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CAS No. : | 5509-65-9 | MDL No. : | MFCD00007655 |
Formula : | C6H5F2N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ODUZJBKKYBQIBX-UHFFFAOYSA-N |
M.W : | 129.11 | Pubchem ID : | 79647 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 30.76 |
TPSA : | 26.02 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) : | -6.07 cm/s |
Log Po/w (iLOGP) : | 1.48 |
Log Po/w (XLOGP3) : | 1.44 |
Log Po/w (WLOGP) : | 2.4 |
Log Po/w (MLOGP) : | 2.34 |
Log Po/w (SILICOS-IT) : | 1.99 |
Consensus Log Po/w : | 1.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.04 |
Solubility : | 1.17 mg/ml ; 0.0091 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.59 |
Solubility : | 3.3 mg/ml ; 0.0256 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.56 |
Solubility : | 0.357 mg/ml ; 0.00277 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 3,6.1 |
Precautionary Statements: | P501-P261-P270-P240-P210-P233-P243-P241-P242-P271-P264-P280-P370+P378-P337+P313-P305+P351+P338-P361+P364-P303+P361+P353-P332+P313-P301+P310+P330-P304+P340+P311-P403+P233-P403+P235-P405 | UN#: | 1992 |
Hazard Statements: | H301+H311+H331-H315-H319-H226 | Packing Group: | Ⅲ |
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 |
---|---|---|
52% | With sodium perborate In acetic acid at 80 - 90℃; for 1 h; | Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80° C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90° C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10percent THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52percent). MS (ESI) m/z 160 ([M+H]+). |
52% | With sodium perborate In acetic acid at 80 - 90℃; for 1 h; | Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80° C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90° C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10percent THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52percent). MS (ESI) m/z 160 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: With bromine; acetic acid In water at 20℃; for 0.25 h; Stage #2: With sodium carbonate In water |
b) Preparation of intermediate 2; 2,6-difluorobenzeneamine (3.0g, 22.56 mmoles) was dissolved in acetic acid (10 ml). Bromine (1.2 ml) was added to the solution. The mixture was stirred for 15 minutes at room temperature. After evaporation of the solvent, the residue was treated with an aqueous solution of sodium carbonate. The aqueous solution was extracted with dichloromethane. The organic extract was dried over MgSC>4 and was evaporated. Yield : 92percent of intermediate 2. |
91.7% | With bromine In ice-water; acetic acid | 1a) 507.5 g of 2,6-difluoroaniline are added to 2500 ml of acetic acid, the mixture is cooled to 10° C., and a solution of 195 ml of bromine in 250 ml of acetic acid is added dropwise at 10-15° C. over the course of 3 hours. The mixture is subsequently stirred at room temperature for a further 1 hour and poured into 5000 ml of ice-water, the precipitated crystals are filtered off with suction and washed a number of times with a total of 3000 ml of ice-water, and the crystals are dried over Al2O3 under reduced pressure, giving 4-bromo-2,6-difluoroaniline, yield 91.7percent, GC 99.6percent. |
84% | at 20℃; for 2 h; Cooling with ice | 2,6-Difluoroaniline (20.0 g, 0.15 mol, 1.0 eq) was dissolved in of glacial acetic acid (70 mL). The mixture was cooled with an ice bath and bromine (27.6 g, 0.16 mol, 1.1 eq) dissolved in acetic acid (10 mL) was added dropwise. During the addition the product precipitated. After stirring for 2 h at room temperature Na2SO3-solution (1.3 g Na2SO3 in 400 mL water) was added. The product was filtered off, washed with water and dried to afford a colorless solid (27.7 g, 84percent). TLC [Silica, DCM]: Rf = 0.71. 1H NMR (300 MHz, CDCl3): δ = 7.08-6.89 (m, 2H), 3.73 (s, 2H). 13C NMR (75 MHz, CDCl3): δ = 151.9 (dd, J = 244.1, 8.6 Hz), 123.6 (t, J = 16.2 Hz), 115.1-114.6 (m), 107.2 (t, J = 11.7 Hz). 19F NMR (282 MHz, CDCl3): δ = 131.1 (d, J = 7.1 Hz). LRMS (ESI): m/z 207.9 (calcd. 208.0 for C6H579BrF2N [M+H]+). |
80.7% | With N-Bromosuccinimide In dichloromethane at 20℃; for 3 h; | To a solution of 2,6-difluoroaniline (1 g, 7.75 mmol) in 20 mL of dry DCM was added NBS (1.96 g, 9.29mmol). The mixture was stirred at room temperature for 3 hours. The mixture was filtered andconcentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 50/1 to 20/1) to afford the title compound (1.61 g, 80.7percent yield) as a yellow solid. LCMS (ESI) calc’d for C6H4BrF2N [M+H]: 208, found: 208. |
