* 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 n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.833333 h; Stage #2: With Triisopropyl borate In tetrahydrofuran; hexanes at 20℃; for 1.75 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexanes; water at 30℃;
To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at -78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60percent) as a white powder: mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M-H)-; HPLC purity 97.8percent; Anal (C7H6BFO2) C, H.
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.166667 h; Stage #2: With Trimethyl borate In tetrahydrofuran; hexanes at -78 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; hexanes; water at 20℃; for 1 h;
Dissolve [1-BROMO-2- (1-ETHOXY-ETHOXYMETHYL)-4-FLUORO-BENZENE] (5.4g, 19.5 mmol) in dry THF (100 mL) and cool to-78 °C under nitrogen. Add butyl lithium (2.5M in Hexanes, 10.2 mL, 25.4 mmol) dropwise at-78 °C. Upon complete addition, stir the reaction at-78 [°C] for 10 minutes and then add trimethyl borate (4.4 mL, 39 mmol) and warm the reaction to room temperature. Pour the reaction into IN [HC1] (100 mL) and stir for 1 hour. Extract the biphasic mixture with ether three times. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo. Triturate the oily residue with cold hexanes to yield 2.1 g (70percent) of the title compoud as a white solid NMR (d6- DMSO) [C19.] 18 (s, 1H), 7.70 (dd, J= 8.2, 5.8 Hz, 1H), 7.20 (dd, [J= 9.] 5,2. 7 Hz, 1H), 7.11 (m, 1H), 4.92 (s, 1H).
Stage #1: With n-butyllithium In tetrahydrofuran at -70℃; for 0.5 h; Inert atmosphere Stage #2: at 30℃; for 5 h; Inert atmosphere Stage #3: With hydrogenchloride In tetrahydrofuran; water at 40℃; for 6 h;
(3) Under nitrogen protection, 32.5 g of compound III was added to 250 ml of tetrahydrofuran, and cooled to -70 ° C, 55 ml of n-butyllithium was added dropwise, and the reaction was started for 0.5 h with the addition of n-butyllithium. Sampling liquid phase tracking, adding 39 ml of triisopropyl borate, adding dropwise, heating to 30 ° C, reaction for 5 h, Sampling liquid phase tracking, after completion of the reaction, adding 150 ml of water and 40 mL of 2 mol / l hydrochloric acid, adjusting the pH to 3, layering the organic layer, extracting the aqueous layer with ethyl acetate 3 times each time 50 ml, combining the organic layer, using saturated salt Washed with water, dried over anhydrous sodium sulfate, filtered and evaporated The intermediate was dissolved in 90 ml of tetrahydrofuran, and then added with 23 mL of 6 mol/L HCl, heated to 40 ° C, and reacted for 6 h, extracted with 100 ml of ethyl acetate and 300 ml of water, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate three times each time. 50 ml, the organic layer was combined, washed with saturated brine and concentrated to dryness to give a crude product; Add 50ml of deionized water to the crude product, adjust the pH to 14 with 5percent sodium hydroxide solution, stir the impurities, filter the filtrate, decolorize the filtrate with activated carbon once, add ethyl acetate to elute, take the water layer and add hydrochloric acid. The pH was adjusted to 1, and the solid was precipitated. The organic layer was separated by adding 50 ml of dichloromethane. The aqueous layer was extracted twice with dichloromethane (50 ml), and the organic layer was combined. Dry with anhydrous sodium sulfate and filter. The benzoxaborolane antifungal drug was concentrated under reduced pressure in a yield of 80percent.
Reference：
[1] Patent: CN108358961, 2018, A, . Location in patent: Paragraph 0016; 0057; 0058-0060; 0064-0066; 0069; 0073-0075
4
[ 1061223-45-7 ]
[ 174671-46-6 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 20℃; for 4 h;
A mixture of crude (4-fluoro-2-(hydroxymethyl) phenyl)boronic acid (3 g) and 10percent H2S04 solution (20 mL) is stirred at room temperature for 4 hrs. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried on anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is treated with MTBE to afford benzo[c] [l,2]oxaborole-l,5(3H)-diol (Yield: 81percent; Purity: 95percent).
To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at -78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60percent) as a white powder: mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M-H)-; HPLC purity 97.8percent; Anal (C7H6BFO2) C, H.
Reference：
[1] Patent: US2007/286822, 2007, A1, . Location in patent: Page/Page column 60-61
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4447 - 4450
Directly to the next step.The reaction solution containing the compound represented by the formula (III) obtained above is slowly heated to reflux the reaction solution in 5 to 10 minutes,The reaction solution was allowed to react for 2 hours while maintaining the reflux.The reaction solution was poured into about 140 ml of ice water,Stirring,Precipitated as a white solid 4.1 g,The resulting white solid,Mp: 126 to 129 ° C,The structure was confirmed by NMR analysis.
Reference：
[1] Patent: CN106467557, 2017, A, . Location in patent: Paragraph 0022; 0034; 0035
13
[ 850567-57-6 ]
[ 174671-46-6 ]
[ 1447933-60-9 ]
[ 2357-33-7 ]
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 27, p. 9050 - 9058
With hydrogenchloride; In tetrahydrofuran; at 30℃;Product distribution / selectivity;
To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at -78 C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30 C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder: mp 118-120 C.; 1H NMR (300 MHz, DMSO-d6) delta (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M-H)-; HPLC purity 97.8%; Anal (C7H6BFO2) C, H.
With n-butyllithium; Triisopropyl borate; In tetrahydrofuran; hexane; at -78 - 20℃; for 2.25h;Product distribution / selectivity;
To a solution of 3 (4.88 mmol) and triisopropyl borate (1.35 mL, 5.86 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (1.6 mol/L in hexanes; 6.7 mL, 10.7 mmol) dropwise over 15 min at -78 C. under nitrogen atmosphere, and the mixture was stirred for 2 h while allowing to warm to room temperature. The reaction was quenched with 2N HCl, and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography and treated with pentane to give 0.41 mmol of I. 6.2 Results Analytical data for exemplary compounds of structure I are provided below. 6.2.a 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10) Analytical data for this compound is listed in 4.2.j.
To a solution of 3 (4.88 mmol) in toluene (20 mL) was added triisopropyl borate (2.2 mL, 9.8 mmol), and the mixture was heated at reflux for 1 h. The solvent, the generated isopropyl alcohol and excess triisopropyl borate were removed under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and cooled to -78 C. n-Butyllithium (3.2 mL, 5.1 mmol) was added dropwise over 10 min, and the mixture was stirred for 1 h while allowing to warm to room temperature. The reaction was quenched with 2N HCl, and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 1.54 mmol of I. 7.2 Results Analytical data for exemplary compounds of structure I are provided below. 7.2.a 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10) Analytical data for this compound is listed in 4.2.j.
To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at -78 C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30 C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder: mp 118-120 C.; 1H NMR (300 MHz, DMSO-d6) delta (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M-H)-; HPLC purity 97.8%; Anal (C7H6BFO2) C, H.
Dissolve [1-BROMO-2- (1-ETHOXY-ETHOXYMETHYL)-4-FLUORO-BENZENE] (5.4g, 19.5 mmol) in dry THF (100 mL) and cool to-78 C under nitrogen. Add butyl lithium (2.5M in Hexanes, 10.2 mL, 25.4 mmol) dropwise at-78 C. Upon complete addition, stir the reaction at-78 [C] for 10 minutes and then add trimethyl borate (4.4 mL, 39 mmol) and warm the reaction to room temperature. Pour the reaction into IN [HC1] (100 mL) and stir for 1 hour. Extract the biphasic mixture with ether three times. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo. Triturate the oily residue with cold hexanes to yield 2.1 g (70%) of the title compoud as a white solid NMR (d6- DMSO) [C19.] 18 (s, 1H), 7.70 (dd, J= 8.2, 5.8 Hz, 1H), 7.20 (dd, [J= 9.] 5,2. 7 Hz, 1H), 7.11 (m, 1H), 4.92 (s, 1H).
