Structure of 188416-20-8
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CAS No. : | 188416-20-8 |
Formula : | C16H14Cl2F3N5O |
M.W : | 420.22 |
SMILES Code : | Cl.CC(C1=C(F)C(Cl)=NC=N1)C(O)(CN1C=NC=N1)C1=C(F)C=C(F)C=C1 |
MDL No. : | MFCD11113103 |
InChI Key : | ISUMRMYBGZGUMY-UHFFFAOYSA-N |
Pubchem ID : | 46941602 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.7% | Under nitrogen atmosphere, 9.35 g of zinc powder and 0.47 g of lead are introducedto 53 mL of dry tetrahydrofuran (THF) and the mixture is agitated for 3 hours under reflux. The reaction mixture is cooled to 25C and agitated continuously for 16 hours. In a separate container, 7.42 g of iodine is dissolved into 21 mL of dry tetrahydrofuran (THF) and the resultant solution is added dropwise to the reaction mixture over 80 minutes. Next, the reaction mixture is warmed to 45C and then cooled to 0C.[119] At room temperature, 6.53 g of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone and 7.01 g of 6-(1-bromo ethyl)-4-chloro-5-fluoropyrimidine are dissolved into 53 mL of tetrahydrofuran (THF) and the resultant solution is added dropwise gradually to the reaction mixture, while maintaining the reaction temperature at 5C or lower. The reaction mixture is warmed to 25C and 8.84 g of glacial acetic acid dissolved in 84 mL of purified water is added dropwise to the reaction mixture. The solid metal residueis removed by filtering, the solvent is distilled off under reduced pressure, and the reaction product is extracted twice with 84 mL of ethyl acetate (EA). The extract is washed with 3.22 g of disodium ethylenediamine tetraacetate dihydrate dissolved in 161 mL of purified water, and further washed with 30 mL of saline. The organic layer is concentrated to a final volume of 56 mL, and a solution containing 1.2 g of hydrochloric acid in 6 mL of isopropanol is added dropwise thereto at 25C. The resultant crystals are filtered, washed with 5 mL of EA, and dried under reduced pressure for 12 hours at 50C to obtain 5.99 g of the target compound (yield 48.7%, purity 96.2%, HPLC, detected at a wavelength of 256 nm, 18C 4.6 X 250 mm, mobile phase 60% ACN, flow rate 1 mL/min).[120] 1H-NMR (200MHz, DMSO-d6) δ (ppm) : 8.85(1H), 8.731H), 7.93(1H), 7.28~7.16(2H), 6.95~6.89(1H), 5.83(1H), 4.81(1H), 4.54(1H), 3.92(1H), 1.13(3H). | |
A mixture of zinc dust (300 gm; from step I above) and lead powder (15.2 gm) in tetrahydrofuran (1000 mL) at ambient temperature was stirred under anhydrous condition with nitrogen blanketing. The stirred mixture was heated to 45 C.-50 C. and then cooled to 30 C.-35 C. followed by the addition of bromine (180 gm) at 45 C.-50 C. The reaction mixture was stirred for 30 minutes. A solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (200 gm; Formula III) in dichloromethane (1800 mL) was added to the reaction mixture at 45 C.-50 C. followed by cooling to 30 C.-40 C. To the reaction mixture, a solution of 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (entire quantity from Step II) in dichloromethane (200 mL) was added at 30 C.-40 C. This was stirred for 30 minutes to 2 hours and then cooled to 15 C.-20 C. Acetic acid (300 gm) was added to it. The mixture obtained was filtered and washed with dichloromethane (2*400 mL). The solvents were recovered under reduced pressure at 45 C.-50 C. to provide an oily residue. To the oily residue, dichloromethane (1000 mL) was added. This mixture was stirred and cooled to 15 C.-20 C. followed by the addition of de-ionized water (1000 mL) and concentrated hydrochloric acid (200 mL). This was allowed to settle and the layers were separated. The organic layer was washed with 2% w/v aqueous ethylenediaminetetraacetic acid solution (EDTA solution; 1000 mL) at 15 C.-20 C. De-ionized water (1000 mL) was added to the organic layer and pH was adjusted with about 40% w/v aqueous sodium hydroxide solution (98 mL) at 15 C.-20 C. This was allowed to settle and the layers were separated. The solvent was recovered from the organic layer under reduced pressure (50-500 torr) at 35 C.-45 C. and oily residue was obtained. Acetone (400 mL) was added to the residue, stirred and then solvent was recovered under reduced pressure (50-500 torr) at 35 C.-45 C. To the so obtained oily residue, acetone (1000 mL) was further added, the mixture was stirred and then cooled to 20 C.-25 C. To the resultant mixture, isopropanol hydrochloride (180 gm) was added and it was stirred for about 2 hours at 20 C.-25 C. The slurry so obtained was cooled to 0 C.-5 C. and stirred for 60 minutes at 0 C.-5 C. The solid obtained was filtered and washed with acetone (600 mL) at the same temperature. The solid was dried at 40 C.-50 C. % Yield: 47.8 w.r.t compound of Formula III % HPLC purity: 95.91% | ||
