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CAS No. : | 2003-10-3 | MDL No. : | MFCD03094283 |
Formula : | C9H6BrF3O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | TZIYNLSEBAYCBZ-UHFFFAOYSA-N |
M.W : | 267.04 | Pubchem ID : | 2778386 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 49.51 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.6 cm/s |
Log Po/w (iLOGP) : | 2.0 |
Log Po/w (XLOGP3) : | 3.28 |
Log Po/w (WLOGP) : | 4.44 |
Log Po/w (MLOGP) : | 3.24 |
Log Po/w (SILICOS-IT) : | 3.75 |
Consensus Log Po/w : | 3.34 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.68 |
Solubility : | 0.0556 mg/ml ; 0.000208 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.31 |
Solubility : | 0.13 mg/ml ; 0.000486 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.49 |
Solubility : | 0.00862 mg/ml ; 0.0000323 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.85 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P301+P330+P331-P280-P305+P351+P338-P310 | UN#: | 3261 |
Hazard Statements: | H314 | 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 |
---|---|---|
81.7% | With pyridinium perbromide hydrobromide In toluene at 0 - 20℃; for 5 h; | Reference Example 6 Synthesis of 2-bromo-3'-trifluoromethylacetophenone To a toluene solution (423 mL) of commercially available 3'-trifluoromethylacetophenone (79.6 g, 0.423 mol) was added pyridinium bromide perbromide (135.4 g, 0.423 mol) under ice cooling and stirred for 5 hours while heating up to room temperature. The reaction liquid was ice cooled again, followed by dropwise adding 400 mL of distilled water to stop reaction and fractionation. A toluene layer was washed with 400 mL of a saturated aqueous solution of sodium bicarbonate, followed by drying with magnesium sulfate anhydride and concentration under reduced pressure and distillation under reduced pressure to obtain an objective compound (92.35 g, 81.7percent). 1H-NMR (200 MHzFT,TMS,CDCl3) 4.46(2H,s), 7.66(1H,brt,J=7.9Hz), 7.88(1H,brd,J=7.6Hz), 8.19(1H,brd,J=7.5Hz), 8.25(1H,brs) b.p. 92°C /3 mmHg |
78% | With bromine In dichloromethane at 20℃; for 4 h; | EXAMPLE 54; 4-{4-r4-(3-Trifluoromethyl-phenyl)-lH-imidazol-2-yl1-piperidin-l-yl}-lH-pyrazolo- r3,4-(/1pyrimidine hydrochloride; To a 22L 4-necked round bottom flask (fitted with addition funnel, nitrogen blanket, condenser, scrubber and mechanical stirrer) add: 3-trifluoromethyl- acetophenone (1500 g, 1.00 equiv; 7.97 moles) and dichloromethane (7.5L). Stir the resulting clear, colorless solution at room temperature while adding a solution of bromine (127 '4 g; 1.00 equiv; 7.97 moles) in dichloromethane at room temperature via addition funnel over 4 hours. Quench the reaction by slow addition of saturated aqueous NaHCψ3 (2000 mL), controlling the temperature by ice bath to less than 25 0C. Separate the phases and wash the organic layer with saturated aqueous sodium chloride (2000 mL), then dry the solution over sodium sulfate, filter and concentrate to a clear colorless oil. Purify this crude oil by silica gel chromatography (step gradient, 20percent to 50percent CH2Cl2 in heptane) to afford 2-Bromo-l-(3-trifluoromethyl-phenyl)-ethanone (1667g, 6.24 mol, 78percent) as a clear, colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.7% | With pyridinium perbromide hydrobromide; In toluene; at 0 - 20℃; for 5h; | Reference Example 6 Synthesis of 2-bromo-3'-trifluoromethylacetophenone To a toluene solution (423 mL) of commercially available 3'-trifluoromethylacetophenone (79.6 g, 0.423 mol) was added pyridinium bromide perbromide (135.4 g, 0.423 mol) under ice cooling and stirred for 5 hours while heating up to room temperature. The reaction liquid was ice cooled again, followed by dropwise adding 400 mL of distilled water to stop reaction and fractionation. A toluene layer was washed with 400 mL of a saturated aqueous solution of sodium bicarbonate, followed by drying with magnesium sulfate anhydride and concentration under reduced pressure and distillation under reduced pressure to obtain an objective compound (92.35 g, 81.7%). 1H-NMR (200 MHzFT,TMS,CDCl3) 4.46(2H,s), 7.66(1H,brt,J=7.9Hz), 7.88(1H,brd,J=7.6Hz), 8.19(1H,brd,J=7.5Hz), 8.25(1H,brs) b.p. 92C /3 mmHg |
78% | With bromine; In dichloromethane; at 20℃; for 4h; | EXAMPLE 54; 4-{4-r4-(3-Trifluoromethyl-phenyl)-lH-imidazol-2-yl1-piperidin-l-yl}-lH-pyrazolo- r3,4-(/1pyrimidine hydrochloride; To a 22L 4-necked round bottom flask (fitted with addition funnel, nitrogen blanket, condenser, scrubber and mechanical stirrer) add: 3-trifluoromethyl- acetophenone (1500 g, 1.00 equiv; 7.97 moles) and dichloromethane (7.5L). Stir the resulting clear, colorless solution at room temperature while adding a solution of bromine (127 '4 g; 1.00 equiv; 7.97 moles) in dichloromethane at room temperature via addition funnel over 4 hours. Quench the reaction by slow addition of saturated aqueous NaHCtheta3 (2000 mL), controlling the temperature by ice bath to less than 25 0C. Separate the phases and wash the organic layer with saturated aqueous sodium chloride (2000 mL), then dry the solution over sodium sulfate, filter and concentrate to a clear colorless oil. Purify this crude oil by silica gel chromatography (step gradient, 20% to 50% CH2Cl2 in heptane) to afford 2-Bromo-l-(3-trifluoromethyl-phenyl)-ethanone (1667g, 6.24 mol, 78%) as a clear, colorless oil. |
With bromine; In acetic acid; | PREPARATION 1 m-(Trifluoromethyl)phenacyl Bromide m-(Trifluoromethyl)acetophenone (10 g, 0.054 mol) was dissolved in 100 ml acetic acid. Bromine (9.1 g, 0.057 mol) was separately dissolved in 20 ml acetic acid and added portionwise over 0.5 hours to the acetophenone solution. The mixture was stirred for 15 hours, poured onto 150 g ice and extracted with 300 ml ether. The organic layer was washed 1*300 ml H2 O, 1*300 ml saturated NaCl, dried (MgSO4) and evaporated to yield title product as a pale yellow liquid. |
With bromine; In 1,4-dioxane; for 0.166667h; | Example 127 2-Bromo-1-(3-trifluoromethyl)-ethanone To a stirred solution of 1-(3-trifluoromethyl-phenyl)-ethanone (6.15 g, 32.8 mmol) (Aldrich) in dioxane (20 mL) was added dropwise a solution of bromine (5.27 g, 32.9 mmol) in dioxane (60 mL). After addition, the mixture was stirred for 10 minutes, concentrated in vacuo, and the residue chromatographed on silica gel (4:1 hexane/dichloromethane) to provide 2-bromo-1-(3-trifluoromethyl)-ethanone. | |
With bromine; In diethyl ether; at 20℃; for 1h; | Intermediate 3a: 2-bromo-l-('3-(trifluoromethyl phenyl')ethanone. Into a 250-mL round bottom flask, was placed a solution of l-(3-(trifluoromethyl)phenyl)ethanone (5 g, 26.57 mmol, 1.00 equiv) in ether (80 mL). To this was added dropwise a solution of Br2 (4.26 g, 26.66 mmol, 1.00 equiv) in ether (20 mL) with stirring over 1 hr and the resulting solution was stirred an additional 1 h at room temperature. The mixture was washed with 2x30 mL of NaHS03 and 1x30 mL of brine, then dried over anhydrous sodium sulfate and concentrated under vacuum to give 5.2 g (crude) of 2-bromo-l-(3- (trifluoromethyl)phenyl)ethanone as yellow oil. | |
With copper(ll) bromide; In chloroform; ethyl acetate;Reflux; | Example 17; iV-(5-(2-cyanophenoxy)-4-(3-(trifluoromethyl)phenyl)thiazol-2~yI)-2-(4- (ethylsulfonyl)phenyl)acetamide; Step 1:; To a solution of l-(3-(trifluoromethyl)phenyl)ethanone (5 g) in chloroform (30 mL) and ethyl acetate (30 mL) was added copper(II) bromide (7.5 g). The reaction mixture was refluxed overnight. Solvent was removed to give 3-(trifluoromethyl)benzoyl bromide (6 g) as a brown oil. MS(ES+) m/z 253 (MH ). | |
With N-Bromosuccinimide; trimethylsilyl trifluoromethanesulfonate; In acetonitrile; at 40℃;Darkness; | General procedure: Ketone (1 eq) and N-bromosuccinimide (NBS) (2 eq) were solved in acetonitrile and trimethylsilyl trifluoromethanesulfonate (TMS-OTf) (1 eq) was added. The reactions were stirred at T = 40 C until completeness, diluted with diethyl ether (2 ml), washed with H2O (3 x 2 ml), dried over Na2SO4 and concentrated under reduced pressure. This procedure provided bromoketones intermediates in 75-90% overall yield, with purities generally >90% as determined by HPLC-MS. The compounds was used without further purification. | |
With tetra-N-butylammonium tribromide; In acetonitrile; at 20℃; for 12h; | General procedure: (i) The commercial available 8a-8l (4 mmol, 1.0 equiv.)was respectively dissolved in acetonitrile (50 mL), adding tetrabutylammoniumtribromide(4 mmol, 1.0 equiv.) later. The mixture was stirred overnight under roomtemperature until the solution turned light yellow or colorless. The solventwas removed in vacuo, the residue wasextracted with dichloromethane and washed with water. The organic layers werecombined and concentrated under vacuum to provide the crude products 9a-9l, which using for next step withoutany purification. | |
With bromine; In dichloromethane; | 1- (3- (Trifluoromethyl) phenyl) ethanone (1 g, 5.3 mmol) was dissolved in 10 mL of dichloromethane. Take liquid bromine (280muL, 5.3 mmol) was dissolved in 5 mL of methylene chloride and slowly added dropwise to the supernatant. Fast response, the color of bromine immediately disappeared. After the reaction is complete, wash with saturated brine, wash with saturated sodium carbonate, dry over anhydrous sodium sulfate, concentrate and use directly in the next step. | |
With copper(ll) bromide; In chloroform; ethyl acetate; for 16h;Reflux; | Example 1. Synthesis of 2-(3-(trifluoromethyl)phenyI)imidazo[l,2-a]pyridin-8-amine (14): Step 1) Preparation of2-bromo-l-(3-(trifluoromethyl)phenyl)ethanone (11): A mixture containing l-(3-(trifluoromethyl)phenyl)ethanone (10; 3.0 g, 15.94 mmol) and CuBr2 (5.34 g, 23.94 mmol) in 1:1 EtOAcZCHCl3 (150 mL) was stirred under reflux for 16 h. After filtration, the crude product, 2-bromo-l-(3- (trifluoromethyl)phenyl)ethanone 11, was obtained by concentration as a tan syrup (4.37 g, yield: 72%). This material was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.1% | In toluene for 24h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(i), (ii) H2O; Multistep reaction; | ||
In toluene | 14.a EXAMPLE 14 a. A stirred mixture of 15.9 g (0.11 mole) of 1-pyrrolidino-1-cyclohexene, 28.0 g (0.11 mole) of m-trifluoromethylphenacyl bromide, and 100 ml. of toluene is heated under reflux for 2 hours, diluted with water, and refluxed for 2 hours. The layers are separated, and the organic phase is dried and concentrated to a liquid. Distillation provides 2-(m-trifluoromethylphenacyl)cyclohexanone as a liquid, b.p. 137°-138° C. (0.075 mm). | |
In toluene | 19.a a. a. 2-(m-Trifluoromethylphenacyl)cyclohexanone SPC42 A stirred mixture of 15.9 g. (0.11 mole) of 1-pyrrolidino-1-cyclohexene, 28.0 g. (0.11 mole) of m-trifluoromethylphenacyl bromide, and 100 ml. of toluene was heated under reflux for 2 hours, diluted with water and refluxed for 2 hours. The layers were separated, and the organic phase was dried and concentrated to 25 g. of liquid. Distillation provided 12.0 g. (42%) of liquid, b.p. 137°-138° (0.075 mm.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.6% | In ethanol at 80℃; for 3h; | 1.1. Chemistry experimental procedure A of intermediates 3a-j General procedure: Some of the intermediates 3a-j were commercially unavailable or expensive, so the compounds were obtained by the following chemistry experimental procedure A. To a solution of bromoacetophenone analogue (1 mmol) in anhydrous ethanol (30 mL), thiourea (1 mmol) was added, and the mixture solution was stirred at 80 °C for 3 h. The completion of the reaction was monitored by TLC. The mixed solution was concentrated under reduced pressure to remove the solvent, and the saturated NaHCO3 solution was added to adjust the pH to 8~9. Large amounts of solids were observed to precipitate out of the solution. The solid was collected by suction filtration, washed with anhydrous ethanol and dried in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography eluting with a gradient of ethyl acetate/petroleum ether mixture to afford pure intermediates 3a-j |
93.6% | In ethanol at 80℃; for 3h; | 1.1. Chemistry experimental procedure A of intermediates 3a-j General procedure: Some of the intermediates 3a-j were commercially unavailable or expensive, so the compounds were obtained by the following chemistry experimental procedure A. To a solution of bromoacetophenone analogue (1 mmol) in anhydrous ethanol (30 mL), thiourea (1 mmol) was added, and the mixture solution was stirred at 80 °C for 3 h. The completion of the reaction was monitored by TLC. The mixed solution was concentrated under reduced pressure to remove the solvent, and the saturated NaHCO3 solution was added to adjust the pH to 8~9. Large amounts of solids were observed to precipitate out of the solution. The solid was collected by suction filtration, washed with anhydrous ethanol and dried in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography eluting with a gradient of ethyl acetate/petroleum ether mixture to afford pure intermediates 3a-j |
In ethanol for 0.5h; Heating; Yield given; |
With 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene on polystyrene.HL In tetrahydrofuran for 0.5h; Heating; | ||
In ethanol Reflux; | 17.2 Step 2:; To a solution of 3-(trifluoromethyl)benzoyl bromide (6 g) in ethanol (100 mL) was added thiourea (5.0 g). The reaction mixture was refluxed overnight. Solvent was removed. The residue was triturated with ethyl acetate to give 4-(3-(trifluoromethyl)phenyl)thiazol-2-amine (5 g) as a white solid. MS(ES^> m/z 245 (MH4). | |
In ethanol for 3h; Reflux; | General procedure: (iii) A mixture of the above synthetic 9a-10n(calculate to yield 100% for last step, 4 mmol, 1.0 equiv.) and thiourea (4.4 mmol,1.1 equiv.) in anhydrous ethanol (50 mL) was refluxed for 3 h. After that, thesolvent was removed in vacuo andwashed with cold ether. Then the mixture was extracted dichloromethane (3*15mL) and washed with saturated aqueous NaHCO3. The combined organicphases were dried with anhydrous Na2SO4. Then removingthe solvent, the residue was purified by silica gel column (hexane/EtOAc=8:1 to4:1) and dried under vacuum to give 4-arylthiazol-2-amine 10a-10n, yieldwas 50~90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: 2-amino-5-chlorothiazole; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone In acetone for 3h; Heating; Stage #2: With hydrogenchloride In ethanol for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sulfur; diethylamine In ethanol at 45℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Diethyl amine; zinc(II) chloride In <i>tert</i>-butyl alcohol; benzene at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Stage #1: 3-(4-chlorophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone In N,N-dimethyl-formamide for 70h; | 2 Example 2: 3-(4-Chlorophenyl)-1-{2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl}-1,4- diazaspiro[4.5]dec-3-en-2-oneTo a stirred, room temperature solution of 3-(4-chlorophenyl)-1 ,4-diazaspiro[4.5]dec-3-en- 2-one D4 (0.129g; 0.49mmol) in DMF (3ml) under argon was added 60% sodium hydride dispersion in mineral oil (0.024g; 0.58mmol) in one portion. After a further 5 minutes 2- bromo-1-[3-(trifluoromethyl)phenyl]ethanone (0.157g; 0.58mmol) was added in one portion and the resultant solution allowed to stand for 70 hours. Brine (100ml) was added and the mixture extracted with ethyl acetate (2 x 50ml). Combined organics were dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by MDAP to afford the title compound as a pale orange solid (0.036g; 16%). 1H NMR (CDCI3) δ: 1.20 - 1.33 (1 H, m), 1.46 - 1.51 (2H, d), 1.70 - 1.80 (4H, m), 1.87 - 1.91 (1 H, d), 1.95 - 2.10 (2H, m), 4.86 (2H, s), 7.42 - 7.49 (2H, m), 7.65 - 7.70 (1 H, t, J = 7.6Hz), 7.88 - 7.91 (1 H, d, J = 8Hz), 8.20 - 8.23 (1 H, d, J = 8Hz), 8.27 (1 H, s), 8.44 - 8.48 (2H, m). Mass Spectrum (Electrospray LC/MS) Found 449 (MH+). C23H2035CIF3N2O2 requires 448. Ret. time 3.96 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 1.) EtOH, RT, 1 h, 2.) EtOH, refux, 3 h 2: 96 percent / KOH / ethanol / 3 h / Heating 3: 1.) carbonyldiimidazole / 1.) DMF, RT, 30 min, 2.) DMF, 2 h 4: 100 percent / sodium azide / dimethylformamide / 2 h / 90 °C 5: 95 percent / triphenylphosphine / dimethylformamide; H2O / Ambient temperature | ||
Multi-step reaction with 3 steps 1: 1.) EtOH, RT, 1 h, 2.) EtOH, refux, 3 h 2: 96 percent / KOH / ethanol / 3 h / Heating 3: 1.) carbonyldiimidazole (CDI) / 1.) DMF, RT, 30 min, 2.) DMF, 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 65.1 percent / toluene / 24 h / Ambient temperature 2: 79.1 percent / p-toluenesulfonic acid monohydrate / benzene / 2 h / Heating 3: 66 percent / H2 / PtO2 / acetic acid / 18 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.6% | With potassium carbonate In chloroform at 20℃; | 7 Reference Example 7 Synthesis of 3-hydroxy-5-methyl-2-[2-oxo-2-(3-trifluoromethylphenyl)-ethyl]-cyclohex-2-enone To a chloroform solution (240 mL) of 2-bromo-3'-trifluoromethylacetophenone (63.5 g, 0.238 mol) obtained in Reference Example 6 and 5-methyl-1,3-cyclohexanedione (30 g, 0.238 mol) was added potassium carbonate (32.9 g, 0.238 mol) and stirred at room temperature over night. The reaction liquid was filtered and white solid obtained, which was suspended in distilled water (300 mL), followed by dropwise adding a concentrated HCl solution (300 mL) under ice cooling, extracting with ethyl acetate (700 mL) and ethanol (50 mL), drying with sodium sulfate anhydride, concentration of thus obtained organic layer under reduced pressure, adding ethyl acetate (200 mL) to residue obtained, stirring in suspension at room temperature for 4 hours and filtering off crystal to obtain an objective compound (25.7 mg, 34.6%).1H-NMR (200 MHzFT,TMS,CDCl3) 1.06(3H,d,J=5.9Hz), 1.98-2.63(5H,complex), 3.77(1H,d, J=13.6Hz), 4.29(1H,d,J=13.6Hz), 7.63(1H,brt,J=7.6Hz), 7.87(1H,brd,J=7.8Hz), 8.43-8.52(2H,complex), 9.64(1H,s) MS(ESI) m/z 31.3 [M+H]+ |
34.6% | Stage #1: 5-methylcyclohexan-1,3-dione; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone With potassium carbonate In chloroform at 20℃; Stage #2: With hydrogenchloride; water In water at 0℃; | |
With hydrogenchloride; potassium carbonate In chloroform; water | R.2 Synthesis of 3-hydroxy-5-methyl-2-[2-oxo-2-(3-trifluoromethylphenyl)ethyl]cyclohex-2-enone Reference Example 2 Synthesis of 3-hydroxy-5-methyl-2-[2-oxo-2-(3-trifluoromethylphenyl)ethyl]cyclohex-2-enone Potassium carbonate (32.9 g, 0.238 mol) was added to a solution of the 2-bromo-3'-trifluoromethylacetophenone obtained in Reference Example 1 (63.5 g, 0.238 mol) and 5-methyl-1,3-cyclohexanedione (30 g, 0.238 mol) in chloroform (240 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered and the white solid obtained was suspended in distilled water (300 ml), followed by adding dropwise thereto concentrated hydrochloric acid (30 ml) under ice-cooling. The resulting mixture was extracted with ethyl acetate (700 ml) and ethanol (50 ml) and the extract solution was dried over anhydrous sodium sulfate. The dried extract solution was filtered and the organic layer thus obtained was concentrated under reduced pressure. To the resulting residue was added ethyl acetate (200 ml), followed by suspending and stirring at room temperature for 4 hours. The crystals were collected by filtration to obtain the desired compound (25.7 g, 34.6%). 1H-NMR(200MHzFT,TMS,CDCl3) 1.06(3H,d,J=5.9Hz),1.98-2.63(5H,complex),3.77(1H,d,J-13.6Hz),4.29(1H,d, J=13.6Hz),7.63(1H,brt,J=7.6Hz),7.87(1H,brd,J=7.8Hz), 8.43-8.52(2H,complex),9.64(1H,s) MS(ESI,POS) m/z 313 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium carbonate In chloroform at 20℃; | 1 Reference Example 1 Reference Example 1 Synthesis of 3-hydroxy-2-[2-oxo-2-(3-trifluoromethylphenyl)ethyl]-5-phenylcyclohex-2-enone To a chloroform solution (2 mL) of 2-bromo-3'-trifluoromethylacetophenone (534.1 mg, 2 mmol) and 5-phenyl-1,3-cyclohexanedione (376.5 mg, 2 mmol) was added potassium carbonate (276.4 mg, 2 mmol) and stirred under suspension at room temperature over night. The reaction liquid was added with ethyl acetate (5 mL), to filter off undissolved substance, followed by concentration of thus obtained organic layer under reduced pressure and purification of concentrated residue using silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain a crude product, which was further purified by suspension (hexane 1 ml/ethyl acetate about 0.2 ml) to obtain an objective compound (257.8 mg, 35.0%). MS (ESI) m/z 375 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 18h; | 35 A clear, pale amber solution of compound 35.4 (0.050 g, 0.194 mmol) in DMF (5 mL) was treated with 2-bromo-l-(3- trifluoromethylphenyl)-ethanone (0.0674 g, 1.30 mmol), and the reaction progress was monitored by LCMS. After 2 hours, DIPEA (12.6 mg, 0.097 mmol) was added. After an additional 16 hours, the reaction mixture was diluted with ethyl acetate (50 mL), extracted with 2:1 :1 water / saturated NaHCO3 / brine (3X), extracted with brine EPO (25 niL), dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel radial chromatography (4:l->6:4 hexane / ethyl acetate) to afford compound35.5 (0.040 g, 49%). LCMS: m/z: 422 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2-{6-Methoxy-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-4H-1,4-benzoxazin-4-yl}acetonitrile | 18.A Step A Step A 2-{6-Methoxy-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-4H-1,4-benzoxazin-4-yl}acetonitrile The procedure is as in Steps A, B and C of Example 14, with the replacement of 2-bromoacetophenone with 2-bromo-1-[3-(trifluoromethyl)phenyl]-1-ethanone in Step A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | 16 EXAMPLE 16 EXAMPLE 16 In the same manner as in Example 1, methyl 4-carbamoylbenzoate was reacted with 3-trifluoromethylphenacyl bromide to obtain methyl 4-[4-(3-trifluoromethylphenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 21%. Pale yellow prisms. Melting Point: 134 to 135° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | 45 EXAMPLE 45 EXAMPLE 45 In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 3-trifluoromethylphenacyl bromide to obtain methyl 3-[4-(3-trifluoromethylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 72%. Colorless prisms. Melting point: 105 to 106° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol | 2-Amidino-4-(3-trifluoromethylphenyl)thiazole Hydrobromide 2-Amidino-4-(3-trifluoromethylphenyl)thiazole Hydrobromide N-Amidinothiourea (0.663 g, 5.62 mM) was added to a solution of 3(trifluoromethyl)phenacylbromide (1.5 g, 5.62 mM) in EtOH (10 mL) and the reaction mixture was heated at reflux for 3 hours (h). The mixture was concentrated in vacuo to one half volume and the resulting solid precipitate was isolated. This solid was washed with EtOH and dried in vacuo to give the title compound as a solid: melting point (mp) 219°-221° C.; 1 H NMR (DMSO d6): δ 8.28 (m, 5H), 8.07 (s, 1H), 7.71 (m, 2H); MS: 287 (MH+). | |
In ethanol | 2-Amidino-4-(3-trifluoromethylphenyl)thiazole Hydrobromide 2-Amidino-4-(3-trifluoromethylphenyl)thiazole Hydrobromide N-Amidinothiourea (0.663 g, 5.62 mM) was added to a solution of 3-(trifluoromethyl)phenacylbromide (1.5 g, 5.62 mM) in EtOH (10 mL) and the reaction mixture was heated at reflux for 3 hours (h). The mixture was concentrated in vacuo to one half volume and the resulting solid precipitate was isolated. This solid was washed with EtOH and dried in vacuo to give the title compound as a solid: melting point (mp) 219°-221° C.; 1 H NMR (DMSO d6): δ 8.28 (m, 5H), 8.07 (s, 1H), 7.71 (m, 2H); MS: 287 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; sodium hydroxide; ethyl acetate n-hexane; ethanol; 2-Nonanone; water | R.11 gamma-Oxo-alpha-(phenylmethyl)-3-(trifluoromethyl)benzenebutanoic acid REFERENCE EXAMPLE 11 gamma-Oxo-alpha-(phenylmethyl)-3-(trifluoromethyl)benzenebutanoic acid A sample of 1.714 g of sodium hydride (60% in oil) is washed with hexane under argon. To the solid sodium hydride is added 65 ml of dry tetrahydrofuran. To the mixture cooled to 0° C. is added dropwise 10.72 g of diethyl benzylmalonate. The mixture is stirred for 15 minutes and a solution of 11.44 g of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone in 15 ml of tetrahydrofuran added dropwise. The ice bath is removed and the mixture stirred at room temperature overnight. The mixture is filtered and the filtrate concentrated under vacuum. The residue (19.3 g) is chromatographed by HPLC over silica gel on a Waters-Prep 500A instrument with hexane-ethyl acetate (10:1) as solvent to give 7.35 g of yellow oil. To the preceding compound (7.35 g) stirring in 30 ml of ethanol and 15 ml of water, while being cooled in an ice bath, is added slowly in several portions, 3.36 g of sodium hydroxide pellets. After 15 minutes, the ice bath is removed and the mixture is refluxed for 4 hours. The mixture is concentrated and the aqueous residue diluted with 35 ml of water, extracted with 20 ml of ether, and acidified with 6N hydrochloric acid (20 ml). The mixture is extracted with three 25 ml portions of dichloromethane, the extract dried (Na2 SO4) and the solvent removed to give a yellow solid. The solid is dissolved in 45 ml of hexane-acetone (8:1) and the solution chilled to give 5.16 g of [2-oxo-2[3-(trifluoromethyl)phenyl]ethyl](phenylmethyl)propanedioic acid as white crystals, m.p. 145°-147° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine | 6.1 6-1. 6-1. Production of S-[2-oxo-(3-trifluoromethylphenyl)ethyl]acetate STR154 In 300 ml of ether was dissolved 4.3 g (56 mmoles) of thioacetic acid, followed by adding thereto 5.7 g (56 mmoles) of triethylamine. A solution of 15 g (56 mmoles) of α-bromo-3-trifluoromethylacetophenone in 50 ml of ether was added dropwise at room temperature over a period of 15 minutes. After completion of the dropwise addition, the reaction was carried out with refluxing for 1.5 hours. After completion of the reaction, the insoluble materials were filtered off and the filtrate was concentrated under reduced pressure to obtain 15.4 g of the desired compound. Physical property: crystals. Yield: 87%. 1 H-NMR [CDCl3 /TMS, δ values (ppm)] 2.43 (s, 3H), 4.40 (s, 2H), 7.64-8.26 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | 118.c 118c 118c N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2- hydroxy-2-(3-trifluoromethylphenyl)morpholine from 3-trifluoromethyl-phenacyl bromide and N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxyethanamine. Yield: 56% of theory, M.p.: <20° C. Calculated: C 60.92; H 5.78; N 3.09; Found: C 61.13; H 5.92; N 2.93. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In <i>N</i>-methyl-acetamide | 10.a 1-(2-Dimethylaminoethyl)-2-(3-trifluoromethylphenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole a. A solution of 32.6 g of m-trifluoromethylphenacyl bromide in 10 ml. of dimethylformamide is added dropwise to a stirred solution of 20 g (0.12 mole of 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran [Example 1 (a)] and 100 ml. of dimethylformamide. After 2 hours, the mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried over magnesium sulfate, and concentrated to an oil. The oil is chromatographed on silica gel with benzene and chloroform mixtures to give 2,3,5,6-tetrahydro-3-(3-trifluoromethylphenacyl)thiopyran-4-one as an oil. Infrared and nuclear magnetic resonance spectra are consistent with the assigned structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In <i>N</i>-methyl-acetamide; water | 45.a EXAMPLE 45 a. A solution of 106.8 g (0.4 mole) of m-trifluoromethylphenacyl bromide in dry dimethylformamide is added dropwise to a cooled solution of 74.4 g (0.45 mole) of 1-pyrrolidino-1-cycloheptene in dry dimethylformamide. After stirring at ambient temperature for 5 hours, water is added and the mixture is stirred overnight. The reaction mixture is poured into 1500 ml. of water and extracted with chloroform. The chloroform solution is washed with water, dried, and concentrated to a red oil, which is stirred at 60° C. for 1 hour in a high vacuum. Upon cooling, the oil solidifies to an orange solid of 2-(m-trifluoromethylphenacyl)cycloheptanone, m.p. 55°-60° C. The above structure is consistent with infra red and nuclear magnetic resonance spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone With sodium azide In tetrahydrofuran; water at 20℃; Stage #2: toluene-4-sulfonic acid With triphenylphosphine In tetrahydrofuran; water at 0 - 20℃; for 6h; | 54 Charge 2-bromo-l-[3(trifluoromethyl)phenyl]-l-ethanone (1664.7 g; 1.00 equiv; 6.23 moles) and tetrahydrofuran (7500 mL) to a 12 L 3-necked round bottom flask (fitted with water-cooled condenser, nitrogen blanket, mechanical stirrer and cooling bath. Charge sodium azide (425.6 g; 1.05 equiv; 6.55 moles) in one portion. Rinse into the flask with water (135 mL). Stir the pale yellow slurry at RT under nitrogen. After 6 hours, add water (260 mL) and continue to stir overnight. Filter the resulting orange slurry over a thin pad of Celite and rinse with THF (IL). Divide the resulting solution into two equal portions (5146.5 g each). Charge two identical 22 L 3-necked round bottom flask (fitted with addition funnel, water-cooled condenser, nitrogen blanket, mechanical stirrer and cooling bath) with triphenylphosphine (889 g, 3.43 mol, 1.1 eq), p- toluenesulfonic acid monohydrate (1304 g, 6.86 mol, 2.2 eq) and THF (5.6L). Add the two portions of intermediate mixture via addition funnels to the individual flasks over four hours, controlling the foaming from nitrogen evolution by addition rate and the temperature by use of an ice bath. On completion of addition stir the slurry at ambient temperature for two hours, then filter solids from both reactors onto the same filter. Wash both flasks and the combined cake with a total THF (4 L). Dry in a vacuum oven at 40 0C overnight to afford (2-Amino-l-(3-trifluoromethyl-phenyl)-ethanone)-, p-toluene sulfonate (1 : 1) as a white, crystalline solid (234Og, 6.23 mol, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.16% | at 185℃; for 3h; | 99 Preparation 99; 4-(3-Trifluoromethyl-phenyl)- IH -imidazole; Add formamide (15 mL; 32.72 equiv; 376.99 mmoles; 15.00 mL; 16.98 g) and 2-Bromo-l-(3-trifluoromethyl-phenyl)-ethanone (3.077 g ; 1.00 equiv; 11.52 mmoles; 3.08 g) to a sealed tube and heat to 1850C for 3 hours. Pour the reaction into NaηCθ3 and dilute with EtOAc, wash with water, saturated aqueous sodium chloride and dry over Na2SO4, filter, and concentrate to dryness. Take the crude mixture and purify by flash chromatography on silica eluting with dichloromethane (DCM)/methanol 0-10%. Collect fractions with product and remove solvent to give 4-(3-Trifluoromethyl-phenyl)- IH- imidazole (1.373 g; 0.56 equiv; 6.47 mmoles; 1.37 g; 56.16% yield). MS (ES): m/z = 213.0 [M + H]. |
at 185℃; for 2h; Neat (no solvent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone With sodium diformamide In acetonitrile at 80℃; for 1h; Stage #2: With hydrogenchloride In methanol at 80℃; for 2h; | ii Step (ii) 2-Amino-1-(3-(trifluoromethyl)phenyl)ethan-1-one hydrochloride To a stirred solution of 2-bromo-1-(3-(trifluoromethyl)phenyl)ethan-1-one (276.0 g, 1033.51 mmol) in MeCN (2750 mL) was added sodium diformylamide (147.32 g, 1550.27 mmol). The reaction mixture was heated at 80 °C for 1 h then concentrated under reduced pressure. The residue was diluted with MeOH (900 mL) and cone. HC1 (680 mL). The mixture was then heated at 80 °C for 2 h, and allowed to cool to rt and the mixture was concentrated under reduced pressure. The residue was stirred with isopropyl alcohol (1800 mL) to form a precipitate which was filtered off and collected with suction, washed with isopropyl alcohol (200 mL) and dried under reduced pressure to afford 2-amino-1-(3-(trifluoromethyl)phenyl)ethan-1-one hydrochloride (223.0 g, 930.48 mmol, 90% yield). LCMS: Method H, 2.59 min, MS: ES+ 204.0. |
86% | Stage #1: 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone With hexamethylenetetramine In tetrachloromethane at 20℃; Stage #2: With hydrogenchloride; ethanol; water at 20℃; | 6 Preparation 6; 2-Amino- 1 -(3 -(trifluoromethvDphenvDethanone hydrochloride; Add 3-(trifluoromethyl)phenacyl bromide (10 g, 37.4 mmol) to a solution of hexamethylenetetramine (HMTA) (5.80 g, 41.3 mmol) in carbon tetrachloride (100 mL). Stir at room temperature overnight. Filter the precipitate and suspend the filter cake in ethanol (200 mL). Dilute the mixture with concentrated hydrochloric acid (28 mL), and stir the mixture at room temperature overnight. Filter the precipitate, and concentrate the filtrate in vacuo to provide an off-white solid. Recrystallize the solids from hot 1% concentrated hydrochloric acid in 2-propanol taking care not to cool below room temperature to provide 2-amino-l-(3-(trifluoromethyl)phenyl)ethanone hydrochloride (7.67 g, 86%). MS(APCI): m/z = 204 [M + H]. |
57% | With hexamethylenetetramine In tetrachloromethane |
Multi-step reaction with 2 steps 1: dichloromethane 2: hydrogenchloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butanone for 18h; Reflux; | 1.2 Step 2) Preparation of8-nitro-2-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine (13): A mixture containing crude 2-bromo-l-(3-(trifluoromethyl)phenyl)ethanone (11; 1.53 g, 5.73 mmol) and 3-nitropyridin-2-amine (12; 664 mg, 4.77 mmol) in 2-butanone (20 ml) was stirred under reflux for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by chromatography (elution with 4: 1 petroleum ether/EtOA) to afford 8-nitro-2-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine 13 as a brown oil (480 mg, yield: 14%). MS (ESI) calculated for C14H8F3N3O2 307.06; found 308 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In butanone for 18h; Reflux; | 5.1 Example 5. Synthesis of 2-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-8- carboxylic acid (26):Step 1) Preparation of ethyl 2-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-8- carboxylate (25): A mixture of ethyl 2-aminonicotinate (24; 778 mg, 4.7 mmol) and 2-bromo-l-(3- (trifluoromethyl)phenyl)ethanone (11; 1.5 g, 5.6 mmol) in 2-butanone (20 mL) was stirred under reflux for 18 h. The reaction mixture was cooled to room temperature. The resulting precipitate was collected by filtration, washed with cold acetone and dried to give ethyl 2- (3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-8-carboxylate 25 as a pale solid (2.01 g, yield: 68% ). MS (ESI) calculated for CnH13F3N2O2 334.09; found 335 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | In acetonitrile at 90℃; for 12h; | 15.1 Example 15. Synthesis of N-(thiazol-2-yl)-2-(3-(trifluoromethyl)phenyl)imidazo[l,2- a]pyrazine-8-carboxamide (Compound 138): Step 1) Preparation of methyl 2-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyrazine-8- carboxylate (66): A mixture containing 2-bromo-l-(3-(trifluoromethyl)phenyl)ethanone (11; 5.04 g, 14 mmol), methyl 3-aminopyrazine-2-carboxylate (65; 1.53 g, 10 mmol) in CH3CN (30 mL) was stirred at 900C for 12 h. Upon cooling to room temperature, the reaction mixture was poured into water and the resulting precipitate was collected by filtration, washed with water and dried to afford methyl 2-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyrazine-8- carboxylate 66 (2.05 g, 34%). MS (ESI) calculated for C15H10F3N3O2 321.07; found: 322 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In acetonitrile; at 20℃; for 16h;Reflux; | 2-Bromo-1-[3-(trifluoromethyl)phenyl]ethanone (6.38 g, 23.9 mmol) and potassium carbonate (3.30 g, 23.9 mmol) were added at room temperature to an acetonitrile (50 mL) solution of <strong>[22532-61-2]<strong>[22532-61-2]2-bromo-6-hydroxybenzaldehyd</strong>e</strong> (4.0 g, 19.9 mmol), and the mixture was heated to reflux for 16 hours. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 90:10?40:60) to give 4.4 g of the titled compound (yield 60%). Melting point: 91-92 C. (methanol).1H-NMR (CDCl3) delta: 7.39 (1H, t, J=8.1 Hz), 7.49-7.62 (3H, m), 7.71 (1H, t, J=7.5 Hz), 7.91 (1H, d, J=7.8, 1.2 Hz), 8.25 (1H, d, J=7.8 Hz), 8.32 (1H, s). |
60% | With potassium carbonate; In acetonitrile; for 16h;Reflux; | To a solution of <strong>[22532-61-2]<strong>[22532-61-2]2-bromo-6-hydroxybenzaldehyd</strong>e</strong> (4.0 g, 19.9 mmol) in acetonitrile (50 mL) were added 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (6.38 g, 23.9 mmol) and potassium carbonate (3.30 g, 23.9 mmol) at room temperature, and the mixture was heated under reflux for 16 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 90:10?40:60) to give the title compound (4.4 g, yield 60%). melting point 91 - 92C (methanol). 1H-NMR (CDCl3) delta : 7.39 (1 H, t, J = 8.1 Hz), 7.49 - 7.62 (3 H, m), 7.71 (1 H, t, J = 7.5 Hz), 7.91 (1 H, d, J = 7.8, 1.2 Hz), 8.25 (1 H, d, J = 7.8 Hz), 8.32 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water In acetonitrile at 125℃; for 0.833333h; | 15.1 Example 15: 4-[2,5-Dioxo-4-hydroxymethyl-3-methyl-4-(3-trifluoromethylphenyl)imidazolidin-l-yl]-2- trifluoromethyl-benzonitrile (Method A)Step I: l(3-Trifluoromethylphenyl)-2-hydroxyethanone; [00319] A solution of 2-bromo-l-[3-(trifluoromethyl)phenyl]ethanone (1 g) in acetonitrile (2.5 mL) and water (10 mL) is treated under microwave irradiation (125°C, 50 min). The same experiment is repeated five times. All the vials are collected, extracted with DCM, dried over magnesium sulfate and concentrated under vacuum to give the desired compound. δ 1H NMR (CDCl3): 4.96 (s, 2H); 7.70 (m, IH); 7.93 (d, IH); 8.14 (d, IH), 8.22 (s, IH) | |
With sodium formate In ethanol; water at 70℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol for 2h; Reflux; | 1 2-Amino-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.48); Step 1; A mixture of 10.17 g (36.83 mmole) of 2-bromo-1-(3-trifluoromethyl-phenyl)-ethanone, 4.07 g (41.98 mmole) of potassium thiocyanate and ethanol was heated at reflux for 2 hours. The cooled mixture was concentrated under reduced pressure. The residue was taken up in 225 mL of ethyl acetate, washed three times with 50 mL of water, then 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8.85 g of 2-thiocyanato-1-(3-trifluoromethyl-phenyl)-ethanone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol for 16h; Reflux; | 103a {4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methanol {4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methanol A mixture of 2-amino-2-thioxoethyl 2,2-dimethylpropanoate (7.38 g), 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (7.50 g) and ethanol (150 mL) was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with diluted aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give crude {4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl 2,2-dimethylpropanoate (about 10 g) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In ethanol for 14h; Reflux; | 1c ethyl 1-({4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)-1H-pyrazole-4-carboxylate (Example 1 c) ethyl 1-({4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)-1H-pyrazole-4-carboxylate To a solution of the compound (2.99 g, 14.0 mmol) obtained in Example 1b in ethanol (30 mL) was added 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (3.74 g, 14.0 mmol), and the mixture was heated under reflux for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with diluted aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (4.90 g, 91%) as a colorless solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (3 H, t, J=7.1 Hz), 4.30 (2 H, q, J=7.3 Hz), 5.69 (2 H, s), 7.52 - 7.59 (2 H, m), 7.61 (1 H, d, J=7.8 Hz), 8.01 (1 H, s), 8.05 (1 H, d, J=7.6 Hz), 8.11 (1 H, s), 8.16 (1 H, s) LCMS(ESI+)M+H: 382. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-amino-thiazole; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone In acetone Reflux; Stage #2: With hydrogenchloride In water Reflux; Stage #3: With ammonium hydroxide In water | 5.1.2. Synthesis of the compounds 3a,e,j,n, 4a,b, 6f-k,m, 7e,j, 8o, 9o (Scheme 1), 28a,b, 32a,b (Scheme 2) General procedure: The appropriate 2-amino-derivative (1, 26, 27) (20 mmol) was dissolved in 100 mL of acetone and treated with an equivalent of the appropriate 2-bromoacetylderivative 2. The reaction mixture was refluxed for 1-5 h (according to a TLC test). Compounds 3a, 4b, 28b, 32a,b were separated from the acetone solution as hydrobromides and the free bases were prepared. In all the other cases, the reaction mixture was cooled, the solid product was separated by filtration and the resulting intermediate salt (νCO absorption was confirmed around 1700 cm-1) was used in the subsequent step without further purification. It was refluxed for 1-4 h with 200 mL of 2N HCl and, before complete cooling, the solution was cautiously basified by dropwise addition of 15% NH4OH. The solid product obtained was collected by filtration. All the derivatives were crystallized from ethanol except 32b (chloroform/petroleum ether), with a yield of 23% (28b), 35-60% (3a, 4a,b, 6f-k,m, 7e,j, 28a, 32a,b;) and 70-85% (3e,j,n, 8o, 9o). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol at 75℃; | 3 Intermediate 3b: 5-(3-(trifluoromethyl phenyl)thiazol-2-amine. Into a 100-mL round bottom flask, was placed a solution of 2-bromo-l-(3-(trifluoromethyl)phenyl)ethanone (2.5 g, 9.40 mmol, 1.00 equiv) in methanol (50 mL), and thiourea (710 mg, 9.33 mmol, 1.00 equiv). The resulting solution was stirred overnight at 75°C in an oil bath. The reaction mixture was cooled with a water/ice bath. The solids were collected by filtration. The residue was dissolved in 200 mL of ethyl acetate. The resulting mixture was washed with 1x50 mL of sodium hydroxide (1 N) and 2x50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 2.2 g (96%) of 5-(3-(trifluoromethyl)phenyl)thiazol-2-amine as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With bromine In dichloromethane at 20℃; for 4h; Inert atmosphere; Large scale reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide In tetrahydrofuran; water at 20℃; Inert atmosphere; Large scale reaction; | ||
With sodium azide In water; acetone at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile / 16 h / Reflux 2.1: hydrazine hydrate / ethylene glycol / 2 h / 130 °C 2.2: 2 h / 160 °C 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 16 h / 90 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile / 16 h / 80 °C 2.1: hydrazine hydrate / ethylene glycol / 2 h / 130 °C 2.2: 2 h / 20 - 160 °C 3.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,2-dimethoxyethane / 16 h / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetonitrile / 16 h / Reflux 2.1: hydrazine hydrate / ethylene glycol / 2 h / 130 °C 2.2: 2 h / 160 °C 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 16 h / 90 °C / Inert atmosphere 4.1: sodium hydroxide; water / ethanol / 2 h / 60 °C 5.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 5 h / 10 - 35 °C | ||
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetonitrile / 16 h / 80 °C 2.1: hydrazine hydrate / ethylene glycol / 2 h / 130 °C 2.2: 2 h / 20 - 160 °C 3.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,2-dimethoxyethane / 16 h / 85 °C / Inert atmosphere 4.1: sodium hydroxide / ethanol / 2 h / 20 - 60 °C 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 16 h / Reflux 2.1: hydrazine hydrate / ethylene glycol / 2 h / 130 °C 2.2: 2 h / 160 °C 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 16 h / 90 °C / Inert atmosphere 4.1: sodium hydroxide; water / ethanol / 2 h / 60 °C | ||
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 16 h / 80 °C 2.1: hydrazine hydrate / ethylene glycol / 2 h / 130 °C 2.2: 2 h / 20 - 160 °C 3.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,2-dimethoxyethane / 16 h / 85 °C / Inert atmosphere 4.1: sodium hydroxide / ethanol / 2 h / 20 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: triphenylphosphine; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone In toluene at 80℃; for 5h; Inert atmosphere; Stage #2: With sodium carbonate In dichloromethane; water at 20℃; for 18h; Ionic liquid; | |
In toluene at 20℃; for 18h; | ||
Stage #1: triphenylphosphine; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone In ethyl acetate at 20℃; Stage #2: With sodium hydroxide In dichloromethane; water at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone With borane-THF; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; toluene at 15 - 20℃; for 1.70833h; Cooling with ice; Stage #2: With methanol; sodium hydroxide In tetrahydrofuran; toluene at 20℃; for 1.63333h; | (R)-2-(3-Trifluoromethylphenyl)-oxirane Solutions of4.006 g (15 mmol) of 2-bromo-1-(3-trifluoromethylphenyl)-ethanone, 15mL of anhydrous tetrahydrofuran and 15 mL of 1M borane-THF in tetrahydrofuran were addedsimultaneously to a stirring solution of 1.5 mL of 1M (R)-(3aR)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][l,3,2]oxazaborole in toluene and 15 mL of anhydroustetrahydrofuran, cooled in an ice water bath at ca. 15 degrees, over 12.5 minutes. The coolingbath was removed and the mixture stirred at room temperature. After 1.5 h, ca. 0.48 g ofmethanol was added dropwise (gas evolution) and the mixture stirred for 5 minutes, then 15 mLof2 M sodium hydroxide was added over 3 minutes. The mixture was stirred at roomtemperature. After 1.5 h, the mixture was concentrated under reduced pressure to remove thetetrahydrofuran, and the remaining aqueous phase was extracted twice with diethyl ether. Thecombined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentratedunder reduced pressure to give 2.553 g (90%) of(R)-2-(3-trifluoromethyl-phenyl)oxirane as alight amber liquid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 2.87 (dd, J=5.27, 2.51 Hz, 1 H) 3.12(dd, J=5.27, 4.02 Hz, 1 H) 4.04 (dd, J=4.27, 2.51 Hz, 1 H) 7.54-7.58 (m, 2 H) 7.60 (s, 1 H) 7.62-7.67 (m, 1 H). |
2.553 g | Stage #1: 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone With borane-THF; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; toluene at 15 - 20℃; for 1.70833h; Inert atmosphere; Stage #2: With methanol In tetrahydrofuran; toluene for 0.0833333h; Inert atmosphere; Stage #3: With sodium hydroxide In tetrahydrofuran; water; toluene at 20℃; for 1.5h; Inert atmosphere; | I Intermediate B (R)-2-(3-Trifluoromethylphenyl)-oxirane Solutions of 4.006 g (15 mmol) of 2-bromo-l-(3-trifluoromethyl-phenyl)-ethanone, 15 mL of anhydrous tetrahydrofuran and 15 mL of 1M borane-THF in tetrahydrofuran were added simultaneously to a stirring solution of 1.5 mL of 1M (R)-(3aR)-tetrahydro-l-methyl-3,3- diphenyl-lH,3H-pyrrolo[l,2-c][l,3,2]oxazaborole in toluene and 15 mL of anhydrous tetrahydrofuran, cooled in an ice water bath at about 15 degrees, over 12.5 minutes. The cooling bath was removed and the mixture stirred at room temperature. After 1.5 hours, ca 0.48 g of methanol was added dropwise (gas evolution) and the mixture stirred for 5 minutes, then 15 mL of 2 M sodium hydroxide was added over 3 minutes. The mixture was stirred at room temperature. After 1.5 hours, the mixture was concentrated under reduced pressure to remove the tetrahydrofuran, and the remaining aqueous phase was extracted twice with diethyl ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2.553 g (90%) of (R)-2-(3-trifluoromethyl- phenyl)oxirane as a light amber liquid. 1H NMR (400 MHz, DMSO-J6) δ ppm 2.87 (dd, 7=5.27, 2.51 Hz, 1 H) 3.12 (dd, 7=5.27, 4.02 Hz, 1 H) 4.04 (dd, 7=4.27, 2.51 Hz, 1 H) 7.54 - 7.58 (m, 2 H) 7.60 (s, 1 H) 7.62 - 7.67 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With ethyloxirane at 120℃; for 0.5h; Sealed tube; Microwave irradiation; Green chemistry; | General procedure for pyrrolo[1,2-c]pyrimidines (4-70). General procedure: A stirred mixture of pyrimidine 1 (2.5 mmole), 2-bromoacetophenone 2 (2.5 mmole) and non-symmetrical electron deficient alkynes 3 (3.5 mmole) in 15 mL 1,2-epoxybutane was placed into an sealed microwave reactor at120 °C for 30 min. The reaction mixture was cooled to room temperature, partly of the solvent was removed in vacuum, 5mL of MeOH was added under a gentle stirring and themixture was left overnight at 5-10 °C . The solid formed was filtered-off, washed on the filter with a mixture of diethylether-MeOH 2:1 and crystallized from CHCl3/MeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With ethyloxirane at 120℃; for 0.5h; Sealed tube; Microwave irradiation; Green chemistry; | General procedure for pyrrolo[1,2-c]pyrimidines (4-70). General procedure: A stirred mixture of pyrimidine 1 (2.5 mmole), 2-bromoacetophenone 2 (2.5 mmole) and non-symmetrical electron deficient alkynes 3 (3.5 mmole) in 15 mL 1,2-epoxybutane was placed into an sealed microwave reactor at120 °C for 30 min. The reaction mixture was cooled to room temperature, partly of the solvent was removed in vacuum, 5mL of MeOH was added under a gentle stirring and themixture was left overnight at 5-10 °C . The solid formed was filtered-off, washed on the filter with a mixture of diethylether-MeOH 2:1 and crystallized from CHCl3/MeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With ethyloxirane; at 120℃; for 0.5h;Sealed tube; Microwave irradiation; Green chemistry; | General procedure: A stirred mixture of pyrimidine 1 (2.5 mmole), 2-bromoacetophenone 2 (2.5 mmole) and non-symmetrical electron deficient alkynes 3 (3.5 mmole) in 15 mL 1,2-epoxybutane was placed into an sealed microwave reactor at120 C for 30 min. The reaction mixture was cooled to room temperature, partly of the solvent was removed in vacuum, 5mL of MeOH was added under a gentle stirring and themixture was left overnight at 5-10 C . The solid formed was filtered-off, washed on the filter with a mixture of diethylether-MeOH 2:1 and crystallized from CHCl3/MeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate In acetonitrile at 80℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate In acetonitrile at 80℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol Reflux; | 7 4.1.5. General procedure for the synthesis of aminoarylthiazole analogues (Hantzsch synthesis) General procedure: Haloketones (1 eq) were conjugated with thioureas (1 eq) in anhydrous EtOH (1 ml). Reaction was stirred at reflux from 2 to 24 h until the reaction was judged complete (HPLC-MS). The mixture was then extracted with ethyl acetate (3 x 3 ml). The organic phases were concentrated in vacuum and lyophilized. Products were verified by HPLC and MS and purified with preparative HPLC. Relevant fractions were collected and concentrated to afford the desired product in 40-95% yields, with purity of >95% as determined by HPLC-MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine In tetrahydrofuran at 20℃; for 24h; | General procedure for preparation of umbelliferone β keto ether derivatives (7a-n) and (8a-o); General procedure: The appropriate bromoketone (6a-o) (1.7 mmol) and triethylamine (1.6 mmol) were added to as olution of either7-hydroxy-4-methyl-2H-chromen-2-one 4 (1.4 mmol)or 7-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one 5 (1.4 mmol) in THF (20 mL). The mixture was stirred at room temperature for 24h, filtered and the solvent was evaporated under reduced pressure.The solid residue was purified by column chromatography eluting with DCM/MeOH 9:1 to afford (7a-n) and (8a-o). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In tetrahydrofuran; at 20℃; for 24h; | General procedure: The appropriate bromoketone (6a-o) (1.7 mmol) and triethylamine (1.6 mmol) were added to as olution of either7-hydroxy-4-methyl-2H-chromen-2-one 4 (1.4 mmol)or <strong>[575-03-1]7-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one</strong> 5 (1.4 mmol) in THF (20 mL). The mixture was stirred at room temperature for 24h, filtered and the solvent was evaporated under reduced pressure.The solid residue was purified by column chromatography eluting with DCM/MeOH 9:1 to afford (7a-n) and (8a-o). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran Reflux; | General procedure for the synthesis of compounds A1-A10 General procedure: A mixture of 1-aryl-2-bromoethanone 1 (12mmol) and pyridine derivatives 2 (10mmol) in THF was heated to reflux overnight. The solvent was removed under reduced pressure and the residue was used directly for the subsequent step without further purification. (0021) The pyridinium salt 3 (10mmol) was suspended in CH3CN (60mL) at 0°C and then potassium carbonate (20mmol) was added portion-wise to maintain the temperature at 0°C. After 30min, ethyl propiolate (11mmol) was added dropwise at 0°C, and the resulting mixture was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure and the residue was diluted with water, extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography to afford 4. (0022) LiOH (5mmol) was added to the solution of compound 4 (1mmol) in THF (8mL), MeOH (8mL) and H2O (2mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and 1N HCl solution was added to the residue. The precipitated product was filtered and washed with water to afford 5. (0023) To a mixture of the aforementioned compound 5 (0.5mmol), HATU (0.75mmol) in dried CH2Cl2 was added DIPEA (3.0mmol), and the solution was stirred at 0-10°C for 20min. Then (R)-3-aminoquinuclidine dihydrochloride (0.55mmol) was slowly added with 10min. The mixture was stirred at room temperature for 3h. The solvent was removed and the residue was extracted with CH2Cl2/MeOH (20/1). The combined organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with CH2Cl2/MeOH/ammonium hydroxide (100/10/1) to afford compound 6. (0024) To a round-bottom flask was added 6 (0.5mmol) and CH2Cl2 (10mL). The mixture was stirred and heated until a complete solution was obtained. Then the hydrochloric acid/EtOH solution was added dropwise over a 5min period. Granular, white solid began to form during the addition of the acid solution. The mixture was cooled to ambient temperature and stirred overnight. The solid was collected by suction filtration, the filter cake was washed with acetone and the solid was dried in a vacuum oven to afford the target compound of the white crystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 20 - 60℃; for 0.5h; Inert atmosphere; Microwave irradiation; | 112 (Z) -5-bromo-6-methoxy-N’-(2 -oxo-2 -(3-(trzfluoromethyl) phenyl) ethoxy) picolinimidamide: To a stirred solution of 5-bromo-N’ -hydroxy-6-methoxypicolinimidamide (750 mg, 3 mmol) in DMF (7.5 mL) at room temperature under an argon atmosphere were added potassium carbonate (841 mg, 6 mmol) and 2-bromo-1-(3-(trifluoromethyl) phenyl) ethan-1-one (1.2 g, 5 mmol). The reaction mixture was stirred for 30 mm at 60 °C in microwave. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford (Z)-5-bromo-6-methoxy-iV-(2-oxo-2-(3 -(trifluoromethyl) phenyl) ethoxy) picolinimidamide (1 g, crude) as yellow solid used in the next step without further purification.[0654] LCMS: 24.0%; 431.8 (M+2); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 2.94 mm; mobile phase: 0.025% Aq TFA+5% ACN: ACN+5% 0.025% Aq TFA; T/B%: 0.01/5, 0.5/5, 3/100, 5/100; flow rate: 1.2 mL/min) (Gradient); TLC: 20% EtOAc/ Hexane (R1 0.6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethanolamine; Eosin Y In methanol at 20℃; for 4h; Inert atmosphere; Irradiation; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: acetoacetic acid methyl ester With sodium hydride In tetrahydrofuran at 0℃; Stage #2: 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone In tetrahydrofuran at 0 - 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In ethanol at 25℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine In ethanol at 100℃; for 0.0833333h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine In dichloromethane | 2 2 - ((2-hydroxyphenyl) thio) -1- (3- (trifluoromethyl) phenyl) ethanone2 -Bromo-1- (3- (trifluoromethyl) phenyl) ethanone (635 mg, 2.4 mmol) was weighed and dissolved in 5 mL of methylene chloride. The addition of Triethylamine (333 [mu] L, 2.4 mmol) was added. 2-Mercaptophenol (164 μL, 1.59 mmol) was added. After the reaction was completed, 20 mL was addedDichloromethane, dilute hydrochloric acid, saturated brine, dried over anhydrous sodium sulfate, concentrated and passed through a silica gel column to give a pale yellow oil. Yield 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide at 85℃; for 0.75h; | Step 2. (2-(bis(4-methoxybenzyl)amino)-4-(3-chlorophenyl)thiazol-5-yl)(2-chlorophenyl)methanone General procedure: b. To a solution of N-(bis(4-methoxybenzyl)carbamothioyl)-3-chlorobenzamide (0.40 g, 0.88 mmol) in DMF (4 mL) was added 2-bromo-1-(2-chlorophenyl)ethanone (0.29 g, 1.23 mmol). The mixture was warmed to 85°C for 45 min, and then the solvent was removed in vacuo. The crude residue was purified by chromatography on silica gel (Hex/EtOAc 100/0 to 60/40) to afford c (0.73 g, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-oxo-1,2-dihydro-pyridine-4-carbonitrile; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone In dimethyl sulfoxide; acetonitrile at 0℃; for 0.166667h; Stage #2: With potassium carbonate In dimethyl sulfoxide; acetonitrile at 0℃; for 1h; | 8.A Step A: 2-oxo- 1 -(2-oxo-2-(3 -(trifluoromethyl)phenyl)ethyl)- 1 ,2-dihydropyridine-4-carbonitrile To a solution of 2-oxo-1,2-dihydropyridine-4-carbonitrile (4.50 g, 37.5 mmol) in DM50 (25mL) and acetonitrile (25 mL) was added 2-bromo- 1 -(3-(trifluoromethyl)phenyl)ethanone (13.0 g, 48.7mmol) at 0 °C. The solution was stirred at 0 °C for 10 mm before K2C03 (7.77 g, 56.2 mmol) was added. The solution was stirred at 0 °C for 1 h, then partitioned betweenwater (150 mL) and ethyl acetate (3x1 50 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated to give 2-oxo- 1 -(2-oxo-2-(3 -(trifluoromethyl)phenyl)ethyl)- 1 ,2-dihydropyridine-4-carbonitrile as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Stage #1: 2,3-methylenedioxy-9-hydroxy-10-methoxy-1,13-cycloprotoberberine chloride With potassium hydroxide In N,N-dimethyl-formamide for 0.25h; Stage #2: 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone In N,N-dimethyl-formamide at 68 - 75℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With oxygen; eosin y In N,N-dimethyl-formamide at 20℃; for 36h; Schlenk technique; Irradiation; | |
69% | With oxygen; eosin y In N,N-dimethyl-formamide for 36h; Irradiation; Schlenk technique; Green chemistry; | 6 Embodiment 6 Compound 1f (0.5 mmol, 140.6 mg), compound 2a (2 mmol, 224 vL), was added to a 25 mL Schlenk tube. Eosin Y (0.005 mol, 3.6 mg), N,N-dimethylformamide (2 mL). The system was then reacted for 36 hours in the presence of a 12 W green LED lamp in oxygen. After the reaction was completed, it was extracted with ethyl acetate (10 mL × 3). Drying over anhydrous magnesium sulfate, removing the solvent by rotary evaporator, adsorption on silica gel, The product 3f was obtained by simple column chromatography in a yield of 69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.2 g | With potassium carbonate In dichloromethane at 20℃; for 5h; | 2.A Preparation of 2- [methyl(phenylmethyl)aminol -1- [3-(trifluoromethyl)phenyll - ethanone 1:1 hydrochloride To a solution of 2-bromo-1-[3-(trifluoromethyl)phenyll-ethanone (8.6 g, 32.2 mmol) and N-methyl-benzenemethanamine (3.7 g, 30.6 mmol) in dichloromethane (300 mL) wasadded potassium carbonate (8.9 g, 64.4 mmol) and the resulting mixture was stirred at room temperature for 5 h. Water (20 mL) was added and stirred for an additional 3 h. The organic layer was separated, washed with brine, dried over Mg504, filtered and concentrated under reduced pressure to yield a light yellow oil. The crude oil was diluted with diethyl ether (100 mL), and a solution of aqueouse hydrochloric acid in diethyl ether (15 mL, 2 M) wasadded over 10 mm at room temperature. The resulting white slurry was filtered, washed withdiethyl ether (20 mL), and suction-dried to provide the title product as a white solid (9.2 g).1H NMR (dmso-d6) ö 2.81 (br s, 3H), 4.29 (br s, 1H), 4.47-4.52 (m, 1H), 5.07-5.16 (m, 2H),7.48 (br s, 3H), 7.62 (br s, 2H), 7.88 (br t, 1H), 8.14 (br d, 1H), 8.27 (d, 2H), 10.39 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: 2,6-di-tert-butyl-4-(2-hydroxybenzylidene)-2,5-cyclohexadiene-1-one; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone With caesium carbonate In acetonitrile at 20℃; for 1.5h; Inert atmosphere; Stage #2: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In acetonitrile at 50℃; for 8h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In ethanol for 5h; Reflux; | 3.2.6. Synthesis of the Target Compounds A General procedure: A mixture of -bromophenylethanone (2.05 mmol, 1.0 equiv.) and intermediate 4 (2.25 mmol,1.10 equiv.) was dissolved in ethanol (20 mL) and then heated at reflux for 5 h. Upon completion of thereaction the liquid was filtered and the solid formed was washed with saturated potassium carbonatesolution. The crude product was purified by column chromatography on basic alumina to give thevarious target compounds in yields ranging from 55% to 94%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol for 5h; Reflux; | 3.2.6. Synthesis of the Target Compounds A General procedure: A mixture of -bromophenylethanone (2.05 mmol, 1.0 equiv.) and intermediate 4 (2.25 mmol,1.10 equiv.) was dissolved in ethanol (20 mL) and then heated at reflux for 5 h. Upon completion of thereaction the liquid was filtered and the solid formed was washed with saturated potassium carbonatesolution. The crude product was purified by column chromatography on basic alumina to give thevarious target compounds in yields ranging from 55% to 94%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In ethanol for 5h; Reflux; | 3.2.6. Synthesis of the Target Compounds A General procedure: A mixture of -bromophenylethanone (2.05 mmol, 1.0 equiv.) and intermediate 4 (2.25 mmol,1.10 equiv.) was dissolved in ethanol (20 mL) and then heated at reflux for 5 h. Upon completion of thereaction the liquid was filtered and the solid formed was washed with saturated potassium carbonatesolution. The crude product was purified by column chromatography on basic alumina to give thevarious target compounds in yields ranging from 55% to 94%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With water; hydrogen bromide In tetrahydrofuran at 120℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In ethanol at 80℃; for 2h; Sealed tube; | 4.6.1. Procedure 1: general procedure for the synthesis of aminothiazoles and thiazoles (1-18, 22-31, 32-34, 48-50, 52-53) General procedure: A solution of appropriate arylthiourea (1 eq.) or arylthioamide(1 eq.) and aryl-2-bromoethanone (1 eq.) in anhydrous ethanol washeated in a sealed tube at 80 C for 2 h. The progress of reactionwasmonitored by TLC. Ethanol was removed from the reaction mixtureand the resulted residue was washed with aq. NaHCO3. Theaqueous layer was extracted with CH2Cl2 (3 times) and the combinedorganic layer was dried over anhydrous Na2SO4. The filtratewas concentrated in vacuo and the crude product was purified onTeledyne Isco Combiflash Rf purification machine to afford correspondingthiazoles in moderate to good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With sodium hydrogencarbonate In methanol for 12h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In acetone at 20℃; for 1h; Inert atmosphere; | 4.2. General procedure for the synthesis of 2,3-disubstituted indoles (4a-z & 4aa-ac) General procedure: Acetone (1.5 mL) was added to a mixture of 2-(tosylamino)phenyl p-quinone methide (1a-d, 0.086 mmol, 1 equiv.), bromomethylaryl ketone (2a-x, 0.103 mmol, 1.2 equiv.) followed by the addition of Cs2CO3 (0.103 mmol, 1.2 equiv.). The resulting suspension was stirred at room temperature for an hour. DBU (0.258 mmol, 3 equiv.) was added to the reaction mixture and the reaction mixture was further allowed to stir at 55 °C for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was then purified through a silica gel column, using EtOAc/Hexane mixture as an eluent, to get the pure product (4a-z & 4aa-ac). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With potassium carbonate In acetone at 20℃; for 24h; | |
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; | General procedure: To a solution of 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (1 equiv.), bromide (1.1 equiv.) and TBAI (equiv.) in DMF (0.5 M) was added K2CO3 (1.5 equiv.) at 0 °C, and then stirred at same temperature for 1 hr. After the reaction completed, the reaction mixture poured into water and extracted into EA. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexane/EA as eluent (solvent ratio: 20/1 to 7/1) to yield the product[3]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.37 mg | With potassium fluoride In water; acetonitrile at 25℃; for 3h; Inert atmosphere; | 1.3 Step 3 : /V-(3-Chlorophenyl)-4-[3-(trifluoromethyl)phenyl]thiazol-2-amine o a stirred solution of (3-chlorophenyl)thiourea (200 mg, 857.17 pmol,1 eq) and 2- bromo-l-[3-(trifluoromethyl)phenyl]ethanone (228.90 mg, 857.17 pmol,1 eq) in MeCN (5 mL) and H2O (5 mL) was added KF (49.80 mg, 857.17 pmol,1 eq). The reaction mixture was stirred at 25 °C for 3 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove MeCN. The residue was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL ), dried over Na2SC>4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5pm; mobile phase: [water(0.05%NH3H20+10 mM NH4HC03)-ACN]; B%: 68%-98%,10 min) to yield N-(3- chlorophenyl)-4-[3-(trifluoromethyl)phenyl]thiazol-2-amine (76.37 mg, 213.39 pmol, 24.9% yield, 99.1% purity) as red oil. NMR (400 MHz, DMSO- e) d ppm 10.60 (s,1H), 8.24 (s,1H), 8.23-8.18 (m,1H), 8.05 (t, J= 2.0 Hz,1H), 7.71-7.66 (m, 3H), 7.50 (dd, J= 1.2, 8.2 Hz,1H), 7.37 (t, J= 8.2 Hz,1H), 7.03 (dd, J= 1.4, 8.0 Hz,1H); ES-LCMS m/z 354.9, 356.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: ethyl acetoacetate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone In tetrahydrofuran at 0 - 20℃; | 1.b (b) Synthesis of ethyl 2-acetyl-4-oxo-4-(3-trifluoromethylphenyl)butyYield (Compound I-3-1) Ethyl acetoacetate (439 mg, 4.2 mmol) was added dropwise to a suspension of sodium hydride (60% w/w, 197 mg, 4.7 mmol) in anhydrous THF (20 mL) at 0 °C. After stirring for 30 min, compound I-2-1 (1.25 g, 4.7 mmol) was added dropwise, and then moved to room temperature to react overnight. After adding an appropriate amount of water to the system for quenching, adding an appropriate amount of ethyl acetate, washing with water and satuYield d brine in turn, the organic layer was dried over anhydrous Na2SO4 and concentYield d. The residue was subjected to column chromatography to obtain a pale yellow solid with a yield of 71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 0.5h; Inert atmosphere; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; water for 1.5h; Reflux; | 1 Step 1: 2-(methylsulfonyl)-1 -(3-(trifluoromethyl)phenyl)ethan-1 -one To a solution under N2 of 3-(trifluoromethoxy)phenacyl bromide (250 mg, 0.84 mmol, 1.0 eq) in dioxane (1.5 mL) and H2O (1.5 mL), sodium methanesulfinate (128 mg, 1.26 mmol, 1.5 eq) was added at rt. The reaction mixture was heated at reflux for 1.5 h. The reaction mixture was evaporated. The residue was dissolved in DCM (25 mL), washed with H2O (25 mL). The aq. phase was extracted with DCM (2 x 25 mL). The comb. org. phases were washed with sat. aq. NaCI soln. (50 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by Combiflash (column: 12 g, flow: 25 mL/min, Heptane + 20% TBME/MeOH 8:2) to afford a beige solid. LC-MS (2): tR = 0.78min; no ionization |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: ethyl acetate / 20 °C 1.2: 1 h / 20 °C 2.1: chloroform / 20 °C 3.1: tributylphosphine / toluene / 1 h / 20 °C / Inert atmosphere; Schlenk technique 4.1: methanol / 0.25 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: ethyl acetate / 20 °C 1.2: 1 h / 20 °C 2.1: chloroform / 20 °C 3.1: tributylphosphine / toluene / 1 h / 20 °C / Inert atmosphere; Schlenk technique 4.1: methanol / 0.25 h / 20 °C 5.1: caesium carbonate; cobalt(II) 5,10,15,20-tetraphenylporphyrin / benzene / 20 h / 20 °C / Inert atmosphere; Glovebox |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: ethyl acetate / 20 °C 1.2: 1 h / 20 °C 2.1: chloroform / 20 °C 3.1: tributylphosphine / toluene / 1 h / 20 °C / Inert atmosphere; Schlenk technique |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3.5h; | 16.1 Step 1 - [2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl] 6-[(7-oxo-6,8-dihydro-5H-1,8- naphthyridin-4-yl)oxy]chromane-3-carboxylate 6-[(7-Oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (200mg, 0.59mmol) and K2CO3(244mg, 1.76mmol) were dissolved in dry DMF (5mL) and treated with 3-(trifluoromethyl)phenacyl bromide (173mg, 0.65mmol) portionwise. The reaction was stirred for 2.5 hours at rt, after which time, a second portion of 3- (trifluoromethyl)phenacyl bromide was added (172mg, 0.65mmol) and the reaction was left stirring for 1h. Water (15 mL) was added and the product was extracted with DCM (x3). The combined organic phases were dried over Na2SO4, filtered and the solvent removed under reduce pressure. The product was purified by column chromatography using as eluent a gradient from 0-100% EtOAc in petroleum to give 2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl] 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylate (55mg, 0.10mmol, 18% yield) as yellow solid. UPLC-MS (ES+, short acidic): 1.78 min, m/z 527.4 [M+H]+. |
18% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3.5h; | 16.1 Step 1 - [2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl] 6-[(7-oxo-6,8-dihydro-5H-1,8- naphthyridin-4-yl)oxy]chromane-3-carboxylate 6-[(7-Oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (200mg, 0.59mmol) and K2CO3(244mg, 1.76mmol) were dissolved in dry DMF (5mL) and treated with 3-(trifluoromethyl)phenacyl bromide (173mg, 0.65mmol) portionwise. The reaction was stirred for 2.5 hours at rt, after which time, a second portion of 3- (trifluoromethyl)phenacyl bromide was added (172mg, 0.65mmol) and the reaction was left stirring for 1h. Water (15 mL) was added and the product was extracted with DCM (x3). The combined organic phases were dried over Na2SO4, filtered and the solvent removed under reduce pressure. The product was purified by column chromatography using as eluent a gradient from 0-100% EtOAc in petroleum to give 2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl] 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylate (55mg, 0.10mmol, 18% yield) as yellow solid. UPLC-MS (ES+, short acidic): 1.78 min, m/z 527.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-bromo-1-[3-(trifluoromethyl)phenyl]-1-ethanone; 2-hydroxy-5-(trifluoromethyl)benzonitrile With triethylamine In N,N-dimethyl-formamide at 70℃; Stage #2: With potassium etoxide In ethanol at 80℃; Sealed tube; Stage #3: 2-Bromoacetyl bromide Further stages; | Chemical Synthesis of 5-BDBD Analogs. General procedure: Synthesis of the compounds follows a reported procedure (Fischeret al., 2004) with minor modifications. Intermediate purification is notnecessary and was only performed for the final product. A mixture of 5-substituted-2-hydroxybenzonitrile (a, 250 mg, 1 Eq), 3-substituted-phenacylbromide (b, 1 Eq), and triethylamine (1.1 Eq) in 2.5 ml of dimethylformamidewas stirred at 70C until completion (2-6 hours) wasconfirmed by TLC. The reaction mixture was cooled down to room temperature,diluted with 100 ml of ethyl acetate, and washed with water(3 × 30 ml) and brine (1 × 30 ml). The organic layer was dried oversodium sulfate and evaporated under reduced pressure. The residue(crude c) was dissolved in 10 ml of ethanol, and 1.1 equivalents ofsodium ethoxide were added thereto. The mixture was stirred at 80Cin a sealed tube for 2-12 hours until completion was confirmed byTLC. The reaction mixture was cooled down to room temperature,diluted with 100 ml of ethyl acetate, and washed with water (3 × 30 ml)and brine (1 × 30 ml). The organic layer was dried over sodium sulfateand evaporated under reduced pressure. A stirring mixture of the residue(crude d) and sodium hydrogen carbonate (4 Eq) in 30 ml of chloroformwas cooled down to 0C. Bromoacetyl bromide (1.1 Eq) was slowly added, and the mixture was then stirred for 1-2 hours, until completionwas confirmed by TLC. The mixture was diluted with 100 ml of ethylacetate and washed with a saturated solution of sodium hydrogen carbonate(1 × 30 ml) and with brine (1 × 30 ml). The organic layer wasdried over sodium sulfate and evaporated under reduced pressure. Amixture of the residue (crude e), 7 ml of diethyl ether, NH3-dioxane0.5 M (10 Eq), and 1.5 g of anhydrous sodium sulfate was stirred in asealed tube for 3 days. The mixture was diluted with 100 ml of ethylacetate and washed with water (3 × 50 ml) and with brine (1 × 50 ml).The organic layer was dried over sodium sulfate and evaporated underreduced pressure. The product was purified by flash chromatographyand then triturated with diethyl ether to give the pure product (f).When necessary, an additional purification by preparative high-performanceliquid chromatography (HPLC) was performed. Purity and characterizationwere assessed according to the attached methods.Supporting information regarding synthesized compounds, includinghigh-resolution mass spectrometry and NMR spectroscopy, is given inSupplemental Material. | |
Stage #1: 2-bromo-1-[3-(trifluoromethyl)phenyl]-1-ethanone; 2-hydroxy-5-(trifluoromethyl)benzonitrile With triethylamine In N,N-dimethyl-formamide at 70℃; Stage #2: With potassium etoxide In ethanol at 80℃; Sealed tube; Stage #3: 2-Bromoacetyl bromide Further stages; | Chemical Synthesis of 5-BDBD Analogs. General procedure: Synthesis of the compounds follows a reported procedure (Fischeret al., 2004) with minor modifications. Intermediate purification is notnecessary and was only performed for the final product. A mixture of 5-substituted-2-hydroxybenzonitrile (a, 250 mg, 1 Eq), 3-substituted-phenacylbromide (b, 1 Eq), and triethylamine (1.1 Eq) in 2.5 ml of dimethylformamidewas stirred at 70C until completion (2-6 hours) wasconfirmed by TLC. The reaction mixture was cooled down to room temperature,diluted with 100 ml of ethyl acetate, and washed with water(3 × 30 ml) and brine (1 × 30 ml). The organic layer was dried oversodium sulfate and evaporated under reduced pressure. The residue(crude c) was dissolved in 10 ml of ethanol, and 1.1 equivalents ofsodium ethoxide were added thereto. The mixture was stirred at 80Cin a sealed tube for 2-12 hours until completion was confirmed byTLC. The reaction mixture was cooled down to room temperature,diluted with 100 ml of ethyl acetate, and washed with water (3 × 30 ml)and brine (1 × 30 ml). The organic layer was dried over sodium sulfateand evaporated under reduced pressure. A stirring mixture of the residue(crude d) and sodium hydrogen carbonate (4 Eq) in 30 ml of chloroformwas cooled down to 0C. Bromoacetyl bromide (1.1 Eq) was slowly added, and the mixture was then stirred for 1-2 hours, until completionwas confirmed by TLC. The mixture was diluted with 100 ml of ethylacetate and washed with a saturated solution of sodium hydrogen carbonate(1 × 30 ml) and with brine (1 × 30 ml). The organic layer wasdried over sodium sulfate and evaporated under reduced pressure. Amixture of the residue (crude e), 7 ml of diethyl ether, NH3-dioxane0.5 M (10 Eq), and 1.5 g of anhydrous sodium sulfate was stirred in asealed tube for 3 days. The mixture was diluted with 100 ml of ethylacetate and washed with water (3 × 50 ml) and with brine (1 × 50 ml).The organic layer was dried over sodium sulfate and evaporated underreduced pressure. The product was purified by flash chromatographyand then triturated with diethyl ether to give the pure product (f).When necessary, an additional purification by preparative high-performanceliquid chromatography (HPLC) was performed. Purity and characterizationwere assessed according to the attached methods.Supporting information regarding synthesized compounds, includinghigh-resolution mass spectrometry and NMR spectroscopy, is given inSupplemental Material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: salicylonitrile; 2-bromo-1-[3-(trifluoromethyl)phenyl]-1-ethanone With triethylamine In N,N-dimethyl-formamide at 70℃; Stage #2: With potassium etoxide In ethanol at 80℃; Sealed tube; Stage #3: 2-Bromoacetyl bromide Further stages; | Chemical Synthesis of 5-BDBD Analogs. General procedure: Synthesis of the compounds follows a reported procedure (Fischeret al., 2004) with minor modifications. Intermediate purification is notnecessary and was only performed for the final product. A mixture of 5-substituted-2-hydroxybenzonitrile (a, 250 mg, 1 Eq), 3-substituted-phenacylbromide (b, 1 Eq), and triethylamine (1.1 Eq) in 2.5 ml of dimethylformamidewas stirred at 70C until completion (2-6 hours) wasconfirmed by TLC. The reaction mixture was cooled down to room temperature,diluted with 100 ml of ethyl acetate, and washed with water(3 × 30 ml) and brine (1 × 30 ml). The organic layer was dried oversodium sulfate and evaporated under reduced pressure. The residue(crude c) was dissolved in 10 ml of ethanol, and 1.1 equivalents ofsodium ethoxide were added thereto. The mixture was stirred at 80Cin a sealed tube for 2-12 hours until completion was confirmed byTLC. The reaction mixture was cooled down to room temperature,diluted with 100 ml of ethyl acetate, and washed with water (3 × 30 ml)and brine (1 × 30 ml). The organic layer was dried over sodium sulfateand evaporated under reduced pressure. A stirring mixture of the residue(crude d) and sodium hydrogen carbonate (4 Eq) in 30 ml of chloroformwas cooled down to 0C. Bromoacetyl bromide (1.1 Eq) was slowly added, and the mixture was then stirred for 1-2 hours, until completionwas confirmed by TLC. The mixture was diluted with 100 ml of ethylacetate and washed with a saturated solution of sodium hydrogen carbonate(1 × 30 ml) and with brine (1 × 30 ml). The organic layer wasdried over sodium sulfate and evaporated under reduced pressure. Amixture of the residue (crude e), 7 ml of diethyl ether, NH3-dioxane0.5 M (10 Eq), and 1.5 g of anhydrous sodium sulfate was stirred in asealed tube for 3 days. The mixture was diluted with 100 ml of ethylacetate and washed with water (3 × 50 ml) and with brine (1 × 50 ml).The organic layer was dried over sodium sulfate and evaporated underreduced pressure. The product was purified by flash chromatographyand then triturated with diethyl ether to give the pure product (f).When necessary, an additional purification by preparative high-performanceliquid chromatography (HPLC) was performed. Purity and characterizationwere assessed according to the attached methods.Supporting information regarding synthesized compounds, includinghigh-resolution mass spectrometry and NMR spectroscopy, is given inSupplemental Material. | |
Stage #1: salicylonitrile; 2-bromo-1-[3-(trifluoromethyl)phenyl]-1-ethanone With triethylamine In N,N-dimethyl-formamide at 70℃; Stage #2: With potassium etoxide In ethanol at 80℃; Sealed tube; Stage #3: 2-Bromoacetyl bromide Further stages; | Chemical Synthesis of 5-BDBD Analogs. General procedure: Synthesis of the compounds follows a reported procedure (Fischeret al., 2004) with minor modifications. Intermediate purification is notnecessary and was only performed for the final product. A mixture of 5-substituted-2-hydroxybenzonitrile (a, 250 mg, 1 Eq), 3-substituted-phenacylbromide (b, 1 Eq), and triethylamine (1.1 Eq) in 2.5 ml of dimethylformamidewas stirred at 70C until completion (2-6 hours) wasconfirmed by TLC. The reaction mixture was cooled down to room temperature,diluted with 100 ml of ethyl acetate, and washed with water(3 × 30 ml) and brine (1 × 30 ml). The organic layer was dried oversodium sulfate and evaporated under reduced pressure. The residue(crude c) was dissolved in 10 ml of ethanol, and 1.1 equivalents ofsodium ethoxide were added thereto. The mixture was stirred at 80Cin a sealed tube for 2-12 hours until completion was confirmed byTLC. The reaction mixture was cooled down to room temperature,diluted with 100 ml of ethyl acetate, and washed with water (3 × 30 ml)and brine (1 × 30 ml). The organic layer was dried over sodium sulfateand evaporated under reduced pressure. A stirring mixture of the residue(crude d) and sodium hydrogen carbonate (4 Eq) in 30 ml of chloroformwas cooled down to 0C. Bromoacetyl bromide (1.1 Eq) was slowly added, and the mixture was then stirred for 1-2 hours, until completionwas confirmed by TLC. The mixture was diluted with 100 ml of ethylacetate and washed with a saturated solution of sodium hydrogen carbonate(1 × 30 ml) and with brine (1 × 30 ml). The organic layer wasdried over sodium sulfate and evaporated under reduced pressure. Amixture of the residue (crude e), 7 ml of diethyl ether, NH3-dioxane0.5 M (10 Eq), and 1.5 g of anhydrous sodium sulfate was stirred in asealed tube for 3 days. The mixture was diluted with 100 ml of ethylacetate and washed with water (3 × 50 ml) and with brine (1 × 50 ml).The organic layer was dried over sodium sulfate and evaporated underreduced pressure. The product was purified by flash chromatographyand then triturated with diethyl ether to give the pure product (f).When necessary, an additional purification by preparative high-performanceliquid chromatography (HPLC) was performed. Purity and characterizationwere assessed according to the attached methods.Supporting information regarding synthesized compounds, includinghigh-resolution mass spectrometry and NMR spectroscopy, is given inSupplemental Material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-N'-(p-tolylsulfonyl)benzenesulfonohydrazide; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; |
Tags: 2003-10-3 synthesis path| 2003-10-3 SDS| 2003-10-3 COA| 2003-10-3 purity| 2003-10-3 application| 2003-10-3 NMR| 2003-10-3 COA| 2003-10-3 structure
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H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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