* 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] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 12, p. 2689 - 2695
2
[ 118-48-9 ]
[ 20198-19-0 ]
Reference:
[1] Journal of Organic Chemistry, 1987, vol. 52, # 13, p. 2933 - 2935
3
[ 118-48-9 ]
[ 7726-95-6 ]
[ 4692-98-2 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 50℃; for 2 h;
Bromine (35 mL, 660 mmol) was added dropwise to a suspension of isatoicanhydride (100 g, 610 mmol) in 1.6 L water at 50 °C. This temperature was maintained for an additional 2 hours. After cooling the solution to room temperature, the solid was filtered and washed twice with water and twice with acetone, yielding 125.6 g (85percent) 6-hromo-lH-benzo[d][l,3]oxazine-2,4-dione as a pink solid.
Reference:
[1] Journal of Heterocyclic Chemistry, 2000, vol. 37, # 2, p. 253 - 260
[2] MedChemComm, 2016, vol. 7, # 10, p. 1957 - 1965
[3] Journal fuer Praktische Chemie (Leipzig), 1886, vol. <2> 33, p. 36
5
[ 118-48-9 ]
[ 4693-02-1 ]
Yield
Reaction Conditions
Operation in experiment
97.9%
at 0 - 10℃; for 2 h;
250mL three-necked flask was added concentrated sulfuric acid (100mL), was added slowly with mechanical stirring at 0-10 ° C when isatoic anhydride 1 (30.0g, 0.18mol), after stirring and dissolving the dropwise addition of 65percent concentrated nitric acid (21.4g, 0.22 mol), maintaining the temperature at 0-10 ° C, 1h addition was complete, the reaction was continued and held for 1h, stopped stirring, the reaction mixture was slowly poured into 300mL ice-water mixture, stirred for 20min, fully precipitated solid was filtered, washed with water, dried after obtained 5-nitro isatoic anhydride 2 (37.5g, yield: 97.9percent).
Reference:
[1] Patent: CN103613549, 2016, B, . Location in patent: Paragraph 0033-0035
[2] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 23, p. 8032 - 8042
[3] Chemical Communications, 2013, vol. 49, # 2, p. 190 - 192
[4] Synthetic Communications, 2011, vol. 41, # 22, p. 3265 - 3279
[5] Journal fuer Praktische Chemie (Leipzig), 1884, vol. <2> 30, p. 474
[6] Tetrahedron, 1999, vol. 55, # 34, p. 10447 - 10466
[7] Patent: US2014/121414, 2014, A1, . Location in patent: Paragraph 0044
6
[ 118-48-9 ]
[ 95-53-4 ]
[ 4943-85-5 ]
Reference:
[1] RSC Advances, 2014, vol. 4, # 108, p. 63039 - 63047
[2] Organic and Biomolecular Chemistry, 2012, vol. 10, # 12, p. 2389 - 2391
[3] Journal fuer Praktische Chemie (Leipzig), 1901, vol. <2> 63, p. 244[4] Journal fuer Praktische Chemie (Leipzig), 1902, vol. <2> 65, p. 533
[5] European Journal of Medicinal Chemistry, 1989, vol. 24, # 5, p. 531 - 535
[6] Tetrahedron Letters, 2008, vol. 49, # 41, p. 5840 - 5842
[7] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 2, p. 277 - 289
[8] Journal of Organic Chemistry, 2015, vol. 80, # 9, p. 4736 - 4742
Reference:
[1] Collection of Czechoslovak Chemical Communications, 1988, vol. 53, # 8, p. 1820 - 1844
9
[ 118-48-9 ]
[ 885-70-1 ]
Reference:
[1] Collection of Czechoslovak Chemical Communications, 1988, vol. 53, # 8, p. 1820 - 1844
10
[ 118-48-9 ]
[ 593-51-1 ]
[ 4141-08-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
With triethylamine In N,N-dimethyl-formamide at 40 - 120℃; for 3 h;
General procedure: Isatoic anhydride derivatives were dissolved in dry DMF (30 mL) and treated with the corresponding amine (5 equiv) or a mixture of the amine hydrochloride (5 equiv) and triethylamine (5 equiv). The mixture was heated to 40–120 °C (depending on the amine) for 3–6 h. For workup, the mixture was poured into water (100 mL) and the product was extracted with EtOAc (5 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4and evaporated to dryness. The crude product was purified by column chromatography to obtain the benzamide derivatives.
86%
Stage #1: With triethylamine In ethanol at 20℃; for 0.0833333 h; Stage #2: for 2 h; Inert atmosphere; Reflux
Methylamine hydrochloride (3.10 g, 46.0 mmol), ethanol (50 mL) and triethylamine (6.41 mL, 46.0 mmol) were stirred at room temperature for five minutes then isatoic anhydride (5.00 g, 30.7 mmol) was added. The mixture was heated at reflux for two hours under nitrogen and then allowed to cool to ambient temperature. The resulting mixture was concentrated, and the residue suspended in water (300 mL). The aqueous mixture was extracted with ethyl acetate (3x200 mL) then the combined ethyl acetate phases were washed with brine, dried (sodium sulphate) and evaporated. Chromatography (40 g silica cartridge, 0-80percent ethyl acetate in petroleum benzine 40-60 °C) gave the title compound (12) (3.97 g, 86percent yield) as a pale pink solid; 1H NMR (400 MHz, CDCI3) ? 7.29 (dd, J = 7.9, 1.5 Hz, 1H), 7.19 (ddd, J = 8.4, 7.2, 1.5 Hz, 1H), 6.67 (dd, J = 8.2, 1.1 Hz, 1H), 6.63 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H), 6.11 (s, 1H), 5.46 (s, 2H), 2.95 (d, J = 4.8 Hz, 3H); 13C NMR (101 MHz, CDCI3) ? 170.14, 148.61 , 132.22, 127.23, 117.34, 116.68, 116.38, 26.56. LCMS: rt 2.61 min, m/z 120.2 [M-NHMe]+.