62% | With N-Bromosuccinimide In <i>N</i>-methyl-acetamide | (i) Preparation of 1-(4'-amino-3',5'-difluorobenzyl)imidazole-2-thiol-4-bromo-2,6-difluoroaniline Fifty grams (0.39 mole) of 2,6-difluoroaniline was treated with 71.0 g (0.39 mole) of N-bromosuccinimide in 250 ml of dimethylformamide by the procedure of Mitchell, Lai and Williams, J. Org. Chem., 44, 4733 (1979) to give a total yield of 50.2 g (62percent) of 4-bromo-2,6-difluoroaniline, m.p.: 64°-66° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | at 40℃; for 1.5 h; | B. A solution of 5.1 g (40 mmol) of 2,6-difluoroaniline, 10 mL of alcohol solvent and a few crystals of naphthalene (liquid chromatography internal standard) was placed in a 50 mL flask and heated to 40°C. Solid 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine (2.67 g, 10 mmol) was added with stirring under nitrogen and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. The mixture was cooled to ambient temperature and the solids were recovered by filtration, washed with 10 mL of 2-propanol and then water, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 4 to 6 in the following table. |
84.6% | at 25 - 45℃; for 5.5 - 8 h; | A jacketed 250 mL (milliliter) round bottom flask equipped with a stirrer, condenser, and nitrogen inlet and outlet was loaded with 49.1 g (grams), 0.38 mol (mole) of 2,6-difluoroaniline and 25 g of 1,2-propanediol. The mixture was warmed to 35°C by heating the jacket fluid and a solution of 30.3 g of 93 percent purity (0.10 mol) of 2-chlorosulfonyl-8-fluoro-5-methoxy-[1,2,4]triazolo[1,5-c]pyrimidine in 30.2 g of dichloromethane was added portionwise with stirring under a nitrogen blanket over 3.5 hours. A solid began to form in about one hour and all of the chlorosulfonyl starting material was consumed in 5.5 hours. The resulting mixture was cooled to 20°C and filtered, collecting the solids. The solids were washed 2x40 mL with methanol and then with 112 g of water. The white solid obtained after drying was found to be the title compound with a purity of greater than 99 percent and to amount to 34.2 g (88.9 percent of theory); The preparation of the title compound was carried out as in Example 1 except that some of the parameters were varied. When the reaction was carried out at 25, 35, and 45°C, the time to complete disappearance of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine and the recovered yield of title compound were 6.5 hours/86.5 percent of theory, 5.5 hours/87.9 percent of theory, and 4.9 hours/84.6 percent of theory, respectively. When the amount of 1,2-propanediol was 1.88, 0.95, and 0.48 grams per gram of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]-pyrimidine, the time to complete disappearance of the latter was 3, 5, and 8 hours, respectively. |
83% | at 40℃; for 1.5 h; | B. A solution of 5.1 g (40 mmol) of 2,6-difluoroaniline, 10 mL of alcohol solvent and a few crystals of naphthalene (liquid chromatography internal standard) was placed in a 50 mL flask and heated to 40°C. Solid 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine (2.67 g, 10 mmol) was added with stirring under nitrogen and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. The mixture was cooled to ambient temperature and the solids were recovered by filtration, washed with 10 mL of 2-propanol and then water, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 4 to 6 in the following table. |
82% | at 45℃; for 2 h; | A. A 4.8 g (18 mmol) sample of 2-chlorosulfonyl-8-- fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine was placed in a 50 mL round bottom flask and then the following were added with stirring under nitrogen: 10 mL of an alcohol solvent, 12.9 g (100 mmol) of 2,6-difluoroaniline, and a few crystals of naphthalene (liquid chromatography internal standard). The mixture was heated to the desired temperature and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. When the reaction was complete, the mixture was cooled to 0 to 5°C over a 30-min period and the solids were recovered by filtration, washed with cold solvent, washed with 0.5 N aqueous hydrochloric acid, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 1 to 3 in the table below. |
68% | at 40℃; for 2.5 h; | A. A 4.8 g (18 mmol) sample of 2-chlorosulfonyl-8-- fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine was placed in a 50 mL round bottom flask and then the following were added with stirring under nitrogen: 10 mL of an alcohol solvent, 12.9 g (100 mmol) of 2,6-difluoroaniline, and a few crystals of naphthalene (liquid chromatography internal standard). The mixture was heated to the desired temperature and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. When the reaction was complete, the mixture was cooled to 0 to 5°C over a 30-min period and the solids were recovered by filtration, washed with cold solvent, washed with 0.5 N aqueous hydrochloric acid, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 1 to 3 in the table below. |
