* 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.
Stage #1: With hydrogenchloride; sodium nitrite In dichloromethane; water at 0 - 20℃; for 5 h; Inert atmosphere Stage #2: With potassium iodide In dichloromethane; water at 20℃; for 12 h; Inert atmosphere; Cooling with ice
Under an Ar atmosphere, dimethyl 5-aminoisophthalate (1) (6.27 g, 30.0 mmol) was added to 39 mL of hydrochloric acid (2 M) cooled with ice. After the mixture was stirred at 0° C. or less for several minutes, 21.6 mL of an aqueous solution of NaNO2 (2.52 g, 36.5 mmol, 1.2 eq.) cooled with ice was added dropwise. Further, 30 mL of dichloromethane was added, and the mixture was stirred for 5 hours after reaching room temperature. Then, 70 mL of an aqueous solution of KI (7.47 g, 45.0 mmol, 1.5 eq.) was added dropwise with ice cooling, and the mixture was stirred at room temperature for 12 hours. After the completion of the stirring, the aqueous layer was subjected to extraction with EtOAc, and the organic layer was washed with brine, dried over magnesium sulfate, and then subjected to silica gel chromatography (SiO2, hexane) to isolate a compound 2 (5.285 g, 16.5 mmol, 55percent). (0065) 1H-NMR (400 MHz, CDCl3) δ; 8.62 (t, 1H, J=1.4 Hz), 8.53 (s, 2H, J=1.4 Hz), 3.94 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ 165.2 (2C), 142.9 (2C), 132.6 (2C), 130.2, 93.8, 53.1 (2C), MS (EI) m/z 320 (M+), HRMS Calcd for C10H9IO4: 319.9546. Found: 319.9553. Anal. Calcd for C10H9IO4: C, 37.52; H, 2.83. Found: C, 37.44; H, 2.86.
49%
With hydrogenchloride; potassium iodide; sodium nitrite In water; toluene at -5℃; for 13 h; Heating / reflux
A solution of sodium nitrite (8.63g, 0.125 mol) in water (150 mL) was added to a suspension of 5-amino-benzene-1,3-dicarboxylate (8) (26.16 g, 0.125 mol) in 20percent HCl (75 mL) at -5°C. Toluene (200 mL) and then a solution of potassium iodide (42.00g, 0.50 mol) in water (100 mL) was slowly added to the suspension. After the addition, the reaction mixture was stirred for 12 hours and afterwards refluxed for 1 h. The organic layer was separated and washed three times with water, dried with MgSO4, filtered and concentrated in vacuum. The crude product was recrystallized three times from methanol, giving 5 as light-brown crystals. Yield 49percent. M.p. 103-104 °C. 1H-NMR (400 MHz, CDCl3): δ= 3.95 (s, 6H), 8.53 (d, 2H, J = 1.5 Hz), 8.61 (t, 1H, J = 1.5 Hz). 13C-NMR (100 MHz, CDCl3): δ= 52.6, 93.4, 129.8, 132.3, 142.4, 164.7. MS-EI, m/z (percent): 320 (88) [M+], 289 (100), 261 (25). Rf= 0.54 (silica gel, ethylacetatehexane 3:7 v/v).
Reference：
[1] Inorganic Chemistry, 2015, vol. 54, # 9, p. 4377 - 4381
[2] Journal of the American Chemical Society, 2012, vol. 134, # 49, p. 20110 - 20116
[3] Organic and Biomolecular Chemistry, 2011, vol. 9, # 18, p. 6284 - 6292
[4] Chemical Communications, 2011, vol. 47, # 9, p. 2691 - 2693
[5] Patent: US2018/94017, 2018, A1, . Location in patent: Paragraph 0061; 0064; 0065
[6] Journal of Organic Chemistry, 2006, vol. 71, # 20, p. 7854 - 7857
[7] European Journal of Organic Chemistry, 2007, # 20, p. 3271 - 3276
[8] Patent: EP1972338, 2008, A1, . Location in patent: Page/Page column 13
[9] Organic and Biomolecular Chemistry, 2009, vol. 7, # 13, p. 2761 - 2769
[10] RSC Advances, 2013, vol. 3, # 6, p. 1902 - 1915
[11] Tetrahedron Letters, 2005, vol. 46, # 29, p. 4895 - 4899
[12] Chemistry - A European Journal, 1999, vol. 5, # 1, p. 345 - 355
[13] Crystal Growth and Design, 2012, vol. 12, # 6, p. 2736 - 2739
[14] Crystal Growth and Design, 2016, vol. 16, # 12, p. 7301 - 7307
2
[ 13290-96-5 ]
[ 99-27-4 ]
Yield
Reaction Conditions
Operation in experiment
99 %Chromat.
With hydrogen In tetrahydrofuran; water at 100℃; for 5 h; Autoclave
General procedure: The hydrogenation of nitroarenes was carried out in a Teflon-lined stainless steel autoclave equipped with a pressure gauge anda magnetic stirrer. Typically, a mixture of 0.5 mmol nitroarene, 15molpercent Co/C–N–X catalyst, 100 L n-hexadecane and 2 mL solventwas introduced into the reactor at room temperature. Air in theautoclave was purged several times with H2. Then, the reactionbegan by starting the agitation (600 r/min) when hydrogen was reg-ulated to 1 MPa after the reaction temperature was reached. Afterreaction, the solid was isolated from the solution by centrifuga-tion. The products in the solution were quantified and identifiedby GC–MS analysis (Shimadzu GCMS-QP5050A equipped with a0.25 mm × 30 m DB-WAX capillary column).1H NMR and13C NMRdata were obtained on Bruker Avance III 400 spectrometer usingCDCl3or DMSO-d6 as solvent and tetrmethylsilane (TMS) as aninternal standard. The pure product in the scale-up experimentwas obtained by flash column chromatography (petroleum ether and ethyl acetate).
Reference：
[1] ACS Catalysis, 2015, vol. 5, # 3, p. 1526 - 1529
[2] Journal of the Chemical Society, 1905, vol. 87, p. 1265
[3] Journal fuer Praktische Chemie (Leipzig), 1882, vol. <2> 25, p. 505,515
[4] Australian Journal of Chemistry, 1997, vol. 50, # 12, p. 1159 - 1182
[5] Patent: US2004/82811, 2004, A1,
[6] Green Chemistry, 2015, vol. 17, # 2, p. 898 - 902
[7] ACS Catalysis, 2015, vol. 5, # 9, p. 5264 - 5271
[8] Chinese Journal of Catalysis, 2016, vol. 37, # 1, p. 91 - 97
[9] Journal of Molecular Catalysis A: Chemical, 2016, vol. 420, p. 56 - 65
[10] Catalysis Science and Technology, 2016, vol. 6, # 12, p. 4473 - 4477
[11] ChemCatChem, 2017, vol. 9, # 6, p. 1128 - 1134
[12] Patent: US2680730, 1950, ,
3
[ 67-56-1 ]
[ 99-31-0 ]
[ 99-27-4 ]
Reference：
[1] RSC Advances, 2013, vol. 3, # 6, p. 1902 - 1915
[2] Chemistry - A European Journal, 2018, vol. 24, # 61, p. 16379 - 16387
[3] Chemistry - A European Journal, 2017, vol. 23, # 52, p. 12758 - 12762
[4] Chemical Communications, 2012, vol. 48, # 48, p. 6022 - 6024
4
[ 618-88-2 ]
[ 99-27-4 ]
Reference：
[1] Journal of the Chemical Society, 1905, vol. 87, p. 1265
[2] Journal of the Chemical Society, 1905, vol. 87, p. 1265
5
[ 1459-93-4 ]
[ 99-27-4 ]
Reference：
[1] Patent: US2680730, 1950, ,
6
[ 13290-96-5 ]
[ 99-27-4 ]
Reference：
[1] Journal of the Chemical Society, 1905, vol. 87, p. 1265
7
[ 99-27-4 ]
[ 17449-48-8 ]
Yield
Reaction Conditions
Operation in experiment
44%
Stage #1: With hydrogenchloride; sodium nitrite In water at -5℃; for 0.25 h; Stage #2: With fluoroboric acid In water at 0℃; for 0.5 h; Stage #3: at 110℃;
Concentrated [HC1] (30 ml) was added to a cooled [(-5°C)] suspension of dimethyl 5-amino isophthalate (20 g, 95.6 mmol) in water (75 ml), followed by portionwise addition of [NAN02] (7.5 g, 109 mmol). The reaction mixture was then stirred for 15 min. , after which [HBF4 (18] ml, 100 mmol, 48percent aqueous solution) was added. The resulting mixture was stirred at [0°C] for 30 min. and the precipitate formed was collected by filtration and washed with cold methanol (60 ml) and ether (60 ml). The residue was then decomposed by heating in an oil bath [(~110°C).] The cooled mixture was then diluted with ether, concentrated onto silica gel and purified by flash chromatography with 5percent ethyl acetate hexane as eluant giving 9.0 g (44percent) of product as a white fluffy [SOLID. LH NE (CDC13), 6] [(PPM)] : 8.57 (s, 1H), 7.95 (d, 2H), 3.97 (s, 6H). A suspension of 5-fluoro-isophthalic acid dimethyl ester (1.7 g, 8. 0 mmol) in methanol (41 ml) was treated with 1.0 N sodium hydroxide (7.2 ml, 7.2 mmol). The reaction was left stirring overnight at room temperature. After the solution was concentrated, the residue was dissolved in water and transferred to a separatory funnel. The aqueous layer was washed with dichloromethane (3 times) and then acidified with 1.0 N [HC1] to pH 2. Ethyl acetate was used to extract the precipitate, which was then washed with brine and dried over anhydrous sodium sulphate. After removal of solvent in vacuo, a total of 1.3 g (83percent) of 5-fluoro-isophthalic acid monomethyl ester was isolated as a white [SOLID. LH] NMR (DMSO), [5] (ppm): 8.31 (t, 1H), 7.96 (m, 2H), 3.91 (s, 3H). Triethylamine (2.2 ml, 16.0 mmol) and isobutyl [CHLOROFORMATE] (1.0 ml, 8. 0 mmol) were added to an ice-cooled solution [OF 5-FLUORO-ISOPHTHALIC] acid monomethyl ester (1.3 g, 6.7 mmol) in dichloromethane (20 ml) and then warmed to room temperature. After stirring for 2 h, the reaction mixture was filtered and concentrated. The residue was re-dissolved tetrahydrofuran (10 ml) and then sodium borohydride [(1.] 1 g, 29.02 mmol) in water (3ml) was added drop-wise. After 1 h, the reaction was quenched with methanol and then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Flash column chromatography on silica gel using 30percent ethyl acetate in hexanes afforded 667 mg (54percent) of 3-fluoro-5-hydroxymethyl-benzoic acid methyl ester as a colorless [OIL. 1H] NMR [(CDC13),] [8] (ppm): 7.82 (s, 1H), 7.63 (d, 1H), 7.32 (d, 1H), 4.76 (s, 2H), 3.93 (s, 3H). Ethanol (2 ml) was added to round bottom flask containing 3-fluoro-5-hydroxymethyl- benzoic acid methyl ester (667 mg, 3.6 mmol) and palladium (10 wt. percent on activated carbon, 300 mg) under argon. The flask was evacuated using a water aspirator and then filled with hydrogen from a balloon. After stirring for 2 h, the palladium on carbon was removed by filtration through celite. The filtrate was then concentrated to afford 520 mg (87percent) of 3-fluoro-5-methyl-benzoic acid methyl [ESTER. LH] NMR [(CDC13),] 8 (ppm): 7.65 (s, 1H), 7.51 (d, 1H), 7.08 (d, 1H), 3.91 (s, 3H), 2.40 (s, 3H). 0.5 N Lithium hydroxide (7.4 ml, 3.7 mmol) was added to a solution 3-fluoro-5-methyl- benzoic acid methyl ester (520 mg, 3.1 mmol) in tetrahydrofuran (7.4 ml). The reaction was stirred at [75 C] for 2 h and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH about 2) by the addition of 10percent [HC1] (aq. ). Following extraction of the aqueous layer with ethyl acetate, the organic layer was then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 469 mg (98percent) [OF 3-FLUORO-5-METHYL-BENZOIC] acid as a white solid. 1H NMR (DMSO), d (ppm): 7.62 (s, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 2.38 (s, 3H).
Reference：
[1] Patent: WO2004/14881, 2004, A2, . Location in patent: Page 100-101
[2] Journal of Organic Chemistry, 1969, vol. 34, p. 1960 - 1961
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 31, p. 9896 - 9900[4] Angew. Chem., 2018, vol. 130, p. 10044 - 10048,5
8
[ 99-27-4 ]
[ 13290-96-5 ]
Reference：
[1] Australian Journal of Chemistry, 2017, vol. 70, # 11, p. 1171 - 1179
As shown in Figure 3: 5-amino-isophthalic acid dimethyl ester (10.0 g, 47.6 mmol) in a 500 mL three-necked flask and slowly drop the solution of hydrobromic acid (15percent, 225 mL) dropwise, drop the solution in an ice bath to 5 ° C and slowly add sodium nitrite Solution (2.5 M, 23 mL) was added slowly, and a solution of CuBr (9.8 g) in hydrobromic acid (45percent, 90 mL) was slowly added dropwise to the three-necked flask, keeping the reaction temperature below 5 ° C, The crude product was filtered off, dried and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8/3) to give a white powder (8.28 g), yield 63.4percent. Melting point: 88 to 89
63.4%
at 5 - 20℃; for 2 h;
5-amino-1,3-benzenedicarboxylic acid dimethyl ester (10.0g, 47.6mmol) in 500mL three flask, was slowly added dropwise a solution of hydrobromic acid (15percent, 225mL ), completion of dropwise, the solution was cooled to ice bath 5 ° C, was slowly dropwise with rapid stirring a solution of sodium nitrite (2.5M, 23mL), was slowly added dropwise CuBr (9.8g) in a three-necked flask hydrobromic acid (45percent , 90mL) was added maintaining the reaction temperature below 5 ° C, the addition was complete stirring at room temperature 2h, the crude product was filtered, dried and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8/3) to give white powder A (8.28g), yield 63.4percent
Reference：
[1] Chemical Communications, 2010, vol. 46, # 7, p. 1100 - 1102
[2] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 4, p. 533 - 537
[3] Inorganic Chemistry, 2015, vol. 54, # 9, p. 4377 - 4381
[4] CrystEngComm, 2017, vol. 19, # 11, p. 1464 - 1469
[5] Chinese Journal of Chemistry, 2017, vol. 35, # 8, p. 1289 - 1293
[6] Patent: CN105601472, 2016, A, . Location in patent: Paragraph 0021; 0022
[7] Patent: CN105237337, 2016, A, . Location in patent: Paragraph 0019
[8] Synthesis, 1998, # 12, p. 1742 - 1749
[9] Patent: WO2006/2474, 2006, A1, . Location in patent: Page/Page column 175
[10] Patent: US2008/153802, 2008, A1, . Location in patent: Page/Page column 87
[11] Patent: US2016/2268, 2016, A1, . Location in patent: Paragraph 0156-0157
11
[ 99-27-4 ]
[ 23351-91-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, # 3, p. 529 - 532
12
[ 99-27-4 ]
[ 4371-28-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2007, # 20, p. 3271 - 3276
[2] Journal of Organic Chemistry, 2006, vol. 71, # 20, p. 7854 - 7857
[3] Journal of Organic Chemistry, 2006, vol. 71, # 20, p. 7854 - 7857
[4] Patent: EP1972338, 2008, A1,
[5] Patent: EP1972338, 2008, A1,
13
[ 99-27-4 ]
[ 71176-54-0 ]
Yield
Reaction Conditions
Operation in experiment
70%
With lithium aluminium tetrahydride In tetrahydrofuran for 3 h; Reflux
A solution of dimethyl 5-aminoisophthalate (20.0 g, 96 mmol) in THF (350 mL) was added, dropwise, to a refluxing mixture of 3.75 eq L1AIH4 (13.6 g, 358 mmol) in THF (440 mL) over one hour. The mixture was stirred at reflux for a further two hours, then cooled to room temperature and quenched by the careful addition of MeOH (27 mL) then water (40 mL). After stirring the quenched mixture for two hours it was filtered and concentrated to dryness. The residue was recrystallized (2X) from EtOAc to afford 15 as brownish-yellow crystals (10.2 g, 70 percent).
70%
With lithium aluminium tetrahydride In tetrahydrofuran for 3 h; Reflux
A solution of dimethyl 5-aminoisophthalate (20.0 g, 96 mmol) in THF (350 mL) was added, dropwise, to a refluxing mixture of 3.75 eq L1AIH4 (13.6 g, 358 mmol) in THF (440 mL) over one hour. The mixture was stirred at reflux for a further two hours, then cooled to room temperature and quenched by the careful addition of MeOH (27 mL) then water (40 mL). After stirring the quenched mixture for two hours it was filtered and concentrated to dryness. The residue was recrystallized (2X) from EtOAc to afford 15 as brownish-yellow crystals (10.2 g, 70 percent).
Reference：
[1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 1, p. 161 - 171
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4350 - 4364
[3] Patent: WO2017/177326, 2017, A1, . Location in patent: Page/Page column 59; 64; 68
[4] Patent: WO2018/191278, 2018, A2, . Location in patent: Page/Page column 86; 90; 91; 94; 97
[5] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7588 - 7594
[6] Journal of Medicinal Chemistry, 2010, vol. 53, # 9, p. 3480 - 3488
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10405 - 10413
[8] Bulletin of the Chemical Society of Japan, 2008, vol. 81, # 8, p. 1012 - 1018
[9] Supramolecular Chemistry, 2018, vol. 30, # 10, p. 822 - 831
[10] Journal of the American Chemical Society, 2018, vol. 140, # 40, p. 13011 - 13021
14
[ 99-27-4 ]
[ 120173-41-3 ]
Reference：
[1] Synthesis, 1998, # 12, p. 1742 - 1749
15
[ 99-27-4 ]
[ 944392-68-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2007, # 20, p. 3271 - 3276
[2] Journal of Organic Chemistry, 2006, vol. 71, # 20, p. 7854 - 7857
[3] Organic and Biomolecular Chemistry, 2011, vol. 9, # 18, p. 6284 - 6292
[4] Journal of the American Chemical Society, 2012, vol. 134, # 49, p. 20110 - 20116
[5] RSC Advances, 2013, vol. 3, # 6, p. 1902 - 1915
[6] Inorganic Chemistry, 2015, vol. 54, # 9, p. 4377 - 4381
[7] Patent: CN105601472, 2016, A,
[8] Patent: CN105237337, 2016, A,
[9] CrystEngComm, 2017, vol. 19, # 11, p. 1464 - 1469
[10] Chinese Journal of Chemistry, 2017, vol. 35, # 8, p. 1289 - 1293
[11] Patent: EP1972338, 2008, A1,
16
[ 99-27-4 ]
[ 73183-34-3 ]
[ 944392-68-1 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 5, p. 1923 - 1933
With hydrogenchloride; sodium hydroxide;P2O5; palladium-carbon; In methanol; water;
EXAMPLE 6 Preparation of the 5-amino-1,3-benzenedicarboxylic Acid Dimethyl Ester 5-Nitro-1,3-benzenedicarboxylic acid dimethyl ester (95.7 g, 0.4 mol) and 5% Pd/C (8 g) are loaded into a 2 L hydrogenation vessel equipped with a thermometer and a mechanical stirrer, that contains methanol (0.8 L) and 2M HCl (0.3 L; 0.6 mol). The obtained suspension is maintained under mechanical stirring and purged with nitrogen washings, at the end of which the hydrogenation reaction is carried out at a temperature comprised between 45 and 55 C. The reaction is complete in 2 hours. A nitrogen flow is then passed through the reaction vessel to wash out any hydrogen gas, the catalyst is filtered off and the obtained solution is evaporated under vacuum to yield a solid residue. The obtained product is loaded into a 5 L vessel, equipped with a mechanical stirrer, and containing deionized water (3 L) and 34% HCl (0.1 L). The obtained suspension is filtered from the insoluble residue and 2M NaOH is added to the filtrate up to pH 10. The solid product that crystallizes out is recovered by filtration, washed with deionized water and dried under vacuum in the presence of P2O5 yielding the compound of the title (77.0 g; 0.368 mol, yield: 92%). The 1H-NMR, 13C-NMR, IR and MS are consistent with the indicated structure
With hydrogen; In ethyl acetate; at 30℃; under 750.075 Torr; for 1.0h;Schlenk technique;Catalytic behavior;
General procedure: The substrate (0.5 mmol), NiPd/MIL-101 catalyst (0.023g, Pd 0.2 mol%), and ethyl acetate (4 mL) were added to a Schlenk tube, and the mixture was vigorously stirred with an affixed hydrogenation balloon at room temperature. Following the reaction, the solid catalyst was removed from the solution by filtration and washed with ethyl acetate. The product yields were determined by gas chromatography-mass spectrometry (GC/MS, Shimadzu GCMS- QP5050A) with a 0.25 mm × 30 mDB-WAX capillary column. Parameters were as follows: initialoven temperature, 100 C, 1 min; ramp, 20 C/min; final temperature, 280 C; final time, 5 min.
99%Chromat.
With hydrogen; In tetrahydrofuran; water; at 100℃; under 7500.75 Torr; for 5.0h;Autoclave;
General procedure: The hydrogenation of nitroarenes was carried out in a Teflon-lined stainless steel autoclave equipped with a pressure gauge anda magnetic stirrer. Typically, a mixture of 0.5 mmol nitroarene, 15mol% Co/C-N-X catalyst, 100 L n-hexadecane and 2 mL solventwas introduced into the reactor at room temperature. Air in theautoclave was purged several times with H2. Then, the reactionbegan by starting the agitation (600 r/min) when hydrogen was reg-ulated to 1 MPa after the reaction temperature was reached. Afterreaction, the solid was isolated from the solution by centrifuga-tion. The products in the solution were quantified and identifiedby GC-MS analysis (Shimadzu GCMS-QP5050A equipped with a0.25 mm × 30 m DB-WAX capillary column).1H NMR and13C NMRdata were obtained on Bruker Avance III 400 spectrometer usingCDCl3or DMSO-d6 as solvent and tetrmethylsilane (TMS) as aninternal standard. The pure product in the scale-up experimentwas obtained by flash column chromatography (petroleum ether and ethyl acetate).
Under an Ar atmosphere, dimethyl 5-aminoisophthalate (1) (6.27 g, 30.0 mmol) was added to 39 mL of hydrochloric acid (2 M) cooled with ice. After the mixture was stirred at 0 C. or less for several minutes, 21.6 mL of an aqueous solution of NaNO2 (2.52 g, 36.5 mmol, 1.2 eq.) cooled with ice was added dropwise. Further, 30 mL of dichloromethane was added, and the mixture was stirred for 5 hours after reaching room temperature. Then, 70 mL of an aqueous solution of KI (7.47 g, 45.0 mmol, 1.5 eq.) was added dropwise with ice cooling, and the mixture was stirred at room temperature for 12 hours. After the completion of the stirring, the aqueous layer was subjected to extraction with EtOAc, and the organic layer was washed with brine, dried over magnesium sulfate, and then subjected to silica gel chromatography (SiO2, hexane) to isolate a compound 2 (5.285 g, 16.5 mmol, 55%). (0065) 1H-NMR (400 MHz, CDCl3) delta; 8.62 (t, 1H, J=1.4 Hz), 8.53 (s, 2H, J=1.4 Hz), 3.94 (s, 6H). 13C-NMR (100 MHz, CDCl3) delta 165.2 (2C), 142.9 (2C), 132.6 (2C), 130.2, 93.8, 53.1 (2C), MS (EI) m/z 320 (M+), HRMS Calcd for C10H9IO4: 319.9546. Found: 319.9553. Anal. Calcd for C10H9IO4: C, 37.52; H, 2.83. Found: C, 37.44; H, 2.86.
49%
With hydrogenchloride; potassium iodide; sodium nitrite; In water; toluene; at -5℃; for 13h;Heating / reflux;
A solution of sodium nitrite (8.63g, 0.125 mol) in water (150 mL) was added to a suspension of 5-amino-benzene-1,3-dicarboxylate (8) (26.16 g, 0.125 mol) in 20% HCl (75 mL) at -5C. Toluene (200 mL) and then a solution of potassium iodide (42.00g, 0.50 mol) in water (100 mL) was slowly added to the suspension. After the addition, the reaction mixture was stirred for 12 hours and afterwards refluxed for 1 h. The organic layer was separated and washed three times with water, dried with MgSO4, filtered and concentrated in vacuum. The crude product was recrystallized three times from methanol, giving 5 as light-brown crystals. Yield 49%. M.p. 103-104 C. 1H-NMR (400 MHz, CDCl3): delta= 3.95 (s, 6H), 8.53 (d, 2H, J = 1.5 Hz), 8.61 (t, 1H, J = 1.5 Hz). 13C-NMR (100 MHz, CDCl3): delta= 52.6, 93.4, 129.8, 132.3, 142.4, 164.7. MS-EI, m/z (%): 320 (88) [M+], 289 (100), 261 (25). Rf= 0.54 (silica gel, ethylacetatehexane 3:7 v/v).
3.a
a) Preparation of 3-a: 15 g (70.3 mmol) dimethyl 5-amino-isophthalate were dissolved in 150 ml of pyridine. The reaction solution was cooled to 0° C., at this temperature 12.0 ml (111.7 mmol) dimethylaminosulphonyl chloride were metered in, the mixture was heated to 90° C. and stirred for 12 h. Then it was poured onto 200 ml of 4N HCl and the precipitated crystals were suction filtered. After extraction with diethyl ether and suction filtering again, the residue was dried in the drying cupboard at 40° C. and 17.9 g (64%) of whitish crystals 3-a were obtained.RT (HPLC 1)=4.14 min
64%
With pyridine at 0 - 90℃;
8.a
15 g (70.3 mmol) dimethyl 5-amino-isophthalate were dissolved in 150 ml of pyridine. The reaction solution was cooled to 0° C., at this temperature 12.0 ml (111.7 mmol) dimethylaminosulphonyl chloride were metered in, the mixture was heated to 90° C. and stirred for 12 h. Then it was poured onto 200 ml 4N HCl and the crystals precipitated were suction filtered. After extracting with diethyl ether and suction filtering again, the residue was dried in the drying cupboard at 40° C. and 17.9 g (64%) of whitish crystals 8-a were obtained.RT (HPLC 1)=4.14 min
64%
With pyridine In dichloromethane at 0 - 90℃; for 12h;
2.a
Example 2 a) Preparation of 2-a: 15 g (70.3 mmol) dimethyl 5-amino-isophthalate were dissolved in 150 ml of pyridine. The reaction solution was cooled to 0° C., at this temperature 12.0 ml (111.7 mmol) dimethylaminosulphonyl chloride were metered in, the mixture was heated to 90° C. and stirred for 12 h. Then it was poured onto 200 ml 4N HCl and the precipitated crystals were suction filtered. After extraction with diethyl ether and suction filtering once more, the residue was dried in the drying cupboard at 40° C. and 17.9 g (64%) whitish crystals 2-a were obtained.RT (HPLC 1)=4.14 min.
64%
With pyridine at 90℃;
12.a
15.0 g (70.3 mmol) dimethyl 5-amino-isophthalate were dissolved in 150 ml of pyridine and slowly combined with 12.0 ml (111.7 mmol) N,N-dimethylamidosulphonic acid chloride and stirred overnight at 90° C. Then the reaction solution was combined at ambient temperature with 200 ml 4N HCl and the precipitate was filtered off. The crystals were combined with diethyl ether, filtered off again and dried at 40° C. in the vacuum drying cupboard. Yield 17.9 g (64%) beige crystals 12-a. RT(HPLC 1)=4.14 min
64%
With pyridine at 0 - 90℃;
2.a; B
15 g (70.3 mmol) dimethyl 5-amino-isophthalate were dissolved in 150 ml of pyridine. The reaction solution was cooled to 0° C., at this temperature 12.0 ml (111.7 mmol) dimethylaminosulphonyl chloride were metered in, the mixture was heated to 90° C. and stirred for 12 h. Then it was poured onto 200 ml 4N HCl and the crystals precipitated were suction filtered. After extraction with diethyl ether and suction filtering again, they were dried in the drying cupboard at 40° C. and 17.9 g (64%) whitish crystals 2-a were obtained.RT (HPLC 1)=4.14 min
With lithium aluminium tetrahydride; In tetrahydrofuran; for 3h;Reflux;
A solution of dimethyl 5-aminoisophthalate (20.0 g, 96 mmol) in THF (350 mL) was added, dropwise, to a refluxing mixture of 3.75 eq L1AIH4 (13.6 g, 358 mmol) in THF (440 mL) over one hour. The mixture was stirred at reflux for a further two hours, then cooled to room temperature and quenched by the careful addition of MeOH (27 mL) then water (40 mL). After stirring the quenched mixture for two hours it was filtered and concentrated to dryness. The residue was recrystallized (2X) from EtOAc to afford 15 as brownish-yellow crystals (10.2 g, 70 %).
70%
With lithium aluminium tetrahydride; In tetrahydrofuran; for 3h;Reflux;
A solution of dimethyl 5-aminoisophthalate (20.0 g, 96 mmol) in THF (350 mL) was added, dropwise, to a refluxing mixture of 3.75 eq L1AIH4 (13.6 g, 358 mmol) in THF (440 mL) over one hour. The mixture was stirred at reflux for a further two hours, then cooled to room temperature and quenched by the careful addition of MeOH (27 mL) then water (40 mL). After stirring the quenched mixture for two hours it was filtered and concentrated to dryness. The residue was recrystallized (2X) from EtOAc to afford 15 as brownish-yellow crystals (10.2 g, 70 %).
70%
With lithium aluminium tetrahydride; In tetrahydrofuran; for 3h;Reflux;
A solution of dimethyl 5-aminoisophthalate (20.0 g, 96 mmol) in THF (350 mL) was added, dropwise, to a refluxing mixture of 3.75 eq LiAlFL (13.6 g, 358 mmol) in THF (440 mL) over one hour. The mixture was stirred at reflux for a further two hours, then cooled to room temperature and quenched by the careful addition of MeOH (27 mL) then water (40 mL). After stirring the quenched mixture for two hours it was filtered and concentrated to dryness. The residue was recrystallized (2X) from EtOAc to afford 15 as brownish-yellow crystals (10.2 g, 70 %).
5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.92%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
<Example 7> 5-[2-(4-Adamantan-l-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl esterTo a mixture of (4-adamantan-l-yl-rhohenoxy)-acetic acid (143.2mg, 0.50 mmol), 5-aminoisophthalic acid dimethyl ester (156.9 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N'-ethyl carbodiimideHCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) inDMF (5mL) was added N, N-diisopropylethyamine, redistilled (DIPEA) (0.13 mL, 0.75 mmol). The mixture was stirred overnight, and25 then partitioned between ethyl acetate and 10% HCl. The organic phase washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl <n="28"/>acetatMeOH = 9:3 : 1) to give 5-[2-(4-Adamantan-l-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl ester as a light yellow, solid (195.6 mg, 81.92% yield).1H-NMR (CDCl3, 300 Hz) 8.47 - 8.48 (4H, m, aromatic-H, NH), 7.34 - 7.36 (2H, m, aromatic-H), 6.94 - 6.97 (2H, m, aromatic-H), 4.63 (2H, s, CH2), 3.96 (6H, s, CH3), 2.10 (3H, m, adamantly-H), 1.90 (6H5 m, adamantly-H), 1.77 (6H, m, adamantly-H) .
81.92%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
To a mixture of <strong>[52804-26-9](4-adamantan-1-yl-phenoxy)-acetic acid</strong> (143.2 mg, 0.50 mmol), 5-aminoisophthalic acid dimethyl ester (156.9 mg, 0.75 mmol), N-3-dimethylaminopropyl)-N'-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (5 mL) was added N,N-disopropylethylamine, redistilled (DIPEA) (0.13 mL, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=9:3:1) to give 5-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl ester as alight yellow solid (195.6 mg, 81.92% yield). 1H-NMR (CDCl3, 300 Hz) 8.47-8.48 (4H, m, aromatic-H, NH), 7.34-7.36 (2H, m, aromatic-H), 6.94-6.97 (2H, m, aromatic-H), 4.63 (2H, s, CH2), 3.96 (6H, s, CH3), 2.10 (3H, m, adamantly-H), 1.90 (6H, m, adamantly-H), 1.77 (6H, m, adamantly-H).
Concentrated [HC1] (30 ml) was added to a cooled [(-5C)] suspension of dimethyl 5-amino isophthalate (20 g, 95.6 mmol) in water (75 ml), followed by portionwise addition of [NAN02] (7.5 g, 109 mmol). The reaction mixture was then stirred for 15 min. , after which [HBF4 (18] ml, 100 mmol, 48% aqueous solution) was added. The resulting mixture was stirred at [0C] for 30 min. and the precipitate formed was collected by filtration and washed with cold methanol (60 ml) and ether (60 ml). The residue was then decomposed by heating in an oil bath [(~110C).] The cooled mixture was then diluted with ether, concentrated onto silica gel and purified by flash chromatography with 5% ethyl acetate hexane as eluant giving 9.0 g (44%) of product as a white fluffy [SOLID. LH NE (CDC13), 6] [(PPM)] : 8.57 (s, 1H), 7.95 (d, 2H), 3.97 (s, 6H). A suspension of 5-fluoro-isophthalic acid dimethyl ester (1.7 g, 8. 0 mmol) in methanol (41 ml) was treated with 1.0 N sodium hydroxide (7.2 ml, 7.2 mmol). The reaction was left stirring overnight at room temperature. After the solution was concentrated, the residue was dissolved in water and transferred to a separatory funnel. The aqueous layer was washed with dichloromethane (3 times) and then acidified with 1.0 N [HC1] to pH 2. Ethyl acetate was used to extract the precipitate, which was then washed with brine and dried over anhydrous sodium sulphate. After removal of solvent in vacuo, a total of 1.3 g (83%) of 5-fluoro-isophthalic acid monomethyl ester was isolated as a white [SOLID. LH] NMR (DMSO), [5] (ppm): 8.31 (t, 1H), 7.96 (m, 2H), 3.91 (s, 3H). Triethylamine (2.2 ml, 16.0 mmol) and isobutyl [CHLOROFORMATE] (1.0 ml, 8. 0 mmol) were added to an ice-cooled solution [OF 5-FLUORO-ISOPHTHALIC] acid monomethyl ester (1.3 g, 6.7 mmol) in dichloromethane (20 ml) and then warmed to room temperature. After stirring for 2 h, the reaction mixture was filtered and concentrated. The residue was re-dissolved tetrahydrofuran (10 ml) and then sodium borohydride [(1.] 1 g, 29.02 mmol) in water (3ml) was added drop-wise. After 1 h, the reaction was quenched with methanol and then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Flash column chromatography on silica gel using 30% ethyl acetate in hexanes afforded 667 mg (54%) of 3-fluoro-5-hydroxymethyl-benzoic acid methyl ester as a colorless [OIL. 1H] NMR [(CDC13),] [8] (ppm): 7.82 (s, 1H), 7.63 (d, 1H), 7.32 (d, 1H), 4.76 (s, 2H), 3.93 (s, 3H). Ethanol (2 ml) was added to round bottom flask containing 3-fluoro-5-hydroxymethyl- benzoic acid methyl ester (667 mg, 3.6 mmol) and palladium (10 wt. % on activated carbon, 300 mg) under argon. The flask was evacuated using a water aspirator and then filled with hydrogen from a balloon. After stirring for 2 h, the palladium on carbon was removed by filtration through celite. The filtrate was then concentrated to afford 520 mg (87%) of 3-fluoro-5-methyl-benzoic acid methyl [ESTER. LH] NMR [(CDC13),] 8 (ppm): 7.65 (s, 1H), 7.51 (d, 1H), 7.08 (d, 1H), 3.91 (s, 3H), 2.40 (s, 3H). 0.5 N Lithium hydroxide (7.4 ml, 3.7 mmol) was added to a solution 3-fluoro-5-methyl- benzoic acid methyl ester (520 mg, 3.1 mmol) in tetrahydrofuran (7.4 ml). The reaction was stirred at [75 C] for 2 h and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH about 2) by the addition of 10% [HC1] (aq. ). Following extraction of the aqueous layer with ethyl acetate, the organic layer was then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 469 mg (98%) [OF 3-FLUORO-5-METHYL-BENZOIC] acid as a white solid. 1H NMR (DMSO), d (ppm): 7.62 (s, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 2.38 (s, 3H).
With pyridine; In dichloromethane; at 20℃; for 2h;
5-(4-Benzyloxy-benzenesulfonylamino)-isophthalic acid dimethyl ester (CAB04124):; 4-Benzyloxy-benzenesulfonyl chloride (7.35 g, 26.0 mmol) was added in small portions to a suspension of 5-amino isophtalic acid dimethyl ester (5.23 g, 25.0 mmol) in DCM (100 ml) and pyridine (10 ml). The resulting clear yellow solution was stirred for 2 hours at room temperature, the volatile solvents were removed under reduced pressure, the solid residue was suspended in MeOH (125 ml) and the mixture was heated to reflux for 10 minutes. The off white solid was filtered off, washed with water and cold MeOH and dried under high vacuum. Yield 10.93 g (96%). ¹H-NMR (400 MHz, DMSO-d6) 8 3.87 (6H, s, 2 x -OCH3), 5.13 (2H, s), 7.17 (2H, d, J = 9.0 Hz), 7.30-7.44 (5H, m), 7.74 (2H, d, J = 9.0 Hz), 7.98 (2H, d, J = 1.6 Hz), 8.12 (1H, t, J = 1.6 Hz), 10.77 (1H, br s); ¹3C-NMR (100.5 MHz, DMSO-d6) 8 53.1,70.2, 115.8,124.2, 125.0, 128.4,128.6, 128.9, 129.3, 131.1, 131.6, 136.6, 139.6, 162.3, 165.3; MS (FAB+): m/z 456.2 (30%, [C23H22N07S] (at)), 71.0 (100%); HRMS (FAB+) calcd for C23H21NO7: 455.09940; found, 455.10091. HPLC (ACS80) tr = 2.059 min (99.8%).
2.5 g (11.7 mmol) dimethyl 5-amino-isophthalate were suspended in 40 ml of pyridine, slowly combined with 3.3 g (17.8 mmol) 13-a and stirred overnight at 90 C. Then the reaction solution was combined with 50 ml 4N HCl while cooling with an ice bath and the precipitate was filtered off. The crystals were dissolved in dichloromethane, filtered through a phase separation cartridge and the filtrate was evaporated down i. vac. Yield 2.7 g (64%) brown crystals 13-b. RT(HPLC 1)=4.30 min
With Sodium hydrogenocarbonate In dichloromethane at 20℃; for 24h;
With Sodium hydrogenocarbonate In chloroform at 20℃; Cooling with ice;
General synthetic procedure for compounds 2-25.
General procedure: Disubstitutedaromatic amines (1 mmol) were dissolved with chloroform (4 mL). Afteradding sodium bicarbonate (1.2 mmoL), the mixture was agitated underice bath for 15 min. Then chloroacetyl chloride (1.5 mmoL) was addeddropwise to the mixture. The reaction solution was transferred to room temperature and stirred for 2 h. After the end of reaction, the solutionwas diluted with chloroform (15 mL) and washed by water (2 × 20 mL),×and then sodium sulfate was added to dehydrate. The solvent wasevaporated under a vacuum to obtain the crude product 2a to 25a,which were used for subsequent reaction without purification.
With Sodium hydrogenocarbonate In chloroform at 20℃; Cooling with ice;
General synthetic procedure for compounds 2-25.
General procedure: Disubstitutedaromatic amines (1 mmol) were dissolved with chloroform (4 mL). Afteradding sodium bicarbonate (1.2 mmoL), the mixture was agitated underice bath for 15 min. Then chloroacetyl chloride (1.5 mmoL) was addeddropwise to the mixture. The reaction solution was transferred to room temperature and stirred for 2 h. After the end of reaction, the solutionwas diluted with chloroform (15 mL) and washed by water (2 × 20 mL),×and then sodium sulfate was added to dehydrate. The solvent wasevaporated under a vacuum to obtain the crude product 2a to 25a,which were used for subsequent reaction without purification.
1 Example 1: Synthesis of dimethyl 5-aminoisophthalate (compound 4A)
Weigh 5-aminoisophthalic acid (15.00g, 82.64mmol) in the reaction flask, add 75mL methanol to dissolve, slowly add thionyl chloride (24.57g, 206.61mmol) dropwise to the system under stirring, after adding the system The temperature was raised to 65 °C and the reaction was refluxed for 7 h until the conversion of the raw materials was complete.The reaction solution was cooled to room temperature, 500 mL of water was added and stirred to dissolve, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. A large amount of solids were precipitated in the system. Dry in an oven to obtain compound 4A, 15.76 g of white solid, yield: 91%,
With oxone; In dichloromethane; water; for 6.0h;Inert atmosphere;
The method was adapted from that of Priewisch and Ruck-Braun.[47] 1,3-Dimethyl-5-aminoisophthalate (2.1 g, 10 mmol) was dissolved in dichloromethane (80 mL). To this solution was added Oxone (12 g, 20 mmol) dissolved in water (250 mL). The two-phase mixture was stirred vigorously for 6 h under N2. The organic layer was removed and the aqueous layer was washed with dichloromethane (350 mL). The combined organic layers were washed with HCl (1 M, 200 mL), saturated aqueous NaHCO3 solution (200 mL), H2O (200 mL) and brine (200 mL),and dried over MgSO4. The solvent was removed by rotary evaporation, giving an impure yellow product.
dimethyl 5-(2-((2-oxo-2-phenyl-1λ2-ethyl)amino)acetamido)isophthalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;
41; 19.1 Step 1. Preparation of Dimethyl 5-(2-((2-oxo-2-phenyl-l 2- ethyl)amino)acetamido)isophthalate 105
A solution of dimethyl 5-aminoisophthalate (5 g, 24 mmol), Z-Gly-OH (5 g, 24 mmol), EDC (5 g, 26.3 mmol), HOBt (3.6 g, 26.3 mmol), NMM (2.9 mL, 26.3 mmol) in DMF (50 mL) was stirred overnight at room temperature. Upon completion, the reaction mixture was diluted with ethyl acetate (250 mL) and washed with each 1M HC1 (2 x 100 mL), saturated sodium bicarbonate (1 x 100 mL) and brine (2 x 100 mL). Dry on magnesium sulfate, filter and concentrate to dryness to afford Dimethyl 5-(2-((2-oxo-2-phenyl- - ethyl)amino)acetamido)isophthalate as a colorless solid (7.2 g, 79%).
79%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;
19.1 Step 1. Preparation of Dimethyl 5-(2-((2-oxo-2-phenyl-l 2-ethyl)amino)acetamido)- isophthalate 105
A solution of dimethyl 5-aminoisophthalate (5 g, 24 mmol), Z-Gly-OH (5 g, 24 mmol), EDC (5 g, 26.3 mmol), HOBt (3.6 g, 26.3 mmol), MM (2.9 mL, 26.3 mmol) in DMF (50 mL) was stirred overnight at room temperature. Upon completion, the reaction mixture was diluted with ethyl acetate (250 mL) and washed with each 1M HC1 (2 x 100 mL), saturated sodium bicarbonate (1 x 100 mL) and brine (2 x 100 mL). Dry on magnesium sulfate, filter and concentrate to dryness to afford Dimethyl 5-(2-((2-oxo-2-phenyl-l 2- ethyl)amino)acetamido)isophthalate as a colorless solid (7.2 g, 79%).
