2,4-Dichloro-6-morpholino-1,3,5-triazine

To a solution of cyanuric acid (230.5 g, 1, 250 mmol) in acetone (2.25 L) was added dropwise a solution of morpholine (98.0 g, 1, 125 mmol) and triethylamine (113.0g, 1, 125 mmol) in acetone (2.25 L) at 5° C. The resulting mixture was poured into water. White precipitates were collected and washed with methanol to give 2, 4-dichloro-6-morpholino-1, 3, 5-triazine (231.9 g, 986.9 mmol) as white crystal in 88percent yield. MS m/z: 234(MCyanuric chloride (13.66 g, 74 mmol) was dissolved in methylene chloride (100 mL) at -78° C., followed by the addition of diisopropylethylamine (12.9 mL, 74 mmol). The reaction mixture was stirred for 5 minutes. Morpholine (6.46 mL, 74 mmol) was added dropwise into the reaction mixture in 10 min. The resulting white precipitate was filtered, washed with water, and dried to afford the desired intermediate in quantitative yield (17 g, 100percent).To a stirred solution of cyanuric chloride (5.0 g, 27 mmol) in acetone (50 ml) was added dropwise a solution of morpholine (1.7 g, 19 mmol) and triethylamine (1.9 g, 19mmol) in acetone (50 ml) at – 20 °C. The resulting mixture was quenched with water, filtered, washed with water and cold methanol and dried to give 2 (4.3 g, 96percent): white powder; To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in CHIntermediate 1: Synthesis of 4-(4-(2-(Difluoromethyl)-lH-benzoidHmidazol-l-yl)-6- (piperazin-l-yl)-l, 3, 5-triazin-2-yl)morpholine (A3) A6 A3 -(4, 6-dichloro-l, 3, 5-triazin-2-yl)morpholine - (A4) o a stirred solution of cyanuric chloride (10.0 g, 54 mmol, 1.4 equiv) in acetone (100 ml) was added dropwise a solution of morpholine (3.4 g, 1 equiv) and triethylamine (3.9 g, 1 equiv) in acetone (100 ml) at -20 °C, then quenched with HTo a stirred solution of cyanuric chloride (10.0 g, 54 mmol) in acetone (100 ml) a solution of morpholine (3.4 g, 39 mmol) in acetone (100 ml) and triethylamine (3.9 g, 39 mmol) were added at -20 °C. The mixture was then quenched with HTo a solution of cyanuric chloride (10.0 g, 54.2 mmol, 1.0 eq.) in dichloromethane (200 mL) was added morpholine (9.49 mL, 108.4 mmol, 2.0 eq) dropwise at 10°C. The reaction mixture was stirred at this temperature for 6 h, diluted with dichloromethane (200mL) and mixed with a saturated aqueous solution of NaHSO4 (50 mL). The phases were separated. The organic phase was successively washed with a saturated aqueous solution of NaHSO4 (2 x 50 mL), dried over anhydrous Na2504, filtered and evaporated under reduced pressure to yield pure title compound as a white solid (11 .7 g, 92percent yield). Cyanuric chloride 1 (20.0 g, 0.10 mol) was dissolved indichloromethane (200 mL) at -78 °C, followed by the additionof diisopropylethylamine (17.93 mL, 0.10 mol). Thereaction mixture was stirred for 5 minutes at -78 °C. Morpholine(9.61 mL, 0.10 mol) was added drop-wise to thereaction mixture for 10 min and stirred for 30 min at -78 °C.The resulting white precipitate was filtered, washed withwater (100 mL) followed by diethyl ether (50 mL) and driedto afford 23.5 g (92.15percent) of 4-(4, 6-dichloro-1, 3, 5-triazin-2-yl)morpholine 2 as white solid. 1H NMR (400 MHz, DMSOd6)δ 3.76 (t, J = 5.2 Hz, 4H), 3.66 (t, J = 5.2 Hz, 4H); 13CNMR (100 MHz, DMSO-d6) δ 169.17, 149.95, 65.49, 44.29;LC-MS (ESI) m/z Calcd. for C7H8Cl2N4O: 234.01, found:235.27 [M+H]+.To a stirred solution of cyanuric chloride (10 g, 0.054 mol) in anhydrous THF (150 mL), morpholine (5.65 g, 0.065 mol) was added at 0-5 °C. Cyanuric chloride (3.0 g, 16.3 mmol) was dissolved in acetone (30 mL) and crushed ice (30 g) and cooled to _10 ° C, A mixture of triethylamine (6.0 g, 59.4 mmol) and morpholine (2.84 g, 32.7 mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour.Add water (50mL), embracing the film Hai, filtered white solid, washed, So dry4- (4, 6-dichloro-1, 3, 5-diazin-2-yl) morpholine (4.30 g, 86percent).Reagents and conditions: (a) morpholine, DIPEA, DCM, -78°C - RT, 84.7percent; (b) 2-(difiuoromethyl)-lH-benzimidazole, KSynthesis of 2, 4-dichloro-6-morpholine-4-yl-[1, 3, 5]-triazine Synthesis of intermediate 3 was performed in one step as shown in Figure 1. A solution of morpholine 2 (8.9 mL, 100 mmol) in 38 mL water was added dropwise into the suspension of cyanuric chloride 1 (18.4 g, 100 mmol) in 100 mL acetone at 0 °C. The mixture was stirred at 0 °C for 1 h. A solution of 50 mL Na4-(4, 6-dichloro-l, 3, 5-triazin-2-yl)morpholine (8): To a stirred solution of cyanuric chloride 7 (lg; 5.42mmol) in dimethoxy ethane (50 mL) at 30°C, morpholine (470.1 uL; 5.42 mmol) was added dropwise. The reaction mixture was vigorously stirred for 3h at - 30°C then warmed up to room temperature and washed with HCl 3N, water, brine and finally dried over anhydrous Na45 g (244 mmol) of cyanuric chloride was dissolved in 900 ml of a mixed solvent of dichloromethane: tetrahydrofuran (1: 1 (by volume)) and cooled to 0 ° C. 18.9 ml (219 mmol) , And N-diisopropylethylamine (38.1 ml, 219 mmol) in 150 ml of dichloromethane was added and the mixture was stirred at 0 ° C for 2 hours. After the reaction was completed, the resulting reaction mixture was distilled under reduced pressure, diluted with dichloromethane, and washed successively with a saturated aqueous sodium bicarbonate solution and distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting solid was diluted with ethyl acetate (300 mL), washed with ethyl acetate, and filtered under reduced pressure. The resulting solid was dried under reduced pressure to give 43.8 g (Yield: 76percent) of the title compound.To a stirred solution of cyanuric chloride (18.4 g, 10 mmol) in acetone (100 ml) and crushed ice (500 g), a mixture of triethylamine (30.0 g, excess) and morpholine (8.7 g, 10 mmol) was added at −10° C. After the addition, reaction mixture was stirred at room temperature and for 1 hour and diluted with 50 ml water. Separated white solid was filtered and washed with water. The white solid was dried and filtered. The crude product was found to be pure and taken to next step with out purification. Yield: 18 g, 76percent; (M+H) 236.4General procedure: The cyanuric chloride 1 (1 equiv) was added in dry CHAlternatively method 1 for the synthesis of 4-(4, 6-dich/oro-1, 3, 5-triaziπ-2- yl)morpholin according to EP1020462B1; :Cyanuric chloride (10.0 g, 54.0 mmol) dissolved in acetone (100 ml) was cooled to -5 An aqueous solution of morpholine (0.87 g, 10 mmol)was slowly added dropwise to a solution of cyanuricchloride (1.84 g, 10 mmol) in aqueous at −15 to −5 °C.The reaction mixture was stirred at −15 °C for 0.5 h andthen at room temperature for 1 h. After removal of thesolvent, the residue was extracted with CH2Cl2.The extractwas washed with brine, dried over MgSO4 and concentratedto give 1.56 g white solide as 4m, yield 66.3percent, 1H NMR (300 MHz, CDCl3) δ 3.93–3.84 (4H, m), 3.79–3.71 (4H, m); IR(KBr): 3414, 1617, 1362, 841 cm-1;ESI-MS C7H8Cl2N4O (m/z): 234.0 (M + H)+.Cyanuric chloride (5, Scheme 2; 4.979 g, 27.0 mmol) was dissolved in acetone (50 mL) and cooled to -20 °C. Morpholine (8, Scheme 2; 0.7 eq., 1.654 g, 19.0 mmol) and triethylamine (0.7 eq., 1.922 g, 19.0 mmol) were mixed in an addition funnel, and added dropwise to the cooled reaction flask.The reaction stirred for 15 min before being quenched with cold water (500 mL). The solid material wasallowed to settle in the flask before being filtered through a Buchner funnel, and was washed with coldmethanol. The solid white material was dried overnight using a high-vacuum pump, and then, furtherpurified using column chromatography (silica) with 20percent ethyl acetate in hexanes as the eluent. Whiteproduct (9a, Scheme 2) [65] was collected (2.903 g, 12.4 mmol, 65percent). 1H-NMR (300 MHz, CDCl3) δ 3.89(dd, J = 5.6, 4.0 Hz, 4H), 3.80–3.64 (m, 4H). 