* 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.
Method F1: 2,4-Dichloro-6-methoxyquinazoline (x-a) To a mixture of 6-methoxyquinazoline-2,4(1H, 3H)-dione (9.63 g, 50.2 mmol) in POCl3 (150 mL) was added N,N-dimethylaniline (0.5 mL). The resulting mixture was stirred at 120° C. for 2 h. After the reaction was completed, POCl3 was removed in vacuo, and the residue was added to ice-water slowly. The pH was adjusted to ˜7 by slowly adding NaHCO3 (sat.) at 0° C., then a precipitate formed. The solid was collected and dried in vacuo to give 11.2 g of 2,4-dichloro-6-methoxyquinazoline in a 98percent yield as a brown solid. LCMS m/z=229.1, 231.0 (M+1) (Method B) (retention time=1.87 min). 1H-NMR (400 MHz, DMSO-d6): δ 7.89 (d, J=9.2 Hz, 1H), 7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 3.91 (s, 3H).
98%
With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 120℃; for 12 h;
To a mixture of 6-methoxyquinazoline-2,4 (1H, 3H) -dione (9.63 g, 50.2 mmol) in POCl 3 (150 mL)N, N-dimethylaniline (0.5 mL) was added.The resulting mixture was stirred at 120 ° C. for 2 hours.After the reaction was complete, the POCl 3 was removed in vacuo and the residue was slowly added to ice water.When the pH was adjusted to about 7 by the slow addition of saturated NaHCO 3 at 0 ° C., a precipitate formed.The solid was collected and dried under vacuum to afford 11.2 g of 2,4-dichloro-6-methoxyquinazoline as a brown solid (98percent yield).
82%
for 5 h; Reflux
A suspension of 6-methoxy-1H-quinazoline-2,4-dione (0.85 g, 4.42 mmol) and N,N-dimethylaniline (1.66 mL, 2.6 mmol) in phosphoryl chloride (6 mL, 65.5 mmol) was heated under reflux for 5 h. The reaction mixture was cooled and poured into a beaker with ice, the precipitate was filtered off, washed with water and dried under vacuum to provide 0.82 g (82percent yield). 1H NMR (DMSO-d6) δ 8.01 (d, 1H), 7.03-7.80 (dd, 1H), 7.5 (d, 1H), 4.0 (s, 3H).
74%
Stage #1: at 20℃; for 0.5 h; Stage #2: for 14 h; Reflux
General procedure: 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 87percent yield (513 mg).
69%
for 16 h; Reflux
A solution of 6-methoxyquinazoline- 2,4(lH,3H)-dione (5 g, 26.0 mmol) in trichloro phosphorus oxide (30 mL) was refluxed for 16 hours. After cooling down to ambient temperature, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2percent methanol in dichloromethane to afford 2,4-dichloro-6-methoxyquinazoline as a yellow solid: MS (ESI, m/z): 229 A [M + 1]+; 1H MR (300 MHz, CDC13) δ 7.90 (d, J= 9.3 Hz, 1H), 7.61 (dd, J= 2.7 Hz, 6.6 Hz, 1H), 7.41 (d, J= 2.7 Hz, 1H), 4.00 (s, 3H).
28%
for 6 h; Reflux
To a solution of 6-methoxyquinazoline-2,4(lH,3H)-dione (5.10 g, 26.6 mmol) in POCI3 (30 mL) was added N,N-diethylaniline (2.4 mL, 15.0 mmol). The mixture was refluxed for 6 hours. The excess POCI3 was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL), the organic layer was washed with sat.NaHCC>3 (30 mL), dried over Na2S04, filtered and concentrated to give the crude product which was purified by silica gel column (PE / EtOAc=20 / 1) to give the product (1.70 g, yield 28percent).
3.6 g
at 110℃;
2,4-dichloro-6-methoxyquinazoline N,N-dimethylamine (6.3 mL, 50 mmol) was added into a mixed solution of 6-methoxyquinazolin-2,4(1H,3H)-dione (4.8 g, 25.0 mmol) prepared in Step 1 in phosphorus oxychloride (50 mL), and then they were stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture was added into ice water and then basified to pH 9 with sodium hydroxide. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=5/1) to give the titled compound (3.6 g) as a yellow solid.
Reference：
[1] Patent: US2015/307477, 2015, A1, . Location in patent: Paragraph 1497
[2] Patent: JP6121658, 2017, B2, . Location in patent: Paragraph 1096; 1099
[3] Patent: US2010/68197, 2010, A1, . Location in patent: Page/Page column 17
[4] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 11, p. 2439 - 2444
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7717 - 7727
[6] Patent: WO2015/188368, 2015, A1, . Location in patent: Page/Page column 89
[7] Journal of Medicinal Chemistry, 1995, vol. 38, # 18, p. 3547 - 3557
[8] Patent: WO2012/83165, 2012, A1, . Location in patent: Page/Page column 96
[9] Journal of the Chemical Society, 1948, p. 1759,1765
[10] Journal of Medicinal Chemistry, 1995, vol. 38, # 14, p. 2763 - 2773
[11] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2297 - 2300
[12] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
[13] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 75 - 80
[14] Patent: US2016/90374, 2016, A1, . Location in patent: Paragraph 0122
[15] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2755 - 2766
With N,N-dimethyl-aniline; trichlorophosphate; at 120℃; for 2h;
Method F1: 2,4-Dichloro-6-methoxyquinazoline (x-a) To a mixture of 6-methoxyquinazoline-2,4(1H, 3H)-dione (9.63 g, 50.2 mmol) in POCl3 (150 mL) was added N,N-dimethylaniline (0.5 mL). The resulting mixture was stirred at 120 C. for 2 h. After the reaction was completed, POCl3 was removed in vacuo, and the residue was added to ice-water slowly. The pH was adjusted to ?7 by slowly adding NaHCO3 (sat.) at 0 C., then a precipitate formed. The solid was collected and dried in vacuo to give 11.2 g of 2,4-dichloro-6-methoxyquinazoline in a 98% yield as a brown solid. LCMS m/z=229.1, 231.0 (M+1) (Method B) (retention time=1.87 min). 1H-NMR (400 MHz, DMSO-d6): delta 7.89 (d, J=9.2 Hz, 1H), 7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 3.91 (s, 3H).
98%
With trichlorophosphate; In N,N-dimethyl-aniline; at 120℃; for 12h;
To a mixture of 6-methoxyquinazoline-2,4 (1H, 3H) -dione (9.63 g, 50.2 mmol) in POCl 3 (150 mL)N, N-dimethylaniline (0.5 mL) was added.The resulting mixture was stirred at 120 C. for 2 hours.After the reaction was complete, the POCl 3 was removed in vacuo and the residue was slowly added to ice water.When the pH was adjusted to about 7 by the slow addition of saturated NaHCO 3 at 0 C., a precipitate formed.The solid was collected and dried under vacuum to afford 11.2 g of 2,4-dichloro-6-methoxyquinazoline as a brown solid (98% yield).
82%
With trichlorophosphate;N,N-dimethyl-aniline; for 5h;Reflux;
A suspension of 6-methoxy-1H-quinazoline-2,4-dione (0.85 g, 4.42 mmol) and N,N-dimethylaniline (1.66 mL, 2.6 mmol) in phosphoryl chloride (6 mL, 65.5 mmol) was heated under reflux for 5 h. The reaction mixture was cooled and poured into a beaker with ice, the precipitate was filtered off, washed with water and dried under vacuum to provide 0.82 g (82% yield). 1H NMR (DMSO-d6) delta 8.01 (d, 1H), 7.03-7.80 (dd, 1H), 7.5 (d, 1H), 4.0 (s, 3H).
74%
General procedure: 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).
74%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 125℃; for 3h;
A mixture of 6-methoxyquinazoline-2,4(lH,3H)-dione (1 g, 5.2 mmol) and DIPEA (1.34 g, 10.4 mmol) POCI3 (10 mL) was stirred at 125 C for 3 h. The reaction mixture was cooled to RT, added dropwise to water (100 mL) and extracted with DCM (100 mL*2). The organic layers were dried over Na2S04, filtered and concentrated to afford 2,4-dichloro-6-methoxyquinazoline (880 mg, 74%) as a yellow solid. MS Calcd.: 228 MS Found: 229 ([M+H]+).
69%
With trichlorophosphate; for 16h;Reflux;
A solution of 6-methoxyquinazoline- 2,4(lH,3H)-dione (5 g, 26.0 mmol) in trichloro phosphorus oxide (30 mL) was refluxed for 16 hours. After cooling down to ambient temperature, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2,4-dichloro-6-methoxyquinazoline as a yellow solid: MS (ESI, m/z): 229 A [M + 1]+; 1H MR (300 MHz, CDC13) delta 7.90 (d, J= 9.3 Hz, 1H), 7.61 (dd, J= 2.7 Hz, 6.6 Hz, 1H), 7.41 (d, J= 2.7 Hz, 1H), 4.00 (s, 3H).
