(1R,2S,5R)-5-Methyl-2-(1-methylethyl)cyclohexyl (2R,5S)-5-(4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl)-1,3-oxathiolane-2-carboxylate

(2R,5S)-5-(4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl)-1,3-Oxathiolane-2-carboxylic acid, (1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl ester is Off-White Solid

Fluorocytosine (22.4 g, 0.173 mol, 1.1 molar equivalents), Hexamethyl disilazane (HMDS) (100 ml, 0.477 mol, 3.1 molar equivalents) and trimethylsilyl chloride (TMSCL), ( 1 1.2 ml) were mixed at 25-30°C under Nitrogen atmosphere. The reaction mixture was heated up to 120- 130°C to get clear solution and excess solvent was distilled out under vacuum at 90- 100°C to get the residue of silylated fluorocytosine. The residue of silylated fluorocytosine was cooled to room temperature and fresh dichlorome thane (100 ml) was added (solution A). In a separate flask L-menthyl-5R-acetoxy- l , 3-oxathiolane-2R-carboxylate (50 g, 0.151 mol, 1.0 molar equivalents), dichloromethane (250 ml) and zirconium tetrachloride (ZrCU) (17.6 g, 0.075 mole, 0.5 molar equivalents) were mixed under nitrogen atmosphere (solution B). Presilylated fluorocytosine solution A was added into solution B at 25-30°C and reaction mixture was stirred at the same temperature for 6 hrs. The reaction was monitored by HPLC or thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 10-20°C and precooled ( 10-20°C) water (250 ml) was added under stirring. pH was adjusted at 8 to 8.5 using triethylamine under stirring. The layers were separated and the organic layer was washed with 250 ml of water. The organic layer was concentrated under vacuum to get the residue. The residue was dissolved in methanol (200 ml) and n- heptane (100 ml) under stirring. The said solution was added into water (200 ml). The isolated solid was filtered and washed with water followed by n-heptane. The solid was dried under vacuum at 40-45°C. Yield: 48.5 g (80 percent). Chiral Purity: 99.94 percent; 0.06 percent undesired isomer. Ή NMR (DMSO-d6) δ (ppm): 0.70-0.99 (m, 10H), 1.02- 1.10 (m, 2H), 1.39- 1.49 8 (m, 2H), 1.63- 1.66 8 (d, 2H), 1.88- 1.95 8 (m, 2H), 3.20-3.24 8 (m, 1H), 3.53-3.57 8 (m, 1H), 4.66-4.72 (m, 1H), 5.71 8 (s, 1H), 6.29- 6.30 8 (d, 1H), 7.69 (s, 1H), 7.94 8 (s, 1H), 8.16-8. 18 8 (d, 1H); i3C NMR (DMSO- d6): 16.5, 20.9, 22.2.3.2, 26.1 , 31.8, 34, 35.8, 46.8, 76, 78.3, 89.5, 125.4, 135.2, 137.6, 153.4, 158, 169.8; IR (KBr) (cm-i): 3323, 3083, 2956, 2869, 1754, 1687, 1640, 1513, 1348, 1287, 1 178, 1090, 940, 774, 678, 498; MS (EI) m/z = 400 (M+ l); [a]Preparation of (5-Fluoro-2-trimethylsilanyloxy-pyrimidin-4-yl)- trimethylsilanyl-amine5-fluorocytosine (100 g), hexamethyldisilazane (400 mL) and ammonium sulphate (5 g) were charged at 25 720 g Emtricitabine Intermediate IV 7.2 L dichloromethane was added, 20 mL DMF, Cooled to 0 ~ 5 deg C, A solution of 192 mL of thionyl chloride in 1.2 L of dichloromethane was added dropwise. After stirring for 2 hours at 10-15 ° C, Concentrated under reduced pressure, Then add 2.2 L of toluene and cool for use. 324 g of 5-fluorocytosine, 12g ammonium sulfate, 600mL hexamethyldisilazane, 960 mL of toluene was added, Heated to reflux for 1 to 2 hours. Slightly cooled to below 90 deg C, Add dropwise 350 mL of triethylamine, It was heated to reflux, but not vigorous. The chlorinated solution prepared above was added dropwise, Wash with 240 mL of toluene. Reflux for 2 to 3 hours, Cooled to 30 ~ 35 deg C, Dropping a solution of 180 mL triethylamine in water 2.9 L, Cooled to 15 ~ 20 deg C, Stirred for 1 hour, 2.9 L of n-heptane was dropped, Stir for 16 hours, filter, Washed, Emtricitabine Intermediate III was obtained after drying, 504g, Yield 50.5percent HPLC purity 98.17percent.720 g Emtricitabine Intermediate IV 7.2 L dichloromethane was added, 20mLDMF, cooled to 0 ~ 5 , A solution of 192 mL of thionyl chloride in 1.2 L of dichloromethane was added dropwise.After stirring at 10-15 ° C for 2 hours, concentrated under reduced pressure, Then add 2.2 L of toluene and cool for use.324 g of 5-fluorocytosine, 12 g of ammonium sulfate, 600 mL of hexamethyldisilazane, 960 mL of toluene was added and the mixture was heated to reflux1 ~ 2 hours. Slightly cooled to below 90 , 350mL triethylamine dropwise, heated to reflux but not severe.The chlorinated solution prepared above was added dropwise and washed with 240 mL of toluene. Refluxed for 2 to 3 hours, cooled to 30 to 35 ° C, and added dropwise 2.9 mL of a solution of 180 mL of triethylamine in water, cooled to 15 to 20 ° C and stirred for 1 hour, 2.9 L of n-heptane was added dropwise and the mixture was stirred for 16 hours, filtered, washed with water and dried to yield Emtricitabine Intermediate III, 504g, yield 50.5percentHPLC purity 98.17percent.

An intermediate in the synthesis of Emtricitabine (E525000). A reverse transcriptase inhibitor. It is an effective antiviral agent against HIV, HBV, and other viruses replicating in a similar manner. A nucleoside analog structurally related to Lamivudine (L172500).

Molecular Weight:399.5
XLogP3:3.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:5
Exact Mass:399.16280565
Monoisotopic Mass:399.16280565
Topological Polar Surface Area:120
Heavy Atom Count:27
Complexity:669
Defined Atom Stereocenter Count:5
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes