AKOS B033273

Step 2: Preparation of 3-chloro-4-(2-pyridylmethoxy)aniline from the nitrobenzene product of was accomplished with catalytic hydrogenation using platinum on carbon. A typical hydrogenation was done using 6 volumes of THF, 2percent by weight of 5percent Pt/C (50percent water wet), at 25 psi and at 25-30° C. for approximately 4-6 hours. The reaction is slightly exothermic and the temperature will rise to about 30-35° C. Cooling is necessary to maintain the temperature below 30° C. As a specific example, a mixture of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene (0.15 kg, 0.57 mole) and 2percent (w/w) of 5percent Pt/C (6.0 g) in tetrahydrofuran (0.90 L) was hydrogenated at 25 psi for at least 5 hours. The mixture was filtered through a celite pad and washed with tetrahydrofuran (0.60 L). The filtrate was distilled to a volume of about 0.75 L and ethanol (1.12 L) was added. Distillation was continued to a volume of about 0.75 L and ethanol (2.85 L) was added. The mixture may be used 'as is' in the step of Example 3 below. ; Performing the hydrogenation in isopropyl alcohol (IPA), methanol (MeOH), or ethanol (EtOH) may result in the product being contaminated with late eluting impurity that partially precipitates out on standing in solution. It was found that performing the hydrogenation in a solvent where both the product and starting material are soluble, such as tetrahydrofuran (THF), resulted in greater product purity and required much less solvent. Thus, THF is a preferred solvent for this step. Experimental results showing the effect of different reaction conditions are shown in Table 2. For the larger scale runs, the first aniline intermediate was not isolated (NI) before proceeding with the next step.TABLE 2 Hydrogenation to Form First Aniline Intermediate 5percent Scale (g) Pt/C** Solvent Vol Time (h) Yield (percent) 2.0 1 IPA 50 3 79.6 18 2.0 5 EtOH 60 3100* The above product (13.2 g, 0.05 mol), iron powder (11.2 g, 0.2 mol) and 12 M HCl (4 mL, 0.05 mol) were added into 90percent EtOH/HTo a solution of 2-[(2-chloro-4-nitrophenoxy)methyl]pyridine from Example 5A (6.65 g, 25.1 mmol) in ethanol (120 mL) was added zinc powder (8.22 g, 126 mmol), and the mixture was heated to 602-(2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (2.4 g, 9.07 mmol) is suspended in MeOH (30 ML) and treated wet 5percent Pt/C (Degussa type, ALDRICH, 0. 8 g). The flask is flushed with hydrogen gas from a balloon and the reaction mixture is stirred under hydrogen atmosphere until reaction is complete by TLC (ca 2 hours). The reaction mixture is filtered through a Celite plug and the solvent is removed under reduced pressure. The crude product is redissolved in DCM, dried (MGS04) and concentrated to yield 1.7 g (7.23 mmol, 80percent) of the desired product.Step B: Preparation of 3-chloro-4-(2-pyridylmethoxy)aniline from the nitrobenzene product of was accomplished with catalytic hydrogenation using platinum on carbon. A typical hydrogenation was done using 6 volumes of THF, 2percent by weight of 5percent Pt/C (50percent water wet), at 25 psi and at 25-30° C. for approximately 4-6 hours. The reaction is slightly exothermic and the temperature will rise to about 30-35° C. Cooling is necessary to maintain the temperature below 30° C. As a specific example, a mixture of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene (0.15 kg, 0.57 mole) and 2percent (w/w) of 5percent Pt/C (6.0 g) in tetrahydrofuran (0.90 L) was hydrogenated at 25 psi for at least 5 hours. The mixture was filtered through a celite pad and washed with tetrahydrofuran (0.60 L). The filtrate was distilled to a volume of about 0.75 L and ethanol (1.12 