* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Chemical Communications, 2015, vol. 51, # 93, p. 16613 - 16616
2
[ 610-94-6 ]
[ 73183-34-3 ]
[ 653589-95-8 ]
Yield
Reaction Conditions
Operation in experiment
86%
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In 1,4-dioxane for 12 h; Inert atmosphere
Under nitrogen protection,Methyl o-bromobenzoate (2.15 g, 10 mmol),bis(pinacolato)diboron(3.05g, 12mmol),Potassium acetate (3.92 g, 40 mmol),[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.49 g, 0.5 mmol)It was added to 150 mL of dioxane and heated to 85 ° C for 12 hours.After the completion of the reaction, the dioxane was removed by distillation under reduced pressure, and the product was extracted with dichloromethane.Washed three times with saturated aqueous sodium chloride solution,After distilling off the dichloromethane under reduced pressure,The crude product was purified by column chromatography eluting with petroleum ether: methylene chloride = 3:1 (v/v) to give a solid, 2.25 g, yield 86percent.The results of 1H NMR, 13C NMR, MS and elemental analysis indicated that the obtained compound was the object product.
84.9%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In toluene for 12 h; Inert atmosphere; Reflux
The dried 2 L reactor under nitrogen to 2-bromo-ethyl acetate 100 g (0.465 mol), bis(pinacolato)diboron 177.1 g (0.698 mol), [1,1 '- bis (diphenylphosphino) ferrocene ] dichloropalladium put 10.2 g (14 mmol), potassium acetate 136.9 g (1.395 mol) and 1000 mL of toluene was refluxed for 12 hours. Then filtered hot, the filtrate was concentrated under reduced pressure, and then separated by column chromatography to give the compound 96 g (yield: 84.9percent) represented by the [intermediate 7-c].
78.8%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In toluene for 12 h; Reflux
2-bromoethyl acetate in 2L reactor 100 g (465 mmol), bis (pinacolato Collet Sat) dieboronic 177.1 g (698mmol), [1,1'- bis (diphenylphosphino) ferrocene]dichloropalladium 10.2 g put (14 mmol), potassium acetate 136.9 g (1395 mmol) and1000 mL of toluene was refluxed for 12 hours. Then filtered hot, the filtrate wasconcentrated under reduced pressure, and then separated by column chromatography togive the compound 96 g (yield: 78.8percent).
62%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In toluene for 10 h; Reflux
Intermediate 1-d was synthesized according to Reaction Scheme 4 below.To a 500 mL round bottom flask reactor was added 2-bromo-methylbenzoate (14 g, 65 mmol), bispinacolatodiboron (10.4 g, 41 mmol), palladium (II) Diphenylphosphino) ferrocene (1.4 g, 1 mmol), potassium acetate (6.7 g, 68 mmol) and toluene (140 ml) were added and the mixture was refluxed with stirring for 10 hours. After completion of the reaction, the solid is filtered off and the filtrate is concentrated under reduced pressure. Separation by column chromatography gave intermediate 1-d. (10.5 g, 62percent).
Reference：
[1] Patent: CN108424344, 2018, A, . Location in patent: Paragraph 0062; 0063; 0064; 0074
[2] Patent: KR2015/111106, 2015, A, . Location in patent: Paragraph 0383-0386
[3] Patent: KR2016/2328, 2016, A, . Location in patent: Paragraph 0589-0591
[4] Patent: KR2017/139895, 2017, A, . Location in patent: Paragraph 0395; 0414-0419
[5] Green Chemistry, 2012, vol. 14, # 3, p. 661 - 667
[6] Patent: WO2017/178338, 2017, A1, . Location in patent: Page/Page column 39
[7] Patent: WO2017/178339, 2017, A1, . Location in patent: Page/Page column 36
3
[ 93-58-3 ]
[ 73183-34-3 ]
[ 653589-95-8 ]
Reference：
[1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 2009, vol. 131, p. 5058 - 5059
[3] Journal of the American Chemical Society, [4] Journal of the American Chemical Society, 2009, vol. 131, p. 5058 - 5059
[5] Journal of the American Chemical Society, [6] Journal of the American Chemical Society, 2009, vol. 131, p. 5058 - 5059
[7] Chemical Communications, 2010, vol. 46, # 1, p. 159 - 161
[8] Chemical Communications, 2010, vol. 46, # 1, p. 159 - 161
[9] Journal of the American Chemical Society, 2014, vol. 136, # 41, p. 14345 - 14348
4
[ 17763-70-1 ]
[ 73183-34-3 ]
[ 653589-95-8 ]
Yield
Reaction Conditions
Operation in experiment
18%
With potassium acetate In N,N-dimethyl-formamide at 80℃; for 16 h;
In 5 mL of anhydrous DMF was added B3a (150 mg, 0.5 mmol), PdCl2dppf.CH2Cl2 (40 mg, 0.05 mmol), bis(pinacolato)diboron (190 mg, 0.75 mmol) and KOAc (147 mg, 1.5 mmol). The reaction was allowed to stir at 80° C. for 16 h. Upon cooling to room temperature, the reaction was filtered twice through celite and the resulting filtrate was concentrated and purified on a silica gel column eluting with 5percent EtOAc in hexanes yielding B3 in 18percent yield (24 mg, 0.09 mmol). 1H NMR (400 MHz, CDCl3) δ=7.93 (d, J=7.7 Hz, 1H), 7.50 (m, 2H), 7.40 (m, 1H), 3.91 (s, 3H), 1.42 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=133.8, 133.0, 132.5, 129.2, 128.9, 128.5, 84.4, 74.3, 25.6. ESI-MS(+): m/z 262.88 [M+H]+.
Reference：
[1] Chemical Communications, 2011, vol. 47, # 28, p. 7968 - 7970
[2] Patent: US2011/312905, 2011, A1, . Location in patent: Page/Page column 40
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 41, p. 14345 - 14348
[2] Journal of the American Chemical Society, 2017, vol. 139, # 1, p. 91 - 94
trans-(3R,13bS,Sa)-13b-methyl-3-phenyl-2,3-dihydro-13bH-benz[e]oxazolo[3,2-a]-6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-pyrido[2,3-c]azepin-5-one[ No CAS ]
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 80℃; for 16h;
In 5 mL of anhydrous DMF was added B3a (150 mg, 0.5 mmol), PdCl2dppf.CH2Cl2 (40 mg, 0.05 mmol), bis(pinacolato)diboron (190 mg, 0.75 mmol) and KOAc (147 mg, 1.5 mmol). The reaction was allowed to stir at 80° C. for 16 h. Upon cooling to room temperature, the reaction was filtered twice through celite and the resulting filtrate was concentrated and purified on a silica gel column eluting with 5percent EtOAc in hexanes yielding B3 in 18percent yield (24 mg, 0.09 mmol). 1H NMR (400 MHz, CDCl3) delta=7.93 (d, J=7.7 Hz, 1H), 7.50 (m, 2H), 7.40 (m, 1H), 3.91 (s, 3H), 1.42 (s, 12H). 13C NMR (100 MHz, CDCl3) delta=133.8, 133.0, 132.5, 129.2, 128.9, 128.5, 84.4, 74.3, 25.6. ESI-MS(+): m/z 262.88 [M+H]+.
With dihydrogen peroxide; at 20℃;pH 7.5;HEPES buffer;Kinetics;
In the development of ROS-activated proMMPi, we employed a relatively underutilized self-immolative protecting group with several apparent advantages over previously described systems. The use of self-immolative linkers has become increasingly popular in drug development, molecular sensors, and polymeric delivery systems.1, 19-21 Linkers that undergo self-immolative elimination upon removal of the protecting group can release an active species through a 1,6-benzyl elimination (FIG. 19). This reaction is thermodynamically driven by the release of CO2 when a carbonate or carbamate ester linkage is employed.21-23 However, in the development of proMMPi, it was found that the use of an ether linkage between the activating group and the inhibitor was preferred over the more commonly used carbonate ester linkage (compare compound B1 vs. B2 in FIG. 19) due to better synthetic accessibility, superior hydrolytic stability, and comparably fast cleavage kinetics. Recently, this ether linkage was utilized in studies on ROS-sensitive luciferase probes24 and protease-sensitive fluorophores.22 Nonetheless, there are essentially no studies on the generality and utility of this promising linking strategy. This report investigates the scope of this ether-connected, self-immolative proinhibitor strategy with a variety of functional groups and MBGs.Here we further investigate the behavior of different activation strategies using related, but distinct self-immolative linkers for coupling to the MBGs. All of the strategies studied here use boronic ester protecting groups that can be selectively removed by H2O2. A series of methyl salicylate derivatives containing phenol, thiophenol, aniline, and benzylamine leaving groups were investigated using either an ether linkage, a carbonate/carbamate ester linker, or no linker to the boronic ester protecting group (FIG. 19 and FIG. 20). In addition, we looked at a variety of MBGs protected with a boronic ester self-immolative leaving group to expand our inventory of MBGs for use in novel metalloprotein prodrugs.Compounds B1-B3 were designed to release methyl salicylate in the presence of H2O2 using a self-immolative ether linkage (B1), a carbonate ester linkage (B2), or no self-immolative linker (B3) to directly compare three possible designs of a prodrug scaffold. The syntheses of these compounds are described in Example 3. Compounds B1-B3 were first examined for activation in the presence of H2O2 using UV-Vis spectroscopy. To a solution of the boronic ester derivative in HEPES buffer (50 mM, pH 7.5) was added H2O2 and the change in absorbance was monitored over time. As shown in FIG. 20 for compound B1, the absorbance over time shows an increase at 302 nm indicative of the emergence of methyl salicylate with a clear isobestic point at 293 nm. Similar results were obtained with compounds B2 and B3. While compounds B1 and B2 achieved >90percent cleavage within 45 min using an 18-fold excess of H2O2 (FIG. 24-25), deprotection of compound B3 required a 180-fold excess of H2O2 to realize cleavage in a comparable time frame. Release of methyl salicylate for all three compounds was confirmed by HPLC (FIG. 26-27).The rates of conversion to methyl salicylate were determined by monitoring the change in absorbance under pseudo first-order reaction conditions with an excess of H2O2. The calculated rate constants are presented in Table 2. Consistent with earlier reports, the carbonate ester derivative B2 displayed the fastest rate of conversion, but B2 also underwent spontaneous hydrolytic cleavage in buffer, whereas compound B1 was stable in buffer over a 4 h period (data not shown). Introduction of the carbonate group into the self-immolative linker of B2 leads to hydrolytic instability facilitated by nucleophilic attack of water at the carbonyl position which is not possible in compound B1.25 Interestingly, while the hydrolytic stability of B3 was comparable to the ether linkage used in B1, the rate of conversion for B3 was about two orders of magnitude slower than either B1 or B2, suggesting that use of self-immolative linker facilitates conversion to the desired active compound. TABLE 2 Pseudo first-order rate constants calculated with an excess of H2O2. Compoundk (M-1s-1) B1 1.12 +/- 0.04 B2 2.7 +/- 0.1 B3 0.031 +/- 0.002 B10 3.1 +/- 0.5 B11 5.9 +/- 0.2 B12 3.5 +/- 0.3 B13 2.9 +/- 0.1 B14 4.1 +/- 0.2 Based on the behavior of compounds B1-B3, the most promising linking strategy is the benzyl ether linkage seen in compound B1. The benzyl ether linkage shows excellent stability in buffer while maintaining rapid cleavage kinetics upon activation. Therefore, we investigated the use of this motif with other leaving groups. Compounds B4-B7 were synthesized to study the effects of using sulfur (B4), aniline (B5-B6), or benzyl amine (B7) leaving groups. Evaluation with UV-Vis absorption spectroscopy of B4-B7 in the presence of H2O2 showed no cleavage of the protecting group (FIG. 29-32). Further evalua...
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In 1,4-dioxane; for 12h;Inert atmosphere;
Under nitrogen protection,Methyl o-bromobenzoate (2.15 g, 10 mmol),bis(pinacolato)diboron(3.05g, 12mmol),Potassium acetate (3.92 g, 40 mmol),[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.49 g, 0.5 mmol)It was added to 150 mL of dioxane and heated to 85 ° C for 12 hours.After the completion of the reaction, the dioxane was removed by distillation under reduced pressure, and the product was extracted with dichloromethane.Washed three times with saturated aqueous sodium chloride solution,After distilling off the dichloromethane under reduced pressure,The crude product was purified by column chromatography eluting with petroleum ether: methylene chloride = 3:1 (v/v) to give a solid, 2.25 g, yield 86percent.The results of 1H NMR, 13C NMR, MS and elemental analysis indicated that the obtained compound was the object product.
84.9%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; for 12h;Inert atmosphere; Reflux;
The dried 2 L reactor under nitrogen to 2-bromo-ethyl acetate 100 g (0.465 mol), bis(pinacolato)diboron 177.1 g (0.698 mol), [1,1 '- bis (diphenylphosphino) ferrocene ] dichloropalladium put 10.2 g (14 mmol), potassium acetate 136.9 g (1.395 mol) and 1000 mL of toluene was refluxed for 12 hours. Then filtered hot, the filtrate was concentrated under reduced pressure, and then separated by column chromatography to give the compound 96 g (yield: 84.9percent) represented by the [intermediate 7-c].
78.8%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; for 12h;Reflux;
2-bromoethyl acetate in 2L reactor 100 g (465 mmol), bis (pinacolato Collet Sat) dieboronic 177.1 g (698mmol), [1,1'- bis (diphenylphosphino) ferrocene]dichloropalladium 10.2 g put (14 mmol), potassium acetate 136.9 g (1395 mmol) and1000 mL of toluene was refluxed for 12 hours. Then filtered hot, the filtrate wasconcentrated under reduced pressure, and then separated by column chromatography togive the compound 96 g (yield: 78.8percent).
62%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; for 10h;Reflux;
Intermediate 1-d was synthesized according to Reaction Scheme 4 below.To a 500 mL round bottom flask reactor was added 2-bromo-methylbenzoate (14 g, 65 mmol), bispinacolatodiboron (10.4 g, 41 mmol), palladium (II) Diphenylphosphino) ferrocene (1.4 g, 1 mmol), potassium acetate (6.7 g, 68 mmol) and toluene (140 ml) were added and the mixture was refluxed with stirring for 10 hours. After completion of the reaction, the solid is filtered off and the filtrate is concentrated under reduced pressure. Separation by column chromatography gave intermediate 1-d. (10.5 g, 62percent).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 2h;
Step 1 : A stirred mixture of A-22.1 (30.0 g, 140 mmol), A-22.2 (38.8 g, 154 mmol), Pd(dppf)CI2-DCM (1 1 .4 g, 14.0 mmol) and potassium acetate (54.7 g, 558 mmol) in dioxane (300 mL) is heated at 100°C for 2 h. After cooling the reaction is quenched with water and EA and the mixture filtered through a pad of celite. The phases are separated and the organic layer is dried, filtered and concentrated. The residue is purified by flash column chromatography (1 - 2percent EA in hexane) to obtain A-22.3. ESI-MS: 263 [M+H]+; HPLC (Rt): 2.54 min (method J)
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 2h;
A stirred mixture of A-23.1 (30.0 g, 140 mmol), A-23.2 (38.8 g, 154 mmol), Pd(dppf)Cl2DCM (11.4 g, 14.0 mmol) and potassium acetate (54.7 g, 558 mmol) in dioxane (300 mL) is heated at 10000 for 2 h. After cooling, the reaction is quenched with water and EA and the mixture filtered through a pad of celite. The phases are separated and the organic layer is dried, filtered and concentrated. The residue is purified by flash column chromatography (1-2percent EA in hexane) to obtain A-23.3. ESI-MS: 263 [M+H] HPLC (Rt): 2.54 mm (method J)
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 150℃; for 1h;Microwave irradiation;
A mixture of <strong>[653589-95-8]methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate</strong> (2.0 g), 2,6-dichloropyrimidine (1.4 g), sodium carbonate (2.4 g), tetrakis(triphenylphosphine)palladium(0) (0.44 g), water (2.0 mL) and DME (10 mL) was stirred at 150° C. for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.60 g).[0584]1H NMR (300 MHz, CDCl3) delta 3.75 (3H, s), 7.49-7.67 (4H, m), 7.90 (1H, dd, J=7.3, 1.3 Hz), 9.01 (1H, d, J=1.3 Hz).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; toluene; at 100℃; for 12h;
2 L said reactor [Reaction Formula 7-2 ] 69.0 g (0.197 mol) obtained at the [intermediates 7-b] known as a raw material of the obtained at the [intermediates 7-c] Reaction Formula 7-3 ] 67.1 g (0.256 mol), tetrakis (triphenyl phosphine) palladium 6.8 g (6 mmol), 68.1 g (0.493 mol) potassium carbonate, 345 ml 1, 4-dioxane classified as a carcinogenic substance, Into a 345 mL 1,4-dioxane, toluene, 345 mL, 138 mL of distilled water was stirred at 100 for 12 hours. Reaction after the valve temperature a high temperature to the normal temperature after concentrated organic layer by extracting with ethyl acetate after the chromatography column derivative is represented by the following [intermediates 7-d] 57.0 g (71.4percent yield) is obtained.
Intermediate Compound f (1g, 2.2 mmol), 1-bromonaphthalene-2-carboxylic acid (649mg, 2.5 mmol) and tripotassium phosphate monohydrate (1.5g, 6.5 mmol) was suspended in water / toluene / dioxane mixture (1: 1: 1,30ml) in.The solution was degassed and saturated with argon.Then add tris (o - tolyl) phosphine (79mg, 0.3 mmol) and palladium acetate (II) (9.7mg, 0.04 mmol).The reaction mixture was heated to boiling for 7 hours under a protective gas atmosphere.The phases were separated,Aqueous phase and washed with toluene.The organic phase was dried by Na2SO4 and evaporated in a rotary evaporator.Silica gel with toluene and AlOx mixture was filtered and evaporated in a rotary evaporator.Vacuum drying cabinet in the yellow solid was dried without further purification. The resulting mixture 20ml of THF was added dropwise three yellow solid cerium chloride (III) (600mg, 2.37 mmol) and 20ml of THF in.The reaction mixture was stirred at room temperature for 1 hour,Then cooled to 0°C.At this temperature was added dropwise methyl magnesium chloride (1.25ml, THF in the 3M).The reaction mixture was stirred overnight.20ml of water was added to the batch,Then use the batch was filtered THF.Mother liquor phases were separated.The organic phase was dried by Na2SO4 and evaporated in a rotary evaporator.Vacuum drying cabinet in the yellow solid was dried without purification. The yellow solid and polyphosphoric acid (2.1g, 21.5 mol) was suspended in 30ml of dichloromethane.Was slowly added dropwise methanesulfonic acid (1.4ml, 21.5 mol).The reaction mixture was stirred for 1 hour.Add 30ml of ethanol.The batch was filtered,And the remaining residue was recrystallized from toluene.Produced 809mg (75percent of theory) of a yellow solid.Purity 97percent (HPLC).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 2-methyltetrahydrofuran; water; at 100℃; for 15h;
Step 2: A stirred mixture of A-22.3 (25.0 g, 95.4 mmol), A-22.4 (12.0 g, 104.9 mmol), Pd(dppf)CI2-DCM (7.78 g, 9.54 mmol) and sodium carbonate (40.4 g, 381 .5 mmol) in 2-methyl tetrahydrofuran (300 mL) and water (150 mL) is heated at 100°C for 15 h. The reaction is cooled to RT and quenched with water and EA and filtered through a pad of celite. The layers are separated, the organic layer is dried, filtered and concentrated. The residue is purified by flash column chromatography on silica gel (EA hexane = 1 :4) to provide 15.0 g of A-22.5. ESI- MS: 215 [M+H]+; HPLC (Rt): 1 .42 min (method K)
15 g
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 2-methyltetrahydrofuran; water; at 100℃; for 15h;
A stirred mixture of A-23.3 (25.0 g, 95.4 mmol), A-23.4 (12.0 g, 105 mmol), Pd(dppf)Cl2DCM (7.78 g, 9.54 mmol) and sodium carbonate (40.4 g, 382 mmol) in 2-methyl tetrahydrofuran (300 mL) and water (150 mL) is heated at 100°C for 15 h. The reaction is cooled to RT and quenched with water and EA and filtered through a pad of celite. The layersare separated, the organic layer is dried, filtered and concentrated. The residue is purified by flash column chromatography on silica gel (EAlhexane = 1:4) to provide 15.0 g of A-23.5. ESIMS: 215 [M+H] HPLC (Rt): 1.42 mm (method G)
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; toluene; for 12h;Reflux;
Intermediate 1-e was synthesized according to Reaction Scheme 5 below.Intermediate 1-c (31.7 g, 100 mmol), Intermediate 1-d (20 g, 76 mmol), potassium carbonate (26.4 g, 191 mmol), tetrakis triphenylphosphine palladium (2.2 g, 2 mmol), 80 mL of water, 150 mL of toluene and 150 mL of 1,4-dioxane, and the mixture is refluxed for 12 hours. After completion of the reaction, the reaction product is separated into layers, and the organic layer is concentrated under reduced pressure. Separation by column chromatography gave Intermediate 1-e. (26 g, 70percent).
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In toluene; for 24h;Reflux;
Intermediate 2-g was synthesized according to Scheme 17 below.Intermediate 2-f (25 g, 50 mmol), Intermediate 1-d (7.8 g, 30 mmol) and tris (dibenzylideneacetone) dipalladium (15 g, 86 mmol) were added to a 500 mL round bottom flask reactor. ,2'-dicyclohexylphosphino-2 ', 6'-dimethoxphenyl (1.2 g, 8.6 mmol),Tri-potassium phosphate (50 g, 258 mmol),Add 250 mL of toluene and stir at reflux for 24 hours. After completion of the reaction, the mixture was concentrated and separated by column chromatography to obtain an intermediate 2-g. (19 g, 63percent).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 5h;Reflux; Inert atmosphere;
Stepl. Add 20-1 lOOmmol to a mixed solvent of toluene, ethanol and water, add 1 equivalent of 20-2, 3 equivalents of sodium carbonate, 0.01 equivalent of tetrakistriphenylphosphine palladium under nitrogen protection, and react at reflux temperature. 5h, after completion of the reaction, the silica gel column was passed to obtain 85 mmol of product 20-3.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 80℃; for 12h;Inert atmosphere;
Under a nitrogen atmosphere,Compound 5 (2.62 g, 10 mmol),Compound 4 (3.69 g, 10 mmol),Potassium carbonate (3.45g, 25mmol),Tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) was dissolved in 12 mL of deionized water and 80 mL of toluene.The mixture was heated to 80 ° C for 12 hours. After the reaction is completed, the product is extracted with dichloromethane.Washed three times with saturated aqueous sodium chloride solution,After removing the organic phase solvent,The crude product was purified by petroleum ether: methylene chloride = 6:1 (v/v) eluted with EtOAc.Recrystallization from petroleum ether / ethyl acetate gave 3.52 g of solid.The yield was 83percent.The results of 1H NMR, 13C NMR, MS and elemental analysis indicated that the obtained compound was the object product.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere; Sealed tube;
Compound 16C (1 g, 1.0 eq), 16D (1.27 g, 1.1 eq) were dissolved in 20 mL 1,4-dioxane, then added 2M K2C03 in water (3 mL). The mixture was flushed with N2, then added PdCl2(dppf)CH2Cl2 (0.33 g, 0.1 eq). The resulting mixture was heated at 90C for 2hrs in a sealed-tube. The reaction mixture was diluted with 100 mL ethyl acetate, washed with water and brine. The crude mixture was directly purified on ISCO silica gel column to provide 16E (1.06g, yield 85%).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; toluene;Reflux;
10.8 g (19 mmol) of [Formula 13-e] in a 250 ml round bottom flask,6.4 g (24 mmol) of methyl 2- (4,4,5,5, -tetramethyl-1,3,2-dioxaborolyl) benzoate,0.4 g (1 mmol) of tetrakis (triphenylphosphine) palladium (0),7.8 g (56 mmol) of potassium carbonate,54 ml of 1,4-dioxane,Toluene 54ml,21 ml of water was added thereto, and the mixture was refluxed and stirred. After confirming the TLC, the reaction was terminated, cooled to room temperature, extracted with ethyl acetate / water, the organic layer was separated and concentrated under reduced pressure, and the concentrate was separated by a column.The separated solution was concentrated under reduced pressure and recrystallized with methylene chloride / hexane to give 7.9 g (yield: 66.7%) of the compound represented by [Formula 13-f].
