| 98% |
With triethylamine In tetrahydrofuran at 0 - 20℃; |
A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (4.98 g, 28.7 mmol) and triethylamine (4.82 mL, 62.3 mmol) in tetrahydrofuran (75 mL) was cooled to 0° C. using an ice bath. Methanesulfonyl chloride (2.46 mL, 31.8 mmol) in tetrahydrofuran (12.5 mL) was added slowly to the reaction. Once the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction, and the mixture extracted with ethyl acetate (2.x.150 mL). The combined organic phase was washed with brine (2.x.100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil (7.11 g, 98percent).1HNMR (CDCl3): δ 1.45 (s, 9H), 3.07 (s, 3H), 4.08-4.12 (m, 2H), 4.26-4.30 (m, 2H), 5.18-5.23 (m, 1H).LCMS Rt=2.53 minutes MS m/z 151.98 [M-Boc+H]+. |
| 96% |
With triethylamine In dichloromethane at 20℃; |
To a solution of compound 108A (2.0 g, 11.55 mmol) in dichloromethane (10 mL) was added MsCl (1.455 g, 12.70 mmol) followed by TEA (1.519 g, 15.01 mmol). The mixture was stirred at rt overnight. The reaction was quenched with water and extracted with additional dichloromethane. The organic layer was washed, dried and concentrated to dryness to afford compound 108B (2.8 g, 96percent) as a white solid. 1H NMR (400 MHz, CDC13): δ 5.22-5.18 (m, 1H), 4.30-4.25 (m, 2H), 4.12-4.08 (m, 2H), 3.06 (s, 3H), 1.45 (s, 9H). |
| 96% |
With triethylamine In dichloromethane at 0 - 20℃; |
To a stirred, cooled (0 °C) solution of terf-butyl 3-hydroxyazetidine-1 -carboxylate (500 mg, 2.89 mmol in DCM (5 mL) was added triethylamine (0.90 ml_, 6.46 mmol) followed by methanesulfonyl chloride (0.25 mL, 3.21 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into saturated brine and extracted twice with EtOAc. The combined organic layers were dried over Na2SC>4 and filtered. Solvent was removed under reduced pressure. The remaining material was purified on silica gel eluting with a 0percent-50percent EtOAc-hexanes gradient. The appropriate fractions (identified by TLC, silica gel, 50percent EtOAc/hexanes, ΚΜηθ4 stain) were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (699 mg, 96percent) as a colorless oil that slowly solidified. 1H NMR (400 MHz, CD3SOCD3) δ 1 .39 (s, 9 H), 3.25 (s, 3 H), 3.88-3.94 (m, 2 H), 4.19-4.36 (m, 2 H), 5.22-5.28 (m, 1 H); LC-MS (LC-ES) M+H-terf-Bu = 196. |
| 94% |
With triethylamine In dichloromethane at 0℃; for 1 h; |
Example 20: 3-(2'-Trifluoromethyl-biphenyl-3-yloxy)-azetidine; Step A: Preparation of 3-Methanesulfonyloxy-azetidine-1 -carboxylic acid tert-butyl ester. To 3-hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (1.21 g, 6.99 mmol) and Et3N (0.85 g, 1.2 ml_, 8.4 mmol) in CH2CI2 (35 ml_) at 0 0C was added methanesulfonyl chloride (0.88 g, 0.60 ml_, 7.7 mmol). After 1 h, brine was added and the reaction extracted with CH2CI2 (2X). The combined organics were dried to give 1.65 g (94percent) of 3-methanesulfonyloxy-azetidine-1 - carboxylic acid tert-butyl ester a yellow solid that was used without further purification. 1H NMR (CDCI3): 5.20 (tt, J = 6.7, 4.2 Hz, 1 H), 4.28 (ddd, J = 10.3, 6.7, 1.2 Hz, 2H), 4.10 (ddd, J = 10.4, 4.2, 1.1 Hz, 2H), 3.07 (s, 3H), 1.44 (s, 9H). |
| 94% |
With triethylamine In dichloromethane at 20℃; for 2 h; |
To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (1, 3.15 g. 18.3 mmol) and triethylamine (12.7 ml, 91.5 mmol) in CH2Cl2 (100 mL) was added dropwise methanesulfonyl chloride (4.17 g, 36.6 mmol) at room temperature. The reaction stirred for 2 h. The mixture was diluted with EtOAc (300 mL), washed with water (100 mL) and brine (100 mL), dried (Na2SO4), filtered and concentrated to afford the title compound (4.3 g, 94percent) as a light brown oil: 1H NMR (500 MHz, CDCl3) δ 5.16-5.23 (m, 1H), 4.25-4.30 (m, 2H), 4.07-4.12 (m, 2H), 3.06 (s, 3H), 1.44 (s, 9H) |
| 93% |
With triethylamine In dichloromethane at 0 - 20℃; for 20 h; |
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (97percent, 5.0 g, 28 mmol) in dichloromethane (50 mL) was treated with triethylamine (7.8 mL, 56 mmol) and cooled to 0° C. A solution of methanesulfonyl chloride (2.28 mL, 29.3 mmol) in dichloromethane was added drop-wise to the cold reaction, which was maintained at 0° C. for 2 h, then allowed to warm to room temp over the next 18 h.
Solvents were removed in vacuo and the residue was taken up in ether and filtered:
The filtrate was concentrated in vacuo, and the residue purified via silica gel chromatography (Eluant: 5:1 heptane:EtOAc, then 2:1 heptane:EtOAc) to provide C6 as a solid. Yield: 6.5 g, 26.0 mmol, 93percent. LCMS m/z 503.1 (2M+1).
1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 3.06 (s, 3H), 4.09 (ddd, J=10.4, 4.2, 1.2, 2H), 4.27 (ddd, J=10.4, 6.6, 1.2 Hz, 2H), 5.19 (tt, J=6.6, 4.2 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ28.23, 38.33, 56.45 (br), 67.25, 80.29, 155.80.
|
| 92% |
With triethylamine In tetrahydrofuran at 20℃; for 4 h; Cooling with ice |
Tert-butyl 3-hydroxyazetidin-1-carboxylate (2.0 g, 11.5 mmol) was dissolved in 50mL tetrahydrofuran, and triethylamine (2.34 g, 23.1 mmol) was added.
Under the condition of ice water bath, methanesulfonyl chloride (1.58 g, 13.8 mmol) was added slowly.
The resultant mixture was warmed to room temperature, and further reacted for 4 h.
After the reaction, the solvent was removed by rotary evaporation, and to the residue,50mL waterwas added.
After extraction with ethyl acetate (3*50mL), the organic phases were combined, dried with anhydrous sodium sulphate, and filtrated.
The solvent was removed by rotary evaporation to obtain the product (2.67 g, yield: 92percent). |
| 91% |
With diethylamine In dichloromethane at 0 - 20℃; |
To a solution of compound (2-3) (466 mg; 2.69 mmol) with Et3N (0.75 mL; 5.38 mmol) and 4-(dimethylamino)-pyridine (33 mg, 0.269 mmol) in 10 mL of CH2Cl2 at 0 C. was added methanesulfonyl chloride (0.25 mL 3.23 mmol). The resulting mixture of brown color solution was stirred at 0 C. to room temperature for overnight. The reaction mixture was quenched with NaHCO3, then partitioned between CH2Cl2 (200 mL) and saturated NaHCO3 solution (50 mL). The organic layer was dried (Na2SO4), then filtered through silica gel pad, eluted with hexane: EtOAc/1:1; the filtrate was concentrated by vacuum to give 614 mg (2-4) as yellow oil (91percent yield). 1H NMR (400 MHz, chloroform-D) ? ppm 1.43 (s, 9H) 3.05 (s, 3H) 4.08 (dd, J=10.36, 4.29 Hz, 2H) 4.26 (dd, J=10.36, 6.82 Hz, 2H) 5.11-5.26 (m, 1H). |
| 91% |
With dmap; triethylamine In dichloromethane at 0 - 20℃; |
To a solution of compound (2-3) (466 mg; 2.69 mmol) with Et3N (0.75 mL; 5.38 mmol) and 4-(dimethylamino)-pyridine (33 mg, 0.269 mmol) in 10 mL of CH2CI2 at 0°C was added methanesulfonyl chloride (0.25 mL 3.23 mmol). The resulting mixture of brown color solution was stirred at 0°C to room temperature for overnight. The reaction mixture was quenched with NaHCO3, then partitioned between CH2CI2 (200 mL) and saturated NaHCO3 solution (50 mL). The organic layer was dried (Na2SO4), then filtered through silica gel pad, eluted with hexane: EtOAc/1:1; the filtrate was concentrated by vacuum to give 614mg (2-4) as yellow oil (91percentyield). 1H NMR (400 MHz, chloroform-D) 6 ppm 1.43 (s, 9 H) 3.05 (s, 3 H) 4.08 (dd, ^10.36, 4.29 Hz, 2 H) 4.26 (dd, J=10.36, 6.82 Hz, 2 H) 5.11 - 5.26 (m, 1 H). |
| 83% |
With triethylamine In dichloromethane at 20℃; for 1 h; |
Alcohol 61 (928 mg, 5.3 mmol), Et3N (Ig, 10.7 mmol), in CH2Cl2 (20 mL), was added MsCl (733 mg, 6.4 mmol), were allowed to stirr for 1 hours at room temperature. Then the reaction mixture was diluted with diluted with CH2Cl2 (20 mL) <n="45"/>and the organic layer washed with brine (20 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated. Purification of the resulting crude by flash silica gel chromatography provided the mesolate compound (1.11 g, 83percent) as an oil. |
