* 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.
With sodium tetrahydroborate In tetrahydrofuran at 5 - 25℃; for 4 h;
The feed solution for the reaction was prepared by dissolving 455 g of 4-bromophthalic anhydride in 545 g of THF at 25° C. This solution was then added to the reducing agent, which was prepared as a slurry of 48 g of sodium borohydride in 450 g THF pre-cooled to 5° C prior to the addition of said solution. As the starting material was added to the reducing agent slurry, an increase in temperature from 5°C to 15°C was noted. After approximately 3 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 25° C. Neutralisation of the excess sodium borohydride was performed by the careful addition of 300 g water and 150 g hydrochloric acid (as a 32percent aqueous solution). The pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 25° C to 32° C. Phase separation was achieved by heating the mixture to 55° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase and a clear organic phase. The lower, aqueous, phase (600 g) was removed, following which the organic phase was washed with aqueous NaCl solution (400 g, 10percent w/w) to remove the residues of H3BO3 formed during the work-up, then the aqueous THF (750 g) was distilled off from the organic phase over a temperature range of 70 to 77° C in a reboiler. Aqueous ethanol (700 g, 95percent) and water (150 g) were added to the organic phase residue, which was heated to reflux. Crude 5-bromophthalide was then crystallized by controlled cooling of the solution from 75° C to 30° C over a period of one hour, following which the temperature was held constant at 30° C for a further one hour. The crystallized material was filtered and washed with 250 g aqueous ethanol (95percent). The filtration residue thus formed (272 g, LOD-23percent) was found to contain approximately 80percent 5-bromophthalide and 20percent 6- bromophthalide. In order to further purify the desired product, a slurry of 260 g of the wet, crude 5-bromophthalide was prepared in 540 g of ethanol containing 5percent water at 25° C. This slurry was then heated TO 70-80° C, and held at that temperature for one hour. Re-crystallization of the 5-bromophthalide was achieved by lowering the temperature from 80° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 150 g of aqueous 95percent ethanol, following which 180 g of wet residue was dried AT 80° C for a period of 2 hours. The dried product thus formed (145 g) was subjected to HPLC and NMR analysis, and was found to contain >98percent 5-bromophthalide. The yield was approximately 35percent.
15%
With sodium tetrahydroborate In DMF (N,N-dimethyl-formamide) at 5 - 25℃; for 4 h;
The feed solution for the reaction was prepared by dissolving 57 g of 4-bromophthalic anhydride in 53 g of DMF at 25° C. This solution was then added to the reducing agent, which was prepared as a slurry of 9.5 g of sodium borohydride in 100 g DMF, pre-cooled to 5° C prior to addition of said solution. After approximately 3 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour. Neutralisation of the excess sodium borohydride was performed by careful addition of the reaction mixture to a solution of 200 g water and 62 g concentrated HC1. The precipitate, in the form of a paste, was filtered on a Buchner filter, and washed with 200 g water. 85 g of a wet mixture of isomers was obtained. It was impossible to crystallize 5-bromophthalide from DMF. However, the crystallization of the mixture was carried out in 140 g ethanol to give 30.9 g of the wet, crude product containing 70percent 5-bromophthalide. In order to further purify the desired product, a slurry of 30.3 g of the wet, crude 5-bromphthalide was prepared in 50 , G of ethanol at 25° C. This slurry was then heated to 75° C and held at that temperature for one hour. Re- crystallization of the 5-bromophthalide was achieved by lowering the temperature from 75 to 25° C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with ethanol, prior to being dried at 80° C for a period of two hours. The dried product thus formed (8.1 g) was subjected to HPLC and NMR analysis, and was found to contain approximately 90percent 5-bromophthalide. The overall yield of 5-bromophthalide was approximately 15percent.
With sodium tetrahydroborate In 1,2-dimethoxyethane at 20 - 30℃; for 4 h;
The feed solution for the reaction was prepared by dissolving 227 g of 4-bromophthalic anhydride in 300 g of ethylene glycol dimethyl ether at 20° C. This solution was then added to the reducing agent, which was prepared as a slurry of 22.7 g of sodium BOROHDYRIDE in 200 g ethylene glycol dimethyl ether at 20°C. As the starting material was added to the reducing agent slurry, an increase in temperature from 20°C to 30°C was noted. After approximately 3.0 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 26° C. Neutralisation of the excess sodium borohydride was performed by the careful addition of 200 g water and 70 g hydrochloric acid (as a 32percent aqueous solution). The pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 26° C to 31° C. Phase separation was achieved by heating the mixture to 50° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase and a clear organic phase. The lower, aqueous, phase (223 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (200 g, 15percent w/w) to remove the residues of H3BO3 formed during the work-up, then the aqueous ethylene glycol dimethyl ether (262 g) was partially distilled off from the organic phase over a temperature range of 74 to 91° C in a reboiler. Crude 5-bromophthalide was then crystallized from the organic phase residue by controlled cooling of said residue from 91°C to 25° C over a period of one hour, following which the temperature was held constant at 25° C for a further one hour. The crystallized material was filtered and washed with aqueous 50percent ethylene glycol dimethyl ether. The filtration residue thus formed was found to contain approximately 80percent 5-bromophthalide and 20percent 6-bromophthalide. In order to further purify the desired product, a slurry of 240 g of the wet, crude 5-bromophthalide was prepared in 240 g of aqueous 90percent ethylene glycol dimethyl ether at 25° C. This slurry was then heated to 85° C to obtain a solution, and re-crystallisation of the 5-bromophthalide was achieved by lowering the temperature from 85° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 90 g of aqueous 90percent ethylene glycol dimethyl ether, following which 97 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (83 g) was subjected to HPLC analysis, and was found to contain >99percent 5-bromophthalide. The direct yield was approximately 38percent.
33%
With sodium tetrahydroborate In tetrahydrofuran at 5 - 25℃; for 3.5 h;
The feed solution for the reaction was prepared by dissolving 197 g of 4-bromophthalic anhydride in 250 g of THF at 25° C. This solution (density = 1.15 g/ml) was then added to the reducing agent, which was prepared as a slurry of 18.5 g of sodium borohydride in 150 g THF pre-cooled to 5° C prior to the addition of said solution. As the starting material was added to the reducing agent slurry, an increase in temperature from 5°C to 15°C was noted. After approximately 2.5 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 25° C. Neutralisation of the excess sodium borohydride was performed by the careful addition of 120 g water and 60g hydrochloric acid (as a 32percent aqueous solution). The pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 25° C to 30° C. Phase separation was achieved by heating the mixture to 58° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase having a density of 1.15 G/ML, and a clear organic phase having a density of 1.03 g/ml. The lower, aqueous, phase (159 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (140 g, 10percent w/w) to remove the residues of H3BO3 formed during the work-up, then the THF (267 g) was partially distilled off from the organic phase over a temperature range of 70 to 75° C in a reboiler. Crude 5-bromophthalide was then crystallized from the organic phase residue (317 g) by adding 30 g water and controlled cooling of said residue from 75° C to 30° C over a period of one hour, following which the temperature was held constant at 30° C for a further one hour. The crystallized material was filtered and washed with 100g THF. The filtration residue thus formed (113 g, LOD-25percent) was found to contain approximately 90percent 5-bromophthalide and 10percent 6-bromophthalide. In order to further purify the desired product, a slurry of 100 g of the wet, crude 5-bromophthalide was prepared in 140 g of THF containing 6percent water at 25° C. This slurry was then heated to 60° C, and held at that temperature for one hour. Re-crystallization of the 5-bromophthalide was achieved by lowering the temperature from 60° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 40 g of THF, following which 65 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (53 g) was subjected to HPLC and NMR analysis, and was found to contain >98percent 5-bromophthalide. The direct yield was approximately 33percent. The filtrate contained approximately 21 g of a recoverable mixture of 5-bromophthalide (70percent) and 6- bromophthalide (30percent). The overall yield of this process (after recycling the mother liquor) was between 37 and 40percent.
With sodium tetrahydroborate In 1,2-dimethoxyethane at 20 - 30℃; for 4 h;
The feed solution for the reaction was prepared by dissolving 227 g of 4-bromophthalic anhydride in 300 g of ethylene glycol dimethyl ether at 20° C. This solution was then added to the reducing agent, which was prepared as a slurry of 22.7 g of sodium BOROHDYRIDE in 200 g ethylene glycol dimethyl ether at 20°C. As the starting material was added to the reducing agent slurry, an increase in temperature from 20°C to 30°C was noted. After approximately 3.0 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 26° C. Neutralisation of the excess sodium borohydride was performed by the careful addition of 200 g water and 70 g hydrochloric acid (as a 32percent aqueous solution). The pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 26° C to 31° C. Phase separation was achieved by heating the mixture to 50° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase and a clear organic phase. The lower, aqueous, phase (223 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (200 g, 15percent w/w) to remove the residues of H3BO3 formed during the work-up, then the aqueous ethylene glycol dimethyl ether (262 g) was partially distilled off from the organic phase over a temperature range of 74 to 91° C in a reboiler. Crude 5-bromophthalide was then crystallized from the organic phase residue by controlled cooling of said residue from 91°C to 25° C over a period of one hour, following which the temperature was held constant at 25° C for a further one hour. The crystallized material was filtered and washed with aqueous 50percent ethylene glycol dimethyl ether. The filtration residue thus formed was found to contain approximately 80percent 5-bromophthalide and 20percent 6-bromophthalide. In order to further purify the desired product, a slurry of 240 g of the wet, crude 5-bromophthalide was prepared in 240 g of aqueous 90percent ethylene glycol dimethyl ether at 25° C. This slurry was then heated to 85° C to obtain a solution, and re-crystallisation of the 5-bromophthalide was achieved by lowering the temperature from 85° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 90 g of aqueous 90percent ethylene glycol dimethyl ether, following which 97 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (83 g) was subjected to HPLC analysis, and was found to contain >99percent 5-bromophthalide. The direct yield was approximately 38percent.
33%
With sodium tetrahydroborate In tetrahydrofuran at 5 - 25℃; for 3.5 h;
The feed solution for the reaction was prepared by dissolving 197 g of 4-bromophthalic anhydride in 250 g of THF at 25° C. This solution (density = 1.15 g/ml) was then added to the reducing agent, which was prepared as a slurry of 18.5 g of sodium borohydride in 150 g THF pre-cooled to 5° C prior to the addition of said solution. As the starting material was added to the reducing agent slurry, an increase in temperature from 5°C to 15°C was noted. After approximately 2.5 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 25° C. Neutralisation of the excess sodium borohydride was performed by the careful addition of 120 g water and 60g hydrochloric acid (as a 32percent aqueous solution). The pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 25° C to 30° C. Phase separation was achieved by heating the mixture to 58° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase having a density of 1.15 G/ML, and a clear organic phase having a density of 1.03 g/ml. The lower, aqueous, phase (159 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (140 g, 10percent w/w) to remove the residues of H3BO3 formed during the work-up, then the THF (267 g) was partially distilled off from the organic phase over a temperature range of 70 to 75° C in a reboiler. Crude 5-bromophthalide was then crystallized from the organic phase residue (317 g) by adding 30 g water and controlled cooling of said residue from 75° C to 30° C over a period of one hour, following which the temperature was held constant at 30° C for a further one hour. The crystallized material was filtered and washed with 100g THF. The filtration residue thus formed (113 g, LOD-25percent) was found to contain approximately 90percent 5-bromophthalide and 10percent 6-bromophthalide. In order to further purify the desired product, a slurry of 100 g of the wet, crude 5-bromophthalide was prepared in 140 g of THF containing 6percent water at 25° C. This slurry was then heated to 60° C, and held at that temperature for one hour. Re-crystallization of the 5-bromophthalide was achieved by lowering the temperature from 60° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 40 g of THF, following which 65 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (53 g) was subjected to HPLC and NMR analysis, and was found to contain >98percent 5-bromophthalide. The direct yield was approximately 33percent. The filtrate contained approximately 21 g of a recoverable mixture of 5-bromophthalide (70percent) and 6- bromophthalide (30percent). The overall yield of this process (after recycling the mother liquor) was between 37 and 40percent.
