[chloro(methoxy)phosphoryl]oxymethane

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A mixture of 17 g of 2-ethoxy-4hydroxy-5-cyano-thiazole, 14 g of potassium carbonate, 13 g of O,O-dimethyl chlorophosphate and 150 ml of acetone was stirred for 3 hours at room temperature and the mixture was concentrated to dryness. The residue was added to an aqueous sodium chloride solution which was then extracted with ethyl ether. The ether extracts were washed with an aqueous 2% sodium hydroxide solution, dried and evaporated to dryness to obtain 14.4 g of 2-ethoxy-4-dimethoxyphosphoryloxy-5-cyano-thiazole as an oil with a refractive index n D 23 = 1.5056. the mixture was concentrated to dryness The residue was added to an aqueous sodium chloride solution which was then extracted with ethyl ether The ether extracts were washed with an aqueous 2% sodium hydroxide solution dried evaporated to dryness

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.7 g of potassium carbonate and 7.7 g of O,O-dimethyl chlorophosphate were added to a solution of 11 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 16 hours at 20° C. and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in ether. The ether solution was washed with water containing 100 g/l of sodium chloride and then with 0.1 N sodium hydroxide solution containing 100 g/l of sodium chloride. The ether phase was dried and treated with activated carbon, filtered and concentrated to dryness to obtain 12.5 g of 2-cyano-3-(dimethoxyphosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 =1.511. was filtered The filtrate was evaporated to dryness under reduced pressure the residue was dissolved in ether The ether solution was washed with water containing 100 g/l of sodium chloride with 0.1 N sodium hydroxide solution containing 100 g/l of sodium chloride The ether phase was dried treated with activated carbon filtered concentrated to dryness

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.7 g of potassium carbonate and 7.7 g of O,O-dimethyl chlorophosphate were added to a solution of 11 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 16 hours at 20° C. and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in ether. The ether solution was washed with water containing 100 g/l of sodium chloride and then with 0.1 N sodium hydroxide solution containing 100 g/l of sodium chloride. The ether phase was dried and treated with activated carbon, filtered and concentrated to dryness to obtain 12.5 g of 2-cyano-3-(dimethoxyphosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 =1.511. was filtered The filtrate was evaporated to dryness under reduced pressure the residue was dissolved in ether The ether solution was washed with water containing 100 g/l of sodium chloride with 0.1 N sodium hydroxide solution containing 100 g/l of sodium chloride The ether phase was dried treated with activated carbon filtered concentrated to dryness

反応条件: temp:41.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 500 mL, 3-neck flask equipped with an overhead mechanical stirrer and pressure equalizing addition funnel was charged with L-alaninol (12.5 g, 166.4 mmol), triethylamine (29 mL, 208 mmol, 1.25 equiv) and dichloromethane (125 mL). The reaction solution was cooled to +2° C. and treated with dimethoxyphosphoryl chloride (20 mL, 183 mmol, 1.10 equiv) over 40 minutes while maintaining an internal temperature >+8° C. The reaction mixture was stirred with ice bath cooling for 1 hour at which point the reaction was complete by TLC analysis (silica gel, 93:6:1 DCM/MeOH/NH4OH and 6/3/1 CHCl3/MeOH/NH4OH; KMnO4 stain). Additional triethylamine (25.5 mL, 182.5 mmol, 1.10 equiv) was added to the reaction mixture and methanesulfonyl chloride (14.9 mL, 191 mol, 1.15 equiv) was added drop-wise over 45 minutes while maintaining an internal temperature <+10° C. The resulting reaction mixture was stirred with ice bath cooling for 1.0 hour after which time TLC analysis indicated the reaction was complete. Potassium hydroxide solution (3 M, 220 mL, 650 mmol, 4.0 equiv) was slowly added to the stirred reaction mixture while maintaining an internal temperature <+16° C. The reaction was continued with agitation for 6 hours, after which time the aqueous layer was separated and discarded. Saturated NaHCO3 solution (35 mL) was added and the biphasic mixture heated to 40-42° C. Distillation was started and a first fraction of 90 mL of dichloromethane was collected. When the temperature reached 50° C., a second fraction was collected until the batch temperature was 65° C. The mixture was heated at 65° C. for another 1 hour and then cooled to ambient temperature. Dichloromethane (90 mL) was added and the mixture stirred for 10 minutes before separation. The dichloromethane layer was concentrated under reduced pressure. The residue was dissolved in heptanes (15 mL) and concentrated under reduced pressure to remove the residual water. This azeotropic drying was repeated two more times. The resulting 4a was obtained as a light yellow liquid (20.9 g, 76% yield, 95.40% GC purity). A colorless sample was prepared by short path distillation (80-85° C.@15 mm Hg vacuum). Optical rotation c=1.00, ethanol, 25.0° C., +39.3°. 1H NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 3.76 (s, 3H), 2.65-2.50 (m, 1H), 2.42-2.31 (m, 1H), 1.92 (dt, J=3.6, 1.2 Hz, 1H), 1.28 (dd, J=5.4, 1.2 Hz, 3H). A 500 mL, 3-neck flask equipped with an overhead mechanical stirrer addition funnel The reaction solution was cooled to +2° C. while maintaining an internal temperature >+8° C cooling for 1 hour at which was added drop-wise over 45 minutes while maintaining an internal temperature <+10° C The resulting reaction mixture was stirred with ice bath cooling for 1.0 hour after which time TLC analysis while maintaining an internal temperature <+16° C after which time the aqueous layer was separated Saturated NaHCO3 solution (35 mL) was added Distillation a first fraction of 90 mL of dichloromethane was collected reached 50° C. a second fraction was collected until the batch temperature was 65° C The mixture was heated at 65° C. for another 1 hour cooled to ambient temperature Dichloromethane (90 mL) was added the mixture stirred for 10 minutes before separation The dichloromethane layer was concentrated under reduced pressure The residue was dissolved in heptanes (15 mL) concentrated under reduced pressure to remove the residual water This azeotropic drying

