1-Chloroethyl cyclohexyl carbonate

Colorless or pale yellow liquid

Cyclohexy alcohol (1.4 g, 13.97 mmol) was dissolved in CHCyclohexanol (0.50 g, 5.0 mmol) and pyridine (0.40 ml, 5.0 mmol) were dissolved in 10 ml dichloromethane and the mixture cooled to -78 ºC. a solution of 1-chloroethyl carbonochloridate (0.54 ml, 5.0 mmol) dissolved in 2 ml dichloromethane was added drop-wise and with stirring.Preparation ; Preparation of 1 -iodoethyl cyclohexylcarbonate(1) Preparation of 1-chloroethyl cyclohexylcarbonateCyclohexanol (19 ml, 0.18 mol) was dissolved in methylene chloride (300 ml), and pyridine (14.8 ml, 0.18 mol) was added thereto while ice-cooling. 1-Chloroethyl chloroformate (20 ml, 0.185 mol) was slowly added to the reaction mixture over 15 minutes. The reaction mixture was slowly heated to room temperature and then stirred for 16 hours. The reaction mixture was sequentially washed with water, brine, and 5percent sodium thiosulfate solution, dried over anhydrous magnesium, and then filtered. The filtrate was distilled under a reduced pressure to obtain 26.06 g of 1-chloroethyl cyclohexylcarbonate (yield: 70percent). 1) In a 1000 ml reaction flask, 238 g of trichloromethyl chloroformate was added, Open stirring, cooling to -10 ~ 0 by adding 2.4g pyridine, Dropping 106 g of triacetaldehyde, dropping the process for 6 hours, After the addition was complete, stirring was continued for 2 h, 247 g of pyridine was added, The temperature to be mixed is 20 ° CAfter the addition of cyclohexanol 240 g, After completion of the dropwise addition, stirring was continued for 3 h.After completion of the reaction, 120 g of water was added, The organic phase was separated from crude 1-chloroethylcyclohexylpropyl carbonate.(2) The crude product of 1-chloroethylcyclohexylpropyl carbonate was put into a distillation reaction flask, Control the bottle temperature below 130 , Vacuum vacuum distillation, That is to get1-chloroethylcyclohexylpropylCarbonate461g, The yield was 93percent and the purity was greater than 99.5percent.Sodium iodide (4.48 g, 29.88 mmol) was dissolved in anhydrous CH3CN (30 mL). Compound 6 (1.20 g, 5.98 mmol) and anhydrous CH3CN (3 mL) were added and stirred for 5.5 hours at 50 C. After filtering and concentration, the residue was diluted with ether and re-concentrated to give 1.21 g of carbonic acid cyclohexyl ester 1-iodo-ethyl ester 7 (Yield: 69%). 1H-NMR (CDCl3, 500 MHz) delta 1.25-1.40 (m, 3H), 1.41-1.58 (m, 3H), 1.70-1.78 (m, 2H), 1.85-1.95 (m, 2H), 2.22 (d, J=7.0 Hz, 3H), 4.66-4.71 (m, 1H), 6.77 (q, d=7.0 Hz, 1H).Sodium iodide (4.48g, 29.88 mmol) was dissolved in anhydrous CH3CN (30 mL). Compound 6 (1.2Og, 5.98 mmol) and anhydrous CH3CN (3 mL) were added and stirred for 5.5 hours at 500C. After filtering and concentration, the residue was diluted with ether and re-concentrated to give 1.21 g of carbonic acid cyclohexyl ester 1-iodo-ethyl ester 7 (Yield: 69%). 1HNMR(CDCI3, 500 MHz) delta 1.25-1.40(m, 3H), 1.41-1.58(m, 3H), 1.70-1.78(m, 2H), 1.85-1.95(m, 2H), 2.22(d, J=7.0 Hz, 3H), 4.66-4.71 (m, 1H), 6.77(q, d=7.0 Hz, 1 H).Chloroethyl chloroformate (4 ml) was added to a solution of cyclohexyl alcohol (4.3 ml) and pyridine (3.3 ml) in dichloromethane (60 ml) at -78C, and they were stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated to obtain crude (a) Production of 1-Iodoethyl Cyclohexyl Carbonate A solution of 1.65 g of (2) Preparation of 1-iodoethyl cyclohexylcarbonate; 1-chloroethyl cyclohexylcarbonate (2.6 g, 13 mmol) prepared in Step (1) was dissolved in acetonitrile (80 ml), and sodium iodide (8.5 g, 56.7 mmol, 4.36 eq) was added thereto. The reaction mixture was stirred at 600C for 70 minutes and then filtered. The filtrate was cooled to room temperature and then distilled under a reduced pressure to remove the solvent. The resulting residue was extracted with water and diethyl ether. The separated organic layer was washed with 5% sodium thiosulfate solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was distilled under a reduced pressure to obtain 2.68 g of 1-iodoethyl cyclohexylcarbonate. The product was immediately used in subsequent reactions due to its instability. 1H-NMR(200MHz, CDCI3) delta 0.9-2.2(m, 10H), 2.20(d, J=5.8Hz, 3H), 4.60-4.80(m, 1 H), 6.81 (q, J=5.8Hz, 1 H).To a solution (25 mL) of 1-chloroethyl cyclohexylcarbonate (5.0 g) in carbon disulfide were added sodium iodide (6.8 g) and zinc chloride (0.25 g) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was poured into ice water (100 mL) and the mixture was extracted twice with diethyl ether (50 mL). The organic layers were combined and washed with 10% aqueous sodium sulfite solution (30 mL), saturated aqueous sodium hydrogen carbonate (30 mL) and water (30 mL). The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give cyclohexyl 1-iodoethylcarbonate (6.10 g) as a liquid.