* 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 the American Chemical Society, 1942, vol. 64, p. 2644,2646
2
[ 619-17-0 ]
[ 19815-17-9 ]
Reference:
[1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[2] Spectroscopy Letters, 2012, vol. 45, # 7, p. 530 - 540,11
[3] Patent: WO2014/120346, 2014, A1,
[4] Patent: CN103360382, 2016, B,
[5] Patent: CN103382182, 2016, B,
[6] Journal of the American Chemical Society, 2016, vol. 138, # 33, p. 10554 - 10560
[7] Patent: US2016/376298, 2016, A1,
[8] Patent: US2017/174638, 2017, A1,
3
[ 77287-34-4 ]
[ 619-17-0 ]
[ 20872-93-9 ]
Yield
Reaction Conditions
Operation in experiment
86.6%
at 150℃; for 16 h;
2-amino-4-nitrobenzoic acid (7.28g, 40.0mmol) and ammonium formate (3.78g, 60.0mmol) were added to 1OmL of formamide, heated to 150 ° C, incubated 16h, cooled to room temperature, Precipitation of solid,Filtered, washed with isopropanol and dried to give 6.62 g of 86 mg as a brown needles of 7-nitro-3H-quinazolin-4-one in 86.6percent yield.
83%
at 140℃;
General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 °C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2*2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 .x. 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 .x. 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
Reference:
[1] Journal of the American Chemical Society, 2016, vol. 138, # 33, p. 10554 - 10560
[2] Patent: US2017/174638, 2017, A1, . Location in patent: Paragraph 0045
[3] Tetrahedron Letters, 2003, vol. 44, # 24, p. 4455 - 4458
[4] Patent: CN103382182, 2016, B, . Location in patent: Paragraph 0113; 0115-0117
[5] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
[6] Journal of the American Chemical Society, 1908, vol. 30, p. 810
[7] Yakugaku Zasshi, 1942, vol. 62, p. 66,68; dtsch. Ref. S. 24[8] Chem.Abstr., 1951, p. 1580
[9] Patent: WO2014/120346, 2014, A1, . Location in patent: Page/Page column 33
[10] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
[11] Chemistry and Biodiversity, 2018, vol. 15, # 6,
4
[ 3473-63-0 ]
[ 619-17-0 ]
[ 20872-93-9 ]
Yield
Reaction Conditions
Operation in experiment
84%
at 130℃; for 18 h;
A mixture of 2-amino-4-nitrobenzoic acid (10.0 g, 54.93 mmol) was refluxed at 130° C. for 18 h in methoxyethanol (50 mL) and formamidine acetate (11.43 g, 109.81 mmol). The clear reaction mixture was cooled to room-temperature to form a yellowish precipitant. The solvent was removed under vacuum, and the precipitant was washed several times with aqueous ammonia (0.01 M). The solid was dried in vacuo to yield 8.9 g (84percent) of a light yellow powder. 1H NMR Data: dmso-d6-ppm (δ); 12.68 (1H), 8.37 (d, 1H), 8.33 (d, 1H), 8.26 (1H) and 8.23 (dd, 1H).
Example 8Synthesis of 7-aminoquinazolin-4-one 4-Nitroanthranilic acid (10.0 g, 54.9 mmol) and formamidine hydrochloride (6.63 g, 82.4 mmol) were ground together in a mortar and pestle to produce a fine, intimate mixture. The mixture was placed in a 250 mL round-bottom flask, and spread evenly over the surface. The flask was placed in an oilbath at 200° C. The solid underwent a color change, and a distillate was seen on the side of flask, but did not really melt. After 30 min the flask was removed from the heating bath. 0.3M sodium hydroxide solution (150 mL) was added to the cooled flask, the black solid mass was broken up with a spatula, and stirred for 1 h. The solid was filtered off and washed with water. The filtrate was discarded. The black solid was suspended in dichloromethane/methanol (10:1) and filtered through a plug of silica, eluting with the same solvent until no more product came off. The material was one spot by TLC, plus black baseline material, but was poorly soluble, so a large volume of solvent was needed.The filtrate was evaporated to dryness and the solid residue triturated with a little methanol and filtered to give 7-nitroquinazoline-4-one (4.65 g, 44percent).
Reference:
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3860 - 3873
[2] Patent: US2008/161297, 2008, A1, . Location in patent: Page/Page column 46
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 11, p. 3235 - 3239
6
[ 64392-62-7 ]
[ 619-17-0 ]
[ 20872-93-9 ]
Reference:
[1] Journal of Organic Chemistry, 1986, vol. 51, # 5, p. 616 - 620
7
[ 619-17-0 ]
[ 20872-93-9 ]
Reference:
[1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
8
[ 541-41-3 ]
[ 77-78-1 ]
[ 619-17-0 ]
[ 73043-80-8 ]
Reference:
[1] Journal of the Indian Chemical Society, 1979, vol. 56, # 7, p. 708 - 711
9
[ 7664-93-9 ]
[ 342045-62-9 ]
[ 610-36-6 ]
[ 619-17-0 ]
Reference:
[1] Journal of the American Chemical Society, 1909, vol. 31, p. 847
10
[ 619-17-0 ]
[ 31930-18-4 ]
Reference:
[1] Antimicrobial Agents and Chemotherapy, 2005, vol. 49, # 9, p. 3755 - 3761
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5080 - 5092
[4] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 3, p. 497 - 506
[5] Patent: WO2006/12374, 2006, A1, . Location in patent: Page/Page column 180-181
[6] Patent: US2003/225106, 2003, A1, . Location in patent: Page 86
[7] Journal of Agricultural and Food Chemistry, 2015, vol. 63, # 31, p. 6883 - 6889
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] European Journal of Medicinal Chemistry, 1994, vol. 29, # 12, p. 925 - 940
[3] Patent: EP1719771, 2006, A1, . Location in patent: Page/Page column 51
[4] Journal of Agricultural and Food Chemistry, 2015, vol. 63, # 31, p. 6883 - 6889
15
[ 530-62-1 ]
[ 619-17-0 ]
[ 63480-10-4 ]
Reference:
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 7979 - 7991
[2] Patent: US2011/263559, 2011, A1, . Location in patent: Page/Page column 20
16
[ 619-17-0 ]
[ 87376-25-8 ]
Reference:
[1] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 3, p. 497 - 506
17
[ 619-17-0 ]
[ 78468-34-5 ]
Yield
Reaction Conditions
Operation in experiment
91%
With borane-THF In tetrahydrofuran at 0 - 30℃; for 1 h; Inert atmosphere
With borane-THF In tetrahydrofuran at 20℃; for 12 h;
To a solution of 2-amino-4-nitrobenzoic acid (1.00 g, 5.49 mmol) in THF (20 mL) at room temperature was added BH3THF (21.96 mL, 21.96 mmol) dropwise via an addition funnel. The reaction mixture was stirred at room temperature for 12h. The reaction was then cooled in an ice bath and quenched by slow addition ofmethanol (100 mL). The mixture was concentrated and the residue was transferred toa separatory funnel containing saturated aqueous NaHCO3 solution (50 mL). The aqueous layer was extracted with ether (3 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated. The residue was suspended in water, filtered and dried to afford (2-amino-4-nitrophenyl)methanol (650 mg, 70percent yield) as an orange solid: ‘H NMR (400MHz, DMSO-d6) ö 7.46 (d, J=2.0 Hz, 1H), 7.38 - 7.35 (m, 2H), 5.57 (s, 2H), 5.34 (t, J5.4 Hz, 1H), 4.43 (d, J5.5 Hz, 2H).
Reference:
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[2] Patent: WO2015/6100, 2015, A1, . Location in patent: Page/Page column 113
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5080 - 5092
[4] Patent: US2003/195201, 2003, A1,
[5] Journal of Organic Chemistry, 2010, vol. 75, # 20, p. 7033 - 7036
[6] Patent: WO2015/95795, 2015, A1, . Location in patent: Paragraph 0585
2-amino-4-nitrobenzoic acid (7.28g, 40.0mmol) and ammonium formate (3.78g, 60.0mmol) were added to 1OmL of formamide, heated to 150 C, incubated 16h, cooled to room temperature, Precipitation of solid,Filtered, washed with isopropanol and dried to give 6.62 g of 86 mg as a brown needles of 7-nitro-3H-quinazolin-4-one in 86.6% yield.
83%
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.
at 150℃; for 1h;Microwave irradiation;
Step A: 7-nitroquinazolin-4(3H)-one A mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 82 mmol) and formamide (8 mL, 201.5 mmol) in a microwave reaction vessel was heated in a microwave reactor at 150 C for 1 h. The resulting slurry was cooled to room temperature, stirred with aqueous NaHC03, filtered and the solid was washed with water and Et20 then vacuum dried to provide 7-nitroquinazolin-4(3H)-one as a dark brown solid. LCMS calc. = 192.03; found = 192.16 (M+H)+.
at 130 - 135℃; for 4h;
General procedure: Compound 18 was prepared accordingto the procedure previously reported.39 A mixture of anthranilicacid 11 (0.1 mol) and formamide (18 g, 0.4 mol) was heated at130-135 C. After the mixture had been stirred for 4 h, water(40 mL) was added. The reaction mixture was cooled to 60 C,and water (20 mL) was added to the mixture. After the mixturehad been stirred for 30 min, the precipitated product wasfiltered off with suction. The crude products were recrystallizedwith ethanol to give compound 18 in yields of 80-95%.
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.
2-Amino-4-nitrobenzoic acid 1a (2.21 g, 10 mmol) and urea (6.0 g, 100 mmol) were stirred at 160 C for 6 h, then cooled to 100 C and water (60 mL) was added. The solution was stirred for 5 min, the formed precipitate was filtered off, washed with cold water and further suspended in 0.5 N NaOH. The mixture was refluxed for 5 min, then cooled to rt. The pH was adjusted to 2 with conc. HCl. Crude 2a was filtered off, washed with MeOH/H2O (1:1), dried in vacuo to give 2a (1.85 g, 90% yield) as light-brown powder. MS (ESI + APCI) m/z: 206.0 [M-H]-.
To a solution of 2-amino-4-nitrobenzoic acid (102 g, 560 mmol) in MeOH (1.5 L) was added slowly concentrated sulfuric acid (0.030 L, 560 mmol). The resulting solution was heated at about 75 C for about 3 days. After cooling, the product was neutralized by addition of aqueous NaOH solution until pH- 10. The crude product was extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and concentrated to provide methyl 2-amino-4-nitrobenzoate (100 g, 91%). LC/MS (Table 1, Method ar) R = 1.85 mm; MS m/z 197.1 (M+H).
90%
Example 9Synthesis of 6-chloro-7-aminoquinazolin-4-one Methanol (500 mL) and concentrated H2SO4 (25 mL) were added to 4-nitroanthranilic acid (30.0 g, 165.0 mmol) and the reaction mixture was heated at reflux for 48 h. The resulting solution was concentrated and saturated NaHCO3 (200 mL) was added. The aqueous layer was extracted with EtOAc (2×150 mL). The combined organic extracts were washed with water (100 mL), and brine (100 mL), dried over Na2SO4, filtered, and concentrated to give the methyl ester (29.0 g, 90%) as an intense orange solid.
88%
With thionyl chloride;Heating / reflux;
Example 160; 2-phenyl-4-(piperidin-3-ylamino)-lH-indole-7-carboxamide; methyl 2-amino-4-nitrobenzoate; To a solution of 2-amino-4-nitrobenzoic acid (24 g, 0.132 mol) in MeOH (500 mL) is slowly added thionyl chloride (96 mL). The resulting solution is refluxed overnight. Upon cooling, the crystalline product is isolated by filtration and drying under high vacuum (22.9 g, 88%). 1H NMR delta 7.90 (d, 1 H) 7.67 (d, 1 H) 7.25 (dd, 1 H) 7.13 (s, 2 H) 3.84 (s, 3 H).
With thionyl chloride; at 0℃; for 8h;Reflux;
An oven dried 250 nil two-neck round bottom flask was discharged with 2-amino-4- nitrobenzoic acid (10.0 g, 54.94 mmol) and dissolved in 100 mL of methanol. To this solution SOCl2 (12 ml) was added drop by drop using addition funnel at 0 C. The reaction mixture gradually was reflu ed for a period of 8 hours using calcium sulphate guard tube, Volatiles were removed using in vacuo evaporation and the residue was quenched with deionized water. The crude residue was filtered and washed several times with saturated solution of sodium bicarbonate till TLC showed complete removal of starting carboxylic acid. The crude amino ester was dried and the resultant yellow solid amino ester (8.0 g, 40.81 mmol, 1 equiv.) was taken in a 250 ml round bottom flask and dissolved in 12 N H2S04 (100 mL) at 0 C. NaN02 (3.38 g, 48,98 mmol, 1.2 equiv.) was dissolved in minimum amount of water and added drop wise to the above mixture at -10 C. Stirring was continued at the same temperature for a period of 2 hours. Urea (1 g) was added to the mixture to remove if any excess nitrous acid remained in the reaction mixture. In a separate beaker was dissolved KI ( 13.55 g, 81.62 mmol, 2,0 equiv.) in 20 ml of deionized water and kept stirring at a temperature of -10 C. To this solution of KI was added the diazonium hydrochloride salt obtained above at -10 C drop wise using addition funnel. Stirring of the reaction continued for a period of 8 hours at room temperature. The reaction mixture was diluted with 100 ml of EtOAc and 100 ml of deionized water. Small amount of iodine liberated in the iodination reaction was quenched by the addition of sodium dithionite. Organic layer was separated and was sequentially treated with saturated NaHC03, saturated brine, and anhydrous Na2S04 followed by the adsorption of silica gel. Flash chromatography using EtOAc: petroleum ether (1 :3) afforded the iodo compound 8 as a light yellow solid (12.53 g, 70% yield). [0393] FontWeight="Bold" FontSize="10" I NMR (400 MHz, CDC13, TMS) delta: 3.99 (s, 3H), 7.90 (d, i l l J = 8.70 Hz), 8.22-8.28 (dd, I Ji = 2.29 Hz, J2 - 8.24 Hz), 8.80 (d. 1 1 1. J = 2.29 Hz), 13C NMR (100 MHz, CDC13) 6. 53.11, 93.42, 122.72, 131.13, 135.80, 140.97, 148.83, 165,71 ,
With sulfuric acid;Heating / reflux;
Description 9: Methyl 2-amino-4-nitrobenzoate; Concentrated sulphuric acid (4 rmL) was added dropwise to a solution of 4-nitroanthranilic (2g, 11 mmol) in methanol (4OmL) and the solution was heated under reflux overnight. The solvent was evaporated, the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried (magnesium sulphate), evaporated and triturated with ether to give the title compound (1.5g) as a yellow solid.
With ammonium sulfate; In ethanol; at 100℃; for 1.08333h;Microwave irradiation;
First, 80 g of phthalic anhydride was added to a 500 mL four-necked flask, and 180 mL of concentrated sulfuric acid was slowly added thereto. After stirring for 10 minutes, the mixture was placed in a water bath and 60 g of fuming nitric acid was added dropwise at 70 C. After the completion of the dropwise addition, the reaction was stirred at 70 C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature with an ice bath and filtered. The residue was washed three times with water and then dissolved in 100 mL of distilled water. Keeping at 55 C for 1 h, filtering, drying the residue to obtain 4-nitrophthalic acid; 100g of 4-nitro phthalic acid added to four-necked flask, to which was added 30mL of acetic anhydride, stirred until solid was completely dissolved at 90 deg.] C, temperature was raised to 120 deg.] C and dissolved,Stirring at 90 C until all the solid dissolved, dissolved and heated to 120 C and maintained at this temperature for 2h, and side reaction while stirring, after cooling the reaction to room temperature, filtration, take the filter cake washed with ether 2, Dried at 40 C for 4 hours to obtain 4-nitrophthalic anhydride; 20 g of urea was added to a 500-mL three-necked flask, placed in a water bath, and the 4-nitrophthalic anhydride was added to the flask in 3 portions at a controlled temperature of 5 C, And the temperature was gradually raised to 70 C after the completion of the addition, so that 4-nitrophthalic anhydride was completely dissolved, and the temperature was lowered to 45 C. The flask was evacuated and 10 mL of the solid was precipitated when no more solid precipitated And then the mixture was stirred for 20 min at 400 rpm. After stirring, the mixture was cooled to room temperature, filtered, washed with distilled water and dried at 50 C. Giving 4-nitro-2-carbamoylbenzoic acid; To a 500 mL four-necked flask, 40 mL of a 10% aqueous solution of sodium hypochlorite was placed in an ice bath, and 100 g of the 4-nitro-2-carbamoylbenzoic acid obtained above was added thereto at 0 C. The temperature was increased to 30 C, After the reaction, the reaction was cooled to -5 C, and immediately after cooling, the mixture was suction filtered and the residue was dried at 60 C to obtain 2-amino-4-nitrobenzoic acid. To a 250 mL three-necked flask, 15 g of the 2-amino-4-nitrobenzoic acid obtained above was added, and 90 mL of absolute ethanol was added thereto. The mixture was refluxed at 100 C for 1 hour. After refluxing, 50 mL of 9% Ammonium sulfate solution, in the 800W microwave heating continue to return under 5min, hot filter, wash the residue to pH 7, the combined filtrate, pour 50g ice water and stir quickly, standing 5min after the crude product precipitation, with the quality The crude product was dissolved in 30% hydrochloric acid and filtered. The filtrate with 30% ammonia water quality adjusted to pH 3, solid precipitation after the filter, the residue placed 60 drying, can be 2,4-diaminobenzoic acid.
