| 82.8% |
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; |
Intermediate (v); 3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-l-carboxylic acid tert-butyl ester; A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)-(- )-N-BOC-3-hydroxypyrrolidine (purchased from Aldrich, 10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight at a temperature from about 0 C to rt. TLC (5% MeOH in DCM for SM and DCM for product) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred for 30 min. and 100 mL of DCM was added. The organic layer was washed with H3PO4 (IM, 2 x 5OmL), followed by <n="27"/>NaHCθ3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8 %). MS: 363 (M+Na+); TLC (DCM) Rf= 0.3.1H NMR (CDCl3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, IH), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H). |
| 82.8% |
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; |
Intermediate (ix); 3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-l-carboxylic acid tert-butyl ester; A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)- (-)-N-BOC-3-hydroxypyrrolidine (purchased from Aldrich) (10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight from O0C to rt. TLC (5 % MeOH in DCM) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred 30 min. 100 mL of DCM was added. The organic layer was washed with H3PO4 (IM, 2 x 5OmL), followed by NaHCO3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8 %). MS: 363 (M+Na+); TLC (DCM) Rf= 0.3. 1H NMR (CDCl3, 300MHz): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, IH), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H). |
| 75% |
With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; |
Intermediate (iii) (R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester To a 2L round-bottom flask equipped with a mechanical stirring rod and a250ml addition funnel was added p-tosyl chloride (58g, 305mmol, 1.5eq) and 600ml of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65ml) and DMAP (2.65g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38g, 203 mmol, 1.0eq) in 200 ml of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 mL), and brine (200 mL). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 75Og silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52g, 75%). MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H). |
| 75% |
With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice-water bath; |
Intermediate (ix)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 ml addition funnel was added p-tosyl chloride (58 g, 305mmol, 1 .5 eq) and 600 ml of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65 g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 ml of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 mL), and brine (200 mL). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52g, 75%).MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1H NMR (CDCIs, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H). |
| 75% |
With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; |
Intermediate (v)(R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester To a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 ml addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 ml of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65 g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 eq) in 200 ml of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic layer was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 mL), and brine (200 mL). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52 g, 75%).MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H). |
| 75% |
With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; |
Intermediate (i) (R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCIs, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H). |
| 75% |
With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; |
Intermediate (i)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCIs, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H). |
| 75% |
With triethylamine;dmap; In dichloromethane; at 20℃;cooling with ice-water; |
Intermediate (i)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H). |
| 75% |
With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; |
Intermediate (i)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H). |
| 74% |
With pyridine; at 20℃; for 16h; |
To a stirred solution of R-(-)-N-Boc-3-pyrrolidinol (5.03 g, 26.9 mmol) in pyridine (30.0 mL) was added p-TsCl (5.63 g, 30.0 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (200.0 mL) and 1.0 N hydrochloric acid (200.0 mL) and separated. The organic layer was washed with water (2 * 100 mL), saturated sodium chloride (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 80:20 to 50:50 heptane/ethyl acetate) to provide tert-butyl 3-(tosyloxy)pyrrolidine-1-carboxylate (6.79 g, 74%) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.05 (br s, 1H), 3.48-3.38 (m, 4H), 2.46 (s, 3H), 2.17-1.91 (m, 1H), 1.91-1.71 (m, 1H), 1.46 (s, 9H). |
| 25% |
With dmap; triethylamine; In dichloromethane; at 20℃; for 10h;Inert atmosphere; |
A mixture of (R) -tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.3 mmol) , p-methyl benzene sulfonic chloride (1.5 g, 8.0 mmol) , triethylamine (1.1 g, 11 mmol) and N, N-dimethylaminopyridine (65 mg, 0.53 mmol) in DCM (10 mL) was stirred at rt for 10 h and diluted with water (20 mL) . The resulting mixture was extracted with DCM (10 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 5/1 to give (R) -tert-butyl 3- (tosyloxy) pyrrolidine-1-carboxylate as colorless liquid (460 mg, 25) .1H NMR (400 MHz, CDCl3) : δ ppm 7.79 (d, J 8.0 Hz, 2H) , 7.35 (d, J 7.7 Hz, 2H) , 5.04 (s, 1H) , 3.38-3.50 (m, 4H) , 2.45 (s, 3H) , 1.97-2.15 (m, 2H) , 1.43 (m, 9H) and MS-ESI: m/z 286.20 [M-55] +. |
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