(1) 9.15 g of cyclohexanol was dissolved in 150 mL of methylene chloride, to which 7.4 mL of pyridine was added followed by dropwise addition of 10 mL of 1-chloroethyl chloroformate in an ice bath, and this mixture was stirred for 2 hours at room temperature. Then, a sodium chloride solution was added to the reaction mixture and the organic phase was separated therefrom. After the resultant organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled out under reduced pressure to yield 18.6 g of To a 10 L dry reactor, anhydrous acetonitrile 3.29 L, anhydrous sodium iodide 947 g, Under the condition of water bath, the temperature is controlled to be 20-25 DEG C, 313 g of molecular sieve anhydrous calcium chloride is slowly added under stirring, and the mixture is stirred for 20 min after addition, heated to 45-50 DEG C, and rapidly droppedfimasartan potassium salt monohydrate (1 g, 1.8 mmol)Was added dimethylformamide (8 mL)After dissolving, Potassium iodide (30 mg, 0.18 mmol), 1-Chloroethyl cyclohexyl carbonate(0.40 mL, 2.2 mmol) was added, The reaction mixture was stirred at room temperature overnight. After the ethyl acetate was added to the reaction mixture, The organic layer was washed with brine.The washed organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, The crude product was purified by column chromatography (ethyl acetate: n-hexane = 3: 1) to give the title compound (0.71 g, 59%, foamy solid).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 40% ' 60% yield.General procedure: To a solution of 1.00 g (2.843 mmol) of 2-chloro-3-(methylsulfanyI)-N-(1-methyl-1H-tetrazol-5-yl)-4-(trifluoromethyl)benzamide are in 20 ml of acetonitrile are added at room temperature 911 mg (5.97 mmol) of 1-chloroethyl ethyl carbonate and 825 mg (5.97 mmol) of potassium carbonate and the mixture is boiled under reflux for 9 h. The reaction mixture is concentrated and then dissolved in 20 ml of ethyl acetate and 20 ml of water are added and extracted. The aqueous phase is extracted twice more with 20 ml of ethyl acetate each time. The combined organic phases are washed with saturated NaCI solution, dried and concentrated. The residue is purified by RP-HPLC (acetonitrile/water).; By analogy to the abovementioned preparation method, by reacting 1.00 g (2.719 mmol) of 2-chloro-3-(methylsulfanyl)-N-(1-methyl-1H-tetrazol-5-yl)-4-(trifluoromethyl)benzamide with 1234 mg (5.97 mmol) of To the potassium salt of cefotiam (compound IIa) in the above step (1)The residue (theoretical yield 0.89 kg)Add formamide 8.0kg, Cooling to between -10 ~ 0 , Lithium iodide 53g.Temperature control at 5 ~ 10 , 0.64 kg of chlorocyclohexyl carbonate (Compound III)Stir 0.5-1h.Temperature control 5 ~ 10 , The reaction mixture was transferred to a pre-prepared 5% sodium bisulfite solution (8.9kg)Add ethyl acetate twice, each 8.9kg, The above organic phases are combined, The organic phase 1 was obtained after washing with 9 kg of saturated sodium chloride aqueous solution.Control the temperature at 5 ~ 10 , To the organic layer 1, 10.7 kg of a 15% hydrochloric acid aqueous solution was added, Stir 10 ~ 20min after standing liquid, The aqueous phase 1 was obtained and the aqueous phase 1 was washed with 1, 2-dichloroethane.The aqueous phase 1 was cooled to 0 ~ 10 , The pH was adjusted to 6.8-7.0 with saturated potassium bicarbonate solution.Continue to control the temperature to 0 ~ 10 , 11.0kg of methylene chloride was added to stand still and separated to obtain an organic phase.Continue to control the temperature 0 ~ 10 , The organic phase was washed with saturated brine (9.6 kg) to give an organic phase 2.After the organic phase 2 was added with anhydrous magnesium sulfate (0.9 kg) and dried, Filtration, filtrate stand-by. Temperature T'15 , After the system is concentrated at P?-0.09 MPa to about 50% of the original volume, Slowly add cyclohexane 10.5kg.After cooling to 0 ~ 5 , stirring a lot of solid precipitation 1-2h.Filtered to give a solid cefotiam ester free base (Compound Iv), to be used.

Molecular Weight:206.66
XLogP3:3.5
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:206.0709720
Monoisotopic Mass:206.0709720
Topological Polar Surface Area:35.5
Heavy Atom Count:13
Complexity:166
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes