* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 22, p. 3679 - 3686
[3] Patent: US2014/315888, 2014, A1,
[4] Patent: EP2865266, 2015, A1,
[5] Patent: US5620978, 1997, A,
13
[ 74784-70-6 ]
[ 79456-30-7 ]
Yield
Reaction Conditions
Operation in experiment
96 g
With N-Bromosuccinimide In chloroform at 20 - 80℃; for 1.5 h; Cooling with ice
Production Example 59-1 71 g of N-bromosuccinimide was added to a mixture of 65 g of 5-trifluoromethyl-pyridine-2-ylamine and 100 mL of chloroform by being divided into 5 portions under ice water-cooling, The temperature was elevated to room temperature and the mixture was stirred for 1 hour. Then, the mixture was heated to 80°C and was heated and stirred for 3C minutes. After allowing the mixture to cool to room temperature, a saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the mixture, which was then subjected to extraction using chloroform. A combined organic layer was dried using sodium sulfate, and then, was condensed under reduced pressure. The residue was subjected to silicagel column chromatography to obtain 96 g of 3-bromo-5-trifluoromethyl-pyridin-2-ylamine. 3-bromo-5-trifluoromethyl-pyridin-2-ylamine 1H-NMR (CDCl3) δ: 8.27 (1H, d), 7.86 (1H, d), 5.38 (2H, brs).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 12, p. 1715 - 1720
[2] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 19, p. 2777 - 2782
[3] Patent: US5861419, 1999, A,
[4] Patent: US6046217, 2000, A,
[5] Patent: US6004950, 1999, A,
[6] Patent: EP1012142, 2004, B1, . Location in patent: Page 27
[7] Patent: EP1015431, 2005, B1, . Location in patent: Page/Page column 23
[8] Patent: EP2865266, 2015, A1, . Location in patent: Paragraph 0676
14
[ 79456-29-4 ]
[ 74784-70-6 ]
[ 79456-30-7 ]
Reference：
[1] Patent: US4349681, 1982, A,
15
[ 74784-70-6 ]
[ 211308-82-6 ]
Yield
Reaction Conditions
Operation in experiment
69%
Stage #1: With sulfuric acid; iodine; acetic acid; periodic acid In water at 85℃; for 18 h; Stage #2: With sodium hydroxide In water at 20℃;
[0183] To 2-amino 5-trifluoromethyl pyridine, (50g, 308mmol) was added acetic acid (50OmL), followed by pre-mixed water (35mL) and concentrated sulfuric acid (5mL) and stirred until completely solubilised. Periodic acid (13.3g, 58mmol) was added followed by iodine (31.2g, 123mmol) and then the reaction mixture was heated to 85 0C for 18 hours. [0184] The reaction mixture was allowed to cool to room temperature and then carefully basified with 4M NaOH solution to pH 10-14. This gave a precipitate which was isolated by filtration and stirred in water (.1 litre), filtered and dried to give the product as a brown powder (61.38g, 69percent).
67%
With sulfuric acid; iodine; acetic acid; periodic acid In water at 80℃; for 16 h; Inert atmosphere
[0522] To a stirred solution of 5-(trifluoromethyl) pyridin-2-amine (100 g, 617 mmol) in acetic acid (1 Lit) at room temperature under an argon atmosphere were added concentratedsulfuric acid (5 mL), periodic acid (26 g, 123 mmol) and iodine (62 g, 246 mmol). The reaction mixture was stirred at 80 °C for 16 h. After consumption of starting material (by TLC), the reaction mixture was basified with sodium hydroxide solution (200 mL) at 0 °C, to obtain the solid. The solid was filtered and concentrated in vacuo to obtain 3-iodo-5- (trifluoromethyl) pyridin-2-amine (120 g, 67percent) as an off-white solid. ‘H NMR (DMSO-d6 500 MHz): 8.27 (s, 1H), 8.16 (s, 1H), 6.87 (brs, 2H); TLC: 10percent EtOAc Hexane (R1 0.4).
14.3 g
With iodine; silver sulfate In ethanol at 10 - 35℃;
To a mixture of 5-(trifluoromethyl)pyridin-2-amine (12.0 g), silver(I) sulfate (23.1 g) and ethanol (400 mL) was added iodine (37.6 g) in several parts at room temperature, and the reaction mixture was stirred overnight at room temperature. To the reaction solution was added saturated aqueous sodium thiosulfate solution, and the mixture was stirred for 30 min, and neutralize with 1N aqueous sodium hydroxide solution. The insoluble substance was removed by filtration, the filtrate was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (14.3 g). MS (APCI+): [M+H]+ 289.0
With sulfuric acid; nitric acid; at 0 - 20℃;Inert atmosphere;
General procedure: 2-Aminopyridine 7 (0.020 mol) was added to ice-cold concentrated sulfuric acid and the resulting solution was treated with concentrated nitric acid (1.09 mL, 0.024 mol), which was added slowly so as to maintain the reaction temperature in 0-5 C range.The resulting solution was stirred at 0-5 C for 1 h, warmed up to rt and stirred at that temperature overnight. It was then poured over ice and the pH was adjusted to 7-8 with 10% aq NaOH solution. The resulting precipitate was collected by filtration, washed with water and dried at 60 C overnight to provide analytically pure 2-amino-3-nitropyridines.
25%
With sulfuric acid; nitric acid; In water; at 80℃; for 48h;
5-(trifluoromethyl)pyridin-2-amine (1700.0 mg, 10.49 mmol) was dissolved in conc. H2SO4 (10.0 mL), and then conc. HNO3 (1.7 mL, 26.22 mmol) was slowly added thereto. The reaction mixture was stirred at 80 C. for 48 hours, then added to ice water, alkalized with 1N NaOH aqueous solution (pH=9) and then extracted with EtOAc (200.0 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then distilled under reduced pressure. The residue was purified by column chromatography (n-Hex:EtOAc=50:50) on silica. The fractions containing the product were collected and evaporated to obtain yellow solid compound of 3-nitro-5-(trifluoromethyl)pyridin-2-amine (538.0 mg, 25%). [0777] LCMS ESI (+): 208 (M+1) [0778] 1H-NMR (300 MHz, CDCl3); delta: 8.67 (d, 1H, J=1.7 Hz), 8.59 (d, 1H, J=1.7 Hz), 7.92 (bs, 1H), 6.10 (bs, 1H)
With sulfuric acid; nitric acid; at 0 - 80℃; for 48h;
Example 100 [6-TRIFLUOROMETHYL-2- [4- (3-TRIFLUOROMETHYL-PYRIDIN-2-YL)-PIPERAZIN-1-YL]-3H-] [IMIDAZO [4, 5-B] PYRIDINE,] trifluoroacetic acid salt. (a) [3-NITRO-5-TRIFLUOROMETHYL-PYRIDIN-2-YLAMINE.] To a 250-mL, round-bottomed flask was added [5-TRIFLUOROMETHYL-PYRIDIN-] 2-ylamine (8.3 g, 51.2 mmol, Matrix Scientific) and H2SO4 (49 mL). The resulting mixture was cooled to [0 C,] and [HN03] (8.2 mL) was added dropwise. The mixture was heated to [80 C] for [48] h, cooled to room temperature and added dropwise into a vigorously stirred ice-water (500 mL). After the addition, the mixture was basified to pH 9 with [1 ON NAOH] and extracted with EtOAc (2 x [500] mL). The combined organic extracts were dried over [MGS04] and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with [ETOAC/HEXANE] (1: 2) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 208 (M+1).
With sulfuric acid; nitric acid; at 20 - 70℃; for 1h;
Step A: 3-nitro-5-(trifluoromethyl) pyridin-2-amine <n="49"/>To a solution of 5~(trifluoromethyl)pyridine-2-amine (l.lg, 6.79mmol) dissolved in sulfuric acid (2OmL) at room temperature was added nitric acid (0.475 g, 6.79mmol). After heating to 700C for Ihr, the reaction mixture was cooled to room temperature and diluted with EtOAc and ice. The organic layer was separated, washed with sat. sodium bicarbonate aq. and brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient solvent mixture (5% MeOH-DCM to 15% MeOH-DCM) to give the title compound (680 mg). LC/MS: m/z 208(M+H). 1H-NMR (500MHz, CD3OD): delta 8.60 (d, 1H), 8.67 (d, 1H).
With sodium hydroxide; bromine; In hexane; acetic acid;
Step 1: 2-Amino-3-bromo-5-trifluoromethylpyridine To a solution of 2-amino-5-trifluoromethylpyridine (9 g) in acetic acid (75 mL) at r.t. was added bromine (5.8 mL) slowly. After 1 h, the acid was neutralized by the careful addition of sodium hydroxide (10N) at 0 C. The resulting orange precipitate was dissolved in ether and washed successively with saturated potassium carbonate, saturated Na2 SO3 and brine, dried and concentrated. The residual solid was stirred vigorously in hexane for 1 h to provide, after filtration, the title compound as a white solid (10.2 g).
With sodium hydroxide; bromine; In hexane; acetic acid;
Step 1 2-Amino-3-bromo-5-trifluoromethylpyridine To a solution of 2-amino-5-trifluoromethylpyridine (9 g) in acetic acid (75 mL) at r.t. was added bromine (5.8 mL) slowly. After 1 h, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0 C. The resulting orange precipitate was dissolved in ether and washed successively with saturated potassium carbonate, saturated Na2 SO3 and brine, dried and concentrated. The residual solid was stirred vigorously in hexane for 1 h to provide, after filtration, the title compound as a white solid (10.2 g).
With bromine; In acetic acid; at 20℃; for 1h;
To a solution of 2-amino-5-trifluoromethylpyridine (9 g) in acetic acid (75 mL) at r.t. was added bromine (5.8 mL) slowly. After 1 h, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0C. The resulting orange precipitate was dissolved in ether and washed successively with saturated potassium carbonate, saturated Na2SO3 and brine, dried and concentrated. The residual solid was stirred vigorously in hexane for 1 h to provide, after filtration, the title compound as a white solid (10.2 g).
With bromine; acetic acid; at 18 - 25℃; for 1h;
EXAMPLE 13-(4-Methylsulfonyl)phenyl-2-pyrrolidin-1-yl-5-trifluoromethylpyridineStep 1: 2-Amino-3-bromo-5-trifluoromethylpyridine To a solution of 2-amino-5-trifluoromethylpyridine (9 g) in acetic acid (75 mL) at r.t. was added bromine (5.8 mL) slowly. After 1 h, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0C. The resulting orange precipitate was dissolved in ether and washed successively with saturated potassium carbonate, saturated Na2SO3 and brine, dried and concentrated. The residual solid was stirred vigorously in hexane for 1 h to provide, after filtration, the title compound as a white solid (10.2 g).
96 g
With N-Bromosuccinimide; In chloroform; at 20 - 80℃; for 1.5h;Cooling with ice;
Production Example 59-1 71 g of N-bromosuccinimide was added to a mixture of 65 g of 5-trifluoromethyl-pyridine-2-ylamine and 100 mL of chloroform by being divided into 5 portions under ice water-cooling, The temperature was elevated to room temperature and the mixture was stirred for 1 hour. Then, the mixture was heated to 80C and was heated and stirred for 3C minutes. After allowing the mixture to cool to room temperature, a saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the mixture, which was then subjected to extraction using chloroform. A combined organic layer was dried using sodium sulfate, and then, was condensed under reduced pressure. The residue was subjected to silicagel column chromatography to obtain 96 g of 3-bromo-5-trifluoromethyl-pyridin-2-ylamine. 3-bromo-5-trifluoromethyl-pyridin-2-ylamine 1H-NMR (CDCl3) delta: 8.27 (1H, d), 7.86 (1H, d), 5.38 (2H, brs).
Phenyl chloroformate (620mg, 3.96 mmol) was added to a solution of 5-(trifluoromethyl)pyridin-2-amine (615 mg, 3.79 mmol) and pyridine (323 mg, 4.08 mmol) in ACN (50 mL) at 0C. After stirring the solution overnight at room temperature, the reaction was quenched with H20. The resulting precipitate was filtered, dried and used without further purification. The product was a white solid (905mg, 3.21 mmol, 84% yield).
