* 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.
2-Amino-3-methylbenzoic acid (100 g, 0.66 mol), formamidine acetate (206 g, 1 .98 mol) and formamide (26 mL, 0.6600 mol) were mixed in a 2L R.B fitted with Mechanical stirrer. The reaction mixture was heated at 160 °C for 16h. The reaction completion was monitored by LCMS. After completion, the reaction mixture was cooled to was RT and diluted with 2N NaOH solution (300 mL). After stirring at the same temperature for 15min, the reaction mixture neutralised with 1.5N HCI solution. The solid precipitated was filtered off, washed with ice cold water and dried under vacuum to yield (90 g, 86percent yield) of the titled compound as an off white solid. H NMR (DMSO-d6, 400MHz) δ 12.21 ( bs, 1 H), 8.10 (s, 1 H), 7.95-7.93 (dd, J = 8.8, 7.9 Hz, 1 H), 7.65-7.63 (d, J = 7.9 Hz, 1 H), 7.39-7.35 (t, J = 15.2 Hz, 1 H), 2.51 (s, 3H).
78%
at 140℃;
General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 °C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2*2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 .x. 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 .x. 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
Reference：
[1] Patent: WO2013/96194, 2013, A1, . Location in patent: Page/Page column 28-29
[2] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2794 - 2809
[4] Chemische Berichte, 1905, vol. 38, p. 3555
[5] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153
[6] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 8, p. 1203 - 1207
[7] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 662 - 669
[8] Medicinal Chemistry Research, 2014, vol. 23, # 5, p. 2584 - 2595
[9] Journal of Agricultural and Food Chemistry, 2014, vol. 62, # 36, p. 8928 - 8934
[10] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
2
[ 4389-45-1 ]
[ 3473-63-0 ]
[ 77287-34-4 ]
[ 19181-54-5 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 180℃; for 3 h;
2-Amino-3-methylbenzoic acid (125 g, 0.820 mol), formamidine acetate (257 g, 2.46 mol) and formamide (32.5 mL, 0.8200 mol) wereminxed in a 2L R.B fitted with Mechanical stirrer. The reactionminxture was heated at 180 °C for 3h. The reaction completion was monitored by LCMS. After completion, the reactionminxture was cooled to RT and diluted with 2N NaOH solution (300 mL). After stirring at the same temperature for 15 min, the reactionminxture neutralized with 1 .5N HC1 solution. The solid precipitated was filtered off, washed with ice cold water and dried under vacuum to yield 8-methyl-3H-quinazolin-4-one (125 g, 94percent) as an off white solid. 1H NMR (400 MHz, DMSO-d6, ppm) 12.2 (bs, 1H), 8.1 (s, 1H), 8.0 (d, J = 7.8 Hz, 1H), 7.7 (d, J = 7.2 Hz, 1H), 7.4 (t, J = 7.6 Hz, 1H), 2.5 (s, 3H); LC/MS(ESI)161 (M+H).
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 17, p. 6089 - 6099
7
[ 18503-89-4 ]
[ 1885-32-1 ]
[ 19181-54-5 ]
[ 1332493-28-3 ]
[ 1332493-36-3 ]
[ 1332493-35-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 17, p. 6089 - 6099
8
[ 58421-80-0 ]
[ 19181-54-5 ]
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 3561
9
[ 5437-38-7 ]
[ 19181-54-5 ]
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 3555
10
[ 620-22-4 ]
[ 19181-54-5 ]
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 3555
11
[ 99-04-7 ]
[ 19181-54-5 ]
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 3555
12
[ 19181-54-5 ]
[ 58421-80-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
at 120℃; for 12 h; Inert atmosphere
Phosphorous oxychloride (800 mL) was taken in a 2 L round bottom flask under nitrogen. To this was added 8-Methylquinazolin-4(3H)-one (125 g) in portions. The reactionminxture refluxed at 120 °C for 12h. Reaction completion was monitored by TLC and LCMS. After completion, the reactionminxture was cooled to RT and evaporated to dryness under reduced pressure. The resulted residue was dissolved in DCM (500 mL) and quenched slowly into an ice cold solution of saturated K2C03 with constant stirring. Then the organic layer was separated and washed with brine solution, dried over sodium sulfate and concentrated under vacuum to afford 4-chloro-8-methylquinazoline (120 g, 86percent) as yellow solid. This was taken for next step without further purification. MS: m/z = 179/18 1 [M+Hj.
35%
With trichlorophosphate In acetonitrileReflux
b. Preparation of Compound 12b To a solution of 8-methylquinazolin-4(3H)-one 12a (1.1 g, 6.92 mmol) in 155 ml ACN was added 10.1 mL POCl3. The reaction mixture is refluxed until completion, cooled to room temperature. The solvent was removed under vacuum, and the crude product was purified in ISCO using Ethyl acetate: hexane solvent system to afford the pure product (430 mg, 35percent yield). 1H NMR (CDC13, 400 MHz) δ 9.06 (s, 1H), 8.12 (d, J= 8.4 Hz, 1H), 7.80 (d, J = 6.9 Hz, 1H), 7.61 (m, 1H), 2.78 (s, 3H).
35%
With trichlorophosphate In acetonitrileReflux
To a solution of 8-methylquinazolin-4(3H)-one 12a (1.1 g, 6.92 mmol) in 155 ml ACN was added 10.1 mE P0C13. The reaction mixture is refluxed until completion, cooled to room temperature. The solvent was removed under vacuum, and the crude product was purified in ISCO using Ethyl acetate:hexane solvent system to afford the pure product (430 mg, 35percent yield). 1H NMR (CDCl3, 400 MHz) ö 9.06 (s, 1-H), 8.12 (d, J=8.4 Hz, 1H), 7.80 (d, J=6.9 Hz, 1-H), 7.61 (m, 1H), 2.78 (s, 3H).
Reference：
[1] Patent: WO2017/106607, 2017, A1, . Location in patent: Paragraph 00224
[2] Synthetic Communications, 2011, vol. 41, # 24, p. 3644 - 3653
[3] Patent: WO2013/106756, 2013, A2, . Location in patent: Page/Page column 40
[4] Patent: US9822108, 2017, B2, . Location in patent: Page/Page column 42
[5] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 8, p. 1203 - 1207
[6] Organic Letters, 2010, vol. 12, # 3, p. 552 - 555
[7] Patent: WO2013/96194, 2013, A1, . Location in patent: Page/Page column 29
[8] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 662 - 669
[9] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4968 - 4974
[10] Medicinal Chemistry Research, 2014, vol. 23, # 5, p. 2584 - 2595
[11] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4885 - 4888
[12] Bioorganic Chemistry, 2018, vol. 80, p. 433 - 443
Step A Preparation of 8-methylquinazolin-4(3H)-one 2-Amino-3-methylbenzoic acid (1.00 g, 0.0066 mol) and formamide (12 mL) were heated together at 130 C. for 20 hr. under nitrogen. After cooling to room temperature, the solid was filtered off, washed with diethyl ether and dried in vacuo to leave 8-methylquinazolin-4(3H)-one (1.19 g). 1 H-NMR 400 MHz (CD3 OD): delta 8.06 (m, 2H), 7.68 (d, 1H), 7.41 (t, 1H), 2.59 (s, 3H); EI-MS 160 (M+).
With 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphorine; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 20h;Inert atmosphere;
General procedure: Quinazolin-4(3H)-ones (3, 0.5 mmol), HCCP (173.9 mg, 0.5 mmol, 1 equiv), DIPEA (323.8 mg, 2.5 mmol, 5 equiv), and MeCN (2 mL) were added to a nitrogen purged vial. The reaction mixture was stirred at room temperature for 1 h as activation time. The reactions were monitored by TLC. Then N-containing nucleophile (3.0 mmol, 6 equiv) was added, and the reaction mixture was stirred at room temperature for an appropriate time. After the mixture was concentrated under reduced pressure, the residue was purified by chromatography on silica gel to afford the corresponding products 4-aminoquinazolines (4-29).
tert-butyl 4-hydroxy-4-((8-methyl-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
To a solution of <strong>[19181-54-5]8-methylquinazolin-4(3H)-one</strong> (20 mg, 0.125 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (33 mg, 0.156 mmol) in DMF (0.625 mL) was added cesium carbonate (122 mg, 0.375 mmol). The reaction mixture was stirred at 80 C. for 16 h, then cooled to room temperature, diluted with ethyl acetate (0.5 mL) and washed with water (0.5 mL). The organic layer was concentrated under reduced pressure to afford tert-butyl 4-hydroxy-4-((8-methyl-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate, which was used without further purification. LCMS: (ESI) m/z 396.29 [M+Na].
2-Amino-3-methylbenzoic acid (125 g, 0.820 mol), formamidine acetate (257 g, 2.46 mol) and formamide (32.5 mL, 0.8200 mol) wereminxed in a 2L R.B fitted with Mechanical stirrer. The reactionminxture was heated at 180 C for 3h. The reaction completion was monitored by LCMS. After completion, the reactionminxture was cooled to RT and diluted with 2N NaOH solution (300 mL). After stirring at the same temperature for 15 min, the reactionminxture neutralized with 1 .5N HC1 solution. The solid precipitated was filtered off, washed with ice cold water and dried under vacuum to yield 8-methyl-3H-quinazolin-4-one (125 g, 94%) as an off white solid. 1H NMR (400 MHz, DMSO-d6, ppm) 12.2 (bs, 1H), 8.1 (s, 1H), 8.0 (d, J = 7.8 Hz, 1H), 7.7 (d, J = 7.2 Hz, 1H), 7.4 (t, J = 7.6 Hz, 1H), 2.5 (s, 3H); LC/MS(ESI)161 (M+H).
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