* 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.
With sodium carbonate In 1,2-dimethoxyethane; water for 5 h; Reflux
The mixture of 2-chloro-4,6-dimorpholin-4-yl-[1,3,5]triazine (2, 30 g, 0.105 mol) 4-aminophenylboronic acid pinacol ester (3, 25.7 g, 0.117 mol, Boron Molecular), sodium carbonate (23 g , 0.21 mol) and tetrakistriphenylphosphine palladium (1 g, O.δwt percent Aldrich) in water (150 ml) and dimethoxyethane (DME, 450 ml) was heated at reflux for 5 hours. The reaction mix was cooled to the room temperature and filtered through paper filter. The layers of the filtrate were separated, the organic layer was washed with brine and concentrated. The residue was dissolved in methylene chloride, washed with brine, dried over sodium sulfate and concentrated. The solids were triturated with diethyl ether, filtered, and air dried to give the beige solids (31.5 g, 0.092 mol). Yield 88percent; Mass: 343.1 (M+H)+.
83%
With sodium carbonate In 1,2-dimethoxyethane; water for 24 h; Reflux
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite.(TM).. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83percent yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
83%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane for 24 h; Reflux
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite™. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83percent yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
73.5%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane for 24 h; Reflux; Inert atmosphere
Synthetic method: 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)bismorpholine (3.0 g, 10.52 mmol) was dissolved in DME (30 mL) and added sequentially. Pd(PPh3)4 (0.12g, 0.10mmol), 2.0M Na2CO3 solution (6.40mL) and 4-aminoPhenylboronic acid pinacol ester (3.46 g, 15.78 mmol) was refluxed for 24 h under N2. Evaporate the solvent under reduced pressure and dissolve the residueIn CH 2 Cl 2 (50 mL), it was washed twice with water (50 mL×2), once with saturated NaCl (30 mL), and dried over anhydrous Na 2 SO 4 . Steaming under reduced pressureThe solvent and the residue were separated by column chromatography, eluent: EA/PE = 1/1 to give the desired product 2.65 g, yield: 73.50percent.
52%
With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 110℃; for 24 h; Inert atmosphere
General procedure: A mixture of compound 7a (5 mmol), 4-aminophenylboronic acid pinacol ester (10 mmol), Pd(Ph3P)4 (0.1 mmol), Na2CO3 (10 mmol) in 1,4-dioxane/H2O (20 mL) was stirred at 110 °C for 24 h under Ar. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo and then extracted with EtOAc. The organic layer was evaporated to give a residue, which was purified by chromatography (petroleum ether/EtOAc, 5:1) to give pure product as a yellow solid, yield 59percent.
Reference：
[1] Patent: WO2010/96619, 2010, A1, . Location in patent: Page/Page column 27-28
[2] Patent: US2009/291079, 2009, A1, . Location in patent: Page/Page column 37
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 6, p. 2636 - 2645
[4] Patent: US2017/119778, 2017, A1, . Location in patent: Paragraph 0929
[5] Patent: CN108191837, 2018, A, . Location in patent: Paragraph 0179; 0180
[6] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 721 - 733
2
[ 7597-22-0 ]
[ 330793-01-6 ]
[ 1197159-91-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 17, p. 7524 - 7538
3
[ 7597-22-0 ]
[ 89415-43-0 ]
[ 1197159-91-3 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 1, p. 42 - 47
4
[ 619-72-7 ]
[ 1197159-91-3 ]
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 1, p. 62 - 66
[2] Patent: CN108456183, 2018, A,
5
[ 29366-73-2 ]
[ 1197159-91-3 ]
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 1, p. 62 - 66
[2] Patent: CN108456183, 2018, A,
6
[ 6601-22-5 ]
[ 1197159-91-3 ]
Reference：
[1] Patent: CN108191837, 2018, A,
7
[ 50534-08-2 ]
[ 1197159-91-3 ]
[ 1885-14-9 ]
[ 1197160-78-3 ]
Yield
Reaction Conditions
Operation in experiment
17.8%
Stage #1: With pyridine In N,N-dimethyl-formamide at 5 - 20℃; Stage #2: at 90℃; for 12 h;
0.43 g of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (1.26 mmol) was dissolved in 5 mL of DMF, then 0.23 g of pyridine (3 mmol) was added and placed In the ice bath, the temperature is below 5 ° C,0.18 g of phenyl chloroformate (1.15 mmol) dissolved in 3 mL of DMF was added dropwise. After the addition is completed,The reaction was carried out at room temperature. After completion of the reaction, 0.27 g of (4-aminophenyl)(4-(dimethylamino)piperidin-1-yl)methanone (1.1 mmol) was added, and the mixture was heated to 90 ° C for 12 h.After the reaction was completed, the reaction solution was poured into 50 mL of water, a large amount of solid was precipitated, stirred for 20 min, and suction filtered to give a solid.0.2g. The purification was carried out by column chromatography, and the mobile phase was obtained by DCM: methanol: methanol ammonia solution = 10:1: 0.2, and finally, 0.11 g of solid was obtained, yield 17.8percent.
