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CAS No. : | 5190-68-1 | MDL No. : | MFCD00228682 |
Formula : | C8H5ClN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GVRRXASZZAKBMN-UHFFFAOYSA-N |
M.W : | 164.59 | Pubchem ID : | 78864 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 44.55 |
TPSA : | 25.78 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.47 cm/s |
Log Po/w (iLOGP) : | 1.98 |
Log Po/w (XLOGP3) : | 2.59 |
Log Po/w (WLOGP) : | 2.28 |
Log Po/w (MLOGP) : | 1.86 |
Log Po/w (SILICOS-IT) : | 2.62 |
Consensus Log Po/w : | 2.27 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.16 |
Solubility : | 0.113 mg/ml ; 0.000684 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.78 |
Solubility : | 0.273 mg/ml ; 0.00166 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.94 |
Solubility : | 0.0191 mg/ml ; 0.000116 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.28 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338+P310-P332+P313-P403+P233-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H315-H318-H335 | Packing Group: | Ⅲ |
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 |
---|---|---|
58% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at 25℃; for 1 h; Inert atmosphere | General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 molpercent), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.7% | With thionyl chloride Reflux; | 4.2 Preparation of intermediate 4-chloroquinazoline 14.6 g (0. lmol) quinazolin-4 (3H) -one In a 250 ml single-necked flask, 50 ml of thionyl chloride was used as solvent, The temperature was raised to reflux for 4-6 hours. After the TLC monitoring reaction was complete, the reaction solution was poured into water and stirred for 30 minutes. The mixture was filtered and washed with anhydrous ether to give 10.96 g of a reddish brown solid in a yield of 92.7% |
92.7% | With thionyl chloride Reflux; | 3.2 2) Preparation of 4-chloroquinazoline Take 14.6 g (0.1 mol) of quinazolin-4(3H)-one in a 250 ml single-mouth flask and use 50 ml of thionyl chlorideas a solvent, and raise the temperature to reflux for 4-6 hours. After the reaction was monitored by TLC, aftercooling, the reaction solution was poured into water and stirred for 30 min, filtered and washed with anhydrous ether to obtain 10.96 g of a red-brown solid with a yield of 92.7%. |
92.7% | With thionyl chloride Reflux; | 3.2 2) The Preparation of Intermediate 4-chloroqui- nazoline Quinazolin-4(3H)-one(14.6 g, 0.1 mol) was dissolved in 50 mL sulfuryl dichloride, and then heated to reflux for 4-6 h. After the reaction was over by Thin-Layer Chromatography monitoring, the mixture was poured into ice water and stirred for about 30 min, filtered and washed the solid with anhydrous diethyl ether to get 10.96 g 4-chloroquinazoline as brown solid with yield of 92.7%. |
92.7% | With thionyl chloride Reflux; | 3.2 2) Preparation of 4-chloroquinazoline Take 14.6 g (0.1 mol) of quinazolin-4(3H)-one in a 250 ml single-mouth bottle and 50 ml of thionyl chloride as a solvent.The temperature was raised to reflux for 4-6 hours.After the TLC monitoring reaction was completed, the reaction solution was poured into water and stirred for 30 minutes after cooling.Filtered and washed with anhydrous ether to give a red-brown solid was 10.96g, 92.7% yield. |
92.7% | With thionyl chloride Reflux; | 3.2 2) Preparation of 4-chloroquinazoline Take 14.6g (0.1mol) of quinazolin-4 (3H) -one in a 250ml single-necked bottle, 50ml of sulfoxide chloride as a solvent, and warm to reflux for 4-6 hours.After the reaction was monitored by TLC, the reaction solution was poured into water and stirred for 30min after cooling,Filtration and washing with anhydrous ether gave 10.96 g of red-brown solid in 92.7% yield. |
92.7% | With thionyl chloride for 6h; Reflux; | 3.2 2) Preparation of 4-chloroquinazoline 14.6 g (0.1 mol) of quinazolin-4 (3H)-one is taken into a 250 ml flask with one neck, 50 ml of thionyl chloride is used as the solvent. The mixture is heated for reflux reaction for 4-6 h. After the reaction was complete monitored by TLC, the reaction solution is cooled, then poured into water for stirring for 30 min, and filtered. The filter cake is washed with absolute ether to obtain 10.96 g of reddish brown solid, with a yield of 92.7%. |
92.7% | With thionyl chloride Reflux; | 3.2 2) Preparation of 4-chloroquinazoline Take 14.6g (0.1mol) of quinazolin-4(3H)-one in a 250ml single-necked flask, with 50ml of thionyl chloride as a solvent, and heat to reflux for 4-6 hours. After the reaction was monitored by TLC, the reaction solution was poured into water and stirred for 30 min after cooling, filtered and washed with anhydrous ether to obtain 10.96 g of a reddish brown solid with a yield of 92.7%. |
89% | With trichloroisocyanuric acid; triphenylphosphine In toluene for 3.5h; Heating; | |
85% | With trichlorophosphate at 100℃; for 0.166667h; MW irradiation; | |
83.3% | With thionyl chloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane for 5h; Reflux; | 1.3 (3) Synthesis of 4-chloro-quinazoline : Round bottom flask quinazolin -4 (3H) - one (2.92g, 20mmol), 20ml of thionyl chloride, 10ml1,2- dichloroacetylAlkyl and 0.5mlDMF, 5H reflux, the reaction was complete, most of the solvent was distilled off, cooled to room temperature, 30mL of chloroform was added to the residue andTogether poured into water, saturated with K2CO3 solution to adjust the pH to 6-8, liquid separation, the mother liquor washed with water several times, separated, removing solvent, to obtain yellowSolid, recrystallized from petroleum ether to give white crystals, 2.74g mass (3.29 g of a theoretical mass), 83.3% yield. |
82% | With trichlorophosphate at 0℃; for 9h; Reflux; | 3 4.3. General procedure for synthesis of substituted 4-chloroquinazolines General procedure: To phosphoryl chloride (30 ml, 0.32 mol), the selected quinazolin-4(3H)-one (10 mmol) was added at 0 C and stirred for 10 min.The resulting mixture was then refluxed for 9 h. After removal ofexcess solvent, the residue was dissolved in ice-water (50 ml)and the solution was neutralized with ammonium hydroxide.The solution was extracted three times with dichloromethane(50 ml). The organic layer was washed with brine (100 ml), driedover MgSO4, and the solvent was removed under reduced pressure.The formed solid was recrystallized from ethanol. For further usethe structure of the compounds were confirmed by NMR. |
81.8% | With trichlorophosphate In N,N-dimethyl-formamide at 70℃; for 5h; | 1.2 4-chloroquinazoline (8) A mixture of compound 7 (7.25g, 0.05mol) and 70ml of DMF was stirred at room temperature, then 5.5ml (0.75mol) of POCl3 was added into the mixture slowly. The mixture was heated at 70°C for 5h. The excess POCl3 was removed in vacuo. Then 100ml of ice water was added slowly into the reaction mixture to result in a brown solid. The precipitate was filtered out and dried, then the dried solid was refluxed in toluene to obtain a yellow powder. Finally, the yellow powder was dispersed in 10% of sodium carbonate and heated to reflux to result in 6.78g of yellow solid with a yield of 81.8%. m.p.94~96°C. IR (KBr) 3074.09, 1701.67, 1646.80, 1613.87, 1571.53, 1475.54, 1439.57, 759.67, 685.21cm-1; UV-VIS(CH3OH), λ/nm: 225, 264, 311nm; 1H NMR (400 MHz, CD3OD)δ 9.14 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.76 - 7.67 (m, 2H). ESI-MS for C8H5N2Cl [M+H]+: calcd: 164.59, found: 164.08. Anal. Calcd for C8H5N2Cl: C, 58.38; H, 3.06; N, 17.02. Found: C, 58.06; H, 3.11; N, 17.05. |
81% | With thionyl chloride In 1,2-dichloro-ethane; N,N-dimethyl-formamide Reflux; | 1.5 (5) Synthesis of 4-chloroquinazoline: Add quinazolinone (20.53 mmol), 5 drops of DMF, 1,2-dichloroethane (15 mL) and thionyl chloride (30 mL) in a 100 mL three-necked flask.The reaction was completed after heating to reflux for 1 to 2 hours.The solvent was recovered and distilled under reduced pressure to give a yellow solid.After dissolving in methylene chloride, the pH was made alkaline with a saturated sodium carbonate solution.The mixture was separated and washed with water three times. The organic phase was collected, dried and concentrated to give a pale yellow solid. Get white crystals. The yield was 81%. |
80% | With triethylamine; trichlorophosphate In toluene at 20 - 95℃; for 4h; | 6.5. 4-Chloroquinazoline (12b) To a 250 mL round-bottomed flask were added quinazolin-4(3H)-one(13b) (2.00 g, 13.7 mmol), trimethylamine (3 mL), and toluene (30 mL).The mixture was cooled to 0 C, and phosphorus oxychloride (2 mL) wasadded. The reaction mixture was stirred at room temperature for 1 h.The reaction was then heated to 95 C for 3 h. After monitoring thereaction by TLC, the reaction mixture was cooled to room temperatureand diluted with 30 mL of ethyl acetate. The solution was then washedwith 10 mL of ice cold water, 10 mL of saturated NaHCO3, 10 mL ofwater, 5 mL of 1 N HCl, 10 mL of water, 10 mL of saturated NaHCO3 and10 mL of saturated NaCl. The organic layer was dried over Na2SO4,filtered and concentrated to obtain 12b as a yellow solid (1.79 g, 80%).TLC Rf = 0.85 (MeOH:CHCl3; 1:5); mp, 144.2-146.1 C (lit.56145-147.5 C); 1H NMR, DMSO-d6 (400 MHz): 7.59-7.63 (dt, 1H, J1 =1.09, J2 = 7.23, J3 = 8.01, Ar), 7.76-7.78 (d, 1H, J = 8.24, Ar),7.89-7.92 (dt, 1H, J1 = 1.47, J2 = 7.24, J3 = 8.29, Ar), 8.15-8.17 (d, 1H,J = 7.03, Ar), 8.58 (s, 1H, Ar). |
77% | With phosphorus(V) chloride; trichlorophosphate for 2h; Heating; | |
75% | With thionyl chloride In N,N-dimethyl-formamide for 3h; Reflux; | 1.4 (4) Synthesis of 4-chloroquinazoline (IV-1) With a thermometer,The quinazoline-4(3H)-one (7.30g, 0.05mol) was added to the three-necked flask of the electromagnetic stirring and reflux condenser.Thionyl chloride (200 mL) and DMF (0.4 mL) were heated under reflux for 3 hours.The solution was concentrated under reduced pressure, cooled, and then added with 500 mL of dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate and distilled water.Dry the organic phase with anhydrous Na2SO4.Filter by suction and concentrate the filtrate under reduced pressure.Obtained a white solid,Recrystallization from ethanol gave 4-chloroquinazoline (IV-1) (6.15 g, 75%) |
74% | With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 20℃; for 5h; Reflux; | 4.2. General procedure for the synthesis of intermediates 2a-g To a suspension of the starting material quinazolinone 1a(146 mg, 1 mmol, 1eq) in phosphorus oxychloride (280 μL, 3 mmol,3eq) was added N,N-dimethyl aniline (135 μL, 128 mmol, 1.05 eq)dropwise at ambient temperature. Then the reaction mixture washeated to reflux for 5 h. The excess phosphorus oxychloride wascollected under reduced pressure. To the slurry was added crushedice and stirred for 10 min. The precipitate was collected by filtration,and then dried under vacuum to afford 4-choloroquinazoline(2a) as off-white solid (122 mg, 74%). The product was used for thenext step without further purification. This procedure was alsoapplied to the preparation of intermediates 2b-g. |
73% | With N-chloro-succinimide; triphenylphosphine In 1,4-dioxane for 4h; Heating; | |
72% | With diethylamine; trichlorophosphate at 100℃; for 0.166667h; Microwave irradiation; | 4.1.33. 4-Chloro-quinazoline (21) 26 (230 mg, 1.57 mmol) was heated with POCl3 (362 mg, 2.36 mmol) and N,N-diethylamine (1.0 ml) 10 min at 100 °C using Biotage Initiator microwave synthesizer. The resulting reaction mixture was dissolved in ethyl acetate (50 ml) and washed with HCl (1 M) (3× 50 ml). The organic phase was dried (Na2SO4) and evaporated to dryness. The crude product was purified by flash chromatography (silica gel) eluting with EtOAc/PE 1:10 to give 21 (187 mg, 72%). 1H NMR (DMSO-d6): δ 8.46 (s, 1H); 8.18 (dd, 1H, J = 7.9, 0.9 Hz); 7.87 (t, 1H, J = 7.6 Hz); 7.77 (d, 1H, J = 8.1 Hz); 7.59 (t, 1H, J = 7.6 Hz). 13C NMR (DMSO-d6): δ 160.0; 146.5; 145.6; 134.6; 127.2; 126.0; 125.0; 122.0. |
72% | With N-ethyl-N,N-diisopropylamine; trichlorophosphate for 2.5h; Reflux; | |
60% | Stage #1: 4-Hydroxyquinazoline With N-ethyl-N,N-diisopropylamine In toluene for 1h; Reflux; Stage #2: With trichlorophosphate In toluene at 80℃; | |
59% | With trichlorophosphate at 120℃; for 2h; | 64.2 Step-2: Synthesis of 4-chloroquinazoline: The stirred solution of quinazolin- 4(3H)-one (0.15 g, 1.02 mmol, 1 eq) in 1 mL of POCl3 was heated at 120 °C for 2 h. After completion reaction mixture was diluted with water (150 mL) and extracted using ethyl acetate (3 × 50 mL). Combined organic layer was washed with water (3 × 30 mL), dried over anhydrous sodium sulphate. Removal of solvent under reduced pressure afforded 4- chloroquinazoline (100 mg, 59%). LCMS: 165 [M+1]+ . |
55% | With thionyl chloride; N,N-dimethyl-formamide | |
54.5% | With phosphorus(V) chloride; trichlorophosphate for 24h; Heating; | |
53% | With thionyl chloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane at 140℃; for 5h; | |
50% | With trichlorophosphate for 9h; Reflux; | 1 5.3. General procedure for the preparation of substituted 4-chloroquinazolines (5-8) General procedure: The selected quinazolin-4(3H)-one (10 mmol) was mixed with 10 ml phosphoryl chloride and was then stirred under reflux for 9 h. After completion of the reaction the solvent was evaporated under reduced pressure. Ice-water was added to the residue and the formed precipitatewas neutralized with ammonium hydroxide and was filtered off. 5.3.1 4-Chloroquinazoline (5) The product was synthesized from compound (1) and recrystallized from ethanol to yield pale yellow solid (50%). 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.17-8.12 (m, 1H), 7.91-7.86 (m, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.63-7.57 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 160.01, 147.16, 144.23, 135.22, 127.85, 126.40, 124.24, 122.02. |
30% | With Ph3PCl(1+)*succinimide(1-) at 130℃; for 2h; | |
With phosphorus(V) chloride; trichlorophosphate | ||
With phosphorus(V) chloride; trichlorophosphate | ||
With phosphorus(V) chloride; trichlorophosphate for 5.5h; Heating; | ||
With 2,3-Dimethylaniline; trichlorophosphate In toluene for 4h; Heating; | ||
With trichlorophosphate at 90℃; | ||
With thionyl chloride at 70℃; for 1h; | 11 Example 11 - Preparation of compound 11 in table 1 - N-(2,3-difluorophenyl)-2-[4-(quinazolin-4-ylamino)-1H-pyrazol-1-yl]acetamide A mixture of quinazolin-4 (3H)-ONE (0.146 g, 1.0 mmol) and 1 drop of dimethylformamide in thionyl chloride (3 ml) was heated at 70°C for 1 hour. The mixture was evaporated under reduced pressure and the residue suspended in dimethylacetamide (5 ml). 2-(4-AMINO-LH-PYRAZOL-1-YL)-N-(2, 3-difluorophenyl) acetamide (0.252 g, 1.0 mmol) was added and the mixture was then heated at 80°C for 1 hour. The reaction mixture was allowed to cool to room temperature and then acetonitrile (20 ml) was added and the resultant solid filtered to leave compound 11 in table 1 (0.220 g, 58% yield): H-NMR (DMSO D6) : 11.82 (br s, 1H), 10.39 (br s, 1H), 9.00 (s, 1H), 8.78 (d, 1H), 8.42 (s, 1H), 8.10 (d, 1H), 8.04 (s, 1H), 7. 84 (m, 2H), 7.65 (m, 1H), 7.20 (m, 2H), 5. 22 (s, 2H); MS (+VEESI) : 381 (M+H) +. | |
With trichlorophosphate | ||
With thionyl chloride In 1,2-dichloro-ethane; benzene Heating / reflux; | ||
With N-ethyl-N,N-diisopropylamine; trichlorophosphate for 5h; Reflux; | -(4-methylpiperazin-1-yl)quinazoline (10) Quinazolin-4(3H)-one (500 mg, 3.42 mmol) was added to a mixture of DIPEA (0.66 ml, 3.76 mmol) and POCl3 (5 ml) and the mixture was heated at reflux. After 5 hours, the mixture was poured over crushed ice and the aqueous layer was extracted with DCM. Drying over Na2SO4 and removal of the solvent gave a solid that was filtered over a pad of silica using DCM as eluent. The white solid that was obtained this way was dissolved in EtOAc (25 ml), after which N-methylpiperazine (1.0 ml) was added. After stirring at r.t. for 1.5 hours the reaction mixture was diluted with EtOAc and washed with water (pH 10-11 with 1M NaOH) and brine. Drying over Na2SO4 and removal of the solvent gave 625 mg (2.47 mmol, 72%) of the title compounds as a yellow oil. | |
With thionyl chloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane | ||
With phosphorus(V) chloride; trichlorophosphate Reflux; | ||
With trichlorophosphate at 110℃; for 2h; | ||
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene at 0 - 90℃; for 3h; | 1 General procedure for the preparation of compounds 8a and 8f General procedure: POCl3 (2.4 mmol) was slowly added to a cooled (0 °C) suspension of 3,4-dihydroquinazolin-4-one (2.0 mmol) and diisopropylamine (2.6 mmol) in toluene (10 mL) and the resultant mixture was stirred at 90 °C for 3 h. The mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL), and dried over sodium sulfate. The product (4-chloroquinazoline) was purified by column chromatography (hexane/ethyl acetate 95:5). | |
With thionyl chloride; N,N-dimethyl-formamide Reflux; Inert atmosphere; | ||
With triethylamine; trichlorophosphate at 90℃; for 2h; | ||
With thionyl chloride In N,N-dimethyl-formamide Reflux; | ||
Stage #1: 4-Hydroxyquinazoline With trichlorophosphate In N,N-dimethyl-formamide at 100 - 105℃; Stage #2: With triethylamine In chloroform; lithium hydroxide monohydrate Cooling with ice; | 4-Chloroquinazoline (4) A mixture of quinazolin-4(3H)-one 3 (0.4 g, 2.5 mmol) in POCl3 (25 mL) and N,N-dimethylforamide(DMF) (0.12 mL) was stirred under reflux (100-105°C) for 5-6 h. The excess POCl3 was removed by vacuo. The residue was poured into a mixture of chloroform (50 mL), ice water (80 mL) and triethylamine (5 mL) then neutralized with saturated NaHCO3 solution. The chloroform layer was separated, dried over Na2SO4 and filtered. The solvent was removed by distillation to give yellow solid of 4-chloroquinazoline 4. The resulting compound was stored at 0°C without a further purification.13) Yield 62.5%, mp100-102°C, spectral data as reported.14) | |
With trichlorophosphate | ||
With trichlorophosphate at 120℃; for 16h; | 1.2 Step two is the formation of a 4-chloroquinazoline In one approach, the crude product from step one is mixed with phosphorus oxycholoride in a molar 1:10 and heated at about 120 °C for 16 hours. After the reaction iscomplete, the mixture is cooled and excess phosphorus oxycholoride is removed by rotary evaporation. An organic solvent, such as dichloromethane, is added to dissolve the solid, followed by pH adjustment of resulting solution to about 7-8 by addition ammonia. The resulting mixture is extracted with dichloromethane, dried and purified by column chromatography. | |
With thionyl chloride In N,N-dimethyl-formamide Reflux; | ||
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 0℃; Reflux; | 4.1.2. General procedure for preparation of 4-chloroquinazolines 2a-h General procedure: To a magnetically stirred solution of phosphorus oxychloride (20 mL) and N,N-dimethylaniline (1 mL) at 0 °C was added portion wise 2-(un-substituted/substituted) quinazolin-4(3H)-one 1a-h (3.0 g). The reaction mixture was refluxed for 8 h. The reaction mixture was then poured onto ice water and the pH adjusted to alkaline with 2 N NaOH. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4 and filtered, and the solvent was removed by distillation. The obtained solid was recrystallized from ethanol to give 2a-h [11-15]. | |
With trichlorophosphate In acetonitrile at 110℃; for 0.0833333h; Microwave irradiation; | 1.1-Chloro-6,7-dimethoxyisoquinoline General procedure: A solution of 6,7-dimethoxyisoquinolin-1(2H)-one(200 mg, 0.97 mmol), phosphoryl trichloride (0.268 mL, 2.92 mmol) inacetonitrile (5 mL) was stirred at 110° C for 5 minutes under microwaveirradiation. The reaction was quenched with a saturated aqueous sodium bicarbonatesolution and stirred at ambient temperature for 1 h. It was filtered throughcelite and washed with ethyl acetate. The filtrate was concentrated to dryness.The crude material was purified by flash chromatography, eluting with heptanesand ethyl acetate (1:0 to 0:1) to give the desired product as a gum (99 mg,45.4 %). | |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 100 - 105℃; | General method for the preparation of heterocyclic thioamides General procedure: Method B. To a cold solution of heterocyclic amide (2.5 mmol)in POCl3 (25 mL) was added dimethylaniline (2.5 mmol). Thereaction mixture was stirred under reflux (100-105 °C) for1.5-2 h. The excess POCl3 was removed under reduced pressure. The residue was poured into a mixture of chloroform(50 mL), ice water (80 mL) and ammonia (5 mL). The chloroform layer was separated, dried over Na2SO4 and filtered. Tothis chloroform solution of the in situ generated chloroheterocycles was added (0.69 g, 2.5 mmol) of N-cyclohexyl dithiocarbamate cyclohexylammonium salt. The reaction mixture was refluxed at 61 °C for 12 h. The reaction mixture was evaporatedunder reduced pressure and 25 mL of ethanol was added to thesolid residue. The yellowish-orange precipitate was filtered togive the desired product. The crude compounds were pureenough for analytical purposes. Purification of products foranalysis was achieved by crystallization from the appropriatesolvent; chromatographed with the appropriate eluent or byrepeated dissolution in KOH and reprecipitation by acetic acid. | |
With thionyl chloride In 1,2-dichloro-ethane; N,N-dimethyl-formamide for 4.5h; Reflux; | 1.1 (1) intermediate 4 - dichloroquinazoline synthesis To the 100 ml round-bottom flask is added O-aminobenzoic acid 11.5 g (83.83 mmol) and formamide 15.1 g (335.41 mmol), mixed heating to 135 - 145 °C, reaction 5 h, after the reaction by adding 100 ml water, cooled to 60 °C when adding a large amount of water, stirring 30 min, cooling to room temperature, filtered, to obtain brownish solid, anhydrous ethanol in for re-crystallization, to obtain white flocculent solid, is quinazoline -4 - one; to the 100 ml round-bottom flask is added in the quinazoline -4 - ketone (36.32mmol), thionyl chloride (37 ml), 1, 2 - dichloroethane (17 ml) and DMF (1 ml), reflux 4.5h, after the reaction is complete evaporate most of the solvent, cooling to room temperature, is added to the residual liquid 30 ml chloroform and then poured into water, saturated K2CO3Aqueous solution to adjust the pH to 6 - 8, liquid, washing several times stock solution, liquid, desolvation, get the yellow solid, recrystallization, to obtain white crystal, is 4 - dichloroquinazoline. | |
With thionyl chloride; N,N-dimethyl-formamide for 8h; Reflux; | General Synthesis of 4-chloroquinazoline analogues 3a-3j from 4-quinazolone analogues 2a-2j. General procedure: A mixture of 4-quinazolone analogues 2a-2j (8.0 mmol) in SOCI2 (27.4 mL) containing DMF (2 drops) was refluxed for 8 h. SOCI2 was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed with saturated NaHCO3 solution and brine, respectively, dried over anhydrous Na2S04 and then concentrated under reduced pressure to yield the compounds 3a-3j (65.1-88.9percent yield) as white or off-white solid. | |
With thionyl chloride In N,N-dimethyl-formamide for 5h; Reflux; | 4.1.2. General procedure for the syntheses of intermediate 2 General procedure: A mixture of 4-hydroxyquinazoline (0.02 mol) in SOCl2 (20 mL)containing DMF (2 drops) was refluxed for 5 h. SOCl2 was removedunder reduced pressure, and the residue was dissolved in dichloromethane(DCM). The solution was washed with NaHCO3 solutionand brine, dried over anhydrous Na2SO4, and concentrated under reducedpressure to obtain the desired compound as a yellow solid. | |
With trichlorophosphate at 100℃; for 4h; | ||
Stage #1: 4-Hydroxyquinazoline With phosphorus(V) chloride; trichlorophosphate for 4h; Reflux; Stage #2: With ammonium hydroxide | ||
With thionyl chloride; N,N-dimethyl-formamide Reflux; | ||
With N,N-dimethyl-formamide for 15h; Reflux; Inert atmosphere; | ||
With thionyl chloride at 120℃; for 5h; | ||
With trichlorophosphate In N,N-dimethyl-formamide at 85℃; | 3.2.3 Synthetic procedures for intermediates 5 General procedure: Substituted quinazolin-4(3H)-one (6.5mmol) was dissolved in phosphorus oxychloride (12mL) and DMF (0.5mL), stirred and refluxed at 85 °C until the reaction was completed. It was poured into ice water, and filtered under reduced pressure to obtain intermediates 5. | |
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide | ||
With trichlorophosphate at 100℃; for 2h; | General procedure: To a solution of intermediates 7a-7i (1 equiv.) and ammonium formate (3 equiv.) in EtOH was added trimethyl orthoformate (3 equiv.). The mixture was heated under reflux for 5-8h. After the addition was completed, TLC analysis indicated the reaction was complete. After cooled to room temperature, the mixture was filtered, and the solid was collected and dried to give a crude intermediates 8a-8i for the next step. A solution of the corresponding intermediates 8a-8i (1 equiv.) in POCl3 (10 equiv.) was stirred at 100°C for 2h. After the addition was completed, TLC analysis indicated the reaction was complete. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to give a crude intermediates 9a-9i for the next step. Then, a solution of corresponding intermediates 9a-9i (1 equiv.), methyl 4-(aminomethyl)-benzoate hydrochloride (1 equiv.) and DIPEA (4 equiv.) in IAP was stirred at 90°C for 6-8h, at which time TLC analysis indicated the reaction was completed. After cooled to room temperature, the mixture was filtered, and the solid was collected to give intermediates 10a-10i, which was used directly in the next step without purification. | |
With thionyl chloride at 120℃; for 5h; | 2 Compounds6a-jwere synthesized through a three-step route as illustrated in Scheme 2.The first step, as described forcompounds4a-j, was chlorinated with thionyl chloride to give the 4-chloro-quinazoline derivative5a-j.A mixture of compound 2 and thionyl chloride was stirred at 120 °C for 5 hours.Then, the resulting mixture was evaporated under reduced pressure to give a residue, which was redissolved in 50 ml of water.Then, the mixturewas neutralized with a solution ofNaHCO35% and extracted with DCM (3x15 mL).The organic layers were combinedand filtered overanhydrous Na2SO4.The solvent was removed under reduced pressureto giveintermediates5a-j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.7% | In isopropyl alcohol for 6h; Reflux; | 1.3 compounds 9a-9j General procedure: A mixture of compound 8 (1.65g, 0.01mol) and 0.01mol of aniline derivatives in 20ml of isopropanol was heated to reflux for 6h. The mixture was cooled to room temperature. The precipitate was filtered out and recrystallized from ethanol to result in the target compounds. |
83% | In isopropyl alcohol at 110℃; Sealed tube; Microwave irradiation; | 4.1.10. General procedure for the preparation of compounds 33e40 General procedure: 4-chloroquinazoline (164 mg, 1 mmol) was added to isopropanol(5 mL) with the corresponding substituted aniline derivative(1 mmol) and sealed in a microwave tube. The mixture washeated by 100W microwave irradiation to 110 C for a period of15e30 min to completion of the reaction, as indicated by TLC. Theformed precipitate was filtered off, washed with 10 mL isopropanoland dried in vacuo. If no precipitate was formed, the solvent wasremoved under reduced pressure and the remaining solid recrystallized from ethanol. 4.1.10.1. N-phenylquinazolin-4-amine (33). The compound wassynthesized from 4-chloroquinazoline (165 mg, 1 mmol) and aniline(93.1 mg, 1 mmol) as described in the general procedure forcompounds 33e40 to yield 33 as a olorless solid (184 mg, 83 %), mp226e227 C. 1H NMR (500 MHz, DMSO-d6) d 9.76 (s, 1H), 8.62e8.51(m, 2H), 7.90e7.81 (m, 3H), 7.78 (dd, J 8.3, 1.3 Hz, 1H), 7.66e7.59(m, 1H), 7.43e7.35 (m, 2H), 7.16e7.09 (m, 1H). 13C NMR (126 MHz,DMSO-d6) d 157.91, 154.61, 149.82, 139.28, 133.09, 128.56, 127.92,126.33, 123.86, 123.10, 122.60, 115.30. Anal. Calcd. for C14H11N3: C,76.00; H, 5.01; N, 18.99. Found: C, 76.15; H, 5.05; N, 18.65. |
61% | With diethylaminomethylpolystyrene; polymer-supported Et3N In N,N-dimethyl-formamide; butan-1-ol at 100℃; for 16h; |
61% | at 150℃; for 0.25h; Microwave irradiation; Neat (no solvent); | 4.1.1. Phenyl-quinolin-2-yl-amine (12a) General procedure: A mixture of 2-chloroquinoline 17 (200 mg, 1.22 mmol) and aniline (455 mg, 4.89 mmol) was heated 15 min at 150 °C using microwave synthesizer. The resulting reaction mixture was dissolved in ethyl acetate (50 ml) and washed with saturated Na2CO3 (2× 50 ml) and H2O (2× 50 ml). The organic phase was dried (Na2SO4) and evaporated to leave a clear oil. This oil was purified by flash chromatography (silica gel) eluting with dichloromethane to give 12a as a light brown solid (133 mg, 49%). |
In isopropyl alcohol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With cyclohexylaminodithiocarboxylic acid, cyclohexylammonium salt In chloroform at 61℃; for 12h; | General method for the preparation of heterocyclic thioamides General procedure: Method A. To a solution of chloroheterocycles (2.5 mmol) inCHCl3 (25 mL) was added (0.69 g, 2.5 mmol) of N-cyclohexyldithiocarbamate cyclohexylammonium salt. The reaction mixture was refluxed at 61 °C for 12 h. The reaction mixture wasevaporated under reduced pressure and 25 mL of ethanol wasadded to the solid residue. The yellowish-orange precipitatewas filtered to give the desired product. The crude compounds were pure enough for analytical purposes. Purification of products for analysis was achieved by crystallization from theappropriate solvent; chromatographed with the appropriateeluent or by repeated dissolution in KOH and reprecipitation byacetic acid. The filtrate was evaporated once again and the solidobtained was crystalized from ethanol water to give symmetrical dicyclohexylthiourea (3). |
With potassium hydrosulfide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With hydrazine hydrate In ethanol for 4h; Reflux; | 4.2. Preparation of 4-hydrazinylquinazoline (4) [24] Compound 3 (10 mmol) and hydrazine hydrate 85% (30 mmol) in 50 mL of ethanol was heated under reflux for 4 h. The reaction mixture was concentrated and allowed to cool. The solid product obtained was filtered, washed with water and dried. Recrystallization with ethanol afforded the desired solid compound 4, mp. 163-164 °C in 64% yield. 1H NMR (DMSO-d6, 600 MHz) δ 4.73 (s, 2H, NH2), 7.45 (s, 1H, Ar-H), 7.69 (d, 2H, J = 31.2 Hz, Ar-H), 8.16 (s, 1H, Ar-H), 8.47 (s, 1H, CH), 9.64 (s, 1H, NH). |
55% | With hydrazine hydrate In ethanol Reflux; | General procedure for the synthesis of 2-hydrazinylpyridine and derivatives (1b-1v) General procedure: To 2-chloropyridine (1.1 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (2 mL) dropwise at room temperature. The mixture was refluxed until completion as monitored by TLC. The reaction mixture was cooled, ethanol was removed by evaporation. Then, the residue was partitioned between ethyl acetate and water. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give the product, which was used for the following cyclization reaction without purification. |
With hydrazine hydrate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With phosphorus pentachloride; trichlorophosphate for 0.333333h; Heating / reflux; | X.1 Phosphorus oxychloride (64mL,687mmol) and phosphorus pentachloride (14.89g, 71.50mmol) were added to 4-hydroxyquinazoline (7.94g, 52.3mmol), and the solution was stirred for 20 minutes under reflux. The reaction mixture was evaporated in vacuo, and the residue was dissolved in chloroform. The chloroform solution was poured on an ice bath, concentrated aqueous ammonia was added to adjust the pH to 10, then, the solution was partitioned. The aqueous layer was extracted with chloroform, and the combined chloroform layers were washed with water. The organic layer was dried over anhydrous magnesium sulfate, then, evaporated in vacuo, and the title compound (8.03g,48.8mmol,93%) was obtained. This was used in the next reaction without purification. 1H-NMR Spectrum (DMSO-d6) δ(ppm) : 7.64(1H, dd, J=7.2, 8.0Hz), 7.81(1H, d, J=8.0Hz), 7.93(1H, ddd, J=0.8, 7.2, 8.0Hz), 8.16(1 H, dd, J=0.8, 8.0Hz), 8.86 (1H, brs). |
92% | With trichlorophosphate at 100℃; for 4h; | 3 4.1.3. Synthesis of 4-chloroquinazoline (6) 4.1.3 Synthesis of 4-chloroquinazoline (6) A suspension of quinazolin-4-ol (5) (2 g) in POCl3 (30 mL) was heated at 100 °C for 4 h. After cooling, the mixture was concentrated under reduced pressure and the ice was added to the residue. The pH was adjusted to 6 with ammonia to allow precipitation. The filter cake was washed with water and dried to give 4-chloroquinazoline (6). White powder, yield: 92%, mp: 93-94 °C. 1H NMR (300 MHz; CDCl3): 7.69 (t, J = 7.5 Hz, 1H); 7.90-8.04 (m, 2H); 8.22 (d, J = 8.3 Hz, 1H); 8.99 (s, 1H). MS (ESI+) m/z 165.0 (M+H)+. Anal. Calcd for C8H5ClN2: C, 53.38; H, 3.06; N, 17.02. Found: C, 53.54; H, 3.02; N, 17.08. |
89.7% | With thionyl chloride for 3h; Reflux; | 1.2 (2) Synthesis of 4-chloroquinazoline: Add 29.2g (0.2mol) 4-hydroxyquinazoline to a 250mL single-necked flask, add 150g SOCl2 (solvent/reactant), heat to reflux with stirring, react for 3h to dissolve all 4-hydroxyquinazoline, TLC method Trace the reaction until the 4-hydroxyquinazoline reaction is complete. After the reaction was completed, the excess SOCl2 was distilled off under reduced pressure. The obtained yellow solid was washed repeatedly with petroleum ether and dried by suction filtration to obtain 29.5 g of light yellow solid with a yield of 89.7%. |
88% | Stage #1: 4-quinazolinol With trichlorophosphate at 140℃; for 0.166667h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 24.a A mixture of 4-hydroxyquinazoline (2.56 g, 17.5 mmol) and POCl3 (8.0 mL, 88 mmol) was stirred at 140° C. (oil bath) for 10 min. The homogeneous light amber solution was then allowed to cool to RT before concentrating under reduced pressure at 70° C. The translucent residue was dissolved in DCM (25 mL), and the homogeneous yellow solution was partitioned with ice and 1 M NaHCO3 to pH ~6 (paper) (~20 mL aq layer). The organic layer was dried twice (Na2SO4), filtered through a 0.22 micron filter, and concentrated under reduced pressure (bath<40° C.) to provide the title compound as a yellow solid (2.53 g, 88%). 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.30 (ddd, 1H), 8.11 (m, 1H), 8.00 (m, 1H), 7.77 (m, 1H). |
88% | Stage #1: 4-quinazolinol With trichlorophosphate at 140℃; for 0.166667h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 7.a EXAMPLE 7; 4-Quinazolin-4-yl-piperidine-1-carboxylic acid (4-isopropyl-phenyl)-amide; a. 4-chloro-quinazoline; A mixture of 4-hydroxyquinazoline (2.56 g, 17.5 mmol) and POCl3 (8.0 mL, 88 mmol) was stirred at 140° C. (oil bath) for 10 min. The homogeneous light amber solution was then allowed to cool to rt before concentrating under reduced pressure at 70° C. The translucent residue was dissolved in DCM (25 mL), and the homogeneous yellow solution was partitioned with ice and 1 M NaHCO3 to pH 6 (paper) (20 mL aq layer). The organic layer was dried twice (Na2SO4), filtered through a 0.22 micron filter, and concentrated under reduced pressure (bath <40° C.) to provide the title compound as a yellow solid (2.53 g, 88%). 1H-NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.30 (ddd, 1H), 8.11 (m, 1H), 8.00 (m, 1H), 7.77 (m, 1H). |
88% | Stage #1: 4-quinazolinol With trichlorophosphate at 140℃; for 0.166667h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 24.a EXAMPLE 24; (4-Isopropyl-phenyl)-carbamic acid 1-quinazolin-4-yl-pyrrolidin-3-yl ester (Compound No. 24); a. 4-chloro-quinazoline; A mixture of 4-hydroxyquinazoline (2.56 g, 17.5 mmol) and POC13 (8.0 mL, 88 mmol) was stirred at 140° C. (oil bath) for 10 min. The homogeneous light amber solution was then allowed to cool to RT before concentrating under reduced pressure at 70° C. The translucent residue was dissolved in DCM (25 mL), and the homogeneous yellow solution was partitioned with ice and 1 M NaHCO3 to pH 6 (paper) (20 mL aq layer). The organic layer was dried twice (Na2SO4), filtered through a 0.22 micron filter, and concentrated under reduced pressure (bath<40° C.) to provide the title compound as a yellow solid (2.53 g, 88%). 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.30 (ddd, 1H), 8.11 (m, 1H), 8.00 (m, 1H), 7.77 (m, 1H). |
88% | Stage #1: 4-quinazolinol With thionyl chloride; N,N-dimethyl-formamide for 2h; Reflux; Stage #2: With sodium hydrogencarbonate In dichloromethane | 8 Example 8A mixture of 4-hydroxyquinazoline (1.20 g, 8.21 mmol) in SOCI2 (27.4 ml_) containing DMF (2 drops) was refluxed for 2 h. SOCI2 was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed with saturated NaHCO3 solution and brine, respectively, dried over anhydrous Na2SO4 and then concentrated under reduced pressure to yield the desired compound (1.19 g, 88% yield) as a white solid. 1H NMR (400 MHz, CDCI3): δ 9.06 (s, 1H), 8.29 (m, 1H), 8.09 (m, 1 H), 7.98 (m, 1 H), 7.75 (m, 1H). MS (ESI): Calcd. for C8H6CIN2: 165, found 165 (M+H)+. |
88% | With thionyl chloride; N,N-dimethyl-formamide for 2h; Reflux; | 24 Example 24 [0181] A mixture of 4-hydroxyquinazoline ( .20 g, 8.21 mmol) in SOCI2 (27.4 mL) containing DMF (2 drops) was refluxed for 2 h. SOCI2 was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed with saturated NaHCO3 solution and brine, respectively, dried over anhydrous Na2S04 and then concentrated under reduced pressure to yield the compound (1 .19 g, 88% yield) as white solid. 1H NMR (400 MHz, CDCI3): δ 9.06 (s, 1 H), 8.29 (m, 1 H), 8.09 (m, H), 7.98 (m, H), 7.75 (m, 1 H). MS (ESI): Calcd. for C8H6CIN2: 165, found 165 (M+H)+. |
87% | With trichloroacetonitrile; triphenylphosphine In toluene for 0.333333h; Reflux; | |
85% | With phosphorus pentachloride; trichlorophosphate | |
78.8% | With phosphorus pentachloride In trichlorophosphate for 2h; Heating; | |
76% | With N,N-diethylaniline; trichlorophosphate In benzene for 3h; Heating; | |
75% | With thionyl chloride In N,N-dimethyl-formamide for 3h; Reflux; | 2.1.3. General Procedure for 4a-4c General procedure: A mixture of 4-hydroxyquinazoline (50 mmol, 1.0eq) and thionyl chloride(200mL) containing DMF (0.4mL) was refluxed for 3 h. The reaction was cooled, excess thionyl chloride was removed under reduced pressure and the residue was diluted in dichloromethane (500 mL). The solution was sequentially washed with saturated aqueous sodium hydrogen carbonate solution (2 x 250 mL) and brine, respectively, dried over anhydrous Na2SO4 and then concentrated organic phase under reduced pressure to provide the compound as a white solid (4a) [44]. The procedure described for the synthesis of compound 4a can also be applied to the synthesis of compounds 4b-4c. 2.1.3.1. 4-chloroquinazoline(4a)Yield 75%; 1H NMR (400 MHz, DMSO): δ 7.74~7.78(m, 1H), 7.97~8.01 (m, 1H), 8.10 (d, J = 8.4 Hz,1H), 8.30 (d,J = 8.4 Hz,1H), 9.07 (s,1H). |
68% | With trichlorophosphate Reflux; | 4-chloroquinazoline (108) (0490) 4-Quinazolinol (292 mg, 2.00 mmol) was refluxed in POCl3 overnight. It was cooled to room temperature and poured into ice water, neutralized with Na2C03. The precipitation was filtered out and washed with water, dried by pulling air through. Product was obtained as light yellow solid. (224mg, 68% yield). 1H NMR (400 MHz, chloroform-c ) δ 9.06 (s, 1H), 8.30 (ddd, J = 8.4, 1.4, 0.7 Hz, 1H), 8.15- 8.07 (m, 1H), 7.99 (ddd, J = 8.5, 7.0, 1.4 Hz, 1H), 7.76 (ddd, J= 8.3, 6.9, 1.2 Hz, 1H). |
65% | With phosphorus pentachloride; trichlorophosphate at 118 - 120℃; for 4h; | |
53% | Stage #1: 4-quinazolinol With N-ethyl-N,N-diisopropylamine; trichlorophosphate for 15h; Heating / reflux; Stage #2: With potassium carbonate In water; ethyl acetate | 4-Hydroxyquinazoline 21 (0.8 g, 5.5 mmol) and N,N-diisopropylethylamine (0.5 ml) were refluxed in phosphorus oxychloride (11.0 ml) for 15 h. Phosphorus oxychloride was distilled under reduced pressure, the resulting oil was diluted with ethyl acetate washed with K2CO3 solution, dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 6 (0.48 g, 58%)A solution of 5-amino-2-Chloro-phenol 18a and 4-chloroquinazoline 22 (1.1 equiv), triethylamine (2.0 equiv) in isopropanol was refluxed with stirring for 1 h. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to give 23a. EPO A solution of 23a (0.115 g, 0.42 mmol) and Cs2CO3 (0.163 g, 0.5 mmol) in acetone (5.0 ml) was treated with 3,3-dimethylallyl bromide (0.059 ml, 0.5 mmol) at room temperature. After 9 h, the reaction mixture was diluted with EtOAc and washed with aqueous NH4Cl solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 63a (0.09 g, 63%).Scheme 8c. Synthesis for Quinazoline 63b. |
27% | With N-succinimide chlorotriphenylphosphonium salt for 0.05h; microwave irradiation; | |
With trichlorophosphate at 100℃; for 2h; | ||
With trichlorophosphate at 100℃; for 3h; | ||
With N-chloro-succinimide; triphenylphosphine | ||
With trichlorophosphate at 100℃; for 0.25h; microwave irradiation; | ||
With trichlorophosphate at 115 - 118℃; for 2h; | 4 Synthesis of 4-Chloro quinazoline Synthesis of 4-Chloro quinazoline 4-Quinazolone (5 g, 34.2 mmol), phosphorus pentachloride (10.26 g, 47.9 mmol) and phosphorus oxychloride (40 ml) were refluxed for two hours at 115-118 C. The phosphorus oxychloride was removed in vacuo and the residue was extracted in ether. The entire mixture was then poured into a vessel containing crushed ice and again extracted with ether. The ether layer was then washed with sodium bicarbonate and dried. The ether was then removed under reduced pressure and the crude material was recrystallized from hexanes to afford the product. | |
With thionyl chloride; N,N-dimethyl-formamide at 78℃; Inert atmosphere; | ||
With thionyl chloride; N,N-dimethyl-formamide at 80℃; Reflux; | ||
With triethylamine; trichlorophosphate In toluene for 4h; Reflux; | ||
With N,N-dimethyl-formamide; trichlorophosphate Reflux; | 28 Example 28 Synthesis of 4 - chloroquinazoline (F17) 100 mmol of 4-hydroxyquinazoline was added to 50 ml of POCl3,3 drops of DMF were then added dropwise,Heated to reflux.After completion of the reaction,The reaction solution was removed under reduced pressure,To give the object product as an oil. | |
With phosphorus pentachloride; trichlorophosphate at 115 - 118℃; for 2h; | 12A Synthesis of 4-Chloro quinazoline 4-Quinazolone (5 g, 34.2 mmol), phosphorus pentachloride (10.26 g, 47.9 mmol) and phosphorus oxychloride (40ml) were refluxed for two hours at 115-11 8C. The phosphorus oxychloride was removed in vacuo and the residue was extracted in ether. The entire mixture was then poured into a vessel containing crushed ice and again extracted with ethet The ether layer was then washed with sodium bicarbonate anddried. The ether was then removed under reduced pressure and the crude material was recrystallized from hexanes to afford the product. | |
With N,N-dimethyl-formamide; trichlorophosphate Reflux; | 27 EXAMPLE 28 Synthesis of the compound 4-chloroquinazoline (F17) 100 mmol 4-hydroxyquinazoline was added into 50 ml POCl3, and then 3 drops of DMF was added dropwise, allowed for heating reflux. After the reaction was complete, the reaction solution was removed under reduced pressure to give an oily target product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine In ethanol; dichloromethane | 1 Example 1 Example 1 3-Chloroaniline (7.3 g) was added to a mixture of 4-chloroquinazoline (9 g), triethylamine (6.2 ml) and methylene chloride (90 ml). The mixture was stirred at ambient temperature for 30 minutes and evaporated. The residue was dissolved in ethanol (250 ml) and the solution was heated to reflux for 30 mintues. The mixture was allowed to cool to ambient temperature and to stand for 4 hours. The precipitate was filtered off and washed with cold ethanol. There was thus obtained 4-(3--chloroanilino)quinazoline hydrochloride (11 g, 68%), m.p. 218-225°C. Elemental Analysis: Found C, 57.4; H, 3.8; N, 14.1; C14H11 Cl12N3 requires C, 57.6; H, 3.8; N, 14.4%. |
In isopropyl alcohol Heating; | ||
In ethanol for 0.5h; Heating; |
Stage #1: 4-chloroquinazoline; 3-chloro-aniline In ethanol for 0.25h; Heating; Stage #2: With hydrogenchloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; N,N-dimethyl-formamide; | EXAMPLE 2 4-[2-[4-(t-Butyl)phenyl]ethoxy]quinazoline To a solution of 1.1 g of sodium hydride in 50 ml of DMF, 4.0 g of 2-[4-(t-butyl)phenyl]ethanol was added, and the mixture was stirred at room temperature for one hour. Then 3.6 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred at room temperature overnight. The mixture was then poured into a mixture of ice in water. The product was extracted into CH2 Cl2, and the resulting solution was concentrated to dryness. TLC showed one major spot and five minor spots. The product was purified by HPLC (silica gel, CH2 Cl2). The fractions containing the major product were collected and concentrated, giving 1.9 g of the title product. Yield: 28.4%. M.P. 70-71 C. The compound of Example 2 was prepared on a larger scale, using a preferred process, as follows: To 54 L of methylene chloride, and 1.8 L of pyridine, 6.5 Kg of 4-hydroxyquinazoline was added, and the mixture was cooled to -5 to 10 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With polymer-supported Et3N In tetrahydrofuran at 65℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 5h; | 71 4- (4-METHOXY-PHENOXY)-QUINAZOLINE To a stirred solution of 4-methoxyphenol (75 mg, 0.60 mmol) and 4-chloro- quinazoline (125 mg, 76 mmol) in 3 mL OF DMF was added sodium hydride (60% oil suspension, 30 mg, 0.75 mmol) at 0°C, then the reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction was quenched by adding 50 uL of water and diluted with 25 mL of ethyl acetate. It was washed with water (25 mL x 3), saturated NaCI, dried over anhydrous MGS04, filtered and concentrated. The residue was purified by chromatography (25% ethyl acetate/hexanes) to give the title compound (134 mg, 0.53 mmol, 89%). 1H NMR (CDC13) : 8.78 (s, 1H), 8.38 (m, 1H), 7.89-8. 02 (m, 2H), 7.67 (m, 1H), 7.19 (m, 1H), 7.00 (m, 1H), 3.86 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In ISOPROPYLAMIDE at 70℃; for 8h; | 26 Reference Example 26; Synthesis of N-{6-(3-chloro(2-thienyl))-4-oxo-5-[2-(quinazolin-4-ylamino)ethyl](3-hydropyrrolo[3,2-d]pyrimidin-7-yl)}benzamide N-[5-(aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamide (45 mg) and 4-chloroquinazoline (16.5 mg) were dissolved in dimethylacetamide (2.9 mL), and triethylamine (27.7 μL) was added thereto and the mixture was stirred at 70° C. for 3 hours. Triethylamine (13.9 μL) was further added to the reaction mixture and the solution was stirred at 70° C. for 5 hours. The reaction solution was cooled to room temperature and purified by fraction HPLC, to obtain the title compound (44.3 mg, 82%) as a white solid. The HPLC retention time, NMR data and ESI/MS data of the compound are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.7% | With ammonium hydroxide; In water; | EXAMPLE 53 N-[2-(2-naphthyl)ethyl]-4-quinazolinamine A mixture of 1.0 g of 4-chloroquinazoline and 2.0 g of 2-(2-naphthyl)ethyl amine was heated under nitrogen to 165-170 C. for one hour. The mixture was cooled and then 200 ml of a 50/50 mixture of ammonium hydroxide/water was added. The product was extracted into CH2 Cl2, and the resulting solution was treated with charcoal and filtered. The solution was then concentrated to dryness, and the residue was recrystallized from a mixture of pentane and CH2 Cl2 to give: 0.480 g of the title product. Yield: 26.7%. M.P. 172-174 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water; N,N-dimethyl-formamide; toluene; | EXAMPLE 85 4-[2-(1,1'-biphenyl)-4-ylethoxy]quinazoline To a solution of 0.53 g of sodium hydride in 200 ml of DMF was added 2.2 g of 2-[(1,1'-biphenyl)-4-yl]ethanol, and the mixture was stirred at room temperature for one hour. Then 1.8 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred at room temperature for another three hours. The mixture was then poured into a mixture of ice in water. The solid phase was collected and washed with water. TLC showed two spots. The product was purified using HPLC (silica gel, CH2 Cl2) giving 1.1 g of the title product. Yield: 30.6%. M.P. 72-74 C. The following is another, preferred process for preparing the title product: A suspension of 8.2 g of 4-chloroquinazoline and 9.9 g of 2-[(1,1'-biphenyl)-4-yl]ethanol in 250 mL of toluene saturated with HCl gas was heated to 50 C. for four hours. Then an additional 3.6 g of 4-chloroquinazoline were added, and heating to 50 C. was continued for one hour. Then the mixture was cooled, ice water was added, and the pH was adjusted to 8.5 using dilute sodium hydroxide. The toluene layer was separated, washed with brine, and filtered through phase separating paper. The toluene solution was placed in a freezer overnight. A small amount of hydroxyquinazoline crystallized, and was separated by filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1,2-dichloro-ethane In dimethyl sulfoxide; N,N-dimethyl-formamide Reflux; | 1.5 (5) 4 - Dichloroquinazoline synthesis For 100 ml three-neck bottle is sequentially added in the quinazolinone (20.53 mmol), 5 drops of DMF, 1, 2 - dichloroethane (15 ml) and thionyl chloride (30 ml), after stiring, heating reflux for 1 - 2 hr to completion of the reaction. Recovering the solvent, distilled under reduced pressure to get the yellow solid. After the dichloromethane is used for dissolving, saturated sodium carbonate solution to adjust pH to alkaline. Liquid, three times, the collection of organic phase, drying, concentration, a yellow solid, petroleum ether recrystallization. To obtain white crystal. Yield 81%. |
60% | With N-ethyl-N,N-diisopropylamine; trichlorophosphate for 2h; Heating / reflux; | 23 Formamide (12 ml) was added to methyl 2-aminobenzoate (2.0 g), and the mixture was stirred at 160°C overnight. The reaction mixture was cooled to room temperature, water was added to the cooled mixture, and the mixture was extracted with chloroform/methanol. The solvent was removed from the organic layer by distillation under the reduced pressure, and the residue was used in the next reaction without purification. Ethyldiisopropylamine (1.6 g) and phosphorus oxychloride (3.8 g) were added to the residue, and the mixture was stirred under reflux for 2 hr. The reaction mixture was cooled to room temperature, and the cooled mixture was poured into an ice cooled saturated aqueous sodium bicarbonate solution. The mixture was stirred for 10 min and was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and water in that order and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give 4-chloroquinazoline (1.03 g, yield 60%). Dimethylsulfoxide (2.5 ml) was added to 5,6-dimethyl-[2,2']bipyridinyl-3-ol (50 mg), 4-chloroquinazoline (82 mg), and cesium carbonate (244 mg), and the mixture was stirred at 120°C overnight. The reaction mixture was cooled to room temperature, water was added to the cooled mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate as developing phase to give the title compound (27 mg, yield 33%). 1H-NMR (CDCl3, 400 MHz): δ 2.41 (s, 3H), 2.63 (s, 3H), 7.04 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 7.49 (s, 1H), 7.58 - 7.68 (s, 2H), 7.86 - 8.00 (m, 3H), 8.18 (d, J = 4.6 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.63 (s, 1H) Mass spectrometric value (ESI-MS, m/z): 351 (M+Na)+ |
With trichlorophosphate at 115℃; for 8h; | General procedures for the preparation of substituted 4-chloroquinazolines (3a and 3b) General procedures for the preparation of substituted 4-chloroquinazolines (3a and 3b) In a dry flask, quinazolin-4(1H)-one (4.38 g, 30 mmol) and POCl3 (19.2 mL, 210 mmol) were added sequentially, and then the mixture was stirred at 115 °C for 8 h. The reaction mixture was concentrated under reduced pressure, cooled to room temperature, and then poured into ice water. Excess saturated sodium hydrogen carbonate solution was added to neutralize the generated acid, and then the mixed solution was extracted with CH2Cl2 (3 * 60 mL).;The product 4-chloroquinazoline (3a) was obtained after the organic phase was combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 3a was directly used in the next step without further purification [18] ;4-Chloro-6,7-dimethoxyquinazoline (3b) was synthesized following the same procedures. |
With thionyl chloride | ||
With trichlorophosphate at 115℃; | ||
With thionyl chloride at 90℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In benzene; | Preparation 4. Compound No. 86 To a solution of 3.3 g (0.02 mol) of 4-chloroquinazoline in 50 ml of benzene were added 2.0 g (0.02 mol) of triethylamine and 3.0 g (0.02 mol) of 2-benzyloxyethylamine, and the mixture was heated, with stirring, at 60~70 C. for 5 hours. After completion of the reaction, the benzene was evaporated under reduced pressure, and the resulting crystals were washed with water, collected by filtration, dried and recrystallized from benzene/n-hexane, affording 3.7 g of 4-[2-(benzyloxy)ethyl]aminoquinazoline in the form of colorless needles. m.p. 111~113 C. Elementary analysis (%): Calcd: C, 73.09; H, 6.14; N, 15.04. Found: C, 72.98; H, 6.11; N, 14.69. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogenchloride In water Reflux; | 1 [0015] Raw material I (10 mmol) and raw material IIa (10mmol) are dissolved in 50ml water and 4.2ml concentratedHCl (12mol/L), and react under reflux for about 0.1-5h. The reaction is then stopped and subjected to filtration to provideIntermediate IIIa upon drying. 0039] Following the General Method I for the preparation of the intermediate IIIa, a white solid (intermediate M-1) ofthe weight 2.47g was obtained with 4-chloroquinazoline (1.64g, 10mmol) (prepared according to General Method III)and p-aminobenzoic acid (1.37g, 10mmol). The yield was 94%. |
94% | With hydrogenchloride In water Reflux; | 1 Example 1 General procedure: Raw material 1 (10 mmol) and raw material IIa (10 mmol) are dissolved in 50 ml water and 4.2 ml concentrated HCl (12 mol/L), and react under reflux for about 0.1-5 h. The reaction is then stopped and subjected to filtration to provide Intermediate IIIa upon drying. Example 1 V-1 N-(2-aminophenyl)-4-(quinazoline-4-amino)benzamide Following the General Method I for the preparation of the intermediate IIIa, a white solid (intermediate M-1) of the weight 2.47 g was obtained with 4-chloroquinazoline (1.64 g, 10 mmol) (prepared according to General Method III) and p-aminobenzoic acid (1.37 g, 10 mmol). The yield was 94%. |
In N,N-dimethyl-formamide Microwave; |
With triethylamine In isopropyl alcohol at 80℃; | 3.1.8. General preparation of quinazoline-4-ylaminobenzoic acid and quinazoline-4-ylaminomethylbenzoic acid intermediates (7-12) General procedure: Either 4-chloroquinzoline or 2-phenyl-4-chloroquinzoline was reacted with an equivalent amount of the corresponding aminobenzoic acid or aminomethylbenzoic acid derivative in the presence of an equivalent amount of triethylamine using anhydrous isopropanol as a solvent. The reaction was performed under 80 °C until the starting materials were consumed. The solid furnished out of the reaction, after solvent evaporation, was washed with hot water to remove triethylamine HCl and used in the next step without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | To a solution of 5-amino-2-cyano-phenol 18b, 4-chloroquinazoline 22 (1.1 equiv) in 10% aqueous EtOH 37% HCl (1.0 equiv) was added; the solution was stirred at 9O0C for 6 h. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated. The crude product was purified by flash chromatography on silica gel to give 23b.A solution of 23b (0.1 g, 0.38 mmol) and Cs2CO3 (0.149 g, 0.46 mmol) in acetone (5.0 ml) was treated with 3,3-dimethylallyl bromide (0.054 ml, 0.46 mmol) at room temperature. After 9 h, the reaction mixture was diluted with EtOAc and washed with aqueous NH4Cl solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 63b (0.077 & 61%).Scheme 9c. Synthesis for Quinazoline 63b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine; In isopropyl alcohol; for 1h;Heating / reflux; | 4-Hydroxyquinazoline 21 (0.8 g, 5.5 mmol) and N,N-diisopropylethylamine (0.5 ml) were refluxed in phosphorus oxychloride (11.0 ml) for 15 h. Phosphorus oxychloride was distilled under reduced pressure, the resulting oil was diluted with ethyl acetate washed with K2CO3 solution, dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 6 (0.48 g, 58percent)A solution of 5-amino-2-Chloro-phenol 18a and 4-chloroquinazoline 22 (1.1 equiv), triethylamine (2.0 equiv) in isopropanol was refluxed with stirring for 1 h. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to give 23a. EPO <DP n="41"/>A solution of 23a (0.115 g, 0.42 mmol) and Cs2CO3 (0.163 g, 0.5 mmol) in acetone (5.0 ml) was treated with 3,3-dimethylallyl bromide (0.059 ml, 0.5 mmol) at room temperature. After 9 h, the reaction mixture was diluted with EtOAc and washed with aqueous NH4Cl solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 63a (0.09 g, 63percent).Scheme 8c. Synthesis for Quinazoline 63b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: tert-butyl (1-benzhydrylazetidin-3-yl)carbamate With ammonium formate In methanol at 60℃; for 4h; Stage #2: 4-chloroquinazoline With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 80℃; | 88.1 The (l-benzhydrylazetidin-3-yl)-carbamic acid tert-butyl ester (500 mg, 1.48 mmol), Pd/C (10% w/w, 157 mg, 0.07 mmol), and ammonium formate (932 mg, 14.8 mmol) were weighed into a 25 RBF equipped with a condenser, degassed 3 times, and suspended/dissolved in 6 mL of methanol. The mixture was heated to 60C for 4 hours to completion and was allowed to cool to room temperature. The mixture was filtered through a plug of celite washed with ethanol, and the filtrate was concentrated in vacuo. The residue was re-dissolved in 30 mL of DCM, dried over Na2S04, filtered, and concentrated in vacuo to afford the crude intermediate. The intermediate and 4-chloroquinazoline (268 mg, 1.63 mmol) were dissolved in 6 mL of NMP, then treated with diisopropylethyl amine (515 1L, 2.96 mmol). The solution was heated to 80 °C overnight to completion affording an orange mixture. After cooling to room temperature, the solution was diluted with ethyl acetate and poured into diluted NaHC03 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9: 1 MeOH: EtOAc) to afford the pure (1-quinazolin-4-yl-azetidin-3-yl)-carbamic acid tert-butyl ester as a tan solid (390 mg, 88%). lH NMR (DMSO-d6, 400 MHz) 8 8.47 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.78 (t, J= 7.6 Hz, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.67 (m, 1H), 7.48 (t, J= 7.6 Hz, 1H), 4.73 (m, 2H), 4.50 (m, 1H), 4.30 (m, 2H), 1.41 (s, 9H). LCMS (APCI+) m/z 301 [M+H] + ; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 4-chloroquinazoline In N,N-dimethyl-formamide at 0 - 20℃; | 82.1 To a stirred suspension of NaH (60%, 0.146 g, 3.65 mmol) in DMF (15 mL) was added dropwise a solution of 4-Hydroxypiperidine-l-carboxylic acid tert-butyl ester (0.611 g, 3.04 mmol) in DMF (5 mL) at 0 °C. The reaction was stirred for 1 hour and then 4- chloroquinazoline (0.500 g, 3.04 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was partitioned between H20 and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes: EtOAc, 2: 1) to give 4-(Quinazolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.76 g, 76%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With hexamethyldistannane; lithium chloride In 1,4-dioxane Heating / reflux; | 86.1 To a 25 mL flask was charged 4-Trifluoromethanesulfonyloxy-3, 6- dihydro-2H-pyridine-l-carboxylic acid benzyl ester (prepared from 4-Oxo-piperidine-1- carboxylic acid benzyl ester according to the literature: Wustrow, D. J. et. al. (1991), Synthesis, 993-995.1. 14 g, 3.12 mmol), 4-chloroquinazoline (0.512 g, 3.12 mmol), lithium chloride (0.397 g, 9.36 mmol), Pd (PPh3) 4 (0.180 g, 0.156 mmol) and hexamethyl ditin (1.02 g, 3.12 mmol). 1,4-Dioxane (20 mL) was added and the reaction was degassed with N2 for 15 minutes. The mixture was stirred at reflux overnight. After cooling, the black suspension was poured into saturated aqueous potassium fluoride solution. The mixture was diluted with EtOAc and stirred for 2 hours. The organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes: EtOAc, 2: 3) to give 4-Quinazolin-4-yl-3,6- dihydro-2H-pyridine-l-carboxylic acid benzyl ester (0.790 g, 73%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) 6 9.27 (s, 1H), 8.19 (d, J= 7.2 Hz, 1H), 8.07 (d, J= 8. 8 Hz, 1H), 7.91 (m, 1H), 7.62 (t, J= 7.2 Hz, 1H), 7.41 (m, 6H), 6.18 (m, 1H), 5.23 (s, 2H), 4.32 (s, 2H), 3.85 (t, J= 5.6 Hz, 1H), 2.80 (br s, 2H). LCMS (APCI+) m/z 346 [M+H] + ; Rt = 3.16 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 0.416667h; Microwave irradiation; | 1.3 3) Preparation of intermediate K-2 4-chloroquinazoline (2.5 g, 15.2 mmol) was weighed and dissolved in NMP (10 mL).1-Boc piperazine (3.1 g, 16.7 mmol) and DIEA (3.95, 30.4 mmol) were added in sequence, and microwave reaction was carried out at 120 ° C for 25 min.The reaction solution was poured into 120 mL of ice water, and a white precipitate was precipitated, which was extracted with ethyl acetate (20 mL×3), and the organic phase was combined and washed successively with ammonium chloride (15 mL×3), brine (20 mL×3), anhydrous Dry over sodium sulfate, filter, and distill the solvent under reduced pressure to give a crude material.Purification by column chromatography gave intermediate K-2 (4.3 g).The elution system was petroleum ether/ethyl acetate (9:1). |
88% | With N-ethyl-N,N-diisopropylamine at 120℃; for 0.416667h; Microwave irradiation; | 7 7) Preparation of intermediate E-2 Weigh 4-chloroquinazoline (2.5 g, 15.2 mmol),Dissolved with NMP (10 mL) and added 1-tert-butoxycarbonylpiperazine (3.1 g, 16.7 mmol)And DIEA (3.95, 30.4mmol), microwave reaction at 120 ° C for 25 min,The reaction solution was poured into 120 mL of ice water, and a white precipitate was precipitated and extracted with ethyl acetate (20 mL×3).The organic phases were combined and washed with ammonium chloride (15 mL×3) and brine (20 mL×3).Dry over anhydrous sodium sulfate, filter, and dilute the solvent under reduced pressure to give crude.Purification by column chromatography gave Intermediate E-2 (4.3 g).Off-white solid, yield 88% |
With potassium carbonate In N,N-dimethyl-formamide Reflux; | 4.2.5. Synthesis of 2-phenyl-4-(piperazin-1-yl)quinazoline General procedure: Potassium carbonate (1.38 g, 10 mmol) was added to a suspension of 4-chloro-2-phenylquinazoline (1.2 g, 5 mmol) and 1-Boc-piperazine (0.93 g, 5 mmol) in 7 ml DMF. The reaction was heated while refluxing and monitored using TLC. Once finished, the reaction was acidified with acetic acid and a white precipitate formed. The product was filtered and partitioned (CH2Cl2: water 1:1). The organic layer was concentrated under pressure and white solid was formed. The white solid was added to 50 ml methanolic HCl and stirred for 1 h followed by the neutralization with NaHCO3. The precipitate (white solid, 1.18 g, 81.4% yield) was filtered and used in the next step without further purification. |
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol for 20h; Heating / reflux; | 1A.1 To a solution of 4-chloroquinazoline (2.0 g, 12.2 mmol) (Tobe, Masanori, et al., Bioorg Med. CZzem. 2003, 11 (3), 383) and DIEA (3.2 mL, 18.2 mmol) in 40 mL IPA was added Boc-piperazine (1.96 g, 12.81 mmol). The reaction mixture was heated to reflux and stirred for 20 hours, after which it was cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in dichloromethane (DCM) and washed with 1N NaOH. The organic layer was dried (Na2S04), filtered, and concentrated by rotary evaporation. The resulting oil was dissolved in 25 mL dioxane, and 4M HCl/dioxane (46 mL, 182 mmol) was added dropwise. The suspension was sonicated for 2 minutes and stirred 13 hours at room temperature, after which the reaction mixture was concentrated to dryness by rotary evaporation. The resulting amine HC1 salt was dissolved in 2N NaOH and extracted with DCM. The organic layer was dried (Na2S04), filtered, and concentrated by rotary evaporation. The resulting oil was purified on silica (9: 1: 0.02 DCM/MeOH/NH4OH) to give 4- piperazinylquinazoline as a yellow oil (2.5 g, 96%). 1H NMR (CDC13, 400 MHz) 8 8.74 (s, 1H), 7.92-7. 86 (m, 2H), 7.76-7. 70 (m, 1H), 7.48-7. 42 (m, 1H), 3.75 (t, J= 4.9 Hz, 4H), 3.09 (t, J= 4.9 Hz, 4H), 1.89 (br s, 1H). Rt 0.70. MS (ESI+) [M+H] + 215. | |
In N,N-dimethyl-formamide at 150℃; for 0.333333h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate In ethanol; toluene for 6h; Reflux; | 9 Example 9A mixture of 4-chloroquinazoline (658 mg, 4.0 mmol), 3-nitrophenylboronic acid (935 mg, 5.6 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol) and 2M K2CO3 solution (4.0 mL, 8.0 mmol) in toluene (30.0 ml_) and ethanol (2.0 ml_) was refluxed for 6 h. The reaction mixture was cooled down and water was added. The resulting mixture was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc 10:1 to 1 :1) to yield the desired compound (771 mg, 77% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCI3): δ 9.43 (s, 1 H), 8.69 (m, 1 H), 8.45 (ddd, J = 1.0, 2.4, 8.4 Hz, 1 H), 8.17 (m, 2H), 8.05 (ddd, J = 0.8, 1.2, 2.0 Hz, 1H), 7.99 (m, 1 H), 7.80 (m, 1 H), 7.69 (m, 1H). MS (ESI): Calcd. for C14H10N3O2: 252, found 252 (M+H)+. |
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene for 6h; Reflux; | 25 Example 25 [0182] A mixture of 4-chloroquinazoline (658 mg, 4.0 mmol), 3- nitrophenylboronic acid (935 mg, 5.6 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol) and 2M K2C03 solution (4.0 ml_, 8.0 mmol) in toluene (30.0 mL) and ethanol (2.0 mL) was refluxed for 6 h. The reaction mixture was cooled down and water was added. The resulting mixture was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc 10:1 to 1 :1 ) to yield the desired compound (771 mg, 77% yield) as a pale yellow solid.1H NMR (400 MHz, CDCI3): δ 9.43 (s, 1 H), 8.69 (m, 1 H), 8.45 (ddd, J = 1 .0, 2.4, 8.4 Hz, 1 H), 8.17 (m, 2H), 8.05 (ddd, J = 0.8, 1 .2, 2.0 Hz, H), 7.99 (m, 1 H), 7.80 (m, 1 H), 7.69 (m, 1 H). MS (ESI): Calcd. for C14H10N3O2: 252, found 252 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine In isopropyl alcohol at 80℃; for 1.5h; | 3.1.4. 4-(4-(5-Ethylpyrimidin-2-yl)piperazin-1-yl)quinazoline (3) A mixture of 1 (72 mg, 0.377 mmol), 4-chloroquinzoline (61 mg, 0.377 mmol), and triethylamine (38 mg, 0.377 mmol) in isopropanol (5 ml) was refluxed at 80 °C for 1.5 h. The solid separated out of the reaction was filtered, washed with hot solvent and dried to afford compound 3 which was obtained as a yellow solid (61 mg, 50% yield); mp: >250 °C. The purity of 3 was confirmed using HPLC (97.27%, Rt = 9.987). 1H NMR (DMSO-d6): δ 1.13 (t, J = 7.56 Hz, 3H), 2.45 (q, J = 7.56 Hz, 2H), 3.95 (t, J = 5.28 Hz, 4H), 4.16 (t, J = 5.28 Hz, 4H), 7.68 (ddd, J = 1.38 Hz, J = 6.84 Hz, J = 8.4 Hz, 1H), 7.96 (m, 2H), 8.22 (d, J = 8.4 Hz, 1H), 8.31 (s, 2H), 8.82 (s, 1H). 13C NMR (DMSO-d6): δ 15.63, 21.91, 42.85, 48.78, 113.28, 121.66, 125.04, 126.69, 126.88, 134.78, 143.5, 149.89, 157.19, 159.95, 162.51. MS: calcd 320.17 for C18H20N6 [M]+; found, 320.39 [M]+. |
50% | With triethylamine In isopropyl alcohol at 80℃; for 1.5h; | 3 Example 3Preparation of 4-(4-(5-ethylpyrimidin-2-yl)piperazin-1-yl)quinazoline (3)A mixture of 1 (72 mg, 0.377 mmol), 4-chloroquinzoline (61 mg, 0.377 mmol), and triethylamine (38 mg, 0.377 mmol) in isopropanol (5 ml) was refluxed at 80° C. for 1.5 hr. The solid separated out of the reaction was filtered, washed with hot solvent and dried to afford compound 3 which was obtained as a yellow solid (61 mg, 50% yield); mp: >250° C. The purity of 3 was confirmed using HPLC (97.27%, Rt=9.987). 1H-NMR (DMSO-d6): δ 1.13 (t, J=7.56 Hz, 3H), 2.45 (q, J=7.56 Hz, 2H), 3.95 (t, J=5.28 Hz, 4H), 4.16 (t, J=5.28 Hz, 4H), 7.68 (ddd, J=1.38 Hz, J=6.84 Hz, J=8.4 Hz, 1H), 7.96 (m, 2H), 8.22 (d, J=8.4 Hz, 1H), 8.31 (s, 2H), 8.82 (s, 1H). 13C-NMR (DMSO-d6): δ 15.63, 21.91, 42.85, 48.78, 113.28, 121.66, 125.04, 126.69, 126.88, 134.78, 143.5, 149.89, 157.19, 159.95, 162.51. MS: calcd 320.17 for C18H20N6 [M]+; found, 320.39 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 3-piperidinopropan-1-ol With sodium In tetrahydrofuran at 20℃; for 1h; Stage #2: 4-chloroquinazoline In tetrahydrofuran at 20℃; for 24h; | 11 General procedure for the preparation of compounds 8c-h General procedure: Sodium (1.2 mmol) was added to a solution of an alcohol (1.0 mmol) in dry THF and the mixture was stirred at rt for 1 h. 4-Chloroquinazoline [22] (6, 1.0 mmol) was then added, and the resultant solution was stirred at rt for 24 h. The mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL) and dried over sodium sulfate. The products were purified by column chromatography (hexane-ethyl acetate 8:2). |
Stage #1: 3-piperidinopropan-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h; Stage #2: 4-chloroquinazoline In tetrahydrofuran; mineral oil at 20℃; for 24h; | 2 General procedure for the preparation of compounds 8a and 8f General procedure: POCl3 (2.4 mmol) was slowly added to a cooled (0 °C) suspension of 3,4-dihydroquinazolin-4-one (2.0 mmol) and diisopropylamine (2.6 mmol) in toluene (10 mL) and the resultant mixture was stirred at 90 °C for 3 h. The mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL), and dried over sodium sulfate. The product (4-chloroquinazoline) was purified by column chromatography (hexane/ethyl acetate 95:5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 2-(N,N-dimethylamino)ethanol With sodium In tetrahydrofuran at 20℃; for 1h; Stage #2: 4-chloroquinazoline In tetrahydrofuran at 20℃; for 24h; | 9 General procedure for the preparation of compounds 8c-h General procedure: Sodium (1.2 mmol) was added to a solution of an alcohol (1.0 mmol) in dry THF and the mixture was stirred at rt for 1 h. 4-Chloroquinazoline [22] (6, 1.0 mmol) was then added, and the resultant solution was stirred at rt for 24 h. The mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL) and dried over sodium sulfate. The products were purified by column chromatography (hexane-ethyl acetate 8:2). |
Stage #1: 2-(N,N-dimethylamino)ethanol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h; Stage #2: 4-chloroquinazoline In tetrahydrofuran; mineral oil at 20℃; for 24h; | 2 General procedure for the preparation of compounds 8a and 8f General procedure: POCl3 (2.4 mmol) was slowly added to a cooled (0 °C) suspension of 3,4-dihydroquinazolin-4-one (2.0 mmol) and diisopropylamine (2.6 mmol) in toluene (10 mL) and the resultant mixture was stirred at 90 °C for 3 h. The mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL), and dried over sodium sulfate. The product (4-chloroquinazoline) was purified by column chromatography (hexane/ethyl acetate 95:5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; | 3 4.3.4 General procedure: A mixture of appropriate quinazoline substrate (4- chloroquinazoline, or 4-chloro-2-trifluoromethylquinazoline or 4- chloro-2-methylquinazoline 1) (500 mg, 1 equiv), tetrakis(- triphenylphosphine)palladium(0) (0.05 equiv), copper iodide (0.05 equiv), cesium carbonate (1.5 equiv), appropriate alkyne (1.5 equiv), and dry DMF (10 mL) was stirred under N2 at room temperature for 3 h. Water was then added and the mixture was extracted with CH2Cl2 (2 20 mL). The organic layer was washed withwater (5 200 mL), dried over Na2SO4, filtered, and evaporated. The crude residue was purified by column chromatography (silica gel, appropriate eluent) and washed with petroleum ether to give the corresponding coupling products |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; | 3 4.3.3 General procedure: A mixture of appropriate quinazoline substrate (4- chloroquinazoline, or 4-chloro-2-trifluoromethylquinazoline or 4- chloro-2-methylquinazoline 1) (500 mg, 1 equiv), tetrakis(- triphenylphosphine)palladium(0) (0.05 equiv), copper iodide (0.05 equiv), cesium carbonate (1.5 equiv), appropriate alkyne (1.5 equiv), and dry DMF (10 mL) was stirred under N2 at room temperature for 3 h. Water was then added and the mixture was extracted with CH2Cl2 (2 20 mL). The organic layer was washed withwater (5 200 mL), dried over Na2SO4, filtered, and evaporated. The crude residue was purified by column chromatography (silica gel, appropriate eluent) and washed with petroleum ether to give the corresponding coupling products |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.8% | With potassium carbonate In acetonitrile at 30 - 50℃; for 8h; Inert atmosphere; | General Procedure for the Preparation of Intermediates 4a to 4f. General procedure: A 100mL oven-dried round bottom flask charged with 1.62g (10.0mmol) (E)-4-(2-hydroxy-phenyl)-3-butylene-2-one or 4-(4-hydroxy-phenyl)-3-butylene-2-one, 1.65g (10.0mmol) 4-chloroquinazoline, and 3g potassium carbonate in dry acetonitrile (20mL) was placed at room temperature. The reaction mixture was stirred further for 8h at 30 to 50°C. In the reaction mixture, the excess K2CO3 was filtered out, and the solvent was removed by evaporation. The crude product was recrystallized with anhydrous ethanol solvent to yield 75% to 86% of intermediates 4a to 4f. The data for 4a to 4f are shown below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.8% | With potassium carbonate In acetonitrile at 30 - 50℃; for 8h; Inert atmosphere; | General Procedure for the Preparation of Intermediates 4a to 4f. General procedure: A 100mL oven-dried round bottom flask charged with 1.62g (10.0mmol) (E)-4-(2-hydroxy-phenyl)-3-butylene-2-one or 4-(4-hydroxy-phenyl)-3-butylene-2-one, 1.65g (10.0mmol) 4-chloroquinazoline, and 3g potassium carbonate in dry acetonitrile (20mL) was placed at room temperature. The reaction mixture was stirred further for 8h at 30 to 50°C. In the reaction mixture, the excess K2CO3 was filtered out, and the solvent was removed by evaporation. The crude product was recrystallized with anhydrous ethanol solvent to yield 75% to 86% of intermediates 4a to 4f. The data for 4a to 4f are shown below. |
76.8% | With potassium carbonate In acetonitrile at 30 - 40℃; for 3.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With caesium carbonate In acetonitrile at 20℃; for 2h; Inert atmosphere; Reflux; | 1.3.1 4-(1-Phenylethoxy)quinazoline (3a) General procedure: 4-Chloroquinazoline(1) (100 mg, 0.610 mmol) was mixedwith 1-phenylethanol (2a) (89 mg,0.730 mmol), Cs2CO3 (238 mg, 0.729 mmol) and acetonitrile(2 mL). The reaction was stirred under nitrogen atmosphere at reflux for 3.5 h,then cooled to rt and diluted with EtOAc (50 mL). The organic phase was washedwith sat. aq. KHCO3 (25 mL), water (2×25 mL) and brine (30 mL), driedover Na2SO4 and concentrated in vacuum. The crude productwas absorbed onto Celite 545 and purified by silica-gel column chromatography (n-pentane/EtOAc, 1/1). This gave 129 mg(0.516 mmol, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 1-piperidinoethanol With sodium In tetrahydrofuran at 20℃; for 1h; Stage #2: 4-chloroquinazoline In tetrahydrofuran at 20℃; for 24h; | 10 General procedure for the preparation of compounds 8c-h General procedure: Sodium (1.2 mmol) was added to a solution of an alcohol (1.0 mmol) in dry THF and the mixture was stirred at rt for 1 h. 4-Chloroquinazoline [22] (6, 1.0 mmol) was then added, and the resultant solution was stirred at rt for 24 h. The mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL) and dried over sodium sulfate. The products were purified by column chromatography (hexane-ethyl acetate 8:2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In tetrahydrofuran; for 4h;Reflux; | General procedure: A solution of 4-chloroquinazoline [22] (6, 1.0 mmol) and appropriate amine (1.1 mmol) in dry THF (5 mL) was heated under reflux for 4 h. The mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL) and dried over sodium sulfate. The products were purified by column chromatography (ethyl acetate 1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 4-chloroquinazoline In chloroform for 0.5h; Cooling with ice; Stage #2: 1,4-phenylenediamine With triethylamine In chloroform at 20℃; for 24h; | 4-(4-Aminoanilino)quinazoline (5) A solution of 4-chloroquinazoline 4 (0.16 g, 0.95 mmol) in chloroform (10 mL) was cooled in an ice-bath for 30 min. A solution of p-pheneylenediamine (0.1 g, 0.95 mmol), triethylamine (1 mL) in chloroform was added dropwise to the reaction mixture in about 15 min. The mixture was allowed to reach the room temperature and left stirring overnight. The formed precipitate was filtered and recrystallized from chloroform to give 4-(4-aminoanilino)-quinazoline 5 as yellow needle crystals.15) Yield 66%, mp>300°C, spectral as reported.16) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; at 25℃; for 1h;Inert atmosphere; | General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 mol%), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.29 g | With triethylamine; In isopropyl alcohol; for 5.5h;Reflux; | (3-Phenoxyphenyl)methanamine (1.55 g, 7.79 mmol) was taken up in 60 mL of IPA, and 15 mL of volatile material was removed by distillation. The mixture was cooled, and TEA (1.50 mL, 10.7 mmol) and 4-chloroquinazoline (1.20 g, 7.32 mmol) in 15 mL of IPA were added. The mixture was heated at reflux for 5.5 hr, and then stirred at room temperature overnight. Then, the volatile components were evaporated, and the residue was partitioned between DCM (3x70 mL) and 5% Na2C03 (40 mL). The combined organic phases were dried over Na2S04, filtered, and concentrated. SPE, eluting with 25% and then 55% EA/Hex, gave product fractions that were combined and concentrated to yield an orange solid. Recrystallization from EA/Hex gave a pink solid, and then from MeOH gave 1.29 g of a light pink solid. R 0.19 (50% EA/Hex); mp 146.5- 148.0 C; 1H NMR (CDC13) delta 8.66 (s, 1H), 7.83 (d, 1H, J=8.5 Hz), 7.77 (d, 1H, J=8.1 Hz), 7.71 (m, 1H), 7.42 (m, 1H), 7.30 (m, 3H), 7.10 (m, 2H), 7.04 (br s, 1H), 6.99 (m, 2H), 6.90 (m, 1H), 6.44 (m, IH, NH), 4.84 (m, 2H, AB); C NMR (CDC13) delta 159.5, 157.9, 157.0, 155.5, 149.6, 140.4, 132.9, 130.3, 130.0, 128.7, 126.3, 123.7, 122.6, 120.9, 119.2, 118.3, 117.9, 115.1, 45.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.2% | With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 90℃; | 36 4.1.36. N-(3-Bromo-2-methylphenyl)quinazolin-4-amine (7j) 4.1.36 N-(3-Bromo-2-methylphenyl)quinazolin-4-amine (7j) A mixture of 4-chloroquinazoline (251 mg, 1.53 mmol), 3-bromo-2-methylaniline (360 mg, 1.83 mmol) and DIPEA (208 mg, 1.53 mmol) in i-PrOH (10 mL) was stirred at 90 °C for 4 h. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue product was purified on a silica gel column using petroleum ether/EtOAc (1:1, v/v) as eluent to afford 7j (369 mg, 77.2%) as a white solid. MS (ESI) m/z 314.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.46-8.44 (d, J = 8.20 Hz, 1H), 8.42 (s, 1H), 7.88-7.84 (t, J = 14.90 Hz, 1H), 7.79-7.77 (d, J = 8.20 Hz, 1H), 7.65-7.60 (t, J = 14.90 Hz, 1H), 7.60-7.58 (d, J = 8.20 Hz, 1H), 7.37-7.35 (d, J = 8.20 Hz, 1H), 7.25-7.21 (t, J = 15.80 Hz, 1H), 2.23 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.6% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water for 12h; Reflux; | 3.2.1. Synthesis of the Main Ligand and [(CN)2Ir(μ-Cl)]2 Chloride-Bridged Dimer 4-Chloro-quinazoline (6 mmol), 4-(triuoromethyl)phenylboronic acid (5 mmol),Na2CO3 (10 mmol), and Pd(PPh3)4 (0.1 mmol) were added to 40 mL THF/H2O (3:1,v/v) and the mixture was refluxed at 75 C for 12 h. The organic phase was extracted withCH2Cl2 and purified by silica gel column chromatography (CH2Cl2/petroleum ether 1:2(v/v)). A total of 1.24 g main ligand 4tfmpq as white powder was obtained with a yieldof 75.6%.IrCl3 (2.14 mmol) and 4tfmpq (5.14 mmol) were added to a 2-ethoxyethanol and watermixture. Then the solution was heated at 110 C for 12 h. After the addition of water,the precipitated red powder of [(4tfmpq)2Ir(μ-Cl)]2 chloride-bridged dimer was ltered,washed, and dried in vacuum with a yield of 84.7% (2.8 g). |
70% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 75℃; Inert atmosphere; Reflux; | |
With palladium diacetate; potassium carbonate; triphenylphosphine In ethanol; toluene for 12h; Inert atmosphere; Reflux; |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 70℃; for 12h; | ||
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 70℃; for 12h; | ||
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 70℃; for 12h; | ||
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In isopropyl alcohol at 20℃; for 12h; | 6.6. General method for the synthesis of compounds 1-10 General procedure: To a 100 mL round-bottomed flask substituted-4-chloroquinazolines(1 equivalent), appropriate anilines (1.2 equivalents) and isopropanol(10 mL) were added and stirred at room temperature for 12 h. Thecompounds precipitated as HCl salts, which were filtered and dried invacuo over P2O5 to afford the desired compounds. |
65% | With hydrogenchloride In isopropyl alcohol for 1h; Reflux; | 5.1.6. 6-Methoxy-N1-(4'-quinazolyl)-1,2,3,4-tetrahydroquinoline(4f) A mixture of 4-chloroquinazoline (2b, 170 mg, 1.04 mmol) and6-methoxy-1,2,3,4-tetrahydroquinoline (3, 180 mg, 1.10 mmol) ini-PrOH (15 mL) with a drop of HCl (conc.) was refluxed for 1 hmonitored by TLC until the reaction was completed. The mixturewas poured into ice-water, adjusted to neutral pH with NaHCO3,extracted with EtOAc three times, and dried over anhydrousNa2SO4. After removal of solvent, the product was purified on a silicachromatographic column with gradient elution (MeOH/CH2Cl20-5%) to furnish 193 mg of 4f in 65% yield, light yellow solid |
64.9% | With hydrogenchloride In water; isopropyl alcohol for 1h; Reflux; | 27 Example 27 4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinazoline (Compound 36) 4-Chloroquinazoline (170 mg, 1.04 mmol) and 6-methoxy-1,2,3,4-tetrahydroquinoline (180 mg, 1.10 mmol) were added into i-PrOH (15 ml), 1 drop of concentrated hydrochloric acid was added, and the resulting mixture was reacted under refluxing for 1 hour to obtain 193 mg of target Compound 36, yield 64.9%, yellow solid. mp 94∼95°C; 1H NMR (CDCl3): δ ppm 2.11 (2H, f, J = 6.4 Hz, 3'-CH2), 2.87 (2H, t, J = 6.8 Hz, 4'-CH2), 3.80 (3H, s, OCH3), 4.05 (2H, t, J = 6.4 Hz, 2'-CH2), 6.56 (1 H, dd, J = 8.4 and 2.8 Hz, ArH-7'), 6.65 (1 H, d, J = 8.8Hz, ArH-8'), 6.79 (4H, d, J = 2.8 Hz, ArH-5'), 7.21 (1 H, td, J = 8.8 and 1.2Hz, ArH-6), 7.49 (1 H, d, J = 8.4 Hz, ArH-5), 7.68 (1 H, td, J = 8.8 and 2.0Hz, ArH-7), 7.89 (1 H, d, J = 8.4 Hz, ArH-8), 8.86 (1 H, s, ArH-2). MS m/z (%): 292(M+1, 100). |
64.9% | With hydrogenchloride In water; isopropyl alcohol for 1h; Reflux; | 27 Example 27 4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinazoline (Compound 36) Example 27 4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinazoline (Compound 36) [0205] 4-Chloroquinazoline (170 mg, 1.04 mmol) and 6-methoxy-1,2,3,4-tetrahydroquinoline (180 mg, 1.10 mmol) were added into i-PrOH (15 ml), 1 drop of concentrated hydrochloric acid was added, and the resulting mixture was reacted under refluxing for 1 hour to obtain 193 mg of target Compound 36, yield 64.9%, yellow solid. mp 9495° C.; 1H NMR (CDCl3): a ppm 2.11 (2H, f, J=6.4 Hz, 3′-CH2), 2.87 (2H, t, J=6.8 Hz, 4′-CH2), 3.80 (3H, s, OCH3), 4.05 (2H, t, J=6.4 Hz, 2′-CH2), 6.56 (1H, dd, J=8.4 and 2.8 Hz, ArH-7′), 6.65 (1H, d, J=8.8 Hz, ArH-8′), 6.79 (4H, d, J=2.8 Hz, ArH-5′), 7.21 (1H, td, J=8.8 and 1.2 Hz, ArH-6), 7.49 (1H, d, J=8.4 Hz, ArH-5), 7.68 (1H, td, J=8.8 and 2.0 Hz, ArH-7), 7.89 (1H, d, J=8.4 Hz, ArH-8), 8.86 (1H, s, ArH-2). MS m/z (%): 292(M+1, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene at 100℃; Inert atmosphere; | Synthesis of 4-(3,5-dimethylphenyl)quinazoline Synthesis of 4-(3,5-dimethylphenyl)quinazoline (3,5-Dimethylphenyl)boronic acid (5.75 g, 38.4 mmol), 4-chloroquinazoline (5.05 g, 30.7 mmol), and K2CO3 (8.48 g, 61.4 mmol) were dissolved in toluene (150 mL) and water (30 mL). The mixture was degassed by bubbling it with nitrogen for 30 minutes and adding tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (1.78 g, 1.53 mmol). The mixture was then held at 100°C overnight. Upon completion of the reaction, the mixture was cooled to room temperature, extracted with toluene, and washed with brine and water. The organic solution was filtered and evaporated. The crude product was purified by column chromatography using a gradient mixture of ethyl acetate (EA) (from 20 to 65%) in heptanes. The white powder product was recrystallized three times from heptanes to give colorless crystals (5.0 g, 70% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 8h; | General procedures for the preparation of substituted N-(3-aminobenzyl)- quinazolin-4-amines (4a and 4b) A solution of 3-aminobenzylamine (1.7 g, 14 mmol) and triethylamine (1 mL) dissolved in CH2Cl2 (10 mL) was slowly added to a solution of 4-chloroquinazoline (3a, 1.15 g, 7 mmol) dissolved in CH2Cl2 (20 mL). Then, the mixture was stirred at room temperature for 8 h. After the reaction mixture was concentrated, 20 mL of water was added, and the products were extracted with CH2Cl2 (3 * 30 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified through chromatography on a silica gel column by using petroleum/EtOAc (1/2) as eluent to obtain the key intermediate N-(3-aminobenzyl)- quinazolin-4-amine 4a (1.60 g, 91.1percent yield) as a white solid. N-(3-aminobenzyl)-6,7- dimethoxyquinazolin-4-amine (4b) was obtained following the same procedures. 4.2.4.1. N-(3-aminobenzyl)quinazolin-4-amine (4a). M.p.172.1e174.9 C. 1H NMR (500 MHz, DMSO-d6) d (ppm): 8.74 (t,J 5.7 Hz, 1H), 8.46 (s, 1H), 8.32 (d, J 8.3 Hz, 1H), 7.80e7.76 (m,1H), 7.70 (d, J 8.2 Hz, 1H), 7.54e7.51 (m, 1H), 6.96 (t, J 7.7 Hz,1H), 6.51 (d, J 7.5 Hz, 1H), 6.43 (d, J 7.9 Hz, 1H), 4.68 (d,J 5.8 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) d (ppm): 159.88,155.62, 149.70, 149.14, 140.45, 132.98, 129.22, 127.97, 126.06, 123.18,120.00, 115.45, 115.07, 112.87, 44.06. ESI-HRMS (m/z): calcd. forC15H14N4 [MH]: 251.12967; found, 251.13015. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With tetrabutylammomium bromide; sodium hydroxide; In butanone; for 1h; | General procedure: To a stirred solution of commercial chloro derivative (1 equiv) and tetrabutylammonium bromide in 10 mL of a mixture of 20% NaOH and 2-butanone (1:2) were added phenol (1 equiv). After 1 h at room temperature, the reaction was quenched by water, and then the aqueous solution was extracted with EtOA c(3 10 mL), washed with a solution of NaOH 1 N, and dried over MgSO4. The solvent was removed under reduced pressure. 4.1.2.1. 4-(3-Chloro-4-fluoroaryloxy)quinazoline (4). Compound 4 was purified in heptane and filtered while hot as a white solid (4%). Mp: 122-124 C. 1H NMR (DMSO-d6): d (ppm) 7.41-7.48 (m, 1H, ArH), 7.57 (dd, 1H, J = 9.0 and 9.0 Hz, ArH), 7.75-7.84 (m,2H, ArH), 7.98-8.10 (m, 2H, 2 ArH), 8.34-8.40 (m, 1H, ArH), 8.65 (s, 1H, ArH). LC-MS (APCI+): m/z calcd for C14H8ClFN2O275 [(M+H)+ for 35Cl] and 277 [(M+H)+ for 37Cl]. HRMS (ESI (M+H)+ m/z) calcd for C14H8ClFN2O275.0382. Found 275.0377. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride In tetrahydrofuran at 50℃; for 0.5h; Microwave irradiation; | General procedure for synthesis of compounds 3, 12-44. General procedure: A mixture of the corresponding 4-chloro quinozoline or quinoline (0.1 mmol), pyrazole amine (0.12 mmol) and 1M HCl (0.05 mmol) in THF (1 mL) was irradiated under microwave condition at 50 °C for 30 min. The reaction mixture was partitioned between hydrogen carbonate saturated aqueous solution and dichloromethane, the organic phase was dried oversodium sulfate and concentrated in vacuum, the residue was purified by silica gel chromatography (dichloromethane/MeOH + 10% of aqueous NH3= 10:1) to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.3g | With calcium carbonate; In acetonitrile; at 100℃; for 3h; | The 4-chloro-quinazoline (0.95g), calcium carbonate (3.5g) and (4-hydroxy-phenyl)-carbamic acid T-butyl ester (0.90g) adds to the second grade nitrile (10 ml), and the mixture in 100 C stirring 3 hours. The water is added to this reaction solution, and the aqueous layer is extracted with ethyl acetate. The combined organic layer with saturated aqueous salt solution to wash, then concentrated. The resulting residue with silica gel column chromatography (hexane: ethyl acetate = 100:0 ? 0:100) purification, to obtain the title compound (1.3g), which has the following physical property value. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | In the three-port flask add isoferulate acid methyl ester (0.83g, 4mmol), by adding 30 ml of acetonitrile are added after dissolving (1.66g, 12mmol) anhydrous potassium carbonate and 0.20g potassium iodide, is heated in the reflow device for 5 min, then adding (0.66g, 4mmol) 4-chloriquine oxazoline, the reaction introduced 50 C stirring, reaction to 6h substantially complete after-reaction of, after finishing the reaction, cooling to room temperature, filtered, get desolution of the yellow solid, crystalline anhydrous ethanol, to obtain white solid, quality 0.88g (theoretical quality 1.35g), yield 65.2%, m.p.151 . 4-152.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.5% | With triethylamine In ethanol at 20℃; for 5h; Reflux; | 6 Preparation of compound 3795 Take 1 · 65g (0 · olmol)4-chloroquinazoline and 2.17 g (0 · olmol) 2- (1- (4-methoxyphenyl) -1H-pyrazol-4-yl) ethanamine in 50 ml of ethanol at room temperature with stirring g (0.02 mol) of triethylamine, heated to reflux for 5 hours. After the TLC monitoring reaction was complete, the solvent was distilled off under reduced pressure, extracted with ethyl acetate (3 X 50 ml) and the organic phase was washed with 50 ml of saturated brine(Eluting with ethyl acetate and petroleum ether (boiling range 60-90 ° C) in a volume ratio of 1: 3) to give 2.71 g of a white solid, the yield was 78.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine In butan-1-ol at 125℃; for 1h; Inert atmosphere; Microwave irradiation; | General procedure A (SNAr) General procedure: Heteroaryl chloride (1.0 eq), the corresponding amino alcohol (1.1 eq) and triethylamine (1.5 eq), were dissolved in n-BuOH (1 mL). The resulting reaction mixture was degassed with argon and irradiated in a commercial microwave apparatus at 125 °C (30 W) for 1 h. Upon completion the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (methanol : dichloromethane; 1:9) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine In butan-1-ol at 125℃; for 1h; Inert atmosphere; Microwave irradiation; | General procedure A (SNAr) General procedure: Heteroaryl chloride (1.0 eq), the corresponding amino alcohol (1.1 eq) and triethylamine (1.5 eq), were dissolved in n-BuOH (1 mL). The resulting reaction mixture was degassed with argon and irradiated in a commercial microwave apparatus at 125 °C (30 W) for 1 h. Upon completion the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (methanol : dichloromethane; 1:9) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With DBN In 1-methyl-pyrrolidin-2-one at 80℃; for 1.5h; Inert atmosphere; | 8 General procedure for the synthesis of 4-acylquinazoline 6 General procedure: Under argon atmosphere, to a dry THF, DMF, or NMP solution (10ml) of 4-chloroquinazoline (164mg, 1mmol) and azolium salts (1mmol), a base (2mmol) was added and stirred. The organic layer was extracted three times with ethyl acetate and then washed with saturated brine for one time. Then, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/n-hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: N-aminopyridin-1-ium iodide With potassium carbonate In acetonitrile at 20℃; for 1.5h; Stage #2: 4-chloroquinazoline In acetonitrile Reflux; | 4.2 Preparation of pyridinium N-(heteroaryl) aminides 1 General procedure: Potassium carbonate (1.86g, 13.5mmol) was added to a solution of N-aminopyridinium iodide (1g, 4.5mmol) in acetonitrile (20mL) and the reaction mixture was vigorously stirred for 90minat room temperature to give a dark purple solution. To the reaction mixture was added a solution of the corresponding haloheterocycle (4.7mmol) in acetonitrile (5mL). The mixture was stirred and heated under reflux until all starting material had been consumed (detected by TLC). The inorganic salts were filtered off on Celite and the filtrate was evaporated in vacuo. The product was purified by chromatography on silica gel using ethanol as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.7% | With dmap In isopropyl alcohol at 25℃; for 12h; | 4 Example 4: Preparation of Methoxyphenylbenzo[d]azapinequinazoline (I) 0.943 g (5.73 mmol) of 4-chloroquinazoline (III) and 2.20 g (6.32 mmol) of compound (II), 1.40 g (11.46 mmol) of 4-dimethylaminopyridine,30 ml of isopropanol was added to a 100 ml three-necked flask, stirred at room temperature at 25 ° C, and detected by TLC (extension agent ethyl acetate / petroleum ether = 1:3 (v / v)), reaction for 12 hours,The reaction was turned off, the solvent was evaporated, and the obtained concentrate was dissolved in 20 ml of tetrahydrofuran to obtain a solution, and 4.0 g of column chromatography silica gel (300-400 mesh chromatography silica gel) was added to the solution.After mixing, the solvent is distilled off to obtain a mixture of the dried concentrate and silica gel, and the mixture is packed in a column, and then a 5:1 volume ratio of petroleum ether/ethyl acetate mixed solution is used as an eluent.Elution, TLC tracking detection (extension agent ethyl acetate / petroleum ether = 1:3 (v / v)), the eluate containing the compound of formula (I) was collected according to TLC detection (Rf value is 0.5),The concentrated liquid is concentrated,Drying at 50 ° C gave the white solid product of formula (I) in a yield of 88.7%.1H NMR and IR were the same as in Example 1. |
In chloroform at 40℃; for 10h; | 1.20 g (5.73 mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87 mmol) of compound (II), 3.62 g (45.76 mmol) of pyridine were successively12 ml of chloroform was added to a 50 ml reaction flask.Heat to 40°C,TLC follow-up test (developer is ethyl acetate/petroleum ether=1:3(v/v)),Stir the reaction for 10 hours and turn off the reaction.The reaction solution evaporates the solvent,The resulting concentrate was dissolved in 10 ml of ethyl acetate,Obtain the solution,To the solution was added 3.0 g of column chromatography silica gel (300 to 400 mesh chromatography silica gel).After mixing, evaporate the solvent,A mixture of dry concentrate and silica gel,Pack the mixture,Then use a 1:10 volume ratio of petroleum ether/ethyl acetate as eluent.Elution, TLC trace detection (developer ethyl acetate/petroleum ether=1:3 (v/v)),Collect compounds containing formula (IV) according to TLC testThe eluent (Rf value is 0.5),The collected solution was concentrated and dried at 50°C to give the product as a pale yellow solid of the formula (IV).Yield 85.1%. (4) Preparation of 4-chloroquinazoline by the method of reference (Rao, G.-W. et al. ChemMed Chem, 2013, 8(6), 928-933), and according to Example 1, 4-chloro-6- The nitroquinazoline was replaced with 4-chloroquinazoline. The other operations were the same as in Example 1, and the quinazoline compound (g) was synthesized. The structure is as follows: | |
With pyridine In chloroform at 40℃; for 10h; | 7.3 General procedure: 1.20 g (5.73 mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87 mmol) of compound (II), 3.62 g (45.76 mmol) of pyridine, 12 ml of chloroform were sequentially added to 50 ml of the reaction flask, heated to 40 ° C, TLC tracking detection (developing agent was ethyl acetate / petroleum ether = 1:3 (v / ν)), the reaction was stirred for 10 hours, and the reaction was closed. The reaction solution was evaporated to dryness, and the obtained concentrate was dissolved in 10 ml of ethyl acetate to obtain a solution. 3.0 g of column chromatography silica gel (300-400 mesh chromatography silica gel) was added into the solution, and after mixing, the solvent was distilled off to obtain a mixture of the dried concentrate and silica gel. The mixture was packed into a column, then with petroleum ether/ethyl acetate mixed solution of 1:10 in a volume ratio as a eluent carried out the elution, and detected by TLC (developing solvent was ethyl acetate / petroleum ether = 1:3 (v/) ν)), the eluate containing the compound of the formula (IV) (Rf value: 0.5) was collected according to the TLC detection , the collected liquid was concentrated, and dried at 50 ° C to obtain a pale yellow solid product of the formula (IV). Yield 85.1%, melting point 164~166° C. Prepared by the method of Rao, G.-W. et al. Chem Med Chem, 2013, 8 (6), 928-933)To 4-chloroquinazoline, according to Example 1, 4-chloro-6-nitroquinazoline was replaced with 4-chloroquinazoline, and other operations were carried out.Example 1, a quinazoline compound (d) was synthesized, and the structure is as follows: |
With pyridine In chloroform at 40℃; for 10h; | 17.3 Example 1: Preparation of nitrobenzo[d]azepinequinazoline (IV) General procedure: 1.20 g (5.73 mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87 mmol) of compound(II), 3.62 g (45.76 mmol) of pyridine, 12 ml of chloroform was added to a 50 ml reaction flask, heated to 40 ° C, and traced by TLC (extension agent was ethyl acetate / petroleum ether = 1:3 (v / v) The reaction was stirred for 10 hours, the reaction was turned off, and the solvent was evaporated. The obtained concentrate was dissolved in ethyl acetate (10 ml) to give a solution, and 3.0 g of column chromatography silica gel (300-400) was added to the solution. The column chromatography silica gel), after mixing, the solvent is distilled off to obtain a mixture of the dried concentrate and silica gel, the mixture is packed in a column, and then eluted with a petroleum ether/ethyl acetate mixed solution of 1:10 by volume. , elution, TLC tracking detection (extension agent is ethyl acetate / petroleum ether = 1:3 (v / v)), the eluate containing the compound of formula (IV) is collected according to TLC detection (Rf value 0.5), the collected eluate was concentrated and dried at 50 ° C to give a pale yellow solid product of formula (IV), yield: 85.1%; 4-chloroquinazoline was prepared by the method of Rao, G.-W. et al. Chem Med Chem, 2013, 8 (6), 928-933, and according to Example 1, 4-chloro- The 6-nitroquinazoline was replaced with 4-chloroquinazoline, and the other procedure was the same as in Example 1. The quinazoline compound (d) was synthesized, and the structure is as follows: | |
With pyridine In chloroform at 40℃; for 10h; | 1 Example 5: Preparation of 6-nitroquinazoline (IV) General procedure: 1.20 g (5.73 mmol) of 4-chloro-6-nitroquinazoline(III) and 2.39 g (6.87 mmol) in this order Compound(II), 3.62 g (45.76 mmol) of pyridine,12 ml of chloroform was added to a 50 ml reaction flask and heated to 40 °C. TLC tracking detection (extension agent is ethyl acetate / petroleum ether = 1:3 (v / v)), the reaction was stirred for 10 hours, the reaction was closed, the reaction solution was evaporated, and the obtained concentrate was added with 10 ml of ethyl acetate. The solution is dissolved to obtain a solution, and 3.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) is added to the solution, and after mixing, the solvent is distilled off to obtain a mixture of the dried concentrate and silica gel, and the mixture is mixed. The column was then eluted with a petroleum ether/ethyl acetate mixed solution of 1:10 in a volume ratio, eluted by TLC (extension agent was ethyl acetate / petroleum ether = 1:3 (v / v)) The eluate containing the compound of the formula (IV) (Rf value: 0.5) was collected according to the TLC test, and the collected eluate was concentrated and dried at 50 ° C to obtain a pale yellow solid product of the formula (IV). 85.1%, | |
With pyridine In chloroform at 40℃; for 10h; | 23.4 Example 1:Preparation of 6-nitroquinazoline (IV) General procedure: 1.20 g (5.73 mmol) in turn4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87 mmol) of compound (II), 3.62 g (45.76 mmol) of pyridine,12 ml of chloroform was added to the 50 ml reaction flask.Heat to 40 ° C, TLC tracking detection (developing agent is ethyl acetate / petroleum ether = 1:3 (v / v)), stirring reaction for 10 hours,The reaction is turned off, and the reaction solution is evaporated to remove the solvent.The obtained concentrate was dissolved by adding 10 ml of ethyl acetate to obtain a solution.To the solution, 3.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) was added, and after mixing, the solvent was distilled off.a mixture of dried concentrate and silica gel,Pack the mixture,Then eluted with a petroleum ether/ethyl acetate mixed solution of 1:10 in a volume ratio as an eluent.TLC tracking detection (extension agent is ethyl acetate / petroleum ether = 1:3 (v / v)),The eluate containing the compound of the formula (IV) was collected according to the TLC test (Rf value was 0.5), and the collected liquid was concentrated.Drying at 50 ° C gives the pale yellow solid product of formula (IV).The yield is 85.1%, | |
With pyridine In chloroform at 40℃; for 10h; | 23.4; 24.4 Example 1: Preparation of 6-nitroquinazoline (IV) General procedure: 1.20 g (5.73 mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87 mmol) of compound (II),3.62g (45.76mmol) of pyridine and 12ml of chloroform were added to a 50ml reaction flask,Heating to 40°C, TLC tracking detection (developing solvent is ethyl acetate/petroleum ether = 1:3 (v/v)), stirring and reacting for 10 hours,The reaction was closed, the solvent was evaporated from the reaction solution, and 10 ml of ethyl acetate was added to the resulting concentrate to dissolve it.To obtain a dissolving solution, add 3.0 grams of column chromatography silica gel (300-400 mesh column chromatography silica gel) to the dissolving solution,After mixing, evaporate the solvent to obtain a mixture of the dried concentrate and silica gel.Then use the petroleum ether/ethyl acetate mixed solution with a volume ratio of 1:10 as the eluent to elute,TLC tracking detection (developing agent is ethyl acetate/petroleum ether=1:3(v/v)),Collect the eluent containing the compound represented by formula (IV) (Rf value is 0.5) according to TLC detection,The collected liquid was concentrated and dried at 50°C to obtain a pale yellow solid product represented by formula (IV).The yield was 85.1%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | 4-Chloroquinazoline (105mg, 0.64mmol) was added to a solution of 3 (pamidronic acid, 100mg, 0.43mmol) and K2CO3 (149mg, 1.08mmol) in water (10mL). The resulting reaction mixture was kept at 95C for 24h. The resulting suspension was filtered. The filtrate was concentrated under vacuum and the reaction crude residue was washed three times with hot CHCl3 (3×20mL). The white solid, recovered by decantation from chloroform, was dissolved in water (2mL). The solution was acidified to pH=1 with 4N HCl obtaining pale yellow crystals of 20 that were isolated by filtration and washed with water (5mL). Yield: 128mg (82%). 1H NMR (500MHz, D2O/NaOD, delta): 2.13-2.21 (m, 2H), 3.62-3.65 (m, 2H), 7.36-7.38 (m, 1H), 7.45-7.47 (m, 1H), 7.61-7.63 (m, 1H), 7.94-7.96 (m, 1H), 8.14 (s, 1H). 31P NMR (202MHz, D2O/NaOD, delta): 18.5 (s, 2P). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 4-chloroquinazoline; 4-amino-1-hydroxybutylidenebisphosphonic acid With potassium carbonate In water at 95℃; for 20h; Reflux; Stage #2: With hydrogenchloride In water at 5℃; for 24h; | [1-Hydroxy-4-(quinazolin-4-ylamino)butane-1,1-diyl]bis(phosphonic acid) (21). 4-Chloroquinazoline (79mg, 0.48mmol) was added to a solution of 4 (alendronic acid, 80mg, 0.32mmol) and K2CO3 (111mg, 0.80mmol) in water (10mL). The resulting reaction mixture was kept at 90°C for 20h. The resulting suspension was filtered. The filtrate was evaporated under vacuum and the reaction crude residue was washed three times with hot CHCl3. The white solid, recovered from chloroform by decantation, was dissolved in water (3mL). The obtained solution was acidified to pH=1 with 4N HCl and kept overnight at 5°C. The obtained crystals of 21 were isolated by filtration and washed with water (5mL). Yield: 102mg (83%). 1H NMR (500MHz, D2O/NaOD, δ): 1.92-2.12 (m, 4H), 3.51-3.53 (m, 2H), 7.54-7.57 (m, 1H), 7.67 (d, 1H, J=8.3Hz), 7.79-7.82 (m, 1H), 8.12 (d, 1H, J=8.3Hz), 8.34 (s, 1H). 31P NMR (202MHz, D2O/NaOD, δ): 18.5 (s, 2P). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 4-chloroquinazoline; (5-amino-1-hydroxypentane-1,1-diyl)bis(phosphonic acid) With potassium carbonate In water at 95℃; for 18h; Reflux; Stage #2: With hydrogenchloride In water at 5℃; for 24h; | [1-Hydroxy-5-(quinazolin-4-ylamino)pentane-1,1-diyl]bis(phosphonic acid) (22). 4-Chloroquinazoline (74mg, 0.45mmol) was added to a solution of 8 (80mg, 0.30mmol) and K2CO3 (104mg, 0.75mmol) in water (10mL), and the resulting reaction mixture was kept at 90°C for 18h. The resulting suspension was filtered. The filtrate was concentrated under vacuum and the reaction crude residue was washed three times with hot CHCl3. The white solid recovered from chloroform by decantation was dissolved in water (4mL). The obtained solution was acidified to pH=1 with 4N HCl and kept overnight at 5°C. The obtained crystals of 22 were isolated by filtration and washed with water (5mL). Yield: 106mg (91%). 1H NMR (500MHz, D2O/NaOD, δ): 1.65-1.75 (m, 4H), 1.88-1.94 (m, 2H), 3.52-3.55 (m, 2H), 7.51-7.54 (m, 1H), 7.64 (m, 1H), 7.77-7.80 (m, 1H), 7.99 (m, 1H), 8.29 (s, 1H). 31P NMR (202MHz, D2O/NaOD, δ): 18.7 (s, 2P). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In isopropyl alcohol; at 110℃;Sealed tube; Microwave irradiation; | General procedure: 4-chloroquinazoline (164 mg, 1 mmol) was added to isopropanol(5 mL) with the corresponding substituted aniline derivative(1 mmol) and sealed in a microwave tube. The mixture washeated by 100W microwave irradiation to 110 C for a period of15e30 min to completion of the reaction, as indicated by TLC. Theformed precipitate was filtered off, washed with 10 mL isopropanoland dried in vacuo. If no precipitate was formed, the solvent wasremoved under reduced pressure and the remaining solid recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.7% | With N-ethyl-N,N-diisopropylamine; In ethanol;Reflux; | General procedure: Thiophenemethylamine 3a-3c (7 mmol, 1.4 eq) and Hunig's base (1.29g, 10 mmol, 2 eq) was added to the solution of 4-chloroquinazoline 4a-4c (5mmol, 1.0eq) in EtOH (50mL). The reaction mixture was heated at reflux for 6 hours. Upon completion, the reaction mixture was cold to room temperature and the solid was precipitated, filtered to afford the crude product. The crude product was purified by recrystallization to provide the title compound (5a-5i). |
84.7% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 6h;Reflux; | With a thermometer,Add 4-chloroquinazoline (IV-1) (5 mmol, 0.82 g) to a 500 mL three-necked flask of electromagnetic stirring and reflux condenser.Ethanol (50 mL), 5-chlorothiophene-2-methylamine (III-2) (7 mmol, 1.02 g),Hunig's base (1.29 g, 10 mmol), heated to reflux for 6 h.The reaction is complete, cooling,a white solid precipitated,Recrystallization from ethanol to give N-((5-bromothien-2-yl)methyl)quinazolin-4-amine(1.17g, 84.7%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.1% | With triethylamine In ethanol at 90℃; for 24h; | (S)-4-(1-(2-((7H-purin-6-yl)amino)propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (4k) General procedure: To a suspension of intermediate 15(1.04 g, 4.0 mmol) and 6-chloro-7H-purine (640.0 mg, 4.0 mmol) inEtOH (20.0 ml) Et3N (80.1 mg, 0.62 mmol) was added. The reactionmixture was heated to 90 C and stirred for 24 h. The resultingmixture was concentrated under reduced pressure and purified by column chromatography using a solvent gradient of 1-5% MeOH inDCM to give the compound 4k as a white solid. Yield: 970.0 mg,64.2%. |
20 mg | With triethylamine In acetonitrile at 90℃; | 10 Example 10 Synthesis of the compound SKLB-C4661 in the present invention Intermediate (S) -4- (1- (2-aminopropyl) -1H-pyrazol-3-yl) -2-chlorobenzonitrile was synthesized by the method described in Example 1 (c).4-chloroquinazoline (75 mg, 0.46 mmol), (S) -4- (1- (2-aminopropyl) -1H-pyrazol-3-yl) -2-chlorobenzonitrile (100 mg, 0.38 mmol) And triethylamine (46.5 mg, 0.46 mmol) were dissolved in acetonitrile (2 ml), heated to 90 ° C, and stirred overnight.Cool to room temperature, concentrate the solvent, add 5% DCM / MeOH to dissolve, apply the sample by wet method, purify it with a silica gel column, first isolate the impurities by eluting with pure EA, and then elute with 2% DCM / MeOH. SKLB-C4661. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With triethylamine; In ethanol; at 0 - 80℃; for 5h; | 4-Chloroquinazoline (100.0 mg, 0.61 mmol) and <strong>[29968-78-3]2-(4-nitrophenyl)ethan-1-amine hydrochloride</strong> (246.0 mg, 1.22 mmol) were dissolved in EtOH (3.0 mL) and cooled to 0C, and Et3N (425.0muL, 3.05 mmol) was added thereto. The reaction mixture was stirred at 80C for 5 hours and distilled under reduced pressure. The residue was extracted with EtOAc. The organic layer was washed with brine, dried with Na2SO4, filtered and distilled under reduced pressure. The residue was purified by column chromatography (CH2Cl2:MeOH=20:1) on silica. The fractions containing the product were collected and evaporated to obtain the white solid compound,N-(4-nitrophenethyl)quinazolin-4-amine (40.0 mg, 22%).[477][478]1H NMR (300 MHz, DMSO-d6) delta = 8.52 - 8.45 (m, 1H), 8.39 (t,J= 5.3 Hz, 1H), 8.22 - 8.13 (m, 3H), 7.80 - 7.72 (m, 1H), 7.71 - 7.65 (m, 1H), 7.61 - 7.45 (m, 3H), 3.82 (q,J= 6.7 Hz, 2H), 3.13 (t,J= 7.1 Hz, 2H)[479]LC/MS ESI (+): 295 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.6% | With triethylamine In N,N-dimethyl-formamide at 90℃; | 6 Example 6: Preparation of compound 16- (1) 0.16 g (0.001 mol) 4-chloroquinazoline and 0.25 g (0.001 mol) 4-oxo-2-spiro (piperidin-4-yl) -benzopyran hydrochloride were added to 20 ml DMF.Add 0.15g (0.015mol) of triethylamine, heat to 90 for 2-6 hours,After the reaction was monitored by TLC, the solvent was distilled off under reduced pressure, and ethyl acetate (3 × 50 ml) was added for extraction.The organic phase was washed with 50ml of saturated brine, and after desolvation, the residue was subjected to column chromatography (eluent was ethyl acetate and petroleum ether (boiling range 60-90 ° C), volume ratio was 1: 4) to obtain 0.25g of oily solid, The yield was 72.6%. |
With triethylamine In N,N-dimethyl-formamide at 90℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Dissolve 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (155.5 mg, 0.729 mmol) in 20 ml of DMF,Add sodium hydride (120mg, 3mmol) under ice bath and stir for 30 minutes,Add 3-chloroquinoline (100mg, 0.6mmol), react at room temperature for 0.5 hours, pour ice water (30ml), and extract twice with ethyl acetate (20ml).The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain a brown liquid (120 mg, 58% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate In isopropyl alcohol at 70℃; for 5h; | |
69% | With potassium carbonate In isopropyl alcohol at 70℃; for 5h; | 2 4-Chloro-quinazolinewas reacted with 1-benzylpiperidin-4-amine in the presence ofK2CO3.A solution of eachof intermediates5a-jand 1-benzylpiperidin-4-amine (1 mmol) in2-propanol (10 mL) wasstirred at room temperature for 10 min, then K2CO3(165.5 mg, 1.2 mmol) was added.The mixture was stirred at 70 °C until the reaction was complete (5 hours).The resulting mixture was evaporated under reduced pressure to give a residue, which was redissolved in 50 ml of DCM.The mixture was filtered and the DCM layer was evaporated under reduced pressure to give a white solid.The crude product was further purified by column chromatography (DCM/methanol = 100:5) to obtain target compounds6a-j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate In dimethyl sulfoxide at 110℃; for 12h; | Synthesis of N-(4-(4-(trifluoromethyl)phenoxy)phenyl)quinazolin-4-amine. 4- Chloroquinazoline (CAS: 5 190-68-1, 700 mg, 4.3 mmol), 4-(4- (trifluoromethyl)phenoxy)aniline (CAS: 57478-19-0, 1.08 g, 4.3 mmol) and potassium carbonate (587 mg, 4.3 mmol) were dissolved in 15 mL of DMSO. The reaction was heated to 110°C for 12 hours. The reaction was concentrated in vacuo and the residue was dissolved in CH2C12 and washed with 5% acetic acid solution (2x), water and brine. The organic phase was collected, dried over sodium sulfate (Na2504), filtered and then concentrated in vacuo. Crude material obtained was purified by silica gel column chromatography with a 50% ethyl acetate : CH2C12 solvent system to give 1.27 g (78%) of N-(4-(4- (trifluoromethyl)phenoxy)phenyl)quinazolin-4-amine. Recrystallization from boiling isopropanol or CH3CN afforded lightly colored crystals. 1H NMR (300 MHz, CDCl3) 8.75 (s, 1H), 7.93 (dd, J = 8.3, 1.3 Hz, 2H), 7.87-7.74 (m, 2H), 7.74 (s, 1H), 7.58 (dd, J = 8.5, 7.1 Hz, 4H), 7.16 -7.02 (m, 4H). 19F NMR (282 MHz, CDCl3)) -61.72 (s, 3F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With palladium diacetate; sodium carbonate; triphenylphosphine In 1,2-dimethoxyethane; water at 100℃; for 22h; Inert atmosphere; | 4.3. General procedure for Suzuki-Miyaura cross-coupling reactions General procedure: A mixture of 4-chloroquinazoline or 7-bromo-4-chloroquinazoline(1 mmol), the appropriate boronic acid (1.1 or 2.2 mmol, respectively),Pd(AcO)2 (5 mol%), PPh3 (10 mol%), aqueous Na2CO3 (5 mmol,dissolved in the minimum amount of water), and glyme (5 mL) wasdegassed by bubbling Ar through for 10 min. The reaction mixture wasstirred in a pressure tube at the indicated temperature (100-140 °C) for 22-23 h. After removing the glyme under reduced pressure, the reaction mixture was diluted with water and extracted with CH2Cl2 ( × 3). The combined organic layers were dried (MgSO4), filtered through a short pad of Celite, and concentrated under vacuum. The crude product was purified by flash chromatography on neutral alumina (eluent, mixturesof hexanes/EtAcO of increasing polarity and a few drops of Et3N) and/or washing with the indicated solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With palladium diacetate; sodium carbonate; triphenylphosphine In 1,2-dimethoxyethane; water at 130℃; for 23h; Inert atmosphere; | 4.3. General procedure for Suzuki-Miyaura cross-coupling reactions General procedure: A mixture of 4-chloroquinazoline or 7-bromo-4-chloroquinazoline(1 mmol), the appropriate boronic acid (1.1 or 2.2 mmol, respectively),Pd(AcO)2 (5 mol%), PPh3 (10 mol%), aqueous Na2CO3 (5 mmol,dissolved in the minimum amount of water), and glyme (5 mL) wasdegassed by bubbling Ar through for 10 min. The reaction mixture wasstirred in a pressure tube at the indicated temperature (100-140 °C) for 22-23 h. After removing the glyme under reduced pressure, the reaction mixture was diluted with water and extracted with CH2Cl2 ( × 3). The combined organic layers were dried (MgSO4), filtered through a short pad of Celite, and concentrated under vacuum. The crude product was purified by flash chromatography on neutral alumina (eluent, mixturesof hexanes/EtAcO of increasing polarity and a few drops of Et3N) and/or washing with the indicated solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With palladium diacetate; sodium carbonate; triphenylphosphine In 1,2-dimethoxyethane; water at 130℃; for 22h; Inert atmosphere; | 4.3. General procedure for Suzuki-Miyaura cross-coupling reactions General procedure: A mixture of 4-chloroquinazoline or 7-bromo-4-chloroquinazoline(1 mmol), the appropriate boronic acid (1.1 or 2.2 mmol, respectively),Pd(AcO)2 (5 mol%), PPh3 (10 mol%), aqueous Na2CO3 (5 mmol,dissolved in the minimum amount of water), and glyme (5 mL) wasdegassed by bubbling Ar through for 10 min. The reaction mixture wasstirred in a pressure tube at the indicated temperature (100-140 °C) for 22-23 h. After removing the glyme under reduced pressure, the reaction mixture was diluted with water and extracted with CH2Cl2 ( × 3). The combined organic layers were dried (MgSO4), filtered through a short pad of Celite, and concentrated under vacuum. The crude product was purified by flash chromatography on neutral alumina (eluent, mixturesof hexanes/EtAcO of increasing polarity and a few drops of Et3N) and/or washing with the indicated solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In dimethyl sulfoxide at 80℃; for 2.3h; Sealed tube; | 6 General Procedure 1 : Coupling of Amines to Aryl Chlorides. General procedure: An aryl chloride, an amine, K2CO3, and solvent were added to a pressure vial. The vial was sealed with a screw cap, having sometimes been flushed with N2and placed in a preheated oil bath with stirring. After the indicated reaction time, the vial was removed from the bath and the mixture was allowed to cool. The reaction mixture was diluted with EtOAc and the resulting solution was washed with H2O (sometimes basified) multiple times. The organic layers were sometimes back extracted and washed with brine. The organic layer was collected, dried with a drying agent, filtered, and concentrated. Purification of the residue by the indicated method(s) yielded the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.09% | With triethylamine; In isopropyl alcohol; at 80℃; for 4h; | To a mixture of l-(4-bromophenyl)ethanamine (100 mg, 422.77 umol, 1 eq, HC1) and TEA (171 mg, 1.69 mmol, 4 eq ) in i-PrOH (2 mL) was added 4-chloroquinazoline (77 mg, 465.04 umol, 1.1 eq) and the mixture was stirred at 80C for 4 hours. The reaction was concentrated in vacuo. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=10/l to 2:1) to give N-[l-(4-bromophenyl)ethyl]quinazolin-4- amine (250 mg, 761.72 umol, 90.09% yield, 2 batches in parallel) as a white solid. ESI (0406) [M+H] = 328.3/330.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 75℃; for 5h; | 1 Synthesis of Intermediate A-2 4-chloroquinazoline (1.16 g, 7.03 mmol), dibenzo[b,d]furan-4-ylboronic acid (1.19 g, 7.74 mmol), Pd(PPh3)4 (0.57 g, 0.49 mmol), and K2CO3 (1.46 g, 10.6 mmol) were mixed with 30 mL of tetrahydrofuran and 15 mL of distilled water and were stirred at 75° C. for 5 hours, and then cooled to room temperature. An organic layer was extracted therefrom by using ethyl acetate, anhydrous magnesium sulfate (MgSO4) was added thereto to remove water, and the residue obtained by depressurizing the filtrate obtained by filtration was purified by performing column chromatography under a condition of ethyl acetate:hexane=1:10 to obtain 1.49 g (89%) of Intermediate A-2. The obtained compound was confirmed by LCMS and 1H NMR. 1H-NMR (CDCl3) δ9.28 (s, 1H), 8.20 (d, 1H), 7.96 (d, 1H), 7.76 (m, 3H), 7.56 (m, 1H), 7.20 (d, 1H), 2.34 (s, 3H) MS: m/z 239.09 [(M+1)+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With quinazoline In tetrahydrofuran; water at 100℃; for 0.166667h; Microwave irradiation; | 1.3. Synthesis of 6-halo-2-phenyl-substituted 4-anilinoquinazolines General procedure: In a microwave vial, the given aniline (1.05 equiv), 4-chloro-6-halo-2-phenylquinazoline (1.0 equiv), and a mixture of THF/H2O 1:1 (6 mL.mmol-1 ofquinazoline) were added. The reaction mixture was stirred further for theindicated times at 100 °C in a microwave reactor after which the reaction wasquenched with saturated aqueous NaHCO3 solution. The aqueous phase wasextracted with AcOEt (3 ×), the organic layers were dried with MgSO4, andconcentrated under reduced pressure. After that, flash column chromatographyusing suited hexanes/ethyl acetate mixtures afforded the isolated products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.46% | With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 16h; | S4.d Step d) A mixture of benzyl N-cyclopentyl-N- [4- [ (2R, 3S) -3- [ [4-methyl-3- (trif luoromethyl) phenyl] carbamoyl] -2-piperidyl] phenyl] carbamate (150 mg, 258.78 μmol) , 4-chloro quinazoline (60 mg, 364.54 μmol) and DIEA (100.33 mg, 776.33 μmol, 135.22 μL) in DMSO (0.5 mL) was stirred at 100 for 16 hr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc 60 mL (30 mL x 2) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 gSilica Flash Column, Eluent of 0100%Ethyl acetate/Petroleum ether gradient 35 mL/min) to give the crude benzyl N-cyclopentyl-N- [4- [ (2R, 3S) -3- [ [4-methyl-3- (trifluoromethyl) phenyl] carbamoyl] -1-quinazolin-4-yl-2-piperidyl] phenyl] carbamate (94 mg, 99.61 μmol, 38.49%yield, 75%purity) as light yellow solid. The crude was further purified by prep-HPLC (basic condition) column: Xtimate C18 10μ 250 mm x50mm; mobile phase: [water (0.04%NH3H2O+10mM NH4HCO3) -ACN] ; B%: 80%-100%, 8 min) to give compound benzyl N-cyclopentyl-N-[4-[(2R,3S)-3-[[4-methyl-3-(trifluoromethyl)phenyl]carbamoyl]-1-quinazolin-4-yl-2-piperidyl]phenyl]carbamate (77 mg, 105.53 μmol, 79.46%yield, 97%purity) as a white solid.1H NMR (400 MHz, CDCl3) δ 1.33 -1.44 (m, 2 H) , 1.49 (br s, 4 H) , 1.82 -1.96 (m, 3 H) , 2.14 -2.24 (m, 1 H) , 2.30 -2.41 (m, 1 H) , 2.44 (d, J=1.25 Hz, 3 H) , 3.40 -3.53 (m, 2 H) , 4.08 (br d, J=13.05 Hz, 1 H) , 4.44 -4.57 (m, 1 H) , 5.09 (s, 2 H) , 6.30 (br d, J=4.02 Hz, 1 H) , 7.09 (d, J=8.53 Hz, 2 H) , 7.16 (br s, 2 H) , 7.20 -7.26 (m, 4 H) , 7.46 -7.58 (m, 3 H) , 7.64 (br d, J=8.28 Hz, 1 H) , 7.76 -7.84 (m, 2 H) , 7.94 (dd, J=8.28, 5.02 Hz, 2 H) , 8.41 (br s, 1 H) , 8.78 (s, 1 H) . LC-MS: (ES) m/z 708.3 (M+H+) . |
79.46% | With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 16h; | S4.d Step d) A mixture of benzyl N-cyclopentyl-N- [4- [ (2R, 3S) -3- [ [4-methyl-3- (trif luoromethyl) phenyl] carbamoyl] -2-piperidyl] phenyl] carbamate (150 mg, 258.78 μmol) , 4-chloro quinazoline (60 mg, 364.54 μmol) and DIEA (100.33 mg, 776.33 μmol, 135.22 μL) in DMSO (0.5 mL) was stirred at 100 for 16 hr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc 60 mL (30 mL x 2) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 gSilica Flash Column, Eluent of 0100%Ethyl acetate/Petroleum ether gradient 35 mL/min) to give the crude benzyl N-cyclopentyl-N- [4- [ (2R, 3S) -3- [ [4-methyl-3- (trifluoromethyl) phenyl] carbamoyl] -1-quinazolin-4-yl-2-piperidyl] phenyl] carbamate (94 mg, 99.61 μmol, 38.49%yield, 75%purity) as light yellow solid. The crude was further purified by prep-HPLC (basic condition) column: Xtimate C18 10μ 250 mm x50mm; mobile phase: [water (0.04%NH3H2O+10mM NH4HCO3) -ACN] ; B%: 80%-100%, 8 min) to give compound benzyl N-cyclopentyl-N-[4-[(2R,3S)-3-[[4-methyl-3-(trifluoromethyl)phenyl]carbamoyl]-1-quinazolin-4-yl-2-piperidyl]phenyl]carbamate (77 mg, 105.53 μmol, 79.46%yield, 97%purity) as a white solid.1H NMR (400 MHz, CDCl3) δ 1.33 -1.44 (m, 2 H) , 1.49 (br s, 4 H) , 1.82 -1.96 (m, 3 H) , 2.14 -2.24 (m, 1 H) , 2.30 -2.41 (m, 1 H) , 2.44 (d, J=1.25 Hz, 3 H) , 3.40 -3.53 (m, 2 H) , 4.08 (br d, J=13.05 Hz, 1 H) , 4.44 -4.57 (m, 1 H) , 5.09 (s, 2 H) , 6.30 (br d, J=4.02 Hz, 1 H) , 7.09 (d, J=8.53 Hz, 2 H) , 7.16 (br s, 2 H) , 7.20 -7.26 (m, 4 H) , 7.46 -7.58 (m, 3 H) , 7.64 (br d, J=8.28 Hz, 1 H) , 7.76 -7.84 (m, 2 H) , 7.94 (dd, J=8.28, 5.02 Hz, 2 H) , 8.41 (br s, 1 H) , 8.78 (s, 1 H) . LC-MS: (ES) m/z 708.3 (M+H+) . |
Tags: 5190-68-1 synthesis path| 5190-68-1 SDS| 5190-68-1 COA| 5190-68-1 purity| 5190-68-1 application| 5190-68-1 NMR| 5190-68-1 COA| 5190-68-1 structure
[ 1429782-21-7 ]
4-Chloro-2,6-dimethylquinazoline
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[ 39576-83-5 ]
2,4-Dichloro-8-methylquinazoline
Similarity: 0.88
[ 1429782-21-7 ]
4-Chloro-2,6-dimethylquinazoline
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[ 39576-83-5 ]
2,4-Dichloro-8-methylquinazoline
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