* 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 5-bromo-2-hydroxybenzoate (231 g, 1 mol) was dissolved in concentrated sulfuric acid (500 mL).The ice bath is cold to 0°C.A mixture of concentrated nitric acid (108 g, 1.1 mol) and concentrated sulfuric acid (120 mL), which had been cooled to 0°C, was slowly added.The dropping rate was controlled so that the temperature of the reaction system was not higher than 5°C.After the addition was complete, the ice bath was removed and the system allowed to naturally warm to room temperature and react at room temperature for 3.5 hours. After completion of the reaction monitored by TLC, the mixture was poured into crushed ice (2 L) and stirred until the crushed ice melted completely and the system precipitated a large amount of pale yellow solid. The solid was filtered, neutralized with stirring in ice water, and dried.Methyl yellow 5-bromo-2-hydroxy-3-nitrobenzoate (243 g) was obtained, yield 88percent.
85%
With sulfuric acid; nitric acid In water at 0 - 5℃;
Example 114 Bmethyl 5-bromo-2-hydroxy-3-nitrobenzoate; To a mixture of methyl 5-bromo-2-hydroxybenzoate (150 g, 0.65 mol) in concentrated H2SO4 (320 mL) below 0° C. was added dropwise a mixture of concentrated HNO3 (69.2 g, 0.71 mol) and concentrated H2SO4 (97 mL) with stirring below 5° C. After the addition, the mixture was stirred at this temperature for 3 hr. The reaction mixture was poured into crash ice and the precipitate was collected, washed with cold water, hot ethanol and dried to give methyl 5-bromo-2-hydroxy-3-nitrobenzoate (153 g, yield 85percent). 1H-NMR (400 MHz,CDCl3-d) δ 4.04 (s, 3H), 8.25 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 11.92 (s, 1H); LC-MS (ESI) m/z 278 [M+1]+.
Reference：
[1] Patent: CN107573336, 2018, A, . Location in patent: Paragraph 0096; 0097; 0098
[2] Patent: US2009/197863, 2009, A1, . Location in patent: Page/Page column 56
[3] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 3, p. 624 - 630
6
[ 67-56-1 ]
[ 89-55-4 ]
[ 4068-76-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 0 - 70℃; for 40 h; Heating / reflux
Intermediate III: 6- (aminomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one; Step a) Formation of methyl-5-bromosalicylate; To a solution of 5-BROMOSALICYLIC acid (200 G, 0.92 mol) in METHANE . (2 L) was added thionylchloride (440 g, 3.7 mol) at 0°C with stirring and then allowed to reflux at 70°C for 40H. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10percent cold aqueous NAHC03 solution (2X1 L), brine and dried. The solvent was removed UNDER vacuum to give the title compound as a low melting point solid (190 g, 89percent). TLC: PetEther/EtOAc, 7:3, Rf: 0.6
89%
at 0 - 70℃; for 40 h; Heating / reflux
To a solution of 5-bromosalicylic acid (200 g, 0.92 mol) in methanol (2 L) was added thionylchloride (440 g, 3.7 mol) at 0°C with stirring and then allowed to reflux at 70°C for 40h. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10percent cold aqueous NaHCO3 solution (2 x 1 L), brine and dried. The solvent was removed under vacuum to give the title compound as a low melting point solid (190 g, 89percent). TLC: PetEther/EtOAc, 7: 3, Rf: 0. 6
81%
for 12 h; Reflux
5-Bromo-2-hydroxybenzoic acid (2.17 g, 10 mmol) was dissolved in methanol (50 ml_) and sulfuric acid (100percent, 1 ml_) and heated at rx for 12 h. After cooling and neutralization (NaHCO3, aq, sat), the white precipitate was filtered off and washed with water and dried, furnishing 1.92 g (81percent) of intermediate I.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2621 - 2625
[2] Journal of Materials Chemistry, 1996, vol. 6, # 8, p. 1297 - 1307
[3] Organic Letters, 2014, vol. 16, # 19, p. 5140 - 5143
[4] Patent: WO2005/12280, 2005, A1, . Location in patent: Page/Page column 46-47
[5] Patent: WO2005/11685, 2005, A1, . Location in patent: Page/Page column 41
[6] Organic Letters, 2009, vol. 11, # 21, p. 4790 - 4793
[7] Journal of the American Chemical Society, 2001, vol. 123, # 43, p. 10429 - 10435
[8] Patent: WO2009/138758, 2009, A2, . Location in patent: Page/Page column 73
[9] Journal of Fluorine Chemistry, 1995, vol. 74, p. 69 - 76
[10] Gazzetta Chimica Italiana, 1886, vol. 16, p. 402
[11] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
[12] Synthetic Communications, 2000, vol. 30, # 4, p. 689 - 699
[13] Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 583 - 588
[14] Angewandte Chemie, International Edition, 2009, vol. 48, # 23, p. 4226 - 4228
[15] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1555 - 1564
[16] Medicinal Chemistry Research, 2014, vol. 23, # 7, p. 3274 - 3286
[17] Polyhedron, 2017, vol. 128, p. 18 - 29
[18] Journal of the American Chemical Society, 2018, vol. 140, # 9, p. 3412 - 3422
7
[ 119-36-8 ]
[ 4068-76-2 ]
Yield
Reaction Conditions
Operation in experiment
99.6%
With bromine; sodium hydrogencarbonate In chloroform
REFERENCE EXAMPLE 2 Synthesis of methyl 5-bromosalicylate STR22 To a mixture of 152 g (1.0 mole) of methyl salicylate and 500 ml of chloroform were added dropwise with stirring a solution of 172 g (1.08 mole) of bromine in 300 ml of chloroform at about 10° C. over a period of 6 hours. After the addition, the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water and then with an aqueous solution of sodium bicarbonate. Removal of the solvent gave 230 g of substantially pure methyl 5-bromosalicylate in 99.6percent yield, M.P. 59° to 61.5° C.
98%
With bromine In dichloromethane at 20℃; for 6 h;
To a solution of methyl salicylate S1(15.2 g, 0.1 mol) in dichloromethane (100 ml) was added dropwise bromine (1 N solution in dichloromethane, 1.1 equiv) for 6h, then concentrated, the residue was poured into the saturated sodium sulphite, The resulting yellow precipitate was recovered by filtration and washed with petroleum ether to obtain the light yellow solid S2. (yield: 98percent). 1H-NMR (300MHz, CDCl3): δ ppm 10.7(s, 1H), 7.97 (d, J = 2.52 Hz, 1H), 7.55 (dd, J = 8.91, 2.52 Hz, 1H), 6.90 (d, J = 8.91 Hz, 1H), 3.98 (s, 3H).
87.4%
With bromine In chloroform at 10 - 20℃;
Methyl paraben (152 g, 1 mol) was dissolved in chloroform (600 mL).Under ice-cooling, a solution of liquid bromine (176 g, 1.1 mol) in chloroform (300 mL) was carefully added dropwise. The dropping rate was controlled so that the temperature of the system was not higher than 10°C. After the addition, the system was slowly warmed to room temperature and stirred overnight. The reaction was monitored by TLC on the following day. After removing the solvent and excess bromine in vacuo, the system was dissolved in dichloromethane (1 L). Separately washed with water (1L), saturated aqueous sodium hydrogencarbonate solution, 1percent sodium dithionite solution, and water (1L), dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain a crude product. The crude product was recrystallized from methanol to give 201 g of white crystals in a yield of 87.4percent.
84%
With N-Bromosuccinimide; thiourea In acetonitrile at 20℃; for 2 h;
General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
83%
With bromine In acetic acid
(a) Methyl 5-bromo-2-hydroxybenzoate Br2 (52 g) was slowly added to a stirred solution of methyl salicylate (50 g; 330 mmol) in 300 mL acetic acid. The reaction mixture was stirred at rt. for 10 h, poured on ice-water and the precipitate recrystallized from MeOH, giving the sub-title compound in a 83percent yield.
83%
With bromine In chloroform at 10 - 20℃;
Example 114 Amethyl 5-bromo-2-hydroxybenzoate; To a solution of methyl 2-hydroxybenzoate (152 g, 1.0 mol) in chloroform (500 mL) was added dropwise with stirring a solution of bromine (172 g, 1.08 mol) in chloroform (300 mL) at 10° C. After the addition, the solution was stirred at room temperature overnight. The mixture was diluted with dichloromethane (500 mL), washed with water (1 L.x.3), saturated sodium bicarbonate solution (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was re-crystallized from methanol to give methyl 5-bromo-2-hydroxybenzoate (192 g, yield 83percent) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 3.96 (s, 3H), 6.89 (d, J=8.8 Hz, 1H), 7.52-7.55 (dd, J=8.8 Hz, J=2 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 10.7 (s, 1H); LC-MS (ESI) m/z 233 [M+1]+.
83%
With bromine In acetic acid at 20℃; for 10 h;
[0312] Br2 (52 g) was slowly added to a stirred solution of methyl salicylate (50 g; 330 mmol) in 300 mL acetic acid. The reaction mixture was stirred at rt. for 10 h, poured onto ice-water and the precipitate recrystallized from MeOH, giving the sub-title compound in a 83percent yield.
Reference：
[1] Patent: US4634768, 1987, A,
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4537 - 4543
[3] Patent: CN107573336, 2018, A, . Location in patent: Paragraph 0093; 0094; 0095
[4] Synthetic Communications, 2007, vol. 37, # 4, p. 581 - 585
[5] Tetrahedron, 2017, vol. 73, # 46, p. 6564 - 6572
[6] Patent: US6291475, 2001, B1,
[7] Patent: US2009/197863, 2009, A1, . Location in patent: Page/Page column 56
[8] Patent: US2004/229900, 2004, A1, . Location in patent: Page 16
[9] Journal of Organic Chemistry, 1985, vol. 50, # 23, p. 4468 - 4473
[10] Chemische Berichte, 1869, vol. 2, p. 275
[11] Gazzetta Chimica Italiana, 1886, vol. 16, p. 402
[12] Roczniki Chemii, 1954, vol. 28, p. 139,141[13] Chem.Abstr., 1955, p. 8869
[14] Patent: EP1308439, 2003, A1,
[15] Tetrahedron, 2010, vol. 66, # 34, p. 6928 - 6935
Reference：
[1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4537 - 4543
15
[ 4068-76-2 ]
[ 141761-82-2 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 3, p. 624 - 630
16
[ 667-27-6 ]
[ 4068-76-2 ]
[ 1131587-78-4 ]
Yield
Reaction Conditions
Operation in experiment
50%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24 h;
To a solution of methyl 5-bromo-2-hydroxybenzoate (409 mg, 1.77 mmol) in DMF (5 mL) was added potassium carbonate (367 mg, 2.67 mmol) and ethyl 2-bromo-2,2-difluoroacetate (280 μ^, 2.13 mmol). The resulting mixture was heated at 80 °C for 24 hrs. The resulting solution was cooled to RT, diluted with ether and washed sequentially with water, 10percent aq. HCl, water and brine. The organic extract was then dried over Na2S04, filtered and the filtrate concentrated in vacuo. Further purification by way of column chromatography (S1O2, gradient elution, Hex to 2:1 (v/v) Hex: EtOAc) afforded methyl 5-bromo-2- (difluoromethoxy)benzoate as a yellow oil (250 mg, 50percent yield).
[00347] To a solution of Example 33a (20 g, 92.1 mmol) in DCM (150 mL) was added SOCl2 (13 g, 110.6 mmol) and DMF (1 mL). The mixture was heated to 50C and stirred for 2 h. After cooling to room temperature, the mixture was concentrated. MeOH (100 mL) was added into the mixture, which was stirred for another 30 min. The solvent was removed to give the desired product Example 33b (21 g, yield 100%) as a white solid. LCMS [M+l]+ =231.0/233.0
89%
With thionyl chloride; at 0 - 70℃; for 40h;Heating / reflux;
Intermediate III: 6- (aminomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one; Step a) Formation of methyl-5-bromosalicylate; To a solution of 5-BROMOSALICYLIC acid (200 G, 0.92 mol) in METHANE . (2 L) was added thionylchloride (440 g, 3.7 mol) at 0C with stirring and then allowed to reflux at 70C for 40H. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10% cold aqueous NAHC03 solution (2X1 L), brine and dried. The solvent was removed UNDER vacuum to give the title compound as a low melting point solid (190 g, 89%). TLC: PetEther/EtOAc, 7:3, Rf: 0.6
89%
With thionyl chloride; at 0 - 70℃; for 40h;Heating / reflux;
To a solution of 5-bromosalicylic acid (200 g, 0.92 mol) in methanol (2 L) was added thionylchloride (440 g, 3.7 mol) at 0C with stirring and then allowed to reflux at 70C for 40h. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10% cold aqueous NaHCO3 solution (2 x 1 L), brine and dried. The solvent was removed under vacuum to give the title compound as a low melting point solid (190 g, 89%). TLC: PetEther/EtOAc, 7: 3, Rf: 0. 6
81%
With sulfuric acid; for 12h;Reflux;
5-Bromo-2-hydroxybenzoic acid (2.17 g, 10 mmol) was dissolved in methanol (50 ml_) and sulfuric acid (100%, 1 ml_) and heated at rx for 12 h. After cooling and neutralization (NaHCO3, aq, sat), the white precipitate was filtered off and washed with water and dried, furnishing 1.92 g (81%) of intermediate I.
With sulfuric acid; for 22h;Reflux;
Into a 250 ml round-bottom flask was charged 5-bromosalicylicacid (20 g, 92.16 mmol), methanol (110 ml) and concentratedH2SO4 (12 ml). The mixture was stirred under reflux for 22 h. Uponcooled to room temperature, the precipitated white solid, viz.methyl 5-bromosalicylate, was filtered by suction, and washedwith cold methanol solvent, which was directly used for the nextstep without further purification (18.0 g, 84.7%).
With thionyl chloride; at 0 - 65℃; for 48.16h;
General procedure: Methyl 4-bromosalicylate (1 mol) was dissolved in methanol(25 mL), and thionyl chloride was added dropwise under ice-cooling,after 10 min, The mixture was stirred at 65 C for 48 h. and monitoredby TLC. After the reaction was completed, excess methanol was evaporated,the residue was extracted with ethyl acetate and aqueous sodiumcarbonate, and the organic phase was added to anhydrous sodiumsulfate and concentrated to obtain intermediate 6a.The compounds 6b-6h were prepared analogously.
In DMF (N,N-dimethyl-formamide); at 140℃; for 20h;
Step b) Formation of methyl-5-cyano salicylate; To a solution OF METHYL-5-BROMOSALICYLATE (190 g, 0. 822 mol) in dry DMF (1.75 L) was added CUCN (175 g, 1. 94 MOL) and the reaction mixture was heated to 140C with stirring under N2 for 20H. The reaction mixture was cooled, quenched with water (4 L) and stirred for 45 min. The product was extracted with EtOAc (3 X 1. 5 L), dried and concentrated to give crude product. The aqueous layer was acidified with 1. 5 N HCl to pH 3 and further extracted with EtOAc (2 x 1 L). The combined organic layer was dried and concentrated. The CRUDE product was treated with 10% CHLOROFORM in PETETHER (200 mL) and the solid filtered off. The solid was further washed with 3% EtOAc in PETETHER (200 mL) and dried to give the title compound (80 g, 55%). TLC: PetEther/EtOAc, 8 : 2, RI : 0. 6
55%
To a solution of methyl-5-bromosalicylate (190 g, 0.822 mol) in dry DMF (1.75 L) was added CUCN (175 g, 1.94 mol) and the reaction mixture was heated to 140C with stirring under N2 for 20h. The reaction mixture was cooled, quenched with water (4 L) and stirred for 45 min. The product was extracted with EtOAc (3 x 1.5 L), dried and concentrated to give crude product. The aqueous layer was acidified with 1.5 N HCI to pH 3 and further extracted with EtOAc (2 X 1 L). The combined organic layer was dried and concentrated. The crude product was treated with 10% chloroform in PetEther (200 ML) and the solid filtered off. The solid was further washed with 3% EtOAc in PetEther (200 mL) and dried to give the title compound (80 g, 55%). TLC: PETETHER/ETOAC, 8: 2, RF : 0. 6
With sulfuric acid; nitric acid; at 0 - 20℃; for 3.5h;
Methyl 5-bromo-2-hydroxybenzoate (231 g, 1 mol) was dissolved in concentrated sulfuric acid (500 mL).The ice bath is cold to 0C.A mixture of concentrated nitric acid (108 g, 1.1 mol) and concentrated sulfuric acid (120 mL), which had been cooled to 0C, was slowly added.The dropping rate was controlled so that the temperature of the reaction system was not higher than 5C.After the addition was complete, the ice bath was removed and the system allowed to naturally warm to room temperature and react at room temperature for 3.5 hours. After completion of the reaction monitored by TLC, the mixture was poured into crushed ice (2 L) and stirred until the crushed ice melted completely and the system precipitated a large amount of pale yellow solid. The solid was filtered, neutralized with stirring in ice water, and dried.Methyl yellow 5-bromo-2-hydroxy-3-nitrobenzoate (243 g) was obtained, yield 88%.
85%
With sulfuric acid; nitric acid; In water; at 0 - 5℃;
Example 114 Bmethyl 5-bromo-2-hydroxy-3-nitrobenzoate; To a mixture of methyl 5-bromo-2-hydroxybenzoate (150 g, 0.65 mol) in concentrated H2SO4 (320 mL) below 0 C. was added dropwise a mixture of concentrated HNO3 (69.2 g, 0.71 mol) and concentrated H2SO4 (97 mL) with stirring below 5 C. After the addition, the mixture was stirred at this temperature for 3 hr. The reaction mixture was poured into crash ice and the precipitate was collected, washed with cold water, hot ethanol and dried to give methyl 5-bromo-2-hydroxy-3-nitrobenzoate (153 g, yield 85%). 1H-NMR (400 MHz,CDCl3-d) delta 4.04 (s, 3H), 8.25 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 11.92 (s, 1H); LC-MS (ESI) m/z 278 [M+1]+.
A mixture of a methyl aminobenzoic ester (1.0 mmol), a 2- fluorpnitrobenezene (0.5 mmol) and CS2CO3 (0.33 g, 1.0 mol) in DMF (3 mL) was stirred at 400C for 2 h. The mixture was diluted with EtOAc (10 mL) and washed with 2 M aqueous NaOH-solution (2 x 5 mL), dried (Na2SO4), concentrated, flash chromatographed (SiO2, toluene:heptane:EtOAc-system), and concentrated. The residue was taken up in THF (4 mL), 1 M aqueous LiOH (3 mL) was added and the resulting mixture was stirred at 8O0C for 1 h, and then allowed to obtain room temperature. 2 M aqueous HCl was added until a pH of 2 was reached. The aqueous phase was extracted with EtOAc (3 x). The combined organic phases were dried (Na2SO4) and concentrated. The residue was taken up in EtOH and a mixture of K2CO3 (0.35 g, 2.55 mmol) and Na2S2O4 (0.44 g, 2.5 mmol) in water was added and the resulting mixture was stirred for 1 h. The mixture was diluted with water and washed with 1 M aqueous NaOH-solution (2 x 5 mL) and then dried (Na2SO4) and concentrated.[0254] The residue was taken up in CH3CN, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (143 mg 0.75 mmol), 1- hydroxybenzotriazole hydrate (160 mg, 0.75 mmol), triethylamine (31 1 muL, 2.25 mmol), and lambdaA,N-dimethylaminopyridine (catalytic amount) were added. The resulting mixture was heated in a capped tube using microwave assisted heating (1400C, 10 min). The mixture was diluted with EtOAc, washed with saturated aqueous NaHCpsi3-solution, dried (Na2SO4) and concentrated. The residue was taken up in dioxane and added to a mixture OfTiCl4 (0.55 mL, 0.55 mmol, 1 M in toluene) and piperazine (0.22 g, 2.5 mmol) in dioxane at 500C. The resulting mixture was, stirred at 1000C over night, and then allowed to obtain room temperature. To the mixture was added aqueous HCl (3 mL, 2 M) and then the aqueous phase <n="89"/>was extracted with EtOAc (2 x 4 mL). To the aqueous phase was added aqueous NaOH (6 mL, 2 M) and the resulting suspension was extracted with EtOAc (3 x 3mL). The combined organic phases were concentrated and purified by HPLC.; 4-Fluoro-3-nitro toluene (78 mg, 0.5 mmol) and methyl 5-bromo-2- hydroxybenzoate (231 mg, 1 mmol) were reacted according to GP6 to give 13 mg of the title compound (189JO63A). MS (ESI) 372 (MH4). Purity for MH+ (UV/MS) 100/100.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;
70%
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 16h;
1
To a solution of 5-bromo-2-hydroxy-benzoic acid methyl ester (2.5 g, 1.0 equiv) in DMF (20 mL) was added K2CO3 (4.5 g, 3.0 equiv) and then propargyl bromide (2.3 mL, 1.4 equiv). The resulting solution was allowed to stir at room temperature for 16 hr and then diluted with water and extracted with Et2O. The organic phase was washed with 5% NaOH and brine and then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, hexane/acetone) to give the desired phenyl ether (2.1 g, 70%).
