* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11126 - 11146
2
[ 553-94-6 ]
[ 586-35-6 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With acetic acid In water at 150℃; for 2 h; Stage #2: With oxygen In water at 180℃; for 4 h;
Example 6; This example illustrates the production of 2- bromoterephthalic acid from 2-bromo-l , 4-dimethylbenzene . In a stirred autoclave with internal cooling coil and reflux condenser, 2-bromo-l, 4-dimethylbenzene (541 mmol) was combined with a solution containing Co (OAc) 2 -4H2O (0.625 mmol), Mn (OAc) 2.bul. 4H2O (0.625 mmol), Zr(OAc)4 (0.15 mmol), and NaBr (0.525 mmol) in 500 g of 97percent acetic acid. The mixture was stirred at a constant rate using a gas dispersing stirrer for better gas mixing and the mixture was heated to 150°C for 2 h followed by increasing the temperature to 180°C for 4 h. While the reaction was heating, air was continuously blown through the system with 400 psig (2.76 MPa) back pressure. After reaction completion, the pressure was released and the reactor was allowed to cool to 50°C. The product was discharged, rinsing the reactor twice with 50 g acetic acid to collect further product. The white solid was <n="18"/>collected via suction filtration, washed with water, and dried under vacuum to yield 113 g (85percent) of the product 2- bromoterephthalic acid as a white solid with a purity of 99percent, as determined by 1H NMR.
51%
With potassium permanganate In water at 70℃; for 12 h;
To a solution of 2-bromo-1 ,4-dimethyl-benzene (20 g, 108.1 mmol) in water (400 ml) was added potassium permanganate (69 g, 432.3 mmol) in portions at ambient temperature. The reaction mass was heated at 70°C for 12 h. The dark coloured reaction mass was cooled to room temperature and acidified to pH 2 using 2N HCI. Aqueous solution extracted with ethyl acetate (3X100 ml). Combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography over silicagel with cyclohexane/ethyl acetate 85:15 to 50:50 as eluent to obtain 2-bromoterephthalic acid (13.5 g, 51 percent of theoretical yield) as a white solid. H NMR (400 MHz, DMSO-c/6) δ ppm 7.80 - 7.84 (m, 2 H) 7.98 (dd, J=7.91 , 1.63 Hz, 2 H) 8.14 (d, J=1 .51 Hz, 2 H) 13.62 (br. s., 2 H) MS [M-H] " : 244.9 (rt 0.87-0.92 min)
47%
Stage #1: With potassium permanganate In water for 6 h; Reflux Stage #2: With hydrogenchloride In water at 0 - 5℃;
Preparation ID) dimethyl 2-amino-5-fluoro-l,4-benzenedicarboxylate; Step 1:; A mixture of 2-bromo-p-xylene (18.5 g, 100 mmole) and KMnO4 (15.8 g; 100 mmole) in water (225 ml) was refluxed for 2 h under stirring. After the disappearance of KMnO4- color, TLC showed the presence of starting material. Additional KMnO4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, another lot Of KMnO4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, however, the reaction was worked up. The mixture was cooled to RT and filtered. The filtrate was extracted with ethyl acetate (2 X 25 ml). The ethyl acetate layer was dried and evaporated to recover 6.15 g (33percent) of the starting material. The aqueous filtrate was concentrated to half volume on a rotavap. The concentrated aqueous mixture was cooled to 0-50C and acidified to pH 2 with cone. HCl. The precipitated solid was filtered and washed with water and dried to yield 11.39 g (47percent) of 2-bromo terephthalic acid as a colorless solid. 1H NMR in CD3OD-(I4 δ ppm : 7.86 (IH, d, J = 7.8 Hz, Ar-H), 8.05 (IH, dd, J = 8.4 Hz 1.6 Hz, Ar-H), 8.28 (IH, d, J = 1.6 Hz, Ar-H).
Reference：
[1] Patent: WO2008/82501, 2008, A1, . Location in patent: Page/Page column 16-17
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3553 - 3557
[3] Journal of Coordination Chemistry, 2012, vol. 65, # 18, p. 3205 - 3215
[4] CrystEngComm, 2016, vol. 18, # 36, p. 6914 - 6925
[5] Patent: WO2015/97276, 2015, A1, . Location in patent: Page/Page column 46; 47
[6] Patent: WO2010/59549, 2010, A1, . Location in patent: Page/Page column 23-24
[7] Chlorine Alkali News, 1953, # 11, p. 44,48[8] Chem.Abstr., 1955, p. 7523
[9] Journal of Organic Chemistry USSR (English Translation), 1968, vol. 4, p. 1547 - 1550[10] Zhurnal Organicheskoi Khimii, 1968, vol. 4, p. 1609 - 1613
[11] Patent: US1867766, 1928, ,
[12] Tetrahedron, 2009, vol. 65, # 42, p. 8738 - 8744
[13] Polymer, 2016, vol. 87, p. 260 - 267
[14] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 23, p. 5797 - 5801
3
[ 7697-26-9 ]
[ 586-35-6 ]
Reference：
[1] Chemische Berichte, 1879, vol. 12, p. 616
[2] Gazzetta Chimica Italiana, 1886, vol. 16, p. 282
[3] Patent: WO2015/176267, 2015, A1, . Location in patent: Page/Page column 73
4
[ 90001-43-7 ]
[ 586-35-6 ]
Reference：
[1] Journal of Organic Chemistry, 1964, vol. 29, p. 2034 - 2036
2-Bromo terephthalic acid (204 mmol,Methanol (MeOH) 0.4M and20 mmol of sulfuric acid (H2SO4) was added to a round flask, and the mixture was refluxed for 5 hours. Next, the reaction solution was filtered and washed to obtain a reaction product in a yield of 98%
93%
With thionyl chloride; at 0 - 20℃;
Example 13Dimethyl 2-bromoterephthalate; Intermediate-4 To a round bottom flask was added <strong>[586-35-6]2-bromoterephthalic acid</strong> (10.0 g, 40.8 mmol) in methanol (120 mL). The suspension was cooled to 0 C. and thionyl chloride (11.9 mL, 163 mmol) was added dropwise. The reaction mixture was allowed to warm to rt and was stirred overnight. The mixture was concentrated, sat. NaHCO3 was added and extracted with DCM (3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford dimethyl 2-bromoterephthalate (10.4 g, 93%). LC-MS: (FA) ES+274; 1H NMR (400 MHz, CDCl3) delta 8.31 (d, J=1.6 Hz, 1H), 8.00 (dd, J=8.1, 1.6 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 3.96 (s, 3H), 3.95 (s, 3H).
92%
With sulfuric acid; at 60℃; for 6h;Inert atmosphere; Large scale;
In nitrogen atmosphere, <strong>[586-35-6]2-bromoterephthalic acid</strong> (30.0 kg, 122.4mol) was suspened in methanol (95 kg), cooled to about 5 C, and 98 weight % sulfuric acid (33.0 kg) was added and the mixture was stirred at 60 C for 6 hours. TLC is confirmed for the end of reaction, the reaction mixture is then cooled to the room temperature, methyl tert-butyl ether (220.0 kg) was added and the organic layer was washed with water (180.0 kg), and NaHCO3 aqueous solution (8 weight %, 180.0 kg) and salt water (24 weight %, 180.0 kg) , dried using anhydrous magnesium sulfate (6.0 kg) , concentrated under reduced pressure to obtain the title compound as pale yellow crystals (30.40 kg, yield 92.0%).
83%
With thionyl chloride; at 0 - 20℃;Inert atmosphere;
To a solution of <strong>[586-35-6]2-bromoterephthalic acid</strong> (2.0 g, 8.2 mmol) in MeOH (20 mL) at 0 00 underN2was added thionyl chloride (5.8 g, 49 mmol) dropwise. The resulting mixture was stirred atroom temperature overnight. The mixture was concentrated and the residue partitioned between DCM (20 mL) and saturated aqueous NaHCO3 (15 mL). The aqueous phase was extracted with DCM (3 x 10 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (3 x 10 mL), brine (3 x 10 mL), dried (Na2SO4), filtered and concentrated to give the title compound (1.85 g, 83%) as a white solid. 1H NMR (400 MHz,ODd3) 6 8.30 (d, J = 1.6 Hz, 1 H), 7.99 (dd, J = 8.0, 1.2 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H),3.95 (s, 3H), 3.94 (s, 3H); LCMS RT 2.63 mm; m/z 273,275 [M+H]+
To a mixture of <strong>[586-35-6]2-bromoterephthalic acid</strong> (2.0 g, 8.2 mmol) and DMF (0.3 mL) in DCM (20 mL) was added oxalyl chloride (15.6 g, 123 mmol) and the mixture stirred at room (0570) temperature overnight. The reaction was then concentrated and the residue diluted with MeOH (50 mL) at 0 C and stirred for 10 min. The solvent was removed under reduced pressure to give the title product as a yellow oil that was used for the next step directly. LCMS: RT 2.61 min; m/z 273.0, 275.0 [M+H] +.
With potassium permanganate In water; <i>tert</i>-butyl alcohol at 90℃; for 16h;
42.1 Step 1: 2-Bromoterephthalic acid
To a solution of 3-bromo-4-methylbenzoic acid (15.0 g, 69.8 mmol) in 200.0 mL of 1:1 mixture of t-butanol and water, was added potassium permanganate (62.8 g, 398 mmol). The reaction mixture was heated at 90°C for 16 h. Thereafter, reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and residue was further acidified with concentrated hydrochloric acid. The resultant solution was further diluted with water (10.0 mL) and the resulting precipitates were collected via filtration. The precipitates were further dried to provide 2-bromoterephthalic acid as a crude white solid. The crude residue was purified by column chromatography using eluent 60-70% ethyl acetate in n-hexane to afford the titled compound 2- bromoterephthalic acid (15.1 g, 88.0 % yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 2H), 8.15 (d, J = 1.6 Hz, 1H), 7.98 (dd, J = 8.0, 1.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H).
With permanganate(VII) ion
With potassium permanganate In water; <i>tert</i>-butyl alcohol Reflux;
A Step A: 2-bromoterephthalic acid (5-1)
To a mixture of 3-bromo-4-methyl-benzoic acid (bOg, 46.5 mmol) in t-BuOH (50 mL) and H20(50 ml), was added KMnO4 (43 g, 5.7 eq) at room temperature. The mixture was refluxedovernight. After cooling to 50 °C, the hot reaction was filtrated and the residue was washed withH20. The filtrate was acidified to pH=2 with concentrated HC1, and then concentrated to 100 mland extracted with EtOAc (100 mL) twice. The combined organic layers were washed with water, brine, dried over Na2 SO4 and concentrated in vacuo to afford compound 5-1 which was used in the next step without further purification.
With 2,2'-azobis(isobutyronitrile); oxygen; cobalt(II) diacetate tetrahydrate; acetic acid; sodium bromide; at 130℃; under 9000.9 Torr; for 1.5h;Green chemistry;
2,5-Dimethylbromobenzene 25 g (135.1 mmol, 1.0 eq), AIBN 521 mg (3.2 mmol, 0.024 eq),Co(OAc) 2·4H2O 1.6 g (6.6 mmol, 0.049 eq), NaBr 459 mg (4.5 mmol, 0.033 eq), dissolved in HOAc 250 mL (10V).Stir the whole solution, increase the temperature of the outer bath of the reaction coil to 130 C, adjust the coil pressure to 1.2 MPa with oxygen, and start the materialing. The system residence time is 1.5 h and the oxygen is 3 to 5 eq.The system was directly pumped into 375 mL of purified water, and the pH of the system was adjusted to 12-14 with NaOH solids.The aqueous phase was extracted twice with 125 mL MTBE, and the aqueous phase was adjusted to pH 1 with concentrated HCl.A large amount of solid was precipitated, and 29.8 g of the target product was obtained by filtration, yield 90%.
