| 100% |
With triethylamine; In dichloromethane; at 20℃; for 16h; |
To a solution of tetrahydro-2H-pyran-4-ol (4.5 g, 44 mmol) in DCM (200 mL) was added TEA (5.4 g, 53.5 mmol) and MeSO2C1 (3.73 mL, 50 mmol) at ice-bath temperature. The reaction mixture was stirred at rt for 16 h. The reaction was quenched with water and the organic layer was washed with brine, dried and concentrated to give 7.9 g of the title compound (100%). ?H NMR (400 MHz, CDC13): oe 1.84-1.93 (2H, m), 2.03-2.08 (2H, m), 3.05 (3H, s), 3.52-3.58 (2H, m), 3.92-3.97 (2H, m), 4.87-4.94 (1H, m). |
| 100% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; |
To a solution of tetrahydro-2H-pyran-4-ol (500 mg, 4.90 mmol) in DCM (16 mL) was added TEA (0.882 mL, 6.36 mmol) followed by MsCl (0.458 mL, 5.87 mmol) at 0 C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM, washed with water, 2 N aq. HCl, saturated aq. NaHCO3, and brine successively, dried over Na2SO4, filtered and concentrated in vacuo to afford tetrahydro-2H-pyran-4-yl methanesulfonate (882 mg, 100%) as a colorless oil, which was used for the next reaction without further purification. 1H-NMR (CDCl3, Varian, 400 MHz): delta 1.84-1.92 (2H, m), 2.03-2.07 (2H, m), 3.04 (3H, s), 3.52-3.58 (2H, m), 3.92-3.97 (2H, m), 4.87-4.93 (1H, m). |
| 100% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; |
A solution of tetrahydropyran-4-ol (2.0 g, 20 mmol) and diisopropylethylamine (3.00 g, 23.5 mmol) in DCM (20 mL) was cooled to 0 C and methanesulfonyl chloride (2.50 g, 21.5 mmol) was added drop wise and stirred at rt for 2 h. The mixture was concentrated to dryness to give the title Compound (3.72 mg, 100% yield), which was used in the next step directly |
| 100% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2.5h; |
To a solution of tetrahydro-2H-pyran-4-ol (2 g, 20 mmol) in DCM (20 mL) at 0 C was added DIEA (3 g, 23,5 mmol), and methanesulfonyl chloride (2.46 g, 21.5 mmol). The reaction mixture was stirred at 0 C for 1 hr, then at room temperature for 1.5 hrs. The mixture was poured into water, extracted into DCM. The organic layer was separated, washed with water, brine, dried over Na2S04, and concentrated to give the title compound. (3.72 mg, quantitative). |
| 100% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; |
A solution of tetrahydropyran-4-ol (2.0 g, 20 mmol) and diisopropylethylamine (3.00 g, 23.5 mmol) in DCM (20 mL) was cooled to 0 C and methanesulfonyl chloride (2.50 g, 21.5 mmol) was added dropwise and stirred at rt for 2 h. Themixture was concentrated to dryness to give the title compound (3.72 mg, 100% yield), which was used in the next step directly. |
| 100% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2.5h; |
To a solution of tetrahydro-2H-pyran-4-ol (2 g, 20 mmol) in DCM (20 mL) at 0 was added DIEA (3 g, 23.5 mmol), and methanesulfonyl chloride (2.46 g, 21.5 mmol). The reaction mixture was stirred at 0 for 1 hr, then at room temperature for 1.5 hrs. The mixture was poured into water, extracted into DCM. The organic layer was separated, washed with water, brine, dried over Na 2SO 4, and concentrated to give the title compound. (3.72 mg, quantitative). |
| 99% |
With triethylamine; In dichloromethane; at 0 - 20℃; |
4-Hydroxytetrahydropyran (4.86 g, 47.6 mmol) was dissolved in DCM (40 mL) and triethylamine (6.95 mL, 49.9 mmol). The reaction mixture was cooled to 0 0C and a solution of methanesulfonyl chloride (5.72 g, 49.9 mmol) in DCM (10 mL) was added dropwise. The reaction mixture was stirred at 0 0C for 5 min and then allowed to warm to room temperature and stirred for 20 h. The solvents were removed in vacuo to give a white residue which was partitioned between EtOAc and H2O. The aq phase was extracted with EtOAc (2 x 100 niL). The organic layers were combined, dried (MgSO4) and the solvents were removed in vacuo to give tetrahydro-2H-pyran-4-yl methanesulfonate (8.53 g, 99%) as a colourless gum which solidified on standing. |
| 96% |
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 12h; |
General procedure: In the following Reaction Scheme A-2 Butyl 4-hydroxypiperidine-1-carboxylate (1 eq.) Or tetrahydro-2H-p yr-4-ol (1 eq.),Methanesulfonyl chloride (MsCl, 1 eq.),Triethylamine (Et3N, 1 eq.) And 4-dimethylaminopyridine (DMAP, 0.4 eq.) Were dissolved in dichloromethane at 0 C and stirred at room temperature for 12 hours.Water was added to the reaction solution at 0 C and extracted three times with dichloromethane.The combined organic solvent layers were dried with magnesium sulfate and concentrated.This was purified by column chromatography to obtain a compound substituted with methanesulfonate.Subsequently, 4-iodo-1H-pyrazole (1 eq.) Was dissolved in DMF, cooled to 0 C, 60% sodium hydride (NaH, 1.2 eq.) Was added to the solution and the mixture was stirred at room temperature for 1 hour.The previously obtained compound (1.1 eq) was added to the reaction solution, and the mixture was heated and stirred at 100 C.Water was added to the reaction solution at 0 C, extracted three times with ethyl acetate, and the combined organic solvent layer was dried over magnesium sulfate.The obtained organic solvent layer was concentrated and purified by column chromatography to obtain an intermediate. |
| 94% |
With triethylamine; In toluene; at 20℃;Industry scale; |
Step 1: Synthesis of Methansulfonic acid tetrahydropyran-4-yl ester 10 kg tetrahydropyran-4-ol are dissolved in a mixture of 50 L toluene and 10.4 kg triethylamine. 11.55 kg methanesulfonyl chloride in 100 ml toluene are added while maintaining the internal temperature below 20 C. by cooling, and the addition funnel is rinsed with 50 ml toluene. The stirring is continued for one hour. The precipitate is filtered and the filter cake is washed twice with 20 L toluene each. The filtrate is concentrated by vaccum evaporation (60 L were distilled of), seeding crystals and 50 L methylcyclohexane are added. The suspension is cooled to 2 C. After 1 h the product is isolated by filtration, washed with 30 L methylcyclohexane and dried at 30 C. 16.6 kg of the product are obtained as a white solid. Yield: 94%; 1H NMR (400 MHz, DMSO-d6) delta ppm 1.62-1.73 (2H, m), 1.92-2.00 (2H, m), 3.19 (3H, s), 3.42-3.49 (2H, m), 3.77-3.83 (2H, m), 4.80-4.88 (1H, m). |
| 94% |
With triethylamine; In toluene; at 20℃; |
10 kg Compound 23 are dissolved in a mixture of 50 L toluene and 10.4 kg triethylamine. 11.55 kg methane sulfonyl chloride in 100 mL toluene are added while maintaining the internal temperature below 20 C. by cooling, and the addition funnel is rinsed with 50 mL toluene. The stirring is continued for 1 h. The precipitate is filtered and the filter cake is washed twice with 20 L toluene each. The filtrate is concentrated by vacuum evaporation (60 L are removed by distillation), seeding crystals and 50 L methylcyclohexane are added. The suspension is cooled to 2 C. After 1 h the product is isolated by filtration, washed with 30 L methylcyclohexane and dried at 30 C. 16.6 kg of the product are obtained as a white solid. Yield: 94%; 1H NMR (400 MHz, DMSO-d6) delta ppm 1.62-1.73 (2H, m), 1.92-2.00 (2H, m), 3.19 (3H, s), 3.42-3.49 (2H, m), 3.77-3.83 (2H, m), 4.80-4.88 (1H, m). |
| 94% |
With triethylamine; In toluene; at 20℃; for 1h;Industry scale; |
S nthesis of Compound A7Step 1: Synthesis of Compound A3a 10 kg of compound A2 are dissolved in a mixture of 50 L toluene and 10.4 kg triethylamine. 11.55 kg methanesulfonyl chloride in 100 ml toluene are added while maintaining the internal temperature below 20 C by cooling, and the addition funnel is rinsed with 50 ml toluene. The stirring is continued for one hour. The precipitate is filtered and the filter cake is washed twice with 20 L toluene each. The filtrate is concentrated by vaccum evaporation (60 L were distilled of), seeding crystals and 50 L methylcyclohexane are added. The suspension is cooled to 2C. After 1 h the product is isolated by filtration, washed with 30 L methylcyclohexane and dried at 30C. 16.6 kg of compound A3a are obtained as a white solid. Yield: 94%; 1H NMR (400 MHz, DMSO-d6) delta ppm 1.62- 1.73 (2H, m), 1.92-2.00 (2H, m), 3.19 (3H, s), 3.42- 3.49 (2H, m), 3.77-3.83 (2H, m), 4.80-4.88 (1H, m). |
| 94.5% |
With triethylamine; In dichloromethane; at 0 - 20℃; |
To a solution of tetrahydro-2H-pyran-4-ol (4 mL, 41.11 mmol) in DCM (60 mL) was added TEA (9 mL, 63.9 mmol) at 0. After stirring 5 min, methanesulfonyl chloride (3.5 mL, 45 mmol) was added slowly to the mixture. The resulting mixture was stirred for 1 h and warmed to rt, and then further stirred overnight. The reaction mixture was diluted with water (50 mL) . The resulting mixture was extracted with DCM (100 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo to give a light yellow solid product (7 g, 94.5) .[1586]MS (ESI, pos. ion) m/z: no response. |
| 90% |
With triethylamine; In dichloromethane; at 0℃; for 1h; |
TEA (13 g, 129 mmol, 3 equiv.) was added to the step a product (4.3 g, 43 mmol, 1 equiv.) in DCM (43 mL) and the mixture was cooled to 0 C. Mesyl chloride (4.47 g, 43 mmol, 1 equiv.) was added and the mixture was stirred for 1 h at 0 C. The mixture was then washed with iced water (1×50 mL) and the phases were separated. The organic phase was dried over Na2SO4 and concentrated under reduced pressure, 7 g (90% yield) of the product being obtained as a yellow solid. |
| 80.9% |
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; |
As shown in step 2-i of Scheme 2, methanesulfonyl chloride (12 mL, 0.155 mol) was added dropwise to a mixture of tetrahydro-2H-pyran-4-ol (15.83 g, 0.155 mol), triethylamine (21.6 mL, 0.155 mol), and dimethylaminopyridine (1.89 g, 0.015 mol) in 200 mL of DCM at 00C. The reaction was warmed to room temperature and stirred for 16 hours. The organics were washed with water, washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed under reduced pressure to provide tetrahydro-2H-pyran-4- yl methanesulfonate (Compound 1010, 22.6 g, 80.9% yield) as a yellow solid: 1H NMR (300 MHz, CDCl3) delta 4.90 (qn, J=4.2 Hz, IH), 3.95 (dt, J=12.0, 4.2 Hz, 2H), 3.59-3.51 (m, 2H), 3.04 (s, 3H), 2.08-2.01 (m, 2H), 1.94-1.82 (m, 2H). |
| 60% |
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1.5h; |
To a solution of 8b (l .Og, 9.8mmol) and TEA (1.12g, 1 l .lmmol) in THF (1OmL) cooled by ice-bath, was added methanesulfonyl chloride (1.19g, 10.4mmol) drop-wise. The resulting mixture was stirred at room temperature for 1.5h, then filtrated. The solid was washed with ethyl acetate. The combined filtrate was evaporated and the residue was dissolved in ethyl acetate (3OmL), washed with brine (15mL*2), dried over Na2SO4 and evaporated to afford 8c (l .Og, 60%). |
| 45% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 5h;Inert atmosphere; |
To a solution of tetrahydro-211-pyran-4-ol (5 g, 49.0 mmol) and triethylamine (5.94 g, 58.7 rnmol) in DCM (100 mL) was added mesyl chloride (16.8 g, 146.9 mmol) dropwise at 0 C under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h. Water (100 mL) was added and extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the titlecompound (4 g, 45%) as a yellow solid. 1fl NMR (400 MHz, CDC13) 6 4.85 - 4.81 (m 11-I),3.90-3.87 (m, 211), 3.52 - 3.46 (m, 211), 2.99 (s, 3H), 2.01 - 1.97 (in, 2H), 1.83 - 1.80 (m,2H). |
| 45% |
With triethylamine; In dichloromethane; at 0 - 25℃; for 5h;Inert atmosphere; |
To a solution of tetrahydro-2H-pyran-4-ol (5 g, 49.0 mmol) and triethylamine (8.2 mL,58.7 mmol) in DCM (100 mL) was added mesyl chloride (16.8 g, 146.9 mmol) dropwise at 0 Cunder a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h. Water (100mL) was added and extracted with DCM (100 mL x 2). The combined organic layers were driedover anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (4 g,45%) as a yellow solid. ?H NIVIR (400 IVIHz, CDC13) 4.85 - 4.81 (m 1H), 3.90 - 3.87 (m, 2H),3.52 - 3.46 (m, 2H), 2.99 (s, 3H), 2.01 - 1.97 (m, 2H), 1.83 - 1.80 (m, 2H). |
|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h; |
To a solution of tetrahydro-4H-pyran-4-ol (3.62 g) and triethylamine (5.6 mL) in tetrahydrofuran (35 mL) was added methanesulfonyl chloride (2.93 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration. To the filtrate were addedN,N-dimethylformamide (70 mL), 4-benzyloxy-2-hydroxybenzaldehyde (5.39 g) and cesium carbonate (23 g), and the mixture was stirred at 80C for 12 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 4/1 - 2/1) to give 4-benzyloxy-2-(tetrahydro-4H-pyran-4-yl-oxy)benzaldehyde (4.58 g). This material was dissolved in ethanol (70 mL). To the solution was added sodium borohydride (0.28 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 3/1 - 1/1) to give the title compound (4.45 g).1H-NMR (CDCl3) delta ppm: 1.75-1.85 (2H, m), 1.95-2.05 (2H, m), 2.11 (1H, t, J=6.3Hz), 3.5-3.65 (2H, m), 3.9-4.0 (2H, m), 4.45-4.55 (1H, m), 4.63 (2H, d, J=6.3Hz), 5.05 (2H, s), 6.5-6.6 (2H, m), 7.19 (1H, d, J=7.7Hz), 7.3-7.45 (5H, m) |
|
With dmap; triethylamine; In dichloromethane; at 20℃; for 3h; |
Example 95A (enantiomer 1)Step I: tetrahydro-2H-pyran-4-yl methanesulfonate; P At r.L to a solution of tetrahydro-4H-pyran-4-ol (90 uL, . mmol; Aldrich, Cat. No. 198234) in methylene chloride (3 mL) was added methanesulfonyl chloride (91 uL, 1.2 mmol), followed by triethylamine (0.20 mL, 1.5 mmol) and 4-dimethylaminopyridine (12 mg, 0.098 mmol). The mixture was stirred at r.L for 3 h. It was diluted with methylene chloride. The solution was washed with water and brine, dried over l^SCv After filtration, the filtrate was concentrated to yield 0.21 g of the product (crude) which was directly used in the next step reaction without further purification. |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h; |
To a solution of 4-hydroxytetrahydropyran (4.5 g, 44 mmol) (Aldrich) in dichloromethane (90 mL) at 0 C. was added triethylamine (5.4 g, 53 mmol), and methanesulfonyl chloride (3.73 mL, 48 mmol, Aldrich). The reaction mixture was stirred at 0 C. for 1 h, then at room temperature for 1.5 h. The mixture was poured into water, extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give crude methanesulfonic acid tetrahydropyran-4-yl ester as a white solid (Yield 8 g, 100%). |
|
With triethylamine; In dichloromethane; at 20℃; for 1h; |
To a mixture of tetrahydro-2H-pyran-4-ol (U-1 ) (1.02 g, 10 mmol) and Et3N (1 mL) in dried DCM (20 mL) was added MsCI (2 mL) dropwise. The reaction was stirred at room temperature for 1 h, then washed with water. The organic layer was separated, dried over Na2S04, and concentrated to afford the title compound (1.8 g). |
|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃;Inert atmosphere; |
Step A: Preparation of tetrahydro-2H-pyran-4-yl methanesulfonate: To a solution of tetrahydro-2H-pyran-4-ol (2.5 g, 24.5 mmol) in DCM (40 mL) was added DIEA (6.40 mL, 36.7 mmol) at 0 C and allowed to stir under nitrogen for 10 minutes. Methane sulfonyl chloride (2.18 mL, 28.1 mmol) was added slowly. The reaction was allowed to proceed for 1 hour at 0 C. The reaction was partitioned between 100 mL of DCM and 50 mL of 0.5 M hydrochloric acid. The layers were separated and the organic layer was then washed sequentially with water, saturated sodium bicarbonate, and brine. The organic layer was dried over MgSO t, filtered, and concentrated under reduced pressure and dried on high vacuum to afford tetrahydro-2H-pyran-4-yl methanesulfonate (4.4 g, 24.4 mmol, 99.7% yield). |
|
With triethylamine; In dichloromethane; at 20℃; for 1h; |
Tetrahydro-2H-pyran-4-yl methanesulfonate (U-2) To a mixture of tetrahydro-2H-pyran-4-ol (U-1) (1.02 g, 10 mmol) and Et3N (1 mL) in dried DCM (20 mL) was added MsCl (2 mL) dropwise. The reaction was stirred at room temperature for 1 h, then washed with water. The organic layer was separated, dried over Na2SO4, and concentrated to afford the title compound (1.8 g). |
|
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 1h; |
To an ice-cooled solution of oxan-4-ol (1.00 g, 9.79 mmol), Et3N (1.36 ml, 9.79 mmol) and catalytic amount DMAP in 20 ml of CH2Cl2 was added dropwise MsCl (0.76 ml, 9.79 mmol). The resulting mixture was stirred for 1 h and diluted with water. The mixture was extracted with CH2Cl2. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was pure enough for use in the next step (1.65 g, 93.5 % yield). |
| 16.2 g |
With triethylamine; In dichloromethane; at 20℃; for 1h; |
To a solution of tetrahydro-2H-pyran-4-ol (10.0 g) and triethylamine (19.1 mL) in dichloromethane (100 mL) was added dropwise methanesulfonyl chloride (10.7 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and dichloromethane was added. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the titlecompound (16.2 g) .XH NMR (400 MHz, CDC13) delta 1.84-1.93 (2H, m) , 2.03-2.08 (2H, m) , 3.04 (3H, s), 3.52-3.58 (2H, m) , 3.92-3.98 (2H, m) , 4.88-4.94 (1H, m) . |
| 29.4 g |
With triethylamine; In tetrahydrofuran; at 20 - 30℃; for 12h; |
Step 1: Tetrahydro-2H-pyran-4-yl methanesulfonate To a solution of tetrahydro-2H-pyran-4-ol (20 g) in tetrahydrofuran (150 mL) and triethylamine (28.5 mL) is slowly added methanesulfonyl chloride (15.5 mL), while keeping the temperature below 30 C. The mixture is stirred for 12 hours at room temperature. The precipitate is filtered off and washed twice with tetrahydrofuran. The combined organic phases are concentrated and partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 29.4 g; TLC: rf=0.36 (silicagel, petrole ether/ethyl acetate 1:1); Mass spectrum (ESI+): m/z=198 [M+NH4]+. |
| 29.4 g |
With triethylamine; In tetrahydrofuran; at 20 - 30℃; for 12h; |
To a solution of tetrahydro-2H-pyran-4-ol (20 g ) in tetrahydrofuran (150 mL) and triethylamine (28.5 mL) is slowly added methanesulfonyl chloride (15.5 mL), while keeping the temperature below 30C. The mixture is stirred for 1 2 hours at room temperature. The precipitate is filtered off and washed twice with tetrahydrofuran. The combined organic phases are concentrated and partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 29.4 g; TLC: rf = 0.36 (silicagel, petrole ether/ethyl acetate 1 :1 ); Mass spectrum (ESI+): m/z = 198 [M+NH4]+. |