Reference：
[1] Patent: CN108456183, 2018, A, . Location in patent: Paragraph 0125-0127
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;
General procedure: To a solution of 500 mg (1.75 mmol) of the compound prepared in step 1) of Example 6 and 290 mg (2.10 mmol) of 4-hydroxyphenylboronic acid,Dioxane: distilled water (5: 1 (volume ratio)) mixed solvent (15 ml), and 2.6 ml of a 2N aqueous sodium carbonate solutionMmol) and tetrakis (triphenylphosphine) palladium (0) (40 mg, 0.04 mmol) were added and the mixture was stirred at 90 C for 4 hours. reactionAfter the completion of the reaction, the resulting reaction mixture was cooled to room temperature, and then the celite-filled filter was washed with ethyl acetate,The filtrate was filtered and the resulting filtrate was washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate,Pressure filtration and vacuum distillation. The resulting solid was dissolved in a mixed solvent of ethyl acetate: dichloromethane (1: 1 (volume ratio)) 10And the mixture was stirred at room temperature for 30 minutes. The resulting mixture was washed with ethyl acetate and filtered under reduced pressure.The resulting solid was dried under reduced pressure to give 400 mg (yield: 67%) of the title compound.
2
[ 7597-22-0 ]
[ 214360-73-3 ]
[ 1197159-91-3 ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 5h;Reflux;
The mixture of 2-chloro-4,6-dimorpholin-4-yl-[1,3,5]triazine (2, 30 g, 0.105 mol) 4-aminophenylboronic acid pinacol ester (3, 25.7 g, 0.117 mol, Boron Molecular), sodium carbonate (23 g , 0.21 mol) and tetrakistriphenylphosphine palladium (1 g, O.deltawt % Aldrich) in water (150 ml) and dimethoxyethane (DME, 450 ml) was heated at reflux for 5 hours. The reaction mix was cooled to the room temperature and filtered through paper filter. The layers of the filtrate were separated, the organic layer was washed with brine and concentrated. The residue was dissolved in methylene chloride, washed with brine, dried over sodium sulfate and concentrated. The solids were triturated with diethyl ether, filtered, and air dried to give the beige solids (31.5 g, 0.092 mol). Yield 88%; Mass: 343.1 (M+H)+.
83%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 24h;Reflux;
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83% yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
83%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 24h;Reflux;
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83% yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
76%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; for 5h;Inert atmosphere; Reflux;
4-(4-chloro-6-morpholino-l,3,5-triazin-2-yl)morpholine (7 g, 24.50 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (6.00 g, 27.37 mmol), sodium carbonate (5.37 g, 50.71 mmol), and Tetrakis (233.33 mg, 201.92 umol) were charged in a round bottom flask and dissolved in a mixture of water (30.62 mL) and DME (91.87 mL) under a nitrogen atmosphere. The reaction was heated to reflux for 5 hours and cooled to room temperature. Two layers were visible and the organic layer was collected, washed with brine (1 x 25 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated, and the remaining residue was resuspended in DCM (100 mL) and washed with brine (2 x 50 mL) before being dried over anhydrous sodium sulfate and concentrated under reduced pressure. The remaining solid was triterated with MTBE (50 mL) and filtered to give 6.4 g of Compound 17A (76%) as an off-white solid (M+H = 343.2)
73.5%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 24h;Reflux; Inert atmosphere;
Synthetic method: 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)bismorpholine (3.0 g, 10.52 mmol) was dissolved in DME (30 mL) and added sequentially. Pd(PPh3)4 (0.12g, 0.10mmol), 2.0M Na2CO3 solution (6.40mL) and 4-aminoPhenylboronic acid pinacol ester (3.46 g, 15.78 mmol) was refluxed for 24 h under N2. Evaporate the solvent under reduced pressure and dissolve the residueIn CH 2 Cl 2 (50 mL), it was washed twice with water (50 mL×2), once with saturated NaCl (30 mL), and dried over anhydrous Na 2 SO 4 . Steaming under reduced pressureThe solvent and the residue were separated by column chromatography, eluent: EA/PE = 1/1 to give the desired product 2.65 g, yield: 73.50%.