69%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;
A solution of 5-(trifluoromethyl)pyridin-2-amine (100 mg, 0.617 mmol) and N,N-diisopropylethylamine (159.5 mg, 215 muL, 1.234 mmol) in 5 mL CHzClz was treated with phenyl chloroformate (106 mg, 85 muL, 0.68 mmol) and left to stir for 3 h at rt. Solution was diluted with EtOAc and washed twice with 1 N HCl and 1 time with brine. The organic layer was dried (Na2S04) and concentrated to provide a white solid. Tituration with 10% EtOAc in hexanes gave 120 mg (69%, 0.42 mmol) of the above compound as a white solid. (at)H-NMR (DMSO-d6) No. 11.26 (s, 1H), 8.70 (s, 1H), 8.22 to 8.16 (m, 1H), 7.99 (d, J = 8 Hz, 1H), 7.45 to 7.40 (m, 2H), 7.30 to 7.20 (m, 3 H)
69.2%
With pyridine; In dichloromethane; at -5 - 25℃; for 1.16667h;
Phenyl 5-(tnfluoromethyl)pyridin-2-ylcarbamate. To a stirred solution ot 5-(trifluoromethyl)pyndin-2-amine 108 (20 g, 123 5 mmol) in dichloromethane (85 mL) at -5C was slowly added phenyl carbonochlo?date 109 (21 2 g, 136 mmol) over 10 mm. At -5C, pyridine ( 1 1 1 mL, 136 mmol) was then added drop wise to the reaction mixture. After heating the reaction mixture to a temperature of about 250C and stirring for 1 h, a precipitate gradually formed The precipitate was filtered and washed with dichloromethane and ethyl acetate to provide 24 1 g of 110 as a white solid (69 2% yield) 1H NMR (400 MHz, DMSO-d6) delta 1 1 3 (br s, I H), 8 75-8 70 (m, I H), 8 24-8 17 (m, I H), 8 05-7 98 (m, I H), 7 50-7 40 (m, 2H),7 33-7 22 (m, 2H)
In pyridine; chloroform;
A. Trifluoromethyl-pyridin-2-yl)-carbamic acid phenyl ester Dissolve <strong>[74784-70-6]2-amino-5-trifluoromethylpyridine</strong> (162 mg, 1.0 mmole) in pyridine (2.0 mL) under nitrogen at room temperature. Add drop wise phenyl chloroformate (0.125 mL, 1.0 mmole) to the reaction mixture at room temperature. Stir the mixture for 24 hours and new spot is noticed in TLC (30% EtOAc/hexane). Evaporate the reaction mixture under vacuo and purify the crude by flash column chromatography on a silica gel using CHCl3 to afford (5-Trifluoromethyl-pyridin-2-yl)-carbamic acid phenyl ester as a white solid.
In pyridine;
EXAMPLE 8 Preparation of Phenyl N-(5-Trifluoromethyl-2-pyridinyl)carbamate Phenyl chloroformate (1.92 g, 12.3 mmol) was added to a stirring solution of <strong>[74784-70-6]2-amino-5-trifluoromethylpyridine</strong> (2.0 g, 12.3 mmol) in pyridine (20 mL) at a rate which maintained the temperature at 21 C. The mixture was stirred for an additional 0.5 hr and the resulting precipitate was collected by filtration, extracted with ether, then dried to obtain 2.33 g (67 percent of theory) of the title compound as white crystals melting at 203 C. 1H NMR delta 7.25 (m, 3), 7.45 (m, 2), 8.0 (d, 2), 8.2 (d, 1), 8.7 (s,1), 11.25 (s,1). Elemental Analysis: Calcd. for C13 H9 F3 N2 O 2: C, 55.33; H, 3.21; N, 9.93. Found: C, 55.55; H, 3.22; N, 9.80.
In tetrahydrofuran; at 0℃; for 18.5h;
B. (5-TRIFLUOROMETHYL-PYRIDIN-2-YL)-CARBAMIC acid phenyl ester.; A solution of 2- amino-5-triflouromethyl pyridine (4 g) in tetrahydrofuran (50 mL) was cooled to 0 C (ice bath) and stirred for 30 min. A solution of phenyl chloroformate (3.1 mL) in tetrahydrofuran (50 mL) was then added dropwise to the mixture via an addition funnel. After 18 h the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (500 mL), and washed with 1 N sodium bicarbonate (250 mL). The organic layer was dried (NA2SO4), and the solvent was removed. Chromatography of the solid (SI02 ; 0-1 % 2 M ammonia in methanol/dichloromethane) gave the title compound as a white solid (3 g). mp: 203.6-204. 8 C.
1.2 g
With pyridine; In dichloromethane; at 0 - 20℃; for 0.5h;Inert atmosphere;
To a solution of phenyl carbonochloridate (1.72 g, 1 1.0 mmol) in dichloromethane (20.0 ml_) was added 5-(trifluoromethyl)pyridin-2-amine (1.62 g, 10.0 mmol) at room temperature under N2. Pyridine (0.870 g, 1 1.0 mmol) was then added to the reaction at 0 C and the resulting mixture stirred for 0.5 h. The reaction mixture was poured into water and extracted with ethyl acetate followed by drying with sodium sulfate. After concentration, the residue was purified with the column chromatography (eluent: dichloromethane: petroleum ether (1 :2)) to afford 1.2 g of the title compound. NMR (400 MHz, DMSO) d 1 1 .24 (s, 1 H), 8.70 (d, J = 0.9 Hz, 1 H), 8.18 (dd, J = 8.9, 2.3 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 7.43 (dd, J = 1 1.0, 4.8 Hz, 2H), 7.31 - 7.18 (m, 3H).
With sodium t-butanolate;palladium diacetate; CyJohnPhos; In toluene; at 200℃; for 0.5h;Microwave irradiation;
Example 17 (5-Trifluoromethyl-pyridin-2-yl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine The title compound was synthesized in a manner similar to Example 1 with modifications to Step E as follows: Step E. To a solution of 4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (38 mg, 0.12 mmol), 4-trifluoromethyl-amino-pyridine (28 mg, 0.17 mmol), and NaOtBu (16 mg, 0.16 mmol) in toluene (1.2 mL) in a microwave vial was added a solution of Pd(OAc)2 (0.4 mg, 0.002 mmol) and 2-(dicyclohexylphosphino)biphenyl (DCPB) (1.2 mg, 0.004 mmol) in toluene (1 mL). The mixture was flushed with N2(g) and heated in a microwave at 200 C. for 30 min. The mixture was cooled, filtered through a plug of diatomaceous earth, and concentrated. The residue was purified (FCC) to afford the title compound (35 mg, 66%). MS (ESI): mass calcd. for C20H16F6N6, 454.13; m/z found, 453.2 [M+H]+. 1H NMR (CDCl3): 8.65 (s, 1H), 8.61 (d, J=8.8 Hz, 1H), 8.54-8.51 (m, 1H), 8.41-8.38 (m, 1H), 7.95-7.85 (m, 2H), 7.64 (s, 1H), 7.01-6.95 (m, 1H), 3.67-3.57 (m, 4H), 3.31-3.25 (m, 2H), 3.14-3.07 (m, 2H).
4-chloro-2-methylsulfonyl-7-(3-trifluoromethylpyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine[ No CAS ]
[ 74784-70-6 ]
Example 348[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With sodium t-butanolate;palladium diacetate; CyJohnPhos; In toluene; at 200℃; for 2h;
Example 348 2-(Methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine The title compound was synthesized in a manner similar to Example 53 with modifications to Step C in Example 52 as follows: Step C. To a solution of 4-chloro-2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (400 mg, 1.07 mmol), 4-trifluoromethyl-amino-pyridine (208 mg, 1.28 mmol), and NaOtBu (144 mg, 1.5 mmol) in toluene (4 mL) in a microwave vial was added a solution of Pd(OAc)2 (3.7 mg, 0.016 mmol) and 2-(dicyclohexylphosphino)biphenyl (DCPB) (11.9 mg, 0.034 mmol) in toluene (1 mL). The mixture was flushed with N2(g) and heated in a microwave at 200 C. for 2 h. The mixture was cooled, filtered through a plug of diatomaceous earth, and concentrated. The residue was purified (FCC) to afford the title compound (230 mg, 48%). MS (ESI): mass calcd. for C21H18F6N6O2S, 532.11; m/z found, 533.1 [M+H]+. 1H NMR (CDCl3): 8.67 (d, J=8.9 Hz, 1H), 8.56-8.54 (m, 1H), 8.42-8.40 (m, 1H), 8.03-8.00 (m, 1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H), 7.85 (s, 1H), 7.03-6.98 (m, 1H), 3.70-3.65 (m, 2H), 3.63-3.59 (m, 2H), 3.39-3.36 (m, 2H), 3.32 (s, 3H), 3.19-3.15 (m, 2H).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); johnphos; In toluene; at 90℃; for 24h;
Example 176 N2-(2,6-Dimethyl-phenyl)-N7-(5-trifluoromethyl-pyridin-2-yl)-thiazolo[5,4-d]pyrimidine-2,7-diamine To a sealed tube under N2 was added (7-chloro-thiazolo[5,4-d]pyrimidin-2-yl)-(2,6-dimethyl-phenyl)-amine (72.0 mg, 0.26 mmol), 5-trifluoromethyl-pyridin-2-ylamine (50 mg, 0.2 mmol), Pd2(dba)2 (10 mg, 0.01 mmol), 2-(di-t-butylphosphino)biphenyl (13 mg, 0.04 mmol), sodium t-butoxide (29 mg, 0.31 mmol) and freshly distilled toluene (2 mL). The resulting mixture was heated to 90 C. After 24 h, the mixture was filtered through a plug of diatomaceous earth, eluding with EtOAc (20 mL). The filtrate was concentrated and the crude residue was purified by reverse phase HPLC to provide the title compound (7.2 mg, 6.5%). MS (ESI): mass calcd. for C19H15F3N6S, 416.1; m/z found, 417.0 [M+H]+. 1H NMR (CD3OD): delta 9.04-8.96 (m, 1H), 8.93-8.81 (m, 1H), 8.46 (dd, J=8.81, 2.26 Hz, 1H), 8.21-8.09 (m, 1H), 7.25-7.05 (m, 3H), 2.32 (s, 6H).
(5-trifluoromethylpyridin-2-yl)-[7-(3-trifluoromethylpyridin-2-yl)cinnolin-4-yl]amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 90℃;
To a de-gassed mixture of 4-chloro-7- (3-trifluoromethyl-pyridin-2-yl)-cinnoline (1rnmol), cesium carbonate (2 mmol), 2-amino-trifluoromethyl pyridine (1 mmol) in dioxane (10 mL) under nitrogen, add Pd2dba3 (0.05 mmol) and xantphos (0.05 mol; Sigma-Aldrich Corp. , St. Louis, MO). Stir the mixture at 90C overnight, concentrate, and extract with EtOAc. Dry over NaZS04, and concentrate under vacuum. Purify by column chromatography eluting with dichloromethane/methanol/ammonium hydroxide mixture to give (5-trifluoromethyl-pyridin-2-yl)- [7-(3-trifluoromethyl-pyridin-2-yl)-cinnolin-4-yl]-amine.
(7-bromo-quinazolin-4-yl)-(5-trifluoromethyl-pyridin-2-yl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 230℃; for 0.0333333h;
2. (7-bromo-quinazolin-4-yl)-(5-trifluoromethyl-pyridin-2-yl)-amine Heat a mixture of <strong>[573675-55-5]7-bromo-4-chloro-quinazoline</strong> (200 mg, 0.821 mmol) and 2-amino- 5-trifluoromethyl-pyridine (239 mg, 1.48 mmol) at 230C for 2 minutes. Cool and partition the solid residue between ethyl acetate (EtOAc) and 10% NaOH. Dry the EtOAc layer (Na2SO4), remove the solvent under reduced pressure, and purify via flash chromatography to yield (7-bromo-quinazolin-4-yl)- (5-trifluoromethyl-pyridin-2-yl)-amine as a yellow solid. Mass Spec (M+1) 369.0 (retention time 1.21 minutes). When tested for capsaicin receptor agonist activity as described in Example 7, this compound has an EC50 of less than 1 micromolar.
