1-chloroethyl benzoate

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

Procedure: A solution of the starting [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (19.22 mmol, 5 g) in dry DMF (100 mL) was treated with N,N-diisopropylethylamine (76.88 mmol, 13.39 mL). The reaction mixture was stirred for 30 minutes at ambient temperature after which benzoic acid-1-chloroethyl ester (57.66 mmole, 10.65 g, synthesis described below) was added. The mixture was then stirred at 70° C. for 36 hours, cooled to ambient temperature and diluted with citric acid (2% aqueous solution, 70 mL). The product was extracted with ethyl acetate (3×50 mL), washed with sodium bicarbonate (3%) and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was flash chromatographed on silica gel. Elution with a gradient of 2 to 8% methanol in chloroform afforded 1.66 g (15.5%) of a stereoisomer of [2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphonic acid bis[1-(benzoyloxy)ethyl]ester (example 8) [MS (ES+): m/e 557 (M+H)] and 0.73 g (6.8%) of a less polar diastereoisomer of [2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphonic acid bis[1-(benzoyloxy)ethyl]ester (example 9) [MS (ES+): m/e 557 (M+H)]. was added cooled to ambient temperature The product was extracted with ethyl acetate (3×50 mL) washed with sodium bicarbonate (3%) and brine The organic layer was dried over magnesium sulfate filtered evaporated to dryness chromatographed on silica gel Elution with a gradient of 2 to 8% methanol in chloroform

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloroethyl benzoate (6.30 g, 34.12 mmol) and sodium iodide (23.0 g, 153.56 mmol) were combined in acetonitrile (150 mL) and heated to 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether and dichloromethane were added to the residue and the solids were filtered off and the filtrate was concentrated under reduced pressure. After silica gel chromatography using ethyl acetate in hexanes the residue was combined with sodium iodide (4.70 g, 31.39 mmol) in acetonitrile (50 mL) and heated to 60° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether was added, the solids were filtered off and the filtrate was concentrated under reduced pressure. Chromatography on silica gel using ethyl acetate in hexanes provided 1-iodoethyl benzoate as a pale yellow oil (3.67 g, 39% yield). The reaction mixture was concentrated under reduced pressure Diethyl ether and dichloromethane were added to the residue the solids were filtered off the filtrate was concentrated under reduced pressure heated to 60° C. for 1.5 hours The reaction mixture was concentrated under reduced pressure Diethyl ether was added the solids were filtered off the filtrate was concentrated under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloroethyl benzoate (6.30 g, 34.12 mmol) and sodium iodide (23.0 g, 153.56 mmol) were combined in acetonitrile (150 mL) and heated to 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether and dichloromethane were added to the residue and the solids were filtered off and the filtrate was concentrated under reduced pressure. After silica gel chromatography using ethyl acetate in hexanes the residue was combined with sodium iodide (4.70 g, 31.39 mmol) in acetonitrile (50 mL) and heated to 60° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether was added, the solids were filtered off and the filtrate was concentrated under reduced pressure. Chromatography on silica gel using ethyl acetate in hexanes provided 1-iodoethyl benzoate as a pale yellow oil (3.67 g, 39% yield). The reaction mixture was concentrated under reduced pressure Diethyl ether and dichloromethane were added to the residue the solids were filtered off the filtrate was concentrated under reduced pressure heated to 60° C. for 1.5 hours The reaction mixture was concentrated under reduced pressure Diethyl ether was added the solids were filtered off the filtrate was concentrated under reduced pressure

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

Procedure: Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (12) (3.0 g, 7.9 mmol) dissolved in 30 mL of anhydrous toluene was reacted with 4.4 g (23.7 mmol) of 1-chloroethyl benzoate (23) in the presence of 2.6 g (9.5 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 3.2 g of a mixture of the title compound (39a) and (3R/S)-4,4-dimethyl-3-(phenylmethoxy)-3,4,5-trihydrofuran-2-one (2a). MS (ESI) m/z 548.97 (M+Na)+. After work-up, the crude material was purified by silica gel column chromatography a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent

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

Procedure: Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (15) (0.4 g, 0.99 mmol) dissolved in 5 mL of anhydrous toluene was reacted with 0.55 g (3.0 mmol) of 1-chloroethyl benzoate (23) in the presence of 0.33 g (1.1 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.6 g of a mixture of the title compound (38a) and (3R)-4,4-dimethyl-3-(1,1,2,2-tetramethyl-1-silapropoxy)-3,4,5-trihydrofuran-2-one (4a). MS (ESI) m/z 573.01 (M+Na)+. After work-up, the crude material was purified by silica gel column chromatography a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent

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

Procedure: By the procedure of the preceding Preparation, freshly distilled benzoyl chloride (58.0 mL, 70.3 g, 500 mmole) was reacted with acetaldehyde (27.9 mL, 22.0 g, 500 mmol), added at a rate such that the reaction temperature did not exceed 5° C. during the addition. When the addition was complete, the orange solution was allowed to warm to room temperature, then treated with water (100 mL) and methylene chloride (100 mL). The pH was adjusted to 7.0 and the organic layer was isolated, washed with water (100 mL), brine (100 mL), dried (Na2SO4) and concentrated in vacuo to a dark brown oil (83.0 g). 1H NMR indicated less than 0.5% hexanoyl chloride in the product mixture. TLC (CH2Cl2) showed two UV active spots (Rf 0.60, 0.65). A 10.0 g aliquot of the oil was chromatographed on silica gel (methylene chloride) affording 7.3 g of title product as the less polar (Rf 0.65 ) component: 1H NMR (CDCl3) 1.88 (d, J=6 Hz, 3H), 6.78 (q, J=6 Hz, 1H), 7.15-7.70 (m, 3H), 7.70-8.20 (m, 2H). added at a rate such that the reaction temperature did not exceed 5° C. during the addition When the addition the organic layer was isolated washed with water (100 mL), brine (100 mL) dried (Na2SO4) concentrated in vacuo to a dark brown oil (83.0 g) A 10.0 g aliquot of the oil was chromatographed on silica gel (methylene chloride)

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

Procedure: A solution of the starting [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (19.22 mmol, 5 g) in dry DMF (100 mL) was treated with N,N-diisopropylethylamine (76.88 mmol, 13.39 mL). The reaction mixture was stirred for 30 minutes at ambient temperature after which benzoic acid-1-chloroethyl ester (57.66 mmole, 10.65 g, synthesis described below) was added. The mixture was then stirred at 70° C. for 36 hours, cooled to ambient temperature and diluted with citric acid (2% aqueous solution, 70 mL). The product was extracted with ethyl acetate (3×50 mL), washed with sodium bicarbonate (3%) and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was flash chromatographed on silica gel. Elution with a gradient of 2 to 8% methanol in chloroform afforded 1.66 g (15.5%) of a stereoisomer of [2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphonic acid bis[1-(benzoyloxy)ethyl]ester (example 8) [MS (ES+): m/e 557 (M+H)] and 0.73 g (6.8%) of a less polar diastereoisomer of [2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphonic acid bis[1-(benzoyloxy)ethyl]ester (example 9) [MS (ES+): m/e 557 (M+H)]. was added cooled to ambient temperature The product was extracted with ethyl acetate (3×50 mL) washed with sodium bicarbonate (3%) and brine The organic layer was dried over magnesium sulfate filtered evaporated to dryness chromatographed on silica gel Elution with a gradient of 2 to 8% methanol in chloroform

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

Procedure: A solution of the starting [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (19.22 mmol, 5 g) in dry DMF (100 mL) was treated with N,N-diisopropylethylamine (76.88 mmol, 13.39 mL). The reaction mixture was stirred for 30 minutes at ambient temperature after which benzoic acid-1-chloroethyl ester (57.66 mmole, 10.65 g, synthesis described below) was added. The mixture was then stirred at 70° C. for 36 hours, cooled to ambient temperature and diluted with citric acid (2% aqueous solution, 70 mL). The product was extracted with ethyl acetate (3×50 mL), washed with sodium bicarbonate (3%) and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was flash chromatographed on silica gel. Elution with a gradient of 2 to 8% methanol in chloroform afforded 1.66 g (15.5%) of a stereoisomer of [2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphonic acid bis[1-(benzoyloxy)ethyl]ester (example 8) [MS (ES+): m/e 557 (M+H)] and 0.73 g (6.8%) of a less polar diastereoisomer of [2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphonic acid bis[1-(benzoyloxy)ethyl]ester (example 9) [MS (ES+): m/e 557 (M+H)]. was added cooled to ambient temperature The product was extracted with ethyl acetate (3×50 mL) washed with sodium bicarbonate (3%) and brine The organic layer was dried over magnesium sulfate filtered evaporated to dryness chromatographed on silica gel Elution with a gradient of 2 to 8% methanol in chloroform

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloroethyl benzoate (6.30 g, 34.12 mmol) and sodium iodide (23.0 g, 153.56 mmol) were combined in acetonitrile (150 mL) and heated to 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether and dichloromethane were added to the residue and the solids were filtered off and the filtrate was concentrated under reduced pressure. After silica gel chromatography using ethyl acetate in hexanes the residue was combined with sodium iodide (4.70 g, 31.39 mmol) in acetonitrile (50 mL) and heated to 60° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether was added, the solids were filtered off and the filtrate was concentrated under reduced pressure. Chromatography on silica gel using ethyl acetate in hexanes provided 1-iodoethyl benzoate as a pale yellow oil (3.67 g, 39% yield). The reaction mixture was concentrated under reduced pressure Diethyl ether and dichloromethane were added to the residue the solids were filtered off the filtrate was concentrated under reduced pressure heated to 60° C. for 1.5 hours The reaction mixture was concentrated under reduced pressure Diethyl ether was added the solids were filtered off the filtrate was concentrated under reduced pressure