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With palladium diacetate; sodium carbonate; triphenylphosphine In tetrahydrofuran; water at 60℃; for 16 h; Inert atmosphere
General procedure: All solvents and solutions used for this reaction were sparged with argonfor 15 minutes. In a round-bottomed flask was dissolved 4,6-dichloropyrimidine (1.5 equiv.) inTHF (1 M), under argon atmosphere. The arylboronic acid (1.0 equiv.), palladium acetate (0.02equiv., 2 molpercent), triphenylphosphine (0.04 equiv., 4 molpercent) and 1 M aqueous Na2CO3 solution(2.0 equiv.) were added and the mixture was stirred at 60 °C, overnight. After cooling to roomtemperature, the aqueous layer was extracted with Et2O and the organic layers were combined,washed with brine, dried over MgSO4, filtered and evaporated under vacuum. The crude materialwas purified by flash column chromatography to obtain the desired product.
47.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 120℃; for 8 h; Inert atmosphere; Sealed tube
2 g (0.011 mol) of 4-trifluoromethylbenzeneboronic acid was weighed out,4,6-dichloropyrimidine (1.60 g, 0.011 mol)Tetrakis (triphenyl palladium 0.15g with 2.5 g of anhydrous sodium carbonate was placed in a 120 mL sealed tube,A mixture of tetrahydrofen sitan 30 mL and 20 mL of deionized water was placed in a sealed tube as a solvent, and a stirrer was added and the stopper was capped.The whole device was purged with nitrogen for 3 to 4 times, placed in an oil bath and heated to 120 ° C for about 8 hours with stirring on a magnetic stirrer.After completion of the reaction, the sealing tube was cooled to room temperature, and the solution in the sealed tube was placed in a rotary vial, and the tetrahydrofuran solvent was distilled off under reduced pressure by rotary evaporator. And then extracted with ethyl acetate and water organic products 3 ~ 4 times, vacuum distillation solvent to petroleum ether: ethyl acetate 10: 1 will be steamed after the productionThe samples were separated by column chromatography and separated by separate column chromatography using dichloromethane to give about 1.28 g of a white solid in 47.2percent yield.
2.7 g
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 130℃; for 7 h;
Example 21 2-[(4-Fluoro-benzenesulfonyl)-methyl-amino]-N-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4- ylmethyl] - acetamide A solution of 4-(trifluoromethyl)phenylboronic acid (5.0 g, 25.8 mmol), 4,6-dichloropyrimidine (3.92 g, 25.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (362 mg, 516 μιηο) and sodium carbonate (8.2 g, 77.4 mmol, Eq: 3) in a three solvent mixture of 50 mL DME, 7.5 mL ethanol and 7.5 mL water was heated at 130°C for 7 h. Upon cooling to rt, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with three times with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2S04. Filtration followed by removal of volatiles under reduced pressure gave a dark red solid. The mixture was purified by flash chromatography (5percent diethyl ether in hexane) to give 4-chloro-6-(4-trifluoromethyl- phenyl)-pyrimidine(2.76g) as a white solid.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 299 - 302
[2] Patent: CN106632488, 2017, A, . Location in patent: Paragraph 0167-0169
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3497 - 3514
[4] Patent: US2006/241296, 2006, A1, . Location in patent: Page/Page column 27
[5] Patent: WO2010/134478, 2010, A1, . Location in patent: Page/Page column 165
[6] Patent: WO2014/49047, 2014, A1, . Location in patent: Page/Page column 63
[7] Patent: WO2015/28989, 2015, A1, . Location in patent: Page/Page column 86
With palladium diacetate; sodium carbonate; triphenylphosphine; In tetrahydrofuran; water; at 60℃; for 16h;Inert atmosphere;
General procedure: All solvents and solutions used for this reaction were sparged with argonfor 15 minutes. In a round-bottomed flask was dissolved 4,6-dichloropyrimidine (1.5 equiv.) inTHF (1 M), under argon atmosphere. The arylboronic acid (1.0 equiv.), palladium acetate (0.02equiv., 2 mol%), triphenylphosphine (0.04 equiv., 4 mol%) and 1 M aqueous Na2CO3 solution(2.0 equiv.) were added and the mixture was stirred at 60 C, overnight. After cooling to roomtemperature, the aqueous layer was extracted with Et2O and the organic layers were combined,washed with brine, dried over MgSO4, filtered and evaporated under vacuum. The crude materialwas purified by flash column chromatography to obtain the desired product.
47.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; at 120℃; for 8h;Inert atmosphere; Sealed tube;
2 g (0.011 mol) of 4-trifluoromethylbenzeneboronic acid was weighed out,4,6-dichloropyrimidine (1.60 g, 0.011 mol)Tetrakis (triphenyl palladium 0.15g with 2.5 g of anhydrous sodium carbonate was placed in a 120 mL sealed tube,A mixture of tetrahydrofen sitan 30 mL and 20 mL of deionized water was placed in a sealed tube as a solvent, and a stirrer was added and the stopper was capped.The whole device was purged with nitrogen for 3 to 4 times, placed in an oil bath and heated to 120 C for about 8 hours with stirring on a magnetic stirrer.After completion of the reaction, the sealing tube was cooled to room temperature, and the solution in the sealed tube was placed in a rotary vial, and the tetrahydrofuran solvent was distilled off under reduced pressure by rotary evaporator. And then extracted with ethyl acetate and water organic products 3 ~ 4 times, vacuum distillation solvent to petroleum ether: ethyl acetate 10: 1 will be steamed after the productionThe samples were separated by column chromatography and separated by separate column chromatography using dichloromethane to give about 1.28 g of a white solid in 47.2% yield.
(a) 4-Chloro-6-[4-(trifluoromethyl)phenyl]pyrimidine. To a 500-mL, round-bottomed flask was added 4,6-dichloropyrimidine (14 g, 95 mmol, Aldrich), 4-(trifluoromethyl)phenylboronic acid (6.0 g, 32 mmol, Aldrich), acetonitrile (95 mL) and 1 M aqueous solution of sodium carbonate (95 mL). The mixture was deoxygenated by sparging with N2 for 15 min, and Pd(PPh3)4 (1.9 g, 1.6 mmol, Strem) was added. The resulting yellow mixture was heated at 80 C. with stirring for 15 h. After allowing to cool to 25 C., the mixture was evaporated under reduced pressure. The residue was diluted with 10% aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient: 1.5-10% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 259 [M+1].
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 6h;
To 40 ml of 1,4-dioxane, 3 g of 4, 6-dichloropyrimidine, 5.57 g of potassium carbonate, 0.7 g of tetrakis (triphenylphosphine) palladium and 4.2 g of 4- trifluoromethylphenylboronic acid were added. This mixture was stirred at 100C for 6 hours. The reaction mixture was poured into an aqueous saturated ammonium chloride solution and then extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to obtain 1.6 g of 4-chloro-6- (4- trifluoromethylphenyl) pyrimidine . 4-chloro-6- ( 4-trifluoromethylphenyl) pyrimidineH-NMR: 7.74-7.77 (m, 3H) , 8.15-8.18 (m, 2H) , 9.04(s,lH)
2.7 g
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 130℃; for 7h;
Example 21 2-[(4-Fluoro-benzenesulfonyl)-methyl-amino]-N-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4- ylmethyl] - acetamide A solution of 4-(trifluoromethyl)phenylboronic acid (5.0 g, 25.8 mmol), 4,6-dichloropyrimidine (3.92 g, 25.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (362 mg, 516 muiotaetaomicron) and sodium carbonate (8.2 g, 77.4 mmol, Eq: 3) in a three solvent mixture of 50 mL DME, 7.5 mL ethanol and 7.5 mL water was heated at 130C for 7 h. Upon cooling to rt, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with three times with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2S04. Filtration followed by removal of volatiles under reduced pressure gave a dark red solid. The mixture was purified by flash chromatography (5% diethyl ether in hexane) to give 4-chloro-6-(4-trifluoromethyl- phenyl)-pyrimidine(2.76g) as a white solid.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In acetonitrile; at 80 - 100℃; for 42h;Inert atmosphere; Reflux;
