* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With hydrogen In methanol at 50℃; Inert atmosphere Stage #2: With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In methanol at 40℃;
Example 4: One pot preparation of 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (BrMIP); A 2 L round bottom flask equipped with an magnetic stirrer, an argon inlet and a temperature probe was charged with the commercially available 3M solution of MeMgCI (600 mL, 1.80 mol) in THF. The solution was cooled to -10 °C, and a solution of acetophenone FMAP (170 g, 1 .01 mol) in dry DCM (800 mL) was added dropwise, maintaining the internal temperature below 0 °C. The reaction mixture was then aged at temperature 0 °C for 2 hours. The reaction was quenched with 2M HCI (aq) (900 mL) in a dropwise fashion, maintaining the internal temperature below 20 °C (Caution: very exothermic). The quenched reaction was then aged at 20 °C for 1 hour and the layers were cut. The organic phase was washed with water (1000 mL) and brine (800 mL) and was concentrated under reduced pressure to 220 g. The concentrate contains FMOL and MIPEN in ratio 5:6 estimated by HNMR with total assay of both products ~0.97 mol).The NMR and HPLC showed that the obtained product was substantially free of starting material FMAP, analyzed by HPLC and NMR using identification standard, prepared according to Example 2.A part of above concentrate (94 mL, 73 g of total FMOL/MIPEN, ~0.42 mol) was diluted with MeOH, purged with N2 and 5percent Pd-C (1 .70 g, 0.2 molpercent) was added. The mixture was purged with hydrogen and placed under 3 bar at 50 °C until the reaction was complete based on HPLC analysis. The catalyst was removed by filtration through Celite.(R).. The obtained solution was transferred to a new flask and 1 ,3-dibromo-5,5-dimethylhydantoin (60.7 g, 208 mmol) was added in portions, maintaining the temperature below 40 °C (Caution: exothermic reaction). Eight hours after the completion of the 3-dibromo-5,5-dimethylhydantoin addition, the reaction was complete by HPLC. The reaction was quenched with NaHS03 (5.0 g) and mixed for another 15 minutes. The solution was concentrated to 1/5 of volume and diluted with water (500 mL). The resulting mixture was extracted with petroleum ether (300 mL) and then the organic phase was washed with water (500 mL), 1 M NaOH (aq) (250 mL), water (500 mL) and brine (200 mL). The organic phase was dried over Na2S04, filtered and the solvent removed under reduce pressure to yield BrMIP as a slightly yellow oil (93.03 g, 91 percent according to FMAP). H NMR (CDCI3) δ 1 .22 (d, J = 6.9 Hz, 6H, 2*Me), 3.14 (sept., J = 6.9 Hz, 1 H), 3.85 (s, 3H), 6.60 (d, J = 1 1.8 Hz, 1 H), 7.37 (d, J =8.0 Hz, 1 H). The product BrMIP was substantially free of desmethyl impurity BrMET, analyzed by HPLC and NMR using identification standard, prepared according to Example 2.
With hydrogen bromide; hydrogen In methanol; water at 20℃; for 0.25 h; Inert atmosphere
The solution of BrMIPEN (1.58 g, 6.4 mmol) and 62percent HBr (0.15 mL) in MeOH (15 mL) was purged with N2 and 5percent Pd-C (0.05 molpercent) was added. The mixture was purged with hydrogen and placed under 60 PSI at room temperature until the reaction was complete based on HPLC analysis (15 min). The catalyst was removed by filtration through celite and the solvent was removed under reduced pressure to yield BrMIP as a colorless oil (1.56 g, 98percent). 1H NMR (CDCl3) δ 1.22 (d, J = 6.9 Hz, 6H), 3.14 (sept., J = 6.9 Hz, 1 H), 3.85 (s, 3H), 6.60 (d, J = 11.8 Hz, 1H), 7.37 (d, J =8.0 Hz, 1H).
98%
With 5%-palladium/activated carbon; hydrogen bromide; hydrogen In methanol at 20℃; for 0.25 h; Inert atmosphere
Process using Pd/C, 62percent HBr: The solution of BrMIPEN (1.58 g, 6.4 mmol) and 62percent HBr (0.15 mL) in MeOH (15 mL) was purged with N2 and 5percent Pd-C (0.05 molpercent) was added. The mixture was purged with hydrogen and placed under 60 PSI at room temperature until the reaction was complete based on HPLC analysis (15 min). The catalyst was removed by filtration through celite and the solvent was removed under reduced pressure to yield BrMIP as a colorless oil (1 .56 g, 98percent). 1 H NMR (CDCIj) 0 1.22 (d, J = 6.9 Hz, 6H), 3.14 (sept., J = 6.9 Hz, 1 H), 3.85 (s, 3H), 6.60 (d, J = 11.8 Hz, 1 H), 7.37 (d, J =8.0 Hz, 1 H).; Process using Pd/C, thiophene: The solution of BrMIPEN (5.10 g, 19.4 mmol) in MeOH (30 mL) was purged with N2 and thiophene (2.55 mg, 0.05 mol percent) was added, followed by of 5percent Pd-C (0.05 molpercent). The mixture was purged with hydrogen and placed under 60 PSI at room temperature until the reaction was complete based on HPLC analysis. The catalyst was removed by filtration through celite and the solvent was removed under reduced pressure to yield BrMIP as a colorless oil (4.08 g, 85percent). The overall yield for the 4-step process from acetophenone FMAP as described above was up to 82 percent. The product was substantially free of desmethyl impurity, preferably free of 1 -bromo-5-ethyl-4-fluoro-2- methoxy benzene (BrMET) and contains no polysiloxanes as determined by NMR and HPLC.
88%
With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran at 30 - 35℃; for 12 h; Autoclave; Inert atmosphere
In 1L autoclave, THF 600 g, 1-bromo-4-fluoro-2-methoxy-5-(1-methylvinyl) benzene 239.5.5 g (0.98 mol), and 5percent Pd / C 2.5g were added, the autoclave was closed, nitrogen replacement was carried out 3-4 times, the hydrogen pressure was maintained at 0.5-1.0 MP, and the temperature was maintained between 30-35°C, and reacted for 12 hours. Sampling GC analysis was carried out 1-bromo-4-fluoro-2-methoxy-5- (1-methylvinyl) benzene <0.2percent. After completion of the reaction, the hydrogen in the kettle was replaced with nitrogen, filtered, and Pd / C was recovered. The filtrate was concentrated to recycle THF. The residual material was distilled under reduced pressure, a light yellow oily liquid was collected as 213 g of 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene. GC content of 99.5percent,Yield 88percent.
Reference：
[1] Patent: EP2468735, 2012, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2013/91696, 2013, A1, . Location in patent: Page/Page column 41
[3] Patent: CN106083536, 2016, A, . Location in patent: Paragraph 0047; 0048
3
[ 958029-46-4 ]
[ 944317-92-4 ]
Yield
Reaction Conditions
Operation in experiment
62%
With 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid In 1,2-dichloro-ethane at -20 - -10℃; for 0.25 h; Inert atmosphere
To a flask equipped with a magnetic stirrer, a nitrogen inlet and a temperature probe was charged with tetramethyldisiloxane (17 mL, 0.1 mol) and 1 ,2-dichloroethane (65 mL), cooled to -20°C, and then TFA (10 mL) was added. Then, a solution of carbinol of formula 4 (Scheme 6) (26.3 g, 0.1 mol) in DCE (90 mL) was added dropwise, maintaining the internal temperature below -10 °C. The reaction mixture was aged for 15 min at -10 °C. The reaction mixture was transferred into saturated NaHC03 (120 mL), stirred for 5 min, and the layers were cut. The bottom organic layerwas washed twice with saturated NaHC03 (2x100 mL) and brine (50 mL), dried over Na2SO+ and finally filtered. The solvent was removed under reduced pressure to give brown oil (26.3 g) which was then purified by distillation using 10 cm Vigreux column at 102-104 °C and 5 mbar to yield 5 as a colorless oil (15.2 g, 62 percent). 1H NMR (CDC ) δ 1 .22 (d, J = 6.9 Hz, 6H), 3.14 (sept., J = 6.9 Hz, 1 H), 3.85 (s, 3H), 6.60 (d, J = 11.8 Hz, 1 H), 7.37 (d, J =8.0 Hz, 1 H). The product was contaminated with ~ 5percent of siloxanes.
Conversion of Aryl Bromide 4 to Boronic Acid 5:A 75 L glass reaction vessel was charged with 1.87 kg of aryl bromide 4 (7.6 MoI), which was added as 6.4 kg of a 29.1 wt% solution of 4 in toluene. This solution was diluted with 5.6 L of THF. The vessel was flushed with nitrogen, and tri-isopropylborate (1.35 eq, 2.35 L, 10.3 MoI) was added. The mixture was cooled to < -70 0C. Then 5. 9L of 1.6 M n-BuLi in hexanes (9.5 MoI) was added slowly over 4 hours, maintaining a temperature of < -55 0C. Thirty minutes after completion of the n-BuLi addition, the reaction was complete by LC analysis. The reaction was warmed to -35 0C and quenched into 3.0 M H2SO4 solution (5.6 L). The aqueous phase after the quench should be acidic (pH ~ 2). MTBE (7.5 L) was added to the mixture to dilute the organic layer. The mixture was stirred (15 min) and the aqueous layer was cut away. The organic layer was washed with another 5.6 L of a 3.0 M H2SO4 solution (15 min). After separating layers again, the organic MTBE/Toluene layer was extracted twice with 1 M KOH (15.1 L first and then 7.6 L). The two KOH extractions were combined, diluted with 2- propanol (6.4 L), and cooled to 150C. Then the solution was slowly acidified to pH ~ 2 using 3.0 M sulphuric acid (~ 7.6 L) while maintaining temperature at 15-20 0C. The resulting slurry was stirred for Ih and then filtered. The filter cake was washed with water (2 x 6 L) and dried under an air flow for 1 day. The filtered solid was placed in an oven under vacuum at 5O0C for 2-3 days to decompose a diaryl impurity and to dry the solid. The off-white crystalline solid was isolated to yield boronic acid 5.
With n-butyllithium; Triisopropyl borate; In tetrahydrofuran; hexane; toluene; at -70 - -55℃; for 4.5h;
A 75 L glass reaction vessel was charged with 1.87 kg of aryl bromide 4 (7.6 MoI), which was added as 6.4 kg of a 29.1 wt% solution of 4 in toluene. This solution was diluted with 5.6 L of THF. The vessel was flushed with nitrogen, and tri-isopropylborate (1.35 eq, 2.35 L, 10.3 MoI) was added. <n="22"/>The mixture was cooled to < -70 0C. Then 5. 9L of 1.6 M n-BuLi in hexanes (9.5 MoI) was added slowly over 4 hours,, maintaining a temperature of < -55 0C. Thirty minutes after completion of the n-BuLi addition, the reaction was complete by LC analysis. The reaction was warmed to -35 0C and quenched into 3.0 M H2SO4 solution (5.6 L). The aqueous phase after the quench should be acidic (pH ~ 2). MTBE (7.5 L) was added to the mixture to dilute the organic layer. The mixture was stirred (15 min) and the aqueous layer was cut away. The organic layer was washed with another 5.6 L of a 3.0 M H2SO4 solution (15 min). After separating layers again, the organic MTBE/Toluene layer was extracted twice with 1 M KOH (15.1 L first and then 7.6 L). The two KOH extractions were combined, diluted with 2- propanol (6.4 L), and cooled to 150C. Then the solution was slowly acidified to pH ~ 2 using 3.0 M sulphuric acid (~ 7.6 L) while maintaining temperature at 15-20 0C. The resulting slurry was stirred for Ih and then filtered. The filter cake was washed with water (2 x 6 L) and dried under an air flow for 1 day. The filtered solid was placed in an oven under vacuum at 500C for 2-3 days to decompose a diaryl impurity and to dry the off-white crystalline solid, which was boronic acid 5.
With potassium carbonate In tetrahydrofuran Reflux;
1.E
lOg (0.0405 mol) product 4, 11.05g(0.04455 mol) 2-methoxycarbonyl-4- trifiuromethylphenylboronic acid, 2.45g tetra-(triphenylphosphine) palladium, 16g anhydrous potassium carbonate and 100 ml tetrahydrofuran were added into a 250 mL 3-neck fiaskto form a suspension. The mixture was heated to reflux overnight, then cooled to room temperature, filtered, poured into 300 mL water, and was extracted by 3><300 mL ethyl acetate. The organic phase was washed by saturated NaCl solution, dried by anhydrous Na2S04 and distilled under vacuum to obtain a yellow solid. Recrystallization in ethyl acetate gave 7.82g of product 5.
With caesium carbonate; catacxium A In N,N-dimethyl-formamide at 145℃; for 24h; Molecular sieve; Inert atmosphere;
8
Outside the glovebox, a 100 mL Schlenk flask equipped with a magnetic stir bar was charged with commercially available 3-(trifluoromethyl)benzoic acid (BFA) (3.09 g, 16.2 mmol) and bromoanisole BrMIP (3.60 g, 14.6 mmol). The flask was transferred to glovebox (%O2 ≤0.005) and Pd(OAc)2 (157 mg, 5 mol %), n-butyl-di-1-adamantylphosphine (530 mg, 10 mol %), Cs2CO3 (11.92 g, 36.6 mmol) and powdered dry molecular sieves 3 Å (1.0 g) were added. The flask was closed with the rubber septum and taken out of the glovebox. Anhydrous DMF degassed with nitrogen was added through the septum and the obtained mixture was first stirred at room temperature for 1 h under the positive pressure of nitrogen, and then placed in a preheated oil bath (145 °C) for 24 h. The reaction mixture was cooled to room temperature and quenched with 2M HCl (100 mL). Ethylacetate (50 mL) was added and the resulting suspension was stirred for 15 min, filtered through a pad of celite and the layers were cut. The water layer was extracted with ethyl acetate (50 mL) and all organic phases were combined, washed with brine (50 mL) and evaporated under reduced pressure to obtain a yellow oil. The crude product was purified by column chromatography to give 4'-fluoro-5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acid as a colorless oil (3.11g, 60%). 1H NMR (DMSO-d6) δ 0.95 (d, J = 8.0, 6H), 3.36 (s, 1H), 626 (d, J =12.0, 1H), 6.83 (d, J = 8.0, 1H), 7.03 (d, J = 8.0, 1H), 7.25 (m, 1H), 7.74 (s, 1H).
60%
With caesium carbonate In N,N-dimethyl-formamide at 145℃; for 24h; Inert atmosphere; Molecular sieve;
8
Example 8: Preparation of biaryl of Formula XII' (R6=COOH); Outside the glovebox, a 100 mL Schlenk flask equipped with a magnetic stir bar was charged with commercially available 3-(trifluoromethyl)benzoic acid (BFA) (3.09 g, 16.2 mmol) and bromoanisole BrMIP (3.60 g, 14.6 mmol). The flask was transferred to glovebox (%02 <0.005) and Pd(OAc)2 (157 mg, 5 mol %), n-butyl-di-1 - adamantylphosphine (530 mg, 10 mol %), Cs2C03 (1 1.92 g, 36.6 mmol) and powdered dry molecular sieves 3 A (1 .0 g) were added. The flask was closed with the rubber septum and taken out of the glovebox. Anhydrous DMF degassed with nitrogen was added through the septum and the obtained mixture was first stirred at room temperature for 1 h under the positive pressure of nitrogen, and then placed in a preheated oil bath (145 °C) for 24 h. The reaction mixture was cooled to room temperature and quenched with 2M HCI (100 mL) . Ethylacetate (50 mL) was added and the resulting suspension was stirred for 15 min, filtered through a pad of celite and the layers were cut. The water layer was extracted with ethyl acetate (50 mL) and all organic phases were combined, washed with brine (50 mL) and evaporated under reduced pressure to obtain a yellow oil. The crude product was purified by column chromatography to give 4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- carboxylic acid as a colorless oil (3.1 1 g, 60%). H NMR (DMSO-d6) δ 0.95 (d, J = 8.0, 6H), 3.36 (s, 1 H), 6.26 (d, J = 12.0, 1 H), 6.83 (d, J = 8.0, 1 H), 7.03 (d, J = 8.0, 1 H), 7.25 (m, 1 H), 7.74 (s, 1 H).
With lithium diisopropylmagnesium chloride; In toluene; at 0 - 10℃; for 2h;
A 1 L four-necked flask was charged with 4-fluoro-1-bromo-2-methoxy-5-isopropylbenzene (49.4 g, 0.2 mol).Triisopropyl borate (37.6 g, 0.2 mol), toluene 350 mL,Add lithium diisopropylmagnesium chloride (42.8 g, 0.28 mol),Maintain the temperature of 0 ~ 10 C reaction for 2h;Add water, stir the phase separation,The organic phase was collected, the organic phase was transferred to a 1 L four-necked flask, and a NaOH solution was added dropwise.Stirring the phases;The NaOH phase was collected, and sulfuric acid was added dropwise to adjust the pH to 1.0, and suction filtration was performed.Drying gives (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid with a purity of 99.2%.The molar yield was 96.8%.
91%
With n-butyllithium; In tetrahydrofuran; hexane; toluene; at -80 - -35℃; for 0.5h;Inert atmosphere;
A 500 mL dry flask was charged with 2-bromo-5-fluoro-4-isopropylanisole (compound of formula 4, Scheme 3) (24.6 g, 0.1 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri-isopropylborate (32 mL, 0.14 mol) was added. The mixture was cooled to -80 C. Then 10 M n-BuLi in hexanes (12.5 mL, 0.125 mol) was added slowly, maintaining a temperature below -55C. Thirty minutes after completion of the n-BuLi addition, the reaction was warmed to -35C and quenched into 3 M H2S04 solution (75 mL, 0.225 mol). DIPE (200 mL) was added to the mixture to dilute the organic layer. The mixture was stirred (15 min) and the aqueous layerwas cut away. The organic layerwas washed with 3.0 M H2S04 (75 mL). The organic phase was extracted three times with 1 M NaOH (200 mL first and then 50 mL and 50 mL). The three NaOH extractions were combined, diluted with 2-propanol (85 mL), and cooled to 15 "C. Then the solution was slowly acidified to pH ~ 2 using 3 M H2SO4 (70 mL) while maintaining temperature at 15-20 C. The resulting slurry was stirred for 1 hour and then filtered. The filter cake was washed with water (3 x 30 mL) and dried under an air flow for 1 day. The filtered solid was placed in an oven under vacuum at 50 C for 2-3 days to decompose a diaryl impurity and to dry the solid. The white crystalline solid was isolated to yield boronic acid of formula 5 (Scheme 3) (19.23 g, 91 %): mp 100-102 C; H NMR (CDCI3) delta 1.25 (d, J = 6.9 Hz, 6H), 3.17 (sept, J = 6.9 Hz, 1 H), 3.88 (s, 3H), 5.83 (S, 2H), 6.59 (d, J = 12 4 Hz, 1 H), 7.72 (d, J = 6.6 Hz, 1 H). The impurity 5-ethyl-4-fluoro-2-methoxyphenylboronic acid (-4%), which is formed from 1-bromo-5-ethyl-4-fluoro- 2-methoxybenzene (BrMET) present in the starting material under the conditions described in Step 4, was detected in the product.
86%
Step 4a. 4-Fluoro-5-isopropyl-2-methoxyphenylboronic acid i-PrMgOLiCI/THF or n-Bu Li/toluene TMEDA then added to (i-PrO)3B heptane, - 20 C A mixture of 2-bromo-4-isopropyl-5-fluoroanisole (85.4 wt%, 8.71 g, 30.1 mmol) and TMEDA (6.1 ml, 40.6 mmol) was placed in an oven-dried 100 ml 3 necked flask equipped with a magnetic stirrer and reflux condenser. The mixture was placed under ah inert atmosphere by applying a vacuum/nitrogen cycle three times, and then i-PrMgCl*LiCl in THF (1.07 M, 38.0 ml, 40.6 mmol) was added slowly. The resulting brownish grey solution was warmed to 40 C and was aged at that temperature for 3 hours, after which it was cooled to room temperature. In a separate oven-dried 250 ml, 3 necked flask equipped with a mechanical stirrer was placed isopropyl borate (11.2 ml, 48.2 mmol) solution in heptane (22 ml), and the mixture was cooled to -20 C. To this was added the Grignard solution, while maintaining the internal temperature at or below -20 C over 30 min. After the addition was complete, the mixture was aged 30 min at -20 C, then 3 M H2S04 (45 ml) was added, allowing the internal temperature to rise to ca. 20 C. The resulting biphasic mixture was transferred to a separatory funnel with the aid of THF/heptane (1/1, 7 ml), and the aqueous layer was removed. The organic layer was extracted with 2 M KOH (30 ml) followed by 2 M KOH (15 ml). The combined KOH extracts were transferred to a 250 ml 3-necked flask equipped with a mechanical stirrer with the aid of IP A (8ml). The clear, pale yellow solution was cooled to 10 C, and 3 M H2S0 (15 ml) was added slowly over 30 min. The resulting thick slurry was aged for an hour at 10C, then was filtered to collect the solid. The solid was washed with water (45 ml), 5% NaHC03 (45 ml), and finally with water (90 ml). The white crystalline solid thus obtained was dried under vacuum with a nitrogen sweep overnight to afford 5.57g, 98.26 wt% (Yield = 86%, corrected for purity).
82.71%
With n-butyllithium; In tetrahydrofuran; toluene; at -80 - -70℃; for 3h;Inert atmosphere;
Argon gas is continuously fed into a 2L three-neck flask equipped with a mechanical stirrer, a Y-shaped tube, and a thermometer.10-0.9 g of 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene, 324 mL of tetrahydrofuran, 324 mL of toluene, and 130 mL of triisopropyl borate. The system was cooled down to -80 to -70C, and 253 mL of 2mol/L n-butyllithium was added dropwise to the system. The temperature drop was -80 to -70C. The addition was completed.After the incubation -80 ~ -70 C reaction 3h.The reaction solution was slowly poured into 1000 mL of dilute hydrochloric acid with a concentration of 1.2 M, and methyl tert-butyl ether (300 mL) was added. After stirring for 10 min, the mixture was allowed to stand for 5 min, and the aqueous phase was extracted with 500 mL of methyl tert-butyl ether. 10 min, stand for 5 min, and combine the organic phases. Add 1.0 L of 1M aqueous sodium hydroxide solution while stirring the organic phase, stirring10min, let stand 5min liquid.The organic phase obtained by liquid separation was further added with 300 mL of aqueous sodium hydroxide solution, stirred for 10 minutes, and allowed to stand for 5 minutes to separate liquids, and the organic phase was temporarily stored.Combine the aqueous phase, temperature control 0 ~ 15 C, with concentrated hydrochloric acid about 160mL adjust the system to pH = 1 ~ 2, temperature 0 ~ 15 C stirring 0.5h, filtration, filter cake rinse with water, bake to constant weight to give a white solid 4-(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acid, 71.63 g (yield of 82.71%,4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acidLC = 99.68%,
A 500 mL dry flask was charged with 2-bromo-5-fluoro-4-isopropylanisole (compound of formula 4, Scheme 3) (24.6 g, 0.1 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri-isopropylborate (32 mL, 0.14 mol) was added. The mixture was cooled to -80 C. Then 10 M n-BuLi in hexanes (12.5 mL, 0.125 mol) was added slowly, maintaining a temperature below -55C. Thirty minutes after completion of the n-BuLi addition, the reaction was warmed to -35C and quenched into 3 M H2SO4 solution (75 mL, 0.225 mol). DIPE (200 mL) was added to the mixture to dilute the organic layer. The mixture was stirred (15 min) and the aqueous layer was cut away. The organic layer was washed with 3.0 M H2SO4 (75 mL). The organic phase was extracted three times with 1 M NaOH (200 mL first and then 50 mL and 50 mL). The three NaOH extractions were combined, diluted with 2-propanol (85 mL), and cooled to 15 C. Then the solution was slowly acidified to pH ~ 2 using 3 M H2SO4 (70 mL) while maintaining temperature at 15-20 C. The resulting slurry was stirred for 1 hour and then filtered. The filter cake was washed with water (3 x 30 mL) and dried under an air flow for 1 day. The white crystalline solid was isolated to yield boronic acid of formula 5 (Scheme 3) (19.23 g, 91%): mp 100-102 C; 1H NMR (CDCl3) delta 1.25 (d, J = 6.9 Hz, 6H), 3.17 (sept., J = 6.9 Hz, 1H), 3.88 (s, 3H), 5.83 (s, 2H), 6.59 (d, J =12.4 Hz, 1H), 7.72 (d, J = 6.6 Hz, 1H). The impurity 5-ethyl-4-fluoro-2-methoxyphenylboronic acid (~4%), which is formed from 1-bromo-5-ethyl-4-fluoro-2-methoxybenzene (BrMET) present in the starting material under the conditions described in Step 4, was detected in the product.
