* 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.
With boron tribromide In dichloromethane at 0 - 20℃; for 2 h;
To a cooled (0 °C), stirred solution of 5-methoxy-2-methyl-1H-indole (3.5 g, 21.7 mmol) in dichloromethane (200 mL), boron tribromide 1 M in dichloromethane solution (10 mL, 108 mmol) was added drop-wise. The reaction mixture was allowed to stir at RT for 2 h, before being poured into ice water, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (Na2SO), filtered, and concentrated in vacuo to afford the title compound (3.13 g, 98percent). MS m/z (relative intensity, 70 eV) 147 (M+,82), 146 (bp), 118 (16), 117 (14), 91 (11). ESIMS: m/z 148.0 (M + H)+.1H NMR (CD3OD, 400 MHz) δ: 2.34 (s, 3H), 5.94 (s, 1H), 6.55 (dd,J = 8.59, 2.34 Hz, 1H), 6.79 (d, J = 2.34 Hz, 1H), 7.05 (d, J = 8.59 Hz, 1H). 13C NMR (CD3OD, 101 MHz) δ: 13.50, 99.71, 104.65, 110.73,111.54, 131.27, 132.87, 137.34, 151.07.
93%
With boron tribromide In dichloromethane; water
A solution of boron tribromide (32.5 ml, 341 mmol) in methylene chloride (60 ml) was added in portions to a solution of 5-methoxy-2-methylindole (25 g, 155 mmol) in methylene chloride (250 ml) cooled at -45° C. After stirring for 15 minutes at -30° C., the mixture was warmed up to ambient temperature and stirred for 1 hour. Methylene chloride (300 ml) was added in portions and the mixture was cooled to 0° C. Water was added in portions and the mixture was adjusted to pH6 with 4N sodium hydroxide. The organic layer was separated. The aqueous layer was extracted with methylene chloride and the organic layers were combined, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluding with ethyl acetate/methylene chloride (1/9 followed by 15/85) to give 5-hydroxy-2-methylindole (21.2 g, 93percent).
0.376 g
With boron tribromide In dichloromethane at 20℃; for 3.25 h; Cooling with ice
To a stirred, ice-cooled solution of 5-methoxy-2-methylindole (0.444 g, 3.00 mmol) in dry DCM (30 mL), 1.0 M solution of BBr3 in DCM (15.0 mL, 15 mmol) was added dropwise over 15 min. The reaction mixture was allowed to warm to rt and stirred at rt for 3h. It was then cooled in ice-bath again and excess BBr3 was quenched with slow addition of MeOH (5 mL). The volatiles were removed in vacuo and the residue diluted with water and pH adjusted with 10percent aq K2CO3 to give a suspension. The solid was collected by vacuum filtration, washed with water and dried. The crude product was purified on silica gel (2percent MeOH in DCM) to give 0.376 g 2-methylindole-5-ol. MS (MH+): 148.
