hexadecyl methanesulfonate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1,3-propanediol (4.07 kg) and NMP (30 L). The reaction was cooled to −5 to 5° C. and kept under a nitrogen atmosphere. Sodium hydride (1.07 kg, 60% in mineral oil) was cautiously added portion-wise. After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. A solution of hexadecyl methanesulfonate 4 (4.39 kg) dissolved in NMP (10 L) was added slowly to the reaction mixture at 20 to 55° C. The resulting solution was stirred for 12 to 28 hours at 20 to 35° C. The reaction was monitored by GC-MS and was considered complete when the conversion rate was >95%. The reaction mixture was cooled down to −5 to 5° C. and slowly diluted with water (15 L). The reaction was extracted with ethyl acetate (2×25 L). The organic phase was washed with water (20 L), dried over Na2SO4 and concentrated to give a brown oil. The crude product was dissolved in methanol (20 L) and aged at 20 to 30° C. for 12 hours. The resulting solid impurities were filtered and discarded and the filtrate was concentrated. Acetonitrile (40 L) was added to the concentrate and the mixture was aged 5 to 15° C. for 16 hours. The solid was filtered and dried at 25 to 30° C. to afford 5 as a white solid (3.1 kg, 77%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. After the addition was added slowly to the reaction mixture at 20 to 55° C The resulting solution was stirred for 12 to 28 hours at 20 to 35° C The reaction mixture was cooled down to −5 to 5° C. The reaction was extracted with ethyl acetate (2×25 L) The organic phase was washed with water (20 L) dried over Na2SO4 concentrated to give a brown oil aged at 20 to 30° C. for 12 hours The resulting solid impurities were filtered the filtrate was concentrated Acetonitrile (40 L) was added to the concentrate the mixture was aged 5 to 15° C. for 16 hours The solid was filtered dried at 25 to 30° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1-hexadecanol 3 (3.78 kg), anhydrous dichloromethane (40 L) and diisopropylethylamine (2.21 kg). The reaction mixture was cooled to −5 to 5° C. and methanesulfonyl chloride (1.87 kg) was added at a controlled rate over 2 hours to ensure that the reaction temperature was kept below 5° C. After the addition was complete, the mixture was warmed to 20 to 30° C. and stirred for one to two hours. The reaction was monitored by GC-MS and was deemed complete when the conversion rate was ≧95%. The reaction was maintained at 20 to 30° C. while being diluted with water (15 L). The organic layer was separated, washed with water (0.50 kg), and concentrated to dryness to yield 4 as a light yellow solid (4.87 kg, 96%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. was kept below 5° C After the addition the mixture was warmed to 20 to 30° C. The reaction was maintained at 20 to 30° C. The organic layer was separated washed with water (0.50 kg) concentrated to dryness

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1-hexadecanol 3 (3.78 kg), anhydrous dichloromethane (40 L) and diisopropylethylamine (2.21 kg). The reaction mixture was cooled to −5 to 5° C. and methanesulfonyl chloride (1.87 kg) was added at a controlled rate over 2 hours to ensure that the reaction temperature was kept below 5° C. After the addition was complete, the mixture was warmed to 20 to 30° C. and stirred for one to two hours. The reaction was monitored by GC-MS and was deemed complete when the conversion rate was ≧95%. The reaction was maintained at 20 to 30° C. while being diluted with water (15 L). The organic layer was separated, washed with water (0.50 kg), and concentrated to dryness to yield 4 as a light yellow solid (4.87 kg, 96%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. was kept below 5° C After the addition the mixture was warmed to 20 to 30° C. The reaction was maintained at 20 to 30° C. The organic layer was separated washed with water (0.50 kg) concentrated to dryness

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

Procedure: adding a solution of hexadecyl methanesulfonate dissolved in N-methylpyrrolidinone to form the 3-(hexadecyloxy)propan-1-ol.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 7.769 g (40 mM) of 5-hydroxymethyl-2-phenyl-1,3-dioxane n1 and 2.08 g (52 mM) of 60% sodium hydride in oil in 150 ml of anhydrous benzene is heated at 50° C. for 1 hour then a solution of 17.28 g (54 mM) of n-hexadecyl methanesulfonate in 50 ml of anhydrous benzene is added. The reaction mixture is heated under refluxing for 7 hours. The product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Crystallization of the residue from n-pentane-methanol affords 16.203 g (97% yield) of the titled compound n2. The reaction mixture is heated under refluxing for 7 hours The ethyl acetate layer is washed with saturated aqueous sodium chloride dried over anhydrous magnesium sulfate evaporated Crystallization of the residue from n-pentane-methanol

