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[ CAS No. 616-79-5 ]

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CAS No. :616-79-5 MDL No. :MFCD00017039
Formula : C7H6N2O4 Boiling Point : 437.9°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :182.13 g/mol Pubchem ID :12032
Synonyms :

Safety of [ 616-79-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
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[ 616-79-5 ] Synthesis Path-Upstream   1~17

  • 1
  • [ 616-79-5 ]
  • [ 19815-16-8 ]
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 ]
YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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 ]
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  • [ 74173-77-6 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2755 - 2766
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  • [ 57-13-6 ]
  • [ 616-79-5 ]
  • [ 32618-85-2 ]
YieldReaction ConditionsOperation 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
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  • [ 32618-85-2 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 8, p. 824 - 829
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  • [ 616-79-5 ]
  • [ 4693-02-1 ]
YieldReaction ConditionsOperation 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
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Reference: [1] Chemical Communications, 2014, vol. 50, # 43, p. 5748 - 5751
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YieldReaction ConditionsOperation 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
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  • [ 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
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  • [ 49592-84-9 ]
Reference: [1] Patent: WO2015/138919, 2015, A1,
  • 16
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  • [ 77242-30-9 ]
YieldReaction ConditionsOperation in experiment
98% With borane-THF In tetrahydrofuran at 0 - 30℃; for 23 h; Inert atmosphere 5.1.123
6,7-Didehydro-17-methyl-6'-nitroquinolino[2',3':6,7]morphinan-3,14β-diol (29b)
Compound 29b was prepared from compound 23b according to the procedure used to prepare compound 24a.
Yield, 92percent; a yellow oil.
IR (neat): 3365, 2918, 1612, 1528, 1345, 1239, 1051, 755 cm-1. 1H NMR (400 MHz, CDCl3) δ: 1.27-1.35 (1H, m), 2.11 (1H, dt, J = 5.3, 12.8 Hz), 2.25 (1H, dt, J = 2.8, 12.0 Hz), 2.36-2.48 (1H, m), 2.43 (3H, s), 2.90-3.00 (2H, m), 2.96 (1H, d, J = 18.0 Hz), 3.10 (1H, d, J = 18.0 Hz), 3.27 (1H, d, J = 18.0 Hz), 3.52 (1H, d, J = 17.6 Hz), 3.65 (1H, d, J = 17.6 Hz), 6.63 (1H, dd, J = 2.4, 8.4 Hz), 6.93 (1H, d, J = 2.4 Hz), 7.01 (1H, d, J = 8.4 Hz), 7.34 (1H, d, J = 9.6 Hz), 7.61 (1H, dd, J = 2.0, 9.6 Hz), 7.67 (1H, s), 8.29 (1H, d, J = 2.0 Hz), two protons (OH) were not observed. 13C NMR (100 MHz, CDCl3) δ: 23.9, 35.8, 36.1, 39.1, 40.4, 42.9, 45.3, 61.4, 69.2, 112.6, 115.0, 121.7, 123.3, 125.6, 127.0, 128.3, 129.2, 131.0, 137.2, 140.3, 144.4, 147.0, 155.2, 162.0. HRMS (ESI) Calcd for C24H24N3O4 [M+H]+: 418.1767. Found: 418.1748.
98%
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
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