Structure of 267243-64-1
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| CAS No. : | 267243-64-1 |
| Formula : | C21H21ClFN5O4 |
| M.W : | 461.87 |
| SMILES Code : | O=[N+](C1=CC2=C(NC3=CC=C(F)C(Cl)=C3)N=CN=C2C=C1OCCCN4CCOCC4)[O-] |
| English Name : | N-(3-Chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroquinazolin-4-amine |
| MDL No. : | MFCD12032146 |
| InChI Key : | QVZKEQDJKMFEDU-UHFFFAOYSA-N |
| Pubchem ID : | 10600107 |
| Num. heavy atoms | 32 |
| Num. arom. heavy atoms | 16 |
| Fraction Csp3 | 0.33 |
| Num. rotatable bonds | 8 |
| Num. H-bond acceptors | 8.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 123.99 |
| TPSA ? Topological Polar Surface Area: Calculated from |
105.33 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.38 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.97 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.21 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.06 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.09 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.34 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-5.05 |
| Solubility | 0.00415 mg/ml ; 0.00000898 mol/l |
| Class? Solubility class: Log S scale |
Moderately soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-5.88 |
| Solubility | 0.000605 mg/ml ; 0.00000131 mol/l |
| Class? Solubility class: Log S scale |
Moderately soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-7.18 |
| Solubility | 0.0000308 mg/ml ; 0.0000000667 mol/l |
| Class? Solubility class: Log S scale |
Poorly soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.3 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<3.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.39 |
* 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 |
|---|---|---|
| 90% | With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 0.5h; | 5.1 Step 1: The preparation of N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroquinazolin-4-amine Starting material: N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine was prepared according to the method in J. Med Chem 2009, 52, 6880-6888. [0321] 6-nitro-4-(3-chloro-4-fluorophenylamino)-7-fluoro-quinazoline (1 eq.) and morpholine-propanol (1.5 eq.) were dissolved in DMSO (10 ml), the solution was stirred for 5 mins with a water bath. A solution of potassium tert-butoxide (3.0 eq.) in DMSO (5 ml) was added slowly to the solution mentioned-above in drops, the mixture was stirred at room temperature for further 30 mins. After the reaction finished, the mixture was diluted with 100 ml water and pH was adjusted to neutral with concentrated hydrochloric acid, then stirred for 30 mins, large amount of yellow solid was precipitated, then filtering, the filter cake was washed with water twice and dried to give yellow solid of N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroquinazolin-4-amine (yield 90%). [0322] 1H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 9.21 (s, 1H), 8.67 (s, 1H), 8.16 (dd, J1=7.0 Hz, J2=3.0 Hz, 1H), 7.82-7.78 (m, 1H), 7.49-7.45 (m, 2H), 4.34 (t, J=6.5 Hz, 2H), 3.58 (t, J=4.0 Hz, 4H), 2.46 (t, J=6.5 Hz, 2H), 2.38 (brs, 4H), 1.97-1.92 (m, 2H). HRMS (ESI): m/z calcd for (C21H21ClFN5O4+H)+: 462.1344. found: 462.1344. |
| 87.9% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; | 1 Example one: At room temperature, 3-(morpholin-4-yl)-1-propanol (4.35 g, 30 mmol) and solvent N,N-dimethylformamide (DMF) 100 mL were added to the reaction flask,Potassium tert-butoxide (3.36g, 30mmol) was added with stirring until all were dissolved. Add 7-fluoro-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine (II) (3.36g, 10mmol), continue to stir the reaction for 3-4 hours, TLC detection The reaction is complete. Reduce the temperature to 10-15°C, add water and adjust the pH to neutral with dilute hydrochloric acid, a solid precipitates out, slowly stir and crystallize at 0-5°C for 2-3 hours, filter with suction and dry under reduced pressure to obtain N-(3-chloro-4- Fluorophenyl)-7-(3-morpholine-4-propoxy)-6-nitroquinazolin-4-amine (III) 4.05 g, yield 87.9%. |
| 67% | With Lithium 1,1,1,3,3,3-hexamethyldisilazide In tetrahydrofuran at 0 - 75℃; Inert atmosphere; |
| 58% | Stage #1: 3-morpholin-4-ylpropan-1-ol With sodium In tetrahydrofuran at 20℃; for 2h; Stage #2: N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine In tetrahydrofuran Further stages.; | |
| With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 25℃; for 0.5h; | 2.1.4 General procedure: To a suspensionof N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (1.68 g, 5 mmol) and (S)-tetrahydrofuran-3-ol (0.66 g,7.5 mmol) in DMSO (10 mL) at 25 C was added t-BuOK (1.68 g,15 mmol). After a further 30 min reaction, sufficient water wasadded to ensure complete precipitation, and the solid was collectedby filtration, washed by water twice and dried to give thepure yellow solid. | |
| With potassium <i>tert</i>-butylate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 0 - 20℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97.6% | In tetrahydrofuran | C Step C A solution of 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholino)propoxy]-6-nitroquinazoline (62.9 g, 136.2 mmol) in tetrahydrofuran (THF) (1200 mL) was hydrogenated over Raney Nickel (20 g) at 50 psi and 23° C. for 17.67 hours. Further Raney Nickel (20 g) was added, and the mixture was hydrogenated a further 4.33 hours under the same conditions. The reaction mixture was celite filtered, and the solvent was removed under reduced pressure to give 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholino)propoxy]quinazoline (57.81 g, 97.6% corrected) as a pale greenish solid. 1H NMR (DMSO-d6): δ 9.40 (s, 1H, NH), 8.38 (s, 1H, H-2), 8.20 (dd, J=2.5, 7.0 Hz, 1H, H-2'), 7.79 (ddd, J=2.5, 4.5, 9.0 Hz, 1H, H-6'), 7.40 (s, 1H H-5), 7.40 (t, J=9.1 Hz, 1H, H-5'), 7.08 (s, 1 H, H-8), 5.38 (brs, NH2), 4.19 (t, J=6.1 Hz, ArOCH2), 3.58 (t, J=4.4 Hz, 4 H, H-2 morpholino), 2.49 (t, J=7.0 Hz, 2 H, NCH2), 2.36 (brs, 4 H, H-3 morpholino), 1.97 (pentet, J=6.5 Hz, 2 H, H-2 propoxy). |
| 90.5% | With iron(III) chloride; pyrographite; hydrazine hydrate In tetrahydrofuran at 35 - 40℃; | 4-5 Example 4: At room temperature, add N-(3-chloro-4-fluorophenyl)-7-(3-morpholine-4-propoxy)-6-nitroquinazolin-4-amine (III ) (2.31g, 5mmol) and solvent tetrahydrofuran (THF) 50mL, heated to 35-40 °C. 80% hydrazine hydrate solution (2.45 g, 40 mmol) was added dropwise to the reaction system to keep the system slightly boiling (a catalytic amount of ferric chloride and activated carbon can be added to catalyze the reaction). After the dropwise addition was completed, the temperature was slowly raised to maintain the reflux reaction for 3 to 4 hours, and the end point of the reaction was monitored by TLC. The temperature was reduced to below 45°C, suction filtration, the filter cake was washed with tetrahydrofuran, and the filtrate was distilled under reduced pressure. The residue was recrystallized from methanol, and the resulting solid was dried in vacuo to give a yellow-green solid N-(3-chloro-4-fluorophenyl)-6-amino-7-(3-morpholine-4-propoxy)quinazole Pyridine-4-amine (IV) 1.95g, yield 90.5%. |
| 78% | With iron; acetic acid In ethanol for 0.5h; Heating; |
| 50% | With sodium tetrahydroborate; nickel(II) chloride hexahydrate In methanol; dichloromethane at 0 - 20℃; for 0.5h; | 5.2 Step 2: The preparation of N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4,6-diamine [0323] N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroquinazolin-4-amine (1.0 eq.) obtained in previous step and NiCl2 6H2O (2.0 eq.) were dissolved in DCM/ MeOH (32 ml:8 ml), the mixture was stirred at 0° C. for 5 min, and NaBH4 (4.0 eq.) was added in batches, then ice bath was removed and the mixture was recovered to room temperature naturally, stirred for further 30 mins. After the reaction finished, the mixture was concentrated to dryness under reduced pressure and gave a crude product which was purified by column chromatography (mobile phase 10:1 DCM/MeOH) to give a light yellow solid of N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4,6-diamine. (50% yield). [0324] 1H NMR (500 MHz, DMSO) δ 9.39 (s, 1H), 8.37 (s, 1H), 8.20 (d, J=4.5 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.41-7.38 (m, 2H), 7.08 (s, 1H), 5.35 (s, 2H), 4.20 (t, J=5.5 Hz, 2H), 3.59 (t, J=4.5 Hz, 4H), 3.18 (d, J=5.0 Hz, 2H), 2.40 (s, 4H), 2.01-1.96 (m, 2H). HRMS (ESI): m/z calcd for (C21H23ClFN5O2+H)+: 432.1603. found: 432.1613. |
| With tin(II) chloride dihdyrate In ethyl acetate at 90℃; for 1h; | ||
| With sodium tetrahydroborate; nickel(II) chloride hexahydrate In dichloromethane; water at 0℃; for 0.5h; | 2.1.5 General procedure: To a suspension of (S)-N-(3-chloro-4-fluorophenyl)-6-nitro-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-amine (2.03 g, 5 mmol) and NiCl2 6H2O (2.38 g, 10.0 mmol) in DCM/MeOH (32 mL: 8 mL) at 0 °C was added NaBH4 (0.76 g, 20 mmol). After a further 30 min reaction, the reaction was evaporated in vacuo and the residue was purified by silica gel (eluent DCM/MeOH = 10:1) to give light yellow solid. | |
| With iron; ammonium chloride In ethanol; water at 80℃; for 3h; | 5.2. Preparation of compounds 1-5 Compounds 1-4 were prepared following the Patent:US2003/158408 A1, 2003. Compound 4 (414 mg, 0.9 mmol) wasdissolved in ethanol (4 ml) and water (2ml). Iron powder (251mg, 4.5 mmol) and ammonium chloride (240 mg, 4.5 mmol) werethen added, and the resulting mixture was heated to 80°C for 3h. The reaction mixture was cooled to room temperature and filteredthrough Celite. The ethanol was removed in vacuo, and theresulting residue was basified with saturated sodium bicarbonateand extracted with ethyl acetate three times. The organic layer was separated and dried using anhydrous sodium sulfate, concentrated to afford 324 mg of yellow solid (84%). 1H NMR (400 MHz,DMSO d6) d 1.95-2.02 (m, 2H), 2.39 (bs, 4H), 2.51 (t, J = 7.2 Hz,2H), 3.59 (t, J = 4.4 Hz, 4H), 4.20 (t, J = 6.4 Hz, 2H), 5.36 (s, 2H),7.08 (s, 1H), 7.37-7.42 (m, 2H), 7.78-7.82 (m, 1H), 8.19 (dd, J =2.8, 6.8 Hz, 1H), 8.37 (s, 1H), 9.38 (s, 1H). | |
| With hydrogen In tetrahydrofuran at 20℃; for 3h; Heating / reflux; | 1 One-pot Reaction for the Preparation of (3-chloro-4-fluorophenyl)-[7-( 3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine (1). Example 1 One-pot Reaction for the Preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine (1). 150 g 7-fluoro-6-nitroquinazolin-4(3H)-one (III) are suspended in 600 ml thionyl chloride and, after addition of 6 ml DMF, boiled under reflux for 24 hrs.. A clear solution hereby results.. About 350 ml thionyl chloride are distilled off in a vacuum.. The resulting coarsely crystalline suspension is mixed with about 600 ml toluene.. About 800 ml are distilled off in a vacuum.. This distillation was further repeated 3 times with, in each case, 600 ml fresh toluene.. In the case of the last distillation, the toluene is distilled off as far as possible.. There results a coarsely crystalline suspension which, at all times, remains well stirrable. The almost dry residue is mixed with 1.2 l of a tetrahydrofuran/tert.-butanol mixture (7:3).. The resulting suspension is cooled to about 10° C. With good stirring and cooling, a solution of 114 g 3-chloro-4-fluoroaniline and 258 g 3-morpholin-4-yl-propan-1-ol (VI) in 300 ml THF/tert.-butanol (7:3) is added dropwise over the course of about 20 min. so that the temperature in the reactor remains between 10° C. and 15° C. The initially yellowish suspension becomes thinner and colours orange in the course of the addition. One allows the reaction mixture slowly to come to room temperature and subsequently stirs it at room temperature for at least 24 hrs. To the yellow-orange suspension is added dropwise, with good stirring and gentle cooling during the course of about 20 min., a solution of 324 g potassium tert.-butylate in 1.86 l tetrahydrofuran so that the temperature in the reactor remains between 15° C. and 20° C. After addition of about 1/3 of the potassium tert.-butylate/THF solution, the whole reaction mixture becomes dark red coloured. After about 30 minutes of further stirring, the mixture is immediately stirred into a mixture of 5.4 kg ice, 6.0 1 ethanol and 1.8 l hydrochloric acid (PH of the solution about 8).. There hereby first results a yellow-orange solution.. After brief stirring, a yellow product crystallizes out.. The resulting suspension is further stirred for about 5 hrs at about 0° C. and subsequently filtered with suction.. The filter cake is washed twice with, in each case, 500 ml ice-cold ethanol. The product is pre-dried in a circulating air cabinet first at 40° C. and subsequently at 60° C. to constant weight (yield: 316.5 g =95.5%; HPLC purity: 98.48 rel. %; H2O (K.F.) 3.69% m.p. 257° C. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: 72 percent / CH2Cl2; propan-2-ol / 0.5 h / 20 °C 2.1: Na / tetrahydrofuran / 2 h / 20 °C 2.2: 58 percent / tetrahydrofuran |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: 72 percent / CH2Cl2; propan-2-ol / 0.5 h / 20 °C 2.1: Na / tetrahydrofuran / 2 h / 20 °C 2.2: 58 percent / tetrahydrofuran | ||
| Multi-step reaction with 2 steps 1: dichloromethane; ethanol / 0.25 h / 20 °C 2: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 0.5 h / 25 °C | ||
| Multi-step reaction with 2 steps 1: isopropyl alcohol / 90 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran; <i>tert</i>-butyl alcohol / 0 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: 78 percent / Fe; aq. HOAc / ethanol / 0.5 h / Heating 2: 38 percent / EDCI*HCl; Et3N / N,N-dimethyl-acetamide |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 86% | at 90℃; for 12 - 18h; | 9.B [0146] Procedure B. A suspension of 10.5 grams of (3-chloro-4-fluoro-phenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-amine and 76 mL of acetic anhydride was stirred and heated to 90° C. for about 12-18 hours. The reaction mixture was cooled and distilled under vacuum to remove about 60 mL of acetic anhydride and cooled to 35+/-5° C. To the resulting slurry was charged 10 mL heptane followed by 33 mL MTBE and stirred at 0-5° C. The product was filtered and washed with cold MTBE and dried in a vacuum oven at 45-50° C. to yield 9.85 g (86% yield) of N-(3-chloro-4-fluoro-phenyl)-N-[7-(3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-acetamide. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrogenchloride In tetrahydrofuran; thionyl chloride; ethanol; N,N-dimethyl-formamide; toluene; <i>tert</i>-butyl alcohol | 1 One-pot reaction for the preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine (i) EXAMPLE 1 One-pot reaction for the preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine (i) 150 g 7-fluoro-6-nitroquinazolin-4(3H)-one (III) are suspended in 600 ml thionyl chloride and, after addition of 6 ml DMF, boiled under reflux for 24 hrs. A clear solution hereby results. About 350 ml thionyl chloride are distilled off in a vacuum. The resulting coarsely crystalline suspension is mixed with about 600 ml toluene. About 800 ml are distilled off in a vacuum. This distillation was further repeated 3 times with, in each case, 600 ml fresh toluene. In the case of the last distillation, the toluene is distilled off as far as possible. There results a coarsely crystalline suspension which, at all times, remains well stirrable. The almost dry residue is mixed with 1.2 l of a tetrahydrofuran/tert.-butanol mixture (7:3). The resulting suspension is cooled to about 10° C. With good stirring and cooling, a solution of 114 g 3-chloro-4-fluoroaniline and 258 g 3-morpholin-4-yl-propan-1-ol (VI) in 300 ml THF/tert.-butanol (7:3) is added dropwise over the course of about 20 min. so that the temperature in the reactor remains between 10° C. and 15° C. The initially yellowish suspension becomes thinner and colours orange in the course of the addition. One allows the reaction mixture slowly to come to room temperature and subsequently stirs it at room temperature for at least 24 hrs. To the yellow-orange suspension is added dropwise, with good stirring and gentle cooling during the course of about 20 min., a solution of 324 g potassium tert.-butylate in 1.86 l tetrahydrofuran so that the temperature in the reactor remains between 15° C. and 20° C. After addition of about 1/3 of the potassium tert.-butylate/THF solution, the whole reaction mixture becomes dark red coloured. After about 30 minutes of further stirring, the mixture is immediately stirred into a mixture of 5.4 kg ice, 6.0 l ethanol and 1.8 l hydrochloric acid (pH of the solution about 8). There hereby first results a yellow-orange solution. After brief stirring, a yellow product crystallises out. The resulting suspension is further stirred for about 5 hrs at about 0° C. and subsequently filtered with suction. The filter cake is washed twice with, in each case, 500 ml ice-cold ethanol. The product is pre-dried in a circulating air cabinet first at 40° C. and subsequently at 60° C. to constant weight (yield: 316.5 g=95.5%; HPLC purity: 98.48 rel. %; H2O (K.F.) 3.69% m.p. 257° C. | |
| With hydrogenchloride In tetrahydrofuran; thionyl chloride; ethanol; N,N-dimethyl-formamide; toluene; <i>tert</i>-butyl alcohol | 1 EXAMPLE 1 EXAMPLE 1 One-Pot Reaction for the Preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine (I). 150 g 7-fluoro-6-nitroquinazolin-4(3H)-one (III) are suspended in 600 ml thionyl chloride and, after addition of 6 ml DMF, boiled under reflux for 24 hrs. A clear solution hereby results. About 350 ml thionyl chloride are distilled off in a vacuum. The resulting coarsely crystalline suspension is mixed with about 600 ml toluene. About 800 ml are distilled off in a vacuum. This distillation was further repeated 3 times with, in each cape, 600 ml fresh toluene. In the case of the last distillation, the toluene is distilled off as far as possible. There results a coarsely crystalline suspension which, at all times, remains well stirrable. The almost dry residue is mixed with 1.2 l of a tetrahydrofuran/tert.-butanol mixture (7:3). The resulting suspension is cooled to about 10° C. With good stirring and cooling, a solution of 114 g 3-chloro-4-fluoroaniline and 258 g 3-morpholin-4-yl-propan-1-ol (VI) in 300 ml THF/tert.-butanol (7:3) is so added dropwise over the course of about 20 min. that the temperature in the reactor remains between 10° C. and 15° C. The initially yellowish suspension becomes thinner and colours orange in the course of the dropping in. One allows the reaction mixture slowly to come to room temperature and subsequently stirs at room temperature for at least 24 hrs. To the yellow-orange suspension is so added dropwise, with good stirring and gentle cooling during the course of about 20 min., a solution of 324 g potassium tert.-butylate in 1.86 l tetrahydrofuran that the temperature in the reactor remains between 15° C. and 20° C. After addition of about 1/3 of the potassium tert.-butylate/THF solution, the whole reaction mixture becomes dark red coloured. After about 30 minutes after-stirring, the mixture is immediately stirred into a mixture of 5.4 kg ice, 6.0 l ethanol and 1.8 l hydrochloric acid (pH of the solution about 8). There hereby first results a yellow-orange solution. After brief stirring, a yellow product crystallises out. The resulting suspension is after-stirred for about 5 hrs at about 0° C. and subsequently filtered off with suction. The filter cake is after-washed twice with, in each case, 500 ml ice-cold ethanol. The product is pre-dried in a circulating air cabinet first at 40° C. and subsequently at 60° C. to constant weight (yield: 316.5 g=95.5%; HPLC purity: 98.48 rel. %; H2O (K.F.) 3.69% m.p. 257° C. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | In P2O5; ice-water; water; dimethyl sulfoxide | B Step B A solution of potassium trimethylsilanolate (57.73 g, 0.45 mol) in dimethyl sulfoxide (DMSO) (150 mL) was added dropwise over 50 minutes to a bright yellow slurry of 4-[(3-chloro4-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline (50.503 g, 150 mmol) and 3-(4-morpholino)propan-l-ol (32.67 g, 225 mmol) in DMSO (250 mL), stirred vigorously under N2 on a 25° C. water bath. Immediate deep red color, and by the end of the addition the reaction mixture was a deep red-black viscous mixture. After 6 hours the reaction mixture was poured slowly onto stirred ice-water (4 L) containing saturated Na2CO3 solution (150 mL). After standing for 13 hours the orange-red slurry was collected by Buchner filtration. The precipitate was rinsed with dilute NaOH solution (0.05 M, 500 mL; 0.02 M, 500 mL), dilute NaHCO3 solution (saturated/5, 500 mL) and water (2*500 mL), and air dried for 4 hours, and then overnight at 50° C. in a vacuum oven over P2O5 to give 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholino)propoxy]-6-nitroquinazoline (62.47 g, 89% corrected) as a bright orange-yellow solid. 1H NMR (DMSO-d6): δ 10.11 (s, 1H, NH), 9.18 (s, 1H, H-5), 8.65 (s, 1H, H-2), 8.15 (dd, J=2.4, 6.8 Hz, 1H, H-2'), 7.79 (ddd, J=2.7, 4.3, 9.0 Hz, 1H, H-6'), 7.45 (t, J=9.0 Hz, 1 H, H-5'), 7.44 (s, 1H, H-8), 4.32 (t, J=6.1 Hz, ArOCH2), 3.57 (t, J=4.5 Hz, 4 H, H-2 morpholino), 2.45 (t, J=6.5 Hz, 2 H, NCH2), 2.34 (brs, 4 H, H-3 morpholino), 1.93 (pentet, J=6.5 Hz, 2 H, H-2 propoxy). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95.5% | Stage #1: 7-fluoro-6-nitro-3H-quinazolin-4-one With thionyl chloride; N,N-dimethyl-formamide for 24h; Heating / reflux; Stage #2: 3-morpholin-4-ylpropan-1-ol; 3-chloro-4-fluorophenylamine In tetrahydrofuran; <i>tert</i>-butyl alcohol at 10 - 20℃; for 24h; Stage #3: With hydrogenchloride; potassium <i>tert</i>-butylate more than 3 stages; | 8 Example 8; Preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine [0143] One hundred fifty g of 7-fluoro-6-nitroquinazolin-4(3H)-one was suspended in 600 mL of SOCl2 and, after addition of 6 mL of DMF, boiled under reflux for about 24 h, resulting in a clear solution. About 350 mL of SOCl2 was distilled off under vacuum, and the resulting coarse crystalline suspension was admixed with about 600 mL of toluene. Approximately 800 mL of the resultant solution was distilled off under vacuum. The distillation was repeated three times with, in each case, 600 mL of fresh toluene. In the last distillation, most of the toluene was distilled off, resulting in a coarse crystalline suspension. The nearly dry residue was mixed with 1.2 L of a THF/t-BuOH mixture (7:3 v/v), and the resulting suspension was cooled to about 10° C. A solution of 114 g of 3-chloro-4-fluoroaniline and 258 g of 3-morpholin-4-yl-propan-1-ol in 300 mL of a THF/ t-BuOH mixture (7:3 v/v) was added drop-wise with stirring and cooling over the course of about 20 min so that the temperature in the reactor remained at a temperature between 10° C. and 15° C. The initially yellowish suspension became less viscous and changed to a yellow-orange color during addition of the 3-chloro-4-fluoroaniline and 3-morpholin-4-yl-propan-1-ol solution. The resulting reaction mixture was allowed to slowly reach room temperature and was subsequently stirred at room temperature for at least 24 h. [0144] With stirring and cooling, a solution of 324 g of t-BuOK in 1.86 L of THF was added drop-wise to the yellow-orange suspension over the course of about 20 min so that the temperature in the reactor remained between 15° C. and 20° C. After the addition of about one-third of the t-BuOK/THF solution, the reaction mixture turned dark red. Once all of the t-BuOK/THF solution was added, the reaction mixture was stirred for an additional 30 min and subsequently stirred into a mixture of 5.4 kg of ice, 6.0 L EtOH and 1.8 L HCl (pH of the solution about 8). The reaction mixture was initially yellow-orange, but after brief stirring, a yellow product crystallized out. The resulting suspension was stirred for about 5 h at about 0° C. and subsequently filtered off with suction. The filter cake was washed twice with 500 mL aliquots of ice-cold EtOH. The product of the one-pot synthesis, (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine, was initially dried in a circulating air cabinet at 40° C. and was subsequently dried at 60° C. to constant weight (yield: 316.5 g=95.5%; HPLC purity: 98.48 rel. %; H2O (by K. F.) 3.69%; mp 257° C.). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: (3-chloro-4-fluorophenyl)-[7-(3-morpholino-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine With caesium carbonate In acetonitrile at 20℃; for 0.25h; Stage #2: acetyl chloride In acetonitrile at 0℃; for 0.333333h; | 9.A Example 9; Preparation of N-(3-chloro-4-fluoro-phenyl)-N-[7-(3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-acetamide [0145] Procedure A. A suspension of 10 g of (3-chloro-4-fluoro-phenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-amine and 14 g of cesium carbonate in 150 mL of dry acetonitrile was vigorously stirred at room temperature for 15 min. After cooling to 0° C. and further stirring for 15 min, a solution of 2 g of acetyl chloride in 20 mL of acetonitrile was added drop-wise over 20 min. After stirring for 15 min, the beige-colored suspension was poured into 500 mL of an ice/water mixture. The beige precipitate was filtered off by suction, washed three times with 50 mL of water each and dried in a circulating air drier at 80° C. to furnish 10.0 g of N-(3-chloro-4-fluoro-phenyl)-N-[7-(3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-acetamide (mp 154° C., MS: MG 503). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: nickel(II) chloride hexahydrate; sodium tetrahydroborate / dichloromethane; methanol / 0.5 h / 0 - 20 °C 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2.5 h / 20 °C / Cooling with ice 2.2: 0 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1: sulfuric acid; nitric acid / 2 h / 0 - 100 °C 2: thionyl chloride / N,N-dimethyl-formamide / 4 h / Reflux 3: dichloromethane; ethanol / 0.25 h / 20 °C 4: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 0.5 h / 25 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: thionyl chloride / N,N-dimethyl-formamide / 4 h / Reflux 2: dichloromethane; ethanol / 0.25 h / 20 °C 3: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 0.5 h / 25 °C | ||
| Multi-step reaction with 3 steps 1: thionyl chloride; N,N-dimethyl-formamide / Reflux 2: isopropyl alcohol / 90 °C 3: potassium <i>tert</i>-butylate / tetrahydrofuran; <i>tert</i>-butyl alcohol / 0 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate; nickel(II) chloride hexahydrate / water; dichloromethane / 0.5 h / 0 °C 2.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 2.42 h / 0 - 45 °C 2.2: 0 - 20 °C |