methanesulfonic acid 6-(4-fluoro-2-hydroxymethylphenyl)-5-[4-(2-piperidin-1-ylethoxy)benzoyl]naphthalen-2-yl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 75℃;
Charge a 100 mL round bottom flask with [TRIFLUORO-METHANESULFONIC] acid 6- [METHANESULFBNYLOXY-L- [4- (2-PIPERIDIN-L-YL-CTHOXY)-BENZOYL]-NAPHTHALEN-2-YL] ester (2.3 g, 3. [8] [MMOL),] 5-fluoro-3H-benzo [c] [1, 2] oxaborol-l-ol (1.16 g, 7.6 mmol) and Pd (PPh3) 4 (220 mg, 0.19 mmol) and purge with nitrogen. Add degassed DME (36 mL) and 2M [NA2C03] (4 mL) to the flask and plunge into a [75 C] oil bath and stir overnight. Pour the reaction into saturated aqueous sodium bicarbonate and extract with methylene chloride. Wash the organic layer with water and dry with sodium sulfate. Filter and concentrate to an amber foam. Purify the crude material on silica gel (1% to 6% methanol in methylene chloride) to yield 1.6 g (73%) of the title compound as a tan [FOAM.'H] NMR [(CDC13)] [7.] 98 (d, J= 8. 4 Hz, 1H), 7.90 (d, J= 2.5 Hz, [1H),] 7.60 (bs, 3H), 7.43 (d, J= 8.4 Hz, [1H),] 7. 35 (d, [J=] 8.6 Hz, [1H),] 7.23 (bs, [1H),] 6.90-6. 70 (m, 4H), 4.40-4. 25 (m, 2H), 4.12 (m, 2H), 3.23 (s, 3H), 2.76 [(T,] [J=] 5.4 Hz, 2H), 2.49 (bs, 4H), 1.59 (m, [5H),] 1.45 (m, [1H).] LCMS mass spectrum (ion spray): m/z = 600.2 (M+Na).
Example 1 Preparation of Sample 1 (0138) 3.20 g of <strong>[174671-46-6]<strong>[174671-46-6]5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol</strong>e</strong> (21.2 mmol) and 3.20 g of ethylene glycol (51.6 mmol) are heated in 40 g of toluene. The toluene water azeotrope is distilled out of the system until the head temperature reached 110 C. The toluene is removed via rotary evaporator and the excess ethylene glycol is removed by kugelrohr distillation at about 20 torr and 100 C. bath temperature. Recrystallization from toluene generates 2.95 g of white crystals, mp 145-149 C. Proton nmr shows spectra and integration consistent with the two to one product below:
Example 4 Preparation of Sample 4 (0142) 3.0 g of <strong>[174671-46-6]<strong>[174671-46-6]5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol</strong>e</strong> (19.9 mmol) and 2.5 g of 1,2-propanediol (propylene glycol; 32.9 mmol) are heated in 40 g of toluene. The toluene water azeotrope is distilled out of the system until the head temperature reached 110 C. The toluene is removed via rotary evaporator and the excess propylene glycol is removed by kugelrohr distillation at about 20 torr and 110 C. bath temperature. Recrystallization from hexane generates 3.49 g of white crystals, mp 65.5-68.5 C. Proton NMR shows spectra and integration consistent with the two to one product.
3.49 g
In toluene; at 110℃;
3.0 g of <strong>[174671-46-6]<strong>[174671-46-6]5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol</strong>e</strong> (19.9 mmol) and 2.5 g of 1,2-propanediol (propylene glycol; 32.9 mmol) are heated in 40 g of toluene. The toluene water azeotrope is distilled out of the system until the head temperature reached 110 C. The toluene is removed via rotary evaporator and the excess propylene glycol is removed by kugelrohr distillation at about 20 torr and 110 C bath temperature. Recrystallization from hexane generates 3.49 g of white crystals, mp 65.5-68.5 C. Proton NMR shows spectra and integration consistent with the two to one product.
Example 3 Preparation of Sample 3 (0141) 3.17 g of <strong>[174671-46-6]<strong>[174671-46-6]5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol</strong>e</strong> (21.0 mmol) and 3.22 g of pinacol (27.3 mmol) are heated in 40 g of toluene. The toluene water azeotrope is distilled out of the system until the head temperature reached 110 C. The toluene is removed via rotary evaporator and the excess pinacol is removed by kugelrohr distillation at about 20 torr and 120 C. bath temperature. Recrystallization from hexane generates 3.21 g of white crystals, mp 81-89 C. Proton NMR shows spectra and integration consistent with the two to one product.
3.21 g
In toluene; at 110℃;
3.17 g of <strong>[174671-46-6]<strong>[174671-46-6]5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol</strong>e</strong> (21.0 mmol) and 3.22 g of pinacol (27.3 mmol) are heated in 40 g of toluene. The toluene water azeotrope is distilled out of the system until the head temperature reached 110 C. The toluene is removed via rotary evaporator and the excess pinacol is removed by kugelrohr distillation at about 20 torr and 120 C bath temperature. Recrystallization from hexane generates 3.21 g of white crystals, mp 81-89 C. Proton NMR shows spectra and integration consistent with the two to one product.
3.20 g of <strong>[174671-46-6]<strong>[174671-46-6]5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol</strong>e</strong> (21.2 mmol) and 3.20 g of ethylene glycol (51.6 mmol) are heated in 40 g of toluene. The toluene water azeotrope is distilled out of the system until the head temperature reached 110 C. The toluene is removed via rotary evaporator and the excess ethylene glycol is removed by kugelrohr distillation at about 20 torr and 100 C bath temperature. Recrystallization from toluene generates 2.95 g of white crystals, mp 145-149 C. Proton nmr shows spectra and integration consistent with the two to one product below:
potassium 1,1,5-trifluoro-1,3-dihydro-2,1-benzoxaborolate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
In water; acetone; for 0.5h;
Aqueous potassium hydrogen difluoride solution (Sigma-Aldrich Chemical, 3.0 Molar (M) solution; 4.01 grams (g)) is added to <strong>[174671-46-6]1-hydroxy-5-fluoro-1,3-dihydro-2,1-benzoxaborole</strong> (1.6 g, 10.54 millimoles (mmol)) dissolved in acetone (5 g). The mixture is mixed for 30 minutes (min), whereupon the acetone is removed by rotary evaporation, and the water is removed by azeotropic distillation with toluene using a Dean-Stark trap. The resulting solid suspension is filtered, washed with diethyl ether and air dried to give the desired difluoroboronate salt, potassium 1,1,5-trifluoro-1,3-dihydro-2,1-benzoxaborolate salt (2.02 g, 95%). NMR spectra are consistent with the proposed structure.
Directly to the next step.The reaction solution containing the compound represented by the formula (III) obtained above is slowly heated to reflux the reaction solution in 5 to 10 minutes,The reaction solution was allowed to react for 2 hours while maintaining the reflux.The reaction solution was poured into about 140 ml of ice water,Stirring,Precipitated as a white solid 4.1 g,The resulting white solid,Mp: 126 to 129 C,The structure was confirmed by NMR analysis.
tert-butyl ((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)dimethylsilane[ No CAS ]
[ 174671-46-6 ]
Yield
Reaction Conditions
Operation in experiment
With sodium periodate; ammonium acetate; In water; acetone; at 20℃; for 10h;
To a solution of tert-butyl((5-fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)dimethylsilane (5.13g, 0.014 mol) in Acetone (50 mL), sodium periodate (8.9 g, 0.042 mol), ammonium acetate (2.4 g, 0.031 mol) in water is added. After stirring at room temperature for 10 hr, 2.5N HCI (40 mL) is added, and the mixture is stirred at room temperature overnight. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried on anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is treated with MTBE to afford 5-fluoro- l,3-dihydro-l-hydroxy-2,l-benzoxaborole (Tavaborole 1) (Yield: 83%; Purity: 94%).
5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate[ No CAS ]
[ 174671-46-6 ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium hydroxide; In methanol; at 20℃; for 4h;
To a solution of 5-fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl acetate (5 g) in Methanol (40 mL), NaOH (2eq) is added and stirred for 4 hrs at RT. Solvent is removed at reduced pressure. The obtained crude is taken in mixture of THF (30 mL) and water (15 mL), and treated with concentrated HCI (7.5 ml). After completion of the reaction (usually completes in 12 hrs at RT), product is extracted with ethyl acetate and concentrated at reduced pressure to give the solid. The obtained compound is dissolved in aqueous NaOH solution (30 mL, 1 eq NaOH), washed with ethyl acetate, then acidified with aqueous HCI. The precipitated white solid is filtered, washed with water and dried (Yield: 80%; Purity: 99.8%).
2-(acetoxymethyl)-4-fluorophenylboronic acid[ No CAS ]
[ 174671-46-6 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; at 80℃; for 10h;
A mixture of 2-(acetoxymethyl)-4-fluorophenylboronic acid (3 g) and HCI (4N HCI, 30 mL) is stirred at 80 C for 10 hrs. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with water (until water layer becomes neutral), dried over Na2S04 and evaporated in vacuo to yield 5-fluoro-l,3-dihydrobenzo[c][l,2]oxaborole (Tavaborole 1) (Yield: 93%; Purity: 92%).
(5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol[ No CAS ]
[ 174671-46-6 ]
Yield
Reaction Conditions
Operation in experiment
77%
With hydrogenchloride; In 1,4-dioxane; water; at 20℃;
Preparation of 5-fluorobenzo[c][l,2]oxaborol-l(3H)-ol (Tavaborole 1) To a solution of 5-fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl methanol (5 g) in 1,4-dioxane (30 mL) and water (15 mL), and treated with concentrated HCI (7.5 ml). After completion of the reaction (usually completes in 5-6 hrs at RT), product is extracted with ethyl acetate and concentrated at reduced pressure to give the solid. The obtained compound is dissolved in aqueous NaOH solution (30 mL, 1 eq NaOH), washed with ethyl acetate, then acidified with aqueous HCI. The precipitated white solid is filtered, washed with water and dried (Yield: 77%; Purity: 99.6%).
A mixture of crude (4-fluoro-2-(hydroxymethyl) phenyl)boronic acid (3 g) and 10% H2S04 solution (20 mL) is stirred at room temperature for 4 hrs. Water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried on anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is treated with MTBE to afford benzo[c] [l,2]oxaborole-l,5(3H)-diol (Yield: 81%; Purity: 95%).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); bromine; In dichloromethane; at 34 - 37℃; for 6h;
N-bromosuccinimide (144.51 g), AIBN (31.99 g), and catalytic quantity of bromine (2.07 g) was added to a slurry of 2-methyl-4-fluorophenylboronic acid (100.0 g) in methylene dichloride (5000.0 ml) at 34 to 37C. The resulting reaction mixture was heated to reflux for 6 hrs. The reaction mass was washed with water at 33 to 37C. The methylene chloride layer was added to a solution of sodium hydroxide(150.0 gm sodium hydroxide into 1500.0 ml water) at 10 to 20C and the methylene chloride layer was separated. The pH of aqueous layer was adjusted to pH 2-3 with conc.HCl. Compound of formula V:not detected, Compound of formula XIV: 0.9%, purity(HPLC): 98.9%. The solid was filtered and dried in oven at 45 to 50C for 12 h. The crude compound was dissolved in ethyl acetate (450.0 ml)and to this was added charcoal and stirred at 40C for lh. The reaction mass was filtered and concentrated under vacuum. The solid was dissolved in ethanol and to this water (2.5:6.0) was added. The product obtain 5- Fluoro-l,3-dihydro-l-hydroxy-2,l-benzoxaborole was filtered. Purity (HPLC): 99.9%, Compound of formula XIV: Not detected by HPLC. NuMuKappa (300 MHz, DMSO-d6): delta 4.97, 7.13-7.19 , 7. 23-7. 26, 7.73-7.77, 9.24.
(((2-bromo-5-fluorobenzyl)oxy)methanetriyl)tribenzene[ No CAS ]
[ 174671-46-6 ]
Yield
Reaction Conditions
Operation in experiment
80%
(3) Under nitrogen protection, 32.5 g of compound III was added to 250 ml of tetrahydrofuran, and cooled to -70 C, 55 ml of n-butyllithium was added dropwise, and the reaction was started for 0.5 h with the addition of n-butyllithium. Sampling liquid phase tracking, adding 39 ml of triisopropyl borate, adding dropwise, heating to 30 C, reaction for 5 h, Sampling liquid phase tracking, after completion of the reaction, adding 150 ml of water and 40 mL of 2 mol / l hydrochloric acid, adjusting the pH to 3, layering the organic layer, extracting the aqueous layer with ethyl acetate 3 times each time 50 ml, combining the organic layer, using saturated salt Washed with water, dried over anhydrous sodium sulfate, filtered and evaporated The intermediate was dissolved in 90 ml of tetrahydrofuran, and then added with 23 mL of 6 mol/L HCl, heated to 40 C, and reacted for 6 h, extracted with 100 ml of ethyl acetate and 300 ml of water, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate three times each time. 50 ml, the organic layer was combined, washed with saturated brine and concentrated to dryness to give a crude product; Add 50ml of deionized water to the crude product, adjust the pH to 14 with 5% sodium hydroxide solution, stir the impurities, filter the filtrate, decolorize the filtrate with activated carbon once, add ethyl acetate to elute, take the water layer and add hydrochloric acid. The pH was adjusted to 1, and the solid was precipitated. The organic layer was separated by adding 50 ml of dichloromethane. The aqueous layer was extracted twice with dichloromethane (50 ml), and the organic layer was combined. Dry with anhydrous sodium sulfate and filter. The benzoxaborolane antifungal drug was concentrated under reduced pressure in a yield of 80%.
Take TAV-A (3kg, 12mol, 1 eq) dissolved in 30L of anhydrous methanol, at 5 C,Sodium borohydride (454 g, 12 mol, 1 eq) was added in portions.The reaction was stirred at room temperature for 1 hour. TLC monitors the disappearance of raw materials.2 mol/L of dilute hydrochloric acid (about 18 L) was added to the reaction solution.The pH was adjusted to 2, and the reaction was stirred at room temperature for 1 hour.The TLC monitoring intermediate disappeared. Quenched by adding 20L of water, minusThe methanol was evaporated to dryness and methanol was recovered. Then, a 1 mol/L sodium hydroxide aqueous solution was slowly added dropwise to the remaining aqueous solution to adjust the pH to 6-8, that is, the solid was precipitated, stirred for 2 hours, and filtered.Dry to constant weight at room temperature to obtain a white solid tavaborole (1.66 kg, yield 91%).
With hydrogenchloride; water; In tetrahydrofuran; at 25 - 30℃; for 24h;
8.0 gm compound of formula (II) of was added to the stirred solution of THF (53.3 ml) at 25C-30C. Water (26.6 ml) & concentrated hydrochloric acid (36.6 ml) were added and stirred at 25C-30C for 24 hrs. The pH of resulting solution was adjusted to 7-8 using sodium hydroxide at 25C-30C. The phases were separated and aqueous phase was extracted with methylene chloride (10x2 ml). The obtained MDC phase was mixed with THF layer and solvent was removed under reduced pressure at 50C. Aqueous solution of sodium hydroxide (25 ml, 30%) was added and stirred for 15 minutes. The solution was filtered to remove tritanol and pH of the solution was adjusted to 1-3 by using concentrated hydrochloric acid (20 ml) at 15C-20C. The solid was filtered and dissolved in methylene chloride (30 ml). The resulting solution was washed with acidic brine (10 ml, 20%) and solvent was removed under reduced pressure to obtain Tavaborole (1.0 gm); Purity: 99.79%.
5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole ethanolamine[ No CAS ]
[ 174671-46-6 ]
Yield
Reaction Conditions
Operation in experiment
1.6 g
With L-Tartaric acid; In water; at 50 - 55℃; for 2h;
A solution of L-tartaric acid (2.88 gm) was prepared in water (37.5 ml) and was heated to 50 C-55 C. Tavaborole ethanol amine salt (2.5 gm) was added portion wise at the same temperature in 1 hour and the reaction mass was further maintained at same temperature for another 1 hour. The obtained solid was filtered, washed with water and dried under vacuum to obtain the tittle compound Tavaborole (1.6 gm) (HPLC purity = 99.96%).
2-(4-fluoro-2-tritylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane[ No CAS ]
[ 174671-46-6 ]
Yield
Reaction Conditions
Operation in experiment
2.45 g
With hydrogenchloride; tetrabutylammomium bromide; water; In toluene; at 25 - 30℃; for 21h;
10.0 gm compound of formula (III) of was added to the stirred solution of toluene (100 ml) at 25C-30C. TBAB (0.5 gm) was added. After the addition of concentrated hydrochloric acid (35 ml), the mixture was stirred for 21 hours at 25C-30C. The resulting solution was diluted with aqueous sodium hydroxide (1.61 gm in 8.5 ml water) at 15C-20C and filtered through hyflo bed. The phases were separated and concentrated hydrochloric acid (5 ml) was added to the aqueous layer at 15C-20C and stirred for 30 minutes. The obtained solid was filtered and washed with chilled water (20 ml) and dried at 50C under vacuum for 24 hrs to obtain Tavaborole (2.45 gm); Purity: 99.92%.
With tetrakis-(triphenylphosphine)-palladium In ethanol; water monomer at 95℃; for 4h; Inert atmosphere;
Synthesis of (2-{5-[(l-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-l,3-thiazol-4-yl}-5- fluorophenyl)methanol
A mixture of 4-bromo-5-[( 1 -ethyl- 1H-pyrazol-4-yl)methyl] -2 -methyl- 1 ,3 -thiazole (210 mg, 0.73 mmol), 5 -fluoro- 1 ,3 -dihydro-2, 1 -benzoxaborol- 1 -ol (223 mg, 1.47 mmol), Pd(PPh3)4(85 mg, 0.073 mmol) and disodium carbonate (156 mg, 1.47 mmol), in EtOH (5 mL), water (2.5 mL), and toluene (lmL) was stirred at 95 °C for 4 h under an N2 atmosphere. The reaction was filtered, and the filtrate was diluted with EA (50 mL), washed with brine (2 x 20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (0→30% EtOAc in PE) to give (2-{5-[(l-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-l,3-thiazol-4-yl}-5-fluorophenyl)methanol (220 mg, 47%). LC/MS ESI (m/z): 332 [M+H]+.
47%
With tetrakis-(triphenylphosphine)-palladium In ethanol; water monomer at 95℃; for 4h; Inert atmosphere;
Synthesis of (2-{5-[(l-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-l,3-thiazol-4-yl}-5- fluorophenyl)methanol
A mixture of 4-bromo-5-[( 1 -ethyl- 1H-pyrazol-4-yl)methyl] -2 -methyl- 1 ,3 -thiazole (210 mg, 0.73 mmol), 5 -fluoro- 1 ,3 -dihydro-2, 1 -benzoxaborol- 1 -ol (223 mg, 1.47 mmol), Pd(PPh3)4(85 mg, 0.073 mmol) and disodium carbonate (156 mg, 1.47 mmol), in EtOH (5 mL), water (2.5 mL), and toluene (lmL) was stirred at 95 °C for 4 h under an N2 atmosphere. The reaction was filtered, and the filtrate was diluted with EA (50 mL), washed with brine (2 x 20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (0→30% EtOAc in PE) to give (2-{5-[(l-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-l,3-thiazol-4-yl}-5-fluorophenyl)methanol (220 mg, 47%). LC/MS ESI (m/z): 332 [M+H]+.
Stage #1: (2-bromo-5-fluorophenyl)methanol With n-butyllithium In tert-butyl methyl ether; toluene at -70℃; for 0.166667h; Inert atmosphere;
Stage #2: Trimethyl borate In tert-butyl methyl ether; toluene at -70 - 0℃; for 2h;
1; 8; 10; 11 Example 1
In a 3L reaction flask, add 2-bromo-5-fluorobenzyl alcohol (100g, 488mmol), toluene (1600mL), methyl tert-butyl ether (600mL), cool down to -70°C, and add n-butyllithium (290g, 1073mmol, 2.2eq) under nitrogen protection was added dropwise and the temperature was controlled to -70°C. After the addition was completed, the mixture was stirred for 10 minutes, and trimethyl borate (111.5 g, 1073 mmol, 2.2 eq) was added dropwise at the same temperature. After the addition was completed, the temperature was gradually raised to 0°C. and stirred for 2 hours. TLC detected that the reaction of the raw materials was complete.The temperature was controlled to be below 25°C, 2M dilute hydrochloric acid (500 mL) was added dropwise, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was concentrated to dryness to obtain crude tavaborole with a liquid phase purity of 73%.The crude tavaborole was dissolved in a 10% aqueous sodium hydroxide solution (350 g), n-heptane (200 mL) was added to extract once, and the layers were separated. 2M dilute hydrochloric acid (640 mL) was added dropwise to the aqueous phase, stirred for 30 minutes, a solid was precipitated, and the pH of the mother liquor was detected to be less than 1.After filtering and drying, the finished product tavaborole is obtained. Among them, the yield of tavaborole was 60%, and the purity was >99.9%.
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