* 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] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1980, vol. 16, # 3, p. 275 - 277[2] Khimiya Geterotsiklicheskikh Soedinenii, 1980, vol. 16, # 3, p. 366 - 368
[3] Zeitschrift fuer Chemie, 1869, p. 104
[4] Chemische Berichte, 1893, vol. 26, p. 1733
[5] Chemische Berichte, 1925, vol. 58, p. 1784
[6] Helvetica Chimica Acta, 1972, vol. 55, # 1, p. 198 - 205
[7] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, # 7, p. 2240 - 2245
[8] Patent: EP2345636, 2011, A1, . Location in patent: Page/Page column 22
6
[ 6946-14-1 ]
[ 2458-12-0 ]
Reference：
[1] Chem. Zentralbl., 1912, vol. 83, # I, p. 136
7
[ 60710-80-7 ]
[ 2458-12-0 ]
Reference：
[1] Chemische Berichte, 1894, vol. 27, p. 2165
8
[ 4478-10-8 ]
[ 2458-12-0 ]
Reference：
[1] Gazzetta Chimica Italiana, 1888, vol. 18, p. 303
9
[ 859816-42-5 ]
[ 2458-12-0 ]
Reference：
[1] Gazzetta Chimica Italiana, 1888, vol. 18, p. 303
10
[ 861525-09-9 ]
[ 2458-12-0 ]
Reference：
[1] Chem. Zentralbl., 1912, vol. 83, # I, p. 136
11
[ 99-94-5 ]
[ 2458-12-0 ]
Reference：
[1] Chemische Berichte, 1893, vol. 26, p. 1733
12
[ 90178-80-6 ]
[ 2458-12-0 ]
Reference：
[1] Chemische Berichte, 1894, vol. 27, p. 2165
13
[ 874-86-2 ]
[ 2458-12-0 ]
Reference：
[1] Chemische Berichte, 1894, vol. 27, p. 2165
14
[ 67-56-1 ]
[ 2458-12-0 ]
[ 18595-18-1 ]
Yield
Reaction Conditions
Operation in experiment
94.9%
at 5℃; for 6 h; Reflux
3-amino-4-methylbenzoic acid (60.5g, 0.40mol) was dissolved in anhydrous methanol (1.5 L of), stirred and cooled to 5 . Was slowly added dropwise thionyl chloride (103.6g, 0.87mol), the dropwise addition was stirred at reflux for 6h. Cooling to room temperature, the reaction solution was concentrated under reduced pressure, the residue was diluted with ice water (1.2 L of), plus 5percent of NaHCO3 neutralized to pH7.5. The aqueous layer with ethyl acetate (3 × 600mL) extraction, the organic layer was mixed (2 × 500mL) and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid intermediate (11) 62.7 g, yield 94.9percent.
94.9%
at 5℃; for 6 h; Reflux
3-amino-4-methylbenzoic acid (60.5 g, 0.40 mol) was dissolved in anhydrous methanol (1.5 L), and the resultingsolution was cooled to 5°C with stirring. Thionyl chloride (103.6 g, 0.87 mol) was slowly added dropwise, and the reactionmixture was stirred under reflux for 6 h after the addition. After cooled to room temperature, the reaction mixture wasconcentrated under reduced pressure, and the residue was diluted with ice water (1.2 L), followed by neutralization topH 7.5 by adding 5percent NaHCO3. The aqueous layer was extracted with ethyl acetate (33600 mL), and the combinedorganic layer was washed with saturated brine (23500 mL), dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure to obtain intermediate (11) as a white solid (62.7 g, yield: 94.9percent).MP 114-116°C1 H NMR (400 MHz, CDCl3): 2.19 (s, 3H), 3.73 (br s, 2H), 3.87 (s, 3H), 7.09 (m, 1H), 7.34-7.37 (m, 2H).
Reference：
[1] Patent: CN105693520, 2016, A, . Location in patent: Paragraph 0184; 0185; 0186; 0187; 0188; 0189
[2] Patent: EP3067351, 2016, A1, . Location in patent: Paragraph 0083; 0084
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6724 - 6731
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2423 - 2435
15
[ 2458-12-0 ]
[ 82998-57-0 ]
Reference：
[1] Chemische Berichte, 1893, vol. 26, p. 1733
16
[ 2458-12-0 ]
[ 5162-82-3 ]
[ 82998-57-0 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 5, p. 1333 - 1337
Reference：
[1] European Journal of Inorganic Chemistry, 2006, # 5, p. 980 - 987
[2] Chemical Biology and Drug Design, 2014, vol. 83, # 5, p. 592 - 599
[3] European Journal of Organic Chemistry, 2018, vol. 2018, # 34, p. 4731 - 4739
21
[ 2458-12-0 ]
[ 745048-63-9 ]
Yield
Reaction Conditions
Operation in experiment
89%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 1.16667 h; Inert atmosphere
To a solution of acid 24 (81 g, 535.8 mmol) in DMF (500 mL) was added NBS portionwise at 0 °C. The mixture was stirred at 0 °C for 70 min. The mixture was poured into H2O (1 L) with stirring. The product was precipitated and filtered. The solid was washed with H2O and the solid was dried under vacuum at 50 °C for 24 h to obtain the bromide (109 g, 89percent)To a solution of bromide (109 g, 473.8 mmol) in MeOH (900 mL) was added thionyl chloride (70 mL, 947.6 mmol) dropwise at 0 °C. The mixture was warmed up to r.t. and stirred at 65 °C for 18 h. The mixture was evaporated in vacuo. The residue was diluted with EtOAc (500 mL) and washed with aq. sat'd NaHCO3 solution (700 mL.x.3). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the ester 25 (107 g, 92percent).To a solution of ester 25 (60.4 g, 229 mmol) in CCl4 (900 mL) were added NBS (49.0 g, 275 mmol) and AIBN (3.80 g, 22.9 mmol). The mixture was stirred at 85 °C for 15 h. The mixture was cooled to room temperature and filtered off through celite to remove insoluble solids. The filtrate was evaporated in vacuo to obtain the crude benzyl bromide.To a solution of benzyl bromide (93.6 g, 273 mmol) in DMF (500 mL) was added NaOAc (56 g, 683 mmol). The mixture was stirred at room temperature for 20 h and diluted with EtOAc. The organic layer was washed with aq. 50percent NaCl solution and dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was tritulated with MeOH and the titled compound was precipitated as a solid. The solid was filtered off, washed with MeOH, and dried under vacuum to obtain the product (36 g, 51percent, 2 steps). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.71 (s, 2H), 5.19 (s, 2H), 3.94 (s, 3H), 2.19 (s, 3H); MH+ 321.To a solution of acetate (33.5 g, 104.1 mmol) in THF/MeOH/H2O (250 mL/250 mL/90 mL) was added lithium hydroxide monohydrate (13.1 g, 312 mmol). The mixture was stirred at room temperature for 15 h. The mixture was evaporated in vacuo to remove organic solvents. The residue was diluted with H2O, cooled to 0 °C and acidified with aq. 1 N HCl solution. The titled compound 26 was precipitated as a solid, filtered off and washed with H2O. The solid was dried under vacuum at 50 °C for 15 h to obtain the product (27.2 g, 96percent). MH+ 265.
89%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 1 h; Inert atmosphere
the bromination at the 6-position of 3-amino-4-methylbenzoic acid 23 using NBS yields bromide 24 in 89percent yield
87%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 5 - 15℃; for 1 h;
To a cooled solution (5° C.) of 3-amino-4-methylbenzoic acid (412.2 g, 2.72 mole) in DMF (2.2 L) was added N-bromosuccinimide (495.1 g, 2.78 mole) in small portions at such a rate that the reaction mixture temperature was kept below 15° C. After being stirred for one hour, the reaction mixture was poured onto ice water (1.2 L) with stirring. The solid that formed was filtered, and the filter cake was washed with ice water (3*2 L) and then dried at 60° C. to give a pink solid. Yield: 546 g (87percent). 1H NMR (DMSO-d6, 300 MHz): δ 7.20 (s, 1H), 7.04 (s, 1H), 2.05 (s, 3H).
87%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 5 - 15℃; for 1 h;
To a cooled solution (5° C.) of 3-amino-4-methylbenzoic acid (412.2 g, 2.72 mole) in DMF (2.2 L) was added N-bromosuccinimide (495.1 g, 2.78 mole) in small portions at such a rate that the reaction mixture temperature was kept below 15° C. After being stirred for one hour, the reaction mixture was poured onto ice water (1.2 L) with stirring. The solid that formed was filtered, and the filter cake was washed with ice water (3*2 L) and then dried at 60° C. to give a pink solid. Yield: 546 g (87percent). 1H-NMR (DMSO-d6, 300 MHz): δ 7.20 (s, 1H), 7.04 (s, 1H), 2.05 (s, 3H).
85%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 15℃; for 2 h; Inert atmosphere
5-Amino-2-bromo-4-methylbenzoic acid[0116] 3-amino-4-methylbenzoic acid (24.72 g, 162 mmol) was dissolved in anhydrous DMF (140 mL). The solution was then cooled to 0 - 5ºC and N-bromosuccinimide (29.70 g, 163.5 mmol) was added portionwise at a rate that the reaction mixture was kept below 15 ºC. The mixture was reacted for 2 hours and then poured into ice/water (150 g) with stirring. The produced solid was filtered and washed with cool water (3 x 120 mL). The filter cake was dissolved with EtOAc (800 mL) and washed with water (3 × 200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo to afford 5-amino-2-bromo-4-methylbenzoic acid as a pink solid (31.59 g, 85percent yield).
85%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 15℃; for 2 h; Inert atmosphere
In a round-bottom flask equipped with magnetic stirring and inert atmosphere, 3- amino-4-methylbenzoic acid (24.72 g, 162 mmol) was dissolved in anhydrous DMF (140 mL). The solution was then cooled to 0 - 5^C and /V-bromosuccinimide (29.70 g, 163.5 mmol) was added portionwise at a rate that the reaction mixture was kept below 15 2C. The mixture was reacted for 2 hours and then poured into ice/water (150 g) with stirring. The produced solid was filtered and washed with cool water (3 x 120 mL). The filter cake was dissolved with EtOAc (800 mL) and washed with water (3 x 200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under vacuum to afford 5-amino-2-bromo-4-methylbenzoic acid as a pink solid (31.59 g, 85percent yield).
83%
With N-Bromosuccinimide In DMF (N,N-dimethyl-formamide) at 20℃; for 3 h;
Example 14 Preparation of 3-Amino-6-bromo-4-methylbenzoic Acid (19) A mixture of 3-amino-4-methylbenzoic acid (13) ((13) (5.1525 g, 34.08 mmol)) and DMF (30 ML) is cooled to about 5° C., whereupon N-bromosuccinimide (6.230 g, 35 mmol) is added in small portions, at a rate such that the reaction temperature stays below 10° C. The reaction mixture is then stirred at ambient temperature for about 3 hours and is then added to ice water (150 ML).The solids that form are filtered and dried to provide 3-Amino-6-bromo-4-methylbenzoic Acid (19) ((19) (6.5439 g, 83percent yield).
