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Chemical Structure| 196603-96-0
Chemical Structure| 196603-96-0
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Product Details of [ 196603-96-0 ]

CAS No. :196603-96-0 MDL No. :MFCD09955370
Formula : C15H11BrFN3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :XIHOMGRMQWNHHB-UHFFFAOYSA-N
M.W : 364.17 Pubchem ID :135503852
Synonyms :

Calculated chemistry of [ 196603-96-0 ]

Physicochemical Properties

Num. heavy atoms : 22
Num. arom. heavy atoms : 16
Fraction Csp3 : 0.07
Num. rotatable bonds : 3
Num. H-bond acceptors : 5.0
Num. H-bond donors : 2.0
Molar Refractivity : 85.25
TPSA : 67.27 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.81 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.73
Log Po/w (XLOGP3) : 3.82
Log Po/w (WLOGP) : 4.41
Log Po/w (MLOGP) : 2.7
Log Po/w (SILICOS-IT) : 3.26
Consensus Log Po/w : 3.38

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.84
Solubility : 0.00521 mg/ml ; 0.0000143 mol/l
Class : Moderately soluble
Log S (Ali) : -4.93
Solubility : 0.0043 mg/ml ; 0.0000118 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.53
Solubility : 0.000107 mg/ml ; 0.000000294 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 2.57

Safety of [ 196603-96-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 196603-96-0 ]

* 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 [ 196603-96-0 ]
  • Downstream synthetic route of [ 196603-96-0 ]

[ 196603-96-0 ] Synthesis Path-Upstream   1~16

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YieldReaction ConditionsOperation in experiment
99%
Stage #1: for 1.5 h; Heating / reflux
Stage #2: With ammonia In methanol; water
4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin-7-ol Intermediate 2-3 (1.30 g, 2.86 mmol) was dissolved in trifluoroacetic acid (15 mL) and the solution was heated to reflux for 1.5 hours. The solution was cooled to room temperature and concentrated under reduced pressure. Methanol (20 mL) was added to the remaining brown solid and the pH was adjusted to 11 with concentrated ammonium hydroxide. The mixture was concentrated under reduced pressure and dried under high vacuum before purification by flash column chromatography on silica gel (20 g), eluting with 5-20percent methanol in dichloromethane. The experiment generated 2-4 (1.03 g, 99percent yield) as a light yellow solid. (at)H NMR (300 MHz, DMSO-d6): No. 10.5 (br s, 1 H), 9.53 (br s, 1 H), 8.34 (s, 1 H), 7.81 (s, 1 H), 7.63 (d, 1 H, J = 9.6 Hz), 7.54 (dd, 1 H, J = 8.4,7.8 Hz), 7.44 (d, 1 H, J = 8.4 Hz), 7.12 (s, 1 H), 3.95 (s, 3H). 13C NMR (75 MHz, DMSO-d6): No. 156.77, 156.49, 152.92,152.62, 148.62,146.74, 129.40, 127.39, 126.46 (d, J = 12 Hz), 119.23 (d, J = 23.2 Hz), 117.4 (d, J = 8.3 Hz), 109.96, 108.08, 102.23, 56.09.
93% for 1 h; Reflux After the reaction mixture was evaporated, the mixture was added cold aqueous NaHCO3 and concentrated NH3.H2O, and pH of solution was then adjusted to 10. The resulted precipitate was filtered, washed with water and Et2O, and dried under vacuum to give 3a (2.91 g, 91percent) as a white solid.
85%
Stage #1: for 1 h; Reflux
Stage #2: With ammonium hydroxide In methanol
A solution of 7-(Benzyloxy)-N-(4-bromo-2-fluorophenyl)-6-methoxyquinazolin-4-amine (3.5 g, 6.16 mmol, 1.00 equiv) and trifluoroacetic acid (30 mL) was heated at reflux for about 1 hour and then cooled to about 0° C.
The resulting solids were collected by filtration, and then dissolved in methanol (50 mL).
The pH value of the resulting solution was then adjusted to 9-10 with ammonium hydroxide (25percent).
The resulting mixture was concentrated in vacuo and washed water and ether to give the title product as a gray solid (2.0 g, yield 85percent).
1H NMR (300 MHz, DMSO) δ: 10.35 (s, 1H), 9.46 (s, 1H), 9.30 (s, 1H), 7.79 (s, 1H), 7.66 (dd, J=9.9, 1.8Hz, 1H), 7.45-7.57 (m, 2H), 7.07 (s, 1H), 3.96 (s, 3H); LC-MS: m/z=364/366 (MH)+.
82% for 0.833333 h; Heating / reflux A solution of 7-BENZYLOXY-4- (4-BROMO-2-FLUOROANILINO)-6-METHOXYQUINAZOLINE hydrochloride (9.4g, 19. 1MMOL) in TFA (90MOL) was heated at reflux for 50 minutes. The mixture was allowed to cool and was poured on to ice. The resulting precipitate was collected by filtration and dissolved in methanol (70ML). The solution was adjusted to pH9-10 with concentrated aqueous ammonia solution. The mixture was concentrated to half initial volume by evaporation. The resulting precipitate was collected by filtration, washed with water and then ether, and dried under vacuum to give 4- (4-BROMO-2-FLUOROANILINO)-7-HYDROXY-6- methoxyquinazoline (5.66g, 82percent). H NMR Spectrum: (DMSOd6; CD3COOD) 3.95 (s, 3H); 7.09 (s, 1H); 7.48 (s, 1H); 7.54 (t, 1H); 7.64 (d, 1H); 7.79 (s, 1H); 8.31 (s, 1H) MS-ESI: 366 [MH] + Elemental analysis: Found C 49.5 H 3.1 N 11.3 CISHNN302BRF Requires C 49.5 H 3.0 N 11.5percent
44% for 2 h; Heating The compound (2.3g, 5.06 mmol) obtained in <Step 7> was diluted with trifluoroacetic acid (10 mL) and the solution was stirred by heating for 2 hours. The solution was neutralized successively with methanol and water, basified with a ammonium hydroxide solution, and the resulting solid was filtered to obtain the title compound (1.0g, 44percent). NMR(300 MHz, DMSO-d6):<5 8.25(s, 1H), 7.74(s, 1H), 7.64(d, J = 10.2 Hz, 1H), 7.50-7.47(m, 2H), 7.20(brs, 1H, NH), 7.01 (s, 1H), 3.92(s, 3H).MS(ESI+, m/z): 364 [M+H]+

Reference: [1] Patent: WO2005/97134, 2005, A2, . Location in patent: Page/Page column 17-18; figure 2
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3222 - 3226
[3] Patent: US2010/75916, 2010, A1, . Location in patent: Page/Page column 16
[4] Patent: WO2005/13998, 2005, A1, . Location in patent: Page/Page column 75-76
[5] Patent: WO2012/30160, 2012, A2, . Location in patent: Page/Page column 52
[6] Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5369 - 5389
[7] Patent: US2009/238808, 2009, A1,
[8] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4080 - 4083
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Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5369 - 5389
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3222 - 3226
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5104 - 5107
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Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5369 - 5389
[2] Patent: WO2012/30160, 2012, A2,
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Reference: [1] Patent: WO2012/30160, 2012, A2,
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4080 - 4083
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Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5369 - 5389
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Reference: [1] Patent: WO2012/30160, 2012, A2,
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Reference: [1] Patent: WO2012/30160, 2012, A2,
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Reference: [1] Patent: WO2012/30160, 2012, A2,
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Reference: [1] Patent: WO2012/30160, 2012, A2,
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3222 - 3226
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4080 - 4083
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Reference: [1] Patent: CN108558828, 2018, A,
[2] Patent: CN108558828, 2018, A,
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5104 - 5107
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4080 - 4083
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4080 - 4083
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Reference: [1] Patent: CN108558828, 2018, A,
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Reference: [1] Patent: CN108558828, 2018, A,
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