* 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 hydrogen bromide; copper(I) bromide; sodium nitrite In water at 0℃;
The synthesis of bromoacetal 6 from phthalimide (7) is shown in FIG. 11. Based on reactions described in the literature, these transformations were carried out on large scale, and some steps were improved. Nitration of 200 g of phthalimide (7) gives 146 g of 5-nitrophthalimide (8). Reduction of 8 by catalytic hydrogenation, according to the literature procedure, is a bottleneck in the synthesis because of the large volume of solvent needed. With a 2 L Parr hydrogenator pressure vessel, 30 g of 8 is converted to 25 g of amine 9. The next step is also a reduction; aminophthalide 10 is obtained quantitatively from 9 by copper-catalyzed reaction with zinc in aqueous base. Steps b and c could be combined by treating 8 with zinc dust and copper(II) sulfate in 2 M aq. sodium hydroxide. This variation, which is not shown in FIG. 11, removes the bottleneck, potentially allowing 100 g of 10 to be prepared in one step from 146 g of 9. The reaction conditions for the steps shown in FIG. 11 are as follows: a) HNO3, H2SO4, 0° C., 56percent ; b) 5percent Pd/C, H2, EtOAc, 97percent ; c) Zn, CuSO4, 6 M NaOH, 5° C. then heated at 70-80° C. 16 h, 100percent ; d) NaNO2, 4 M HBr, followed by CuBr at 0° C.; e) DIBAL, toluene, -42° C.; f) BF3 OEt2, MeOH, RT.Aminophthalide 10 is converted to bromophthalide 11 in 76percent yield by means of the Sandmeyer reaction. 36 g of 11 was prepared in one batch. Reduction of 11 with diisobutylaluminum hydride gives bromolactol 12, a novel compound in this series, in 77percent yield. Bromoacetal 6 was then prepared in 96percent yield by reaction of 12 with boron trifluoride etherate in methanol. 6 was also prepared on a 3 g scale. Overall, the synthesis of 6 shown in Scheme 3 is very effective, because the yields are generally high and only the last two steps (e and f) require chromatography for product purification.
76.8%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 1 h; Stage #2: With copper(I) bromide In water at 20℃;
20 g (0.13 mol) of 5-aminoisobenzofuranone, 30 ml of 47percent HBr solution was added to a 250 ml three-necked flask, and the temperature was slowly controlled at 0 ° C.Then slowly adding 5 ml of an aqueous solution of sodium nitrite, wherein sodium nitrite contains 10.16 g (0.14 mol), and stirring for 1 h;20.56g (0.14mol) of cuprous bromide is dissolved in 5ml of 47percent hydrobromic acid solution, slowly added dropwise to the diazonium salt solution prepared above, and reacted at room temperature for 1h-3h;Filtration, washing with water and recrystallization from isopropanol gave a white powder, i.e., 5-Bromophthalide, 21.6 g, yield 76.8percent.
Reference：
[1] Patent: US2011/77394, 2011, A1, . Location in patent: Page/Page column 15
[2] Patent: CN108383833, 2018, A, . Location in patent: Paragraph 0013
[3] Journal of the Chemical Society, 1931, p. 867,869
[4] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1195 - 1204
[5] European Journal of Medicinal Chemistry, 2010, vol. 45, # 5, p. 1941 - 1946
2
[ 68837-59-2 ]
[ 64169-34-2 ]
Yield
Reaction Conditions
Operation in experiment
59%
With potassium bromate; sodium hydrogensulfite In water; ethyl acetate at 20℃; for 40 h;
Potassium bromate (3 mmol) in water (1.1 mL) was added to a solution of 4-bromo-2-methylbenzoic acid (1 mmol) in ethyl acetate (3 mL); then, a solution of sodium bisulfite (3 mmol) in water (3 mL) was slowly dripped. The resulting two-phase mixture was stirred at 20°C for 40 hours. After completion, the organic phase was separated, and the aqueous layer extracted with ethyl acetate (3 x 3 mL); the unified organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo, affording the desired product as a white solid [5]. Yield: 59percent. TLC (cyclohexane – ethyl acetate 8:2): Rf = 0.38. Mp: 155°C. 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.79 (d, J = 8.5 Hz, 1H, H7), 7.73 – 7.64 (m, 2H, H4,6), 5.30 (s, 2H, CH2).
23%
With sodium bromate; sodium hydrogen sulfate In water; ethyl acetate for 24 h; Reflux
To a combined mixture of S17-1 (80 g, 0.37 mol, 1.0 eq.) in EtOAc (700 mL) and NaBrO3 (168 g, 1.12 mol, 3.0 eq.) in water (400 mL) was added slowly a solution OfNaHSO4 (134 g, 1.12 mol, 3.0 eq.) in water (900 mL) over a period of 30 min. The resulting mixture was stirred at reflux for 24 h. After cooling down, the organic layer was separated, the aqueous phase was further extracted with EtOAc(500 mLx3). The combined organic layers was washed with saturated aqueousNa2CO3 solution (500 mL), dried over anhydrous Na2SO4, filtered, and then concentrated to dryness under reduced pressure to give the desired product S 17-2 (18 g, 23 percent) as a white solid: 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J= 8.4 Hz, 1 H), 7.67-7.65 (m, 2 H), 5.29 (s, 2 H).
Reference：
[1] Tetrahedron Letters, 2001, vol. 42, # 9, p. 1647 - 1649
[2] Arzneimittel-Forschung/Drug Research, 2005, vol. 55, # 10, p. 588 - 597
[3] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 754 - 763
[4] Patent: WO2010/132670, 2010, A2, . Location in patent: Page/Page column 170-171
[5] Synthetic Communications, 2003, vol. 33, # 19, p. 3435 - 3453
3
[ 38568-41-1 ]
[ 64169-34-2 ]
Yield
Reaction Conditions
Operation in experiment
48%
With diisobutylaluminium hydride In dichloromethane; toluene at -30 - 20℃; for 1 h; Inert atmosphere
General procedure: A solution of Phthalic acid diethyl ester (1g, 4.5 mmol)in CH2Cl2 at -30°C was treated with DIBAL-H (11.25 mL,11.25 mmol, 1 M solution in toluene). The reaction mixture was allowed to stir for next 1h at room temperature and quenched with saturated NH4Cl solution and 1 M HCl at 0°C. After warming up to room temperature more CH2Cl2 was added, organic layer was separated, washed with brine solution, dried over Na2SO4 and concentrated in vacuo.Chromatography on silica gel with hexane-EtOAc (1:1) asthe eluent afforded the phthalide 4a.
Reference：
[1] Letters in Organic Chemistry, 2016, vol. 13, # 2, p. 127 - 134
4
[ 6941-75-9 ]
[ 64169-34-2 ]
Yield
Reaction Conditions
Operation in experiment
48.5%
With hydrogenchloride; sodium tetrahydroborate In ethanol; water at 20 - 85℃; for 7 h;
Sodium borohydride (12.6 g, 330 mmol) was added to a mixed solvent of ethanol (300 mL) and water (50 mL)Add 5-bromophthalimide in 4 batches with stirring at 20-30 ° C(30.0 g, 132 mmol, stirred for 30 min after each addition).After the addition was complete, the reaction was incubated for 2h, hydrochloric acid solution (mass percent concentration 18percent, 180g, 883.5mmol) was added dropwise at 20-30 ° C, heated to 75-85 ° C after dropping,The reaction was incubated 3h, evaporated to ethanol under reduced pressure to give an aqueous white solid.Solid plus toluene (225ml), water (300ml), 45-55 ° C for 30min, to clarify the upper and lower.The layers were separated and the aqueous layer was extracted with toluene (150 mL * 1).The combined toluene layers were washed with saturated brine (150 ml * 1).Divided toluene layer, add water 225ml, sodium hydroxide (6g), stirred at 80 for 3h. The hot toluene is removed by hot section and extracted with toluene (50 ml * 1).Sub-water layer was cooled to 30 ° C dropwise hydrochloric acid (21.0g), heated to 75-85 ° C, incubated for 2-3h.Drop to 50 ° C and extract with toluene (225 ml * 1, 150 ml * 1).Toluene was combined and washed with water (50 ml * 1).Atmospheric pressure concentrated toluene layer to 5.5X, slowly cooled to 50 precipitated white crystals, 50 stirring 1h, then slowly cooled to 0-5 incubated 1h.Filtration and crystallization from ice-toluene (60 ml) gave a white 5-bromophthalide (13.7 g, 48.5percent yield) after drying in vacuo. HPLC: 98.0percent.
Reference：
[1] Patent: CN107082769, 2017, A, . Location in patent: Paragraph 0019; 0020; 0021; 0022
5
[ 171011-37-3 ]
[ 64169-34-2 ]
[ 19477-73-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 12, p. 2445 - 2452
[2] ChemCatChem, 2014, vol. 6, # 1, p. 109 - 112
[3] Tetrahedron, 2014, vol. 70, # 13, p. 2286 - 2293
6
[ 86-90-8 ]
[ 64169-34-2 ]
Yield
Reaction Conditions
Operation in experiment
35%
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.
Reference：
[1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 14, p. 2644 - 2649
17
[ 136918-14-4 ]
[ 64169-34-2 ]
Reference：
[1] Patent: US2011/77394, 2011, A1,
18
[ 85-44-9 ]
[ 64169-34-2 ]
Reference：
[1] Patent: CN107082769, 2017, A,
19
[ 6968-28-1 ]
[ 64169-34-2 ]
Reference：
[1] Patent: CN107082769, 2017, A,
20
[ 67832-11-5 ]
[ 64169-34-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 754 - 763
21
[ 888030-82-8 ]
[ 64169-34-2 ]
Reference：
[1] Synlett, 2006, # 5, p. 801 - 803
22
[ 171011-37-3 ]
[ 64169-34-2 ]
[ 19477-73-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 12, p. 2445 - 2452
[2] ChemCatChem, 2014, vol. 6, # 1, p. 109 - 112
[3] Tetrahedron, 2014, vol. 70, # 13, p. 2286 - 2293
23
[ 86-90-8 ]
[ 64169-34-2 ]
[ 19477-73-7 ]
Yield
Reaction Conditions
Operation in experiment
38%
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.
Reference：
[1] Asian Journal of Chemistry, 2011, vol. 23, # 4, p. 1829 - 1832
26
[ 64169-34-2 ]
[ 171011-37-3 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 1, p. 339 - 351
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 49, p. 15364 - 15368[3] Angew. Chem., 2016, # 128, p. 15590 - 15594,5
[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1954, vol. 238, p. 2246
27
[ 64169-34-2 ]
[ 670256-21-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With sodium hydroxide; water In methanolHeating / reflux Stage #2: With hydrogenchloride In water
5-Bromo phthalide (9 g, 0.042 mol) was refluxed with 2 (N) aqueous sodium hydroxide (100 ml) in methanol (150 ml) for overnight. The reaction mixture was concentrated under reduced pressure. Concentrated mass was diluted with water and acidified with dilute HCl. The solid precipitates was filtered and residue was washed with cold water and cold ethyl acetate and dried to give the sub-title compound (9.7 g, 100percent) as white solid.
94%
With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 16 h;
Lithium hydroxide (3.45 g, 70.42 mmol, 3.0 eq) was added to a solution of 5-bromophthalide (5.0 g, 23.47 mmol, 1.0 eq) in THF/MeOH/ H2O (2:1:1, 80 mL) and stirred at rt for 16 h, then the solvent was concentrated to afford a residue which was diluted with water (100 mL), adjusted to pH = 3 with HCl (2 N) and extracted with EtOAc (100 mL x 3). The organic layers were collected, dried (Na2SO4), filtered, and concentrated in vacuo to give title product (3.47 g, yield: 94percent) as a white solid, which was used in the next step without further purification. ESI-MS (M+H)+: 231.11H NMR (400 MHz, CD3OD) : 7.88-7.86 (m, 2H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 4.90 (s, 2H)
15.6 g
at 20℃; for 3 h;
Compound I (15.0 g) was added to 2N aqueous lithium hydroxide solution (105 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with 4N hydrochloric acid, and the resulting solid was filtered. The resultant was dried under reduced pressure to give Compound II (15.6 g).
Reference：
[1] Patent: US2008/15237, 2008, A1, . Location in patent: Page/Page column 33
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 16, p. 7144 - 7167
[3] Patent: WO2015/89327, 2015, A1, . Location in patent: Paragraph 0375
[4] Bulletin de la Societe Chimique de France, 1954, p. 769,772
[5] Journal of the Chemical Society, 1931, p. 867,869
[6] Journal of the American Chemical Society, 2010, vol. 132, # 46, p. 16374 - 16376
[7] Patent: EP2612848, 2013, A1, . Location in patent: Paragraph 0259 - 0261; 0337 - 0339; 0406 -0408; 0423 - 0425
28
[ 67-56-1 ]
[ 64169-34-2 ]
[ 670256-21-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With water; lithium hydroxide In tetrahydrofuran at 20℃; for 16 h;
[0338j Lithium hydroxide (3.45 g, 70.42 mmol, 3.0 equiv) was added at room temperature over several minutes to a solution of 5-bromophthalide (5.0 g, 23.47 mmol, 1.0 equiv) in a 2:1:1 solution of THF/MeOH/ H20 (80 mL) and the reaction mixture was stirred at room temperature for 16 h. After removal of the solvent, the residue was diluted with water (100 mL), adjusted to pH = 3 with HC1 (2 N) and extracted with EtOAc (100 mL x 3). The organic layers were collected, dried (Na2SO4), filtered, and concentrated via rotary evaporator to give title product (3.47 g, yield: 94percent) as a white solid, which was used in the next step withoutfurther purification. ESI-MS (M+H) : 231.1. ‘H NMR (400 MHz, CD3OD) (5: 7.88-7.86 (m, 2H), 7.45 (dd, J= 8.4, 2.0 Hz, 1H), 4.90 (s, 2H).
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[2] Patent: US2015/259331, 2015, A1,
30
[ 64169-34-2 ]
[ 868066-91-5 ]
Reference：
[1] Synlett, 2006, # 5, p. 801 - 803
31
[ 64169-34-2 ]
[ 1455091-10-7 ]
Reference：
[1] Patent: WO2013/134660, 2013, A1,
32
[ 64169-34-2 ]
[ 108-95-2 ]
[ 57830-14-5 ]
Yield
Reaction Conditions
Operation in experiment
63%
With potassium carbonate; acetylacetone; copper(I) bromide In N,N-dimethyl-formamide at 90℃; Inert atmosphere
Add phenol (20.4g, 0.22mol) and DMF 50mL to the reaction flask and start stirring.5-Bromoisobenzofuran-1(3H)-one (34.0 g, 0.16 mmol), acetylacetone (3.2 g, 0.03 mol), cuprous bromide (3.6 g, 0.03 mol), potassium carbonate (at room temperature) 30.8g, 0.22mol), three times of nitrogen replacement, heating to 90 ° C, stirring reaction overnight, adding 1000 mL of purified water to the reaction solution, suction filtration, the filter cake was dissolved in 800 mL of dichloromethane, and the organic phase was washed with 800 mL of 1N hydrochloric acid solution, with purified water. 1000 mL washing, drying the organic phase, and concentrating to dryness under reduced pressure to give a yellow solid.The title compound 2b (22.5 g, 63percent) was obtained.
72.22 g
With 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate; copper(l) chloride In 1-methyl-pyrrolidin-2-one at 130℃; for 64 h;
A mixture of 5-bromo-3H-isobenzofuran- 1 -one (75.9 g, 0.36 mol) (Sigma-Aldrich), phenol (67.1 g, 0.713 mol), CuCl (17.6 g, 0.178 mol), 2,2,6,6-tetramethyl-heptane-3,5-dione (TMHD, 7.33 mL) and cesium carbonate (232.3 g, 0.713 mol) in NMP (200 mL) was heated at 130 °C for 64 h. After cooled, reaction mixture was poured into ice/2M HCl mixture (1 L). The mixture was then refluxed for 1 h. After cooled, the solid was collected, rinsed with water and dried in vacuo to provide the title compound (72.22 g, 0.32 mol). lH NMR in DMSO-d6, δ in ppm: 7.82 (dd, 1 H, J = 1.6 Hz, 7.6 Hz), 7.51-7.40 (m, 2 H), 7.3-7.1 (m, 5 H), 5.31 (s, 2 H).
Reference：
[1] Patent: CN108341777, 2018, A, . Location in patent: Paragraph 0199-0202
[2] Patent: WO2013/134660, 2013, A1, . Location in patent: Paragraph 0166
[3] Patent: WO2014/14834, 2014, A1, . Location in patent: Paragraph 0234
5-Bromo phthalide (9 g, 0.042 mol) was refluxed with 2 (N) aqueous sodium hydroxide (100 ml) in methanol (150 ml) for overnight. The reaction mixture was concentrated under reduced pressure. Concentrated mass was diluted with water and acidified with dilute HCl. The solid precipitates was filtered and residue was washed with cold water and cold ethyl acetate and dried to give the sub-title compound (9.7 g, 100%) as white solid.
94%
With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 16h;
Lithium hydroxide (3.45 g, 70.42 mmol, 3.0 eq) was added to a solution of 5-bromophthalide (5.0 g, 23.47 mmol, 1.0 eq) in THF/MeOH/ H2O (2:1:1, 80 mL) and stirred at rt for 16 h, then the solvent was concentrated to afford a residue which was diluted with water (100 mL), adjusted to pH = 3 with HCl (2 N) and extracted with EtOAc (100 mL x 3). The organic layers were collected, dried (Na2SO4), filtered, and concentrated in vacuo to give title product (3.47 g, yield: 94%) as a white solid, which was used in the next step without further purification. ESI-MS (M+H)+: 231.11H NMR (400 MHz, CD3OD) : 7.88-7.86 (m, 2H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 4.90 (s, 2H)
15.6 g
With water; lithium hydroxide; at 20℃; for 3h;
Compound I (15.0 g) was added to 2N aqueous lithium hydroxide solution (105 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with 4N hydrochloric acid, and the resulting solid was filtered. The resultant was dried under reduced pressure to give Compound II (15.6 g).
With hydrogen bromide; copper(I) bromide; sodium nitrite; In water; at 0℃;
The synthesis of bromoacetal 6 from phthalimide (7) is shown in FIG. 11. Based on reactions described in the literature, these transformations were carried out on large scale, and some steps were improved. Nitration of 200 g of phthalimide (7) gives 146 g of 5-nitrophthalimide (8). Reduction of 8 by catalytic hydrogenation, according to the literature procedure, is a bottleneck in the synthesis because of the large volume of solvent needed. With a 2 L Parr hydrogenator pressure vessel, 30 g of 8 is converted to 25 g of amine 9. The next step is also a reduction; aminophthalide 10 is obtained quantitatively from 9 by copper-catalyzed reaction with zinc in aqueous base. Steps b and c could be combined by treating 8 with zinc dust and copper(II) sulfate in 2 M aq. sodium hydroxide. This variation, which is not shown in FIG. 11, removes the bottleneck, potentially allowing 100 g of 10 to be prepared in one step from 146 g of 9. The reaction conditions for the steps shown in FIG. 11 are as follows: a) HNO3, H2SO4, 0 C., 56% ; b) 5% Pd/C, H2, EtOAc, 97% ; c) Zn, CuSO4, 6 M NaOH, 5 C. then heated at 70-80 C. 16 h, 100% ; d) NaNO2, 4 M HBr, followed by CuBr at 0 C.; e) DIBAL, toluene, -42 C.; f) BF3 OEt2, MeOH, RT.Aminophthalide 10 is converted to bromophthalide 11 in 76% yield by means of the Sandmeyer reaction. 36 g of 11 was prepared in one batch. Reduction of 11 with diisobutylaluminum hydride gives bromolactol 12, a novel compound in this series, in 77% yield. Bromoacetal 6 was then prepared in 96% yield by reaction of 12 with boron trifluoride etherate in methanol. 6 was also prepared on a 3 g scale. Overall, the synthesis of 6 shown in Scheme 3 is very effective, because the yields are generally high and only the last two steps (e and f) require chromatography for product purification.
76.8%
20 g (0.13 mol) of 5-aminoisobenzofuranone, 30 ml of 47% HBr solution was added to a 250 ml three-necked flask, and the temperature was slowly controlled at 0 C.Then slowly adding 5 ml of an aqueous solution of sodium nitrite, wherein sodium nitrite contains 10.16 g (0.14 mol), and stirring for 1 h;20.56g (0.14mol) of cuprous bromide is dissolved in 5ml of 47% hydrobromic acid solution, slowly added dropwise to the diazonium salt solution prepared above, and reacted at room temperature for 1h-3h;Filtration, washing with water and recrystallization from isopropanol gave a white powder, i.e., 5-Bromophthalide, 21.6 g, yield 76.8%.
With potassium bromate; sodium hydrogensulfite; In water; ethyl acetate; at 20℃; for 40h;
Potassium bromate (3 mmol) in water (1.1 mL) was added to a solution of 4-bromo-2-methylbenzoic acid (1 mmol) in ethyl acetate (3 mL); then, a solution of sodium bisulfite (3 mmol) in water (3 mL) was slowly dripped. The resulting two-phase mixture was stirred at 20C for 40 hours. After completion, the organic phase was separated, and the aqueous layer extracted with ethyl acetate (3 x 3 mL); the unified organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo, affording the desired product as a white solid [5]. Yield: 59%. TLC (cyclohexane - ethyl acetate 8:2): Rf = 0.38. Mp: 155C. 1H-NMR (300 MHz, CDCl3) delta (ppm) 7.79 (d, J = 8.5 Hz, 1H, H7), 7.73 - 7.64 (m, 2H, H4,6), 5.30 (s, 2H, CH2).
23%
With sodium bromate; sodium hydrogen sulfate; In water; ethyl acetate; for 24h;Reflux;
To a combined mixture of S17-1 (80 g, 0.37 mol, 1.0 eq.) in EtOAc (700 mL) and NaBrO3 (168 g, 1.12 mol, 3.0 eq.) in water (400 mL) was added slowly a solution OfNaHSO4 (134 g, 1.12 mol, 3.0 eq.) in water (900 mL) over a period of 30 min. The resulting mixture was stirred at reflux for 24 h. After cooling down, the organic layer was separated, the aqueous phase was further extracted with EtOAc(500 mLx3). The combined organic layers was washed with saturated aqueousNa2CO3 solution (500 mL), dried over anhydrous Na2SO4, filtered, and then concentrated to dryness under reduced pressure to give the desired product S 17-2 (18 g, 23 %) as a white solid: 1H NMR (400 MHz, CDCl3): delta 7.77 (d, J= 8.4 Hz, 1 H), 7.67-7.65 (m, 2 H), 5.29 (s, 2 H).
With 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 60℃; for 3h;
75.0 g (0.35 mol) of 4-bromo-2-methylbenzoic acid and 600 g of dichloroethane were added to a three-necked reaction flask, and mixed to obtain a mixture one, and N-bromosuccinimide was added to the mixture one 68.3 g (0.38 mol), azobisisobutyronitrile 3.3 g (0.02 mol), mixed well to obtain mixture two, the mixture two was heated to 60 C., and reacted for 3 hours;After the reaction was completed, a reaction solution was obtained. The reaction solution was washed once with a 5% potassium carbonate aqueous solution, once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 71.8 g of 5-bromophthalide. Yield 96.6%,The purity was 98.5% by liquid chromatography
A 500 mL RB flask was charged with aluminum (III) chloride (4.1 g, 31 mmol) and 10 mL of 1, 2-dichloroethane (90 ml, 1142 mmol) , then cooled to 00C. A separate 250 mL flask was charged with 90 mL of 1, 2-dichloroethane (90 ml, 1142 mmol) and cooled to 00C; methylamine (gas) (1.8 g, 59 mmol) was bubbled through the solution for 10 minutes. The dichloroethane solution was slowly poured into the aluminum chloride solution, resulting in the formation of a thick white slush. This was warmed to room temperature. 5-bromoisobenzofuran-1 (3H) -one (5.00 g, 23 mmol) was added in one portion and the reaction mixture was stirred for 2.5 hours and quenched with water. The mixture was filtered to remove the solid impurities, then the filtrate was washed with 0.5N aqueous HCl (100 mL) and brine (200 mL) . The organic layer was dried with MgSO4, filtered, and concentrated to give a white solid. This was triturated with EtOAc and filtered to give 4-bromo-2- (hydroxymethyl) -N-methylbenzamide (3.34 g, 58% yield) as a white solid.
2-Benzyl-4-bromo-benzoic acid (239):239 Ste p l3,5-Dibromo-3H-isobenzofuran-l-one (B3): The mixture of 5-bromo-3H-isobenzofuran-l- one (A3) (51.5g, 242 mmol) in bromobenzene (10OmL) is heated to 158C. Bromine (18.8mL, 363 mmol) is added dropwise to the mixture over 2h. The mixture is stirred for another 30 min. at 158C. The bromobenzene is removed by distillation under vacuum. The residue is vacuum dried 1 hour at 1200C to yield a black crystalline residue. Recrystallization: The residue is193 <n="195"/>dissolved in hot isopropyl ether (30OmL). Activated charcoal (1 g) is added, stirred and filtered while hot. The filtrate is cooled in ice-water bath (00C) over night. The solid is filtered and is rinsed with cold isopropyl ether (2 x 1OmL) and vacuum dry over KOH (KOH) to yield 3,5-dibromo-3H-isobenzofuran-l-one (B3) (38g, 54%, mp: 1000C).
49%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; for 2.5h;Reflux;
10199] 3,5-Dibromoisobenzofuran-1(3H)-one (21b) In a25 mE round bottom flask was added 5 -bromoisobenzothran1(3H)-one (499 mg, 2.34 mmol), N-bromosuccinimide (421mg, 2.37 mmol), 2,2?-azobis(2-methylpropionitrile) (38 mg,0.23 mmol), and chloroform (10 mE). The mixture wasrefluxed for 2.5 hours, then cooled to room temperature andquenched with sat. aq. NaHCO3 (10 mE). The organic layerwas removed, washed with water (10 mE), washed with brine(5 mE), and concentrated on to silica. The crude product waspurified by flash column chromatography using 10% ethylacetate in hexanes to yield 21b as a white solid in 49% yield.10200] ?H NMR (500 MHz, CDC13) oe 7.74-7.83 (m, 3H),7.36 (s, 1H). ECMS does not ionize.
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; for 24h;Reflux;
Example 1A3,5-Dibromo-3H-isobenzofuran-1-oneTo a suspension of <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (5 g, 23.5 mmol) in anhydrous carbon tetrachloride (50 mL) was added N-bromosuccinimide (4.18 g, 23.5 mmol) and a catalytic amount of benzoyl peroxide. The reaction mixture was heated under reflux for 2.5 hours. After cooling, the precipitated solid was filtered off, and the filtrate was concentrated on a rotary evaporator. The residual solid was partitioned between methylene chloride and water. The organic phase was washed with brine, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes to yield the title compound. MS (ESI) m/z 290 (M+H)+.
With N-Bromosuccinimide; In tetrachloromethane; for 0.5h;Reflux; Photolysis;
5-Bromoisobenzofuran-l(3H)-one (1.0 g, 4.69 mmol), NBS (835 mg, 4.69 mmol), and carbon tetrachloride (15.6 mL) were heated to reflux in a 50 mL flask carrying a reflux condenser equipped with a drying tube. The reaction mixture was exposed to light of an ordinary 100-W unfrosted light bulb placed 6-8" from the flask. After 30 min, the succinimide was removed by filtration and the filtrate was concentrated under atmospheric pressure to give crude 3,5-dibromoisobenzofuran-l(3H)-one. To 3,5-dibromoisobenzofuran-l(3H)-one was added methanol directly to afford 5-bromo-3-methoxyisobenzofuran-l(3H)-one. LC/MS: [(M+l)]+ = 244
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane;Reflux;
Example 13:A solution of <strong>[64169-34-2]5-bromophthalide</strong> (1.Og, 4.7 mmol, 1.0 equiv) and NBS (850 mg, 4.7 mmol, 1.0 equiv) in carbon tetrachloride (15 mL) was treated with AIBN (50 mg, cat.) and heated to reflux overnight. The hot reaction mixture was filtered and the filtrate concentrated to a yellowish solid (1.38g, quant.). Crude H NMR indicated this material contained ca. 80% of the desired 3,5-dibromophthalide, and it was carried on without further purification. An aliquot of this crude material (250 mg, 0.69 mmol, 1.0 equiv) in 95% ethanol (6 mL) was treated with phenelzine sulfate (175 mg, 0.75 mmol, 1.1 equiv) and NaHCO3 (250 mg, 2.8 mmol, 4.0 equiv). After stirring overnight at ambient temperature, the reaction mixture was diluted with diethyl ether, washed with dilute NaOH, dilute HCl, and saturated NaHCO3, then dried over Na2SO4 and concentrated. Purification of the residue using flash silica gel chromatography (gradient of 3- 12% ethyl acetate/hexanes) provided 6-bromo-2-phenethyl-l-phthalazinone (147 mg, 0.45 mmol, 65%) as a white solid. This crude phthalazinone (147 mg, 0.45 mmol) was converted, via Methods 1 and 2, to compound 13 (81 mg, 62%) which was isolated as a white solid. [M-H]- = 293.1 m/z. Activity: A
Multi-step reaction with 2 steps
1: Br2 / CCl4 / Heating; irradiation
2: water / Heating
Multi-step reaction with 2 steps
1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / 1,2-dichloro-ethane / Reflux
2: water monomer / 2 h / Reflux
Stage #1: 5-bromo-3H-isobenzofuran-1-one With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene at 20 - 85℃; Inert atmosphere;
Stage #2: With water monomer at 100℃; for 1h;
Stage #1: 5-bromo-3H-isobenzofuran-1-one With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In 1,2-dichloro-ethane at 85℃; for 1h; Inert atmosphere;
Stage #2: With water monomer at 100℃; for 1h; Inert atmosphere;
Stage #1: 5-bromo-3H-isobenzofuran-1-one With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene at 85℃;
Stage #2: With water monomer In benzene at 100℃; for 1h;
Multi-step reaction with 2 steps
1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / chloroform / 24 h / 65 °C / Reflux
2: water monomer / 2 h / 100 °C / Reflux
Multi-step reaction with 2 steps
1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / 1,2-dichloro-ethane / 1 h / 85 °C
2: water monomer / 1 h / 100 °C
Stage #1: 5-bromo-3H-isobenzofuran-1-one With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride for 3h; Inert atmosphere; Reflux;
Stage #2: With water monomer for 2h; Reflux;
2-Oxopropyl 2-Formylbenzoates 1; General Procedure
General procedure: Under argon atmosphere, the respective phthalide (7 mmol, 1.0equiv) was dissolved in CCl4 (35 mL, 0.2 M). NBS (7.7 mmol, 1.1 equiv)and AIBN (0.7 mmol, 0.1 equiv) were added and the reaction mixture was refluxed for 3 h. After stirring for another 1 h at 0 °C, the mixture was filtered, and the filtrate was concentrated under reduced pressure. H2O (25 mL) was then added and the suspension was refluxed 2h. After cooling to r.t., EtOAc was added and the phases were separated.The aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic phases were dried (anhyd MgSO4), filtered, and concentrated under reduced pressure to give the crude corresponding 2-formylbenzoic acid.
23 g
Stage #1: 5-bromo-3H-isobenzofuran-1-one With N-Bromosuccinimide In Carbon tetrachloride for 24h; Reflux; Irradiation;
Stage #2: With water monomer In tetrahydrofuran; acetone for 24h; Reflux;
Multi-step reaction with 2 steps
1.1: bromine / phenyl bromide / 2.5 h / 158 °C
2.1: sodium hydroxide; water monomer / 3 h / 80 °C / Heating / reflux
2.2: 1 h / 0 °C
Stage #1: 5-bromo-3H-isobenzofuran-1-one With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In chloroform Reflux;
Stage #2: With water monomer Reflux;
Multi-step reaction with 2 steps
1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / Carbon tetrachloride / Reflux; Irradiation
2: water monomer / 2 h / 100 °C
Stage #1: 5-bromo-3H-isobenzofuran-1-one With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene at 85℃; for 1h; Inert atmosphere;
Stage #2: With water monomer at 105℃; for 1h;
Multi-step reaction with 2 steps
1.1: N-Bromosuccinimide / 1,2-dichloro-ethane / 80 °C
1.2: 12 h / 80 °C
2.1: water monomer / 2 h / 105 °C
Multi-step reaction with 2 steps
1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / 1,2-dichloro-ethane / 12 h / 80 °C
2: water monomer / 2 h / 105 °C
Stage #1: 5-bromo-3H-isobenzofuran-1-one With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In 1,2-dichloro-ethane at 85℃;
Stage #2: With water monomer at 100℃; for 1h;
With sodium tetrahydroborate; In tetrahydrofuran; at 5 - 25℃; for 4h;
The feed solution for the reaction was prepared by dissolving 455 g of <strong>[86-90-8]4-bromophthalic anhydride</strong> 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 5C to 15C was noted. After approximately 3 hours, all of the <strong>[86-90-8]4-bromophthalic anhydride</strong> 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 32% 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, 10% 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, 95%) 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 (95%). The filtration residue thus formed (272 g, LOD-23%) was found to contain approximately 80% 5-bromophthalide and 20% 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 5% 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 25C 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 95% 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 >98% 5-bromophthalide. The yield was approximately 35%.
~ 15%
With sodium tetrahydroborate; In DMF (N,N-dimethyl-formamide); at 5 - 25℃; for 4h;
The feed solution for the reaction was prepared by dissolving 57 g of <strong>[86-90-8]4-bromophthalic anhydride</strong> 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 <strong>[86-90-8]4-bromophthalic anhydride</strong> 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 70% 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 90% 5-bromophthalide. The overall yield of 5-bromophthalide was approximately 15%.
With sodium tetrahydroborate; In tetrahydrofuran; toluene; at 5 - 25℃; for 3.5h;Conversion of starting material;
Three reactions were carried out essentially as described in Example 1 using different solvent systems. The conversion of the starting material was determined after the completion of the addition of the 4-BPAn solution, by gas chromatography (GC). The results of this determination are presented in Table III. EXAMPLE Solvent Conversion of 4-BPAn BY GC, AREA % 13 Toluene/THF (1:1) 85 14 1,4-dioxane 50 50 15 Methyl tertbutyl ether
With sodium tetrahydroborate; In 1,4-dioxane; at 5 - 25℃; for 3.5h;Conversion of starting material;
Three reactions were carried out essentially as described in Example 1 using different solvent systems. The conversion of the starting material was determined after the completion of the addition of the 4-BPAn solution, by gas chromatography (GC). The results of this determination are presented in Table III. EXAMPLE Solvent Conversion of 4-BPAn BY GC, AREA % 13 Toluene/THF (1:1) 85 14 1,4-dioxane 50 50 15 Methyl tertbutyl ether
With sodium tetrahydroborate; In tert-butyl methyl ether; at 5 - 25℃; for 3.5h;Conversion of starting material;
Three reactions were carried out essentially as described in Example 1 using different solvent systems. The conversion of the starting material was determined after the completion of the addition of the 4-BPAn solution, by gas chromatography (GC). The results of this determination are presented in Table III. EXAMPLE Solvent Conversion of 4-BPAn BY GC, AREA % 13 Toluene/THF (1:1) 85 14 1,4-dioxane 50 50 15 Methyl tertbutyl ether
With sodium tetrahydroborate; In 1,2-dimethoxyethane; at 20 - 30℃; for 4h;
The feed solution for the reaction was prepared by dissolving 227 g of <strong>[86-90-8]4-bromophthalic anhydride</strong> 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 20C. As the starting material was added to the reducing agent slurry, an increase in temperature from 20C to 30C was noted. After approximately 3.0 hours, all of the <strong>[86-90-8]4-bromophthalic anhydride</strong> 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 32% 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, 15% 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 91C 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 50% ethylene glycol dimethyl ether. The filtration residue thus formed was found to contain approximately 80% 5-bromophthalide and 20% 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 90% 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 25C 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 90% 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 >99% 5-bromophthalide. The direct yield was approximately 38%.
~ 33%
With sodium tetrahydroborate; In tetrahydrofuran; at 5 - 25℃; for 3.5h;
The feed solution for the reaction was prepared by dissolving 197 g of <strong>[86-90-8]4-bromophthalic anhydride</strong> 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 5C to 15C was noted. After approximately 2.5 hours, all of the <strong>[86-90-8]4-bromophthalic anhydride</strong> 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 32% 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, 10% 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-25%) was found to contain approximately 90% 5-bromophthalide and 10% 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 6% 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 25C 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 >98% 5-bromophthalide. The direct yield was approximately 33%. The filtrate contained approximately 21 g of a recoverable mixture of 5-bromophthalide (70%) and 6- bromophthalide (30%). The overall yield of this process (after recycling the mother liquor) was between 37 and 40%.
With sodium tetrahydroborate; In tetrahydrofuran;Conversion of starting material;
Operating essentially as described in Example 1, the effect of changing the molar ratio of sodium borohydride : 4- bromophthalic anhydride (NaBH4: 4-BPAn) on the conversion of <strong>[86-90-8]4-bromophthalic anhydride</strong> to 5-bromophthalide (5-BP) and 6- bromophthalide (6-BP) was investigated. HPLC was used in order to determine the relative amounts of the starting material and products. The results are presented in Table II. Table II EXAMPLE MOLAR RATIO COMPOSITION BY HPLC, AREA % NaBH4 : 4-BPAn 4-BPAn 5-BP 6-BP 8 0. 60 2. 9 60. 7 36. 4 9 0. 56 3. 5 60. 9 35. 6 10 0. 53 5. 1 59. 2 35. 2 11 0. 50 8. 4 58. 8 32. 8 From the results shown in Table II, it follows that the optimal NaBH4 : 4-BPAn molar ratio is approximately 0. 56- 0.58, which corresponds to a weight ratio of approximately 962 g NaBH4 to 1 kg 4-BPAn. It is apparent from the results, that the ratio NaBH4 : 4-BPAn in THF is lower than the ratio NaBH4: 4-BPAn in DMF, according to example 3. This is a further unexpected advantage of the use of ether solvents: when an ether solvent such as THF is used in the reduction reaction, lesser quantities of the reducing agent (e. g. , sodium borohydride) are required to accomplish the reaction in comparison to a corresponding reaction in DMF.
With sodium tetrahydroborate; In tetrahydrofuran; at 3 - 37℃;Product distribution / selectivity;
Four reactions were carried out essentially as described in Example 1 at four different temperature ranges: 3-7 C, 10- 15 C, 10-25 C and 23-37 C. The selectivity of the reaction for 5-bromophthalide was determined following the phase separation, by gas chromatography (GC) or by HPLC. The results of this determination are presented in Table I. Table I SELECTIVITY BY HPLC, AREA % EXAMPLE TEMPERATURE C 5-Bromophthalide 6-Bromophthalide 3-7 60 40 10-25 57 43 10-15 58 42 7 23-37 56 44
To a stirring room temperature solution of <strong>[86-90-8]4-bromophthalic anhydride</strong> (3.00 g, 13.22 mmol) in ethanol (10 mL) and tetrahydrofuran (50 mL), under a blanket of nitrogen, add sodium borohydride (1.96 g, 52.86 mmol), in portions. Stir this mixture at ambient temperature for 8 hours and then quench with 2N HC1 (12 mL) and then excess water. Extract the resulting aqueous mixture with diethyl ether then ethyl acetate. Wash the combined extracts with water and brine; dry (sodium sulfate) and concentrate them in vacuo to give a mixture of 5-bromo-3H-isobenzofuran-l-one and 6-bromo-3H- isobenzofuran-1-one, 2.78 g (98%). Use as is without purification. Place the mixture of 5-bromo-3H-isobenzofuran-l-one and 6-bromo-3H- isobenzofuran-1-one (1.50 g, 7.04 mmol), bis (pinacolato) diboron (2.06 g, 8.10 mmol), PdCl2 (dppf) 2'CH2Cl2 (180 mg, 0.246 mmol), potassium acetate (2.07 g, 21.13 mmol) and anhydrous dimethyl sulfoxide (22 mL) in a round bottom flask. Put the reaction in an oil bath and stir it at 85C for 8 hours. Cool the dark brown colored reaction to ambient temperature, quench with ample water and extract the resulting aqueous mixture with dichloromethane. Wash the combined extracts with water and brine; then dry (sodium sulfate) and evaporate them in vacuo. Purify the resulting dark solid on a flash column (silica gel; 0%-20% gradient of THF in CH2C12 then 5% MeOH/20% THF/CH2C12) to provide the product as a mixture of the two title components, 785 mg (43%).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 18h;Inert atmosphere; Large scale;
Preparation of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-isobenzofuran-l-one (the compound of formula (IX))Dimethylformamide (1.5L) was sparged with nitrogen for half an hour. Then 5-bromo- 3H-isobenzofuran-l-one (150g, 704mmol), bis(pinacolato)diboron (215g, 847mmol), potassium carbonate (207g, 2.12mol), and Pd(II) acetate (7.9g, 35mmol) were added, and the mixture was heated to 80-105C for 20 hours. The mixture was cooled to 40C and poured into water (4.5L). A solid was isolated by filtration and dried in an oven at elevated temperature under vacuum. The solid was stirred with ethyl acetate (3L) for 2.5 hours, and undissolved material was removed by filtration though a plug of celite. The filtrate was concentrated using a rotary evaporator under vacuum using a water bath for heating, final volume approximately 400mL. The mixture was heated to reflux, allowed to cool to ambient temperature, and cooled with an ice-water bath for approximately half an hour. The title compound was isolated by filtration, washed with ice cold ethyl acetate (two portions of 50ml_ each), and dried in an oven at 40C using vacuum. Yield 76g (41%). HH-NMR (300 MHz, DMSO-d6) delta (ppm) 7.99-7.95 (m, 1H), 7.87-7.83 (m, 2H), 5.43 (s, 2H), 1.34 (s, 12H). A second crop was obtained from the mother liquor and washings; yield 5.6g (3%). NMR as for the first crop
65.7%
With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 50 - 80℃; for 16h;Inert atmosphere;
To a stirring solution of 5-bromoisobenzofuran-l(3H)-one (500 mg, 2.34 mmol) in dioxane (30 mL) purged with argon was addedbis(triphenylphosphine)palladium(II)chloride (50 mg, 0.070 mmol) and heated to 50 C. To this was added bis(pinacolato)diboron (1.2 g, 4.6 mmol) and potassium acetate (460 mg, 4.69 mmol) and the resultant reaction mixture was stirred at 80 C for 16 h. The reaction mixture was cooled to RT, filtered through celite bed and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isobenzofuran-l(3H)-one (Compound-B) as a solid (400 mg, 65.7%)
57%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;
Step 1: 5-(Tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 ,3-dihydro-2-benzofuran- 1-oneIn a 100 mL round-bottomed flask was added <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (1.00 g, 4.69 mmol), bis(pinacolato)diboron (1.31 g, 5.16 mmol), PdC12(dppf)-CH2C12 adduct(0.383 g, 0.469 mmol), and potassium acetate (1.15 g, 11.7 mmol) in dioxane (20 mL) to give a suspension. The flask was equipped with a reflux condenser and heated to 80 C with stirring under nitrogen for 16 h. The reaction was partitioned between ethyl acetate (100 mL) and water (50 mL), and the organic layer was dried with Na2SO4, filtered, and concentrated. The reaction mixture was purified using ISCO silica gel chromatography (40 g column, gradient from 0% to 100% EtOAc/hexanes) to give thetitle compound (0.695 g, 57%). ?H NMR (400MHz, DMSO-d6) oe 7.97 (s, 1H), 7.85 (s,2H), 5.43 (s, 2H), 1.33 (s, 12H) HPLC RT = 0.76 mm (Column: Waters Acquity BEHC182.0 x 50 mm; Mobile Phase A: 10:90 ACN:water with 0.1% TFA; Mobile Phase B:90:10 ACN:water with 0.1% TFA; Temperature: 40C; Gradient: 0-100% B over 1.5mm; Flow: 1 mL/min).
57%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;
In a 100 ml, round-bottomed flask was added <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (1.00 g, 4.69 mmol), bis(pinacolato)diboron (1.31 g, 5.16 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.383 g, 0.469 mmol), and potassium acetate (1.15 g, 11.7 mmol) in dioxane (20 mL) to give a suspension. The flask was equipped with a reflux condenser and heated to 80 C. with stirring under nitrogen for 16 h. The reaction was partitioned between ethyl acetate (100 mL) and water (50 mL), and the organic layer was dried with Na2SO4, filtered, and concentrated. The reaction mixture was purified using ISCO silica gel chromatography (40 g column, gradient from 0% to 100% EtOAc/hexanes) to give the title compound (0.695 g, 57%). 1H NMR (400 MHz, DMSO-d6) delta 7.97 (s, 1H), 7.85 (s, 2H), 5.43 (s, 2H), 1.33 (s, 12H) HPLC RT=0.76 min (Column: Waters Acquity BEH C182.0×50 mm; Mobile Phase A: 10:90 ACN:water with 0.1% TFA; Mobile Phase B: 90:10 ACN:water with 0.1% TFA; Temperature: 40 C.; Gradient: 0-100% B over 1.5 min; Flow: 1 mL/min).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; dimethyl sulfoxide; at 90℃; for 4h;
Combine 5-bromo-3H-isobenzofuran-l-one (1.0 g, 4.7 mmol), bis- pinocalatodiboron (1.8 g, 7.0 mmol), [1, 1'-bis (diphenylphosphino) - ferocene] dichloropaladium (II) complex with dichloromethane (188 mg, 0.2 mmol) and potassium acetate (1.4 g, 14.0 mmol) in a 100 mL flask with a septum. Add dimethyl sulfoxide (25 mL) and heat in a 90C oil bath for 4 hours. Cool the resulting slurry to room temperature and dilute with water (100 mL). Extract the resulting slurry with dichloromethane (6 x 50 mL). Wash the combined organic layers with brine (40 mL), dry (Na2S04), filter and concentrate in vacuo to obtain 1.3 g of a mixture of the title product and bis-pinocalatodiboron (1 : 0.06), which is used without further purification.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃;Inert atmosphere;
Example 35: Synthesis of 5-(5-Fluoro-4-hydroxymethyl-pyridin-3-yl)-3H-isobenzofuran- 1 -one Step 1 : 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3H-isobenzofuran-1-one (35a) A 100 round bottom flask was charged with <strong>[64169-34-2]5-bromo-3H-isobenzofuran-1-one</strong> (750 mg, 3.52 mmol), bis(pinacolato)diboron (894 mg, 3.52 mmol), potassium acetate (691 mg, 7.04 mmol) and 1,4-dioxane (25 mL). The reaction mixture was evacuated and flushed with N2 twice followed by addition of PdClz(dppf).CH2CI2 adduct (144 mg, 0.176 mmol). The reaction was stirred under N2 at 100 "C overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water twice. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was purified using silica gel flash chromatography employing heptane-ethyl acetate(7:3) to afford 5-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-3H-isobenzofuran-1-one.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; water; at 80℃; for 48h;Inert atmosphere;
Step 1: Preparation of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-benzofuran-1(3H)-one A mixture of <strong>[64169-34-2]5-bromo-2-benzofuran-1(3H)-one</strong> (500 mg, 2.34 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (653 mg, 2.57 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichlorometahne(1:1) (96 mg, 0.12 mmol), and potassium acetate (689 mg, 7.02 mmol) in dioxane (12 mL) was heated at 80 C. for 48 hours under nitrogen. After cooling to room temperature, water was added and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and filtered through a Celite pad. The filtrate was concentrated and used to the next reaction with no purification. (unstable on silica gel)
With bis(diphenylphosphino)palladium(II); potassium acetate; In toluene; at 80℃; for 2h;Microwave irradiation;
Step A: 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-benzofuran-l(3H)-one To a microwave tube containing a stir bar was added 5-bromo-2-benzofuran-l (3H)-one (0.10 g, 0.47 mmol), Bis(pinacolato)diboron (0.12 g, 0.47 mmol), bis(diphenylphosphino)palladium(II) (0.010 g, 0.014 mmol), potassium acetate (0.14 g, 1.4 mmol) and anhydrous toluene (10 mL). The resulting mixture was capped and heated at 80 C for 2 h. The reaction mixture was diluted with benzene and washed successively with water and brine. The organic layer was then dried (Na2S04), filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexanes/EtOAc = 1/1) to provide 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-benzofuran-l(3H)-one. LC/MS: [(M+l)]+ =261.
With potassium acetate; In toluene; at 80℃; for 2h;
[0200] To a microwave tube containing a stir bar was added 5-bromo-2-benzofuran-1 (3H)-one (0.10 g, 0.47 mmol),Bis(pinacolato)diboron (0.12 g, 0.47 mmol),bis(diphenylphosphino)palladium(II) (0.010 g, 0.014 mmol), potassium acetate (0.14 g, 1.4 mmol) and anhydrous toluene(10 mL). The resulting mixture was capped and heated at 80 C for 2 h. The reaction mixture was diluted with benzeneand washed successively with water and brine. The organic layer was then dried (Na2SO4) filtered, and concentrated.The resulting residue was purified by silica gel column chromatography (hexanes/EtOAc = 1/1) to provide 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-benzofuran-1(3H)-one. LC/MS: [(M+1)]+ =261.
To a stirring room temperature solution of 4-bromophthalic anhydride (3.00 g, 13.22 mmol) in ethanol (10 mL) and tetrahydrofuran (50 mL), under a blanket of nitrogen, add sodium borohydride (1.96 g, 52.86 mmol), in portions. Stir this mixture at ambient temperature for 8 hours and then quench with 2N HC1 (12 mL) and then excess water. Extract the resulting aqueous mixture with diethyl ether then ethyl acetate. Wash the combined extracts with water and brine; dry (sodium sulfate) and concentrate them in vacuo to give a mixture of 5-bromo-3H-isobenzofuran-l-one and 6-bromo-3H- isobenzofuran-1-one, 2.78 g (98%). Use as is without purification. Place the mixture of 5-bromo-3H-isobenzofuran-l-one and 6-bromo-3H- isobenzofuran-1-one (1.50 g, 7.04 mmol), bis (pinacolato) diboron (2.06 g, 8.10 mmol), PdCl2 (dppf) 2'CH2Cl2 (180 mg, 0.246 mmol), potassium acetate (2.07 g, 21.13 mmol) and anhydrous dimethyl sulfoxide (22 mL) in a round bottom flask. Put the reaction in an oil bath and stir it at 85C for 8 hours. Cool the dark brown colored reaction to ambient temperature, quench with ample water and extract the resulting aqueous mixture with dichloromethane. Wash the combined extracts with water and brine; then dry (sodium sulfate) and evaporate them in vacuo. Purify the resulting dark solid on a flash column (silica gel; 0%-20% gradient of THF in CH2C12 then 5% MeOH/20% THF/CH2C12) to provide the product as a mixture of the two title components, 785 mg (43%).
Example 3 A mixture of 5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02 mol) and Cu(CN)2 (2.3 g, 0.02 mol) in NMP (60 mL) were stirred at 140° C. for 3hrs. Then solvent was removed by distilation under reduced pressure and the residue was refluxed in water (150 mL) for 10 minutes and allowed to cool to room temperature. Filtration and followed by drying in vacuo give the crude 5-cyano-3H-isobenzofuran-1-one (2.1 g) (HPLC 97percent).
tetrakis(triphenylphosphine)palladium (0); In N,N-dimethyl-formamide;
Example 1 A mixture of Zn(CN)2 (2.4 g, 0.02 mol) and 5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02 mol) in DMF (80 mL) were stirred at room temperature under an atmosphere of argon for 30 minutes. Then dissolved oxygen was removed by bubbling argon through the reaction mixture for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium (0) (1.2 g, 0.00096 mol,). Then the reaction was heated at 75° C. for 3 hrs, and then the solvent was removed under reduce pressure and the residue poured into water (150 mL). Filtration and followed by drying in vacuo give the crude 5-cyano-3H-isobenzofuran-1-one (2.8 g) (HPLC 95percent).
With NaCN;tetrakis(triphenylphosphine)palladium (0); In N,N-dimethyl-formamide;
Example 2 A mixture of Zn(CN)2 (0.3 g, 0.00256 mol), NaCN (1 g, 0,02 mol) and 5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02 mol) in DMF (80 mL) were stirred at room temperature under an atmosphere of argon for 30 minutes. Then dissolved oxygen was removed by bubbling argon through the reaction mixture for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium (0) (1.2 g, 0.00096 mol). Then the reaction was heated at 75° C. for 3 hrs, and then the solvent was removed under reduce pressure and the residue poured into water (150 mL). Filtration and followed by drying in vacuo give the crude 5-cyano-3H-isobenzofuran-1-one (2.7 g) (HPLC 94percent).
With triethylamine;tetrakis(triphenylphosphine) palladium(0); copper(I) iodide; In N,N-dimethyl-formamide;
Preparation 9 Preparation of 5-[3-(Tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-3H-isobenzofuran-1-one To a mixture of <strong>[64169-34-2]5-bromophthalide</strong> (20.00 g, 9.39 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (5.3 ml, 37.6 mmol), copper(I) iodide (0.645 g, 3.39 mmol), triethylamine (1.90 g, 18.8 mmol) in DMF (20 ml), was added tetrakis(triphenylphosphine)palladium (1.30 g, 1.13 mmol). The mixture was heated at 65 C. under argon for 16 hours, cooled to room temperature and diluted with diethyl ether (250 ml). The filtrate was washed with brine (4*100 ml), dried over anhydrous Na2SO4, and concentrated to give a dark-reddish residue. Purification of the residue mixture by silica gel column chromatography, eluted with a gradient of EtOAc, led to 5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-3H-isobenzofuran-1-one as a white solid (2.23 g, 87%). 1H NMR (500 MHz, DMSO-d6) delta ppm 1.50 (m, 4H) 1.69 (m, 2H) 3.49 (m, 1H) 3.77 (m, 1H) 4.50 (m, 2H) 4.83 (m, 1H) 5.40 (s, 2H) 7.63 (d, J=6.83 Hz, 1H) 7.77 (s, 1H) 7.84 (d, J=7.81 Hz, 1H); LR MS (EI): 272 (M+).
Method 0 : 4-bromo-2- (hydroxymethyl) -N- (2,2,2- trifluoroethyl) benzamide; [00134] To a stirred suspension of aluminium trichloride (4.07 g, 30.5 mmol) in dichloroethane (60 ml) cooled to 5C under a nitrogen atmosphere was added the solution of trifluoroethylamine (5.84 g, 38.7 mmol) at such a rate to keep the temperature of the reaction mixture below 100C. After complete addition the reaction mixture was allowed to warm up to room temperature and stirred at this temperature for 4 hours. After this time bromophthalide powder (5 g, 23.5 mmol) was added in one portion and the reaction mixture was then heated to 800C for 18 hours. TLC showed complete conversion from starting material to product and the reaction was carefully quenched with iced water (100 ml) and stirred for 30 minutes until all the ice melted. Dichloromethane was added and the mixture was filtered through a pad of silica and washed with copious amounts of DCM to remove the aluminium residues. The filtrate was separated and the aqueous layer was further extracted with DCM (2 x 100 ml) . The organic layers were combined and dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white powder (3.37 g, 46% yield) . 1H NMR (DMSO D6, 400 MHz) 4.02-4.11 (2H, m) , 4.60-4.61 (2H, m) , 5.43- 5.46 (H, m) , 7.36-7.39 (H, d) , 7.55-7.57 (H, m) , 7.76 (H, s) and 9.09-9.12 (H, m) ; MS (ES+) 312, (ES") 310.
To a stirred suspension of aluminium trichloride (5.30 g, 39.8 mmol) in DCE (50 ml_) at 0C was added 2,2,2-trifluoroethylamine (5 g, 50.5 mmol). This was stirred for 4 h before addition of <strong>[64169-34-2]5-bromophthalide</strong> (5.30 g, 39.8 mmol) in one portion, and then heated to 80C for 17 h. The mixture was quenched with iced water (100 ml_) and stirred for 30 min. DCM (50 ml_) was added and the mixture was filtered through silica. The organic layers were washed with H2O (3 x 100 ml_) and the aqueous layers were back-extracted into DCM (50 ml_). The combined organic layers were dried (MgSO ), filtered and concentrated to give an off-white solid. The crude mixture (2.2 g) containing -50% residual 5- bromophthalide was progressed to the next step. LCMS (ES+) 312, 314 (M+H)+
To a stirred suspension of aluminum chloride (8.14 g, 61.0 mmol) in CH2CI2 at 0C under argon was added 2,2,2-trifluoroethanamine (6.08 mL, 77 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 4 h. 5- bromoisobenzofuran-l(3H)-one (10.0 g, 46.9 mmol) was added to the reaction mixture, and heated at 80C overnight. The reaction was carefully quenched with ice water (150 mL) and stirred until the ice was melted. The resulting mixture was diluted with CH2CI2 (150 mL) and filtered through a pad of silica, eluting with additional CH2C12. The layers were separated, and the aqueous layer was extracted with CH2Cl2(3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 4-bromo-2-(hydroxymethyl)-N- (2,2,2-trifhioroethyl)benzamide. LRMS (ESI) calc'd for CioHi0BrF3N02[M+H]+: 312, 314 (1 : 1), found 312, 314 (1 : 1).
To a stirred suspension of aluminum chloride (8.14 g, 61.0 mmol) in CH2C12 at 0C under argon was added 2,2,2-trifluoroethanamine (6.08 ml, 77 mmol). The reaction mixture wasallowed to warm up to room temperature and stirred for 4 h. <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (10.0 g, 46.9 mmol) was added to the reaction mixture, and heated at 80C overnight. The reaction was carefully quenched with ice water (150 mL) and stirred until the ice was melted. The resulting mixture was diluted with CH2C12 (150 mL) and filtered through a pad of silica, eluting with additional CH2C12. The layers were separated, and the aqueous layer was extractedwith CH2C12 (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 4-bromo-2-(hydroxymethyl)-N-(2,2,2-trifluoroethyl)benzamide. LRMS (ESI) calc?d for C,0H,0BrF3NO2 [M+H]: 313, found 313.
[00486] Intermediate 44a: 2-[4-bromo-2-(hydroxymethyl)phenyl]propan-2-oI[00487] Bromo(methyl)magnesium (4.5mL, 9.ggmmol) was slowly added to a solution of <strong>[64169-34-2]5-bromo-3H-isobenzofuranone</strong> (850mg, 3.ggmmol) in dry THF (4OmL) at 0 C, under a nitrogen atmosphere,and the mixture was stirred at room temperature overnight. The mixture was cooled to 0 C and sat. aq. NH4CI (3OmL) was slowly added. The two layers were separated and the aqueous extracted with EtOAc (3 x 3OmL). The combined organic layers were washed with brine (5OmL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was filtered through a plug of silicagel using an eluent of 50% EtOAc in heptane. The filtrate was concentrated to afford 2-[4-bromo-2-(hydroxymethyl)phenyl]propan-2-ol (91 8mg, 3.74mmol, 94% yield) as a light grey solid which wasused in the next step without further purification.1H NMR (CDCI3, 400MHz) O/ppm: 7.49 (1H, d, J= 2.0Hz), 7.39 (1H, dd, J= 8.4Hz, 2.0Hz), 7.18(1H, d, J= 8.4Hz), 4.80 (2H, d, J= 3.2Hz), 3.58 (1H, brs), 2.99 (1H, brs), 1.67 (6H, 5).MS Method 2: RT: 1.40 mi mlz 208.8/210.8 [M+H]
82%
A solution of <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (2.00 g, 9.4 mmol) in dry tetrahydrofuran (100 mL) under argon was cooled in an ice bath. Methylmagnesium bromide (9.3 mL, 28.0 mmol, 3M in diethylether) was added drop wise and the resulting mixture was left to warm to room temperature overnight. The reaction mixture was cooled to 0 C. and saturated aqueous ammonium chloride added. The mixture was extracted with ethyl acetate and the organics were dried over magnesium sulfate, filtered and concentrated. The crude product was filtered through a plug of silica with 50% ethyl acetate in heptane to give 2-(4-bromo-2-(hydroxymethyl)phenyl)propan-2-ol (1.90 g, 82%) was isolated as a colorless oil. 1H NMR (CDCl3, 400 MHz) delta ppm 7.45 (1H, s), 7.35 (1H, d), 7.14 (1H, d), 4.76 (2H, s) 1.64
To a flask containing a stir bar was added 5-bromo-2-benzoiran-l(3//)-ne (12.0 g, 56.3 mmol) and NBS (15 g, 84 mmol). Triflic acid (50 mL) was then added at O 0C and the resulting mixture was allowed to warm to it and stir for 2 days. TLC analysis of the reaction mixture showed complete reaction. The reaction mixture was poured into ice and the organic layer was separated, washed with brine, water, dried over Na2SO4, filtered, and concentrated to dryness. The residue was then absorbed into silica gel and subjected for purification over a silica MPLC column to give 4,5-dibromo-2-benzofuran-l(3No.)-one. LC-MS: M+l = 291
With N-Bromosuccinimide; trifluorormethanesulfonic acid; In acetonitrile; at 0℃; for 48h;
To a flask containing a stir bar was added commercially available 5-bromo-2-benzofuran-l(3H)-one (12.0 g, 56.3 mmol) and NBS (15 g, 84 mmol). Triflic acid (50 mL) was added at 0 C and the resulting mixture was stirred for 2 days. TLC analysis of the reaction mixture showed a complete reaction; the reaction mixture was poured into an ice and the organic layer separated. The organic layer was washed with aq. NaCl, water, dried over Na2S04, filtered and concentrated to dryness, it was then absorbed onto silica gel and subjected for purification over a silica column to give the title compound.
With N-Bromosuccinimide; trifluorormethanesulfonic acid; at 60℃; for 16h;
INTERMEDIATE 33 4,5-Dibromo-2-benzofuran-l(3H)-one To a mixture of 5-bromo-2-benzofuran-l(3H)-one (2.0 g, 9.4 mmol) and NBS (2.2 g, 12 mmol) was added trifluoromethanesulfonic acid (10 ml) and the mixture was heated to 60 C for 16 hours. TLC showed two new spots, along with some unreacted SM. MPLC purification provided 4,5-dibromo-2-benzofuran-l(3H)-one. LC-MS (IE, m/z): 292 [M + 1]+.
With N-Bromosuccinimide; In trifluorormethanesulfonic acid; at 0 - 20℃; for 48h;
To a fiask containing a stir bar was added <strong>[64169-34-2]5-bromo-2-benzofuran-1(3H)-one</strong> (12.0 g, 56.3 mmol) and NBS (15 g, 84 mmol). Triflic acid (50mL) was then added at o Oc and the resulting mixture was allowed to warm to rt and stir for 2days. TLC analysis of the reaction mixture showed complete reaction. The reaction mixture waspoured into ice and the organie layer was separated, washed with brine, water, dried oyer Na2504, filtered, and concentrated. The residue was then absorbed into silica gel and subjected for purification by MPLC column to giye title compound. LC-MS (IE, miz): 291 [M + 11+.
With N-Bromosuccinimide; trifluorormethanesulfonic acid; at 60℃; for 16h;
[0177] To a mixture of <strong>[64169-34-2]5-bromo-2-benzofuran-1(3H)-one</strong> (2.0 g, 9.4 mmol) and NBS (2.2 g, 12 mmol) was addedtrifluoromethanesulfonic acid (10 ml) and the mixture was heated to 60 C for 16 hours. TLC showed two new spots,along with some unreacted SM. MPLC purification provided 4,5-dibromo-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 292[M + 1]+.
With tri tert-butylphosphoniumtetrafluoroborate;palladium diacetate; In N,N-dimethyl-formamide; at 85℃;Inert atmosphere;
A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)- one (100 g, 469 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(l ,3- dioxolan-2-ylmelhyl)zinc solution (1.033 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 0C for 5 h. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 0C for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichlromethane to afford 5-(l;3-dioxolan-2-ylmethyl)-2-benzofuran-l(3/i)-one. MS: m/z 221 (M+l)+.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere;
Step A: 5-(l,3-Dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one: A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)-one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(l,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 C for 5 hours, checked by HPLC-MS, then stirred at 85 C for 5 more hours. The mixture was then allowed to return to RT for overnight. 2-MethylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgS04, filtered and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in DCM to afford the title compound. LC-MS (IE, m/z): 221 [M+l]+.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere;
Step A: 5 -( 1 ,3 -Dioxolan-2-ylmethyl -2-benzofuran- 1 (3H)-one : A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)-one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(l ,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 C for 5 hours, checked by HPLC-MS, then stirred at 85 C for 5 more hours. The mixture was then allowed to return to RT for overnight. 2-MethylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgS04, filtered and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in DCM to afford the title compound. LC-MS (IE, m/z): 221 [M+l ]+.
With tert-butylphosphonium tetrafluoroborate; palladium diacetate; In N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere;
Step A: 5-(l,3-dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.7 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)-one (100 g, 470 mmol). DMF (1.9 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(l ,3-dioxolan- 2-ylmethyl)zinc solution (1.0 L, 520 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 C for 5 h. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 C for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methyltetrahydrofuran (2.0 L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methyltetrahydrofuran. The organic layers were combined, washed three times with brine, dried over MgSC"4, filtered, and concentrated. The resulting residue was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0->20% ethyl acetate in dichloromethane to afford 5-(l,3-dioxolan-2-ylmethyl)-2-benzofuran- l(3H)-one. MS: m/z 221 (M+l)+.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere;
A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)-one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(l,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 C for 5 h. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 C for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2- methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgS04, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichloromethane to afford 5-(l,3- dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one. LC-MS (IE, m/z): 221 [M+l]+.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃;Inert atmosphere;
A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)-one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(l ,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 C for 5 h. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 C for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgS04, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichloromethane to afford 5-(l,3-dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one. LC-MS (IE, m/z): 221 [M+l]+.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere;
A three-neck 5 round bottomed fiask equipped with a stir bar, firestone yalye, thermocouple, condenser and heating mantie wascharged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (IJ) acetate (250 mg, 1.1 mmol) and <strong>[64169-34-2]5-bromo-2-benzofuran-1(3H)-one</strong> (100 g, 470 mmol). DMF (1.88 L) was added to the fiask, and the mixture was degassed three times by alternating yacuum and nitrogen purge. Commercially ayailable bromo(1,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was agam degassed three times. Themixture was then heated at 85 OC for 5 h. Analysis by HPC-MS indicated the reaction was not complete. The mixture was stirred at 85 OC for 5 more h. The mixture was then allowed to return to room temperature for oyernight. 2-methylTHF (2) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted agam with 2-methylTHF. The organic layers were combined, washed three times with brine (4each), dried oyer Mg504, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichloromethane to afford 5-( 1 ?3-dioxolan-2-ylmethyl)-2-benzofuran- 1 (3H)-one. LC-MS (IE, miz): 221 [M+ 11+.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 20 - 80℃;Inert atmosphere;
A three-neck 5L round bottomed flask equipped with a stir bar, Firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-1(3H)- one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassedthree times by alternating vacuum and nitrogen purge. Commercially available bromo( 1,3 - dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 OC for 5 h. Analysis by HPLCMS indicated the reaction was not complete. The mixture was stirred at 85 OC for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 mm. The layers were separated and theaqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichlromethane to afford 5 -(1,3 -dioxolan-2-ylmethyl)-2-benzofuran- 1(311)-one. LC-MS (IE, m/z): 221 [M+1]+.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 20 - 85℃; for 26h;Inert atmosphere;
Step A: 5-(l,3-Dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one: A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)-one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(l,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via cannula and the mixture was again degassed three times. The mixture was then heated at 85C for 5 h. Analysis by HPLC-LC/MS indicated the reaction was not complete. The mixture was stirred at 85C for 5 more h. The mixture was then allowed to return to rt for 16 h. 2-MethylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgS04, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichloromethane to afford 5-(l,3-dioxolan-2- ylmethyl)-2-benzofuran-l(3H)-one. LC/MS (IE, m/z): 221 [M+l]+.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere;
A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve,thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphoniumtetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo- 2-benzofuran-1(3H)-one (100 g, 470 mmol). DMF (1.88 L)was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo( 1,3 -dioxolan-2-ylmethyl)zinc solution (1 .03 L, 516 mmol) was added viacannula and the mixture was again degassed three times. The mixture was then heated at 85 C for 5 hr. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 C for 5 more h. The mixture was then cooled to return to room temperature for overnight. 2-MethylTHF (2L) and brine were added, and the mixture was stirred for 5 mm. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers werecombined, washed three times with brine (4L each), dried over Mg504, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichloromethane to afford the title compound. MS [M+H] =221.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere;
A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphoniumtetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo- 2-benzofuran-1(3H)-one (100 g, 470 mmol). DMF (1.88 L)was added to the flask, and themixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added viacannula and the mixture was again degassed three times. The mixture was then heated at 85 Cfor 5 hr. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 C for 5 more h. The mixture was then cooled to return to room temperature for overnight.2-MethylTHF (2L) and brine were added, and the mixture was stirred for 5 mm. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over Mg504, filtered, andconcentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichloromethane to afford the title compound. MS [M+H] =221.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere;
Step A: 5-(l ,3-Dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one: A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)-one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(l ,3-dioxolan-2- ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 C for 10 h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgSC^, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichloromethane to afford 5-(l,3-dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere;
Step A: 5-(l,3-Dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one: A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)-one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(l,3-dioxolan-2- ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 C for 10 h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgS04, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichloromethane to afford 5-(l,3-dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 20 - 85℃;Inert atmosphere;
A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and <strong>[64169-34-2]5-bromo-2-benzofuran-1(3H)-one</strong> (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 C for 5 h. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 C for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichlromethane to afford 5-(1,3-dioxolan-2-ylmethyl)-2-benzofuran-1(3H)-one. LC-MS (IE, m/z); 221 [M+1]+.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere;
A three-neck 5 L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and <strong>[64169-34-2]5-bromo-2-benzofuran-1(3H)-one</strong> (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via cannula and the mixture was again degassed three times. The mixture was then heated at 85 C. for 5 hr. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 C. for 5 more h. The mixture was then cooled to return to room temperature for overnight. 2-MethylTHF (2 L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4 L each), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichloromethane to afford the title compound. MS [M+H]+=221.
With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere;
A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser andheating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.7 mmol), palladium (II) acetate(250 mg, 1.1 mmol) and <strong>[64169-34-2]5-bromo-2-benzofuran-1(3H)-one</strong> (100 g, 470 mmol). DMF (1.9 L) was added to the flask, andthe mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc solution (1.0 L, 520 mmol) was added via canula and the mixture was again degassed threetimes. The mixture was then heated at 85 C for 5 h. Analysis by HPLC-MS indicated the reaction was not complete.The mixture was stirred at 85 C for 5 more h. The mixture was then allowed to return to room temperature for overnight.2-methyltetrahydrofuran (2.0 L) and brine were added, and the mixture was stirred for 5 min. The layers were separatedand the aqueous layer was extracted again with 2-methyltetrahydrofuran. The organic layers were combined, washedthree times with brine, dried over MgSO4,filtered, and concentrated. The resulting residue was purified by flash chromatography(1.5 kg silica cartridge), eluting with 0->20% ethyl acetate in dichloromethane to afford 5-(1,3-dioxolan-2-ylmethyl)-2-benzofuran-1(3H)-one. MS: m/z 221 (M+1)+.
With diisobutylaluminium hydride; In dichloromethane; toluene; at -78℃; for 1.5h;
Step 1: To a stirred solution of <strong>[64169-34-2]5-bromo-2-benzofuran-1(3H)-one</strong> (12.60 g; 59.15 mmol; 1 eq.) in dichloromethane (591 mL) cooled to -78 C was added DIBAL (59.15 ml; 1mol/1; 59.15 mmol; 1 eq.) (1 M solution in toluene) dropwise and the mixture was stirred at -78 C, After 60 minutes, approximately 10% more DTBAL solution was added (6 mL) and the reaction left for additional 30 minutes. Before proceeding with the work up, celite was added to the reaction mix, followed up with addition of water (2.64 mL), then 15% NaOH (2.64 niL) and water (6.6 mL). The reaction mix was removed from bath and left to reach RT, then stirred at RT for 40 mm before filtering it over celite. The filtered solution was dried over Na2SO4, filtered and concentrated to dryness to give 5-bromo-1,3-dihydro-2-benzofuran-1-ol as a white solid, Partial Yield: 10.0 g. The celite cake was transferred to a round bottom flask and stirred with DCM for 30 minutes, filtered and dried over Na2SO4 filtered again and concentrated to give additional 1.3 g of product and a total of 11.3 g were obtained (89% yield).
77%
The synthesis of bromoacetal 6 from phthalimide (7) is shown in FIG. 11. Based on reactions described in the literature, these transformations were carried out on large scale, and some steps were improved. Nitration of 200 g of phthalimide (7) gives 146 g of 5-nitrophthalimide (8). Reduction of 8 by catalytic hydrogenation, according to the literature procedure, is a bottleneck in the synthesis because of the large volume of solvent needed. With a 2 L Parr hydrogenator pressure vessel, 30 g of 8 is converted to 25 g of amine 9. The next step is also a reduction; aminophthalide 10 is obtained quantitatively from 9 by copper-catalyzed reaction with zinc in aqueous base. Steps b and c could be combined by treating 8 with zinc dust and copper(II) sulfate in 2 M aq. sodium hydroxide. This variation, which is not shown in FIG. 11, removes the bottleneck, potentially allowing 100 g of 10 to be prepared in one step from 146 g of 9. The reaction conditions for the steps shown in FIG. 11 are as follows: a) HNO3, H2SO4, 0 C., 56% ; b) 5% Pd/C, H2, EtOAc, 97% ; c) Zn, CuSO4, 6 M NaOH, 5 C. then heated at 70-80 C. 16 h, 100% ; d) NaNO2, 4 M HBr, followed by CuBr at 0 C.; e) DIBAL, toluene, -42 C.; f) BF3 OEt2, MeOH, RT.Aminophthalide 10 is converted to bromophthalide 11 in 76% yield by means of the Sandmeyer reaction. 36 g of 11 was prepared in one batch. Reduction of 11 with diisobutylaluminum hydride gives bromolactol 12, a novel compound in this series, in 77% yield. Bromoacetal 6 was then prepared in 96% yield by reaction of 12 with boron trifluoride etherate in methanol. 6 was also prepared on a 3 g scale. Overall, the synthesis of 6 shown in Scheme 3 is very effective, because the yields are generally high and only the last two steps (e and f) require chromatography for product purification.
13 g
With diisobutylaluminium hydride; In dichloromethane; at -78℃; for 2h;
To a solution of <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (21.3 g, 100 mmol) in DCM (200 mL) was added diisobutylaluminum hydride (184 g, 130 mmol) at -78 C. The reaction was stirred at -78 C. until the reaction was complete (?2 h). 10 mL water was added, and 10 mL 4M NaOH (aq.) was added, then 40 mL was water was added, the mixture was stirred at room temperature for 30 mins. The mixture was filtered, the filtrate was concentrated. The resulting solid was purified by flash column chromatography (petroleum ether:EtOAc 100:0 to 80:20) to provide 285 5-bromo-1,3-dihydroisobenzofuran-1-ol (13 g, 60.4 mol) as a white solid. MS (ESI): m/z 196.9 [M-16+1]+.
With potassium acetate In 1,4-dioxane; water at 100℃; for 4h;
28.i
Example 28: Preparation of 4-(l-(2-chloro-6-(trifluoromethyl)benzoyl)-/H-in dazol-3- -2-(difluoromethyl)benzoic acidG-5 28 i) Preparation of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isobenzo furan-l(3H - one (G-l)A mixture of 5-bromoisobenzofuran-l(3H)-one (1.5 g, 7.0 mmol), 4,4,4',4', 5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.1 g, 8.5 mmol), KOAc (2.1 g, 21 mmol), dppf (0.16 g, 0.28 mmol) and Pd(dppf)Cl2 (0.26 g, 0.35 mmol) in dioxane (30ml) was heated at 100 °C for 4 h. The mixture was cooled down and concentrated under reduced pressure. The residue was diluted with H20, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, and concentrated. The residue was purified by flash chromatography (PE: EA = 5: 1) to give the title compound as a white solid. LCMS (ESI)xalc. Ci4Hi8B04 [M+H]+: 261, found: 261
With Oxone; 2-iodo-3,4,5,6-tetramethylbenzoic acid; In water; acetonitrile; at 30℃; for 10h;Green chemistry;
General procedure: In a typical experiment, a round bottom flask containing 4-6mL of acetonitrile/water mixture (1:1) was charged with 0.5-1.0mmol of the diol, 5mol% of TetMe-IA, and oxone (2equiv). The resulting mixture was stirred at rt for benzylic diols and at 45C for aliphatic diols. At the end of the reaction, as judged from TLC analysis, little water was added to dissolve the inorganic salts, and the organic matter was extracted with EtOAc at least two times. The combined extract was dried over anhydrous Na2SO4, concentrated in vacuo to obtain the crude product, which was subjected to silica-gel column chromatography using ethyl acetate/pet ether to isolate the pure product.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In ethanol; at 85℃; for 16h;Inert atmosphere;
5-bromoisobenzofuran-l(3H)-one (5.00 g, 23.5 mmol) was combined with potassium vinyltrifluoroborate (4.72 g, 35.2 mmol), PdCl2(dppf)CH2Cl2 (1.91 g, 2.35 mmol) and TEA (6.54 mL, 46.9 mmol) in ethanol (50 mL). The reaction mixture was purged with nitrogen gas and stirred at 85 C for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3 x 50 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography using CombiFlash (Redisep-40 g, 15 % EtOAc in -hexane) to give Intermediate 1-3 A (3.60 g, 83.0 %) as an off white solid. 1H NMR (300 MHz, DMSO^e) delta ppm 5.41 (s, 2 H), 5.49 (d, J= 10.9 Hz, 1 H), 6.07 (d, J = 17.4 Hz, 1 H), 6.90 (dd, J= 17.8, 10.9 Hz, 1 H), 7.65-7.72 (m, 1 H), 7.76 (s, 1 H), 7.78-7.86 (m, 1 H). LCMS (Method R), retention time: 0.64 min, (M+H) 161.1
65.3%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In N,N-dimethyl-formamide; at 100℃;
10 g (0.04 mol) of <strong>[64169-34-2]5-bromophthalide</strong> and 8.18 g (0.06 mol) of potassium vinyl trifluoroborate were added to a 250 ml three-necked flask.3 g (0.003 mol) of catalyst PdCl2(dppf)-CH2Cl2, 10 ml of triethylamine, 50 ml of DMF as solvent,Nitrogen protection, set the temperature of 100 C reaction 5-10h;The mixture was poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated.The petroleum ether: dichloromethane (3:1) system was passed through a column, and dried in an oven to obtain 4.9 g of a pale yellow solid, yield 65.3%.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In ethanol; for 8h;Inert atmosphere; Reflux;
5-Bromophthalide (50g, 235 mmol), potassium vinyl trifluoroborate (62.9 g, 469 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (9.58 g, 11.7 mmol) were added to ethanol (500 mL) then TEA (65.4 mL, 469 mmol) was added. The reaction mixture was degassed then heated at reflux for 8 h. The reaction was worked up by diluting with ethyl acetate and washing with brine twice. The organic layer was dried and evaporated to dryness. The crude product was purified by MPLC (silica, 600g column) with 25% EtOAc/hexane (3 L) then with 30% EtOAc/Hexane (2 L) to yield the title compound.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In ethanol; for 8h;Reflux;
Step A: 5-ethenyl-2-benzofuran-1(3H)-one: 5-Bromophthalide (50g, 235 mmol), potassium vinyltrifluoroborate (62.9 g, 469 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (9.58 g, 11.7 mmol) wereadded to ethanol (500 mL) then TEA (65.4 mL, 469 mmol) was added. The reaction mixture wasdegassed then heated at reflux for 8 h. The reaction was worked up by diluting with ethyl acetate and washing with brine twice. The organic layer was dried and evaporated to dryness. The crudeproduct was purified by MPLC (silica, 600g column) with 25% EtOAc/hexane (3 L) then with30% EtOAc/Hexane (2 L) to yield the title compound.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In ethanol; for 8h;Reflux;
Step A: 5-ethenyl-2-benzofuran-1(3H)-one: 5-Bromophthalide (50g, 235 mmol), potassium vinyl trifluoroborate (62.9 g, 469 mmol), and PdC12(dppf)-CH2C12 Adduct (9.58 g, 11.7 mmol) were added to ethanol (500 mL) then TEA (65.4 mL, 469 mmol) was added. The reaction mixture wasdegassed then heated at reflux for 8 h. The reaction was worked up by diluting with ethyl acetate and washing with brine twice. The organic layer was dried and evaporated to dryness. The crude product was purified by MPLC (silica, 600g column) with 25% EtOAc/hexane (3 L) then with 30% EtOAc/Hexane (2 L) to yield the title compound
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In ethanol; for 8h;Reflux;
5-Bromophthalide (50g, 235 mmol), potassium yinyl trifluoroborate (62.9 g, 469 mmol), and PdC12(dppf)-CH2C12 Adduct (9.58 g, 11.7 mmol) were added to ethanol (500 mL) then TEA (65.4 mL, 469 mmol) was added. The reaction mixture was degassed then heated at reflux for 8 h. The reaction was worked up by diluting with ethyl acetateand washing with brine twice. The organie layer was dried and eyaporated to dryness. The crudeproduct was purified by MPLC (silica, 600g column) with 25% EtOAclhexane (3 L) then with30% EtOAc/Hexane (2 L) to yield the title compound.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In ethanol; for 8h;Reflux;
5-Bromophthalide (50g, 235 mmol), potassium vinyl trifluoroborate (62.9g, 469 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (9.58 g, 11.7 mmol) were added to ethanol (500 mL) then TEA (65.4mL, 469 mmol) was added. The reaction mixture was degassed then heated at reflux for 8 h. The reaction wasworked up by diluting with ethyl acetate and washing with brine twice. The organic layer was dried and evaporatedto dryness. The crude product was purified by MPLC (silica, 600g column) with 25% EtOAc/hexane (3 L) then with30% EtOAc/Hexane (2 L) to yield the title compound
With potassium carbonate; acetylacetone; copper(I) bromide; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere;
Add phenol (20.4g, 0.22mol) and DMF 50mL to the reaction flask and start stirring.5-Bromoisobenzofuran-1(3H)-one (34.0 g, 0.16 mmol), acetylacetone (3.2 g, 0.03 mol), cuprous bromide (3.6 g, 0.03 mol), potassium carbonate (at room temperature) 30.8g, 0.22mol), three times of nitrogen replacement, heating to 90 C, stirring reaction overnight, adding 1000 mL of purified water to the reaction solution, suction filtration, the filter cake was dissolved in 800 mL of dichloromethane, and the organic phase was washed with 800 mL of 1N hydrochloric acid solution, with purified water. 1000 mL washing, drying the organic phase, and concentrating to dryness under reduced pressure to give a yellow solid.The title compound 2b (22.5 g, 63%) was obtained.
72.22 g
With 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate; copper(l) chloride; In 1-methyl-pyrrolidin-2-one; at 130℃; for 64h;
A mixture of 5-bromo-3H-isobenzofuran- 1 -one (75.9 g, 0.36 mol) (Sigma-Aldrich), phenol (67.1 g, 0.713 mol), CuCl (17.6 g, 0.178 mol), 2,2,6,6-tetramethyl-heptane-3,5-dione (TMHD, 7.33 mL) and cesium carbonate (232.3 g, 0.713 mol) in NMP (200 mL) was heated at 130 C for 64 h. After cooled, reaction mixture was poured into ice/2M HCl mixture (1 L). The mixture was then refluxed for 1 h. After cooled, the solid was collected, rinsed with water and dried in vacuo to provide the title compound (72.22 g, 0.32 mol). lH NMR in DMSO-d6, delta in ppm: 7.82 (dd, 1 H, J = 1.6 Hz, 7.6 Hz), 7.51-7.40 (m, 2 H), 7.3-7.1 (m, 5 H), 5.31 (s, 2 H).
With potassium carbonate; copper(I) bromide; In N,N-dimethyl-formamide; acetylacetone; at 85℃;
j0234j A reactor was charged with DMF (68 Kg), and stirring was initiated. The reactor was then charged with phenol (51 Kg), acetylacetone (8 Kg), 5-bromophthalide (85 Kg), copper bromide (9 Kg), and potassium carbonate (77 Kg). The mixture was heated above 85 C and maintained until reactioncompletion and then cooled. Water was added. Solid was filtered and washed with water. Solid was dissolved in dichloromethane, and washed with aqueous HC1 and then with water. Solvent was removed under pressure and methanol was added. The mixture was stirred and filtered. Solid was washed with methanol and dried in an oven giving 5-phenoxyphthalide (Yield: 72%, HPLC: 99.6%).
With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Reflux;
Step C: tert-Butyl 4-[(l-Oxo-l,3-dihydro-2-benzofuran-5-yl)sulfanyllpiperidine-l-carboxylate A solution of tert-butyl 4-sulfanylpiperidine-l-carboxylate (490 mg, 2.3 mmol) in 20 mL of anhydrous 1,4-dioxane was added 5-bromo-2-benzofuran-l(3H)-one (500 mg, 2.3 mmol), DIEA (596 mg, 4.62 mmol), tris(dibenzylideneacetone)dipalladium (0) (190 mg, 0.12 mmol) and Xantphos (67 mg, 0.12 mmol), and the mixture was heated at reflux under a nitrogen atmosphere overnight. The reaction mixture was concentrated under vacuum, and the resulting residue was purification by prep-TLC (Petrol ether/EtOAc = 2: 1) to provide tert-butyl 4-[(l-oxo-l,3-dihydro- 2-benzofuran-5-yl)sulfanyl]piperidine- 1 -carboxylate. 1H-NMR (400 MHz, CDC13) δ ppm 7.72 (d, J= 8.4 Hz, 1H), 7.60 -7.62 (m, 2H), 5.23 (s, 2H), 3.93-3.97 (m, 2H), 2.72-2.82 (m, 3H), 1.89-1.93 (m, 2H), 1.43-1.49 (m, 2H), 1.39 (s, 9H).
With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Reflux;
[0142] A solution of <strong>[134464-79-2]tert-butyl 4-sulfanylpiperidine-1-carboxylate</strong> (490 mg, 2.3 mmol) in 20 mL of anhydrous 1,4-dioxanewas added 5-bromo-2-benzofuran-1(3H)-one (500 mg, 2.3 mmol), DIEA (596 mg, 4.62 mmol), tris(dibenzylideneacetone)dipalladium (0) (190 mg, 0.12 mmol) and Xantphos (67 mg, 0.12 mmol), and the mixture was heated at reflux undera nitrogen atmosphere overnight. The reaction mixture was concentrated under vacuum, and the resulting residue waspurification by prep-TLC (Petrol ether/EtOAc = 2:1) to provide tert-butyl 4-[(1-oxo-1,3-dihydro-2-benzofuran-5-yl)sulfanyl]piperidine-1-carboxylate.1H-NMR (400 MHz, CDCl3) δ ppm 7.72 (d, J= 8.4 Hz, 1H), 7.60 ∼7.62 (m, 2H), 5.23 (s, 2H), 3.93∼3.97 (m, 2H), 2.72∼2.82(m, 3H), 1.89∼1.93 (m, 2H), 1.43∼1.49 (m, 2H), 1.39 (s, 9H).
With sodium methylate; In N,N-dimethyl-formamide; at 130℃; for 10h;
5-Bromoisobenzofuran-1(3H)-one (18.0 g, 84.5 mmol) was dissolved in DMF (18 mL), and 3-fluorophenol (11.5 mL, 126.8 mmol) and sodium methoxide (28% methanol solution, 24 g, 126.8 mmol) were added. A trap bulb of an evaporator was connected, a nitrogen balloon was set, and the mixture was refluxed under heating at 130C for 10 hr. The reaction mixture was allowed to cool to room temperature, water (100 mL) and 4 mol/L aqueous sodium hydroxide solution (30 mL) were added, and the mixture was washed once with each of diethyl ether (200 mL) and toluene (550 mL). The aqueous layer was adjusted to pH 1-2 by adding 4 mol/L hydrochloric acid (about 20 mL), ethanol (70 mL) was added to a dark-brown aqueous solution, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by suction filtration with a Hirsch funnel, and washed twice with a mixed solvent of ethanol/water =1/1 (20 ml) to give 4-bromo-2-[(3-fluorophenoxy)methyl]benzoic acid (20.5 g, 75%). ESIMS m/z: 323, 325 (M - H)-; 1H NMR (270MHz, CDCl3, delta): 5.48 (s, 2H), 6.66-6.86 (m, 3H), 7.21-7.32 (m, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H).
69%
With methanol; sodium methylate; In N,N-dimethyl-formamide; at 120℃; for 23h;
To a stirred solution of <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (9.5 g, 45 mmol) in DMF (10 mL) was added 3-fluorophenol (6.1 mL, 67 mmol) and sodium methoxide (28% methanol solution, 13 g, 67 mmol), and the solution was stirred for 23 h at 120 C. The reaction mixture was cooled at room temperature, and was pored into 4 M NaOH. The mixture was washed with toluene and diethyl ether. The water layer was acidified with 4 M HCl, and diluted by ethanol. The mixture was stirred overnight and the resultant soid was filtered, washed with water/EtOH = 1/1, and dried under reduced pressure to give 4-bromo-2-((3-fluorophenoxy)methyl)benzoic acid (S2b) (10 g, 69%) as a white solid. 1H NMR (270 MHz, CDCl3): delta 5.48 (s, 2H), 6.66-6.86 (m, 3H), 7.21-7.32 (m, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H). The proton of carboxylic acid was not observed. LC/MS (ESI, [M - H]-, m/z) 323.
4-bromo-N-cyclopropyl-2-(hydroxymethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
To a solution of cyclopropanamine (160 mg, 2.8 mmol) in toluene (8 mL) at 0C was added A1Me3 (1.3 mL, 2.6 mmol). After 5 mi <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong>(0.5 g, 2.4 mmol) was added. The reaction mixture was allowed to warm to rt over a period of 10 mm. After 16 h, the reaction mixture was quenched with the addition of iN NaOH (10 mL). The resulting reaction mixture was diluted with EtOAc, washed with water and brine. The organic phase was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified silica gel chromatography eluting with 0-10% MeOH/DCM to give Compound 595a (0.53 g, 83% yield) as a yellow solid. HPLC RT = 0.70 mm (LCMS Method 0). MS(ES): m/z = 272.2 [M+H]. ?H NMR (400MHz, CD3OD) oe 7.76 - 7.68 (m, 1H), 7.53 - 7.47 (m, 1H), 7.36 (s, 1H), 4.68 (s, 2H), 2.84 (tt, J=7.4, 3.7 Hz, 1H), 0.84 - 0.77 (m, 2H), 0.65 - 0.57 (m, 2H).
83%
To a solution of cyclopropanamine (160 mg, 2.8 mmol) in toluene (8 mL) at 0 C. was added -AlMe3 (1.3 mL, 2.6 mmol). After 5 min, <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (0.5 g, 2.4 mmol) was added. The reaction mixture was allowed to warm to rt over a period of 10 min. After 16 h, the reaction mixture was quenched with the addition of 1N NaOH (10 mL). The resulting reaction mixture was diluted with EtOAc, washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified silica gel chromatography eluting with 0-10% MeOH/DCM to give Compound 595a (0.53 g, 83% yield) as a yellow solid. HPLC RT=0.70 min (LCMS Method O). -MS(ES): m/z=272.2 [M+H]+. -1H NMR (400 MHz, CD3OD) delta 7.76-7.68 (m, 1H), 7.53-7.47 (m, 1H), 7.36 (s, 1H), 4.68 (s, 2H), 2.84 (tt, J=7.4, 3.7 Hz, 1H), 0.84-0.77 (m, 2H), 0.65-0.57 (m, 2H)
Step 1 : 4-bromo-A/-cyclopropyl-2-(hydroxymethyl)benzamide [00297] A solution of cyclopropylamine (0.98 mL, d = 0.824, 14.1 mmol) in dry CH2CI2 (35 mL) was treated with AIMe3 (2 M in hexanes, 7.0 mL, 14 mmol) and the mixture stirred for 15 min. 5-Bromoisobenzofuran-1 (3/-/)-one (2.00 g, 9.39 mmol) was added in two portions 60 s apart and the reaction mixture was then stirred at 40 C for 1 6 h. After cooling to rt, the reaction vessel was placed in a cold water bath and 1 M HCI (1 00 mL) was added cautiously. The resulting slurry was extracted with CH2CI2 (4 x 75 mL), dried (Na2S04) and concentrated to yield the title compound as a white powder.
With water; lithium hydroxide; In tetrahydrofuran; at 20℃; for 16h;
[0338j Lithium hydroxide (3.45 g, 70.42 mmol, 3.0 equiv) was added at room temperature over several minutes to a solution of 5-bromophthalide (5.0 g, 23.47 mmol, 1.0 equiv) in a 2:1:1 solution of THF/MeOH/ H20 (80 mL) and the reaction mixture was stirred at room temperature for 16 h. After removal of the solvent, the residue was diluted with water (100 mL), adjusted to pH = 3 with HC1 (2 N) and extracted with EtOAc (100 mL x 3). The organic layers were collected, dried (Na2SO4), filtered, and concentrated via rotary evaporator to give title product (3.47 g, yield: 94%) as a white solid, which was used in the next step withoutfurther purification. ESI-MS (M+H) : 231.1. ?H NMR (400 MHz, CD3OD) (5: 7.88-7.86 (m, 2H), 7.45 (dd, J= 8.4, 2.0 Hz, 1H), 4.90 (s, 2H).
5-(1-phenylethyl)isobenzofuran-1(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With pyridine; nickel(II) iodide; 4,4'-dimethyl-2,2'-bipyridines; magnesium chloride; zinc; In N,N-dimethyl acetamide; at 25℃; for 16h;Inert atmosphere; Glovebox; Schlenk technique;
General procedure: To a flame-dried Schlenk tube equipped with a stir bar was loaded aryl bromide (0.3 mmol, 100 mol%) and benzyl chloride (0.6 mmol, 200 mol%), followed by addition of ligand 1b (0.03 mmol, 10 mol%), zinc powder (39 mg, 0.6 mmol, 300 mol%), and MgCl2 (28.6 mg, 0.3 mmol, 100 mol%). The tube was moved into an anhydrous glove box, then NiI2 (9.4 mg, 0.03 mmol, 10 mol%) was added. The tube was capped with a rubber septum and moved out of the glove box. N,N-Dimethylacetamide (1 mL) and pyridine (24 muL, 0.3 mmol, 100 mol%) were added by using a syringe. The mixture was stirred for 16 h under N2 atmosphere at 25 C, then directly loaded onto a silica column without work-up. The residue in the reaction vessel was rinsed with small amount of petroleum ether. Flash column chromatography provided the product as a solid or oil.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 100℃; for 24h;Inert atmosphere;
A solution of 5-bromoisobenzofuran-1(3H)-one (2.0 g, 9.4 mmol), K2C03 (3.9 g, 28.2 mmol), Pd(PPh3)4 (1.1 g, 0.94 mmol) and <strong>[28741-08-4]octylboronic acid</strong> (3.0 g, 18.8 mmol) intoluene (40 mL) was stirred under N2 at 100C for 24 h. The reaction mixture was added with EtOAc (100 mL), which was washed by brine (100 mL). The organic layer dried over Na2504, concentrated and the residue was purified by silica gel flash column to give 5- octylisobenzofuran-1(3H)-one (1.26 g, 54% yield) as colorless oil.
With N-Bromosuccinimide; acetic acid; In chloroform; for 5h;Inert atmosphere; Reflux;
0.67 g (5 mmol, 1 equiv.) Of compound I are added at room temperature (2-Benzofuranone, Homemade, Journal of the American Chemical Society, 136 (49), 17180-17192; 2014) Add 15 mL of chloroform and 10mL acetic acid composition of the mixed solution, Stirring, Add under nitrogen protection N-bromobutanimide 1.067 g (6 mmol, 1.2 equiv.). Slow heating caused by reflux, After stirring for 5h, Dianban confirm the end of the reaction, The reaction liquid in the refrigerator for half an hour, Filter to remove the solid, Vacuum distillation, Washed, extraction, The organic phase was dried to give 1.06 g of crude product, which is, The mixture of compound IIa and compound IIb is to be directly cast into one reaction.
tert-butyl 4-(1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With tris-(dibenzylideneacetone)dipalladium(0); In Petroleum ether;
Step 3: tert-Butyl 4-(1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate To a solution of 5-bromo-3H-isobenzofuran-1-one (45 g, 211.24 mmol, 1.00 eq) and tert-butyl piperazine-1-carboxylate (39.34 g, 211.24 mmol, 1.00 eq) in dioxane (500 mL) was added tris(dibenzylideneacetone)dipalladium(0) (19.34 g, 21.12 mmol, 0.10 eq), 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene (12.22 g, 21.12 mmol, 0.10 eq) and potassium phosphate (89.68 g, 422.48 mmol, 2.00 eq). The mixture was heated to 100 C. for 16 hr under nitrogen protection. The mixture was filtered through a pad of celite and filtrate was concentrated in vacuum. The residue was triturated in ethyl acetate: petroleum ether (500 mL, v/v=1:2). Tert-Butyl 4-(1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (50 g, 122.5 mmol, 58% yield, 78% purity) was obtained as yellow solid.
5-Bromoisobenzofuran-1(3H)-one (10.00 g, 47.2 mmol),Benzyltriethylammonium chloride (2.20g, 9.4mmol), boron trifluoride diethyl ether (1.20mL, 9.40mmol), xylene (50mL) was added to the reaction flask, and the reaction solution was replaced with nitrogen three times and then heated to 110 C. Reaction for 30 min. Next, thionyl chloride (8.60 mL, 118.0 mmol) was slowly added dropwise to the above reaction solution, and the mixture was heated to 130 C for 6 hours, cooled to 40-50 C, and the reaction was quenched by dropwise addition of methanol (20 mL). The reaction solution is evaporated under reduced pressure to give a solvent.The title compound 1b (11.40 g, 93.0%) was obtained.
5-(cyclohexylmethyl)isobenzofuran-1(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.7%
With palladium diacetate; potassium carbonate; catacxium A; In 1,4-dioxane; water; at 80℃; for 12h;
5-Bromoisobenzofuran-1(3H)-one (2.5g, 11.8mmol), <strong>[27762-64-7](cyclohexylmethyl)boronic acid</strong>(2.00 g, 14.2 mmol), palladium acetate (0.13 g, 0.59 mmol), n-butylbis(1-adamantyl)phosphine (4.24 g, 1.18 mmol), potassium carbonate (3.3 g, 23.6 mmol), 1, 4-Dioxane (50 mL) and water (5 mL) were added to a reaction flask, and the mixture was warmed to 80 C for 12 h, and the reaction was monitored by TLC until the reaction was completed and the reaction was stopped. After cooling to room temperature, the solvent was evaporated under reduced pressure and the title compound was obtained by silica gel chromatography.72b (1.8g, 66.7%).
With phenylsilane; potassium hydroxide In tetrahydrofuran for 4h; Schlenk technique; Inert atmosphere; Reflux;
3. General procedure for synthesis of products (2)
General procedure: Isobenzofuran-1(3H)-one (0.4 mmol), KOH (0.4 mmol), PhSiH3 (1.2 mmol), dried THF (2 mL) were charged in a Schlenk tube(15 mL) under N2 atmosphere. The mixture was refluxed for 4 h. After cooling to rt, the reaction was quenched with EtOH(0.5-1 mL). Solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica gel with petroleum ether-ethyl acetate as the eluent to afford the desired product.
tert-butyl ((1S,2S)-2-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)cyclohexyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With Quinuclidine; (1,2-dimethoxyethane)dichloronickel(II); [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; potassium carbonate; 4,4'-di-tert-butyl-2,2'-bipyridine; In acetonitrile; at 20℃; for 22h;Irradiation;
Step 1. tert-butyl ((1S,2S)-2-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)cyclohexyl)carbamate (19-2a) To 5-bromoisobenzofuran-1(3H)-one (19-1a, 500 mg, 2.35 mmol), <strong>[121282-70-0]tert-butyl ((1S,2S)-2-hydroxycyclohexyl)carbamate</strong> (13-1a, 505 mg, 2.35 mmol), NiCl2(glyme) (26 mg, 0.12 mmol), dtbbpy (32 mg, 0.12 mmol), Ir[(dF(CF3)ppy)2dtbbpy]PF6 (26 mg, 0.023 mmol), quinuclidine (26 mg, 0.24 mmol) and K2CO3 (324 mg, 2.35 mmol) was added MeCN (30 mL) and the resulting mixture was stirred vigorously for 22 h under irradiation of blue LED light at room temperature. The reaction mixture was then concentrated to dryness and the crude material was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to afford 19-2a (732 mg, 1.93 mmol, 82% yield) as a white powder. MS [M-tBu+H]+=292.1.
trans-tert-butyl (2-hydroxycyclobutyl)carbamate[ No CAS ]
tert-butyl (trans-2-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)cyclobutyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With 2,2,6,6-tetramethyl-piperidine; (1,2-dimethoxyethane)dichloronickel(II); [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine; In acetonitrile; at 20℃; for 16h;Inert atmosphere; Irradiation;
Step 2. Racemic tert-butyl (trans-2-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)cyclobutyl)carbamate (30-3a) To <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (19-1a, 300 mg, 1.41 mmol), racemic trans-tert-butyl-3-hydroxycyclopentyl)carbamate (30-2a, 440 mg, 2.35 mmol), NiCl2(glyme) (15.5 mg, 0.070 mmol), dtbbpy (18.9 mg, 0.070 mmol), and Ir[(dF(CF3)ppy)2dtbbpy]PF6 (15.8 mg, 0.014 mmol) under an atmosphere of nitrogen was added MeCN (4.7 mL) and 2,2,6,6-tetramethylpiperidine (40-2, 286 mul, 1.69 mmol) and the resulting mixture was stirred vigorously for 16 hours under irradiation of blue LED light at room temperature. The reaction mixture was filtered through a short pad of Celite and concentrated to dryness. The crude material was purified by silica gel chromatography eluting with 0% to 100% EtOAc (with 1% Et3N modifier) in heptane to afford 30-3a (445 mg, 1.39 mmol, 99% yield) as a white solid. MS [M-tBu+H]+=320.3.
(S)-tert-butyl 2-(((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)methyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.5%
With methanesulfonato(2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2′,4′,6′-tri-isopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II); caesium carbonate In toluene at 90℃; for 6h; Inert atmosphere;
50.1 Step 1: (S)-tert-butyl 2-(((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (86)
Reference: Angew. Chem. Int. Ed., 2011, 50, 9943. To a reaction vialwas added 5-bromophthalide (98.4 mg, 0.462 mmol), Boc-L-prolinol (281.6 mg, 1.399 mmol), cesium carbonate (231.1 mg, 0.709 mmol), and RockPhos G3 Pd catalyst (27.6 mg, 0.033 mmol) and the vial was evacuated and backfilled with nitrogen three times. Toluene (2.0 mL) was added and the resulting mixture was stirred at 90 °C for 6 hours. The solution was diluted with ethyl acetate (80 mL) and washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL), and brine (20 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude product was diluted with dichloromethane and purified by silica gel chromatography (eluting with 0-100% EtOAc in heptane) to afford the product. The material was further purified by basic mass triggered reverse phase HPLC (eluting with 35-60% ACN in water with 10 mM NH4OH as modifier). Fractions containing desired product were combined and concentrated to afford (S)-tert-butyl 2-(((1-oxo-1,3-dihydroisobenzofuran-5- yl)oxy)methyl)pyrrolidine-1-carboxylate 86 (100.9 mg, 0.303 mmol, 65.5 % yield).as a yellow solid. LCMS [M+H]+: 334.4. 1H NMR (400 MHz, Methylene Chloride-d2) δ 7.80 (d, J = 8.5 Hz, 1H), 7.12 (dd, J = 8.5, 2.2 Hz, 1H), 7.04 (s, 1H), 5.26 (s, 2H), 4.26 (s, 1H), 4.17 (d, J = 4.4 Hz, 1H), 4.03 (s, 1H), 3.40 (d, J = 7.6 Hz, 2H), 2.13 - 2.02 (m, 2H), 2.02 - 1.95 (m, 1H), 1.95 - 1.85 (m, 1H), 1.49 (s, 9H).
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