 3 h The suspension was cooled filtered washed with toluene dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,2,5-trimethyl-1,3-dioxan-4,6-dione II (17.4 g, 110 mmol), 4-acetoxy-azetidinone I (28.7 g, mmol) and K2CO3 (15.2 g, 110 mmol) were mixed in dry acetonitrile (150 mL, KF=5.6 mg/mL), and the mixture was aged at 45°-50° for 14 hours. Upon completion, the reaction mixture was cooled to room temperature and water (150 mL) was added. The organic layer was separated and the aqueous layer was back extracted with acetonitrile (100 mL). Combined organic extracts were washed with brine (100 mL) and concentrated to ca. 50 mL in volume. The mixture was then diluted with heptane (200 mL) and concentrated to 50 mL. Additional heptane (150 mL) was added and the mixture was aged at room temperature for crystallization. The resulting product was collected by filtration, washed with heptane (50 mL) and dried under vacuum at 40-50 for 15 hours to give an off-white crystalline solid (30.9 g, 80.2 mmol). A second crop was obtained by concentrating the combined filtrate and washed to ca. 50 mL in and aging at room temperature to give a white, fluffy solid (2.07 g, 5.4 mmol). Combined yield was 85.6%. Melting Range (° C.) 78-83 d. The organic layer was separated the aqueous layer was back extracted with acetonitrile (100 mL) Combined organic extracts were washed with brine (100 mL) concentrated to ca. 50 mL in volume The mixture was then diluted with heptane (200 mL) concentrated to 50 mL Additional heptane (150 mL) was added the mixture was aged at room temperature for crystallization The resulting product was collected by filtration washed with heptane (50 mL) dried under vacuum at 40-50 for 15 hours

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,2,5-trimethyl-1,3-dioxan-4,6-dione II (17.4 g, 110 mmol), 4-acetoxy-azetidinone I (28.7 g, mmol) and K2CO3 (15.2 g, 110 mmol) were mixed in dry acetonitrile (150 mL, KF=5.6 mg/mL), and the mixture was aged at 45°-50° for 14 hours. Upon completion, the reaction mixture was cooled to room temperature and water (150 mL) was added. The organic layer was separated and the aqueous layer was back extracted with acetonitrile (100 mL). Combined organic extracts were washed with brine (100 mL) and concentrated to ca. 50 mL in volume. The mixture was then diluted with heptane (200 mL) and concentrated to 50 mL. Additional heptane (150 mL) was added and the mixture was aged at room temperature for crystallization. The resulting product was collected by filtration, washed with heptane (50 mL) and dried under vacuum at 40-50 for 15 hours to give an off-white crystalline solid (30.9 g, 80.2 mmol). A second crop was obtained by concentrating the combined filtrate and washed to ca. 50 mL in and aging at room temperature to give a white, fluffy solid (2.07 g, 5.4 mmol). Combined yield was 85.6%. Melting Range (° C.) 78-83 d. The organic layer was separated the aqueous layer was back extracted with acetonitrile (100 mL) Combined organic extracts were washed with brine (100 mL) concentrated to ca. 50 mL in volume The mixture was then diluted with heptane (200 mL) concentrated to 50 mL Additional heptane (150 mL) was added the mixture was aged at room temperature for crystallization The resulting product was collected by filtration washed with heptane (50 mL) dried under vacuum at 40-50 for 15 hours

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,2,5-trimethyl-1,3-dioxan-4,6-dione II (17.4 g, 110 mmol), 4-acetoxy-azetidinone I (28.7 g, mmol) and K2CO3 (15.2 g, 110 mmol) were mixed in dry acetonitrile (150 mL, KF=5.6 mg/mL), and the mixture was aged at 45°-50° for 14 hours. Upon completion, the reaction mixture was cooled to room temperature and water (150 mL) was added. The organic layer was separated and the aqueous layer was back extracted with acetonitrile (100 mL). Combined organic extracts were washed with brine (100 mL) and concentrated to ca. 50 mL in volume. The mixture was then diluted with heptane (200 mL) and concentrated to 50 mL. Additional heptane (150 mL) was added and the mixture was aged at room temperature for crystallization. The resulting product was collected by filtration, washed with heptane (50 mL) and dried under vacuum at 40-50 for 15 hours to give an off-white crystalline solid (30.9 g, 80.2 mmol). A second crop was obtained by concentrating the combined filtrate and washed to ca. 50 mL in and aging at room temperature to give a white, fluffy solid (2.07 g, 5.4 mmol). Combined yield was 85.6%. Melting Range (° C.) 78-83 d. The organic layer was separated the aqueous layer was back extracted with acetonitrile (100 mL) Combined organic extracts were washed with brine (100 mL) concentrated to ca. 50 mL in volume The mixture was then diluted with heptane (200 mL) concentrated to 50 mL Additional heptane (150 mL) was added the mixture was aged at room temperature for crystallization The resulting product was collected by filtration washed with heptane (50 mL) dried under vacuum at 40-50 for 15 hours