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

実験手順: Dimethyl erucyl phosphate (Compound 70) To a solution of erucyl alcohol (0.50 g, 1.5 mmol) in dry CH2Cl2 (10 mL) was added N-methylimidazole (0.14 mL, 1.7 mmol) followed by the addition of dimethyl chlorophosphate (0.20 mL, 1.9 mmol). After 20 hours, the reaction mixture was concentrated and subjected to silica-gel column chromatography [eluent: hexane/ethyl acetate, 66/33, v/v] to give dimethyl phosphate Compound 70 (0.59 g, 89%) as an oil. the reaction mixture was concentrated

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

実験手順: Dimethyl erucyl phosphate (Compound 70) To a solution of erucyl alcohol (0.50 g, 1.5 mmol) in dry CH2Cl2 (10 mL) was added N-methylimidazole (0.14 mL, 1.7 mmol) followed by the addition of dimethyl chlorophosphate (0.20 mL, 1.9 mmol). After 20 hours, the reaction mixture was concentrated and subjected to silica-gel column chromatography [eluent: hexane/ethyl acetate, 66/33, v/v] to give dimethyl phosphate Compound 70 (0.59 g, 89%) as an oil. the reaction mixture was concentrated

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

実験手順: Dimethylchlorophosphate (1.44 g; 10 mmol) dissolved in dichloromethane (4 ml) was slowly added dropwise to a mixture cooled to 0° C. of (1R,2S)-2-amino-3-fluoro-1-(4-methylsulfonylphenyl)-1-propanol (2.47 g; 10 mmol) in acetonitrile (15 ml) and dichloroethane (15 ml) containing triethylamine (1.39 ml; 10 mmol). was slowly added dropwise to a mixture

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

実験手順: To a solution of N-((1S)-1-{[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide (500 mg, 1.04 mmol) in dry CH2Cl2 (10 mL) under N2, was added dimethyl chlorophosphate (748 mg, 5.18 mmol) followed by DMAP (660 mg, 5.41 mmol) at rt. After 30 min, TLC (95:5 EtOAc/MeOH) showed ˜50% conversion, so an additional portion of dimethyl chlorophosphate (748 mg, 5.18 mmol) and DMAP (660 mg, 5.41 mmol) were added. After an additional 30 min, the reaction was quenched with saturated aqueous NH4Cl and diluted with CH2Cl2. The aqueous layer was back-extracted with CH2Cl2 and the combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% EtOAc; isocratic on Analogix) to give 475 mg (77%) of the title compound as a pale yellow oil. LC/MS (ES) m/e 592.4 (M+H)+. Note that the product was contaminated with ˜1 eq of the starting dimethyl chlorophosphate/dimethyl hydrogenphosphate reagent and carried on as is. After an additional 30 min the reaction was quenched with saturated aqueous NH4Cl diluted with CH2Cl2 The aqueous layer was back-extracted with CH2Cl2 the combined organics were dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (100% EtOAc; isocratic on Analogix)

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

実験手順: Dimethyl erucyl phosphate (Compound 70) To a solution of erucyl alcohol (0.50 g, 1.5 mmol) in dry CH2Cl2 (10 mL) was added N-methylimidazole (0.14 mL, 1.7 mmol) followed by the addition of dimethyl chlorophosphate (0.20 mL, 1.9 mmol). After 20 hours, the reaction mixture was concentrated and subjected to silica-gel column chromatography [eluent: hexane/ethyl acetate, 66/33, v/v] to give dimethyl phosphate Compound 70 (0.59 g, 89%) as an oil. the reaction mixture was concentrated

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

実験手順: Dimethyl erucyl phosphate (Compound 70) To a solution of erucyl alcohol (0.50 g, 1.5 mmol) in dry CH2Cl2 (10 mL) was added N-methylimidazole (0.14 mL, 1.7 mmol) followed by the addition of dimethyl chlorophosphate (0.20 mL, 1.9 mmol). After 20 hours, the reaction mixture was concentrated and subjected to silica-gel column chromatography [eluent: hexane/ethyl acetate, 66/33, v/v] to give dimethyl phosphate Compound 70 (0.59 g, 89%) as an oil. the reaction mixture was concentrated