77.5%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 15℃; for 1 h;
Step 1: Preparation of 5-amino-2-bromo-4-methylbenzoic acid To a cooled solution (5° C.) of 3-amino-4-methylbenzoic acid (3.02 g, 20 mmol) in DMF (20 mL) was added NBS (3.38 g, 19 mmol) in small portions at such a rate that the reaction mixture temperature was kept below 15° C. After being stirred for one hour, the reaction mixture was poured onto ice water (100 mL) with stirring. The solid formed was collected by filtration, and the filter cake was washed with ice water (3*100 mL) and then dried at 60° C. under high vacuum to give 5-amino-2-bromo-4-methylbenzoic acid (3.55 g, yield 77.5percent) as a pink solid. MS: m/z=230.0 (M+1, ESI+).
Reference：
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 2662 - 2675
[2] Patent: WO2011/159067, 2011, A2, . Location in patent: Page/Page column 28
[3] Patent: US2007/275907, 2007, A1, . Location in patent: Page/Page column 19
[4] Patent: US2008/242596, 2008, A1, . Location in patent: Page/Page column 15
[5] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 19, p. 5632 - 5635
[6] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 24, p. 6877 - 6881
[7] ChemMedChem, 2010, vol. 5, # 6, p. 827 - 831
[8] Patent: EP2573088, 2013, A1, . Location in patent: Paragraph 0116; 0117
[9] Patent: WO2013/45495, 2013, A1, . Location in patent: Page/Page column 41
[10] Patent: US2004/167194, 2004, A1, . Location in patent: Page 26
[11] Patent: US2013/131017, 2013, A1, . Location in patent: Paragraph 0380; 0581
[12] Chinese Chemical Letters, 2013, vol. 24, # 2, p. 131 - 133
[13] Monatshefte fur Chemie, 2015, vol. 146, # 10, p. 1715 - 1721
To a solution of 3-amino-4-methyl benzoic acid (2.0 g, 13.2 mmol) in water (25 mL) and 1N sodium hydroxide (25 mL) was added di-tert-butyl dicarbonate (4.3 g, 19.8 mmol) and the reaction was stirred for 18 hours at ambient temperature. The reaction was partitioned between ethyl acetate and 5percent aqueous citric acid. The organic layer was washed with water and brine and dried over magnesium sulfate. The material was filtered and concentrated to provide the protected aniline as a pink solid (3.3 g, quantitative yield).
91%
at 50℃;
A mixture of commercially-available 4-amino-3-methylbenzoic acid (100 g, 0.66 mol) and di-tertbutyl dicarbonate (150 g, 0.68 mol) in THF (1000 mL) was slowly heated to 50°C overnight. The resulting mixture was cooled to rt and the solvent was removed on a rotary evaporator. The resulting solids were triturated with hexanes and dried in vacuo to afford 151 g (91percent) of the crude BOC-protected aniline intermediate as a light pink solid. To the above, light-pink solid was added 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (127 g, 0.66 mol), HOBt (90 g, 0.66 mol), and DMF (1000 ml), and the resulting mixture was stirred at rt for 30 minutes followed by addition of methoxyamine hydrochloride (55 g, 0.66 mol) in one portion. After stirring for 10 min, the mixture was cooled using an ice bath. Diisopropyl-ethylamine (250 ml, 1.4 mol) was added at such a rate so as to maintain the internal reaction temperature below 25°C. After the addition was complete, the ice bath was removed and the reaction was stirred overnight at rt. The reaction mixture was partitioned between 0.5 L of water and 1.5 L of EtOAc and the resulting layers were separated. The aqueous portion was extracted with additional EtOAc (400 mL x 3), and the combined organic extracts were washed with, water (300 mL x 3), cold 0.5 N aqueous HC1 (400 mL x 2), and water (500 mL). The product was then extracted with cold 0.5 N aqueous NaOH (300 mL x 3) and the combined basic aqueous extracts were neutralized to pH = 8 by a slow addition of cold 0.5 N aqueous HC1. The resulting solid which precipitated was collected by filtration and washed with cold water.'The wet solid was decolorized in hot EtOH with active charcoal to give 106 g of white solid as the BOC-protected N-methoxyamide intermediate. To a slurry of the above solid (91 g, 0.32 mol) in 1,4-dioxane (400 mL) at rt was added a 4M solution of HC1 in dioxane (400 mL), and the resulting mixture was stirred at rt overnight. Diethyl ether (1000 mL) was added and the precipitated solid was collected by filtration and triturated with a hot EtOH/H20 mixture (4: 1 v/v). Drying the resulting solid in vacuo afforded 53 g of the pure hydrochloride salt (1D) as a white solid. 1H NMR (d6-DMSO) : 6 9.5-9. 9 (br. s, 1H), 7.75 (s, 1H), 7.55 (d, 1H), 7.36 (d, 1H), 3.70 (s, 3H), 2.38 (s, 3H).
88%
at 50℃;
A suspension of 3-amino-4-methylbenzoic acid (20.0 g, 132 mmol) and N-(tert-butoxycarbonyl)anhydride (30.0 g, 219 mmol) in THF (200 mL) was heated and stirred at 50 °C overnight. The resulting mixture was cooled to rt. The solvent was evaporated in vacuo, and the crude product was recrystallized from EtOAc to afford 7 (29.1 g, 88 percent) as a pink solid. 1H NMR (DMSO-d6): δ 12.8 (s, 1H), 8.66 (s, 1H), 7.97 (s, 1H), 7.59 (dd, J=2.0, 8.0Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 3.25 (s, 3H), 1.47 (s, 9H).
Reference：
[1] Patent: US2012/142708, 2012, A1, . Location in patent: Page/Page column 23
[2] Patent: WO2005/42537, 2005, A1, . Location in patent: Page/Page column 46; 47
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3700 - 3705
[4] European Journal of Organic Chemistry, 2001, # 2, p. 311 - 322
[5] Journal of Medicinal Chemistry, 2008, vol. 51, # 1, p. 4 - 16
[6] Angewandte Chemie - International Edition, 2017, vol. 56, # 47, p. 14918 - 14922[7] Angew. Chem., 2017, vol. 129, # 47, p. 15114 - 15118,5
24
[ 2458-12-0 ]
[ 641569-94-0 ]
Reference：
[1] Chemical Biology and Drug Design, 2014, vol. 83, # 5, p. 592 - 599
(Synthetic Example 29) Synthesis of 4-methyl-3-(L- r -glutamylamino)benzoic acid (Compound No. 29) 500mg of 4-Methyl-3-nitrobenzoic acid was dissolved in 5mL of methanol and 10mL of a dioxane solution containing 4N hydrogen chloride. After stirring the mixture at room temperature for 2 days, a solvent was removed to obtain a crude product. The obtained crude product was dissolved in 10mL of methanol, and Pd/C in catalyst quantity was acted thereon under hydrogen atmosphere at room temperature overnight. After filtering out the catalyst, a solvent was removed to obtain a crude product. 165mg of the obtained crude product, 303mg (1mmol) of Boc-Glu-OtBu hydrochloride and 400mg (about 1.3mmol) of HATU were dissolved in 1mL of DMF. 0.26mL of DIEA was added thereto and stirred overnight. The reaction solution was diluted with water-acetonitrile and purified in accordance with the purification process A to obtain 0.31g of a protected form of the intended compound. 3mL of THF, 1.5mL of methanol and 1.5mL of water were added to the obtained protected form, and then 26mg (0.82mmol) of lithium hydroxide monohydrate was further added thereto. After stirring the mixture for 2 hours, a solvent was removed. 3mL of THF, 1.5mL of methanol and 1.5mL of water were again added thereto, then 26mg (0.82mmol) of lithium hydroxide monohydrate was further added thereto and stirred for 2 hours. After adding 2mL of ethyl acetate thereto, a solvent was removed. Then, 3mL of a trifluoroacetic acid was added thereto and stirred at room temperature for 2 hours. After removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound. 1H-NMR (D20) delta : 7.74-7.77(m,1H), 7.30-7.36(m,1H), 3.75-3.81(m,1H), 2.55-2.62(m,2H), 2.10-2.20(m,5H) ESI-MS : 279[M-H]-, 281[M+H]+
To a solution of 3-amino-4-methyl benzoic acid (2.0 g, 13.2 mmol) in water (25 mL) and 1N sodium hydroxide (25 mL) was added di-tert-butyl dicarbonate (4.3 g, 19.8 mmol) and the reaction was stirred for 18 hours at ambient temperature. The reaction was partitioned between ethyl acetate and 5% aqueous citric acid. The organic layer was washed with water and brine and dried over magnesium sulfate. The material was filtered and concentrated to provide the protected aniline as a pink solid (3.3 g, quantitative yield).
91%
In tetrahydrofuran; at 50℃;
A mixture of commercially-available 4-amino-3-methylbenzoic acid (100 g, 0.66 mol) and di-tertbutyl dicarbonate (150 g, 0.68 mol) in THF (1000 mL) was slowly heated to 50C overnight. The resulting mixture was cooled to rt and the solvent was removed on a rotary evaporator. The resulting solids were triturated with hexanes and dried in vacuo to afford 151 g (91%) of the crude BOC-protected aniline intermediate as a light pink solid. To the above, light-pink solid was added 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (127 g, 0.66 mol), HOBt (90 g, 0.66 mol), and DMF (1000 ml), and the resulting mixture was stirred at rt for 30 minutes followed by addition of methoxyamine hydrochloride (55 g, 0.66 mol) in one portion. After stirring for 10 min, the mixture was cooled using an ice bath. Diisopropyl-ethylamine (250 ml, 1.4 mol) was added at such a rate so as to maintain the internal reaction temperature below 25C. After the addition was complete, the ice bath was removed and the reaction was stirred overnight at rt. The reaction mixture was partitioned between 0.5 L of water and 1.5 L of EtOAc and the resulting layers were separated. The aqueous portion was extracted with additional EtOAc (400 mL x 3), and the combined organic extracts were washed with, water (300 mL x 3), cold 0.5 N aqueous HC1 (400 mL x 2), and water (500 mL). The product was then extracted with cold 0.5 N aqueous NaOH (300 mL x 3) and the combined basic aqueous extracts were neutralized to pH = 8 by a slow addition of cold 0.5 N aqueous HC1. The resulting solid which precipitated was collected by filtration and washed with cold water.'The wet solid was decolorized in hot EtOH with active charcoal to give 106 g of white solid as the BOC-protected N-methoxyamide intermediate. To a slurry of the above solid (91 g, 0.32 mol) in 1,4-dioxane (400 mL) at rt was added a 4M solution of HC1 in dioxane (400 mL), and the resulting mixture was stirred at rt overnight. Diethyl ether (1000 mL) was added and the precipitated solid was collected by filtration and triturated with a hot EtOH/H20 mixture (4: 1 v/v). Drying the resulting solid in vacuo afforded 53 g of the pure hydrochloride salt (1D) as a white solid. 1H NMR (d6-DMSO) : 6 9.5-9. 9 (br. s, 1H), 7.75 (s, 1H), 7.55 (d, 1H), 7.36 (d, 1H), 3.70 (s, 3H), 2.38 (s, 3H).
88%
In tetrahydrofuran; at 50℃;
A suspension of 3-amino-4-methylbenzoic acid (20.0 g, 132 mmol) and N-(tert-butoxycarbonyl)anhydride (30.0 g, 219 mmol) in THF (200 mL) was heated and stirred at 50 C overnight. The resulting mixture was cooled to rt. The solvent was evaporated in vacuo, and the crude product was recrystallized from EtOAc to afford 7 (29.1 g, 88 %) as a pink solid. 1H NMR (DMSO-d6): delta 12.8 (s, 1H), 8.66 (s, 1H), 7.97 (s, 1H), 7.59 (dd, J=2.0, 8.0Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 3.25 (s, 3H), 1.47 (s, 9H).
With triethylamine triflouroacetate; In dimethyl sulfoxide; at 95℃; for 65.0h;
Example 55 Synthesis of 4-Methyl-3-(3-pyrimidin-4-yl-pyridin-2- ylamino) -benzoic acid; 4- (2-Chloro-pyridin-3-yl)-pyrimidine (10.4 g, 54 mmol), 3- amino-4-methylbenzoic acid (19.4 g, 128 mmol), 17 g Et3N-TFA salt (The liquid Et3N-TFA reagent was generated by adding 2.5 mL TFA dropwise to a 0 C solution of 3 mL Et3N in isopropanol, then concentrating by rotary evaporator followed by 30 minutes under high vacuum. ), and 15 mL DMSO were mixed together in a sealed tube under argon. The mixture was stirred at 95 C for 65 h. 'After cooling to RT, the residue was sonicated in 100 mL methanol to break up the solids, then filtered to obtain product as a yellow solid. MS m/z = 307 [M+H]+. Calc'd for C17H14N402: 306.33.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 5 - 15℃; for 1.08h;Inert atmosphere;
NBS (11.87 g, 66.15 mmol) was added portionwise to 3-amino-4-methylbenzoic acid (10.00 g,10 66.15 mmol) in DMF (50 mL) at 5C over a period of5 minutes so that the temperature did not riseabove 15C. The resulting solution was stirred at 5C for 1 h. The reaction mixture was poured onto ice water (250 mL) with stirring. The resulting solid was filtered, washed with ice cold water anddried to afford the title compound (15.21 g, 100%) as a pale pink solid; 1H NMR (400 MHz,DMSO) 2.04- 2.09 (3H, m), 5.21 (2H, s), 7.06 (lH, s), 7.21 (lH, d), 12.84 (lH, s).
89%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 1.16667h;Inert atmosphere;
To a solution of acid 24 (81 g, 535.8 mmol) in DMF (500 mL) was added NBS portionwise at 0 C. The mixture was stirred at 0 C for 70 min. The mixture was poured into H2O (1 L) with stirring. The product was precipitated and filtered. The solid was washed with H2O and the solid was dried under vacuum at 50 C for 24 h to obtain the bromide (109 g, 89%)To a solution of bromide (109 g, 473.8 mmol) in MeOH (900 mL) was added thionyl chloride (70 mL, 947.6 mmol) dropwise at 0 C. The mixture was warmed up to r.t. and stirred at 65 C for 18 h. The mixture was evaporated in vacuo. The residue was diluted with EtOAc (500 mL) and washed with aq. sat'd NaHCO3 solution (700 mL×3). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the ester 25 (107 g, 92%).To a solution of ester 25 (60.4 g, 229 mmol) in CCl4 (900 mL) were added NBS (49.0 g, 275 mmol) and AIBN (3.80 g, 22.9 mmol). The mixture was stirred at 85 C for 15 h. The mixture was cooled to room temperature and filtered off through celite to remove insoluble solids. The filtrate was evaporated in vacuo to obtain the crude benzyl bromide.To a solution of benzyl bromide (93.6 g, 273 mmol) in DMF (500 mL) was added NaOAc (56 g, 683 mmol). The mixture was stirred at room temperature for 20 h and diluted with EtOAc. The organic layer was washed with aq. 50% NaCl solution and dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was tritulated with MeOH and the titled compound was precipitated as a solid. The solid was filtered off, washed with MeOH, and dried under vacuum to obtain the product (36 g, 51%, 2 steps). 1H NMR (400 MHz, CDCl3) delta 7.84 (s, 1H), 7.71 (s, 2H), 5.19 (s, 2H), 3.94 (s, 3H), 2.19 (s, 3H); MH+ 321.To a solution of acetate (33.5 g, 104.1 mmol) in THF/MeOH/H2O (250 mL/250 mL/90 mL) was added lithium hydroxide monohydrate (13.1 g, 312 mmol). The mixture was stirred at room temperature for 15 h. The mixture was evaporated in vacuo to remove organic solvents. The residue was diluted with H2O, cooled to 0 C and acidified with aq. 1 N HCl solution. The titled compound 26 was precipitated as a solid, filtered off and washed with H2O. The solid was dried under vacuum at 50 C for 15 h to obtain the product (27.2 g, 96%). MH+ 265.
89%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 1.0h;Inert atmosphere;
the bromination at the 6-position of 3-amino-4-methylbenzoic acid 23 using NBS yields bromide 24 in 89% yield
87%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 5 - 15℃; for 1.0h;
To a cooled solution (5 C.) of 3-amino-4-methylbenzoic acid (412.2 g, 2.72 mole) in DMF (2.2 L) was added N-bromosuccinimide (495.1 g, 2.78 mole) in small portions at such a rate that the reaction mixture temperature was kept below 15 C. After being stirred for one hour, the reaction mixture was poured onto ice water (1.2 L) with stirring. The solid that formed was filtered, and the filter cake was washed with ice water (3*2 L) and then dried at 60 C. to give a pink solid. Yield: 546 g (87%). 1H NMR (DMSO-d6, 300 MHz): delta 7.20 (s, 1H), 7.04 (s, 1H), 2.05 (s, 3H).
87%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 5 - 15℃; for 1.0h;
To a cooled solution (5 C.) of 3-amino-4-methylbenzoic acid (412.2 g, 2.72 mole) in DMF (2.2 L) was added N-bromosuccinimide (495.1 g, 2.78 mole) in small portions at such a rate that the reaction mixture temperature was kept below 15 C. After being stirred for one hour, the reaction mixture was poured onto ice water (1.2 L) with stirring. The solid that formed was filtered, and the filter cake was washed with ice water (3*2 L) and then dried at 60 C. to give a pink solid. Yield: 546 g (87%). 1H-NMR (DMSO-d6, 300 MHz): delta 7.20 (s, 1H), 7.04 (s, 1H), 2.05 (s, 3H).
85%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 15℃; for 2.0h;Inert atmosphere;
5-Amino-2-bromo-4-methylbenzoic acid[0116] 3-amino-4-methylbenzoic acid (24.72 g, 162 mmol) was dissolved in anhydrous DMF (140 mL). The solution was then cooled to 0 - 5ºC and N-bromosuccinimide (29.70 g, 163.5 mmol) was added portionwise at a rate that the reaction mixture was kept below 15 ºC. The mixture was reacted for 2 hours and then poured into ice/water (150 g) with stirring. The produced solid was filtered and washed with cool water (3 x 120 mL). The filter cake was dissolved with EtOAc (800 mL) and washed with water (3 × 200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo to afford 5-amino-2-bromo-4-methylbenzoic acid as a pink solid (31.59 g, 85% yield).
85%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 15℃; for 2.0h;Inert atmosphere;
In a round-bottom flask equipped with magnetic stirring and inert atmosphere, 3- amino-4-methylbenzoic acid (24.72 g, 162 mmol) was dissolved in anhydrous DMF (140 mL). The solution was then cooled to 0 - 5^C and /V-bromosuccinimide (29.70 g, 163.5 mmol) was added portionwise at a rate that the reaction mixture was kept below 15 2C. The mixture was reacted for 2 hours and then poured into ice/water (150 g) with stirring. The produced solid was filtered and washed with cool water (3 x 120 mL). The filter cake was dissolved with EtOAc (800 mL) and washed with water (3 x 200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under vacuum to afford 5-amino-2-bromo-4-methylbenzoic acid as a pink solid (31.59 g, 85% yield).
83%
With N-Bromosuccinimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 3.0h;
Example 14 Preparation of 3-Amino-6-bromo-4-methylbenzoic Acid (19) A mixture of 3-amino-4-methylbenzoic acid (13) ((13) (5.1525 g, 34.08 mmol)) and DMF (30 ML) is cooled to about 5 C., whereupon N-bromosuccinimide (6.230 g, 35 mmol) is added in small portions, at a rate such that the reaction temperature stays below 10 C. The reaction mixture is then stirred at ambient temperature for about 3 hours and is then added to ice water (150 ML).The solids that form are filtered and dried to provide 3-Amino-6-bromo-4-methylbenzoic Acid (19) ((19) (6.5439 g, 83% yield).
77.5%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 15℃; for 1.0h;
Step 1: Preparation of 5-amino-2-bromo-4-methylbenzoic acid To a cooled solution (5 C.) of 3-amino-4-methylbenzoic acid (3.02 g, 20 mmol) in DMF (20 mL) was added NBS (3.38 g, 19 mmol) in small portions at such a rate that the reaction mixture temperature was kept below 15 C. After being stirred for one hour, the reaction mixture was poured onto ice water (100 mL) with stirring. The solid formed was collected by filtration, and the filter cake was washed with ice water (3*100 mL) and then dried at 60 C. under high vacuum to give 5-amino-2-bromo-4-methylbenzoic acid (3.55 g, yield 77.5%) as a pink solid. MS: m/z=230.0 (M+1, ESI+).
56.1
Step 1. Preparation of (3-amino-4-methyl-phenyl)-carbamic acid tert-butyl ester; The title compound was prepared according to the procedure decribed in J. Med. Chem. 1994,37, 636-646. To 4-methyl- benzene-1,3-diamine (4.93 g, 40.4 mmol), MeOH (220 mL) and triethylamine (5.1 mL, 36.7 mmol) was added di-tert-butyl dicarbonate (8.00 g, 36.7 mmol). The mixture was stirred overnight at RT and concentrated. The residue was dissolved in EtOAc and extracted with 10% aqueous NaHC03. The organic layer was dried over Na2S04, filtered and concentrated about 90% of the way. At this point the product which precipitated out of solution, was filtered and washed with EtOAc to yield (3-amino-4-methyl-phenyl) -carbamic acid tert-butyl ester.
With hydrogenchloride; sulfuric acid; sodium nitrite;copper(I) chloride; In methanol; water;
(1) Preparation of methyl 4-methyl-3-chlorobenzoate To 4-methyl-3-aminobenzoic acid (7.5 g, 0.05 mol) was added conc. hydrochloric acid (50 ml). The obtained suspension was ice-cooled, and a solution obtained by dissolving sodium nitrite (4 g, 0.05 mol) in water (20 ml) was added. After 30 minutes, copper(I) chloride (5.5 g, 0.055 mol) was added, and the reaction mixture was stirred at room temperature for 1 hour, and further stirred at 100 C. for 1 hour. After allowing to cool, the precipitate was separated by filtration, washed with water, and dried. It was suspended in 90 ml of methanol, and conc. sulfuric acid (2.6 ml) was added. After refluxing under heating for 4 hours, the reaction mixture was allowed to cool, and methanol was distilled away under reduced pressure. To the residue was added a saturated aqueous sodium hydrogencarbonate solution, and the reaction mixture was extracted with ethyl acetate, and after washing with water and a saturated aqueous sodium chloride solution, was dried over anhydrous sodium sulfate. After distilling the solvent away, the residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (5.8 g, 0.03 mol) (yield 60%).
With hydrogenchloride; potassium acetate; trifluoroborane diethyl ether; In tetrahydrofuran; chloroform; ethyl acetate; acetone;
(a) To a solution of boron trifluoride etherate (18 ml) in chloroform (450 ml, Al2 O3 treated) at -15° was added a solution of 3-amino-4-methylbenzoic acid (15.1 g) in tetrahydrofuran (150 ml) over 15 minutes and the resulting mixture was then stirred for an additional 5 minutes. To this mixture was added t-butyl nitrite (14 ml), and the reaction was warmed to 5°. After stirring for 1 hour, potassium acetate (49 g) and 18-crown-6 (2.65 g) were added. The reaction mixture was allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was evaporated, and 3:7 acetone:ethyl acetate (500 ml) and 1N hydrochloric acid (150 ml) were added. After stirring for 2 hours, brine (150 ml) was added to the mixture and the mixture filtered. The aqueous filtrate was extracted with 3:7 acetone:ethyl acetate (2*100 ml). The combined organic extract was dried (MgSO4) and evaporated. The resulting residue was dissolved in hot acetic acid (250 ml) and 250 ml saturated ethereal HCl and 250 ml ether were added sequentially. After cooling to room temperature, the precipitate was filtered and treated with 3:7 acetone:ethyl acetate (500 ml) and brine (100 ml) for 1 hour. After the phases were separated, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to afford 6-carboxyindazole as a brown solid (9.8 g, 57percent), mp >250°.
With hydrogenchloride; potassium acetate; trifluoroborane diethyl ether; In tetrahydrofuran; chloroform; ethyl acetate; acetone;
(a) To a solution of boron trifluoride etherate (18 ml) in chloroform (450 ml, Al2O3 treated) at -15° was added a solution of 3-amino-4-methylbenzoic acid (15.1 g) in tetrahydrofuran (150 ml) over 15 minutes and the resulting mixture was then stirred for an additional 5 minutes. To this mixture was added t-butyl nitrite (14 ml), and the reaction was warmed to 5°. After stirring for 1 hour, potassium acetate (49 g) and 18-crown-6 (2.65 g) were added. The reaction mixture was allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was evaporated, and 3:7 acetone:ethyl acetate (500 ml) and 1N hydrochloric acid (150 ml) were added. After stirring for 2 hours, brine (150 ml) was added to the mixture and the mixture filtered. The aqueous filtrate was extracted with 3:7 acetone:ethyl acetate (2 x 100 ml). The combined organic extract was dried (MgSO4) and evaporated. The resulting residue was dissolved in hot acetic acid (250 ml) and 250 ml saturated ethereal HCl and 250 ml ether were added sequentially. After cooling to room temperature, the precipitate was filtered and treated with 3:7 acetone:ethyl acetate (500 ml) and brine (100 ml) for 1 hour. After the phases were separated, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to afford 6-carboxyindazole as a brown solid (9.8 g, 57percent), mp >250°.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 18 - 25℃; for 2h;
A
Intermediate A; 4-[ 1 -(3-amino-4-methyl-benzoyl)-4-piperidyl]benzonitrile; A solution of 3-amino-4-methyl benzoic acid (4.05 g, 26.792 mmol), 4-(4'-cyanophenyl) piperidine (5 g, 26.79 mmol), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [EDAC] (5.64 g, 29.47 mmol, 1.1 eq) and DMAP (328 mg, 2.68 mmol, 0.1 eq) in DMF (60 mL) was stirred at ambient temperature for 2 hrs. Ethyl acetate (200 mL) was added and the resulting solution was washed sequentially with KHSO4 solution (100 mL of 2M), and brine (100ml); a precipitate formed and was filtered off to give the title compound as a colourless solid (5.25 g), 1H NMR (300.073 MHz, DMSO- d6, 30 0C) δ 1.47 - 1.67 (2H, m), 1.68 - 1.89 (2H, m), 2.05 (3H, s), 2.68 - 3.15 (3H, m), 3.59 - 4.13 (IH, m), 4.22 - 4.76 (IH, m), 4.97 (2H, s), 6.45 - 6.53 (IH, m), 6.63 (IH, s), 6.90 - 6.99 (IH, m), 7.44 - 7.54 (2H, m), 7.71 - 7.81 (2H, m), m/z 320 (M+H)+.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 2h;
A
Intermediate A4-[ 1 -(3-amino-4-methyl-benzoyl)-4-piperidyl]benzonitrileA solution of 3-amino-4-methyl benzoic acid (4.05 g, 26.792 mmol), 4-(4'-cyanophenyl) piperidine (5 g, 26.79 mmol), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [EDAC] (5.64 g, 29.47 mmol, 1.1 eq) and DMAP (328 mg, 2.68 mmol, 0.1 eq) in DMF (60 mL) was stirred at ambient temperature for 2 hrs. Ethyl acetate (200 mL) was added and the resulting solution was washed sequentially with KHSO4 solution (100 mL of 2M), and brine (100ml); a precipitate formed and was filtered off to give the title compound as a colourless solid (5.25 g), 1H NMR (300.073 MHz, d6-DMSO, 30 0C) δ 1.47 - 1.67 (2H, m), 1.68 - 1.89 (2H, m), 2.05 (3H, s), 2.68 - 3.15 (3H, m), 3.59 - 4.13 (IH, m), 4.22 - 4.76 (IH, m), 4.97 (2H, s), 6.45 - 6.53 (IH, m), 6.63 (IH, s), 6.90 - 6.99 (IH, m), 7.44 - 7.54 (2H, m), 7.71 - 7.81 (2H, m), m/z 320 (M+H)+.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 2h;
Intermediate A4-[ 1 -(3-amino-4-methyl-benzoyl)-4-piperidyl]benzonitrileA solution of 3-amino-4-methyl benzoic acid (4.05 g, 26.792 mmol), 4-(4'-cyanophenyl) piperidine (5 g, 26.79 mmol), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [EDAC] (5.64 g, 29.47 mmol, 1.1 eq) and DMAP (328 mg, 2.68 mmol, 0.1 eq) in DMF (60 mL) was stirred at ambient temperature for 2 hrs. Ethyl acetate (200 mL) 0 was added and the resulting solution was washed sequentially with KHSO4 solution (100 mL of 2M), and brine (100ml); a precipitate formed and was filtered off to give the title compound as a colourless solid (5.25 g), 1H NMR (300.073 MHz, DMSO- d6, 30 °C) δ 1.47 - 1.67 (2H, m), 1.68 - 1.89 (2H, m), 2.05 (3H, s), 2.68 - 3.15 (3H, m), 3.59 - 4.13 (IH, m), 4.22 - 4.76 (IH, m), 4.97 (2H, s), 6.45 - 6.53 (IH, m), 6.63 (IH, s), 6.90 - 6.99 (IH, s m), 7.44 - 7.54 (2H, m), 7.71 - 7.81 (2H, m), m/z 320 (M+H)+.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 18 - 25℃; for 2h;
A
Intermediate A; 4-[l-(3-amino-4-methyl-benzoyl)-4-piperidyl]benzonitrile; A solution of 3-amino-4-methyl benzoic acid (4.05 g, 26.792 mmol), 4-(4'-cyanophenyl) piperidine (5 g, 26.79 mmol), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide 5 hydrochloride [EDAC] (5.64 g, 29.47 mmol, 1.1 eq) and DMAP (328 mg, 2.68 mmol, 0.1 eq) in DMF (60 mL) was stirred at ambient temperature for 2 hrs. Ethyl acetate (200 mL) was added and the resulting solution was washed sequentially with KHSO4 solution (100 mL of 2M), and brine (100ml); a precipitate formed and was filtered off to give the title compound as a colourless solid (5.25 g), 1H NMR (300.073 MHz, DMSO- d6, 30 0C) δ 0 1.47 - 1.67 (2H, m), 1.68 - 1.89 (2H, m), 2.05 (3H, s), 2.68 - 3.15 (3H, m), 3.59 - 4.13 (IH, m), 4.22 - 4.76 (IH, m), 4.97 (2H, s), 6.45 - 6.53 (IH, m), 6.63 (IH, s), 6.90 - 6.99 (IH, m)5 7.44 . 7.54 (2H, m), 7.71 - 7.81 (2H, m), m/z 320 (MH-H)+.
Stage #1: 3-amino-p-toluic acid With hydrogenchloride; sodium nitrite In water for 0.5h;
Stage #2: With sodium acetate In water
Stage #3: sodium tert-butyl thiolate In water for 2h;
14.B
To a stirred solution of aqueous HCl (15 niL of cone HCl in 50 mL of water) was added 3-amino~4-methyl benzoic acid (14 A, 5.0 g; 33.0 mmol). The mixture was cooled in an ice- water bath followed by slow addition of a solution of sodium nitrite (I.I eq, 2.50 g) in water (12 mL). The mixture was stirred for 30 min at which point the mixture was a homogeneous dark solution. A saturated aqueous solution of sodium acetate was added until pH 6 was attained. Sodium t-butylthiolate (0.5 eq, 1.85 g) was added in one portion. The reaction was stirred for 2 h and the resulting precipitate was collected by filtration (whatman No.1), washed with water (20 mL) and concentrated in vacuo to provide the product 14B (2.7 g; 64 %) as a tan solid.
N'-(acridin-9-yl)-3-amino-4-methylbenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.24%
Stage #1: 3-amino-p-toluic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran Cooling with ice;
Stage #2: (acridin-9-yl)hydrazine With triethylamine In tetrahydrofuran Cooling with ice;
General procedure for the synthesis of substituted benzoic acid N'-acridin-9-yl hydrazide (AA-11 to AA-112)
General procedure: 1.5 equivalents of substituted carboxylic acid was added totetrahydrofuran (THF) and allowed to stir till complete dissolution. To it was added 1.5 equivalent of hydroxy-O-benzotriazole (HOBt) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide*HCl (EDC*HCl) and stirred for 15-20 min at ice-cold condition. To this solution were added triethylamine (TEA) and 1.5 equivalent of 9-hydrazinylacridine. The reaction was run at ice-cold condition till completion and worked up with dichloromethane (DCM), washed with dil. HCl and sodium bicarbonate (NaHCO3). DCM layer was collected, and solvent was evaporated under reduced pressure. The final solid product was crystallized. The characterization details are given below:
Stage #1: 3-amino-p-toluic acid; 2,6-difluoro-3-hydroxy-benzaldehyde With acetic acid at 0 - 20℃; for 3h;
Stage #2: With sodium cyanoborohydride at 0 - 20℃; for 16h;
9 Example 9: Synthesis of Additional Exemplary Photoprobe Compounds
To a solution of 3-amino-4-methylbenzoic acid (4.00 g, 26.5 mmol, 1 eq.) in acetic acid (80 mL) was added 2,6-difluoro-3-hydroxybenzaldehyde (5.01 g, 31.7 mmol, 1.2 eq.) at 0 °C. The reaction was slowly warmed to room temperature and stirred at room temperature for 3 h. The reaction mixture was again cooled to 0 °C. NaCNBH3 (3.32 g, 52.9 mmol, 2.0 eq.) was added, in small portions. The reaction mixture was allowed to warm to room temperature, then was stirred at room temperature for 16 h. The resulting reaction mixture was poured into ice-cold water (500 mL). The resulting precipitate was collected by filtration and washed with water (3 x 25 mL). The obtained solid was dried under high vacuum to afford 26 as a white solid (6.00 g, 62% yield).1H NMR (400 MHz, DMSO-d6) δ 12.48 (br s, 1H), 9.74 (s, 1 H), 7.22 (d, J = 1.2 Hz, 1 H), 7.13 (dd, J = 7.6, 1.6 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 6.86 - 6.83 (m, 2H), 5.38 (t, J = 5.6 Hz, 1 H), 4.36 (d, J = 5.2 Hz, 2 H), 2.11 (s, 3H). MS (ESI-MS): m/z calcd for C15H13F2NO3+ = 294.09, found 294.16.
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