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CAS No. : | 202475-60-3 | MDL No. : | MFCD01862614 |
Formula : | C16H15N3O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HOZUXBLMYUPGPZ-UHFFFAOYSA-N |
M.W : | 297.31 | Pubchem ID : | 3794 |
Synonyms : |
Jak3 inhibitor I;WHI-P131;WHI-P131, WHI P-131, WHI P131, Janex 1
|
Num. heavy atoms : | 22 |
Num. arom. heavy atoms : | 16 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 84.09 |
TPSA : | 76.5 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.98 cm/s |
Log Po/w (iLOGP) : | 2.37 |
Log Po/w (XLOGP3) : | 3.0 |
Log Po/w (WLOGP) : | 3.1 |
Log Po/w (MLOGP) : | 1.65 |
Log Po/w (SILICOS-IT) : | 2.2 |
Consensus Log Po/w : | 2.46 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.85 |
Solubility : | 0.0422 mg/ml ; 0.000142 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.27 |
Solubility : | 0.0159 mg/ml ; 0.0000536 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.57 |
Solubility : | 0.000804 mg/ml ; 0.0000027 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.47 |
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: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; | 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline was prepared by the condensation of 4-chloro-6,7-dimethoxyquinazoline with 4-aminophenol as outlined below in Scheme 2 above. Specifically, a mixture of 4-chloro-6,7-dimethoxyquinazoline (448 mg, 2 mmols) and 4-aminophenol (2.5 mmols) in EtOH (20 ml) was heated to reflux. After refluxing for 4 to 24 hours, an excess amount of Et3N was added, and the solvent was concentrated to give the crude product which was recrystallized from DMF. | |
Heating; | General procedure: 4-Chloro-6,7-dimethoxyquinazoline 3 and the required nucleophile were heated in solvent either thermally or using microwave heating until no further reaction was observed. On cooling, the hydrochloride salt was isolated by filtration. Alternative isolation procedures were employed if precipitation did not occur. Additional purification by preparative HPLC or flash column chromatography was employed in some cases. Spectroscopic data for compounds 4 [13], 6-9 [14-16], 20-21 [13], 25 [13], 28 [17] and 30 [18] are in agreement with those reported in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.29% | 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline yield 84.29%; m.p. 245.0-248.0. C.; UV(MeOH) lambdamax: 203.0, 222.0, 251.0, 320.0 nm; IR(KBr) numax: 3428, 2836, 1635, 1516, 1443, 1234 cm-1; 1H NMR(DMSO-d6): 11.21(s, 1H, -NH), 9.70(s, 1H, -OH), 8.74(s, 1H, 2-H), 8.22(s, 1H, 5-H), 7.40(d, 2H, J=8.9 Hz, 2',6'-H), 7.29(s, 1H, 8-H), 6.85(d, 2H, J=8.9 Hz, 3',5'-H), 3.98(s, 3H, -OCH3), 3.97(s, 3H, -OCH3); GC/MS m/z 298 (M++1, 100.00), 297(M+, 26.56), 296(M+-1, 12.46); Anal. (C16H15N3O3HCl) C, H, N. | |
claim 30 , wherein the quinazoline compound is selected from: 4-(3',5'-dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(3'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(2'-hydroxy-naphthyl-3')-amino-6,7-dimethoxyquinazoline, 4-{4'-[2"-(4"'-aminophenyl)-hexafluoropropyl]phenyl}-amino-6,7-dimethoxyquinazoline, and 4-(3'-trifluoromethoxylphenyl)-amino-6,7-dimethoxyquinazoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 18.0h; | 4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol), 2-chloroacetophenone(0.93g, 6mmol) and anhydrous K2CO3 (1.38g, 10mmol) were added to 50mL of DMF, stirred at room temperature for 18h, reactionAfter completion, pour into an appropriate amount of ice water, filter to obtain a crude product, dry, and silica gel column chromatography (dichloromethane: methanol = 7:1) to obtain the target., yellow solid powder, yield 85%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 18.0h; | 4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol), 2,4'-dichloroacetophenone(1.13g, 6mmol) and anhydrous K2CO3 (1.38g, 10mmol) were added to 50mL of DMF, stirred at room temperature for 18h, reactionAfter completion, pour into an appropriate amount of ice water, filter to obtain a crude product, dry, and silica gel column chromatography (dichloromethane: methanol = 7:1) to obtain the target., yellow solid powder, yield 90%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 18.0h; | 4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol),2-Chloro-4'-methoxyacetophenone (1.01 g, 6 mmol) and anhydrous K2CO3 (1.38 g, 10 mmol) were added to 50 mL of DMF and stirred at room temperature.After 18 h, after completion of the reaction, the mixture was poured into an appropriate amount of ice water, and filtered to give a crude product, which was evaporated to silica gel column chromatography (dichloromethane:methanol = 5:1)Yellow solid powder,The yield is 88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 18.0h; | 4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol),2-Chloro-4'-methoxyacetophenone (1.11 g, 6 mmol) and anhydrous K2CO3 (1.38 g, 10 mmol) were added to 50 mL of DMF and stirred at room temperature.After 18 h, after completion of the reaction, the mixture was poured into an appropriate amount of ice water, and filtered to give a crude product, which was dried, and silica gel column chromatography (dichloromethane:methanol = 5:1)Yellow solid powder,The yield was 83%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 18.0h; | 4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol),2-Chloro-4'-hydroxyacetophenone (1.03 g, 6 mmol) and anhydrous K2CO3 (1.38 g, 10 mmol) were added to 50 mL of DMF and stirred at room temperature for 18 h.After the completion of the reaction, the mixture was poured into an appropriate amount of ice water, and filtered to give a crude product, which was dried and purified by silica gel chromatography (dichloromethane:methanol = 3:1)Standard molecule, light yellow solid powder, yield 73%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 18.0h; | 4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol),2-Chloro-2',3'-difluoroacetophenone (1.15 g, 6 mmol) and anhydrous K2CO3 (1.38 g, 10 mmol) were added to 50 mL of DMF and stirred at room temperature.After 18 h, after completion of the reaction, pour into an appropriate amount of ice water and suction to give a crude product.The target molecule was obtained as a yellow solid powder, yield: 79%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 12.0h; | Chloroacetamide (0.47 g, 5 mmol) was dissolved in DMF (30 mL).To the above solution was added <strong>[202475-60-3]4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline</strong> (0.89 g, 3 mmol) and anhydrous K2CO3 (0.69 g, 5 mmol), and stirred at room temperature.12h, after the reaction is completed, pour into an appropriate amount of ice water, and filter by suction to obtain a crude product, which is dried.Silica gel column chromatography (dichloromethane: methanol = 2:1)The target molecule, yellow solid powder, yield 88%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h; | 2-Chloro-N-methylacetamide (0.54 g, 5 mmol) was dissolved in DMF (30 mL) and 4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (0.89 g, 3 mmol) and anhydrous K2CO3 (0.69 g, 5 mmol) at room temperatureStir the reaction for 15 h. After the reaction is completed, pour into an appropriate amount of ice water and filter by suction to obtain a crude product.Silica gel column chromatography (dichloromethane:methanol = 3:1) afforded the title compound as a yellow solid powder, yield 90%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | 2-Chloro-N,N-dimethylacetamide (0.61 g, 5 mmol) was dissolved in DMF (30 mL).(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (0.89g, 3mmol) and anhydrous K2CO3 (0.69g, 5mmol), stirred at room temperature for 16h, after the reaction is completed, poured Into the appropriate amount of ice water, suction filtered to obtain a crude product,Dry, silica gel column chromatography (dichloromethane: methanol = 4:1) to give the target molecule, yellow solid powder, yield 87% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 15.0h; | 2-Chloro-N,N-diethylacetamide (0.75 g, 5 mmol) was dissolved in DMF (30 mL).(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (0.89g, 3mmol) and anhydrous K2CO3 (0.69g, 5mmol), stirred at room temperature for 15h, after the reaction is completed, poured Into the appropriate amount of ice water, suction filtered to obtain a crude product,Drying, silica gel column chromatography (dichloromethane:methanol = 4:1) afforded the title compound as a yellow solid powder, yield 81%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 22h; | Chloroacetamide-N-methanol (0.62 g, 5 mmol) was dissolved in DMF (30 mL).To the above solution was added 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (0.89 g, 3 mmol) and anhydrous K2CO3 (0.69 g, 5 mmol), and stirred at room temperature. 22h,After the completion of the reaction, the mixture was poured into an appropriate amount of ice water, and filtered to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 2:1) to give the title compound as a yellow solid powder with a yield of 53%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 24.0h; | The above N-(2-chloroacetyl)tetrahydropyrrole was directly dissolved in DMF (30 mL), and <strong>[202475-60-3]4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline</strong> was added to the above solution. (0.89g, 3mmol) with anhydrous K2CO3 (0.69g, 5mmol) at room temperatureStir the reaction for 24 h. After the reaction is completed, pour into an appropriate amount of ice water and filter to obtain a crude product.Drying, silica gel column chromatography (dichloromethane:methanol = 3:1) afforded the desired compound as a yellow solid powder, yield 53%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 20.0h; | The above N-chloroacetylmorpholine was directly dissolved in DMF (30 mL), and 4-(4'-hydroxyphenyl) was added to the above solution.Amino-6,7-dimethoxyquinazoline (0.89 g, 3 mmol) and anhydrous K2CO3 (0.69 g, 5 mmol), stirred at room temperature20h, after the reaction is completed, pour into an appropriate amount of ice water, and filter by suction to obtain a crude product, which is dried.Silica gel column chromatography (dichloromethane:methanol = 3:1) gave the title compound as a yellow solid powder, yield 57%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 24.0h; | The above N-chloroacetylpiperazine was directly dissolved in DMF (30 mL).To the above solution was added <strong>[202475-60-3]4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline</strong> (0.89 g, 3 mmol) and anhydrous K2CO3 (0.69 g, 5 mmol), and stirred at room temperature.After 24 h, after completion of the reaction, pour into an appropriate amount of ice water and suction to give a crude product.The target molecule was obtained as a yellow solid powder, yield 43% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 24.0h; | The above 2-chloro-1-(4-methylpiperazinyl)ethanone was directly dissolved in DMF (30 mL).To the above solution was added <strong>[202475-60-3]4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline</strong> (0.89 g, 3 mmol) and anhydrous K2CO3 (0.69 g, 5 mmol), and stirred at room temperature. 24h,After the reaction is completed, pour into an appropriate amount of ice water, and filter by suction to obtain a crude product, which is dried.Silica gel column chromatography (dichloromethane:methanol = 2:1) gave the desired compound as a yellow solid powder (yield: 46%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 24.0h; | The above 2-chloro-1-(4-ethylpiperazinyl)ethanone was directly dissolved in DMF (30 mL), and 4-(4'-hydroxyphenyl)amino-6,7-dimethyl was added to the above solution. Oxyquinazoline (0.89 g, 3 mmol) and anhydrous K2CO3 (0.69 g, 5 mmol), oftenStir the reaction for 24 h under temperature. After the reaction is completed, pour into an appropriate amount of ice water and filter to obtain a crude product.Drying, silica gel column chromatography (dichloromethane:methanol = 2:1) afforded the title compound as a yellow solid powder, yield 51% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 18.0h; | 