2-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-1,5-naphthyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;
To a de-gassed mixture of 4-CHLORO-2-METHOXY-7- [3- (TRIFLUOROMETHYL) PYRIDIN-2-YL]- [1, 5] NAPHTHYRIDINE (1 MMOL), cesium carbonate (2 mmol), 2-amino-trifluoromethyl pyridine (1 mmol) in dioxane (10 mL) under nitrogen, add Pd2dba3 (46 mg) and xantphos (29 mg). Stir the mixture at 100C for 3 hours, cool, add water (10 mL) and extract with EtOAc. Dry the combined extracts over NA2S04, concentrate under vacuum. Purify by chromatography eluting with DICHLOROMETHANE/METHANOL/AMMONIUM hydroxide mixture to give the title compound. MS 435.98 (M H NMR 8 (CDCl3) 8.95 (1H, d), 8.90 (1H, s), 8.58 (1H, s), 8. 38 (1H, d), 8.30 (1H, s), 8.19 (1H, d), 8.06 (1H, s), 7.88 (1H, d), 7.55 (1H, M), 7.05 (1H, s), 4.16 (3H, s).
7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)-pyridin-2-yl]quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;
To a de-gassed mixture of 4-chloro-7- [3- (trifluoromethyl) pyridin-2-yl] quinoline (0.5 mmol), cesium carbonate (1 mmol), 2-amino-trifluoromethyl pyridine (0.5 mmol) in dioxane (5 mL) under nitrogen add Pd2dba3 (23 mg) and xantphos (15 mg). Stir the mixture at 100C for 3h, cool, add water (8 mL) and extract with EtOAc. Dry over NA2S04, concentrate under vacuum. Purify by chromatography eluting with DICHLOROMETHANE/METHANOL/AMMONIUM hydroxide mixture and triturate with ether/hexane to give the title compound. MS 435 (M+1). 1H NMR No. (CDCL3) 8.73 (1H, d), 8.56 (1H, s), 8.51 (1H, s), 8.40 (2H, d), 8.11-8. 09 (3H, m), 7.85 (1H, d), 7.67 (1H, d), 7.53 (1H, d), 7.47 (1H, dd).
3-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)-pyridin-2-yl]pyrido[2,3-b]pyrazin-8-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;
To a de-gassed mixture of 3- [3- (trifluoromethyl) pyridin-2-yl] pyrido [2,3-b] pyrazin-8- amine (72 mg, 0.25 MMOL), cesium carbonate (162 mg, 0.5 mmol), 2-amino-trifluoromethyl pyridine (45 mg, 0.25 mmol) in dioxane (5 mL) under nitrogen, add PD2DBA3 (11 mg) and xantphos (7 MG). Stir the mixture AT 100C for 3 hours, cool, add water (10 mL) and extract with EtOAc. Dry over NA2SO4, concentrate under vacuum. Purify by chromatography eluting with DICHLOROMETHANE/METHANOL/AMMONIUM hydroxide mixture to give the title compound. MS 437 (M + 1).'H NMR 6 (CDCI3) 9.42 (1H, s), 9.28 (1H, s), 9.11 (1H, d), 8.95 (1H, d), 8. 90 (IH, d), 8.72 (1H, s), 8.25 (1H, d), 7.89 (1H, d), 7.61 (1H, dd), 7.13 (1H, d).
7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)-pyridin-2-yl]-1,8-naphthyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 20h;
Heat a mixture of 5-CHLORO-2- (3- (TRIFLUOROMETHYL) PYRIDIN-2-YL)- [1, 8 NAPHTHYRIDINE (62, mg, 0.2 MMOL), 2-AMINO-5-TRIFLUOROMETHYLPYRIDINE (32.4 mg, 0.2 MMOL), xantphos (11.6 mg, 0.02 MMOL), PD2 (dba) 3 (18.3 mg, 0.02 mmol) and CS2CO3 (130 mg, 0.4 mmol) in dioxane (2.0 mL) at 100C for 20 hours. Cool the mixture, concentrate under vacuum, dilute with EtOAc/ water (5.0 mL each), filter through celite, wash celite with EtOAc (2 x 5 mL) and dry combined organic layers with MGS04. Filter the dried extract and concentrate under vacuum to afford crude product. Purify by preparative TLC using EtOAc as eluent to afford title compound as a yellow SOLID. H NMR (400 MHZ, DMSO-D6) 8 10.15 (s, 1H), 9.1 (d, 1H, J=2.2 Hz), 9.0 (d, 1H, J=I. L Hz), 8.95 (d, IH, J=1.2 Hz), 8.68 (S, IH), 8. 50 (d, 1H, J=1. 3 Hz), 8.43 (d, 1H, J=2.0 Hz), 8. 12 (dd, 1H), 8.0 (d, 1H, J=2. 2 Hz), 7.81 (m, 1H), 7.49 (d, 1H, J=2. 2 Hz). MS = 436.08 (M+H).
2-methoxymethyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-[1,8]naphthyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;
C. 2-Methoxymethyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5- (TRIFLUOROMETHYL) PYRIDIN-2-YL]- [1, 8] NAPHTHYRIDIN-4-AMINE is prepared according to the procedure shown in Scheme 2, as follows : To a de-gassed MIXTURE OF 4-CHLORO-2-METHOXYMETHYL-7- (3-TRIFLUOROMETHYL-PYRIDIN-2- YL)- [1, 8] naphthyridine (1 mmol), cesium carbonate (2 mmol), 2-amino-trifluoromethyl pyridine (1 mmol) in dioxane (10 mL) under nitrogen, add PD2DBA3 (0. 05 mmol) and xantphos (0.05 mol). Stir the mixture at 90C overnight, concentrate, and extract with EtOAc. Dry over NA2SO4 and concentrate under vacuum. Purify by column chromatography eluting with DICHLOROMETHANE/METHANOL/AMMONIUM hydroxide mixture to give 2-METHOXYMETHYL-7- [3- (trifluoromethyl) PYRIDIN-2-YL]-N- [5- (TRIFLUOROMETHYL) PYRIDIN-2-YL]- [1, 8] naphthyridin-4- amine. MS 480 (M+L). LH NMR 6 (COOL3) 8.88 (1H, d), 8.62 (1H, s), 8.18 (1H, d), 8. 07 (1H, s), 7.88 (1H, dd), 7.84 (1H, d), 7.56 (1H, d), 7.54 (1H, d), 7.30 (1H, d), 4.77 (2H, s), 3.52 (3H, s), 2.63 (1H, BR S).
2-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-1,8-naphthyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;
To a de-gassed mixture of 4-CHLORO-2-METHOXY-7- (3-TRIFLUOROMETHYL-PYRIDIN-2-YL)- [1, 8] NAPHTHYRIDINE (1 MMOL), cesium carbonate (2 mmol), 2-AMINOTRIFLUOROMETHYL pyridine (1 mmol) in dioxane (10 mL) under nitrogen, add PD2DBA3 (0.05 mmol) and xantphos (0.05 MOL). Stir the mixture at 90C overnight, concentrate, and extract with EtOAc. Dry over NA2S04 and concentrate under vacuum. Purify by column chromatography eluting with dichloromethane/methanol/ammonium hydroxide mixture to give the title compound.
In methanol; 1,2-dimethoxyethane; at 80℃; for 14.0h;
To a mixed solution of 5-(trifluoromethyl)pyridin-2-amine (835 mg, 5.15 mmol) in 1,2-dimethoxyethane (12.9 mL) and methanol (12.9 mL) was added ethyl bromopyruvate (776 μL, 6.18 mmol), and the mixture was stirred for 14 hours at 80C. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography to give ethyl 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (amount 557 mg, yield 42%).
42%
In methanol; 1,2-dimethoxyethane; at 80℃; for 14.0h;
5- (Trifluoromethyl) Pyridine-2-amine (835 mg, 5.15 mmol)In a mixed solution of 1,2-dimethoxyethane (12.9 mL) and methanol (12.9 mL)Ethyl bromopyruvic acid (776 μL, 6.18 mmol) was added, and the mixture was stirred at 80 C. for 14 hours.Residue after concentrating the reaction under reduced pressureWas purified by silica gel column chromatography to obtain ethyl 6- (trifluoromethyl) imidazole [1,2-a]pyridine-2-carboxylate (yield 557 mg, yield 42%).
In ethanol; at 20 - 80℃; for 66.0h;
(a) 6-Trifluoromethyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of 3-bromo-2-oxo-propionic acid ethyl ester (6.4 mL, 50.9 mmol, Aldrich) and 5-trifluoromethyl-pyridin-2-ylamine (1.65 g, 10.2 mmol, Maybridge) in EtOH (20 mL) was heated at 80 C. for 48 h, and left at room temperature for 18 h. The white solid that precipitated was filtered, and the filter cake was rinsed with ether (10 mL), and dried in vacuo to provide the title compound. MS (ESI, pos. ion.) m/z: 258 (M+1).
With Sodium hydrogenocarbonate; In ethanol; at 85℃; for 4.0h;
To a solution of 5-(trifluoromethyl)pyridin-2-amine (4.0 g, 25 mmol) in ethanol (40 mL) were added ethyl 3-bromo-2-oxo-propanoate (3.7 mL, 30 mmol) and sodium bicarbonate (4.1 g, 49 mmol) at room temperature. The reaction mass was heated at 85 C for 4 hours. After completion, the reaction mass 5 was added to ice cold water, solid was precipitated and the obtained solid was filtered through a Buchner funnel to afford ethyl 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate. This material was used as such in the next step. LCMS (Method 2): Rt = 1.35 min, m/z= 259 (M+H)+.
With Sodium hydrogenocarbonate; In ethanol; at 85℃; for 4.0h;
To a solution of 5-(trifluoromethyl)pyridin-2-amine (4.0 g, 25 mmol) in ethanol (40 mL) were added ethyl 3-bromo-2-oxo-propanoate (3.7 mL, 30 mmol) and sodium bicarbonate (4.1 g, 49 mmol) at room temperature. The reaction mass was heated at 85 C for 4 hours. After completion, the reaction mass 5 was added to ice cold water, solid was precipitated and the obtained solid was filtered through a Buchner funnel to afford ethyl 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate. This material was used as such in the next step. LCMS (Method 2): Rt = 1.35 min, m/z= 259 (M+H)+.
[0183] To 2-amino 5-trifluoromethyl pyridine, (50g, 308mmol) was added acetic acid (50OmL), followed by pre-mixed water (35mL) and concentrated sulfuric acid (5mL) and stirred until completely solubilised. Periodic acid (13.3g, 58mmol) was added followed by iodine (31.2g, 123mmol) and then the reaction mixture was heated to 85 0C for 18 hours. [0184] The reaction mixture was allowed to cool to room temperature and then carefully basified with 4M NaOH solution to pH 10-14. This gave a precipitate which was isolated by filtration and stirred in water (.1 litre), filtered and dried to give the product as a brown powder (61.38g, 69%).
67%
With sulfuric acid; iodine; acetic acid; periodic acid; In water; at 80℃; for 16h;Inert atmosphere;
[0522] To a stirred solution of 5-(trifluoromethyl) pyridin-2-amine (100 g, 617 mmol) in acetic acid (1 Lit) at room temperature under an argon atmosphere were added concentratedsulfuric acid (5 mL), periodic acid (26 g, 123 mmol) and iodine (62 g, 246 mmol). The reaction mixture was stirred at 80 C for 16 h. After consumption of starting material (by TLC), the reaction mixture was basified with sodium hydroxide solution (200 mL) at 0 C, to obtain the solid. The solid was filtered and concentrated in vacuo to obtain 3-iodo-5- (trifluoromethyl) pyridin-2-amine (120 g, 67%) as an off-white solid. ?H NMR (DMSO-d6 500 MHz): 8.27 (s, 1H), 8.16 (s, 1H), 6.87 (brs, 2H); TLC: 10% EtOAc Hexane (R1 0.4).
With iodine; silver sulfate; In N,N-dimethyl-formamide; at 20℃; for 14h;
Step A (S)-N-((2-amino-5-(trifluoromethyl)pyridin-3-yl)methyl)-2-phenylbutanamide (3-2) A solution of 5-(trifluoromethyl)pyridin-2-amine (3-a with R4=CF3, 1.6 g, 9.87 mmol) (Maybridge Chemical company, Cornwall, England) in N,N-dimethylformamide (30 mL) was treated at room temperature with silver sulfate (3.1 g, 9.87 mmol) and iodine (2.5 g, 9.87 mol). The reaction mixture was stirred for 14 h and filtered. The filtrated solution was concentrated in vacuo. The residue was chromatographed (SiO2, 25% ethyl acetate in hexanes) to give 5-(trifluoromethyl)-3-iodopyridin-2-amine (3-b, with R4=CF3).
With iodine; silver sulfate; In ethanol; at 20℃; for 48h;
EXAMPLE 13Compound 16N-(1,2-dimethyl-1H-benzimidazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide13.1 2-amino-3-iodo-5-(trifluoromethyl)pyridine; 2 g (12.34 mmol) of 2-amino-5-trifluoromethylpyridine, 3.85 g (12.34 mmol) of silver sulfate and 80 ml of ethanol are placed in a 500 ml two-necked flask equipped with a magnetic stirrer. 3.13 g (12.34 mmol) of iodine powder are then added portionwise to the reaction medium stirred at room temperature. The reaction mixture is then stirred at room temperature for 48 hours. The resulting yellow suspension is filtered, the precipitate is rinsed with ethanol and the filtrate is evaporated under reduced pressure. The residue thus obtained is taken up in dichloromethane (200 ml). The organic phase is washed successively with aqueous 5% sodium hydroxide solution, with water and then with saturated aqueous sodium chloride solution. It is dried over sodium sulfate and concentrated under reduced pressure. The resulting solid is purified by chromatography on a column of silica, eluting with a mixture of n-heptane and ethyl acetate. 1.71 g (5.94 mmol) of product are obtained in the form of a pink powder.1H NMR (DMSO D6), delta (ppm): 8.3 (s, 1H); 8.1 (s, 1H); 6.8 (s, NH2).
With N-iodo-succinimide; acetic acid; In water; at 70℃; for 3h;
e) 2-amino-3-iodo-5-trifluoromethyl-pyridine can be prepared as follows: A mixture of 4.0 g of 2-amino-5-trifluoromethyl-pyridine and 6.2 g of N-iodo succinimide in 110 cm3 of acid acetic is heated at 70 C. for three hours, then cooled to room temperature and concentrated under vacuum. The residue is taken up slowly in 60 cm3 of water saturated with sodium bicarbonate, then 60 cm3 of water. The solid which precipitates is filtered and then dried under vacuum to obtain 6.68 g of 2-amino-3-iodo-5-trifluoromethyl-pyridine in the form of a beige solid with the following characteristics: LC-MS: retention time: 3.72 min; LC-MS-DAD-ELSD: 289(+)=(M+H)(+).
With iodine; silver sulfate; In ethanol; at 20℃;
Example 5; Compound 5N-(2-methyl benzothiazol-5-yl)-5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide5.1 2-amino-3-iodo-5-trifluoromethylpyridine2 g (12.34 mmol) of 2-amino-5-trifluoromethylpyridine, 3.85 g (12.34 mmol) of silver sulfate and 80 mL of ethanol are introduced into a 500 mL two-necked flask equipped with a magnetic stirrer. 3.13 g (12.34 mmol) of iodine powder are then added portionwise to the reaction medium stirred at room temperature. The reaction mixture is then stirred at room temperature for 48 hours. The resulting yellow suspension is filtered, the precipitate is rinsed with ethanol and the filtrate is evaporated under reduced pressure. The residue is taken up in 100 mL of dichloromethane. This solution is washed successively with 20 mL of aqueous 5% sodium hydroxide solution, 20 mL of water and 20 mL of saturated aqueous sodium chloride solution and then dried over sodium sulfate and concentrated under reduced pressure. The resulting solid is purified by chromatography on a column of silica, eluting with a mixture of n-heptane and ethyl acetate. 1.71 g of product are obtained in the form of a pink powder.1H NMR (DMSO D6), delta (ppm): 8.3 (s, 1H); 8.1 (s, 1H); 6.8 (s, 2H).
14.3 g
With iodine; silver sulfate; In ethanol; at 10 - 35℃;
To a mixture of 5-(trifluoromethyl)pyridin-2-amine (12.0 g), silver(I) sulfate (23.1 g) and ethanol (400 mL) was added iodine (37.6 g) in several parts at room temperature, and the reaction mixture was stirred overnight at room temperature. To the reaction solution was added saturated aqueous sodium thiosulfate solution, and the mixture was stirred for 30 min, and neutralize with 1N aqueous sodium hydroxide solution. The insoluble substance was removed by filtration, the filtrate was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (14.3 g). MS (APCI+): [M+H]+ 289.0
N-[5-(trifluoromethyl)pyridin-2-yl]-7-[5-(trifluoromethyl)-1,3-thiazol-4-yl]-1,8-naphthyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110℃;
In a sealed tube, combine 5-chloro-2-[5-(trifluoromethyl)-l,3-thiazol-4-yl]-l,8-naphthyridine (100 mg, 0.317 mmol), 2-amino-5-trifluoromethyl-pyridine and Cs2CO3 (341 mg, 0.951 mmol), and dissolve in dry dioxane (5 mL). Bubble argon through the solution for five minutes. Add Pd2dba3 (29 mg, 0.0317 mmol) and xantphos (19 mg, 0.0317 mmol) and bubble argon through the solution for an additional five minutes. Seal the tube and heat at HO0C overnight. Cool the mixture and dilute with EtOAc. Filter the solution through Celite. Concentrate the filtrate under reduced pressure. Purify the residue by preparatory TLC, eluting with EtOAc/hexane (3:1) to yield the title compound. 1H NMR (CDCl3) 8 9.11 (br m, IH), 8.98 (s, IH), 8.63 (d, IH), 8.58 (d, IH), 8.28 (d, IH), 8.10 (br m, IH), 7.87 (dd, IH), 7.80 (br m, IH), 7.21 (d, IH). LC/MS (MH+) 442.06; retention time 1.24 minutes.
EXAMPLE 9 Into the same 300 ml four-necked flask as used in Example 1, 16.2 g (0.1 mol) of 2-amino-5-trifluoromethylpyridine, 20.9 g (0.115 mol) of <strong>[3481-09-2]N-chlorophthalimide</strong> and 150 g of toluene were added, and the reaction was carried out at 80 C. for one hour under heating with stirring. During the reaction, formation of 2-chloroamino-5-trifluoromethylpyridine was confirmed.
N-[5-(trifluoromethyl)pyridin-2-yl]-7-[4-(trifluoromethyl)pyridazin-3-yl]-1,8-naphthyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110℃;
In a sealed tube, dissolve 5-chloro-2-[4-(trifluoromethyl)pyridazin-3-yl]-l,8-naphthyridine (115 mg, 0.370 mmol), 2-amino-5-trifluoromethyl-pyridine (75 mg, 0.463 mmol) and Cs2CO3 (398 mg, 1.22 mmol) in dry dioxane (5 mL). Bubble argon through the solution for five minutes. Add Pd2dba3 (34 mg, 0.037 mmol) and xantphos (22 mg, 0.037 mmol) and bubble argon through the solution for an additional five minutes. Seal the tube and heat at HOC overnight. Cool the mixture and dilute with ethyl acetate. Filter the solution through Celite. Concentrate the filtrate under reduced pressure. Purify the crude residue by PTLC eluting with CH2Cl2/MeOH/NH4OH (95/5/1) to yield the title compound. 1H NMR (CDCl3) delta 9.54 (d, IH), 9.07 (br s, IH), 8.71 (d, IH), 8.64 (s, IH), 8.20 (d, IH), 8.8 (br m, 2H), 7.96 (d, IH), 7.89 (d, IH), 7.25 (d, IH). LC/MS (MH+) 436.09. The IC50 is less than 1 micromolar in the assay provided in Example 6.
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110℃;
In a sealed tube, dissolve 4-(5-chloro-l,8-naphthyridin-2-yl)-5-(trifluoromethyl)- pyrimidin-2-ol (237 mg, 0.725 mmol), 2-amino-5-trifluoromethyl-pyridme (176 mg, 1.09 mmol), and CS2CO3 (709 mg, 2.18 mmol) in dry dioxane (7 mL). Bubble argon through the solution for five minutes. Add Pd2dba3 (66 mg, 0.0725 mmol) and xantphos (42 mg, 0.0725 mmol) and bubble argon through the solution for an additional five minutes. Seal the tube and heat at HOC overnight. Cool the mixture and dilute with Et2O. Filter the solution through Celite. Discard the filtrate. Wash the Celite bed with MeOH. Concentrate the methanolic filtrate under reduced pressure. Purify the crude residue by silica gel chromatography eluting with CH2Cl2ZMeOH (90/10) to yield the title compound. LC/MS (MH+) 453.10.
5-chloro-2-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine[ No CAS ]
[ 74784-70-6 ]
[7-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 14h;
4. [7-(6-Methoxy-3-trifluo?-omethyl-pyridin-2-yl)-[l,8]naphthyridin-4-yl]-(5-trifluoro7nethyl- pyridin-2-yl)-amine To a de-gassed mixture of 5-chloro-2-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)- [l,8]naphthyridine (68 mg, 0.2 mmol), cesium carbonate (98 mg, 0.3 mmol), 2-amino-5- EPO <DP n="57"/>trifluoromethyl pyridine (37 mg, 0.22 mmol) in dioxane (5 mL) under nitrogen, add Pd2dba3 (12 mg) and xantphos (8 mg). Stir the mixture at 1000C for 14 hours, cool, add water (20 mL) and extract with EtOAc. Dry the combined extracts over Na2SO4, concentrate under vacuum. Purify by chromatography eluting with DCM/MeOH/ammonium hydroxide mixture to give the title compound. 1H NMR delta (CDCl3) 9.01 (IH, brs), 8.59-8.62 (2H, m), 7.98-8.01 (2H, m), 7.91-7.84 (2H, m), 7.23- 7.26 (2H, m), 6.90 (IH, d), 3.99 (3H, s). The IC50 determined as described in Example 6 is less than 1 micromolar.
With bromine; sodium thiosulfate; acetic acid; In water;
EXAMPLE 4 Preparation of 2-Amino-3-bromo-5-trifluoromethylpyridine In a 100 ml four necked flask equipped with the same equipments as those used in Example 3 were placed 3 g of 2-amino-5-trifluoromethylpyridine and 30 ml of acetic acid to provide a homogeneous solution. 4.4 g of bromine was dropwise added thereto while cooling the flask with ice water at 10 to 20 C., and after completion of the dropwise addition, the mixture was reacted for 1 hour. The reaction product was poured into 200 ml of water, washed with an aqueous solution of sodium thiosulfate and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated off. The solid thus obtained was washed with n-hexane to obtain 3.5 g of the desired product.
1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (5-trifluoromethylpyridin-2-yl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
To a solution of l-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-iH-pyrazole-3- carboxylic acid (1.00 g, 2.65 mmol) in DCM (20 ml) was added 5 drops of DMF followed by 5 ml oxalyl chloride. The reaction mixture was stirred for one hour at room temperature, concentrated and the crude acid chloride redissolved in DCM (20 ml). DMAP (0.98 g, 8.03 mmol) was added followed by 5-(trifluoromethyl)pyridine-2-amine (0.49 g, 3 mmol). The reaction mixture was stirred at room temperature overnight then water was added and the product extracted with DCM (x2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Flash chromatography (heptane - heptane : EtOAc 90 : 10) gave 0.67 g (49%) of the title compound as a colorless solid.
N-(5-(trifluoromethyl)pyridin-2-yl)pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With dmap; In N,N-dimethyl-formamide; at 120℃; for 18h;
Example 4 N-(5 -( trifluoromethyl)pyridin-2-yl)pyrazole-3 -carboxamideA mixture of intermediate (I) (188 mg, 1.0 mmol), DMAP (122 mg, 1.0 mmol) and 2-amino-5-(trifluoromethyl)pyridine (170 mg, 1.0 mmol) in DMF (7 mL) was stirred at 12O0C for 18 h and allowed to cool to rt. HCl (aq., IM, 10 mL) was added and the mixture was extracted with EtOAc (2x20 mL). The combined extracts were washed with water, NaCl (sat., aq.), dried (MgSO4) and concentrated. Crystallisation from EtOAc/pentane followed by crystallisation from EtOH/water furnished the title compound as a white powder (Yield: 95.3 mg, (35%)). MS (M"+eta) m/z = 257 1H-NMR (DMSO-J6, 400 MHz), delta 13.64 (br s, IH), 10.04 (br s, IH)5 8.75 (s, IH), 8.37 (d, IH), 8.24 (d, IH), 7.93 (bs, IH), 6.93 (br s, IH)
5-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With dmap; In dichloromethane; at 60℃; for 18h;
Example 5S-Chloro-iV-fS-ftrifluoromethvDpYridin-l-vDpyrazole-S-carboxamide A mixture of intermediate (III) (140 mg, 0.5 mmol), DMAP (133 mg5 1.0 mmol) and, <strong>[74784-70-6]2-amino-5-trifluoromethylpyridine</strong> (186 mg, 1.0 mmol) in CH2Cl2 (15 mL) was stirred at 6O0C for 18 h and allowed to cool to rt. The solid was collected by filtration and washed with CH2Cl2. The solid was dissolved in EtOAc (20 mL) and washed with HCl (aq., 2M, 2x10 mL), NaCl (sat., aq.), dried (MgSO4) and concentrated. Crystallisation from EtOH/water gave the title compound as white crystals (Yield: 81.7 mg, (52%)). MS (M++H) m/z = 2911H-NMR(DMSO-J6, 400 MHz), delta 14.14 (br s, IH), 11.38 (br s, IH), 8.80 (s, IH), 8.26-8.80 (m, 2H)5 7.37 (s, IH)
1,2,3-triazole-4-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
A mixture of l,2,3-triazole-4-carboxylic acid (65 mg, 0.50 mmol), SOCl2 (1 mL) and DMF (1 drop) was heated at 40 0C for 2 h. The mixture was concentrated and the residue was dried in vacuo. A mixture of the resulting solid, DMAP (83 mg, 0.68 mmol) and the relevant arylamine (2.0 mmol) in CH2Cl2 (5 mL) was stirred at the indicated temperature for the indicated period of time and then concentrated. The residue was dissolved in EtOAc (20 mL), washed with HCl (aq, 2M, 2x5 mL) and NaCl (aq, sat, 5 mL), dried (MgSO4) and concentrated. The residue was purified by chromatography (eluent EtO Ac/heptane, 1 : 1) to give the title product.
EXAMPLE 614-(Aminomethyl)-l-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-N-(5-(trifluoromethyl)pyridin-2- yl)piperidine-4-carboxamide; <n="189"/>6 IA. ferf-Butyl 4-cyano-4-(5-(trifluoromethyl)pyridin-2-ylcarbamoyl)piperidine- 1 - carboxylateHATU (1121 mg, 2.95 mmol) was added in one portion to l-(tert-butoxycarbonyl)-4- cyanopiperidine-4-carboxylic acid (Example 26A) (500mg, 1.97 mmol) and DIPEA (1.030 ml, 5.90 mmol) in DMA (5ml) at 2O0C under nitrogen. The resulting solution was stirred at 20 0C for 10 minutes then 2-amino-5-(trifluoromethyl)pyridine (383 mg, 2.36 mmol) added. The reaction mixture was stirred at 50 0C for 6 hours then at 20 0C for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2 x 50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford and triturated with diethyl ether to afford tert-butyl 4- cyano-4-(5-(trifluoromethyl)pyridin-2-ylcarbamoyl)piperidine-l -carboxylate (554 mg, 70.7 %) as a white solid.IH NMR (400.13 MHz, DMSO-d6) delta 1.42 (9H, s), 2.00 - 2.07 (2H, m), 2.25 (2H, d), 2.97 (2H, s), 4.04 (2H, d), 8.19 - 8.27 (2H, m), 8.80 (IH, t), 11.38 (IH, s) <n="190"/>MS m/e M-H 397
With triethylamine; In dichloromethane; at -5 - 20℃; for 2.25h;
N-(5-(trifluoromethyl)pyridin-2-yl)pivalamide 5-(trifluoromethyl)pyridin-2-amine (15 g, 92.5 mmole) was taken up in DCM (190 ml) under nitrogen and NEt3 (16 ml, 115.7 mmole) was added. The solution was cooled to -5 C., a solution of trimethyl acetyl chloride (12.5 ml, 101.8 mmole) in DCM (65 ml) was added dropwise, and the mixture was stirred for a further 15 minutes in an ice bath. The mixture was then stirred for 2 hours at RT. The suspension was washed with H2O (150 ml), then with dilute NaHCO3 solution, and the organic phase was dried over MgSO4. After filtering off the drying agent and removing the solvent on a rotary evaporator the residue was crystallized. N-(5-(trifluoromethyl)pyridin-2-yl)pivalamide (20.8 g, 91) was obtained.
With sodium t-butanolate;palladium diacetate; CyJohnPhos; In toluene; at 20 - 90℃; for 18h;
Example 94[2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine To a mixture of 7-chloro-2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidine (120 mg, 0.36 mmol), 2-(dicyclohexylphosphino)biphenyl (25 mg, 0.07 mmol), palladium acetate (8.0 mg, 0.04 mmol), and 5-trifluoromethyl-pyridin-2-ylamine (88 mg, 0.54 mmol) in toluene (3 mL) was added NaOtBu (49 mg, 0.51 mmol) at rt. The mixture was heated to 90 C. for 18 h under N2. The reaction mixture was cooled and filtered through a pad of diatomaceous earth, eluting with EtOAc (30 mL). The filtrate was concentrated and the crude residue was purified using preparative reverse-phase HPLC to afford the title compound a colorless solid (95 mg, 58%). MS (ESI): mass calcd. for C18H10Cl2F3N5S, 455.0; m/z found, 456.0 [M+H]+. 1H NMR ((CD3)2SO): 9.76 (s, 1H), 8.73-8.71 (m, 2H), 8.50 (d, J=8.8 Hz, 1H), 8.23 (dd, J=8.9, 2.4 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 7.45 (dd, J=8.5, 7.7 Hz, 1H), 4.83 (s, 2H).
1-(4-(benzyloxy)phenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)-1H-imidazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
2-Amino-5- (trifluoromethyl) pyridine (404 mg, 2.49 mmol) was dissolved in dichloromethane (2.5 ml) under argon and trimethylaluminium (1.25 ml, 2.0 M in toluene, 2.5 mmol) was carefully added during 5 min. The solution was stirred at ambient temperature for 1.5 h and, as a result, a 0.66 M solution of an amidation reagent was obtained. 3.75 ml (2.5 mmol) of this stock solution was added to ethyl 1- [4- (benzyloxy) phenyl]-2-(2, 4-dichlorophenyl)-5-methyl-lH-imidazole-4-carboxylate, prepared as described in Ex. 1, Step 2, (400 mg, 0.83 mmol) and the reaction solution was stirred at 45C overnight. The reaction solution was cooled to 0C and quenched with HC1 (aq, 2 M, 7.5 ml). The mixture was diluted with dichloromethane and neutralized by addition of KOH (aq, 2 M). The organic phase was separated and the aqueous phase was extracted further with dichloromethane. The collected organic phases were washed with H20 before drying with Na2S04. The solvent was removed under reduced pressure and purification by preparatory HPLC gave the title compound (319 mg, 64%) as a solid. 'H NMR (400 MHz) 8 9.89 (s, NH), 8.54 (s, 1H), 8.50 (d, 1H), 7.92-7. 88 (m, 1H), 7.40- 7.33 (m, 5H), 7.27-7. 20 (m, 3H), 7.03-6. 91 (m, 4H), 5.02 (s, 2H), 2.50 (s, 3H). MS m/z 597 (M+H) +.
Preparation of compound 13b: 3-(6-chloropyrazin-2-yl)-6- (trifluoromethyl)imidazo[1,2-a]pyridine13a (328 mg, 1.92 mmol) was dissolved in dioxane-water (6 ml_:3 mL) and treated with NBS (285 mg, 1.60 mmol) in one portion which gave a light yellow solution.Solution stirred for 10 min at room temperature. 2-amino-5-(trifluoromethyl)pyhdine(260 mg, 1.60 mmol) was added and the reaction mixture was heated in the microwave for 10 min at 100 0C. The crude reaction was diluted with EtOAc (35 mL) and NaHCO3 (sat, aq) (20 ml_). The aqueous phase was back extracted with EtOAc (25 ml_) The combined extracts were washed with brine (35 ml_) then dried (MgSO4) filtered and concentrated. The crude product was purified by column chromatography (EtOAc/MeOH) which gave the title compound 13b as a beige solid (265 mg, 45%). 1 H NMR (300 MHz, DMSO-c/6) delta ppm 7.76 (dd, J=9.4, 1.9 Hz, 1 H) 8.00 (d, J=9.4 Hz, 1 H) 8.67 (s, 1 H) 8.83 (s, 1 H) 9.39 (s, 1 H) 10.04 (s, 1 H).
To a solution of bis (trichloromethyl) carbonate (59.3 mg, 0.200 mmol) in tetrahydrofuran (2 mL) were added N- [6- (3- aminophenoxy) -7-cyano-l, 3-benzothiazol-2- yl] cyclopropanecarboxamide (200 mg, 0.571 mmol) produced inExample 3(vi) and triethylamine (158 muL, 1.14 mmol) at 4C, and the mixture was stirred at the same temperature for 30 min. 5- (Trifluoromethyl) pyridin-2-amine (185 mg, 1.14 mmol) was added to the reaction mixture, and the mixture was stirred at 500C for 2 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) , washed successively with saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL) , and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100?10/90) , and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane (1/1) to give the title compound (113 mg, 37%) as a white powder.1H-NMR (DMSO-d6, 300 MHz) delta 0.92 - 1.09 (4H, m) , 1.98 - 2.14 (IH, m), 6.77 - 6.89 (IH, m) , 7.16 (IH, d, J = 8.9 Hz), 7.26 - 7.33 (IH, m) , 7.35 - 7.45 (IH, m) , 7.49 (IH, t, J = 2.2 Hz), 7.80 (IH, d, J = 8.9 Hz), 8.04 (IH, d, J = 8.9 Hz), 8.11 (IH, dd, J = 8.9, 2.4 Hz), 8.54 - 8.71 (IH, m) , 9.82 (IH, s) , 10.16 ( IH, s ) , 12 . 99 ( IH , br s ) .
To a stirred solution of 5-(trifluoromethyl)pyridin-2-amine (0.405 g, 2.5 mmol) in a mixture of ethanol (12.5 mL) and acetic acid (0.25 mL) at room temperature was added 3,4-dimethoxy-5-nitrobenzaldehyde (0.53 g, 2.5 mmol). The reaction was heated at reflux temperature for two hours then ethanol was evaporated. The oily residue was dissolved in a mixture of methanol (17 mL) and 1,2-dimethoxyethane (7.5 mL), whereupon 1-(isocyanomethylsulfonyl)-4-methylbenzene (TOSMIC) (0.73 g, 3.75 mmol) and potassium carbonate (0.69 g, 5 mmol) were added in one portion. The resulting mixture was stirred at reflux temperature for 3 hours. The reaction was evaporated to dryness, and then taken up in dichloromethane (50 ml). The organic phase was washed with water (50 mL) and then dried over anhydrous magnesium sulphate, filtered and evaporated to leave brown oil. Column chromatography over silica gel (petroleum ether-ethyl acetate 9:1) gave 2-(5-(3,4-dimethoxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine, 0.542 g (55%).
With triethylamine; HATU; In N,N-dimethyl-formamide; at 75℃; for 2h;microwave irradiation;
To a solution of 5-(trifluoromethyl)pyridin-2-amine (52) (0.162g, lmmol), 2-(4-(tert- butoxycarbonyl)-2-oxopiperazin- 1 -yl)acetic acid (44) (0.257g, lmmol), and HATU (0.46g, 1.3mmol) in DMF 3ml was added triethylamine (0.3ml, 3 mmol). The mixture was heated in a microwave at 75C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by automated flash chromatography using pet ether and ethyl acetate as eluents. Yield 0.15g, 50%. LCMS m/z 401.9 (M+H+).
bis(2-amino-5-trifluoromethylpyridinium) tetrachlorocuprate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.5%
In water; at 20℃; for 336h;
2-Amino-5-(trifluoromethyl)pyridine (0.601 g, 3.76 mmol) was dissolved in 15 ml of H2O and 0.5 ml (60% xs) of 12 M HCl. A solution of copper(II) chloride dihydrate (0.253, 1.88 mmol) in 15 ml of distilled H2O was added while stirring affording a sky blue solution. After two weeks of slow evaporation at room temperature, yellow triangular crystals were collected by filtration, washed with tBuOH, and dried to give 0.935 g (93.5% yield). IR (KBr, cm-1): nu 3317 (s, -NH2 asym str), 3177 (s, -NH2 sym str), 1674 (s, -NH2 scissor), 1637 (s), 1556 (w), 1469 (w), 1427 (w), 1373 (m), 1327 (s, C-NH2 str), 1180 (m, C-CF3 str), 1132 (s), 1072 (s), 838 (m), 643 (m), 618 (m), 598 (m), 508 (w). CHN found (calculated): C 27.38 (27.12), N 10.33 (10.54), H 2.41 (2.28).