Reference：
[1] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 578 - 588
[2] Patent: US2003/212055, 2003, A1,
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 5, p. 1940 - 1956
[4] Research on Chemical Intermediates, 2010, vol. 36, # 8, p. 975 - 983
[5] Bioorganic and medicinal chemistry, 2004, vol. 12, # 17, p. 4685 - 4700
[6] European Journal of Organic Chemistry, 2003, # 9, p. 1681 - 1686
[7] Patent: EP1154774, 2005, B1, . Location in patent: Page/Page column 67
[8] Patent: WO2010/66684, 2010, A2, . Location in patent: Page/Page column 50-51
[9] Patent: WO2014/183300, 2014, A1, . Location in patent: Page/Page column 36
2
[ 7598-91-6 ]
[ 13314-85-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 3094 - 3102
[2] Research on Chemical Intermediates, 2010, vol. 36, # 8, p. 975 - 983
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 867 - 891
[4] Journal of the Chemical Society, 1951, p. 2029,2031
[5] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 15, p. 1991 - 1996
3
[ 30891-22-6 ]
[ 13314-85-7 ]
Reference：
[1] Journal of Organic Chemistry, 1984, vol. 49, # 25, p. 4833 - 4838
[2] Chemistry Letters, 1997, # 7, p. 679 - 680
4
[ 106-51-4 ]
[ 13314-85-7 ]
Reference：
[1] Research on Chemical Intermediates, 2010, vol. 36, # 8, p. 975 - 983
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 867 - 891
With caesium carbonate; In dimethyl sulfoxide; at 105℃; for 2h;
(ii) 2-methyl-5-(2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-yloxy)indole. A solution of 7-chloro-2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridine (1.55 g, 5 mmol), and <strong>[13314-85-7]5-hydroxy-2-methylindole</strong> (1.18 g, 8 mmole) in DMSO (40 ml) was purged with argon for minutes at ambient temperature prior to addition of freshly crushed Cs2CO3 (4.88 g, 15 mmol). The resultant reaction mixture was heated at 105 C. for 2 hours. After cooling to room temperature, the crude reaction mixture was poured into cold water (300 ml). The precipitate that formed was collected by filtration to give 2.4 g of a brown solid which was purified by silica gel chromatography. Elution with CH2Cl2: CH3OH (96:4) and evaporation of the appropriate fractions gave 1.61 g (77%) of a yellow solid. 1H NMR (DMSO-d6): delta11.14 (1H, s), 8.51 (1H, d, J=5.4 Hz), 7.98 (1H, s), 7.35 (1H, d, J=8.6 Hz), 7.29 (1H, d, J=2.3 Hz), 6.88 (1H, dd, J=2.3, 8.6 Hz), 6.62 (1H, d, J=5.4 Hz), 6.16 (1H, s), 4.36-4.25 (1H, m), 3.93-3.75 (2H, m), 3.59-3.49 (1H, m), 3.46-3.36 (1H, m), 3.27 (3H, s), 2.39 (3H, s), 2.06-1.83 (4H, m).
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;
Example 9 A suspension of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13g, 0.4mmol), <strong>[13314-85-7]5-hydroxy-2-methylindole</strong> (74mg, 0.5mmol) and potassium carbonate (83mg, 0.6mmol) in DMF (1.5ml) was stirred at 100C for 2 hours. After cooling to ambient temperature, water (20ml) was added. The precipitate was collected by filtration, washed with water and dried under vacuum at 60C to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (80mg, 46%). 1H NMR Spectrum: (DMSOd6, CF3CO2D) 1.9-2.0(m, 2H); 2.05-2.2(m, 2H); 2.25-2.4(m, 2H); 2.43(s, 3H); 3.05-3.2(m, 2H); 3.35-3.5(m, 2H); 3.65-3.75(m, 2H); 4.12(s, 3H); 4.35-4.5(t, 2H); 7.0(dd, 1H); 7.35(d, 1H); 7.42(d, 1H); 7.6(s, 1H); 7.85(s, 1H); 9.15(s, 1H) MS (ESI): 433 (MH)+
7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide; at 80℃; for 3h;
A solution of 7-benzyloxy-4-chloroquinazoline (2g, 7.4mmol), <strong>[13314-85-7]5-hydroxy-2-methylindole</strong> (1.3 g, 8.9 mmol), (prepared as described for the starting material in Example 48), in DMF (20 ml) containing potassium carbonate (1.53 g, 11.1 mmol) was stirred at 80C for 3 hours. After cooling, the mixture was poured in portions into ice/water. The precipitate was filtered and washed with water and dried under vacuum. The solid was dissolved in methylene chloride and was purified by column chromatography eluding with ethyl acetate and methylene chloride (1/1) to give 7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (2.28 g, 81 %). MS-ESI: 382 [MH]+. 1H NMR Spectrum: (DMSOd6) 2.41 (s, 3H), 5.4 (s, 2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.4 (d, 1H), 7.4-7.5 (m, 4H), 7.55 (d, 2H), 8.32 (d, 1H), 8.6 (s, 1H).
6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 11 Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13g, 0.4mmol), (prepared as described for the starting material in Example 10), was reacted with <strong>[13314-85-7]5-hydroxy-2-methylindole</strong> (74mg, 0.5mol) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (137mg, 79%). 1H NMR Spectrum: (DMSOd6) 1.3-1.45(m, 2H); 1.7-1.95(m, 5H); 2.15(s, 3H); 2.4(s, 3H); 2.8(d, 2H); 3.98(s, 3H); 4.05(d, 2H); 6.14(s, 1H); 6.88(d, 1H); 7.29(s, 1H); 7.32(d, 1H); 7.35(s, 1H); 7.6(s, 1H); 8.45(s, 1H) MS (ESI): 433 [MH]+
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonia; potassium carbonate; In N,N-dimethyl-formamide; at 95℃; for 2h;
Example 67 A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (100mg, 0.29mmol), <strong>[13314-85-7]5-hydroxy-2-methylindole</strong> (53mg, 0.36mmol), (prepared as described for the starting material in Example 48), and potassium carbonate (62mg, 0.44mmol) in DMF (2ml) was heated at 85C for 3 hours, followed by heating at 95C for 2 hours. After cooling, ice/water (15ml) was added and the precipitate was collected by filtration and dried under vacuum. The solid was purified by column chromatography eluding with methylene chloride/methanol (95/5) followed by methylene chloride/methanol/3M ammonia in methanol (95/3/2) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (71mg, 54%). MS - ESI: 447 [MH]+ 1H NMR Spectrum: (DMSOd6) 1.35-1.4 (m, 2H), 1.45-1.55 (m, 4H), 1.92-2.0 (m, 2H), 2.3-2.4 (m, 4H), 2.40 (s, 3H), 2.4-2.5 (m, 2H), 3.97 (s, 3H), 4.22 (t, 2H), 6.15 (s, 1H), 6.9 (d, 1H), 7.27 (s, 1H), 7.8 (d, 1H), 7.35 (s, 1H), 7.58 (s, 1H), 8.48 (s, 1H)
6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;
Example 14 A solution of 4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (115mg, 0.28mmol), (prepared as described for the starting material in Example 12), <strong>[13314-85-7]5-hydroxy-2-methylindole</strong> (50mg, 0.33mmol) and potassium carbonate (60mg, 0.42mmol) in DMF (1.5ml) was stirred at 100C for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluding with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5 and 1/0/9) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (60mg, 41%). 1H NMR Spectrum: (DMSOd6) 1.3-1.45(m, 2H); 1.75-1.92(m, 3H); 2.02(t, 2H); 2.4(s, 3H); 2.7(t, 2H); 2.95(d, 2H); 3.05(s, 3H); 4.0(s, 3H); 4.05(d, 2H); 6. 15(s, 1H); 6.85(dd, 1H); 7.25(s, 1H); 7.3(d, 1H); 7.38(s, 1H); 7.6(s, 1H); 8.45(s, 1H) MS (ESI): 525 [MH]+
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 5h;
Example 153 A mixture of 4-chloro-6-methoxy-7-(3-(N -methyl-N -methylsulphonylamino)propoxy)quinazoline (360 mg, 1.00 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (215 mg, 1.56 mmol) and <strong>[13314-85-7]5-hydroxy-2-methylindole</strong> (162 mg, 1.10 mmol) in DMF (8.0 ml) was stirred at 100 C for 5 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue was purified by silica column chromatography eluding with methanol (2.5 to 5%) in dichloromethane. The resulting solid was recrystallized from ethyl acetate, filtered and washed with diethyl ether to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(N -methyl-N -methylsulphonylamino)propoxy)quinazoline (166mg, 35%). 1H NMR Spectrum: (DMSOd6) 2.06 (m, 2H), 2.38 (s, 3H), 2.79 (s, 3H), 2.89 (s, 3H), 3.24 (t, 2H), 3.96 (s, 3H), 4.21 (t, 2H), 6.11 (br s, 1H), 6.87 (dd, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.35 (s, 1H), 7.57 (s, 1H), 8.46 (s, 1H) and 10.98 (s, 1H) MS (ESI): 471 (MH)+