A 500 mL dry flask was charged with 2-bromo-5-fluoro-4-isopropylanisole (compound of formula 4, Scheme 3) (24.6 g, 0.1 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri-isopropylborate (32 mL, 0.14 mol) was added. The mixture was cooled to -80 C. Then 10 M n-BuLi in hexanes (12.5 mL, 0.125 mol) was added slowly, maintaining a temperature below -55C. Thirty minutes after completion of the n-BuLi addition, the reaction was warmed to -35C and quenched into 3 M H2SO4 solution (75 mL, 0.225 mol). DIPE (200 mL) was added to the mixture to dilute the organic layer. The mixture was stirred (15 min) and the aqueous layer was cut away. The organic layer was washed with 3.0 M H2SO4 (75 mL). The organic phase was extracted three times with 1 M NaOH (200 mL first and then 50 mL and 50 mL). The three NaOH extractions were combined, diluted with 2-propanol (85 mL), and cooled to 15 C. Then the solution was slowly acidified to pH - 2 using 3 M H2SO4 (70 mL) while maintaining temperature at 15-20 C. The resulting slurry was stirred for 1 hour and then filtered. The filter cake was washed with water (3 x 30 mL) and dried under an air flow for 1 day. The filtered solid was placed in an oven under vacuum at 50 C for 2-3 days to decompose a diaryl impurity and to dry the solid. The white crystalline solid was isolated to yield boronic acid of formula 5 (Scheme 3) (19.23 g, 91%): mp 100-102 C; 1H NMR (CDCl3) delta 1.25 (d, J = 6.9 Hz, 6H), 3.17 (sept., J = 6.9 Hz, 1H), 3.88 (s, 3H), 5.83 (s, 2H), 6.59 (d, J = 12.4 Hz, 1 H), 7.72 (d, J = 6.6 Hz, 1H).
Example 5: Preparation of 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid (MIPB) from BrMIP; A 2 L dry flask was charged with BrMIP (98.4 g, 0.4 mol) and dissolved in toluene (320 mL) and THF (320 mL). The resulting solution was flushed with argon, and triisopropyl borate (128 mL, 0.56 mol) was added. The mixture was cooled to -80 C. Then 10 M n-BuLi in hexanes (50 mL, 0.5 mol) was added slowly, maintaining a temperature below -55C. Thirty minutes after completion of the n-BuLi addition, the reaction was warmed to - 35C and quenched into 3 M H2S04 solution (300 mL, 0.9 mol). DIPE (800 mL) was added to the mixture to dilute the organic layer. The mixture was stirred (15 min) and the aqueous layer was cut away. The organic layer was washed with 3.0 M H2S04 (75 mL). The organic phase was extracted three times with 1 M NaOH (800 mL first and then twice with 200 mL). The three NaOH extractions were combined, diluted with 2-propanol (340 mL), and cooled to 15 C. Then the solution was slowly acidified to pH ~ 2 using 3 M H2S04 (280 mL) while maintaining temperature at 15-20 C. The resulting slurry was stirred for 1 hour and then filtered. The filter cake was washed with water (3 x 90 mL) and dried under an air flow for 1 day. The off-white crystalline solid was isolated to yield MIPB (77.0 g, 91 %). mp 100-102 C; H NMR (CDCI3) delta 1.25 (d, J = 6.9 Hz, 6H), 3.17 (sept., J = 6.9 Hz, 1 H), 3.88 (s, 3H), 5.83 (s, 2H), 6.59 (d, J = 12.4 Hz, 1 H), 7.72 (d, J = 6.6 Hz, 1 H).The product MIPB was substantially free of desmethyl impurity METB, analyzed by HPLC and NMR using identification standard, prepared according to Example 2.
Step 4a. 4-Fluoro-5-isopropyl-2-methoxyphenylboronic acid A mixture of 2-bromo-4-isopropyl-5-fluoroanisole (85.4 wt %, 8.71 g, 30.1 mmol) and TMEDA (6.1 ml, 40.6 mmol) was placed in an oven-dried 100 ml 3 necked flask equipped with a magnetic stirrer and reflux condenser. The mixture was placed under an inert atmosphere by applying a vacuum/nitrogen cycle three times, and then i-PrMgCl.LiCl in THF (1.07 M, 38.0 ml, 40.6 mmol) was added slowly. The resulting brownish grey solution was warmed to 40 C. and was aged at that temperature for 3 hours, after which it was cooled to room temperature. In a separate oven-dried 250 ml, 3 necked flask equipped with a mechanical stirrer was placed isopropyl borate (11.2 ml, 48.2 mmol) solution in heptane (22 ml), and the mixture was cooled to -20 C. To this was added the Grignard solution, while maintaining the internal temperature at or below -20 C. over 30 min. After the addition was complete, the mixture was aged 30 min at -20 C., then 3 M H2SO4 (45 ml) was added, allowing the internal temperature to rise to ca. 20 C. The resulting biphasic mixture was transferred to a separatory funnel with the aid of THF/heptane (1/1, 7 ml), and the aqueous layer was removed. The organic layer was extracted with 2 M KOH (30 ml) followed by 2 M KOH (15 ml). The combined KOH extracts were transferred to a 250 ml 3-necked flask equipped with a mechanical stirrer with the aid of IPA (8ml). The clear, pale yellow solution was cooled to 10 C., and 3 M H2SO4 (15 ml) was added slowly over 30 min. The resulting thick slurry was aged for an hour at 10 C., then was filtered to collect the solid. The solid was washed with water (45 ml), 5% NaHCO3 (45 ml), and finally with water (90 ml). The white crystalline solid thus obtained was dried under vacuum with a nitrogen sweep overnight to afford 5.57 g, 98.26 wt % (Yield=86%, corrected for purity).
General procedure: A 500 mL dry flask was charged with 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (BrMIP) (24.60 g, 0.10 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri- isopropylborate (32 mL, 0.1 mol) was added. The mixture was cooled to -80 C. Then 2.5 n-BuLi in hexanes (48 mL, 0.12 mol) was added slowly, maintaining a temperature below -55C. After completion of the n-BuLi addition, the reaction mixture was slowly warmed (1 hour) to -10C and water (120 mL) was added, followed by commercially available 2-bromo-5-(trifluoromethyl)benzonitrile (Formula VI', X = Br, R2 = CN) (25.00 g, 0.10 mmol) and the catalyst, 1 , 1 bis( di-tertbutylphosphino)ferrocene palladium dichloride (265 mg, 0.8 mol%) addition. The organic layer turns dark brown immediately. The biphasic mixture is aged at room temperature with vigorous stirring for 12 hours. The aqueous layer was removed and the organic layer was washed with 1 M NaOH (aq) (100 mL), water (300 mL) and filtered through silica gel. The solvent was removed under reduced pressure to yield brown oil which was crystallized from EtOH/water (300/100 mL). The resulting slurry was filtered and the filter cake was washed with cold 50% EtOH. The product was dried at 40 C under vacuum to yield 4'-fluoro-5'- isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (Formula VII', Ri = CN, R2 = isopropyl) as a pale white solid (25.20 g, 75%). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula Vlh and Vll2 are prepared and listed in Table 3 and Table 4, respectively. For NMR data and melting points see Table 1 and 2.
General procedure: A 500 mL dry flask was charged with 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (BrMIP) (24.60 g, 0.10 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri- isopropylborate (32 mL, 0.1 mol) was added. The mixture was cooled to -80 C. Then 2.5 n-BuLi in hexanes (48 mL, 0.12 mol) was added slowly, maintaining a temperature below -55C. After completion of the n-BuLi addition, the reaction mixture was slowly warmed (1 hour) to -10C and water (120 mL) was added, followed by commercially available 2-bromo-5-(trifluoromethyl)benzonitrile (Formula VI', X = Br, R2 = CN) (25.00 g, 0.10 mmol) and the catalyst, 1 , 1 bis( di-tertbutylphosphino)ferrocene palladium dichloride (265 mg, 0.8 mol%) addition. The organic layer turns dark brown immediately. The biphasic mixture is aged at room temperature with vigorous stirring for 12 hours. The aqueous layer was removed and the organic layer was washed with 1 M NaOH (aq) (100 mL), water (300 mL) and filtered through silica gel. The solvent was removed under reduced pressure to yield brown oil which was crystallized from EtOH/water (300/100 mL). The resulting slurry was filtered and the filter cake was washed with cold 50% EtOH. The product was dried at 40 C under vacuum to yield 4'-fluoro-5'- isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (Formula VII', Ri = CN, R2 = isopropyl) as a pale white solid (25.20 g, 75%). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula Vlh and Vll2 are prepared and listed in Table 3 and Table 4, respectively. For NMR data and melting points see Table 1 and 2.
General procedure: A 500 mL dry flask was charged with 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (BrMIP) (24.60 g, 0.10 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri- isopropylborate (32 mL, 0.1 mol) was added. The mixture was cooled to -80 C. Then 2.5 n-BuLi in hexanes (48 mL, 0.12 mol) was added slowly, maintaining a temperature below -55C. After completion of the n-BuLi addition, the reaction mixture was slowly warmed (1 hour) to -10C and water (120 mL) was added, followed by commercially available <strong>[1483-55-2]2-bromo-5-(trifluoromethyl)benzonitrile</strong> (Formula VI', X = Br, R2 = CN) (25.00 g, 0.10 mmol) and the catalyst, 1 , 1 bis( di-tertbutylphosphino)ferrocene palladium dichloride (265 mg, 0.8 mol%) addition. The organic layer turns dark brown immediately. The biphasic mixture is aged at room temperature with vigorous stirring for 12 hours. The aqueous layer was removed and the organic layer was washed with 1 M NaOH (aq) (100 mL), water (300 mL) and filtered through silica gel. The solvent was removed under reduced pressure to yield brown oil which was crystallized from EtOH/water (300/100 mL). The resulting slurry was filtered and the filter cake was washed with cold 50% EtOH. The product was dried at 40 C under vacuum to yield 4'-fluoro-5'- isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (Formula VII', Ri = CN, R2 = isopropyl) as a pale white solid (25.20 g, 75%). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula Vlh and Vll2 are prepared and listed in Table 3 and Table 4, respectively. For NMR data and melting points see Table 1 and 2.
General procedure: A 500 mL dry flask was charged with 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (BrMIP) (24.60 g, 0.10 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri- isopropylborate (32 mL, 0.1 mol) was added. The mixture was cooled to -80 C. Then 2.5 n-BuLi in hexanes (48 mL, 0.12 mol) was added slowly, maintaining a temperature below -55C. After completion of the n-BuLi addition, the reaction mixture was slowly warmed (1 hour) to -10C and water (120 mL) was added, followed by commercially available 2-bromo-5-(trifluoromethyl)benzonitrile (Formula VI', X = Br, R2 = CN) (25.00 g, 0.10 mmol) and the catalyst, 1 , 1 bis( di-tertbutylphosphino)ferrocene palladium dichloride (265 mg, 0.8 mol%) addition. The organic layer turns dark brown immediately. The biphasic mixture is aged at room temperature with vigorous stirring for 12 hours. The aqueous layer was removed and the organic layer was washed with 1 M NaOH (aq) (100 mL), water (300 mL) and filtered through silica gel. The solvent was removed under reduced pressure to yield brown oil which was crystallized from EtOH/water (300/100 mL). The resulting slurry was filtered and the filter cake was washed with cold 50% EtOH. The product was dried at 40 C under vacuum to yield 4'-fluoro-5'- isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (Formula VII', Ri = CN, R2 = isopropyl) as a pale white solid (25.20 g, 75%). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula Vlh and Vll2 are prepared and listed in Table 3 and Table 4, respectively. For NMR data and melting points see Table 1 and 2.
General procedure: A 500 mL dry flask was charged with 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (BrMIP) (24.60 g, 0.10 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri- isopropylborate (32 mL, 0.1 mol) was added. The mixture was cooled to -80 C. Then 2.5 n-BuLi in hexanes (48 mL, 0.12 mol) was added slowly, maintaining a temperature below -55C. After completion of the n-BuLi addition, the reaction mixture was slowly warmed (1 hour) to -10C and water (120 mL) was added, followed by commercially available 2-bromo-5-(trifluoromethyl)benzonitrile (Formula VI', X = Br, R2 = CN) (25.00 g, 0.10 mmol) and the catalyst, 1 , 1 bis( di-tertbutylphosphino)ferrocene palladium dichloride (265 mg, 0.8 mol%) addition. The organic layer turns dark brown immediately. The biphasic mixture is aged at room temperature with vigorous stirring for 12 hours. The aqueous layer was removed and the organic layer was washed with 1 M NaOH (aq) (100 mL), water (300 mL) and filtered through silica gel. The solvent was removed under reduced pressure to yield brown oil which was crystallized from EtOH/water (300/100 mL). The resulting slurry was filtered and the filter cake was washed with cold 50% EtOH. The product was dried at 40 C under vacuum to yield 4'-fluoro-5'- isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (Formula VII', Ri = CN, R2 = isopropyl) as a pale white solid (25.20 g, 75%). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula Vlh and Vll2 are prepared and listed in Table 3 and Table 4, respectively. For NMR data and melting points see Table 1 and 2.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