13C-NMR (75 MHz, CDCl3) δ 170.38, 164.04, 66.36, 44.45.2, 4, 6-trichloro-1, 3, 5-triazine (5.0g, 27.33mmol) was dissolved in CH2, 4, 6-Trichloro-1, 3, 5-triazine (5.0 g, 27.33 mmol) was dissolved in CHSynthetic method: DIPEA (8.91 mL, 49.70 mmol) was added to a 50 mL reaction flask.After morpholine (4.33 g, 49.70 mmol) and CH 2 Cl 2 (100 mL) were dissolved, 2, 4, 6-trichloro-1, 3, 5-triazine (10.0 g, 54.67 mmol) was added.After cooling to -5 ° C, the reaction solution was slowly added to react at a low temperature for 0.5 h, and then the temperature was raised to 0 ° C for 12 h.After the TLC reaction was completed, H 2 O (100 mL) was added, and the CH 2 Cl 2 layer was separated, and the aqueous phase was extracted once with CH 2 Cl 2 (100 mL).The organic layers were combined and washed once with saturated NaCl (100 mL).Dry with anhydrous Na2SO4.The solvent was evaporated under reduced pressure to give a crude product.Column chromatography purification (PE / EtOAc = 5 / 1) gave a white solid 6.94 g, yield: 59.7percent;To a white suspension of 2, 4, 6-trichloropyrimidine (6000 mg, 32.54 mmol) in DCM (60 mL) was added 1M aqueous NaHCOExample EH: 3-[4-((35)-Hydroxymethyl-3, 4-dihydro-li-isoquinolin-2-yl)- 6-morpholin-4-yl-[l, 3, 5]triazin-2-yl]-phenol Step 1:Compound [2] (20 g, 108.4mmol, 1 eq) was dissolved in acetone (100 mL): water (30 mL). An acetone solution (10 mL) of morpholine (9.44 mL, 108.4 mmol, 1 eq) was added dropwise at 0°C. The reaction mass was stirred at 0°C for 3hrs; a solid formed during reaction and was filtered off. The filtrate was concentrated and again diluted with acetone:water::3: l ; the precipitated solid was filtered again, both the solids were combined and dried to give compound[20] as white solid (14 g, 55percent). (M+l = 235)Step 1 Compound [2] (20 g, 108.4mmol) was dissolved in acetone ( 100 ml): water (30 ml). An acetone solution ( 10 ml) of morpholine (9.44 ml, 108.4 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 3hrs; a solid formed during reaction and was filtered off. The filtrate was concentrated and again diluted with acetone: water (3: 1 ); the precipitated solid was filtered again, both the solids were combined and dried to give compound [20] as white solid (14 g, 55percent). ESIMS: 235 (MTo a cooled (-60° C.) solution of cyanuric chloride (1)(3.00 g, 16.26 mmol) in ethyleneglycol dimethylether (40 ml) was added a solution of the appropriate amine (2.80 ml, 32.5 mmol) in water (1.4 ml). General Procedure A-1 : Triazine/pyrimidine substitution10 11Starting material 10 (2, 4, 6-trichloro-1 , 3, 5-triazine or 2, 4, 6-trichloropyrimidine, 1 .0 eq.) is suspended in DCM. Morpholine (1.0 eq.) is slowly added during 20 min at -50 ° C . The reaction mixture is stirred at -50°C for 25 min before it is poured on water (60 ml_). The layers are separated and the water layer is washed twice with DCM and with EtOAc. The combined organic layers are treated with MgS0Cyanuric chloride (10.0 g, 54.2 mmol, 1.0 eq.) is dissolved in methylene chloride (60 ml), and morpholine (4.70 ml, 54.2 mmol, 1.0 eq.) is added drop by drop to the reaction mixture at -50°C, stirred for 20 min at the same temperature and poured into water. After extraction with methylene chloride and ethyl acetate (two times), the organic layers are dried over MgS0General procedure: General Procedure A-1: Triazine/pyrimidine substitution Starting material 10 (2, 4, 6-trichloro-1, 3, 5-triazine or 2, 4, 6-trichloropyrimidine, 1.0 eq.) is suspended in DCM. Morpholine (1.0 eq.) is slowly added during 20 min at −50° C. The reaction mixture is stirred at −50° C. for 25 min before it is poured on water (60 mL). The layers are separated and the water layer is washed twice with DCM and with EtOAc. The combined organic layers are treated with MgSOCyanuric chloride (10.0 g, 54.2 mmol, 1.0 eq.) is dissolved in methylene chloride (60 ml), and morpholine (4.70 ml, 54.2 mmol, 1.0 eq.) is added drop by drop to the reaction mixture at -50° C., stirred for 20 min at the same temperature and poured into water.

Molecular Weight:235.07
XLogP3:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:234.0075163
Monoisotopic Mass:234.0075163
Topological Polar Surface Area:51.1
Heavy Atom Count:14
Complexity:181
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes