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CAS No. : | 785-56-8 | MDL No. : | MFCD00000387 |
Formula : | C9H3ClF6O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WAKMMQSMEDJRRI-UHFFFAOYSA-N |
M.W : | 276.56 | Pubchem ID : | 101856 |
Synonyms : |
|
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P321-P363-P405-P501 | UN#: | 3265 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
100% | With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0℃; for 1h; | Preparation of 3, 5-bis(trifluoromethyl)benzoyl chloride (71)To a solution of <strong>[725-89-3]3,5-bis(trifluoromethyl)benzoic acid</strong> (70) (1.6 g, 6.2 mmol) and oxalyl chloride (0.6 mL, 6.8 mmol) in dichloromethane (30 mL) at 0 C was addedN? ,N? dimethylfomamide (10 drops). The solution was stirred for 1 hour. The resultant solution was concentrated in vacuo to afford 3,5-bis(trifluoromethyl)benzoyl chloride (71) (1.7g, 100%). |
With thionyl chloride; In chloroform; at 20℃; for 1.25h;Heating / reflux; | In the first instance , 3,5 -Bis trifluoro methyl benzoyl chloride which is used as one of the starting materials is prepared as follows.Thionyl chloride (576.0 g, 4.8mol) is added over a period of 15 min to a solution of3,5 -Bis trifluoro methyl benzoic acid (Lancaster) (250.0 g, 0.97mol) in chloroform (2.5 L) atroom temperature. The reaction mixture is heated to reflux temperature for lhour. The excess of thionyl chloride is removed by co-distillation with chloroform under reduced pressure atMO0 C. After the end of the distillation, the resulting 3,5-Bis trifMoro methyl benzoyl chloride is ' cooled down to room temperature and dissolved in 400 ml chloroform. A solution of 4-methyl-3-nitroaniline (92.0 g, 0.60mol) in chloroform (1.2 L) is cooled to -5 C and triethyl amine (304.8 g, 3.0mol) of is added.. 3,5-Bis trifluoro methyl benzoyl chloride in chloroform is added drop wise at -5 C over a period of 60-75 min. The resulting suspension is stirred for 1 hr at -5 C. The suspension is distilled to a residual volume of 800 ml and filtered ,washed with chilled chloroform (200ml) and dried in vacuum to give 160.0 g of novel (3,5-Bis trifluoromethyl) - N-(4rmjBmyl-3-nitro-phenyl)-)-benzamide(Xin) where R represents methyl, X-represents CH and n=2 (68%) as cream colored crystals (98.2% purity by HPLC) MR-123-130C. | |
With thionyl chloride;N,N-dimethyl-formamide; In chloroform; at 20℃; for 1.25h;Heating / reflux;Product distribution / selectivity; | In the first instance, 3,5 -Bis trifluoro methyl benzoyl chloride which is used as one of the starting material is prepared as follows:Trnqnyl chloride (2.04 kg. 17.2mol) is added over a period of 15 min to a solution of ' '3,5 -Bis trifluoro methyl benzoic acid (855.0 g, 3.3mol) and D.M.F.(9 ml) in chloroform (9 L) at room temperature. The reaction mixture is heated to reflux temperature for lhour. The excess of thionyl chloride is removed by co-distillation with chloroform under reduced pressure at 40 C. After the end of the distillation, the resulting 3,5-Bis trifluoro methyl benzoyl chloride is cooled down to room temperature and dissolved in 700 ml chloroform.A solution of N-(5-ammo-2-memylphenyl)-(3-pyridyl)-2-pyrimidine amine of the formula (XVIT) (0.73kgs, 2.64mol) in chloroform (9L) is cooled to -5 C and triethyl amine (1.03 kg, 10.2mol) of is added. 3,5-Bis trifluoro methyl benzoyl chloride in chloroform is added drop wise at -5 C over a period of 60-75 min. The resulting suspension is stirred for 1 hr at -5 C. The suspension is filtered, washed with D.M. water and methanol vacuum to give 1.3 kg of wet crude title compound which on recrystallization from methanol yielded 0.82 kgs (60%) of (3,5 - Bis trifluoromethyl)-N- [4 - methyl - 3 - (4-pyridm-3-yl-pyrimidin-2- ylamino) - phenyl] -benzamide(I) where Rrepresents methyl, X represents CH and n=2 as cream colored crystals " (99.9% purity by HPLC) MR-248-250C |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 4.5h; | To a 0 C. solution of <strong>[725-89-3]3,5-bis(trifluoromethyl)benzoic acid</strong> (129 mg, 0.50 mmol) in CH2Cl2 (1 mL) was added oxalyl chloride (0.375 mL, 0.75 mmol, 2M in CH2Cl2) and DMF (1 drop). The reaction was stirred at 0 C. for 30 min and was then warmed to RT and was stirred for 4 h. The mixture was concentrated in vacuo. To a solution of the acid chloride residue in CH2Cl2 (3 mL) was added 5-bromopyrazin-2-amine (130 mg, 0.75 mmol) and pyridine (0.061 mL, 0.75 mmol). The reaction was stirred at RT for 18 h and was diluted with CH2Cl2 (6 mL), and was washed with 0.5 N aqueous HCl (1 mL, 2×), water (1 mL), sat. aqueous NaHCO3 (1 mL), and Brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed (SiO2) to provide the Part A compound (40 mg, 19% yield) as a white solid. | |
With thionyl chloride; In chloroform; at 20℃; for 1.25h;Reflux;Product distribution / selectivity; | Thionyl chloride (576.0 g, 4.8 mol) was added over a period of 15 min to a solution of 3,5-bis trifluoro methyl benzoic acid (Lancaster) (250.0 g, 0.97 mol) in chloroform (2.5 L) at room temperature. The reaction mixture was heated to reflux temperature for 1 hour. The excess of thionyl chloride was removed by co-distillation with chloroform under reduced pressure. After the end of the distillation, the resulting 3,5-bis trifluoro methyl benzoyl chloride was cooled down to room temperature and dissolved in 400 ml chloroform. A solution of 4-methyl-3-nitroaniline (92.0 g, 0.60 mol) in chloroform (1.2 L) was cooled to -5 C. and triethyl amine (304.8 g, 3.0 mol) was added. 3,5-bis trifluoro methyl benzoyl chloride in chloroform was added drop wise at -5 C. over a period of 60-75 min. The resulting suspension was stirred for 1 hr at -5 C. The suspension was distilled to a residual volume of 800 ml and filtered, washed with chilled chloroform (200 ml) and dried in vacuum to give 160.0 g of novel (3,5-bis trifluoromethyl)-N-(4-methyl-3-nitrophenyl)-)-benzamide (68%) as cream colored crystals (98.2% purity by HPLC) MR-123-130 C. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 4h; | [0186] To the <strong>[725-89-3]3,5-bis(trifluoromethyl)benzoic acid</strong> or the 4-chloro-3- (trifluoromethyl)benzoic acid dissolved in dichloromethane, was added oxalyl chloride (1 .5 equiv.) and drops of dimethylformamide at 0 00. The reaction mixture was stirred at room temperature for 4 hours then all solvents were removed under vaccuo. The desired 4-chloro-3-(trifluoromethyl)benzoyl chloride and 3,5-bis(trifluoromethyl)benzoyl chloride were used without further purification. | |
With thionyl chloride; | To a solution of 3-Iodo-4- methyl aniline (0.7 equiv) in THF (6times) under nitrogen atmosphere was added 3,5-bis trifluoromethylbenzoyl chloride (1 equiv, prepared from the reaction of 3,5-bis trifluoromethylbenzoic acid and SOCl2) in THF at room temperature for 30minutes followed by drop wise addition of (i-Pr)2EtN (4 equiv) and 4- DMAP (0.2 equiv). After stirring at ambient temperature for 3h, the reaction mixture was quenched with water. The resulting mixture was extracted with ethyl acetate, concentrated and the compound was collected by adding hexane and filtration (44% yield). | |
With thionyl chloride; at 20 - 85℃; for 3h;Inert atmosphere; | General procedure: Synthesis of amides from the carboxylic acid: A 100 mL round bottom flask was charged with carboxylic acid (11 mmol) to which thionyl chloride (10 mL) was added dropwise under flow of argon at room temperature. The reaction mixture was refluxed for 3 h at 85 C, then the excess SOCl2 was removed in vacuo to afford the crude acid chloride on one hand, whereas in another flask solution of 8-aminoquinoline (10 mmol) and NEt3 (11 mmol) in dichloromethane (20 mL) was stirred for 10-15 minutes. Deprotonated amine was added to a solution of acid chloride at 0 C. The reaction was allowed to warm to room temperature and stirred overnight for complete conversion. Upon completion, it was quenched with saturated NaHCO3 solution and extracted with CH2Cl2 three times. These extracts were combined and dried over NaSO4. After evaporation in vacuum, the crude amide product was purified by flash column chromatography (Hexane: ethyl acetate 10:1) through silica gel. | |
