1-dimethoxyphosphoryl-3-phenoxypropan-2-one

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

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

Procedure: A solution of 33.2 g (268 mmoles) dimethyl methylphosphonate (Aldrich) in 360 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 118 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 22.2 g (134 mmole) methyl 2-phenoxy acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 14 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 175 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 172°-175° (0.5 mm) to give 24.6 g dimethyl 2-oxo-3-phenoxypropylphosphonate. the reaction temperature less than -70° (20 minutes) After 3.5 hours at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 100 ml portions of chloroform (3x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled

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

Procedure: Under the argon atmosphere, dimethyl-(3-phenoxy-2-oxopropyl)-phosphonate (826 mg, 3.20 mmol) and potassium phosphate (679 mg, 3.20 mmol) were added to a THF solution (16 mL) of the compound (634 mg, 1.60 mmol) produced in Example 13, and the mixture was stirred at room temperature for one day. The reaction solution was added to an aqueous saturated ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate two times. The collected organic layers were washed with a saturated saline, and dried with anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and purified with a column apparatus (Hiflash-SI, Size L, hexane→ethyl acetate: hexane=4:6) manufactured by Yamazen Corporation to obtain a titled compound (426 mg) having the following physical property values. the aqueous layer was extracted with ethyl acetate two times The collected organic layers were washed with a saturated saline dried with anhydrous sodium sulfate The solution was concentrated under reduced pressure purified with a column apparatus (Hiflash-SI, Size L, hexane→ethyl acetate: hexane=4:6)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl methylphosphonate (18 ml, 0.166 mol) was addded to anhydrous THF (150 ml) under argon atmosphere and cooled to -78° C. After 20 min. a solution of n-butyl lithium in hexane (1.59N, 108.8 ml, 0.173 mmol) was added to the mixture. After being stirred for 30 min. a solution of methyl phenoxyacetate (10 ml, 0.069 mmol) in 10 ml of anhydrous THF was added, and the reaction mixture was stirred successively for 30 min. at -78° C. and for 30 min. at room temperature, and acidified with acetic acid. After confirming a weakly acidic pH of the solution thus obtained, THF was distilled out. Water (50 ml) was added to the residue, and the resulting mixture was extracted with ethyl acetate (150 ml×3). The combined organic layers were washed with 100 ml of water and with 100 ml of brine, dried over anhydrous sodium sulfate, and concentrated. The oily product was distilled under reduced pressure to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (14.65 g, 0.057 mol, yield: 82.3%). B.p.: 145°-147° C./0.1 mmHg. The product was identified by the following data. was added thus obtained THF was distilled out Water (50 ml) was added to the residue the resulting mixture was extracted with ethyl acetate (150 ml×3) The combined organic layers were washed with 100 ml of water and with 100 ml of brine dried over anhydrous sodium sulfate concentrated The oily product was distilled under reduced pressure

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

Procedure: Under the argon atmosphere, dimethyl-(3-phenoxy-2-oxopropyl)-phosphonate (826 mg, 3.20 mmol) and potassium phosphate (679 mg, 3.20 mmol) were added to a THF solution (16 mL) of the compound (634 mg, 1.60 mmol) produced in Example 13, followed by stirring at room temperature for one day. The reaction solution was added to an aqueous saturated ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate twice. The collected organic layers were washed with a saturated saline, and dried with anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and purified with a column apparatus (Hiflash-SI, Size L, hexane→ethyl acetate:hexane=4:6) manufactured by Yamazen Corporation to obtain a titled compound (426 mg) having the following physical property values. the aqueous layer was extracted with ethyl acetate twice The collected organic layers were washed with a saturated saline dried with anhydrous sodium sulfate The solution was concentrated under reduced pressure purified with a column apparatus (Hiflash-SI, Size L, hexane→ethyl acetate:hexane=4:6)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 4-L reactor equipped with a mechanical stirrer, under nitrogen, was charged with (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (Cayman Chemical Catalog #70030, 99.2 g, 0.362 mol) in dichloromethane and lithium chloride (16.7 g, 0.398 mol) dissolved in tetrahydrofuran. Dimethyl 2-oxo-3-phenoxypropylphosphonate (102.7 g, 0.398 mol) is added neat and rinsed with dichloromethane (50 mL). Some lithium chloride precipitated from solution when the THF and DCM solutions were mixed. The mixture was stirred under nitrogen and cooled to −20° C. After adding the phosphonate and subsequent stirring and cooling, the precipitated lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (40.2 g, 0.398 mol) was added neat via addition funnel and the temperature was held at −5° C. and stirred at this temperature for 19 hours. The temperature was adjusted to 0° C. and treated with 5% aqueous citric acid and the layers were separated. The organic layer was dried over magnesium sulfate and filtered. The crude product was purified on silica gel, eluted with ethyl acetate-hexanes (1:1). The desired product precipitated from the product-rich fractions as a white fluffy solid. After further purification of mixed fractions, all the purified product crystallized from MTBE to afford the title intermediate (74.4 g, 50.6%) as a white solid. A 4-L reactor equipped with a mechanical stirrer, under nitrogen rinsed with dichloromethane (50 mL) Some lithium chloride precipitated from solution when the THF and DCM solutions were mixed After adding the phosphonate subsequent stirring cooling the precipitated lithium chloride dissolved After stirring for 2.5 hours was held at −5° C. stirred at this temperature for 19 hours was adjusted to 0° C. the layers were separated The organic layer was dried over magnesium sulfate filtered The crude product was purified on silica gel eluted with ethyl acetate-hexanes (1:1) The desired product precipitated from the product-rich fractions as a white fluffy solid After further purification of mixed fractions all the purified product crystallized from MTBE

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

Procedure: A solution of 33.2 g (268 mmoles) dimethyl methylphosphonate (Aldrich) in 360 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 118 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 22.2 g (134 mmole) methyl 2-phenoxy acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 14 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 175 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 172°-175° (0.5 mm) to give 24.6 g dimethyl 2-oxo-3-phenoxypropylphosphonate. the reaction temperature less than -70° (20 minutes) After 3.5 hours at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 100 ml portions of chloroform (3x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled

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

Procedure: A solution of 33.2 g (268 mmoles) dimethyl methylphosphonate (Aldrich) in 360 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 118 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 22.2 g (134 mmole) methyl 2-phenoxy acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 14 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 175 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 172°-175° (0.5 mm) to give 24.6 g dimethyl 2-oxo-3-phenoxypropylphosphonate. the reaction temperature less than -70° (20 minutes) After 3.5 hours at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 100 ml portions of chloroform (3x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled

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

Procedure: A solution of 33.2 g (268 mmoles) dimethyl methylphosphonate (Aldrich) in 360 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 118 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 22.2 g (134 mmole) methyl 2-phenoxy acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 14 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 175 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 172°-175° (0.5 mm) to give 24.6 g dimethyl 2-oxo-3-phenoxypropylphosphonate. the reaction temperature less than -70° (20 minutes) After 3.5 hours at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 100 ml portions of chloroform (3x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled

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

Procedure: A solution of 33.2 g (268 mmoles) dimethyl methylphosphonate (Aldrich) in 360 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 118 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 22.2 g (134 mmole) methyl 2-phenoxy acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 14 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 175 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 172°-175° (0.5 mm) to give 24.6 g dimethyl 2-oxo-3-phenoxypropylphosphonate. the reaction temperature less than -70° (20 minutes) After 3.5 hours at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 100 ml portions of chloroform (3x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled

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

Procedure: A solution of 33.2 g (268 mmoles) dimethyl methylphosphonate (Aldrich) in 360 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 118 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 22.2 g (134 mmole) methyl 2-phenoxy acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 14 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 175 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 172°-175° (0.5 mm) to give 24.6 g dimethyl 2-oxo-3-phenoxypropylphosphonate. the reaction temperature less than -70° (20 minutes) After 3.5 hours at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 100 ml portions of chloroform (3x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled

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

Procedure: A solution of 33.2 g (268 mmoles) dimethyl methylphosphonate (Aldrich) in 360 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 118 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 22.2 g (134 mmole) methyl 2-phenoxy acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 14 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 175 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 172°-175° (0.5 mm) to give 24.6 g dimethyl 2-oxo-3-phenoxypropylphosphonate. the reaction temperature less than -70° (20 minutes) After 3.5 hours at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 100 ml portions of chloroform (3x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled