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To a solution of 3-bromo-1, 1, 1-trifluoroacetone (2.19 g, 11.53 mmol) in 25 mL t-BuOH was added urea (2.77 g, 46.1 mmol). The solution was refluxed for 7 hours. Then the mixture of reaction was cooled to room temperature, concentrated in vacuo to remove the solvent. The white solid obtained was dissolved in DCM and to the mixture was added sat.NaHCO3 to adjust pH value to 8.0. The water layer was extracted with DCM for three times. The organic layer was combined, washed with brine, dried over Na2SO4, concentrated and purified by column chromatography on silica gel (PE:EtOAc=3:1) to give ST-246-1 [4-(trifluoromethyl)oxazol-2-amine] as white wax solid (1.1 g, 63%).
N-[4-(trifluoromethyl)-1,3-oxazol-2-yl]-9H-xanthene-9-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
dmap; In pyridine; dichloromethane; at 0 - 20℃;
a) 4-Trifluoromethyl-oxazol-2-ylamine: The <strong>[35629-71-1]4-trifluoromethyl-oxazol-2-ylamine</strong> is obtained using the procedure described in the literature [Crank and Foulis, J. Med. Chem. 14:1075 (1971)]. [0079] b) 9H-Xanthene-9-carboxylic acid (4-trifluoromethyl-oxazol-2-yl)-amide: To a solution of 150 mg (0.99 mmol, 1.0 equiv.) <strong>[35629-71-1]4-trifluoromethyl-oxazol-2-ylamine</strong> and 6 mg (0.05 mmol, 0.05 equiv.) of N,N-dimethylamino pyridine in 2 ml of dry pyridine is added a solution of 245 mg (0.99 mmol) 9-xanthene-carboxylic acid chloride (CAS: [26454-53-5]) in 2 ml of methylene chloride dropwise at 0 C. The mixture is stirred 1 h at 0 C. and then at room temperature overnight. The mixture is poured into a well stirred mixture of 30 ml of methylene chloride and 30 ml of water. The organic phase is separated. The aqueous phase is extracted twice with 30 ml of methylene chloride. The combined organic phases are washed with 25 ml of water, dried over magnesium sulfate, and concentrated. The crude product (590 mg, yellow solid) yields, after recristallisation from ethyl acetate/hexane 250 mg (0.66 mmol, 66%) of 9H-xanthene-9-carboxylic acid (4-trifluoromethyl-oxazol-2-yl)-amide as white cristals, m.p. 222 C. and MS: m/e=361.2 (M+H+)
2-(4,4-difluorobut-3-enylthio)4-trifluoromethyloxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane;
EXAMPLE VI.4 This example illustrates a preparation of 2-(4,4-difluorobut-3-enylthio)4-trifluoromethyloxazole (Compound VI.4). 2-Amino-4-trifluoromethyloxazole (0.84 g) in dichloromethane (25 cm3) containing bis-(4,4-difluorobut-3-enyl)disulfide (2.71 g) at 0 C. was stirred and treated dropwise with tert.butyl nitrite (0.62 g) under nitrogen. The reaction solution was evaporated under reduced pressure and the residue fractionated by chromatography (silica, eluant hexane) to give Compound VI.4 (0.35 g). M+ =259; 1 H NMR: delta 2.50(2H,m); 3.26(3H,t); 4.28(1H,m); 7.95(1H,q); (oil).
(RS)-2-fluoro-9-xanthene-carboxylic acid[ No CAS ]
[ 714971-89-8 ]
Yield
Reaction Conditions
Operation in experiment
38%
c) (RS)-2-Fluoro-9H-xanthene-9-carboxylic acid (4-trifluoromethyl-oxazol-2-yl)-amide: To a solution of 883 mg (1.80 mmol, 1.1 equiv.) of 1,1'-carbonylbis(3-methylimidazolium) triflate (CBMIT) [Saha et al., J. Am. Chem. Soc. 111:4856 (1989)] in 3 ml of nitromethane at 10 C. are added 400 mg (1.64 mmol) of (RS)-2-fluoro-9-xanthene-carboxylic acid. The resulting suspension is allowed to warm up to room temperature and is stirred another 15 min. 4-Trifluoromethyl-oxazol-2-ylamine (274 mg, 1.80 mmol, 1.1 equiv.) is added and the mixture is stirred at room temperature for 16 h. The resulting light red viscous mixture is extracted with a mixture of 45 ml methylene chloride, 5 ml of methanol and 50 ml of water. The organic phase is separated. The aqueous phase is extracted twice with 30 ml methylene chloride/methanol 9:1. The combined organic phases are washed with 30 ml of water, dried over sodium sulfate and concentrated in vacuo. The crude product (630 mg, light red solid) is purified by flash chromatography on silicagel using methylene chloride as eluant. One obtains after recristallisation from ethyl acetate/hexane 233 mg (0.62 mmol, 38%) of (RS)-2-fluoro-9H-xanthene-9-carboxylic acid (4-trifluoromethyl-oxazol-2-yl)-amide as a white solid, m.p. 241 C. and MS: m/e=379.1(M+H+).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 1h;Inert atmosphere; Microwave irradiation;
General procedure: To an oven-dried microwave vial was added ethyl 2-amino-1,3-oxazole-5-carboxylate (546 mg, 3.50 mmol), Cs2CO3 (2279 mg, 6.99 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. 2,4-Dichloropyridine (0.378 mL, 3.50 mmol) was added via syringe, followed by 1,4-dioxane (18 mL) (degassed) and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. CH2Cl2 (40 mL) was added to the crude reaction mixture together with silica (5 g). The solvents were removed under reduced pressure and the crude product was purified by flash silica chromatography with CH2Cl2 (containing 1% methanolic ammonia) as eluent.The resulting brown solid was triturated with Et2O to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (626 mg, 67%) as a pale yellow solid, which was collected by filtration and dried under vacuum.
S. 6-methyl-2-(4-(trifluoromethyl)cvclohexyl)-3-(4-(trifluoromethyl)oxazol-2-yl)pyrimidin- 4(3H)-one (cis isomer; Compound 35)To a solution of 2-amino-4-(trifluoromethyl)-oxazole (14.3 mmol) in DCE (30 mL) under nitrogen add trimethylaluminum (2 M in hexane, 7.2 mL, 14.3 mmol). Stir the mixture at RT for 30 min and add a solution of methyl 3-(4-(trifluoromethyl)- cyclohexanecarboxamido)but-2-enoate (2.8 g, 9.55 mmol) in DCE (10 mL). Stir the mixture at 900C for overnight, cool to RT, quench with saturated Rochelle's salt, and extract with EtOAc. Dry over Na2SO4, and concentrate under vacuum. Purify using flash chromatography (ethyl acetate/hexanes eluent) to give the title compound.
ethyl 7-chloro-4-oxo-1-(4-(trifluoromethyl)oxazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In acetonitrile;
General procedure: To a solution of 5 (6.64 g, 20.87 mmol) and triethylamine (7.2 mL, 50.23 mmol) dissolved in dry acetonitrile (70 mL) was added RNH2 (10.00 mmol) in portions and stirred for 12 h at room temperature, then concentrated under reduced pressure and the residue was purified by silica gel column chromatography(CH2Cl2 : CH3OH = 50:1) to give the title compounds 6a-d.
7-chloro-1-(3-(4-(trifluoromethyl)oxazol-2-yl-amino)propyl)-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium hydrogencarbonate; In N,N-dimethyl-formamide; for 8h;Reflux;
In a reaction flask equipped with a stirrer, a condenser and a thermometer,3.93 g (0.01 mol) of Intermediate IV-1, 2.00 g (0.02 mol) of potassium bicarbonate,30 ml of N, N-dimethylformamide and 1.53 g (0.01 mol)4- (trifluoromethyl) -2-aminooxazole,Reflux the reaction 8h, TLC showed the reaction was complete, the insoluble matter was filtered off, the solvent was evaporated,The residue was subjected to silica gel column chromatography to give Compound I-4 as a white solid in a yield of 85% and a purity of 99.2%(HPLC normalization method)
tert-butyl 4-(trifluoromethyl)oxazol-2-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
To a solution of ST-246-1, <strong>[35629-71-1]4-(trifluoromethyl)oxazol-2-amine</strong> (1.3 g, 8.55 mmol), in 17 mL anhydrous CH3CN was added Boc2O (5.6 g, 25.7 mmol), Et3N (3.6 ml, 25.7 mmol) and DMAP (209 mg, 1.71 mmol). The solution was stirred at 40 C. for 2 hrs. When the reaction was completed, the mixture of reaction was concentrated in vacuo to remove the solvent. The resulting residue was then diluted with H2O and extracted with EtOAc. The combined organic extracts were dried with Na2SO4, concentrated to give a residue and the residue was purified by column chromatography on silica gel (PE:EtOAc=25:1) to give the intermediate as colorless wax solid (2.3 g, 77%). To a stirred solution of the intermediate (220 mg, 0.63 mmol) in DCM (6 mL) at 0 C. was added dropwise TFA (600 muL). The reaction mixture was stirred at 0 C. for 1 h and sat. NaHCO3 was added to basify the solution. The organic layer was separated, and the aqueous phase was further extracted with DCM. The combined organic extracts were dried with Na2SO4, concentrated and purified by column chromatography on silica gel (PE:EtOAc=25:1 to 5:1) to give tert-butyl 4-(trifluoromethyl)oxazol-2-ylcarbamate (ST-246-2) as white solid (142 mg, 90%).
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