Reference:
[1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2280 - 2292
[2] Patent: WO2013/75167, 2013, A1, . Location in patent: Page/Page column 29
11
[ 118-48-9 ]
[ 74-89-5 ]
[ 4141-08-6 ]
Yield
Reaction Conditions
Operation in experiment
99%
for 2.5 h;
Isatoic anhydride (25 g, 150 mmol) was combined with water (150 mL). Methylamine in THF (2.0 M, 150 mL) was added to the isatoic anhydride solution over thirty minutes. The mixture was stirred for 2 hours and then extracted with ethyl acetate. The organic layer was washed with water, then brine and dried over MgSO4, filtered and concentrated to yield an off-white powder (24 g, 99percent). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 7.22 (m, 1H), 6.67 (m, 2H), 6.06 (br s, 1H), 5.52 (br s, 2H), 2.99 (d, 3H, J = 4.8 Hz).
97%
for 0.333333 h;
Example 3: Synthesis of Compound XIII-1; Step 1: Preparation of 2-Amino-N-meth lbenzamide (2); To a stirred suspension of Isatoic anhydride (1, 10 g, 61.3 mmol) in 1 ,4-dioxane ( 100 mL), methyl amine gas was passed for 20 min. The progress of the reaction was monitored by thin layerchromatography (TLC), and complete conversion of compound 1 to compound 2 was observed. The reaction mixture was then Filtered through Filter paper; and the solvent was evaporated from the filtrate under reduced pressure to afford 2-Amino-N-methylbenzamide as a brown solid (2, 9 g, 97 percent). NMR (CDClj): δ 7.39-7.10 (m, 2H), 6.70-6.60 (m, 2H), 3.00 (s, 3H).
97.8%
at 20℃; for 16 h;
Intermediate C1 2-amjno- .yen.-rnethvfbenz3mide Isatoic anhydride (10 g, 81.3 mmoi) was suspended in tetrahydrofuran (200 mi) and treated dropwise with methyiamine in methanol (40 percent, 10 mL) with stirring. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure to afford the product 2-amino-W-methylbenzamide (9 g, yield 97.8 percent). NMR (400 MHz, CDCi3) δ ppm 7.14-7.32 (m, 2H), 8.60-6.72 (m, 2H), 6.05 (br s, 1 H), 2.97 (d, 3H, J = 5.0 Hz).
92%
at 20℃; for 1 h;
To a suspension of 16.3 g (100 MMOL) of ISATOIC anhydride in 100mL of H2O is added portionwise 100mL of 2N methylamine-tetrahydrofuran solution (200 MMOL) at room temperature. The reaction mixture is stirred for 1 hour and then extracted with AcOEt. The organic layer is washed with H20 and brine, dried over NA2SO4, and concentrated uhder reduced pressure to give 13.79 g of desired product, 2-amino-N-methyl-benzamide (92 MMOL, 92percent) as colorless solid. NMR (400MHZ, CD3, 5) : 2.97 (d, 3H, J = 4.52 Hz), 5.49 (bs, 1H), 6.07 (bs, 1H), 6.64 (ddd, 1H, J = 8.04, 7.56, 1.0 Hz), 6.68 (dd, 1H, J = 8.32, 1.0 HZ), 7.20 (ddd, 1H, J = 8.32, 7.56, 1.52 Hz), 7.29 (dd, 1H, J = 8.04, 1.52 Hz).
91.5%
at 20℃;
10216] To a solution of benzoxazine ketone 16.30 g (0.1 mol) in 150 mE acetonitrile was slowly dropwise added 40percent methylamine aqueous solution at room temperature until the solid disappeared, about 80 ml methylamine aqueous solution was added. Then the reaction mixture was continued stirring at room temperature for another 0.5 hours and monitored by TEC. Afier the reaction was over, the mixture was concentrated under reduced pressure, the residual was filtered and washed with 50 ml of water and 50 ml of petroleum ether successively, then dried to give 13.73 g 2-amino-N-methyl- benzamide as white solid with yield of 91.5percent, m.p. 78-79° C. 10217] 3) The Preparation of 2-(2-chloroacetamido)-N- methylbenzamide
91.5%
at 20℃; for 0.5 h;
To a solution of benzoxazine ketone 16.30g (0.1mol) in 150 mL acetonitrile was slowly dropwise added 40percent methylamine aqueous solution at room temperature until the solid disappeared, about 80ml methylamine aqueous solution was added. Then the reaction mixture was continued stirring at room temperature for another 0.5 hours and monitored by TLC. After the reaction was over, the mixture was concentrated under reduced pressure, the residual was filtered and washed with 50ml of water and 50ml of petroleum ether successively, then dried to give 13.73g 2-amino-N-methylbenzamide as white solid with yield of 91.5percent, m.p. 78-79°C.