With potassium carbonate In N,N-dimethyl-formamide; toluene at 20℃; for 16h;
Intermediate 29: Methyl 5-bromo-2-(nron-2-vn- 1-vloxv)benzoate
A solution of methyl 5-bromo-2-hydroxybenzoate (25.0 g, 108 minol) in DMF (100 mL) atroom temperature was treated with potassium carbonate (23.9 g, 173 minol) then 3-bromoprop-1-yne (8O% w/w in toluene, 14.0 mL, 130 minol) and the resulting brown minxture was stirred at this temperature for 16 h. The minxture was then diluted with water (100 mL) and the aqueous phase was extracted three times with Et20. The combined organics were washed twice with water, dried over MgSO4 and concentrated in vacuo to give a yellow oil which rapidly crystallised. This residue wastriturated with Et20 to give methyl 5-bromo-2-(prop-2-yn-1-yloxy)benzoate (13.8 g, 47%) as a white solid. The mother liquors were concentrated in vacuo. A second trituration of the residue obtained with Et20 /pentane gave methyl 5-bromo-2-(prop-2-yn-1-yloxy)benzoate (9.81 g, 34%) as a very pale yellow solid. The mother liquors were concentrated in vacuo. Purification of the residue obtained by flash chromatography on silica gel (50 g column, 2O% GLOBAL gradient (AcOEt in hexanes)) gavemethyl 5-bromo-2-(prop-2-yn-1-yloxy)benzoate (3.91 g, 13%) as a yellow solid.LCMS (method high pH): Retention time 1.12 min [M+H] =269 and 271 (1 Br)
[0314] Methyl 5-bromo-2-hydroxybenzoate (190.8 g; from step (c) above) and CuCN (73.9 g) were refluxed in DMF (500 mL) for 7 h. The temperature was allowed to decrease to 80 C. and HCl (500 mL) and FeCl3 (165.0 g) were added. The reaction mixture was stirred for 30 min., concentrated and partitioned between H2O and DCM. The organic layer was dried, concentrated the residue recrystallized from methylethyl ketone giving the sub-title compound in a 61% yield.
In N,N-dimethyl-formamide; at 140℃; for 20h;Inert atmosphere;
A suspension of methyl 5-bromo-2-hydroxybenzoate (2g, 8.66 mmol) and copper cyanide (1.861 g, 20.78 mmol) in DMF (30 ml) was stirred under nitrogen at 140C for 20 h. The reaction mixture was then cooled, quenched with water (120 ml) and extracted with ethyl acetate (3 x 80 ml). The organic phase was washed with saturated brine (50 ml), dried over sodium sulphate and evaporated in vacuo to yield the title compound as a white solid. 1 g.MS (electrospray): m/z, [M+H]+ = 178
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 40℃; for 2h;
A mixture of a methyl aminobenzoic ester (1.0 mmol), a 2- fluoronitrobenezene (0.5 mmol) and Cs2CO3 (0.33 g, 1.0 mol) in DMF (3 mL) was stirred at 40°C for 2 h. The mixture was diluted with EtOAc (10 mL) and washed with 2 M aqueous NaOH-solution (2 x 5 mL), dried (Na2S04), concentrated, flash chromatographed (Si02, toluene: heptane : EtOAc-system), and concentrated. The residue was taken up in THF (4 mL), 1 M aqueous LiOH (3 mL) was added and the resulting mixture was stirred at 80°C for 1 h, and then allowed to obtain room temperature. 2 M aqueous HC1 was added until a pH of 2 was reached. The aqueous phase was extracted with EtOAc (3 x). The combined organic phases were dried (Na2S04) and concentrated. The residue was taken up in EtOH and a mixture of K2C03 (0.35 g, 2.55 mmol) and Na2S204 (0.44 g, 2.5 mmol) in water was added and the resulting mixture was stirred for 1 h. The mixture was diluted with water and washed with 1 M aqueous NaOH-solution (2 x 5 mL) and then dried (Na2S04) and concentrated. [0252] The residue was taken up in CH3CN, 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (143 mg 0.75 mmol), 1- hydroxybenzotriazole hydrate (160 mg, 0.75 mmol), triethylamine (311 uL, 2.25 mmol), and N,N-dimethylaminopyridine (catalytic amount) were added. The resulting mixture was heated in a capped tube using microwave assisted heating (140°C, 10 min). The mixture was diluted with EtOAc, washed with saturated aqueous NaHC03-solution, dried (Na2S04) and concentrated. The residue was taken up in dioxane and added to a mixture of TiC14 (0.55 mL, 0.55 mmol, 1 M in toluene) and piperazine (0.22 g, 2.5 mmol) in dioxane at 50°C. The resulting mixture was stirred at 100°C over night, and then allowed to obtain room temperature. To the mixture was added aqueous HC1 (3 mL, 2 M) and then the aqueous phase was extracted with EtOAc (2 x 4 mL). To the aqueous phase was added aqueous NaOH (6 mL, 2 M) and the resulting suspension was extracted with EtOAc (3 x 3mL). The combined organic phases were concentrated and purified by HPLC.; Example 99-2-Bromo-8-mghyl-1 1- (piperazin-1-yl)-dibenzorb, fl rl, 4] oxazgpin (189JO63A); [0253] 4-Fluoro-3-nitrotoluene (78 mg, 0.5 mmol) and methyl 5-bromo-2- hydroxybenzoate (231 mg, 1 mmol) were reacted according to GP6 to give 13 mg of the title compound (189JO63A). MS (ESI) 372 (MH+). Purity for MH+ (UV/MS) 100/100.
With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 2h;
A mixture of a methyl aminobenzoic ester (1.0 mmol), a 2- fluoronitrobenezene (0.5 mmol) and Cs2CO3 (0.33 g, 1.0 mol) in DMF (3 niL) was stirred at 4O0C for 2 h. The mixture was diluted with EtOAc (10 mL) and washed with 2 M aqueous NaOH-solution (2 x 5 mL), dried (Na2SO4), concentrated, flash chromatographed (SiO2, toluene:heptane:EtOAc-system), and concentrated. The residue was taken up in THF (4 mL), 1 M aqueous LiOH (3 mL) was added and the resulting mixture was stirred at 800C for 1 h, and then allowed to obtain room temperature. 2 M aqueous HCl was added until a pH of 2 was reached. The aqueous phase was extracted with EtOAc (3 x). The combined organic phases were dried (Na2SO4) and concentrated. The residue was taken up in EtOH and a mixture Of K2CO3 (0.35 g, 2.55 mmol) and Na2S2O4 (0.44 g, 2.5 mmol) in water was added and the resulting mixture was stirred for 1 h. The mixture was diluted with water and washed with 1 M aqueous NaOH-solution (2 x 5 mL) and then dried (Na2SO4) and concentrated.[0289] The residue was taken up in CH3CN, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (143 mg 0.75 mmol), 1- hydroxybenzotriazole hydrate (160 mg, 0.75 mmol), triethylamine (311 muL, 2.25 mmol), and N,N-dimethylaminopyridine (catalytic amount) were added. The resulting mixture was heated in a capped tube using microwave assisted heating (14O0C, 10 min). The mixture was diluted EPO <DP n="106"/>with EtOAc, washed with saturated aqueous NaHC03-solution, dried (Na2SO4) and concentrated. The residue was taken up in dioxane and added to a mixture of TiCl4 (0.55 mL, 0.55 mmol, 1 M in toluene) and piperazine (0.22 g, 2.5 mmol) in dioxane at 500C. The resulting mixture was stirred at 1000C over night, and then allowed to obtain room temperature. To the mixture was added aqueous HCl (3 mL, 2 M) and then the aqueous phase was extracted with EtOAc (2 x 4 mL). To the aqueous phase was added aqueous NaOH (6 mL, 2 M) and the resulting suspension was extracted with EtOAc (3 x 3mL). The combined organic phases were concentrated and purified by HPLC.; Example 99 - 2-Bromo-8-methyl-l l-fpiperazin-l-yl)-dibenzor,/iri^1oxazepme (IB9JO63A)[0290] 4-Fluoro-3-nitrotoluene (78 mg, 0.5 mmol) and methyl 5-bromo-2- hydroxybenzoate (231 mg, 1 mmol) were reacted according to GP6 to give 13 mg of the title compound (189JO63A). MS (ESI) 372 (MH4). Purity for MH+ (UV/MS) 100/100.
With hydrogenchloride; FeCl3;CuCN; In N,N-dimethyl-formamide;
(b) Methyl 5-cyano-2-hydroxybenzoate Methyl 5-bromo-2-hydroxybenzoate (190.8 g; from step (a) above) and CuCN (73.9 g) were refluxed in DMF (500 mL) for 7 h. The temperature was allowed to decrease to 80 C. and HCl (500 mL) and FeCl3 (165.0 g) were added. The reaction mixture was stirred for 30 min., concentrated and partitioned between H2O and DCM. The organic layer was dried, concentrated the residue recrystallized from methylethyl ketone giving the sub-title compound in a 61% yield.
With chloramine-T; sodium iodide In N,N-dimethyl-formamide for 14h; Inert atmosphere;
31.a Step a
Reference Example 31 [Step a] To a solution of compound 1 (10.0 g, 43.3 mmol) in N,N-dimethylformamide (50.0 mL) were added sodium iodide (7.82 g, 52.1 mmol) and chloramine-T trihydrate (14.4 g, 51.2 mmol) under a nitrogen atmosphere, and the mixture was stirred for 14 hr. The reaction solution was filtered through celite, to the obtained filtrate were added aqueous sodium thiosulfate solution and ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M-hydrochloric acid, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was recrystallized from ethyl acetate to give compound 2 (13.9 g, 90.3%) . MS(ESI)m/z: 356(M+1)+.
60.2%
With chloramine-T; sodium iodide In N,N-dimethyl-formamide at 20℃; for 6h;
59.9%
With chloramine-T; sodium iodide In N,N-dimethyl-formamide at 20℃; for 6h;
1.A; 80.A A) Methyl 5-bromo-2-hydroxy-3-iodobenzoate
Methyl 5-bromo-2-hydroxybenzoate (10 g, 43.3 mmol) was dissolved in dry DMF (43 ml). Sodium iodide (7.79 g, 51.9 mmol) was added followed by chloramine-T (12.8 g, 51.9 mmol) (reaction immediately turned dark) and the reaction was stirred at room temperature. The reaction was monitored by LCMS. After 6 hours, the reaction was diluted with water and extracted with ether and then EtOAc. Combined organics were dried with magnesium sulfate, filtered, and concentrated in vacuo. The resulting pale yellow solid was recrystallized from EtOH (30 mL) to give methyl 5-bromo-2-hydroxy-3- iodobenzoate (9.26 g, 25.9 mmol, 59.9 % yield).1H NMR (400 MHz, Chloroform-d) δ 11.57 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 3.99 (s, 3H); MS (ESI+) m/z = 356.9 (M+H)+.