L) was added. Distillation was continued to a volume of about 0.75 L and ethanol (2.85 L) was added. The mixture may be used 'as is' in the step of Example 3 below. ; Performing the hydrogenation in isopropyl alcohol (IPA), methanol (MeOH), or ethanol (EtOH) may result in the product being contaminated with late eluting impurity that partially precipitates out on standing in solution. It was found that performing the hydrogenation in a solvent where both the product and starting material are soluble, such as tetrahydrofuran (THF), resulted in greater product purity and required much less solvent. Thus, THF is a preferred solvent for this step. Experimental results showing the effect of different reaction conditions are shown in Table 2. For the larger scale runs, the first aniline intermediate was not isolated (NI) before proceeding with the next step. TABLE 2 Hydrogenation to Form First Aniline Intermediate 5percent Scale (g) Pt/C** Solvent Vol Time (h) Yield (percent) 2.0 1 IPA 50 3 79.6 18 2.0 5 EtOH 60 3100* 2-CHLORO-4-NITRO PHENOL 10G (57.6 MMOL, 1EQ), 2-PYCOLYL CHLORIDE hydrogen chloride 9.45g (57.6 mmol, 1 eq) cesium carbonate 41.3 (126.8 mmol, 2.2 eq) and sodium iodide 8. 64G (57.6 mmol, 1 eq) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, YIELDING 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8G, 52percent) as a red solid. 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8 g, 30. 2MMOL, 1 eq) and 8. 44g iron (151.1 mmol, 5 eq) were mixed in 100 mL acetic acid and 50 mL ethyl acetate and were stirred at rt overnight. The reaction mixture was filtered through celite pad. The filtrate was concentrated in vacuo and neutralized with sat. NA2CO3 solution. The solution was extracted with ethyl acetate and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 30percent ethyl acetate/hexane yielding 3. 2G of 3-Chloro-4- (pyridin-2-ylmethoxy)-phenylamine as a white solid (52percent). 1H-NMR (CDCL3) No. 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H), . 6.80 (d, 1H), 7.22 (m, 1 H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H) ; LCMS RT = 0.89 min; [M+H]+= 235.1.2-chloro-4-nitro phenol 1Og (57.6 mmol, leq), 2-pycolyl chloride hydrogen chloride 9.45g (57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide 8.64g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8g, 52percent) as a red solid. 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and 8.44g iron (151.1 mmol, 5 equiv) were mixed in 100 mL acetic acid and 50 mL EtOAc and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52percent) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, IH), 6.76 (d, IH), . 6.80 (d, IH), 7.22 (m, IH), 7.64 (d, IH), 7.73 (td, IH), 8.55 (m, IH); LCMS RT = 0.89 min; [M+H]+ = 235.1.Example 71; 4-f [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino) [1]benzothieno[2, 3-d] pyrimidin-7-ol; Step 1. Preparation of 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine; EPO 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2 mmol, 1 equiv) and iron (8.44 g, 151.1 mmol, 5 equiv) were mixed in acetic acid (100 mL) and EtOAc (50 mL) and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2-(2-Chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2 mmol, 1 equiv) and 8.44 g iron (151.1 mmol, 5 equiv) in 100 mL acetic acid and 50 mL EtOAc were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated NaGeneral procedure: 10percentPt/C (0.40 g, 0.2 mmol) was added to a suspension of the nitro derivative (2a−2d)(1.7 mmol) in methanol (50.0 mL). The reaction mixture was stirred underhydrogen atmosphere at room temperature overnight. The mixture was thenfiltered through celite and the filtrate was evaporated