28%
With N,N-diethylaniline; trichlorophosphate; for 6h;Reflux;
To a solution of 6-methoxyquinazoline-2,4(lH,3H)-dione (5.10 g, 26.6 mmol) in POCI3 (30 mL) was added N,N-diethylaniline (2.4 mL, 15.0 mmol). The mixture was refluxed for 6 hours. The excess POCI3 was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL), the organic layer was washed with sat.NaHCC>3 (30 mL), dried over Na2S04, filtered and concentrated to give the crude product which was purified by silica gel column (PE / EtOAc=20 / 1) to give the product (1.70 g, yield 28%).
3.6 g
With dimethyl amine; trichlorophosphate; at 110℃;
<Step 2> 2,4-dichloro-6-methoxyquinazoline N,N-dimethylamine (6.3 mL, 50 mmol) was added into a mixed solution of 6-methoxyquinazolin-2,4(1H,3H)-dione (4.8 g, 25.0 mmol) prepared in Step 1 in phosphorus oxychloride (50 mL), and then they were stirred at 110 C. overnight. After cooling to room temperature, the reaction mixture was added into ice water and then basified to pH 9 with sodium hydroxide. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=5/1) to give the titled compound (3.6 g) as a yellow solid.
4-(benzylamino)-2-chloro-6-methoxyquinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium acetate; In tetrahydrofuran; water; at 65℃;
One equivalent of the crude 2,4-dichloroquinazoline, 1.1 equivalents of sodium acetate, and 1.1 equivalents were combined in a round bottom flask and mixed with a three to one solution of tetrahydrofuran and water to afford a 0.1 M solution. The reaction was heated to 65 C. and monitored until no starting material was seen by TLC or LC-MS. The reaction was diluted with ethyl acetate and the organic layer separated. This organic layer was washed three times with equal amounts of water and then dried over sodium sulfate. The crude 4-amino-substituted-2-chloroquinazoline was then purified by column chromatography using hexane and ethyl acetate.
With phosphorus pentachloride; trichlorophosphate; for 9h;Reflux;
General procedure: Phosphorus pentachloride (12.5 g, 60.0 mmol) and phosphorus oxychloride (46.00 mL, 502.50 mmol) were sequentially added to a 250 mL of a single jar, and6-fluoroquinazolin-2, 4- (1H, 3H) -dione(3.60 g, 20.00 mmol) was slowly added under stirring. The reaction mixture was gradually warmed to reflux and reacted. After the reaction of 9 h, the reaction mixture was cooled, the solvent was removed in vacuo, and the residue was slowly poured into a mixture of ice and water (400 mL) . After being stirred for 0.5 h, the resulting mixture was extracted with dichloromethane (250 mL x 3) . The combined organic layers were concentrated. The residue was purified by silica gel column chromatography eluted with (petroleum ether/ethyl acetate (v/v) 30/1) to give the title compound (as a white solid, 3.74 g, 86) .
81.2%
With phosphorus pentachloride; trichlorophosphate; for 9h;Reflux;
General procedure: Step 2) Synthesis of 2, 4-dichloro-6-fluoroquinazoline To phosphorus oxychloride (46.0 mL, 502.5 mmol) was added phosphorous pentachloride (12.5 g, 60.0 mmol) , then 6-fluoroquinazoline-2, 4 (1H, 3H) -dione (3.6 g, 20.0 mmol) was added slowly with stirring. The reaction mixture was heated to reflux and stirred for 9 hours, and then cooled and the solvent was removed in vacuo. To an ice water mixture (400 mL) was added the residue, the mixture was stirred for 0.5 hour and extracted with DCM (250 mL ? 3) . The combined DCM layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography (PE/EtOAc (v/v) =30/1) to give the title compound as a white solid (3.735 g, 86.0 %) .MS (ESI, pos. ion) m/z: 216.9 [M+H] +; and1H NMR (CDCl3, 400 MHz) ? (ppm) : 8.03 (dd, J = 9.2 Hz, 4.9 Hz, 1H) , 7.86 (dd, J = 8.1 Hz, 2.7 Hz, 1H) , 7.79-7.73 (m, 1H) .
81.2%
With phosphorus pentachloride; trichlorophosphate; for 9h;Reflux;
General procedure: Phosphorus pentachloride (12.5g, 60.0mmol), phosphorous oxychloride (46.0mL, 502.5mmol) were added to a 250mL one-neck flask, was slowly added with stirring 6-fluoro-quinazoline -2,4 (1H, 3H) - dione (3.6g, 20.0mmol), the reaction was gradually warmed to reflux, the reaction is stopped after 9 hours, cooled, solvent was distilled off under reduced pressure, the residue was slowly poured into 400mL ice-water mixture. after stirring for 0.5 hours, extracted with dichloromethane (250mL × 3), combined dichloromethane layer was separated and purified directly by column chromatography on silica gel (petroleum ether / ethyl acetate (v / v) = 30/1) to give the title compound (white solid, 3.735g , 86.0%).
59%
General procedure: Using a procedure analogous to that reported by Zhong et al. (Heterocycles 2012, 85, 1417- 1426), a magnetically stirred solution of triphenylphosphine oxide (170 mg, 0.6 mmol) in chlorobenzene (5 mL) at 0 C was treated with triethylamine (400 pL). The solution was then treated dropwise with a solution of triphosgene (630 mg, 2.1 mmol) in chlorobenzene (6 mL) and stirring was continued at rt for 0.5 h. The mixture was then treated with 2-aminobenzonitrile (354 mg, 3 mmol) in one portion and heated at 120 C for 5 hr. The mixture was cooled and stirred for 18 h at rt then water was added and the mixture extracted with EtOAc (3 x 15 mL). The combined organic layers were dried (Na2S04) and concentrated in vacuo to afford a yellow solid which was subjected to flash column chromatography [silica, 1 : 10 v/v EtOAc/Pet spirit elution] to give, after concentration of the appropriate fractions the title compound (268 mg, 45%) as a white solid. Spectral data were consistent with those reported by Zhong et al (2012). 1H NMR (CDCI3, 400 MHz) delta 8.27 (d, J = 8.4 Hz, 1 H), 8.04 - 7.97 (m, 2H), 7.79 - 7.71 (m , 1 H); vmax 1670, 1668, 1616, 1434, 1404, 1290, 1 140, 753, 683 cm"1.
With trichlorophosphate; In N,N-dimethyl-aniline; for 3h;Reflux;
General procedure: 2,4-Dihydroxy-6-chloroquinazoline (M1) (16.0 g, 0.081 mol) was added to the reaction flask.Add phosphorus oxychloride (47 ml, 0.515 mol),N,N-dimethylaniline (31 ml, 0.243 mol) was added dropwise with stirring at room temperature for 3 hours under reflux.Stop heating,Pour into 500ml of ice water.Precipitating a brownish black solid,Filtering,dry,Column chromatography (petroleum ether - ethyl acetate) to give a pale yellow solid 8.74g, yield 46.2%.
in place of 1-(3,4-dimethoxyphenyl)-3-phenoxycarbonylurea, there is produced, respectively: ... (h) 2,4-dichloro-6,7-dimethylquinazoline, (i) 2,4-dichloro-6,7,8-trimethylquinazoline, (j) 2,4-dichloro-8- methoxyquinazoline, (k) 2,4-dichloro-7-methoxyquinazoline, (l) 2,4-dichloro-6-methoxyquinazoline, (m) 2,4-dichloro-7-n-butoxyquinazoline, (n) 2,4-dichloro-6-isopropoxyquinazoline, (o) 2,4-dichloro-6,8-dimethoxyquinazoline, ...
23
[ 105763-77-7 ]
[ 364385-54-6 ]
[ 364386-47-0 ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; water;
Step 1 (1R,2S)-N-tert-Butoxycarbonyl-2-(2-chloro-6-methoxyquinazolin-4-yl)aminocyclohexylamine A solution of 710 mg of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> in 20 mL of methylene chloride was combined with 471 mg of triethylamine and 750 mg of (1S,2R)-2-tert-butoxycarbonylaminocyclohexylamine, and stirred at room temperature for 48 hours. After concentrating, the mixture was combined with water, extracted with methylene chloride, and dried. After solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol 20:1) to obtain 1.20 g of the desirable compound.
2-chloro-6-methoxy-4-phenylamino-quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With aniline;
a) 2-Chloro-6-methoxy-4-phenylamino-quinazoline In a procedure analogous to that of Example 1a <strong>[105763-77-7]2,4-dichloro-6-methoxy-quinazoline</strong> (1.53 g) (prepared as described in J. Chem. Soc. 1948, 1759), aniline (0.8 g) (0.184 g) and N,N-diisopropyl-ethylamine (1.72 g) are reacted together to give 2-chloro-6-methoxy-4-phenylamino-quinazoline as light yellow crystals melting at 177-179 C., Rf (A2) 0.59.
EXAMPLE 86 2,4,6-Trimethoxyquinazoline STR120 5.0 g(0.022 mol) of <strong>[105763-77-7]2.4-dichloro-6-methoxyquinazoline</strong> was suspended in 150 ml of methanol, followed by the gradual addition of 3.5 g of sodium hydride. The obtained mixture was heated under reflux. After several hours, the reaction mixture was concentrate under a reduced pressure, followed by the addition of water. The crystalline precipitate thus formed was recovered by filtration, washed with water and air-dried to give 4.8 g of the title compounds as a crude yellow crystal. m.p.; 143~144; Mass; 221 (M+1)+; NMR delta (CDCl3); 3.90 (3H, s), 4.08 (3H, s), 4.18 (3H, s), 7.36 (1H, d, J=2.8 Hz), 7.39 (1H, dd, J=8.8 Hz, 2.8 Hz), 7.67 (1H, d, J=2.8 Hz).
In methanol; water;
Example 88 2,4,6-Trimethoxyquinazoline STR149 5.0 g (0.022 mol) of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> was suspended in 150 ml of methanol, followed by the gradual addition of 3.5 g of sodium hydride. The obtained mixture was heated under reflux. After several hours, the reaction mixture was concentrate under a reduced pressure, followed by the addition of water. The crystalline precipitate thus formed was recovered by filtration, washed with water and air-dried to give 4.8 g of the title compound as a crude yellow crystal. m.p.; 143~144 Mass; 221 (M+1)+ NMR delta (CDCl3); 3.90 (3H, s), 4.08 (3H, s), 4.18 (3H, s), 7.36 (1H, d, J=2.8Hz), 7.39 (1H, dd, J=8.8Hz, 2.8Hz), 7.67 (1H, d, J=2.8Hz)
B. 2,4-Dichloro-6-methoxyquinazoline 2,4-Dihydroxy-6-methoxyquinazoline (37 g, 0.19M), phosphoryl chloride (95 ml) and dimethylaniline (40 ml) were heated under reflux for 3 hours. After cooling the reaction mixture was poured onto ice and the precipitated solid was filtered off, washed with water and air dried. The product was used immediately in the next stage.
With N,N-dimethyl-aniline; trichlorophosphate; for 4h;Reflux;
Intermediate 50; 2,4-Dichloro-6-methoxyquinazoline 103496-1PA solution of 6-methoxyquinazoline-2,4-diol (Intermediate 51, 1.91 g, 9.94 mmol) and N,N- dimethylaniline (1.260 ml, 9.94 mmol) in POCl3 (13.90 ml, 149.09 mmol) was heated at reflux for 4 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure to give the title product. The title product was used in the subsequent step without any further purification. LCMS: 230 [M+H]+.
With 2,3-Dimethylaniline; trichlorophosphate;
B. 2,4-Dichloro-6-methoxyquinazoline 2,4-Dihydroxy-6-methoxyquinazoline (37 g, 0.19 M), phosphoryl chloride (95 ml) and dimethylaniline (40 ml) were heated under reflux for 3 hours. After cooling the reaction mixture was poured onto ice and the precipitated solid was filtered off, washed with water and air dried. The product was used immediately in the next stage.
b) 7.3 g (0.038 mol) of 5-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione were suspended in 52 ml (0.57 mol) of phosphorus oxychloride and heated to 105 C. for 18 hrs. The mixture was left to cool to room temperature, treated with toluene, cautiously poured on to ice-water and filtered over Dicalite. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated and the residue was chromatographed over silica gel with dichloromethane as the eluent. Yield: 8.0 g (92%) of 2,4-dichloro-6-methoxy-quinazoline as yellowish crystals; m.p. 175-177 C.
ethyl 2-hydroxy-6-methoxy-quinazolin-4-yl-carbazate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.0 g (31%)
In methanol; ice-water; dimethyl sulfoxide;
c) 4.8 g (0.046 mol) of ethyl carbazate were added to a solution of 8.0 g (0.035 mol) of <strong>[105763-77-7]2,4-dichloro-6-methoxy-quinazoline</strong> in 320 ml of dimethyl sulphoxide. The reaction mixture was stirred at 70 C. for 2 hrs. and then poured on to ice-water. The precipitate was filtered off under suction, washed with water and suspended in 50 ml of methanol. The suspension was suction filtered, rinsed with a small amount of methanol and dried in a vacuum. Yield: 3.0 g (31%) of ethyl 2-hydroxy-6-methoxy-quinazolin-4-yl-carbazate as white crystals; m.p. >350 C. MS: me/e (% base peak)=278 (C12 H14 N4 O4+, 7.5), 232 (100), 217 (19), 205 (7.5), 191 (9), 176 (30), 148 (22), 133 (26), 45 (25), 31 (43), 29(38).
Reference Example 7: Synthesis of 2-chloro-4,6-dimethoxyquinazoline A solution of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (0.33 g) in methanol (5 mL) was added sodium methoxide (0.086 g), and the mixture was stirred at room temperature for 6 h. Water was added to the reaction mixture, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol = 50:1) to obtain 2-chloro-4,6-dimethoxyquinazoline (0.20 g). LC/MS: ESI+ (m/z) 225 (M++1)
Reference Example 6: Synthesis of 2-chloro-6-methoxy-4-methylquinazoline To a mixed solution of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (CAS.105763-77-7) (0.15 g), iron (III) acetyl acetonate (0.023 g), N-methyl-2-pyrrolidinone (0.4 mL), and THF(8 mL) was added a solution (0.22 mL) of 3 M methyl magnesium chloride in THF at room temperature, and the mixture was stirred for 12 h. The reaction mixture was added dropwise to a mixture of ice (30 g) and ammonium chloride (0.3 g), and then the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform) and crystallized with diisopropyl ether to obtain 2-chloro-6-methoxy-4-methylquinazoline (0.08 g). LC/MS: ESI+ (m/z): 209 (M++1) 1H-NMR (300 MHz, CDCl3): delta7.93 (d, J=9.0 Hz, 1H), 7.36-7.42 (m, 2H), 3.97 (s, 3H), 2.69 (s, 3H)
With sodium acetate; In tetrahydrofuran; water; at 60 - 70℃; for 3h;
A mixture of <strong>[105763-77-7]2,4-dichloro-6-methoxy-quinazoline</strong> (0.5 g, 2.18 mmol), (4-methoxy-phenyl)-methyl-amine (0.35 g, 2.61 mmol) and sodium acetate (0.21 g, 2.61 mmol) in 8 mL of solvent (1:1 THF:water) was stirred at 60-70 C. for 3 h. The reaction mixture was concentrated and the resulting solid was dissolved in ethyl acetate and filtered through a pad of silica, washing with 40% ethyl acetate/hexane. The filtrate was concentrated under reduced pressure to give 0.7 g of the title compound (98% yield). 1H NMR (DMSO-d6) delta 7.6 (d, 1H), 7.36-7.31 (m, 3H), 7.08-7.05 (dd, 2H), 6.2 (d, 1H), 3.79 (s, 3H), 3.5 (s, 3H), 3.28 (s, 3H); LC-MS (ESI+; 330 ([M+H]+).
With N-ethyl-N,N-diisopropylamine; In ethanol; acetonitrile; at 70℃;
Intermediate 49; 2-Chloro-6-methoxy-iV-( 1 -methyl- lH-imidazol-4-yl)quinazolin-4-amineA mixture of l-methyl-4-nitro-lH-imidazole (Intermediate 1, 1895 mg, 14.91 mmol) and Pd on charcoal (200 mg, 1.88 mmol) in ethanol (12.2 ml) was placed under H2 for 3 hours. After filtration through diatomaceous earth (Celite brand), the filtrate was added to a solution of 2,4- dichloro-6-methoxyquinazoline (Intermediate 50, 2277 mg, 9.94 mmol) in MeCN (12.2 ml) and DIPEA (8680 mul, 49.70 mmol) and the resulting mixture stirred at 70 0C overnight. The reaction mixture was diluted with water and extracted with DCM/MeOH (10%). The title product (710 mg) was collected after filtration as white fluffy solid. LCMS: 291 [M+H]+.
With ammonia; zinc; In dichloromethane; water; at 40℃; for 4h;Inert atmosphere;
To a solution of 2,4-dichloro-6- methoxyquinazoline (3 g, 13.1 mmol) in dichloromethane (50 mL) were added zinc dust (2.57 g, 39.3 mmol), aqueous solution of ammonia (50 mL, 34% w/w) and brine (10 mL). The resulting mixture was stirred for 4 hours at 40 C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was filtered through Celite. The organic layer was collected and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford 2-chloro-6- methoxyquinazoline as a yellow solid: MS (ESI, m/z): 195.2 [M + 1]+; 1H MR (300 MHz, CDC13) delta 9.19 (s, 1H), 7.91 (d, J= 9.3 Hz, 1H), 7.61 (dd, J= 2.7 Hz, 6.6 Hz, 1H), 7.16 (d, J = 2.7 Hz, 1H), 3.96 (s, 3H).
68%
To a solution of 2,4- dichloro-6-methoxyquinazoline (400 mg, 1.75 mmol) in CH2C12 (10 mL) was added brine (10 mL) containing 9% NuEta32Omicron. Then zinc powder (336 mg, 5.25 mmol) was added and the mixture was refluxed for 2 hours. The mixture was diluted with CH2C12 (50 mL) and filtered off, the filtrate was neutralized by 2M HC1 to pH 7. The aqueous layer extracted with CH2C12 (20 mL x2), the combined organic layer washed with brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by silica gel column (PE / EtOAc=5 / 1) to give Intermediate 8 (232 mg, yield 68%). *H NMR (CDC13 300 MHz): delta 9.20 (s, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.40 (dd, J = 9.3, 2.7 Hz, 1H), 7.15 (d, J = 3.0 Hz, 1H), 3.95 (s, 3H).
24%
With ammonium hydroxide; sodium chloride; zinc; In dichloromethane; water; at 50℃; for 48h;
To a solution of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (880 mg, 3.8 mmol) in sat. NaCl (10 mL) and DCM (15 mL) was added NH4OH (4.5 mL) and Zn (750 mg, 11.5 mmol). The reaction mixture was stirred at 50 C for 2 days. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL*2). The combined organic layers were dried over Na2S04, filtered and (0611) concentrated. The residue was purified by silica gel chromatography (PE/EA, 5: 1) to afford 2- chloro-6-methoxyquinazoline (180 mg, 24%) as a yellow solid. 1H NMR (400 MHz, CDCI3): d 3.97 (s, 3H), 7.17 (d, J= 2.8 Hz, 1H), 7.60 (dd, 7= 3.2, 9.2 Hz 1H), 7.90 (d, J= 9.2 Hz, 1H), 9.20 (s, 1H).
A mixture of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (synthesis described in steps 1 and 2 of Intermediate 8) (900 mg, 3.93 mmol), MeZnCl (2.95 mL, 5.90 mmol, 2M in THF) and Pd(PPh3)4 (45.0 mg, 0.0393 mmol) in anhydrous THF (15 mL) was stirred at 60C under N2 atmosphere for 16 hours. After cooling to 25C, the mixture was quenched with saturated aqueous NH4C1 (30 mL), extracted with EtOAc (30 mL x3). The combined organic layers were washed with H20 (30 mL) and brine (30 mL), dried over anhydrous Na2S04i filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column (PE/EtOAc = 30/1 to 20/1) to give Intermediate 9 (370 mg, yield 45%). Structure was confirmed by NOE. *H NMR (CDC13 400 MHz): delta 7.88 (d, J = 9.2 Hz, 1H), 7.55 (dd, / = 9.2, 2.8 Hz, 1H), 7.23 (d, / = 2.8 Hz, 1H), 3.97 (s, 3H), 2.92 (s, 3H).
4-{2-[4-({tert-butoxycarbonyl-[3-(tert-butoxycarbonyl-cyclohexyl-amino)-propyl]-amino}-methyl)-benzylamino]-6-methoxy-quinazolin-4-ylamino}-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
N2-{1-[3-(3-cyclohexylaminopropylamino)propyl]-1H-[1,2,3]-triazol-4-ylmethyl}-6-methoxy-N4-piperidin-4-yl-quinazoline-2,4-di-amine hydrochloride salt[ No CAS ]
With sodium hydroxide; In tetrahydrofuran; water; at 40℃; for 2h;
Method M: 2-Chloro-6-methoxyquinazolin-4-ol (xi-a) A mixture of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (4.20 g, 18.5 mmol, 1.0 eq.) in THF (60 mL) and H2O (60 mL) was treated with NaOH (4.00 g, 100 mmol, 5.4 eq.). The resulting mixture was stirred at 40 C. for 2 h. The reaction color turned to dark green and then a precipitate formed. After the reaction was completed, the mixture was cooled to room temperature. The precipitate was filtered off and the filtrate was concentrated down to 60 mL. The pH was then adjusted to 6 by adding 2N HCl in water. The precipitate which formed was collected and dried in vacuo to give 4.00 g of 2-chloro-6-methoxyquinazolin-4-ol as a grey solid (98%). LCMS m/z=211.1, 213.0 (M+1) (Method B) (retention time=1.11 min)
98%
With sodium hydroxide; In tetrahydrofuran; water; at 40℃; for 2h;
THF (60 mL) and H2 O (60 mL)A mixture of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (4.20 g, 18.5 mmol, 1.0 eq)Was treated with NaOH (4.00 g, 100 mmol, 5.4 eq).The resulting mixture was stirred at 40 C. for 2 hours.The color of the reaction changed to dark green color, and a precipitate was formed. After the reaction was completed, the mixture was cooled to room temperature.The precipitate was filtered off and the filtrate was concentrated to 60 mL.The pH was then adjusted to 6 by adding an aqueous solution of 2 N HCl.The precipitate formed was collected and dried in vacuo to give 4.00 g of 2-chloro-6-methoxyquinazolin-4-ol as a gray solid (98%).
2-chloro-6-methoxy-N-((3-methylfuran-2-yl)methyl)quinazolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With triethylamine; In tetrahydrofuran; for 0.5h;Reflux;
General procedure: To a mixture of 2,4-dichloro-quinazoline 5a (0.459 g,2.31 mmol) in THF (7.7 mL), trimethylamine (Et3N) (0.39 mL,2.77 mmol) and furfuryl amine (0.24 mL, 2.77 mmol) was addeddrop-wise. The reaction was heated to reflux for 30 min. After coolingto rt, the reaction residue was extracted three times with CH2-Cl2 (30 mL), dried over MgSO4, concentrated under reducedpressure, and purified by column chromatography (EtOAc/n-Hex = 2:5) on silica gel to get the title product 6a in 92% yield(552 mg).
(S)-N-{1-(2-chloro-6-methoxyquinazolin-4-yl)pyrrolidin-3-yl}acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
360 mg
In ethanol; at 20℃;
<Step 3> (S)-N-{1-(2-chloro-6-methoxyquinazolin-4-yl)-pyrrolidin-3-yl}acetamide (3S)-(-)-3-acetamidopyrrolidine (419 mg, 3.27 mmol) was added into a reaction solution of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (500 mg, 2.18 mmol) prepared in Step 2 in ethanol (10 mL), and then the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give the titled compound (360 mg) as a yellow solid.
(S)-1-(2-chloro-6-methoxyquinazolin-4-yl)-N-ethylpyrrolidin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
420 mg
In ethanol; at 20℃;
Reference Example 8 (S)-1-(2-chloro-6-methoxy-quinazolin-4-yl)-N-ethylpyrrolidin-3-amine (3S)-(-)-3-(ethylamino)pyrrolidine (373 mg, 3.27 mmol) was added into a mixed solution of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (500 mg, 2.18 mmol) prepared in Step 2 of Reference Example 6 in ethanol (10 mL), and then the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give the titled compound (420 mg) as a pale yellow solid.
(R)-1-(2-chloro-6-methoxyquinazolin-4-yl)piperidin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
420 mg
With N,N-dimethylisopropyl amine; In ethanol; at 20℃;
<Step 1> (R)-1-(2-chloro-6-methoxyquinazolin-4-yl)-piperidin-3-amine (R)-3-aminopiperidine dihydrochloride (567 mg, 3.27 mmol) and N,N-dimethylisopropylamine (570 muL, 3.27 mmol) were added into a mixed solution of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (500 mg, 2.18 mmol) prepared in Step 2 of Reference Example 6 in ethanol (10 mL), and then the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (dichloromethane/methanol=20/1) to give the titled compound (420 mg) as a pale yellow solid.
(S)-1-(2-chloro-6-methoxyquinazolin-4-yl)-N-methylpyrrolidin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
400 mg
In ethanol; at 20℃;
Reference Example 7 (S)-1-(2-chloro-6-methoxy-quinazolin-4-yl)-N-methylpyrrolidin-3-amine (3S)-(-)-3-(methylamino)pyrrolidine (327 mg, 3.27 mmol) was added into a mixed solution of <strong>[105763-77-7]2,4-dichloro-6-methoxyquinazoline</strong> (500 mg, 2.18 mmol) prepared in Step 2 of Reference Example 6 in ethanol (10 mL), and then the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give the titled compound (400 mg) as a pale yellow solid.
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