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CAS No. : | 6968-28-1 | MDL No. : | MFCD00043538 |
Formula : | C8H5BrO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AZXKGUVDIORSED-UHFFFAOYSA-N |
M.W : | 245.03 | Pubchem ID : | 81428 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | at 140℃; for 2 h; | A solution of 4-bromophthalic acid (5 g, 0.02 mol) and acetic anhydride (30 mL) was heated for 2 h at 140 °C. The reaction mixture was cooled to room temperature and the excess of acetic anhydride was removed under reduced pressure. The residue was washed with petroleum ether and then 4-bromophthalic anhydride was obtained as white solid. Yield: 3.8 g, 84percent, mp: 104-106 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With borane-THF In tetrahydrofuran at 0 - 20℃; for 3 h; | To a solution of 4-bromophthalic acid (3.0 g, 12.24 [MMOL)] in 30 mL of THF was added a solution of borane-THF complex (1. OM) dropwise at 0 [°C.] The solution was warmed to rt and stirred for 3 h. The reaction mixture was quenched by addition of HCI (2N) at 0 [°C.] The product was extracted with ethyl acetate and washed with sat. [NACI,] dried over [NA2SC4,] and concentrated under reduced pressure to afford 2.8 g (100percent) of 4-bromo-2- hydroxymethylbenzyl alcohol as a [COLORLESS OIL.APOS;H] NMR [(CDCK)] 7.28 (m, 2 H), 7.26 (m, 1 H), 4.69 (s, 4 H), 2.80 (bs, [2 H).] To a solution of oxalyl chloride (2.37 mL, 4.607 mmol) in DCM (20 mL) was added dropwise DMSO (1.95 mL) [AT-78 °C.] The mixture was stirred at-78 °C for 30 min and a solution of the diol (1.00 g, 4.607 [MMOL)] was added dropwise. The reaction mixture was stirred for 2 hr and TEA (11.5 mL) was added. The reaction mixture was warmed to rt and water was added. The organic layer was separated and washed with sat. NaCl, dried over Na2SO4, and concentrated under reduced pressure to give [4-BROMO-BENZENE-1,] 2- dicarbaldehyde as a yellow oil (0.450 g, 46percent). A mixture of [4-BROMO-BENZENE-1,] [2-DICARBALDEHYDE] (0.450 g, 2.137 mmol), diethylamino malonate (0.452 g, 2.137 mmol), and sodium ethoxide (0.218 g, 3.20 [MMOL)] in anhydrous ethanol (15 mL) was refluxed for 4 hr. The solution was cooled to rt and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 0. 5percent MeOH in [CHCI3)] to obtain 0.460 g (78percent) of the [7-BROMO-] isoquinoline-3-carboxylic acid ethyl ester which was [HYDROLYZED] according to general procedure C yielding the 0.350 g (85percent) of 7-bromo-isoquinoline-3-carboxylic acid as a white solid. LC/MS [(M/Z)] : 253 (M+1) [+.] [(2S)-AMINO-3-BIPHENYL-4YL-PROPIONIC] acid methyl ester (340 mg, 13.9 [MMOL)] was reacted with 7-bromo-isoquinoline-3-carboxylic acid (350 mg, 13.9 [MMOL)] as described in general procedure A. The resulting compound was hydrolyzed by following general procedure C yielding the title compound (132 mg, 81 percent) as a white solid |
79% | With dimethylsulfide borane complex In tetrahydrofuran at -10 - 55℃; for 15 h; Inert atmosphere | To a solution of acid or diacid (1.0 equiv) in anhydrous THF (4.3 mL per mmol of acid or diacid) at -10 °C under a nitrogen atmosphere was added dropwise a solution of BH3.DMS(1.5-3.0 equiv) in anhydrous THF (0.1 mL per mmol of acid or diacid). The reaction was maintained at -10 °C for 10 min before being heated to 55 °C for 12-16 h. After cooling to rt, an aqueous solution of NaOH (2 M, 4.4 mL per mmol of acid or diacid) was added dropwise and the solution was stirred at rt for 50 min. The organics were extracted with EtOAc, combined, washed with brine, driedover MgSO4 and concentrated in vacuo to afford the desired diol. |
75.9% | With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; | To a stirred solution of 4-bromophthalic acid (9.0 g, 37.55 mmol, 1 equiv) in THF (90 mL) was added drop wise BH3.DMS (35 mL, 375 mmol, 10 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for overnight. The reaction mixture was cooled and quenched with MeOH slowly then evaporated to obtain crude product which was purified by silica gel flash column chromatography. The compound eluted out in 1 .5percent MeOH:DCM. The fractions with product were evaporated to obtain (4-bromo-1 ,2- phenylene)dimethanol as white solid (6.0 g, 75.9percent). (0710) 1H NMR (400 MHz, DMSO-de) δ ppm 4.45 (d, J=5.2 Hz, 2H), 4.51 (d, J=5.2 Hz, 2H), 5.12 (t, J=5.6 Hz, 1 H), 5.20 (t, J=1 1 .4 Hz, 1 H), 7.31 (d, J=8.0 Hz, 1 H), 7.40 (t, J=8.0 Hz, 1 H), 7.54 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bromine; sodium hydroxide In water for 72h; Reflux; | 4-Bromophthalic acid (18) The procedure was modified according to ref 14._ENREF_11 Phthalic anhydride (19.2 g, 6.2 mL, 0.12 mol) was added to a solution of NaOH (4.8 g, 0.12 mol) in water (20 mL). After complete dissolving, bromine was added. The reaction mixture was heated to reflux for 72 h. Then a saturated Na2S2O3 solution (100 mL) was added, the aqueous solution was acidified with conc. HCl (6 mL), and extracted with ethyl acetate (3 x 100 mL). The organic layer was concentrated in vacuo to give the acid 18. Colorless solid, mp 198 °C, yield 14.2 g (95%). C8H5BrO4, Mr = 245.0. 1H NMR (CDCl3): δ [ppm] = 7.62 (d, J = 8.3 Hz, 1H, 5-H), 7.67 (dd, J = 8.3/1.9 Hz, 1H, 6-H), 7.83 (d, J = 1.9 Hz, 1H, 3-H). A signal for COOH protons is not seen in the spectrum. IR (neat): [cm-1] = 2951 (OH), 1697 (C=O). |
