Carbonic acid, 1-chloroethyl ethyl ester

Clear pale yellowish liquid

In the cooling to 0 °C under the 71.5 g (0.5 μM) 1 - chloro ethyl formate ester drop to 40 g and 52.0 g triethylamine 250 ml in toluene solution, about 2 hr after the completion of the dropping, then the temperature to room Temperature the reaction system, the reaction 1 hr, filtered to remove the solid, distilling and getting the intermediate H - 1 is 78.5 g.2-(2-((4-(((1, 1, 1, 3, 3, 3-Hexafluoropropan-2-yl)oxy)carbonyl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenoxy)-2-methylpropanoic acid (1.0 g, 1.85 mmol, as prepared in Example 3) was dissolved in IPA (25 mL) and heated to 60 C. Aqueous sodium hydroxide (2.65M, 1.85 mmol, 0.698 mL) was added in a single portion. The mixture was stirred for 0.5 h and then gradually cooled to 40 C., producing a turbid mixture. The mixture stirred at 40 C. for 1 h and water (0.7 mL) was added portion-wise. The suspension was stirred at 40 C. for 16 h and then cooled to room temperature and stirred 24 h at room temperature. The solid was isolated by vacuum filtration to afford 578 mg (56%) sodium 2-(2-((4-(((1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl)oxy)carbonyl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenoxy)-2-methylpropanoate as a white solid. Separately, a mixture of 1-chloroethyl ethyl carbonate (12 mg, 0.08 mmol, 1.1 equiv) and KI (25 mg, 0.14 mmol, 2.0 equiv) in MeCN (2 mL) was stirred overnight at room temperature prior to addition of a mixture of sodium 2-(2-((4-(((1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl)oxy)carbonyl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenoxy)-2-methylpropanoate (40 mg, 0.07 mmol, 1.0 equiv) and DIPEA (19 mg, 0.14 mmol, 2.0 equiv) in EtOAc (2 mL). The resulting mixture was stirred overnight at 60 C. The reaction was cooled to room temperature, quenched with water (1 mL), and concentrated under reduced pressure. The residue was purified by preparative HPLC to provide 1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl 4-(2-((1-(1-((ethoxycarbonyl)oxy)ethoxy)-2-methyl-1-oxopropan-2-yl)oxy)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (13 mg, 26%) as a colorless oil. 1H NMR (400 MHz, Chloroform-d) delta 7.66-7.51 (m, 1H), 7.46-7.31 (m, 1H), 7.28-7.24 (m, 1H), 7.02-6.95 (m, 1H), 6.87-6.79 (m, 1H), 5.81-5.69 (m, 1H), 4.33-4.15 (m, 2H), 3.82-3.52 (m, 5H), 2.77-2.42 (m, 4H), 1.79-1.64 (m, 6H), 1.55-1.45 (m, 3H), 1.36-1.26 (m, 3H). LCMS (ESI, m/z): 657 [M+H]+.In a reactor equipped with a rectification device, 92.4 g (0.55 mol) of ethyl 1, 3-dimethyl-5-pyrazolecarboxylic acid and 95 g (0.55 mol) of p-tert-butylbenzoacetonitrile were charged, Toluene was used as a solvent. After dehydration under reflux, 224g (0.66mol) of sodium ethoxide solution was added dropwise, The addition was completed within 5 hours, and low-boiling by-products were separated from the top of the column.After the reaction is completed, the solvent and other boilables are distilled off under reduced pressure.Toluene is recyclable.Add anhydrous acetonitrile and 4.5 g (0.03 mol) of sodium iodide to the reactor, 87 g (0.57 mol) of 1-chloroethyl ethyl carbonate was slowly added dropwise under reflux, and the addition was completed within 2 h. After the reaction is completed, cool and separate the liquid phase.Distill off the solvent, 209 g of 1- (2- (4- (tert-butyl) phenyl) -2-cyano-1- (1-ethyl-3-methyl-1H-5-pyrazolyl) ethoxy) ethoxy Ethyl carbonate, The yield was 92.5%, of which the E-form content was 89%.fimasartan potassium salt monohydrate (1 g, 1.8 mmol)Was dissolved in dimethylformamide (8 mL) Potassium iodide (30 mg, 0.18 mmol), General procedure: To a solution of sofosbuvir (530 mg, 1.0 mmol, 1.0 eq.) in DMF(2 mL) cooled in an ice bath was added K2CO3 (138 mg, 1.0 mmol, 1.0 eq.) followed with a 15 min's stir. 1-chloroethyl- or methyl- carbonates(2.0 eq.) was added to the resulted mixture and stirred at roomtemperature for 12 h. The mixture was diluted with EA (50 mL) andthen washed with water (10 mL×3). The organic layer was dried overanhydrous Na2SO4, concentrated in vacuo and purified by silica gelchromatography to afford 8a-8b in 40percent ' 60percent yield. 4.1.3.1. Isopropyl ((S)-(((2R, 3R, 4R, 5R)-5-(3-(1-((ethoxycarbonyl)oxy)ethyl)-2, 4-dioxo-3, 4-di -hydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate(8a). White solid. 1H NMR (400 MHz, CD3OD): delta 7.62'7.65 (m, 1H), 7.39 (t, 2H, J=8.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 7.22 (t, 1H, J=8.0 Hz), 7.05'7.11 (m, 1H), 6.17 (d, 1H, J=18.8 Hz), 5.65'5.68(m, 1H), 4.98 (sep, 1H, J=6.4 Hz), 4.53'4.57 (m, 1H), 4.37'4.43 (m, 1H), 4.13'4.21 (m, 3H), 3.89'3.97 (m, 2H), 1.79'1.82 (m, 3H), 1.33'1.40 (m, 6H), 1.25'1.29 (m, 3H), 1.23 (d, 6H, J=6.4 Hz).ESI+-MS m/z: 646.2 [M+1].

Molecular Weight:152.57
XLogP3:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:152.0240218
Monoisotopic Mass:152.0240218
Topological Polar Surface Area:35.5
Heavy Atom Count:9
Complexity:94.2
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes