* 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.
Methyl 2-bromo-5-fluorobenzoate (159-1). Trimethylsilyl diazomethane (338 ml, 676 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, 0°C solution of 2-bromo-5-fluorobenzoic acid (74 g, 338 mmol) in MeOH (676ml) until a yellow color persisted. Acetic acid was added dropwise until the yellow color dissipated. The solvent was removed in vacuo, and the resisdue was dissolved in CH2Cl2, then filtered through a plug of silica gel, eluting with CH2Cl2. The solvent was removed in vacuo to afford 77 g, 98 percent of 159-1 as a yellow oil.
98%
Stage #1: at 0℃; Stage #2: With acetic acid In methanol; diethyl ether
Trimethylsilyl diazomethane (338 ml, 676 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, 0°C solution of 2-bromo-5-fluorobenzoic acid (74 g, 338 mmol) in MeOH (676ml) until a yellow color persisted. Acetic acid was added dropwise until the yellow color dissipated. The solvent was removed in vacuo, and the resisdue was dissolved in CH2Cl2, then filtered through a plug of silica gel, eluting with CH2Cl2. The solvent was removed in vacuo to afford 77 g, 98 percent of 2λ as a yellow oil.
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 23℃; for 48 h; Inert atmosphere
DBU(1.7 equiv, 1.16 mL, 7.76 mmol) was added to a solution of 2-bromo-5-fluorobenzoic acid (1.0 equiv, 1.0 g, 4.57 mmol) and iodomethane (2.0 equiv, 0.57 mL, 9.14mmol) in CH3CN (11 mL) at 23 °C. After stirring for 48 h, thereaction was quenched with H2O (10 mL) and extracted with Et2O(2 x 10 mL). The combined organic extracts were washed with water (20 mL),brine (20 mL), dried over Na2SO4 and filtrated.Evaporation of the solvent under reduced pressure followed by flashchromatography (SiO2, 95/5 hexane/EtOAc) afforded the desired ester (1.0g, 98percent of yield) as a colorless oil. Rf = 0.50 (95/5 hexane/EtOAc); 1H NMR (400 MHz, CDCl3,25 °C): d 7.63 (dd, J= 8.8, 5.1 Hz, 1H), 7.53 (ddd, J =8.7, 3.1 Hz, 1H), 7.07 (ddd, J = 8.8, 7.6, 3.1 Hz, 1H), 3.94 (s, 3H)ppm.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4393 - 4398
[2] Patent: WO2010/135560, 2010, A1, . Location in patent: Page/Page column 135-136
3
[ 67-56-1 ]
[ 394-28-5 ]
[ 6942-39-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
for 24 h;
Preparation 6; test-butyl [2- (aminomethyl)-4-fluorobenzyl] carbamate; (a) Methyl 2-bromo-5-fluorobenzoate; To a solution of 2-bromo-5-fluorobenzoic acid (3.0 g, 13.7 mmol) in methanol (4 mL) was added HCl-saturated methanol (70 mL). The reaction mixture was stirred for 24 hours and then concentrated. The excess of HC1 was removed by co-evaporation from methanol to give the sub-title compound (97percent), which was used in the next step without further purification. 1H NMR (500 MHz, CDC13) 6 3.96 (s, 3H), 7.09 (dt, 1H), 7.55 (dd, 1H), 7.65 (dd, 1H)
84.7%
for 4 h; Reflux
General procedure: To a solution of 2-bromo-4-fluorobenzoic acid (2.17 g, 10.00 mmol) in methanol (10 mL) was added sulfuric acid (1.63 mL, 30 mmol) , the reaction mixture was refluxed for 4 h.The solvent was removed in vacuo.The mixture was diluted with diethyl ether, and washed water (50 mL * 3) and brine (50 mL * 3), dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (80/1) as eluant to afford colorless liquid. Yield: 88.3percent.This compound was prepared according to the general procedure reported by Baker.13 The spectral data were consistent with that reported in the literature.
50 g
for 8 h; Reflux; Inert atmosphere
In the nitrogen atmosphere,2-bromo-5-fluorobenzoic acid (50.0 g) was added,Sulfuric acid (7 ml) and methanol (500 ml) was stirred at reflux temperature for 8 hours.After the reaction solution was cooled to room temperature,The methanol was distilled off under reduced pressure,And then an aqueous solution of ethyl acetate and sodium hydrogencarbonate was added thereto to carry out liquid separation.The solvent of the organic layer was evaporated under reduced pressure to give methyl 2-bromo-5-fluorobenzoate (50.0 g).
2.7 g
at 0 - 68℃; for 18 h;
Step 1. methyl 2-bromo-5-fluorobenzoate (0904) (0905) To a solution of 2-bromo-5-fluorobenzoic acid (4.00 g, 18.26 mmol) in MeOH (120 mL, anhydrous) was added SOCl2 (3.26 g, 27.40 mmol) dropwise at 0 °C and the mixture was heated at 68 °C for 18 h. TLC (petroleum ether: EtOAc = 5:1) confirmed the desired product. The mixture was concentrated and the residue was mixed with EtOAc (200 mL), washed by NaHCO3 (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated to give methyl 2-bromo-5-fluorobenzoate as a colorless oil. Yield: 2.7 g LCMS method C: Rt = 0.77 min.
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 11, p. 4354 - 4359
[2] Patent: WO2005/75424, 2005, A1, . Location in patent: Page/Page column 114
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 4, p. 245 - 250
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 24, p. 7101 - 7111
[5] Journal of the American Chemical Society, 2010, vol. 132, # 41, p. 14412 - 14414
[6] Patent: US2009/215728, 2009, A1, . Location in patent: Page/Page column 52
[7] Patent: US2011/160212, 2011, A1, . Location in patent: Page/Page column 19
[8] Patent: TWI574948, 2017, B, . Location in patent: Page/Page column 118
[9] Patent: WO2017/214367, 2017, A1, . Location in patent: Page/Page column 187
With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 0 - 100℃; for 1 h;
Preparation 22; Preparation of 2-bromo-5-fluorobenzoic acid; A suspension of 2-amino-5-fluorobenzoic acid (0.465 g, 3.0 mmol) in 48percent aq. HBr (2.25 mL) was added to NaN02 (0.21 g, 3.15 mmol) dissolved in 0.65 mL of water at 0°C. The resulting solution was treated with CuBr (0.28 g, 1.98 mmol) dissolved in 0.5 mL of 48percent aq. HBr, and the mixture was heated at 100°C for 1 h. After cooling to room temperature, the mixture was extracted with ether three times. The combined organic extracts were washed with brine, dried over MgS04, and concentrated in vacuo to give the crude material as white solid. Recrystalization from cyclo- hexane/EtOAc 15: 1 gave the desired product as white crystals in 73percent yield (0.483 g). LC-MS, Method 4: M+HF = 219. 0, retention time = 1.59 min.
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 2, p. 345 - 352
[2] Journal of the Indian Chemical Society, 1944, vol. 21, p. 112,114
[3] Patent: US5589489, 1996, A,
[4] Patent: US2006/25436, 2006, A1, . Location in patent: Page/Page column 9
7
[ 94569-84-3 ]
[ 394-28-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 36, p. 10806 - 10810[2] Angew. Chem., 2016, vol. 128, p. 10964 - 10968,4
8
[ 202865-66-5 ]
[ 394-28-5 ]
[ 94569-84-3 ]
Reference：
[1] Chinese Journal of Chemistry, 2014, vol. 32, # 2, p. 117 - 122
With sodium hydroxide; potassium permanganate; In water;
a. 2-Bromo-5-fluorobenzoic acid. A suspension of 2-bromo-5-fluorotoluene (50 g) in water (1.2 L) containing potassium permanganate (189 g) and sodium hydroxide (8.3 g) was refluxed for 6 hours, treated with celite, and filtered. The filtrate was extracted twice with ethyl acetate. The aqueous layer was filtered and acidified with concentrated hydrochloric acid and the resulting precipitate was collected to afford the acid (16.33 g): MS: m/z=219; NMR: 7.16 (m,2), 7.71 (m,2).
To <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> 8p (500 mg, 2.28 mmol) was added thionyl chloride (207 muL, 2.85 mmol). The mixture was heated for 1.5 h at 100 C (an additional 1 mL of SOCl2 was added after 20 min). The thionyl chloride was evaporated and the product, 1.1.1. 2-bromo-5-fluorobenzoyl chloride (2p), was used without further purification. 454 mg yield = 84%.
Step 3: (2-Bromo-5-fluorophenyl)( 1 -methylpiperidin-4-yl)methanone; To a suspension of <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (5.0 g, 22.8 mmol) in 1,2- dichloroethane (30 mL) stirred at room temperature was added oxalyl chloride (4.0 mL, 45.7 mmol) in one portion. The reaction mixture was stirred at 70 0C for 6 h and the solvent was evaporated under vacuum. The residue was dissolved in THF (60 mL) and cooled to -78 0C. Then, chloro(l-methylpiperidin-4-yl)magnesium (28.5 mL, 22.8 mmol) was added drop wise. The mixture was stirred at -78 0C for 10 min and was allowed to warm up to rt. The reaction mixture was cooled in an ice bath, water (200 mL) was added and the mixture was extracted with ethyl acetate (2x 100 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Isolute Flash Si; 100 g prepacked), eluting with 0- 15%CH2Cl2/Me0H to give (2-bromo-5-fluorophenyl)(l-methylpiperidin-4-yl)methanone as a yellowish solid. 1H NMR (400 MHz, DMSOd6): delta 7.75 (dd, IH), 7.53 (dd, IH), 7.32 (td, IH),2.97 (tt, IH), 2.76 (d, 2H), 2.15 (s, 3H), 1.94-1.84 (m, 2H), 1.76 (d, 2H), 1.60-1.48 (m, 2H). MS (ESI, Q+) m/z 300 (M+ 1).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 25℃; for 4h;
A solution of <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (10.0 g, 45.66 mmol) in dichloromethane (100 ml) was treated at 25 C. with oxalyl chloride (8.0 ml, 91.3 mmol) followed by a drop of N,N-dimethylformamide. The resulting mixture was then stirred for 4 h. The solvent and excess reagent were evaporated in vacuo and the residual oil was dissolved in tetrahydrofuran (100 ml) and added to a mixture of tetrahydrofuran (200 ml ), water (100 ml ) and concentrated ammonium hydroxide (10 ml ). The resulting mixture was then stirred at 25 C. for 20 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 9.51 g (96% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) delta (ppm): 5.9-6.3 (2H, broad, NH2), 7.05 (1H, m, aromatic), 7.42 (1H, dd, J=3.2 Hz and J=8.3 Hz, aromatic), 7.61 (1H, dd, J=5.1 Hz and J=9.1 Hz, aromatic).
With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; for 0.75h;Inert atmosphere;
General procedure: To a 100-mL round-bottom flask, flame-dried and cooled under argon containing 40 mL THF was added 2-bromobenzoic acid (1.98 g, 8.25 mmol), followed by 2-3 drops of DMF. Oxalyl chloride (1.02 mL, 11.8 mmol) was then slowly added over 15 min, causing bubbling and the formation of a bright yellow solution. The reaction was stirred for 30 min. To this was added cyclopropylamine (0.8 mL, 11.8 mmol). After 10 min, triethylamine (3.40 mL, 24.6 mmol) was added slowly, forming a faint yellow precipitate. The reaction was stirred overnight (16 h) at ambient temperature. It was then quenched with 10% HCl (50 mL), dissolving the white precipitate, and then transferred to a 250-mL separatory funnel. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×'s, 50 mL each). The combined organics were then washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the desired product as an off-white solid. It was used crude in the subsequent methylation step.
With thionyl chloride; for 2h;Reflux;
General procedure: Substituted N'-acetyl-2-bromobenzohydrazides(1a-w) were synthesizedaccording to the procedures reported in theliteratures.[1,2]Thionyl chloride (10 mL) was added tosubstituted 2-bromobenzoic acid (5 mol) in a 50 mL round bottom flask, and the reaction mixturewas refluxed for 2 h. The excess amount of thionyl chloride was removed by distillation. Theresulted acid chloride was dissolved in MeOH (20 mL), and then 40% hydrazine hydrate (3 mL)was added. The mixture was refluxed for 2 h and then cooled to room temperature, and the resulting precipitate was collected, washed with distilled water and recrystallized fromethanol.Subsequently,another acylchloride (2 mmol) was added to a solution of substituted 2-bromobenzohydrazide (1 mmol) and pyridine (2 mmol) in NMP (6 mL), the mixture was stirred for12 h, and the resulting solution was poured into ice water. The solid product was filtered andcrystallized from EtOH to get pure 1a-w.
With N,N-dimethyl-formamide; at 20℃; for 5h;Inert atmosphere;
General procedure: To a benzoic acid (10 mmol) solution in CH2Cl2 (20 mL), SOCl2 (5 mL) was added via syringe.After addition of DMF (3 drops), the reaction mixture was stirred for 5 h at room temperature, andthen concentrated to dryness under reduced pressure. The produced acid chloride was dissolvedin CH2Cl2 (30 mL) and cooled under ice bath. Diethylamine (25 mmol) was added dropwise andthe resulting colorless suspension was stirred for 3 h at room temperature. After addition of brine(80 mL) and CH2Cl2 (50 mL), the organic layer was partitioned, washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure to yield the diethylamide which was purified byflash column chromatography to provide the target compound.
Preparation 6; test-butyl [2- (aminomethyl)-4-fluorobenzyl] carbamate; (a) Methyl 2-bromo-5-fluorobenzoate; To a solution of 2-bromo-5-fluorobenzoic acid (3.0 g, 13.7 mmol) in methanol (4 mL) was added HCl-saturated methanol (70 mL). The reaction mixture was stirred for 24 hours and then concentrated. The excess of HC1 was removed by co-evaporation from methanol to give the sub-title compound (97%), which was used in the next step without further purification. 1H NMR (500 MHz, CDC13) 6 3.96 (s, 3H), 7.09 (dt, 1H), 7.55 (dd, 1H), 7.65 (dd, 1H)
84.7%
With sulfuric acid; for 4h;Reflux;
General procedure: To a solution of 2-bromo-4-fluorobenzoic acid (2.17 g, 10.00 mmol) in methanol (10 mL) was added sulfuric acid (1.63 mL, 30 mmol) , the reaction mixture was refluxed for 4 h.The solvent was removed in vacuo.The mixture was diluted with diethyl ether, and washed water (50 mL * 3) and brine (50 mL * 3), dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (80/1) as eluant to afford colorless liquid. Yield: 88.3%.This compound was prepared according to the general procedure reported by Baker.13 The spectral data were consistent with that reported in the literature.
sulfuric acid;
methyl 2-bromo-5-fluorobenzoate (for 96; the methyl ester was obtained by reacting 2-bromo-5-fluorobenzoic acid with methanol under catalysis with sulfuric acid: 1H NMR: 7.8, m, 1H, 7.65, m, 1H, 7.4, m, 1H, 3.85, s, 3H),
With sulfuric acid; for 21h;Reflux;
To a solution of (R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (18, 30 mg) in dichloromethane (1 mL) was added TFA (0.5 mL), and the mixture was stirred at RT for 3 h. The mixture was carefully neutralized with NaHCO3 (aq, saturated), and extracted with CH2Cl2 (10 mL×3). The combined extracts were dried over Na2SO4 and concentrated to give the crude product. This was purified by column chromatography on silica gel, and eluted with 92:6:2 dichloromethane-methanol-ammonia to provide (R)-3-(3-aminopiperidin-1-yl)-4-(3-fluorobenzyl)-6-methyl-1,2,4-triazin-5(4H)-one (19). MS: m/z, 396 (100%, M+1), 398 (100%).
50 g
With sulfuric acid; for 8h;Reflux; Inert atmosphere;
In the nitrogen atmosphere,2-bromo-5-fluorobenzoic acid (50.0 g) was added,Sulfuric acid (7 ml) and methanol (500 ml) was stirred at reflux temperature for 8 hours.After the reaction solution was cooled to room temperature,The methanol was distilled off under reduced pressure,And then an aqueous solution of ethyl acetate and sodium hydrogencarbonate was added thereto to carry out liquid separation.The solvent of the organic layer was evaporated under reduced pressure to give methyl 2-bromo-5-fluorobenzoate (50.0 g).
2.7 g
With thionyl chloride; at 0 - 68℃; for 18h;
Step 1. methyl 2-bromo-5-fluorobenzoate (0904) (0905) To a solution of 2-bromo-5-fluorobenzoic acid (4.00 g, 18.26 mmol) in MeOH (120 mL, anhydrous) was added SOCl2 (3.26 g, 27.40 mmol) dropwise at 0 C and the mixture was heated at 68 C for 18 h. TLC (petroleum ether: EtOAc = 5:1) confirmed the desired product. The mixture was concentrated and the residue was mixed with EtOAc (200 mL), washed by NaHCO3 (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated to give methyl 2-bromo-5-fluorobenzoate as a colorless oil. Yield: 2.7 g LCMS method C: Rt = 0.77 min.
To a stirred solution of <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (5.0 g, 21.9 mmol) at -70 C. in tetrahydrofuran (30 ml) was added dropwise a 1.6M n-butyllithium solution in hexane (44 ml, 70.1 mmol) over a period of 1 hour. After 3 hours, a solution of 1-benzyl-4-piperidone (8.5 g, 43.8 mmol) in tetrahydrofuran (20 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into a stirred mixture of water (150 ml) and ether (150 ml). The aqueous layer was extracted with ether (2*40 ml), acidified with HCl 5 N (20 ml) to pH 2 and boiled for 1 hour. The mixture was cooled to 0 C., basified (pH 10) with NaOH 5 N and rapidly extracted with dichloromethane (3*80 ml). The combined extracts were washed with water (80 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was chromatographed on silica gel (eluent: heptane/ethylacetate 1:1) to yield 2.27 g (33%) of 1'-benzyl-5-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one as light yellow solid. MS m/e: 312 (M+H+).
To a 72 L round bottom flask, equipped with an overhead stirrer, thermocouple, water-cooled condenser, and nitrogen inlet, was charged methanol (18 L). 2-Bromo-5-fluorobenzoic acid (4.00 kg), trimethyl orthoformate (3.876 kg), were then charged with stirring, followed by the addition 96% sulfuric acid (0.373 kg). The resulting solution was refluxed at 63 C. and aged for 10-16 hr, while the by-product (methyl formate) was removed during the reaction. The reaction mixture was monitored by HPLC (conversion was >99%). The reaction mixture was concentrated, then diluted with ethyl acetate (16 L), and cooled to 20 C. 2 M potassium hydrogen phosphate (4.82 L) was then added to adjust the pH to 6.5-7. The mixture was then transferred to a 100 L nalgene extractor. After phase cut, the organic layer was washed with 10% NaHCO3 (4 L), 25% brine (4 L), and then concentrated under reduced pressure. The residual oil was dissolved in toluene (6 L), and concentrated. This operation was done one more time. The remaining oil was dissolved in DMF (total vol. 9.2 L). The resulting solution was used for next step. HPLC conditions: column: Zorbax, Rx C8 250*4.6 mm; temperature: 30 C.; detection: 210 nm; mobile phase: 0.1% aq H3PO4 (A)/MeCN (B); gradient: 90:10 (A)/(B) to 10:90 over 15 min, 10:90 hold for 5 min, 10:90 to 90:10 (A)/(B) over 10 seconds; flow rate: 1 mL/min; retention time for the desired monoester; 13.6 min. Evaporation of a sample to dryness gave a colorless oil: 1H NMR (400 MHz, CDCl3) delta: 7.64 (dd, J=8.8, 5.0 Hz, 1H), 7.53 (dd, J=8.8, 3.1 Hz, 1H), 7.08 (td, J=8.8, 3.1 Hz, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) delta: 165.4, 161.3 (d, J=240.0 Hz), 135.9, 133.4, 120.0 (d, J=20.0 Hz), 118.5 (d, J=20.0 Hz), 116.1, 52.7.
With dmap; copper; copper(II) oxide; In acetonitrile; at 20℃;Heating / reflux;
Example 44; Preparation of 2-[((2R)-2-[(tert-butoxycarbonyl)((2S)-2-[tert-butyl(dimethyl)silyl]oxy}-3-phen- oxypropyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)oxy]-5-fluorobenzoic acid; Argon was bubbled through a mixture of tert-butyl ((2S)-2-[tert-butyl (dimethyl) silyl] oxy}-3- phenoxypropyl) { [ (2R)-6-hydroxy-3, 4-dihydro-2H-chromen-2-yl] methyl} carbamate (Preparation 10, 100 mg, 0.184 mmol), <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (Preparation 22, 40. 3 mg, 0.184 mmol), N, N- dimethyl-4-aminopyridine (44.9 mg, 0.368 mmol), copper (II) oxide (21.9 mg, 0.276 mmol), and copper powder (17.5 mg, 0.276 mmol) in acetonitrile (3.5 mL) at room temperature, and then the reaction mixture was heated at reflux for 3 hours. At this point, additional N, N-dimethyl-4-amino- pyridine (44.9 mg, 0.368 mmol), copper (II) oxide (21.9 mg, 0.276 mmol), and copper powder (17.5 mg, 0.276 mmol) were added to the mixture. The mixture was maintained at reflux overnight. After cooling to room temperature, the mixture was diluted with CH2Cl2 and washed three times with 1 N HCI, washed with brine, dried over MgS04, and concentrated in vacuo. The residue was further purified through preparative TLC (eluant: CH2ClJMeOH 50: 1) to give the desired product in 34% yield (43 mg). LC-MS, Method 3: M+H+ = 682.5, retention time = 3.54 min.
With hydrogen bromide; copper(I) bromide; sodium nitrite; In water; at 0 - 100℃; for 1h;
Preparation 22; Preparation of 2-bromo-5-fluorobenzoic acid; A suspension of 2-amino-5-fluorobenzoic acid (0.465 g, 3.0 mmol) in 48% aq. HBr (2.25 mL) was added to NaN02 (0.21 g, 3.15 mmol) dissolved in 0.65 mL of water at 0C. The resulting solution was treated with CuBr (0.28 g, 1.98 mmol) dissolved in 0.5 mL of 48% aq. HBr, and the mixture was heated at 100C for 1 h. After cooling to room temperature, the mixture was extracted with ether three times. The combined organic extracts were washed with brine, dried over MgS04, and concentrated in vacuo to give the crude material as white solid. Recrystalization from cyclo- hexane/EtOAc 15: 1 gave the desired product as white crystals in 73% yield (0.483 g). LC-MS, Method 4: M+HF = 219. 0, retention time = 1.59 min.
To a stirred solution of 78a (5 g, 22.8 mmol) in THF (47 mL) maintained under a N2 atmosphere was added K2CO3 (9.4 g, 68.4 mmol), CuBr (0.25 g, 1.14 mmol); and p-fluorobenzylamine (3 g, 24 mmol) and the mixture stirred at 60 C. overnight. The reaction was cooled in an ice bath and a solution of EDTA-2H2O (0.604 g) and water (22 mL) was added dropwise via addition funnel. The mixture was stirred at RT for an additional 0.5 h after which the THF was evaporated. The residual aqueous solution was cooled to 0 C. and 6N HCl (29 mL) was added dropwise with vigorous stirring. The resulting heterogeneous mixture was stirred overnight, the solid was filtered and washed with copious amounts of H2O then isooctane. The solid was dried in vacuo to afford 5.05 g (84%) of 78b.
(2-Bromo-5-fluoro-phenyl)-methanol (25B): 2-Bromo-5-fluoro-benzoic acid (2.8 g, 12. 8 mmol) was dissolved in THF at 0° C. and 25 ml of a 1M solution of borane in THF was added. The reaction mixture was heated to reflux for 16 hours, cooled to room temperature, and poured into ethyl acetate and 1N HCl. The organic layer was washed with 1N NaOH, brine, dried over magnesium sulfate, filtered, and concentrated to give (2-bromo-5-fluoro-phenyl)-methanol as a white solid, 1.7 g, 8.3 mmol, 65percent. 1H NMR (500 MHz, CDCl3) 7.47 ppm (1H, m), 7.27 ppm (1H, m), 6.85 ppm (1H, m), 4.69 ppm (2H, s).
151 parts of 5-fluoroanthranilic acid of m.p. 182-182.5 C. are obtained with a purity of 99.8% (HPLC), corresponding to a yield of 97.2% of theory, based on <strong>[394-28-5]5-fluoro-2-bromobenzoic acid</strong>.
Methyl 2-bromo-5-fluorobenzoate (159-1). Trimethylsilyl diazomethane (338 ml, 676 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, 0C solution of 2-bromo-5-fluorobenzoic acid (74 g, 338 mmol) in MeOH (676ml) until a yellow color persisted. Acetic acid was added dropwise until the yellow color dissipated. The solvent was removed in vacuo, and the resisdue was dissolved in CH2Cl2, then filtered through a plug of silica gel, eluting with CH2Cl2. The solvent was removed in vacuo to afford 77 g, 98 % of 159-1 as a yellow oil.
98%
Trimethylsilyl diazomethane (338 ml, 676 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, 0C solution of 2-bromo-5-fluorobenzoic acid (74 g, 338 mmol) in MeOH (676ml) until a yellow color persisted. Acetic acid was added dropwise until the yellow color dissipated. The solvent was removed in vacuo, and the resisdue was dissolved in CH2Cl2, then filtered through a plug of silica gel, eluting with CH2Cl2. The solvent was removed in vacuo to afford 77 g, 98 % of 2lambda as a yellow oil.
To a RB flask equipped with an addition funnel is charged acid 7, 2-Me-THF and DMF. The solution is then cooled to 70C and oxalyl chloride is added dropwise over 30 min at < 15 0C.After the addition is complete, the reaction mixture is warmed to it and aged for 45 min. Upon complete consumption of the acid, the reaction mixture is then charged dropwise into another flask containing cold (9 0C) mixture of concentrated NH4OH and 2-Me-THF over 1.5 h, while maintaining the temperature around 20-250C. To the reaction mixture is added water (100 mL)15 to dissolve some solids and the resulting biphasic layer is transferred to a separatory funnel. The aqueous layer is separated and the organic layer is washed with 1 N HCl (50 mL) and with brine (100 mL). The final organic layer is then solvent switched to toluene to give a final slurry concentration of 15 vol. The slurry is then hheated to 110 0C to get a clear solution, which is then cooled slowly to RT. Crystallization is typically observed to occur at 1000C and after aging at rt overnight, heptane (10 vol) is then added, followed by a Ih of age. The suspension is then filtered and the wet cake is washed with cold 1 :1 heptane :toluene and dried under a stream of N2 to give the product in 46.9 g (94.7%).
94.7%
To a RB flask equipped with an addition funnel is charged acid 7a, 2-Me-THF and DMF. The solution is then cooled to 70C and oxalyl chloride is added dropwise over 30 min at < 15 0C. After the addition is complete, the reaction mixture is warmed to rt and aged for 45 min. Upon complete consumption of the acid, the reaction mixture is then charged dropwise into another flask containing cold (9 0C) mixture of concentrated NH4OH and 2-Me-THF over 1.5 h, while maintaining the temperature around 20-250C. To the reaction mixture is added water (100 mL) to dissolve some solids and the resulting biphasic layer is transferred to a separatory funnel. The aqueous layer is separated and the organic layer is washed with 1 N HCl (50 mL) and with brine (100 mL). The final organic layer is then solvent switched to toluene to give a final slurry concentration of 15 vol. The slurry is then hheated to 1 10 0C to get a clear solution, which is then <n="17"/>cooled slowly to RT. Crystallization is typically observed to occur at 1000C and after aging at rt overnight, heptane (10 vol) is then added, followed by a Ih of age. The suspension is then filtered and the wet cake is washed with cold 1 :1 heptane:toluene and dried under a stream of N2 to give the product in 46.9 g (94.7%).
With sulfuric acid; nitric acid; at 5 - 10℃; for 2.5h;Inert atmosphere;
To a 3 liter round bottom flask was charged with 500 ml H2SO4. Fuming nitric acid was added (40 mL) and the mixture gently stirred. <strong>[394-28-5]2-Bromo-5-fluorobenzoic acid</strong> (60 g, 219 mmol) was added in 5 g portions over 90 minutes at 5-10C. The mixture was stirred for 60 minutes at which time the reaction was completed. The mixture was poured into 1 liter of an ice/water mixture and extracted with EtOAc (3x600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 minutes. The soild was collected on filter to provide 2-bromo-5-fluoro-3-nitrobenzoic acid as yellow solid (35 g, 49%). To the solution of 2-bromo-5-fluoro-3-nitrobenzoic acid (35 g) in MeOH (400 mL) was added SOCl2 (40 mL) drop-wise at 10-15 C. The reaction was then stirred at 65C for 1 h. After cooling to room temperature, the solvent was evaporated in vacuum to afford a residue, which was chromatographed on silica gel using gradient eluant of 0-100% EtOAc in hexane to provide methyl 2-bromo-5-fluoro-3-nitrobenzoate (20g, 84%). To a solution of 2-bromo-5-fluoro-3-nitrobenzoate (20 g, 278 mmol) in EtOH/CH3COOH (200 mL/ 200 mL) was added iron powder (25 g, 55mmol). The mixture was vigorously stirred and heated to 85 C for 1h. After cooling, the mixture was diluted with water and basified with NaHCO3 (PH=8), extracted with ethyl acetate (450mlx3). The combined organic layer was washed with brine (500ml), dried over MgSO4, filtered, and evaporated in vacuum. The residue was applied to flash column chromatography (silica gel) to give methyl 3-amino-2-bromo-5- fluorobenzoate (15.6 g,87%) as red oil. To a solution of 3-amino-2-bromo-5-fluorobenzoate (2.48 g, 10 mmol) in MeOH (80 mL) was added Pd/C (0.5 g, 5%, 50% water), the mixture was stirred at atmosphere of hydrogen for about 6.0 h. Then the mixture was filtered, washed with MeOH (10 mL). The filtrate was concentrated and recrystallized with MeOH (2.5 mL) to afford methyl 3-amino-5-fluorobenzoate (1.48 g, 88%) as a brown solid.
49%
With sulfuric acid; nitric acid; at 5 - 10℃; for 2.5h;
To a 3 liter round bottom flask was charged with 500 ml H2SO4. Fuming nitric acid was added (40 mL) and the mixture gently stirred. <strong>[394-28-5]2-Bromo-5-fluorobenzoic acid</strong> (60 g, 219 mmol) was added in 5 g portions over 90 minutes at 5-10 C. The mixture was stirred for 60 minutes at which time the reaction was completed. The mixture was poured into 1 liter of an ice/water mixture and extracted with EtOAc (3*600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 minutes. The solid was collected on filter to provide 2-bromo-5-fluoro-3-nitrobenzoic acid as yellow solid (35 g, 49%).
49%
With sulfuric acid; nitric acid; at 5 - 10℃; for 2.5h;
A 3 L reaction flask was charged with concentrated sulfuric acid (500 mL), carefully fuming nitric acid (40 mL) was added and the mixture was stirred carefully.The mixture was cooled to 5-10 C and <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (60 g, 219 mmol) was added in multiple portions at 5 g each for about 90 minutes.The mixture was stirred for one hour, the raw material disappeared.The reaction mixture was poured into 1 liter of ice water mixture,Ethyl acetate (600 mL) was extracted three times. Organic combination,Dry over anhydrous magnesium sulfate and concentrate under reduced pressure to give a yellow solid.The solid was suspended in n-hexane and stirred for 30 minutes, filtered,The filter cake was dried to give 2-bromo-5-fluoro-3-nitrobenzoic acid,As a yellow solid (35 g, 49%).
28%
With sulfuric acid; nitric acid; at 15 - 25℃; for 1h;
PREPARATION 25; Preparation of dimethyl 3,6-difluorobiphenylene-1 ,8-dicarboxylate; A. <strong>[394-28-5]2-Bromo-5-fluorobenzoic acid</strong> (44.00 g, 200.00 mmol) was dissolved in a mixture of concentrated sulfuric acid (350 mL) and fuming sulfuric acid (10 ml_, 20% SO3). To the above solution was added 90% nitric acid (30 mL) at 15 - 25 0C. The reaction mixture was stirred at ambient temperature for 1 hour and poured in ice (1 Kg). The solid residue was collected, washed with water and dried. The filtrate was extracted with ethyl acetate (1 L). The extract was dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography and the solid obtained after removal of solvent was combined with the solid obtained earlier to afford 2-bromo-5-fluoro-3-nitrobenzoic acid in 28% yield (14.50 g): 1H NMR (300 MHz, DMSO-d6) delta 8.20 (dd, J = 7.8, 3.0 Hz, 1 H), 7.89 (dd, J = 8.3, 3.0 Hz, 1 H).
With sulfuric acid; nitric acid; at 0 - 10℃; for 0.075h;
Fuming nitric acid (30 ml, 671 mmol) was added drop-wise to a stirred solution of sulfuric acid (400 ml, 7504 mmol) over a period of 10 min at 0C and the resulting mixture was allowed to stir over a period of 5 min at same temperature. To this reaction mixture was added <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (50 g, 228 mmol) in portion- wise over a period of 90 min. at 0C, and the reaction mixture was stirred for 3 h at 5 - 10C. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice cold water (2 lit) and the resulting yellow coloured solid was collected by filtration. The filtrate was extracted with ethyl acetate (3 x 100 ml). The combined organic layer was dried over anhydrous sodium sulphate, and filtered, and the solvent was removed under reduced pressure to obtain a crude intermediate. Both crude intermediates were mixed and dried under reduced pressure to give a crude product. To the crude product (50 g, 189 mmol) in methanol (350 ml) was added sulfuric acid (10 ml, 188 mmol) at 0C and the reaction mixture was stirred at 70C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude residue, which was dissolved in ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (500 mL), dried over anhydrous sodium sulfate, and filtered, and the solvent was removed under reduced pressure to obtain a crude product which was purified by flash chromatography over silica gel (100 - 200 mesh) using 15-20% ethyl acetate in hexane as an eluent to obtain the title compound (14 g, 26.6%). (0178) NMR (400 MHz, CDC13): delta 7.65 (dd, J = 7.8, 3.0 Hz, 1H), 7.56 (dd, J = 6.9, 3.0 Hz, 1H), 3.99 (s, 3H). (0179) MS: m/z 278 (M+l) & 280 (M+3).
With copper(I) oxide; copper; potassium carbonate; In 1,2-dimethoxyethane; at 130℃; for 14h;
Example 88; <n="125"/>5-Fluoro-2-(6-(2-(trifluoromethyl)phenyl)pyridin-3-ylamino)benzoic acidIn a schlenck tube, a mixture of Intermediate 52 (0.91 mmol, 0.200 g), <strong>[394-28-5]2-bromo-5- fluorobenzoic acid</strong> (0.94 mmol, 0.225 g), Cu (0.16 mmol, 0.010 g), Cu2O (0.06 mmol, 0.009 g), K2CO3 (1.01 mmol, 0.140 g) in diethoxyethane (1.5 ml) was heated at 13O0C for 14 hours, under nitrogen atmosphere. The crude mixture was diluted with water and ethyl acetate and filtered through celite. The organic phase was evaporated and the solid residue was purified by reverse phase using a water/acetonitril/methanol solvent gradient affording 0.092 g (yield 27%) of the expected product. . 1H NMR (400 MHz, DMSO-cfe): 7.4 (m, 2H), 7.4 (d, J=8.2 Hz, 1 H), 7.6 (d, J=7.8 Hz,1H), 7.7 (m, 2H), 7.8 (m, 2H), 7.9 (d, J=7.4 Hz, 1H), 8.5 (d, J=2.3 Hz, 1H), 9.6 (s, 1H).ESI/MS (m/e, %): 377 [(M+1 )+, 100].
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 10 - 20℃;
Example 7 Synthesis of N-Biphenyl-4-yl-3-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (46 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10 C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered, then purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 40 mg (37%) of N-biphenyl-4-yl-3-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 524.09 (M+1)+, 96%. 1H NMR: (CDCl3): delta 9.6 (d, 1H), 7.6 (m, 7H), 7.42 (t, 2H), 7.34 (t, 1H), 7.0 (m, 2H), 3.96 (m, 2H), 3.7 (m, 4H), 3.5 (d, 2H), 3.3 (m, 2H).
A suspension of nickel bromide (5 mmol, 1.09 g), bipyridyl (5 mmol, 0.78 g) and zinc dust (200 mmol, 13.08 g) in 200 mL dry acetonitrile was magnetically stirred, treated with 2,2'-disulfanediyldianiline (52 mmol, 12.92 g) and heated in an oil bath set at 75 C. for 30 min after reaching maximum internal temperature. At the end of this period the reaction mixture was treated with <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (100 mmol, 21.90 g) in portions and stirred at 75 C. for 1 h and the oil bath was removed. The reaction mixture was cooled to the room temperature, transferred to a 1-neck flask and concentrated under reduced pressure. The resulting dark solid was suspended in 200 mL of methanol, cooled in ice and was treated with 100 mL of trifluoro acetic acid by adding through a dropping funnel. The resulting dark solution was stirred for 30 min until all the gas evolution stopped and filtered through a 3 cm pad of diatomous earth and the filtration pad was washed using a total of 400 mL methanol. The resulting gray suspension was refluxed for 1.5 h, cooled to the room temperature and stirred for 16 h and filtered to get a solid. The filtrate was evaporated and the resulting foam was treated with 300 mL 15% ammonium chloride solution and 500 mL ethyl acetate. The suspension was treated with solid sodium bicarbonate until pH 6-7 (16.8 g, 20 mmol). The resulting white suspension was stirred for 1 h and filtered. The solid residue was washed with 500 mL ethyl acetate. The organic layer from the filtrate was separated from the aqueous layer, dried over sodium sulfate and evaporated to yield an oil which was suspended in 200 mL ether, stirred for 1 h, filtered and the solid was washed with 100 mL ether. Combined solids were stirred with 250 mL hot methanol for 10 min and filtered to get the desired 2-(2-aminophenylthio)-5-fluorobenzoic acid as a solid. (17.42 g, 66%) MS (M+1) 264; 1H NMR (300 MHz, DMSO-d6) delta ppm 3.06-3.45 (m, 1H) 4.84-5.70 (m, 2H) 6.53-6.70 (m, 2H) 6.82 (d, J=7.6 Hz, 1H) 7.09-7.25 (m, 2H) 7.26-7.36 (m, 1H) 7.66 (dd, J=9.5, 3.0 Hz, 1H).
Example 2 Alternate synthesis of 5-(2-bromo-5-fluorophenyl)-l-ter/-butyl-4-iodo-lH-pyrazole[0235] Readily available <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> was converted to methyl 3-(2- bromo-5-fluorophenyl)-3-oxopropanoate using condensation with 3-methoxy-3- oxopropanoate. Subsequent de-carboxylation gave l-(2-bromo-5-fluorophenyl)ethanone, which was then converted to 5-(2-bromo-5-fluorophenyl)-l-tert-butyl-4-iodo-lH- pyrazole as described in Example 1.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 23℃; for 48h;Inert atmosphere;
DBU(1.7 equiv, 1.16 mL, 7.76 mmol) was added to a solution of 2-bromo-5-fluorobenzoic acid (1.0 equiv, 1.0 g, 4.57 mmol) and iodomethane (2.0 equiv, 0.57 mL, 9.14mmol) in CH3CN (11 mL) at 23 C. After stirring for 48 h, thereaction was quenched with H2O (10 mL) and extracted with Et2O(2 x 10 mL). The combined organic extracts were washed with water (20 mL),brine (20 mL), dried over Na2SO4 and filtrated.Evaporation of the solvent under reduced pressure followed by flashchromatography (SiO2, 95/5 hexane/EtOAc) afforded the desired ester (1.0g, 98% of yield) as a colorless oil. Rf = 0.50 (95/5 hexane/EtOAc); 1H NMR (400 MHz, CDCl3,25 C): d 7.63 (dd, J= 8.8, 5.1 Hz, 1H), 7.53 (ddd, J =8.7, 3.1 Hz, 1H), 7.07 (ddd, J = 8.8, 7.6, 3.1 Hz, 1H), 3.94 (s, 3H)ppm.
To a solution of 2-bromo-5-fluorobenzoic acid (7.92 g, 36.2 mmol) in N,N- dimethylformamide (75 mL) was added potassium carbonate (6.91 g, 50.0 mmol) as a solid in one portion at room temperature. The mixture was stirred for 5 minutes and iodomethane (6.39 g, 45.0 mmol) was added in one portion. The mixture was stirred at ambient temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with additional ethyl acetate (3x) and the combined organic extracts were washed successively with 10% potassium carbonate solution, water and brine. The organic portion was dried (Na2SO4) and concentrated to afford the title compound. 1H NMR (300 MHz, DMSO-J6) delta ppm 3.87 (s, 3 H) 7.41 (td, /=8.56, 3.22 Hz, 1 H) 7.65 (dd, /=8.99, 3.22 Hz, 1 H) 7.81 (dd, /=9.16, 5.09 Hz, 1 H); MS (+DCI/NH3) m/z 250.0 [M+NH4]+.
General procedure: A suspension of 2-amino-3-methoxybenzoic acid (1.67 g, 10 mmol), 2-bromobenzoic acid derivative (11 mmol, 1.1 equiv), K2CO3 (2.77 g, 20 mmol, 2 equiv) and copper powder (0.125 g, 2 mmol, 0.2 equiv) was stirred in EtOH (20 mL) and heated to reflux for 1.5 h. The suspension was cooled to room temperature and H2O (20 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with H2O and the resulting solution was acidified with concentrated HCl to a pH of 2-3. The resulting suspension was stirred for 1 h at 10 C, the solid was filtered and washed with H2O. The product was recrystallized in EtOH/H2O and dried under vacuum.
Step 3: (2-Bromo-5-fluorophenyl)(1-methylpiperidin-4-yl)methanone To a suspension of <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (5.0 g, 22.8 mmol) in 1,2-dichloroethane (30 mL) stirred at room temperature was added oxalyl chloride (4.0 mL, 45.7 mmol) in one portion. The reaction mixture was stirred at 70 C. for 6 h and the solvent was evaporated under vacuum. The residue was dissolved in THF (60 mL) and cooled to -78 C. Then, chloro(1-methylpiperidin-4-yl)magnesium (28.5 mL, 22.8 mmol) was added drop wise. The mixture was stirred at -78 C. for 10 min and was allowed to warm up to rt. The reaction mixture was cooled in an ice bath, water (200 mL) was added and the mixture was extracted with ethyl acetate (2*100 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Isolute Flash Si; 100 g prepacked), eluting with 0-15% CH2Cl2/MeOH to give (2-bromo-5-fluorophenyl)(1-methylpiperidin-4-yl)methanone as a yellowish solid. 1H NMR (400 MHz, DMSO-d6): delta 7.75 (dd, 1H), 7.53 (dd, 1H), 7.32 (td, 1H), 2.97 (tt, 1H), 2.76 (d, 2H), 2.15 (s, 3H), 1.94-1.84 (m, 2H), 1.76 (d, 2H), 1.60-1.48 (m, 2H). MS (ESI, Q+) m/z 300 (M+1).
General procedure: A mixture of 2-iodobenzoic 1a (0.2 mmol), acetylacetone 2a (0.4 mmol), and Cs2CO3 (65.2 mg, 0.20 mmol) in CH3CN was stirred at 100 C. When the reaction was considered complete as determined by TLC analysis, the reaction was allowed to cool to room temperature and quenched by water, and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with water and saturated brine. The organic layers were dried over Na2SO4, filtered. Solvents were evaporated under reduced pressure. The residue was purified by chromatography on silica gel to afford isocoumarins derivatives and isoquinolone derivatives.
With copper(l) iodide; TPGS-450-M; caesium carbonate; In water; at 20℃; for 12h;Inert atmosphere; Green chemistry;
General procedure: A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Substituted 2-halobenzoic acid (1, 0.5 mmol) and amidine hydrochloride (2, 0.75 mmol) or bis(guanidine) sulphate (2, 0.38 mmol) in 2 wt % TPGS-750-M (3 mL) were added under nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the flask. 15 min later, CuI (0.1 mmol, 19 mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for 12 h (see Table 3 in text). After completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (3:1 to 1:1) as eluent to provide the desired product.
Multi-step reaction with 3 steps
1: sulfuric acid; nitric acid / 2.5 h / 5 - 10 °C / Inert atmosphere
2: thionyl chloride / 1 h / 10 - 65 °C / Inert atmosphere
3: acetic acid; iron / ethanol / 1 h / 85 °C / Inert atmosphere
Multi-step reaction with 3 steps
1: nitric acid; sulfuric acid / 2.5 h / 5 - 10 °C
2: thionyl chloride / 1 h / 10 - 65 °C
3: iron; acetic acid / ethanol / 1 h / 85 °C
Multi-step reaction with 3 steps
1: sulfuric acid; nitric acid / 2.5 h / 5 - 10 °C
2: dichloromethane / 1 h / 10 - 65 °C
3: acetic acid; iron / ethanol / 1 h / 85 °C
With polyphosphoric acid (PPA); at 120 - 150℃; for 5h;
General procedure: A mixture of 4-nitro-o-phenylenediamine (3.22g, 21mmol) and substituted benzoic acid 2a-2u (20mmol) in PPA (40mL) was stirred at 120-150C for 5h. The reaction was quenched with water and the pH was adjusted to 6 with saturated NaOH. The filter cake was washed with water and recrystallized from ethyl acetate to give corresponding compounds 3a-3u.
66%
With polyphosphoric acid; at 120 - 150℃; for 5h;
General procedure: A mixture of 4-nitro-o-phenylenediamine (3.22 g, 21 mmol) and substituted benzoic acid 2a-2u (20 mmol) in PPA (40 mL) was stirred at 120-150 C for 5 h. The reaction was quenched with water and the pH was adjusted to 6 with saturated NaOH. The filter cake was washed with water and recrystallized from ethyl acetate to give corresponding compounds 3a-3u. 4.1.1.21 2-(2-Bromo-5-fluorophenyl)-5-nitro-1H-benzo[d]imidazole (3u) Brown powder, mp: yield: 66%, mp: 218-220 C. 1H NMR (300 MHz; DMSO-d6): 7.43 (dd, J = 8.4, 3.0 Hz, 1H); 7.70-7.92 (m, 3H); 8.18 (d, J = 9.0 Hz, 1H); 8.60 (s, 1H); 13.55 (s, 1H). MS (ESI+) m/z 336.0 (M+H)+. Anal. Calcd for C13H7BrFN3O2: C, 46.45; H, 2.10; N, 12.50. Found: C, 46.53; H, 2.11; N, 12.55.
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;
To a round-bottomed flask equipped with an overhead magnetic stirrer, reflux condenser, and nitrogen inlet were added <strong>[394-28-5]2-Bromo-5-fluorobenzoic acid</strong> (1 g, 4.57 mmol), copper iodide (0.045 g, 0.23 mmol), and Cs2C03 (2.98 g, 9.13 mmol). To these solids were added dioxane (7 ml_), water (0.035 ml), 1 H-1 ,2,3-triazole (0.52 ml_, 9.13 mmol), and finally trans-1 ,2-dimethylcyclohexane-1 ,2-diamine (0.145 mL, 0.91 mmol). The mixture was then warmed to 100 C for 4 hrs. Then the mixture was cooled and MTBE and water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 2 with 6N HCI. The aqueous phase was then extracted with DCM (3x). The combined organic layers were dried, and concentrated The residue was purified by FC on S1O2 column (eluting from DCM to DCM:MeOH 95:5) to afford 5-fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (p1 19,0.52 g, y= 55%) as white solid. MS (mlz): 208.2 [MH]+
55%
With copper(l) iodide; caesium carbonate; In 1,4-dioxane;
To a round-bottomed flask equipped with an overhead magnetic stirrer, reflux condenser, and nitrogen inlet were added <strong>[394-28-5]2-Bromo-5-fluorobenzoic acid</strong> (1 g, 4.57 mmol), copper iodide (0.045 g, 0.23 mmol), and Cs2C03 (2.98 g, 9.13 mmol). To these solids were added dioxane (7 ml_), water (0.035 ml), 1 H-1 ,2,3-triazole (0.52 ml_, 9.13 mmol), and finally trans-1 ,2-dimethylcyclohexane-1 ,2-diamine (0.145 ml_, 0.91 mmol). The mixture was then warmed to 100 C for 4 hrs. Then the mixture was cooled and MTBE and water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 2 with 6N HCI. The aqueous phase was then extracted with DCM (3x). The combined organic layers were dried, and concentrated. The residue was purified by FC on Si02 column (eluent : from DCM to DCM : MeOH: 95: 5) to afford 5- fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (p67, 0.52 g, y= 55%) as white solid. MS (mlz): 208.2 [MH]+
With copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1h;Microwave irradiation;
Compound (t): 5-Fluoro-2-(2 -l,2,3-triazol-2-yl)benzoic acidA mixture of 2-bromo-5-methylbenzoic acid (1 eq.), 1,2,3-triazole (2 eq.), (1S,2S)-N1,N2- dimethylcyclohexane-l,2-diamine (1.5 eq.), CS2CO3 (1.5 eq.), and Cul (0.07 eq.) in DMF (0.775 M) was degassed and heated at 120 C for 1 h in a microwave reactor. The reaction was cooled to RT, diluted with MeOH, and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0-100% DCM/EtOAc) to yield the title compound as a yellow oil. MS (ESI) 208 (M+H).
General procedure: To a dried flask containing a magnetic stir bar under an atmosphere of dry argon was added 2-bromobenzoic acid (1.0 equiv) and dry THF (0.5 M). The solution was cooled to -78 C followed by drop-wise addition of n-BuLi (2.0 equiv, 2.5 M in hexane). The reaction mixture was stirred at -78 C for 30 min. Then the reaction mixture was drop-wise added with DMF (1.2 equiv), keep stirring for 3 - 4 hours, and quenched by saturated aqueous NH4Cl. The organic phase was extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude products were used directly for the next step without further purification.
With sulfuric acid; nitric acid; at 0 - 10℃; for 4.5h;
Fuming nitric acid (30 ml, 671 mmol) was added drop wise to a stirred solution of sulfuric acid (400 ml, 7504 mmol) over a period of 10 min at 0C and the resulting mixture was allowed to stir over a period of 5 min at the same temperature. To this reaction mixture was added <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (50 g, 228 mmol) in portion wise over a period of 90 min. at 0C and then was stirred for 3 h at 5 - 10C. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice cold water (2 lit) and yellow colored solid was collected by filtration. The filtrate was extracted with ethyl acetate (3 x 100 ml). The combined organic layer was dried over anhydrous sodium sulphate, filtered and solvent was removed under reduced pressure to obtain crude solid product. Both the crude products were mixed and dried under reduced pressure to give a mixture of 2- bromo-5-fluoro-3-nitrobenzoic acid and 2-bromo-5-fluoro-4-nitrobenzoic acid (70:30; 50 g, 189 mmol, 83%)
To a mixture of 2-bromo-5-fluoro-3-nitrobenzoic acid and 2-bromo-5-fluoro-4-nitro benzoic acid (70:30; 50 g, 189 mmol) in methanol (350 ml) was added sulfuric acid (10 ml, 188 mmol) at 0C and the reaction mixture was stirred at 70C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude residue which was dissolved in ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (500 mL), dried over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure to obtain a crude product which was purified by flash chromatography over silica gel (100 - 200 mesh) using 15-20% ethyl acetate in hexane as an eluent to obtain the title compound (14 g, 26.6%). iH NMR (400 MHz, CDC13): 6 7.65 (dd, J Hz, 1H), 3.99 (s, 3H). MS: m/z 278 (M+l) & 280 (M+3).
The compound of formula II (2.17 g, 10 mmol) was mixed with HATU (3.8 g, 10 mmol) in CH3CN / DMFIn the solution, the chemical formula of formula II is: and R is bromine in formula II. Then add DIPEA (1.29 g,10 mmol) was stirred for 5-10 min and then the intermediate of formula I (1.64 g, 5 mmol) was added and the temperature was raised to 70-80 C.Reaction, stirring 5h, TLC detection reaction after the end of the pressure to remove part of the solvent, adding water and dichloromethane extraction, separation of organicPhase, the organic phase with water stripping 3 times to remove the residual DMF, the organic phase after drying anhydrous sodium sulfate to remove the solvent, the residue and thenUsing ethyl acetate / petroleum ether column separation made of intermediates shown in formula 3.7g, the formula :The yield of the intermediate represented by formula III was calculated to be 70%
With hydrazine hydrate; In methanol; for 2h;Reflux;
General procedure: Substituted N'-acetyl-2-bromobenzohydrazides(1a-w) were synthesizedaccording to the procedures reported in theliteratures.[1,2]Thionyl chloride (10 mL) was added tosubstituted 2-bromobenzoic acid (5 mol) in a 50 mL round bottom flask, and the reaction mixturewas refluxed for 2 h. The excess amount of thionyl chloride was removed by distillation. Theresulted acid chloride was dissolved in MeOH (20 mL), and then 40% hydrazine hydrate (3 mL)was added. The mixture was refluxed for 2 h and then cooled to room temperature, and the resulting precipitate was collected, washed with distilled water and recrystallized fromethanol.Subsequently,another acylchloride (2 mmol) was added to a solution of substituted 2-bromobenzohydrazide (1 mmol) and pyridine (2 mmol) in NMP (6 mL), the mixture was stirred for12 h, and the resulting solution was poured into ice water. The solid product was filtered andcrystallized from EtOH to get pure 1a-w.
tert-butyl 3-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate[ No CAS ]
2-(1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-2-thioxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluorobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In N,N-dimethyl-formamide; at 70℃;Sealed tube; Inert atmosphere;
To a mixture of tert-butyl 3-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1- yl)piperidine-1-carboxylate (74.9 mg, 0.22 mmol), <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (59 mg, 0.26 mmol), Cs2CO3 (110 mg, 0.33 mmol), 1,10-phenanthroline (5 mg), CuI (20 mg) in a septa sealed vial, was added DMF (2 mL) under nitrogen, and the resulting mixture was degassed for 10 min, and heated in the sealed vial at 70 oC overnight. The solvent was removed under high vacuum, the residue was slurried in EtOAc, filtered through Celite, and the Celite pad was washed with MeOH. The combined organic solvents were removed to give the crude product, which was used for the next step. LC-MS tR = 0.97 min.
1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one[ No CAS ]
[ 24424-99-5 ]
[ 394-28-5 ]
2-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluorobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A suspension of crude tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)piperidine-1-carboxylate containing ~20% of tert-butyl 1-(1-(tert- butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine-3- carboxylate (1 g, 3.14 mmol), <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (800 mg, 3.65 mmol), CuI (200 mg, 1.04 mmol), Cs2CO3 (1.5 g, 4.6 mmol) and 1,10-phenanthroline (50 mg, 10 mol%) in DMF (8 mL) was heated at 70 oC for 24 h. The reaction mixture was cooled to RT and filtered through a plug of celite with EtOAc washings. The solvent was removed to afford crude 2-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H- imidazo[4,5-c]pyridin-3-yl)-5-fluorobenzoic acid which was used directly for the next step without further purification. LCMS method C: tR = 4.658 min; [M+H]+ = 457.52.
(20R)-25-methoxy-dammarane-12β,20-diol-3β-yl-2’-bromo-5’-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; for 24h;
General procedure: The 25-OCH3-PPD (1 equiv) was added to a solution of DCC (2 equiv), DMAP (0.2 equiv) and different aromatic groups (1 equiv) in dry dichloromethane and the reaction mixtures were shaken for 24 h. The solvent was removed under reduced pressure to give a white solid. The white solid was dissolved in ethyl ether and washed with NaHCO3 (5%), dried (MgSO4) and concentrated under reduced pressure to give the crude product. The crude products were chromatographed by silica gel and eluted with petroleum ether/ethyl acetate (4:1, 2:1 and 1:1) to give the pure products 1b, 1c and 1a. Using the same procedure described above for the other compounds.
(20R)-25-methoxy-dammarane-20-ol-3β,12β-di-diyl-2’-bromo-5’-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; for 24h;
General procedure: The 25-OCH3-PPD (1 equiv) was added to a solution of DCC (2 equiv), DMAP (0.2 equiv) and different aromatic groups (1 equiv) in dry dichloromethane and the reaction mixtures were shaken for 24 h. The solvent was removed under reduced pressure to give a white solid. The white solid was dissolved in ethyl ether and washed with NaHCO3 (5%), dried (MgSO4) and concentrated under reduced pressure to give the crude product. The crude products were chromatographed by silica gel and eluted with petroleum ether/ethyl acetate (4:1, 2:1 and 1:1) to give the pure products 1b, 1c and 1a. Using the same procedure described above for the other compounds.
4-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)oxy)aniline[ No CAS ]
2-bromo-5-fluoro-N-(4-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)oxy)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.4%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
General procedure: To a 50 mL three-necked round-bottomed flask equippedwith a magnetic stirrer, the key intermediate 3 (0.02 mol),aromatic acid (0.02 mol), and dimethylaminopyridine (0.0002 mol) dissolved in dichloromethane (10 mL), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.03 mol) were added. The reactions were reacted for 8-10 h at room temperature. Then, the solvent wasremoved under vacuum and recrystallized from ethanol to give the pure target compounds 4a-4aa with the yields of 78.0-91.0%.
General procedure: The appropriate amount of polyphosphoric acid (PPA) was placed in a 100 mL round bottom flask and heated to 140 C. The substituted O-phenylenediamine (6 mmol) and substituted 2-bromobenzoic acid (6 mmol) were added and refluxed for 8 h with stirring. After the reaction was completed, it was cooled to 80-100 C, and an appropriate amount of ice-water mixture was poured into the flask, neutralized with a saturated aqueous sodium hydroxide solution, filtered, and the cake was taken and dried to give a solid powder. The crude product was purified by recrystallization from methanol to give the target compound (Z-1 to Z-6 and A-38).
2-(2-bromo-5-fluorophenyl)-5-fluoro-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With polyphosphoric acid; at 140℃;
General procedure: The appropriate amount of polyphosphoric acid (PPA) was placed in a 100 mL round bottom flask and heated to 140 C. The substituted O-phenylenediamine (6 mmol) and substituted 2-bromobenzoic acid (6 mmol) were added and refluxed for 8 h with stirring. After the reaction was completed, it was cooled to 80-100 C, and an appropriate amount of ice-water mixture was poured into the flask, neutralized with a saturated aqueous sodium hydroxide solution, filtered, and the cake was taken and dried to give a solid powder. The crude product was purified by recrystallization from methanol to give the target compound (Z-1 to Z-6 and A-38).
2-bromo-5-fluoro-N-(naphthalen-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.5%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 22℃; for 18h;
<strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> (0.0375 g , 0.17 mmol), l-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(lH-benzotriazol-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0746 g, 0.1967 mmol) were dissolved in /V,/V-di methyl form amide (DMF, 1 mL) and treated with /V,/V-di isopropyl ethyl amine (0.033 mL). The mixture was stirred at 22 C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture and washed with HC1 (5 mL, 1M, twice), saturated NaHCCL solution, and saturated brine, subsequently, and concentrated under vacuum, and purified using normal phase chromatography (4 g Isco silica column, Ethyl acetate-Hexane, 0-20%) gave a white needle crystal (0.0492 g, 83.5%). ' H NMR (300 MHz, CDCL): S 8.13-8.11 (m, 2H), 7.99 (d, / = 9 Hz, 1H), 7.93-7.90 (m, 1H), 7.79 (d, J = 9 Hz, 1H), 7.67 (dd, / = 9 Hz, 3Hz, 1H ), 7.59-7.52 (m, 4H), 7.12 (dt, / = 9 Hz, 3Hz, 1H). Calculated MS for CnHnBrFNO, 343.00; observed, (M + H)+ 345.3.
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