85%
Example 6; This example illustrates the production of 2- bromoterephthalic acid from 2-bromo-l , 4-dimethylbenzene . In a stirred autoclave with internal cooling coil and reflux condenser, 2-bromo-l, 4-dimethylbenzene (541 mmol) was combined with a solution containing Co (OAc) 2 -4H2O (0.625 mmol), Mn (OAc) 2 ? 4H2O (0.625 mmol), Zr(OAc)4 (0.15 mmol), and NaBr (0.525 mmol) in 500 g of 97% acetic acid. The mixture was stirred at a constant rate using a gas dispersing stirrer for better gas mixing and the mixture was heated to 150C for 2 h followed by increasing the temperature to 180C for 4 h. While the reaction was heating, air was continuously blown through the system with 400 psig (2.76 MPa) back pressure. After reaction completion, the pressure was released and the reactor was allowed to cool to 50C. The product was discharged, rinsing the reactor twice with 50 g acetic acid to collect further product. The white solid was <n="18"/>collected via suction filtration, washed with water, and dried under vacuum to yield 113 g (85%) of the product 2- bromoterephthalic acid as a white solid with a purity of 99%, as determined by 1H NMR.
51%
With potassium permanganate; In water; at 70℃; for 12h;
To a solution of 2-bromo-1 ,4-dimethyl-benzene (20 g, 108.1 mmol) in water (400 ml) was added potassium permanganate (69 g, 432.3 mmol) in portions at ambient temperature. The reaction mass was heated at 70C for 12 h. The dark coloured reaction mass was cooled to room temperature and acidified to pH 2 using 2N HCI. Aqueous solution extracted with ethyl acetate (3X100 ml). Combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography over silicagel with cyclohexane/ethyl acetate 85:15 to 50:50 as eluent to obtain 2-bromoterephthalic acid (13.5 g, 51 % of theoretical yield) as a white solid. H NMR (400 MHz, DMSO-c/6) delta ppm 7.80 - 7.84 (m, 2 H) 7.98 (dd, J=7.91 , 1.63 Hz, 2 H) 8.14 (d, J=1 .51 Hz, 2 H) 13.62 (br. s., 2 H) MS [M-H] " : 244.9 (rt 0.87-0.92 min)
47%
Preparation ID) dimethyl 2-amino-5-fluoro-l,4-benzenedicarboxylate; Step 1:; A mixture of 2-bromo-p-xylene (18.5 g, 100 mmole) and KMnO4 (15.8 g; 100 mmole) in water (225 ml) was refluxed for 2 h under stirring. After the disappearance of KMnO4- color, TLC showed the presence of starting material. Additional KMnO4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, another lot Of KMnO4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, however, the reaction was worked up. The mixture was cooled to RT and filtered. The filtrate was extracted with ethyl acetate (2 X 25 ml). The ethyl acetate layer was dried and evaporated to recover 6.15 g (33%) of the starting material. The aqueous filtrate was concentrated to half volume on a rotavap. The concentrated aqueous mixture was cooled to 0-50C and acidified to pH 2 with cone. HCl. The precipitated solid was filtered and washed with water and dried to yield 11.39 g (47%) of 2-bromo terephthalic acid as a colorless solid. 1H NMR in CD3OD-(I4 delta ppm : 7.86 (IH, d, J = 7.8 Hz, Ar-H), 8.05 (IH, dd, J = 8.4 Hz & 1.6 Hz, Ar-H), 8.28 (IH, d, J = 1.6 Hz, Ar-H).
41.7%
With potassium permanganate; In water;Reflux;
To a 2.5 L round-bottom flask were added 2-bromo-p-xylene (55.5 g, 0.3 mol), 1.2 L water, and KMnO4 (94.8 g, 0.6 mol). The mixture was refluxed slowly until the color faded. Then a second KMnO4 (47.4 g, 0.3 mol) was added. After the color faded, a third KMnO4 (47.4 g, 0.3 mol) was added. The reaction was stopped when the solution was colorless again. The mixture was filtered to remove the insoluble salt. The collected filtrates was acidified to pH 3 ~ 4 by HCl when large amount of white solid precipitated from the solution. The crude product was collected by filtration and washed with water, then dried under vacuum to yield 30.6g of 2-bromoterephthalic acid (yield 41.7%).1H NMR (400MHz, DMSO-d6, delta, ppm): 8.15 (d, J = 1.4 Hz, ArH ortho to Br,1H), 7.99 (dd, J = 8.0, 1.5 Hz, ArH meta to Br,1H), 7.84 (d, J = 8.0 Hz, ArH para to Br,1H).
The same procedure as described in Example 1 was performed but using 12.25 g (50.0 mmol) of 2-bromo-p-terephthalic acid as the substrate, 31 g of H2O, a total of 9.94 g (94 mmol) of Na2CO3, 35 mg of CuBr as the copper source and 79 mg of Ligand F. A total of 7.9 g (39 mmol, 78% yield) of 2-hydroxy-terephthalic acid was collected. The purity was determined by 1H NMR to be 97%.
To a suspension of 2-bromoterephthalic acid (25.0 g, 102 mmol) in water (120 ml.) at r.t under N2 atmosphere, was added Na2C03 (21.6 g, 204 mmol) and the reaction mixture was heated at 80 C for 1 h. After 1 h, a solution of N1 ,N2-dimethylcyclohexane-1 ,2-diamine (0.29 g, 2.04 mmol) and copper(ll) bromide (0.22 g, 1 .02 mmol) in water (10.0 ml.) was added to the above reaction mixture, and the mixture was heated at 80 C for 16 h. The reaction mixture was cooled to r.t. and poured onto 2N aqueous HCI (20.0 ml.) and stirred for 15 min, whereupon an off-white solid precipitated. The off white solid was collected by filtration under vacuum and washed with water (2 100 ml.) to get 2- hydroxyterephthalic acid.
With thionyl chloride; N,N-dimethyl-formamide; for 3h;Reflux;
<strong>[586-35-6]2-Bromoterephthalic acid</strong> (750 mg, 3.06 mmol, 1 eq.) was suspended into SOCI2 (5 ml) in the presence of DMF (1 drop), and the solution was refluxed for 3 hr. After cooling to room temperature, evaporating and dried in vacuo, the resulting compound was dissolved in CH2Cl2 (10 ml), and was dropped into a solution of 2-amino-2-methylpropan-1 - ol (750 mg, 8.41 mmol, 2.7 eq.) and DIEA (1.5 ml) in CH2Cl2 (10 ml), and the solution was stirred at room temperature overnight. Saturated NaHC03 aqueous solution was added to the reaction mixture and extracted with EtOAc (x3), and combined organic phase was washed with water and brine, dried over Na2S04, filtered and evaporated to obtain 2-bromo-N1, N -bis(1 -hydroxy-2-methylpropan-2-yl)terephthalamide 4b as a white solid. (922 mg, 78%)1H NMR (400 MHz, DMSO-d6) delta 8.04 (d, 1 H, J = 1 .5 Hz), 7.86 (bs, 1 H), 7.82 (dd, 1 H, J = 7.9, 1 .7 Hz), 7.72 (bs, 1 H), 7.43 (d, 1 H, J = 7.9 Hz), 4.87 (t, 1 H, J = 6.1 Hz), 4.82 (t, 1 H, J = 6.1 Hz), 3.51 (d, 2 H, J = 6.2 Hz), 3.50 (d, 2 H, J = 6.2 Hz), 1 .31 (s, 6 H), 1 .30 (s, 6H).13C NMR (100 MHz, DMSO-d6) delta 167.2, 164.9, 142.3, 137.7, 131 .6, 128.8, 126.9, 1 19.1 , 67.8, 67.5, 55.8, 24.0, 23.9.
With thionyl chloride; N,N-dimethyl-formamide; for 3h;Reflux;
A.5 2-bromo-N1,N4-bis(1-hydroxy-2-methylpropan-2-yl)terephthalamide(4b) <strong>[586-35-6]2-Bromoterephthalic acid</strong> (750 mg, 3.06 mmol, 1 eq.) was suspended into SOCl2 (5 ml) in the presence of DMF (1 drop), and the solution was refluxed for 3 hr. After cooling to room temperature, evaporating and dried in vacuo, the resulting compound was dissolved in CH2Cl2 (10 ml), and was dropped into a solution of 2-amino-2-methylpropan-1-ol (750 mg, 8.41 mmol, 2.7 eq.) and DIEA (1.5 ml) in CH2Cl2 (10 ml), and the solution was stirred at room temperature overnight. Saturated NaHCO3 aqueous solution was added to the reaction mixture and extracted with EtOAc (×3), and combined organic phase was washed with water and brine, dried over Na2SO4, filtered and evaporated to obtain 2-bromo-N1,N4-bis(1-hydroxy-2-methylpropan-2-yl)terephthalamide 4b as a white solid. (922 mg, 78%)
With thionyl chloride; at 100℃; for 5h;
A solution of <strong>[586-35-6]2-bromoterephthalic acid</strong> (5.000 g, 20.41 mmol) in thionyl chloride (20.00 mL, 273 mmol) was heated at 100C for 5 h. The dark colored reaction mass was cooled to room temperature and solvent was evaporated off under reduced pressure. The residual mass was cooled to OoC and methanol (20 ml) and triethylamine (5 ml, 35.5 mmol) were added slowly under nitrogen. The reaction mixture was then stirred for 2 h at ambient temperature. The solution was evaporated to dryness under reduced pressure. The residual mass was dissolved in ethylacetate (100 ml) and washed with water (2X 25ml), followed by 2N HCI (2X 25 ml) and finally with saturated sodium bicarbonate solution. Combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to obtain dimethyl 2-bromobenzene-1 ,4-dicarboxylate (5.5 g, 99% of theoretical yield) as a white solid. H NMR (400 MHz, CHLOROFORM-c/) delta ppm 3.95 (d, J=1 .25 Hz, 3 H) 3.96 (d, J=1 .25 Hz, 3 H) 7.81 (dd, J=8.03, 1.25 Hz, 1 H) 8.00 (d, J=8.03 Hz, 1 H) 8.31 (s, 1 H) MS [M-H] " : 272.9/ 273.9 (rt 1.90-1.97 min)
With thionyl chloride; at 100℃; for 6h;Reflux;
2-bromo-terephthalic acid, 40 mmol, 4.0 M SOCl2 by refluxing for 6 hours in a round flask 100 preparing a 2-bromo-benzene-1,4-dicarboxylic beam nildi chloride (2-bromobenzene-1,4-dicarbonyl dichloride) and then, to remove remaining SOCl2.
With sulfuric acid; nitric acid for 8h; Ambient temperature;
64%
With sulfuric acid; nitric acid at 0 - 100℃; for 20.42h;
1D.2
Step 2:; 2-Bromo terephthalic acid (13.8 g, 56.3 mmole) was slowly added under stirring to cone. H2SO4 (78 ml) at 0-50C over 5 minutes. To the resulting mixture was added 1: 1 mixture of cone. H2SO4 and cone. HNO3 (15 ml) dropwise over 20 min. at 0-50C. The mixture was then heated to 1000C for 2 h. After cooling and stirring for 18 h at ambient temperature, mixture was poured into 100 g of ice-water. The resulting colorless solid was filtered and dried. The solid was recrystallized from ethanol to give 10.5 g (64%) of 2-bromo-5-nitroterephthalic acid. 1H NMR in CD3OD-d4 δ ppm : 3.96 (3H, s, OCH3) 4.01 (3H, s, OCH3) 8.16 (IH, s, ArH) 8.41 (IH, s, ArH).
With sulfuric acid; nitric acid
With sulfuric acid; nitric acid In water for 3h; Heating; Large scale; regioselective reaction;
69 %
Stage #1: 2-bromo-1,4-benzenedicarboxylic acid With sulfuric acid at 0℃;
Stage #2: With sulfuric acid; nitric acid at 0 - 100℃;
1.1; 40.1 [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid
2-Bromoterephthalic acid (13.8 g, 56.32 mmol) was slowly added dropwise to 78 mL of sulfuric acid at 0°C, followed by stirring for 5 minutes to prepare a reaction solution. After mixing 7.5 mL of sulfuric acid and 17.5 mL of nitric acid, the mixture was slowly added dropwise to the reaction solution at 0°C. After the dropwise addition was complete, stirring and reflux were performed at 100° C. for 2 hours. After the reaction was completed, the resultant was cooled to room temperature and stirred for 12 hours. When the reaction was complete, the reaction solution was slowly added dropwise to ice water. The aqueous solution was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure, and the title compound was obtained in an amount of 16 g.
69 %
Stage #1: 2-bromo-1,4-benzenedicarboxylic acid With sulfuric acid at 0℃;
Stage #2: With sulfuric acid; nitric acid at 0 - 100℃;
1.1; 40.1 [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid
2-Bromoterephthalic acid (13.8 g, 56.32 mmol) was slowly added dropwise to 78 mL of sulfuric acid at 0°C, followed by stirring for 5 minutes to prepare a reaction solution. After mixing 7.5 mL of sulfuric acid and 17.5 mL of nitric acid, the mixture was slowly added dropwise to the reaction solution at 0°C. After the dropwise addition was complete, stirring and reflux were performed at 100° C. for 2 hours. After the reaction was completed, the resultant was cooled to room temperature and stirred for 12 hours. When the reaction was complete, the reaction solution was slowly added dropwise to ice water. The aqueous solution was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure, and the title compound was obtained in an amount of 16 g.
With sulfuric acid; at 80℃; for 12h;Inert atmosphere;
A mixture of <strong>[586-35-6]2-bromoterephthalic acid</strong> (5 g, 20.5 mmcl), concentrated H2S04 (4.0 mL) and EtCH (100 mL) was refluxed for 12 h under N2 atmosphere. The mixture was extracted with an excess of Et20, and then the combined organic phase was washed with NaHCO3 aqueous solution, brine and dried over MgSO4. The residue was purified by flash column chromatography on silica gel to afford diethyl 2-bromoterephthalate (5.62 g, 91%) as transparent liquid. 1H NMR (400 MHz, CDCl3, 298K, TMS): 68.3 (d, 1H, J=1.6 Hz), 7.99-8.02 (m, 1H), 7.79 (d, 1H, J=1.6 Hz), 4.38-4.45 (m, 4H), 5.33 (d, 1H, J=11.6Hz) ppm.
1) Synthesis of (2-bromo-4-hydroxymethylphenyl)methanol Under a nitrogen stream, to a solution of 2-bromo-terephthalic acid (5.0 g, 20.4 mmol) in THF (50 ml), a THF solution of BH3 (1.09 M, 74.9 ml) was added dropwise at 0C and the mixture was stirred at room temperature for 4 hours. After addition of THF-water (1:1) to this solution, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution = ethyl acetate:n-hexane (1:2)) to give the titled compound (4.1 g, 92%). 1H-NMR (DMSO-d6) delta: 4.48 (4H, t, J=5.1Hz), 5.27 (1H, t, J=6Hz), 5.37 (1H, t, J=5.7Hz), 7.31 (1H, d, J=7.8Hz), 7.45-7.49 (2H, m) MS (ESI+): 240 [M+Na]+
89%
With borane-THF; Trimethyl borate; In tetrahydrofuran; at 25℃; for 1h;Large scale;
At 30 C, trimethoxy borane (6.34 kg, 61 . 0mol) and borane-tetrahydrofuran complex in tetrahydrofuran solution (1mol/L, 78.9 kg, 88 . 4mol) are added to the mixed solution of 2-bromo-phthalic acid (7.5 kg, 30 . 6mol) in tetrahydrofuran (33.1 kg) , and stirred at 25 C for 1 hour. Furthermore, the reaction mixture is cooled to 19 C, by adding methanol (3.0 kg) and tetrahydrofuran (5.6 kg) of the mixed solution, and stirred for 30 minutes. To the mixed solution methanol (15.0 kg) was added, then the reaction mixture was distilled under reduced pressure to remove the solvent. Methanol (36 kg) was added to the resulting residue , and the solvent was removed by distillation under reduced pressure. Methanol (36 kg) was added to the residue, heated to dissolve (confirmation is dissolved 54 C), the solution is cooled to room temperature, water (60 kg) was added, stirred for 30 minutes. Water was added to the mixed solution, cooled to 0 C, stirred for 1 hour, washed with water (45 kg) 2 times, and dried for 2 hours under reduced pressure, to obtain the title compound (11.8 kg, 54 . 4mol, yield 89%).
89%
With dimethylsulfide borane complex; In tetrahydrofuran; at 70℃; for 4h;Cooling with ice;
<strong>[586-35-6]2-bromoterephthalic acid</strong> 1-7 (15.00 g, 61.22 mmol) was dissolved in 200 mL of anhydrous 26 tetrahydrofuran, and borane dimethylsulfide complex (2.0 M tetrahydrofuran solution) (91.83 mL , 183.65 mmol) was added in ice-bath. Stirred at 70 C for 4 hours after the addition was completed. TLC monitored (UV color) that the reaction was completed, then the reaction was cooled to room temperature, slowly poured into ice-water, extracted with ethylacetate and the combined organic layers were washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 11.90g off-white solid 1-8, yield 89%.
89%
With dimethyl sulfide borane; In tetrahydrofuran; at 0 - 70℃;
To a solution of 2-bromo-terephthalic acid 50 (15.00g, 61.22mmol) in anhydrous THF (200mL) was added 2.0M BH3.SMe2 in THF (91.83mL, 183.65mmol) at 0C. The mixture was stirred for 2hat 70C. After the exothermic reaction was over, the reaction was cooled by ice-water bath. The reaction was quenched by dropwise addition of water. The resulting mixture was extracted with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure to give compound 51 (11.90g, 89%) as an off-white solid.
80%
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 3.75h;Inert atmosphere;
A flame-dried round-bottom flask was charged with S4 (5.5 g, 22.4 mmol) and fitted with a pressure-equalizing addition funnel. The solid was dissolved in THF (100 mL) and cooled to 0oC. To the addition funnel was added BH3*THF (1M in THF, 50 mL, 50 mmol) dropwise over 45 minutes. This mixture was stirred at 0oC for 1 hour, warmed to room temperature, and stirred for 3 hours. The reaction was quenched slowly with the addition of methanol (50 mL) and the mixture was concentrated. The solid residue was dissolved in EtOAc and water (40 mL) and transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (3 x 75 mL), combined organics were washed with brine, dried over Na2SO4 and concentrated to afford a white solid S5 (3.89 g, 80%) which needed no further purification.1H NMR (DMSO-d6, 400 MHz) delta 4.48 (t, 4H), 5.28 (t, 1H), 5.39 (t, 1H), 7.29 (d, 1H, J=7.8), 7.49 (m, 2H) 13C NMR (DMSO-d6, 100 MHz) delta 61.8, 62.4, 120.8, 125.5, 127.9, 129.7, 139.1, 143.3.
58%
With borane-THF; In tetrahydrofuran; water; at 0 - 20℃; for 18h;
To a solution of <strong>[586-35-6]2-bromoterephthalic acid</strong> (3.9 g, 15.9 mmol, 1 eq.) in THF was added BH3THF (iN, 64 mL, 63.6 mmol, 4 eq.) dropwise at 0C. The mixture was stirredrt for 18 h, the reaction was quenched by THF/H20 (1/1, V/V, 30 mL), then extracted with EA (10 mL x 3). The combined organic layers were washed by brine, dried over Na2504, filtered and concentrated. The crude product which was washed by MTBE to afford 2-bromo-1,4- phenylene)dimethanol (2 g, 58%) as a white solid. LRMS : 217(M+H).?H NMR (400MHz, MeOH-d4) d: 7.53 - 7.56 (m, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.27 - 7.33 (m, 1H), 4.69 (s, 2H), 4.61 (s, 2H).
With diborane; In tetrahydrofuran; for 6h;Reflux;
To a suspension of compound 5-1 (7.2 g, 29.3 mmol) in THF (80 mL) was added BH3 (6.0 ml, 2.0 eq) dropwise, then the mixture was refluxed for 6 hr. The reaction was quenched with MeOH (anhydrous) at 0 C slowly, and then concentrated in vacuo to afford compound 5-2, which was used in the next step without further purification. MS (ESI) m / e (M+H): 199.2/201.1.
With thionyl chloride; triethylamine; In methanol; diethyl ether;
Step A: Preparation of Dimethyl-2-bromoterephthalate <strong>[586-35-6]2-Bromoterephthalic acid</strong> (14.2 g) was treated with thionyl chloride (35 ml) and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled and the excess SOCl2 was removed under reduced pressure. The residue was treated with methanol (174 ml) at -10 C. over a one-half hour period followed by triethylamine (17.4 ml). After 15 minutes at room temperature, the methanol was removed under reduced pressure. The residue was then taken up in ethyl ether, washed with water, dried and evaporated which gave a white solid (14.65 g). 1 H-NMR (CDCl3, 200 MHz): delta3.87 (s, CH3); 7.8-8.32 (m, ArH). IR (CH2 Cl2, cm-1): 1720. STR423
N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Cu(OAc)2; In 1,2-dimethoxyethane;
(a) A mixture of 2-bromoterephthalic acid (4.8 g, 0.02 mol), DME (50 ml), Cu(OAc)2 (0.2 g), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol) and K2 CO3 (2.71 g, 0.02 mol) is heated at 135 C. overnight, then at reflux overnight. The reaction mixture is poured into water, acidified with acetic acid and the precipitate which forms is collected by filtration and dried to afford 2.5 g of N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid.
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 2-bromoterephthalic acid (4.8 g, 0.02 mol), DMF (50 ml), Cu(OAc)2 (0.2 g), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol) and K2 CO3 (2.71 g, 0.02 mol) was heated at 135 C. overnight, then at reflux overnight. The reaction mixture was poured into water, acidified with acetic acid and the precipitate which formed was collected by filtration and dried to afford 2.5 g of N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid.
Stage #1: 2-bromo-1,4-benzenedicarboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: pyrrolidine With 4-methyl-morpholine In N,N-dimethyl-formamide at 20℃; for 60h;
With 4-methyl-morpholine; 1,1'-carbonyldiimidazole In water; N,N-dimethyl-formamide
6.a (a)
(a) 3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid 100 g (0.388 mol) 2-bromoterephthalic acid are dissolved in 700 ml N,N-dimethylformamide and slowly combined with 69.2 g (0.427 mol) N,N'-carbonyldiimidazole with stirring. After total dissolution the mixture is stirred for 15 minutes at ambient temperature and then 48.5 ml (0.582 mol) pyrrolidine and 93.9 ml (0.854 mol) N-methylmorpholine are slowly added dropwise one after the other. The mixture is stirred for 2.5 days at ambient temperature and then concentrated in vacuo. The residue is combined with distilled water and acidified with 2-molar hydrochloric acid solution. The aqueous phase is extracted with ethyl acetate. The precipitate formed is suction filtered and dried at 40° C. Yield: 29.4 g (25%) Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1)
(±)-N,N-dimethyl-trans-1,2-diaminocyclohexane; copper(ll) bromide; In methanol; for 8h;Heating / reflux;
In an air and moisture free environment, 8.82 g (163 mmol) of sodium methoxide was combined with 250 g of anhydrous methanol, followed by the addition of 10 g (41 mmol) of <strong>[586-35-6]2-bromoterephthalic acid</strong>. Separately, 274 mg (0.03 mol equiv) of CuBr2 and 386 mg (0.06 mol equiv) of rac-trans-N,N-dimethylcyclohexane-l, 2 -diamine were combined under nitrogen, followed by addition of anhydrous methanol to dissolve. This solution was then added to form the reaction mixture. The reaction mixture was heated to reflux with stirring for 8 h, remaining under a nitrogen atmosphere. After cooling, the product was filtered, washed with MeOH and dried to yield 9.80 g (40.8 mmol) of the white solid as the bis- sodium salt. The purity was determined to be >98% by 1H NMR. The net isolated yield was determined to be 99%.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h;
First, 2 equivalents of Compound 11 and 1 equivalent of bromoterephthalic acid were dissolved in CH2Cl2 as a solvent, and the reaction mixture was subjected to a coupling reaction by using EDC. The reaction mixture was stirred at room temperature for about 20 hours, the resultant product was worked up with water and CH 2C12, and <n="14"/>then Compound 13 was finally obtained at a yield of 88% by using silica gel column chromatography.