68% | at 40℃; for 3 h; | B. A solution of 5.1 g (40 mmol) of 2,6-difluoroaniline, 10 mL of alcohol solvent and a few crystals of naphthalene (liquid chromatography internal standard) was placed in a 50 mL flask and heated to 40°C. Solid 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine (2.67 g, 10 mmol) was added with stirring under nitrogen and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. The mixture was cooled to ambient temperature and the solids were recovered by filtration, washed with 10 mL of 2-propanol and then water, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 4 to 6 in the following table. |
67% | at 30℃; for 3 h; | A. A 4.8 g (18 mmol) sample of 2-chlorosulfonyl-8-- fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine was placed in a 50 mL round bottom flask and then the following were added with stirring under nitrogen: 10 mL of an alcohol solvent, 12.9 g (100 mmol) of 2,6-difluoroaniline, and a few crystals of naphthalene (liquid chromatography internal standard). The mixture was heated to the desired temperature and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. When the reaction was complete, the mixture was cooled to 0 to 5°C over a 30-min period and the solids were recovered by filtration, washed with cold solvent, washed with 0.5 N aqueous hydrochloric acid, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 1 to 3 in the table below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 120℃; for 3.5 h; Inert atmosphere | General procedure: GP3-1: A solution of 2-halo substituted aniline (1.0 eq), potassium ethyl xanthate (1.2 eq or 2.2 eq,typically 2.2 eq) in 10 volume of anhydrous DMF was heated at 100 0Cor 120 0C for 4 hours under nitrogen. TLC monitored the progress ofreaction. After completion, the reaction mixture was cooled to room temperature,diluted with water (10 volume) and neutralized by 1 M HCl solution to pH 5. Theformed precipitate was collected by filtration, rinsed with water, firstlydried by rotavapor, and then dried by oil pump to afford 2-mercaptobenzothiazole.GP3-2: 2-mercaptobenzothiazole in 10 volume ofanhydrous DCM, was added by sulfuryl chloride (SO2Cl2, 1volume) under ice-cooled condition. The mixture was stirred at rt for 1 hour,which was monitored by TLC. After consumption of starting material, the mixturewas diluted by 30 volume of ether, following quenching carefully by addingwater. Stirring was kept for 1 hour to make sure the SO2Cl2was totally consumed and product was released. Organic layer was collected,neutralized by saturated NaHCO3, dried over Na2SO4and purified by silica gel chromatograph to give the pure product, which wasfinally characterized by LC-MS and NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With Iodine monochloride In acetic acid at 20℃; for 0.25 h; | 2, 6-Difluorobenzenamine (3. 0g, 22.56 mmoles) was dissolved in acetic acid (10 ml). Iodine monochloride (3.581g, 22.56 mmoles) was added to the solution. The mixture was stirred for 15 minutes at room temperature. After evaporation of the solvent, the residue was treated with an aqueous solution of sodium carbonate. The aqueous solution was extracted with dichloromethane. The organic extract was dried over MgS04 and was evaporated. Yield: 95percent of intermediate 33. |
95% | Stage #1: With Iodine monochloride; acetic acid In water at 20℃; for 0.25 h; Stage #2: With sodium carbonate In water |
Example A1; a) Preparation of intermediate 1; 2,6-difluorobenzeneamine (3.0g, 22.56 mmoles) was dissolved in acetic acid (10 ml).Iodine monochloride (3.58lg, 22.56 mmoles) was added to the solution. The mixturewas stirred for 15 minutes at room temperature. After evaporation of the solvent, theresidue was treated with an aqueous solution of sodium carbonate. The aqueoussolution was extracted with dichloromethane. The organic extract was dried overMgSCU and was evaporated. Yield : 95percent of intermediate 1. |
51% | With silver(I) nitrite; iodine In dichloromethane at 0 - 20℃; for 1 h; | Step 1: 4-Amino-3,5-difluoro-benzonitrile; To a suspension of iodine (5.59g, 22.0mmol) and AgNO2 (6.85g, 22.0mmol) in EPO <DP n="79"/>methylene chloride was added a solution of 2,6-difluoroaniline (2.58g, 20.0mmol) in methylene chloride at O0C, and the mixture was stirred for 30min at O0C and 30min at ambient temperature. The reaction was quenched with Na2S2O3. The reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (hexane/ethylacetate = 15/1) to yield a yellow solid (2.57mg, 51percent). |