* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 16, p. 5337 - 5348
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 18, p. 3869 - 3878
[3] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[4] Patent: WO2014/89546, 2014, A1,
[5] Chinese Journal of Chemistry, 2014, vol. 32, # 6, p. 538 - 544
[6] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1933 - 1935
[7] Asian Journal of Chemistry, 2016, vol. 28, # 1, p. 95 - 98
[8] Patent: CN103382182, 2016, B,
[9] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 393 - 405
[10] Patent: CN106432205, 2017, A,
[11] Patent: CN106083836, 2016, A,
2
[ 616-79-5 ]
[ 17329-31-6 ]
Reference：
[1] Tetrahedron Letters, 2003, vol. 44, # 24, p. 4455 - 4458
[2] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
3
[ 77287-34-4 ]
[ 616-79-5 ]
[ 6943-17-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 170℃; for 4 h;
(1-1) Preparation of 6-nitro-3H-quinazolin-4-one150 g of 2-amino-5-nitro-benzoylic acid was added to 200 ml of formamide, the resulting solution was heated to 170 °C for 4 hours, and cooled to 100°C . 500 ml of ice water was added thereto, stirred for 1 hour, and the resulting mixture was filtered under a reduced pressure. The resulting residue was washed with water to obtain a solid, which was dried at 40 °C for 15 hours to obtain the title compound of formula (14O g, 90percent).1H-NMR (DMSO-d6, 300MHz): δ 8.77 (d, J=2.7 Hz, IH), 8.55 (dd, J-6.9 Hz, IH), 8.36 (s, IH), 7.84 (d, J=9 Hz, IH).
87%
at 120 - 125℃; for 4 h; Heating / reflux
A solution of 18.2 g of compound 6a (100 mmol) in 76.5 g (64 ml) of formamide (1.7 mol) was heated under reflux for 4 hrs at 120125° C. Solvent was removed under reduced pressure and the crude solid was recrystallized from ethyl alcohol to give 12.7 g of compound 7a (yield, 87 percent). 1H-NMR (300 MHz, d6-DMSO): δ 8.13 (m, 2H), 7.84 (m, 1H), 7.68 (m, 1H), 7.55 (m, 1H).
79%
at 150℃; for 1 h;
Intermediate 5: 6-aminoquinazolin-4(3H)-oneIntermediate 5A: [00200] In a 2 mL microwave vial was placed formamide (1.5 mL, 37.8 mmol) and 5-nitroanthranilic acid (917 mg, 5.04 mmol) to give a yellow suspension. The mixture was heated under microwave at 150 0C for 60 min. The mixture was diluted with EtOAc (1 L) and washed with NaHCO3 (Sat. 200 mL) and brine (200 mL). The organic layer was dried by MgSO4 and concentrated to yield Intermediate 5A (760 mg, 79percent yield). 1H NMR (400 MHz, DMSO-d6) d ppm 7.85 (d, J=8.79 Hz, 1 H) 8.31 (s, 1 H) 8.54 (dd, J=9.23, 2.64 Hz, 1 H) 8.79 (d, J=2.64 Hz, 1 H) 12.77 (s, 1 H).
79%
at 150℃; for 1 h; Microwave irradiation
Intermediate 4: 6-aminoquinazolin-4(3H)-one; Intermediate 4A: [00200] In a 2 mL microwave vial was placed formamide (1.5 mL, 37.8 mmol) and 5-nitroanthranilic acid (917 mg, 5.04 mmol) to give a yellow suspension. The mixture was heated under microwave at 150 0C for 60 min. The mixture was diluted with EtOAc (IL) and washed with NaHCO3 (Sat. 200 mL) and brine (200 mL). The organic layer was dried by MgSO4 and concentrated to yield Intermediate 4A (760 mg, 79percent yield).
79%
at 180℃; for 1.5 h;
[00165] A. 2246-5 gr 5-nitro anthranilic acid and 15 ml formamide were heated at 180° 1.5 hours. Water was added to the cooled solution and the solid filtered, washed with water and dried to give 4.1 gr, 79percent yield, light-yellow solid. NMR DMSO d6 [8] 8.80 [(LH,] d, J=2.6 Hz, H5), 8.54 [(LH,] dd, J=9.0, 2.6 Hz, [H7),] 8.32 [(LH,] s, [H2),] 7. 86 [(LH,] d, J=9.0 Hz, H8).
72%
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.
55%
at 90 - 95℃;
2.55 g (0.014 mol) of 2-amino-5-nitrobenzoic acid (IV) were added to 15 mL of formamide,Stirred at 90 & lt; 0 & gt; C until dissolved,The temperature was controlled at 90-95 ° C and 5 mL of phosphorus oxychloride was slowly added dropwise with vigorous stirring.After completion of the dropwise addition, stirring was continued for 20 min,Cool to room temperature and pour into cold water.After the precipitate is completely precipitated, it is filtered, dried in vacuo,To give the object compound (Va) in a yield of 55percent
51.6%
at 120℃; for 16 h;
2-Amino-5-nitrobenzoic acid(7.28 g, 40.0 mmol) was added to 60 mL of formamide, heated to 120 ° C, incubated for 16 h, cooled to room temperature, precipitated a solid, filtered, washed with isopropanol and dried to give 6-nitro-3H -quinolineOne was obtained in a yield of 51.6percent.
Reference：
[1] Patent: WO2006/71017, 2006, A1, . Location in patent: Page/Page column 34
[2] Tetrahedron Letters, 2002, vol. 43, # 21, p. 3911 - 3913
[3] Tetrahedron Letters, 2003, vol. 44, # 24, p. 4455 - 4458
[4] Patent: US2005/187231, 2005, A1, . Location in patent: Page/Page column 14
[5] Tetrahedron, 2013, vol. 69, # 15, p. 3182 - 3191
[6] Patent: WO2008/79759, 2008, A1, . Location in patent: Page/Page column 90
[7] Patent: WO2008/79836, 2008, A2, . Location in patent: Page/Page column 89
[8] Patent: WO2004/13091, 2004, A2, . Location in patent: Page 64
[9] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
[10] Patent: CN106146410, 2016, A, . Location in patent: Paragraph 0027; 0028
[11] Patent: CN103382182, 2016, B, . Location in patent: Paragraph 0329; 0331-0333
[12] Journal of the American Chemical Society, 1919, vol. 41, p. 2061
[13] Journal of Medicinal Chemistry, 2005, vol. 48, # 16, p. 5337 - 5348
[14] Patent: US6339099, 2002, B1, . Location in patent: Page column 43, 44
[15] Patent: US2005/191238, 2005, A1, . Location in patent: Page/Page column 61
[16] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6880 - 6888
[17] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1933 - 1935
4
[ 3473-63-0 ]
[ 616-79-5 ]
[ 6943-17-5 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 124℃; for 1 h; Microwave irradiation
A mixture of 2-amino-5-nitrobenzoic acid (36.9 g, 0.203 mol) and formamidine acetate (42.5 g, 0.360 mol) in ethylene glycol monomethyl ether (150mL) was heated under reflux for 30 h, or the reaction vessel was open and heated under microwave irradiation for 1 h at 124 °C. After completion of the reaction, the excess ethyleneglycol monomethyl ether was removed by vacuo. The residue was washed by 0.01 M ammonia water to give compound (2) [78 percent thermal, 92 percent microwave], m.p.: 283 °C [Lit. m.p.: 283-285 °C]
78.5%
Reflux
To a 100 mL three-necked flask was added 2-amino-5-nitrobenzoic acid (3.64 g, 20 mmol)Acetamidine acetate (4.16 g, 40 mmol)50 mL of ethylene glycol monomethyl ether,Reflux reaction.TLC monitoring, after the reaction, the reaction solution into the beaker,Set at -20 freezer overnight, filtered yellow solid 3.0g,Yield 78.5percent
Reference：
[1] Asian Journal of Chemistry, 2016, vol. 28, # 1, p. 95 - 98
[2] Patent: CN106083836, 2016, A, . Location in patent: Paragraph 0178; 0179; 0180
[3] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 393 - 405
5
[ 6313-33-3 ]
[ 616-79-5 ]
[ 6943-17-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3860 - 3873
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 11, p. 3235 - 3239
6
[ 616-79-5 ]
[ 6943-17-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 18, p. 3869 - 3878
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
7
[ 616-79-5 ]
[ 74173-77-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 9, p. 2797 - 2807
[2] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 75 - 80
[3] Patent: WO2015/200534, , A2, [3] Patent: , 2015, ,
[5] Patent: CN102250075, 2016, B,
[6] Patent: WO2018/114700, 2018, A1,
8
[ 57-13-6 ]
[ 616-79-5 ]
[ 74173-77-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2755 - 2766
9
[ 57-13-6 ]
[ 616-79-5 ]
[ 32618-85-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 200℃; for 2 h; Inert atmosphere
[00413] A mixture of 2-amino-5-nitrobenzoic acid (20 g, 109.8 mmol) and urea (33 g, 549.1 mmol) was heated at 200 °C for 2 hours. The resulting mixture was washed with water, and the resulting solid was filtered and dried to give 6-nitroquinazoline-2,4(lH,3H)-dione (26 g, quantitative) as a yellow solid.
99%
at 100 - 160℃;
(Step 1) (0753) A mixture of 2-amino-5-nitro-benzoic acid (30 g, 164.71 mmol) and urea (99 g, 1647.14 mmol) was stirred overnight at 160°C. The reaction mixture was cooled to 100°C, and water (300 mL) was added thereto. The resulting precipitate was washed successively with water, acetic acid (50 mL) and methanol (100 mL), and dried to give 6-nitroquinazoline-2,4(1H,3H)-dione (33.8 g, 163 mmol, 99percent) as a yellow solid. 1H-NMR (300MHz, DMSO-d6):δ7.32(1H,d,J=9.1Hz),8.45(1H,dd,J=9.1,2.6Hz),8.58(1H,d,J=2.6 Hz),11.65(2H,brs).
99%
at 160℃;
A mixture of 2-amino-5-nitro-benzoic acid (30 g, 164.71 mmol) and urea (99 g, 1647.14 mmol) was heated at 160°C with stirring overnight. The mixture was cooled, water (300 mL) was added thereto, and the precipitate was collected by filtration. The precipitate was washed with AcOH (50 mL) and MeOH (100 mL) to give 6-nitroquinazoline-2,4(1H,3H)-dione (33.8 g, 163 mmol, 99percent) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.32 (1H, d, J=9.1 Hz), 8.45(1H,dd,J=9.1,2.6 Hz), 8.58(1H,d,J=2.6 Hz), 11.65(2H,brs).
95%
at 160℃; for 4 h; Microwave irradiation
A mixture of 2-Amino-5-nitrobenzoic acid (3200 mg, 17.04 mmol) and urea (10338.4 mg, 170.43 mmol) was stirred for 4 hours at 1 60 °C in a CEM® microwave apparatus. The reaction crude was triturated in water (20 ml) and filtered. (0393) Resulting solid was separated by filtration and aqueous filtrate extracted twice with ethyl acetate (2 x 25 ml). Combined organic layers were dried over Na2S04, filtered, concentrated to dryness at low pressure and resulting solid mixed with the previous one obtained by filtration. Final trituration in methanol (5 ml) and filtration of combined solids afforded pure title compound (3353.7 mg, yield 95 percent). Rt = 1 .25 min; MS (ESI) m/z: 206.0 [M-H]", [M-H]" calculated: 206.0. 1H NMR (400 MHz, DMSO-c/e) δ 1 1 .72 (s, 2H), 8.59 (d, J = 2.7 Hz, 1 H), 8.45 (dd, J = 9.0, 2.7 Hz, 1 H), 7.32 (d, J = 9.0 Hz, 1 H).
94%
at 150 - 200℃; Sonographic reaction
Step A: Preparation of 6-nitro-1H-quinazoline-2,4-dione. Urea (9.89 g, 0.165 mol) and 5-nitroanthranilic acid (6.00 g, 32.9 mmol) were heated to 200° C. with vigorous stirring for 1 h. The melt was allowed to cool to 150° C., and water (150 mL) was slowly added. The resulting slurry was sonicated for 1 h and stirred vigorously for an additional 2 h. It was then cooled to 0° C., and the precipitate was collected and rinsed with water to yield the titled compound (6.43 g, 94percent yield). This material was dried in a vacuum oven and used without further purification. This compound did not yield MS data.
80%
at 150℃; for 10 h;
The mixture of 2-amino-5-nitrobenzoic acid (10.0 g, 0.055 mol) and urea (32.2 g, 0.54 mol) was stirred at 150 °C for 10 h. The reaction mixture was cooled to 100 °C and then water (50 mL) was added to quench the reaction. The crude product was obtained by filtration, and then washed with water (50 mL .x. 3). After dried under vacuum condition, compound 2a was obtained as yellow solid (9.1 g, 80percent); mp >300 °C; 1H NMR (DMSO-d6) δ 7.24 (d, J = 9.0 Hz, 1H, ArH), 8.36 (dd, J1 = 9.0 Hz, J2 = 2.7 Hz, 1H, ArH), 8.55 (d, J = 2.7 Hz, 1H, ArH).
79.4%
at 200℃; for 0.166667 h; Microwave irradiation
The compound 2-amino-5-nitrobenzoic acid (1.5 g, 8.24 mmol) was weighed in a microwave tube and urea (2.23 g, 37.1 mmol) was added to perform microwave reaction (power: 200 W; temperature: 200 ° C.). The reaction 10min, water 30ml, filtered, the filter cake washed with water 30ml × 3, dried to give a yellow solid 9.1g, yield: 79.4percent.
72.8%
Stage #1: at 200℃; for 1 h; Inert atmosphere; Neat (no solvent) Stage #2: With sodium hydroxide In water Stage #3: With acetic acid In water
Example 896-Nitroquinazoline-2,4(lH,3H)-dione A mixture of 2-amino-5-nitrobenzoic acid (0.588 g, 3.23 mmol) and urea (1.164 g, 19.38 mmol) was heated at 200°C under N2 for 1 h. The mixture was cooled to room temperature and 4 M NaOH was added until pH = 14. It was acidified to pH = 5.0 via addition of AcOH. The mixture was filtered and the yellow solid was dried to give the title compound (0.49 g, 72.8percent) as a yellow solid. MS: m/z 208.1 [M+l] +.
72.8%
at 200℃; for 1 h; Inert atmosphere
A mixture of 2-amino-5-nitrobenzoic acid (0.588 g, 3.23 mmol) and urea (1.164 g, 19.38 mmol) was heated at 200° C. under N2 for 1 h. The mixture was cooled to room temperature and 4 M NaOH was added until pH=14. It was acidified to pH=5.0 via addition of AcOH. The mixture was filtered and the yellow solid was dried to give the title compound (0.49 g, 72.8percent) as a yellow solid. MS: m/z 208.1 [M+1]+.
53%
at 160℃; for 48 h;
A mixture of 14 (10.0 g, 54.91 mmol) and urea (98.93 g, 1647.2mmol) was heated to 160 C for 48 h. After complete consumption of starting material, the reaction mixture was cooled to 100 C and water (10 mL) was added to the reaction mixture. The reaction mixture was filtered and washed with water; solid residue was dissolvedin 0.5 N NaOH solution. Then the reaction mixture was heated at 100 C for 40 min. The reaction mixture was cooled to0 C and 1 N HCl (aq.) was added to adjust pH = 5. Light yellow precipitatewas filtered, washed with water and dried under vacuumto give compound 15a (6.0 g, 53percent) as a light yellow solid. MS(ESI) m/z: 206.1 (MH). 1H NMR (400 MHz, DMSO-d6): d 7.31(d, 1H, J = 9.04 Hz), 8.44 (dd, 1H, J = 2.60 Hz, 8.96 Hz), 8.57 (d, 1H,J = 2.64 Hz), 11.66 (br s, 2H).
Reference：
[1] Patent: WO2015/200534, , A2, . Location in patent: Paragraph 00413[1] Patent: , 2015, , . Location in patent: Paragraph 00413
[3] Patent: EP2975031, 2016, A1, . Location in patent: Paragraph 0753
[4] Patent: EP3192791, 2017, A1, . Location in patent: Paragraph 0461
[5] Patent: WO2018/114700, 2018, A1, . Location in patent: Page/Page column 22; 52-53
[6] Patent: US2010/204226, 2010, A1, . Location in patent: Page/Page column 60
[7] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 9, p. 2797 - 2807
[8] Patent: CN102250075, 2016, B, . Location in patent: Paragraph 0408-0410
[9] Patent: WO2012/130166, 2012, A1, . Location in patent: Page/Page column 51-52
[10] Patent: US2014/23642, 2014, A1, . Location in patent: Page/Page column 0429
[11] Synlett, 2013, vol. 24, # 16, p. 2102 - 2106
[12] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 3, p. 721 - 736
[13] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 75 - 80
[14] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 677 - 683
10
[ 616-79-5 ]
[ 32618-85-2 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 8, p. 824 - 829
11
[ 32315-10-9 ]
[ 616-79-5 ]
[ 4693-02-1 ]
Yield
Reaction Conditions
Operation in experiment
75%
at 70℃; for 12 h;
General procedure: A 500 mL single neck round-bottomed flask equipped with a football-shaped PTFE stirring bar (16 mm × 37 mm) was chargedwith 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol,1.0 equiv) followed by the addition of tetrahydrofuran (230 mL,0.2 molar) and solid triphosgene (13.7 g, 46.3 mmol, 1.0 equiv)resulting in a suspension. The reaction vessel was placed into afitted metal heating mantle and the neck was equipped with a24/40 Liebig condenser. The suspension was stirred (500 rpm)and the heating mantle set to 70 °C. The suspension becamehomogenous before a white solid precipitated out after about30 minutes at 70 °C. The heterogeneous reaction mixture wasaged for 12 hours then cooled to room temperature (25 °C). Theslurry was poured into a 600 mL beaker equipped with overheadmechanical stirrer (PTFE 75 mm paddle) containing250 mL of deionized water. With vigorous stirring, the mixturebecame homogenous followed by precipitation of a pale whitesolid. The solid was collected by vacuum filtration on aBüchner funnel (7.6 cm diameter) with Whatman 1 filter paper(70 mm) and air pulled through for 5 minutes. The material was transferred to a 250 mL Erlenmeyer flask equipped with cylindricalstir bar and 50 mL of methanol was added. The slurrywas stirred for 10 minutes and then collected by vacuum filtration.The filter cake was dried under vacuum (0.1 mmHg at 25 °C) for 12 hours to afford 9b as a white powder (90percent yield).
Reference：
[1] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 2529 - 2536
[2] Tetrahedron Letters, 2014, vol. 55, # 26, p. 3607 - 3609
[3] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 978 - 982
[4] Journal of Agricultural and Food Chemistry, 2015, vol. 63, # 31, p. 6883 - 6889
12
[ 75-44-5 ]
[ 616-79-5 ]
[ 4693-02-1 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 43, p. 5748 - 5751
13
[ 616-79-5 ]
[ 16313-65-8 ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran for 0.166667 h; Stage #2: at 20℃; for 17 h; Inert atmosphere
Example 125 Preparation of 2-(3,5-Dimethoxyphenyl)-6-(pyridin-4-ylamino)quinazolin-4(3H)-one To a mixture of 2-amino-5-nitro-benzoic acid (12.9 g, 81.9 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) (17.3 g, 90.1 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (12.2 g, 90.1 mmol) in THF (200 mL) was added 4-methylmorpholine (NMM) (9.91 mL, 90.1 mmol). After 10 minutes, ammonium hydroxide (50percent v/v, 50 mL) was added. The mixture was stirred at room temperature under nitrogen for 17 hours. Solvent was removed under reduced pressure. Water was added. The solid separated was filtered, washed with aqueous NaHCO3 solution, and with water, and dried in air, to afford 2-amino-5-nitro-benzamide as a yellow solid. Yield: 9.88 g (66percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7952 - 7976
[3] Patent: US9238640, 2016, B2, . Location in patent: Page/Page column 154
[4] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 18, p. 3869 - 3878
14
[ 616-79-5 ]
[ 19230-50-3 ]
Reference：
[1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 2009, vol. 131, p. 251 - 262
[3] Organic Letters, 2011, vol. 13, # 24, p. 6488 - 6491
[4] Tetrahedron, 2005, vol. 61, # 42, p. 10113 - 10121
[5] Magnetic Resonance in Chemistry, 1989, vol. 27, # 11, p. 1007 - 1011
[6] Tetrahedron, 2000, vol. 56, # 27, p. 4777 - 4792
[7] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 5031 - 5037
[8] Patent: WO2014/189370, 2014, A1, . Location in patent: Page/Page column 28-29
[9] Organic Letters, 2018, vol. 20, # 2, p. 345 - 348
15
[ 616-79-5 ]
[ 49592-84-9 ]
Reference：
[1] Patent: WO2015/138919, 2015, A1,
16
[ 616-79-5 ]
[ 77242-30-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
With borane-THF In tetrahydrofuran at 0 - 30℃; for 23 h; Inert atmosphere
Stage #1: With borane-THF In tetrahydrofuran for 1 h; Reflux Stage #2: With hydrogenchloride In ethyl acetate
5-Nitroanthranilic acid (5.0 g, 27.45 mmol) is dissolved in THF (100 mL) and 1 M borane/THF complex (55 mL, 54.9 mmol) is added. The mixture is heated to reflux for 1 h. Analysis by TLC indicates complete consumption of starting material. The volatiles are removed in vacuo and the residue is dissolved in ethyl acetate (150 mL). The organic phase is washed with 1 N HCl, saturated NaHCO3, and saturated NaCl. Evaporation provides 10.8 g (98percent) of a dark brown oil product which is used directly in the next reaction; 1H-NMR (500 MHz, CDCl3); δ 4.61 (s, 2 H), 6.62 (s, 1 H), 8.01 (m, 2 H).
73%
With borane-THF In tetrahydrofuran at 0 - 23℃;
EXAMPLE A1 (2-Amino-5-nitro-phenyl)-methanol CAS-No. [77242-30-9] To a solution of commercially available 5-nitroanthranilic acid (28.37 g, 156 mmol; HPLC 1.428 min) in tetrahydrofuran (900 mL) at 0° C. was cannulated a 1 M sol. of borane.tetrahydrofuran complex (500 mL, 500 mmol) [gas[evolution], but almost no exothermic reaction]. The cooling bath was removed and the mixture was stirred at 23° C. for 16 h. Then water (142 mL) was added [strong gas evolution upon addition of the first ca. 30[mL]] followed by 1 M HCl (71 mL) and the resulting yellow mixture was stirred at 23° C. for 1 h. Then a 1 M solution of potassium carbonate in water (35 mL) was added and the entire reaction mixture was concentrated in vacuum on a rotary evaporator to remove all tetrahydrofuran, the resulting yellow precipitate was diluted with ice water (-100 mL), the precipitate was filtered off, washed with ice water and dried in vacuum to give a yellow solid (19.0 g, 73percent; HPLC 0.998 min 100percent). 1H NMR (300 MHz, DMSO-d6) δ=4.39 (d, 3J(H,H)=5.4 Hz, 2H, C2OH), 5.32 (t, 3J(H,H)=5.4 Hz, 1H, O), 6.46 (bs, 2H, N2), 6.65 (d, 4J(H,H)=9.0 Hz, 1H, H3), 7.89 (dd, 4,5J(H,H)=8.7, 2,7 Hz, 1H, H4), 8.05 (d, 5J(H,H)=2.7 Hz, H6); MS (ISN) m/e=167.1 [(M-H)-].
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[2] Patent: US2014/121415, 2014, A1, . Location in patent: Paragraph 0050
[3] Patent: US2010/63037, 2010, A1, . Location in patent: Page/Page column 20
[4] Journal of Organic Chemistry, 2010, vol. 75, # 20, p. 7033 - 7036
[5] Patent: WO2015/164308, 2015, A1,
17
[ 91538-60-2 ]
[ 77242-30-9 ]
[ 616-79-5 ]
Reference：
[1] Journal of the Indian Chemical Society, 1931, vol. 8, p. 59,65
(1-1) Preparation of 6-nitro-3H-quinazolin-4-one150 g of 2-amino-5-nitro-benzoylic acid was added to 200 ml of formamide, the resulting solution was heated to 170 C for 4 hours, and cooled to 100C . 500 ml of ice water was added thereto, stirred for 1 hour, and the resulting mixture was filtered under a reduced pressure. The resulting residue was washed with water to obtain a solid, which was dried at 40 C for 15 hours to obtain the title compound of formula (14O g, 90%).1H-NMR (DMSO-d6, 300MHz): delta 8.77 (d, J=2.7 Hz, IH), 8.55 (dd, J-6.9 Hz, IH), 8.36 (s, IH), 7.84 (d, J=9 Hz, IH).
87%
at 120 - 125℃; for 4h;Heating / reflux;
A solution of 18.2 g of compound 6a (100 mmol) in 76.5 g (64 ml) of formamide (1.7 mol) was heated under reflux for 4 hrs at 120125 C. Solvent was removed under reduced pressure and the crude solid was recrystallized from ethyl alcohol to give 12.7 g of compound 7a (yield, 87 %). 1H-NMR (300 MHz, d6-DMSO): delta 8.13 (m, 2H), 7.84 (m, 1H), 7.68 (m, 1H), 7.55 (m, 1H).
79%
at 150℃; for 1h;
Intermediate 5: 6-aminoquinazolin-4(3H)-oneIntermediate 5A: [00200] In a 2 mL microwave vial was placed formamide (1.5 mL, 37.8 mmol) and 5-nitroanthranilic acid (917 mg, 5.04 mmol) to give a yellow suspension. The mixture was heated under microwave at 150 0C for 60 min. The mixture was diluted with EtOAc (1 L) and washed with NaHCO3 (Sat. 200 mL) and brine (200 mL). The organic layer was dried by MgSO4 and concentrated to yield Intermediate 5A (760 mg, 79% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 7.85 (d, J=8.79 Hz, 1 H) 8.31 (s, 1 H) 8.54 (dd, J=9.23, 2.64 Hz, 1 H) 8.79 (d, J=2.64 Hz, 1 H) 12.77 (s, 1 H).
79%
at 150℃; for 1h;Microwave irradiation;
Intermediate 4: 6-aminoquinazolin-4(3H)-one; Intermediate 4A: [00200] In a 2 mL microwave vial was placed formamide (1.5 mL, 37.8 mmol) and 5-nitroanthranilic acid (917 mg, 5.04 mmol) to give a yellow suspension. The mixture was heated under microwave at 150 0C for 60 min. The mixture was diluted with EtOAc (IL) and washed with NaHCO3 (Sat. 200 mL) and brine (200 mL). The organic layer was dried by MgSO4 and concentrated to yield Intermediate 4A (760 mg, 79% yield).
79%
at 180℃; for 1.5h;
[00165] A. 2246-5 gr 5-nitro anthranilic acid and 15 ml formamide were heated at 180 1.5 hours. Water was added to the cooled solution and the solid filtered, washed with water and dried to give 4.1 gr, 79% yield, light-yellow solid. NMR DMSO d6 [8] 8.80 [(LH,] d, J=2.6 Hz, H5), 8.54 [(LH,] dd, J=9.0, 2.6 Hz, [H7),] 8.32 [(LH,] s, [H2),] 7. 86 [(LH,] d, J=9.0 Hz, H8).
72%
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 × 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 × 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.
55%
With trichlorophosphate; at 90 - 95℃;
2.55 g (0.014 mol) of 2-amino-5-nitrobenzoic acid (IV) were added to 15 mL of formamide,Stirred at 90 & lt; 0 & gt; C until dissolved,The temperature was controlled at 90-95 C and 5 mL of phosphorus oxychloride was slowly added dropwise with vigorous stirring.After completion of the dropwise addition, stirring was continued for 20 min,Cool to room temperature and pour into cold water.After the precipitate is completely precipitated, it is filtered, dried in vacuo,To give the object compound (Va) in a yield of 55%
51.6%
at 120℃; for 16h;
2-Amino-5-nitrobenzoic acid(7.28 g, 40.0 mmol) was added to 60 mL of formamide, heated to 120 C, incubated for 16 h, cooled to room temperature, precipitated a solid, filtered, washed with isopropanol and dried to give 6-nitro-3H -quinolineOne was obtained in a yield of 51.6%.
at 150℃; for 0.333333h;microwave irradiation;
Synthesis of 6-Nitro-4(3H)-quinazolone A mixture of 5-nitroanthranilic acid (2 g, 14.6 mmol) and formamide (2.9 ml, 72 mmol) is irradiated at 150 C in a microwave (power: 60 W) until TLC shows completion of reaction (20 minutes). After cooling, the reaction mixture is rinsed with ethyl acetate and evaporated under reduced pressure. The crude is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above product.
at 120℃;
General procedure: The mixtures of anthranilic acid or respective 5-substituted-2-aminobenzoicacid (1) (1 mmol) and an excess of formamide (10 mmol) in around-bottom flask were heated at 120 C with stirring for 3-5 h. Thereaction was checked by TLC. After the starting materials completelydisappeared, the resulting mixtures were cooled to room temperatureand then poured into ice-cold water. The light or dark brown precipitateswere formed. The precipitates were filtered and washed threetimes with water (20 mL each) and dried to give quinazoline-4(3H)-onederivatives (2). These intermediates were used for the next step withoutfurther purification.
1.1 (1) Synthesis of Intermediate I:
Weigh out 2-amino-5-nitrobenzoic acid (5.46g, 30mmol) and transfer it to a 250mL flask, add 80mL of acetic anhydride, then heat to reflux, and react for 12h. Cool to room temperature, filter, and rinse the obtained solid with a petroleum ether-ethyl acetate mixture to obtain 5.75 g of intermediate I as a pale yellow solid, with a yield of 93%;
85%
Reflux;
4.1.14. Synthesis of 2-methyl-6-nitro-4H-benzo[d][1,3]oxazin-4-one 7b
2-Amino-5-nitrobenzoic acid 1b (5.0 g, 1.0 equiv) was refluxed in Ac2O (10.0 equiv) until the consumption of starting materials(TLC monitoring). The excess of solvents were evaporated under vacuum to obtain the residue that washed with n-hexane(310 ml), filtered and dried under vacuum to obtain title compound 7b as a brown solid. 2-Methyl-6-nitro-4H-benzo[d][1,3]oxazin-4-one 7b: yield 85%; silica gel TLCRf = 0.55 (Ethyl acetate/n-hexane 50% v/v); mp 220-221C;dH(400 MHz, DMSO-d6) 2.51 (3H, s), 7.82 (1H, d, J 8.8),8.66 (1H, dd,J 2.8, 8.8), 8.77 (1H, d,J 2.8);dC(100 MHz, DMSOd6) 22.2, 118.3, 124.2, 128.8, 131.6, 146.8, 151.4, 159.0, 164.5;m/z (ESI negative) 205.08 [MH]. Experimental in agreement with reported data.
64%
for 2h; Heating / reflux;
109.a (4-METHOXY-PHENYL)- (2-METHYL-6-NITRO-QUINAZOLIN-4-YL)-METHYL-AMINE
2-Methyl-6-nitro-4H-benzo [d] [1, 3] oxazin-4-one. A mixture of 2-amino-5- nitrobenzoic acid (2.0 g, 10.9 mmol) in 20 mL of acetic anhydride was refluxed for 2 h. The reaction mixture was cooled to room temperature and the resulting precipitate was collected and washed with cold diethylether and dried under vacuum to obtain the title compound (1.45 g, 7.01 mmol, 64%). 1H NMR (CDC13) : 9.05 (d, J= 2.4, 1H), 8.61 (dd, J = 9. 0,2. 7, 1H), 7.71 (d, J = 7.9, 1H), 2. 55 (s, 3H).
35%
Reflux;
at 110℃; for 5h;
Microwave irradiation;
for 1h; Reflux;
Synthesis of 6,8-substituted-2-methyl-4H-3,1-benzoxazin-4-one (2a-d)
General procedure: The appropriate anthranilic acid (0.05 mol) was refluxed with acetic anhydride (0.20 mol) for 1 h. The excess aceticanhydride was distilled away under reduced pressure. Theproducts (6,8-disubstituted-2-methyl-4H-3,1-benzoxazin-4-one) were separated and used without further purification.
2-Amino-5-nitrobenzoic acid (500 mg, 2.75 mmol) was dissolved in 0.5 M NaOH (5 mL) at 70 C. The resulting solution was allowed to cool to 0 C and the treated with concentrated HCl (1mL). To the mixture was added dropwise a solution of sodium nitrite (196 mg, 2.84 mmol) in water (2.5 mL). After stirring for 0.5 h, a solution of potassium iodide (913 mg, 5.5 mmol) inwater (2.5 mL) was added dropwise to the mixture. The resulting solution was stirred for 1 h and allowed to warm to room temperature. After stirring for 12 h, the precipitate was collected by filtration, washed with water, and dried invacuo. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 1/1) to give 5-nitro-2-iodobenzoic acid [5] (453 mg, 56%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) delta 8.80 (1H, d, J = 2.8Hz), 8.29 (1H, d, J = 8.7 Hz), 8.03 (1H, dd, J = 8.7, 2.8 Hz). A solution of 5-nitro-2-iodobenzoic acid (293 mg, 1.0mmol) in thionyl chloride (1.3 mL) was heated at reflux with stirring for 2 h. The resulting solution was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH2Cl2 (3.3 mL). To the mixture were added isopropylamine (71 mg, 1.2 mmol)and triethylamine (304 mg, 3.0 mmol) at 0 C under a nitrogen atmosphere. After stirring at room temperature for 21 h,the resulting solution was diluted with EtOAc. The mixture was washed with 10% HCl, saturated aqueous NaHCO3, water, and brine; dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by recrystallization from hexane and CHCl3 to give 22 (69 mg, 21% in 2 steps) as colorless needles.
2-Amino-5-nitrobenzoic acid (6d, 1.82 g, 10 mmol) was dissolved in DMSO (50 mL) and 30% H2S04 (50 mL) was added. The resulting mixture was heated for two hours at 50 C. The reaction was cooled to 0 C and a solution of NaN02 (970 mg, 14 mmol) in water (25 mL) was added. The mixture was stirred at 0 C for one hour, whereupon a solution of KI (5.0 g, 30 mmol) in H20 (10 mL) was added and the mixture was stirred for 1 hour at room temperature. Next, another portion of KI (5 g, 30 mmol) in H20 (10 mL) was added and the mixture was stirred for an additional hour. EtOAc (100 mL) was added and the reaction was quenched with saturated aqueous NaHS03 (100 mL). The organic layer was washed with water (2 x 100 mL) and brine (100 mL) and subsequently dried over MgS04. The solvents were evaporated under reduced pressure and the crude product was obtained as yellow solid (12.0 g, 120%). 7d was not further purified and used as a crude in the following reaction. 1H-NMR (400 MHz, CD3OD) delta: 8.54 (d, J = 2.7 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 8.7, 2.7 Hz, 1H). 13C-NMR (75 MHz, CD3OD) delta: 168.0, 149.2, 144.1, 139.2, 127.1, 125.8, 103.0, 49.6, 49.3, 49.1, 48.8, 48.5. FT-IR max (cm"1): 2932, 1722, 1588, 151, 1342, 1295, 1022, 1234, 728. HRMS (EI+) m/z calcd for C7H4N04I [M]'+ 292.9185, found 292.9184.
With ammonia; potassium carbonate; copper(I) bromide In N,N-dimethyl-formamide at 150℃; for 1h;
With ammonium hydroxide; copper(l) iodide at 200℃; for 6.5h; Autoclave; Green chemistry;
2.1. Amination reactions
General procedure: In a typical experiment, p-CNB (1 g, 6.35 mmol), CuI (0.635 mmol),commercial 25% aqueous NH3 solution (10 mL, NH3/p-CNB molar ratio21/1) were loaded into a 50 mL stainless steel reactor and sealed. Thematerial of the autoclave used is AISI 316 L, for which the compositionis Cr 16-18%, Ni 10-14%, Mo 2-3%, MnQ2%, Si Q1%, CQ0.03%,SQ0.03%, PQ0.045%, and the other part is Fe. After being heated to200 °C, the reaction was conducted while stirring with a magneticstirrer (1200 rpm). The pressure of the vapor phase (NH3 and H2O) wasabout 3 MPa at the reaction temperature. After stirring for 1 h, the reactorwas cooled to room temperature and the reaction mixture wasseparated by centrifugation. The solid substrate and product were dissolvedin ethanol and analyzed by a gas chromatograph (Shimadzu GC-2010) equipped with a capillary column (Rtx-5 capillary column: 30m×0.25mm ×0.25 Tm, carrier: N2) and a flame ionization detector(FID) and gas chromatograph-mass spectrometer (GC-MS, Agilent 5890,HP-5). o-Xylene was used as an internal standard for quantitativeanalysis. The liquid phase was also analyzed by gas chromatograph andno p-CNB or p-NAN were detected. The carbon balance was near 99%and trace amount of other unidentified byproducts were observed.
Take a 25 ml single-mouth flask, add 5 ml of methanol and 0.5 g of 2-amino-5-nitrobenzoic acid in turn, stir, slowly add 1 ml of concentrated sulfuric acid, and reflux at 80 C. for 3 hours.After TLC monitored the reaction, the methanol was decontaminated under vacuum.Saturated sodium carbonate solution was added dropwise to adjust the pH to 9 and 5 ml of dichloromethane was added.The liquid was separated, the organic layer was washed 3 times with saturated sodium chloride, and the aqueous layers were combined.Extract twice with dichloromethane and combine the organic layers.The organic phase was dried over anhydrous sodium sulfate for 1 hour. After the petroleum ether was separated by 4:1 from ethyl acetate on a silica gel column, an off-white solid methyl 2-amino-5-nitrobenzoate (0.52 g) was obtained with a yield of 96.6%.
93.2%
With chloro-trimethyl-silane; for 12h;Reflux;
By refluxing 5-nitroanthranilic acid and trimethylsilyl chloride (TMSCI) in a methanol solvent for 12 hours, 2-bromo-nitrobenzoic acid methylester was prepared. Yield: 93.2% [0349] White solid [0350] 1H-NMR (400 MHz, CDCl3) delta 8.00(d, J=8.8 Hz, 1H), 7.50(d, J=2.2 Hz, 1H), 7.40(dd, J=8.8, 2.2 Hz, 1H)
93%
With sulfuric acid; In toluene; for 24h;Reflux;
5-nitroanthranilic acid (lg, 5.5mmol) was suspended in MeOH (20mL) and 0.5ml of concentrated H2SO4 was added. Heating was begun and the solids began to dissolve as the temperature reached reflux. The mixture was allowed to heat at reflux for 24 hours, then allowed to cool to room temperature over the weekend. Toluene (20ml) was added and the bulk of the methanol (MeOH) was boiled off. The solution was heated to 95C for 3 hours and concentrated. The material was dissolved in ethyl acetate (EtOAc) and washed with saturated NaHC03 (3x50mL) then brine. The organic layer was dried (Na2S04), filtered and concentrated to a yellow solid, lg. 93% yield.
79%
With thionyl chloride;Heating / reflux;
Step 1: Methyl 2-amino-5-nitrobenzoateA suspension (0.55 M) of 2-amino-5-nitrobenzoic acid in MeOH was treated with thionyl chloride (3 eq.).The reaction mixture was heated to reflux overnight. After cooling down, the reaction was treated with water and extracted with EtOAc. The combined organic layers were washed with NaHC?3 (saturated solution), brine and dried. Evaporation of the solvent afforded (79%) the title compound as a yellow powder. 1H NMR (300 MHz, DMSO-ds, 300 K) ? 3.88 (s, 3H), 6.89 (d, IH, J 9.3), 7.80 (bs, 2H), 8.08(dd, IH, J 9.3, 2.8), 8.58 (d, IH, J 2.6) MS (ES+) m/z 197 (M+H)+.
With chloride derivative; at 0℃;Reflux;
General procedure: II, IV, and VIII: Thionyl chloride was added dropwise toa solution of benzoic acid derivative (I, III, and VII) in anhydrousmethyl alcohol at 0C. After this addition, the mixture was stirred atreflux for 8?12 hours. The reaction mixture was basified with 10%sodium bicarbonate, and ethyl acetate was added. The organic layerwas dried over anhydrous MgSO4, filtered, and the solvent wasevaporated to give the products II, IV, and VIII.
With sulfuric acid; at 15 - 90℃; for 60h;
Step 1: methyl 2-amino-5-nitrobenzoateTo a solution of 2-amino-5-nitrobenzoic acid (10 g, 54.9 mmol) in MeOH (150 mL) was added H2S04 (4 mL, 75 mmol) at 15C. The mixture was stirred at 90C for 60 h. LCMS showed the reaction was nearly completed. Then the mixture was treated with sat. NaHCO3 solution to pH8.The precipitate was collected to give the title compound which was used for the next step without further purification.?H NMR (CDC13, 400MHz): oe 8.85 (d, J= 2.2 Hz, 1H), 8.14 (dd, J= 9.3, 2.2 Hz, 1H), 6.68 (d, J = 9.3 Hz, 1H), 3.94 ppm (s, 3H). MS (ESI) m/z 197.2 (M+H).
Example 125 Preparation of 2-(3,5-Dimethoxyphenyl)-6-(pyridin-4-ylamino)quinazolin-4(3H)-one To a mixture of 2-amino-5-nitro-benzoic acid (12.9 g, 81.9 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) (17.3 g, 90.1 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (12.2 g, 90.1 mmol) in THF (200 mL) was added 4-methylmorpholine (NMM) (9.91 mL, 90.1 mmol). After 10 minutes, ammonium hydroxide (50% v/v, 50 mL) was added. The mixture was stirred at room temperature under nitrogen for 17 hours. Solvent was removed under reduced pressure. Water was added. The solid separated was filtered, washed with aqueous NaHCO3 solution, and with water, and dried in air, to afford 2-amino-5-nitro-benzamide as a yellow solid. Yield: 9.88 g (66%).
65%
Add 9.1g to a dry 100 mL round bottom flask2-amino-5-nitrobenzoic acid,Slowly add 10mL SOCl2,Add 3 drops of DMF as a catalyst,Reflow reaction at 65 C for 3 h,The excess SOCl2 was removed by rotary evaporation.Dissolve 3 mL of ammonia in 16 mL of dichloroethane.Add 5.8g of sodium carbonate,Maintain the temperature 10-15 C,Slowly adding a solution of dichloroethane containing the acid chloride prepared above,After 1 h, the temperature was raised to 25 C for 3 h.Filtering,The filtrate was diluted with dilute hydrochloric acid (2 × 50 mL),10% NaHCO3 (2 x 50 mL),Wash with saturated NaCl (2 x 50 mL) and water (2 x 50 mL).After drying with anhydrous magnesium sulfate,Decompressed product2-amino-5-nitrobenzamide 5.9g,The yield was 65%.
5,5'-dinitro-(2,2'-diselenobisbenzoic acid)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
General procedure: 2-Amino benzoic acid (0.1 mol), HCl (20 ml) and H2O (20 ml) were added to a beaker and the mixture was cooled at 0 C. An aqueous solution of sodium nitrite (0.11 mol) (30%) was added slowly added and the reaction mixture was stirred for 30 min. The mixture was then poured into an aqueous solution of disodium diselenide (0.05 mol) and the resulting solution was stirred at room temperature for another 3 h before the pH was adjusted with aqueous HCl (10%) to a value of 2-3. Precipitation occurred and the final products were obtained by filtration.
69%
With hydrogenchloride; disodium diselenide; sodium nitrite; In water; at 20℃; for 2h;Cooling with ice;
WeighedNaOH (7.5 g, 0.2 mol),Insurance powder (8.8 g, 85%, 0.05 mol),Selenium powder (7.5 g, 0.1 mol)Followed by addition of 60 L of water,The temperature was raised to 50 C,Stirring reaction 3h,To obtain a black solution of sodium biselenide.WeighedNitro-2-aminobenzoic acid(18.3 g, 0.10 mol)1: 1 hydrochloric acid (37.5 mL) was stirred and mixed,Under ice-cooling, a solution of sodium nitrite (8.0 g, 0.13 mol) in water (17.5 mL) was slowly added dropwise to give a solution of chlorinatedNitro-2-benzoic acid diazonium salt. A solution of 5-nitro-2-benzoic acid diazonium chloride was added dropwise at room temperature with stirringSodium biselenide solution, and the mixture was stirred for 2 h. PH test paper that the solution was alkaline, filtration reactionOf selenium powder. The reaction mixture was acidified with hydrochloric acid, stirred for 2 h, filtered and the filter cake was washed with water and dried to give brownColor solid (17.0 g, 69%)
a 5-nitroanthranilic acid methyl ester To a stirred solution of 5-nitroanthranilic acid (10 g, 55 mmol) in methanol (300 mL) at 0 C. was added dropwise ethereal diazomethane generated from Diazald (34.5 g, 110 mmol). After stirring for 2 h the reaction was evaporated to give analytically pure product as a yellow solid (10.77 g, 100%). TLC Rf 0.81 (5% MeOH/CHCl3); 1 H NMR (CDCl3 / DMSO-d6) delta3.9 (3H, s), 6.84 (1H, d, J=9 Hz), 7.6 (2H, br s), 8.7 (1H, dd), 8.72 (1H, d, J=3 Hz)
With trichlorophosphate In toluene for 8h; Reflux;
45.32%
Stage #1: 1-amino-2-carboxy-4-nitrobenzene With dichlorosulfoxide In toluene for 15h; Reflux;
Stage #2: piperidin-2-one In toluene at 20℃; for 4h;
4.1.1 2-Nitro-7, 8, 9, 10-tetrahydroazepino [2, 1-b] quinazolin-12(6H)-one (17)
General procedure: 10g (0.1mol) of 2-amino-5-nitrobenzoic acid 16 was dissolved in dry toluene (50ml) in a 500-ml round-bottomed flask, and 25ml of thionyl chloride (0.25mol) was added to it. The reaction mixture was refluxed for 3h under anhydrous conditions overnight. After 12h, excess thionyl chloride and toluene were removed by using rota vapor. Toluene (100ml) and 9g (0.1mol) of caprolactam were added to the reaction mixture under cold conditions and stirred at room temperature for 4h. Progress of the reaction was monitored on TLC. The reaction mixture was basified with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate extract was dried and distilled under reduced pressure, which yielded a crude product. The crude product was purified by column chromatography. (hexane: ethyl acetate: 90:10) to give a solid product 17 in 55.7% yield;
45.32%
Stage #1: 1-amino-2-carboxy-4-nitrobenzene With dichlorosulfoxide In toluene for 15h; Reflux;
Stage #2: piperidin-2-one In toluene at 20℃; for 4h;
4.1.1 2-Nitro-7, 8, 9, 10-tetrahydroazepino [2, 1-b] quinazolin-12(6H)-one (17)
General procedure: 10g (0.1mol) of 2-amino-5-nitrobenzoic acid 16 was dissolved in dry toluene (50ml) in a 500-ml round-bottomed flask, and 25ml of thionyl chloride (0.25mol) was added to it. The reaction mixture was refluxed for 3h under anhydrous conditions overnight. After 12h, excess thionyl chloride and toluene were removed by using rota vapor. Toluene (100ml) and 9g (0.1mol) of caprolactam were added to the reaction mixture under cold conditions and stirred at room temperature for 4h. Progress of the reaction was monitored on TLC. The reaction mixture was basified with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate extract was dried and distilled under reduced pressure, which yielded a crude product. The crude product was purified by column chromatography. (hexane: ethyl acetate: 90:10) to give a solid product 17 in 55.7% yield;
5-Nitroanthranilic acid (5.0 g, 27.45 mmol) is dissolved in THF (100 mL) and 1 M borane/THF complex (55 mL, 54.9 mmol) is added. The mixture is heated to reflux for 1 h. Analysis by TLC indicates complete consumption of starting material. The volatiles are removed in vacuo and the residue is dissolved in ethyl acetate (150 mL). The organic phase is washed with 1 N HCl, saturated NaHCO3, and saturated NaCl. Evaporation provides 10.8 g (98%) of a dark brown oil product which is used directly in the next reaction; 1H-NMR (500 MHz, CDCl3); delta 4.61 (s, 2 H), 6.62 (s, 1 H), 8.01 (m, 2 H).
73%
With borane-THF; In tetrahydrofuran; at 0 - 23℃;
EXAMPLE A1 (2-Amino-5-nitro-phenyl)-methanol CAS-No. [77242-30-9] To a solution of commercially available 5-nitroanthranilic acid (28.37 g, 156 mmol; HPLC 1.428 min) in tetrahydrofuran (900 mL) at 0 C. was cannulated a 1 M sol. of borane.tetrahydrofuran complex (500 mL, 500 mmol) [gas[evolution], but almost no exothermic reaction]. The cooling bath was removed and the mixture was stirred at 23 C. for 16 h. Then water (142 mL) was added [strong gas evolution upon addition of the first ca. 30[mL]] followed by 1 M HCl (71 mL) and the resulting yellow mixture was stirred at 23 C. for 1 h. Then a 1 M solution of potassium carbonate in water (35 mL) was added and the entire reaction mixture was concentrated in vacuum on a rotary evaporator to remove all tetrahydrofuran, the resulting yellow precipitate was diluted with ice water (-100 mL), the precipitate was filtered off, washed with ice water and dried in vacuum to give a yellow solid (19.0 g, 73%; HPLC 0.998 min 100%). 1H NMR (300 MHz, DMSO-d6) delta=4.39 (d, 3J(H,H)=5.4 Hz, 2H, C2OH), 5.32 (t, 3J(H,H)=5.4 Hz, 1H, O), 6.46 (bs, 2H, N2), 6.65 (d, 4J(H,H)=9.0 Hz, 1H, H3), 7.89 (dd, 4,5J(H,H)=8.7, 2,7 Hz, 1H, H4), 8.05 (d, 5J(H,H)=2.7 Hz, H6); MS (ISN) m/e=167.1 [(M-H)-].
[00413] A mixture of 2-amino-5-nitrobenzoic acid (20 g, 109.8 mmol) and urea (33 g, 549.1 mmol) was heated at 200 C for 2 hours. The resulting mixture was washed with water, and the resulting solid was filtered and dried to give 6-nitroquinazoline-2,4(lH,3H)-dione (26 g, quantitative) as a yellow solid.
99%
In water; at 100 - 160℃;
(Step 1) (0753) A mixture of 2-amino-5-nitro-benzoic acid (30 g, 164.71 mmol) and urea (99 g, 1647.14 mmol) was stirred overnight at 160C. The reaction mixture was cooled to 100C, and water (300 mL) was added thereto. The resulting precipitate was washed successively with water, acetic acid (50 mL) and methanol (100 mL), and dried to give 6-nitroquinazoline-2,4(1H,3H)-dione (33.8 g, 163 mmol, 99%) as a yellow solid. 1H-NMR (300MHz, DMSO-d6):delta7.32(1H,d,J=9.1Hz),8.45(1H,dd,J=9.1,2.6Hz),8.58(1H,d,J=2.6 Hz),11.65(2H,brs).
99%
at 160℃;
A mixture of 2-amino-5-nitro-benzoic acid (30 g, 164.71 mmol) and urea (99 g, 1647.14 mmol) was heated at 160C with stirring overnight. The mixture was cooled, water (300 mL) was added thereto, and the precipitate was collected by filtration. The precipitate was washed with AcOH (50 mL) and MeOH (100 mL) to give 6-nitroquinazoline-2,4(1H,3H)-dione (33.8 g, 163 mmol, 99%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): delta 7.32 (1H, d, J=9.1 Hz), 8.45(1H,dd,J=9.1,2.6 Hz), 8.58(1H,d,J=2.6 Hz), 11.65(2H,brs).
95%
at 160℃; for 4h;Microwave irradiation;
A mixture of 2-Amino-5-nitrobenzoic acid (3200 mg, 17.04 mmol) and urea (10338.4 mg, 170.43 mmol) was stirred for 4 hours at 1 60 C in a CEM microwave apparatus. The reaction crude was triturated in water (20 ml) and filtered. (0393) Resulting solid was separated by filtration and aqueous filtrate extracted twice with ethyl acetate (2 x 25 ml). Combined organic layers were dried over Na2S04, filtered, concentrated to dryness at low pressure and resulting solid mixed with the previous one obtained by filtration. Final trituration in methanol (5 ml) and filtration of combined solids afforded pure title compound (3353.7 mg, yield 95 %). Rt = 1 .25 min; MS (ESI) m/z: 206.0 [M-H]", [M-H]" calculated: 206.0. 1H NMR (400 MHz, DMSO-c/e) delta 1 1 .72 (s, 2H), 8.59 (d, J = 2.7 Hz, 1 H), 8.45 (dd, J = 9.0, 2.7 Hz, 1 H), 7.32 (d, J = 9.0 Hz, 1 H).
94%
In water; at 150 - 200℃;Sonographic reaction;
Step A: Preparation of 6-nitro-1H-quinazoline-2,4-dione. Urea (9.89 g, 0.165 mol) and 5-nitroanthranilic acid (6.00 g, 32.9 mmol) were heated to 200 C. with vigorous stirring for 1 h. The melt was allowed to cool to 150 C., and water (150 mL) was slowly added. The resulting slurry was sonicated for 1 h and stirred vigorously for an additional 2 h. It was then cooled to 0 C., and the precipitate was collected and rinsed with water to yield the titled compound (6.43 g, 94% yield). This material was dried in a vacuum oven and used without further purification. This compound did not yield MS data.
80%
at 150℃; for 10h;
The mixture of 2-amino-5-nitrobenzoic acid (10.0 g, 0.055 mol) and urea (32.2 g, 0.54 mol) was stirred at 150 C for 10 h. The reaction mixture was cooled to 100 C and then water (50 mL) was added to quench the reaction. The crude product was obtained by filtration, and then washed with water (50 mL × 3). After dried under vacuum condition, compound 2a was obtained as yellow solid (9.1 g, 80%); mp >300 C; 1H NMR (DMSO-d6) delta 7.24 (d, J = 9.0 Hz, 1H, ArH), 8.36 (dd, J1 = 9.0 Hz, J2 = 2.7 Hz, 1H, ArH), 8.55 (d, J = 2.7 Hz, 1H, ArH).
79.4%
at 200℃; for 0.166667h;Microwave irradiation;
The compound 2-amino-5-nitrobenzoic acid (1.5 g, 8.24 mmol) was weighed in a microwave tube and urea (2.23 g, 37.1 mmol) was added to perform microwave reaction (power: 200 W; temperature: 200 C.). The reaction 10min, water 30ml, filtered, the filter cake washed with water 30ml × 3, dried to give a yellow solid 9.1g, yield: 79.4%.
75%
at 160℃; for 12h;
In a dry 100 mL round bottom flask, 9.11 g of 2-amino-5-nitrobenzoic acid and 21.62 g of urea were added, reacted at 160 C for 12 h, cooled to 100 C, and added with 20 mL of water and stirred for 1 h. Cool to room temperature, suction and wash with water to give a crude material. The crude product was stirred in 100 mL of 1 mol/L sodium hydroxide solution for 1 h, filtered and dried to give 7.8 g of 6-nitro-2,4-(1Eta,3Eta)-quinazolinedione, yield 75%.
72.8%
Example 896-Nitroquinazoline-2,4(lH,3H)-dione A mixture of 2-amino-5-nitrobenzoic acid (0.588 g, 3.23 mmol) and urea (1.164 g, 19.38 mmol) was heated at 200C under N2 for 1 h. The mixture was cooled to room temperature and 4 M NaOH was added until pH = 14. It was acidified to pH = 5.0 via addition of AcOH. The mixture was filtered and the yellow solid was dried to give the title compound (0.49 g, 72.8%) as a yellow solid. MS: m/z 208.1 [M+l] +.
72.8%
at 200℃; for 1h;Inert atmosphere;
A mixture of 2-amino-5-nitrobenzoic acid (0.588 g, 3.23 mmol) and urea (1.164 g, 19.38 mmol) was heated at 200 C. under N2 for 1 h. The mixture was cooled to room temperature and 4 M NaOH was added until pH=14. It was acidified to pH=5.0 via addition of AcOH. The mixture was filtered and the yellow solid was dried to give the title compound (0.49 g, 72.8%) as a yellow solid. MS: m/z 208.1 [M+1]+.
53%
at 160℃; for 48h;
A mixture of 14 (10.0 g, 54.91 mmol) and urea (98.93 g, 1647.2mmol) was heated to 160 C for 48 h. After complete consumption of starting material, the reaction mixture was cooled to 100 C and water (10 mL) was added to the reaction mixture. The reaction mixture was filtered and washed with water; solid residue was dissolvedin 0.5 N NaOH solution. Then the reaction mixture was heated at 100 C for 40 min. The reaction mixture was cooled to0 C and 1 N HCl (aq.) was added to adjust pH = 5. Light yellow precipitatewas filtered, washed with water and dried under vacuumto give compound 15a (6.0 g, 53%) as a light yellow solid. MS(ESI) m/z: 206.1 (MH). 1H NMR (400 MHz, DMSO-d6): d 7.31(d, 1H, J = 9.04 Hz), 8.44 (dd, 1H, J = 2.60 Hz, 8.96 Hz), 8.57 (d, 1H,J = 2.64 Hz), 11.66 (br s, 2H).
at 160℃;Inert atmosphere; Sealed tube;
A mixture of 2-amino-5-nitro-benzoic acid 7 (1.5 g, 1.0 equiv) and urea (10 equiv) was heated at 160 C in a sealed tube. The reaction was stirred until consumption of starting material (TLC monitoring). The mixture was cooled down to rt, quenched with H2O (20 ml) and the obtained precipitate was collected by filtration, washed with H2O (3 * 20 ml) and dried under vacuum to give titled compound 8 as a pale brown solid.
[0095] The synthesis of quinazoline core may preferably be optimized as demonstrated in the below synthesis of EGFR inhibitors. The title compound was purified by HPLC to about greater than or equal to 98% purity.
78%
With boric acid; at 110 - 160℃; for 7h;
5 g of 2-amino-5-nitrobenzoic acid (purchased from Guangtuo Chemical (Shanghai) Co., Ltd.) was added to the reaction flask,About 50 mL of formamide was added,Stirring up to 110-120 C after the solid dissolved,Then add a small amount of boric acid as a catalyst,The temperature was raised to 150 C to 160 C and reacted at this temperature for about 7 hours.After TLC detection (developing solvent: dichloromethane: methanol = 10: 1)The reaction of 2-amino-5-nitrobenzoic acid was found to be complete.The solid is precipitated by natural cooling (about about 70 C solid precipitation).After cooling to room temperature,Filter cake washed once,To obtain khaki solid,The solid was dried at room temperature to give a solid 4.2 g.TLC showed a single point (developing agent methyl tert-butyl ether: methanol / 20: 1) detection, the yield of 78%, can be directly used in the next step reaction.
With boric acid; at 110 - 150℃; for 7h;
5 g of 2-amino-5-nitrobenzoic acid (purchased from Guangtuo Chemical (Shanghai) Co., Ltd.) was added to the reaction flask,And then about 50 mL of formamide was added and the solid was dissolved by stirring to 110-120 C,And then add a small amount of boric acid as a catalyst, heated to 150 C reaction, at this temperature for about 7h reaction.After TLC detection (developing solvent: dichloromethane: methanol / 10: 1)It was found that 2-amino-5-nitrobenzoic acid was completely reacted. Precipitated by the natural cooling of the crystal (about 70 solid precipitation).Cooled to room temperature after filtration, filter cake washed once, get khaki solid,The solid was dried at room temperature to give a solid 4.2 g. TLC showed single point (developing agent methyl tert-butyl ether:Methanol = / 20: 1), LC purity 92%, yield 78%
General procedure: A 500 mL single neck round-bottomed flask equipped with a football-shaped PTFE stirring bar (16 mm × 37 mm) was chargedwith 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol,1.0 equiv) followed by the addition of tetrahydrofuran (230 mL,0.2 molar) and solid triphosgene (13.7 g, 46.3 mmol, 1.0 equiv)resulting in a suspension. The reaction vessel was placed into afitted metal heating mantle and the neck was equipped with a24/40 Liebig condenser. The suspension was stirred (500 rpm)and the heating mantle set to 70 C. The suspension becamehomogenous before a white solid precipitated out after about30 minutes at 70 C. The heterogeneous reaction mixture wasaged for 12 hours then cooled to room temperature (25 C). Theslurry was poured into a 600 mL beaker equipped with overheadmechanical stirrer (PTFE 75 mm paddle) containing250 mL of deionized water. With vigorous stirring, the mixturebecame homogenous followed by precipitation of a pale whitesolid. The solid was collected by vacuum filtration on aBuechner funnel (7.6 cm diameter) with Whatman 1 filter paper(70 mm) and air pulled through for 5 minutes. The material was transferred to a 250 mL Erlenmeyer flask equipped with cylindricalstir bar and 50 mL of methanol was added. The slurrywas stirred for 10 minutes and then collected by vacuum filtration.The filter cake was dried under vacuum (0.1 mmHg at 25 C) for 12 hours to afford 9b as a white powder (90% yield).
Reflux; Inert atmosphere;
General procedure: To the solution of appropriate 2-aminobenzoic acid in dried THF or 1,4- dioxane was added triphosgene (0.35 eq). The mixture was stirred under reflux for 4-8 hrs. Then the solvent was removed in vacuo to give the isotaic anhydride as a solid in theoretical yield. 1H NMR indicated the product was of sufficient purity and was used in the next step without further purification.
In tetrahydrofuran; at -5 - 20℃; for 15h;
General procedure: A mixture of anthranilic acid (40 mmol) and tetrahydrofuran (THF, 100 mL) was stirred at -5 C for 30 min. Then, triphosgene (40 mmol) was dissolved in THF (20 mL) and added dropwise to the above mixture. After that, the mixture was stirred for 5 h at -5C, followed by 10 h at room temperature. The solvent was removed under reduced pressure, and the residue was washed with ether, and dried to afford compound 2 in yield of 85-95%.
In N,N-dimethyl-formamide; at 100℃; for 0.25h;Inert atmosphere; Microwave irradiation;
Methyl 2-amino-5-nitrobenzoate (7) and methyl 2-amino-4-nitrobenzoate(20) are commercially available but quite expensive. Both products can beefficiently synthesized according to our previous works8 from the cheaper 5-nitro- and 4-nitroanthranilic acids which were treated by dimethylformamidedimethylacetal(DMF-DMA, 2.5 equiv) in dimethylformamide (DMF) at 100 Cfor 15 min under microwaves to afford 5 and 20 in excellent yields (92% and95%, respectively) after acidic work-up.
5-Nitroanthranilic acid 1b (1.5 g, 1.0 equiv) was treated with benzoyl chloride 2a (1.1 equiv) in DCM (25 ml) followed by dropwise addition of TEA (1.5 equiv) at 0C. The reaction mixture was treated according to general procedure a, previously reported, to give the title compound 3d as a pale yellow solid. 2-Benzamido-5-nitrobenzoic acid3d: yield 85%; silica gel TLC Rf= 0.45 (Ethyl acetate/n-hexane 50% v/v); mp 175-176C; dH(400 MHz, DMSO-d6) 7.66 (2H, t, J 7.2), 7.73 (1H, t,J 7.2), 8.02(2H, d,J 7.2), 8.55 (1H, dd,J 2.8, 9.2), 8.20 (1H, d,J 2.8), 8.97 (1H,d,J 9.2), 12.54 (1H, s, exchange with D2O, NH); dC (100 MHz,DMSO-d6) 117.6, 121.0, 127.6, 128.2, 130.1, 133.8, 134.6, 142.3,147.3, 147.3, 166.1, 169.5. Experimental in agreement with reported data
In 2-methoxy-ethanol; at 124℃; for 1h;Microwave irradiation;
A mixture of 2-amino-5-nitrobenzoic acid (36.9 g, 0.203 mol) and formamidine acetate (42.5 g, 0.360 mol) in ethylene glycol monomethyl ether (150mL) was heated under reflux for 30 h, or the reaction vessel was open and heated under microwave irradiation for 1 h at 124 C. After completion of the reaction, the excess ethyleneglycol monomethyl ether was removed by vacuo. The residue was washed by 0.01 M ammonia water to give compound (2) [78 % thermal, 92 % microwave], m.p.: 283 C [Lit. m.p.: 283-285 C]
78.5%
With 2-methoxy-ethanol;Reflux;
To a 100 mL three-necked flask was added 2-amino-5-nitrobenzoic acid (3.64 g, 20 mmol)Acetamidine acetate (4.16 g, 40 mmol)50 mL of ethylene glycol monomethyl ether,Reflux reaction.TLC monitoring, after the reaction, the reaction solution into the beaker,Set at -20 freezer overnight, filtered yellow solid 3.0g,Yield 78.5%
2-amino-5-nitro-N-(oxetan-3-ylmethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.0%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 10 - 35℃; for 72h;
(Step 1) (1078) To a solution of 2-amino-5-nitrobenzoic acid (1.045 g, 5.74 mmol), <strong>[6246-05-5]3-aminomethyloxetane</strong> (500 mg, 5.74 mmol) and DIEA (3.51 mL, 20.09 mmol) in DMF (10 mL) was added T3P (50% ethyl acetate solution, 3.88 mL, 6.60 mmol) at room temperature, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate/hexane to give 2-amino-5-nitro-N-(oxetan-3-ylmethyl)benzamide (1.010 g, 4.02 mmol, 70.0%) as a yellow solid. 1H-NMR(300MHz,DMSO-d6):delta3.05-3.26(1H,m),3.52(2H,dd,J=7.0,5.9Hz),4.34(2H,t,J=6.1Hz),4.64(2H, d d,J=8.0,6.1Hz),6.80(1H,d,J=9.1Hz),7.75(2H,brs),8.02(1H,dd,J=9.3 ,2.5Hz),8.49(1H,d,J=2.7Hz),8.81(1H,t,J=5.3Hz).
2-amino-N-(cyclopropylmethyl)-5-nitrobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 10 - 35℃; for 3h;
(Step 1) (1100) To a solution of 2-amino-5-nitrobenzoic acid (10 g, 54.90 mmol), aminomethylcyclopropane (4.76 mL, 54.90 mmol) and DIEA (33.6 mL, 192.17 mmol) in DMF (50 mL) was added T3P (50% ethyl acetate solution, 37.1 mL, 63.14 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give 2-amino-N-(cyclopropylmethyl)-5-nitrobenzamide (11.10 g, 47.2 mmol, 86%) as a yellow solid. 1H-NMR(300MHz,CDCl3):delta0.22-0.40(2H,m),0.52-0.68(2H,m),0.98-1.20(1H,m),3.29(2H,dd,J=7.2,5.3Hz),6.36(1H,brs),6.53(2H,brs),6. 65(1H,d,J=9.1Hz),8.09(1H,dd,J=9.1,2.3Hz),8.36(1H,d,J=2.3Hz).
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 35℃; for 24h;
(Step 1) (0958) To a solution of 2-amino-5-nitrobenzoic acid (5.0 g, 27.45 mmol) in DMF (100 mL) were added ethylamine (2 mol/L, THF solution, 41.18 mL, 82.35 mmol), DIEA (47.81 mL, 274.51 mmol) and HATU (13.57 g, 35.69 mmol), and the mixture was stirred at room temperature for 24 hr. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10?20% ethyl acetate/hexane) to give 2-amino-N-ethyl-5-nitrobenzamide (5.0 g, 93.32%) as a yellow solid. MS (API) :208 (M-H)
93.32%
With diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20 - 25℃; for 24h;
To a stirred solutionof 14 (5.0 g, 27.45 mmol) in dry DMF (100 mL) at 25 C wereadded EtNH2 (2 M sol in THF, 41.18 mL, 82.35 mmol), DIPA(47.81 mL, 274.51 mmol) and HATU (13.57 g, 35.69 mmol). Reactionmixture was stirred at rt for 24 h. After complete consumptionof 14, DMF was distilled off under reduced pressure to get thecrude. Crude mass was quenched with ice-water and organic partwas extracted with ethyl acetate (5 100 mL), washed with water(3 100 mL), dried over anhydrous Na2SO4 and concentratedunder reduced pressure to give crude which was purified by normalsilica gel column chromatography using 10-20% ethyl acetatein hexane as an eluent to afford 2-amino-N-ethyl-5-nitrobenzamide(5.0 g, 93.32%) as yellow solid. MS (ESI) m/z: 208.0 (MH).1H NMR (400 MHz, DMSO-d6): d 1.12 (t, 3H, J = 7.20 Hz), 3.22-3.32 (m, 2H), 6.78 (d, 1H, J = 9.24 Hz), 7.77 (br s, 2H), 8.01 (dd,1H, J = 9.16 Hz, 2.36 Hz), 8.48 (d, 1H, J = 2.36 Hz), 8.69 (br s, 1H).
General procedure: In a standard 30 mL Pyrex vessel (G30 tube, Monowave 300) or in a 1L PTFE reaction vessel, antranilic acid 1a or 1b (Monowave 300: 5 mmol; Masterwave 0.3 mol) was dissolved in EtOAc (1 M, Monowave 300: 5 mL; Masterwave BTR: 300 mL). Then DMF-DMA (2.5 equiv, Monowave 300: 12.5 mmol, 1.7 mL; Masterwave BTR: 750 mmol, 100 mL) was added under stirring. The mixture was heated under microwave irradiation at 100 C for 15 min with the Monowave 300 or for 20 min with the Masterwave BTR. After cooling to 60 C, an aqueous solution of hydrochloric acid (4 mol % or 2 equiv) was added to the mixture. The solution was heated under microwave irradiation at 100 C for 30 min. After cooling to 60 C, the warm reaction mixture was poured into a beaker containing water [20 mL (small scale) or 800 mL (large scale)] at r.t. After 10 min stirring, the precipitate was filtered off and rinsed with water. Solid products 3a and 3b were dried under vacuum. Methyl 2-Amino-5-nitrobenzoate (3a; CAS: 3816-62-4). Yield: 0.794 g (81%; Monowave 300); 48.54 g (82%; Masterwave); yellow solid; mp 165-167 C (Lit.27 169 C). IR: 3469, 3358, 3038, 2964, 1703, 1627, 1313, 1249, 1125, 1068, 827 cm-1. 1H NMR (300 MHz, DMSO-d6): delta = 8.56 (d, J = 2.8 Hz, 1 H, H-6), 8.07 (dd, J = 9.3, 2.8 Hz, 1 H, H-4), 7.83 (br. s, 2 H, NH2), 6.88 (d, J = 9.3 Hz, 1 H, H-3), 3.85 (s, 3 H, OMe). 13C NMR (75.4 MHz, DMSO-d6): delta = 166.4, 155.8, 135.1, 128.9, 128.3, 116.8, 107.5, 52.1, 39.5.
2-[(3-hydroxy-5-methyl-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
General procedure: 2 mmol of 5-nitroanthranilic acid is dissolved in hydrochloric acid (in 5 ml water). Then, the solution is cooled to 0e5 C withstirring. Sodium nitrite (2 mmol) inwater (5 ml) is gradually addedto this solution over 15 min period at 0e5 C while stirring. Thereaction mixture is stirred for 2 h at this temperature. The resultingdiazonium salt solution is then added dropwise to a well-cooledand stirred solution of malononitrile (2 mmol) in sodium acetate(2 g) dissolves in 20 mLwater. The pH is maintained at 4e6 throughthe coupling process by adding sodium acetate. Stirring iscontinued for 4 h at 0e5 C. The precipitated products diluted withcold water (50 mL), filtered off, washed with water several times,and dried. The obtained product is recrystallized from DMF-H2Omixture. Hydrazine hydrate (0.5 mL) is added to a solution of thisobtained product (3 mmol) in 20 ml ethanol. The reaction mixtureis heated under reflux for 4e6 h and then cooled at room temperature.Upon water being added, precipitate product is filtered,washed with water several times, and dried. The obtained product2-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid (A)is recrystallized from DMF-H2O mixture.
2-[(3,5-dimethyl-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
General procedure: 2 mmol of 5-nitroanthranilic acid is dissolved in hydrochloric acid (in 5 ml water). Then, the solution is cooled to 0e5 C withstirring. Sodium nitrite (2 mmol) inwater (5 ml) is gradually addedto this solution over 15 min period at 0e5 C while stirring. Thereaction mixture is stirred for 2 h at this temperature. The resultingdiazonium salt solution is then added dropwise to a well-cooledand stirred solution of malononitrile (2 mmol) in sodium acetate(2 g) dissolves in 20 mLwater. The pH is maintained at 4e6 throughthe coupling process by adding sodium acetate. Stirring iscontinued for 4 h at 0e5 C. The precipitated products diluted withcold water (50 mL), filtered off, washed with water several times,and dried. The obtained product is recrystallized from DMF-H2Omixture. Hydrazine hydrate (0.5 mL) is added to a solution of thisobtained product (3 mmol) in 20 ml ethanol. The reaction mixtureis heated under reflux for 4e6 h and then cooled at room temperature.Upon water being added, precipitate product is filtered,washed with water several times, and dried. The obtained product2-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid (A)is recrystallized from DMF-H2O mixture.
2-[(5-amino-3-methyl-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
General procedure: 2 mmol of 5-nitroanthranilic acid is dissolved in hydrochloric acid (in 5 ml water). Then, the solution is cooled to 0e5 C withstirring. Sodium nitrite (2 mmol) inwater (5 ml) is gradually addedto this solution over 15 min period at 0e5 C while stirring. Thereaction mixture is stirred for 2 h at this temperature. The resultingdiazonium salt solution is then added dropwise to a well-cooledand stirred solution of malononitrile (2 mmol) in sodium acetate(2 g) dissolves in 20 mLwater. The pH is maintained at 4e6 throughthe coupling process by adding sodium acetate. Stirring iscontinued for 4 h at 0e5 C. The precipitated products diluted withcold water (50 mL), filtered off, washed with water several times,and dried. The obtained product is recrystallized from DMF-H2Omixture. Hydrazine hydrate (0.5 mL) is added to a solution of thisobtained product (3 mmol) in 20 ml ethanol. The reaction mixtureis heated under reflux for 4e6 h and then cooled at room temperature.Upon water being added, precipitate product is filtered,washed with water several times, and dried. The obtained product2-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid (A)is recrystallized from DMF-H2O mixture.
2-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
General procedure: 2 mmol of 5-nitroanthranilic acid is dissolved in hydrochloric acid (in 5 ml water). Then, the solution is cooled to 0e5 C withstirring. Sodium nitrite (2 mmol) inwater (5 ml) is gradually addedto this solution over 15 min period at 0e5 C while stirring. Thereaction mixture is stirred for 2 h at this temperature. The resultingdiazonium salt solution is then added dropwise to a well-cooledand stirred solution of malononitrile (2 mmol) in sodium acetate(2 g) dissolves in 20 mLwater. The pH is maintained at 4e6 throughthe coupling process by adding sodium acetate. Stirring iscontinued for 4 h at 0e5 C. The precipitated products diluted withcold water (50 mL), filtered off, washed with water several times,and dried. The obtained product is recrystallized from DMF-H2Omixture. Hydrazine hydrate (0.5 mL) is added to a solution of thisobtained product (3 mmol) in 20 ml ethanol. The reaction mixtureis heated under reflux for 4e6 h and then cooled at room temperature.Upon water being added, precipitate product is filtered,washed with water several times, and dried. The obtained product2-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid (A)is recrystallized from DMF-H2O mixture.
After adding 80 parts of water to 18.2 parts of 5-nitroanthranilic acid (manufactured by Tokyo Chemical Industry Co., Ltd.), 0.4 part of sodium hydroxide was added and dissolved. Under cooling with ice, 19.7 parts of 35% sodium nitrite aqueous solution was added, then 26.2 parts of 35% hydrochloric acid was added little by little to dissolve and the mixture was stirred for 2 hours to obtain a suspension containing a diazonium salt. Meanwhile, 23.9 parts of <strong>[90-51-7]6-amino-4-hydroxy-2-naphthalenesulfonic acid</strong> (manufactured by Tokyo Chemical Industry Co., Ltd.) was suspended in 100 parts of water, and the pH was adjusted to 9.0 with sodium hydroxide It was adjusted. Here, the suspension containing the diazonium salt was dropped by a pump over 15 minutes. After completion of the dropwise addition, the mixture was further stirred for 30 minutes to obtain a red suspension. After stirring the suspension for 1 hour, the orange solid obtained by filtration was dried at 60 C. under reduced pressure to obtain 32.7 parts of the compound represented by the formula (I-1).
2-(2'-hydroxycarbonyl-5'-nitrophenyl)amino-5-iodo-1,4-dimethylbenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With copper(l) iodide; copper; potassium carbonate; In pentan-1-ol; for 30h;Reflux; Inert atmosphere;
Under a nitrogen atmosphere,In a 100 ml two-necked eggplant flask equipped with a reflux condenser5-nitroanthranilic acid 13 (0.912 g, 5.01 mmol),5 (3.58 g, 10.0 mmol), copper (0.161 g, 2.53 mmol),Copper iodide (0.383 g, 2.01 mmol), potassium carbonate (0.864 g, 6.25 mmol),1-Pentanol (45 ml) was added and the mixture was heated under reflux for 30 hours. After cooling to room temperature,After adding methanol and stirring thoroughly, insoluble matter was removed by Celite filtration.The filtrate was concentrated with an evaporator, DMF was added to dissolve,A small amount of concentrated hydrochloric acid was added to make Congo red acid. More water is added,The resulting precipitate was filtered off. The filtrate was dried, washed with a large amount of hexane,After filtering again, it was washed with a large amount of water.The filtrate was dried to obtain yellow powder 14 (1.65 g, 3.99 mmol, 80%).From 1 H NMR, 2 wt% of <strong>[1124-08-9]2,5-diiodo-p-xylene</strong> as a raw material was contained.
With bis(trichloromethyl) carbonate; In tetrahydrofuran; at 60℃; for 10h;
2-Amino-5-nitrobenzoic acid (0.785 g, 4.5 mmol) was dissolved in 10 mL of THF and heated to 60 C, triphosgene (0.45 g, 1.5 mmol) was added and the reaction was stirred for 10 h. The reaction progress was monitored by TLC analysis. The solution was cooled to room temperature, and the isatoic anhydride intermediate was filtered and collected. Cold 1N ammonia was added to the collected intermediate, and the mixture was stirred for 24 h at 4 C. The turbid solution was filtered and washed with water and ether to give 0.430 g (2.3 mmol, 48%) of Compound4as a yellow solid. Spectra matched those reported by the Integrated Spectral Database System of Organic Compounds (AIST, Japan).1H NMR (400 MHz, DMSO-d6) delta 8.56 (d,J= 2.6 Hz, 1H), 8.21 (s, 1H), 8.02 (dd,J= 9.2, 2.6 Hz, 1H), 7.90 (s, 2H), 7.41 (s, 1H), 6.80 (d,J= 9.2 Hz, 1H).13C}1H} NMR (101 MHz, DMSO-d6) delta 170.1, 156.2, 135.2, 128.0, 126.9, 116.4, 112.5.
With dmap; 1,2-dichloro-ethane; In tetrahydrofuran; dichloromethane; at 20℃; for 3h;
5-nitroanthranilic acid (1.05 g, 5.7 mmol) was dissolved in 1:1 mixture of DCM and THF kept under inert atmosphere and EDO (2.2 g, 11.5 mmol), DMAP (0.35 g, 2.9 mmol) and n5 hexanol (0.7 mL, 5.6 mmol) were successively added to the yellow solution. Mixture wasstirred vigorously at room temperature for 3 hours. During the course of reaction, a lot of yellow precipitate was formed which slowly dissolved. Volatiles were removed under reduced pressure and the residue was dissolved in DCM and the solution was washed thrice with saturated NaHCO3 solution, thrice with water and finally with brine solution. Evaporationof solvent afforded the crude product as red oil. Pure compound was isolated as bright yellow solid after purification by column chromatography using 60% dcm/hexane mixture.Yield: 1.4 g (90%). 1H NMR (500 MHz, DMSO) O 8.59 (d, J= 2.7, 1H), 8.09 (dd, J= 9.3, 2.8, 1H), 7.85 (5, 2H), 6.90 (d, J = 9.4, 1H), 4.27 (t, J = 6.6, 2H), 1.73 (t, J = 7 Hz, 2H), 1.44-1.36 (m, 2H), 1.35-1.29 (m, 4H), 0.88 (t, J= 6.9, 3H). 130 NMR (125 MHz, DMSO) O 165.9,155.8, 135.1, 128.8, 128.1, 116.7, 107.6, 64.7, 30.8, 28.0, 25.1, 21.9, 13.8.
With copper(l) iodide; copper; potassium carbonate; In N,N-dimethyl-formamide; at 165℃; for 3h;
7.28 g of 2-amino-5-nitrobenzoic acid, 7.46 g of <strong>[6280-89-3]2-chloro-5-methoxybenzoic acid</strong>, 5.52 g of K2CO3, 0.378 g of copper powder, and 1.14 g of CuI were added to a round-bottomed flask and mixed, then DMF was allowed to react at reflux temperature for 3 hours. After cooling, it was filtered, and dilute hydrochloric acid was added to the filtrate until the solution became weakly acidic. The solid product was 2-((2-carboxy-4-methoxyphenyl) amino) -5-methoxybenzoic acid, which was stirred and filtered with suction.
With copper(l) iodide; copper; potassium carbonate; In N,N-dimethyl-formamide; at 165℃; for 3h;
7.28 g of 2-amino-5-nitrobenzoic acid, 6.98 g of <strong>[2252-50-8]2-chloro-5-fluorobenzoic acid</strong>, 5.52 g of K2CO3, 0.378 g of copper powder, and 1.14 g of CuI were added to a round-bottomed flask, and then DMF was added, The reaction was left at reflux temperature for 3 hours. After cooling, the solution was filtered. Dilute hydrochloric acid was added to the filtrate until the solution became weakly acidic. The solid product was 2-((2-carboxy-4-fluorophenyl) amino) -5-methoxybenzoic acid after stirring and suction filtration.
With copper(l) iodide; copper; potassium carbonate; In N,N-dimethyl-formamide; at 165℃; for 3h;
7.28 g of 2-amino-5-nitrobenzoic acid, 6.82 g of <strong>[6342-60-5]2-chloro-5-methylbenzoic acid</strong>, 5.52 g of K2CO3, 0.378 g of copper powder, and 1.14 g of CuI were added to a round-bottom flask and mixed, and then DMF was added. And allowed to react at reflux temperature for 3 hours. After cooling, the solution was filtered, and dilute hydrochloric acid was added to the filtrate until the solution became weakly acidic. The solid product was 2-((2-carboxy-4-methylphenyl) amino) -5-methoxybenzoic acid after stirring and suction filtration.
1-2 Compound B2a:
To a solution of 2-amino-5 -nitro benzoic acid (8.0 g, 30 mmol), triethylamine (7.8 g, 72 mmol) in CH2CI2 was added decanoyl chloride (12.0 g, 63 mmol) dropwise. The reaction solution was then stirred at room temperature overnight. After filtering out any solid, the filtrate was concentrated and the residue was subject to silica gel column (hexane/CH2Ch, from 2/1 to 1/1) to afford the pure benzoxazinone B2a as a white solid (6.39 g, 67%). 'H NMR (400 MHz, CDCh): 6 9.05 (s, 1H), 8.61 (d, J= 8.0 Hz, 1H), 7.73 (d, J= 4.0 Hz, 1H), 2.74 (t, J= 12.0 Hz, 2H), 1.85 (m, 2H), 1.36-1.29 (m, 12H), 0.89 (t, J= 12.0 Hz, 3H). 13C NMR (75 MHz, CDCh): 6 116.6, 157.9, 150.7, 146.4, 130.5, 128.2, 124.4, 117.2, 34.9, 31.7, 29.3, 29.2, 29.1, 29.0, 25.9, 22.6, 14.0. MS (ESI) m/z: [M+H]+ Calcd. for C17H23N2O4 319.2; Found 319.2.
With magnesium(II) nitrate hexahydrate; water; sodium hydroxide In methanol; acetonitrile at 20℃; for 12h;
2.2. Synthesis of [Mg(H2O)6].L2.2bipy.H2O I
Mg(NO3)2 ·6H2O (0.26 g; 1.0 mmol) was dissolved in 10 mL distilled water. After that 2-3 drops of 1.0 N NaOH were added to above solution to make it slightly alkaline. LH (0.18 g; 1.0 mmol) and bipy (0.16 g; 1.0 mmol) were dissolved in 10 mL mixture of methanol-acetonitrile (1:1). After the addition of both solutions, the resulting solution was stirred for 12 hr at room temperature and allowed to evaporate slowly. Yellow colored crystals were separated out by filteration within 2 weeks and dried well (69% yield). M.p. > 300 °C. Elemental analysis for I : C34H40MgN8O15 (M.W. = 825.05 g mol -1 ); Calcd: C, 49.50; H, 4.89; N, 13.58; Found: C, 49.12; H, 4.71; N, 13.60. IR (cm-1 ) selected bonds: = 3417(s) (O-H), 3139 (b) (N-H), 1684-1596 (s) (COO-) asy , 1489 (s) (COO-) sy , 1384-1326 (s) (N-O), 1069 (m) (C-O), 806-614 (m) (Mg-O) (b = broad, m = medium, s = strong).
tert-butyl (R)-2-(3-(2-methoxy-4-fluorophenyl)-6-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12.4%
Stage #1: N-(tert-butoxycarbonyl)-D-proline; 2-amino-5-nitro-benzoic acid With pyridine; triphenyl phosphite at 100℃; for 0.666667h;
Stage #2: 4-fluoro-2-methoxyaniline at 80℃; for 0.333333h;
26.1 Step 1. Synthesis of tert-butyl (R) 2-(3-(2-methoxy-4-fluorophenyl)-6-nitro-4-oxo-3,4- dihydroquinazolin-2-yl) pyrroli-dine-1-carboxylate (1o).
5-Nitroanthranilic acid (182.13 mg, 1.00 mmol) and N-Boc-D-proline (280.00 mg, 1.30 mmol) were dissolved in dry pyridine (5 mL). Triphenyl phosphite (0.80 mL, 3.00 mmol) was added to the mixture and the reaction mixture was heated at 100 °C with MWI for 2×20 min.2-methoxy-4- fluoroaniline (169.36 mg, 1.20 mmol) was added to the mixture and the reaction mixture was heated at 80 °C with MWI for 2×10 min. Pyridine was removed in vacuo and the residue was diluted with CH2Cl2 (60 mL) and washed with 1N aqueous HCl (20 mL). The organic layer was subsequently washed with H2O (20 mL) and then brine (20 mL). The separated organic extract was dried over anhydrous Na2SO4. Once filtered, the solvent was evaporated under reduced pressure. The residue was purified by Waters LC- 150 Prep system (5% MeOH/ H2O ~70 % MeOH/ H2O) to afford 1o (60.00 mg, 12.4%) as off-white solid.1H NMR (500 MHz, CDCl3) d 9.04 (dd, J = 11.9, 2.4 Hz, 1H), 8.45 (ddd, J = 22.8, 9.0, 2.5 Hz, 1H), 7.71 (dd, J = 24.5, 9.0 Hz, 1H), 7.49-7.14 (m, 1H), 6.86- 6.66 (m, 2H), 4.60-4.42 (m, 1H), 3.79-3.63 (m, 4H), 3.50-3.30 (m, 1H), 2.09-1.72 (m, 4H), 1.36 (s, 4H), 1.21 (s, 5H). MS (ESI) m/z: 485 (M+1)+.
Stage #1: 1-amino-2-carboxy-4-nitrobenzene With dichlorosulfoxide In toluene for 15h; Reflux;
Stage #2: epsilon-caprolactam In toluene at 20℃; for 4h;
4.1.1 2-Nitro-7, 8, 9, 10-tetrahydroazepino [2, 1-b] quinazolin-12(6H)-one (17)
10g (0.1mol) of 2-amino-5-nitrobenzoic acid 16 was dissolved in dry toluene (50ml) in a 500-ml round-bottomed flask, and 25ml of thionyl chloride (0.25mol) was added to it. The reaction mixture was refluxed for 3h under anhydrous conditions overnight. After 12h, excess thionyl chloride and toluene were removed by using rota vapor. Toluene (100ml) and 9g (0.1mol) of caprolactam were added to the reaction mixture under cold conditions and stirred at room temperature for 4h. Progress of the reaction was monitored on TLC. The reaction mixture was basified with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate extract was dried and distilled under reduced pressure, which yielded a crude product. The crude product was purified by column chromatography. (hexane: ethyl acetate: 90:10) to give a solid product 17 in 55.7% yield; 1H NMR (300MHz, MeOD): δ 1.85-1.94 (m, 6H), 3.17-3.20 (m, 2H), 4.46-4.49 (m, 2H), 7.77 (d, J=9Hz, 1H), 8.57 (dd, J=9Hz, J= 3Hz, 1H), 9.00 (d, J=3Hz, 1H).
55.7%
Stage #1: 1-amino-2-carboxy-4-nitrobenzene With dichlorosulfoxide In toluene for 15h; Reflux;
Stage #2: epsilon-caprolactam In toluene at 20℃; for 4h;
4.1.1 2-Nitro-7, 8, 9, 10-tetrahydroazepino [2, 1-b] quinazolin-12(6H)-one (17)
10g (0.1mol) of 2-amino-5-nitrobenzoic acid 16 was dissolved in dry toluene (50ml) in a 500-ml round-bottomed flask, and 25ml of thionyl chloride (0.25mol) was added to it. The reaction mixture was refluxed for 3h under anhydrous conditions overnight. After 12h, excess thionyl chloride and toluene were removed by using rota vapor. Toluene (100ml) and 9g (0.1mol) of caprolactam were added to the reaction mixture under cold conditions and stirred at room temperature for 4h. Progress of the reaction was monitored on TLC. The reaction mixture was basified with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate extract was dried and distilled under reduced pressure, which yielded a crude product. The crude product was purified by column chromatography. (hexane: ethyl acetate: 90:10) to give a solid product 17 in 55.7% yield; 1H NMR (300MHz, MeOD): δ 1.85-1.94 (m, 6H), 3.17-3.20 (m, 2H), 4.46-4.49 (m, 2H), 7.77 (d, J=9Hz, 1H), 8.57 (dd, J=9Hz, J= 3Hz, 1H), 9.00 (d, J=3Hz, 1H).
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