70.9% | Stage #1: phthalic anhydride With sodium hydroxide In water at 40 - 95℃; for 1h; Stage #2: With bromine In water at 40 - 95℃; | 1; a Example one Phthalic anhydride (100 g, 674 mmol), sodium hydroxide (61.6 g, 1482 mmol, 96%) was added to water (300 mL)Heated to 40 ° C, the reaction was stirred for 1h; then slowly drop the liquid bromine at 40 ° C, dropping slowly warming to 80-85 ° C.Stirring at 80-85 ° C for 30min, continuing to heat to 90-95 ° C,Stir the reaction 10-15h, brown fade, TLC test confirmed the reaction was complete,Cool to below 10 , keep 1h, suction filtered, rinsed with ice water (200ml), rinsed to a solid white without yellow or brown.The white solid was transferred to a three-necked flask and 180 g of water was added. The mixture was stirred and heated to reflux. The mixture was incubated for 2 hours to dissolve the mixture, and the pH was adjusted to 3.Hydrochloric acid (19ml) was added, adjusted to pH = 1, extracted with ethyl acetate (200mL * 2) and the ethyl acetate layer was washed with 25% sodium chloride solution (200mL).The solvent was distilled off under reduced pressure,After drying, white 5-bromophthalic acid (117.3 g, yield 70.9%) was obtained. |
68% | Stage #1: phthalic anhydride With bromine; sodium hydroxide In water at 90℃; for 7h; Stage #2: With hydrogenchloride In water |
68% | Stage #1: phthalic anhydride With sodium hydroxide In water Stage #2: With bromine In water at 90℃; for 7h; Stage #3: With hydrogenchloride In water | 5 General procedure for the preparation of 4a, 4b, 4d and 4f To sodium hydroxide (2.4 g, 0.06 mol) dissolved in water (20 mL) was added phthalic anhydride (4.44 g, 0.03 mol). When complete solution was obtained, bromine (9.4 g, 3 mL, 0.06 mol) was incrementally added, while stirring, over 1 h. The reaction mixture was heated to 90 °C and allowed to react under reflux for 6 h. After standing for 10 h, the white solids that crystallized out of solution were filtered, washed with cold water, and analyzed as monosodium 4-bromophthalic acid salt. The total product was dissolved in hot water, and the pH was adjusted to about 1.5 by addition of concentrated hydrochloric acid. The resulting solution was evaporated to dryness on a rotary evaporator and extracted with acetone to give 4-bromophthalic acid. Yield: 5.0 g, 68%, mp: 164-166 °C. |
With sodium hydroxide; bromine | ||
Stage #1: phthalic anhydride With sodium hydroxide In water Stage #2: With bromine In water at 20 - 90℃; Stage #3: With hydrogenchloride In water | ||
Multi-step reaction with 2 steps 1: sodium hydroxide; bromine / water / 7 h / 90 °C 2: hydrogenchloride / water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sulfuric acid at 79℃; for 0.5h; Microwave radiation; | 8.1 1.0 ml of concentrated sulphuric acid is added to a solution of 1.0 g of 4-bromophthalic acid in 20 ml of ethanol. The reaction medium is irradiated at 79° C. with microwave radiation (power 50 W) for 30 minutes. The reaction medium is concentrated under reduced pressure and extracted with ethyl acetate. The solution is washed with water and dried over sodium sulphate, then filtered to produce, after concentrating under reduced pressure, 1.08 g of the expected product. Yield: 88% |
79% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine at 20℃; | |
67% | With sulfuric acid for 53h; Reflux; | 1 Synthesis of diethyl 4-bromophthalate (1) A solution of 4-bromophtalic acid (2.55 g, 10.4 mmol) and sulphuric acid (0.4 ml) in dry EtOH (70ml) was refluxed 53 hours. The reaction mixture was diluted with CH2CI2 (100 ml), neutralized with 5 % aq. NaHCO3 (30 ml), washed with H2O (40 ml) and dried with Na2SO4. The product was purified by FC (silica gel, CH2CI2). Yield: 2.1 1 g (67 %). 1H NMR (CDCI3): δ (ppm) 7.82 (d, J=1 .9 Hz, 1 H), 7.66 (dd, J=1 .9 Hz, J=8.3 Hz, 1 H), 7.62 (d, J=8.3 Hz, 1 H), 4.37 (q, J=7.1 Hz, 4H), 1 .37 (t, J=7.1 Hz, 6H) 13C NMR (CDCI3): δ (ppm) 167.00, 166.77, 134.71 , 134.25, 132.16, 131 .02, 130.95, 125.97, 62.42, 62.25, 14.47. Maldi-TOF MS for Ci2Hi3BrO4: calculated 300.00 and 302.00, found 300.94 and 302.94 (M + 1 ). |
With hydrogenchloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With acetic anhydride; at 140℃; for 2h; | A solution of 4-bromophthalic acid (5 g, 0.02 mol) and acetic anhydride (30 mL) was heated for 2 h at 140 C. The reaction mixture was cooled to room temperature and the excess of acetic anhydride was removed under reduced pressure. The residue was washed with petroleum ether and then 4-bromophthalic anhydride was obtained as white solid. Yield: 3.8 g, 84%, mp: 104-106 C. |
In acetic anhydride; at 130 - 135℃; for 2h; | 5-Bromophthalic acid (116 g, 473 mmol) was added to acetic anhydride (300 mL), heated to 130-135 C and reacted under reflux for 2 h.The resulting oily substance was evaporated to dryness under reduced pressure and the temperature was slowly lowered to 20 C to precipitate a yellow solid. Stirring was continued for 30 min at 20 C, suction filtered and rinsed with n-heptane (120 mL)Compaction, pumping to no droplets.Solid 5-bromophthalic anhydride was transferred to a flask,Under mechanical stirring, urea (49.8 g, 826 mmol) was added and the mixture was heated to 110-120 C and stirred for 6 h.Cooled to 70 , add 95% ethanol (1000ml), heated to 75-85 , stirred for 2h, slowly cooled to 30 , stirred for 1h, and then slowly cooled to 0-5 for 1h,Filtered by suction, rinsed with ice-ethanol (120 ml) and dried in vacuo at 70 C gave a pale yellow 5-bromophthalimide (65.6 g, 61.3% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide | ||
With ethanol; barium(II) oxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium hydroxide; potassium permanganate In water for 7h; | |
48% | With potassium permanganate In water at 20℃; for 12h; Sonication; | |
With potassium permanganate |
With potassium permanganate; Aliquat 336; sodium carbonate for 0.75h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium bromate; sulfuric acid In water at 90℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With acetic anhydride; triethylamine In acetonitrile Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With acetic anhydride; triethylamine In acetonitrile Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-bromophthalic acid; Wang resin With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 24h; Stage #2: 3-Phenylpropan-1-amine With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 18h; Stage #3: In N,N-dimethyl-formamide for 0.333333h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With ammonium thiocyanate at 160℃; for 0.166667h; | |
Multi-step reaction with 2 steps 1: acetic anhydride / 2 h / 140 °C 2: urea / 2 h / 160 °C | ||
Multi-step reaction with 2 steps 1: acetic anhydride / 2 h / 130 - 135 °C 2: urea / ethanol / 10 h / 0 - 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With bromine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 67 percent / NiCl2 / 1 h / 160 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 68 percent / NiCl2 / 160 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 60 percent / NiCl2 / 0.5 h / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 67 percent / NiCl2 / 1 h / 160 °C 5: 35 percent / DBU / 20 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 67 percent / NiCl2 / 1 h / 160 °C 5: 63 percent / DBU / 20 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 68 percent / NiCl2 / 160 °C 5: 28 percent / DBU / ethanol / 50 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 60 percent / NiCl2 / 0.5 h / 150 °C 5: 36 percent / DBU / ethanol / 20 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 67 percent / NiCl2 / 1 h / 160 °C 5: 34 percent / CuCl2; DBU / ethanol / 40 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 67 percent / NiCl2 / 1 h / 160 °C 5: 35 percent / ZnCl2; DBU / ethanol / 40 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 68 percent / NiCl2 / 160 °C 5: 53 percent / ZnCl2; DBU / ethanol / 20 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 68 percent / NiCl2 / 160 °C 5: 48 percent / CuCl2; DBU / ethanol / 20 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 60 percent / NiCl2 / 0.5 h / 150 °C 5: 48 percent / CuCl2; DBU / ethanol / 40 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / NH4SCN / 0.17 h / 160 °C 2: 83 percent / aq. NH3 / 20 h / 20 °C 3: 63 percent / COCl2 / dimethylformamide / 20 - 70 °C 4: 60 percent / NiCl2 / 0.5 h / 150 °C 5: 33 percent / ZnCl2; DBU / ethanol / 40 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: Ac2O / 4 h / Heating 2: AlCl3 / 48 h / Heating 3: polyphosphoric acid / 2 h / 130 - 140 °C 4: n-BuLi / tetrahydrofuran / 20 h / 20 - 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: Ac2O / 4 h / Heating 2: AlCl3 / 48 h / Heating 3: polyphosphoric acid / 2 h / 130 - 140 °C 4: n-BuLi / tetrahydrofuran / 20 h / 20 - 40 °C 5: aq. Na2CO3 / Pd(PPh3)4 / toluene; methanol / 24 h / Heating 6: TBAF / tetrahydrofuran / 1 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: Ac2O / 4 h / Heating 2: AlCl3 / 48 h / Heating 3: polyphosphoric acid / 2 h / 130 - 140 °C 4: n-BuLi / tetrahydrofuran / 20 h / 20 - 40 °C 5: aq. Na2CO3 / Pd(PPh3)4 / toluene; methanol / 24 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: AlBr3 / CS2 2: PBr5 3: aq. KMnO4, Py |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 3h; | To a solution of 4-bromophthalic acid (3.0 g, 12.24 [MMOL)] in 30 mL of THF was added a solution of borane-THF complex (1. OM) dropwise at 0 [C.] The solution was warmed to rt and stirred for 3 h. The reaction mixture was quenched by addition of HCI (2N) at 0 [C.] The product was extracted with ethyl acetate and washed with sat. [NACI,] dried over [NA2SC4,] and concentrated under reduced pressure to afford 2.8 g (100%) of 4-bromo-2- hydroxymethylbenzyl alcohol as a [COLORLESS OIL.'H] NMR [(CDCK)] 7.28 (m, 2 H), 7.26 (m, 1 H), 4.69 (s, 4 H), 2.80 (bs, [2 H).] To a solution of oxalyl chloride (2.37 mL, 4.607 mmol) in DCM (20 mL) was added dropwise DMSO (1.95 mL) [AT-78 C.] The mixture was stirred at-78 C for 30 min and a solution of the diol (1.00 g, 4.607 [MMOL)] was added dropwise. The reaction mixture was stirred for 2 hr and TEA (11.5 mL) was added. The reaction mixture was warmed to rt and water was added. The organic layer was separated and washed with sat. NaCl, dried over Na2SO4, and concentrated under reduced pressure to give [4-BROMO-BENZENE-1,] 2- dicarbaldehyde as a yellow oil (0.450 g, 46%). A mixture of [4-BROMO-BENZENE-1,] [2-DICARBALDEHYDE] (0.450 g, 2.137 mmol), diethylamino malonate (0.452 g, 2.137 mmol), and sodium ethoxide (0.218 g, 3.20 [MMOL)] in anhydrous ethanol (15 mL) was refluxed for 4 hr. The solution was cooled to rt and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 0. 5% MeOH in [CHCI3)] to obtain 0.460 g (78%) of the [7-BROMO-] isoquinoline-3-carboxylic acid ethyl ester which was [HYDROLYZED] according to general procedure C yielding the 0.350 g (85%) of 7-bromo-isoquinoline-3-carboxylic acid as a white solid. LC/MS [(M/Z)] : 253 (M+1) [+.] [(2S)-AMINO-3-BIPHENYL-4YL-PROPIONIC] acid methyl ester (340 mg, 13.9 [MMOL)] was reacted with 7-bromo-isoquinoline-3-carboxylic acid (350 mg, 13.9 [MMOL)] as described in general procedure A. The resulting compound was hydrolyzed by following general procedure C yielding the title compound (132 mg, 81 %) as a white solid |
79% | With dimethylsulfide borane complex; In tetrahydrofuran; at -10 - 55℃; for 15h;Inert atmosphere; | To a solution of acid or diacid (1.0 equiv) in anhydrous THF (4.3 mL per mmol of acid or diacid) at -10 C under a nitrogen atmosphere was added dropwise a solution of BH3.DMS(1.5-3.0 equiv) in anhydrous THF (0.1 mL per mmol of acid or diacid). The reaction was maintained at -10 C for 10 min before being heated to 55 C for 12-16 h. After cooling to rt, an aqueous solution of NaOH (2 M, 4.4 mL per mmol of acid or diacid) was added dropwise and the solution was stirred at rt for 50 min. The organics were extracted with EtOAc, combined, washed with brine, driedover MgSO4 and concentrated in vacuo to afford the desired diol. |
75.9% | With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; | To a stirred solution of 4-bromophthalic acid (9.0 g, 37.55 mmol, 1 equiv) in THF (90 mL) was added drop wise BH3.DMS (35 mL, 375 mmol, 10 equiv) at 0C. The reaction mixture was warmed to room temperature and stirred for overnight. The reaction mixture was cooled and quenched with MeOH slowly then evaporated to obtain crude product which was purified by silica gel flash column chromatography. The compound eluted out in 1 .5% MeOH:DCM. The fractions with product were evaporated to obtain (4-bromo-1 ,2- phenylene)dimethanol as white solid (6.0 g, 75.9%). (0710) 1H NMR (400 MHz, DMSO-de) delta ppm 4.45 (d, J=5.2 Hz, 2H), 4.51 (d, J=5.2 Hz, 2H), 5.12 (t, J=5.6 Hz, 1 H), 5.20 (t, J=1 1 .4 Hz, 1 H), 7.31 (d, J=8.0 Hz, 1 H), 7.40 (t, J=8.0 Hz, 1 H), 7.54 (s, 1 H). |
To a solution of 3 g (12.2 mmol) 4-bromo-phthalic acid in 24 mL of 1,2-dimethoxyethane, at 0 C. 1.394 g (36.8 mmol) of sodium borohydride are added in 10 portions. After stirring for 15 min, a solution of 4.61 mL (36.5 mmol) boron trifluoride etherate in 8 mL of 1,2-dimethoxyethane is added within 10 min. After stirring for 10 min at 0 C., the mixture is allowed to warm up to RT and stirring is continued for 2 h. The reaction mixture is then slowly added onto 40 g of crushed ice and the aqueous mixture is evaporated with ethyl acetate. The combined ethyl acetate extracts are washed with water and brine, dried with sodium sulfate and evaporated. The residual yellow oil (crude material) is purified by chromatography using a 120 g silica gel column on a Combi-Flash Companion (Isco Inc.) chromatography apparatus. A gradient of dichloromethane/ethyl acetate 0->50% ethyl acetate is used. The title compound is obtained as an oil which crystallizes on standing: m.p. 79-81 C., HPLC tR=1.94 min, MS-ES+: (M+H)+=214+216. | ||
To a solution of 3 g (12.2 mmol) 4-bromo-phthalic acid in 24 mL of 1,2- dimethoxyethane, at 0 0C 1.394 g (36.8 mmol) of sodium borohydride are added in 10 portions. After stirring for 15 min, a solution of 4.61 mL (36.5 mmol) boron trifluoride etherate in 8 mL of 1,2-dimethoxyethane is added within 10 min. After stirring for 10 min at 0 0C, the mixture is allowed to warm up to RT and stirring is continued for 2 h. The reaction mixture is then slowly added onto 40 g of crushed ice and the aqueous mixture is evaporated with ethyl acetate. The combined ethyl acetate axtracts are washed with water and brine, dried with sodium sulfate and evaporated. The residual yellow oil (crude material) is purified by chromatography using a 120 g silica gel column on a Combi-Flash Companion (Isco Inc.) chromatography apparatus. A gradient of dichloromethane/ethyl acetate 0 -> 50 % ethyl acetate is used. The title compound is obtained as an oil which crystallizes on standing: m.p. 79- 81 0C, HPLC tR = 1.94 min, MS-ES+: (M+H)+ = 214 + 216. | ||
Reference Example 22 1,2-Bis(hydroxymethyl)-4-bromobenzene To THF solution (40 mL) comprising 4-bromophtahalic acid (1.0 g, product of Tokyo Chemical Industry, Co., Ltd.), borane-dimethylsulfide (2.0 M THF solution, product of Aldrich Company, 5.1 mL), was added at room temperature, followed by refluxing under heating for 16 hours. Methanol was added to the reaction solution, and liquid separation was carried out by using saturated sodium bicarbonate solution and saturated brine in order. Then, the aqueous layer was extracted with ethyl acetate and the collected organic layer was dried over sodium sulfate. Thus solids were removed by filtration, the filtrate was dried under reduced pressure and obtained residues were subjected to flash column chromatography (using 4/1 to 0/1 (v:v) hexane/ethyl acetate as an eluent) to obtain the title compound (784 mg). MASS: 214.8 (M-H), RT 1.07 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | EXAMPLE 25 5-Bromo-1,1,3,3-tetramethyl-1,3-dihydroisobenxofuran A solution of 5.0 g of 4-bromophthalic acid dissolved in 200 ml of absolute methyl alcohol is saturated with dry hydrogen chloride gas and allowed to stir at room temperature for 20 hours. The reaction mixture is evaporated in vacuo, kept under high vacuum overnight to give 5.13 g of dimethyl-4-bromophthalate as a pale yellow oil. 1 H-NMR (CDCl3): delta 3.90 (s, 3H); 3.92 (s, 3H); 7.62 (d, J=8.3 Hz, 1H); 7.67 (dd, J=8.3 Hz, 1.8 Hz, 1H); 7.84 (d, J=1.8 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In ethanol; water for 3h; Heating / reflux; | 20.1 EXAMPLE 20; 2-f2-r2-(4-Methylpiperazin-1-yl)phenvnethyl>-5-phenylisoindole-1,3-dione;. Step 1 : 4-Bromo-phthalic acid (1.00 g, 4.08 mmol), phenylboronic acid (0.52 g, 4.26 mmol), tetrakis(triphenylphosphine)palladium (0) and K2CO3 in EtOH/ water (40 mL/4 ml.) were refluxed for 3 hrs then concentrated. The residue was dissolved in water and washed with EtOAc (2x50 mL). The aqueous phase was acidified with 1 N HCI and extracted with EtOAC (2x200 mL). The extracts were washed with water and brine, dried (MgSO4) and concentrated to a sticky white solid (1.17g) which was shown by NMR to be a mixture of mono esterified regioisomers, biphenyl-3,4-dicarboxylic acid 3-ethyl ester and biphenyl-3,4- dicarboxylic acid 4-ethyl ester (MS-AP/CI - 271 , MH+). These were used as a mixture without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | With tetrabutylammomium bromide; trisodium tris(3-sulfophenyl)phosphine; palladium diacetate; potassium carbonate In water for 0.5h; Inert atmosphere; Microwave irradiation; | |
79.8% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triphenylphosphine In tetrahydrofuran for 12h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: toluene / 24 h / 140 °C 2: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: borane-THF / -78 - 20 °C 1.2: Reflux 2.1: borane-THF / -78 - 20 °C 3.1: sodium cyanoborohydride / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: borane-THF / -78 - 20 °C 1.2: Reflux 2.1: borane-THF / -78 - 20 °C 3.1: sodium cyanoborohydride / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: sulfuric acid / dichloromethane / -70 - 20 °C / High pressure 2: triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / toluene / 80 °C / Inert atmosphere 3: diethylamino-sulfur trifluoride / dichloromethane / 0 - 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h 5: hydrogen; palladium 10% on activated carbon / ethanol / 4 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sulfuric acid / dichloromethane / -70 - 20 °C / High pressure 2: triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / toluene / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sulfuric acid / dichloromethane / -70 - 20 °C / High pressure 2: triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / toluene / 80 °C / Inert atmosphere 3: diethylamino-sulfur trifluoride / dichloromethane / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: sulfuric acid / dichloromethane / -70 - 20 °C / High pressure 2: triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / toluene / 80 °C / Inert atmosphere 3: diethylamino-sulfur trifluoride / dichloromethane / 0 - 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: sulfuric acid / dichloromethane / -70 - 20 °C / High pressure 2: triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / toluene / 80 °C / Inert atmosphere 3: diethylamino-sulfur trifluoride / dichloromethane / 0 - 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h 5: palladium 10% on activated carbon; tritium / ethanol / 4 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid In dichloromethane at -70 - 20℃; High pressure; | 4.a Synthesis of 1,2-Di-tert-butyl 4-bromobenzene-l,2-dicarboxylate (UB-12f555) 5g (20.4mmol, lequiv.) of 4-bromophthalic acid and 50 ml of dry DCM were added into a high pressure reactor. Concentrated sulfuric acid (0.5ml) was added, and the mixture was cooled to -70°C. 30 ml of isobutylene was condensed and added to the mixture in one portion. The reaction mixture was stirred in a closed reactor, at room temperature overnight. The reaction was then assessed by TLC, which showed complete consumption of starting material. The reactor was opened, and the mixture was stirred to release residual isobutylene. To the mixture 60 ml of 10% NaOH solution was added and the DCM was evaporated. The residue was extracted with 2x80 ml of ethyl acetate, the combined organics were washed with brine and dried over Na2SC"4. After evaporation a yellowish brown oil was obtained. Yield: 7.3g (20.5 mmol, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: borane-THF / tetrahydrofuran / -40 - 0 °C 2.1: dmap; 1H-imidazole / dichloromethane / 20 °C 3.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 3.2: -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: borane-THF / tetrahydrofuran / -40 - 0 °C 2.1: dmap; 1H-imidazole / dichloromethane / 20 °C 3.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: tert.-butyl lithium / tetrahydrofuran; pentane / 0.25 h / -78 °C 4.2: 1.5 h / -10 °C 4.3: -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: borane-THF / tetrahydrofuran / -40 - 0 °C 2.1: dmap; 1H-imidazole / dichloromethane / 20 °C 3.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: tert.-butyl lithium / tetrahydrofuran; pentane / 0.25 h / -78 °C 4.2: 1.5 h / -10 °C 4.3: -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: borane-THF / tetrahydrofuran / -40 - 0 °C 2.1: dmap; 1H-imidazole / dichloromethane / 20 °C 3.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: tert.-butyl lithium / tetrahydrofuran; pentane / 0.25 h / -78 °C 4.2: 1.5 h / -10 °C 4.3: -78 - 20 °C 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: borane-THF / tetrahydrofuran / -40 - 0 °C 2.1: dmap; 1H-imidazole / dichloromethane / 20 °C 3.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: tert.-butyl lithium / tetrahydrofuran; pentane / 0.25 h / -78 °C 4.2: 1.5 h / -10 °C 4.3: -78 - 20 °C 5.1: resin Dowex 50WX2 / methanol / 2 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: borane-THF / tetrahydrofuran / -40 - 0 °C 2: dmap; 1H-imidazole / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sulfuric acid / 53 h / Reflux 2: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 2.5 h / 55 °C / Inert atmosphere 3: tetrabutyl ammonium fluoride / dichloromethane / 1.5 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: sulfuric acid / 53 h / Reflux 2: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 2.5 h / 55 °C / Inert atmosphere 3: tetrabutyl ammonium fluoride / dichloromethane / 1.5 h / 20 °C / Inert atmosphere 4: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 55 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: sulfuric acid / 53 h / Reflux 2: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 2.5 h / 55 °C / Inert atmosphere 3: tetrabutyl ammonium fluoride / dichloromethane / 1.5 h / 20 °C / Inert atmosphere 4: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 55 °C / Inert atmosphere 5: phosphorus tribromide / chloroform / 1.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sulfuric acid / 53 h / Reflux 2: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 2.5 h / 55 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: acetic anhydride / 2 h / 140 °C 2: urea / 2 h / 160 °C 3: copper(l) iodide; potassium carbonate / N,N-dimethyl-formamide / 6 h / 130 °C / Inert atmosphere 4: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: acetic anhydride / 2 h / 140 °C 2: urea / 2 h / 160 °C 3: copper(l) iodide; potassium carbonate / N,N-dimethyl-formamide / 6 h / 130 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: acetic anhydride / 2 h / 140 °C 2: urea / 2 h / 160 °C 3: copper(l) iodide; potassium carbonate / N,N-dimethyl-formamide / 6 h / 130 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium hypochlorite; ruthenium(III) chloride trihydrate; sulfuric acid; tetrabutylammomium bromide In water; 1,2-dichloro-ethane at 23℃; for 0.333333h; Green chemistry; | General Procedure for Oxidationof Naphthalene General procedure: In a 250-mL three necked flask equipped with pH and temperature sensor were placed 40 mL of aq. NaOCI (10 % Assay) at room temperature. The pH at the aqueous phase was brought to pH 9 ± 0.1 by addition of 20 % (v/v) H2SO4. To this aqueous NaOCl solution; mixture of naphthalene (0.81 g, 5 mmol), RuCl3*3H2O (0.0065 g,0.5 mol%), tetrabutyl ammonium bromide (0.040 g, 2.5 mol%) and 10 mL of 1,2-dichloroethane were added. Stirring was commenced with a mechanical stirrer and reaction continued at room temperature (23 ± 2 °C) duringthe period of 10-30 min. The pH was controlled during the reaction by using manual addition of 20 % of NaOH to keep the pH at 9 ± 0.1. After the hypochlorite solution was used up (reaction shows colour change from yellow to white cloudy) a few drops of hypochlorite solution were added to reoxidize the ruthenium catalyst. The phases were separated and an aqueous phase is acidified with dilute 20 % aq. H2SO4 to brought pH at 2.5-3. The acidic solution containing organic products was extracted with diethylether (30 x 3 = 90 mL); solvent evaporation resulted into crude 3-chlorophthalic acid (0.842 g, 4.2 mmol). Derivatization of phthalic acids using N, O-bis(trimethylsilyl)trifluoroacetamide with 1 % trimethylchlorosilane (BSTFA) was performed for gc analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.8 g | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; triethylamine; triphenylphosphine In 1,4-dioxane; water for 2h; Inert atmosphere; Reflux; | 3.1 3.1 4′-Benzyloxy-biphenyl-3,4-dicarboxylic acid 4′-benzyloxy-biphenyl-3,4-dicarboxylic acid is prepared from commercially available [4-(benzyloxy)phenyl]-boronic acid and 5-bromo-phthalic acid. To a solution of sodium carbonate (31.27 g, 295.1 mmol) in dist. water (135 ml) is added 1,4-dioxane (210 ml), 5-bromo-phthalic acid (14.46 g, 59.0 mmol) and [4-(benzyloxy)phenyl]-boronic acid (14.82 g, 65.0 mmol) followed by bis(triphenylphosphine)palladium(II) dichloride (0.83 g, 1.2 mmol), triphenylphosphine (0.31 g, 1.2 mmol) and triethylamine (0.12 g, 1.2 mmol) under nitrogen atmosphere. The reaction mixture is heated at reflux for 2 hs. After cooling to room temperature, 400 ml dist. water is added and the reaction mixture is neutralized with conc. HCl acid to pH1 under cooling. The precipitated crude product is filtrated, washed with dist. water, and further purified by recrystallization from acetonitrile to provide gray crystals of 4′-benzyloxy-biphenyl-3,4-dicarboxylic acid (15.8 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With copper(l) iodide; potassium carbonate; hydrazine hydrate In water at 90℃; for 9h; Further stages; | 1 4-bromophthalic acid 25.0g (0.10 mol),Potassium carbonate 29.0g (0.21 mol),Copper iodide 1.0g (0.005 mol),Water 75.6g,100% hydrazine hydrate 11.1g of (0.22 mol) was mixed,This was heated to 90 ,9 hours under heating and stirring.After cooling to room temperature,Was filtered to remove insoluble matter containing precipitated optionally copper,It was washed with water 21.2g.The pH of the resulting filtrate has become a 9.0,The desired product at this stage was completely dissolved.To the filtrate 36% hydrochloric acid 47.3g (0.47 mol) for 20 minutesOverAdditionThenPale yellow powder-like crystals precipitated,After the addition, the pH was 3.5.The precipitated crystals were collected by filtration,After washing with water 30.2g,40 ,Vacuum (1Torr)In dried for 10 hours to give 4-hydrazino phthalate 17.6 g.Purity as determined by the absolute calibration method of HPLC analysis is 96%,The yield was 84%.Reaction, even water in the solvent proceeds smoothly by this method,Acid precipitation and filtrationIs hydrazinocarboxylic aryl carboxylic acid obtained by a simple operation of,As compared to the following Comparative Examples 1 and 2 were good in results. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: chloro-trimethyl-silane; 4-bromophthalic acid In methanol at 20℃; for 12h; Cooling with ice; Stage #2: With thionyl chloride for 1.5h; Reflux; Stage #3: methyl 3-(isobutylamino)propanoate hydrochloride With pyridine In dichloromethane for 3h; Cooling with ice; Overall yield = 897 mg; | Methyl 4-bromo-2-{N-isobutyl-N-[2-(methoxylcarbonyl)ethyl]carbamoyl}benzoate (20a) and Methyl 5-bromo-2-{N-isobutyl-N-[2-(methoxylcarbonyl)ethyl]carbamoyl}benzoate (20b) 19a,b (900 mg, 3.5 mmol) was added to a vigorously stirred solution of SOCl2 (10 mL) and the mixture was heated to reflux for 1.5 h. The reflux condenser was replaced by a Liebig microdistillation apparatus to remove SOCl2. The residue was dissolved in CH2Cl2 (20 mL). Under ice cooling pyridine (823 mg, 10.4 mmol, 0.838 mL, 3 equiv.) and 6.HCl (668 mg, 4.2 mmol, 1.2 equiv.) were added. After 3 h, the mixture was concentrated in vacuo, the residue was suspended in sat. NaHCO3 and the mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo and the residue was purified by automatic fc (Biotage, Cartridge SNAP 100g, cyclohexane / ethyl acetate = 2 : 1, Rf = 0.28) to give 20a and 20b as a 1 : 1 mixture of regioisomers. Colorless oil, yield 897 mg (64%). C17H22BrNO5, Mr = 400.3. 1H NMR (CDCl3): δ [ppm] = 0.72 - 0.87 (m, 6H, NCH2CH(CH3)2), 1.80 - 1.94 (m, 1H, NCH2CH(CH3)2), 2.79 - 2.90 (m, 4H, CH2CH2CO2CH3), 3.70 - 3.73 (m, 3H, Ar-CO2CH3), 3.72 - 3.85 (m, 2H, CH2N), 3.84 - 3.87 (m, 3H, CO2CH3), 7.1 (d, J = 8.1 Hz, 0.5H, Ar-H), 7.40 (dd, J = 14.5/2.0 Hz, 0.5H, Ar-H), 7.55 - 7.58 (m, 0.5H, Ar-H), 7.68 (dd, J = 8.17/2.0 Hz, 0.5H, Ar-H), 7.87 (d, J = 8.4 Hz, 0.5H, Ar-H), 8.15 (d, J = 2.0 Hz, 0.5H, Ar-H). HPLC (method 1): tR = 20.21 min, purity 89.5%. The ratio of the regioisomers is 20a : 20b = 46 : 54. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 660 mg 2: 700 mg | Stage #1: chloro-trimethyl-silane; 4-bromophthalic acid In methanol at 20℃; for 12h; Cooling with ice; Stage #2: With thionyl chloride for 1.5h; Reflux; Stage #3: methyl 3-(isobutylamino)propanoate hydrochloride Overall yield = 897 mg; Further stages; | Methyl 8-bromo-2-isobutyl-5-hydroxy-1-oxo-2,3-dihydro-1H-2-benzazepine-4-carboxylate (21a) and Methyl 7-bromo-2-isobutyl-5-hydroxy-1-oxo-2,3-dihydro-1H-2-benzazepine-4-carboxylate (21b) Under N2 at 0 °C a dispersion of NaH (60% w/w in mineral oil, 370 mg, 15 mmol) was added slowly to a solution of 20a and 20b (2 g, 5 mmol) in THF (50 mL). After 0.5 h at rt, the mixture was heated to reflux for 1.5 h. Ater cooling down to rt, it was, concentrated in vacuo and the residue was suspended in 1 M HCl. The aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give a 1:1 mixture of the enol esters 21a and 21b. The residue was purified by automatic fc (Biotage, Cartridge SNAP 100 g, cyclohexane / ethyl acetate gradient 90 : 10 to 10 : 90) to give the enol esters 21a and 21b in pure form.21a (Rf = 0.16, cyclohexane / ethyl acetate = 4 : 1): Colorless solid, mp 98 °C, yield 660 mg (36%). C16H18BrNO4, Mr = 368.2. 1H NMR (CDCl3): δ [ppm] = 0.93 (d, J = 7.0 Hz, 6H, NCH2CH(CH3)2), 2.08 - 2.15 (m, 1H, NCH2CH(CH3)2), 3.29- 3.38 (m, 1H, NCH2CH(CH3)2), 3.42 - 3.62 (m, 1H, NCH2CH(CH3)2), 3.65 - 3.78 (m, 1H, 3-CH2), 3.91 (d, J = 2.8 Hz, 3H, CO2CH3), 4.03 - 4.17 (m, 1H, 3-CH2), 7.62 (d, J = 7.2 Hz, 1H, 6-CH), 7.92 (dd, J = 7.2/2.0 Hz, 1H, 7-CH), 8.42 (d, J = 2.0 Hz, 1H, 9-CH), 12.54 (s, 1H, OH). IR (neat): [cm-1] = 1729 (C=O), 1635 (C=O), 1611 (NC=O). 21b (Rf = 0.20, cyclohexane / ethyl acetate = 4 : 1): Colorless solid, mp 92 °C, yield 700 mg (38%). C16H18BrNO4, Mr = 368.2. 1H NMR (CDCl3): δ [ppm] = 0.92 (d, J = 7.0 Hz, 6H, NCH2CH(CH3)2), 2.10 - 2.19 (m, 1H, NCH2CH(CH3)2), 3.28 - 3.37 (m, 1H, NCH2CH(CH3)2), 3.42 - 3.62 (m, 1H, NCH2CH(CH3)2), 3.72 - 3. 80 (m, 1H, 3-CH2), 3.90 (d, J = 2.8 Hz, 3H, CO2CH3), 4.03 - 4.17 (m, 1H, 3-CH2), 7.67 (dd, J = 7.5/2.0 Hz, 1H, 7-CH), 7.74 (d, J = 2.0 Hz, 1H, 6-CH), 8.02 (d, J = 8.2 Hz, 1H, 9-CH), 12.54 (s, 1H, OH). IR (neat): [cm-1] = 1728 (C=O), 1632 (C=O), 1613 (NC=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol at 20℃; for 12h; Cooling with ice; Overall yield = 94 %; Overall yield = 13.9 g; | 4-Bromo-2-(methoxycarbonyl)benzoic acid (19a) and 5-Bromo-2-(methoxycarbonyl)benzoic acid (19a) Under ice cooling TMS-Cl (0.97 g, 8.98 mmol) was added dropwise to a vigorously stirred mixture of 18 (1.834 g, 7.49 mmol) in abs. H3COH (25 mL). The mixture was stirred for 12 h at rt. Then 1 M NaOH was added until pH 10. The mixture was extracted with CH2Cl2 (2 x 75 mL) to remove the dimethyl ester. Then the aqueous layer was acidified with 1 M HCl until pH 1 and extracted with ethyl acetate (2 x 75 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo to give the monomethyl esters 19a and 19b as a regioisomeric mixture. Pale yellow oil, yield 13.9 g (94%). C9H7BrO4, Mr = 259.1. Rf = 0.22 (CH2Cl2 : H3COH = 9 : 1). 1H NMR (CDCl3): δ [ppm] = 3.92 (s, 3 x 0.5 H, CO2CH3), 3.93 (s, 3 x 0.5 H , CO2CH3), 7.61 (d, J = 8.2 Hz, 0.5 H, 6-H), 7.69 - 7.72 (m, 0.5 H, Ar-H), 7.72 - 7.76 (m, 0.5 H, Ar-H), 7.79 - 7.81 (m, 0.5 H, Ar-H), 7.81 - 7.83 (m, 0.5 H, Ar-H), 8.03 (d, J = 2.0 Hz, 0.5 H, Ar-H). The ratio of the regioisomers is 1 : 1. A signal for COOH proton is not seen in the spectrum. IR (neat): [cm-1] = 2950 (OH), 1711 (C=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: dimethylsulfide borane complex / tetrahydrofuran / 15 h / -10 - 55 °C / Inert atmosphere 2.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 2.2: 14 h / -78 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: dimethylsulfide borane complex / tetrahydrofuran / 0 - 20 °C 2: oxalyl dichloride; dimethyl sulfoxide; triethylamine / dichloromethane / 8 h / -65 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sulfuric acid; at 95℃; | 4-bromophthalic acid (5 g, 20.4 mmol) was dissolved in methanol (100 mL) and treated with sulfuric acid (1 mL) and dimethyl sulfate (5 mL, 52.7 mmol). The mixture was heated overnight at 95 C. The methanol was removed and the residue was neutralized by the slow addition of sodium bicarbonate (50 mL, saturated aqueous). Sodium carbonate (4.5 g) was added and the mixture was extracted with ethyl acetate (3 x), the combine solution was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate 0 - 50% in hexane) to afford pure dimethyl 4-bromophthalate (5.5 g, 99% yield). |
With sulfuric acid; In N,N-dimethyl-formamide; at 70℃; for 24h; | Add 6g to 80mL methanol4-bromophthalic acid (0.024 mol),Slowly add 6 mL of concentrated sulfuric acid with stirring.It was refluxed at 70 C for 24 hours, cooled to room temperature, and dried.The resulting solid was dissolved in ethyl acetate and then aqueous sodium hydrogen carbonate (5%)Wash to neutral, dry anhydrous sodium sulfate, filter, spin dry,A white solid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / toluene / 1 h / 80 °C / Inert atmosphere 1.2: 1.5 h / 145 °C / Inert atmosphere 2.1: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate / toluene; methanol; water / 24 h / Inert atmosphere 3.1: palladium diacetate; silver trifluoroacetate; acetic acid; glycine / water / 36 h / 100 °C / Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / toluene / 1 h / 80 °C / Inert atmosphere 1.2: 1.5 h / 145 °C / Inert atmosphere 2.1: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate / toluene; methanol; water / 24 h / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 4-bromophthalic acid With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 80℃; for 1h; Inert atmosphere; Stage #2: 1-hexylheptylamine With acetic acid at 145℃; for 1.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sulfuric acid / toluene / 2 h / Dean-Stark; Reflux 2: palladium diacetate; triphenylphosphine; potassium acetate / tetrahydrofuran / 12 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sulfuric acid In toluene for 2h; Dean-Stark; Reflux; | Dibutyl 4-Bromophthalate (4) To a suspension of 4-bromophthalic acid (25.0 g, 102 mmol, 1 equiv) in toluene (400 mL), nBuOH (100 mL, 1.09 mol, 10 equiv) and H2SO4 (2 mL) were added. The reaction mixture was refluxed using a Dean-Stark head for 2 h and then cooled to r.t. Thereafter the resulting mixture was carefully poured into water (300 mL), and the obtained two-phase mixture was extracted with toluene (2 × 100 mL). The combined organic extract was dried over Na2SO4 and then evaporated to dryness. The residue was purified by vacuum distillation (138-140 °C, 0.7 mbar) to give 4. Yield: 28.0 g (78%); colorless oil. IR (neat): 2960m, 2935w, 2874w, 1723s, 1589w, 1254s, 1122s, 1088s, 1068s, 939m, 890w, 838m, 767m, 696w cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.79 (s, 1 H), 7.61 (m, 2 H), 4.28 (q, J = 6.5 Hz, 4 H), 1.60-1.78 (m, 4 H), 1.32-1.48 (m, 4 H), 0.86-1.02 (m, 6 H). 13C NMR (150 MHz, CDCl3): δ = 168.4, 168.2, 134.2, 133.6, 131.5, 130.5, 130.3, 125.3, 65.7, 65.5, 30.33, 30.32, 19.0, 13.5. HRMS: m/z calcd for C16H21BrO4: 356.0623; found: 356.0591. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; tetrabutylammomium bromide In N,N-dimethyl-formamide at 100℃; for 12h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In ethanol at 4 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | In ethanol at 4 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | In ethanol at 4 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | In ethanol at 4 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sulfuric acid | 82.1 Step 82.1 Preparation of diisopropyl 4-bromophthalate 4-Bromophthalic acid (1 g, 4.1 mmol) was esterified with isopropyl alcohol by the standard Fisher esterification using sulfuric acid as a catalyst. Standard workup afforded the diester, diisopropyl 4- bromophthalate (0.974 g, 73% yield) Without further purification, the product was used in the following step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.1% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water at 70℃; for 16h; Inert atmosphere; | 1 300 g of water, 300 g of ethanol, 300 g of potassium carbonate (1.30 mol), 15 g of 1,4-phenylenediboronic acid (0.091 mol) in a 1 L four-necked flask equipped with a stirrer, thermometer, cooling tube and nitrogen inlet. ), 53.2 g (0.217 mol) of 4-bromophthalic acid was charged, and the inside of the system was stirred while being replaced with nitrogen. When the nitrogen substitution was sufficiently completed, 2.5 g (2.16 mmol) of tetrakis (triphenylphosphine) palladium was added, the temperature was raised to 70 ° C., and the reaction was carried out for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, the insoluble matter was filtered off, and the reaction solution was recovered. Next, a flask containing 470 g of 35% hydrochloric acid was heated to 70 ° C., a reaction solution was gradually added dropwise thereto for acidification, the temperature was lowered to 50 ° C., and the solid content was recovered by filtration. Wash the recovered solids with 600 g of water andBy drying under reduced pressure at 120 ° C., 34.6 g of paraterphenyltetracarboxylic acid (process yield 94.1%, LC purity 91.5%) was obtained. |
Tags: 6968-28-1 synthesis path| 6968-28-1 SDS| 6968-28-1 COA| 6968-28-1 purity| 6968-28-1 application| 6968-28-1 NMR| 6968-28-1 COA| 6968-28-1 structure
[ 74346-19-3 ]
4-Bromo-2,6-dimethylbenzoic acid
Similarity: 0.93
[ 74346-19-3 ]
4-Bromo-2,6-dimethylbenzoic acid
Similarity: 0.93
[ 74346-19-3 ]
4-Bromo-2,6-dimethylbenzoic acid
Similarity: 0.93
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