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[ CAS No. 383432-38-0 ] {[proInfo.proName]}

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Chemical Structure| 383432-38-0
Chemical Structure| 383432-38-0
Structure of 383432-38-0 * Storage: {[proInfo.prStorage]}
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Product Details of [ 383432-38-0 ]

CAS No. :383432-38-0 MDL No. :MFCD11983048
Formula : C27H27N5O3 Boiling Point : -
Linear Structure Formula :- InChI Key :LLVZBTWPGQVVLW-SNAWJCMRSA-N
M.W : 469.54 Pubchem ID :9874913
Synonyms :

Calculated chemistry of [ 383432-38-0 ]

Physicochemical Properties

Num. heavy atoms : 35
Num. arom. heavy atoms : 22
Fraction Csp3 : 0.19
Num. rotatable bonds : 10
Num. H-bond acceptors : 6.0
Num. H-bond donors : 2.0
Molar Refractivity : 136.73
TPSA : 98.26 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.13 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.8
Log Po/w (XLOGP3) : 4.28
Log Po/w (WLOGP) : 4.84
Log Po/w (MLOGP) : 2.26
Log Po/w (SILICOS-IT) : 4.79
Consensus Log Po/w : 3.99

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -5.25
Solubility : 0.00262 mg/ml ; 0.00000559 mol/l
Class : Moderately soluble
Log S (Ali) : -6.06
Solubility : 0.000413 mg/ml ; 0.000000879 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -9.44
Solubility : 0.000000171 mg/ml ; 0.0000000004 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 3.73

Safety of [ 383432-38-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 383432-38-0 ]

* 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.

  • Upstream synthesis route of [ 383432-38-0 ]
  • Downstream synthetic route of [ 383432-38-0 ]

[ 383432-38-0 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 537705-05-8 ]
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YieldReaction ConditionsOperation in experiment
59%
Stage #1: With borane-THF; 2-methyl-but-2-ene In tetrahydrofuran at 0 - 5℃; for 1.5 h; Nitrogen atmosphere
Stage #2: at 20 - 35℃; for 1.58333 h;
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 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 molpercent) and Pd (OAc) 2 (4.5 mg, 0.02 MMOL, 1 molpercent) 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 NACI 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, Si02, EtOAc/MeOH = 9/1. The title compound was obtained as light yellow crystals (0.55 g, 59 percent). 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-5APOS;, H-6APOS;), 6.91 (d, J=8.7Hz, 1 H, H-2APOS;), 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). APOS;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. 25°C Injection Volume 10 LL of a ca. 0.5percent solution in ACN/H20 9/1 Eluent B ACN Eluent C 0.01 mmol NH40Ac in H2O pH = 6.0 Gradient 0 min B = 30percent, C = 70 percent Gradient 20 min B = 85percent, C = 15 percent
59%
Stage #1: at 0 - 5℃; for 1.5 h;
Stage #2: at 0 - 35℃; for 1.5 h;
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 percent) and Pd(OAc)2 (4.5 mg, 0.02 mmol, 1 mol percent) 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, 59percent). Rf=0.16 (EtOAc/MeOH=9/1). 1H-NMR (CDCl3, 250 MHz): δ=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): δ=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.
Reference: [1] Patent: WO2004/56802, 2004, A1, . Location in patent: Page 15-16
[2] Patent: US2005/192298, 2005, A1, . Location in patent: Page/Page column 7
  • 2
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YieldReaction ConditionsOperation in experiment
90% With sodium hydroxide In 2-methyltetrahydrofuran; water for 1 h; To a stirring solution of [6- (3-amino-propenyl)-quinazolin-4-yl]- [3-methyl-4- (6-methyl- pyridin-3-yloxy)-phenyl]-amine bis hydrochloride (1.0 g, 2.12 MMOL) in 10.0 ml of 2-METHYLTETRAHYDROFURAN was added 10.0 ml of 1 N sodium hydroxide solution. Thereafter was added the methoxy ACETYLCHLORIDE (0.254 g, 2.34 MMOL). After 1 hour the reaction was deemed complete by HPLC. Reaction was washed with process water. Displaced the 2-METHYLTETRAHYDROFURAN with ethyl acetate. Off white solid was filtered off to give a 90-94percent yield. 1H NMR (300 MHZ, D2O) : No. 8.46 (s, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 7.97 (d, J=7.2 Hz, 1 H), 7.70 (d, J=9.2 Hz, 1 H), 7.68 (s, 1H), 7.60 (d, J=6.4 Hz, 1 H), 7.27 (dd, 2H), 6.98 (d, J=8.0 Hz, 1H), 6.73 (d, J=16 Hz, 1H), 6.49 (dt, J=16 Hz, 1 H), 4.09 (d, J=4.8 Hz, 2H), 3.95 (s, 2H), 3.45 (s, 3H), 2.49 (s, 3H), 2.25 (s, 3H).
Reference: [1] Patent: WO2004/89934, 2004, A1, . Location in patent: Page 28
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Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
  • 4
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Reference: [1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
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Reference: [1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[3] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[4] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[5] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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[7] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
  • 6
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Reference: [1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[3] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[4] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[5] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[6] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[7] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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Reference: [1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[3] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[4] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[5] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[6] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[7] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
  • 8
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Reference: [1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[3] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[4] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[5] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[6] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[7] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
  • 9
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Reference: [1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[3] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[4] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[5] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[6] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[7] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[3] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[4] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[5] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[6] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[3] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[4] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[5] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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  • [ 383433-14-5 ]
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Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
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  • [ 98556-31-1 ]
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Reference: [1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
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