* 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 magnesium In tetrahydrofuran at 40℃; Inert atmosphere; Reflux Stage #2: at 0℃; for 2 h;
Magnesium turnings (11.12g, 0.464mol) and anhydrous tetrahydrofuran (600 ml) were placed in a round-bottomed flask fitted with a mechanical stirrer, reflux condenser, pressure equalizing addition funnel and drying tube. 5-Bromo-2,2- difluoro-l,3-benzodioxole (lOOg) was added to the flask under nitrogen atmosphere. The temperature of the reaction mass was raised to 40°C during initiation. Upon initiation, remaining 5-Bromo-2,2-difluoro-l,3-benzodioxole (lOOg) was added drop- wise to the reaction mass. The temperature of the reaction mass was maintained below 40°C. The progress of the reaction was monitored by gas chromatography. The reaction mass was then cooled to 0°C and carbon-dioxide gas was passed for 2 hours at 0°C. The raction was monitored by liquid chromatography for completion. The reaction mass was quenched with 10percent HC1 (230g). The organic layer was separated, concentrated to obtain solid. The solid was washed with water (50g) and dichloromethane (50g), filtered and dried at 60°C under 50mmHg for 2 hours to obtain the title compound. Yield (percent): 70 Purity (percent): 99 (by liquid chromatography)
With bromine In water at 25 - 85℃; for 9 h; Reflux
2, 2-difluoro-l, 3-benzodioxole (200g, 1.27mol) and water (456g, 25.3mol) were placed in a 1000 mL round -bottomed flask fitted with a mechanical stirrer, reflux condenser and pressure equalizing addition funnel. Bromine (284g, 1.77mol) was added drop-wise at 25°C for one hour. During addition, the temperature of the mass was raised from 25°C to 85°C. The temperature of the reaction mass was maintained at 85°C for 8 hours. The progress of the reaction was monitored by liquid chromatography. The temperature of the reaction mass was brought down to 25°C. The layers were separated, the organic layer was washed with sodium bisulphite solution followed by sodium bicarbonate solutionto obtain the title compound. The crude mass was purified by vacuum distillation. Yield (percent) : 80 Purity (percent) : 99.8 (by liquid chromatography)
538 g
at 10 - 70℃;
Example 1Process of preparation of 5-bromo-2,2-difluoro-1,3-benzodioxole A mixture of 2,2-difluoro-l ,3-benzodioxote (560 g) and Hydrogen bromide(l 100 g, Assay 47percent) were taken in a reaction vessel fitted with cold condenser. The reaction mixture was cooled to 10°C and 30 percent Hydrogen Peroxide solution (806 g) was added slowly in lot wise. Upon completion of addition, the temperature of the reaction mixture was cautiously raised to 70°C. The organic layer was separated and washed with 20 percent of sodium metabisulfite and then washed with 20percent of potassium bicarbonate solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was distilled under high vacuum to obtain the title compound. Yield: 538 g
Reference：
[1] Patent: WO2017/46816, 2017, A2, . Location in patent: Page/Page column 9-10
[2] Patent: EP1595877, 2005, A1, . Location in patent: Page/Page column 4
[3] European Journal of Organic Chemistry, 2004, # 1, p. 64 - 68
[4] Patent: WO2016/38627, 2016, A1, . Location in patent: Page/Page column 4
5
[ 663934-09-6 ]
[ 33070-32-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2004, # 1, p. 64 - 68
6
[ 1583-59-1 ]
[ 7439-89-6 ]
[ 33070-32-5 ]
Reference：
[1] Patent: US5633218, 1997, A,
[2] Patent: US4895871, 1990, A,
7
[ 663934-00-7 ]
[ 33070-32-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2004, # 1, p. 64 - 68
8
[ 663934-04-1 ]
[ 33070-32-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2004, # 1, p. 64 - 68
With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tert-butyl XPhos In 1,4-dioxane; water at 100℃; for 17 h; Inert atmosphere
(2) 0.97 g (17.22 mmol) of potassium hydroxide, 0.20 g (0.42 mmol) of di-t-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-(1,1′-biphenyl)-2-yl)phosphine and 0.09 g (0.10 mmol) of tris(dibenzylideneacetone)dipalladium(0) were added in a nitrogen atmosphere to a solution having 2.04 g (8.61 mmol) of 2,2-difluoro-5-bromobenzodioxolane dissolved in 5 ml of 1,4-dioxane and 5 ml of water, followed by stirring at 100° C. for 17 hours. 22 ml of 1M hydrochloric acid was added, and then ethyl acetate was added. The aqueous layer was extracted three times with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (developing solvent: heptane/ethyl acetate=80/20) to obtain 1.42 g (yield: 94.8percent) of 2,2-difluoro-5-hydroxybenzodioxolane as a pale yellow oil. 1H-NMR(300 MHz, CDCl3, δppm): 6.88(d, 1 H, J=8.7 Hz), 6.62(d, 1H, J=2.4 Hz), 6.48(dd, 1H, J=8.7 Hz, 2.4 Hz)
82%
With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide In 1,4-dioxane; water at 100℃; for 16 h; Inert atmosphere
Example 1A 2,2-difluoro-2H-1,3-benzodioxol-5-ol To a mixture of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (10 g, 42.2 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (2.028 g, 4.22 mmol) and potassium hydroxide (4.74 g, 84 mmol) was added degassed water (10 mL). The reaction mixture was sparged with a nitrogen stream for 5 minutes. To the reaction mixture was added a degassed solution of tris(dibenzylideneacetone)dipalladium(0) (0.773 g, 0.844 mmol) in dioxane (10 mL). The combined reaction mixture was sparged with nitrogen for 5-7 minutes. The reaction vial was capped and stirred at 100° C. overnight (16 hours). The reaction mixture was cooled to ambient temperature, and partitioned between ethyl acetate and 1 N HCl solution. The organic fractions were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, maintaining a bath temp at or below 25° C. The residue was purified by flash chromatography using a 220 g silica gel cartridge, eluting with 25-75percent dichloromethane/heptanes to afford 6.02 g of the title compound (82percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 5.51 (s, 1H), 6.50 (dd, J=8.6, 2.5 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.7, 1.4 Hz, 1H); MS (ESI-) m/z 173.1 (M-H)-.
6.43 g
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 10 - 20℃; Stage #2: With Triisopropyl borate In tetrahydrofuran at 20℃; for 0.533333 h; Cooling with ice
To a cold solution of 5-bromo-2,2-difluorobenzo[cf] [l ,3]dioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5-10 minutes while maintaining the temperature in the range of 10-20 °C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 °C and 10percent H2SO4 solution (50 mL) was added slowly which resulted in a slight exotherm to 20 °C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCCb solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of tert-butyl methyl ether and cooled to 0 °C. 30percent Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) was added slowly, followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0-50percent ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil. XH (0700) NMR (400 MHz, DMSO-c) δ ppm 9.75 (s, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.7, 2.5 Hz, 1H). MS (ESI-) m/z 173.1 (M-H)".
6.43 g
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 10 - 20℃; Stage #2: With Triisopropyl borate In tetrahydrofuran at 20℃; for 0.533333 h; Cooling with ice
Example 159A 2,2-difluorobenzofdj '[ 1 , 3]dioxol-5-ol To a cold solution of 5-bromo-2,2-difluorobenzo[cf] [l,3]dioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5-10 minutes while maintaining the temperature in the range of 10-20 °C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 °C and 10percent H2SO4 solution (50 mL) was added slowly which resulted in a slight exotherm to 20 °C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCCb solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of fert-butyl methyl ether and cooled to 0 °C. 30percent Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) was added slowly, followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0-50percent ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil. XH NMR (400 MHz, DMSO-c) δ ppm 9.75 (s, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.7, 2.5 Hz, 1H). MS (ESI-) m/z 173.1 (M-H)".
6.43 g
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 10 - 20℃; Stage #2: With Triisopropyl borate In tetrahydrofuran at 20℃; for 0.533333 h; Stage #3: With sulfuric acid In tetrahydrofuran at 20℃; for 0.25 h;
To a cold solution of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5-10 minutes while maintaining the temperature in the range of 10-20 °C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 °C and 10percent H2SO4 solution (50 mL) was added slowly which resulted in a slight exotherm to 20 °C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCO3 solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of tert-butyl methyl ether and cooled to 0 °C. 30percent Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) was added slowly, followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0~50percent ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.7, 2.5 Hz, 1H); MS (ESI-) m/z 173.1 (M-H)-.
Step 1. Methyl 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate To a solution of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (3 g, 12.66 mmol) in methanol (30 ml) was added Pd(dppf)Cl2 (817 mg, 1.12 mmol) and triethylamine (TEA) (2.56 g, 25.4 mmol). The resulting solution was stirred for 24 h at 100° C. under an atmosphere of CO (g), then concentrated in vacuo. It was purified by silica gel column chromagraphy with 1percent ethyl acetate in petroleum ether to afford methyl 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate as a light yellow oil (1.4 g, 51percent). 1H-NMR (300 MHz, CDCl3) δ 7.88-7.91 (m, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 3.94 (s, 3H).
4-(2,2-difluoro-1,3-benzodioxol-5-yl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 18.0h;
A solution of 5-bromo-2,2-difluoro-1 ,3-benzodioxole (2.65 mmol), 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (3.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 mmol), and cesium carbonate (7.94 mmol) in Lambda/,Lambda/-dimethylformamide (8.0 ml.) and water (2.0 ml_) was heated at 100 0C for 18 h. The reaction mixture was cooled, poured into brine (60 ml_), and extracted with ethyl acetate (3 x 50 ml_). The combined organic layers were dried over magnesium sulfate and decolorizing charcoal, filtered through Celite, and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC and neutralization of the collected fractions afforded the title product as a white solid (50%). ESMS [M+H]+: 250.2.
50%
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 18.0h;
PREPARATION 47 4-(2,2-difluoro-1,3-benzodioxol-5-yl)aniline A solution of 5-bromo-2,2-difluoro-1,3-benzodioxole (2.65 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 mmol), and cesium carbonate (7.94 mmol) in N,N-dimethylformamide (8.0 mL) and water (2.0 mL) was heated at 100 C. for 18 h. The reaction mixture was cooled, poured into brine (60 mL), and extracted with ethyl acetate (3*50 mL). The combined organic layers were dried over magnesium sulfate and decolorizing charcoal, filtered through Celite, and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC and neutralization of the collected fractions afforded the title product as a white solid (50%). ESMS [M+H]+: 250.2.
50%
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 18.0h;
Preparation 27 4-(2,2-difluoro-1,3-benzodioxol-5-yl)aniline A solution of 5-bromo-2,2-difluoro-1,3-benzodioxole (2.65 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 mmol), and cesium carbonate (7.94 mmol) in N,N-dimethylformamide (8.0 mL) and water (2.0 mL) was heated at 100 C. for 18 h. The reaction mixture was cooled, poured into brine (60 mL), and extracted with ethyl acetate (3*50 mL). The combined organic layers were dried over magnesium sulfate and decolorizing charcoal, filtered through Celite, and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC and neutralization of the collected fractions afforded the title product as a white solid (50%). ESMS [M+H]+: 250.2.
With bromine; In water; at 25 - 85℃; for 9h;Reflux;
2, 2-difluoro-l, 3-benzodioxole (200g, 1.27mol) and water (456g, 25.3mol) were placed in a 1000 mL round -bottomed flask fitted with a mechanical stirrer, reflux condenser and pressure equalizing addition funnel. Bromine (284g, 1.77mol) was added drop-wise at 25C for one hour. During addition, the temperature of the mass was raised from 25C to 85C. The temperature of the reaction mass was maintained at 85C for 8 hours. The progress of the reaction was monitored by liquid chromatography. The temperature of the reaction mass was brought down to 25C. The layers were separated, the organic layer was washed with sodium bisulphite solution followed by sodium bicarbonate solutionto obtain the title compound. The crude mass was purified by vacuum distillation. Yield (%) : 80 Purity (%) : 99.8 (by liquid chromatography)
75%
With bromine; iron; at 20 - 30℃;Inert atmosphere; Large scale;
250.0 kg (1.581 kmol) of <strong>[1583-59-1]2,2-difluorobenzodioxole</strong> was placed in a 500 L lined PTFE enamel kettle, and 25.0 kg of iron filings were added under stirring, and the inside of the kettle was replaced with nitrogen. The reaction temperature was controlled at 20 to 30 C, and 250.0 kg (1.564 kmol) of bromine was added dropwise over 8 to 10 hours, and the tail gas was absorbed by liquid alkali. After the completion of the reaction, the reaction system was pumped into another 2000 L reaction vessel containing 1000 kg of cold water, and the temperature was controlled to 30 C or lower. The reaction was quenched by dropwise addition of 100 kg of 25% sodium hydrogen sulfite solution, and the pH of the system was adjusted to 8-9 by dropwise addition of 32% liquid alkali. The temperature was raised to 100 C and the product was distilled off by steam distillation. Approximately 310 kg of a crude 5-bromo-2,2-difluoropipepene ring was obtained, and further separated to obtain a 5-bromo-<strong>[1583-59-1]2,2-difluorobenzodioxole</strong> 250 kg (1.181 kmol), a purity of 99%, and a yield of 75%.
538 g
With hydrogen bromide; dihydrogen peroxide; at 10 - 70℃;
Example 1Process of preparation of 5-bromo-<strong>[1583-59-1]2,2-difluoro-1,3-benzodioxole</strong> A mixture of 2,2-difluoro-l ,3-benzodioxote (560 g) and Hydrogen bromide(l 100 g, Assay 47%) were taken in a reaction vessel fitted with cold condenser. The reaction mixture was cooled to 10C and 30 % Hydrogen Peroxide solution (806 g) was added slowly in lot wise. Upon completion of addition, the temperature of the reaction mixture was cautiously raised to 70C. The organic layer was separated and washed with 20 % of sodium metabisulfite and then washed with 20% of potassium bicarbonate solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was distilled under high vacuum to obtain the title compound. Yield: 538 g
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 100℃; for 24.0h;
Step 1. Methyl 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate To a solution of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (3 g, 12.66 mmol) in methanol (30 ml) was added Pd(dppf)Cl2 (817 mg, 1.12 mmol) and triethylamine (TEA) (2.56 g, 25.4 mmol). The resulting solution was stirred for 24 h at 100 C. under an atmosphere of CO (g), then concentrated in vacuo. It was purified by silica gel column chromagraphy with 1% ethyl acetate in petroleum ether to afford methyl 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate as a light yellow oil (1.4 g, 51%). 1H-NMR (300 MHz, CDCl3) delta 7.88-7.91 (m, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 3.94 (s, 3H).
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3] dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
Step a: 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
Preparation of 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid Step a: 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl esterA solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
Step a: 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
Example 17:; 2, 2-Difluoro-benzo [1, 3] dioxole-5-carboxylic acid methyl ester; A solution of 5-bromo- 2,2-difluoro-benzo [1, 3] dioxole (11. 8 g, 50.0 mmol) and tetrakis (triphenylphosphine) palladium (0) (Pd (PPh3) 4,5. 78 g, 5.00 mmol) in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo [1,3] dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
A solution of 5-bromo-2,2-difluoro-benzo[l,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 0C (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo [1,3] dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
[00192] Methyl 2,2-difluorobenzo[</][l,3]dioxole~5-carboxylate A solution of 5-bromo-2,2-difluorobenzo[rf][l,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 psi) at 75 C (oil bath temperature) for 15 h. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give methyl 2,2-difluorobenzo [d][l,3]dioxole-5-carboxylate (11.5 g), which was used directly in the next step.
With tetrakis(triphenylphosphine) palladium(0); triethylamine; In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tris-(dibenzylideneacetone)dipalladium(0); triethylamine; at 85℃; under 7600.51 Torr;Autoclave;
[00157] Methyl 2.2-difluorobenzo[dl [1.31dioxole-5-carboxylate: To a 200 mL pressure tank reactor (10 atm. in CO), was placed 5-bromo-2,2-difluoro-2H-l,3-benzodioxole (20.0 g, 84.4 mmol, 1.00 equiv), methanol (40 mL), triethylamine (42.6 g, 5.00 equiv.), Pd2(dba)3 (1.74 g, 1.69 mmol, 0.02 equiv), Pd(dppf)Cl2(1.4 g, 1.69 mmol, 0.02 equiv.). The resulting solution was stirred at 85 C under an atmosphere of CO overnight and the reaction progress was monitored by GCMS. The reaction mixture was cooled. The solids were filtered out. The organic phase was concentrated under vacuum to afford 17.5 g of methyl 2,2-difluoro-2H- l,3-benzodioxole-5-carboxylate as a crude solid, which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 75℃; under 2844.39 Torr; for 15.0h;
A. 1 -(2 ,2-Difluoro-benzor 1,31 dioxol-5 -vD-cyclopropanecarboxylic acid; Step a: 2,2-Difluoro-benzofl ,3] 'dioxole-5-carboxylic acid methyl ester; A solution of 5-bromo-2,2-difluoro-benzo[l,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3 )4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 0C (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo [1,3] dioxole-5- carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; for 15.0h;Heating / reflux;
A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With n-butyllithium In tetrahydrofuran at -65 - -60℃; Inert atmosphere;
8.1 Step 1: Example 8b
Example 8a (15.7 g, 0.066 mol), B(OiPr)3 (18.7 g, 0.099 mol), was dissolved in THF (300 mL), the mixture was cooled to -65°C under N2,n-BuLi (32 mL, 0.079 mol) was added dropwise. After addition,the reaction mixture was stirred at -60°C for lh,then warmed to r.t., NH4C1 (200 mL) and EA (200 mL) was added, the mixture was acidified to pH 2-3 by adding HC1 (3 N). The organic phase was separated, washed with water, brine and dried over Na2S04, filtrated and concentrated under reduced pressure to give the desired product (Example 8b, 16 g, yield 100%) as white solid.
73%
Stage #1: 5-bromo-2,2-difluoro-2H-1,3-benzodioxole With n-butyllithium In tetrahydrofuran; hexane for 0.5h; Inert atmosphere; Cooling with acetone-dry ice;
Stage #2: Triisopropyl borate In tetrahydrofuran; hexane at 20℃; for 0.5h;
Stage #3: With acetic acid In tetrahydrofuran; hexane at 20℃; for 0.166667h;
46.1
Step 1: Preparation of 2,2-difluoro-benzo[1,3]dioxole-5-boronic Acid n-BuLi in hexanes (2.5 M solution, 46 mL) was added to anhydrous THF (250 mL) cooled in acetone-dry ice bath under the flow of nitrogen. After 10 min 5-bromo-2,2-difluoro-1,3-benzodioxole (25.0 g) was added dropwise and the resulting solution was stirred for 30 min. Then, boron isopropoxide (30 mL) was added dropwise and the reaction mixture was allowed to reach room temperature over a period of 3 h. Then acetic acid (30 mL) was added in one portion and the resulting mixture was stirred at room temperature for 10 min. The reaction mixture was then diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound was obtained by trituration with hexanes as a white solid (14.2 g, 73% yield). HRMS calcd for C7H5O4BF2 [2M-H-H2O]-385.0324, observed 385.0319.
73%
Stage #1: 5-bromo-2,2-difluoro-2H-1,3-benzodioxole With n-butyllithium In tetrahydrofuran; hexanes
Stage #2: Triisopropyl borate In tetrahydrofuran; hexanes at 20℃;
Stage #3: With acetic acid In tetrahydrofuran; hexanes at 20℃; for 0.166667h;
57.1 Step 1:
Step 1: 2,2-Difluoro-benzo[1,3]dioxole-5-boronic acid n-BuLi in hexanes (2.5 M solution, 46 mL) was added to anhydrous THF (250 mL) cooled in acetone-dry ice bath under the flow of nitrogen. After 10 min 5-bromo-2,2-difluoro-1,3-benzodioxole (25.0 g) was added dropwise and the resulting solution was stirred for 30 min. Then, boron isopropoxide (30 mL) was added dropwise and the reaction mixture was allowed to reach room temperature over a period of 3 h. Then acetic acid (30 mL) was added in one portion and the resulting mixture was stirred at room temperature for 10 min. The reaction mixture was then diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound was obtained by trituration with hexanes as a white solid (14.2 g, 73% yield). HRMS calcd for C7HSO4BF2 [2M-H-H2O]- 385.0324, observed 385.0319.
14.7 g (95%)
With tert.-butyl lithium In diethyl ether; pentane
79.A 2,2-difluoro-1,3-benzodioxol-5-ylboronic acid
EXAMPLE 79A 2,2-difluoro-1,3-benzodioxol-5-ylboronic acid A solution of 1.5M tert-butyllithium in pentane (130 mL, 195 mmol) in diethyl ether (500 mL) at -78° C. was treated with 5-bromo-2,2-difluoro-1,3-benzodioxole (18 g, 76 mmol) in diethyl ether (80 mL), stirred for 1 hour, treated with triisopropylborate (37 mL, 160 mmol), warmed to room temperature over 1 hour, poured into 4M NaOH (700 mL), stirred for 15 minutes, cooled, adjusted to pH 1 with concentrated HCl, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated to provide 14.7 g (95%) of the desired product. 1H NMR (DMSO-d6) δ7.75 (m, 1H), 7.66 (m, 1H), 7.51 (m, 1H), 7.39 (m, 1H), 7.30 (m, 1H).
With n-butyllithium; ammonium chloride In diethyl ether; hexane
89.E 2,2-difluoro-1,3-benzodioxol-5-ylboronic acid
EXAMPLE 89E 2,2-difluoro-1,3-benzodioxol-5-ylboronic acid A solution of 5-bromo-2,2-difluorobenzodioxole (1.18 g, 4.97 mmol) in anhydrous diethyl ether (8 mL) at -78° C. was treated with 2.5M n-BuLi in hexane (2.4 mL, 5.97 mmol), stirred for 1 hour, and treated with triisopropyl borate (1.5 mL, 6.46 mmol). The mixture was slowly warmed to room temperature and stirred for about 18 hours. The reaction was quenched with saturated NH4Cl/10% HCl and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was used directly without further purification. 1H NMR (CD3OD) δ7.26-7.11 (m, 3H).
14.7 g (95%)
With tert.-butyl lithium In diethyl ether; pentane
79.A 2,2-difluoro-1,3-benzodioxol-5-ylboronic acid
EXAMPLE 79A 2,2-difluoro-1,3-benzodioxol-5-ylboronic acid A solution of 1.5M tert-butyllithium in pentane (130 mL, 195 mmol) in diethyl ether (500 mL) at -78° C. was treated with 5-bromo-2,2-difluoro-1,3-benzodioxole (18 g, 76 mmol) in diethyl ether (80 mL), stirred for 1 hour, treated with triisopropylborate (37 mL, 160 mmol), warmed to room temperature over 1 hour, poured into 4M NaOH (700 mL), stirred for 15 minutes, cooled, adjusted to pH 1 with concentrated HCl, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated to provide 14.7 g (95%) of the desired product. 1H NMR (DMSO-d6) δ 7.75 (m, 1H), 7.66 (m, 1H), 7.51 (m, 1H), 7.39 (m, 1H), 7.30 (m, 1H).
With n-butyllithium; ammonium chloride In diethyl ether; hexane
89.E 2.2-difluoro-1,3-benzodioxol-5-ylboronic acid
EXAMPLE 89E 2.2-difluoro-1,3-benzodioxol-5-ylboronic acid A solution of 5-bromo-2,2-difluorobenzodioxole (1.18 g, 4.97 mmol) in anhydrous diethyl ether (8 mL) at -78° C. was treated with 2.5M n-BuLi in hexane (2.4 mL, 5.97 mmol), stirred for 1 hour, and treated with triisopropyl borate (1.5 mL, 6.46 mmol). The mixture was slowly warmed to room temperature and stirred for about 18 hours. The reaction was quenched with saturated NH4Cl/10% HCl and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was used directly without further purification. 1H NMR (CD3OD) δ 7.26-7.11 (m, 3H).
With n-butyllithium In tetrahydrofuran
2.B Step B
Step B Preparation of (2,2-difluoro-1,3-benzodioxol-5-yl)boronic acid A solution of the title compound of Step A (15 g, 63 mmol) in tetrahydrofuran (approximately 200 mL) was cooled to -78° C. under a nitrogen atmosphere. A solution of n-butyllithium (40 mL of a 1.6M solution in hexanes) was added dropwise while maintaining the reaction temperature below -55° C. The reaction mixture was stirred at -78° C. for 20 min before a solution of triisopropylborate (29.4 mL, 127 mmol) in tetrahydrofuran (approximately 50 mL) was added dropwise over 30 min. The reaction was allowed to come to room temperature while stirring for 5 h. The reaction mixture was then partitioned between diethyl ether and 1M hydrochloric acid solution. The organic layer was separated, dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step B as a brown oil (15 g) which was used without further purification.
With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 4h; Inert atmosphere;
9.1-10 INTERMEDIATE 1-10: (2,2-difluoro-l,3-benzodioxol-5-yl)boronic add
n-Butyl lithium 2.5M in hexane (11.36 mL, 28.40 mmol) was added dropwise to a stirred solution of 5-bromo-2,2-difluoro-l,3-benzodioxole (5.0 g, 21.10 mmol) and triisopropyl borate (6.3 g, 33.50 mmol) in THF (60 mL) at -78°C under nitrogen. The resulting solution was stirred at -78°C for 1 h and at room temperature for 3 h. The mixture was hydrolyzed with a saturated aqueous solution of ammonium chloride (20 mL), stirred 30 minutes, an aqueous solution of 3N HC1 (20 mL) was then added and the mixture was extracted with Et20. The organics were washed with brine, dried over MgSCL and concentrated in vacuo to afford the title compound as a yellow oil which was used directly for next step.
With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 4h; Inert atmosphere;
INTERMEDIATE 1-53: (2,2-difluoro-l,3-benzodioxol-5-yl)boronic add
n-Butyl lithium 2.5M in hexane (11.36 mL, 28.40 mmol) was added dropwise to a stirred solution of 5-bromo-2,2-difluoro-l,3-benzodioxole (5.0 g, 21.10 mmol) and triisopropyl borate (6.3 g, 33.50 mmol) in THF (60 mL) at -78°C under nitrogen. The resulting solution was stirred at -78°C for 1 h and at room temperature for 3 h. The mixture was hydrolyzed with a saturated aqueous solution of ammonium chloride (20 mL), stirred 30 minutes, an aqueous solution of 3N HC1 (20 mL) was then added and the mixture was extracted with Et20. The organics were washed with brine, dried over MgS04 and concentrated in vacuo to afford the title compound as a yellow oil which was used directly for next step.
Stage #1: 5-bromo-2,2-difluoro-2H-1,3-benzodioxole With isopropylmagnesium bromide In tetrahydrofuran at 10 - 20℃; Inert atmosphere;
Stage #2: Triisopropyl borate In tetrahydrofuran at 0 - 20℃; for 0.5h;
24.1 Step 1, Preparation of intermediate (2,2-difluorobenzo[d][1,3]dioxol-5-yl)boronic acid
Add 5-bromo-2,2-difluorobenzo[d][1,3]dioxole(0.575mL, 4.22mmol) and 20mL anhydrous THF into a 250mL three-necked flask,After replacing it with argon three times, it was placed at 10°C and stirred. A 2M THF solution (2.81 mL) of isopropylmagnesium bromide was slowly added dropwise into the system, and after the addition was completed, the reaction system was heated to room temperature to continue the reaction overnight. The next day, place the system at 0°C and stir, slowly add triisopropyl borate (1.28 mL, 5.5 mmol), and after the addition is completed, the temperature is raised to room temperature and the reaction is continued for 30 minutes; Then 10% sulfuric acid solution (10 mL) was added, and the reaction was stopped after stirring for 10 min. 10 mL saturated sodium bicarbonate was added, and the mixture was extracted 3 times with 50 mL ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent.A brown liquid was obtained, and the product was directly used in the next step without further purification.
Step A Preparation of 5-bromo-2,2-difluoro- 1,3-benzodioxole Iron powder (2.8 g, 50 mmol) was added to a solution of <strong>[1583-59-1]2,2-difluoro-1,3-benzodioxole</strong> (15.8 g, 100 mmol) in carbon tetrachloride (200 mL) at 0 C. under a nitrogen atmosphere. Bromine (5.2 mL, 100 mmol) was then added to the mixture dropwise over 15 min. The reaction was heated to reflux for 1 h and then stirred at room temperature overnight. The mixture was filtered through Celite and the filtrate was washed with 0.1N sodium thiosulfate solution. The organic layer was then dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step A as an oil (15.2 g, 64%). 1 H NMR (CDCl3): delta6.96 (m, 1H), 7.22 (m,2H).
With bromine; In tetrachloromethane; water;
Step C: Synthesis of 5-bromo-<strong>[1583-59-1]2,2-difluoro-1,3-benzodioxole</strong> as an intermediate A mixture of 15.8 grams (0.1 mole) of <strong>[1583-59-1]2,2-difluoro-1,3-benzodioxole</strong> in 200 mL of carbon tetrachloride was stirred, and 2.8 grams (0.05 mole) of iron powder was added. The reaction mixture was cooled to 0 C., and 5.2 mL (0.1 mole) of bromine was added during a 20 minute period. Upon completion of addition the reaction mixture was cautiously warmed to 75 C. where it was stirred for one hour and then was allowed to cool to ambient temperature where it was stirred for 18 hours. The reaction mixture was taken up in 200 mL water and stirred for 20 minutes. The organic layer was separated and washed with water and then with two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was distilled under high vacuum to yield 11.7 grams of 5-bromo-<strong>[1583-59-1]2,2-difluoro-1,3-benzodioxole</strong>. The nmr spectrum was consistent with the proposed structure.
With triethylamine;tetrakis(triphenylphosphine)palladium (0); In methanol; acetonitrile;
2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine)palladium (0); In methanol; acetonitrile;
Step a: 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
With triethylamine;tetrakis(triphenylphosphine)palladium (0); In methanol; acetonitrile;
Step a: 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55 PSI) at 75 C. (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
Example 1 : 3-(2,2-Difluoro-benzo[1 ,31dioxol-5-ylmethyl)-piperidine-1 -carboxylic acid pyridin-3-ylannide.Step A: 3-(2,2-Difluoro-benzo[1.SIdioxol-delta-ylnnethvD-piperidine-i-carboxylic acid tert-butyl ester.; 1 -Boc-3-methylene piperidine (842 mg, 4.27 mmol) was degassed (neat) for 15 minutes and then treated with a THF solution of 9-BBN (0.5 M in THF, 8.6 ml_, 4.3 mmol). The reaction mixture was refluxed for 2 h, then cooled to rt. The reaction mixture was then added, via cannula, to a preformed solution of 5-bromo-2,2-difluoro-1 ,3-benzodioxole (1.00 g, 4.22 mmol), Pd(dppf)CI2»CH2CI2 (94 mg, 0.128 mmol), and potassium carbonate (746 mg, 5.40 mmol) in DMF/H2O (10 mL/1 ml_). The resultant mixture was heated at 60 0C for 18 h, cooled to rt, poured into water, basified to pH 11 with 1 N NaOH, and extracted with EtOAc (3x). The organic layers were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give 3-(2,2-difluoro-benzo[1 ,3]dioxol-5-ylmethyl)- piperidine-1 -carboxylic acid tert-butyl ester (1.00 g, 67%).
With tetrabutylammomium bromide; palladium diacetate; sodium carbonate; In water; at 150℃; for 0.0833333h;Microwave irradiation; Sealed vessel;
General procedure: Method A. A solution of Pd(OAc)2 (25.2 mg, 0.112 mmol) and triphenylphosphine (147 mg, 0.560 mmol) in absolute ethanol (4 mL) and anhydrous toluene (4 mL) was stirred at RT under nitrogen for 10 min. After that period, commercially available 5-chloro-2-nitrotoluene 4 (646 mg, 3.76 mmol), 4 mL of 2M aqueous Na2CO3, and the appropriate boronic acid R1B(OH)2 (6.03 mmol) were sequentially added. The resulting mixture was heated at 100 C in a sealed vial under nitrogen overnight. After being cooled to RT, the mixture was diluted with water and extracted with EtOAc. The combined organic phase were dried and concentrated. The crude product was purified by flash chromatography over silica gel column using n-Hex/EtOAc or CHCl3/MeOH mixtures as the eluent.
With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tert-butyl XPhos; In 1,4-dioxane; water; at 100℃; for 17h;Inert atmosphere;
(2) 0.97 g (17.22 mmol) of potassium hydroxide, 0.20 g (0.42 mmol) of di-t-butyl(2?,4?,6?-triisopropyl-3,4,5,6-tetramethyl-(1,1?-biphenyl)-2-yl)phosphine and 0.09 g (0.10 mmol) of tris(dibenzylideneacetone)dipalladium(0) were added in a nitrogen atmosphere to a solution having 2.04 g (8.61 mmol) of 2,2-difluoro-5-bromobenzodioxolane dissolved in 5 ml of 1,4-dioxane and 5 ml of water, followed by stirring at 100 C. for 17 hours. 22 ml of 1M hydrochloric acid was added, and then ethyl acetate was added. The aqueous layer was extracted three times with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (developing solvent: heptane/ethyl acetate=80/20) to obtain 1.42 g (yield: 94.8%) of 2,2-difluoro-5-hydroxybenzodioxolane as a pale yellow oil. 1H-NMR(300 MHz, CDCl3, deltappm): 6.88(d, 1 H, J=8.7 Hz), 6.62(d, 1H, J=2.4 Hz), 6.48(dd, 1H, J=8.7 Hz, 2.4 Hz)
82%
With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;
Example 1A 2,2-difluoro-2H-1,3-benzodioxol-5-ol To a mixture of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (10 g, 42.2 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (2.028 g, 4.22 mmol) and potassium hydroxide (4.74 g, 84 mmol) was added degassed water (10 mL). The reaction mixture was sparged with a nitrogen stream for 5 minutes. To the reaction mixture was added a degassed solution of tris(dibenzylideneacetone)dipalladium(0) (0.773 g, 0.844 mmol) in dioxane (10 mL). The combined reaction mixture was sparged with nitrogen for 5-7 minutes. The reaction vial was capped and stirred at 100 C. overnight (16 hours). The reaction mixture was cooled to ambient temperature, and partitioned between ethyl acetate and 1 N HCl solution. The organic fractions were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, maintaining a bath temp at or below 25 C. The residue was purified by flash chromatography using a 220 g silica gel cartridge, eluting with 25-75% dichloromethane/heptanes to afford 6.02 g of the title compound (82% yield). 1H NMR (400 MHz, CDCl3) delta ppm 5.51 (s, 1H), 6.50 (dd, J=8.6, 2.5 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.7, 1.4 Hz, 1H); MS (ESI-) m/z 173.1 (M-H)-.
With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; potassium hydroxide;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 100℃;
To a solution of Compound I (1.0 g), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (190 mg) and potassium hydroxide (474 mg) in a mixture of 1,4-dioxane/water (2.1 mL/2.1 mL) was added Pd2(dba)3 (77 mg), and the resulting mixture was stirred at 100 C. overnight. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to give Compound II (605 mg).
With copper(l) iodide; potassium hydroxide; In water; for 48h;Inert atmosphere; Reflux;
(0104) Firstly, 18.96 g (0.08 mol) of Compound 1 (5-Bromo-2,2-difluorobenzodioxol), 1.52 g (0.008 mol) of CuI, 26.88 g (0.48 mol) of KOH, 200 mL of polyethylene glycol (PEG 400), and 50 mL of water were added into a reaction bottle. Then, the mixture in the reaction bottle was heated to reflux under nitrogen for 48 hours. After the reaction completed, an extraction was performed by using ethyl acetate (EA)/sodium chloride aqueous solution. The organic phase of the extraction solution was collected and concentrated. A column chromatography was performed by using hexane/EA (hexane: EA=8:2) as a mobile phase. The mobile phase after column chromatography was concentrated by the rotary concentrator, and Compound 2 (light yellow liquid) was obtained. The reaction is as follows:
6.43 g
To a cold solution of 5-bromo-2,2-difluorobenzo[cf] [l ,3]dioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5-10 minutes while maintaining the temperature in the range of 10-20 C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 C and 10% H2SO4 solution (50 mL) was added slowly which resulted in a slight exotherm to 20 C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCCb solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of tert-butyl methyl ether and cooled to 0 C. 30% Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) was added slowly, followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0-50% ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil. XH (0700) NMR (400 MHz, DMSO-c) delta ppm 9.75 (s, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.7, 2.5 Hz, 1H). MS (ESI-) m/z 173.1 (M-H)".
6.43 g
Example 159A 2,2-difluorobenzofdj '[ 1 , 3]dioxol-5-ol To a cold solution of 5-bromo-2,2-difluorobenzo[cf] [l,3]dioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5-10 minutes while maintaining the temperature in the range of 10-20 C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 C and 10% H2SO4 solution (50 mL) was added slowly which resulted in a slight exotherm to 20 C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCCb solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of fert-butyl methyl ether and cooled to 0 C. 30% Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) was added slowly, followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0-50% ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil. XH NMR (400 MHz, DMSO-c) delta ppm 9.75 (s, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.7, 2.5 Hz, 1H). MS (ESI-) m/z 173.1 (M-H)".
6.43 g
To a cold solution of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5-10 minutes while maintaining the temperature in the range of 10-20 C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 C and 10% H2SO4 solution (50 mL) was added slowly which resulted in a slight exotherm to 20 C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCO3 solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of tert-butyl methyl ether and cooled to 0 C. 30% Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) was added slowly, followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0~50% ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.75 (s, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.7, 2.5 Hz, 1H); MS (ESI-) m/z 173.1 (M-H)-.
With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;
To a mixture of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (10 g, 42.2 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (2.028 g, 4.22 mmol) and potassium hydroxide (4.74 g, 84 mmol) was added degassed water (10 mL). The reaction mixture was sparged with a nitrogen stream for 5 minutes. To the reaction mixture was added a degassed solution of tris(dibenzylideneacetone)dipalladium(0) (0.773 g, 0.844 mmol) in dioxane (10 mL). The combined reaction mixture was sparged with nitrogen for 5-7 minutes. The reaction vial was capped and was stirred at 100 C. overnight (16 hours). The reaction mixture was cooled to ambient temperature, and partitioned between ethyl acetate and aqueous 1 N HCl solution. The organic fractions were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, maintaining a bath temperature at or below 25 C. The residue was purified by flash chromatography using a 220 g silica gel cartridge, eluting with 25-75% dichloromethane/heptanes to provide the title compound. 1H NMR (400 MHz, CDCl3) delta ppm 5.51 (s, 1H), 6.50 (dd, J=8.6, 2.5 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.7, 1.4 Hz, 1H). MS (ESI-) m/z 173.1 (M-H)-.
6.43 g
To a cold solution of 5-bromo-2,2-difluorobenzo[(f] [l ,3]dioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5- 10 minutes while maintaining the temperature in the range of 10-20 C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 C and 10% H2SO4 solution (50 mL) was added slowly which resulted in a slight exotherm to 20 C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCC>3 solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of teri-butyl methyl ether and cooled to 0 C. 30% Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) was added slowly, followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel(0-50% ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil.JH NMR (400 MHz, DMSO- ) delta ppm 9.75 (s, 1H), 7.12 (d, / = 8.7 Hz, 1H), 6.75 (d, / = 2.4 Hz, 1H), 6.52 (dd, / = 8.7, 2.5 Hz, 1H). MS (ESI-) mJz 173.1 (M-H)
6.43 g
To a cold solution of 5-bromo-2,2-difluorobenzo[dl[1,3ldioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5-10 minutes while maintaining the temperature inthe range of 10-20 C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 C and 10% H2504 solution (50 mL) was added slowlywhich resulted in a slight exotherm to 20 C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCO3 solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of tert-butyl methyl ether and cooled to 0 C. 30% Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) wasadded slowly, followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0-50% ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil. ?H NMR(400 MHz, DMSO-d6) oe ppm 9.75 (s, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H),6.52 (dd, J = 8.7, 2.5 Hz, 1H). MS (ESI-) m/z 173.1 (M-H).
6.43 g
To a cold solution of 5-bromo-2,2-difluorobenzo[(f] [l ,3]dioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5- 10 minutes while maintaining the temperature in the range of 10-20 C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 C and 10% H2SO4 solution (50 mL) was added slowly which resulted in a slight exotherm to 20 C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCC>3 solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of teri-butyl methyl ether and cooled to 0 C. 30% Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) was added slowly, followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0-50% ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil. JH NMR (400 MHz, DMSO- ) delta ppm 9.75 (s, 1H), 7.12 (d, / = 8.7 Hz, 1H), 6.75 (d, / = 2.4 Hz, 1H), 6.52 (dd, / = 8.7, 2.5 Hz, 1H); MS (ESI-) m/z 173.1 (M-H)
6.43 g
To a cold solution of 5-bromo-2,2-difluorobenzo[(f] [l ,3]dioxole (5.75 mL, 42.2 mmol) in tetrahydrofuran (80 mL) was added a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (28.1 mL, 56.1 mmol) within 5- 10 minutes while maintaining the temperature in the range of 10-20 C. The reaction mixture was stirred at the same temperature for another 15 minutes and then allowed to attain room temperature with continued overnight stirring. The reaction mixture was cooled with an ice bath, triisopropyl borate (12.74 mL, 54.9 mmol) was added dropwise over 2 minutes, and stirring at room temperature was continued for 30 minutes. The reaction mixture was cooled to 10 C and 10% H2SO4 solution (50 mL) was added slowly which resulted in a slight exotherm to 20 C. After stirring for 15 minutes, the mixture was partitioned between water and ethyl acetate, and the combined organic extracts were washed with saturated NaHCC>3 solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 100 mL of teri-butyl methyl ether and cooled to 0 C. 30% Hydrogen peroxide solution in water (5.39 mL, 52.7 mmol) was added slowly followed by water (60 mL), and the mixture was stirred overnight while warming up to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed twice with sodium thiosulfate solution and brine. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (1546) (0-50% ethyl acetate in heptane) to give 6.43 g of the title compound as an amber oil. JH NMR (400 MHz, DMSO- ) delta ppm 9.75 (s, 1H), 7.12 (d, / = 8.7 Hz, 1H), 6.75 (d, / = 2.4 Hz, 1H), 6.52 (dd, / = 8.7, 2.5 Hz, 1H); MS (ESI-) mJz 173.1 (M-H)
Multi-step reaction with 7 steps
1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tributylphosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere
1.2: 70 °C
2.1: hydrogenchloride / dimethyl sulfoxide; water / 40 - 75 °C
3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C
4.1: sodium hydroxide / ethanol / 80 °C
5.1: thionyl chloride / toluene / 0.5 h / 60 °C
6.1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C
7.1: formic acid / 8 h / 70 °C
Multi-step reaction with 8 steps
1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tributylphosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere
1.2: 70 °C
2.1: hydrogenchloride / dimethyl sulfoxide; water / 40 - 75 °C
3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C
4.1: sodium hydroxide / ethanol / 80 °C
5.1: thionyl chloride / toluene / 0.5 h / 60 °C
6.1: dmap; triethylamine / toluene; water / 2 h / 2.5 °C
7.1: hydrogenchloride / acetonitrile; water / 40 - 45 °C
8.1: water / 24 h / 20 °C
Multi-step reaction with 7 steps
1.1: bis(dibenzylideneacetone)-palladium(0); sodium phosphate; tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere
1.2: 0.75 h / 70 °C / Inert atmosphere
2.1: hydrogenchloride / dimethyl sulfoxide; water / 1.33 h / 40 - 75 °C
3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C
4.1: sodium hydroxide; water / ethanol / 80 °C
5.1: thionyl chloride / toluene / 0.5 h / 60 °C
6.1: triethylamine; dmap / toluene / 2 h
7.1: formic acid / 8 h / 70 °C
Multi-step reaction with 8 steps
1.1: bis(dibenzylideneacetone)-palladium(0); sodium phosphate; tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere
1.2: 0.75 h / 70 °C / Inert atmosphere
2.1: hydrogenchloride / dimethyl sulfoxide; water / 1.33 h / 40 - 75 °C
3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C
4.1: sodium hydroxide; water / ethanol / 80 °C
5.1: thionyl chloride / toluene / 0.5 h / 60 °C
6.1: triethylamine; dmap / toluene / 2 h
7.1: hydrogenchloride; water / acetonitrile / 40 - 45 °C
8.1: water / 24 h / 20 °C
Multi-step reaction with 7 steps
1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere
1.2: 70 °C
2.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C
3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C
4.1: sodium hydroxide / ethanol / 80 °C
5.1: thionyl chloride / toluene / 0.5 h / 60 °C
6.1: triethylamine; dmap / toluene / 2 h
7.1: formic acid / 8 h / 60 - 80 °C
7.2: 50 - 80 °C
Multi-step reaction with 8 steps
1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere
1.2: 70 °C
2.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C
3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C
4.1: sodium hydroxide / ethanol / 80 °C
5.1: thionyl chloride / toluene / 0.5 h / 60 °C
6.1: triethylamine; dmap / toluene / 2 h
7.1: hydrogenchloride / water; acetonitrile / 40 - 50 °C
8.1: hydrogenchloride / water / 24 h / 20 °C
Multi-step reaction with 7 steps
1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere
1.2: 70 °C / Inert atmosphere
2.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C
3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C
4.1: water; sodium hydroxide / ethanol / 80 °C
5.1: thionyl chloride / toluene / 60 °C
6.1: dmap; triethylamine / toluene / 2 h
7.1: formic acid / 8 h / 70 °C
7.2: 50 - 70 °C
Multi-step reaction with 8 steps
1.1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 0.85 h / 23 °C / Inert atmosphere
1.2: 70 °C / Inert atmosphere
2.1: hydrogenchloride / dimethyl sulfoxide / 40 - 75 °C
3.1: potassium hydroxide; tetraoctyl ammonium bromide / water / 1 h / 70 °C
4.1: water; sodium hydroxide / ethanol / 80 °C
5.1: thionyl chloride / toluene / 60 °C
6.1: dmap; triethylamine / toluene / 2 h
7.1: hydrogenchloride / water; acetonitrile / 45 °C
8.1: water / 24 h / 20 °C
Multi-step reaction with 8 steps
1: sodium phosphate; bis(dibenzylideneacetone)-palladium(0); tri-tert-butyl phosphine / toluene; hexane / 1.67 h / 70 °C / Inert atmosphere
2: hydrogenchloride / dimethyl sulfoxide / 75 °C
3: potassium hydroxide; tetraoctyl ammonium bromide / 1 h / 70 °C
4: sodium hydroxide / ethanol / 80 °C
5: thionyl chloride / toluene / 0.5 h / 60 °C
6: dmap; triethylamine / toluene / 2 h
7: hydrogenchloride / water; acetonitrile / Heating
8: water / 20 °C
5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)thiophene-2-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: 5-bromo-2,2-difluoro-2H-1,3-benzodioxole; C10H10BNO5S With triethylamine In water at 23 - 25℃; for 0.166667h; Inert atmosphere;
Stage #2: With 3-(t-butyl)-4-(2,6-dimethoxyphenyl)-2-(2,4,6-triisopropylbenzyl)-2,3dihydrobenzo[d][1,3]oxaphosphole; palladium diacetate In water; toluene at 25 - 50℃; for 32h; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran for 48h; Inert atmosphere; Reflux;
(0143) Manufacturing Method of Liquid Crystal Compound 3PPI of
(0143) Manufacturing Method of Liquid Crystal Compound 3PPI of (0144) Firstly, 3.55 g (0.015 mol) of Compound 1, 10.8 g (0.045 mol) of Compound 15 (4′-propyl-biphenyl-4-yl) boronic acid, 16.584 g (0.12 mol) of K2CO3, 50 mL of THF, and 5 mL of water were added into a reaction bottle. Then, 0.2 g of tetra(triphenylphosphine)palladium (Pd[P(Ph)3]4) was slowly added into the reaction bottle under nitrogen. Then, the mixture in the reaction bottle was heated to reflux under nitrogen for 48 hours. After the reaction completed, an extraction was performed by using ethyl acetate (EA)/sodium chloride aqueous solution. The organic phase of the extraction solution was collected and concentrated. A column chromatography was performed by using hexane as a mobile phase. The mobile phase after column chromatography was concentrated by the rotary concentrator, and the crude product was obtained. Then, the crude product was recrystallized by using 20 mL of toluene and 50 mL anhydrous alcohol as the solvent, and liquid crystal compound 3PPIof(white solid) was obtained. The final product may be changed by using different Compound 15 (such as, 2PPIof may be obtained by choosing (4′-ethyl-biphenyl-4-yl) boronic acid as Compound 15). The reaction is as follows
Magnesium turnings (11.12g, 0.464mol) and anhydrous tetrahydrofuran (600 ml) were placed in a round-bottomed flask fitted with a mechanical stirrer, reflux condenser, pressure equalizing addition funnel and drying tube. 5-Bromo-2,2- difluoro-l,3-benzodioxole (lOOg) was added to the flask under nitrogen atmosphere. The temperature of the reaction mass was raised to 40C during initiation. Upon initiation, remaining 5-Bromo-2,2-difluoro-l,3-benzodioxole (lOOg) was added drop- wise to the reaction mass. The temperature of the reaction mass was maintained below 40C. The progress of the reaction was monitored by gas chromatography. The reaction mass was then cooled to 0C and carbon-dioxide gas was passed for 2 hours at 0C. The raction was monitored by liquid chromatography for completion. The reaction mass was quenched with 10% HC1 (230g). The organic layer was separated, concentrated to obtain solid. The solid was washed with water (50g) and dichloromethane (50g), filtered and dried at 60C under 50mmHg for 2 hours to obtain the title compound. Yield (%): 70 Purity (%): 99 (by liquid chromatography)
1-butyl-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With [COD(Pd-AlPhos)2]; 1,8-diazabicyclo[5.4.0]undec-7-ene In tert-butyl methyl ether at 60℃; for 16h; Inert atmosphere; Sealed tube; Schlenk technique;
Chemistry
Pharmaceutical Intermediates
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Material Science
For Research Only
110K+ Compounds
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