With norborn-2-ene; palladium diacetate; potassium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 70℃; for 12h;Inert atmosphere;
To a reaction tube equipped with a magnetic stir bar was added the catalyst palladium acetate (4.5 mg, 0.02 mmol), potassium carbonate (69.0 mg, 0.5 mmol), norbornene (37.6mg, 0.4mmol), <strong>[653589-95-8]2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester</strong> (78.6 mg, 0.3 mmol), 4-benzoate morpholinate (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8 mL) and 1,4-dioxane (2.0 mL), it was then heated to 70 C and reacted for 12 hours under an air-protective atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water, a saturated aqueous sodium chloride solution, the organic solvent was dried over dried Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification by column chromatography gave compound I-12 (yellow oily liquid, yield 75%).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80.0℃;Inert atmosphere;
To a suspension of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (200 mg, 763 μmol) and 1 -bromo-4-(trifluoromethyl)benzene (215 mg, 954 μmol) in 1 ,2-dimethoxyethane (3.4 ml) was added under argon a 2 M solution sodium carbonate in water (1 .9 ml, 2.0 M, 3.8 mmol) and tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] (44.3 mg, 38.2 μmol). The mixture was stirred over night at 80 C. Water was added at room temperature and the reaction was extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried, filtered and evaporated. Purification was done by preparative HPLC (column: Reprosil C18 10 μm, 250 x 30 mm, eluent A = water + 0.1 % TFA, B = acetonitrile; gradient: 3 min 10% B; 21 min 95% B; 30 min 95% B; 32 min 10% B; flow: 50 ml/min). Product containing samples were united, the solvents were evaporated and the residue was lyophylized. 123 mg (99 % purity, 57 % yleld) of the title compound were obtained. 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1 .144 (0.72), 2.087 (0.52), 2.518 (0.58), 2.521 (0.63), 2.524 (0.58), 3.487 (0.54), 3.591 (1 .05), 3.733 (0.59), 7.452 (0.56), 7.463 (8.11), 7.465 (8.07), 7.476 (9.24), 7.477 (8.88), 7.509 (14.13), 7.523 (15.11 ), 7.551 (4.41 ), 7.554 (4.34), 7.564 (9.48), 7.566 (8.73), 7.577 (5.81), 7.579 (5.30), 7.666 (5.60), 7.668 (5.62), 7.679 (8.99), 7.681 (8.91), 7.692 (4.07), 7.694 (3.85), 7.773 (16.00), 7.786 (14.17), 7.836 (8.75), 7.838 (8.30), 7.849 (8.05), 7.851 (7.29).
methyl 4'-ethyl[1,1'-biphenyl]-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 90℃; Inert atmosphere;
methyl 4'-ethyl[1 , 1 '-biphenyl]-2-carboxylate
To a suspension of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (200 mg, 763 μmol) and 1 -bromo-4-ethylbenzene (177 mg, 954 μmol) in 1 ,2-dimethoxyethane (3.4 ml) was added under argon a2 M solution sodium carbonate in water (1.9 ml, 2.0 M, 3.8 mmol) and tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] (44.3 mg, 38.2 μmol). The mixture was stirred over night at 90 °C. Water (5 ml) was added at room temperature and the reaction was extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried, filtered and evaporated. Purification was done by preparative HPLC (column: Reprosil C18 10 μm, 250 x 30 mm, eluent A = water + 0.1 % TFA, B = acetonitrile; gradient: 3 min 10% B; 21 min 95% B; 30 min 95% B; 32 min 10% B; flow: 50 ml/min). Product containing samples were united, the solvents were evaporated and the residue was lyophylized. 113 mg (98 % purity,60 % yleld) of the title compound were obtained. 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.89), 0.006 (0.61 ), 1.188 (0.41 ), 1.201 (7.50), 1 .216 (16.00), 1 .231 (7.60), 1 .236 (1 .09), 1 .252 (0.40), 2.625 (1 .83), 2.640 (5.34), 2.655 (5.15), 2.670 (1 .68), 7.194 (4.99), 7.207 (2.71), 7.211 (8.78), 7.252 (7.56), 7.268 (4.17), 7.418 (2.78), 7.433 (3.23), 7.448 (1 .44), 7.450 (1 .39), 7.463 (3.19), 7.465 (2.89), 7.478 (2.02), 7.481 (1 .81), 7.587 (1 .86), 7.590 (1 .99), 7.603 (2.93), 7.605 (3.00), 7.613 (0.51), 7.618 (1 .41), 7.621 (1 .44), 7.638 (0.54), 7.696 (2.86), 7.698 (2.86), 7.711 (2.55), 7.713 (2.45).
methyl 4'-(2,2,2-trifluoroethyl)[1,1'-biphenyl]-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 90℃; Inert atmosphere;
methyl 4'-(2,2,2-trifluoroethyl)[1 ,1'-biphenyl]-2-carboxylate
To a suspension of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (200 mg, 763 μmol) and 1-bromo-4-(2,2,2-trifluoroethyl)benzene (228 mg, 954 μmol) in 1 ,2- dimethoxyethane (4.0 ml) was added under argon a 2 M solution sodium carbonate in water (1.9 ml, 2.0 M, 3.8 mmol) and tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] (44.3 mg, (1189) 38.2 μmol). The mixture was stirred over night at 90 °C. Water was added at room temperature and the reaction was extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried, filtered and evaporated. Purification was done by flash chromatography (n-heptane: ethyl acetate gradient). Product containing samples were united, the solvents were evaporated and the residue was lyophylized. 122 mg (100 % purity, 54 % yleld) of the title compound were obtained. LC-MS (Method 8): Rt = 1.13 min; MS (ESIpos): m/z = 295 [M+H]+ 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 3.324 (16.00), 3.670 (0.73), 3.689 (2.10), 3.709 (2.01), 3.728 (0.63), 7.294 (3.27), 7.307 (4.30), 7.399 (3.13), 7.413 (2.45), 7.444 (1 .47), 7.445 (1 .56), 7.456 (1 .72), 7.458 (1 .75), 7.486 (0.77), 7.488 (0.77), 7.499 (1 .72), 7.501 (1 .63), 7.511 (1 .07), (1192) 7.513 (0.98), 7.616 (0.96), 7.618 (1 .03), 7.628 (1 .61), 7.630 (1 .64), 7.641 (0.73), 7.643 (0.71), 7.747 (1 .57), 7.748 (1 .55), 7.759 (1 .45), 7.761 (1 .39).
methyl 4'-(1,1,1-trifluoro-2-methylpropan-2-yl)[1,1'-biphenyl]-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 90℃; Inert atmosphere;
methyl 4'-(1 ,1 ,1 -trifluoro-2-methylpropan-2-yl)[1 ,1 '-biphenyl]-2-carboxylate
To a suspension of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (200 mg, 763 μmol) and 1 -bromo-4-(1 ,1 , 1 -trifluoro-2-methylpropan-2-yl)benzene(255 mg, 954 μmol, CAS 1225380-05-1 ) in 1 ,2-dimethoxyethane (4.0 ml) was added under argon a 2 M solution sodium carbonate in water (1.9 ml, 2.0 M, 3.8 mmol) and tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] (44.3 mg, 38.2 μmol). The mixture was stirred over night at 90 °C. Water (5 ml) was added at room temperature and the reaction was extracted with ethyl acetate (three times). The combined organic layers were washed with brine dried, filtered and evaporated. Purification was done by preparative HPLC (column: Reprosil C18 10 μm, 250 x 30 mm, eluent A = water + 0.1 % TFA, B = acetonitrile; gradient: 3 min 10% B; 21 min 95% B; 30 min 95% B; 32 min 10% B; flow: 50 ml/min). Product containing samples were united, the solvents were evaporated and the residue was lyophylized. 123 mg (92 % purity, 46 % yleld) of the title compound were obtained. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .591 (16.00), 3.383 (0.81 ), 3.586 (9.92), 3.588 (9.52), 3.614 (0.96), 3.616 (0.94), 7.307 (2.41), 7.326 (2.90), 7.444 (1 .31), 7.463 (1 .64), 7.480 (0.70), 7.499 (1 .59), 7.518 (1 .12), 7.572 (2.69), 7.592 (2.19), 7.610 (1 .05), 7.629 (1 .59), 7.648 (0.77), 7.746 (1.40), 7.766 (1.22).
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