With bromine; zinc(II) chloride; zinc; In tetrahydrofuran; at 15℃;Inert atmosphere; | Nitrogen protection, under 15 ±5 C, adding THF to the flask (80g), compound III (10g), stirring to dissolves clear, adding ZnCl2(6.8g), zinc powder (4.3g), dropping compound IV (15g) THF of (80g) solution, then adding bromine (1.3g), reaction 3 hours after the end of the, post-processing with the embodiment 1, to obtain crude products (11.1g, yield 59.1%), liquid detection of A display impurity content is 0.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation of Voriconazole Camphorsulfonate (wet) from Hydrochloride Salt of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol. Hydrochloride salt of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (180 gm) obtained from Step III of Example 1 or Example 2 or Example 3 was added to methanol (720 mL) at 20 C.-25 C. followed by pH adjustment (8.0-9.0) with 40% w/v aqueous sodium hydroxide solution (50 mL) under nitrogen blanketing. To this reaction mixture, ammonium formate (108.2 gm) was added followed by addition of wet palladium/carbon [Pd/C (2.5% w/w dry, 18 gm)] treated with de-ionized water. The reaction mixture was further heated and stirred at 55 C.-60 C. followed by cooling of the mixture to 30 C.-35 C. The reaction mixture was filtered through hyflobed and washed with methanol (360 mL) first and then with a mixture of de-ionized water (1800 mL) and dichloromethane (900 mL) at 15 C.-20 C. followed by stirring. To the organic layer, de-ionized water (360 mL) was added followed by pH adjustment with 2N hydrochloric acid solution (6 mL) at the same temperature. The solvent was recovered under reduced pressure at 40 C.-45 C. to give residual solid. To the residue acetone (2700 mL) was added followed by addition of the methanolic solution of (1R)-(-)-10-camphorsulfonic acid (99.5 gm in 900 mL methanol) at 40 C.-45 C. Seed of voriconazole camphorsulfonate (0.18 gm) was added to the reaction mixture and the mixture stirred at 40 C.-45 C. for 60 minutes. The slurry so obtained was cooled to 30 C.-35 C. followed by further cooling to 20 C.-25 C. The mixture was stirred for 10-12 hours at 20 C.-25 C. followed by filtration and washing with acetone (180 mL) to give wet voriconazole camphorsulfonate. Wet wt: 91 gm. Voriconazole camphorsulfonate (wet) (entire quantity from Step 4A of Example 4) was added to a stirred mixture of de-ionized water (360 mL) and dichloromethane (360 mL) at 15 C.-25 C. followed by pH adjustment of the mixture to pH 10-11 with 40% w/v aqueous sodium hydroxide solution (16.2 mL). The organic layer was washed with de-ionized water (360 mL) followed by filtration of organic layer through 0.45 micron filter. The filtered layer was further washed with dichloromethane (90 mL) and solvent was recovered under reduced pressure (50-500 torr) at 35 C.-45 C. to give a residual solid. Isopropyl alcohol (450 mL) was added to the residue followed by heating and stirring of the mixture at 60 C.-70 C. until the mixture was dissolved, followed by recovery of isopropyl alcohol under reduced pressure (50-500 torr) at 50 C.-60 C. to obtain a residual volume of 270 mL. The concentrated solution so obtained was heated to 60 C.-70 C. followed by cooling of the solution to 45 C.-50 C. The solution was further cooled to 5 C.-10 C. followed by stirring for 60 minutes at the same temperature. The solid obtained was filtered and washed with isopropyl alcohol (135 mL) followed by drying of the solid under reduced pressure at 50 C.-55 C. until constant weight. %Yield: 42.8% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25 g | With sodium hydroxide; In dichloromethane; water; at 10℃; for 2.0h;pH 11; | 14.0 g of the hydrochloride salt of Compound III was dissolved in 200.0 mL of dichloromethane and 90.0 mL of water, stirred at 10 C., and 40% NaOH was added dropwise to about 7 mL to adjust pH = 11. Continue stirring at 10 C for 2h. After 2h, the layers were separated, and the aqueous layer was extracted once with dichloromethane (50.0 mL). The organic phases were combined, washed with saturated brine, and concentrated to dryness to obtain about 25 g of light yellow oil. The oil was dissolved in a 250 mL single-necked flask (R1). To 200 mL of methanol, add 10.0 g of sodium acetate, 1.3 g of 5% Pd / C (water content: 68%), and hydrogenate at 25 C under normal pressure overnight. The reaction was detected by TLC. The Pd / C was recovered by filtration. The filtrate was concentrated and dried. 70 mL of dichloromethane and 70 mL of water were added. The pH was adjusted to 11 with 40% NaOH aqueous solution. The layers were separated. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated and dried, and added 35 ml of isopropanol and stirred at room temperature for 2 hours. Then add 35mL of petroleum ether and stir rapidly at 5 C for 2h. After filtration, the filter cake was washed twice with cold isopropanol (2 × 5 mL) and dried to obtain about 8.7 g of mixture 4 (yield: 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | 1) Add 20kg FLKZ-SM to 200L hydrogenation reactor,31.68kg of anhydrous methanol and 7.80kg of anhydrous sodium acetate;2) Add 0.20kg 10% wet palladium on carbon, replace the air with nitrogen, and replace the nitrogen with hydrogen,After the replacement, keep at 3545, 0.20.4MPa, and stir for 45 hours;3) TLC detects that the reaction is complete, filtered, the reaction kettle and filter cake were rinsed with 6.34kg of anhydrous methanol, and the combined filtrate was transferred to a 500L ordinary reaction kettle;4) Add 60kg of purified water at 010 under stirring, and cool down to 010 under stirring;5) Add 010 sodium hydroxide aqueous solution while stirring at 010(3.80kg sodium hydroxide is dissolved in 120kg purified water);Keep the temperature of the system at 0-10C during the addition.6) After adding, keep 010 for 1 hour while stirring;7) Filter, rinse the reaction kettle and filter cake with 36kg purified water, and dry the filter cake with air at 45-55C for 12-14 hours.8) The voriconazole racemate was obtained by collecting materials, a white solid of 15.2 kg, and a weight yield of 76%. |
A1360341 [188416-35-5]
3-(6-Chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
Reason: Free-salt
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