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 7.769 g (40 mM) of 5-hydroxymethyl-2-phenyl-1,3-dioxane n1 and 2.08 g (52 mM) of 60% sodium hydride in oil in 150 ml of anhydrous benzene is heated at 50° C. for 1 hour then a solution of 17.28 g (54 mM) of n-hexadecyl methanesulfonate in 50 ml of anhydrous benzene is added. The reaction mixture is heated under refluxing for 7 hours. The product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Crystallization of the residue from n-pentane-methanol affords 16.203 g (97% yield) of the titled compound n2. The reaction mixture is heated under refluxing for 7 hours The ethyl acetate layer is washed with saturated aqueous sodium chloride dried over anhydrous magnesium sulfate evaporated Crystallization of the residue from n-pentane-methanol

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1,3-propanediol (4.07 kg) and NMP (30 L). The reaction was cooled to −5 to 5° C. and kept under a nitrogen atmosphere. Sodium hydride (1.07 kg, 60% in mineral oil) was cautiously added portion-wise. After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. A solution of hexadecyl methanesulfonate 4 (4.39 kg) dissolved in NMP (10 L) was added slowly to the reaction mixture at 20 to 55° C. The resulting solution was stirred for 12 to 28 hours at 20 to 35° C. The reaction was monitored by GC-MS and was considered complete when the conversion rate was ≧95%. The reaction mixture was cooled down to −5 to 5° C. and slowly diluted with water (15 L). The reaction was extracted with ethyl acetate (2×25 L). The organic phase was washed with water (20 L), dried over Na2SO4 and concentrated to give a brown oil. The crude product was dissolved in methanol (20 L) and aged at 20 to 30° C. for 12 hours. The resulting solid impurities were filtered and discarded and the filtrate was concentrated. Acetonitrile (40 L) was added to the concentrate and the mixture was aged 5 to 15° C. for 16 hours. The solid was filtered and dried at 25 to 30° C. to afford 5 as a white solid (3.1 kg, 77%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. After the addition was added slowly to the reaction mixture at 20 to 55° C The resulting solution was stirred for 12 to 28 hours at 20 to 35° C The reaction mixture was cooled down to −5 to 5° C. The reaction was extracted with ethyl acetate (2×25 L) The organic phase was washed with water (20 L) dried over Na2SO4 concentrated to give a brown oil aged at 20 to 30° C. for 12 hours The resulting solid impurities were filtered the filtrate was concentrated Acetonitrile (40 L) was added to the concentrate the mixture was aged 5 to 15° C. for 16 hours The solid was filtered dried at 25 to 30° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1,3-propanediol (4.07 kg) and NMP (30 L). The reaction was cooled to −5 to 5° C. and kept under a nitrogen atmosphere. Sodium hydride (1.07 kg, 60% in mineral oil) was cautiously added portion-wise. After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. A solution of hexadecyl methanesulfonate 4 (4.39 kg) dissolved in NMP (10 L) was added slowly to the reaction mixture at 20 to 55° C. The resulting solution was stirred for 12 to 28 hours at 20 to 35° C. The reaction was monitored by GC-MS and was considered complete when the conversion rate was ≧95%. The reaction mixture was cooled down to −5 to 5° C. and slowly diluted with water (15 L). The reaction was extracted with ethyl acetate (2×25 L). The organic phase was washed with water (20 L), dried over Na2SO4 and concentrated to give a brown oil. The crude product was dissolved in methanol (20 L) and aged at 20 to 30° C. for 12 hours. The resulting solid impurities were filtered and discarded and the filtrate was concentrated. Acetonitrile (40 L) was added to the concentrate and the mixture was aged 5 to 15° C. for 16 hours. The solid was filtered and dried at 25 to 30° C. to afford 5 as a white solid (3.1 kg, 77%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. After the addition was added slowly to the reaction mixture at 20 to 55° C The resulting solution was stirred for 12 to 28 hours at 20 to 35° C The reaction mixture was cooled down to −5 to 5° C. The reaction was extracted with ethyl acetate (2×25 L) The organic phase was washed with water (20 L) dried over Na2SO4 concentrated to give a brown oil aged at 20 to 30° C. for 12 hours The resulting solid impurities were filtered the filtrate was concentrated Acetonitrile (40 L) was added to the concentrate the mixture was aged 5 to 15° C. for 16 hours The solid was filtered dried at 25 to 30° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1-hexadecanol 3 (3.78 kg), anhydrous dichloromethane (40 L) and diisopropylethylamine (2.21 kg). The reaction mixture was cooled to −5 to 5° C. and methanesulfonyl chloride (1.87 kg) was added at a controlled rate over 2 hours to ensure that the reaction temperature was kept below 5° C. After the addition was complete, the mixture was warmed to 20 to 30° C. and stirred for one to two hours. The reaction was monitored by GC-MS and was deemed complete when the conversion rate was ≧95%. The reaction was maintained at 20 to 30° C. while being diluted with water (15 L). The organic layer was separated, washed with water (0.50 kg), and concentrated to dryness to yield 4 as a light yellow solid (4.87 kg, 96%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. was kept below 5° C After the addition the mixture was warmed to 20 to 30° C. The reaction was maintained at 20 to 30° C. The organic layer was separated washed with water (0.50 kg) concentrated to dryness

