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8-methylquinazoline-2,4(1H,3H)-dione (4.50 g, 25.50 mmol) was added to a mixture of phosphorus oxychloride (47.6 mL, 510.9 mmol). The resulting mixture was stirred at 100 °C for 6 hours before it was allowed to cool to ambient temperature. The mixture was slowly poured into water (300 mL) at 40 °C maintaining the internal temperature below 60 °C. Aprecipitate was formed and collected by filtration to provide 2,4-dichloro-8-methylquinazoline (4.30 g, 79percent).
78%
for 3 h; Reflux
General procedure: Quinazolin-2,4(1H,3H)-dione (10 g, 61.7 mmol), DIPEA (22.6 ml, 129 mmol) and POCl3 (4.0 ml) were heated at reflux. After 3 hours the reaction mixture was cautiously poured over crushed ice and stirred vigorously. This aqueous mixture was extracted with CH2Cl2 DCM and the combined organic layers were washed with brine and dried over Na2SO4. Evaporation of the solvent gave a crystalline solid that was dissolved in CH2Cl2 after which it was filtered over a pad of silica using CH2Cl2 as eluent. Removal of the organic phase gave the product as 10.80 g (54.3 mmol, 88percent) of a white solid.
5.28 g
With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline for 4 h; Reflux
<Step 2> 2,4-dichloro-8-methylquinazoline A mixture of 8-methylquinazoline-2,4(1H,3H)-dione (4.88 g, 27.7 mmol) prepared in Step 1, N,N-dimethylaniline (2.8 ml, 22.2 mmol) and phosphorus oxychloride (28 ml) was stirred at reflux for 4 hours. After cooling the reaction mixture to room temperature, the reaction mixture was added into ice water. The resulting solid was filtered, washed with water, and dried in vacuo to give the titled compound (5.28 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H), 7.83 (d, 1H), 7.62 (t, 1H), 2.75 (s, 3H).
Reference：
[1] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 3, p. 254 - 259
[2] Patent: US5064833, 1991, A,
[3] Patent: EP322133, 1991, B1,
[4] Patent: EP322133, 1989, A1,
[5] Synthesis (Germany), 2016, vol. 48, # 8, p. 1226 - 1234
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 461 - 467
[7] Chemische Berichte, 1907, vol. 40, p. 4413
[8] Journal of Medicinal Chemistry, 1995, vol. 38, # 14, p. 2763 - 2773
[9] Patent: EP2226315, 2010, A1, . Location in patent: Page/Page column 17-18
[10] Journal of Medicinal Chemistry, 2011, vol. 54, # 17, p. 6028 - 6039
[11] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
[12] Patent: US2016/90374, 2016, A1, . Location in patent: Paragraph 0172; 0173
[13] Patent: US2016/168140, 2016, A1, . Location in patent: Paragraph 0985
B. Preparation of 2,4-dichloro-8-methylquinazoline Substituting 8-methyl-2,4-quinazolinedione (4.0 g, 0.023 mol) for 8-methoxy-2,4-quinazolinedione and using corresponding molar proportions of the other reagents in Example 1C, gave 2,4-dichloro-8-methylquinazoline (4.12 g, 84%), m.p. 180-230 which was used without further purification.
84%
B. Preparation of 2,4-dichloro-8-methylquinazoline Substituting 8-methyl-2,4-quinazolinedione (4.0 g, 0.023 mol) for 8-methoxy-2,4-quinazolinedione and using corresponding molar proportions of the other reagents in Example 1C, gave 2,4-dichloro-8-methylquinazoline (4.12 g, 84%), m.p. 180-230C which was used without further purification.
79%
With trichlorophosphate; at 100℃; for 6h;
8-methylquinazoline-2,4(1H,3H)-dione (4.50 g, 25.50 mmol) was added to a mixture of phosphorus oxychloride (47.6 mL, 510.9 mmol). The resulting mixture was stirred at 100 C for 6 hours before it was allowed to cool to ambient temperature. The mixture was slowly poured into water (300 mL) at 40 C maintaining the internal temperature below 60 C. Aprecipitate was formed and collected by filtration to provide 2,4-dichloro-8-methylquinazoline (4.30 g, 79%).
78%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; for 3h;Reflux;
General procedure: Quinazolin-2,4(1H,3H)-dione (10 g, 61.7 mmol), DIPEA (22.6 ml, 129 mmol) and POCl3 (4.0 ml) were heated at reflux. After 3 hours the reaction mixture was cautiously poured over crushed ice and stirred vigorously. This aqueous mixture was extracted with CH2Cl2 DCM and the combined organic layers were washed with brine and dried over Na2SO4. Evaporation of the solvent gave a crystalline solid that was dissolved in CH2Cl2 after which it was filtered over a pad of silica using CH2Cl2 as eluent. Removal of the organic phase gave the product as 10.80 g (54.3 mmol, 88%) of a white solid.
With N,N-dimethyl-aniline; trichlorophosphate; at 115℃; for 3.5h;
Second Step A mixture of the product (3.11 g, 17.65 mmol) of the first step, N,N-dimethylaniline (1.8 mL) and POCl3 (18 mL) was stirred at 115C for 3.5 hours. After cooling to room temperature, the reaction mixture was added to ice water (50 mL) and the precipitated solid was collected by filtration, washed with water and then dried to obtain 3.25 g of 2,4-dichloro-8-methylquinazoline (VII)-A which is a kind of the compound (VII) in Scheme 2. [Show Image] 1H-NMR (CDCl3) d (ppm): 2.75 (s, 3H), 7.61 (t, 1H, J = 7.8 Hz), 7.82 (d, 1H, J = 7.8 Hz), 8.10 (d, 1H, J = 7.8 Hz).
5.28 g
With trichlorophosphate; In N,N-dimethyl-aniline; for 4h;Reflux;
<Step 2> 2,4-dichloro-8-methylquinazoline A mixture of 8-methylquinazoline-2,4(1H,3H)-dione (4.88 g, 27.7 mmol) prepared in Step 1, N,N-dimethylaniline (2.8 ml, 22.2 mmol) and phosphorus oxychloride (28 ml) was stirred at reflux for 4 hours. After cooling the reaction mixture to room temperature, the reaction mixture was added into ice water. The resulting solid was filtered, washed with water, and dried in vacuo to give the titled compound (5.28 g) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.12 (d, 1H), 7.83 (d, 1H), 7.62 (t, 1H), 2.75 (s, 3H).
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; for 5h;Inert atmosphere; Reflux;
(0985) A 50 mL round bottom flask with a reflux condenser and stir bar was charged with 14 (1.0 g, 5.7 mmol, 1 eq). The flask was evacuated and back-filled with Ar (×3). POCl3 (2.6 mL, 4.35 g, 28.3 mmol, 5 eq) was added followed by DIPEA (2.0 mL, 1.47 g, 11.3 mmol, 2 eq). The resulting mixture was heated to reflux with stirring. After 5 h the reaction was cooled to room temperature and poured onto ice with vigorous stirring. The resulting suspension was cooled to 0 C. and adjusted to pH?7-8 with NH4OH (aq, concentrated). The solids were collected via vacuum filtration. The solids were suspended in DCM and plug filtered through silica gel, eluting with DCM. The filtrate was concentrated to dryness via rotary evaporation yielding 0.467 g (2.19 mmol, 38% yield) of 15 as a white solid.
With triethylamine; In chloroform; at 20℃; for 1h;
To a stirred solution of 4-nitrobenzylamine hydrochloride (832 mg, 4.41 mmol) and triethylamine (ImL) in CHCl3 (5 mL ) at rt was added 8-methyl-2,4- dichloroquinazoline (850 mg, 4.01 mmol). TLC showed the complete disappearance of the 2,4-dichloroquinazoline after two hours, and a white solid precipitated. Water (15 mL) was added and the solid was collected by filtration and washed with water (0.5 mL). After drying over night at 50 CZ 14 mbar the 2-Chloro-8-methyl-quinazolin-4-yl)-(4-nitro-benzyl)-amine (900mg, yield 68%) was obtained as white solid. MS (ESI) mZz 329 (is taken forward without further purification).
With ammonia; zinc; In dichloromethane; water; for 5h;Reflux;
Third Step To a two-phase solution of a CH2Cl2 solution (25 mL) of the product (3.25 g, 15.26 mmol) of the second step and an aqueous 9% ammonia-containing saturated brine solution (25 mL), a zinc powder (3.25 g) was added, followed by reflux for 5 hours. The reaction mixture was filtered through cerite and then the CH2Cl2 layer was distilled off under reduced pressure. To the resulting aqueous layer residue, ethyl acetate was added and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:5 to 2:7) to obtain 1.71 g of 2-chloro-8-methylquinazoline (III)-A, which is a kind of the compound (III) in Schemes 1 and 2, as a pale yellow powder. [Show Image] 1H-NMR (CDCl3) d (ppm): 2.75 (s, 3H), 7.57 (t, 1H, J = 7.8 Hz), 7.75-7.80 (m, 2H), 9.25 (s, 1H).
<strong>[39576-83-5]2,4-dichloro-8-methylquinazoline</strong> (400 mg, 1.88 mmol) was dissolved in EtOAc (10 ml) after which N-methylpiperazine (0,23 ml, 2.07 mmol) was added dropwise. The mixture was stirred until TLC indicated complete conversion (typically 20 min). After completion the mixture was washed twice with a 1 N NaOH solution and once with brine. After drying over Na2SO4 the solvent was removed and the residual solid was filtered over a short pad of silica using dichloromethane/methanol as solvent. Removal of the solvent yielded 466 mg (97%) of the product as a yellow solid. 1H-NMR (CDCl3) delta (ppm) 7.63 (b, J= 8.4 Hz, 1H), 7.51 (d, J= 7.2 Hz, 1H), 7.27-7.23 (m, 1H), 3.80 (t, J= 4.9 Hz, 4H), 2.61 (s, 3H), 2.55 (t, J= 4.9 Hz, 4H), 2.32 (s, 3H).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 65℃; for 3h;
Step A: N'-(2-Chloro-8-methylquinazolin-4-yn-2-hydroxyacetohydrazide [0191] To a mixture of <strong>[39576-83-5]2,4-dichloro-8-methylquinazoline</strong> (640 mg, 3.00 mmol) and 2- hydroxyacetohydrazide (284 mg, 3 15 mmol), was added 10 mL of THF, followed by diisopropylethylamine (0.745 ml, 4.51 mmol). The reaction was then heated at 65 C for 3 h. It was cooled to RT and was diluted with 10 mL of CH2C12. The resulting mixture was stirred at RT for 30 min. The solid was collected by filtration and washed with CH2C12 to give the title compound. NMR (400 MHz, DMSO) delta 10.41 (brs, 1H), 10.09 (s, 1H), 8.08-8.12 (m, 1H), 7.68-7.72 (m, 1H), 7.41 -7.47 (m, 1H), 5.60-5.66 (m, 1H), 4.02 (d, 2H), 2.50 (s, 3H).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 65℃; for 3h;
To a mixture of <strong>[39576-83-5]2,4-dichloro-8-methylquinazoline</strong> (640 mg, 3.00 mmol) and 2- hydroxyacetohydrazide (284 rng, 3.15 mmol), was added 10 rnL of THF, followed by diisopropylethylamine (0.745 ml, 4.51 mmol). The reaction was then heated at 65C for 3 h. It was cooled to RT and was diluted with 10 mL of CH2C12. The resulting mixture was stirred at RT for 30 mm. The solid was collected by filtration and washed with CH2C12 to give the title compound. 1H NMR (400 MHz, DMSO) oe 10.41 (brs, 111), 10.09 (s, 1H), 8.08-8.12 (m, 1H), 7.68-7.72 (m, 1H), 7.41-7.47 (m, 1H), 5.60-5.66 (m, 1H), 4.02 (d, 2H), 2.50 (s, 3H).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 65℃; for 3h;
To a mixture of <strong>[39576-83-5]2,4-dichloro-8-methylquinazoline</strong> (640 mg, 3.00 mmol) and 2- hydroxyacetohydrazide (284 mg, 3.15 mmol), was added 10 mL of THF, followed by diisopropylethylamine (0.745 ml, 4.51 mmol). The reaction was then heated at 65C for 3 h. It was cooled to RT and was diluted with 10 mL of CH2CI2. The resulting mixture was stirred at RT for 30 min. The solid was collected by filtration and washed with CH2CI2 to give the title compound. H NMR (400 MHz, DMSO) delta 10.41 (brs, 1H), 10.09 (s, 1H), 8.08-8.12 (m, 1H), 7.68-7.72 (m, 1H), 7.41-7.47 (m, 1H), 5.60-5.66 (m, 1H), 4.02 (d, 2H), 2.50 (s, 3H).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In ethyl acetate; at 20 - 65℃;Inert atmosphere; Reflux;
N-Bromosuccinimide (2.44 mL, 28.72 mmol) and AIBN (0.786 g, 4.79 mmol) were added portionwise to a suspension of <strong>[39576-83-5]2,4-dichloro-8-methylquinazoline</strong> (5.10 g, 23.94 mmol) in degassed EtOAc (40 mL) at 65 C under nitrogen. The resulting solution was stirred at reflux for 2 hours 15 mins and at ambient temperature overnight. The mixture was concentrated to provide an orange solid. The solid was triturated with MeOH (25 mL) and filtered to afford 8-(bromomethyl)-2,4-dichloroquinazoline (5.47 g, 78%) as a pale yellow crystalline solid.
With sodium hydroxide; In tetrahydrofuran; for 2h;
(0986) A 100 mL round bottom flask with stir bar was charged with 15 (0.367 g, 1.72 mmol, 1 eq). THF (8 mL) was added. The resulting stirred solution was treated with 1N NaOH (4 mL, 4 mmol, 2.3 eq). After 2 h the volatiles were removed via rotary evaporation. The resulting mixture was adjusted to pH?7 with 1N HCl. The solids were collected via vacuum filtration and air dried. 0.282 g (1.45 mmol, 84% yield) of 16 was isolated as a white solid. Mass spectrum (ESI+): m/z=195 [M+1].
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