A mixture of intermediate I-54 (6.6 g, 0.30 mol, 1.0 eq) and formamide (10 mL, 2.4 mol, 8.0 eq) was stirred at 200° C. for 2 hours and poured onto a mixture of ice and water. The resulting crystals were collected by filtration and dried in vacuo to give intermediate I-55 (7.0 g, 99percent). MS (ESI): m/z 227 (M+H+).
94%
for 4 h; Reflux
Compound E-1 (110 mmmol) was refluxed in formamide for 4 hours to obtain compound E-2 (103 mmol, 94percent).Compound E-2 (100 mmol) was reacted in 28percent ammonia solution at room temperature for 24 hours to obtain compound E-3 (74 mmol, 74percent).Compound E-3 (70 mmol) was dissolved in DMF,The mixture was allowed to react with thionyl chloride in an ice bath for 24 hours to obtain compound E-4 (53 mmol, 75percent).
85%
at 200℃; for 2 h;
A mixture of 5-bromoisobenzofuran-l,3-dione (6.6 g, 29.1 mmol) and formamide (10 mL, 252 mmol) was heated at 200 °C for 2 h. Then the reaction was cooled to rt and poured into H20 (35 mL). The solid was collected by filtration, washed with MeOH (10 mL) and dried in vcauo to give the title compound as an orange solid (5.6 g, 85percent). MS (ESI, pos. ion) m/z: 227.05 [M + H]+.
85%
at 200℃; for 2 h;
5-bromoisobenzofuran-1,3-dione (6.6 g, 29.1 mmol) andFormamide (10 mL, 252 mmol)The mixture was heated to 200 ° C and stirred for 2 hours.Cool to room temperature and pour into water. The collected solid was washed with methanol (10 mL), dried in vacuo,The title compound was obtained as an orange solid (5.6 g, 85percent).
81%
Stage #1: at 200℃; for 2 h; Inert atmosphere Stage #2: at 20℃; for 1.5 h; Inert atmosphere
A mixture of 5-bromoisobenzofuran- 1, 3-dione (2) (13.2 g, 58.1 mmol) and formamide (20 mL) was stirred at 200 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water and stirred for 1.5 h. The mixture was filtered and the solid was dried to give 5-bromoisoindoline-1, 3-dione (3) (11 g, 81 percent yield).1H- NMR (400 MHz, CDC13) 11.44 (s, 1H), 7.95-7.99 (m, 2H), 7.70-7.72 (m, 1H).
76%
at 120℃; for 3 h;
No. I.1-117: 3-Acetyl-7-bromo-4-hydroxyisoquinolin-1(2H)-one A mixture of 5-bromoisobenzofuran-1,3-dione (16.21 g, 17.4 mmol) and formamide (42.5 ml, 48.2 g) was stirred at 120° C. for 3 h and, after cooling to room temperature, added to ice water. The resulting colourless solid was filtered off and concentrated under reduced pressure. This gave 5-bromophthalimide in the form of a colourless solid (12.26 g, 76percent of theory). 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.45 (br. s, 1H), 8.01 (dd, 1H), 7.99 (d, 1H), 7.75 (d, 1H).
61.3%
With urea In ethanol at 0 - 120℃; for 10 h;
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 95percent 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, 61.3percent yield).
58%
at 160℃; for 2 h;
4-Bromophthalic anhydride (2.26 g, 0.01 mol) was added to urea (6.0 g, 0.1 mol). Then the solid mixture was heated till molten, and maintained at 160 °C for 2 h. After cooled, the solid was washed with 100 mL water and recrystallized with ethanol (100 mL). 4-Bromophthalimide was obtained as white solid. Yield: 1.32 g, 58percent, mp: 230-233 °C.
Reference：
[1] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 109
[2] Patent: JP5906522, 2016, B2, . Location in patent: Paragraph 0058; 0059
[3] Chemistry of Materials, 2010, vol. 22, # 18, p. 5258 - 5270
[4] Molecules, 2010, vol. 15, # 8, p. 5561 - 5580
[5] Patent: WO2014/89324, 2014, A1, . Location in patent: Paragraph 0234
[6] Patent: CN104016979, 2017, B, . Location in patent: Paragraph 0596; 0597; 0598
[7] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150
[8] Patent: WO2018/95260, 2018, A1, . Location in patent: Paragraph 058; 061; 0116
[9] Organic Letters, 2013, vol. 15, # 14, p. 3738 - 3741
[10] Patent: US2014/302987, 2014, A1, . Location in patent: Paragraph 0200-0201
[11] Journal of Materials Chemistry C, 2017, vol. 5, # 34, p. 8723 - 8733
[12] Patent: CN107082769, 2017, A, . Location in patent: Paragraph 0017; 0018
[13] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 21, p. 5738 - 5746
[14] Patent: WO2008/44029, 2008, A1, . Location in patent: Page/Page column 214
[15] Patent: WO2008/44041, 2008, A1, . Location in patent: Page/Page column 236
[16] Patent: WO2008/44045, 2008, A1, . Location in patent: Page/Page column 288
[17] Patent: WO2008/44054, 2008, A2, . Location in patent: Page/Page column 132-133
[18] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 14, p. 4159 - 4162
[19] Patent: US2010/152184, 2010, A1, . Location in patent: Page/Page column 80
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.
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 5, p. 1249 - 1256
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10735 - 10741
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 21, p. 5738 - 5746
[4] Chemische Berichte, 1887, vol. 20, p. 1017
[5] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1834 - 1840
[6] Synlett, 2001, # 1, p. 93 - 95
[7] Patent: CN107082769, 2017, A, . Location in patent: Paragraph 0017; 0018
7
[ 85-44-9 ]
[ 86-90-8 ]
Yield
Reaction Conditions
Operation in experiment
85.4%
With N-benzyl-N,N,N-triethylammonium chloride; bromine; sodium hydroxide In water at 45 - 80℃; for 11.7 h;
The present invention provides a process for the preparation of 4-bromo-phthalic anhydride,First, 11.3 g of sodium hydroxide was dissolved in 50 g of water,20 g of phthalic anhydride was added and stirred well, followed by the addition of 0.5 g of benzyltrimethylammonium chloride catalyst and stirring was continued.The reaction was then carried out in three stages of temperature control and three times addition of reactants,The first temperature control temperature is 45 ,The mass of bromine added was 11.5 g and the reaction time was 1.7 hours.The second paragraph temperature control temperature is 70 ,The mass of the added bromine was 10.8 g,Reaction time is 5 hours;The third temperature control temperature is 80 ,3g of sodium hydroxide was added and 10 g of bromine was added thereto to continue the reaction for 5 hours.At the end of the reaction, 15 g of fuming sulfuric acid was added to the product with a mass fraction of 20percentHeating to 96 ° C for acidification,After the acidification was completed, the mixture was cooled to 25 ° C,Then, 15 g of an aqueous solution of sodium bisulfite having a mass fraction of 10percent was added to remove the excess bromine.Ethyl acetate was then added for extraction,After standing for 8 minutes, the organic layer was taken,And the organic layer is distilled to remove the organic solvent,The distillation temperature was 110 ° C,The temperature was then raised to 200 ° C to give crude 4-bromophthalic anhydride.Then 4-bromo-phthalic anhydride in the vacuum of 0.095MPa vacuum distillation under the conditions,And the fractions having a temperature of about 215 ° C were collected,To obtain 4-bromo-phthalic anhydride product.
79%
Stage #1: With bromine; sodium hydroxide In water at 90℃; for 6 h; Stage #2: With thionyl chloride In water at 0℃; Reflux
To a solution of intermediate I-53 (22 g, 0.15 mol, 1.0 eq) in water (150 mL) was added solid NaOH (12 g, 0.30 mol, 2.0 eq) and neat Br2 (8.5 mL, 0.17 mol, 1.1 eq) and the reaction mixture was stirred at 90° C. for 6 hours. The crude reaction mixture was cooled slowly to 0° C. in a refrigerator and the light yellow solids were collected by filtration, washed with cold water and dissolved in neat SOCl2 (60 mL). The reaction mixture was refluxed for 2.5 hours and concentrated by evaporation. The crude reaction product was crystallized from ethyl acetate to give intermediate I-54 (22 g, 79percent). MS (ESI): m/z 228 (M+H+).
71%
Stage #1: With bromine; sodium hydroxide In water at 90℃; for 12 h; Inert atmosphere Stage #2: for 5 h; Reflux; Inert atmosphere
To a solution of phthalic anhydride (1) (22 g, 148.5 mmol, 1.0 equiv) in water (150 mL) was added NaOH (12 g, 300.0 mmol, 2.0 equiv) and neat Br2 (8.5 mL, 165.9 mmol, 1.1 equiv) slowly and the mixture was stirred at 90 °C for 12 h. After that the reaction mixture was cooled to 0 °C and filtered to give a light yellow solid. The solid was washed with cold water (50 mL), dissolved in SOd2 (60 mL) and the mixture was heated to reflux for 5 h. The reaction mixture was concentrated to give a residue, to which DCM (200 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated to give 5-bromoisobenzofuran- 1, 3-dione (2) (20 g, 71percent yield) as a yellow solid. 1H-NMR (400 MHz, CDC13) 8.16-8. 17 (m, 1H), 8.06-8.07 (m, 1H), 7. 89-7.90 (m, 1H).
Reference：
[1] Patent: CN105399712, 2016, A, . Location in patent: Paragraph 0025
[2] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 109
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150
[4] Patent: WO2018/95260, 2018, A1, . Location in patent: Paragraph 058; 060; 0116
[5] Journal of Medicinal Chemistry, 1993, vol. 36, # 22, p. 3417 - 3423
[6] Acta Poloniae Pharmaceutica - Drug Research, 2009, vol. 66, # 1, p. 65 - 68
[7] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 21, p. 5738 - 5746
[8] Molecules, 2016, vol. 21, # 12,
[9] Patent: CN107082769, 2017, A,
8
[ 118-45-6 ]
[ 7439-89-6 ]
[ 86-90-8 ]
Reference：
[1] Patent: US4962206, 1990, A,
9
[ 6941-75-9 ]
[ 86-90-8 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 1, p. 384 - 388[2] Angew. Chem., 2017, vol. 129, # 1, p. 392 - 396,5
10
[ 583-71-1 ]
[ 86-90-8 ]
Reference：
[1] Synlett, 2001, # 1, p. 93 - 95
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1834 - 1840
11
[ 68837-59-2 ]
[ 86-90-8 ]
Reference：
[1] Chemische Berichte, 1887, vol. 20, p. 1017
12
[ 67832-11-5 ]
[ 86-90-8 ]
Reference：
[1] Chemische Berichte, 1887, vol. 20, p. 1017
13
[ 583-75-5 ]
[ 86-90-8 ]
Reference：
[1] Chemische Berichte, 1887, vol. 20, p. 1017
14
[ 118728-51-1 ]
[ 10035-10-6 ]
[ 64-19-7 ]
[ 86-90-8 ]
Reference：
[1] Journal of the American Chemical Society, 1933, vol. 55, p. 430
15
[ 86-90-8 ]
[ 28281-76-7 ]
Reference：
[1] Journal of Natural Products, 2018, vol. 81, # 6, p. 1460 - 1467
16
[ 86-90-8 ]
[ 76240-49-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: at 125℃; for 1 h; Stage #2: at 125℃; for 0.5 h;
A stirred solution of 4-bromophthalic anhydride (50. g, 0.22 mol) in acetic acid (150 mL) was heated at 125 °C for 1 h. The mixture was then cooled to ambient temperature and hydrazine hydrate (1 1 .25 mL, 0.23 mol) was added dropwise over 5 min, resulting in the formation of a thick white solid, further acetic acid (50 mL) was added and the mixture was heated at 125 °C for 30 min. The mixture was cooled and diluted with acetic acid (200 mL) before being filtered. The filter cake was washed with acetic acid (3 x 100 mL) and dried under vacuum. The cake was then dissolved in 5percent (w/w) NaOH solution (250 mL), the suspension was acidified with acetic acid (30 mL) to give a thick white precipitate. The mixture was filtered and the filter cake washed sequentially with water (2 x 200 mL) and methanol (2 x 200 mL), and then dried under vacuum at 40 °C to give a white solid, 6- bromo-2,3-dihydrophthalazine-1 ,4-dione (55 g, 0.23 mol, quant.).1 H NMR (300MHz, DMSO-d6) δ = 8.16 (dd, J = 0.7, 2.0 Hz, 1 H), 7.98 (dd, J = 0.7, 8.4 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 1 .84 (s, 2H)
72.3%
With hydrazine In isopropyl alcohol for 4 h; Heating / reflux
Example 48 and 49: Synthesis of 6-[(2,4-Dichlorophenyl)methyl]amino}-4-chIoro- IH-phthalazin-l-one and T-IKZ^-dichloropheny^methyllaminoJ^-chloro-lH- phthalazin-1-one; <n="67"/>6-Bromo-2,3-dihydro-phthalazine-l,4-dione; A mixture of 5-Bromo-isobenzofuran-l,3-dione (6.Og, 26.4mmol) and hydrazine hydrate (1.5ImL, 32.4mmol) in isopropanol (12OmL) was heated at reflux for 4h. The mixture was allowed to cool and the precipitate was filtered and washed with water (50 mL). The filter cake was dried to afford the title compound (4.6g, 72.3percent) as a white solid. m/z (M+l) = 241.05
Reference：
[1] Patent: WO2016/92326, 2016, A1, . Location in patent: Paragraph 00326
[2] Angewandte Chemie - International Edition, 2007, vol. 46, # 10, p. 1684 - 1687
[3] Patent: WO2008/61108, 2008, A2, . Location in patent: Page/Page column 65-66
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1834 - 1840
[5] Patent: WO2004/99177, 2004, A1, . Location in patent: Page 19-20
[6] Patent: US2010/183551, 2010, A1,
17
[ 86-90-8 ]
[ 82-73-5 ]
[ 36978-41-3 ]
Yield
Reaction Conditions
Operation in experiment
76.19%
at 30℃; for 8 h; Inert atmosphere
General procedure: In a 1000 ml three-necked flask, 18.3 g (0.1 mol) of 4-chlorophthalic anhydride and 18.3 g (0.1 mol) were added 3-chlorophthalic anhydride, 300 g of anisole as solvent, 0.13 g (0.001 mol) of nickel chloride as a catalyst, 0.198 g (0.001 mol) of C-1 as a catalyst ligand, and 0.03 g (0.0003 mol) of sodium bromide as a catalyst Auxiliary, 13 g (0.2 mol) of zinc powder was used as a reducing agent, and the reaction was stirred at 30 ° C for 8 hours under a nitrogen atmosphere. The reaction solution was filtered to remove insoluble solids in the reaction liquid. 300 g of methanol was added to the filtration mother liquor, and the product was precipitated, filtered, and dried to obtain 25.8 g of the product 2,3,3',4'-biphenyltetracarboxylic dianhydride, yield 87.7percent. The synthesis method was the same as in Example 1, except that the types of 4-substituted phthalic anhydride and 3-substituted phthalic anhydride were changed.
Reference：
[1] Patent: CN108250169, 2018, A, . Location in patent: Paragraph 0010; 0055; 0065-0067
18
[ 86-90-8 ]
[ 22803-05-0 ]
Reference：
[1] Patent: US5081291, 1992, A,
19
[ 86-90-8 ]
[ 69189-19-1 ]
Reference：
[1] Research on Chemical Intermediates, 2013, vol. 39, # 1, p. 139 - 146
[2] Synlett, 2013, vol. 24, # 19, p. 2510 - 2514
20
[ 86-90-8 ]
[ 19725-82-7 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1968, vol. 715, p. 159 - 163
21
[ 86-90-8 ]
[ 171011-37-3 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With diisobutylaluminium hydride In toluene at 20℃; for 1.5 h; Cooling with ice Stage #2: With hydrogenchloride In water; toluene at 0 - 20℃; for 1 h;
A 1 M solution of DIBAL-H in toluene (3 mL, 3 mM) was added to an ice-cooled solution of4-bromophthalic anhydride (106 mg, 0.47 mM) in anhyd. toluene (1 mL) and the whole was stirred atroom temperature (rt) for 1.5 h. After slow addition of 10percent HCl aq (0.7 mL) at 0 °C with stirringfollowed by dilution with toluene (1 mL) the mixture was stirred at rt for 1 h, filtered through Celite,and extracted with AcOEt (20 mL × 3). The organic solutions were washed with brine (10 mL), dried(MgSO4), and evaporated. Purification of the residue by column chromatography (SiO2, hexane : AcOEt= 1 : 1) gave 10 (89 mg, 91percent) as colorless solids, mp 67-67.5 °C.
63%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 2 h; Stage #2: With water In tetrahydrofuran; ethyl acetate
Lithium aluminum hydride (2.7 g, 70.5 mmol) was suspended in tetrahydrofuran anhydride (100 milliliter), and then a tetrahydrofuran anhydride solution (100 milliliter) of Compound 2 (8 g, 35.3 mmol) was dropped in the suspension at room temperature. After 2 hours stirring, ethylacetate (100 milliliter) and water (100 milliliter) were poured in the resultant reaction solution in this order. Subsequently, the resultant reaction solution was filtrated, and then an organic layer was separated by adding ethylacetate, followed by drying thereof with the use of magnesium sulfate anhydride. The solvent of the organic layer was distilled, and as a result, Compound 3 was obtained. Product Amount: 5.2 g, Yield: 63 percent
52%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 10℃; for 2 h;
A 250-mL round-bottom flask was charged with 5-bromo-1,3-dihydro-2-benzofuran- 1,3-dione (8.00 g, 35.2 mmol, 1.00 equiv) and THF (100 mL). Lithium aluminium hydride (2.69 g, 70.9 mmol, 2.00 equiv) was added at 0°C. The resulting solution was stirred for 2 h at 10 °C and quenched by EtOAc (50 mL). The resulting solution was diluted with water (100 mL). The pH value of the solution was adjusted to 3 with hydrochloric acid (1 mol/L). The resulting solution was extracted with EtOAc (2 x 100 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 4.00 g (52percent yield) of(4-bromo-1,2- phenylene)dimethanol as a white solid. ‘H NMR (300 IVIFIz, Chloroform-cl) ö 7.66 - 7.70 (m, 1H), 7.43 - 7.47 (m, 1H), 7.23 (d, J= 7.8 Hz, 1H), 4.71 (s, 4H), 2.62 (br, 2H).
52%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 10℃; for 2 h;
Example 151: 1,1,1,3,3,3-Hexafluoropropan-2-yl 1-((1,3-dihydroisobenzofuran-5-yl)methyl)- 1,8-diazaspiro[4.5]decane-8-carboxylate Step 1: Synthesis of (4-bromo-1,2-phenylene)dimethano A flask was charged with 5-bromoisobenzofuran-1,3-dione (8.00 g, 35.2 mmol, 1.00 equiv), and THF (100 mL). LAH (2.69 g, 70.9 mmol, 2.00 equiv) was added at 0 C. The resulting solution was stirred for 2 h at 10 C and quenched with EtOAc (50 mL) and diluted with water (100 mL). The pH value of the solution was adjusted to 3 with 1 M HCl. The resulting solution was extracted with EtOAc (2 x 100 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/2) to provide 4.00 g (52percent yield) of (4-bromo-1,2- phenylene)dimethanol as a white solid.1H NMR (300 MHz, Chloroform-d) ^ 7.66– 7.70 (m, 1H), 7.43– 7.47 (m, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.71 (s, 4H), 2.62 (br, 2H).
Reference：
[1] Heterocycles, 2009, vol. 77, # 2, p. 991 - 1005
[2] Synlett, 2013, vol. 24, # 19, p. 2510 - 2514
[3] Research on Chemical Intermediates, 2013, vol. 39, # 1, p. 139 - 146
[4] Patent: EP1659129, 2006, A1, . Location in patent: Page/Page column 100
[5] Patent: WO2017/87854, 2017, A1, . Location in patent: Page/Page column 00315
[6] Patent: WO2017/197192, 2017, A1, . Location in patent: Paragraph 00377
22
[ 86-90-8 ]
[ 87639-57-4 ]
Yield
Reaction Conditions
Operation in experiment
66.1%
With chlorosulfonic acid In methanol
(15-1) Dimethyl 4-bromophthalate Methanol (500 ml) was added to 4-bromophthalic anhydride (50.25 g). Further, chlorosulfonic acid (1 ml) was added thereto. The resultant mixture was heated under reflux overnight and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (39.98 g) as a colorless oil (yield: 66.1percent). 1H-NMR (400 MHz, CDCl3): δ(ppm) 3.90(3H, s), 3.92(3H, s), 7.63(1H, d, J=8.4Hz), 7.68(1H, dd, J=2.0, 8.4Hz), 7.84(1H, d, J=2.0Hz).
With N-benzyl-N,N,N-triethylammonium chloride; bromine; sodium hydroxide; In water; at 45 - 80℃; for 11.7h;Catalytic behavior;
The present invention provides a process for the preparation of 4-bromo-phthalic anhydride,First, 11.3 g of sodium hydroxide was dissolved in 50 g of water,20 g of phthalic anhydride was added and stirred well, followed by the addition of 0.5 g of benzyltrimethylammonium chloride catalyst and stirring was continued.The reaction was then carried out in three stages of temperature control and three times addition of reactants,The first temperature control temperature is 45 ,The mass of bromine added was 11.5 g and the reaction time was 1.7 hours.The second paragraph temperature control temperature is 70 ,The mass of the added bromine was 10.8 g,Reaction time is 5 hours;The third temperature control temperature is 80 ,3g of sodium hydroxide was added and 10 g of bromine was added thereto to continue the reaction for 5 hours.At the end of the reaction, 15 g of fuming sulfuric acid was added to the product with a mass fraction of 20%Heating to 96 C for acidification,After the acidification was completed, the mixture was cooled to 25 C,Then, 15 g of an aqueous solution of sodium bisulfite having a mass fraction of 10% was added to remove the excess bromine.Ethyl acetate was then added for extraction,After standing for 8 minutes, the organic layer was taken,And the organic layer is distilled to remove the organic solvent,The distillation temperature was 110 C,The temperature was then raised to 200 C to give crude 4-bromophthalic anhydride.Then 4-bromo-phthalic anhydride in the vacuum of 0.095MPa vacuum distillation under the conditions,And the fractions having a temperature of about 215 C were collected,To obtain 4-bromo-phthalic anhydride product.
79%
To a solution of intermediate I-53 (22 g, 0.15 mol, 1.0 eq) in water (150 mL) was added solid NaOH (12 g, 0.30 mol, 2.0 eq) and neat Br2 (8.5 mL, 0.17 mol, 1.1 eq) and the reaction mixture was stirred at 90 C. for 6 hours. The crude reaction mixture was cooled slowly to 0 C. in a refrigerator and the light yellow solids were collected by filtration, washed with cold water and dissolved in neat SOCl2 (60 mL). The reaction mixture was refluxed for 2.5 hours and concentrated by evaporation. The crude reaction product was crystallized from ethyl acetate to give intermediate I-54 (22 g, 79%). MS (ESI): m/z 228 (M+H+).
71%
To a solution of phthalic anhydride (1) (22 g, 148.5 mmol, 1.0 equiv) in water (150 mL) was added NaOH (12 g, 300.0 mmol, 2.0 equiv) and neat Br2 (8.5 mL, 165.9 mmol, 1.1 equiv) slowly and the mixture was stirred at 90 C for 12 h. After that the reaction mixture was cooled to 0 C and filtered to give a light yellow solid. The solid was washed with cold water (50 mL), dissolved in SOd2 (60 mL) and the mixture was heated to reflux for 5 h. The reaction mixture was concentrated to give a residue, to which DCM (200 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated to give 5-bromoisobenzofuran- 1, 3-dione (2) (20 g, 71% yield) as a yellow solid. 1H-NMR (400 MHz, CDC13) 8.16-8. 17 (m, 1H), 8.06-8.07 (m, 1H), 7. 89-7.90 (m, 1H).
General procedure: A dried 2-neck round-bottomed flask fitted with a refluxcondenser was charged with <strong>[86-90-8]4-bromophthalic anhydride</strong>(1mmol), corresponding aryl amine (1mmol), access molecularsieves (1g) and glacial acetic acid (25ml). The reactionmixture was refluxed (4-12 h) until the reaction was visibleto be completed on TLC. The reaction mixture was concentratedto dryness under reduced pressure and the residue obtainedwas thoroughly washed with ice cold water and driedto give the desired product 2a-2f [2]. Yield: 75-92%
General procedure: A dried 2-neck round-bottomed flask fitted with a refluxcondenser was charged with <strong>[86-90-8]4-bromophthalic anhydride</strong>(1mmol), corresponding aryl amine (1mmol), access molecularsieves (1g) and glacial acetic acid (25ml). The reactionmixture was refluxed (4-12 h) until the reaction was visibleto be completed on TLC. The reaction mixture was concentratedto dryness under reduced pressure and the residue obtainedwas thoroughly washed with ice cold water and driedto give the desired product 2a-2f [2]. Yield: 75-92%
80%
With acetic acid; at 120℃; for 1h;Molecular sieve; Microwave irradiation;
<strong>[86-90-8]4-bromophthalic anhydride</strong> (10 g, 44.0 mmol),P-methoxyaniline (6.5 g, 52.8 mmol)Was dissolved in 10 mL of glacial acetic acid,Add a certain amount of molecular sieve,And heated in a microwave at 120 C for 1 hour.Neutralized with sodium hydroxide in ice water,Extracted with dichloromethane.Dried over anhydrous magnesium sulfate.After evaporation of the solvent, the residue was purified by silica gel column chromatography,The solid compound 61a (11.6 g, 35.2 mmol) was obtained.Yield 80%.
General procedure: A dried 2-neck round-bottomed flask fitted with a refluxcondenser was charged with <strong>[86-90-8]4-bromophthalic anhydride</strong>(1mmol), corresponding aryl amine (1mmol), access molecularsieves (1g) and glacial acetic acid (25ml). The reactionmixture was refluxed (4-12 h) until the reaction was visibleto be completed on TLC. The reaction mixture was concentratedto dryness under reduced pressure and the residue obtainedwas thoroughly washed with ice cold water and driedto give the desired product 2a-2f [2]. Yield: 75-92%
86%
With acetic acid; at 120℃; for 1h;Molecular sieve; Microwave irradiation;
-bromophthalic anhydride (10 g, 44.0 mmol),Aniline (4.9 g, 52.8 mmol)Was dissolved in 10 mL of glacial acetic acid,Add a certain amount of molecular sieve,And heated in a microwave at 120 C for 1 hour.Neutralized with sodium hydroxide in ice water,Extracted with dichloromethane.Dried over anhydrous magnesium sulfate.After evaporation of the solvent, the residue was purified by silica gel column chromatography,Obtained solid compound 65a (11.4 g, 38 mmol).Yield 86%.
A stirred solution of <strong>[86-90-8]4-bromophthalic anhydride</strong> (50. g, 0.22 mol) in acetic acid (150 mL) was heated at 125 C for 1 h. The mixture was then cooled to ambient temperature and hydrazine hydrate (1 1 .25 mL, 0.23 mol) was added dropwise over 5 min, resulting in the formation of a thick white solid, further acetic acid (50 mL) was added and the mixture was heated at 125 C for 30 min. The mixture was cooled and diluted with acetic acid (200 mL) before being filtered. The filter cake was washed with acetic acid (3 x 100 mL) and dried under vacuum. The cake was then dissolved in 5% (w/w) NaOH solution (250 mL), the suspension was acidified with acetic acid (30 mL) to give a thick white precipitate. The mixture was filtered and the filter cake washed sequentially with water (2 x 200 mL) and methanol (2 x 200 mL), and then dried under vacuum at 40 C to give a white solid, 6- bromo-2,3-dihydrophthalazine-1 ,4-dione (55 g, 0.23 mol, quant.).1 H NMR (300MHz, DMSO-d6) delta = 8.16 (dd, J = 0.7, 2.0 Hz, 1 H), 7.98 (dd, J = 0.7, 8.4 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 1 .84 (s, 2H)
72.3%
With hydrazine; In isopropyl alcohol; for 4h;Heating / reflux;
Example 48 and 49: Synthesis of 6-[(2,4-Dichlorophenyl)methyl]amino}-4-chIoro- IH-phthalazin-l-one and T-IKZ^-dichloropheny^methyllaminoJ^-chloro-lH- phthalazin-1-one; <n="67"/>6-Bromo-2,3-dihydro-phthalazine-l,4-dione; A mixture of 5-Bromo-isobenzofuran-l,3-dione (6.Og, 26.4mmol) and hydrazine hydrate (1.5ImL, 32.4mmol) in isopropanol (12OmL) was heated at reflux for 4h. The mixture was allowed to cool and the precipitate was filtered and washed with water (50 mL). The filter cake was dried to afford the title compound (4.6g, 72.3%) as a white solid. m/z (M+l) = 241.05
5-Bromo-1, 3-isobenzofurandione (14. 8 g, 65.4 mmol) was suspended in acetic acid (150 mL), and treated with hydrazine hydrate at (10 mL) at 80 overnight. The mixture was cooled, filtered, and the residue was washed with methanol. The residue was triturated with 4M NAOH (ca. 250 mL), and filtered. The pale yellow filtrate was acidified with conc. HCL, and filtered. The residue was azeotroped with toluene (x4), and suspended in POC1s (75 mL). N, N-DIISOPROPYLETHYLAMINE (10 mL) was slowly added and the mixture was heated to reflux for 3 h and then concentrated under reduced pressure, suspended in chloroform and filtered. The filtrate was poured onto ice, and the organic phase was washed with sodium bicarbonate solution, followed by brine. The organic phase was dried (sodium sulfate) and filtered through a pad of silica, eluting with chloroform, which after evaporation gave an off-white solid (6.5 g, 36%)
With hydrogenchloride; hydrazine hydrate; In ethanol;
Step 1: 6-bromo-2,3-dihydrophthalazine-1,4-dione Hydrazine monohydrate (2 ml, 33.0 mmol) was added to a suspension of <strong>[86-90-8]4-bromophthalic anhydride</strong> (7.5 g, 33.0 mmol) in ethanol (70 ml) and the resulting mixture was stirred at 90 C. for 24 hr. The volume of the reaction mixture was then reduced to half volume under reduced pressure and the residue was treated 0.5 N aq. HCl (20 mL). The title compound precipitated as a white solid and was collected by filtration (4.86 g, 61%); LRMS ESI+ (M+H)+ 241.
With sodium acetate; acetic acid;Heating / reflux;
5.52 l-f2-CHLQRO-PHENYLV3-r2-(2.6-DIOXO-PIPERIDIN-3-YLV1.3- DIOXO-2.3-DIHYDRO- 1H-ISOINDOL-5-YLMETHYL1-UREAStep .: A mixture of <strong>[86-90-8]4-bromophthalic anhydride</strong> (10.0 g, 44.1 mmol), rac-a- aminoglutarimide hydrochloride (7.25 g, 44.0 mmol) and sodium acetate (3.61 g, 44.0 mmol) in acetic acid (150 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was stirred in water (170 mL) for 3 hours, and the resulting solid was filtered, washed with additional water (80 mL), and dried under vacuum, to afford 13.8 g of 5-bromo-2-(2,6-dioxo-piperidin-3-yl)-isoindole-l ,3-dione, in 93% yield; 1H NMR (DMSO-(Z6) delta 2.03-2.10 (m, IH), 2.43-2.63 (m, 2H), 2.82-2.97 (m, IH), 5.17 (dd, J = 12.8 Hz, J = 5.3 Hz, IH), 7.85-7.88 (d, J = 7.9 Hz, IH), 8.10 (dd, J = 7.9 Hz, J = 1.7 Hz, IH), 8.16 (d, J = 1.7 Hz, IH), 1 1.15 (s, IH); 13C NMR (DMSCW6) delta 21.9, 30.9, 49.2, 125.3, 126.4, 128.5, 130.1, 133.2, 137.6, 165.9, 166.4, 169.7, 172.7; Anal. Calcd for C13H9N2O4Br: C, 46.32; H, 2.69; N, 8.31. Found: C, 46.23; H, 2.47; N, 8.41.
92%
With sodium acetate; In acetic acid; at 20 - 80℃; for 16h;
To a solution of <strong>[86-90-8]4-bromophthalic anhydride</strong> (15.0 g, 66.1 mmol, CAS86-90-8) in acetic acid (225 mL) was added 2,6-dioxopiperidin-3-amine hydrochloride (10.87 g, 66.1 mmol, CAS24666-56-6) and sodium acetate (5.42 g, 66.07 mmol) at rt. The reaction mixture was heated to 80 C. and stirred for 16 h. The resulting reaction mixture was cooled to rt and concentrated on a rotary evaporator. The obtained residue was suspended in water (255 mL) and the resulting mixture was cooled to 0 C. The resulting slurry was stirred at 0 C. for 1 h. The resulting precipitate was filtered, washed with water (60 mL) and dried under vacuum to give the title compound (20.44 g, 92%) as a purple solid. LC-MS (ESI+) m/z 336.9 (M+H)+.
60%
With potassium acetate; acetic acid; at 90℃; for 12h;
To a solution of 3-aminopiperidine-2,6-dione (7.98 g, 48.4 mmol, HCl salt, CAS24666-56-6), KOAc (13.4 g, 136 mmol) in HOAc (200 mL) was added 5-bromoisobenzofuran-1,3-dione (10.0 g, 44.0 mmol, CAS282-73-5). The mixture was then heated to 90 C. and stirred for 12 hours. On completion, the mixture was cooled down to 25 C. and diluted with water (800 mL), and then filtered to give a filter cake. The filter cake was stirred in DCM (20 mL) for 1 hour and filtered to give a filter cake. The filter cake was dried in vacuo to give the title compound (9.00 g, 60% yield) as a blue solid. 1H NMR (400 MHz, DMSO-d6) delta 11.15 (s, 1H), 8.15 (d, J=1.2 Hz, 1H), 8.10 (dd, J=1.6, 8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 5.17 (dd, J=5.6, 12.8 Hz, 1H), 2.95-2.83 (m, 1H), 2.65-2.52 (m, 2H), 2.11-2.00 (m, 1H).
With sodium acetate; acetic acid; for 24h;Heating / reflux;
5.73 l-^-CHLORO-PHENYLVS-rZ-O^-O-METHYL-Z.e-DIOXO- PIPERroiN-3-YL>-1.3-DIOXO-2,3-DIHYDRO-lH-ISQINDOL-S-YLMETHYLl-UREAStep 1: A mixture of <strong>[86-90-8]4-bromophthalic anhydride</strong> (7.53 g, 33.2 mmol), (3S>3- amino-3-methyl-piperidine-2,6-dione hydrobromide (8.00 g, 44.1 mmol) and sodium acetate (2.72 g, 33.2 mmol) in acetic acid (150 mL) was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was stirred in water (170 mL) for 3 hours, and the resulting solid was filtered, washed with additional water (80 mL), and dried, to afford 6.3 g of 5-bromo-2-[(3>S>3-methyI-2,6-dioxo-rhoiperidin-3-yl]-isoindole- 1,3-dione, in 54% yield; 1H NMR (DMSO-J6) delta 1.89 (s, 3H)5 2.01-2.09 (m, IH), 2.53-2.73 (m, 3H), 7.79 (dd, J = 5.7 Hz5 J = 2.7 Hz, IH), 8.06 (m, 2H), 11.04 (s, I H); 13C NMR (DMSO-J6) delta 21.0, 28.5, 29.0, 58.9, 124.9, 125.9, 128.3, 130.0, 133.0, 137.4, 166.6, 167.2, 172.0, 172.1.
5-{(E)=2-[4-((E)-2{1,3-dioxo-3-[3-(triethoxysilyl)propyl]-2,3-dihydro-1H-isoindol-5-yl}vinyl)-2,5-bis(octyloxy)phenyl]vinyl}-2-[3-(triethoxysilyl)propyl]-1H-isoindole-1,3(2H)-dione[ No CAS ]
2-cycloxexyl-5-[4-[4-(2-cyclohexyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)ethynyl]-2,5-bis(octyloxy)phenyl]ethynyl}-1H-isoindole-1,3(2H)-dione[ No CAS ]
6-(tert-Butyl-dimethyl-silanyloxy)-1,4-bis-[(S)-((1S,2R,4S,5R)-5-ethyl-1-aza-bicyclo[2.2.2]oct-2-yl)-(6-methoxy-quinolin-4-yl)-methoxy]-anthraquinone[ No CAS ]
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