under reduced pressureto afford the desired amines (3a−3d).The 3-chloro-4-(pyridin-2-ylmethoxy)aniline used a starting material was prepared as follows:4-amino-2-chlorophenol (2.5 g, 17.4 mmol) was dissolved in DMF (20 ml) to which was added benzaldehyde (1.95 ml, 19.2 mmol) and the reaction mixture was stirred for 10 minutes. Potassium carbonate (9.66 g, 69.9 mmol) was added, followed by picolyl chloride.HCl (3.44 g, 20.9 mmol). The reaction mixture was stirred at 5O1C. A mixture of HATU (197 mg), diisopropylethylamine (90 nul), acetic acid (22 ul) and N-[3-chloro-4-(pyridin-2-ylmethoxy) phenyl]-5-[2-(methylamino) ethoxy] quinazolin-4-amine (150 mg) in DCM (20 ml) was stirred for 2 hours. The solution was washed with water, then brine and concentrated in vacuo. The residue was purified by chromatography using DCM- 5% methanol as eluent to give the title compound as a white solid (114 mg, 69%) ; NMR spectrum (DMSO-d6) 1.95 (s, 3H), 3.00 (s, 3H), 3.89 (t, 2H), 4. 48 (m, 2H), 5.29 (s, 2H), 7.18 (d, 1H), 7.24 (d, 1H), 7.35 (m, 2H), 7.59 (m, 2H), 7.72 (dd, 1H), 7. 85 (dt, 1H), 7.96 (d, 1H), 8.46 (s, 1H), 8.58 (m, 1H), 9.70 (bs, 1H); Mass spectrum WI+ 478. 5. The N-[3-chloro-4-(pyridin-2-ylmethoxy) phenyl]-5-[2- (methylamino) ethoxy] quinazolin-4-amine used as starting material was prepared as follows: DMF (0. 2 ml) was added to a suspension of 5-fluoro-3, 4-dihydro-3H-quinazolin-4-one (1.64 g) in thionyl chloride (10 ml) and the mixture was stirred and heated at 80C for 6 hours. Volatile material was removed by evaporation and the residue was azeotroped with toluene (20 ml). The resulting solid was added portion wise to a vigorously stirred mixture of saturated sodium bicarbonate (50 ml), crushed ice (50 g) and DCM (50 ml) such that the temperature was kept below 5C. The organic phase was separated, dried and concentrated to give 4-chloro-5-fluoroquinazoline (1.82 g, 99%) as a solid which was used without purification; NMR spectrum (CDCl3) 7.35-7. 45 (m, 1H), 7.85-7. 95 (m, 2H), 9.0 (s, 1H). 4-Chloro-5-fluoroquinazoline (6.75 g) was added to a stirred solution of 3-chloro-4- (2- pyridylmethoxy) aniline (9.27 g, obtained as described in Example 15-21 (note u) of WO 96/15118) in IPA (200 ml), and the solution was stirred and heated at reflux for 8 hours. The solution was allowed to cool to ambient temperature overnight and the precipitated solid was filtered off, washed with acetone and dried. The solid was added to 50% aqueous methanol (400 ml) and the mixture was heated on a steam bath until the entire solid had dissolved. The solution was basified by careful addition of aqueous ammonia (0. 880), and the mixture was concentrated to remove methanol. Water (300 ml) was added and the mixture was extracted with DCM (600 ml). The extract was washed with water, and brine, and dried. The solvent was removed by evaporation to give a solid, which was re-precipitated from a mixture of ethyl acetate, tetrahydrofuran and isohexane to give N-[3-chloro-4-(pyridin-2- ylmethoxy) phenyl]-5-fluoroquinazolin-4-amine as a beige solid (6.75 g, 48%); NMR spectrum (DMSO-d6) 5.3 (s, 2H), 7.2-7. 3 (d, 1H), 7.35-7. 5 (m, 2H), 7.5-7. 65 (m, 3H), 7.8 - 7. 95 (m, 3H), 8. 55 (s, 1H), 8. 55-8.6 (d, 1H), 9. 1-9. 2 (bs, 1H) ; Mass spectrum MH 381. Sodium hydride (60% dispersion in mineral oil, 0.63 g) was added to 2- (methylamino) ethanol (0.95 ml), 15-crown-5 (100 ul) and N- [3-chloro-4- (pyridin-2- ylmethoxy) phenyl]-5-fluoroquinazolin-4-amine (1.5 g) in DMA (25 ml) and the reaction heated at 100C for 2 hours. The reaction was cooled, quenched with saturated aqueous ammonium chloride solution to pH 7-8. Addition of a small amount of saturated aqueous sodium hydrogen carbonate solution resulted in the formation of a precipitate, which was filtered, washed with water and dried. The solid was purified by chromatography using DCM - 5% methanol/7N ammonia as eluent to give N- [3-chloro-4- (pyridin-2-ylmethoxy) phenyl]- 5- [2- (methylamino) ethoxy] quinazolin-4-amine as a yellow solid (0.27 g, 45%); NMR spectrum (DMSO-d6) 2.40 (s, 3H), 3.02 (t, 2H), 4.35 (t, 2H), 5. 