* 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.
Intermediate 14. 2-Amino-4-trifluoromethyl-pyrimidine-5-carboxylic acid; A solution of 2-amino-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester (commercially available from Maybridge) (14.9 g) in methanol (300 ml) containing potassium hydroxide (10.65 g) was refluxed for 4h. The solvent was removed under reduced pressure and the residue dissolved in water (150 ml). The aqueous was washed with diethyl ether (75 ml) and then acidified to pH 1 with concentrated hydrochloric acid to afford a white precipitate. The solid was filtered off, washed with water and dried to afford the title compound (12.76 g). NMR (DMSO-d6) 8 7.94 (2H, s), 8.82 (1H, s), 13.30 (1H, s). LC/MS, t = 1.10 min, molecular ion observed [MH+] 208, consistent with C6H4F3N302.
With water; sodium hydroxide; In methanol; at 20℃;
To a solution of 18 (800 mg, 3.40 mmol) in MeOH (20 mL) and water (20 mL) is added NaOH (408 mg, 10.2 mmol). After stirring at room temperature overnight, the mixture is concentrated and the residue is dissolved in water (10 mL) followed by acidified to pH 1 by addition of concentrated aqueous HCI . The precipitate is collected by filtration and dried to give crude 19 (600 mg, 91% yield). (MS: [M+Hf 236,0)
Synthesis of 2-Amino-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester Sodium ethoxide (2 eq, 83.8 mmol, 5.7 g) was added in one portion to a solution of guanidine hydrochloride (4 g, 41.9 mmol) in absolute ethanol (100 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. A dichloromethane solution of 3-methoxy-2-(2,2,2-trifluoro-acetyl)-acrylic acid ethyl ester was then added and the mixture was stirred at ambient temperature for an additional 20 hours. The solvent was then removed by evaporation, water was added to the residue, and the mixture was stirred vigorously for 2 hours then allowed to stand at room temperature. The resulting solid was isolated by filtration, washed with water then dried in vacuo to afford 6.10 g (62% yield) of 2-amino-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester. m/z (M+H)=236.2.
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane;Heating / reflux;
Example 78. 2-f4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino1-4-trifluoromethyl- pyrimidine-5-carboxyIic acid ethyl ester (48); [0237] A mixture of 2-amino-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester (280 mg, 1.2 mmol), l-[2-(4-bromophenoxy)ethyl]pyrrolidine (640 mg, 2.4 mmol), cesium carbonate (1.16 g, 3.6 mmol), and Xantphos (140 mg, 0.24 mmol), Pd2(dba)3 (110 mg, 0.12 mmol) in 20 mL of anhydrous dioxane was degassed with argon for 5 minutes and was refluxed overnight under argon. After cooling down, the solvent was removed under reduced pressure. The crude product was purified silica gel column (3.5 x 16 cm) EPO <DP n="81"/>chromatography using 20% CH3OH in CHCl3 as an eluent to give a pale yellow solid (300 mg, 59%).
ethyl 2-(1H-tetrazol-5-ylamino)-4-(trifluoromethyl)pyrimidine-5-carboxylate[ No CAS ]
[ 149771-09-5 ]
Yield
Reaction Conditions
Operation in experiment
15%; 38%
With sodium acetate; In 1,4-dioxane;Reflux;
General procedure: A mixture ofthe corresponding ester 1a,b (3 mmol), 5-aminotetrazole (0.31 g, 3 mmol) and sodiumacetate trihydrate (0.20 g, 1.5 mmol) in 1,4-dioxane (25 ml) was refluxed for 16-18 h.After the completion of the reaction (TLC monitoring), the reaction mixture was pouredinto cool water (100 ml). The resulting precipitate was filtered off, washed with diethylether and crystallized from ethanol to give compounds 4a,b. The filtrate and washingsolutions after purification of compound 4a were used to obtain compound 5
15%; 38%
With sodium acetate; In 1,4-dioxane;Reflux;
General procedure: a. A mixture of 3 mmol of ester 1a or 1b, 0.31 g(3 mmol) of tetrazol-5-amine, and 0.20 g (1.5 mmol) of sodium acetate in 25 mL of 1,4-dioxane was heated for 16-18 h under reflux. When the reaction was complete(TLC), the mixture was poured into 100 mL of cold water. The precipitate was filtered off, dried, washed with diethyl ether, and recrystallized from ethanol. The filtrates were used to isolate compound 5.
With sodium acetate; In N,N-dimethyl-formamide; at 80℃;
General procedure: Method B.A mixture of the corresponding ester 1a,b (3 mmol), guanidine carbonate (0.27 g, 3mmol) and sodium acetate trihydrate (0.40 g, 3 mmol) in dimethylformamide (15 ml)was stirred under heating (80 ) for 24-26 h. After the completion of the reaction (TLCmonitoring), the reaction mixture was poured into cool water (200 ml). The resultingprecipitate was filtered off and crystallized from ethanol to afford compounds 4a,b.
With sodium acetate; In N,N-dimethyl-formamide; at 80℃;
General procedure: b. A mixture of 3 mmol of ester 1a and 1b, 0.27 g (3 mmol) of guanidine carbonate, and 0.40 g (3 mmol) of sodium acetate in 15 mL of DMF was stirred for 24-26 h at 80C. When the reaction was complete (TLC), the mixture was poured into 200 mL of cold water, and the precipitate was filtered off and recrystallized from ethanol.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