With potassium iodide; sodium nitrite; In concentrated aqueous HCl; water;
Step 1 Preparation of 2-iodo-4-nitrobenzoic acid. To a stirred solution of 4-nitroanthranilic acid (1.82g) in concentrated aqueous HCl (30ml) cooled to -5C was added sodium nitrite (760mg) in water (3ml) keeping the temperature below 0C. The mixture was cooled to -5C and, after 15 minutes, it was added to a solution of potassium iodide (2g) in water (10ml) and stirred for 20 hours. The mixture was diluted with ethyl acetate, and the organic layer washed with 10% aqueous sodium thiosulphate, dried (MgSO4) and concentrated under reduced pressure to give a yellow solid (1.83g) which was used without further purification in Step 2; 1H NMR (270MHz; CDCl3) delta 8.12(1H,d), 8.3(1H,dd), 8.88(1H,d) ppm.
With potassium iodide; sodium nitrite; In water; at 20 - 75℃; for 0.5h;
Reference Example 82; 2-Iodo-N-methoxy-N-methyl-4-nitrobenzamide; [Show Image] An aqueous solution (8 ml) of sodium nitrite (2.27 g) was added to an aqueous solution (40 ml) of 4-nitroanthranilic acid (5.00 g) under ice-cooling. Subsequently, an aqueous solution (6 ml) of potassium iodide (5.47 g) was added to the mixture, followed by stirring at room temperature for 20 minutes, and then the mixture was heated to 75C, followed by further stirring for 10 minutes. After completion of the reaction, sodium hydrogen sulfite was added to the mixture under ice-cooling, and the mixture was extracted with dichloromethane-methanol (10:1, v/v). The organic layer was washed with water and saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent was again dissolved in water and the same operation described in the above was repeated, and the thus obtained residue was used in the subsequent reaction without purification.
With sulfuric acid; potassium iodide; sodium nitrite; In water; at 0 - 20℃;
A 3 L fully jacketed flask equipped with a mechanical stirrer, temperature probe and an addition funnel undera nitrogen atmosphere, was charged with 2-amino-4-nitrobenzoic acid (69.1 g, Combi-Blocks) and sulfuricacid, 1.5 M aqueous (696 mL). The resulting suspension was cooled to 0 C. internal temperature, and asolution of sodium nitrite (28.8 g) in water (250 mL) was added dropwise over 43 minutes with thetemperature kept below 1 C. The reaction mixture was stirred at ca. 0 C. for 1 hour. A solution ofpotassium iodide (107 g) in water (250 mL) was added dropwise over 44 minutes with the internaltemperature kept below 1 C. (Initially addition was exothermic and there was gas evolution). The reactionmixture was stirred 1 hour at 0 C. The temperature was raised to 20 C. and then stirred at ambienttemperature overnight. The reaction mixture became a suspension. The reaction mixture was filtered, and thecollected solid was washed with water. The wet solid (108 g) was stirred in 10% sodium sulfite (350 ml, with200 mL water used to wash in the solid) for 30 minutes. The suspension was acidified with concentratedhydrochloric acid (35 mL), and the solid was collected by filtration and washed with water. The solid wasslurried in water (1 L) and re-filtered, and the solid was left to dry in the funnel overnight. The solid was thendried in a vacuum oven for 2 hours at 60 C. The resulting solid was triturated with dichloromethane (500mL), and the suspension was filtered and washed with additional dichloromethane. The solid was air-dried toprovide the title compound. MS (ESI) m/e 291.8 (M-H)-.
[0001171] 2-Amino-4-nitrobenzoic acid (50 g) was added to a mixture of concentrated H2SO4 (75 mL) and water (750 mL) at 0 C, and the mixture was stirred for 1 hour. To the mixture was added a mixture of sodium nitrite (24.62 g) in water (300 mL) dropwise at 0 C. The resulting mixture was stirred at 0 C for 3 hours. A mixture of sodium iodide (65.8 g) in water (300 mL) was added to above mixture slowly. After the completion of the addition, the resulting mixture was stirred at 0 C for 2 hours, then at room temperature for 16 hours and at 60 C for 2 hours. The resulting mixture was cooled to room temperature and diluted with ice-water (300 mL). The solid was collected by filtration, washed by water (100 mL x 5), and dried in air for 16 hours to give the title compound. MS (LC-MS) m/e 291.9 (M-H)".
A 3L fully jacketed flask equipped with a mechanical stirrer, temperature probe and an addition funnel under a nitrogen atmosphere, was charged with 2-amino-4-nitrobenzoic acid (69.1 g, Combi-B locks) and sulfuric acid, 1.5 M aqueous (696 mL). The resulting suspension was cooled to 0 C internal temperature, and a solution of sodium nitrite (28.8 g) in water (250 mL) was added dropwise over 43 minutes with the temperature kept below 1 C. The reaction mixture was stirred at ca. 0 C for 1 hour. A solution of potassium iodide (107 g) in water (250 mL) was added dropwise over 44 minutes with the internal temperature kept below 1 C. (Initially addition was exothermic and there was gas evolution). The reaction mixture was stirred 1 hour at 0 C. The temperature was raised to 20 C and then stirred at ambient temperature overnight. The reaction mixture became a suspension. The reaction mixture was filtered, and the collected solid was washed with water. The wet solid (~ 108 g) was stirred in 10 % sodium sulfite (350 mL, with ~ 200 mL water used to wash in the solid) for 30 minutes. The suspension was acidified with concentrated hydrochloric acid (35 mL), and the solid was collected by filtration and washed with water. The solid was slurried in water (1L) and re -filtered, and the solid was left to dry in the funnel overnight. The solid was then dried in a vacuum oven for 2 hours at 60 C. The resulting solid was triturated with dichloromethane (500 mL), and the suspension was filtered and washed with additional dichloromethane. The solid was air-dried to provide the title compound. MS (ESI) m/e 291.8 (M-H) .
A 3L fully jacketed flask equipped with a mechanical stirrer, temperature probe and anaddition funnel under a nitrogen atmosphere, was charged with 2-amino-4-nitrobenzoic acid (69.1 g,Combi-Blocks) and sulfuric acid, 1.5 M aqueous (696 mL). The resulting suspension was cooled to 020 oc internal temperature, and a solution of sodium nitrite (28.8 g) in water (250 mL) was addeddropwise over 43 minutes with the temperature kept below 1 C. The reaction mixture was stirred atca. 0 oc for 1 hour. A solution of potassium iodide (107 g) in water (250 mL) was added dropwiseover 44 minutes with the internal temperature kept below 1 oc. (Initially addition was exothermicand there was gas evolution). The reaction mixture was stirred 1 hour at 0 C. The temperature was25 raised to 20 oc and then stirred at ambient temperature overnight. The reaction mixture became asuspension. The reaction mixture was filtered, and the collected solid was washed with water. Thewet solid (- 108 g) was stirred in 10 % sodium sulfite (350 mL, with - 200 mL water used to wash inthe solid) for 30 minutes. The suspension was acidified with concentrated hydrochloric acid (35mL), and the solid was collected by filtration and washed with water. The solid was slurried in water30 (IL) and re-filtered, and the solid was left to dry in the funnel overnight. The solid was then dried ina vacuum oven for 2 hours at 60 C. The resulting solid was triturated with dichloromethane (500mL), and the suspension was filtered and washed with additional dichloromethane. The solid wasair-dried to provide the title compound. MS (ESI) m/e 291.8 (M-H).
A 3L fully jacketed flask equipped with a mechanical stirrer, temperature probe and an addition funnel under a nitrogen atmosphere was charged with 2-amino-4-nitrobenzoic acid (69.1 g, Combi-Blocks) and sulfuric acid, 1.5 M aqueous (696 mL). The resulting suspension was cooled to 0 C internal temperature, and a mixture of sodium nitrite (28.8 g) in water (250 mL) was added dropwise over 43 minutes with the temperature kept below 1 C. The reaction was stirred at ca.0 C for 1 hour. A mixture of potassium iodide (107 g) in water (250 mL) was added dropwise over 44 minutes with the internal temperature kept below 1 C. (Initially addition was exothermic and there was gas evolution). The reaction was stirred 1 hour at 0 C. The temperature was raised to 20 C and then stirred at ambient temperature overnight. The reaction mixture became a suspension. The reaction mixture was filtered, and the collected solid was washed with water. The wet solid (~ 108 g) was stirred in 10 % sodium sulfite (350 ml, with ~ 200 mL water used to wash in the solid) for 30 minutes. The suspension was acidified with concentrated hydrochloric acid (35 mL), and the solid was collected by filtration and washed with water. The solid was slurried in water (1L) and re- filtered, and the solid was left to dry in the funnel overnight. The solid was then dried in a vacuum oven for 2 hours at 60 C. The resulting solid was triturated with dichloromethane (500 mL), and the suspension was filtered and washed with additional dichloromethane. The solid was air-dried to give the title compound.
A 3L fully jacketed flask equipped with a mechanical stiffer, temperature probe and an addition funnel, under a nitrogen atmosphere, was charged with 2-amino-4-nitrobenzoic acid (69.1 g, Combi10 Blocks) and sulfuric acid, 1.5 M aqueous (696 mL). The resulting orange suspension was cooled to 0C internal temperature, and a solution of sodium nitrite (28.8 g) in water (250 mL) was added dropwise over 43 minutes with the temperature kept below 1 C. The reaction was stirred at ca. 0 C for 1 hour. A solution of potassium iodide (107 g) in water (250 mL) was added dropwise over 44 minutes with the internal temperature kept below 1 C. (Initially addition is exothermic and there isgas evolution). The reaction was stirred 1 hour at 0 C. The temperature was raised to 20 C and then stirred at ambient temperature overnight. The reaction mixture became an orange suspension. The reaction mixture was filtered, and the collected orange solid was washed with water. The wet orange solid (-.. 108 g) was stirred in 10 % sodium sulfite (350 nil, with - 200 mL water used to wash in the solid) for 30 minutes. The orange suspension was acidified with concentrated hydrochloric acid (35mL), and the solid was collected by filtration and washed with water. The solid was slunied in water (1L) and re-filtered, and the solid was left to dry in the funnel overnight. The solid was then dried in a vacuum oven for 2 hours at 60 C. The resulting bright orange solid was triturated with dichloromethane (500 mL), and the suspension was filtered and washed with additional dichloromethane. The solid was air-dried to give the title product
A 3L fully jacketed flask equipped with a mechanical stirrer, temperature probe and an addition funnel under a nitrogen atmosphere, was charged with 2-amino-4-nitrobenzoic acid (69.1 g, Combi-Blocks) and sulfuric acid, 1.5 M aqueous (696 mL). The resulting suspension was cooled to 0 C. Internal temperature, and a mixture of sodium nitrite (28.8 g) in water (250 mL) was added dropwise over 43 minutes with the temperature kept below 1 C. The reaction was stirred at ca. 0 C. for 1 hour. A mixture of potassium iodide (107 g) in water (250 mL) was added dropwise over 44 minutes with the internal temperature kept below 1 C. (Initially addition was exothermic and there was gas evolution). The reaction was stirred 1 hour at 0 C. The temperature was raised to 20 C. and then stirred at ambient temperature overnight. The reaction mixture became a suspension. The reaction mixture was filtered, and the collected solid was washed with water. The wet solid (?108 g) was stirred in 10% sodium sulfite (350 ml, with ?200 mL water used to wash in the solid) for 30 minutes. The suspension was acidified with concentrated hydrochloric acid (35 mL), and the solid was collected by filtration and washed with water. The solid was slurried in water (1L) and re-filtered, and the solid was left to dry in the funnel overnight. The solid was then dried in a vacuum oven for 2 hours at 60 C. The resulting solid was triturated with dichloromethane (500 mL), and the suspension was filtered and washed with additional dichloromethane. The solid was air-dried to give the title compound.
A 3 L fully jacketed flask equipped with a mechanical stirrer, temperature probe and an addition funnel, under a nitrogen atmosphere, was charged with 2-amino-4-nitrobenzoic acid (69.1 g, Combi-Blocks) and sulfuric acid, 1.5 M aqueous (696 mL). The resulting orange suspension was cooled to 0 C. internal temperature, and a solution of sodium nitrite (28.8 g) in water (250 mL) was added dropwise over 43 minutes with the temperature kept below 1 C. The reaction was stirred at ca. 0 OC for 1 hour. A solution of potassium iodide (107 g) in water (250 mL) was added dropwise over 44 minutes with the internal temperature kept below 1 C. (Initially addition is exothermic and there is gas evolution). The reaction was stirred 1 hour at 0 C. The temperature was raised to 20 C. and then stirred at ambient temperature overnight. The reaction mixture became an orange suspension. The reaction mixture was filtered, and the collected orange solid was washed with water. The wet orange solid (?108 g) was stirred in 10% sodium sulfite (350 ml, with ?200 mL water used to wash in the solid) for 30 minutes. The orange suspension was acidified with concentrated hydrochloric acid (35 mL), and the solid was collected by filtration and washed with water. The solid was slurried in water (1 L) and re-filtered, and the solid was left to dry in the funnel overnight. The solid was then dried in a vacuum oven for 2 hours at 60 C. The resulting bright orange solid was triturated with dichloromethane (500 mL), and the suspension was filtered and washed with additional dichloromethane. The solid was air-dried to give the title product
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).
In tetrahydrofuran; at 45℃; for 10h;
A mixture of 4-nitroanthranilic acid (9.11 g), triphosgene (4.92 g) and tetrahydrofuran (240 ml) was stirred for 10 hours at 45 C. The precipitated solids were collected by filtration, washed with tetrahydrofuran, and then dried to obtain the target product (700 g). 1H-NMR (DMSO-d6, 300 MHz): delta 7.85 (1H, d, J = 2.3 Hz), 7.95 (1H, dd, J = 8.6, 2.3 Hz), 8.15 (1H, d, J = 8.6 Hz), 12.07 (1H, br).
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%.
Example 8Synthesis of 7-aminoquinazolin-4-one 4-Nitroanthranilic acid (10.0 g, 54.9 mmol) and formamidine hydrochloride (6.63 g, 82.4 mmol) were ground together in a mortar and pestle to produce a fine, intimate mixture. The mixture was placed in a 250 mL round-bottom flask, and spread evenly over the surface. The flask was placed in an oilbath at 200 C. The solid underwent a color change, and a distillate was seen on the side of flask, but did not really melt. After 30 min the flask was removed from the heating bath. 0.3M sodium hydroxide solution (150 mL) was added to the cooled flask, the black solid mass was broken up with a spatula, and stirred for 1 h. The solid was filtered off and washed with water. The filtrate was discarded. The black solid was suspended in dichloromethane/methanol (10:1) and filtered through a plug of silica, eluting with the same solvent until no more product came off. The material was one spot by TLC, plus black baseline material, but was poorly soluble, so a large volume of solvent was needed.The filtrate was evaporated to dryness and the solid residue triturated with a little methanol and filtered to give 7-nitroquinazoline-4-one (4.65 g, 44%).
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃;
To a solution of 2-amino-4-nitro-benzoic acid (9.1 g, 50mmol) in CH2C12 (500 mL) was added EDC (12 gram, 60 mmol) ,HOBt (6.8 g, 50 ramol) , DIEA (12 mL) , and NH3 in MeOH (2M, 40mL). The reaction was stirred at RT for overnight, and aprecipitation formed. The solid was isolated via vacuumfiltration.
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃;
To a solution of 2-amino-4-nitro-benzoic acid (9.1 g, 50 mmol) in CH2Cl2 (500 mL) was added EDC (12 gram, 60 mmol), HOBt (6.8 g, 50 mmol), DIEA (12 mL), and NH3 in MeOH (2M, 40 mL). The reaction was stirred at RT for overnight, and a precipitation formed. The solid was isolated via vacuum filtration.
With borane-THF; In tetrahydrofuran; at 20℃; for 12h;
To a solution of 2-amino-4-nitrobenzoic acid (1.00 g, 5.49 mmol) in THF (20 mL) at room temperature was added BH3THF (21.96 mL, 21.96 mmol) dropwise via an addition funnel. The reaction mixture was stirred at room temperature for 12h. The reaction was then cooled in an ice bath and quenched by slow addition ofmethanol (100 mL). The mixture was concentrated and the residue was transferred toa separatory funnel containing saturated aqueous NaHCO3 solution (50 mL). The aqueous layer was extracted with ether (3 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated. The residue was suspended in water, filtered and dried to afford (2-amino-4-nitrophenyl)methanol (650 mg, 70% yield) as an orange solid: ?H NMR (400MHz, DMSO-d6) oe 7.46 (d, J=2.0 Hz, 1H), 7.38 - 7.35 (m, 2H), 5.57 (s, 2H), 5.34 (t, J5.4 Hz, 1H), 4.43 (d, J5.5 Hz, 2H).
With sodium hydroxide; In tetrahydrofuran; methanol;
(a) (2-Amino-4-nitrophenyl)methan-1-ol. To a solution of 4-nitroanthranilic acid (910 mg, 5.0 mmol, Aldrich) in THF (15 mL), magnetically stirred at 0 C., was added borane-tetrahydrofuran complex (15 mL, 15 mmol, 1.0 M in THF, Aldrich) dropwise. The reaction mixture was heated to reflux overnight. The mixture was then cooled to 0 C. and treated dropwise with MeOH (5 mL) followed by 1 N NaOH (30 mL). After stirring for 30 min at room temperature, the mixture was extracted with EtOAc (2*50 mL). The combined organic phases were washed with satd NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (50% EtOAc/hexane) followed by recrystallization from EtOAc/hexane provided the title product. MS (ESI, pos. ion) m/z: 169 (M+1).
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 90℃; for 4h;Sealed tube; Inert atmosphere;
Step 1 - Preparation of (2-amino-4-nitrophenyl)methanol [0585] To a solution of 2-amino-4-nitrobenzoic acid (10 g, 54.9 mmol) in THF (150 mL), which was stirred in a 500 mL of sealed tube, was slowly added BH3-DMS (15.64 mL, 165 mmol) dropwise at 0 C under N2. The resulting mixture was stirred at 90 C for 4 h, then cooled to 0 C and treated dropwise with MeOH (60 mL). The resulting suspension was concentrated to afford the crude titled compound as a yellow solid, which was directly used in the next step without further purification. LCMS (ESI) calculated for C7H9N203 [M+H]+: 169 found: 169. 1HNMR (CDC13, 400 MHz) delta 7.54 (1H, s), 7.46 (1H, dd, J= 8.0, 1.6 Hz), 7.31 (1H, d, J= 8.4 Hz), 4.60(2H, s).
a) A mixture of 5 g (0.027 mol) of 2-amino-4-nitrobenzoic acid and 16.5 g (0.27 mol) of urea was heated to 160 C. for 2 hrs. and at 180 C. for a further 2 hrs. The resulting brown mass was triturated with 200 ml of methanol, filtered off and dried in a vacuum. 4.8 g (80%) of 7-nitro-1,2,3,4-tetrahydro-quinazoline-2,4-dione were obtained as a white solid; MS: me/e=207 (M+).
Step 1: To a solution of 4-nitro-anthranilic acid (2.200 g, 10.9 mmol, 1 eq) in benzene/methanol (4/1) (100 mL) was added TMSCHN2 (2M in hexanes) (12 mL, 24 mmol, 2.2 eq). The reaction was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 4-nitro-anthranilic acid methyl ester (1.841 g, 86%) as a bright yellow solid. 1H NMR (300 MHz, CDCl3); delta 8.00 (d, 1H), 7.50 (d, 1H), 7.40 (dd, 1H), 3.92 (s, 3H).
With thionyl chloride; trichlorophosphate; In pyridine; methanol; water;
Step 1: A solution of 2-amino-4-nitrobenzoic acid (182 mg, 1 mmol, 1 equiv) in 10 mL of methanol was treated with thionyl chloride in portions until complete reaction. The solvent was evaporated and the residue was dissolved in 10 mL of pyridine. To the solution were added 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1 equiv) and POCl3 (0.93 mL, 10 equiv). The resulting mixture was stirred at rt overnight, quenched by slow addition of water, and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and flash chromatographied to give methyl 2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)amino-4-nitrobenzoate (430 mg, 84%). MS found for C25H26N3O7S (M+H)+: 512.
84%
With thionyl chloride; trichlorophosphate; In pyridine; methanol; water;
Step 1: A solution of 2-amino-4-nitrobenzoic acid (182 mg, 1 mmol, 1 equiv) in 10 mL of methanol was treated with thionyl chloride in portions until complete reaction. The solvent was evaporated and the residue was dissolved in 10 mL of pyridine. To the solution were added 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1 equiv) and POCl3 (0.93 mL, 10 equiv). The resulting mixture was stirred at rt overnight, quenched by slow addition of water, and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and flash chromatographied to give methyl 2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)amino-4-nitrobenzoate (430 mg, 84%). MS found for C25H26N3O7S (M+H)+: 512.
With triethylamine; In N,N-dimethyl-formamide; at 75℃; for 2h;
2,4,6-Trimethylphenylisocyanate (0.292 g, 1.81 mmol) was added to a mixture of 2- amino-4-nitrobenzoic acid (0.300 g, 1.65 mmol) and triethylamine (0.46 mL, 3.3 mmol) in 10 mL of anhydrous DMF. The mixture was heated to 75C for 2 hours.After cooling to room temperature, 2 mL of 6N hydrochloric acid was added and the mixture was diluted with water. The precipitated solid was collected by filtration, washed with water and dried under vacuum to give 0.576 g of a light brown solid containing about 80% of the desired product.; 2,4,6-Trimethylphenylisocyanate (2.92 g, 18.1 mmol) was added to a mixture of 2- amino-4-nitrobenzoic acid (3.00 g, 16.5 mmol) and triethylamine (4.6 mL, 33.0 mmol) in 100 mL of anhydrous DMF. The mixture was heated to 75C for 2 hours. After cooling to room temperature, 20 mL of 6N hydrochloric acid was added and the mixture was diluted with water. The precipitated solid was collected by filtration, washed with water and dried under vacuum to give 5.97 g of a yellow solid. This crude product was carried further without additional purification.
18.A (A)
(A) Synthesis of 4-nitro-N-acetyl-anthranilic acid A solution prepared by dissolving 1 42 g of 4-nitro anthranilic acid in 5 ml of acetic anhydride was heated and stirred at a temperature of 140° C. for 2 hours. The resultant reaction solution was poured onto ice. The resultant deposit was collected by filtration, washed with cold water and then dried. A crude product containing 7-nitro-2-methyl-4H-3,1-benzoxazin-4-one was obtained in an amount of 1.51 g. A portion (829 mg) of the crude product was dissolved in 5 ml of tetrahydrofuran, the resultant solution was mixed with 2 ml of an 1N-sodium hydroxide aqueous solution, and the reaction mixture was heated for 1.5 hours while refluxing. The reaction mixture was acidified with an 1N-hydrochroric acid and extracted with ethyl acetate. The resultant organic phase was washed with a saturated brine, and dried with anhydrors magnesium sulfate. The organic phase was concentrated under a reduced pressure. A final product consisting of 4-nitro-N-acetyl anthranilic acid was obtained in an amount of 890 mg.
2-(2-amino-8-hydroxy-6-sulfo-1-naphthylazo)-4-nitrobenzoic acid, disodium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium acetate trihydrate; acetic acid; sodium nitrite; In sodium hydroxide; water;
EXAMPLE 3 4,4'-Ureylenebis[2-(2-amino-8-hydroxy-6-sulfo-1-naphthylazo)benzoic acid], tetrasodium salt A hot solution of 18.2 g of 4-nitroanthranilic acid in 300 ml of water and 22 ml of 5N sodium hydroxide is filtered and 6.9 g of sodium nitrite is added to the filtrate. The resulting solution is poured over a mixture of 34 ml of concentrated hydrochloric acid, 50 ml of acetic acid and 350 g of crushed ice which is cooled in an ice-salt bath. The mixture is stirred for approximately 15 minutes, then a solution of 41 g of sodium acetate trihydrate in 60 ml of water is added followed by a solution of 25 g of 96% 7-amino-1-naphthol-3-sulfonic acid in 24 ml of 5N sodium hydroxide plus 50 ml of water. The mixture is stirred for approximately 5 minutes, then is warmed on a steam bath to 70 C. and is filtered through diatomaceous earth. The filtrate is concentrated to approximately 500 ml and 35 g of sodium hydroxide plus 50 g of sodium acetate trihydrate is added. The mixture is filtered and the product is washed with a 33% aqueous solution of sodium acetate trihydrate then with ethanol and ether. The product is dried overnight on the abderhalden at 110 C. to give 2-(2-amino-8-hydroxy-6-sulfo-1-naphthylazo)-4-nitrobenzoic acid, disodium salt.
(a) Synthesis of 7-nitroquinazolin-4-one A mixture of 4-nitroanthranilic acid (2.17 g, 11.91 mmol) and formamide (1.5 mL, 38.43 mmol) was heated at 165 C. for 4 hours. The warm reaction mixture was poured into ice/water (30 mL) and the resulting precipitate was collected via filtration, to give an orange solid (2.16 g, 95% yield) which was dried over P2O5. This was used without further purification. 1H nmr; 8.24 (d, 1H), 8.32 (s, 1H), 8.34 (s, 1H), 8.35 (d, 1H).
SynthesisPeptidomimetics 37-44 were synthesized via solid phase peptide synthesis, using Suzuki couplings employing various boronic acids and aryl bromides. Intermediates display hydrophobic substituents from the aromatic spacer (Abz). The simple quinazoline scaffolds derived from commercially available starting materials. The synthesis of the quinazolines cores 45a-b was accomplished by the cyclization of 4-nitroanthranilic acid by the reaction with sodium isocyanate or cyclization employing a carbon dioxide atmosphere with catalytic DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) from 4- and 5-nitro precursors respectively Figure 10. Alkylation was followed by reduction of the nitro group followed by coupling with A- nitrobenzoyl chloride via anilide formation to provide 48a-b. Reduction to the aniline, coupling with AcArg(Pmc)-OH, and deprotection of the guanidine protecting group afforded 50a-b.A convergent synthesis using methyl-4-amino-2-bromobenzoate or methyl-4-aminobenzoate and 4-nitroaniline created non-peptidic inhibitors 56aa-ci, as seen in Figure 13. Suzuki coupling of the bromoaniline with the corresponding boronic acid, employing PdCI2(dppf) as a catalyst, created compounds 51a followed by reductive amination utilizing N-Boc- aminoacetaldehyde produced compounds 52a-c. A series of deprotections followed by guanidinylation of the resulting amine afforded the N-terminal portions of the inhibitor 53a-c. The C-terminal hydrophobic portion of the molecule was synthesized via alkylation of A- nitroaniline with the corresponding bromide and subsequent reduction of the nitro group utilizing tin (II) chloride, producing compounds 55a-i. Coupling of compounds 53a-c and 55a- i followed by Boc deprotection under acidic conditions produced inhibitors 56aa-ci. Inhibitors64a-b were derived from a similar synthesis, but in place of the reductive amination step, 48c was reacted with Boc-Gly-OH to provide the amide intermediate compound 62 which was manipulated in a similar manner to provide inhibitors 64a-b, seen in Figure 16.The synthesis of inhibitors 57aa-fa was designed to employ a late stage Suzuki coupling to provide faster access to a number of derivatives at the R1 position, while keeping R2 as a <n="13"/>benzyl substituent, see Figure 15. Commercially available methyl-4-amino-3-bromobenzoate was saponified under basic conditions followed by amide bond formation with compound 55a to provide compound 59a. This intermediate was then reacted with different boronic acid derivatives PdCI2(dppf) as a catalyst to provide 60aa-fa. A series of functional group transformations provided inhibitors 57aa-fa. The indole scaffold was readily derived from commercially available 4-iodoaniline and Boc- GIy-OH, which were reacted to form iodo-amide compound 65, seen in Figure 17. Sonagashira cross-coupling of compound 65 and ethynyl-trimethyl-silane (TMS-acetylene) followed by removal of the silyl protecting group afforded terminal alkyne compound 66. A consecutive Sonagashira cross-coupling with 2-iodo-4-nitroaniline followed by cycloisomerization employing catalytic copper (II) acetate41 afforded indole scaffold compound 68. Reduction of the nitro to the amine followed by alkylation with the cooresponding bromide provided compound 70a-b. A series of functional group transformations, similar to the reactions depicted in Figures 10 and 13, provided inhibitors 71a-b. It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween. Now that the invention has been described,
Step 1: To a stirred mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 28 mmol) and imidazole (2.2 g, 33 mmol) in acetonitrile (50 mL), was added acetyl chloride (2.3 mL, 33 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (4.5 g, 28 mmol), imidazole (4.1 g, 60 mmol) and triphenyl phosphite (8.7 mL, 33 mmol), and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2*50 mL), ethyl acetate (2*50 mL), and water (50 mL) to give 342-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (4.8 g, 55% yield): HPLC: Waters Symmetry C18, 5 mum, 3.9*150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, 5.69 min (95.4%); 1H NMR (DMSO-d6) delta 2.15-2.25 (m, 1H, CHH), 2.59-2.69 (m, 2H, 2CHH), 2.70 (s, 3H, CH3), 2.79-2.87 (m, 1H, CHH), 5.35 (dd, J=6, 12 Hz, 1H, NCH), 8.20-8.29 (m, 2H, Ar), 8.34 (d, J=2 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) delta 20.60, 23.53, 30.49, 56.85, 120.26, 121.58, 124.35, 128.30, 147.08, 151.30, 157.61, 159.52, 160.09, 172.48; LCMS: MH=317.
49.4%
Step 1: Preparation of 21-2 21-2 To a stirred mixture of 2-amino-4-nitrobenzoic acid (2.0 g, 10.9 mmol) and imidazole (0.88 g, 12.84 mmol) in acetonitrile (40 mL), was added Acetyl chloride (1.02 g, 13.0 mmol) at room temperature.The mixture was stirred at room temperature overnight. To the mixture, was added 3- amino-piperidine-2,6-dione hydrogen chloride (1.78 g, 10.9 mmol) , imidazole (1.60 g, 23.24 mmol) and Phosphorous acid, triphenyl ester (4.03 g, 13.0 mmol) , and heated to reflux overnight. Water (200 mL) was added to the mixture.The suspension was filtered and the solid was stirred for 20min in CH3CN(25 mL). The mixture was filtrated to give 3-(2-methyl-7-nitro-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione 21-2 (1.70 g, 5.37 mmol, 49.4 %) as an off-white solid. LC/MS (ES+): m/z 317.2 [M+H]+
49.4%
To a stirred mixture of 2-amino-4-nitrobenzoic acid (28-1) (2.0 g, 10.9 mmol) and imidazole (0.88 g, 12.84 mmol) in acetonitrile (40 mL), was added Acetyl chloride (25-2) (1.02 g, 13.0 mmol) at room temperature.The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1-2) (1.78 g, 10.9 mmol) , imidazole (1.60 g, 23.24 mmol) and Phosphorous acid, triphenyl ester (4.03 g, 13.0 mmol) , and heated to reflux overnight. Water (200 mL) was added to the mixture. The suspension was filtered and the solid was stirred for 20min in CH3CN(25 mL). The mixture was filtrated to give 3-(2- methyl-7-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (28-2) (1.70 g, 5.37 mmol, 49.4 %) as an off-white solid. LC/MS (ES+): m/z 317 [M + H]+
In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;
Step A:7-Nitro-1H-benzo[d][1,3]oxazine-2,4-dioneInto a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-amino-4-nitrobenzoic acid (54.6 g, 300.00 mmol, 1.00 equiv) in tetrahydrofuran (500 mL), di(1H-imidazol-1-yl)methanone (58.32 g, 360.00 mmol).The resulting solution was stirred for 2 h at 10° C.The solids were collected by filtration to yield 7-nitro-1H-benzo[d][1,3]oxazine-2,4-dione as a yellow solid.
A mixture of 2-amino-4-nitrobenzoic acid (10.0 g, 54.93 mmol) was refluxed at 130 C. for 18 h in methoxyethanol (50 mL) and formamidine acetate (11.43 g, 109.81 mmol). The clear reaction mixture was cooled to room-temperature to form a yellowish precipitant. The solvent was removed under vacuum, and the precipitant was washed several times with aqueous ammonia (0.01 M). The solid was dried in vacuo to yield 8.9 g (84%) of a light yellow powder. 1H NMR Data: dmso-d6-ppm (delta); 12.68 (1H), 8.37 (d, 1H), 8.33 (d, 1H), 8.26 (1H) and 8.23 (dd, 1H).
In ethanol;Reflux;
The 46g (0 · 25mol) 2- amino-4-nitrobenzoic acid and 52g (0 · 5mol) was added formamidine acetate 500mL single-necked round bottom flask was added 200mL ethanol, refluxed 4~6h,The system will have a lot of yellow precipitate. At this point heating was stopped and the system was cooled to about 50 C, part of the ethanol was removed in vacuo to approximately system 50mL, added to the system 30mL, stirred for several minutes after the refrigeration system LH, filtered, the filter cake was washed successively with chilled ethanol (3 X 1o mL) washed with water (2 X 10 mL) and dried under vacuum to obtain the 7-nitro - -quinazolinone 2, khaki-colored crystalline solid 39.6g, yield: 82.8%, m.rho: 282~284 C, IR (KBr) v: 3174,3064,2960,1683,1613,1528,803; this compound was used without further purification was used directly in the next step chlorine substitution reactions.
Multi-step reaction with 3 steps
1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 1 h / 0 °C
1.2: 12 h / 25 °C
2.1: 3 h / Reflux
3.1: calcium chloride; iron / ethanol; water / 2 h / Reflux
Stage #1: 4-Nitroanthranilic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 1h;
Stage #2: N-((4-(pyrrolidin-1-ylmethyl)phenyl)methyl)amine In dichloromethane at 20℃; for 12h;
4.5.1 Methyl 2-amino-4-nitrobenzoate (29) A stirred mixture of 4-nitroanthranilic acid 14 (10.0 g, 54.9 mmol) and DMFDMA (19.1 mL, 143 mmol) in DMF (55 mL) was heated at 105 C (350 W) for 15 min. The resulting mixture was acidified to pH 2 with HCl (8% in water) (80 mL) and heated at 100 C (450 W) for 10 min. After cooling at room temperature, the crude mixture was neutralized with a saturated solution of NaHCO3 and extracted with ethyl acetate. The organic layers were combined and washed with water and brine. After drying over MgSO4, evaporation of solvent gave 29 (10.0 g, yield 93%) as an yellow powder: mp 158 C; IR numax (cm-1) 3493, 3377, 2957, 1699, 1583, 1344, 1245, 1082, 866, 819, 726; 1H NMR (300 MHz, DMSO-d6) delta 7.91 (dd, J=8.7, 1.2 Hz, 1H, HAr), 7.67 (dd, J=2.4, 1.2 Hz, 1H, HAr), 7.25 (ddd, J=8.7, 2.4, 1.2 Hz, 1H, HAr), 7.14 (br s, 2H, NH2), 3.84 (s, 3H, OCH3); 13C NMR (75 MHz, DMSO-d6) delta 166.6, 151.5, 150.8, 132.6, 113.1, 110.8, 108.1, 52.0; HRMS calcd for C8H8N2O4 [M+H]+ 197.0562 found 197.0561.
88%
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.
General procedure for 4a:
General procedure: A mixture of DAG (1 mmol) and anthranilic acid (1.2 mmol) in AcOH (3 mL) was refluxed for 1 h. After completion of the reaction, as indicated by TLC (EtOAc/n-hexane, 2:1), the mixture was cooled and the resulting precipitate was filtered off and washed with CHCl3. Compound 4a was obtained as a white powder.
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.
4-nitro-2-(2-nitroacetamido)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
In water; at 50℃; for 45h;Green chemistry;
General procedure: 2-Aminobenzoic acid (2 mmol) and 1,1-dichloro-2-nitroethene(2.4 mmol) were added to 3 mL of water in a 10 mL round-bottomflask. Then stirred at 50 C, after completion, the product precipitatedfrom the reaction mixture and can be easily separated by filtration,then give the pure product.
(R)-2-amino-N-(1-(4-chlorophenyl)ethyl)-4-nitrobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃;Inert atmosphere;
4-Nitroanthranilic acid (10 g; 54.90 mmol), DCM (25 ml), and TEA (22.96 ml; 165 mmol) were placed in a reaction vessel under nitrogen. (R)-l-(4-Chlorophenyl)ethylamine (7.70 ml; 54.90 mmol) and T3P (38.8 ml; 65.9 mmol; 50 % in EtOAc) were added in this order slowly and stirred overnight at rt. 150 ml of DCM was added and the mixture was washed with 100 ml of water and then twice with 150 ml of water. In the last wash, additionally 100 ml of DCM was used to dissolve precipitation. The organic layer was dried by filtration through a phase separator funnel, evaporated to dryness, and dried under vacuum at 40 C to give 16.7 g of crude (R)-2-amino-N-(l-(4-chlorophenyl)ethyl)-4-nitrobenzamide. - NMR (400MHz, CDC13): delta 1.59 (d, 3H), 5.24 (quint, 1H), 5.80 (br s, 2H), 6.23 (d, 1H), 7.29-7.37 (m, 4H), 7.42-7.44 (m, 1H), 7.50 (dd, 1H).
Multi-step reaction with 3 steps
1: water / 4 h / 165 °C
2: hydrogen; palladium on activated charcoal / methanol / 4 h
3: sodium nitrite; sulfuric acid / water / 2 h / 0 - 20 °C
A solution of 4-nitroanthranilic acid (0.52 g, 2.85 mmol) in absolute ethanol (30 mL) containing KOH (0.16 g, 2.85 mmol) was added to 3-formylchromone (0.5 g, 2.87 mmol) in absolute ethanol(30 mL). The reaction mixture was stirred for 8 h which yielded a yellow product. The pH of the mixture was adjusted to a pH 6.0-7.0 with acetic acid. The precipitate was filtered off, washed several times with ethanol, diethyl ether, and finally air-dried. The ligand was recrystallized from methanol-water. The crystals were dried in a desiccator over anhydrous calcium chloride. Analytical and physical data for the ligand and its metal complexes are listed inTable 1.
(a) Synthesis of 7-nitroquinazolin-4-one A mixture of 4-nitroanthranilic acid (2.17 g, 11.91 mmol) and formamide (1.5 mL, 38.43 mmol) was heated at 165 C. for 4 hours. The warm reaction mixture was poured into ice/water (30 mL) and the resulting precipitate was collected via filtration, to give an orange solid (2.16 g, 95% yield) which was dried over P2O5. This was used without further purification. ?H nmr; 8.24 (d, 1H), 8.32 (s, 1H), 8.34 (s, 1H), 8.35 (d, 1H).
Multi-step reaction with 2 steps
1.1: sulfuric acid; NaNO2 / lithium hydroxide monohydrate / 1.72 h / 0 - 1 °C / Inert atmosphere
1.2: 0 - 20 °C
2.1: tetrahydrofuran / 4.58 h / 0.5 - 65.5 °C
Multi-step reaction with 2 steps
1.1: sulfuric acid; NaNO2 / lithium hydroxide monohydrate / 1.72 h / 0 - 1 °C / Inert atmosphere
1.2: 1.73 h / 0 - 1 °C
2.1: borane-THF / tetrahydrofuran / 1.08 h / 0.5 - 1.3 °C
Multi-step reaction with 2 steps
1.1: sulfuric acid; NaNO2 / lithium hydroxide monohydrate / 1.72 h / 0 °C / Inert atmosphere
1.2: 0 - 20 °C
2.1: borane-THF / tetrahydrofuran / 4.58 h / 0.5 - 65.5 °C
Multi-step reaction with 2 steps
1.1: sulfuric acid; NaNO2 / lithium hydroxide monohydrate / 1.72 h / 0 - 1 °C / Inert atmosphere
1.2: 0.73 h / 0 - 20 °C
2.1: borane-THF / tetrahydrofuran / 4.58 h / 0.5 - 65.5 °C / Cooling with ice
Multi-step reaction with 2 steps
1.1: NaNO2; sulfuric acid / lithium hydroxide monohydrate / 1.72 h / 0 - 1 °C / Inert atmosphere
1.2: 1.73 h / 0 - 20 °C
2.1: borane-THF / tetrahydrofuran / 4.42 h / 0.5 - 65.5 °C
Multi-step reaction with 2 steps
1.1: sulfuric acid; NaNO2 / lithium hydroxide monohydrate / 1.72 h / 0 - 1 °C / Inert atmosphere
1.2: 0 - 20 °C / Inert atmosphere
2.1: borane-THF / tetrahydrofuran / 0.5 - 65.5 °C
Multi-step reaction with 2 steps
1.1: toluene-4-sulfonic acid / lithium hydroxide monohydrate / 0.05 h
1.2: 0.25 h
2.1: boron trifluoride-tetrahydrofuran complex / tetrahydrofuran / 12 h / 0 - 20 °C
Multi-step reaction with 2 steps
1.1: toluene-4-sulfonic acid / acetonitrile / 0.25 h / 20 °C
1.2: 19 h
2.1: BH3 / tetrahydrofuran / 4 h / 65 °C
Multi-step reaction with 2 steps
1.1: toluene-4-sulfonic acid / acetonitrile / 0.25 h / 20 °C
1.2: 19.25 h
2.1: borane-THF / tetrahydrofuran / 4 h / 65 °C
2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)-4-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium hydroxide; In 1,4-dioxane; water; at 0℃; for 10.5h;
(2, 5-dimethylphenoxy)-2, 2-dimethylpentanoyl chlorideDissolved in 1,4-dioxane 15mL in reserve,A mixture of 1.82 g of 2-amino-4-nitrobenzoic acid was added to 1,4-dioxane:Water / 1: 1 15mL mixed solvent, at 0 C conditions by adding 2N sodium hydroxide 10mL, stirring 30 minutes, and then at 0 C under the conditions of the drop of the remaining solution, continue stirring 10 hours, acidification, The ester was extracted, dried over anhydrous magnesium sulfate and subjected to column chromatography to give the title compound (3.6 g, yield 87.0%).
Multi-step reaction with 3 steps
1.1: sulfuric acid / water / 1 h / 0 °C
1.2: 3 h / 0 °C
1.3: 20 h / 0 - 60 °C
2.1: sulfuric acid / water / 16 h / 85 °C
3.1: iron; water; ammonium chloride / ethanol / 4 h / 80 °C
Multi-step reaction with 3 steps
1.1: thionyl chloride / 8 h / 0 °C / Reflux
2.1: sulfuric acid; sodium nitrite / water / 2 h / -10 - 0 °C
2.2: 8 h / -10 - 20 °C
3.1: tin(II) chloride dihdyrate / ethyl acetate / 5 h / Reflux
Multi-step reaction with 3 steps
1.1: sulfuric acid; sodium nitrite / water / 1.72 h / 0 °C / Inert atmosphere
1.2: 0 - 20 °C
2.1: sulfuric acid / 16 h / 85 °C
3.1: iron; water; ammonium chloride / ethanol / 4 h / 20 - 80 °C
Multi-step reaction with 3 steps
1.1: sodium nitrite; sulfuric acid / water / 1.72 h / 0 - 1 °C / Inert atmosphere
1.2: 1.73 h / 0 - 20 °C
2.1: sulfuric acid / 16 h / 85 °C
3.1: ammonium chloride; iron / water; ethanol / 4 h / 20 - 80 °C
3.37 g of 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionyl chloride was dissolved in 25 mL of 1,4-dioxane, 1.82 g of 2-amino-4-nitrobenzoic acid was added to 20 mL of a mixed solvent of 1,4-dioxane: water / 1: 1, 10 mL of 2N sodium hydroxide was added at 0 C. The mixture was stirred for 30 minutes. The solution was added dropwise to the solution at 0 C. Stirring was continued for 10 hours. The mixture was acidified and extracted with ethyl acetate. The residue was dried over anhydrous magnesium sulfate and purified by column chromatography to give 4.14 g of the title compound in a yield of 85.9%.
General procedure: 1a-g (1.0 equiv.) and K2CO3 (3.0 equiv.) were dissolved in MeCN(200 mL), then benzoyl chloride (1.2 equiv.) was slowly added underrt. The solution was stirred at 90 C overnight. After removal ofthe solvent under vacuum, the residue was quenched with 2 N HClsolution. The formed precipitate was collected by filtration andwashed with water, then treated with acetic anhydride (25 mL) andheated under reflux for 2 h. The solid obtained upon concentrationwas collected and refluxed with NH4OAc at 170 C for 5 h. Themixture was poured into water, filtered and washed with CH2Cl2and water successively to give products 2a-g.
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 60℃; for 5h;
2-Amino-4-nitrobenzoic acid (I-A, 0.50 g, 2.7 mmol),Co-named to 50 mL with N,N-carbonyldiimidazole (0.55 g, 3.4 mmol, 1.25 eq)In a round bottom flask, add the appropriate amount of tetrahydrofuran to dissolve and add O-benzylhydroxylamine.(470 muL, 4.1 mmol, 1.5 eq), stir at 60 C for 5 h and directly add 100-200The silica gel was sampled and separated by 200-300 mesh silica gel column chromatography.(The eluent is petroleum ether: ethyl acetate = 12:1) to give the crude intermediate.The crude product was recrystallized from petroleum ether/ethyl acetate to give the intermediate2-Amino-N-(benzyloxy)-4-nitrobenzamide (I-B).2-amino-N-(benzyloxy)-4-nitrobenzamide: yellow solid,Yield 66%,
66%
With 1,1'-carbonyldiimidazole; at 60℃; for 5h;
General procedure: A mixture of 2-amino-4-nitrobenzoic acid or 2-amino-5-nitrobenzoicacid (0.50 g, 2.7 mmol) with N,N-carbonyldiimidazole(0.55 g, 3.4 mmol, 1.25 eq), O-benzylhydroxylamine (470 muL, 4.1 mmol,1.5 eq) in tetrahydrofuran was heated at 60 C under agitation for 5 h.The reaction mixture was concentrated in vacuo and the residue waspurified by silica gel chromatography using ethyl acetate and petroleumether (eluent: petroleum ether: ethyl acetate=12:1) to provide 2 as ayellow solid.2-Amino-N-(benzyloxy)-4-nitrobenzamide: Yellow solid, 66% yield,mp:163-165 C.
(±)-2-ethoxy-2-propyl-7-nitro-1,2-dihydro-4H-benzo[d][1,3]oxazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
at 100℃; for 1.5h;Microwave irradiation; Inert atmosphere;
General procedure: A solution of the anthranilic acid (1.0 mmol) in the orthoester (0.45 mL, 2.0-2.7 equivalents) wasprepared in a 5-mL microwave tube and stirred for 30 s prior to irradiation at the "high absorption"setting. The reaction was performed under N2 at 100 C (400 W) for 0.75-3 h. Upon cooling, the crudeproduct crystallized from the reaction mixture and was purified by trituration from 5% ether in pentane.The following compounds were prepared:2-Methyl-4H-benzo[d][1,3]oxazin-4-one (11a): 130 mg (81%, method 1) and 132 mg (82%, method 2)