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CAS No. : | 359821-38-8 | MDL No. : | MFCD09944516 |
Formula : | C4H7F3N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ACUOJJBRHCFOKT-UHFFFAOYSA-N |
M.W : | 156.11 | Pubchem ID : | 24705143 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 27.24 |
TPSA : | 55.12 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.44 cm/s |
Log Po/w (iLOGP) : | 0.96 |
Log Po/w (XLOGP3) : | -0.26 |
Log Po/w (WLOGP) : | 0.88 |
Log Po/w (MLOGP) : | -0.2 |
Log Po/w (SILICOS-IT) : | 0.27 |
Consensus Log Po/w : | 0.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.38 |
Solubility : | 65.1 mg/ml ; 0.417 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.44 |
Solubility : | 56.8 mg/ml ; 0.364 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.2 |
Solubility : | 9.78 mg/ml ; 0.0627 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.26 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P270-P280-P301+P312+P330-P305+P351+P338-P337+P313-P501 | UN#: | N/A |
Hazard Statements: | H302-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
With 1,3-bis-(diphenylphosphino)propane; potassium carbonate In 1,2-dimethoxyethane; water at 20 - 105℃; for 5h; Inert atmosphere; | 1-1 Reaction condition 1-1 Into a 100 mL pressurized reaction vessel, 3.00 g (6.62 mmol) of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (2-1), 1.24 g (7.95 mmol) of 2-amino-N-(2,2,2-trifluoroethyl)acetic acid amide, 1.1 g (7.95 mmol) of potassium carbonate, 41.0 mg (0.099 mmol) of 1,3-bis(diphenylphosphino)propane, 0.14 g (0.033 mmol) of 5% palladium-carbon (50% water content-produet), and 30 mL of 1,2-dimethoxyethane were charged, and the inside of the reaction vessel was purged with nitrogen and carbon monoxide in this order at room temperature, followed by filling the reaction vessel with carbon monoxide to 1.0 MPa. Then, the reaction vessel was heated to 105°C, and at the same temperature, the reaction was carried out while stirring the reaction mixture for 5 hours. During the reaction, the inside pressure was elevated to maximum of 1.3 MPa. Then, the reaction vessel was cooled down to room temperature, and the pressure inside the reaction vessel was returned to atmospheric pressure, followed by purging the inside of the reaction vessel with nitrogen. Insoluble matters in the reaction solution were filtered off by Celite filtration, and the Celite was washed with ethyl acetate and water. To the resultant filtrate, concentrated hydrochloric acid was added to make the filtrate acidic, and the aqueous phase was separated off, followed by washing the organic phase with a sodium chloride aqueous solution. The organic phase was dried over anhydrous magnesium sulfate, followed by filtering off, and from the resultant organic phase, a solvent was distilled off under reduced pressure. The resultant residue was subjected to crystallization using 3/18 (mL) of ethyl acetate/hexane to obtain 2.54 g (4.57 mmol) of the aimed product as a pale yellow solid. | |
2.54 g | With 5%-palladium/activated carbon; 1,3-bis-(diphenylphosphino)propane; potassium carbonate In 1,2-dimethoxyethane; water at 105℃; for 5h; | 1 [Synthesis Example 1] Manufacture of Compound (1) [Synthesis Example 1] Manufacture of Compound (1) (0247) In a 100 ml pressure reaction vessel, 3.00 g (6.62 mmol) of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (2-1) that was synthesized according to the method described in WO2010/005048, 1.24 g (7.95 mmol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide, 1.1 g (7.95 mmol) of potassium carbonate, 41.0 mg (0.099 mmol) of 1,3-bis(diphenylphosphino)propane, 0.14 g (0.033 mmol) of 5% by mass palladium-carbon (50% aqueous), and 30 ml of 1,2-dimethoxyethane were placed. After the reaction vessel was purged with nitrogen, then with carbon monoxide, the reaction vessel was filled with the carbon monoxide at 1.0 MPa. The temperature was raised to 105° C., and a reaction was performed for 5 hours as stirred at the same temperature. During the reaction, the pressure inside was increased to 1.3 MPa at most. After that, the reaction vessel was cooled to room temperature, the pressure inside of the vessel was reduced to atmospheric pressure, and the reaction vessel was purged with nitrogen. Insoluble matter in the reaction solution was filtered off by celite filtration, and the celite was washed with ethyl acetate and water. The obtained filtrate was made to be acidic by adding concentrated hydrochloric acid. After an aqueous phase was separated, an organic phase was washed with saline. The organic phase was dried with anhydrous magnesium sulfate. After filtering off, a solvent was removed by vacuum distillation. The obtained residue was crystallized with ethyl acetate/hexane=3/18 (ml) to obtain 2.54 g (4.57 mmol) of the target material as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.12% | Stage #1: 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid With diphenyl phosphoryl azide; triethylamine In N,N-dimethyl-formamide for 1h; Cooling with ice; Stage #2: 2-amino-N-(2,2,2-trifluoroethyl)acetamide In N,N-dimethyl-formamide at 20℃; | 1-2 Reaction condition 1-2 A solution of 0.25 g (0.59 mmol) of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoic acid in 3 mL of N,N-dimethylformamide was ice-cooled, and thereto, 0.10 mL (0.72 mmol) of triethylamine and 0.20 g (0.72 mmol) of diphenylphosphoryl azide were added, followed by stirring the resultant reaction mixture under ice cooling for 1 hour. Thereto, further 0.10 g (0.66 mmol) of 2-amino-N-(2,2,2-trifluoroethyl)acetic acid amide was added, and the resultant reaction mixture was stirred at room temperature over one night. The reaction solution was analyzed by high-performance liquid chromatography, and the relative area of the aimed product at 254 nm was found to be 94.12%. |
93.5% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In Isopropyl acetate at 35℃; for 4h; | 1.3; 2.3; 3.3; 4.3 (3) Condensation: put 41.8g (0.1mol) of hydrolyzate and 550g of isopropyl acetate into a 1L reaction flask, add 25.0g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide under stirring (0.16mol),Benzotriazole-N,N,N',N'-Tetramethylurea Hexafluorophosphate37.9g (0.1mol) was incubated at 35°C for 4 hours, the reaction was completed, 80g of water was added and stirred for 20 minutes, the layers were statically separated, the upper organic layer was concentrated under reduced pressure, the temperature was 40°C, and the vacuum was -0.08MPa, and 260g of cyclohexane was added. , cooling and crystallization. After suction filtration, the filter cake was air-dried at 90° C. for 10 hours to obtain 52.0 g of flairana, with a yield of 93.5%. The purity of flerana was 99.5% detected by HPLC, the hydrolyzate was 0.07%, and other unknown single impurities were less than 0.07%. |
87.22% | With N,N-dimethyl-4-aminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; | Intermediate II (105 mg, 0.25 mmol), compound b (52 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58mg, 0.30mmol), 4-dimethylaminopyridine (62mg, 0.50mmol) and 2ml of dichloromethane were added to a 25ml flask , and the reaction was stirred at room temperature overnight. After monitoring the completion of the reaction by TLC (petroleum ether:ethyl acetate=2:1), the system was subjected to column chromatography to obtain 124 mg of Fluralaner in a yield of 87.22%. |
85.73% | Stage #1: 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid With dichloro sulfoxide In benzene at 85℃; for 5h; Stage #2: 2-amino-N-(2,2,2-trifluoroethyl)acetamide With triethylamine In dichloromethane; benzene at 0 - 20℃; for 5.33h; Inert atmosphere; | 5 Example 5: Preparation of Florana (Compound 7) Compound 5 (0.42 g, 1 mmol) was dissolved in 20 mL of benzene, thionyl chloride (0.33 g, 2.8 mmol) was added, heated under reflux at 85°C for 5 h, after the reaction was complete, spin to dryness,Intermediate 0 is obtained.Under nitrogen protection, compound 6 (0.18 g, 1.2 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (0.13 g, 1.3 mmol) was added at 0 °C, stirred for 10 min, and the step of dissolving in 5 mL of dichloromethane ( 1) The obtained intermediate 0 (0.47g) was added dropwise, kept for 10min, the ice bath was removed, and the reaction was carried out at room temperature for 5h. After monitoring the reaction was complete, it was spin-dried, and column chromatography (PE:EA=2.5:1) obtained 0.465 g slightly yellow solid.The yield was 85.73%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In ethyl acetate; toluene at 10 - 20℃; for 1h; Inert atmosphere; | 1-4 Reaction condition 1-4 In a nitrogen atmosphere, a solution of 1.50 g (9.6 mmol) of 2-amino-N-(2,2,2-trifluoroethyl)acetic acid amide in 20 g of ethyl acetate was cooled down to 5°C. and thereto, 1.11 g (11.0 mmol) of triethylamine was added. Into the resultant reaction mixture, a solution of 4.0 g (9.2 mmol) of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydrolsoxazole-3-yl]-2-methylbenzoic acid chloride in 32 g of toluene was dropped at a dropping speed by which the temperature of the reaction solution did not exceed 10°C, and the resultant reaction mixture was stirred at 20°C for 1 hour. After the completion of the reaction, to the reaction mixture, 28 g of water and 28 g of ethyl acetate were added, and an organic phase obtained after the phase separation was washed with a diluted hydrochloric acid (prepared by diluting 2.0 g of concentrated hydrochloric acid with 18.3 g of water) and next with 20 g of brine. To the resultant organic phase, 1.2 g of an activated carbon was added, and the resultant mixture was stirred at 40°C for 1 hour, followed by cooling down the organic phase to 20°C and by removing the activated carbon from the organic phase by Celite filtration. By distilling off a solvent under reduced pressure to concentrate the organic phase, 19.5 g of a solution containing the aimed product was obtained. To the resultant solution, 12 g of ethyl acetate was added, and further, 28 g of hexane was added to cool down the resultant reaction mixture to 5°C. A precipitated crystal was retrieved by reduced pressure-filtration and was dried under reduced pressure to obtain 5.0 g (9.0 mmol) of the aimed product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.8% | Stage #1: 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester With sodium hydroxide In water at 50℃; for 0.166667h; Inert atmosphere; Stage #2: 2-amino-N-(2,2,2-trifluoroethyl)acetamide In water; toluene Inert atmosphere; | 5 Example 5: Step (5) Synthesis of Fluralaner Intermediate 5*(31.78g, 73.53mmol) was placed in a reaction vessel with a thermometer, sodium hydroxide (8.82g, 220.59mmol) and water (290mL) were added, and the reaction was stirred at 50°C for 10 minutes under nitrogen protection. Using a constant pressure dropping funnel, a toluene solution (75 mL) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide (22.96g, 147.06mmol) was slowly added dropwise to the above reaction solution. After the addition is complete, the reaction is kept warm and stirred until the completion of the reaction as monitored by TLC.After the reaction solution was placed at room temperature, it was extracted with ethyl acetate (500mL*3), the organic phases were combined, washed with water (100mL*2 times) and saturated sodium chloride solution (150mL*2), and the organic phase was separated and washed with anhydrous It was dried over magnesium sulfate, filtered, the filtrate was spin-dried, and the crude product was recrystallized with a mixed solvent of ethyl acetate and n-hexane to obtain a white solid of Fluralaner(31.82 g, yield 77.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.6% | With hydroxylamine hydrochloride; zinc trifluoromethanesulfonate In 5,5-dimethyl-1,3-cyclohexadiene; water at 110℃; for 8h; Sealed tube; | 4 Example 4: Preparation of fluralaner Add Zn(OTf)2 (1.82g, 5.0mmol), hydroxylamine hydrochloride (350mg, 5.04mmol), 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-benzonitrile (20.0g, 50.1mmol), 2-ammonia-N-(2,2,2-trifluoroethyl)acetamide (9.4g, 60.2mmol), H2O (1.5g), xylene (40mL), the reaction system was sealed and heated to 110°C for 8 hours. The temperature of the system was naturally cooled, the solvent was removed under high vacuum, the residue was dissolved in ethyl acetate (200 mL), filtered, and the filtrate was decompressed to remove the solvent. The residue was recrystallized by adding ethyl acetate/heptane (50 mL/150 mL) to obtain fluralaner (light yellow solid, 24.7 g, 88.6%). |
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