55%
With chloramine-T; sodium iodide In N,N-dimethyl-formamide at 0℃; for 5h;
1 Synthesis of methyl 5-bromo-2-hydroxy-3-iodobenzoate (230):
Synthesis of methyl 5-bromo-2-hydroxy-3-iodobenzoate (230): Methyl 5- bromo-2-hydroxybenzoate (10 g, 43.3 mmol) and Nal (7.8 g, 52 mmol) were added to 200 mL of DMF. The mixture was cooled to 0 °C and chloroamine-T hydrate (14.7 g, 52 mmol) was added. The reaction mixture was stirred at 0 °C for 5 h, quenched with 200 mL of H20, extracted with EtOAc (500 mL X 3). The combined organic layers were washed with sat. sodium bisulfite and brine, dried over anhydrous Na2S04, concentrated under reduced pressure and purified by silica gel chromatography (20% EtOAc/petroleum ether) to give 8.6 g of methyl 5-bromo-2-hydroxy-3-iodobenzoate (230) (55% yield). LCMS: m/z 356.2 [M- 55]VR = 1.95 min.
52%
With chloramine-T; sodium iodide In N,N-dimethyl-formamide at 20℃;
With potassium carbonate; In N,N-dimethyl-formamide; at 80.0℃; for 24.0h;
To a solution of methyl 5-bromo-2-hydroxybenzoate (409 mg, 1.77 mmol) in DMF (5 mL) was added potassium carbonate (367 mg, 2.67 mmol) and ethyl 2-bromo-2,2-difluoroacetate (280 mu^, 2.13 mmol). The resulting mixture was heated at 80 C for 24 hrs. The resulting solution was cooled to RT, diluted with ether and washed sequentially with water, 10% aq. HCl, water and brine. The organic extract was then dried over Na2S04, filtered and the filtrate concentrated in vacuo. Further purification by way of column chromatography (S1O2, gradient elution, Hex to 2:1 (v/v) Hex: EtOAc) afforded methyl 5-bromo-2- (difluoromethoxy)benzoate as a yellow oil (250 mg, 50% yield).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
2.1.1. General procedure for the synthesis of 2-aroyl-5-halobenzo[b]furan-3-ol compounds 4a-4i.
General procedure: Anhydrous potassiumcarbonate (0.896 mg, 6.4 mmol) was added to amixture of methyl 5halosalicylate (2.1 mmol) and substitutedphenacyl bromide (2.1 mmol) in dried dimethylformamide(DMF, 10 ml) at room temperature while stirring. After 1 h ofstirring, the reaction mixture was poured into ice-cold waterand acidified with 1 N HCl. The precipitate obtained wasfiltered off and crystallized from an appropriate solvent to givethe corresponding products 4a-4i.
91%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
Typical Procedure for the Synthesis of 2-(4-Chlorobenzoyl)-5-bromobenzofuran-3-ol (4g) as an Example
General procedure: Activated (heated at 100 C in a hot-air oven for about 24 h) K2CO3 (896.1 mg,6.4 mmol) was added into a 100-ml, round-bottomed flask containing a stirred mixtureof 5-bromomethyl salicylate (500.0 mg, 2.1 mmol) and 4-chlrophenacyl bromide(601.7, 498.0 mg, 2.1 mmol) in 10 ml of dried DMF at room temperature under nitrogen.The stirring was continued, and the progress of the reaction was monitored byTLC. Most of the reactants had disappeared in about 30 min. However, the reactionmixture was stirred for a total period of 1 h. Then, about 50 g of crushed ice wereadded into the mixture and acidified with 1N HCl. The precipitated solid wascollected by filtration and chromatographed on a silica-gel column by using 1:9,2:8, and 3:7 mixtures of ethyl acetate and petroleum ether to get 700.0 mg of 4g(2.0 mmol, 91%).
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In 1,4-dioxane for 18h; Inert atmosphere; Reflux;
53.3%
Stage #1: 5-bromo-2-hydroxy-benzoic acid methyl ester; bis(pinacol)diborane With potassium acetate In 1,4-dioxane for 0.166667h; Inert atmosphere;
Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane at 60 - 80℃; Inert atmosphere;
4.1.5. General parallel procedure d (Schemes 1-4)
General procedure: The appropriate bromo derivatives (1 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.1 eq.) and KAc (3.0 eq.) were dissolved in dioxane, and the three resulting mixtures were deoxygenated under a stream of N2. After 10 min, PdCl2(dppf) (0.05 eq.) was added, and each mixture was brought to 60-80 C andstirred under N2 for 2-4 h until the reaction was complete, followedby detection using TLC. After the reaction was finished,without further treatment the crude product was subjected to asecond coupling reaction.
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In 1,4-dioxane for 24h; Inert atmosphere; Reflux;
With copper(II) bis(trifluoromethanesulfonate); In 1,2-dichloro-ethane; at 90℃;Sealed tube; Inert atmosphere;
Method one: Weigh two-tert-butyl iodonium triflate (1 mmol), trifluoromethanesulfonic acid ketone(0.1 mmol, 36 mg) was placed in a 25 mL sealed tube, a magnetic particle was added and the mixture was purged with high purity nitrogen three times. Under nitrogen,Add 5-bromo, methyl 2-hydroxybenzoate (1 mmol), 3 mL of dichloroethane, tighten the tube, transfer it to a 90 C oil bathAnd stirred, the reaction overnight. The reaction was monitored by TLC and after the reaction was over, the tube was cooled to room temperature. Add 5 mL to the systemDistilled water, stirred; extracted with ether (5 mL x 3). The organic phases are combined and the solvent is removed on a rotary evaporator to give the crude product; crudeThe product was loaded on silica gel, and the eluant was purified by column chromatography using petroleum ether: ethyl acetate = 7: 1 by volume to obtain pure product2-tert-butyl, 7-bromo accounted ketones, yellow liquid, isolated in 95% yield.
methyl 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate[ No CAS ]
[ 4068-76-2 ]
[ 13987-45-6 ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: methyl 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate; 5-bromo-2-hydroxy-benzoic acid methyl ester With potassium carbonate; lithium chloride In 1,4-dioxane; water for 1.5h; Inert atmosphere;
Stage #2: With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water for 24h; Inert atmosphere; Reflux;
Stage #3: With hydrogenchloride In 1,4-dioxane; water
Multi-step reaction with 2 steps
1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
2: lithium hydroxide monohydrate / methanol; water / 3 h / 20 °C
methyl 5-bromo-2-(2-nitro-4-(trifluoromethoxy)phenoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In N,N-dimethyl-formamide at 60℃;
1 Methyl 5-bromo-2-(2-nitro-4-(trifluoromethoxy)phenoxy)benzoate (AED008-074):
Methyl 5-bromo-2- hydroxybenzoate (2.00 g, 8.66 mmol) was added to a solution of l-fluoro-2-nitro-4- (trifluoromethoxy)benzene (1.26 mL, 8.66 mmol) and K2CO3 (1.56 g, 11.2 mmol) in DMF (12.0 mL). The resulting reaction mixture was stirred at 60 °C overnight, after which LC-MS analysis showed completion. Reaction mixture was allowed to cool to RT and then poured over ice H2O, vigorously stirred for 45 min and insoluble material filtered, washed generously with H2O and allowed to air dry to afford methyl 5-bromo-2- (2-nitro-4-(trifluoromethoxy)phenoxy)benzoate (3.35 g, 89.0 % yield) as a slightly yellow powder, which was used without further purification. NMR (400 MHz, DMSO-t/b) d 8.21 (d, J= 2.9 Hz, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.91 (dd, J= 8.8, 2.6 Hz, 1H), 7.68 (dd, J = 9.2, 3.0 Hz, 1H), 7.32 (d, J= 8.7 Hz, 1H), 7.10 (d, J= 9.3 Hz, 1H), 3.70 (s, 3H). , 9F NMR (376 MHz, DMSO-ifc) d -57.53 (s, 3F). LCMS RT (Method 2) = 3.722 min, m/z 894.8 [2M+Na+].
89%
With potassium carbonate In N,N-dimethyl-formamide at 60℃;
1 Methyl 5-bromo-2-(2-nitro-4-(trifluoromethoxy)phenoxy)benzoate (AED008-074):
Methyl 5-bromo-2- hydroxybenzoate (2.00 g, 8.66 mmol) was added to a solution of l-fluoro-2-nitro-4- (trifluoromethoxy)benzene (1.26 mL, 8.66 mmol) and K2CO3 (1.56 g, 11.2 mmol) in DMF (12.0 mL). The resulting reaction mixture was stirred at 60 °C overnight, after which LC-MS analysis showed completion. Reaction mixture was allowed to cool to RT and then poured over ice H2O, vigorously stirred for 45 min and insoluble material filtered, washed generously with H2O and allowed to air dry to afford methyl 5-bromo-2- (2-nitro-4-(trifluoromethoxy)phenoxy)benzoate (3.35 g, 89.0 % yield) as a slightly yellow powder, which was used without further purification. NMR (400 MHz, DMSO-t/b) d 8.21 (d, J= 2.9 Hz, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.91 (dd, J= 8.8, 2.6 Hz, 1H), 7.68 (dd, J = 9.2, 3.0 Hz, 1H), 7.32 (d, J= 8.7 Hz, 1H), 7.10 (d, J= 9.3 Hz, 1H), 3.70 (s, 3H). , 9F NMR (376 MHz, DMSO-ifc) d -57.53 (s, 3F). LCMS RT (Method 2) = 3.722 min, m/z 894.8 [2M+Na+].
methyl 5-bromo-2-(4-methoxy-2-nitrophenoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;
Methyl 5-bromo-2- hydroxybenzoate (405 mg, 1.75 mmol) was added to a solution of l-fluoro-4-methoxy-2 -nitrobenzene (300 mg, 1.75 mmol) and K2CO3 (315 mg, 2.28 mmol) in DMF (6.00 mL). The resulting reaction mixture was stirred at 100 C for 4 h, after which LC-MS analysis showed completion. Reaction mixture was poured into ice H2O, stirred for 10 min and extracted with EtOAc (2x's). The combined organic layers were washed with H2O, brine, dried over MgS04, filtered and concentrated. Crude residue was purified by flash column chromatography: silica gel with a gradient of 3-15% EtOAc in Hex to afford methyl 5-bromo-2-(4-methoxy- 2-nitrophenoxy)benzoate (315 mg, 47.0 % yield) as golden syrup, which solidified upon standing. NMR (400 MHz, DMSO-ifc) d 7.98 (d, J= 2.6 Hz, 1H), 7.77 (dd, J= 8.8, 2.6 Hz, 1H), 7.64 (d, J= 3.1 Hz, 1H), 7.30 (dd, J = 9.2, 3.1 Hz, 1H), 7.14 (d, J= 9.1 Hz, 1H), 6.97 (d, J= 8.8 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H). LCMS RT (Method 2) = 3.729 min, m/z 787.0 [2M+Na+]
Multi-step reaction with 2 steps
1.1: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 14 h / 90 °C
2.1: boron tribromide / dichloromethane / -78 - 20 °C
2.2: 24 h / 49.84 °C
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