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

Procedure: Potassium metal (1.5 g, 38.36 mmol) and anhydrous benzene (180 ml) were placed in a 500 ml three-neck round-bottomed flask equipped with a reflux condenser, dropping funnel, stir bar, and N2 atmosphere. The reaction mixture was refluxed. When the potassium metal had melted, isopropylidene glycerol (6 ml, 48.25 mmol) was added dropwise and the reaction continued to reflux an additional 2.5 hours. A solution of hexadecyl methane sulfonate (10.0 g, 32.25 mmol) in anhydrous benzene (80 ml) was added dropwise and the reaction refluxed overnight. The heat was removed and the reaction mixture was coled to 0° C. Water was added and the benzene layer was removed, washed with H2O, dried (MgSO4) and filtered. This residue was treated as in METHOD A for the hydrolysis of the acetal group to provide compound 35, rac-1-O-hexadecylglycerol (7.65 g, 75%, based on mesylate 34). equipped with a reflux condenser The reaction mixture was refluxed to reflux an additional 2.5 hours the reaction refluxed overnight The heat was removed was coled to 0° C Water was added the benzene layer was removed washed with H2O dried (MgSO4) filtered This residue was treated as in METHOD A for the hydrolysis of the acetal group

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

Procedure: Potassium metal (1.5 g, 38.36 mmol) and anhydrous benzene (180 ml) were placed in a 500 ml three-neck round-bottomed flask equipped with a reflux condenser, dropping funnel, stir bar, and N2 atmosphere. The reaction mixture was refluxed. When the potassium metal had melted, isopropylidene glycerol (6 ml, 48.25 mmol) was added dropwise and the reaction continued to reflux an additional 2.5 hours. A solution of hexadecyl methane sulfonate (10.0 g, 32.25 mmol) in anhydrous benzene (80 ml) was added dropwise and the reaction refluxed overnight. The heat was removed and the reaction mixture was coled to 0° C. Water was added and the benzene layer was removed, washed with H2O, dried (MgSO4) and filtered. This residue was treated as in METHOD A for the hydrolysis of the acetal group to provide compound 35, rac-1-O-hexadecylglycerol (7.65 g, 75%, based on mesylate 34). equipped with a reflux condenser The reaction mixture was refluxed to reflux an additional 2.5 hours the reaction refluxed overnight The heat was removed was coled to 0° C Water was added the benzene layer was removed washed with H2O dried (MgSO4) filtered This residue was treated as in METHOD A for the hydrolysis of the acetal group

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium metal (1.5 g, 38.36 mmol) and anhydrous benzene (180 ml) were placed in a 500 ml three-neck round-bottomed flask equipped with a reflux condenser, dropping funnel, stir bar, and N2 atmosphere. The reaction mixture was refluxed. When the potassium metal had melted, isopropylidene glycerol (6 ml, 48.25 mmol) was added dropwise and the reaction continued to reflux an additional 2.5 hours. A solution of hexadecyl methane sulfonate (10.0 g 32.25 mmol) in anhydrous benzene (80 ml) was added dropwise and the reaction refluxed overnight. The heat was removed and the reaction mixture was cooled to 0° C. Water was added and the benzene layer was removed, washed with H2O, dried (MgSO4) and filtered. This residue was treated as in METHOD A for the hydrolysis of the acetal group to provide compound 35, rac-1-O-hexadecylglycerol (7.65 g 75%, based on mesylate 34). equipped with a reflux condenser The reaction mixture was refluxed to reflux an additional 2.5 hours the reaction refluxed overnight The heat was removed Water was added the benzene layer was removed washed with H2O dried (MgSO4) filtered This residue was treated as in METHOD A for the hydrolysis of the acetal group