$\"Figure$ <\/a><\/div>\n

Pharmaceutical prodrugs such as tedizolid phosphate (also referred to as TR-701, torezolid phosphate, and TR-701 \u201cfree acid\u201d or FA) have the following formula:<\/p>\n

$\"Figure$ <\/a><\/div>\n

The disodium salt of tedizolid phosphate, has the following structure:<\/p>\n

$\"Figure$ <\/a><\/div>\n

<\/div>\n

…………………………………………………………………………………………………………………………………………………………….<\/div>\n

<\/div>\n

US20100305069<\/a><\/div>\n

Example 1 Preparation of the Phosphate Monohydrogen Diester, Formula III
\nIn this and the following Examples, \u201cFormula III\u201d refers to a compound wherein Z is
\nFigure US20100305069A1-20101202-C00024
\nand M=OH.
\nA 1-L, three-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet\/outlet and thermocouple was charged with the compound of Formula Ia below (16.0 g, 0.0499 mol], THF (320 mL, 20 vol) and Et3N (21.9 g, 0.216 mol, 5.0 equiv.).
\nFigure US20100305069A1-20101202-C00025
\nPOCl3 (3.31 g, 0.0216 mol, 0.5 equiv.) was added dropwise via syringe over 5 minutes. The reaction temperature was maintained below 25\u00b0 C. The batch was aged for 16 hours at room temperature at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction vessel was then immersed in an ice-water bath and a 500-mL addition funnel charged with 320 mL of H2O was attached to the reaction vessel. When the temperature of the reaction reached 2.7\u00b0 C., H2O was added drop wise over 30 minutes. The temperature of the reaction was maintained below 10\u00b0 C. Upon completion of the H2O addition, the ice-water bath was removed and the batch was aged for 3 hours. The solution was transferred to a 2-L round-bottom flask and concentrated under reduced pressure on a rotary evaporator. After removal of most of the THF from the solution, the aqueous mixture was extracted with 5 1-L portions of CH2Cl2:MeOH (9:1). The CH2Cl2 layers were combined and concentrated to a dark oil. This crude material was purified on 200 g of silica gel, eluting with 10% MeOH\/CH2Cl2 to 20% 2 N NH3 in MeOH\/CH2Cl2. Fractions containing mostly the bis-ester (as judged by TLC Rf=0.3 eluting with 20% 2 N NH3 in MeOH\/CH2Cl2) were combined and concentrated under reduced pressure on a rotary evaporator, during which time a white precipitate was observed. The flask containing the slurry was removed from the rotary evaporator and equipped with a magnetic stir bar and allowed to stir while cooling to room temperature over 3 hours, during which time the slurry thickened. The solid was filtered and dried in a vacuum oven at 45\u00b0 C. for 16 hours to give 3.55 g of bis-ester as an off-white solid (20% yield). HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min. This reaction was repeated and the combined lots of the compound of Formula III (6.7 g) were slurried in 100 mL of MeOH (15 vol). The slurry was heated to 40\u00b0 C. for 30 minutes and then allowed to cool to room temperature over 1 hour. The off-white solid was filtered and dried in a vacuum oven at 40\u00b0 C. for 16 hours to give 6.15 g of the compound of Formula III (92% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min.<\/p>\n

Example 2 Preparation of the Diphosphate Dihydrogen Diester, Formula IV
\nIn Examples 2-5, \u201cFormula IV\u201d refers to a compound wherein Z is
\nFigure US20100305069A1-20101202-C00026
\nn=0 and M=O-imidazolium salt.<\/p>\n

A 250-mL 3-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet\/outlet and thermocouple was charged with the compound of Formula IIa below (5.0 g, 11.1 mmol), carbonyldiimidazole (890 mg, 5.55 mmol, 0.5 equiv.) and DMF (100 mL, 20 vol).
\nFigure US20100305069A1-20101202-C00027
\nThe suspension was heated to 50\u00b0 C. and held at that temperature for 4 hours at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction was filtered at 50\u00b0 C. and dried in a vacuum oven at 50\u00b0 C. for 24 hours to give 5.15 g of the imidazolium salt (i.e., the compound of Formula IV) as an off-white solid (98% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 94.5% (AUC), tR=14.6 min.
\nTABLE 1
\nMethod A (Waters XBridge C18 Column)
\nTime (min) Flow (mL\/min) % A % B
\n0.0 1.0 98.0 2.0
\n15.0 1.0 5.0 95.0
\n25.0 1.0 5.0 95.0
\n27.0 1.0 98.0 2.0
\n30.0 1.0 98.0 2.0
\nA = 87% 25 mM ammonium bicarbonate solution in water\/13% Acetonitrile
\nB = Acetonitrile
\nWavelength = 300 nm<\/p>\n