4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol),Ethylchloroacetate(0.74g, 6mmol) and anhydrous K2CO3 (1.38g, 10mmol) were added to 50mL of DMF, stirred at room temperature for 18h, reactionAfter completion, pour into an appropriate amount of ice water, and filter by suction to obtain a crude product. Dry and silica gel column chromatography (dichloromethane:methanol = 5:1), light yellow solid powder, yield 87% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.6% | Stage #1: WHI-P131 With sodium hydride In dimethyl sulfoxide at 20℃; for 0.25h; Stage #2: pinacol (bromomethyl)boronate In dimethyl sulfoxide at 50℃; for 2h; Stage #3: water In dimethyl sulfoxide at 20℃; | 31.2 Step 2: (4-(6,7-dimethoxyquinazolin-4-ylamino)phenoxy)methylboronic acid To a mixture of 4-(6,7-dimethoxyquinazolin-4-ylamino)phenol (100 mg, 0.336 mmol, 1.00 equiv) in dimethyl sulphoxide (3 mL) was added sodium hydride (16 mg, 2.00 equiv) at room temperature. After stirring for 15 min at room temperature, 2-(bromomethyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (111 mg, 0.505 mmol, 1.50 equiv) was added and the resulting mixture was stirred at 50°C for 2 h. After cooled to room temperature, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate and fdtered. The fdtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (methanol: dichloromethane (10:1)) to afford 9.4 mg (7.6%) of (4-(6,7- dimethoxyquinazolin-4-ylamino)phenoxy)methylboronic acid as a yellow solid. MS (ESI, pos. ion) m/z: 356.2 (M+l). -NMR (300 MHz, DMSO-r ppm): d 8.44-8.21 (m, 1H), 7.33-7.12 (m, 4H), 6.96-6.80 (m, 3H), 6.40-6.31 (m, 1H), 3.92-3.78 (m, 5H), 3.28-3.11 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: WHI-P131 With caesium carbonate In dimethyl sulfoxide at 20℃; for 1h; Stage #2: diethyl (bromomethyl)phosphonate In dimethyl sulfoxide at 50℃; | 32.1 Step 1: diethyl (4-(6,7-dimethoxyquinazolin-4-ylamino)phenoxy)methylphosphonate To a mixture of 4-(6,7-dimethoxyquinazolin-4-ylamino)phenol (300 mg, 1.009 mmol, 1.00 equiv) in dimethyl sulphoxide (15 mL) were added cesium carbonate (658 mg, 2.018 mmol, 2.00 equiv) at room temperature. After stirring at room temperature for 1 h, diethyl bromomethylphosphonate (466 mg, 2.018 mmol, 2.00 equiv) was added and the resulting mixture was stirred overnight at 50°C. After cooled to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic layers were washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate and fdtered. The fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (1 : 1)) to afford 250 mg (55%) of diethyl 4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxymethylphosphonate as a grey solid. MS (ESI, pos. ion) m/z: 470.3 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: caesium carbonate / dimethyl sulfoxide / 1 h / 20 °C 1.2: 50 °C 2.1: trimethylsilyl bromide / tetrahydrofuran / 0 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sulphamoyl chloride In N,N-dimethyl acetamide at 20℃; for 1h; Inert atmosphere; | 16.2 Step 2: 4-((6,7-dimethoxyquinazolin-4-yl)amino)phenyl sulfamate To a stirred mixture of 4-((6,7-dimethoxyquinazolin-4-yl)amino)phenol (110 mg, 0.370 mmol, 1.00 equiv) in N,N-dimethylacetamide (4 mL, 43.021 mmol, 116.28 equiv) was added sulfamoyl chloride (86 mg, 0.740 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. After stirring at room temperature for 1 h, the reaction mixture was filtered to give 3.5 mL of a clear solution, which was purified by prep- HPLC with the following conditions Column: XBridge Shield RP18 OBD Column 19x 150 mm, 5 um; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 20 mL/min; Gradient: 28% B to 38% B in 7 min, 220 & 254 nm. The fractions containing the desired product were combined and lyophilized to give 85 mg (61%) of 4-((6,7-dimethoxyquinazolin-4-yl)amino)phenyl sulfamate as an off-white solid. MS (ESI, pos. ion) m/z: 377.0 (M+l). 1H-NMR: (400 MHz, DMSO-rL, ppm) d 9.57 (s, 1H), 8.46 (s, 1H), 8.00 (s, 2H), 7.85-7.83 (m, 3H), 7.31-7.28 (m, 2H), 7.20 (s, 1H), 3.97- 3.93 (m, 6H). |
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