Stage #1: 2-bromo-1,4-benzenedicarboxylic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: 1-ethyl-2-phenyl-1H-indol-5-amine In N,N-dimethyl-formamide at 0 - 20℃; for 18.5h;
2.d; 17
To a solution of a benzoic acid (II) (10 mmol) in dimethylformamide (40 ml) with stirring at 0° C. were added 1-hydroxybenzotriazol (HOBt) (10 mmol) and dicyclohexylcarbodiimide (DCC) (10 mmol). The mixture was left under stirring at 0° C. for 30 minutes and a 5-aminoindole (III) (9 mmol) dissolved in dimethylformamide (20 ml) was added.The mixture was left under stirring at 0° C. for a further 30 minutes, and then at room temperature for 18 hours. The mixture was filtered, 2N hydrochloric acid was added to pH 2, and the precipitate thus formed was filtered off and purified to give compound (I) in which X, Y, Z, R, R' and A have the meanings given above.
With hydrogen fluoride In water; N,N-dimethyl-formamide at 150℃; for 12h;
1.o
270 mg (1 mmol) of FeCl3.6H2O (Alfa Aesar, 98%) and 250 mg (1 mmol) of 2-bromoterephthalic acid (Fluka, 95%) are dispersed in 10 ml of DMF (Fluka, 98%) with 0.2 ml of 5M hydrofluoric acid (SDS, 50%). The mixture is left in a 23 ml Teflon vessel inserted into a metallic PAAR type bomb for 12 hours at 150° C. The solid is recovered by filtration.To eliminate the acid remaining in the pores, the solid is calcined at 150° C. under vacuum for 15 hours.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Scheme 19DIBAL-HDCM Step 1[00262] To the solution of 2-bromoterephthalic acid (CIV) (5.0 g, 20.40 mmol) in DMF was added K2C03 (7.9 g, 57.13 mmol) and CH3I (3.56 mL, 57.13 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with 1 N aqueous HCI, 1 M aqueous K2C03, 10% aqueous Na2S203, brine, dried over anhydrous MgS04, and concentrated under vacuum to give dimethyl 2-bromoterephthalate (CV) (4.82 g, 17.65 mmol, 99% purity, 80% yield). ESIMS found for Ci0H9BrO4 mlz 275.2 (M+2H).
With pyridine; hydrogenchloride In quinoline; water
3.A 2-{2-[4-(3-Aminomethyl-dibenzo[b,f][1,4]thiazepin-11-yl)-piperazin-1-yl]-ethoxy}-ethanol
Step A 11-Oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-3-carboxylic acid A mixture of 2-amino-benzenethiol (1.34 mL, 12.5 mmol), 2-bromo-terephthalic acid (1.54 g, 6.3 mmol), cuprous oxide (0.50 g, 3.5 mmol), quinoline (6.3 mL), and pyridine (0.63 mL) was heated in a 180° C. oil bath under nitrogen for 20 hours, then cooled to room temperature. Concentrated hydrochloric acid (20 mL) was added slowly while cooling in cold water, with stirring. The resulting precipitate was filtered, washed with water, and dried to give crude title compound (2 g). LC-MS: m/z 270 (M-1).
With pyridine; quinoline; copper(II) oxide at 180℃; for 20h; Inert atmosphere;
3.A 11-Oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-3-carboxylic acid
A mixture of 2-amino-benzenethiol (1.34 mL, 12.5 mmol), 2-bromo-terephthalic acid (1.54 g, 6.3 mmol), cuprous oxide (0.50 g, 3.5 mmol), quinoline (6.3 mL), and pyridine (0.63 mL) was heated in a 180 °C oil bath under nitrogen for 20 hours, then cooled to room temperature. Concentrated hydrochloric acid (20 mL) was added slowly while cooling in cold water, with stirring. The resulting precipitate was filtered, washed with water, and dried to give crude title compound (2 g). LC-MS: m/z 270 (M-1).
With pyridine; quinoline; copper(I) oxide for 20h; Heating; Inert atmosphere;
3.A Step A 11-Oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-3-carboxylic acid
A mixture of 2-amino-benzenethiol (1.34 mL, 12.5 mmol), 2-bromo-terephthalic acid (1.54 g, 6.3 mmol), cuprous oxide (0.50 g, 3.5 mmol), quinoline (6.3 mL), and pyridine (0.63 mL) was heated in a 180° C. oil bath under nitrogen for 20 hours, then cooled to room temperature. Concentrated hydrochloric acid (20 mL) was added slowly while cooling in cold water, with stirring. The resulting precipitate was filtered, washed with water, and dried to give crude title compound (2 g). LC-MS: m/z 270 (M-1).
Synthesis of complex 1
An ammonia solution (125 mL, 0.5 mol/L) of AgNO3(0.21 g, 1.25 mmol) and 2-bromoterephthalic acid (0.31 g,1.25 mmol) was added dropwise to an EtOH solution(125 mL) of bpa (0.23 g, 1.25 mmol). The clear mixture was stirred for 15 min and then allowed to evaporate slowly at room temperature. Block-like light white crystalsof [Ag2(bpa)2](Brtp)6H2O (1) were obtained after 4 weeks. Anal. calcd. for C32H39Ag2BrN4O10 (%): C, 41.1; H, 4.2; N, 6.0. Found: C, 41.2; H, 4.3; N, 6.0. IR (KBr)/cm-1: 3333(m), 3030(m), 2925(w), 1933(w), 1606(s),1557(s), 1495(w), 1423(m), 1360(s), 1219(w), 1177(s),1100(m), 1076(w), 1012(m), 991(w), 917(w), 828(s),810(m), 778(s), 718(m), 659(w), 546(m), 488(m), 409(w).
Add 3g to 50mL DMF solvent<strong>[586-35-6]2-bromoterephthalic acid</strong> (0.012 mol) and 4.8 g of potassium hydrogencarbonate (0.048 mol),Stir at room temperature to form a potassium salt.5.79 g of n-bromooctane (0.03 mol) was added to the mixed solution,The reaction was stirred at 90 C for 12 hours. Stop the reaction and allow the solution to cool to room temperature.It was poured into 300 mL of water and extracted with ethyl acetate.Dry over anhydrous sodium sulfate, filter and spin dry solvent.Petroleum ether/ethyl acetate (20/1) for crude productsColumn chromatography for the eluent gave a white solid.
Add 3g to 50mL DMF solvent<strong>[586-35-6]2-bromoterephthalic acid</strong> (0.012 mol) and 4.8 g of potassium hydrogencarbonate (0.048 mol),Stir at room temperature to form a potassium salt.6.64 g of n-bromodecane (0.03 mol) was added to the mixed solution,The reaction was stirred at 90 C for 12 hours. Stop the reaction and allow the solution to cool to room temperature.It was poured into 300 mL of water and extracted with ethyl acetate.Dry over anhydrous sodium sulfate, filter and spin dry solvent.Column chromatography using petroleum ether/ethyl acetate (20/1) as eluentLeave to give a white solid.
In water at 210℃; for 18h; Autoclave; High pressure;
Alternative synthesis of Cr-MIL-101-Br
A mixture of Cr(NO3)3*9H2O (400 mg, 1.00 mmol) and H2BDC-Br linker(245 mg, 1.00 mmol) in water (5 mL) was placed in a 50 mL Teflon-lined stainless steel autoclave and heated at 210 °C for 18 h in a conventional oven. After cooling to room temperature, the green materials were collected by filtration using filter papers, washed with acetone(35 mL) and dried in air. The yield was 310 mg.
With caesium carbonate; palladium; In N,N-dimethyl-formamide; at 80℃; for 6h;
28.4 mmol of 2-bromo terephthalic acid, 56.8 mmol of vinyl borate, 2.84 mmol of Pd catalyst, 85.2 mmol of cesium carbonate (Cs2CO3), and dimethylformamide (DMF) were added to a round- 0.1M was added thereto and stirred to prepare a halogenbenzene mixture. The reaction mixture was reacted at 80 C for 6 hours, and then the reaction solution was filtered and washed to obtain a reaction product in 93% yield.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere;
176 Synthesis of 2-bromo-N1 ,N4-dimethoxy-N1 ,N4-dimethylterephthalamide:
To a stirred solution of 2-bromoterephthalic acid (3.00 g, 12.2 mmol) in DMF (50.0 ml_), at 0 °C under N2 atmosphere, was added HATU (13.9 g, 36.7 mmol), DIPEA (12.8 ml_, 73.5 mmol) followed with N, O-dimethylhydroxylamine hydrochloride (2.99 g, 30.6 mmol), and the reaction mixture was stirred at r.t for 1 h. The reaction mixture was poured on to cold water (100 ml.) and extracted with EtOAc (3 x 100 ml_). The combined the organic extracts were washed with brine (100 ml_), dried over anhydrous Na2S04, filtered and concentrated under vacuum to obtain the crude product. The product was purified by silica gel chromatography using MeOH: CH2CI2 (1 :9). The fractions containing the product were combined and concentrated under vacuum to obtain 2-bromo-N1 ,N4-dimethoxy-N1 ,N4-dimethylterephthalamide
Stage #1: 2-bromo-1,4-benzenedicarboxylic acid; zirconium(IV) chloride In N,N-dimethyl-formamide for 0.25h; Sonication;
Stage #2: In N,N-dimethyl-formamide at 80 - 100℃; for 36h;
UiO-66-Br
ZrCl4 (116.52 mg, 0.50 mmol) and 2-bromoterephthalic acid (61.26 mg, 0.25 mmol) were dissolved in DMF (14.0 mL) and the solution was sonicated for 15 min. The resulting clear solution was heated at 80 °C for 12 h and then held at 100 °C for 24 h. The resulting solid was washed with successive aliquots of fresh DMF (9 times) and EtOH (9 times).
With N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;
46%
With N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃;
5.1 Step 1: Synthesis of 1-[3-bromo-4-[4-(pyrrolidin-1-yl)piperidine-1-carbonyl] benzoyl]-4-(pyrrolidin-1-yl) piperidine
To a solution of 2-bromobenzene-1,4-dicarboxylic acid (1.00 g, 4.08 mmol, 1.00 equiv) in DMF (25.00 mL) was added TBTU (3.12 g, 12.24 mmol, 3.00 equiv) and triethylamine(1.23 g, 12.20 mmol, 2.99 equiv). Then 4-(pyrrolidin-1-yl)piperidine (1.26 g, 8.16 mmol, 2.00 equiv) was added. The mixture was stirred at r.t. overnight. The mixture was poured into 50 mL ice water, EA extracted (3x50 mL). The organic phases were combined and washed by H2O (2x50 mL) and brine (50 mL), dried over anhydrous Na2SO4. The solid was filtered out and concentrated. The residue was purified by silica gel column with DCM/MeOH=5:1.1.00 g desired product was obtained as brown solid (46.00% yield). LC/MS: mass calcd. For C26H37BrN4O2: 516.21, found: 517.05, 519.05 [M+H, M+2+H]+.
46%
With N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃;
5.1 Step 1: Synthesis of 1-[3-bromo-4-[4-(pyrrolidin-1-yl)piperidine-1-carbonyl] benzoyl]-4-(pyrrolidin-1-yl) piperidine
To a solution of 2-bromobenzene-1,4-dicarboxylic acid (1.00 g, 4.08 mmol, 1.00 equiv) in DMF (25.00 mL) was added TBTU (3.12 g, 12.24 mmol, 3.00 equiv) and triethylamine(1.23 g, 12.20 mmol, 2.99 equiv). Then 4-(pyrrolidin-1-yl)piperidine (1.26 g, 8.16 mmol, 2.00 equiv) was added. The mixture was stirred at r.t. overnight. The mixture was poured into 50 mL ice water, EA extracted (3x50 mL). The organic phases were combined and washed by H2O (2x50 mL) and brine (50 mL), dried over anhydrous Na2SO4. The solid was filtered out and concentrated. The residue was purified by silica gel column with DCM/MeOH=5:1.1.00 g desired product was obtained as brown solid (46.00% yield). LC/MS: mass calcd. For C26H37BrN4O2: 516.21, found: 517.05, 519.05 [M+H, M+2+H]+.
With N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;
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