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-[N,N-bis(tert-Butoxycarbonyl)amino]-5-bromomethyl-3-methyl-pyridin (1.6 g, 4.0 mmol) was added to a solution of 2,2,5-trimethyl-1,3-dioxane-4,6-dione (630 mg, 4.0 mmol) and triethylamine (0.58 mL, 4.2 mmol) in dimethyl sulfoxide (40 mL). The reaction mixture was stirred overnight and water (100 mL) was added. The mixture was extracted with EtOAc, the combined organic phases washed with water and brine and dried. Concentration under reduced pressure gave crude 2-[N,N-bis(tert-butoxycarbonyl)amino]-3-methyl-5-(2,2,5-trimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-pyridin (2.06 g) The mixture was extracted with EtOAc the combined organic phases washed with water and brine dried Concentration under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 130 g 2-Bromo-4-fluoro-aniline was dissolved in 700 ml ice and 600 ml 3M hydrochloric acid. The resulting suspension was maintained at ca. 5° C. during the addition of a solution of 47.3 g sodium nitrite in 45 ml water. When the addition was complete, the mixture was stirred 45 min at ca 5° C. The resulting brown suspension was added slowly to a cooled mixture of 108.3 g 2,2,5-trimethyl-1,3-dioxan-4,6-dione and 932 g sodium acetate in 400 ml water and 700 ml ethanol, maintaining the temperature between 3 and 8° C. A yellow precipitate formed. The mixture was stirred a further 2 h at 3-8° C., filtered and the precipitate washed with water and dried under vacuum to afford the title compound as a yellow solid. ISP-MS: m/e 359 ([M+H]+). Yield 231 g, mp 92-93° C. When the addition maintaining the temperature between 3 and 8° C A yellow precipitate formed The mixture was stirred a further 2 h at 3-8° C. filtered the precipitate washed with water dried under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,2,5-trimethyl-1,3-dioxan-4,6-dione II (17.4 g, 110 mmol), 4-acetoxy-azetidinone I (28.7 g, 100 mmol) and K2CO3 (15.2 g, 110 mmol) were mixed in dry acetonitrile (150 mL, KF=5.6 mg/mL), and the mixture was aged at 45-50° for 14 hours. Upon completion, the reaction mixture was cooled to room temperature and water (150 mL) was added. The organic layer was separated and the aqueous layer was back extracted with acetonitrile (100 mL). Combined organic extracts were washed with brine (100 mL) and concentrated to ca. 50 mL in volume. The mixture was then diluted with heptane (200 mL) and concentrated to 50 mL. Additional heptane (150 mL) was added and the mixture was aged at room temperature for crystallization. The resulting product was collected by filtration, washed with heptane (50 mL) and dried under vacuum at 40-50 for 15 hours to give an off-white crystalline solid (30.9 g, 80.2 mmol). A second crop was obtained by concentrating the combined filtrate and washed to ca. 50 mL in and aging at room temperature to give a white, fluffy solid (2.07 g, 5.4 mmol). Combined yield was 85.6%. Melting Range (° C.) 78-83 d. The organic layer was separated the aqueous layer was back extracted with acetonitrile (100 mL) Combined organic extracts were washed with brine (100 mL) concentrated to ca. 50 mL in volume The mixture was then diluted with heptane (200 mL) concentrated to 50 mL Additional heptane (150 mL) was added the mixture was aged at room temperature for crystallization The resulting product was collected by filtration washed with heptane (50 mL) dried under vacuum at 40-50 for 15 hours

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL 3-necked round bottomed flask equipped with a stir bar, thermowell and a condenser connected to a nitrogen line was added 10.0 g (0.0632 mole) of 2,2,5-trimethyl-1,3-dioxane-4,6-dione, 7.7 g (0.0632 mol) of allyl bromide, 21 g (0.152 mol) of potassium carbonate and 200 mL of acetone. The mixture was refluxed with stirring overnight at which time it was allowed to cool, diluted with 200 mL of ethyl ether and filtered through a bed of Celite/activated charcoal. The filtrate was washed with water and brine and dried overnight over anhydrous sodium sulfate. The suspension was filtered and the filtrate evaporated on a rotary evaporator to yield 11 g of 2,2-dimethyl-5-allyl-1,3-dioxane-4,6-dione compound as shown in Formula (IV)) as a clear, colorless oil. To a 500 mL 3-necked round bottomed flask equipped with a stir bar thermowell and a condenser connected to a nitrogen line The mixture was refluxed to cool filtered through a bed of Celite/activated charcoal The filtrate was washed with water and brine dried overnight over anhydrous sodium sulfate The suspension was filtered the filtrate evaporated on a rotary evaporator