| 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. |
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