7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline[ No CAS ]
[ 13314-85-7 ]
[ 1070-89-9 ]
7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; dimethyl sulfoxide;
1M Sodium HMDS in THF (0.84ml, 8.4mmol) was added to a suspension of 7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (105mg, 0.28mmol) and 5-hydroxy-2methylindole (82mg, 0.56mmol), (prepared as described for the starting material in Example 48), in DMSO (1.5ml). After stirring for 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH3 with 2M hydrochloric acid. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluding with methylene chloride/methanol (95/5 followed by 90/10 and 70/30) to give 7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (75mg, 71%). 1H NMR Spectrum: (DMSOd6) 2.4 (s, 3H), 4.06 (s, 3H), 6.15 (s, 1H), 6.82 (d, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.68 (s, 1H), 7.84 (d, 1H), 8.25 (s, 1H), 8.55 (s, 1H)
With caesium carbonate; In water; N,N-dimethyl-formamide;
EXAMPLE 9 A suspension of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol), (prepared as described for the starting material in Example 1), <strong>[13314-85-7]5-hydroxy-2-methylindole</strong> (46 mg, 0.32 mmol) and cesium carbonate (129 mg, 0.39 mmol) in DMF (1 ml) was stirred for 10 minutes at ambient temperature followed by 1.5 hours at 70 C. After cooling, water (5 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluding with methanol/methylene chloride/ethyl acetate (5/45/50) to give 6cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(2-methylindol-5-yloxy)quinoline (30 mg, 23%). 1H NMR Spectrum: (DMSOd6) 2.0 (m, 2H); 2.4 (s, 3H); 2.7 (t, 2H); 2.9 (br s, 4H); 3.1 (br s, 4H); 4.35 (t, 2H); 6.15 (s, 1H); 6.4 (d, 1H); 6.9 (dd, 1H); 7.3 (s, 1H); 7.4 (d, 1H); 7.6 (s, 1H); 8.65 (d, 1H); 8.8 (s, 1H); 11.12 (s, 1H) MS-ESI: 491 [MH]+
With triethanolamine; caesium carbonate; In dichloromethane; N,N-dimethyl-formamide;
EXAMPLE 8 A mixture of 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)4chloro-6-methoxycinnoline (204 mg, 0.5 mmol), <strong>[13314-85-7]5-hydroxy-2-methylindole</strong> (81 mg) and cesium carbonate (326 mg, 1 mmol) in DMF (2.5 ml) was stirred at 90 C. for 2 hours. After cooling, the mixture was filtered, wash ed with DMF and the volatiles were removed under vacuum. The crude product was dissolved in methylene chloride (4 ml) containing TEA (1.5 ml) and was stirred at ambient temperature for 1 hour. The volatiles were removed under vacuum. The residue was partitioned between methylene chloride and 1N aqueous sodium hydroxide. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluding with a gradient of methylene chloride/methanol saturated with ammonia (5/95 to 15/85). The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the precipitate was filtered, washed with ether and dried under vacuum to give 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5yl)cinnoline (42 mg, 20%). 1H NMR Spectrum: (DMSOd6, CF3COOD) 1.58-1.7 (m, 2H); 2.05 (d, 2H); 2.3 (m, 1H); 2.45 (s, 3H); 3.02 (m, 2H); 4.18 (s,3); 4.3 (d, 2H); 6.22 (s, 0.5H, partly exchanged); 7.05 (d, 1H); 7.5 (m, 2H); 7.75 (s, 1H); 7.82 (s, 1H); 8.6 (s,1) MS: 419.6 [MH]+
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