[6-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
5-(Trifluoromethyl)-pyridine-2ylamine (0.47 g, 2.92 mmol) was added to a mixture of sodium hydride (0. 81 g, 33.9 mmol) and N,N-dimethylformamide (6.8 ml_) under nitrogen gas at 25 - 30 C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (0.85 g, 3.39 mmol) was added to the reaction mixture and was stirred for 16 - 18 h. The reaction mixture was cooled to 10 C and methanol (1 .7 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (85 ml_) was added drop-wise to the reaction mixture at 10 C and was stirred for 25 - 30 min. The precipitated product was filtered, washed with water followed petroleum ether. The resulting product was dried at 45 - 50 C for 20 - 22 h. Yield: 0.75 g (59 %); 1H NMR (300 MHz, DMSO-d6): delta 10.6 (s, 1 H), 8.8 (s, 1 H), 8.7 (s, 1 H), 8.2 (s, 1 H), 8.1 (d, 1 H, 9Hz), 8.0 (d, 1 H, 8.7 Hz), 7.7 (s, 1 H), 7.65 (d, 1 H, 8.7 Hz), 7.1 (d, 1 H, 8.4 Hz), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES+): 377 (M+1 ).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
General procedure: To a stirred solution of the amine (0.169mmol), the carboxylic acid (5-22, 0.154mmol), and with or without DMAP (0.154mmol) in DCM (10mL) at room temperature was added EDCI (0.308mmol). The reaction mixture was stirred overnight and then concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/hexane) to afford the desired product (23-152, 169, 170, 175, 176).
With toluene-4-sulfonic acid; In methanol; at 20℃; for 2h;Inert atmosphere;
5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 muiotaetaomicron, Eq: 1.00), 3-chlorobenzaldehyde (91.0 mg, 73.7 mu, 648 muiotaetaomicron, Eq: 1.05) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 muiotaetaomicron, Eq: 0.3) were dissolved in MeOH (2.00 mL). The resulting colorless solution was stirred at rt. To this solution was added dropwise isocyanoethane (34.0 mg, 45.9 mu, 617 muiotaetaomicron, Eq: 1.00) and the corresponding yellow solution was stirred for 2h. To the yellow clear solution was added dropwise water until the mixture got turbid and the product precipitated from the MeOH/water mixture. The solid was filtered off, washed with MeOH/water (1: 1) and hexane and dried under vacuum, to give a yellow solid (111 mg, 53.0%). MS: 339.0 [M]+; 1H- NMR (De-DMSO): delta 8.90 (s, 1H), 8.23 (s, 1H), 8.15 (d, 1H), 7.71 (d, 1H), 7.52 (t, 1H), 7.47- 7.36 (m, 2H), 5.17 (t, 1H), 3.02 (m, 2H), 1.12 (t, 3H).
5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 muiotaetaomicron, Eq: 1.00), <strong>[77123-56-9]3-ethynylbenzaldehyde</strong> (84.3 mg, 648 muiotaetaomicron, Eq: 1.05) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 muiotaetaomicron, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyanopropane (42.6 mg, 58.2 mu, 617 muiotaetaomicron, Eq: 1.00) and the corresponding yellow solution was stirred for 2h. Upon addition of water a yellow precipitate was formed. The solid was filtered off, washed with MeOH/water (1: 1) and dried under vacuum to yield the product as a yellow solid (153 mg, 72.2%). MS: 344.0 [M+H]+; 1H-NMR (D6-DMSO): delta 8.90 (s, 1H), 8.36 (s, 1H), 8.25 (d, 1H), 7.71 (d, 1H), 7.50 (t, 1H), 7.46-7.39 (m, 2H), 5.10 (d, 1H), 4.24 (s, 1H), 3.25 (m, 1H), 1.08 (d, 6H).
With toluene-4-sulfonic acid; In methanol; at 20℃; for 2h;Inert atmosphere;
5-(trifluoromethyl)pyridin-2-amine (200 mg, 1.23 mmol, Eq: 1.00), 3,5-dichlorobenzaldehyde (227 mg, 1.3 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (70.4 mg, 370 muiotaetaomicron, Eq: 0.3) were dissolved in MeOH (1.5 mL). The resulting colorless solution was stirred at rt. To this solution was added dropwise 2-isocyano-2-methylpropane (103 mg, 140 mu, 1.23 mmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2h. To the yellow clear solution was added dropwise water until the mixture got turbid. After stirring for a few additional minutes, the product precipitated. The solid was filtered off, washed with MeOH/water (1: 1) and with hexane and the crystals were dried under vacuum to yield a white solid (231 mg, 46.5%). MS: 402 [M]+; 1H-NMR (D6-DMSO): delta 8.91 (s, 1H), 8.30 (d, 2H), 7.73 (d, 1H), 7.57 (t, 1H), 7.49 (d, 1H), 5.05 (s, 1H), 1.07 (s, 9H).
5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 muiotaetaomicron, Eq: 1.00), <strong>[77123-56-9]3-ethynylbenzaldehyde</strong> (84.3 mg, 648 muiotaetaomicron, Eq: 1.05) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 muiotaetaomicron, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (51.3 mg, 70.2 mu, 617 muiotaetaomicron, Eq: 1.00) and the corresponding yellow solution was stirred for 2h. Water was added, the oil was separated from water/MeOH phase and purified by flash column chromatography (40 g Si02, Hex/EtOAc 100:0 to 0: 100) to yield a yellow solid (120 mg, 54.4%). MS: 357.0 [M]+; 1H-NMR (D6-DMSO): delta 8.89 (s, 1H), 8.38 (s, 1H), 8.27 (d, 1H), 7.72 (d, 1H), 7.52-7.40 (m, 3H), 4.94 (s, 1H), 4.22 (s, 1H), 1.04 (s, 9H).
(R)-tert-butyl 3-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Under ice-cooling, DMF (0.68 mL, 8.7 mmol) and oxalyl chloride (8.0 mL, 92 mmol) were added to a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (20 g, 87 mmol) in THF (1.0 L) such that the inner temperature did not exceed 5C. The resulting reaction solution was stirred under ice-cooling for 30 minutes, and a solution of 2-amino-5-(trifluoromethyl)pyridine (15 g, 92 mmol) and pyridine (15 mL, 0.18 mmol) in THF (0.10 L) was added thereto at -25C such that the inner temperature did not exceed -20C. After stirring the reaction solution under ice-cooling for 3 hours, saturated aqueous sodium chloride solution was added thereto such that the inner temperature did not exceed 5C, and extraction with dichloromethane was carried out. The organic layer was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. Hexane was added to the obtained crude product. The precipitated solids were collected by filtration, and the filtrate was concentrated under reduced pressure. The same purification operation was repeated twice. The obtained solids were combined to obtain 26 g (80%) of (R)-tert-butyl 3-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)piperidine-l-carboxylate (hereinafter referred to as Reference Example Compound 48).
7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[0543] To a solution of phosgene (20% solution in toluene, 0.265 ml, 0.504 mmol) in THF (2 ml) was added triethylamine (0.20 ml, 1.44 mmol). Subsequently, a solution of <strong>[204452-91-5]7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine</strong> (intermediate 4, 100 mg, 0.480 mmol) in THF (2 ml) was added drop wise. The resulting yellow suspension was stirred for 15 min, then 5-(trifluoromethyl)pyridin-2-amine (93 mg, 0.576 mmol) was added and the reaction mixture stirred for 2.5 days. The reaction mixture was diluted with sat. aq. NaHCO3 and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 13.83 (s, 1H), 8.70 (s, 1H), 8.26 (d, 1H), 8.20-8.12 (m, 1H), 7.73 (d, 1H), 7.18 (d, 1H), 5.37 (s, 1H), 4.01-3.93 (m, 2H), 3.39 (s, 6H), 2.86 (t, 2H), 1.98-1.87 (m, 2H). (UPLC-MS 1) tR 1.29 min; ESI-MS 397.0 [M+H]+.
3-chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.51 g
With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 2h;
Production Example 2 (1) [0697] A mixture of 0.81 g of 2-amino-5-trifluoromethylpyridine, 0.78 g of <strong>[57266-69-0]3-chloropicolinic acid</strong>, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 60C for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.51 g of 3-chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide. 3-Chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide 1H-NMR (CDCl3) delta: 10.69 (1H, brs), 8.62 (1H, s), 8.60-8.55(2H, m), 7.99 (1H, dd), 7.92 (1H, dd), 7.49 (1H, dd)
3-chloro-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.35 g
With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 2h;
Production Example 1 (1) [0694] A mixture of 0.81 g of 2-amino-5-trifluoromethylpyridine, 1.13 g of 3-chloro-5-trifluoromethylpicolinic acid, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 60C for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 1.35 g of 3-chloro-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl )picolinamide. 3-Chloro-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl )picolinamide 1H-NMR (CDCl3) delta: 10.51 (1H, brs), 8.83 (1H, brs), 8.64 (1H, brs), 8.56 (1H, d), 8.17 (1H, d), 8.02 (1H, dd)
2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2?,4?, 6?-triisopropyl- 1,1?-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); potassium carbonate; In tert-butyl alcohol; at 110℃; for 10h;Inert atmosphere;
2-((5-(Trifluoromethyl)pyridin-2-yl)amino)isonicotinic acidTo an oven-dried vial containing a stir bar, Brettphos precatalyst (0.101 g, 0.127 mmol), Brettphos (0.068 g, 0.127 mmol), 2-chloroisonicotinic acid (2.0 g, 13 mmol), 5- (trifluoromethyl)pyridin-2-amine (2.68 g, 16.5 mmol) and K2CO3(2.63 g, 19.0 mmol) were added. The solid mixture was purged with N2(degassed and flushed) three times. Then tert-butanol (30 mL) was added. The vial was degassed and flushed with N2three times and the vessel was capped and placed in a preheated oil bath at 110 C for 10 h. The sample was cooled to rt, diluted with ethyl acetate, and washed with water. The aqueous layer was acidified to pH 5-6 and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo to give the desired product (1.35 g, 4.77 mmol, 38% yield). The solid was collected by filtration and dried under vacuo to give more of the desired product (1.9 g, 6.71 mmol, 53% yield). Total yield was 91%: MS (ESI) (m/z): 284.1(M+H)+; 1H NMR (400 MHz, DMSO-d6) delta ppm 13.69 (br. s., 1 H) 10.48 (s, 1 H) 8.58 - 8.67 (m, 1 H) 8.44 (d, J=5.14 Hz, 1 H) 8.25 (s, 1 H) 8.04 (dd, J=9.05, 2.45 Hz, 1 H) 7.94 (d, J=9.05 Hz, 1 H) 7.38 (dd, J=5.14, 1.22 Hz, 1 H);19F NMR (376 MHz, DMSO-de) delta ppm -59.78 (s, 3 F).
2-chloro-5-fluoro-N-(4-phenylpyridin-3-yl)isonicotinamide[ No CAS ]
[ 74784-70-6 ]
5-fluoro-N-(4-phenylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2?,4?, 6?-triisopropyl- 1,1?-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); potassium carbonate; In tert-butyl alcohol; at 110℃; for 18h;
Example 167 5-Fluoro-N-(4-phenylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2- yl)amino)isonicotinamide. A mixture of potassium carbonate (7.84 mg, 0.057 mmol), 2-chloro-5-fluoro-N-(4-phenylpyridin-3-yl)isonicotinamide (12.4 mg, 0.038 mmol), 5-(trifluoromethyl)pyridin-2-amine (12.27 mg, 0.076 mmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l, -biphenyl]-2-yl)phosphine (0.203 mg, 0.378 muiotaetaomicron), Brettphos precatalyst (0.302 mg, 0.378 muiotaetaomicron) in t-butanol (0.7 mL) (degassed) was heated at 110 C for 18 h. The reaction was filtered through a small silica pad and washed with methanol. The filtrate was purified by prep- HPLC (6.0 mg, 35%): 1H NMR (500MHz, DMSO-d6) delta 10.51 (s, IH), 10.45 (br. s., IH), 8.72 (s, IH), 8.63 - 8.54 (m, 2H), 8.42 (s, IH), 8.09 - 8.01 (m, 2H), 7.71 (d, J=8.9 Hz, IH), 7.59 - 7.41 (m, 6H).
2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃;Inert atmosphere;
2-((5-(Trifluoromethyl)pyridin-2-yl)amino)isonicotinamide.The mixture of XANTPHOS (0.087 g, 0.151 mmol), cesium carbonate (0.817 g, 2.509mmol), palladium acetate (0.023 g, 0.100 mmol), 2-chloroisonicotinamide(0.3928 g, 2.509 mmol) and 5-(trifluoromethyl)pyridin-2-amine (0.488g, 3.01 mmol) in Dioxane (15 mL) was heat at 110 C for over night under N2.The reaction was partitioned between ethyl acetate and water. The ethyl acetatelayer was separated and washed with water two more times. The ethyl acetatelayer was separated, dried(Na2S04), filtered andconcentrated to give the crude product as a yellow solid. The product waspurified via flash column eluted with ethyl acetate in hexane from 0 to 100%and gave the desired product as a white solid (0.1937g, 27% yield). MS[ES+] m/e283 [M+H]+; 1H NMR (500MHz, DMSO-d6) delta 9.96 (s, 1H), 8.90 (d, J=2.1Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.19 (br. s., 1H),7.79 (d, J=8.5 Hz, 1H), 7.67 (br. s., 1H), 7.33 (s, 1H), 7.27 (d, J=5.5 Hz,1H).
3-(6-chloropyrazin-2-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
[ 74784-70-6 ]
6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]pyrazin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; In 1,2-dimethoxyethane; at 100℃; for 2h;
Example 44 6-[2-(trifluoromethyl)imidazo[l,2-a]pyridin^ -2-amine (Cpd 190) To 3-(6-chloropyrazin-2-yl)-2-(trifluoromethyl)imidazo[l,2-a]pyridine (63 mg, 0.2 mmol) was added 5-(trifluoromethyl)pyridin-2-amine (81 mg, 0.5 mmol), Pd2dba3 (3 mg, 0.004 mmol), QPhos (3 mg), K3PO4 (100 mg, 0.47 mmol) and DME (1 mL). The reaction mixture was heated at 100 C for 2 hours, then cooled and partitioned between EtOAc and aqueous AcOH. The organic layer was filtered through a plug of silica gel and concentrated. The residue was dissolved in ether, precipitated with hexanes, then partially concentrated and filtered. The crude product was further purified by chromatography on silica gel (gradient ethyl acetate :hexane 1:4 to 1:0), then washed with a mixture of ether and hexane to provide the title compound as an off-white solid (36 mg, 42 %). ]H NMR (DMSO-i delta 10.86 (s, 1H), 9.20 - 9.22 (m, 1H), 8.81 (dt, J = 6.9, 1.3 Hz, 1H), 8.70 - 8.72 (m, 1H), 8.45 (s, 1H), 8.06 (dd, J = 8.8, 2.5 Hz, 1H), 7.85 (dt, J = 9.1, 1.1 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.59 (ddd, J = 9.1, 6.9, 1.3 Hz, 1H), 7.18 (td, J = 6.9, 1.1 Hz, 1H); MS m/z 425 (ESI) [M+H]+.
2,2,2-trifluoro-1-[(1S,4R)-4-(4-iodophenyl)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl]ethanone[ No CAS ]
[ 74784-70-6 ]
2,2,2-trifluoro-1-[(1S,4R)-4-[4-[[5-(trifluoromethyl)-2-pyridyl]amino]phenyl]-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl]ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
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 90℃; for 24h;Inert atmosphere; Schlenk technique;
To an oven-dried schlenk tube were added 2,2,2-trifluoro-l-[(lS,4R)-4-(4-iodophenyl)-5-oxa-2- azabicyclo[2.2.1]heptan-2-yl]ethanone (80 mg, 0.20 mmol), 5-(trifluoromethyl)-2-pyridinamine (39 mg, 0.24 mmol, CAS: 74784-70-6), Xantphos (46 mg, 0.08 mmol, CAS: 161265-03-8), tris(dibenzylidineacetone)dipalladium(0) (73 mg, 0.08 mmol, CAS: 51364-51-3) and Cs2C03 (130 mg, 0.4 mmol). 1,4-Dioxane (3 mL) was added. The reaction mixture was stirred at 90C under N2 atmosphere for 24 hours. Water (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over Na2S04. Volatiles were removed under reduced pressure. The residue was purified by prep-HPLC (C-18 column, mobile phase: A, H20; B, CH3CN with 0.5% NuEta3·Eta20) to give 2,2,2-trifluoro-l-[(lS,4R)-4-[4-[[5-(trifluoromethyl)-2- pyridyl]amino]phenyl]-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl]ethanone (35 mg, 41% yield) as yellow oil.
2-(4-fluorophenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium hydrogencarbonate; In toluene; for 12h;Reflux;
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
2-(3-fluorophenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium hydrogencarbonate; In toluene; for 12h;Reflux;
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
2-(2,4-difluorophenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium hydrogencarbonate; In toluene; for 12h;Reflux;
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
2-(3,4-difluorophenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium hydrogencarbonate; In toluene; for 12h;Reflux;
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
2-[3,5-bis(trifluoromethyl)phenyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium hydrogencarbonate; In toluene; for 12h;Reflux;
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
2-methyl-3-phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With copper acetylacetonate; N-ethyl-N,N-diisopropylamine; 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine; In methanol; at 20℃; for 18h;Inert atmosphere;
General procedure: Under an atmosphere of nitrogen, a 25 mL dry Schlenk flask was placed with Cu(acac)2 (1.6 mg, 0.01 mmol) and ligand A (2.6 mg, 0.012 mmol). Anhydrous MeOH (1.0 mL) was added, and the mixture was magnetically stirred at 20 C for 15 min. Then a solution of 1-phenylprop-2-yn-1-yl acetate 2a (0.24 mmol), 2-aminopyridine 1a (0.2 mmol) and diisopropylethylamine (0.07 mL, 0.4 mmol) in MeOH (0.5 mL) were added dropwise. The reaction flask was kept at room temperature for 6 h. After 1a was completely consumed as monitored by TLC, H2O (10 mL) was added to quench the reaction. The resulting mixture was then extracted three times with diethyl ether (10 mL*3). The combined organic layer was dried over Na2SO4. After evaporation of the volatile solvent under reduced pressure, the residue was purified by flash chromatography on silica gel to afford pure 3a (39 mg, 0.19 mmol) as a brown oil in a yield of 94%.
With sodium hydrogencarbonate; In ethanol; at 90℃; for 2h;
General procedure: Substituted 2-(2-iodophenyl)imidazo[1,2-a]pyridines were synthesized by using the modified method for 1a2. To a solution of 2-bromo-1-(2-iodophenyl)ethanone (975 mg, 3 mmol) and sodium bicarbonate (378 mg, 4.5 mmol, 1.5 eq.) in ethanol (8 mL) was added 2-aminopyridine (282 mg, 3 mmol, 1 eq.) and the reaction mixture was stirred at 90 C for 2 h. The reaction mixture was allowed to cool to room temperature and the volatiles were evaporated. The residue was diluted with water (100 mL) and extracted into dichloromethane (100 mL). The organic layer was extracted into saturated aqueous sodium bicarbonate solution. After that, it was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography (1:1 = n-hexane: AcOEt) to obtain 1b-1k. In the case of 1l, the precipitates were washed with CH2Cl2 followed by recrystallization from n-hexane/CHCl3 to give 1l.
With Sodium hydrogenocarbonate In ethanol; water monomer at 80℃; for 2h;
With Sodium hydrogenocarbonate In ethanol; water monomer at 80℃; for 4h; Sealed tube; Inert atmosphere;
16.A Step A.6-(trifluoromethyl)imidazo[1,2-a]pyridine
To a heavy-walled sealable flask equipped with a magnetic stir bar were added 5-(trifluoromethyl)pyridin-2-amine (2.00 g, 12.3 mmol), sodium bicarbonate (2.59 g, 30.8 mmol), ethanol (30 mL), and 2-chloroacetaldehyde (3.92 mL, 30.8 mmol, 45% weight in H2O), in that order. The flask was sealed with a Teflon screwcap, and the reaction mixture warmed to 80 °C for 4 hours. The mixture was then cooled to room temperature, filtered through silica, poured into water (25 mL), and extracted with ethyl acetate (2 x 25 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (2 x 25 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 - 20% methanol in dichloromethane) to afford the title compound: LCMS m/z 187.1 [M + H]+;1H NMR (400 MHz, CD3OD) δ 9.05 (s, 1 H), 8.01 (s, 1 H), 7.75 - 7.68 (m, 2 H), 7.49 (d, J = 9.4 Hz, 1 H).
2-(2-fluoro-4-(trifluoromethyl)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
370 mg
In ethanol for 4h; Reflux;
1
2-Fluoro-4-trifluoromethylacetophenone (1.03 g) was dissolved in acetic acid (5 ml) and warmed to 40 ° C.Bromine (880 mg) was slowly added dropwise to the solution,And the mixture was stirred as such for 5 hours. Hypo water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried and concentrated to give 2-bromo-1- (2-fluoro-4-trifluoromethylphenyl) ethanone.It was used for the next step without purification.2-Bromo-1- (2-fluoro-4-trifluoromethylphenyl) ethanone prepared in the preceding step was dissolved in ethanol (5 ml), 2-amino-5-trifluoromethylpyridine (520 mg) was added to the solution Additionally,And heated under reflux for 4 hours.The reaction solution was concentrated,The obtained residue was purified by column chromatography,To give the target compound (370 mg).
2-phenyl-7-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With silver trifluoromethane sulfate; In chlorobenzene; at 120℃; for 24h;
General procedure: A mixture of 2-aminopyridine (0.1mmol), alkynoate (0.1mmol) and AgSO3CF3 (30mol%) in chlorobenzene (0.8mL) was stirred at 120C for 24h. After the reaction was finished, water (5mL) was added and the solution was extracted with ethyl acetate (3×5mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
3-bromo-N-(5-(trifluoromethyl)pyridin-2-yl)isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 11h;
5- (Trifluoromethyl) pyridin-2-amine (90 mg, 0.54 mmol),<strong>[13959-02-9]3-bromoisonicotinic acid</strong> (100 mg, 0.5 mmol),1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (100 mg, 0.54 mmol)And pyridine (2 mL) were reacted at 80 C. for 11 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate.The organic layer was washed with 1 M hydrochloric acid aqueous solution, aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate. After removing the anhydrous sodium sulfate by filtration, the solvent was distilled off under reduced pressure to obtain the desired product (40 mg, yield 23%).
3-ethoxy-N-(5-(trifluoromethyl)pyridin-2-yl)isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
3-Ethoxyisonicotinic acid (350 mg, 2.1 mmol), thionyl chloride (750 mg, 6.3 mmol) and toluene (5 mL) were reacted at 90 C. for 2 hours.The reaction solution was concentrated, and the concentrated residue was dissolved in tetrahydrofuran (5 mL).5- (trifluoromethyl) pyridin-2-amine (340 mg, 2.1 mmol) and triethylamine (640 mg, 6.3 mmol) were added and the mixture was reacted at 60 C. for 1 hour.After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. After removal of anhydrous sodium sulfate by filtration, the solvent was distilled off under reduced pressure and the residue was purified by flash chromatography (eluent: n-heptane / ethyl acetate) to give the desired product (0.1 g, yield 15%) Obtained.
3-[[[5-(trifluoromethyl)-2-pyridyl]amino]methyl]benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
To 759 3-cyanobenzylalcohol (0.13 g, 0.95 mmol) and 44 methanesulfonylchloride (0.088 mL, 1.1mmol), 50 pyridine (0.12 mL, 1.4 mmol) was added 12 dichloromethane (4.5 mL), and the mixture wasstirred at room temperature for 6 hr. To the reaction mixture was added 52 water, and the mixture wasextracted with dichloromethane. The organic layer was dried over sodium sulfate. The desiccant was filteredoff, and the solvent was evaporated. To the obtained residue, 831 2-amino-5-(trifluoromethyl)pyridine(0.18 g, 1.1 mmol), 832 tetra-n-butylammonium iodide (0.21 g, 0.56 mmol) and 106 potassiumcarbonate (0.23 g, 1.7 mmol) was added 79 acetonitrile (5.5 mL), and the mixture was stirred at 80 C. for21 hr. The insoluble material was filtered off, concentrated under reduced pressure, and the obtained residuewas purified by silica gel column chromatography (hexane/ethyl acetate) to give the 833 title compound (38 mg , 0.014 mmol, 15%). MS (ESI) m/z 278 (M+H)+
In a 500 ml single-necked flask, bromoacetaldehyde diethyl acetal (43.76 g, 222.1 mmol) was added, 1mol/L HCL (180 mL), and ethanol (15 mL) stirred at room temperature for 30 min, refluxed for 2 h to clarify the solution. Cooled to room temperature, saturated NaHCO3 adjusted to pH to neutral, <strong>[74784-70-6]2-amino-5-trifluoromethylpyridine</strong> (20.00 g, 123.4 mmol) was added and reacted at room temperature for 7h. After completion of the reaction, ethyl acetate (100 mL x 3) was extracted, the organic phase was collected, the solvent was evaporated under reduced pressure,(18.01 g of 6-(trifluoromethyl)imidazo[1,2-a]pyridine yellow-brown crystals were obtained by silica gel column (mobile phase: PE: EA = 2: 1). Yield 78.4%.
1-(2-hydroxyethyl)-1-methyl-3-[5-(trifluoromethyl)-2-pyridyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With sodium hydride; In 2-methyltetrahydrofuran; at 20℃; for 20h;Inert atmosphere;
Sodium hydride (60% in paraffin oil, 0.0907 g, 2.27 mmol) was washed twice under Ar with n-hexane (2 ml). A solution of 2-amino-5-chloropyridine (0.250 g, 1.51 mmol) in 2-MeTHF (2.0 ml) was added slowly. The brown-red suspension was stirred until no more gas evolution was observed and then 3-methyl-2-oxazolidinone (0.3 12 g, 3.02 mmol) wasadded. The resulting reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by careful addition of water and diluted with EtOAc. Phases were separated and aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na2504 and evaporated under reduced pressure to afford a crude residue (0.457 g). Quantitative 1H NMR analysis using trimethoxy benzeneas an internal standard indicated purity of 45% (52% chemical yield). The crude product was purified by silica gel chromatography (eluting with 1-4% MeOH in DCM) to afford 1-(2- hydroxyethyl)-1 -methyl-3-[5-(trifluoromethyl)-2-pyridyl]urea (0.177 g, 99% purity, 44%) as a pale yellow solid.1H NMR (400MHz, d6DMSO) 69.56 (br, 1H), 8.56 (dd, J = 1.5, 0.7 Hz, 1H), 8.03 (dd, J =9.0, 2.6 Hz, 1H), 7.97-7.93 (m, 1H), 5.42 (br, 1H), 3.62 (q, J = 4.9 Hz, 2H), 3.46-3.38 (m,2H), 2.96 (s, 3H).
1-(2-hydroxyethyl)-1-methyl-3-[6-(trifluoromethyl)-2-pyridyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With sodium hydride; In 2-methyltetrahydrofuran; at 20℃; for 20h;Inert atmosphere;
Sodium hydride (60% in paraffin oil, 0.0886 g, 2.31 mmol) was washed twice under Ar withn-hexane (2 ml). A solution of 2-amino-5-chloropyridine (0.250 g, 1.54 mmol) in 2-MeTHF(2.0 ml) was added slowly. The gray suspension was stirred until no more gas evolution was observed and then 3-methyl-2-oxazolidinone (0.318 g, 3.08 mmol) was added. The resulting reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by careful addition of water and diluted with EtOAc. Phases were separated and aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford a crude residue (0.432 g). Quantitative 1H NMR analysis using trimethoxy benzene as an internalstandard indicated purity of 42% (48% chemical yield). The crude product was purified by silica gel chromatography (eluting with 1-4% MeOH in DCM) to afford 1-(2-hydroxyethyl)-3- [6-(trifluoromethyl)-2-pyridyl]urea (0.190 g, 97% purity, 45%) as a white solid.1H NMR (400MHz, CDCl3) 68.18 (d, J = 8.4 Hz, 1H), 8.14 (br, 1H), 7.78 (t, J = 8.1 Hz, 1H),7.29 (d, J = 7.7 Hz, 1H), 3.91-3.83 (m, 2H), 3.59-3.53 (m, 2H), 3.09 (s, 3H), 3.05 (br, 1H).
1,2-diamino-5-(trifluoromethyl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
To a cooled (0 C.) solution of ethyl (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyethanimidate (5.3 g, 19 mmol) in dioxane (23 mL) was added 70% perchloric acid (20 mL, 232 mmol) dropwise. Following the addition, the temperature was maintained at 0 C. for 10 minutes and then ice-cold water (95 mL) was added at once. The resulting precipitate was collected by vacuum filtration and washed with water (caution: this compound has been reported to be potentially explosive when dry). The white solid was immediately dissolved in DCM (40 mL), dried over Na2SO4, and filtered. The filtrate was then added dropwise to a cooled (0 C.) solution of 5-(trifluoromethyl)pyridin-2-amine (1.5 g, 9.3 mmol) in DCM (79 mL). The reaction was allowed to warm to rt and stirred for 2 h. Diethyl ether was added and the resulting white solid was collected by vacuum filtration to provide the title compound (3.5 g, 100%). 1H NMR (600 MHz, DMSO-d6) delta 9.49-8.70 (bm, 2H), 8.64 (s, 1H), 8.09 (m, 1H), 7.19 (d, J=9.4 Hz, 1H), 6.81 (s, 2H), 6.74 (br s, 2H), 2.49 (s, 3H), 2.17 (s, 3H).
2-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;
To a 25 -mL round-bottom flask was placed a solution of 5-(trifluoromethyl)pyridin-2-amine (162 mg, 1.00 mmol) in DCM (10 mL) then DIEA (387 mg, 3.00 mmol) and 2-chloropropanoyl chloride (191 mg, 1.50 mmol) were added. The reaction was stirred for 16 h at rt, then diluted with 50 mL of EtOAc and washed with saturated aqueous NaHC03 solution (2x20 mL), 1M HC1 (2x20 mL), and brine (2x30 mL). The solution was dried over Na2S04 and concentrated under reduced pressure affording 175 mg (69%) of the title compound as a yellow solid. Mass Spectrum (LCMS, ESI pos): Calcd. for C9H9CIF3N2O"1": 253.0 (M+H); Found: 253.0.
2-(3-bromophenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium hydrogencarbonate In acetonitrile for 5h; Reflux;
5.1 Step 1: Preparation of 2-(3-bromophenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine
2-Amino-5- (trifluoromethyl) pyridine(2.00 g, 12.3 mmol), 3-bromophenacyl bromide (3.43 g, 12.3 mmol),And sodium bicarbonate (1.04 g, 12.4 mmol) were added 50 mL of acetonitrile and refluxed for 5 hours.After the reaction is completed, the reaction mixture is cooled to room temperature and the reaction product is separated into water and ethyl acetate.The extracted organic layer was concentrated, and the concentrate was purified by silica gel column chromatography (n-hexane: ethyl acetate, 3: 1 v / v)To obtain 2- (3-bromophenyl) -6- (trifluoromethyl) imidazo [1,2-a] pyridine (2.71 g, 65%).
phenyl(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With iron(III) chloride; In toluene; at 60℃; for 18h;
General procedure: A mixture of 2-aminopyridine (0.2 mmol), 3-phenylpropiolaldehyde (0.2 mmol) and ferric chloride (5 mol%) in toluene (1 mL) was placed in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 60 C for 18 h. After the reaction was finished, water (5 mL) was added and the solution was extracted with ethyl acetate (3×5 mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
General procedure: Synthesis of 3a is representative. To a solution of ethylbenzene (1a, 1 mmol, 107 mg) in ethylacetate:water (5:1, 6 mL) were added NBS (3.5 mmol, 628 mg) and AIBN (0.1 mmol, 16.5 mg) at roomtemperature, and the mixture was stirred at 65 C for 1.5 h. The mixture was concentrated to drynessand then dissolved in water (5 mL), followed by reaction with 2-aminopyridine (2a, 1.2 mmol, 114 mg)and sodium carbonate (5 mmol, 534 mg) for 2 h at 80 C. After completion of the reaction (as indicatedby TLC), the crude product was extracted with ethyl acetate (3 x 10 mL). The combined organic layerwas dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified bysilica gel column chromatography (PE/EA = 8/1-4/1, v/v) to give 3a (78% yield) as a white solid.
6'-bromo-8'-chloro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione[ No CAS ]
[ 74784-70-6 ]
8'-chloro-6'-((5-(trifluoromethyl)pyridin-2-yl)amino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
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 130℃; for 0.5h;Microwave irradiation;
General procedure: A microwave tube was charged with 6'-bromo-8'-chloro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione 3 (1.00 eq.), amine (1.00 eq.), Cs2CO3 (2.00 eq.), Pd2(dba)3 (0.10 eq.), xantphos (0.10 eq.) and 1,4-dioxane (4 mL). The reaction mixture was heated under microwave irradiation at 130 C for 30 min, concentrated under reduced pressure, and purified by flash column chromatography (silica gel, DCM ramping to DCM/CH3OH = 9:1) to yield the desired product.
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 90℃; for 40h;Inert atmosphere;
Under Ar(g), to a mixture of 2-chloropyrazine (1) (252mg, 2.2mmol), 2- amino-5-(trifluoromethyl)pyridine (2) (324mg, 2.0mmol), Cs2C03 (1.30g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13ml_). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15ml_), H20 (10mL) and brine (5mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (354mg, 74%). (0190) LCMS (ES): Found 241.2 [M+Hf.
3-(2-chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
NBS (241 mg, 1.354 mmol) was added to a solution of 2-chloro-4-(2- ethoxyvinyl)pyrimidine (250 mg, 1.354 mmol) in 1,4-dioxane (8 mL) / water (3 mL) and the reaction mixture was stirred for 15 min. 5-(Trifluoromethyl)pyridin-2-amine (220 mg, 1.357 mmol) was added and the reaction mixture heated at 80 C for 3 hours. The mixture was cooled to room temperature and diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, EtOAc/petrol gradient, then MeOH/DCM gradient) to afford 3-(2-chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (234.5 mg, 58%) as a beige solid.; 1H NMR (500 MHz, DMSO-d6) delta 10.26 (s, 1H), 8.95 (s, 1H), 8.78 (d, 1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.84 (dd, 1H); 19F NMR (471 MHz, DMSO-d6) delta-60.86; ESV- MS m/z 299.1 (M+H).
2-[(E)-2-ethoxyvinyl]-4-methylsulfanyl-pyrimidine[ No CAS ]
[ 74784-70-6 ]
3-(4-methylsulfanylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
NBS (165.2 mg, 0.928 mmol) was added to a solution of 2-[(E)-2-ethoxyvinyl]-4- methylsulfanyl-pyrimidine (181.4 mg, 0.924 mmol) in 1,4-dioxane (5.5 mL) and water (2 mL) and the reaction mixture was stirred at ambient temperature for 15 min.5-(Trifluoromethyl)pyridin-2- amine (150 mg, 0.925 mmol) was added and the reaction mixture heated at 65-75 C for 7 hours. The mixture was cooled to ambient temperature and diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc/petrol gradient) to give 3-(4-methylsulfanylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (165 mg, 58%); ESV-MS m/z 311.1 (M+H).
(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-D-alanine[ No CAS ]
[ 74784-70-6 ]
(R)-2-((1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(5-(trifluoromethyl)pyridin-2-yl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;
General procedure: 7 (0.15 g, 0.50 mmol) and the corresponding amine (0.60 mmol) were dissolved in DMF. HATU (0.23 g, 0.60 mmol) and N, N-diisopropylethylamine (96 mg, 0.75 mmol) were added successively. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by silica gel column chromatography (CH2Cl2/MeOH, 20:1) to get the compounds as white solid.
N-(di-p-tolylmethyl)-5-(trifluoromethyl)pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With hydrogen tetrachloroaurate(III) tetrahydrate; diphenylphosphinobenzene-3-sulfonic acid sodium salt In lithium hydroxide monohydrate at 120℃; for 16h; Sealed tube;
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