88%
With acetic acid In ethyl acetate at 20℃; for 2 h;
In a 250 mL reaction flask,16.3 g (0.1 mol) of isatoic anhydride was added100 mL of ethyl acetate,1mL glacial acetic acid,A solution of 15.5 g (0.15 mol) of a 40percent aqueous solution of methylamine was added dropwise at room temperature with stirring,Drop finished,Continue stirring 2h,Thin layer chromatography (TLC)Detection of raw materials disappeared,Ethyl acetate and water were distilled off,13.2 g of a white solid,Yield 88percent.
82%
With triethylamine In tetrahydrofuran; water for 2.5 h;
General procedure: A modified version of the reported procedure was employed.20 To a soln of isatoic anhydride (30 mmol) and Et3N (60 mmol) in H2O (30mL) was added a soln of the appropriate amine (60 mmol) in THF(30 mL) over 30 min. The mixture was stirred for 2 h and then extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with H2O (3 × 30 mL) and brine (3 × 30 mL), then dried over MgSO4, filtered and concentrated to yield the desired amide.
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 164 - 167
[2] Patent: WO2011/140338, 2011, A1, . Location in patent: Page/Page column 41
[3] Patent: WO2012/92880, 2012, A1, . Location in patent: Page/Page column 61
[4] Patent: WO2004/80980, 2004, A1, . Location in patent: Page 110-111
[5] Patent: US2013/225585, 2013, A1, . Location in patent: Paragraph 0215; 0216
[6] Patent: EP2636669, 2013, A1, . Location in patent: Paragraph 0127; 0128
[7] Patent: CN105153113, 2016, B, . Location in patent: Paragraph 0025; 0026; 0027; 0028
[8] Synthetic Communications, 2012, vol. 42, # 1, p. 8 - 24
[9] Synthesis (Germany), 2013, vol. 45, # 21, p. 2998 - 3006
[10] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1281 - 1285
[11] Journal of Combinatorial Chemistry, 2010, vol. 12, # 5, p. 643 - 646
[12] RSC Advances, 2015, vol. 5, # 113, p. 93433 - 93437
[13] Tetrahedron, 2000, vol. 56, # 37, p. 7245 - 7253
[14] European Journal of Organic Chemistry, 2013, # 7, p. 1262 - 1270
[15] Journal fuer Praktische Chemie (Leipzig), 1887, vol. <2> 36, p. 145
[16] Journal fuer Praktische Chemie (Leipzig), 1887, vol. <2> 36, p. 145
[17] European Journal of Medicinal Chemistry, 1989, vol. 24, # 5, p. 531 - 535
[18] Journal of Heterocyclic Chemistry, 1992, vol. 29, # 1, p. 103 - 105
[19] Journal of Organic Chemistry, 1994, vol. 59, # 21, p. 6245 - 6250
[20] Journal of Medicinal Chemistry, 1996, vol. 39, # 15, p. 3019 - 3029
[21] Patent: WO2008/31548, 2008, A1, . Location in patent: Page/Page column 79-80
[22] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 660 - 663
[23] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 11, p. 3156 - 3157
[24] Tetrahedron, 2016, vol. 72, # 10, p. 1330 - 1336
[25] Organic Process Research and Development, 2017, vol. 21, # 5, p. 740 - 747
12
[ 118-48-9 ]
[ 4141-08-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
With methylamine In tetrahydrofuran; methanol
REFERENCE EXAMPLE 12 2-Amino-N-methylbenzamide Isatoic anhydride (10.0 g) was suspended in tetrahydrofuran (200 ml) and treated dropwise with 40percent solution of methylamine in methanol (10.0 ml) with stirring. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure to give the title compound (10.3 g, about 100percent). Melting point: 78.0 to 79.0° C. (recrystallized from ethyl acetate-n-hexane). IR (KBr): 3450, 3333, 1615, 1580, 1539 cm-1. 1H-NMR (CDCl3) δ: 2.97 (3H, d, J=5.0 Hz), 6.05 (1H, bs), 6.60-6.72 (2H, m), 7.14-7.32 (2H, m).
Reference:
[1] Patent: US6407116, 2002, B1,
13
[ 118-48-9 ]
[ 74-89-5 ]
[ 4141-12-2 ]
[ 4141-08-6 ]
Reference:
[1] Journal of Organic Chemistry, 1953, vol. 18, p. 1427,1433, 1437
With methanol In methanol for 6 h; Heating / reflux
EXAMPLE 386B methyl 2-amino-6-hydroxybenzoate [0691] A mixture of Example 386A (1.0 g, 5.6 mmol) and methanol (40 mL) was heated to reflux for 6 hours, concentrated, and purified on a silica gel column eluting with 30percent ethyl acetate in hexanes to provide the desired product, 0.81 g, 86.6percent. 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 5.95 (d, 1H), 6.20 (d, 1H), 6.34 (s, 214), 7.02 (t, 1H), 10.88 (s, 1H); MS (DCI/NH3): m/e 168 (M+H)+.
With water; In 1,4-dioxane; at 20℃; for 7h;Heating / reflux;
Preparation of Compound 7, Sodium Salt; [0065] Into a 250 mL round-bottom flask were measured 10 g (61 mmol) isatoic anhydride, 10.1 g (61 mmol) of 3-(4-aminophenyl) propionic acid, 75 mL of 1,4-dioxane, and 15 mL water. The reaction mixture was stirred and heated to reflux for about seven hours, then cooled to room temperature and stirred overnight. The reaction mixture was cooled to 0 C., then diluted with 50 mL of water. The resulting solid was collected by filtration, dried overnight in a vacuum oven, and used as is in the next reaction.
