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CAS No. : | 978-62-1 | MDL No. : | MFCD00218820 |
Formula : | C15H8ClF6NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CHILCFMQWMQVAL-UHFFFAOYSA-N |
M.W : | 383.67 | Pubchem ID : | 5081913 |
Synonyms : |
IKK2 Inhibitor V
|
Num. heavy atoms : | 25 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.13 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 77.69 |
TPSA : | 49.33 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.51 cm/s |
Log Po/w (iLOGP) : | 2.75 |
Log Po/w (XLOGP3) : | 5.82 |
Log Po/w (WLOGP) : | 7.45 |
Log Po/w (MLOGP) : | 4.69 |
Log Po/w (SILICOS-IT) : | 4.89 |
Consensus Log Po/w : | 5.12 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.91 |
Solubility : | 0.000471 mg/ml ; 0.00000123 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.63 |
Solubility : | 0.0000907 mg/ml ; 0.000000236 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -6.66 |
Solubility : | 0.0000832 mg/ml ; 0.000000217 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.07 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
85.5% | With phosphorus trichloride In toluene for 3 h; Heating / reflux | A mixture of 5-chlorosalicylic acid(6.90g, 40mmol), 3,5-bis(trifluoromethyl)aniline(9.16g, 40mmol), phosphorus trichloride(1.74mL, 20mmol) and toluene(80mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(240mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(13.12g, 85.5percent) as a light yellow solid.1H-NMR(DMSO-d6): δ 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s). |
62% | With phosphorus trichloride In chlorobenzeneMicrowave irradiation | General procedure: All salicylanilides(1a-8d) were synthesized via a previously described microwave assisted (MicroSYNTH Milestone) method.25 Briefly,the appropriately substituted salicylic acid (1 eq) and the substituted aniline (1 eq) were suspended or dissolved in chlorobenzene(1 mL/0.15 mmol of acid). Phosphorus trichloride (PCl3) was added(0.5 eq) and the mixture was stirred (600 rpm) and radiated(530 W) for 30–60 min. The mixture was filtrated while hot and was let cool, initially at r.t. and overnight at 4 °C. The formed pre-cipitate was filtered and recrystallized with ethanol or mixture of hexane/AcOEt in order to afford the final compounds with yields of 41–83percent. |
57% | With trichlorophosphate In toluene for 6 h; Inert atmosphere; Reflux | To 30 ml and of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux. Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure. The mixture was dissolved in 60 ml and of ethylacetate, which was washed with water (40 ml*2). The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57percent). m.p: 172-173° C.; 1H-NMR (300 MHz, DMSO-d6): δ 7.05 (1H, d, J=8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.85 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.45 (2H, s), 10.85 (1H, s), 11.39 (1H, s). |
28% | With pyridine; phosphorus trichloride In toluene for 12 h; Inert atmosphere; Reflux | General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley’s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6–7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex). |
28% | With pyridine; phosphorus trichloride In tolueneInert atmosphere; Reflux | Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley’s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28percent). mp 172 - 173 oC. 1H NMR (DMSO-d6) δ 11.37(brs, 1H), 10.91(s, 1H), 8.43(s, 2H), 7.85-7.88(m, 2H), 7.49(dd, J1=8.7Hz, J2=2.9Hz, 1H), 7.05(d, J=8.7Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; dichloromethane;Reflux; | General procedure: General Method of Salicylanilide Synthesis9. [0081] A suspension of the salicylic acid derivative and aniline in xylenes (0.1 to 0.5 M) was warmed to reflux, and then a solution of phosphorous trichloride in CH2Cl2 (CAUTION: CH2Cl2 boils off rapidly at this temperature Apparatus should be constructed to allow distillation of CH2Cl2) or xylenes was introduced dropwise. When the reaction was complete, as determined by TLC or HPLC-MS, the reaction mixture was rapidly transferred while hot by pipette, cannulation, or decanting to a beaker and allowed to cool under rapid stirring. This action removed tarry residue which may accumulate on the reaction vessel walls during the reaction. Typically the product crystallized from the reaction solvent as it cooled, or was induced to crystallize upon the slow addition of hexanes when the temperature of the reaction solvent reached 75 to 80° C. Example 1 N-(3-bromophenyl)-5-chloro-2-hydroxybenzamide (3b) Using the method described for compound 3a, 5-chlorosalicylic acid (0.57 g, 3.30 mmol) reacted with 3-bromoaniline (0.36 mL, 3.30 mmol) and 2M PCl3 in CH2Cl2 (0.66 mL, 1.32 mmol) in xylenes (8 mL). The crude product was recrystallized from EtOAc/hexanes. 1H NMR (500 MHz, DMSO-d6) delta 7.024 (m, 2H), 7.354 (m, 3H), 7.474 (m, 1H), 7.660 (m, 1H), 7.895 (m, 1H), 8.056 (s, 1H), 10.482 (s, 1H). HPLC TR 2.84 min; m/z+ 327.85 [M+H]+; m/z- 325.75 [M-H]-, (EM 324.95). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.5% | Example 51 N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Comopund No. 50). Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 85.5percent. 1H-NMR(DMSO-d6): delta 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s). | |
85.5% | With phosphorus trichloride; In toluene; for 3.0h;Heating / reflux; | A mixture of 5-chlorosalicylic acid(6.90g, 40mmol), 3,5-bis(trifluoromethyl)aniline(9.16g, 40mmol), phosphorus trichloride(1.74mL, 20mmol) and toluene(80mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(240mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(13.12g, 85.5percent) as a light yellow solid.1H-NMR(DMSO-d6): delta 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s). |
62% | With phosphorus trichloride; In chlorobenzene;Microwave irradiation; | General procedure: All salicylanilides(1a-8d) were synthesized via a previously described microwave assisted (MicroSYNTH Milestone) method.25 Briefly,the appropriately substituted salicylic acid (1 eq) and the substituted aniline (1 eq) were suspended or dissolved in chlorobenzene(1 mL/0.15 mmol of acid). Phosphorus trichloride (PCl3) was added(0.5 eq) and the mixture was stirred (600 rpm) and radiated(530 W) for 30?60 min. The mixture was filtrated while hot and was let cool, initially at r.t. and overnight at 4 °C. The formed pre-cipitate was filtered and recrystallized with ethanol or mixture of hexane/AcOEt in order to afford the final compounds with yields of 41?83percent. |
57% | With trichlorophosphate; In toluene; for 6.0h;Inert atmosphere; Reflux; | To 30 ml and of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux. Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure. The mixture was dissolved in 60 ml and of ethylacetate, which was washed with water (40 ml*2). The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57percent). m.p: 172-173° C.; 1H-NMR (300 MHz, DMSO-d6): delta 7.05 (1H, d, J=8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.85 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.45 (2H, s), 10.85 (1H, s), 11.39 (1H, s). |
28% | With pyridine; phosphorus trichloride; In toluene; for 12.0h;Inert atmosphere; Reflux; | General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex). |
28% | With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux; | Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28percent). mp 172 - 173 oC. 1H NMR (DMSO-d6) delta 11.37(brs, 1H), 10.91(s, 1H), 8.43(s, 2H), 7.85-7.88(m, 2H), 7.49(dd, J1=8.7Hz, J2=2.9Hz, 1H), 7.05(d, J=8.7Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.4% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; for 5.0h; | 3,4-Methylenedioxyphenylacetic acid(103.1mg, 0.57mmol), WSC * HCl(0.13g, 0.68mmol) and 4-dimethylaminopyridine(10mg) were added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.20g, 0.52mmol) in tetrahydrofuran(5mL), and the mixture was stirred for 5 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound(228mg, 80.4percent) as a white crystal.1H-NMR(DMSO-d6): delta 3.83(2H, s), 5.89(2H, s), 6.56-6.73(2H, m), 6.79(1H, d, J=1.2Hz), 7.37(1H, d, J=8.4Hz), 7.71(1H, dd, J=8.7, 2.4Hz), 7.85(2H, d, J=2.7Hz), 8.32(2H, s), 11.01(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.0% | With pyridine; In tetrahydrofuran; at 0 - 20℃; for 1.0h; | Acetyl chloride(234mg, 3.3mmol)was added to a solution of N-[3,5-bis(trifluoromethylphenyl)]-5-chloro-2-hydroxybenzamide(Compound No. 4; 1.51g, 3mmol) and pyridine(285mg, 3.6mmol) in tetrahydrofuran(6mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 2N Hydrochloric acid was added to the residue obtained by evaporation of the solvent under reduced pressure and the mixture was extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was recrystallized from n-hexane/ethyl acetate to give the title compound(1.06g, 83.0percent) as a white solid.1H-NMR(DMSO-d6): delta 2.22(3H, s), 7.35(1H, d, J=9.0Hz), 7.71(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.88(1H, d, J=2.7Hz), 8.37(2H, s), 11.05(1H, brs). |
83.0% | With pyridine; hydrogenchloride; In tetrahydrofuran; | Example 96 2-Acetoxy-N-[3,5-bis(trifluoromethyl)phenyl)-5-chlorobenzamide (Comopund No. 96). N-(3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(1.51g, 3mmol) and pyridine(285mg, 3.6mmol) were dissolved in tetrahydrofuran(6mL). Acetyl chloride(234mg, 3.3mmol) was added dropwise under ice cooling, and the mixture was stirred at room temparature for 1 hour. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane-ethyl acetate to give the title compound(1.06g, 83.0percent) as a white solid. 1H-NMR(DMSO-d6): delta 2.22(3H, s), 7.35(1H, d, J=9.0Hz), 7.71(111, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.88(1H, d, J=2.7Hz), 8.37(2H, s), 11.05(1H, brs). |
83.0% | With pyridine; In tetrahydrofuran; at 0 - 20℃; for 1.0h; | N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound No. 50; 1.51g, 3mmol) and pyridine(285mg, 3.6mmol) were dissolved in tetrahydrofuran(6mL). Acetyl chloride(234mg, 3.3mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane/ethyl acetate to give the title compound(1.06g, 83.0percent) as a white solid.1H-NMR(DMSO-d6): delta 2.22(3H, s), 7.35(1H, d, J=9.0Hz), 7.71(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.88(1H, d, J=2.7Hz), 8.37(2H, s), 11.05(1H, brs). |
83.0% | With pyridine; In tetrahydrofuran; at 0 - 20℃; for 1.0h; | N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound No. 50; 1.51g, 3mmol) and pyridine(285mg, 3.6mmol) were dissolved in tetrahydrofuran(6mL). Acetyl chloride(234mg, 3.3mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane/ethyl acetate to give the title compound(1.06g, 83.0percent) as a white solid.1H-NMR(DMSO-d6): delta 2.22(3H, s), 7.35(1H, d, J=9.0Hz), 7.71(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.88(1H, d, J=2.7Hz), 8.37(2H, s), 11.05(1H, brs). |
83.0% | With pyridine; In tetrahydrofuran; at 0 - 20℃; for 1.0h; | Acetyl chloride(234mg, 3.3mmol)was added to a solution of N-[3,5-bis(trifluoromethylphenyl)]-5-chloro-2-hydroxybenzamide(Compound No. 4; 1.51g, 3mmol) and pyridine(285mg, 3.6mmol) in tetrahydrofuran(6mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 2N Hydrochloric acid was added to the residue obtained by evaporation of the solvent under reduced pressure and the mixture was extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was recrystallized from n-hexane/ethyl acetate to give the title compound(1.06g, 83.0percent) as a white solid.1H-NMR(DMSO-d6): delta 2.22(3H, s), 7.35(1H, d, J=9.0Hz), 7.71(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.88(1H, d, J=2.7Hz), 8.37(2H, s), 11.05(1H, brs). |
83.0% | With pyridine; In tetrahydrofuran; at 0 - 20℃; for 1.0h; | Acetyl chloride(234mg, 3.3mmol)was added to a solution of N-[3,5-bis(trifluoromethylphenyl)]-5-chloro-2-hydroxybenzamide(Compound No. 4; 1.51g, 3mmol) and pyridine(285mg, 3.6mmol) in tetrahydrofuran(6mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 2N Hydrochloric acid was added to the residue obtained by evaporation of the solvent under reduced pressure and the mixture was extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was recrystallized from n-hexane/ethyl acetate to give the title compound(1.06g, 83.0percent) as a white solid.1H-NMR(DMSO-d6): delta 2.22(3H, s), 7.35(1H, d, J=9.0Hz), 7.71(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.88(1H, d, J=2.7Hz), 8.37(2H, s), 11.05(1H, brs). |
83% | With pyridine; In tetrahydrofuran; at 20℃; for 1.0h; | N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound No. 50; 1.51g, 3mmol) and pyridine(285mg, 3.6mmol) were dissolved in tetrahydrofuran(6mL). Acetyl chloride(234mg, 3.3mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane/ethyl acetate to give the title compound(1.06g, 83.0percent) as a white solid.1H-NMR(DMSO-d6): delta 2.22(3H, s), 7.35(1H, d, J=9.0Hz), 7.71(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.88(1H, d, J=2.7Hz), 8.37(2H, s), 11.05(1H, brs). |
83.0% | With pyridine; In tetrahydrofuran; at 0 - 20℃; for 1.0h; | N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound No. 50; 1.51g, 3mmol) and pyridine(285mg, 3.6mmol) were dissolved in tetrahydrofuran(6mL). Acetyl chloride(234mg, 3.3mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane/ethyl acetate to give the title compound(1.06g, 83.0percent) as a white solid.1H-NMR(DMSO-d6): delta 2.22(3H, s), 7.35(1H, d, J=9.0Hz), 7.71(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.88(1H, d, J=2.7Hz), 8.37(2H, s), 11.05(1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With pyridine; dmap; triethylamine; In tetrahydrofuran; at 0 - 20℃; for 23.5h; | N,N-Dimethylcarbamoyl chloride(304 muL, 3.3mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 1.15g, 3mmol) and pyridine(285mg, 3.6mmol) in tetrahydrofuran(10mL) under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. Triethylamine(0.5mL, 3.6mmol), N,N-dimethylcarbamoyl chloride(304 muL, 3.3mmol) and 4-dimethylaminopyridine(110mg, 0.9mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for further 20 hours. 2N Hydrochloric acid(6mL) and water(30mL) were added to the reaction mixture and it was extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound(1.29g, 94.2percent) as a white solid.1H-NMR(DMSO-d6): delta 2.81(3H, s), 2.98(3H, s), 7.36(1H, d, J=8.7Hz), 7.66(1H, dd, J=8.7, 2.4Hz), 7.80(1H, d, J=2.4Hz), 7.84(1H, s), 8.35(1H, s), 11.03(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | With dmap; triethylamine; In tetrahydrofuran; at 20℃; for 2.0h; | Morpholine-4-carbonyl chloride(73 muL, 0.62mmol), triethylamine(0.2mL, 1.43mmol) and 4-dimethylaminopyridine(10mg) were added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.20g, 0.52mmol) in tetrahydrofuran(3mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with isopropyl ether/n-hexane under suspension to give the title compound(237.2mg, 91.8percent) as a white powder.1H-NMR(DMSO-d6): delta 3.35(4H, s), 3.54(4H, s), 7.37(1H, d, J=9.0Hz), 7.68(1H, dd, J=9.0, 3.0Hz), 7.83(1H, d, J=2.7Hz), 7.87(1H, s), 8.39(2H, s), 11.06(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | With triethylamine; In tetrahydrofuran; at 20℃; for 0.166667h; | Triethylamine(0.15mL, 1.07mmol) and methanesulfonyl chloride(45 muL, 0.58mmol) were added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.20g, 0.52mmol) in tetrahydrofuran(4mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1-->2:1) to give the title compound(214.3mg, 89.2percent) as a white crystal.1H-NMR(DMSO-d6): delta 3.43(3H, s), 7.59(1H, d, J=8.7Hz),7.77(1H, dd, J=9.0, 2.7Hz), 7.87(1H, s), 7.91(1H, d, J=3.0Hz), 8.36(2H, s), 11.14(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.5% | With sodium methylate; at 20℃; for 48.67h; | Metal sodium(1.2mg) was added to anhydrous methanol(2.0mL), and dissolved by stirring at room temperature under argon atmosphere. 5-Chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 200mg, 0.521mmol) was added to the solution. Dimethyl acetylene dicarboxylate(81mg, 0.573mmol) was further added dropwise to the solution for 40 minutes, and the mixture was stirred at room temperature for 48 hours. Brine was added to the reaction mixture and it was extracted with tetrahydrofuran. After the tetrahydrofuran layer was dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(141mg, 51.5percent) as a white solid.1H-NMR(CDCl3): delta 3.14(1H, d, J=16.2Hz), 3.25(1H, d, J=16.2Hz), 3.39(3H, s), 3.79(3H, s), 7.05(1H, d, J=8.7Hz), 7.50(1H, dd, J=8.7, 2.4Hz), 7.93(1H, d, J=2.7Hz), 7.94(2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine; In dichloromethane; at 0 - 20℃; for 1.0h; | Succinic acid dichloride(121mg, 0.8mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.2g, 0.5mmol) and triethylamine(0.5mL) in dichloromethane(8mL) under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate. After the ethyl acetate solution was washed successively with 2N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound(161mg, 66percent) as a light yellow powder.1H-NMR(CDCl3): delta 2.25(1H, dt, J=13.5, 10.0Hz), 2.55(1H, ddd, J=18.0, 10.0, 1.8Hz), 2.75(1H, ddd, J=13.5, 9.3, 2.4Hz), 2.99(1H, dt, J=18.9, 9.3Hz), 7.07(1H, d, J=8.7Hz), 7.58(1H, dd, J=8.7, 2.7Hz), 7.88(2H, s), 8.00(1H, d, J=2.7Hz), 8.01(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.1% | In pyridine; at 60℃; for 4.0h; | N,N-Diethylcarbamoyl chloride(80 muL, 0.63mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.20g, 0.52mmol) in pyridine(3mL), and the mixture was stirred at 60°C for 4 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by isopropyl ether/n-hexane to give the title compound(231.2mg, 92.1percent) as a white crystal.1H-NMR(CDCl3): delta 1.16(3H, t, J=7.2Hz), 1.20(3H, t, J=7.2Hz), 3.41(2H, q, J=7.2Hz), 3.45(2H, q, J=7.2Hz), 7.05(1H, d, J=9.0Hz), 7.44(1H, dd, J=9.0, 2.7Hz), 7.62(1H, s),7.70(1H, d, J=2.7Hz), 8.09(2H, s), 9.25(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | With sodium hydride; In tetrahydrofuran; at 0℃; for 0.25h; | (2) 5-Chloro-2-pivaloyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(Compound No. 1). A solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(0.20g, 0.52mmol) in tetrahydrofuran(3mL) was added to a suspension of 60percent sodium hydride(21.8mg, 0.55mmol) in tetrahydrofuran(3mL) under ice bath, and the mixture was stirred for 5 minutes. Then, pivaloyl chloride(71 muL, 0.57mmol) was added and the mixture was stirred for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with isopropyl ether/n-hexane under suspension to give the title compound(195mg, 80.2percent) as a white crystal. 1H-NMR(DMSO-d6): delta 1.21(9H, s), 7.35(1H, d, J=8.7Hz), 7.70(1H, dd, J=8.7, 2.7Hz), 7.85(2H, d, J=2.4Hz), 8.36(2H, s), 11.10(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.7% | With pyridine; In tetrahydrofuran; at 0 - 20℃; for 2.0h; | Benzoyl chloride(64 muL, 0.55mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 192mg, 0.5mmol) and pyridine(47mg, 0.6mmol) in tetrahydrofuran(5mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. 2N Hydrochloric acid(1mL) and water(50mL) were added to the reaction mixture and it was extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(dichloromethane:methanol=95:5) to give the title compound(226mg, 92.7percent) as a light yellow solid.1H-NMR(DMSO-d6): delta 7.53-7.58(3H, m), 7.70-7.76(1H, m), 7.78(1H, dd, J=9.0, 3.0Hz), 7.80(1H, s), 7.94(1H, d, J=2.7Hz), 8.07-8.10(2H, m), 8.25(2H, s), 11.13(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.5% | With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 1.0h; | Triethylamine(80 mu L, 0.547mmol) and Nicotinoyl chloride hydrochloride(492mg, 0.274mmol) were added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 100mg, 0.261mmol) in N,N-dimethylformamide(1.5mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and it was extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(120mg, 94.5percent) as a white solid.1H-NMR(DMSO-d6): delta 7.60(1H, d, J=8.7Hz), 7.62(1H, ddd, J=8.1, 4.8, 0.9Hz), 7.81(1H, dd, J=8.7, 2.7Hz), 7.81(1H, s), 7.98(1H, d, J=2.4Hz), 8.26(2H, s), 8.43(1H, ddd, J=8.1, 2.1, 1.5Hz), 8.88(1H, dd, J=4.8, 1.5Hz), 9.23(1H, dd, J=2.1, 0.9Hz), 11.16(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.1% | With potassium carbonate; In acetone; for 1.0h;Heating / reflux; | A mixture of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 600mg, 1.6mmol), potassium carbonate(l.lOg, 8.0mmol), ethyl chloroacetate(383mg, 3.2mmol) and acetone(10mL) was refluxed for 1 hour under argon atmosphere. After the reaction mixture was cooled to room temperature, the insoluble matter was filtered off, and the residue obtained by concentration of the filtrate under reduced pressure was diluted with ethyl acetate(15mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound(427mg, 58.1percent) as a white powder.1H-NMR(CDCl3): delta 1.38(3H, t, J=7.2Hz), 4.41(2H, q, J=7.2Hz), 4.79(2H, s), 6.86(1H, d, J=8.7Hz), 7.46(1H, dd, J=8.7, 2.7Hz), 7.62(1H, s), 8.27(1H, d, J=2.7H), 8.52(2H, s), 10.88(1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.0% | With dmap; In tetrahydrofuran; at 20℃; for 3.0h; | N-Methyl-N-phenylcarbamoyl chloride(105.8mg, 0.62mmol), triethylamine(0.2mL, 1.43mmol) and 4-dimethylaminopyridine(10mg) were added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.20g, 0.52mmol) in tetrahydrofuran(3mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with isopropyl ether/n-hexane under suspension to give the title compound(239.3mg, 89.0percent) as a white powder.1H-NMR(DMSO-d6): delta 3.28(3H, s), 7.15-7.34(5H, m), 7.39(1H, d, J=8.4Hz), 7.66(1H, dd, J=8.7, 2.4Hz), 7.81(1H, d, J=2.4Hz), 7.87(1H, s),8.34(2H, s), 11.00(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.0% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; | Triethyamine(0.055mL, 0.39mmol) and isopropyl isocyanate(33.3mg, 0.39mmol) were added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.10g, 0.26mmol) in tetrahydrofuran(2mL) at 0°C under argon atmosphere, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction mixture and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane/ethyl acetate under suspension to give the title compound(33mg, 27.0percent) as a white powder.1H-NMR(CDCl3): delta 1.21(6H, d, J=6.3Hz), 3.84-3.93(1H, m), 5.24(1H, d, J=7.2Hz), 7.07(1H, d, J=8.7Hz), 7.40(1H, dd, J=8.7, 2.7Hz), 7.61(1H, s), 7.72(1H, d, J=2.4Hz), 8.09(2H, s), 9.08(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.4% | With triethylamine; In tetrahydrofuran; at 20℃; for 3.0h; | 5-Chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.20g, 0.52mmol) was dissolved in tetrahydrofuran(5mL). O-Acetylsalicyloyl chloride(0.124g, 0.62mmol) and triethylamine(0.2mL, 1.43mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1), and washed with isopropyl ether/n-hexane under suspension to give the title compound(236.7mg, 83.4percent) as a white powder.1H-NMR(DMSO-d6): delta 2.13(3H, s), 7.29(1H, dd, J=8.4, 1.2Hz), 7.45(1H, td, J=7.8, 1.2Hz), 7.48(1H, d, J=8.7Hz),7.76(1H, td, J=8.4, 1.8Hz), 7.77(1H, dd, J=8.4, 2.4Hz), 7.82(1H, s), 7.94(1H, d, J=2.4Hz), 8.16(1H, dd, J=7.8, 1.5Hz), 8.29(2H, s), 11.12(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 1.0h; | Decanoyl chloride(70 muL, 0.339mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 100mg, 0.261mmol) and triethylamine(50 muL, 0.359mmol) in N,N-dimethylformamide(1.5mL) under argon atmosphere, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and it was extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(125mg, 89.3percent) as a colorless oil.1H-NMR(CDCl3): delta 0.87(3H, t, J=7.2Hz), 1.21-1.33(12H, m), 1.65-1.75(2H, m), 2.61(2H, t, J=7.2Hz), 7.13(1H, d, J=9.0Hz), 7.50(1H, dd, J=8.7, 2.4Hz), 7.66(1H, s), 7.80(1H, d, J=2.4Hz), 8.09(2H, s), 8.38(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 6.0h; | Isopropyl bromide(60 muL, 0.64mmol) and potassium carbonate(143.7mg, 1.04mmol) were added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.20g, 0.52mmol) in N,N-dimethylformamide(4mL), and the mixture was stirred at 60°C for 6 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(164.9mg, 74.5percent) as a white crystal.1H.NMR(CDCl3): delta 1.55(6H, d, J=6.0Hz), 4.85(1H, m), 7.00(1H, d, J=9.0Hz), 7.46(1H, dd, J=8.7, 2.7Hz), 7.63(1H, s), 8.14(2H, s), 8.26(1H, d, J=2.7Hz), 10.47(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1.0h; | 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC * HCl hereafter.; 150mg, 0.8mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 200mg, 0.5mmol) and valeric acid(80mg, 0.8mmol) in dichloromethane(5mL) under argon atmosphere, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was diluted with ethyl acetate, washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=6:1) to give the title compound(250mg, 100percent) as a white powder.1H-NMR(CDCl3): delta 0.89(3H, t, J=7.5Hz), 1.38(2H, sext, J=7.5Hz), 1.70(2H, q, J=7.5Hz), 2.62(2H, t, J=7.5Hz), 7.11(1H, d, J=8.9Hz), 7.46(1H, dd, J=8.7, 2.4Hz), 7.63(1H, s), 7.72(1H, d, J=2.4Hz), 8.07(2H, s), 8.49(1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tetrachloromethane; dmap; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0℃; for 0.666667h; | Carbon tetrachloride(401mg, 5.6mmol), diisopropylethylamine(141mg, 1.1mmol), dimethylaminopyridine(catalytic amount) and dibenzyl phosphite(198mg, 0.7mmol) were added successively to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifIuoromethyl)phenyl]benzamide(compound of Example 1(1); 0.2g, 0.5mmol) in acetonitrile(8mL) at 0°C under argon atmosphere, and the mixture was stirred at the same temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate(50mL). After the ethyl acetate layer was washed successively with 2N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound(338mg, 100percent) as a white powder.1H-NMR(CDCl3): delta 5.04-5.17(4H, m), 7.15(1H, dd, J=9.0, 1.2Hz), 7.22-7.33(11H, m), 7.61(1H, s), 7.85(1H, dd, J=2.7, 0.9Hz)8.20(2H, s), 9.25(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide; In ethanol; water; at 20℃; for 0.0166667h; | 2N Aqueous sodium hydroxide(5mL, 10mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 3.84g, 10mmol) in ethanol(100mL), and the mixture was stirred at room temperature for 1 minute. The solvent was evaporated under reduced pressure to give the title compound(4.06g, 100percent) as a white solid.1H-NMR(DMSO-d6): delta 6.43(1H, d, J=8.7Hz), 6.97(1H, dd, J=8.7, 3.0Hz), 7.59(1H, s), 7.62(1H, d, J=3.0Hz), 8.29(2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.9% | With sulfur trioxide pyridine complex; In pyridine; at 20℃; for 8.0h; | Sulfur trioxide pyridine complex(664mg, 4mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.4g, 1mmol) in pyridine(10mL), and the mixture was stirred at room temperature for 8 hours under argon atmosphere. The residue obtained by evaporation of the solvent under reduced pressure was diluted with ethyl acetate(15mL). After the ethyl acetate layer was washed successively with water and brine, dried over sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized from n-hexane/chloroform to give the title compound(425mg, 87.9percent) as a white powder.1H-NMR(DMSO-d6): delta 7.51(1H, d, J=8.7Hz), 7.61(1H, dd, J=8.7, 2.7Hz), 7.70(1H, d, J=2.7Hz), 7.85(1H, s), 8.36(2H, s), 11.04(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.0% | With dmap; triethylamine; In tetrahydrofuran; at 0 - 20℃; for 32.0h; | A solution of ethyl isonipecotate(786mg, 5.00mmol) and triethylamine(506mg, 5.00mmol) in dichloroethane(5mL) was added to a solution of triphosgene(549mg, 1.85mmol) in dichloroethane(10mL), and the mixture was stirred at room temperature for 1 hour. The residue obtained by evaporation of the reaction mixture under reduced pressure was dissolved in tetrahydrofuran(10mL). A solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 1.92g, 5.00mmol) in tetrahydrofuran(10mL), triethylamine(549mg, 5.00mmol) and 4-dimethylaminopyridine(100mg) were added to the solution under ice cooling, and the mixture was stirred at room temperature for 32 hours. The reaction mixture was washed with diluted hydrochloric acid and the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound(1.814g, 64.0percent) as a white crystal.1H-NMR(CDCl3): delta 1.25(3H, t, J=7.2Hz), 1.63-1.73(2H, m), 1.95-2.00(2H, m), 2.48-2.58(1H, m), 3.05-3.13(1H, m), 3.18-3.25(1H, m), 4.08-4.18(2H, m), 4.15(2H, q, J=7.2Hz), 7.05(1H, d, J=9.0Hz), 7.42(1H, dd, J=9.0, 3.0Hz), 7.62(1H, s), 7.69(1H, d, J=2.7Hz), 8.06(2H, s), 9.13(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.5% | With potassium tert-butylate;18-crown-6 ether; In acetonitrile; at 60℃; for 8.0h; | A solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.2g, 0.5mmol), carbonic acid 1-chloroethyl ethyl ester(119mg, 0.8mmol), potassium tert-butoxide(88mg, 0.5mmol) and 18-crown-6(catalytic amount) in acetonitrile(8mL) was stirred at 60°C for 8 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. After the ethyl acetate solution was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound(56mg, 21.5percent) as a white powder.1H-NMR(CDCl3): delta 1.24(3H, t, J=7.2Hz), 1.85(3H, d, J=5.4Hz), 4.01-4.27(2H, m), 6.50(1H, q, J=5.4Hz), 7.11(1H, d, J=9.0Hz), 7.48(1H, dd, J=9.0, 2.7Hz), 7.64(1H, d, J=0.9Hz), 8.14(1H, d, J=2.7Hz), 8.19(2H, s), 9.83(1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.4% | With 1-methyl-pyrrolidin-2-one; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1.5h; | N-(tert-butoxycarbonyl)-L-valine(135.8mg, 0.62mmol), WSC * HCl(0.20g, 1.04mmol), 4-dimethylaminopyridine(10mg) and N-methyl-2-pyrrolidinone(1.5mL) were added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 1(1); 0.20g, 0.52mmol) in tetrahydrofuran(3mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(277.2mg, 91.4percent) as a white solid.1H-NMR(CDCl3): delta 1.06(3H, d, J=6.9Hz),1.11(3H, d, J=6.9Hz), 1.37(9H, s), 2.24(1H, m), 4.16(1H, t, J=6.9Hz), 5.00(1H, d, J=6.9Hz), 7.22(1H, d, J=9.0Hz), 7.50(1H, dd, J=8.7, 2.7Hz), 7.66(1H, s),8.01(1H, d, J=2.4Hz), 8.26(2H, s), 8.96(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With tetraphosphorus decasulfide; In pyridine; for 3.0h;Reflux; | Compound 1 (1 g, 2.6 mmol, 2.0 equiv) was dissolved in pyridine (8 mL, 0.2 M). Phosphorus pentasulfide (591 mg, 1.3 mmol, 1 equiv) was added, and the mixture was heated to reflux (3 h). The mixture was concentrated under vacuum and mixed with dilute HCl and toluene. The resulting mixture was refluxed (3 h). The mixture was concentrated under vacuum. Water was added to the residue, and it was extracted with EtOAc. The extract was purified by column chromatography (1:10 EtOAc:Hex) to give product 25 (138 mg, 10percent). yellow solid. Mp 68-70 °C. 1H NMR (300 MHz, DMSO-d6): delta 6.96 (d, J = 8.8 Hz, 1H), 7.34 (dd, J1 = 8.7 Hz, J2 = 2.7 Hz, 1H), 7.57 (d, J = 2.7 Hz, 1H), 7.99 (s, 1H), 8.73 (s, 2H), 10.56 (s, 1H), 12.40 (s, 1H). HRMS (APCI), m/z calcd for C15H8ClF6NOS-H: 397.9841, found 397.9836. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4.0h; | To a solution of compound 1 (192 mg, 0.5 mmol, 1.0 equiv) in DMF (1.5 mL, 0.3 M), benzyl bromide (0.07 mL, 0.55 mmol, 1.1 equiv) and potassium carbonate (83 mg, 0.6 mmol, 1.2 equiv) were added. The solution was stirred at room temperature (4 h). The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (20 mL) and then washed with brine. The organic layer was dried (MgSO4) and concentrated under vacuum. The crude product was purified by column chromatography (1:15 EtOAc:Hex) to give product 16 (220 mg, 93percent). White solid. Mp 178-180 °C. 1H NMR (300 MHz, DMSO-d6): delta 5.23 (s, 2H), 7.30-7.34 (m, 4H), 7.47-7.48 (m, 2H), 7.60 (dd, J1 = 11.6 Hz, J2 = 2.7 Hz, 1H), 7.68(d, J = 2.7 Hz, 1H), 7.80 (s, 1H), 8.26 (s, 1H), 10.84 (s, 1H). IR (neat): 3318, 2925, 1669, 1561, 1472, 1381, 1269, 1166, 1121 cm-1. HRMS (APCI), m/z calcd for C22H14ClF6NO2-H: 472.0539, found 472.0542. |
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4.0h; | To a solution 2a (191.8mg, 0.5mmol) in DMF(1.5ml) was added benzyl bromide(0.07ml, 0.55mmol) and potassium carbonate(82.9mg, 0.6mmol). This was stirred at room temp for 4h. The DMF was evaporated and the reaction mixture extracted with ethyl acetate. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography(EA:Hex=1:15) to give compound 2m as a white solid was obtained (220mg, 93percent). mp 178 - 180 oC. 1H NMR(DMSO-d6) delta 10.84(s, 1H), 8.26(s, 1H), 7.80(s, 1H), 7.68(d, J=2.73Hz, 1H), 7.60(dd, J1=11.6Hz, J2=2.7Hz, 1H), 7.47-7.48(m, 2H), 7.30-7.34(m, 4H), 5.23(s, 2H). |
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4.0h; | <strong>[978-62-1]N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide</strong> (191.8 mg) obtained in step 1 was dissolved in dimethylformamide (DMF, 1.5 ml), to which benzylbromide (0.07 ml, 0.55 mmol) and potassium carbonate (K2CO3, 82.9 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Dimethylformamide was distillated under reduced pressure, followed by extraction with ethylacetate (EtOAc). The extracted organic layer was dried over MgSO4, filtered and concentrated. The concentrated reactant was separated by column chromatography (developing solvent: hexane/ethylacetate=15/1) to give 220 mg of the target compound (yield: 93percent). mp. 178-180° C.; 1H-NMR (300 MHz, DMSO-d6) delta 10.84 (s, 1H), 8.26 (s, 1H), 7.80 (s, 1H), 7.68 (d, J=2.73 Hz, 1H), 7.60 (dd, J=11.6 Hz, J=2.7 Hz, 1H), 7.47-7.48 (m, 2H), 7.30-7.34 (m, 4H), 5.23 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | at 100℃; for 4.0h; | A compound of 2a (191.8mg, 0.5mmol) was added in acetic anhydride(0.99ml, 10.5mmol). After stirring at 100? for 4h, the reaction mixture was filtered, washed with hexane and dried in vacuo. The title compound 2l was obtained as a white solid (115.6mg, 54percent). mp 117 - 118 oC. 1H NMR(DMSO-d6) delta 11.06(s, 1H), 8.37(s, 2H), 7.86-7.90(m, 2H), 7.71(dd, J1=8.7Hz, J2=2.6Hz, 1H), 7.36(d, J=8.7Hz, 1H), 2.23(s, 3H). |
54% | In N,N-dimethyl-formamide; at 100℃; for 4.0h; | <strong>[978-62-1]N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide</strong> (191.8 mg) obtained in step 1 was dissolved in dimethylformamide (DMF, 1.5 ml), to which acetic anhydride (0.99 ml, 10.5 mmol) was added. The reaction mixture was stirred at 100° C. for 4 hours, which was filtered and washed with n-hexane. The washed reactant was dried to give 115.6 mg of the target compound (yield: 54percent). mp. 117-118° C.; 1H-NMR (300 MHz, DMSO-d6) delta 11.06 (s, 1H), 8.37 (s, 2H), 7.86-7.90 (m, 2H), 7.71 (dd, J=8.7 Hz, J=2.6 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 2.23 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine; at 80℃; for 3.0h; | N-(3,5-bis(trifluoromethyl)phenyl-5-chloro-2-hydroxybenzamide (3j, 6.47 g, 16.86 mmol) was added to a solution of 12 (4.20 g, 20.22 mmol) in pyridine (35 mL) and the mixture was warmed to 80° C. for three hours. The reaction solution was cooled to rt, diluted with EtOAc (200 mL) and washed four times with 1N HCl (final wash ph about 1 to litmus), once with brine, and dried (MgSO4). Concentration afforded an off-white solid which was triturated with hexanes to provide the product (7.01 g, 75percent) which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 25℃;Inert atmosphere; | General procedure: A dry, 50 mL round bottom flask was charged with a magnetic stir bar then sealed with a septum and flushed with nitrogen. To this was added the salicylic acid derivative (2.0 mmol) and dichloromethane (10 mL). While stirring, SOCl2 (10 mmol) was added dropwise, followed by dimethylformamide (0.05 mmol), and the mixture was allowed to stir at room temperature under nitrogen for 12 hours. At this point, the mixture was concentrated under vacuum to afford the solid acid chloride derivative which was used immediately without further purification. The flask containing the acid chloride was then re-sealed with a septum and placed under a nitrogen atmosphere, and its contents were re-suspended in fresh dichloromethane (20 mL). While stirring, the aniline derivative (4.0 mmol) was added and the resulting opaque mixture was stirred for an additional 18 h. At this point, the mixture was quenched with ice water (5 mL) and phases were separated using a separatory funnel. The aqueous layer was extracted twice with dichloromethane (20 mL) then the organic layers were combined and washed with brine (40 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated under vacuum to afford a crude solid residue. This residue was then re-suspended in dichloromethane (10 mL) and adsorbed onto silica gel (1 g), then chromatographed on a 12 g silica gel column using a solvent gradient of 0-40% ethyl acetate in hexanes over 25 min. The product-containing fractions were combined then concentrated under vacuum to afford the purified salicylamide derivative. |
Tags: 978-62-1 synthesis path| 978-62-1 SDS| 978-62-1 COA| 978-62-1 purity| 978-62-1 application| 978-62-1 NMR| 978-62-1 COA| 978-62-1 structure
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