With thionyl chloride; In 1,2-dichloro-ethane; at 90℃; for 4h; | Add 50 parts of <strong>[725-89-3]3,5-bis(trifluoromethyl)benzoic acid</strong> in parts by mass 15 parts of 1,2-dichloroethane, Mixing for 30 min at a low temperature of 5 C, First increase the temperature to 65 C at 3 C / min, Keep warm until mixing is uniform, Continue to ramp to 90 C at 1 C / min, Add 7 parts of thionyl chloride dropwise, Heating back, Stir the reaction for 4 h until no gas overflows. The gas is absorbed by sodium hydroxide, The product is first distilled to recover excess thionyl chloride. The 85-100 C fraction was collected by distillation under reduced pressure. <strong>[725-89-3]3,5-bis(trifluoromethyl)benzoic acid</strong> chloride was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.8% | With Caswell No. 744A In water monomer; acetone at 0 - 20℃; | Synthesis of carbonyl azides General procedure: To a solution of sodium azide (910 mg, 1.4 equiv.) in water (21 mL) was added a solution of benzoylchloride (10 mmol, 1.0 equiv.) in acetone (15 mL) dropwise at 0 °C. The resulting mixture was warmedup to room temperature and stirred for overnight. Evaporated acetone under reduced pressure andextracted with EtOAc. The resulting organic layer was washed with water twice, dried over MgSO4,filtered, and evaporated. The resulting crude mixture was purified by a silica gel column chromatography(hexane). |
58% | With Caswell No. 744A In water monomer; acetone at 0℃; for 0.5h; | |
With Caswell No. 744A In water monomer; acetone at 20℃; for 11h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 83 percent Chromat. / HCOONH4 / Ru3(CO)12 / dioxane / 20 h / 160 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Into a 1-L autoclave, were charged 100 g (0.36 mol) of 3,5-bis(trifluoromethyl)benzoyl chloride produced in the same manner as in Example 3, 350 g of dry toluene, 90 g (1.08 mol) of anhydrous sodium acetate and 10.9 g of 10percent palladium-carbon. After adding 21.7 g (0.17 mol) of quinoline and 3.6 g (0.11 mol) of sulfur, the contents were refluxed under heating for 5 h. Then, quinoline-S diluted by dry xylene to 250 ml was added. After evacuating the autoclave, the inner pressure was adjusted to 1 MPa by introducing hydrogen. While successively supplying hydrogen to maintain the inner pressure at 1 MPa, the contents were stirred at room temperature for one hour. The temperature was raised to 50°C and the stirring was continued for 2 h. Then, the temperature was returned to room temperature and the stirring was continued for 24 h to complete the reaction. After returning the inner pressure to atmospheric pressure, the reaction product solution was filtered and then washed with toluene. The filtrate was successively washed with a 5percent sodium carbonate aqueous solution and water, and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration and toluene by distillation, the obtained product was analyzed by gas chromatography. It was confirmed that 65.4 g (0.27 mol) of the aimed 3,5-bis(trifluoromethyl)benzaldehyde was produced (yield: 76percent). By vacuum distillation, 63.0 g (0.27 mol) of 3,5-bis(trifluoromethyl)benzaldehyde was isolated (yield: 72percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In toluene at 20℃; for 3h; | A1.a Example A; a. Preparation of intermediate compound 1; Et3N (0.55 mol) was added to a stirring mixture of 7-(phenylmethyl)-1,4-dioxa-8- azaspiro [4.5]decane (prepared according to teachings in W097/24350 of which the content is herein included by reference) (0.5 mol) in toluene (1500 ml). 3,5- Bis (trifluoromethyl)benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then allowed to stand for the weekend and washed three times with water (500 ml, 2 x 250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 245 g of fraction 1 (100 %). Part of this fraction was crystallized from petroleum ether. The precipitate was filtered off and dried, yielding 1.06 g of intermediate compound |
100% | In toluene at 20℃; | A1.a Preparation of the intermediate compounds [EXAMPLE A1] a. Preparation of intermediate compound 1 Preparation of the intermediate compounds [EXAMPLE A1] a. Preparation of intermediate compound 1 Et3N (0. [55] mol) was added to a stirring mixture [OF 7-(PHENYLMETHYL)-1, 4-DIOXA-8-] azaspiro [4.5] decane (0.5 mol) in toluene [(1500ML).] 3,5-Bis (trifluoromethyl) benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then allowed to stand for the weekend and washed three times with water [(500ML,] 2x250ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yielding: 245g [(100%).] Part of this fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yielding: 1.06g of intermediate compound 1. |
100% | With triethylamine In toluene at 20℃; for 3h; | A1.a A. Preparation of the intermediate compounds Example Al a. Preparation of intermediate compound 1 Et3N (0.55 mol) was added to a stirring mixture OF 7- (PHENYLMETHYL)-1, 4-dioxa-8- azaspiro [4. 5] DECANE (0.5 mol) in toluene (1500ML). 3,5-Bis (trifluoromethyl) benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then allowed to stand for the weekend and washed three times with water (500 ml, 2x250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yielding : 245 g (100%). |
100% | With triethylamine In toluene at 20℃; | A.A1.a Et3N (0.55 mol) was added to a stirring mixture of 7- (phenylmethyl)-1, 4-dioxa-8- azaspiro [4.5] decane (0.5 mol) in toluene (1500ml). 3,5-Bis (trifluoromethyl) benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then allowed to stand for the weekend and washed three times with water (500 ml, 2x250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245 g (100%). Part of this fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 1.06 g of intermediate compound 1. |
100% | With triethylamine In toluene at 20℃; | A.A1.a Et3N (0.55 mol) was added to a stirring mixture OF 7-(PHENYLMETHYL)-1, 4-dioxa-8- azaspiro [4.5] decane (0.5 mol) in toluene (1500 ml). 3,5-Bis (trifluoromethyl) benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then allowed to stand for the weekend and washed three times with water (500 ml, 2x250 ML). The organic layer was separated, dried, filtered and the solvent was evaporated. Yielding: 245 g (100%). Part of this fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yielding: 1.06 g of intermediate compound 1. |
100% | With triethylamine In toluene at 20℃; for 48h; | A.A1.a Et3N (0.55 mol) was added to a stirring mixture OF 7-(PHENYLMETHYL)-1, 4-dioxa-8- azaspiro [4.5] decane (0.5 mol) in toluene (1500 ml). 3,5-Bis (trifluoromethyl) benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, allowed to stand for the weekend and washed three times with water (500 ml, 2x250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245 g (100%). Part of this fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 1.06 g of intermediate compound 1. |
50% | With triethylamine In toluene at 20℃; | A1.a Example Al; a. Preparation of intermediate compound 1; Et3N (0.55 mol) was added to a stirring mixture of 7-(phenyhnethyl)-1,4-dioxa-8- azaspiro [4.5]decane (0.5 mol) in toluene (1500 ml). 3,5-Bis(trifluoromethyl)benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then allowed to stand for the weekend and washed three times with water (500 ml, 2 x 250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated yielding 245 g (100 %). Crystallization of 2 gram of this fraction from petroleum ether yielded 1 g of intermediate compound 1. (50 %). |
50% | With triethylamine In toluene at 20℃; | A1.a Example Al a;. Preparation of intermediate compound 1; Et3N (0.55 mol) was added to a stirring mixture of 7-(phenylmethyl)-1,4-dioxa-8- azaspiro [4.5]decane (0.5 mol) in toluene (1500 ml). 3,5-Bis(trifluoromethyl)benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then allowed to stand for the weekend and washed three times with water (500 ml, 2x250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245 g (100 %). Crystallization of 2 gram of this fraction from petroleum ether yielded 1 g of intermediate compound 1. (50 %). |