2-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide Dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With barium dihydroxide; In tetrahydrofuran; ethanol;
EXAMPLE 15 2-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide Dihydrochloride The free base was liberated from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (4.0 gm, 0.020 mole) using barium hydroxide and keeping the process under dry nitrogen. The base thus obtained (0.018 mole) was dissolved in dry tetrahydrofuran, treated with isatoic anhydride (2.04 gm, 0.018 mole) and brought to reflux. The clear, dark brown solution within five minutes became tan-turbid. Reflux was continued for 1 hr, the excess tetrahydrofuran distilled off, and the residue added to boiling ethanol. A small amount of insoluble solid was filtered off. Chilling produced 3.8 g (68%) crystalline amine base, m.p. 241-243 C. The base was converted to the hydrochloride salt by reacting with ethereal hydrogen chloride and recrystallized from either hot water-isopropanol or methanol-methylethylketone (1:1) to yield a crystalline solid melting 280.5-283.5 C. NMR, MS, and IR were satisfactory. MW 318.249. Analysis: Calculated for Cl2 N3 OC14 H21: C, 52.84; H, 6.65; N, 13.20. Found: C, 52.90; H, 6.54; N, 13.24.
EXAMPLE 3 1.2 mols of isopropylamine (125 ml of a 70% strength aqueous solution, density 0.81), 0.2 ml of isopropylamine carbonate and 0.25 mol of <strong>[15572-56-2]isopropylamine hydrochloride</strong> were initially introduced into 1 liter of water. A pH value of 10.6 was set up in the solution. After warming the solution to 45 C., 1 mol (163 g) of isatoic anhydride was added over a period of 30 minutes. The pH value fell to 8.1 in the course of the reaction. At the same time, water-insoluble, colorless anthranilic acid isopropylamide precipitated.
2-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide Dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With barium dihydroxide; In tetrahydrofuran; ethanol;
EXAMPLE 14 2-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide dihydrochloride. The free base was liberated from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (4.0 gm, 0.020 mole) using barium hydroxide and keeping the process under dry nitrogen. The base thus obtained (0.018 mole) was dissolved in dry tetrahydrofuran, treated with isatoic anhydride (2.04 gm, 0.018 mole) and brought to reflux. The clear, dark brown solution within five minutes became tan-turbid. Reflux was contined for 1 hr, the excess tetrahydrofuran distilled off, and the residue added to boiling ethanol. A small amount of insoluble solid was filtered off. Chilling produced 3.8 g (68%) crystalline amine base, m.p. 241-243 C. The base was converted to the hydrochloride salt by reacting wiht etheralhydrogen chloride and recrystallized from either hot water-isopropanol or methanol-methylethylketone (1:1) to yield a crystalline solid melting 280.5-283.5 C. NMR, MS, and IR were satisfactory. MW 318.249. Analysis: Calculated for C12 N3 OC14 H21: C, 52.84; H, 6.65; N, 13.20 Found: C, 52.90; H, 6.54; N, 13.24
2-Amino-3,5-dimethylbenzamide. Liquid phosgene (55 g.) is added to a stirred solution of 30.1 g. (0.182 mol.) of <strong>[14438-32-5]2-amino-3,5-dimethylbenzoic acid</strong> in 300 ml. of dioxane. The temperature is raised to 40-45 C. and held for 2 hr. The mixture is stirred overnight at room temperature and filtered. The filter cake is washed with diethyl ether, giving 33 g. (95%) of 6,8-dimethyl-2H-3, 1-benzoxazine-2,4(1H)-dione; m.p.>300 C. The isatoic anhydride is then added to 435 ml. of 1 M. NH4 OH. The mixture is stirred overnight at room temperature, brought to reflux for 2 hr. cooled, filtered, and crystallized (EtOH), giving 13.4 g. (47%) of product, m.p. 162-167 C. Anal. Calcd. for C9 H12 N2 O: C, 65.83; H, 7.37; N, 17.06. Found: C, 65.71; H, 7.42; N, 16.89.
(S)-3-neopentyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Following the procedure described in J. Med. Chem. 1999, 42, 5241 , lsatoic anhydride 64a (1.2 mmol) and the L-£-butyl leucine (1.2 mmol) in dry pyridine (4.0 ml.) were heated at 1 15C for 19 h under nitrogen. The solution was evaporated and diphenyl ether (4 mL) was added. The heterogeneous mixture was heated at 1800C for 3 h. Intermediate64a3, was obtained after purification on silica gel using EtOAc and hexanes.
Intermediate 8; 2-Amino-N-(2,2,2-trifluoroethyl)benzamide A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol), 15 mL water, and triethylamine (4.69 mL, 0.033 mol). (2,2,2-trifluoroethyl)amine hydrochloride (4.98 g, 0.036 mol) was added slowly to the reaction mixture. After 16 h, the reaction mixture was concentrated to dryness. The crude product was purified silica gel column (EtOAc/Hexanes) to afford the title compound as a white solid (3.42 g, 51%): Mass (M+H)+=120, 219.
Example 4Preparation of 2-Amino-N-(2-methyl-2H-indazol-6-yl)-benzamide; A solution of 34.9 g isatinic anhydride, 30 g <strong>[50593-30-1]6-amino-2-methyl-2H-indazole</strong> and 12.2 ml acetic acid in 94 ml 2-butanol were stirred for 6 hours at 100 C. After evaporation of 70 ml 2-butanol, 45 ml methanol were added and after further 45 min. at 65 C. the reaction was cooled to room temperature. The suspension was filtered and the solution was distilled to remove the methanol. At 45 C. about 45 ml ethyl acetate and 30 ml triethylamine were added. To this solution, 250 ml MTBE were added slowly at 45 C. to precipitate the title compound as a pale material that was filtered off. After drying, 47 g (86%) of 2-Amino-N-(2-methyl-2H-indazol-6-yl)-benzamide were isolated.1H-NMR (300 MHz, CDCl3): delta=4.18 (s, 3H); 6.29 (s, 2H); 6.56 (t, 1H); 6.72 (d, 1H); 7.16 (dt, 1H); 7.25 (dd, 1H); 7.55-7.65 (m, 2H); 8.05 (s, 1H); 8.20 (s, 1H); 9.95 (s, 1H).
To a stirring solution of Fmoc-Dap-OH (2500 mg, 7.66 mmol) and sodium carbonate (812 mg, 7.66 mmol) in acetonitrile/water 1 :1 (48 ml), isatoic anhydride (1499 mg, 9.19 mmol) in acetonitrile (24 ml) was added and the mixture was stirred at room temperature overnight. The mixture was acidified to pH 2 with 5% aqueous KHS04 and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure.
General procedure: Sodium hydride (0.011 mol) was added to a solution of isatoic anhydride 2 (0.01 mol) in anhydrous DMF (30 mL) and stirred for 1 h at room temperature. The required haloalkane 3 (0.011 mol) was added and the reaction mixture stirred for a further 18 h. The reaction mixture was poured onto ice and water (200 mL) to precipitate the product which was filtered, washed with water and dried then recrystallised from a suitable solvent. Reagents 2a (1.63 g), sodium hydride (0.26 g) and 3k (2.72 g) gave 4t (1.02 g, 31%) when purified by column chromatography, mobile phase: dichloromethane, Rf = 0.59: mp 153-154 C; 1H NMR (270 MHz CDCl3): d 5.27 (2H, s), 6.62 (1H, d, J = 8.4 Hz), 7.18-7.55 (11H, m), 8.12 (1H, dd, J = 7.8, 1.6 Hz); 13C NMR (270 MHz; CDCl3): d 47.01, 112.06, 114.99, 124.24, 126.77, 128.45, 128.49, 128.85, 129.23, 130.76, 130.89, 131.69, 137.19, 141.31, 148.65, 158.52; Anal. Calcd for C21H15NO3: C, 76.58; H,4.59; N, 4.25. Found: C, 76.47; H, 4.40; N, 4.27.
DIAD (0.9 mL, 1 eq) in THF (2 mL) was added dropwise to a stirred solution containing (l-isopentyl-lH-benzo[d]imidazol-2-yl)methanol (1.0 g), RhoRho1¾ (1.2 g, 1 eq) and isatoic anhydride (748 mg, leq) in THF (30 mL) and stirred overnight. The reaction was concentrated to a light brown residue that was taken up in DMF (20 mL) and treated with <strong>[42303-42-4]ethyl <strong>[42303-42-4]1-aminocyclopropanecarboxylate hydrochloride</strong></strong> (1.05 g, 1.5 eq) and heated to 75C for 48 h. Aqueous workup between Et20 and water gave a brown foam (11.2 g) . This crude ester was dissolved in 2 M NaOH / EtOH (4: 1, 10 mL) and warmed to 70C for 5 h. The cooled reaction was concentrated, taken up in 2M NaOH and washed with Et20. The aqueous phase was acidified to pH 4 with 2M HCl and extracted into EtOAc (2 x 25 mL). This gave an impure brown foam which was purified on silica gel with isohexane / EtOAc (3:1 to 1 :1) as eluant. This gave the desired acid as the more polar component as a cream solid (279mg, 15%). ? NMR (400 MHz, DMSO): delta 8.85 (1H, s), 8.8 (1H, t), 7.58 (1H, d), 7.48 (1H, d),7.349 (1H, dd), 7.18 (3H, m), 6.93 (1H, d), 6.55 (1H, t), 4.68 (2H, d), 4.29 (2H, m), 1.67 (1H, sept), 1.578 (2H, m), 1.085 (2H, m), 0.94 (8H, d). LC/MS 421.5 (MH+).
General procedure: A mixture of isatoic anhydride 1 (1 mmol), isatin 2 (1 mmol), phenyl hydrazine 3 (1 mmol), 0.3 g (0.6 mmol) alum, and 10 ml EtOH in a 50 ml flask was stirred at reflux for time period asindicated in Table 1. After completion of the reaction (monitored by TLC, ethylacetate/n-hexane,1:1), 25 ml EtOH was added to the reaction mixture, and recrystallized from ethanol to afford pure product.
3-(3-(2-aminobenzamido)phenyl)propanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
In ethanol; for 1.5h;Reflux;
General procedure A: The amine (1.0 eq.) was dissolved in boiling ethanol (c = 0.2 M) and isatoic anhydride (2.0 eq.) was added. The mixture was heated for 1.5 hours under reflux, cooled to room temperature and filtered. Subsequently, the solvent was evaporated under reduced pressure and the product was isolated by column chromatography on silica.
General procedure: 7.1.13. Solution-phase synthesis of library compounds 21Isatoic anhydride (20) (0.1 mmol) was partitioned into reaction vials and treated with aniline (0.10 mmol) in toluene (1.0 mL) at 100 °C for 12 h. The mixture in each vessel was allowed to coolto ambient temperature, and the solvent was removed under reduced pressure. The residue in each vessel was dissolved in pyridine(1.0 mL) and treated with compound 37 (0.10 mol) at ambient temperature for 12 h. The mixture was then treated with polymer-bound tris(2-aminoethyl)amine for 12 h and filtered off. The filtrate was collected in vials and the solutions were evaporatedin vacuo to afford anthranilamide derivatives 21, which were analyzed by HPLC and MS. 21a; FAB-MS m/z 443 [M+H]+, 21b; FABMS m/z 443 [M+H]+, 21c; FAB-MS m/z 443 [M+H]+, 21d; FAB-MS m/z 463 [M+H]+, 21e; FAB-MS m/z 463 [M+H]+, 21g; FAB-MS m/z459 [M+H]+, 21h; FAB-MS m/z 489 [M+H]+, 21i; FAB-MS m/z 493[M+H]+, 21j; FAB-MS m/z 513 [M+H]+, 21k; FAB-MS m/z 521[M+H]+, 21l; FAB-MS m/z 472 [M+H]+, 21m; FAB-MS m/z 457 [M+H]+, 21n; FAB-MS m/z 471 [M+H]+, 21o; FAB-MS m/z 430[M+H]+, 21p; FAB-MS m/z 444 [M+H]+, 21q; FAB-MS m/z 444[M+H]+, 21r; FAB-MS m/z 444 [M+H]+, 21s; FAB-MS m/z 460 [M+H]+, 21t; FAB-MS m/z 449 [M]+, 21u; FAB-MS m/z 433[M+H]+, 21v; FAB-MS m/z 469 [M+H]+, 21w; FAB-MS m/z 480[M+H]+. Compound 21f was obtained from 2-amino-5-chloro-3-hydroxy-40-methoxybenzanilide using the methods described forthe synthesis of compound 19 as a colorless solid (423 mg, 56percent):
ethyl 4-{2-[(2-aminophenyl)carbonyl]hydrazinyl}benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
516 mg
Step 2: Ethyl 4-{2-[(2-aminophenyl)carbonyl]hydrazinyl}benzoate: To a solution of Step 1 intermediate (2 g, 9.25 mmol) in ethanol (30 mL) was added DIPEA (1.4 mL, 0.87 mmol) and stirred for 15 min at RT. Isatoic anhydride (1.5 g, 9.250 mmol) was added to the reaction mixture and refluxed for 16 h. The reaction mixture was concentrated under reduced pressure to yield a sticky residue which was purified by silica gel column chromatography to yield 516 mg of the title product as off white solid; 1H NMR (300 MHz, DMSO-i) delta 1.27 (t, J = 6.9 Hz, 3H), 4.22 (q, J = 6.9 Hz, 2H), 6.39 (br s, 2H), 6.55 (t, J = 6.9 Hz, 1H), 6.71-6.79 (m, 3H), 7.19 (t, J = 6.9 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 8.51 (br s, 1H), 10.48 (br s, 1H).
2,5-dioxo-2,3,4,5-tetrahydro-4-benzodiazepine-3-acetic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
With pyridine; at 120℃; for 18h;
Isatoic anhydride (compound l) (1 g, 6.13 mmol) and <strong>[2886-33-1]L-aspartic acid dibenzyl ester p-toluenesulfonate salt</strong> (compound 6) (1 g, 6.13 mmol) are dissolved in pyridine to form a chemical solution, and the chemical solution is heated to 120 C. and reacted for 18 hours. Afier 18 hours, the reaction solution is cooled to room temperature, and drops of 6N HC1 are added gradually to acidify the reaction solution to a pH value of 1. The acidified reaction solution is extracted by ethyl acetate, and the combined organic layer is washed by saturated salt water to remove the salts, and then anhydrous magnesium sulfate is used for drying and filtering. The filtered solution is concentrated to form a crude product, and the crude product is re-crystallized by ethyl acetate and water to obtain the final white solid product which is the compound 7A(0.36g,18%) Analysis Data of Compound 7A ?H-NMR (300 MHz, DMSO-d5): oe 2.78 (dd, 1H),2.90 (dd, 1H), 4.07 (ddd, 1H), 5.07 (s, 2H), 7.10 (d, 1H), 7.27 (dd, 1H), 7.33 (m, 5H), 7.75 (dd, 1H), 8.62 (dd, 1H), 10.4 (s, NH); ?3C-NMR(75 MHz, DMSO-d5): oe 171.3, 170.4, 168.1, 137.0, 136.4, 132.8, 130.9, 128.8, 128.4, 128.1, 126.7, 124.7,121.5, 66.0, 49.1, 33.1
2‐(4‐(dimethylamino)phenyl)quinazolin‐4(3H)‐one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
General procedure: A mixture of the benzyl amine (1 mmol) and isatoic anhydride (1 mmol, 163 mg) in DMSO (1 mL) was stirred for 2 h at 120C. Next, CuBr (10 mol%, 14.3 mg), TBAB (0.5 mol%, 1.4 lL) and K2CO3 (1 mmol, 138 mg) were added to the reaction mixture and stirring was continued for 6 h at 120C under air. Upon reaction completion (TLC) the reaction mixture was cooled, quenched with water (3 mL), and stirring continued for 15 min at ambient temperature. The resulting precipitate was filtered, washed with H2O, and the residue purified by column chromatography using n-hexane-EtOAc (4:1) as eluent.
With triethylamine; In acetonitrile; for 2h;Reflux;
Glycine benzyl ester p-toluenesulfonate (100.0 g, 0.296 mol),The addition of a suspension of acetonitrile (500 ml) and triethylamine (31.4 g, 0.311 mol) to isatoic anhydride (48.3 g, 0.296 mol)It is carried out by adding it little by little under mechanical stirring. The mixtureWhile monitoring by HPLC,Reflux for 2 hours. After completion of the reaction, the solvent was removed by evaporation,Add water (500 ml). The mixture was filtered and the product was washed with water (50 ml)next,Dry under reduced pressure at 60 C for 12 hours. 77.5 g (92.1%) of a white peach colored solid matter are obtained.
3-(4-chlorophenyl)-4-(1,2-dihydro-4-oxo-2-phenylquinazolin-3(4H)-yl)butanoic acid[ No CAS ]
C24H21ClN2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propyl sulfonic acid-functionalized SBA-15; In neat (no solvent); at 110℃; for 2h;
General procedure: To the mixture of isatoic anhydride (160 mg, 1 mmol),gabapentin or baclofen (1 mmol), and aromatic aldehyde(1 mmol), SBA-Pr-SO3H (0.02 g) was added, and then itwas stirred at 110 C for an appropriate period of time.After completion of the reaction, the mixture of productswas dissolved in hot EtOH to remove the heterogeneouscatalyst. Then, the solvent was evaporated and extractedusing EtOAc and then washed with water. Some productscontained a mixture of two diastereoisomers. Further purificationwas done using crystallization in water/EtOH (1:4).
3-(4-chlorophenyl)-4-(1,2-dihydro-2-(4-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl)butanoic acid[ No CAS ]
C25H23ClN2O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propyl sulfonic acid-functionalized SBA-15; In neat (no solvent); at 110℃; for 2h;
General procedure: To the mixture of isatoic anhydride (160 mg, 1 mmol),gabapentin or baclofen (1 mmol), and aromatic aldehyde(1 mmol), SBA-Pr-SO3H (0.02 g) was added, and then itwas stirred at 110 C for an appropriate period of time.After completion of the reaction, the mixture of productswas dissolved in hot EtOH to remove the heterogeneouscatalyst. Then, the solvent was evaporated and extractedusing EtOAc and then washed with water. Some productscontained a mixture of two diastereoisomers. Further purificationwas done using crystallization in water/EtOH (1:4).
3-(4-chlorophenyl)-4-(2-(4-fluorophenyl)-1,2-dihydro-4-oxoquinazolin-3(4H)-yl)butanoic acid[ No CAS ]
C24H20ClFN2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propyl sulfonic acid-functionalized SBA-15; In neat (no solvent); at 110℃; for 2h;
General procedure: To the mixture of isatoic anhydride (160 mg, 1 mmol),gabapentin or baclofen (1 mmol), and aromatic aldehyde(1 mmol), SBA-Pr-SO3H (0.02 g) was added, and then itwas stirred at 110 C for an appropriate period of time.After completion of the reaction, the mixture of productswas dissolved in hot EtOH to remove the heterogeneouscatalyst. Then, the solvent was evaporated and extractedusing EtOAc and then washed with water. Some productscontained a mixture of two diastereoisomers. Further purificationwas done using crystallization in water/EtOH (1:4).
3-(4-chlorophenyl)-4-(1,2-dihydro-4-oxo-2-p-tolylquinazolin-3(4H)-yl)butanoic acid[ No CAS ]
C25H23ClN2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propyl sulfonic acid-functionalized SBA-15; In neat (no solvent); at 110℃; for 2h;
General procedure: To the mixture of isatoic anhydride (160 mg, 1 mmol),gabapentin or baclofen (1 mmol), and aromatic aldehyde(1 mmol), SBA-Pr-SO3H (0.02 g) was added, and then itwas stirred at 110 C for an appropriate period of time.After completion of the reaction, the mixture of productswas dissolved in hot EtOH to remove the heterogeneouscatalyst. Then, the solvent was evaporated and extractedusing EtOAc and then washed with water. Some productscontained a mixture of two diastereoisomers. Further purificationwas done using crystallization in water/EtOH (1:4).
3-(4-chlorophenyl)-4-(1,2-dihydro-2-(4-bromophenyl)-4-oxoquinazolin-3(4H)-yl)butanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propyl sulfonic acid-functionalized SBA-15; In neat (no solvent); at 110℃; for 2h;
General procedure: To the mixture of isatoic anhydride (160 mg, 1 mmol),gabapentin or baclofen (1 mmol), and aromatic aldehyde(1 mmol), SBA-Pr-SO3H (0.02 g) was added, and then itwas stirred at 110 C for an appropriate period of time.After completion of the reaction, the mixture of productswas dissolved in hot EtOH to remove the heterogeneouscatalyst. Then, the solvent was evaporated and extractedusing EtOAc and then washed with water. Some productscontained a mixture of two diastereoisomers. Further purificationwas done using crystallization in water/EtOH (1:4).
3-(4-chlorophenyl)-4-(2-(4-chlorophenyl)-1,2-dihydro-4-oxoquinazolin-3(4H)-yl)butanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propyl sulfonic acid-functionalized SBA-15; In neat (no solvent); at 110℃; for 2h;
General procedure: To the mixture of isatoic anhydride (160 mg, 1 mmol),gabapentin or baclofen (1 mmol), and aromatic aldehyde(1 mmol), SBA-Pr-SO3H (0.02 g) was added, and then itwas stirred at 110 C for an appropriate period of time.After completion of the reaction, the mixture of productswas dissolved in hot EtOH to remove the heterogeneouscatalyst. Then, the solvent was evaporated and extractedusing EtOAc and then washed with water. Some productscontained a mixture of two diastereoisomers. Further purificationwas done using crystallization in water/EtOH (1:4).
3-(4-chlorophenyl)-4-(2-(4-nitrophenyl)-1,2-dihydro-4-oxoquinazolin-3(4H)-yl)butanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propyl sulfonic acid-functionalized SBA-15; In neat (no solvent); at 110℃; for 2h;
General procedure: To the mixture of isatoic anhydride (160 mg, 1 mmol),gabapentin or baclofen (1 mmol), and aromatic aldehyde(1 mmol), SBA-Pr-SO3H (0.02 g) was added, and then itwas stirred at 110 C for an appropriate period of time.After completion of the reaction, the mixture of productswas dissolved in hot EtOH to remove the heterogeneouscatalyst. Then, the solvent was evaporated and extractedusing EtOAc and then washed with water. Some productscontained a mixture of two diastereoisomers. Further purificationwas done using crystallization in water/EtOH (1:4).
4-(2-(4-tert-butylcyclohexyl)-1,2-dihydro-4-oxoquinazolin-3(4H)-yl)-3-(4-chlorophenyl)butanoic acid[ No CAS ]
C28H35ClN2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propyl sulfonic acid-functionalized SBA-15; In neat (no solvent); at 110℃; for 2h;
General procedure: To the mixture of isatoic anhydride (160 mg, 1 mmol),gabapentin or baclofen (1 mmol), and aromatic aldehyde(1 mmol), SBA-Pr-SO3H (0.02 g) was added, and then itwas stirred at 110 C for an appropriate period of time.After completion of the reaction, the mixture of productswas dissolved in hot EtOH to remove the heterogeneouscatalyst. Then, the solvent was evaporated and extractedusing EtOAc and then washed with water. Some productscontained a mixture of two diastereoisomers. Further purificationwas done using crystallization in water/EtOH (1:4).
With sodium hydroxide; In 1,4-dioxane; at 100℃; for 12h;
To a mixture of isatoic anhydride (5.00g, 31mmol) and cyclohexyl methanol (7.08g, 62mmol) dissolved in 35mL 1,4-dioxane, NaOH was added (0.10g, 2.5mmol). The mixture was heated at 100C under reflux for 12h and subsequently poured into 120mL water. The remaining solution was extracted three times with 100mL diethyl ether and the combined organic phases were dried over Na2SO4. After evaporation of the diethyl ether, the remaining reddish oil was distilled under vacuum over a 20cm Vigreux column. The product passed over at 152C (0.15Torr). At room temperature, the product crystalized to give 6.42g (yield 89%) of a white powder. mp: 42-43C; H NMR (400MHz, CDCl3) delta 1.06 (m, 2H, 4?-Hax, 6?-Hax); 1.24 (m, 3H, 4?-Heq, 5?-Hax, 6?-Hax); 1.58-1.99 (m, 6H, 2?-Heq, 3?-H, 5?-Heq, 7?-H); 4.08 (d, 2H, 3J=6.4Hz, 1?-H); 5.72 (br s, 2H, NH); 6.64 (m, 2H, 3-H, 5-H); 7.25 (dt, 1H, 3J=7.6Hz, 4J=1.6Hz, 4-H); 7.88 (dd, 1H, 3J=8.2Hz, 4J=1.6Hz, 6-H); C NMR (100MHz, CDCl3) delta 25.9 (C4?, C6?); 26.5 (C5?); 29.9 (C3?, C7?); 37.4 (C2?); 69.5 (C1?); 111.1 (C1); 116.3 (C3); 116.8 (C5); 131.3 (C6); 134.1 (C4); 150.7 (C2); 168.3 (C7); EI-MS (70eV): m/z (rel. int.)=233 [M+] (100), 137 (73), 119 (59), 92 (14); HR-EI-MS: m/z=233.1415; C14H19NO2 [M+] requires 233.1416.
General procedure: beta-Cyclodextrin (30 mol %), isatoic anhydride (1.0 mol eq.) and substituted isatin (1.0 mol eq.), were mixed in 8 mL water followed by stirring for 0.5 h at room temperature. Then primary amine (1.0 mol eq.) was added and reaction mixture was stirred vigorously upto disappearance of reactants on TLC (monitored by silica TLC). After completion reaction mixture was extracted by ethyl acetate and evaporated under reduced pressure. Solid residue was further crystallized by methanol and filtrate was kept for catalyst recovery.