| 29.4 g |
With triethylamine; In tetrahydrofuran; at 20 - 30℃; for 12h; |
To a solution of tetrahydro-2H-pyran-4-ol (20 g ) in tetrahydrofuran (150 mL) and triethylamine (28.5 mL) is slowly added methanesulfonyl chloride (15.5 mL), while keeping the temperature below 30C. The mixture is stirred for 12 hours at room temperature. The precipitate is filtered off and washed twice with tetrahydrofuran. The combined organic phases are concentrated and partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 29.4 g; TLC: rf = 0.36 (silicagel, petrole ether/ethyl acetate 1 :1 ); Mass spectrum (ESI+): m/z = 198 [M+NH4]+. |
|
With dmap; triethylamine; In dichloromethane; at 0℃; for 1h; |
General procedure: To a solution of 1-(2,6-dichloro-3-fluorophenyl)ethan-1-one 11 (20.00 g, 96.60 mmol) in 100 mL of MeOH was added portionwise NaBH4 (7.31 g, 193.21 mmol). The resulting mixture was stirred at room temperature for 2 h and then quenched with 20 mL of water. After the removal of MeOH under vacuum, the residue was extracted with EA and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to afford 1-(2,6-dichloro-3-fluorophenyl)ethan-1-ol, which was pure enough for use in the next step. 1H NMR (400 MHz, CDCl3) delta 7.26 (dd, J = 4.8, 8.8 Hz, 1H), 7.02 (dd, J = 8.0, 8.8 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 2.86 (br, 1H), 1.64 (d, J = 6.8 Hz, 3H). To a solution of 1-(2,6-dichloro-3-fluorophenyl)ethan-1-ol (19.00 g, 90.89 mmol) in 150 mL of CH2Cl2 was added Et3N (13.27 mL, 95.43 mmol) and catalytic amount of DMAP. The resulting solution was cooled in an ice bath and added dropwise MsCl (7.39 mL, 95.43 mmol). After complete addition of MsCl, the reaction mixture was maintained in the ice bath for 1 h and then 30 mL of water was added to the reaction mixture. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford 1-(2,6-dichloro-3-fluorophenyl)ethyl methanesulfonate (12), which was pure enough for use in the next step. Yield: 84%. |
|
With triethylamine; In dichloromethane; at 20℃; |
A flask was charged with 4-hydroxytetrahydropyran (3.00 g, 29.4 mmol), Methanesulfonyl chloride (2.39mL, 30.9 mmol), triethylamine (8.20 mL, 58.8 mmol), and CH2Cl2. The resulting mixture was stirred overnight at room temperature. The reaction mixture was then washed with saturated aqueous NaHCO3 (100 mL) and water (100 mL), dried over Na2SO4, filtered and concentrated under reducedpressure. The crude product thus obtained was used without further purification. |
|
With triethylamine; In dichloromethane; at 20℃; for 2h; |
To a solution of tetrahydro-2H-pyran-4-ol (612 mg, 6 mmol) in DCM (5 mL) was added EtsN (1002 uL, 7.2 mmol) and MsCI (510 uL, 6.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. After that the mixture wasconcentrated to give a white solid which was used for next step directly. |
|
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; |
To a stirred solution of tetrahydro-2H-pyran-4-ol (1.0 g, 10.0 mmol) in DCM (25 mL) was added Et3N (1.5 mL, 11.0 mmol) slowly at 0 C, followed by the addition of MsCl (0.9 mL, 11.0 mmol) and DMAP (60 mg, 0.5 mmol). The mixture was stirred at rt overnight, then diluted with DCM (25 mL), and washed with water (30 mL x 2). The separated organic layer was dried over anhydrous Na2S04, and concentrated in vacuo to give the crude product as light yellow oil (1.6 g, 88%>). The crude product was used in the next step without further purification. |
|
With triethylamine; In dichloromethane; at 0 - 25℃; for 3.16667h; |
To a solution of tetrahydro-2H-pyran-4-ol (25 g, 245 mmol) and triethyl amine (40.1 ml, 294 mmol) in CH2CI2 (500 ml) at 0C was added dropwise methanesulfonylchloride (20.7 ml, 269 mmol) over a period of 40 min, keeping the temperature between 0 - 4C. The reaction mixture was then allowed to stir at 0C for lhr. The cooling bath was removed and the mixture was stirred for another 90 mins at 25C. The mixture was washed with water (2 x 125ml), dried over anhydrous Na2S04, filtered and concentrated under vacuum to get methanesulfonic acid tetrahydro-pyran-4-yl ester (38 g, 86%; crude) as a liquid that was used in the next step without any further purification. |
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With triethylamine; In dichloromethane; at 0 - 20℃; |
PREPARATION 22 PREPARATION OF l-(TETRAHYDRO-2H-PYRAN-4-YL)-4-(4,4,5,5-TETRAMETHYL-l,3,2- DIOXA AZOLE A. To a cooled (0 C) solution of tetrahydro-2H-pyran-4-ol (5.00 g, 49.0 mmol) in dichloromethane (85 mL) was added triethylamine (5.95 mL, 58.8 mmol), followed by the addition of methanesulfonyl chloride (6.74 mL, 58.8 mmol). The mixture was stirred at room temperature overnight, diluted with dichloromethane (85 mL), then sequentially washed with 0.5 N hydrochloric acid solution (40 mL), saturated sodium bicarbonate (50 mL), water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to afford the crude product tetrahydro-2H-pyran-4-yl methanesulfonate (8.6 g, 97.4%) as a pale yellow solid. 1H NMR (400 Hz, CDC13) delta 4.95-4.85 (m, 1H), 3.97-3.90 (m, 2H), 3.57-3.51 (m, 2H), 3.04 (s, 3H), 2.08-2.02 (m, 2H), 1.93-1.84 (m, 2H). |
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With triethylamine; In dichloromethane; at 0 - 25℃; for 3.16667h; |
Step 1: Methanesulfonic acid tetrahydro-pyran-4-yl esterTo a solution of tetrahydro-2H-pyran-4-ol (25 g, 245 mmol) and triethyl amine (40.1 ml, 294 mmol) in CH2C12 (500 ml) at 0C was added dropwise methanesulfonylchloride (20.7 ml, 269 mmol) over a period of 40 mm, keeping the temperature between 0 - 4C. The reaction mixture was then allowed to stir at 0C for lhr. The cooling bath was removed and the mixture was stirred for another 90 mins at 25C. The mixture was washed with water (2 x 125m1), dried over anhydrous Na2504, filtered and concentrated under vacuum to get methanesulfonic acid tetrahydro-pyran-4-yl ester (38 g, 86%; crude) as liquid that was used in the next step without any further purification. |
| 15.5 g |
With triethylamine; In dichloromethane; at 0℃; for 1h; |
To a solution of tetrahydro-2H-pyran-4-ol (10.0 g) in DCM (200 mL)was added TEA (12.9 g) and methanesulfonyl chloride (11.3 g). The mixture was stirred at 0C for 1 hour, and then washed with H20. The organic layer was dried over Na2SO4 and concentrated to afford10 tetrahydro-2H-pyran-4-yl methanesulfonate (15.5 g). |
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With triethylamine; In dichloromethane; at 0 - 25℃; for 3.16667h; |
Step 1: Methanesulfonic acid tetrahydro-pyran-4-yl ester To a solution of tetrahydro-2H-pyran-4-ol (25 g, 245 mmol) and triethyl amine (40.1 ml, 294 mmol) in CH2Cl2 (500 ml) at 0 C. was added dropwise methanesulfonylchloride (20.7 ml, 269 mmol) over a period of 40 min, keeping the temperature between 0-4 C. The reaction mixture was then allowed to stir at 0 C. for 1 hr. The cooling bath was removed and the mixture was stirred for another 90 mins at 25 C. The mixture was washed with water (2*125 ml), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to get methanesulfonic acid tetrahydro-pyran-4-yl ester (38 g, 86%; crude) as liquid that was used in the next step without any further purification. |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere; |