52%
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 110℃; for 24h;Inert atmosphere;
General procedure: A mixture of compound 7a (5 mmol), 4-aminophenylboronic acid pinacol ester (10 mmol), Pd(Ph3P)4 (0.1 mmol), Na2CO3 (10 mmol) in 1,4-dioxane/H2O (20 mL) was stirred at 110 C for 24 h under Ar. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo and then extracted with EtOAc. The organic layer was evaporated to give a residue, which was purified by chromatography (petroleum ether/EtOAc, 5:1) to give pure product as a yellow solid, yield 59%.
To a mixture of <strong>[1197159-91-3]4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline</strong> (0.20 g 0.40 mmoles) in methylene chloride (80 mL) at 0 C. was added triphosgene (0.25 mg, 0.84 mmoles) and triethylamine (3 mL). The mixture was stirred for 20 minutes at 0 C. and 4-amino pyridine (0.10 g 0.83 mmoles) was added to the reaction mixture and stirred for another 2 hours at room temperature. The solvent was evaporated and the residue was submitted to the HPLC using acetonitrile/TFA as mobile phase to give 98.2 mg (36% yield) of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea. (M+H)=463.3.
36%
To a mixture of <strong>[1197159-91-3]4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline</strong> (0.20 g 0.40 mmoles) in methylene chloride (80 mL) at 0 C. was added triphosgene (0.25 mg, 0.84 mmoles) and triethylamine (3 mL). The mixture was stirred for 20 minutes at 0 C. and 4-amino pyridine (0.10 g 0.83 mmoles) was added to the reaction mixture and stirred for another 2 hours at room temperature. The solvent was evaporated and the residue was submitted to the HPLC using acetonitrile/ TFA as mobile phase to give 98.2 mg (36% yield) of 1-[4-(4,6-dimophorlin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea. (M+H)=463.3.
N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 16h;
To a mixture of 2, 2-difluoroacetic acid (20 mg, 0.21 mmol), HBTU (76 mg, 0.2 mmol), and DIEA (52 mg, 0.40 mmol) in 2 mL of DMF was added 4-(4,6-dimorpholino-1,3,5-triazin-2-yl) aniline (40 mg, 0.12 mmol). The reaction was stirred at 60 C. 16 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2, 2-difluoroacetamide (23 mg, 46% yield). HPLC: Rt=2.19 min; MS 421 [M+H].
To a stirred mixture of <strong>[1197159-91-3]4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline</strong> (140 mg, 0.40 mmoles) and a catalytic amount of dimethylaminopyridine (DMAP) in methylene chloride 100 (mL), was added a small excess of aryl isocyanate (0.61 mmoles). The mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated to half of its original volume and the separated precipitate was collected by filtration and washed with methanol (15 ml) and then with diethyl ether. In some cases the crude product obtained was purified by Silica gel column chromatography by eluting it with appropriate solvents, depending upon the polarity of the products.The following compounds were prepared according to Procedure A:Example 2Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-3-ylureaStarting from <strong>[1197159-91-3]4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline</strong> (0.08 g 0.23 mmoles) and 3-pyridyl isocyanate (30 mg, 0.25 mmoles) the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with 10% MeOH: ethyl acetate. Yield; 60 mg (56%); (M+H)=463.5.
56%
With dmap; In dichloromethane; at 20℃; for 48h;
General procedure: To a stirred mixture of <strong>[1197159-91-3]4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline</strong> (140 mg, 0.40 mmoles) and a catalytic amount of dimethylaminopyridine (DMAP) in methylene chloride 100 (mL), was added a small excess of aryl isocyanate (0.61 mmoles). The mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated to half of its original volume and the separated precipitate was collected by filtration and washed with methanol (15 ml) and then with diethyl ether. In some cases the crude product obtained was purified by Silica gel column chromatography by eluting it with appropriate solvents, depending upon the polarity of the products.
