| 96% |
With trichlorophosphate for 18h; Heating / reflux; |
1.1
A suspension of 2,4-quinazolinedione (5.0 g, 30.8 mmol) in neat phosphorylchloride (50 niL) was heated under reflux for 18 h. The reaction mixture was concentrated under vacuum. The crude product was purified by chromatography (Silica gel) using ethyl acetate and hexane (1:4) to give 2,4- dichloroquinazoline as white solid (4.8 g, 96%). 1H NMR (CDCl3): 8.29 (ddd, J= 8.4, 2.1 and 0.9 Hz, IH), 8.04-8.00 (m, 2H), 7.75* (ddd, J= 8.1, 4.8 and 3.0 Hz5 IH). |
| 95% |
With trimethylamine; trichlorophosphate at 0 - 5℃; for 7h; |
|
| 95% |
With triethylamine; trichlorophosphate at 120℃; for 7h; |
|
| 92% |
With N,N-diethylaniline; trichlorophosphate for 5h; Reflux; |
|
| 90% |
With N-ethyl-N,N-diisopropylamine; trichlorophosphate for 4h; Reflux; |
|
| 89.4% |
With 1-(1-methylpropyl)piperidine; trichlorophosphate at 80 - 85℃; for 0.333333h; |
|
| 88% |
With N-ethyl-N,N-diisopropylamine; trichlorophosphate for 3h; Reflux; |
2,4-dichloroquinazoline (22)
General procedure: Quinazolin-2,4(1H,3H)-dione (10 g, 61.7 mmol), DIPEA (22.6 ml, 129 mmol) and POCl3 (4.0 ml) were heated at reflux. After 3 hours the reaction mixture was cautiously poured over crushed ice and stirred vigorously. This aqueous mixture was extracted with CH2Cl2 DCM and the combined organic layers were washed with brine and dried over Na2SO4. Evaporation of the solvent gave a crystalline solid that was dissolved in CH2Cl2 after which it was filtered over a pad of silica using CH2Cl2 as eluent. Removal of the organic phase gave the product as 10.80 g (54.3 mmol, 88%) of a white solid. 1H-NMR (CDCl3) δ (ppm) 8.28-8.25 (m, 1H), 7.99-7.97 (m, 2H), 7.76-7.72 (m, 1H). |
| 88% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 5h; Reflux; |
|
| 87% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate |
|
| 87.6% |
Stage #1: 1,2,3,4-tetrahydro-quinazoline-2,4-dione With trichlorophosphate In toluene at 20℃; for 0.25h; Inert atmosphere;
Stage #2: With tri-n-propylamine In toluene at 55 - 110℃; for 5h; Inert atmosphere; |
|
| 87% |
With triethylamine; trichlorophosphate for 7h; Reflux; |
1. General procedure for the preparation of (1/3-allyl-2-methyl-1H/3H-benzimidazol-5-yl)-(2-chloro-quinazolin-4-yl)-amine (4a, 4b):
1H-quinazolin-2,4-dione (5 g, 0.03 mol), triethylamine (6.43 ml, 0.05 mol) andPOCl3 (25 ml, 0.27 mol) were refluxed for 7 h. Distilled off excess POCl3 under vacuum and crushed icewas added to the residue. Reaction mixture was then stirred for 1 hr at 0-5 oC. Filtered the solid product,washed with water and dried to give yellow solid of 2,4-dichoro-quinazoline (2) with 87% yield. |
| 87% |
Stage #1: 1,2,3,4-tetrahydro-quinazoline-2,4-dione With trichlorophosphate at 20℃; for 0.5h;
Stage #2: With N,N-diethylaniline for 14h; Reflux; |
1 4.1.3.1. 2,4-Dichloroquinazoline (5a).
A mixture of quinazoline-2,4(1H,3H)-dione 4a (0.48 g, 2.96 mmol) in POCl3 (3.31 mL,35.52 mmol) was stirred at room temperature for 30 min. AfterN,N-diethylaniline (0.167 mL, 0.86 mmol) was added drop-wise,the reaction mixture was heated to reflux for 14 h. After cooling to rt, remained POCl3 was removed under reduced pressure. Thereaction residue was extracted three times with CH2Cl2 (30 mL),dried over MgSO4, concentrated under reduced pressure, and purifiedby column chromatography (EtOAc/n-Hex = 1:9) on silica gelto get the title product 5a in 87% yield (513 mg). 1H NMR(300 MHz, DMSO-d6) d ppm 8.32 (d, J = 8.4 Hz, 1H), 8.18 (tt,J = 8.7, 1.5 Hz, 1H), 8.06 (dd, J = 7.8, 0.6 Hz, 1H), 7.92 (tt, J = 7.8,0.9 Hz, 1H). |
| 87% |
With triethylamine; trichlorophosphate at 106℃; for 18h; Inert atmosphere; |
|
| 86% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 7h; Heating; |
|
| 86% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 7h; Heating; |
|
| 86% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 7h; Heating; |
|
| 86% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 7h; Heating / reflux; |
1.A EXAMPLE I; 1-(3,4-DIMETHOXY-PHENYL)-3-[CIS-4-(4-DIMETHYLAMINO-QUINAZOLIN-2-YLAMINO)-CYCLOHEXYL]- urea hydrochloride; STEP A: SYNTHESIS OF 2.4-DICHLORO-QUINAZOLINE
To a suspension of 1H-quinazoline-2,4-dione (150 g, 925 mmol) in POCl3 (549 mL, 5.89 molt was added dimethyl-phenyl-amine (123 mL, 962 mmol). The mixture was stirred at reflux for 7 hr and concentrated. The solution was poured into ice water, and the aqueous layer as extracted with CHC13 (three times). The combined organic LAYER novas dried over MgSO4, filtrated, concentrated, and purified by flash chromatography (silica gel, 50% CHCl3 in hexane to 10% EtOAc in CHCL3) to give 2,4-dichloro-quinazoline (159 g, 86%) as a pale yellow solid. CIMS M/E 199, M+; 1H NMR (300 MHZ, CDCL3) No. 7.71-7.81 (m, 1 H), 7. 95-8. 04 (m, 2 H), 8.27 (dt, J=S. 3, 1. 1 HZ, I H). |
| 80% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 7h; Reflux; |
5.1.9.2. 2,4-Dichloroquinazoline (3b)
The reaction mixture of compound 2b (0.50 g, 3.09 mmol), POCl3 (4.3 mL) and N,N-dimethylaniline (1.6 mL) was stirred at reflux for 7 h. The excess POCl3 was removed by evaporation. The residue was dissolved in EtOAc which was washed with cold diluted HCl aqueous solution in order to remove the N,N-dimethylaniline. The organic phase was adjusted to pH 5-6 with saturated NaHCO3. The water phase was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4, concentrated to give the crude product which was purified by column chromatography on silica gel (petroleum ether/EtOAc = 50:1) to afford compound 3b, which was recrystalized with methanol as yellow solid (0.49 g, 80%); mp 116-117 °C; HRMS (ESI): m/z, calcd for C8H5Cl2N2 [M+H+]: 198.9829 found 198.9832. |
| 79% |
With trichlorophosphate In DMF (N,N-dimethyl-formamide) at 110℃; for 17h; |
54
A solutionof quinazoline-2, 4 (1H,3H)-dione (1.0 g, 6.17 mmol) and POC13 (20ml) inDMF (96 ml) was heated at 110 C for 17 hours. The resulting solution was cooled down and poured onto ice with stirring. Once the ice melted, the solid material was filtered and dissolved in DCM (100 ml). The solution was washed with water once and concentrated to give product as a white solid (970 mg,79%). aH NMR 8 7.90 (m, 1 H), 8.03(m, 1 H), 8.815 (m,1 H), 8.28(m, 1 H). |
| 79.6% |
Stage #1: 1,2,3,4-tetrahydro-quinazoline-2,4-dione With trichlorophosphate for 0.5h;
Stage #2: With <i>N</i>,<i>N</i>-dimethyl-aniline for 7h; Reflux; |
1.b (b) 2,4-Dichloroquinazoline
1H-Quinazolin-2,4-one (0.5 g, 3.09 mmol),4.3 mL phosphorus oxychloride added to the reaction flask,After stirring for 0.5h,1.6 mL of N, N-dimethylaniline was added,Reflux reaction for about 7h.The excess phosphorus oxychloride was distilled off under reduced pressure, and the remaining phosphorus oxychloride was taken out with chloroform. The residue was dissolved in ethyl acetate, and the excess N, N-dimethylaniline was removed with cold dilute hydrochloric acid to separate the water Phase, the organic phase was adjusted with saturated sodium bicarbonate pH = 5-6, the aqueous phase was extracted with ethyl acetate, the organic phase was combined, washed sequentially with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous magnesium sulfate, Mobile phase: ethyl acetate / petroleum ether = 50/1) to give crude product 0.649g. The crude product was recrystallized from 6 mL of methanol to give 0.489 g of a yellow flocculent solid. Yield: 79.6% |
| 76% |
With trichlorophosphate at 20℃; for 48.05h; Heating / reflux; |
30-A
Synthesis 30-A; (S)-tert-Butyl 3-(2-chloroquinazolin-4-ylamino)pyrrolidine-1-carboxylate; Phosphorous oxychloride (30 ml_, 191.00 mmol) was added dropwise over 3 minutes to quinazoline-2,4-dione (2.01 g, 6.17 mmol) at room temperature and the solution was heated at reflux for 48 hours. The reaction mixture was concentrated and the residue was added to iced water (100 ml.) and the aqueous phase was extracted with dichloromethane (2 x 125 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a pale yellow solid (0.944 g, 76%) which was used crude in the next step. |
| 75% |
Stage #1: 1,2,3,4-tetrahydro-quinazoline-2,4-dione With trichlorophosphate In toluene at 50 - 105℃; Inert atmosphere;
Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 120℃; for 24h; Inert atmosphere; |
|
| 75% |
Stage #1: 1,2,3,4-tetrahydro-quinazoline-2,4-dione With trichlorophosphate In toluene at 50℃; for 0.166667h; Inert atmosphere;
Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 105 - 120℃; for 23h; Inert atmosphere; |
|
| 75% |
With trichlorophosphate at 100℃; for 24h; |
4.1.8 General methodology for the synthesis of 2,4-dichloroquinazolines
General procedure: In a 100mL flask equipped with a reflux condenser, the reaction mixture containing the quinazolinediones (1.00g) and POCl3 (15mL; 24.77g; 161.53mmol) was stirred and heated at 100°C for 24h. Isolation was performed by the slow addition of the reaction medium over a mixture of ice and water with vigorous stirring. The resulting precipitate was filtered under a vacuum and purified by filtration through silica gel using dichloromethane as the eluent. |
| 72% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 115℃; for 5h; |
|
| 72% |
With tri-n-propylamine; trichlorophosphate In toluene at 110℃; for 4h; |
2,4-dichloroquinazoline (3)
To a solution of (1H)-Quinazolin-2, 4-dione (2) (18.7 g, 11.5 mM) in dry toluene (150 ml) was treated with phosphoryl trichloride (37.4 ml, 2 ml/g intermediate 2) carefully at ambient temperature. After stirring for 15 min, the mixture was heated to an internal temperature of 50 oC, and tri-n-propylamine (20 ml) was added over a period of time at a rate that maintains the internal temperature below 65 oC. The reaction mixture was then heated to 110oC for over 4 h to obtain a clear dark brown solution. The reaction mixture was cooled to ambient temperature. The solvent was removed by vacuum then treated with DCM (100 ml). The organic layer was washed with water (50ml), 5% NaOH (10 ml) and water (50 ml) to obtain a clear brown solution. The solvent was removed by vacuum to obtain a dark brown solid. To the residue was added heptane (100 ml), and the mixture was heated to an internal temperature of 90oC to obtain a clear yellow solution with brown insolvable solid. The solvent was collected while its temperature was still high, then cooled to 5 oC to obtain a light yellow solid (16.5 g, 72%). |
| 71% |
With trichlorophosphate for 48h; Reflux; |
POCl3 (40 ml) was stirred at room temperature for 20 min and was then added to a flask containing 2,4- quinolinedione (10 g, 0.06 mol). The mixture was heated to reflux for 48 h. The brown solution was cooled to 50°C, poured into cold water (0°C, 40 ml) while stirring vigorously. The aqueous mixture was maintained at a temperature below 30°C during the quench. The cold precipitate was filtered, washed with cold water (3x60 ml) and dried under high vacuum to afford 8 g (0.04 mol) of 2,4-dichloroquinazoline (71%). m.p.: 118°C; NMR (300MHz, DMSO-d6) δ 7.58 (t, J=7.6 Hz, 1H), 7.84 (t, 7=6.5 Hz, 2H), 8.16 (d, J=6.9 Hz, H). |
| 68.6% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 20 - 120℃; for 24h; |
|
| 68% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 120℃; for 4h; Inert atmosphere; |
1 Step 1 . Synthesis of 2,4-dichloroquinazoline (Compound A6, Scheme 4)
N,N-dimethylaniline (0.33 ml, 2.60 mmol), was dropwise added to an ice cold suspension of 1 H-quinazoline-2,4-dione (200 mg, 1 .23 (0487) Cl mmol) in POC (1 .15 ml). The reaction crude was then stirred at (0488) 120 °C under N2 for 4 hours, cold to room temperature, poured onto ice cold water, the resulting solid filtrated and rinsed with cold water to finally yield titled compound (1 67 mg, yield 68 %). 1H NMR (400 MHz, CDC ) δ 7.73-7.77 (m, 1 H), 7.97-8.03 (m, 2H), 8.27 (d, 1 H, J = 8.4 Hz). |
| 68.6% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 120℃; for 24h; |
3 was obtained by adding dimethylaniline (640.5 mg, 5.26 mmol) to a mixture of benzoylenurea (800 mg, 4.93 mmol) in POCl3 (10 ml) at room temperature. The reaction mixture was stirred at 120° C. for 24 h. The reaction mixture was quenched with ice-cold water. The reddish solid, compound 3, was precipitated, vacuum filtered, and then washed with hexane and dried under vacuum. It was used without further purification (672.3 mg, 68.6%). 1H NMR (400 MHz, CDCl3) δ 8.27 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 8.03-8.00 (m, 2H), 7.77-7.73 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 164.0, 155.1, 152.4, 136.2, 129.3, 128.0, 126.1, 122.4. LC-MS (ESI, formic) m/z 199.0 [M+H]+. |
| 67% |
With triethylamine; trichlorophosphate for 7h; Reflux; |
2,4-Dichloroquinazoline (II).
Quinazoline-2,4(1H,3H)-dione (I) (5 g, 0.03 mol), triethylamine(6.43 mL, 0.05 mol), and POCl3 (25 mL, 0.27 mol)were refluxed for 7 h (monitored by TLC in toluene-acetone (5 : 5). After the excess POCl3 was distilled off under vacuum, crushed ice was added to the residue. Reaction mixture was then stirred for 1 h at 0-5°C. The solid product was filtered, washed with water, and dried to give yellow solid of 2,4-dichoroquinazoline (II).Yield 67%; mp 116-117°C. |
| 63% |
With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline for 5h; Reflux; |
|
| 62% |
With diethylamine; trichlorophosphate at 150℃; for 0.25h; Microwave irradiation; |
4.1.36. 2,4-Dichloro-quinazoline (24)
A mixture of 1H,3H-quinazoline 2,4-dione 23 (1.00 g, 6.15 mmol), POCl3 (2.83 g, 18.5 mmol) and N,N-diethylamine (3.0 ml) was heated 15 min at 150 °C using Biotage Initiator microwave synthesizer. The resulting reaction mixture was dissolved in ethyl acetate (100 ml) and washed with H2O (2× 100 ml) and saturated Na2CO3 (2× 100 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 1:20 to give 24 (754 mg, 62%). 1H NMR (CDCl3): δ 8.27 (d, 1H, J = 8.4 Hz); 8.02-8.00 (m, 2H); 7.75 (m, 1H). |
| 61% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 5h; Inert atmosphere; Reflux; |
|
| 61% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 0℃; for 4h; Reflux; |
|
| 59% |
With trichlorophosphate at 115℃; Inert atmosphere; Schlenk technique; |
|
| 57% |
With phosphorus(V) chloride; trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline for 24h; Reflux; Inert atmosphere; |
|
| 56% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 110℃; for 24h; |
1.1. 2,4-dichloroquinazoline (10).
To a suspension of 1H,3H-quinazoline-2,4-dione(10.0 g, 61.7 mmol) in POCl3 (37 mL) was added dropwiseN,N-dimethylaniline (7.8 mL, 1.0 equiv.). The mixture was heated to 110 °C and kept at reflux for 24h. The solution was cooled to room temperature and poured onto an ice watermixture. The precipitated solid was collected through filtration, washed with H2Oand dried. The crude solid purified by column chromatography (100%CH2Cl2)afforded 10 as a white solid in 56%yield. 1H NMR (400 MHz, CDCl3) δ: 8.29 - 8.23 (m, 1H),8.03 - 7.96 (m, 2H), 7.77 - 7.72 (m, 1H); ESI-MS: 200 [M + H]+. |
| 52% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 5h; Reflux; |
2.1.2. Synthesis of 2,4-dichloroquinazoline (1b)
This compound was prepared according to the method ofSamrin et al. [35] with some modifications. Compound 1a(2 mmol) and phosphorus oxychloride (POCl3, 1.5 ml) wererefluxed in the presence of N,N-dimethylaniline (0.15 ml) for5 hours. After cooling to room temperature, the reaction solutionwas poured into vigorously stirring the ice-water mixtureand stirred for 20 min and then resulting pink-red precipitatewas filtered. The precipitate was dissolved in nhexaneand the insoluble residue was filtered off. The organicsolvent was evaporated under vacuum to furnish purecompound 1b. (52% yield; mp 119.4oC; mp 116-117oC [35]) |
| 51% |
With phosphorus(V) chloride; trichlorophosphate at 135℃; |
1.2 Example 1: Preparation of AWY103
(2) 1 g of intermediate B was added1With POCl3And PCl5The reaction was refluxed at 135 ° C to give the intermediate C10.63 g, yield 51%; the intermediate C1A. 1H NMR (400 MHz, CDCl33(M, 1H), 8.02 (d, J = 1.0 Hz, 1H), 8.01 (dd, J = 2.4, 0.9 Hz, 1H), 7.80-7.70 (m, 1H); specific reaction equation as follows: |
| 34% |
With trichlorophosphate for 18h; Reflux; |
1
A suspension of 1H-quinazoline-2,4-dione (10 g, 62 mmol), POCl3 (50 mL, 546 mmol) and N,N-dimethylaniline (1 mL, 7.9 mmol) was heated to reflux for 18 h. The reaction mixture was cooled to room temperature and poured slowly onto ice and extracted with CH2Cl2. The combined extracts were filtered through Na2SO4 and concentrated to give 4.2 g (34%) of 2,4-dichloro-quinazoline as a white solid. |
| 34% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In toluene for 18h; Reflux; |
2
A suspension of l/f-quinazoline-2,4-dione (10 g, 62 mmol), POCl3 (50 mL, 546 mmol) and JV^-dimethylaniline (1 mL, 7.9 mmol) was heated to reflux for 18 h. The reaction mixture was cooled to room temperature and poured slowly onto ice and extracted with CH2Cl2. The combined extracts were filtered through Na2SO4 and concentrated to give 4.2 g (34%) of 2,4-dichloro- quinazoline as a white solid. |
| 34% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 3h; Reflux; |
Intermediate 8: 3-{4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl}-1H-indole-7-carboxylic acid
Λ/, ν-dimethylaniline (33.4 g, 276 mmol, 1 .0 eq) was added dropwise to a solution of 2,4 (1 H, 3H)-quinazolinedione (50 g, 276 mmol, 1 .0 eq) in POCI3 (300 ml) and the mixture was heated to reflux for 3 hrs. The solution was cooled to room temperature, poured onto ice water and the resulting precipitate was filtered off and washed with water. The solid was dissolved in EtOAc and washed with water and brine. The organic fraction was dried over Na2S04, filtered, concentrated under reduced pressure, and washed with petroleum ether to give the corresponding dichloro-derivative (20 g, 34% yield).Ethyl-3-oxobutanoate (31.2 g, 240 mmol, 2.0 eq) was added dropwise to a suspension of NaH (6 g, 156 mmol, 1 .3 eq) in THF (520 ml) at 0 °C. After stirring at 0 °C for 1 h and removal of THF under reduced pressure, a solution of 2,4-dichloroquinazoline (24 g, 120 mmol, 1.0 eq) in toluene (350 ml) was added and the reaction mixture was heated to reflux for 30 min. After removal of toluene under reduced pressure, NH4OH (320 ml) was added. After stirring for 20 min, the mixture was concentrated to remove NH4OH. EtOAc (100 ml) and water (50 ml) were added to the mixture, that was filtered to give 2-(2- chloroquinazolin-4-yl)acetamide (14.4 g, 54 % yield).1 -Methylpiperazine (34 g, 339 mmol, 5.0 eq) was added to a solution of 2-(2- chloroquinazolin-4-yl)acetamide (14.4 g, 65 mmol, 1.0 eq) in NMP (250 ml) and stirred at 50 °C for 30 min. After cooling to room temperature, EtOAc (100 ml) was added and the suspension was filtered to give 2-(2-(4-methylpiperazin-1 -yl)quinazolin-4-yl)acetamide (10.5 g, 55 % yield).fert-BuOK (215 ml_, 121 mmol, 3.0 eq) was added to a solution of 2-(2-(4-methylpiperazin- 1 -yl)quinazolin-4-yl)acetamide (10.5 g, 36.8 mmol, 1.0 eq) and Intermediate 2 (10.5 g, 40.5 mmol, 1.1 eq) in anhydrous THF (250 ml) at room temperature and the mixture was stirred for about 30 min, quenched with water, extracted with EtOAc, washed with brine, dried over Na2S04, concentrated and purified by column chromatography (silicagel) to give the methyl-ester of intermediate 8 (1 1 g, 60 % yield). |
| 33% |
Stage #1: 1,2,3,4-tetrahydro-quinazoline-2,4-dione With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 100℃; for 16h;
Stage #2: With lithium hydroxide monohydrate In dichloromethane at 0℃; |
161
2-(2,4-Difluoro-phenyl)-4-piperazin-1-yl-quinazoline was prepared as in Example 112 except that instead of reacting the quinazoline-2,4-dione with dimethylpiperazine, tripropylamine, and phosphorous oxychloride, the following were carried out. Quinazoline-2,4-dione (10.0 g, 61.7 mmol) was dissolved in phosphorous oxychloride (56 mL, 617 mmol) and treated slowly with dimethylaniline (15.6 mL, 123 mmol). The reaction mixture was heated to 100° C., stirred for 16 h, cooled and concentrated. The residue was dissolved in dichloromethane, cooled to 0° C., and carefully treated with water to quench the remaining phosphorous oxychloride. The organic layer was separated, washed twice with water, dried over sodium sulfate (anhydrous), filtered and concentrated. The residue was recrystallized from hot isopropanol:water (10:1) to afford 4.0 g (33%) of 2,4-Dichloro-quinazoline. 2,4-Dichloro-quinazoline (1.0 g, 5.0 mmol) in THF (10 mL) was treated dropwise with methylpiperazine (0.56 mL, 5.0 mmol) and stirred at for 2 h. An additional 0.28 mL (2.5 mmol) methylpiperazine was added and the mixture was stirred another 1.5 h. Dichloromethane and 5% NaOH were added, and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel (0-10% methanol in dichloromethane) afforded 1.27 g. (96%) of 2-Chloro-4-(4-methyl-piperazin-1-yl)-quinazoline. MS (APCI) M+1=327.1; Elemental analysis found for C18H16F2N4.HCl: C, 57.13; H, 5.10; N, 13.99; Cl, 9.87; 1H NMR (400 MHz, CD30D-D4) d ppm 3.5 (m, 4 H) 4.1 (m, 4 H) 7.1 (m, 2 H) 7.7 (ddd, J=8.4, 6.9, 1.3 Hz, 1 H) 7.9 (ddd, J=8.4, 7.0, 1.5 Hz, 1 H) 8.0 (ddd, J=8.5, 1.3, 0.6 Hz, 1 H) 8.1 (m, 2 H). |
| 20% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 100℃; for 18h; Inert atmosphere; |
|
| 11% |
With trichloroisocyanuric acid; triphenylphosphine In toluene for 3h; Heating; |
|
|
With trichlorophosphate |
|
|
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate |
|
|
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 5h; Heating; |
|
|
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 16h; Heating; |
|
|
In ethyl acetate; <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate |
56.a 2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl)-acetamide
a) To a suspension of 1H,3H-quinazolin-2,4-dione (10.0 g, 61.7 mmol) in POCl3 (37.0 mL) is added dropwise N,N-dimethylaniline (7.8 mL, 1.0 eq.). The mixture is heated to 1 10° C. and kept at reflux for 35 h. The solution is cooled to RT and poured onto an ice-water mixture. The precipitate is filtered off and washed with H2O. The solid is redissolved in AcOEt and washed with H2O and brine. The organic phase is dried over Na2SO4 and evaporated to afford crude 2,4-dichloro-quinazoline which can be recrystallized from toluene/pentane. EI-MS: 198 [M-H]+, 163 [M-Cl]+; |
|
With trichlorophosphate In hexane; <i>N</i>,<i>N</i>-dimethyl-aniline |
17 2,4-Dichloroquinazoline
EXAMPLE 17 2,4-Dichloroquinazoline A mixture of benzoyleneurea (20.0 g), phosphorus oxychloride (100 ml) and N,N-dimethylaniline (12 ml) is,refluxed for five hours. After stirring overnight at room temperature, the mixture is heated to reflux once more for an additional four hours. The cooled mixture is then poured into ice and the precipitate collected. The precipitate is purified on silica gel column with 5% methanol/chloroform as eluent. The isolated product is triturated in ether/hexane and collected to obtain the title compound (6.9 g). The following compound is obtained by the same procedure as Example 17, by using 6-chloro-(1H,3H)-quinazolin-2,4-dione prepared by Example 15: 2,4,6-Trichloroquinazoline. |
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With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline |
9 Step A-Preparation of 2,4-Dichloroquinazoline
Step A-Preparation of 2,4-Dichloroquinazoline Benzoyleneurea was treated with phosphorus oxychloride and N,N-dimethylaniline according to the procedure described in R. Ife et al., J. Med. Chem. 1995, 38(14), 2763, to give a nearly quantitative yield of 2,4-dichloroquinazoline as an off-white solid, which was used immediately in the next step. |
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With trichlorophosphate In hexane; <i>N</i>,<i>N</i>-dimethyl-aniline |
R.13 2,4-dichloroquinazoline STR80
Reference example 13 2,4-dichloroquinazoline STR80 A mixture of benzoyleneurea (20.0 g), phosphorus oxychloride (100 mL) and N,N-dimethylaniline (12 mL) was refluxed for five hours. After stirring overnight at room temperature, the mixture was heated to reflux once more for an additional four hours. The cooled mixture was then poured into ice and the precipitate collected. The precipitate was purified on silica gel column with 5% methanol/chloroform as eluent. The isolated product was triturated in ether/hexane and collected to obtain the title compound (6.9 g). The following compound was obtained by the same procedure as Reference example 13, by using 6-chloro-(1H,3H)-quinazolin-2,4-dione prepared by Reference example 11. |
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In ice-water; trichlorophosphate |
1.a 2,3,5,6-Tetrahydro-1,2,4-triazolor[4,3-c]quinazoline-3,5-dione
a) 1.2 g (7.4 mmol) of 1,2,3,4-tetrahydroquinazoline-2,4-dione were suspended in 10 ml (74 mmol) of phosphorus oxychloride and heated to 120° C. for 24 hrs. The reaction mixture was left to cool to room temperature and poured on to ice-water. The brown precipitate was dried and chromatographed over silica gel with methylene chloride as the eluent. There were obtained: 331 mg (22%) of 2,4-dichloroquinazoline as white crystals; MS: me/e=198, 200 (M+). |
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With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 130℃; for 5h; |
29
Benzoyleneurea (40 g, 0.25 mol) was dissolved in POCl3 (200 ml), N,N-dimethylaniline (13.2 ml, 0.113 mol) was added and the mixture heated at 130° C. for 5 h. The mixture was then cooled to rt and added to ice; after standing at rt overnight, the mixture was filtered to give a solid which was purified by column chromatography (CH2Cl2) to give the title compound 29, 14 5 g. 1H NMR (CDCl3) δ 7.67-7.74 (m, 1H), 7.94-7.98 (m, 2H), 8.22 (d, J=8.8 Hz, 1H). |
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With trichlorophosphate Reflux; |
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With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 5h; Reflux; |
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With N,N-diethylaniline; trichlorophosphate for 96h; Reflux; |
1.1 1.
A solution of 25 g of benzoyleneurea and 12 mL of diethyl aniline in 200 mL of phosphorus oxychloride is refluxed for 4 days after which excess phosphorus oxychloride is removed on a rotovap and the remaining residue poured onto ice. The mixture is then extracted with ethyl acetate and the combined organic extracts washed with water, 1 N NaOH solution, dried and concentrated. The residue is recryscalized from isopropanol to provide 11 g of the dichloroquinazoline as off-white needles (m.p. 64-66 °C). |
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With trichlorophosphate Heating; |
3.c
The reaction mixture of quinazoline-2,4(1H,3H)-dione (1 g) and dimethylaniline (0.5 mL) in POCl3 (5 mL) was heated overnight. The reaction mixture was poured into ice. The precipitant was filtered and collected resulting in a grey color solid (2,4-dichloroquinazoline). |
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With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 110℃; for 3h; |
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With trichlorophosphate at 20℃; for 48h; Reflux; |
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With trichlorophosphate |
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With 4-dimethylaminopyridine; trichlorophosphate for 4h; Reflux; |
I-47
2,4-Dichloroquinazoline [0267] A mixture of lH-quinazoline-2,4-dione (2.850 g, 17.5 mmol), dimethylaminopyridine (1.6 mL) in POCI3 (8 mL) was refluxed for 4 h. The resulting solution was poured onto ice and the product collected via filtration. 1H NMR (DMSO- 6) 8.35-8.30 (m, 1H), 8.19 (ddd, 1H), 8.09-8.04 (m, 1H), 7.93 (ddd, 1H). |
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With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 110℃; for 3h; Inert atmosphere; |
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With N,N-dimethyl-formamide; trichlorophosphate for 48h; Reflux; |
1.1.2. 2,4-dichloroquinazoline (2)
General procedure: A mixture of commercially available 2,4-(1H,3H)-quinazolinedione (6.0 mmol), POCl3 (5 mL) and N,N-DMF (catalytic amount) was stirred and heated under reflux for 48 h. The solvents were removed under vacuum and cold water (0 °C, 25 mL) and chloroform (25 mL) were added. The organic layer was washed with water (3 × 20 mL) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the product was used immediately without further purification. |
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With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 14h; Reflux; |
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With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline Reflux; |
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With triethylamine; trichlorophosphate Reflux; |
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With ((1,3,5-triazine-2,4,6-triyl)tris(oxy))tris(triphenylphosphonium) chloride In neat (no solvent) at 170 - 180℃; for 2h; |
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With trichlorophosphate In N,N-dimethyl-formamide |
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| 14.5 g |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 5h; Inert atmosphere; Reflux; |
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With N,N-diethylaniline; trichlorophosphate In acetonitrile Reflux; |
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With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate Heating; |
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With trichlorophosphate Alkaline conditions; |
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With phosphorus(V) chloride; trichlorophosphate at 120℃; for 6h; Inert atmosphere; |
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With Sodium hydrogenocarbonate; trichlorophosphate In hexane; <i>N</i>,<i>N</i>-dimethyl-aniline; benzene |
I EXAMPLE I
EXAMPLE I A mixture of 100 g of 2,4(1H, 3H)-quinazolinedione, 300 ml of phosphorus oxychloride, and 45 ml of N,N-dimethylaniline was heated at reflux for 6 hours. The reaction mixture was cooled slightly and poured over ice. The resulting mixture, which consisted of about 6 liters, was divided between two four-liter separatory funnels and was extracted with a total of 6 liters of benzene. The benzene extracts were combined and washed successively with several volumes of water, 5 percent sodium bicarbonate solution, and then with water until the washes were neutral to litmus. The organic phase were combined, dried over anhydrous sodium sulfate, and filtered. The benzene was removed by distillation and the residue was crystallized from a solvent mixture consisting of 500 ml of benzene and 1,500 ml of hexane. Filtration afforded 72 g of a brown solid which was recrystallized from 2.5 liters of hexane to yield 43 g of pure 2,4-dichloroquinazoline; m.p. 116°-118°. The following analytical data were obtained: Calculated for C8 H4 Cl2 N2: C, 48.28; H, 2.03; Cl, 35.62; N, 14.07. Found: C, 47.99; H, 2.23; Cl, 35.39; N, 13.82. |
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With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene Reflux; |
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With N-ethyl-N,N-diisopropylamine; trichlorophosphate In acetonitrile at 100℃; for 6h; |
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With triethylamine; trichlorophosphate at 0 - 5℃; for 7h; Reflux; |
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With trichlorophosphate for 7h; Reflux; |
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| 510 mg (57%) |
With trichlorophosphate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate |
A.650.A A.
A. 2,4-Dichloroquinazoline Benzoyleneurea (732 mg, 4.5 mmol) and 4 mL of phosphorous oxychloride were refluxed under nitrogen over night. The reaction mixture was poured into 50 mL of ice water, and the precipitate filtered. The precipitate was washed with additional cold water and triturated with petroleum ether. The solid was dried to yield 510 mg (57%) mp 114-115° C. mass spec (ESI) m/z=199, (M+H)+base. |
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With triethylamine; trichlorophosphate for 7h; Reflux; |
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With triethylamine; trichlorophosphate for 6h; Reflux; |
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