28 (s, 2H), 7.12 (d, 1H), 7.25 (d, 1H), 7.31 (d, 1H), 7.37 (m, 1H), 7.57 (d, 1H), 7.71 (dd, 1H), 7. 85 (m, 2H), 8.10 (d, 1H), 8. 51 (s, 1H), 8. 58 (m, 1H), 10.57 (bs, 1H) ; Mass spectrum 436. 5.4-Chloro-5-fluoroquinazoline (6.75 g) was added to stirred solution of 3-chloro-4- (2- pyridylmethoxy) aniline (9.27 g) (obtained as described in of WO 96/15118) in IPA (200 ml), and the solution was stirred and heated under reflux for 8 hours. The solution was allowed to cool to ambient temperature overnight and the precipitated solid was filtered off, washed with acetone and dried. The solid was added to 50% aqueous methanol (400 ml) and the mixture was heated on a steam bath until all the solid had dissolved. The solution was basified by careful addition of aqueous ammonia (0. 880), and the mixture was concentrated to remove methanol. Water (300 ML) was added and the mixture was extracted with DCM (600 ml). The extract was washed with water and saturated brine and dried. The solvent was removed by evaporation to give a solid, which was re-crystallised from a mixture of ethyl acetate, tetrahydrofuran and isohexane to give 4- (3-CHLORO-4- (2-PYRIDYLMETHOXY) anilino) -5- fluoroquinazoline as beige crystals (6.75 g, 48%); NMR spectrum (DMSO-d6) 5.3 (s, 2H), 7.2-7. 3 (d, 1H), 7.35-7. 5 (m, 2H), 7.5-7. 65 (m, 3H), 7.8-7. 95 (m, 3H), 8.55 (s, 1H), 8. 55-8.6 (d, 1H), 9.1-9. 2 (br s, 1H) ; Mass spectrum MI+ 381.4.4-Chloro-5-fluoroquinazoline (6.75 g) was added to stirred solution OF 3-CHLORO-4- (2- PYRIDYLMETHOXY) aniline (9.27 g, obtained as described in of WO 96/15118) in IPA (200 ml), and the solution was stirred and heated at reflux for 8 hours. The solution was allowed to cool to ambient temperature overnight and the precipitated solid was filtered off, washed with acetone and dried. The solid was added to 50% aqueous methanol (400 ml) and the mixture was heated on a steam bath until all the solid had dissolved. The solution was basified by careful addition of aqueous ammonia (0.880), and the mixture was concentrated to remove methanol. Water (300 ml) was added and the mixture was extracted with DCM (600 ml). The extract was washed with water, and brine, and dried. The solvent was removed by evaporation to give a solid, which was re-precipitated from a mixture of ethyl acetate, tetrahydrofuran and isohexane to give N-[3-chloro-4-(pyridin-2-ylmethoxy) phenyl] -5- fluoroquinazolin-4-amine as a beige solid (6.75 g, 48%) ; NMR spectrum (DMSO-d6) 5.3 (s, 2H), 7.2-7. 3 (d, 1H), 7.35-7. 5 (M, 2H), 7.5-7. 65 (m, 3H), 7. 8-7. 95 (m, 3H), 8.55 (s, 1H), 8.55-8. 6 (d, 1H), 9.1-9. 2 (bs, 1H) ; Mass spectrum MH 381.2- [(4- ( [3-Chloro-4-(at)pyridin-2-ylmethoxy)phenyl] amino} quinazolin-5- yl)oxy] acetamide To a suspension of 4- {[3-chloro-4-(pyridin- 2- ylmethoxy)phenyl] amino} quinazolin- 5-ol (200 mg, 0.52 mmol) in DMA (15 ml) was added potassium carbonate (359 mg, 2.60 mmol) and 2-bromoacetamide (80 mg, 0.58 mmol). The reaction was sonicated for 5 minutes in an ultrasonic cleaning bath and then stirred for 16 hours at room temperature. The solvent was removed in vacuo, water was then added to the residue and the resultant precipitate was filtered and washed with water. The solid was crystallised from ethyl acetate to give the title compound as an off-white solid (30 mg, 13%) ; NMR spectrum: 4.86 (s, 2H), 5.31 (s, 2H), 6.97 (d, 1H), 7.26 (d, 1H), 7.39 (m, 2H), 7.60 (d, 1H), 7.62 (s, 1H), 7.76 (t, 1H), 7.83 (s, 1H), 7.90 (td, 1H), 8.04 (dd, 1H), 8.34 (d, 1H), 8.57 (s, 1H), 8.62 (d, 1H), 10.96 (s, 1H) : Mass spectrum: MH+ 436; The 4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl] amino }quinazolin-5-ol used as starting material was obtained as follows: DMF (0.2 ml) was added to a suspension of 5-fluoro-3, 4-dihydro-3H-quinazolin-4- one (1.64 g) in thionyl chloride (10 ml) and the mixture was stirred and heated at 80 C for 6 hours. Volatile material was removed by evaporation and the residue was azeotroped with toluene (20 ml). The resulting solid was added portionwise to a vigorously stirred mixture of saturated sodium bicarbonate (50 ml), crushed ice (50 g) and DCM (50 ml) such that the temperature was kept below 5 C. The organic phase was separated, dried and concentrated to give 4-chloro-5-fluoroquinazoline as a solid (1.82 g, 99%), which was used without purification; NMR spectrum: (CDC13) 7.35-7.45 (m, 1H), 7.85-7.95 (m, 2H), 9.0 (s, 1H); 4-Chloro-5-fluoroquinazoline (6.75 g) was added to a stirred solution of 3-chloro- 4-(2-pyridyhnethoxy)aniline (obtained as described in of WO 96/15118, 9.27 g) in IPA (200 ml), and the solution was stirred and heated under reflux for 8 hours. The solution was allowed to cool to ambient temperature overnight and the precipitated solid was filtered off, washed with acetone and dried. The solid was added to 50% aqueous methanol (400 ml) and the mixture was heated on a steam bath until all of the solid had dissolved. The solution was basified by careful addition of aqueous ammonia (0.880), and the mixture was concentrated to remove methanol. Water (300 ml) was added and the mixture was extracted with DCM (600 ml). The extract was washed with water and saturated brine and dried. The solvent was removed by evaporation to give a solid, which was re-crystallised from a mixture of ethyl acetate, tetrahydrofuran and isohexane to give N [3-chloro-4-(pyridin-2-yhnethoxy)phenyl]-5-fluoroquinazolin-4-amine as beige crystals (6.75 g, 48%) ; NMR spectrum: 5.3 (s, 2H), 7.2-7.3 (d, 1H), 7.35-7.5 (m, 2H), 7.5-7.65 (m, 3H), 7.8-7.95 (m, 3H), 8.55 (s, 1H), 8.55-8.6 (d, 1H), 9.1-9.2 (b s, 1H); Mass spectrum: MH+ 381.4; N-Acetylethanolamine (24.3 ml, 0.264 mol) was added slowly to a suspension of sodium hydride (60% dispersion in mineral oil, 25.28 g, 0.632 mmol) in dry DMA (400 ml). Upon complete addition, the mixture was stirred for 30 minutes. N-[3-Chloro-4- (pyridin-2-yhnethoxy)phenyl]-5-fluoroquinazolin-4-amine (40 g, 0.105 mol) was added in one portion and the mixture was heated at 120 C for 18 hours. Saturated ammonium chloride (15 ml) was added to the cooled reaction mixture and stirred for 10 minutes. The DMA was removed in vacuo, water (1000 ml) was added to the residue and stirred for 1 hour. The resultant precipitate was filtered and air-dried. The solid was washed with diethyl ether (2 x 200 ml). This was then stirred in hot ethyl acetate (300 ml) and the cool mixture was filtered to give 4-{[3-chloro-4-(pyridin-2- ylmethoxy)phenyl]amino}quinazolin-5-ol as a tan solid (31.1 g, 78%) ; NMR spectrum: 5.28 (s, 2H), 6.63-6.81 (m, 2H), 7.22 (d, 1H), 7.32-7.39 (m, 1H), 7.39-7.52 (m, 2H), 7.57 (d, 1H), 7.87 (t, 1H), 7.97 (s, 1H), 8.33 (s, 1H), 8.58 (d, 1H) ; Mass spectrum: MH+ 379.

Molecular Weight:234.68
XLogP3:2.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:234.0559907
Monoisotopic Mass:234.0559907
Topological Polar Surface Area:48.1
Heavy Atom Count:16
Complexity:215
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes