| 82% |
With sodium bis(2-methoxyethoxy)aluminium dihydride In toluene at 40 - 50℃; for 1.5h; Inert atmosphere; |
1.B.1 Step 1: Preparation of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol
A reactor was loaded with toluene (300 mL) and 3,3,3-trifluoro-2,2-dimethylpropanoic acid (30 g, 192.2 mmol), capped, purged under nitrogen. The reaction was set to control the internal temperature to 40° C. A solution of Vitride (65% in toluene. approximately 119.6 g of 65% w/w, 115.4 mL of 65% w/w, 384.4 mmol) was set up for addition via syringe, and addition was begun at 40° C., with the target addition temperature between 40 and 50° C. The reaction was stirred at 40° C. for 90 min. The reaction was cooled to 10° C. then the remaining Vitride was quenched with slow addition of water (6 mL). A solution of 15% aq NaOH (30 mL) was added in portions, and solids precipitated half way through the base addition. Water (60.00 mL) was added. The mixture was warmed to 30° C. and held for at least 15 mins. The mixture was then cooled to 20° C. The aqueous layer was removed. The organic layer was washed with water (60 mL×3), and then washed with brine (60 mL). The washed organic layer was dried under Na2SO4, followed with MgSO4. The mix was filtered through Celite, and the cake washed with toluene (60.00 mL) and pulled dry. The product 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (22.5 g, 82%) was obtained as clear colorless solution. |
| 82% |
With aluminum In toluene at 40 - 50℃; for 1.5h; Inert atmosphere; |
1; 1.1 Step 1: Preparation of 3,3,3-trifluoro-2,2-dimethylpropan-l-ol
A reactor was loaded with toluene (300 mL) and 3,3,3-trifluoro-2,2- dimethylpropanoic acid (30 g, 192.2 mmol), capped, purged under nitrogen. The reaction was set to control the internal temperature to 40 °C. A solution of Vitride (65% in toluene approximately 119.6 g of 65 %w/w, 115.4 mL of 65 %w/w, 384.4 mmol) was set up for addition via syringe, and addition was begun at 40 °C, with the target addition temperature between 40 and 50 °C. The reaction was stirred at 40 °C for 90 min. The reaction was cooled to 10 °C then the remaining Vitride was quenched with slow addition of water (6 mL). A solution of 15 % aq NaOH (30 mL) was added in portions, and solids precipitated half way through the base addition. Water (60.00 mL) was added. The mixture was warmed to 30 °C and held for at least 15 mins. The mixture was then cooled to 20 °C. The aqueous layer was removed. The organic layer was washed with water (60 mL x 3), and then washed with brine (60 mL). The washed organic layer was dried under Na2SC>4, followed with MgSCri. The mix was filtered through Celite, and the cake washed with toluene (60.00 mL) and pulled dry. The product 3,3,3-trifluoro-2,2-dimethyl-propan-l-ol (22.5 g, 82%) was obtained as clear colorless solution. |
| 82% |
With sodium bis(2-methoxyethoxy)aluminium dihydride In toluene at 40 - 50℃; for 1.5h; Inert atmosphere; |
12.I.B; 12.III.B.1 Step 1: 3,3,3-Trifluoro-2,2-dimethylpropan-1-ol (5)
A reactor was charged with toluene (300 mL) and 3,3,3-trifluoro-2,2-dimethylpropanoic acid (30 g, 192.2 mmol) and was capped and purged under nitrogen. The reaction was set to control the internal temperature to 40° C. A solution of Vitride (65% in toluene, approximately 119.6 g of 65% w/w, 115.4 mL of 65% w/w, 384.4 mmol) was set up for addition via syringe, and addition was begun at 40° C., with the target addition temp between 40 and 50° C. The reaction was stirred at 40° C. for 90 min. The reaction was cooled to 10° C. the remaining Vitride was quenched with slow the addition of water (6 mL). A solution of 15% aq NaOH (30 mL) was added in portions, and solids precipitated half way through the base addition. Water (60.00 mL) was added. The mixture was warmed to 30° C. and held for at least 15 mins. The mixture was then cooled to 20° C. The aqueous layer was removed. The organic layer was washed with water (60 mL×3), and then washed with brine (60 mL). The washed organic layer was dried under Na2SO4, followed with MgSO4. The mix was filtered through Celite, and the cake was washed with toluene (60.00 mL) and pulled dry. The product 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (22.5 g, 82%) was obtained as clear colorless solution. |
| 79% |
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 25h; Inert atmosphere; |
1.B 3,3,3-Trifluoro-2,2-dimethyl-propan-l-ol
[00152] A 1 L 3 neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, and a J-Kem temperature probe. The vessel was charged with lithium aluminum hydride (LAH) pellets (6.3 g, 0.1665 mol) under a nitrogen atmosphere. The vessel was then charged with tetrahydrofuran (200 mL) under a nitrogen atmosphere. The mixture was allowed to stir at room temperature for 0.5 hours to allow the pellets to dissolve. The cooling bath was then charged with crushed ice in water and the reaction temperature was lowered to 0 °C. The addition funnel was charged with a solution of 3,3,3-trifluoro-2,2-dimethyl-propanoic acid (20 g, 0.1281 mol) in tetrahydrofuran (60 mL) and the clear pale yellow solution was added drop wise over 1 hour. After the addition was complete the mixture was allowed to slowly warm to room temperature and stirring was continued for 24 hours. The suspension was cooled to 0 °C with a crushed ice-water in the cooling bath and then quenched by the very slow and drop wise addition of water (6.3 ml), followed by sodium hydroxide solution (15 weight %; 6.3 mL) and then finally with water (18.9 mL). The reaction temperature of the resulting white suspension was recorded at 5 °C. The suspension was stirred at ~5 °C for 30 minutes and then filtered through a 20 mm layer of Celite. The filter cake was washed with tetrahydrofuran (2 x 100 mL). The filtrate was dried over sodium sulfate (150 g) and then filtered. The filtrate was concentrated under reduced pressure to provide a clear colorless oil (15 g) containing a mixture of the product 3,3,3-trifluoro-2,2-dimethyl- propan-l-ol in THF (73 % weight of product ~10.95g, and 27 wt.% THF as determined by 1H-NMR). The distillate from the rotary evaporation was distilled at atmospheric pressure using a 30 cm Vigreux column to provide 8.75 g of a residue containing 60 % weight of THF and 40 % weight of product (-3.5 g). The estimated total amount of product is 14.45 g (79% yield). 1H NMR (400 MHz, DMSO-d6) δ 4.99 (t, J = 5.7 Hz, 1H), 3.38 (dd, J = 5.8, 0.9 Hz, 2H), 1.04 (d, J = 0.9 Hz, 6H). |
| 79% |
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 25h; Inert atmosphere; |
1.C.1 Step 1: 3,3,3-Trifluoro-2,2-dimethyl-propan-l-ol
A 1 L 3 neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, and a J-Kem temperature probe. The vessel was charged with lithium aluminum hydride (LAH) pellets (6.3 g, 0.1665 mol) under a nitrogen atmosphere. The vessel was then charged with tetrahydrofuran (200 mL) under a nitrogen atmosphere. The mixture was allowed to stir at room temperature for 0.5 hours to allow the pellets to dissolve. The cooling bath was then charged with crushed ice in water and the reaction temperature was lowered to 0 oC. The addition funnel was charged with a solution of 3, 3, 3-trifluoro-2,2-dimethyl-propanoic acid (20 g, 0.1281 mol) in tetrahydrofuran (60 mL) and the clear pale yellow solution was added drop wise over 1 hour. After the addition was complete the mixture was allowed to slowly warm to room temperature and stirring was continued for 24 hours. The suspension was cooled to 0 oC with a crushed ice-water in the cooling bath and then quenched by the very slow and drop wise addition of water (6.3 mL), followed by sodium hydroxide solution (15 weight %; 6.3 mL) and then finally with water (18.9 mL). The reaction temperature of the resulting white suspension was recorded at 5 oC. The suspension was stirred at ~5 oC for 30 minutes and then filtered through a 20 mm layer of Celite. The filter cake was washed with tetrahydrofuran (2 x 100 mL). The filtrate was dried over sodium sulfate (150 g) and then filtered. The filtrate was concentrated under reduced pressure to provide a clear colorless oil (15 g) containing a mixture of the product 3,3,3-trifluoro-2,2- dimethyl-propan-l-ol in THF (73 % weight of product ~l0.95g, and 27 wt.% THF as determined by 1H-NMR). The distillate from the rotary evaporation was distilled at atmospheric pressure using a 30 cm Vigreux column to provide 8.75 g of a residue containing 60 % weight of THF and 40 % weight of product (-3.5 g). The estimated total amount of product is 14.45 g (79% yield). 1H NMR (400 MHz, DMSO-d6) d 4.99 (t, J = 5.7 Hz, 1H), 3.38 (dd, J = 5.8, 0.9 Hz, 2H), 1.04 (d, J = 0.9 Hz, 6H). |
| 79% |
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 25h; |
C.1 Step 1: 3,3,3-Trifluoro-2,2-dimethyl-propan-l-ol
A 1 L 3 neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, and a J-Kem temperature probe. The vessel was charged with lithium aluminum hydride (LAH) pellets (6.3 g, 0.1665 mol) under a nitrogen atmosphere. The vessel was then charged with tetrahydrofuran (200 mL) under a nitrogen atmosphere. The mixture was allowed to stir at room temperature for 0.5 hours to allow the pellets to dissolve. The cooling bath was then charged with crushed ice in water and the reaction temperature was lowered to 0 °C. The addition funnel was charged with a solution of 3,3, 3-trifluoro-2, 2-dimethyl-propanoic acid (20 g, 0.1281 mol) in tetrahydrofuran (60 mL) and the clear pale yellow solution was added drop wise over 1 hour. After the addition was complete the mixture was allowed to slowly warm to room temperature and stirring was continued for 24 hours. The suspension was cooled to 0 °C with a crushed ice-water in the cooling bath and then quenched by the very slow and drop wise addition of water (6.3 mL), followed by sodium hydroxide solution (15 weight %; 6.3 mL) and then finally with water (18.9 mL). The reaction temperature of the resulting white suspension was recorded at 5 °C. The suspension was stirred at ~5 °C for 30 minutes and then filtered through a 20 mm layer of Celite. The filter cake was washed with tetrahydrofuran (2 x 100 mL). The filtrate was dried over sodium sulfate (150 g) and then filtered. The filtrate was concentrated under reduced pressure to provide a clear colorless oil (15 g) containing a mixture of the product 3,3,3-trifluoro-2,2-dimethyl- propan-l-ol in THF (73 % weight of product ~l0.95g, and 27 wt.% THF as determined by 1H-NMR). The distillate from the rotary evaporation was distilled at atmospheric pressure using a 30 cm Vigreux column to provide 8.75 g of a residue containing 60 % weight of THF and 40 % weight of product (~3.5 g). The estimated total amount of product is 14.45 g (79% yield). 1H NMR (400 MHz, DMSO-d6) d 4.99 (t, J = 5.7 Hz, 1H), 3.38 (dd, J = 5.8, 0.9 Hz, 2H), 1.04 (d, J = 0.9 Hz, 6H). |
|
Stage #1: 3,3,3-trifluoro-2,2-dimethylpropanoic acid With lithium aluminium tetrahydride In diethyl ether at -15 - -5℃; for 0.25h;
Stage #2: With water; sodium hydroxide In diethyl ether at 0 - 10℃; |
Intermediate 44 3,3,3-Trifluoro-2,2-dimethylpropan-1-ol
A solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (340 g, 2.18 mol) in Et2O (340 mL) was added dropwise to a -15 to -5° C. suspension of LAH (108 g, 2.83 mol) in Et2O (3.1 L), and the mixture was stirred for 15 min. After this time, water (108 mL), 15% aqueous NaOH (108 mL), and more water (324 mL) were added at a rate that maintained the internal temperature at 0-10° C. Anhydrous MgSO4 was then added, and the mixture was stirred for 30 min. The mixture was then filtered, and the filter cake was washed with Et2O. The filtrate and wash were combined and then concentrated to afford the title compound as a pale-yellow liquid. |
|
With lithium aluminium tetrahydride In diethyl ether at -15 - -5℃; for 0.25h; |
3,3,3-Trifluoro-2,2-dimethylpropan-1-ol
A solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (340 g, 2.18 mol) in Et2O (340 mL) was added dropwise to a -15 to -5° C. suspension of LAH (108 g, 2.83 mol) in Et2O (3.1 L), and the mixture was stirred for 15 min. After this time, water (108 mL), 15% aqueous NaOH (108 mL), and more water (324 mL) were added at a rate that maintained the internal temperature at 0-10° C. Anhydrous MgSO4 was then added, and the mixture was stirred for 30 min. The mixture was then filtered, and the filter cake was washed with Et2O. The filtrate and wash were combined and then concentrated to afford the title compound as a pale-yellow liquid. |
|
With lithium aluminium tetrahydride In diethyl ether at -15 - -5℃; for 0.25h; |
3,3,3-Trifluoro-2,2-dimethylpropan-1-ol
A solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (340 g, 2.18 mol) in Et2O (340 mL) was added dropwise to a -15 to -5° C. suspension of LAH (108 g, 2.83 mol) in Et2O (3.1 L), and the mixture was stirred for 15 min. After this time, water (108 mL), 15% aqueous NaOH (108 mL), and more water (324 mL) were added at a rate that maintained the internal temperature at 0-10° C. Anhydrous MgSO4 was then added, and the mixture was stirred for 30 min. The mixture was then filtered, and the filter cake was washed with Et2O. The filtrate and wash were combined and then concentrated to afford the title compound as a pale-yellow liquid. |
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