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[ CAS No. 475108-18-0 ] {[proInfo.proName]}

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Chemical Structure| 475108-18-0
Chemical Structure| 475108-18-0
Structure of 475108-18-0 * Storage: {[proInfo.prStorage]}
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Product Details of [ 475108-18-0 ]

CAS No. :475108-18-0 MDL No. :MFCD15146788
Formula : C22H19ClN4O5 Boiling Point : -
Linear Structure Formula :- InChI Key :SPMVMDHWKHCIDT-UHFFFAOYSA-N
M.W : 454.86 Pubchem ID :9911830
Synonyms :
KRN951;AV-951;KRN-951, Tivozanib
Chemical Name :1-(2-Chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea

Calculated chemistry of [ 475108-18-0 ]

Physicochemical Properties

Num. heavy atoms : 32
Num. arom. heavy atoms : 21
Fraction Csp3 : 0.14
Num. rotatable bonds : 8
Num. H-bond acceptors : 7.0
Num. H-bond donors : 2.0
Molar Refractivity : 120.0
TPSA : 107.74 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.21 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.67
Log Po/w (XLOGP3) : 4.03
Log Po/w (WLOGP) : 5.26
Log Po/w (MLOGP) : 2.11
Log Po/w (SILICOS-IT) : 3.5
Consensus Log Po/w : 3.71

Druglikeness

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

Water Solubility

Log S (ESOL) : -5.16
Solubility : 0.00317 mg/ml ; 0.00000697 mol/l
Class : Moderately soluble
Log S (Ali) : -6.0
Solubility : 0.000459 mg/ml ; 0.00000101 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -8.5
Solubility : 0.00000145 mg/ml ; 0.0000000032 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 3.58

Safety of [ 475108-18-0 ]

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 [ 475108-18-0 ]

* 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 [ 475108-18-0 ]
  • Downstream synthetic route of [ 475108-18-0 ]

[ 475108-18-0 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 1072-67-9 ]
  • [ 1885-14-9 ]
  • [ 286371-44-6 ]
  • [ 475108-18-0 ]
YieldReaction ConditionsOperation in experiment
86.1%
Stage #1: With pyridine In N,N-dimethyl acetamide at 0 - 20℃; for 2 h;
Stage #2: at 80℃; for 5 h;
(6)
Step of conversion to urea compound:
Phenyl chlorocarbonate (601 g) was added dropwise to 3-amino-5-methylisoxazole (377 g), pyridine (1215 g), and N,N-dimethylacetamide (4 L) at 0°C, and the mixture was stirred at 20°C for 2 hr. 4-[(4-Amino-3-chlorophenol)oxy]-6,7-dimethoxyquinoline (847 g) was added to the reaction solution, and the mixture was stirred at 80°C for 5 hr.
The reaction solution was cooled to 5°C. Thereafter, methanol (8.5 L) and water (8.5 L) were added thereto, and the mixture was neutralized with an aqueous sodium hydroxide solution.
The resultant precipitate was collected by filtration, and the filtered product was slurried in water (8.5 L) for washing.
The slurry was filtered, and the filtered product was then dried under the reduced pressure to give N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(5-m ethyl-3-isoxazolyl)urea (1002 g, yield 86.1percent).
1H-NMR (400 MHz, DMSO-d6/ppm); δ 2.37 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 6.50 (s, 1H), 6.54 (d, 1H), 7.26 (dd, 1H), 7.39 (s, 1H), 7.48 (s, 1H), 7.51 (d, 1H), 8.23 (d, 1H), 8.49 (d, 1H), 8.77 (s, 1H), 10.16 (s, 1H)
Reference: [1] Patent: EP1559715, 2005, A1, . Location in patent: Page/Page column 20
  • 2
  • [ 1072-67-9 ]
  • [ 530-62-1 ]
  • [ 286371-44-6 ]
  • [ 475108-18-0 ]
YieldReaction ConditionsOperation in experiment
87% at 40℃; for 3 h; 3 - amino - 5 - methyl isoxazole (98 mg, 1 mmol) dissolved in anhydrous dichloromethane (5 ml) in, added under mixing N, N '- carbonyl diimidazole (356 mg, 2.2 mmol), then add 4 - [(4 (330 mg, 1 mmol) and tetrahydrofuran (5 ml) at 40 ° C under under stirring reaction 3 h, the reaction liquid under reducing pressure to dryness, re-dissolved in ethyl acetate (30 ml), and water extraction 3 times. The collection of ethyl acetate, reduced pressure to dryness, for column purification of silica gel chromatography (1 - 2percent methanol: dichloromethane). Collecting the corresponding elution component reducing dryness, methanol for refining, resulting in white or white solid powder for grips nepal fertile (394.6 mg, 87percent).
Reference: [1] Patent: CN106967058, 2017, A, . Location in patent: Paragraph 0022; 0023; 0025
  • 3
  • [ 55808-09-8 ]
  • [ 286371-44-6 ]
  • [ 475108-18-0 ]
YieldReaction ConditionsOperation in experiment
12.9 g With pyridine In N,N-dimethyl acetamide at 80℃; for 5 h; A solution of 5-methylisoxazol-3-amine (5.3 g, 0.054 mol) and pyridine (17.2 g, 0.22 mol) in dimethylacetamide (30 mL) was stirred and cooled in an ice-water bath. Methyl chloroformate (5.1 g,0.054 mol) was added slowly and keeping the reaction temperature below 10°C. The reaction mixturewas stirred at the ambient temperature for another 2 h to give the methyl (5-methylisoxazol-3-yl)carbamate (14). Then 2-cholo-4-((6,7-dimethoxyquinolin-4-yl)oxy)-aniline 9 (12.0 g, 0.036 mol) was added and the reaction mixture was stirred at 80° C for 5 h. The reaction suspension was cooled to room temperature and added into water (300 mL) and MeOH (100 mL) and stirred for 30 min. The resulting solid was filtered, washed with water (50 mL × 2), and dried at 50°C to give the crude product 1, which was takenup in EtOAc : EtOH = 1:1 (v:v) (60 mL) and heated to reflux for 30 min, then cooled to room temperature for 1 h, the resulting solid was filtered off and washed with EtOAc (20 mL × 2), dried at 50°C for 3 h to afford 1 (12.9 g, 79percent) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 2.35 (s, 3H), 3.93 (s, 3H),3.95 (s, 3H), 6.52 (d, J = 5.2 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 2.4, 8.8 Hz, 1H), 7.42 (s, 1H),7.49 (s, 1H), 7.51 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H), 9.02 (s, 1H),10.42 (s, 1H). ESI-MS (m/z) 455.1 [M+H]+.HPLC: tR: 5.446 min, purity: 98.9percent.
Reference: [1] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887
  • 4
  • [ 1131-62-0 ]
  • [ 475108-18-0 ]
Reference: [1] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887
  • 5
  • [ 4101-32-0 ]
  • [ 475108-18-0 ]
Reference: [1] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887
  • 6
  • [ 13425-93-9 ]
  • [ 475108-18-0 ]
Reference: [1] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887
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