79%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;
19.1; 19a.1; 53.1; 59.1 Example 19Step 1. Preparation of Dimethyl 5-(2-((2-oxo-2-phenyl-l 2- ethyl)amino)acetamido)isophthalate 105
A solution of dimethyl 5-aminoisophthalate (5 g, 24 mmol), Z-Gly-OH (5 g, 24 mmol), EDC (5 g, 26.3 mmol), HOBt (3.6 g, 26.3 mmol), NMM (2.9 mL, 26.3 mmol) in DMF (50 mL) was stirred overnight at room temperature. Upon completion, the reaction mixture was diluted with ethyl acetate (250 mL) and washed with each 1M HC1 (2 x 100 mL), saturated sodium bicarbonate (1 x 100 mL) and brine (2 x 100 mL). Dry on magnesium sulfate, filter and concentrate to dryness to afford Dimethyl 5-(2-((2-oxo-2-phenyl- 2- ethyl)amino)acetamido)isophthalate as a colorless solid (7.2 g, 79%).
79%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;
19.1; 19a.1; 25.1; 26.1 Step 1. Preparation of Dimethyl 5-(2-((2-oxo-2-phenyl-1l2-ethyl)amino)acetamido)- isophthalate 105
A solution of dimethyl 5-aminoisophthalate (5 g, 24 mmol), Z-Gly-OH (5 g, 24 mmol), EDC (5 g, 26.3 mmol), HOBt (3.6 g, 26.3 mmol), NMM (2.9 mL, 26.3 mmol) in DMF (50 mL) was stirred overnight at room temperature. Upon completion, the reaction mixture was diluted with ethyl acetate (250 mL) and washed with each 1M HCl (2 x 100 mL), saturated sodium bicarbonate (1 x 100 mL) and brine (2 x 100 mL). Dry on magnesium sulfate, filter and concentrate to dryness to afford Dimethyl 5-(2-((2-oxo-2-phenyl-1l2- ethyl)amino)acetamido)isophthalate as a colorless solid (7.2 g, 79%).
In 1-methyl-pyrrolidin-2-one; toluene; at 75 - 180℃;Inert atmosphere;
In a nitrogen protection device,Magnetic stirring,And equipped with a spherical condenser trap 250mL three-necked flask,Add 10 g of dimethyl 5-aminoisophthalate and 80 mL of NMP.Under nitrogen protection,Stirred for 30min to obtain a homogeneous solution,Then, 11.9 g of 4-phenylacetylene phthalic anhydride was added,The solution was heated to 75 ° C,Keep 2h;Then 20g of toluene was added,The reaction was gradually warmed to 180 ° C,The generated water is taken out by the water trap;After 6-8h reaction,Cooled to 120 ° C,The mixed solution was poured into excess deionized water,A yellow-green solid was obtained,Suction filtration,Washed and dried.Thus, dimethyl 5- (4-phenylethynylidene) -1,3-dibenzoate was obtained.
hexamethyl 5,5',5"-[benzene-1,3,5-triyltris(azanediyl)]triisophthalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With water; palladium diacetate; potassium carbonate; tert-butyl XPhos In <i>tert</i>-butyl alcohol at 110℃; for 24h; Schlenk technique; Inert atmosphere;
5 2.2. General Pd-catalyzed amination
General procedure: The reported percentages molar ratios are referred to the electrophile. An oven-dried Schlenk tube was charged with Pd(OAc)2 (0.5mol%), phosphine (1.5mol%), tert-butanol. The vessel was evacuated and backfilled with nitrogen 3 times. Water (4.0mol%) was added with Hamilton syringe then the mixture was heated at 110°C for 1min. Aryl halide, K2CO3 (2.4 equivalents) and amine (2.8 equivalents) were added to a second oven-dried Schlenk tube. The catalyst solution was cannulated into the second Schlenk and the reaction mixture was stirred at 110°C overnight. The product was isolated by simple addition of water and centrifugation. 2.2.5 Hexamethyl 5,5',5"-[benzene-1,3,5-triyltris(azanediyl)]triisophthalate (5a) A mixture of 1,3,5-tribromobenzene (120 mg, 0.38 mmol), dimethyl 5-aminoisophthalate (287 mg, 1.37 mmol, 3.6 equivalents), K2CO3 (220 mg, 1.59 mmol, 4.2 equivalents), Pd(OAc)2 (2.5 mg, 3.0 mol%), tBuxPhos (14.5 mg, 9.0 mol%), H2O (1.6 μL, 24 mol%), tert-butanol (3 + 5 mL). After 24 h water (10 mL) was added to the reaction mixture and 5a was isolated as brownish solid in high purity (250 mg, 0.36 mmol, 94%). 1H NMR (400 MHz, DMSO-d6, 25 °C): δ 8.71 (bs, NH, 3H), 7.92 (pt, CHAr, J = 1.4 Hz, 3H), 7.89 (pd, CHAr, J = 1.4 Hz, 6H), 6.53 (s, CHAr, 3H), 3.85 (s, OCH3, 18H). MS (DEP/EI ((+)) Calculated for [M]+ [C36H33N3O12]+: m/z 699.21, found m/z = 699.3. Elemental analysis: calcd (%) for (C36H33N3O12): C 61.80; H 4.75; N 6.01; O 27.44. Found (%): C 61.91; H 4.66; N 5.93; O 27.37.
Stage #1: dimethyl 5-aminoisophthalate With methanol; water; sodium hydroxide at 20℃;
Stage #2: di-<i>tert</i>-butyl dicarbonate In 1,4-dioxane at 20℃;
5.1 Procedure 1: dimethyl 5-azidoisophthalate (2)
To a stirring solution of compound (1) (2.00 g, 8.43 mmol) in water (14.0 mL) at 0 °C was added aqueous HCl (2.0 M; 21.1 mL, 42.2 mmol) followed by a solution of sodium nitrite (1.16 g, 16.9 mmol) in water (6.0 mL). The resulting mixture was stirred at 0 °C for 15 min. To this mixture was added a solution of sodium azide (1.10 g, 16.9 mmol) in water (10 mL) dropwise. After addition was complete, stirring was continued at 0 °C for a further 30 min. The resulting solid precipitate was filtered and washed with water (2 x 5 mL) and then air dried to afford compound (2) (2.20 g, 99%) was as a white solid.1H NMR (300 MHz, DMSO-d6) δ ppm: 8.24 (t, J = 1.5 Hz, 1H), 7.82 (d, J= 1.5 Hz, 2H), 3.91 (s, 6H).
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