N,N?-Diisopropylethylamine (25.6 mL, 147.0 mmol) was added to a solution of tetrahydro-2H-pyran-4-ol (CAS:2081-44-9, 10.0 g, 98.0 mmol) in dry DCM (160 mL) cooled at 0 C. The resulting mixture was stirred for 10 minutes under argon at 0 C. Then methanesulfonyl chloride (CAS:124-63-0, 8.72 mL, 112.7 mmol) was added, and the mixture was stirred at 0 C for 2 h. The reaction mixture was extracted with DCM and 0.5 M HCl. The organic fraction was washed with water, brine and saturated NaHCO3. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the titled compound. |
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With triethylamine; In dichloromethane; at 4 - 20℃; for 1h; |
Methanesulfonyl chloride (1.2 eq.) was added to a solution of tetrahydro-2H-pyran-4-ol (1.0 eq.) and triethylamine (3.0 eq.) in dichloromethane (0.3 M) at 4 . The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was washed with brine, saturated aqueous ammonium chloride, and dried over magnesium sulfate, filtered and concentrated. The resultant residue was purified by flash column chromatography on silica gel to afford tetrahydro-2H-pyran-4-yl methanesulfonate. |
| 6.74 g |
With triethylamine; In dichloromethane; at -10℃; for 0.5h; |
To a -10 C solution of tetrahydro-2H-pyran-4-ol (3.54 g, 34.66 mmol), triethylamine (4.65 g, 45.95 mmol) in DCM (100 mL) was added MsC1 (4.61 g, 40.24 mmol) dropwise. Afterstirring for 30 mm, the reaction mixture was diluted with water (100 mL), extracted with DCM (100 mL, 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2504, filtered and concentrated under reduced pressure to give tetrahydro-2H-pyran-4-yl methanesulfonate (6.74 g). MS: m/z 181 (M+H) . |
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Tetrahydro-pyran-4-ol (1 eq, 4.9 mmol, 0.5 g) is dissolved in dry DCM (10 ml) under an inert atmosphere of argon. NEt3 (3 eq, 14.69 mmol, 2.047 ml) is then added at 00C, followed by methanesulfonyl chloride (1.1 eq, 5.39 mmol, 0.417 ml) and the reaction mixture is stirred at room temperature overnight. The reaction mixture is quenched with NaHCCh (IM, 3ml) and extracted with DCM. This organic portion is washed with water and brine, dried over MgSCM, filtered and concentrated in vacuo to afford the title compound . |
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With triethylamine; In dichloromethane; at 0℃; for 1h; |
To a solution of tetrahydropyran-4-ol (1.0 g, 9.8 mmol) in DCM (5 mL) was added Et3N (triethylamine; 2.73 mL, 20 mmol). To the mixture was added a solution of methanesulfonyl chloride (0.91 mL, 12 mmol) in DCM (dichloromethane; 5 mL) at 0 C. The mixture was stirred at 0 C for 1 hour. Upon completion, the reaction mixture was treated with water (5 mL), and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (10 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to afford tetrahydropyran-4-yl methanesulfonate (1.3 g, crude) as a white solid, which was used directly in the next step. |
| 6.74 g |
With triethylamine; In dichloromethane; at -10℃; for 0.5h; |
At -10 C Tetrahydro-2H-pyran-4-ol (3.54 g, 34.66 mmol),Triethylamine (4.65 g, 45.95 mmol) MsCl (4.61 g, 40.24 mmol) was added to a solution of DCM (100 mL). After stirring for 30 minutes,The reaction was diluted with water (100 mL).The combined organic phases were washed with brine (1×50 mL).Dry with anhydrous Na2SO4,Filter and concentrate under reduced pressure.Tetrahydro-2H-pyran-4-yl methanesulfonate (6.74 g) was obtained. |
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