In dichloromethane; at 20℃; for 5h;Product distribution / selectivity;
The mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl) aniline (4, 49 g, 0.14 mol) and methyl-4-isocyanato benzoate (5, 27.5 g, 0.15 mol) in dichloromethane (700 ml) was stirred at room temperature for 5 hours. To the reaction mixture was added ethyl ether (200 ml) and the solids were filtered. The cake was washed with 1 :1 dichloromethane/ether (200 ml) and ether. methyl 4-(3-(4-(4,6-dimorpholino-1,3,5- triazine-2-yl)ureido)benzoate was obtained as beige solids in 90 % yield (66 g, 0.12 mol); HPLC: 97 % product and 3 % of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl) aniline.
79%
In dichloromethane; at 20℃; for 4h;
17A (2.17 g, 6.33 mmol) and methyl 4-isocyanatobenzoate (1.18 g, 6.65 mmol) were charged in a round bottom flask and dissolved in DCM (31.64 mL). The reaction stirred at room temperature for 4 hours. The product was precipitated with the addition of MTBE (50 mL), and the solid was isolated by vacuum filtration. The powder cake was washed with a 1 : 1 DCM/MTBE (50 mL) before it was dried under vacuum. 2.59 g of Compound 17B (79%) was obtained as an off-white solid (M+H = 520.3).
ethyl 7-((4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)amino)heptanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
100 mg (0.29 mmol) of the compound prepared in step 1) of Example 9 was dissolved in 8 ml of N, N-dimethylformamide,After adding 23 mg (0.58 mmol) of 60% sodium hydride at 0 C and stirring at room temperature for 30 minutes, ethyl-7-bromoheptanoic acid68 [mu] l (0.35 mmol) of TEA were added. After stirring the reaction mixture at 100 & lt; 0 & gt; C for 8 hours, when the reaction is complete,Cool the mixture to room temperature. The resulting reaction mixture was added with distilled water and extracted with ethyl acetate. Separated into resultsThe organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was purified by column chromatography(Ethyl acetate: hexane = 1: 1 (volume ratio)) to obtain the title compound (40 mg, Yield 27%).
ethyl 8-((4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)amino)-8-oxooctanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;
100 mg (0.29 mmol) of the compound prepared in the above step 1) was dissolved in 10 ml of N, N-dimethylformamide, N- (3-Methylaminopropyl) -N'-ethylcarbodiimide hydrochloride (112 mg, 0.58 mmol), N-hydroxybenzotriazole (20 mg)(0.15 mmol),N, N-diisopropylamine152 [mu] l (0.88 mmol)AndMonomethylSUBERATE63 [mu] l (0.35 mmol) ofAfter that,At room temperatureStir for 16 hours. When the reaction is complete, the resulting reaction mixture is diluted with ethyl acetateWashed sequentially with a saturated aqueous sodium bicarbonate solution and distilled water. The resulting organic layer was dried over anhydrous sodium sulfateAfter filtration and filtration under reduced pressure, the residue was purified by column chromatography (ethyl acetate: hexane = 1: 1Phoebe)) to obtain the title compound (35 mg, 58%).
To a stirred mixture of <strong>[1197159-91-3]4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline</strong> (0.140, 0.40 mmoles) in methylene chloride at 0 C. was added triphosgene (0.25, 0.84 mmoles) and Et3N (3 mL). The reaction mixture was stirred for 20 minutes at 0 C. Then 1-(4-aminophenyl)ethanol (0.10 g, 0.73 mmoles) was added to the mixture. The reaction mixture was stirred for about 16 hours at room temperature. The solvent was removed. The residue was dissolved in DMSO and place at HPLC using acetonitrile buffer TFA to give 48 mg (24%) of [4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea. M+H 506.4.
N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4, 5-dihydro-1H-imidazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With mercury dichloride; In N,N-dimethyl-formamide; at 140℃; for 16h;
A mixture of <strong>[1197159-91-3]4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline</strong> (40 mg, 0.12 mmol), imidazolidine-2-thione (15 mg, 0.15 mmol0 and mercury(II) chloride (40 mg, 0.15 mmol) in 2 mL of DMF was stirred at 140 C. 16 hr. Then the reaction mixture was cooled to room temperature and filtered through Celite. The filtration was concentrated and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4, 5-dihydro-1H-imidazol-2-amine (9.0 mg, 22% yield). HPLC: Rt=1.74 min; MS 411 [M+H]
2-chloro-N-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-4-(methylsulfonyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 24h;
General procedure: A solution of compound 8a (1 mmol), 2-chloro-4-methylsulphonylbenzoic acid (1 mmol) and DIEA (2 mmol) in DMF (5 mL), was added HATU (2 mmol). After stirred at room temperature for 24 h, the mixture was diluted with ethyl acetate (20 mL) and the solution was washed with water. The organic layer was concentrated to give the residue, which was purified by silica gel column chromatography (petroleum ether/EtOAc, 1:1) to give a white solid, yield 88percent.
1-(4-chloro-3-(thiophen-3-yl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
General procedure: The mixture of compound 5a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise to the bis(trichloromethyl) carbonate (0.5 mmol) in anhydrous CH2Cl2 (5 mL) at -78 C. After 1 h, the temperature was allowed to warm up to room temperature. The mixture of compound 7a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added in one portion. The mixture was stirred at room temperature for another 2 h and then quenched with saturated Na2CO3. Extract the aqueous solution with CH2Cl2 for three times. The organic layer was concentrated to give the residue, which was purified using flash chromatography (petroleum ether/THF, 1:1) to yield a white solid, yield 30%.
1-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
General procedure: The mixture of compound 5a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise to the bis(trichloromethyl) carbonate (0.5 mmol) in anhydrous CH2Cl2 (5 mL) at -78 C. After 1 h, the temperature was allowed to warm up to room temperature. The mixture of compound 7a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added in one portion. The mixture was stirred at room temperature for another 2 h and then quenched with saturated Na2CO3. Extract the aqueous solution with CH2Cl2 for three times. The organic layer was concentrated to give the residue, which was purified using flash chromatography (petroleum ether/THF, 1:1) to yield a white solid, yield 30%.
1-(4-chloro-3-(pyridin-3-yl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
General procedure: The mixture of compound 5a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise to the bis(trichloromethyl) carbonate (0.5 mmol) in anhydrous CH2Cl2 (5 mL) at -78 C. After 1 h, the temperature was allowed to warm up to room temperature. The mixture of compound 7a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added in one portion. The mixture was stirred at room temperature for another 2 h and then quenched with saturated Na2CO3. Extract the aqueous solution with CH2Cl2 for three times. The organic layer was concentrated to give the residue, which was purified using flash chromatography (petroleum ether/THF, 1:1) to yield a white solid, yield 30%.
1-(4-chloro-3-(pyridin-4-yl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
General procedure: The mixture of compound 5a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise to the bis(trichloromethyl) carbonate (0.5 mmol) in anhydrous CH2Cl2 (5 mL) at -78 C. After 1 h, the temperature was allowed to warm up to room temperature. The mixture of compound 7a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added in one portion. The mixture was stirred at room temperature for another 2 h and then quenched with saturated Na2CO3. Extract the aqueous solution with CH2Cl2 for three times. The organic layer was concentrated to give the residue, which was purified using flash chromatography (petroleum ether/THF, 1:1) to yield a white solid, yield 30%.
1-(6-chloro-[1,1'-biphenyl]-3-yl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
General procedure: The mixture of compound 5a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise to the bis(trichloromethyl) carbonate (0.5 mmol) in anhydrous CH2Cl2 (5 mL) at -78 C. After 1 h, the temperature was allowed to warm up to room temperature. The mixture of compound 7a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added in one portion. The mixture was stirred at room temperature for another 2 h and then quenched with saturated Na2CO3. Extract the aqueous solution with CH2Cl2 for three times. The organic layer was concentrated to give the residue, which was purified using flash chromatography (petroleum ether/THF, 1:1) to yield a white solid, yield 30%.
1-(4-chloro-3-(thiophen-2-yl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
General procedure: The mixture of compound 5a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise to the bis(trichloromethyl) carbonate (0.5 mmol) in anhydrous CH2Cl2 (5 mL) at -78 C. After 1 h, the temperature was allowed to warm up to room temperature. The mixture of compound 7a (1 mmol) and DIEA (1 mmol) in anhydrous CH2Cl2 (5 mL) was added in one portion. The mixture was stirred at room temperature for another 2 h and then quenched with saturated Na2CO3. Extract the aqueous solution with CH2Cl2 for three times. The organic layer was concentrated to give the residue, which was purified using flash chromatography (petroleum ether/THF, 1:1) to yield a white solid, yield 30%.
phenyl (4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With pyridine; In N,N-dimethyl-formamide; at 5 - 20℃; for 2h;
1.71 g of <strong>[1197159-91-3]4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline</strong> (5 mmol) was dissolved in 7 mL DMF(Dimethylformamide), 1.58 g of pyridine (20 mmol) was added and placed in an ice bath. After the temperature was lower than 5 C, 0.86 g of phenyl chloroformate (5.5 mmol) dissolved in 3 mL of DMF was added dropwise. After completion, it was allowed to react at room temperature for 2 h.After the reaction was completed, the reaction solution was poured into 50 mL of ice water, and a large amount of solid was precipitated and stirred for 20 min.Filtering,Obtained 2.1 g of solid,The yield was 90%.
4,4'-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine[ No CAS ]
[ 1197159-91-3 ]
Yield
Reaction Conditions
Operation in experiment
96.6%
With hydrogen; nickel; In tetrahydrofuran; at 20℃; for 20h;
5.17 g of 4,4'-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine (0.014 mol) was dissolved in 300 mL of THF and then added Washed 3.0g Ni (51mmol),After replacing the hydrogen, hydrogen was introduced and stirred at room temperature for 20 h. After the reaction was completed, the reaction solution was filtered through celite.The filtrate was concentrated to dryness.Obtained an orange solid, Weigh 4.63 g. The yield was 96.6%.
Synthetic method: <strong>[1197159-91-3]4-(4,6-bismorpholine 1,3,5-triazin-2-yl)aniline</strong> (2.0 g, 5.84 mmol) was dissolved in CH2Cl2 (20 mL).DMAP (36 mg, 0.29 mmol) was added followed by methyl 4-isocyanobenzoate (1.30 g, 7.33 mmol).The solvent was evaporated under reduced pressure. EtOAc m.The solvent was evaporated under reduced pressure, and the residue was separated by column chromatography.Eluent: DCM / MeOH = 30/1 gave 2.29 g of the desired product.Yield: 75.6%.
0.43 g of <strong>[1197159-91-3]4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline</strong> (1.26 mmol) was dissolved in 5 mL of DMF, then 0.23 g of pyridine (3 mmol) was added and placed In the ice bath, the temperature is below 5 C,0.18 g of phenyl chloroformate (1.15 mmol) dissolved in 3 mL of DMF was added dropwise. After the addition is completed,The reaction was carried out at room temperature. After completion of the reaction, 0.27 g of (4-aminophenyl)(4-(dimethylamino)piperidin-1-yl)methanone (1.1 mmol) was added, and the mixture was heated to 90 C for 12 h.After the reaction was completed, the reaction solution was poured into 50 mL of water, a large amount of solid was precipitated, stirred for 20 min, and suction filtered to give a solid.0.2g. The purification was carried out by column chromatography, and the mobile phase was obtained by DCM: methanol: methanol ammonia solution = 10:1: 0.2, and finally, 0.11 g of solid was obtained, yield 17.8%.
4-(5-hydroxy-4-(1-(2-(piperidin-4-yl)ethyl)-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol hydrogenchloride[ No CAS ]
C63H60F3N11O8[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 181h;
BT-1132 (38.43 mg, 77.17 umol, HC1), 17A (50 mg, 70.16 umol), HOBT (28.44 mg, 210.48 umol) and HATU (32.01 mg, 84.19 umol) were charged in a vial and dissolved in DMF (5 mL). Hunig?s base (9.07 mg, 70.16 umol, 12.22 uL) was added, and the reaction stirred at room temperature for 1 hour. The product was isolated by preparative HPLC (10-35%B, MeCN/water, 0.1% trifluoroacetic acid). The pure fractions were pooled, frozen, and lyophilized to yield 68.9 mg of Compound 18 (79%) as a white lyophilized powder (3.3 lm, M+H = 1157).
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