Synthesis of 4-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine A mixture under N2 of 4,6-dichloropyrimidine (447 mg, 3.00 mmol, 1.00 eq.), 4-(trifluoromethyl)phenylboronic acid (188 mg, 0.99 mmol, 0.33 eq.), Na2CO3 (1.59 g, 15.00mmol, 5.00 eq.) and tetrakis(triphenylphosphine)palladium (0) (173 mg, 0.15 mmol, 0.05eq.) in acetonitrile (5 mL) was stirred at 80 C for 24 hours and further at 100 C for 18hours. The reaction mixture was allowed to cool down to r.t. and concentrated in vacuo.The residue was partitioned between DCM and sat. aq. NaHCO3 soln. The layers were separated. The aq. phase was extracted with DCM. The comb. org. phases were washed with sat. aq. NaCI soln., dried over MgSO4, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 tm, UV/MS, basicconditions) and concentrated in vacuo to afford the title compound as a white solid. LC-MS 4: tR = 0.94 mm; [M+H] = 259.3
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 18h;
To a slurry of 4, 6-dichloropyrimidine (2g, 13.4 mmol), 4-trifluoromethylphenylboronic acid (3.06 g 16.1 mmol) and tripotassium phosphate (5.70 g 26.8 mmol) in 1,4-dioxan (20ml) degassed with nitrogen for 10 minutes was added tetrakis (triphenylphosphine) palladium (0) (0.78 g, 0. 67mmol). The reaction mixture was then heated at 100 C for 18 hours. The reaction mixture was diluted with ethyl acetate and filtered through a pad OF HYFLO. The filtrate was evaporated under reduced pressure to give an oil. The oil was taken up in ethyl acetate and washed with brine. The ethyl acetate extracts were then combined, dried (MGS04) filtered and evaporated under reduced pressure to give a dark red oil. The oil was purified by flash chromatography eluting with hexane (SOOML) hexane/ethyl acetate (10: 1) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give a solid (2.1 g) as a mixture of desired product and 4, 6-bis- [4-trifluoromethylphenyl] pyrimidine (9: 1).
N-(5,6,7,8-Tetrahydronaphthalen-1-yl)-6-(4-(trifluoromethyl)phenyl)-pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 4 N-(5,6,7,8-Tetrahydronaphthalen-1-yl)-6-(4-(trifluoromethyl)phenyl)-pyrimidin-4-amine A mixture of 4-chloro-6-(4-(trifluoromethyl)phenyl) pyrimidine, Example 1(a), (0.26 g, 1.0 mmol) and 1,2,3,4-tetrahydro-1-naphthylamine (0.15 g, 1.0 mmol, Aldrich) in EtOH (1 mL) was heated in a microwave synthesizer at 120 C. for 15 min. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in DCM. The DCM solution was washed with 10% sodium carbonate, dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue purified by silica gel column chromatography (2:1:1 hexane/EtOAc/CHCl3) to give the title compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 370.
(a) tert-Butyl 5-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-ylamino)-2,3-dihydro-1H-inden-2-ylcarbamate. A mixture of 4-chloro-6-(4-(trifluoromethyl)-phenyl)pyrimidine (0.75 g, 2.9 mmol, Example 1(a)) and tert-butyl 5-amino-2,3-dihydro-1H-inden-2-ylcarbamate (1.0 g, 4.1 mmol, J&W pharm. Lab, LLC) in NMP (10 mL) was stirred and heated at 100 C. for 1 h, and at 120 C. for 20 min in a Discover microwave reactor. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (5*40 mL). The combined organic extract was washed with NaHCO3 and brine, dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and purified by silica gel column chromatography (gradient: 2% to 10% 2 M NH3.MeOH in CH2Cl2) to provide the title compound as pale yellow solid. MS (ESI, pos. ion) m/z: 471 [M+1].
A mixture of 4-chloro-6-[4-(trifluoromethyl)-phenyl]pyrimidine from step (a) above (0.35 g, 1.35 mmol) and 8-amino-1,2,3,4-tetrahydronaphthalen-2-ol (0.20 g, 1.2 mmol, prepared analogously to WO 2004/052846) in EtOH (2.5 mL) was heated in a microwave synthesizer at 160 C. for 20 min. The reaction mixture was diluted with EtOAc (100 mL), washed with satd NaHCO3 (50 mL), water (50 mL) and satd NaCl (50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (gradient: 60-80% EtOAc in hexane) followed by re-crystallization of the product from EtOAc/hexane provided the title compound as off-white crystals. M.p.: 178-179 C. MS (ESI, pos. ion.) m/z: 386 [M+1].
1,4-diaza-bicyclo[2.2.2]octane; In water; dimethyl sulfoxide; at 0℃; for 2h;
To a mixture of 3 ml of water, 0.36 g of sodium cyanide and 0.07 g of 1, 4-diazabicyclo [2.2.2] octane, 9 ml of dimethyl sulfoxide and 1.6 g of 4-chloro-6- (4- trifluoromethylphenyl) pyrimidine were added at 0C. This mixture was stirred for 2 hours. The reaction mixture was poured into water and then extracted three times with tert- butyl methyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated to obtain a crude product. This crude product was used in the next step without purification.
With 1,4-diaza-bicyclo[2.2.2]octane; In acetonitrile; at 0℃; for 2h;
4-Chloro-6-(4-(trifluoromethyl)phenyl)pyrimidine (2.55 g, 9.86 mmol) was dissolved in CH3CN (50 ml) and cooled to 0C. Tetrabutylammonium cyanide (4.55 g, 16.9 mmol) and DABCO (3.32 g, 29.6 mmol) were added and the reaction mixture was stirred at 0C for 2 hours. The reaction mixture was then absorbed onto a small amount of silica gel and purified by flash column (0-20% EtOAc over 35 min) to give 6-(4-(trifluoromethyl)phenyl)pyrimidine-4-carbonitrile as a white solid (2.26 g; 92%).
N-(piperidin-4-ylmethyl)sulfamide hydrochloride[ No CAS ]
((1-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)sulfamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere;
General procedure: In a round-bottomed flask were dissolved pyrimidine (1.0 equiv.) and thepiperidine-sulfamide (4 or 5) (1.1 equiv.) in DMF (0.1 M). K2CO3 (1.5 equiv.) was added and themixture was stirred at 90 C overnight. After cooling to room temperature, the solution wasdiluted with CH2Cl2 and was washed with water. The organic layer was dried over MgSO4,filtered and evaporated under vacuum. The crude material was purified by flash columnchromatography to afford the desired product.
N-(2-(piperidin-4-yl)ethyl)sulfamide hydrochloride[ No CAS ]
(2-(1-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)sulfamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere;
General procedure: In a round-bottomed flask were dissolved pyrimidine (1.0 equiv.) and thepiperidine-sulfamide (4 or 5) (1.1 equiv.) in DMF (0.1 M). K2CO3 (1.5 equiv.) was added and themixture was stirred at 90 C overnight. After cooling to room temperature, the solution wasdiluted with CH2Cl2 and was washed with water. The organic layer was dried over MgSO4,filtered and evaporated under vacuum. The crude material was purified by flash columnchromatography to afford the desired product.
4-(2,4,6-trimethylphenyl)-6-(4'-trifluoromethylphenyl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.6%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; at 115℃; for 8h;Sealed tube; Inert atmosphere;
1.27 g (4.92 mmol) of 4-chloro_6_ (4'-trifluoromethylphenyl) pyrimidine was weighed out,(0.85 g, 5.18 mmol) of trimethylbenzeneboronic acid,4 g of tetrakis (triphenylphosphine) palladium and 3 g of anhydrous sodium carbonate were placed in a 120 mL sealed tube,A mixture of tetrahydrofen sitan 30 mL and 20 mL of deionized water was placed in a sealed tube as a solvent, and a stirrer was added and the stopper was capped.The entire device vacuum nitrogen nitrogen replacement 3 ~ 4 times, placed in the oil bath pot,The mixture was heated to 115 C on a magnetic stirrer and refluxed for about 8 h.After the reaction,Sealed to cool to room temperature, the solution inside the sealed tube into the rotary bottle,The tetrahydrofuran solvent was distilled off under reduced pressure by rotary evaporator.The organic product was extracted with ethyl acetate and water for 3 to 4 times. The solvent was distilled off under reduced pressure. The spheroidized product was separated by petroleum ether: ethyl acetate 20: 1,To give a pale yellow solid, about 0.87 g, yield 51.6%.
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