50% | With triethylamine In toluene at 20℃; | A1.a Et3N (0.55 mol) was added to a stirring mixture of 7-(phenylmethyl)-l,4-dioxa-8- azaspiro[4.5]decane (0.5 mol) in toluene (1500 ml). 3,5-Bis(trifluoromethyl)benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then allowed to stand for the weekend and washed three times with water (500 ml, 2x250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245 g (100 %). Crystallization of 2 gram of this fraction from petroleum ether yielded 1 g of intermediate compound 1. (50 %). |
With triethylamine In toluene at 20℃; | A1.a Example Al a. Preparation of intermediate compound 1Et3N (0.55 mol) was added to a stirring mixture of 7-(phenylmethyl)-l,4-dioxa-8- azaspiro[4.5]decane (0.5 mol) in toluene (1500 ml). 3,5-Bis(trifluoromethyl)benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then allowed to stand for the weekend and washed three times with water (500 ml, 2x250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245 g (100 %). Crystallization of 2 gram of this fraction from petroleum ether yielded 1 g of intermediate compound 1. (50 %). | |
With triethylamine In toluene at 20℃; | A.1.a Et3N (0.55 mol) was added to a stirring mixture of 7-(phenyhnethyl)-1,4-dioxa-8- azaspiro [4.5]decane (0.5 mol) in toluene (1500 ml). 3,5-Bis(trifluoromethyl)benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, allowed to stand for the weekend and washed three times with water (500 ml, 2x250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245 g (100 %). Part of this fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 1.06 g of intermediate compound 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With 2-(Dimethylamino)pyridine; triethylamine In dichloromethane at 20℃; for 144h; | DESCRIPTION 7 (1R*,2R*,5S*,6R*)-8-Benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-1-phenyl- 6-phenylsulphonyl-8-azabicyclo [3.2.1] octane A solution of [(1] R*,2R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8- azabicyclo [3.2. 1] octanol (Description 4; 0.98g, 2. [25MMO1),] triethylamine (0. [6MUT),] N, N-dimethylaminopyridine (100mg) and 3, 5-bis [(TRIFLUOROMETHYL) BENZOYL] chloride (0. 6ml, 3. [33MMOL)] in dry dichloromethane [(1 OML)] was stirred at room temperature for 6 days. The reaction mixture treated with saturated aqueous [NAHCO3] and extracted with [DICHLOROMETHANE.] The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane: ethyl acetate 5-30%) to give the title compound (1.05g, [69%).] [8F,] (400 MHz, CDCl3) : 8.38 (2H, s), 8.03 [(1 H,] s), 7.77 (2H, dd, J 1.3Hz, 7.2Hz), 7. [64-7.] 59 (3H, m), 7.50-7. 43 (5H, m), 7.37-7. 22 (4H, m), 5.83 (1H, m), 4.19 [(1H,] d, J 14. 6Hz), 4.06 (1 H, d, J 14. 6Hz), 3.97 (1H, br s), 3.51 (1 H, dd, [J 5.] 4Hz, 9.3Hz), 2.58 (1H, dd, J5. 4Hz, 14.4Hz), 2.34 (1H, dd, J9. 3Hz, 14.4Hz 2.32-2. 00 (3H, m), 1.11 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With dmap; triethylamine In dichloromethane at 20℃; for 20h; | 32 DESCRIPTION 32 (1 R*, 2R*, 5S*, 6R*)-8-benzyl-2-[3, 5-bis(trifluoromethyl)benzoyloxy]-6-cyano-1-phenyl-8-azabicyclo[3. 2. 1] octane 3,5-Bis (trifluoromethyl) benzoyl chloride (2. 76g, 10mmol) was added dropwise to an ice-cold solution of [(1] R*,2R*,5S*,6R*)-8-benzyl-6-cyano-1-phenyl-8- [AZABICYCLO [3.] 2.1] octanol (Description 31; 3g, 9. [4MMOL),] triethylamine (2g, [20MMOL) AND 4-N, N-DIMETHYLAMINOPYRIDINE] (200mg, [1.] [6MMOL)] in [DICHLOROMETHANE] [(30MOI).] The mixture was stirred at room temperature for 20 hours. The mixture was concentrated in vacuo then partitioned between ethyl acetate and brine. The organics were separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 10 and 20% ethyl acetate/iso- hexanes to afford the title compound (4.87g, 93%). 8H [(400MHZ,] CDCl3) : 8.45 (2H, s), 8.07 (1 H, s), 7.57-7. 21 [(1 OH,] m), 5.72 (1 H, s), 4.27 (1H, d, [J 15. OHZ),] 4.09 (1H, d, J15. 0Hz), 3.95 (1H, s), 2.96 (1H, dd, J 4.6Hz, 9.4Hz), 2.59 (1 H, dd, [J 9.] 4Hz, 13.9Hz), 2.42 (1 H, dd, [J 4.] 5Hz, 13.9Hz), 2.36-2. 01 (3H, m), 1.39-1. 33 (1 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine In dichloromethane at 0 - 20℃; for 1h; | 11.1 Step 1: Treat a suspension of sarcosine methyl ester hydrochloride (6.02 g, 43 mmole) in CH2Cl2 (250 ml) at 0°C with 3,5 - bistrifluoromethyl benzoyl chloride (7.7 ml, 42.5 mmole) and Et3N (12.5 ml, 89.7 mmole). Stir the mixture at 20°C for 1 h. Add water (150 ml) to the mixture and separate the organic layer. Dry (MgSO4) and concentrate the organic layer to give crude product. Purify by silica gel chromatography (eluant: EtOAc:hexane (6:4)) to obtain the product 12 g (81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 20.0℃; for 6.0h; | 2-Amino-5-iodo-4-trifluoromethylthiazole (1.0 g) was dissolved in pyridine (2 ml) and 3,5-bis-trifluoromethylbenzoylchloride (0.95 g) was added at room temperature with stirring. The mixture was stirred for 6 hr at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-iodo-4-trifluoromethylthiazol-2-yl)-3,5-bis-trifluoromethylbenzamide (1.3 g), m. p. 172-173 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In benzene; at 20℃; for 2h; | Step A: Synthesis of N-(cis-4-amino-cyclohexyl)-3,5-bistrifluoromethyl-benzamide trifluoroacetate. To a solution of <strong>[247570-24-7]cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester</strong> (2.18 g, 10 mmol) in anhydrous benzene (25 mL) was slowly added 3,5-bistrifluoromethyl benzoyl chloride (2.8 g, 1 eq.) and followed by Et3N (~3mL) at room temperature under N2 atmosphere: formation of solid salts makes stirring difficult. The reaction was stirred vigorously for an additional 2 h at room temperature, washed with sat.-NaHCO3 (3x) and water (1x), dried with MgSO4, and concentrated to give [cis-4-[(3,5-bistrifluoromethyl-benzoylamino)-cyclohexyl]-carbamic acid tert-butyl ester (4.5 g, 99 %), which was used for the next reaction without further purification. ESI MS m/e 455 (M + H)+;1H NMR (400 MHz, CDCl3) delta 8.16 (s, 2 H), 7.98 (s, 1 H), 6.12 (bs, 1 H), 4.58 (bs, 1 H), 4.11 (m, 1 H), 3.69 (bs, 1 H), 1.95~1.65 (m, 8 H), 1.44 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine In ethyl acetate at -10℃; for 0.333333h; | 10.1 (1) Synthesis of N-(2-hydroxyphenyl)-3,5-bistrifluoromethylbenzamide (IV-j) To a 50mL round-bottomed flask was added o-aminophenol II-a (545mg, 5.0mmol), ethyl acetate (20mL) and pyridine (413μL, 5.5mmol) in sequence, at -10°C (-10°C)3,5-bistrifluoromethylbenzoyl chloride III-j (906 μL, 5.0 mmol) was added dropwise under conditions. After the dropwise addition was complete, stirring was continued for about 20 minutes, and the reaction was monitored by TLC until the reaction was complete. 10% HCl solution (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate in a separatory funnel (three times, 100 mL each). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether=1:4) to obtain N-(2-hydroxyphenyl)-3 ,5-bistrifluoromethylbenzamide (IV-j), pale pink solid, 1.48 g, yield: 85%. |
73.6% | With pyridine; sodium hydroxide In ethanol; dichloromethane | 11 Example 11 Example 11 3,5-Bis(trifluoromethyl)-N-(2-hydroxyphenyl)benzamide (Comopund No. 11). 2-Aminophenol(120mg, 1.1mmol) was dissolved in dichloromethane(5mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride(300mg, 1.1mmol) in dichloromethane(3mL) and pyridine(0.5mL) was added dropwise under ice cooling and argon atomosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol(5mL), added dropwise 2 N sodium hydroxide(0.1mL, 0.2mmol), and stirred at room temparature for 30 minutes. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(288mg, 73.6%) as a light pink crystal. mp 183ØC (dec.). 1H-NMR(DMSO-d6, δ): 6.83(1H, td, J=8.0, 1.2Hz), 6.93(1H, dd, J=8.0, 1.2Hz), 7.08(1H, td, J=8.0, 1.6Hz), 7.50(1H, d, J=8.0Hz), 8.35(2H, s), 9.61(1H, s), 10.15(1H, s). |
