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Chemical Structure| 537705-05-8

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Product Details of [ 537705-05-8 ]

CAS No. :537705-05-8
Formula : C21H17IN4O
M.W : 468.29
SMILES Code : CC1=CC=C(OC2=CC=C(NC3=C4C=C(I)C=CC4=NC=N3)C=C2C)C=N1
MDL No. :MFCD28963663

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Application In Synthesis of [ 537705-05-8 ]

* 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.

  • Downstream synthetic route of [ 537705-05-8 ]

[ 537705-05-8 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 537705-06-9 ]
  • [ 98556-31-1 ]
  • [ 537705-05-8 ]
YieldReaction ConditionsOperation in experiment
98% In tetrahydrofuran; at 56℃; for 2.66667h; A 3 neck round bottom flask was fitted with a mechanical stirrer and kept under N2. The flask was charged with the 6-IODO-4-CHLOROQUINAZOLINE (10.0 g, 34.43 mol) and dry THF (35 ML). Thereafter, 3-METHYL-4- (6-METHYL-PYRIDINE-3-YLOXY)-PHENYLAMINE (7.38 g, 34.43 MMOL) and dry THF (45 ml) were added and the yellow suspension was heated to reflux. After 15 minutes most of the reactants went into solution and a fine yellow suspension was obtained. After 25 min, the internal temperature of the reaction mixture was 56C, and precipitation of the desired product started. Heating was continued for a further 2 hours and the reaction mixture was allowed to cool to room temperature while remaining in the oil bath. Yellow crystals were collected by filtration, washed with cold (0C) THF (1 x 10 ml) and dried at 50C, p < 200 mbar. The title compound was obtained as light yellow crystals (15.75g, 98%). Rf = 0.45 (EtOAc/MeOH = 9/1).'H NMR (CDCI3, 300 MHz): 8 = 11.40 (br, s, 1H, NH), 9.29 (d, J = Hz, 1H, H-2), 8.91 (S, 1H, H-2"), 8.36-8. 32 (m, 2H, H-7, H-8), 7.74-7. 73 (m, 2H, H-4", H-5), 7.62 (dd, J, = 8.7Hz, J2 = 2.6Hz, 1 H, H-5") 7.49-7. 46 (m, 2H, H-6', H-5), 7.06 (d, J = 8.7Hz, 1 H, H-2'), 2.54 (s, 3H, CH3), 2.26 (s, 3H, CH3). 13C NMR (CDCI3 + D6-DMSO, 75 MHz): 8 = 159.51, 153.63, 153.17, 152.82, 152.70, 145.26, 141.37, 138.01, 134.75, 134.65, 131.05, 129.10, 128.74, 126.77, 124.86, 124.43, 120.41, 116. 98, 94.89, 23.54, 17.67. The title compound had a tR (min) of 12.13 under the following RP-HPLC conditions: Symmetry Shield RP18, 75 x 4.6 mm; Flow 1.0 mL/min ; 205/210/220/245 nm; Temp. 25C ; Injection Volume: 10 uL OF A CA. 0.5% solution in ACN/H20 9/1; Eluent : B: ACN, C: 0.01 mmol NH40Ac in H20 pH = 6.0 ; and Gradient: 0 min: B = 30%, C = 70 %; and 20 min: B = 85%, C =15%.
98% In tetrahydrofuran; at 56℃; for 2.5h;Heating / reflux; Synthesis of 6-Iodo-[3-methyl-4-(6-methyl-pyridine-3-yloxy)-phenylamino]-quinazoline A 3 neck round bottom flask was fitted with a mechanical stirrer and kept under N2. The flask was charged with the 6-iodo-4-chloroquinazoline (10.0 g, 34.43 mol) and dry THF (35 ml). Thereafter, 3-methyl-4-(6-methyl-pyridine-3-yloxy)-phenylamine (7.38 g, 34.43 mmol) and dry THF (45 ml) were added and the yellow suspension was heated to reflux. After 15 minutes most of the reactants went into solution and a fine yellow suspension was obtained. After 25 minutes, the internal temperature of the reaction mixture was 56 C., and precipitation of the desired product started. Heating was continued for a further 2 hours and the reaction mixture was allowed to cool to room temperature while remaining in the oil bath. Yellow crystals were collected by filtration, washed with cold (0 C.) THF (1*10 ml) and dried at 50 C., p<200 mbar. The title compound was obtained as light yellow crystals (15.75 g, 98%). Rf=0.45 (EtOAc/MeOH=9/1). 1H NMR (CDCl3, 300 MHz): δ=11.40 (br, s, 1H, N), 9.29 (d, J=Hz, 1H, -2), 8.91 (s, 1H, -2"), 8.36-8.32 (m, 2H, -7, -8), 7.74-7.73 (m, 2H, -4", -5), 7.62 (dd, J1=8.7 Hz, J2=2.6 Hz, 1H, H-5") 7.49-7.46 (m, 2H, H-6', H-5), 7.06 (d, J=8.7 Hz, 1H, -2'), 2.54 (s, 3H, C3), 2.26 (s, 3H, C3). 13C NMR (CDCl3+D6-DMSO, 75 MHz): δ=159.51, 153.63, 153.17, 152.82, 152.70, 145.26, 141.37, 138.01, 134.75, 134.65, 131.05, 129.10, 128.74, 126.77, 124.86, 124.43, 120.41, 116.98, 94.89, 23.54, 17.67.
93% In isopropyl alcohol; at 80℃; for 2h; General procedure: To a solution of compound 12 (5.8 g, 20 mmol) in i-PrOH was added anilines (22 mmol) at room temperature (RT). Then the reaction mixture was heated to 80 C for 2 h. After the start material was completed, the mixture was filtered through celite, and the cake was washed by i-PrOH, then dried to obtain the desired compound 13a-f.
In isopropyl alcohol; for 12h;Reflux; Step C: N-(4-(6-methylpyridin-3-yloxy)-3-methylphenyl)-6-iodoquinazolin-4-amine(compound 12.3)[0141] 4-(6-methylpyridin-3-yloxy)-3-methylbenzenamine (812 mg, 3.79 mmol) and 4- chloro-6-iodo-quinazoline (I g, 3.4mmol) were dissolved in isopropanol (50 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford 1.1 g of the clean desired material.

  • 2
  • [ 537705-05-8 ]
  • [ 537705-07-0 ]
  • [ 383432-38-0 ]
YieldReaction ConditionsOperation in experiment
59% 2-METHYL-2-BUTENE (0.59 ML, 5.60 MMOL, 2.8 EQUIV. ) WAS ADDED OVER 1 HOUR TO A COLD (0-5C) SOLUTION OF BH3*THF COMPLEX (1.0 M SOL, 3.0 ML, 3.0 MMOL, 1.5 EQUIV. ) KEPT UNDER N2. The reaction mixture was stirred at this temperature for 30 minutes followed by the addition of 2-METHOXY-ACETIC ACID PROPARGYLAMIDE (255 MG, 2 MMOL, 1.0 EQUIV. ) DISSOLVED IN DRY THF (1 ML) over 15 minutes. The ice-bath was removed and the reaction mixture was warmed to room temperature over 20 minutes. The reaction mixture was then heated at 35C for 1 hour. K2CO3 (0.55 G, 4 MMOL, 2.0 EQUIV. ) DISSOLVED IN DEGASSED H20 (1.2 ML) WAS ADDED OVER 30 minutes to the reaction mixture. During the addition of the first half gas evolution was observed which seized during further addition. 6-lodo- [3-methyl-4- (6-methyl-pyridine-3-yloxy)- PHENYLAMINO]-QUINAZOLINE (1.41 G, 3 MMOL, 1.5 EQUIV. ) WAS ADDED IN THREE PORTIONS GIVING A yellow suspension. PPH3 (21 mg, 0.08 mmol, 4 mol%) and Pd (OAc) 2 (4.5 mg, 0.02 MMOL, 1 mol%) were added each in one portion and the reaction mixture was heated to reflux (65- 68C). After about 30 minutes a yellow solution was obtained and the reaction was monitored by HPLC assay. After 18 hours the reaction mixture was cooled to room temperature followed by the addition of half-saturated NACI solution (10 ml) and EtOAc (10 ML). The organic phase was separated, washed with H2O (5 ML) and concentrated at 50C and a pressure of less than 200 mbar. Purification by plug filtration, Si02, EtOAc/MeOH = 9/1. The title compound was obtained as light yellow crystals (0.55 g, 59 %). Rf = 0.16 (EtOAc/MeOH = 9/1). H-NMR (CDCI3, 250 MHz): 8 =8.71 (s, 1 H, H-2), 8.25 (d, J=1.7 Hz, 1 H, H-8), 7.90 (s, 1 H, H-7), 7.82 (s, 1H, NH), 7.79 (s, 1H, H-5), 7.66 (d, J=2.5Hz, 1H, H-4"), 7.54 (dd, JE=8. 7Hz, J2=2. 6Hz, 1H, H- 5"), 7.15-7. 07 (m, 2H, H-5', H-6'), 6.91 (d, J=8.7Hz, 1 H, H-2'), 6.83 (bt, 1H, NH), 6.65 (d, J=15.9Hz, 1H, H-9), 6.34 and 6.29 (dt, JE=15. 9Hz, J2=6. 1HZ, 1H, H-10), 4.14 (dt, J=6. 1Hz, 2H, CHzOMe), 3.97 (s, 2H, CH2NH), 3.45 (s, 3H, OCH3), 2.53 (s, 3H, CH3), 2.29 (s, 3H, CH3). '3C-NMR (CDCI3, 75 MHz): 8= 169.76 (C=O), 157.90, 154.93, 152.367, 152.23, 150.90, 149.74, 139.34, 134.73, 134.63, 131.16, 130.77, 130.36, 128.85, 129.98, 125.47, 124.66, 123.65, 121.32, 119.51, 119.13, 115.39, 71.96, 59.26, 40.84, 23.57, 16.41. Using reverse phase high performance liquid chromatography tR (min) was found to be 6.02 for the title compound under the conditions shown in the following table. Symmetry Shield 75 x 4.6 mm RP18 Flow 1. 0 mL/min Wavelength 205/210/220/245 nm Temp. 25C Injection Volume 10 LL of a ca. 0.5% solution in ACN/H20 9/1 Eluent B ACN Eluent C 0.01 mmol NH40Ac in H2O pH = 6.0 Gradient 0 min B = 30%, C = 70 % Gradient 20 min B = 85%, C = 15 %
59% Preparation of 2-methyl-2-butene (0.59 ml, 5.60 mmol, 2.8 equiv.) was added over 1 hour to a cold (0-5 C.) solution of BH3*THF complex (1.0 M sol, 3.0 ml, 3.0 mmol, 1.5 equiv.) kept under N2. The reaction mixture was stirred at this temperature for 30 minutes followed by the addition of 2-Methoxy-acetic acid propargylamide (255 mg, 2 mmol, 1.0 equiv.) dissolved in dry THF (1 ml) over 15 minutes. The ice-bath was removed and the reaction mixture was warmed to room temperature over 20 minutes. The reaction mixture was then heated at 35 C. for 1 hour. K2CO3 (0.55 g, 4 mmol, 2.0 equiv.) dissolved in degassed H2O (1.2 ml) was added over 30 minutes to the reaction mixture. During the addition of the first half gas evolution was observed which seized during further addition. 6-Iodo-[3-methyl-4-(6-methyl-pyridine-3-yloxy)-phenylamino]-quinazoline (1.41 g, 3 mmol, 1.5 equiv.) was added in three portions giving a yellow suspension. PPh3 (21 mg, 0.08 mmol, 4 mol %) and Pd(OAc)2 (4.5 mg, 0.02 mmol, 1 mol %) were added each in one portion and the reaction mixture was heated to reflux (65-68 C.). After about 30 minutes a yellow solution was obtained and the reaction was monitored by HPLC assay. After 18 hours the reaction mixture was cooled to room temperature followed by the addition of half-saturated NaCl solution (10 ml) and EtOAc (10 ml). The organic phase was separated, washed with H2O (5 ml) and concentrated at 50 C. and a pressure of less than 200 mbar. Purification by plug filtration, SiO2, EtOAc/MeOH=9/1. The title compound was obtained as light yellow crystals (0.55 g, 59%). Rf=0.16 (EtOAc/MeOH=9/1). 1H-NMR (CDCl3, 250 MHz): delta=8.71 (s, 1H, H-2), 8.25 (d, J=1.7 Hz, 1H, H-8), 7.90(s, 1H, H-7), 7.82 (s, 1H, NH), 7.79 (s, 1H, H-5), 7.66 (d, J=2.5 Hz, 1H, H-4), 7.54 (dd, J1=8.7 Hz, J2=2.6 Hz, 1H, H-5), 7.15-7.07 (m, 2H, H-5', H-6'), 6.91 (d, J=8.7 Hz, 1H, H-2'), 6.83 (bt, 1H, NH), 6.65 (d, J=15.9 Hz, 1H, H-9), 6.34 and 6.29 (dt, J1=15.9 Hz, J2=6.1 Hz, 1H, H-10), 4.14 (dt, J=6.1 Hz, 2H, CH2OMe), 3.97 (s, 2H, CH2NH), 3.45 (s, 3H, OCH3), 2.53 (s, 3H, CH3), 2.29 (s, 3H, CH3). 13C-NMR (CDCl3, 75 MHz): delta=169.76 (CO), 157.90, 154.93, 152.367, 152.23, 150.90, 149.74, 139.34, 134.73, 134.63, 131.16, 130.77, 130.36, 128.85, 129.98, 125.47, 124.66, 123.65, 121.32, 119.51, 119.13, 115.39, 71.96, 59.26, 40.84, 23.57, 16.41.
  • 3
  • [ 537705-05-8 ]
  • [ 486393-59-3 ]
  • [ 383432-38-0 ]
 

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