| 78% |
With triethylamine In dichloromethane at 20℃; Cooling with ice |
Preparation 57 tert-Butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate; tert-Butyl 3-hydroxyazetidine-i-carboxylate (71g, 0.41 mol) was dissolved in dichloromethane (70OmL). Triethylamine (114mL, 0.82 mol) was added and the solution was cooled in an ice bath before the addition of methanesulfonyl chloride (33.4mL, 0.43 mol) as a solution in dichloromethane (10OmL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was dissolved in ether (50OmL), triethylamine hydrochloride was filtered off, and the filtrate was evaporated. The residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (3:1 ) to afford the title compound (80 g, 78percent). 1H NMR (400 MHz, DMSOd6): δ = 1.38 (s, 9H), 3.23 (s, 3H), 3.90-3.94 (m, 2H), 4.19-4.24 (m, 2H), 5.22-5.28 (m, 1 H) ppm. |
| 70% |
With triethylamine In dichloromethane at 0 - 20℃; for 1 h; |
To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.2 g, 6.92 mmol) inDCM (20 mL) was added TEA (2.0 mL, 13.8 mmol) followed by methane sulfonylchloride (0.80 mL, 10.3 mmol, spectrochem) at 0 00. The reaction mixture was stirred atRT for 1 h. Reaction completion was monitored by TLC. Reaction mixture was dilutedwith water and extracted in dichloromethane (2x50 mL). The combined extract waswashed with water, brine solution and dried over anhydrous Na2SO4 and concentrated. The crude product was isolated as pale yellow gum and was used as such for next step without further purification (1.2 g, 70percent). 1H NMR (400 MHz, DMSO-d6): 6 5.26-5.23 (m, 1 H), 4.23 (t, J = 9.6 Hz, 2H), 3.92 (d, J = 6.8 Hz, 2H), 3.24 (s, 3H), 1.37 (s, 9H). LCMS:(Method A) 152.0 (M-Boc-fH), Rt. 3.48 mm, 99.7 percent (Max). |
| 68% |
With triethylamine In dichloromethane at 0 - 20℃; |
To a solution of 3-Hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (2.0 g, 1 1 .2 mmol) and Et3N (3.12 ml, 22.4 mmol) in DCM (20 ml) was added MsCI (0.92 ml, 1 1 .6 mmol) dropwise at 0°C . The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with brine (20 ml) and was extracted with ethyl acetate (20 mL χ 2). The combined organic layers was dried over anhydrous Na2S04, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (eluted with petroleum ether/EtOAc = 10:1 to 2:1 ) to give compound A10-1 (2.0 g, 68 |
| 2.32 g |
With triethylamine In chloroform at 0 - 20℃; for 0.5 h; |
N-Boc-3-hydroxyazetidine (1.73 g) was dissolved in chloroform (20 ml). Triethylamine (2.09 ml) and methanesulfonyl chloride (856 μl) were added thereto at 0°C. After stirring at room temperature for 0.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (2.32 g). Physical properties: m/z[M+H]+ 252.0 |
| 2.32 g |
With triethylamine In chloroform at 0 - 20℃; for 0.5 h; |
N-Boc-3-hydroxyazetidine (1.73 g) was dissolved in chloroform (20 ml). Triethylamine (2.09 ml) and methanesulfonyl chloride (856 μl) were added thereto at 0° C. After stirring at room temperature for 0.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (2.32 g). Physical properties: m/z[M+H]+ 252.0 |
| 2.32 g |
With triethylamine In chloroform at 0 - 20℃; for 0.5 h; |
N-Boc-3-hydroxyazetidine (1.73 g) was dissolved in chloroform (20 ml). Triethylamine (2.09 ml) and methanesulfonyl chloride (856 μl) were added thereto at 0° C. After stirring at room temperature for 0.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (2.32 g). Physical properties: m/z [M+H]+ 252.0 |
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