73.6% | With pyridine In dichloromethane at 0 - 20℃; for 1h; | 11 2-Aminophenol(120mg, 1.1mmol) was dissolved in dichloromethane(5mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride(300mg, 1.1mmol) in dichloromethane(3mL) and pyridine(0.5mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. 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 magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol(5mL). 2N Sodium hydroxide(0.1mL, 0.2mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. 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 solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(288mg, 73.6%) as a light pink crystal. mp 183°C(dec.).1H-NMR(DMSO-d6): δ 6.83(1H, td, J=8.0, 1.2Hz), 6.93(1H, dd, J=8.0, 1.2Hz), 7.08(1H, td, J=8.0, 1.6Hz), 7.50(1H, d, J=8.0Hz), 8.35(2H, s), 9.61(1H, s), 10.15(1H, s). |
73.6% | With pyridine In dichloromethane at 20℃; for 1h; | 11 2-Aminophenol(120mg, 1.1mmol) was dissolved in dichloromethane(5mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride(300mg, 1.1mmol) in dichloromethane(3mL) and pyridine(0.5mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. 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 magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol(5mL). 2N Sodium hydroxide(0.1mL, 0.2mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. 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 solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(288mg, 73.6%) as a light pink crystal. mp 183°(dec.).1H-NMR(DMSO-d6): δ 6.83(1H, td, J=8.0, 1.2Hz), 6.93(1H, dd, J=8.0, 1.2Hz), 7.08(1H, td, J=8.0, 1.6Hz), 7.50(1H, d, J=8.0Hz), 8.35(2H, s), 9.61(1H, s), 10.15(1H, s). |
73.6% | With pyridine In dichloromethane at 0 - 20℃; for 1h; | 11 2-Aminophenol(120mg, 1.1mmol) was dissolved in dichloromethane(5mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride(300mg, 1.1mmol) in dichloromethane(3mL) and pyridine(0.5mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. 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 magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol(5mL). 2N Sodium hydroxide(0.1mL, 0.2mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. 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 solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(288mg, 73.6%) as a light pink crystal. mp 183°C(dec.).1H-NMR(DMSO-d6): δ 6.83(1H, td, J=8.0, 1.2Hz), 6.93(1H, dd, J=8.0, 1.2Hz), 7.08(1H, td, J=8.0, 1.6Hz), 7.50(1H, d, J=8.0Hz), 8.35(2H, s), 9.61(1H, s), 10.15(1H, s). |
With pyridine In xylene at 20℃; for 1h; | ||
With pyridine In ethyl acetate at -10℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine In 1,1-dichloroethane at 20℃; for 20h; | 310 Example 310; 1-f4-r2-Benzvl-1-(3.5-bis-trifluoromethvl-ben2oyl)-piperidin-3-vlamino1-piperidin-1-vl>-ethanone:; A solution of 640 mg (2.03 mmol) 1-[4-(2-Benzyl-piperidin-3-ylamino)-piperidin-1-yl]-ethanone in 56 ml dichloroethane was treated with 1.13 ml (8.12 mmol) triethylamine, 68 mg (0.12 mmol) PS-DMAP followed by 0.37 ml (2.03 mmol) 3,5-Bis-trifluoromethyl-benzoyl chloride at room temperature for 20 hours. The reaction mixture was diluted with methylene chloride. The organic phase was washed with water and saturated brine. The organic phase was then dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (elution with 5% methanol in methylene chloride with 1 ml/100ml of cone ammonium hydroxide) to afford 1.0 gm (89 %) of a pale yellow foam. Mass spectrum APCI m/z = 556 (p+1) This compound is a mixture of cis and trans isomers which was separated by chiral chromatography into a mixture of cis and trans enantiomeric pairs. Chiralcel OD (4.6mmX25 cm) 80 / 20 Heptane / EtOH at 1 ml/min. Retention times: 6.0 min, 6.8 min, 7.5 min and 9.3 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: (3R,7R,8aS)-7-(tert-butyl-diphenylsilanyloxy)-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione With lithium aluminium tetrahydride In tetrahydrofuran Heating / reflux; Stage #2: With sodium hydroxide; water In tetrahydrofuran Stage #3: 3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethyl acetate at 20℃; | 2.3 To a suspension of lithium aluminium hydride (1.8 g) in THF (120 mL) was added a solution of (3R, 7R, 8aS)-7- (tert-butyl-diphenylsilanyloxy)-3- (lH-indol-3- ylmethyl)-hexahydropyrrolo [1,2-a] pyrazine-1,4-dione (4.6 g) in THF (35 mL). The resulting mixture was heated under reflux overnight, then a mixture of water (1.8 mL) and THF (30 mL) was added dropwise followed by aqueous sodium hydroxide (2 M, 2 x 1.8 mL). The formed salts were removed by filtration and the remaining solution was concentrated in vacuo. The residue was suspended in ethyl acetate (100 mL) and THF (20 mL), diisopropylethylamine (5 mL) and 3,5-bis (trifluoromethyl) benzoyl chloride (2 mL) were added and the mixture stirred at room temperature overnight. The mixture was extracted with water, dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, MTBE/hexanes 2: 1) to afford 3,5-bis (trifluoromethyl) benzoic acid (3R, 7R, 8aS)-2- (3, 5-bis (trifluoromethyl) benzoyl)- 3-(1H-indol-3-ylmethyl)-octahydro-pyrrolo [1,2-a] pyrazin-7-yl ester (4.2 g, 65%). MH+ 752 (intermediate 8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With hydrogen sulfide;palladium; In quinoline; water; toluene; | Example 1 60 g of freshly distilled quinoline and 10 g of sulfur were refluxed for 5 hours with stirring. The cooled mixture was diluted with 700 ml of toluene. This gave a solution of a quinoline-sulfur complex containing 100 mg of the complex per ml. 2.5 g of 5percent palladium on barium sulfate, 0.25 ml of the solution of the complex and 250 g of 3,5-bis(trifluoromethyl)benzoyl chloride were placed in a reaction vessel at room temperature with exclusion of water. A gentle stream of hydrogen gas was then passed through the mixture at atmospheric pressure. The mixture was subsequently heated to 100-110° C. and hydrogen gas was continuously introduced at atmospheric pressure. After liberation of acidic offgases had ceased (12 hours), the mixture was cooled, the catalyst was separated off by filtration, and the filtrate was distilled at 27 mbar. A yield of 190.0 g of 3,5-bis(trifluoromethyl)benzaldehyde having a boiling point of 79° C. was obtained. This corresponds to a yield of 86percent of theory. A small amount of a mixture of toluene and 3,5-bis(trifluoromethyl)benzene was obtained as first fraction during the distillation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogenchloride; triethylamine In methanol; dichloromethane | 32 Rac-cis-1-{4-[1-(3,5-Bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone Rac-cis-1-[4-(1-benzyl-3-phenyl-piperidin-4-yl)-piperazin-1-yl]-2,2,2-trifluoro-ethanone (4.60 g, 10.7 mmol) was dissolved in methanol (200 mL) and concentrated hydrochloric acid (1.0 mL) and palladium on charcoal (10%, 700 mg) were added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The crude intermediate was dissolved in dichloromethane (100 mL) and triethylamine (7.25 mL, 51.7 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (2.06 mL, 11.4 mmol) were added. The reaction mixture was stirred at room temperature overnight and than diluted with 100 mL water. The organic phase was separated and the aqueous layer was extracted twice with 100 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with hexane/ethyl acetate/triethyl amine 90:10:1 gave the desired product (5.26 g, 87%) as a white foam, MS: m/e=582.0 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 4h; | [00187] Benzyl (41?)-4-((3i?)-3-[3,5-bis(trifluoromethyl)benzoyl]amino}pyrrolidin-l-yl)azepaiie- 1-carboxylate and benzyl (45)-4-((3/..)-3-[3,5-bis(trifluoromethyl)benzoyl]ammo}pyrrolidin-l- yl)azepane-l-carboxylate ; [00188] To a solution of (3R)-l-benzylρyrrolidin-3-amine (5.00 mL, 28.9 mmol) and Hunig's base (12.6 mL, 723 mmol) in methylene chloride (37 mL) was added a solution of 3,5- bis(trifluoromethyl)benzoyl chloride (5.21 mL, 28.9 mmol) in methylene chloride (5 mL) at 0 0C. The reaction mixture was warmed to RT and stirred for 4 hours. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[(3R)-l-benzylpyrrolidin-3-yl]-3,5- bis(trifluoromethyl)benzamide (11.1 g, 92%). 1H-NMR (CDCl3) δ: 1.70-1.82 (m, IH), 2.22-2.46 (m, 2H), 2.60 (dd, / = 9.9, 6.3 Hz, IH), 2.70-2.80 (m, IH), 2.90-3.01 (m, IH), 3.59-3.70 (m, 2H), 4.57-4.71 (m, IH), 6.58-6.70 (m, IH), 7.20-7.37 (m, 5H), 7.97 (s, IH), 8.17 (s, 2H). MS m/z: 417 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: (+)-(3R,4R)-3-aminomethyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester; 3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride With triethylamine In dichloromethane at 0 - 20℃; for 1h; Stage #2: With sodium hydroxide In dichloromethane; water | 16.b To a solution of 0.36 g (1.3 mmol) (+)-(3R,4R)-3-aminomethyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 0.22 ml (1.6 mmol) triethylamine in 6.5 ml dichloromethane were added 0.26 ml (1.4 mmol) 3,5-bis(trifluoromethyl)benzoyl chloride at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for one hour. Quenching with water was followed by basification with 1 M aqueous sodium hydroxide solution and extraction with three portions of methyl tert.-butyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.62 g (92%) of the title compound as a white solid. MS m/e (%): 517 (M+H+, 21) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In acetonitrile at 0 - 20℃; for 14h; | 2.7 (Step 7) To a solution of the compound (2.81 g) obtained in step 6 and triethylamine (1.2 mL) in acetonitrile (20 mL) was added 3,5-bis(trifluoromethyl)benzoyl chloride (1.10 g) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give the title compound (4.67 g, 98%) as a white powder.MS (ESI+): 529 (M-tBu+2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In ethyl acetate at 20℃; | 5 8-(3, 5-trifluoromethyl-benzoyl)-3-[(R)- 1-phenyl-ethyl]-1-oxa-3, 8-diazaspiro[4.6]undecan-2-one 31 (1R, ctfnfl)). Io a solution of compound 7a (1R, confl) (4.5g, 15.9 mmol) and triethylamine (3.3 ml, 23.9 mmol) in ethyl acetate (80ml) was slowly added and 3,5-(bis trifluoromethyl) benzoyl chloride (3,44 ml, 19.01 mmol). The mixture was stirred for 16 hrs at room temperature after which time TLC analysis showed complete reaction to one product (TLC eluent: DCM/MeOH, 99/1, v/v). Water was added (50 ml) and the water layer was extracted with DCM (2* 100 ml). The combined organic layers was. washed with water (100 ml), dried on MgSO4 and evaporated to dryness. The residue was purified by slica gel column chromatography (eluent: DCM/MeOH, 99/1, v/v) to give compound 31 as an oil (7.7g, 91%). LC-MS: room temperature 2.2 minutes, [M+H]+ 515.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In dichloromethane; water at 20℃; for 1.5h; | 5 Example 5: Pyridine~2«carboxylic acid ((S)-3-f(3.5"bts-trifluoromethyl-benzoyl)-methyl- amino1-4-phenv3- and NaCI-soln , dried (Na;SO«), filtered and concentrated. The crude product was punfted by chromatography {Flashmaster, Hex to Hex EtOAc 3 7 over 35 mm ) to yield 0 21 g (75%) of the title compound as white solid [1 H- NMR (DMSO, 600 MHz) 8 88/8 87 (t, 1H), 8 63/8 57 (d, 1H), 8 13/7 89 (S1 1H)1 8 02-7 92(m, 2H), 7 59-7 57 (m. 1H), 7 51/7 26 (s, 1H)1 7 30-7 06 (m, 6H) 4 94/3 56 (br s, 1H), 3 43-3 16 (m, 2H)1 3 03/2 63 (s, 3H), 2 98-2 80 (m, 2H), 1 99-1 81 (m, 2H), LCMS Rtc = 3 087 mm, (M+Hf ~ 524 0] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate In dichloromethane; water at 20℃; for 1.5h; | 12 Example 12: i-MethvHH-benzoirnidazole^-carboxylic acid f(S)-3-f(3,5-bis- trifluoromethyl-banzoyl)°methyl-amino1-4'βhenvi-butyl>;-arr>;ide:To a solution of 1 - methyl- 1 H-benzoιmtdazole-2-carboxylιc acid ((S)-3-methylamιno-4-pheny.- butyO-amide hydrochloride (100 mg, 0 24 mmol) and 3,5-bιs-trιfluoromethyl-benzoyl chloride - 51 -(74 mg, 0 27 mmol) in DCM (8 ml), potassium carbonate (145 mg 1 05 mmol) in 2 5 mi of water was slowly added and the reaction mixture was stirred at rt for 1 5 h Then, the mixture was diluted with EtOAc, washed with NaHCO3- and NaCI-soln dried (Na2SO11), filtered and concentrated The crude product was purified by chromatography (Flashmaster, Hex to Hex EtOAc 3 7 over 35 mm ) to yield 1 18 mg (84%) of the title compound as white solid. [1 H- NMR (DMSO, 600 MHz) 9 02-8 98 (m, 1H) 8 14/7 91 (s, 1H), 7 72-7 65 (m, 2H), 7 56 (s, 1H)1 7 38 (dd, 1H) 7 32-7 22 (m, 5H) 7 14 (br s, 1H), 7 08 (br s 1H), 4 95/3 61 (br s, 1H) 4 09/4 07 (s 3H), 3 48-3 17 (m, 2H), 3 04/2.65 (s, 3H), 2 97-2 78 (m, 2H), 2 04-1 63 (m 2H), LCMS Rtc = 3 393 mm IM+H]* - 577 0] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In dichloromethane; water at 20℃; for 1.5h; | 10 Example 10: Fvridine-2-carboxyKc acid ^S)-3-ff3tS»bis-trifluoromethyl-ben2θvn»ethvi- aminot-4-phenvI-butvlV-amtde:To a solution of pyndme-2-carboxylιc acid ((S)-3-ethylamιno-4-phenyl-butyl)-amιde hydrochloride (150 mg, 0 45 mmol) and 3,5-bιs-trιfluoromethyl-benzoyl chloride (137 mg, 0 49 mmol) in DCM (8 ml) potassium carbonate (267 mg, 1 93 mmol) in 2 5 ml of water was slowly added and the reaction mixture was stirred at rt for 1 5 h Then, the mixture was diluted with EtOAc washed with NaHCO3- and NaCI-soln , dried (Na2SO4), filtered and concentrated The crude product was punfied by chromatography (Fiashmaster, Hex to Hex.EtOAc 3:7 over 35 mm.) to yield 0.21 g (87%) of the title compound as white solid. [1H- NMR (DMSO 600 MHz) 8 95/8.76 (t, 1 H)1 8.64/8.56 (br s, 1H), 8.14/7 89 (S1 1H), 8 04-7.92 (m. 2H), 7 60-7,03 (m, 8H), 3 70-3 05 (m, 5H), 2 87 (d, 2H), 2.10-1.80 (m, 2H), 1 29/0 78 (t, 3H), LCMS Rtc = 3.226 min, (M+Hf * 538 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: quinoclamine With sodium hydride In tetrahydrofuran; mineral oil for 0.333333h; Stage #2: 3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride In tetrahydrofuran; mineral oil at 20℃; for 4h; | 5 Example 5: 2-(3,5-bistrifluoromethyl)benzamido-2-chloronaphthoquinone (33): A mixture of 2-amino-3-chloronaphthoquinone (207 mg, 1 equiv.) and NaH (48 mg, 1.2 equiv.; 60% dispersion in mineral oil) in THF was stirred vigorously for 20 min. and 3,5- bistrifluoromethylbenzoyl chloride (200 μL, 1.1 equiv.) was added gradually and stirred at room temperature for an additional 4 h. The reaction mixture wsa queched with saturated aqueous ammonium chloride (20 mL) and the organic layer was extracted with EtOAc (2x 20 mL). The solvent was evaporated and the crude product was purified by flash column chromatography over silica gel (eluent: 15% EtOAc/hexanes).Yield: 380 mg, 85%; R/ (3:7 EtOAc/hexanes): 0.85 (UV active); 1H NMR (400 MHz, CDCl3): δ, 8.38 (s, 2H, H-2',6'), 8.32 (br s, IH, NH), 8.20 (ddd, /=7.8, 4.4 & 1.4 Hz, IH, H- 5), 8.15 (ddd, /=7.8, 4.4 & 1.4 Hz, IH, H-8), 8.12 (s, IH, H-4'), 7.77 (ddd, /=7.8, 7.5 & 1.4 Hz, 2H, H-6,7); MALDI-TOF: m/z, 448 (100%, MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 17h; | General procedure: purification. To the 4-chloro-3-(trifluoromethyl)benzoyl chloride or the 3,5- bis(trifluoromethyl)benzoyl chloride in dry dichloromethane was added the 4- (4-am inophenoxy)-N-methylpyrid ine-2-carboxam ide (1 equ iv.) and diisopropylethylamine (DIPEA) (3 equiv.). The mixture was stirred at room temperature for 17 hours then the solvent was concentrated under vaccuo. The crude reaction mixture was purified by column chromatography (dichloromethane/methanol) to provide the 4-(4-(3,5-bis-(trifluoromethyl)- phenylamidophenoxy)-N-methylpyridine-2-carboxamide (SRSI 4-95) and 4-(4-(4-chloro-3-(trifluoromethyl)phenylam ido)phenoxy)-N-methylpyrid ine-2- carboxamide (SRSI 5-1 1), respectively. |
With pyridine In tetrahydrofuran at 20℃; for 2h; | 6.2.2. General procedures for the synthesis of compounds 2-25 In a 25 mL two-necked round flask, aniline derivatives (1 mmol) and catalytic amount of pyridine were placed in anhydrous THF (10 mL) at room temperature. Acyl chloride or sulfonyl chloride compounds were added to the mixture and stirred for 2 h at room temperature. The solvent was removed under vacuum and the crude residue purified by chromatography on a silica gel column using EtOAc/Hexane as eluent (1/10 to 1/2). This procedure afforded the expected coupling product as a white solid from 70% to 95% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In ISOPROPYLAMIDE; at 20℃; for 5h; | (i) Methyl 2-([3,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-5-chlorobenzoate Under ice-cooling, 660 mg (3.56 mmol) of <strong>[5202-89-1]methyl 2-amino-5-chlorobenzoate</strong> was added to a DMAc (10 mL) solution comprising 1.00 g (3.62 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was stirred for a short time. Thereafter, the precipitates were collected by filtration, washed with water, and then air-dried, thereby giving methyl 2-([3,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-5-chlorobenzoate (yield: 99%). 1H-NMR (CDCl3) delta: 4.01 (3H, s), 7.60 (1H, dd, J=9.0, 2.6 Hz), 8.09-8.10 (2H, m), 8.48 (2H, s), 8.85 (1H, d, J=9.0 Hz), 12.29 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In 1,4-dioxane at 20℃; Inert atmosphere; | 4.1.1. General procedure for the preparation of the substituted benzamide 1-39 General procedure: K2CO3 (5 mmol, 5eq) and substituted acyl chloride (1.2 mmol, 1.2 eq) were successively added to a solution of the aniline e (1.0 mmol, 1.0 eq) in 3 mL dry 1, 4 -dioxane and the mixture was stirred at room temperature overnight. 10 mL H2O and 3 mL saturated aqueous Na2CO3 was added to the mixture and it was stirred at room temperature overnight. The precipitated solid was collected by filtration and purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 24h; | 4.1.2. Synthesis of tert-butyl 4-(aryloyl)piperazine-1-carboxylate (3a-3d) General procedure: To a solution of 1-Boc-piperazine 2 (5.37 mmol) in CH2Cl2 was added DIPEA (10.74 mmol) and acyl chloride (8.06 mmol). The reaction mixture was stirred for 24 h. After reaction, the mixture was diluted with satd NaHCO3, extracted with CH2Cl2, dried MgSO4. The crude compound was purified by column chromatography (SiO2, Hexane/EtOAc = 2:1) to afford the desired compound 3a-3d as yellow oil in 66-99% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.7% | Stage #1: (6-chloro-4-iodopyridin-3-yl) methylamine With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; Stage #2: 3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride In tetrahydrofuran at -78 - 20℃; | 72 To a solution of (6-chloro-4-iodo-pyridin-3-yl)-methyl-amine (300 mg, 1.12 mmol, prepared according to WO2006013050) in THF (3 mL) was added dropwise at -78° C. lithium bis(trimethylsilyl)amide (1M solution in THF, 1.17 mL, 1.17 mmol). The reaction mixture was stirred at -78° C. for 30 minutes. Then, 3,5-bis(trifluoromethyl)benzoyl chloride (340 mg, 1.23 mmol, CAS RN 1271-19-8) was added at -78° C. and the reaction was stirred for 30 minutes at this temperature. The reaction mixture was allowed to warm to room temperature, stirred for another 1 hour and then poured on 30 mL H2O and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). Colorless solid (328 mg, 57.7%). MS (TurboSpray): m/z=508.0 [M+H]+. |
57.7% | With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; | 72 To a solution of (6-chloro-4-iodo-pyridin-3-yl)-methyl-amine (300 mg, 1.12 mmol, prepared according to WO2006013050) in THF (3 mL) was added dropwise at -78 °C lithium bzs(trimethylsilyl)amide (1M solution in THF, 1.17 mL, 1.17 mmol). The reaction mixture was stirred at -78 °C for 30 minutes. Then, 3,5-bzs(trifluoromethyl)benzoyl chloride (340 mg, 1.23 mmol, CAS RN 1271-19-8) was added at -78 °C and the reaction was stirred for 30 minutes at this temperature. The reaction mixture was allowed to warm to room temperature, stirred for another 1 hour and then poured on 30 mL H20 and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgS04, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane : EtOAc (100 : 0 to 70 : 30).Colorless solid (328 mg, 57.7%). MS (TurboSpray): m/z = 508.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 4,7-dihydro-1H-indole With methyl magnesium iodide In tetrahydrofuran; diethyl ether at 20℃; for 1h; Inert atmosphere; Reflux; Stage #2: 3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; | (3,5-Bis(trifluoromethyl)phenyl)(4,7-dihydro-1H-indol-2-yl)methanone (5) To a solution of 4 (472 mg, 3.96 mmol) in THF (40 mL), MeMgI (1.61 M in ether, 2.70 mL, 4.35 mmol) was added dropwise at room temperature. After the mixture was refluxed for 1 h and cooled to room temperature, 3,5-bis(trifluoromethyl)benzoyl chloride (790 μL, 4.36 mmol) was added. After the mixture was stirred at room temperature for 12 h, a saturated aqueous NH4Cl solution was added. The water layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CH2Cl2, Rf = 0.45) to give 1.12 g (3.12 mmol) of 5 in 79% yield as yellow solids: mp 169.7-171.0 °C; 1H NMR (300 MHz, CDCl3) δ 9.38 (s, 1H), 8.31 (s, 2H), 8.04 (s, 1H), 6.62 (d, JHH = 2.4 Hz, 1H), 5.95 (d, JHH = 9.9 Hz, 1H), 5.87 (d, JHH = 10.2 Hz, 1H), 3.39 (m, 2H), 3.26 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 180.5, 140.5, 135.7, 131.8 (q, JCF = 34 Hz), 128.9 (d, JCF = 4.6 Hz), 125.4, 124.8 (m, JCF = 4.6 Hz), 123.0 (q, JCF = 271 Hz), 119.0, 118.8; HRMS (+APCI-TOF) Calcd for C17H12F6NO: 360.0818 [(M+H)+]. Found: 360.0813 [(M+H)+]; Anal. Calcd for C17H11F6NO: C, 56.83; H, 3.09; N, 3.90. Found: C, 56.82; H, 3.01; N, 4.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In dichloromethane at 20℃; for 72h; | 1 Preparation of (R)-tert-butyl 2-(2-(3, 5-bis(trifluoromethyl)benzoyl)hydrazinecarbonyl)pyrrolidine-] -carboxylate (73) Preparation of (R)-tert-butyl 2-(2-(3, 5-bis(trifluoromethyl)benzoyl)hydrazinecarbonyl)pyrrolidine-] -carboxylate (73)To a mixture of 3,5-bis(trifluoromethyl)benzoyl chloride (71) (0.85 g, 3.1 mmol) and (R)tert-butyl 2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (72) (0.78 g, 3.4 mmol) indichloromethane (25 mL) was added triethylamine (1.7 mL, 12 mmol). The resultant solution was stirred at room temperature for 72 hours. The solution was then washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo to afford (R)-tert-butyl 2-(2-(3 ,5 - bis(trifluoromethyl)benzoyl)hydrazinecarbonyl)pyrrolidine- 1 -carboxylate (73) (1.34 g, 93%)which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In dichloromethane at 0 - 20℃; | |
85% | With triethylamine In dichloromethane at 0℃; | |
11.1 g | In tetrahydrofuran at 0 - 20℃; Inert atmosphere; |
16.12 g | In tetrahydrofuran at 0 - 20℃; | |
In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.7% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | With copper dichloride In dichloromethane at 0℃; for 68h; Schlenk technique; Reflux; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; | General procedure for the synthesis of benzoate estersvia the acid chloride (GPI) General procedure: A 50 mL Schlenk flask equipped with a magnetic stir bar was charged with an alcohol (5.00mmol, 1.00 equiv.), 4-DMAP (31 mg, 0.25 mmol, 0.05 equiv.), Et3N (5.0 ml, 3.5 g, 35 mmol,7.0 equiv.), and DCM (50 mL). The mixture was cooled to 0 °C, then (trifluoromethyl)benzoylchloride45 (5.50 mmol, 1.10 equiv.) was added dropwise. The reaction mixture was allowed towarm to room temperature, solvent was evaporated under reduced pressure and the residuewas purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydrogencarbonate In dichloromethane at 0 - 20℃; | 5 5.2.1.3 General procedure 3 General procedure: To a solution of N-(3-aminophenyl)-3-bromobenzamide 7b (1 equiv) in CH2Cl2 (0.1 M) were added NaHCO3 (5 equiv) and the appropriate benzoyl chloride (1.2 equiv) at 0°C. The reaction mixture was stirred until the reaction was completed. Then, H2O was added and the whole was extracted with AcOEt×2. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by means of silica gel column chromatography (eluent: n-hexane/AcOEt) to obtain the desired diamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium phosphate In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 49 [4-[[[3,5-Bis-trifluoromethylbenzoyl]amino]methyl]phenyl]boronic acid Example 49: N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]-3,5-bis(trifluoromethyl)benzamide [4-[[[3,5-Bis-trifluoromethylbenzoyl]amino]methyl]phenyl]boronic acid To a solution of 3,5-bis(trifluoromethyl)benzoyl chloride (276 mg, 1.00 mmol) in THF (2 mL) under a nitrogen atmosphere at 0 °C was added potassium phosphate (584.0 mg, 2.75 mmol), followed by 4- aminomethylphenylboronic acid hydrochloride (187 mg, 1.00 mmol). The reaction was allowed to return to rt and stirred overnight. Water was added, and the reaction mixture extracted with EtOAc (3 ×). The combined organics extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford [4-[[[(3,5-bis(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronic acid (378 mg, 0.97 mmol, 97% yield) as an off-white solid. UPLC-MS (ES+, short acidic): 1.68 min, m/z 392.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With dmap; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;Inert atmosphere; | To a solution of 3-Iodo-4- methyl aniline (0.7 equiv) in THF (6times) under nitrogen atmosphere was added 3,5-bis trifluoromethylbenzoyl chloride (1 equiv, prepared from the reaction of 3,5-bis trifluoromethylbenzoic acid and SOCl2) in THF at room temperature for 30minutes followed by drop wise addition of (i-Pr)2EtN (4 equiv) and 4- DMAP (0.2 equiv). After stirring at ambient temperature for 3h, the reaction mixture was quenched with water. The resulting mixture was extracted with ethyl acetate, concentrated and the compound was collected by adding hexane and filtration (44% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.1% | With potassium carbonate In 1,4-dioxane at 20℃; for 3h; Inert atmosphere; | N-(4-(N-Methylmethylsulfonamido)-3-((2-(trifluoromethyl)benzyl)oxy)phenyl)-3,5-bis(trifluoromethyl)benzamide (3). 3,5-Bis(trifluoromethyl)benzoyl chloride was used and stirred at roomtemperature for 3 h. Yield 78.1%, Pale Yellow solid. 1H NMR(400 MHz, DMSO) dH 10.78 (s, 1H), 8.60 (s, 2H), 8.40 (d, 1H), 7.88(d, 1H), 7.83 (d, 1H), 7.77 (t, 1H), 7.69 (s, 1H), 7.62 (t, 1H), 7.43(d, 1H), 7.35 (d, 1H), 5.32 (s, 2H), 3.12 (s, 3H), 2.87 (s, 3H); 13CNMR (100 MHz, DMSO) dC 163.24, 155.34, 140.03, 137.40,134,71, 133.49, 131.54, 130.84, 129.40, 129.10, 126.59, 125.82,124.93, 122.22, 113.69, 106.12, 66.85, 38.17, 37.95. ESI-MS calculatedfor (C25H19N2SO4F9) [MH]: 612.92; Molecular Weight (calculatedfrom structure): 614.48. HPLC mobile phase: 80% ACN with0.5% Formic acid, retention time: 2.40 min, purity: >99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | (S) -3-Amino-2-propanediol (910 mg, 10 mmol) was dissolved in 50 ml of pyridine,Trimethylsilyl chloride (TMSCl, 5.4 g, 50 mmol) was added while cooling to 0 C,After stirring to room temperature for half an hour, re-cooled to 0 C,After adding 3,5-bis (trifluoromethyl) benzoyl chloride (3.0 g, 11 mmol), the mixture was warmed to room temperature for 2-3 hours.Add 5-20 ml of water, continue stirring for half an hour after adding K2C03 or saturated ammonia to neutralize the reaction solution. The crude product mixture obtained after removing the solvent was purified by column chromatography (eluent: dichloromethane: methanol = 20: 1) to give 2.88 g of product 1 (8.7 mmol, 87% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane at 0 - 20℃; for 3.33333h; Inert atmosphere; | N-((1R,2R)-2-(Dimethylamino)-1-(4-nitrophenyl)-3-(trityloxy)propyl)-3,5-bis-(trifluoromethyl)benzamide (7i) General procedure: To a solution of chloramphenicol base (1 g, 2 mmol) and in CH2Cl2 (20 mL) was added the solution of Et3N (1.15 mL, 8 mmol) in CH2Cl2 (10 mL) under N2 atmosphere. After cooling to 0 °C, R3COCl (3 mmol) was added dropwise over 20min. After addition, the reaction mixture was stirred for 3 h at room temperature andthen quenched by water (10 mL). The organic phase was washed with NaHCO3 (20mL), H2O (20 mL), brine (20mL), dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flashchromatography using PE/EA 10:1 to give product 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In dichloromethane at 0 - 20℃; for 3.33333h; Inert atmosphere; | N-((1R,2R)-1-(4-Nitrophenyl)-2-(pyrrolidin-1-yl)-3-(trityloxy)propyl)-3,5-bis-(trifluoromethyl)benzamide (7j) General procedure: To a solution of chloramphenicol base (1 g, 2 mmol) and in CH2Cl2 (20 mL) was added the solution of Et3N (1.15 mL, 8 mmol) in CH2Cl2 (10 mL) under N2 atmosphere. After cooling to 0 °C, R3COCl (3 mmol) was added dropwise over 20min. After addition, the reaction mixture was stirred for 3 h at room temperature andthen quenched by water (10 mL). The organic phase was washed with NaHCO3 (20mL), H2O (20 mL), brine (20mL), dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flashchromatography using PE/EA 10:1 to give product 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine In dichloromethane at 0 - 20℃; for 3.33333h; Inert atmosphere; | N-((1R,2R)-1-(4-Nitrophenyl)-2-(piperidin-1-yl)-3-(trityloxy)propyl)-3,5-bis-(trifluoromethyl)benzamide (7k) General procedure: To a solution of chloramphenicol base (1 g, 2 mmol) and in CH2Cl2 (20 mL) was added the solution of Et3N (1.15 mL, 8 mmol) in CH2Cl2 (10 mL) under N2 atmosphere. After cooling to 0 °C, R3COCl (3 mmol) was added dropwise over 20min. After addition, the reaction mixture was stirred for 3 h at room temperature andthen quenched by water (10 mL). The organic phase was washed with NaHCO3 (20mL), H2O (20 mL), brine (20mL), dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flashchromatography using PE/EA 10:1 to give product 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In dichloromethane at 0 - 20℃; for 3.33333h; Inert atmosphere; | N-((1R,2R)-2-Morpholino-1-(4-nitrophenyl)-3-(trityloxy)propyl)-3,5-bis(trifluoromethyl)benzamide (7l) General procedure: To a solution of chloramphenicol base (1 g, 2 mmol) and in CH2Cl2 (20 mL) was added the solution of Et3N (1.15 mL, 8 mmol) in CH2Cl2 (10 mL) under N2 atmosphere. After cooling to 0 °C, R3COCl (3 mmol) was added dropwise over 20min. After addition, the reaction mixture was stirred for 3 h at room temperature andthen quenched by water (10 mL). The organic phase was washed with NaHCO3 (20mL), H2O (20 mL), brine (20mL), dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flashchromatography using PE/EA 10:1 to give product 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine In dichloromethane at 0 - 20℃; for 3.33333h; Inert atmosphere; | N-((1R,2R)-3-((tert-Butyldimethylsilyl)oxy)-2-(dimethylamino)-1-(4-nitrophenyl)-propyl)-3,5-bis(trifluoromethyl)benzamide (7m) General procedure: To a solution of chloramphenicol base (1 g, 2 mmol) and in CH2Cl2 (20 mL) was added the solution of Et3N (1.15 mL, 8 mmol) in CH2Cl2 (10 mL) under N2 atmosphere. After cooling to 0 °C, R3COCl (3 mmol) was added dropwise over 20min. After addition, the reaction mixture was stirred for 3 h at room temperature andthen quenched by water (10 mL). The organic phase was washed with NaHCO3 (20mL), H2O (20 mL), brine (20mL), dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flashchromatography using PE/EA 10:1 to give product 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In dichloromethane at 0 - 20℃; for 3.33333h; Inert atmosphere; | N-((1R,2R)-3-((tert-Butyldimethylsilyl)oxy)-1-(4-nitrophenyl)-2-(pyrrolidin-1-yl)-propyl)-3,5-bis(trifluoromethyl)benzamide (7n) General procedure: To a solution of chloramphenicol base (1 g, 2 mmol) and in CH2Cl2 (20 mL) was added the solution of Et3N (1.15 mL, 8 mmol) in CH2Cl2 (10 mL) under N2 atmosphere. After cooling to 0 °C, R3COCl (3 mmol) was added dropwise over 20min. After addition, the reaction mixture was stirred for 3 h at room temperature andthen quenched by water (10 mL). The organic phase was washed with NaHCO3 (20mL), H2O (20 mL), brine (20mL), dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flashchromatography using PE/EA 10:1 to give product 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In dichloromethane at 0 - 20℃; for 3.33333h; Inert atmosphere; | N-((1R,2R)-3-((tert-Butyldimethylsilyl)oxy)-1-(4-nitrophenyl)-2-(piperidin-1-yl)-propyl)-3,5-bis(trifluoromethyl)benzamide (7o) General procedure: To a solution of chloramphenicol base (1 g, 2 mmol) and in CH2Cl2 (20 mL) was added the solution of Et3N (1.15 mL, 8 mmol) in CH2Cl2 (10 mL) under N2 atmosphere. After cooling to 0 °C, R3COCl (3 mmol) was added dropwise over 20min. After addition, the reaction mixture was stirred for 3 h at room temperature andthen quenched by water (10 mL). The organic phase was washed with NaHCO3 (20mL), H2O (20 mL), brine (20mL), dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flashchromatography using PE/EA 10:1 to give product 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine In dichloromethane at 0 - 20℃; for 3.33333h; Inert atmosphere; | N-((1R,2R)-3-((tert-Butyldimethylsilyl)oxy)-2-morpholino-1-(4-nitrophenyl)-propyl)-3,5-bis(trifluoromethyl)benzamide (7p) General procedure: To a solution of chloramphenicol base (1 g, 2 mmol) and in CH2Cl2 (20 mL) was added the solution of Et3N (1.15 mL, 8 mmol) in CH2Cl2 (10 mL) under N2 atmosphere. After cooling to 0 °C, R3COCl (3 mmol) was added dropwise over 20min. After addition, the reaction mixture was stirred for 3 h at room temperature andthen quenched by water (10 mL). The organic phase was washed with NaHCO3 (20mL), H2O (20 mL), brine (20mL), dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flashchromatography using PE/EA 10:1 to give product 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 14h; Inert atmosphere; Schlenk technique; | Ethyl 2-(3,5-bis(trifluoromethyl)benzamido)thiazole-4-carboxylate (46). 3,5-Bis(trifluoromethyl)benzoyl chloride (1.91 mL, 2.90 g, 10.5 mmol) were added to asuspension of 1.72 g ethyl 2-aminothiazole-4-carboxylate (45, 10 mmol) and 1.87 mL N,Ndiisopropylethylamine(1.42 g, 11 mmol) in 25 mL THF at 0 °C. The suspension was allowedto warm to room temperature and stirred for additional 14 h. The solvent was removed invacuo, the residue was dissolved in EtOAc and washed three times with 10% (w/w)hydrochloric acid. The organic layers were separated and the solvent was removed in vacuo,yielding a yellow solid (3.93 g, 9.53 mmol, 95%) which was used in the next step without further purification. Mp: 296 °C; 1H NMR (300 MHz, DMSO-d6) δ = 8.69 (s, 2H), 8.40 (s,1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 4.23 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H);13C NMR (75 MHz, DMSO-d6) δ = 170.18, 166.42, 162.39, 142.97, 140.67, 129.75 (q, J =32.7 Hz), 129.07, 128.10, 123.36 (q, J = 272.2 Hz), 122.41, 121.67, 120.21, 59.71, 14.32;GC-MS (EI, 70 eV): tr (min) = 18.5; m/z (%): 213 (35), 241 (100), 384 (40), 412 (17) (M)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In diethyl ether at 0 - 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium carbonate In diethyl ether at 0 - 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | I Synthesis of Compounds 21-22 To a solution of Compound 15e (5-bromo-2,3-dihydro-lH-inden-l-amine) (0.30 g, 1.41 mmol) in DCM (20 mL) was added DIPEA (0.27 g, 2.12 mmol) and 3,5-Bis(trifluoromethyl)benzoyl chloride (0.43 g, 1.56 mmol) at 0°C . After addition, the reaction mixture was slowly warmed to RT and stirred for overnight. After reaction was completed, the solvent was removed under reduced pressure. The residual was diluted with EtOAc and washed with Sat. NH4CI and Sat. NaHC03. The organic phase was dried with MgSC>4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane = 1/5 as elution to afford Compound 21a(N-(5-bromo-2,3-dihydro-lH-inden-l-yl)-3,5-bis(trifluoromethyl)benzamide) (0.32 g, 0.72 mmol, yield 51%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.9% | Stage #1: (6-amino-3,4-dihydroquinolin-1(2H)-yl)(4-chlorophenyl)methanone With trialkylamine In dichloromethane at 20℃; for 0.5h; Stage #2: 3,5-bis(trifluoromethyl)phenyl carboxylic acid chloride In dichloromethane at 20℃; for 1h; | 5.10.1. Synthesis of (N-(1-(4-chlorobenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-nitrobenzamide: (HB-UC-1) (9d): General procedure: Compound 8a (1.7 mmol, 0.5 gm) was dissolved in the dichloromethane.Dropwise trimethylamine (4.9 mmol, 0.46 mL) was added toabove reaction mixture and allowed to stir for 30 min at room temperature.4-nitro benzoyl chloride (1.6 mmol, 0.3 gm) was added to abovereaction mixture and stirring was continued for 1 h. Reaction mixturewas transferred to the crushed ice and extracted with dichloromethanedried over the sodium sulfate and passed through the column for thepurification resulted into yellow colored compound. Dark yellow SolidYield: 65.78%; mp: 206-208 C; IR (KBr, γmax cm 1): 843 (C-Cl), 1530(-NO2), 1599 (C- -O), 1673 (C- -C), 2360 (C-N), 2951 (C-H aliphatic),3015 (C-H aromatic), 3319 (-NH); 1H NMR (400 MHz, DMSO-d6) δPPM: 1.95-1.98 (m, 2H, -CH2), 2.82 (t, J = 5.6 Hz, 2H, -CH2), 3.76 (m,2H, -CH2), 6.74 (s, 1H, Ar-CH), 7.26 (d, J = 8 Hz, 1H, Ar-CH), 7.35 (d, J= 8 Hz, 2H Ar-CH), 7.42 (d, J = 8 Hz, 2H, Ar-CH), 7.71 (s, 1H, Ar-CH),8.14 (d, J = 8.4 Hz, 2H, Ar-CH), 8.35 (d, J = 8.4 Hz, 2H, Ar-CH), 10.49(s, 1H, NH-C- -O); 13C NMR (100 MHz, DMSO-d6) δ PPM: 23.48, 26.48,44.26, 117.74, 120.16, 123.53, 125.14, 128.23(2C), 128.43(2C), 129.09(2C), 129.50(2C), 130.09, 131.91, 134.52, 135.09, 140.47, 149.08,163.50, 167.97; MS (EI) m/z calculated for C23H18ClN3O4 436 for (M +1); found 436.4 (M + 1), 438.4 (for chloro pattern); HPLC Purity:97.58%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 6 Step 6: N-{(1S)-1-[1-{5-[(Cyclopropylcarbonyl)(methyl)amino]pyridin-2-yl}-3-(dimethylamino)-1H-1,2,4- triazol-5-yl]ethyl}-3,5-bis(trifluoromethyl)benzamide To a solution of 137 mg (0.37 mmol) N-(6-{5-[(1S)-1-aminoethyl]-3-(dimethylamino)-1H-1,2,4-triazol- 1-yl}pyridin-3-yl)-N-methylcyclopropanecarboxamide hydrochloride (1:1) in 2 ml dichloromethane were added 0.17 ml (0.99 mmol) N,N.diisopropylethylamine and then a solution of 69 mg (0.25 mmol) 3,5- bis(trifluoromethyl)benzoyl chloride in 2 ml dichloromethane and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and was washed with a 5% NaH2PO4 aqueous solution, bicarbonate solution and then brine. The organic phase was dried over sodium sulfate and the solvent was reduced under pressure. The residue was purified by reversed phase chromatography (H2O/acetonitrile) to provide 116 mg (purity: 97%; yield: 79 %) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; | I-49 Example I-49 (rac)-Methyl 2-(3-{1-[3,5-bis(trifluoromethyl)benzamido]ethyl}pyrazin-2-yl)-1,3-thiazole-5- carboxylate (rac)-Methyl 2-{3-[1-aminoethyl]pyrazin-2-yl}-1,3-thiazole-5-carboxylate (intermediate 28A, 300 mg, 1.14 mmol) and DIPEA (400 L, 2.3 mmol) were dissolved in THF (15.0 mL) and cooled to 0 °C. A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (377 mg, 1.36 mmol) in THF (1.0 mL) was added and stirring was maintained for 30 min. The solvent was distilled, the residue was washed with tert- butylmethyl ether to give 480 mg (84 % yield) of the title compound. LC-MS (method 1): Rt = 1.53 min; MS (ESIpos): m/z = 505 [M+H]+ H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.107 (1.29), 1.260 (1.91), 1.357 (1.65), 1.615 (7.46), 1.626 (7.32), 1.760 (0.75), 2.422 (0.62), 2.651 (0.56), 3.078 (0.46), 3.602 (0.74), 3.910 (16.00), 6.508 (1.21), 6.520 (1.86), 6.530 (1.24), 8.291 (3.48), 8.438 (1.85), 8.474 (0.78), 8.520 (7.94), 8.697 (8.88), 8.783 (3.57), 8.853 (1.55), 9.542 (1.75), 9.553 (1.77). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In dichloromethane at -10 - 20℃; for 17h; Inert atmosphere; | Preparation of the Amides 15a-h; General Procedure General procedure: Under a nitrogen atmosphere the corresponding amine (14a,b; 1 equiv) was dissolved in anhydrous CH2Cl2 (1.9 mL/1 mmol) and then the acyl chloride (1.2 equiv) was added slowly using a syringe. The mixture was cooled to -10 °C and then Et3N (2.4 equiv), dissolved in anhydrous CH2Cl2 (0.6 mL/mmol educt) was added slowly. The reaction mixture was stirred for 1 h at -10 °C and then allowed to warm to room temperature. Stirring was continued for 16 h, then the reaction was quenched by addition of water (20 mL). The reaction mixture was then extracted with CH2Cl2 until the organic layer was colorless. The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo. The crude product was finally purified using column chromatography (EtOAc) and dried in vacuo. |
Tags: 785-56-8 synthesis path| 785-56-8 SDS| 785-56-8 COA| 785-56-8 purity| 785-56-8 application| 785-56-8 NMR| 785-56-8 COA| 785-56-8 structure
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