| 100% |
|
A solution of N-tert-Butoxycarbonyl-(R)-(-)-3-pyrrolidinol (2.0 g, 10.7 mmol) in DCM (28 mL) was treated with TEA (2.9 mL, 21.4 mmol). The solution was cooled to 0C for 30 minutes. Then methanesulfonyl chloride (868 iL, 1 1.2 mmol) was added. The reaction was stirred at 0C for 30 minutes. The reaction was diluted with DCM and washed with saturated NaHCCb(aq). The organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo. The residue was purified by silica chromatography (5-95% EtOAc in Hexanes as the gradient eluent) to afford the title compound (2.83 g, 100% yield). MR (400 MHz, DMSO-d6) δ 5.24 (s, 1H), 3.55-3.38 (m, 3H), 3.31-3.27 (m, 1H), 3.23 (s, 3H), 2.18- 2.08 (m, 2H), 1.40 (s, 9H). |
| 100% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 7h; |
(R)-(-)-N-Boc-3-pyrrolidinol (3-I-1; 3.0 g, 16.0 mmol) was dissolved in anhydrous dichloromethane and then mesyl chloride (MsCl; 1.5 mL, 19.2 mmol) and Triethyl amine (TEA; 2.9 ml, 20.8 mmol) was added slowly at 0 C. to react.After raising the temperature to room temperature, it was reacted for 7 hours.After completion of the reaction, the mixture was extracted three times with saturated aqueous NaCl solution and dichloromethane, dried over anhydrous magnesium sulfate, dried and filtered. The filtrate was concentrated under reduced pressure to obtain 4.3 g (100% yield) of the title compound (3-I-2) through a column chromatography. |
| 99% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 6h; |
Methanesulfonyl chloride (19.7 g, 172 mmol) was added to a solution of (R)-tertbutyl 3-hydroxypyrrolidine-1-carboxylate (25 g, 133 mmol) and triethylamine (20.1 g, 199 mmol) in DCM (500 mL) at 0 C. After stirring at room temperature for 6 h, the reaction mixture was washed with 1 M HC1 (50 mL) and the aqueous layer was extracted with DCM (100 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated to give (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (35 g, 99%) as a yellow oil1H NMR (400 MHz, CDC13) (ppm): 5.28-5.23 (m, 1H), 3.70-3.40 (m, 4H), 3.04 (s, 3H), 2.34-2.07 (m, 2H), 1.46 (s, 9H). |
| 98% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; |
To a mixture of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (1.00 g, 5.34 mmol, 1.00 eq) and triethylamine (1.62 g, 16.0 mmol, 2.23 mL, 3.00 eq) in dichloromethane (15.0 mL) was added methanesulfonyl chloride (917 mg, 8.01 mmol, 620 uL, 1.50 eq) dropwise at 0 C under nitrogen. The mixture was stirred at 20 C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (40.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with saturated sodium bicarbonate (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine -1-carboxylate (1.40 g, 5.28 mmol, 98% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 5.27 (br s, 1H), 3.74 - 3.42 (m, 4H), 3.09 - 3.02 (m, 3H), 2.36 - 2.21 (m, 1H), 2.14 (br d, J = 3.5 Hz, 1H), 2.20 - 2.07 (m, 1H), 1.47 (s, 9H). |
| 92% |
With triethylamine; In toluene; at -30 - 20℃;Product distribution / selectivity; |
Example 2. Synthesis of tert-butyl (R)-3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (2); Procedure A:; To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (200 g, 1.07 mol) and triethylamine (167 g, 1.63 mol) in toluene (700 ml_) at -20 to -30 C was added methanesulfonyl chloride (156 g, 1.36 mol) drop-wise while maintaining the temperature at -10 to -20 0C. The solution was warmed to ambient temperature and allowed to stir. The reaction solution was sampled hourly and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the suspension was filtered to remove the triethylamine hydrochloride. The filtrate was washed with ~600 mL of dilute aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2 as a viscous oil (260 g, 92%) which is used without further purification. 1H NMR (CDCI3, 400 MHz) δ 5.27 (m, 1 H), 3.44 - 3.76 (m, 4H), 3.05 (s, 3H), 2.26 (m, 1 H), 2.15 (m, 1 H), 1.47 (s, 9H). |
| 92% |
With triethylamine; In toluene; at -30 - 20℃;Product distribution / selectivity; |
Example 2. Synthesis of fert-butyl (R)-3-(methylsulfonyloxy)pyrrolidine-1- carboxylate (2) Procedure A: To a solution of te/t-butyl (R)-3-hydroxypyrrolidine-1- carboxylate (200 g, 1.07 mol) and triethylamine (167 g, 1.63 mol) in toluene (700 mL) at -20 to -30 C was added methanesulfonyl chloride (156 g, 1.36 mol) drop-wise while maintaining the temperature at -10 to -20 0C. The solution was warmed to ambient temperature and allowed to stir. The reaction solution was sampled hourly and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the suspension was filtered to remove the triethylamine hydrochloride. The filtrate was washed with ~600 mL of dilute aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2 as a viscous oil (260 g, 92%) which is used without further purification. 1H NMR (CDCI3, 400 MHz) δ 5.27 (m, 1 H), 3.44 - 3.76 (m, 4H), 3.05 (s, 3H), 2.26 (m, 1 H), 2.15 (m, 1 H), 1.47 (s, 9H). |
| 60.2% |
With triethylamine; In dichloromethane; at 0 - 20℃; |
Example 14. fert-Butyl (3S)-3-[4-(2-oxo-2,3-dihydro-1W-benzimidazoI-1- yl)piperidin-1-yl]pyrrolidine-1-carboxylate; Step A. The preparation of terf-butyl (3R)-3-[(methylsulfonyl)oxy]pyrrolidine-1- carboxylate <n="55"/>To (R)-N-Boc-3-pyrrolidiϖol (5g, 26.7mmol) in CH2CI2 (10ml) at O0C was added Et3N (4.12g, 40.7mmol), followed by methylsulfonyl chloride (3.81g, 33.25 mmol) in 1ml of CH2CI2 slowly. The reaction mixture was warmed to RT and stirred overnight. The crude was washed with sat. NaHCO3 solution (1X ), extracted with CH2CI2 (3X ), and dried over MgSO4. After filtration and evaporation, the residue was purified by chromatography on silica gel with 30% EtOAc/hexane to afford the mesylate tert- butyl (3R)-3-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (4.26g, 60.2%). |
|
With triethylamine; In dichloromethane; water; |
PREPARATION 10-2) To a solution of (R)-1-t-butoxycarbonyl-3-hydroxypyrrolidine (32 g) in dichloromethane (300 ml) were added triethylamine (28.6 ml) and then methanesulfonyl chloride (14.6 ml) under nitrogen at -10 C. After stirring at 0 C. for 30 minutes, the solution was washed in turn with water, 1N-hydrochloric acid solution, saturated sodium bicarbonate, and brine. The dried solution was evaporated to give (R)-1-t-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (45 g). IR (CH2 Cl2): 1690 cm-1. NMR (CDCl3, δ): 1.47 (9H, s), 2.9-2.42 (2H, m), 3.00 (3H, s), 3.35-3.75 (5H, m). |
|
With sodium chloride; triethylamine; In tetrahydrofuran; |
5-(1) (3R)-1-t-Butoxycarbonyl-3-methanesulfonyloxypyrrolidine 16.91 ml of triethylamine and 9.36 ml of methanesulfonyl chloride were added, in that order, whilst ice-cooling, to a solution of 25 g of (3R)-1-t-butoxycarbonyl-3-hydroxypyrrolidine dissolved in 250 ml of dry tetrahydrofuran, and the mixture was stirred at 0 to 5 C. for 30 minutes and then at 15 C. for 30 minutes. At the end of this time, the mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 3.10 g of the title compound as a colorless oil. Nuclear Magnetic Resonance Spectrum (CDCl3, 60 MHz) δ ppm: 1.48 (9H. singlet); 1.91-2.45 (2H, multiplet); 3.04 (3H, singlet); 3.26-3.82 (4H, multiplet); 6.1-6.44 (1H, multiplet). |
|
With triethylamine; In water; ethyl acetate; |
C. Preparation of (3R)-N-(t-Butoxycarbonyl)-3-methanesulphonyloxypyrrolidine (3) A dry 10 gallon glass-lined vessel was charged with the alcohol (2) (3.39 kg d.b., 18.1 Mol) and ethyl acetate (50 l) under nitrogen. The solution was cooled to -5 C. and triethylamine (Lancaster B/N 076337, 5.1 l) was added in one portion. Methanesulphonyl chloride (Lancaster B/N 79561, 1.68 l, 21.7 Mol) was added dropwise over 1 h, maintaining the reaction temperature at -5-2 C. On complete addition, the slurry was aged at -5 C. for 30 min. Water (20 1) was added over 10 min and the phases well mixed The aqueous layer was separated and the organics washed with 1M aqueous hydrochloric acid (10 l), saturated sodium bicarbonate (10 1) and dried (Na2 SO4). Solvent evaporation gave the product as a pale yellow oil. |
|
With triethylamine; In water; ethyl acetate; |
C. Preparation of (3R)-N-(t-Butoxycarbonyl)-3-methanesulphonyloxypyrrolidine (3) A dry I0 gallon glass-lined vessel was charged with the alcohol (2) (3.39 kg d.b., 18.1 Mol) and ethyl acetate (50 l) under nitrogen. The solution was cooled to -5 C. and triethylamine (Lancaster B/N 076337, 5.1 l) was added in one portion. Methanesulphonyl chloride (Lancaster B/N 79561, 1.68 1, 21.7 Mol) was added dropwise over 1 h, maintaining the reaction temperature at -5-2 C. On complete addition, the slurry was aged at -5 C. for 30 min. Water (20 l) was added over 10 min and the phases well mixed. The aqueous layer was separated and the organics washed with 1 M aqueous hydrochloric acid (10 l), saturated sodium bicarbonate (10 l) and dried (Na2 SO4). Solvent evaporation gave the product as a pale yellow oil. |
|
With triethylamine; In dichloromethane; at -10 - 0℃; for 1.08333h; |
Methanesulfonyl chloride (5.26mL, 68mmol) was added dropwise over 5 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-HYDROXYPYRROLIDINE-1-CARBOXYLATE (10.6g, 56. 7mmol) and triethylamine (11. 8mL, 85mmol) in dichloromethane (250mL) AT-10C. After stirring for 1 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MGS04), filtered and evaporated IN VACUO TO give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (25: 75 to 50: 50), to give the title compound as an oil |
|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 4h; |
Step 1 : A mixture of f?-1-BOC-3-hydroxy-pyrrolidine (1.0 g, 5.34 mmol) and triethylamine (0.89 ml, 6.41 mmol) in THF (20 ml) was cooled in an ice bath. To this was added methane sulfonyl chloride (0.46 ml, 5.87 mmol). The reaction was then warmed to ambient temperature and allowed to stir for 4 hours. The reaction was quenched with the addition of water, and extracted with ethyl acetate (2x). The organic extracts were combined, washed with saturated NaCI solution, dried over anhydrous MgSO4, filtered and concentrated to provide 1.42 g of a clear oil which was used without further purification. 1H NMR δ (ppm) (CDCI3) 1.48 (9 H, s), 2.05-2.30 (2 H, m), 3.05 (3 H, s), 3.40-3.75 (4 H, m), 5.27 (1 H, br). |
|
With triethylamine; In dichloromethane; at -10 - 0℃; for 0h; |
Methanesulfonyl chloride (5.26mL, 68MMOL) was added dropwise over 5 minutes to a stirred solution OF 1, 1-DIMETHYLETHYL (3R)-3-HYDROXYPYRROLIDINE-1-CARBOXYLATE (10.6g, 56.7mmol) and triethylamine (11. 8mL, 85mmol) in dichloromethane (250ML) AT-10C. After stirring for 1 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MGS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (25: 75 to 50: 50), to give the title compound as an oil. |
|
With triethylamine; In dichloromethane; at -10 - 0℃; for 1.08333h; |
Methanesulfonyl chloride (5.26mL, 68mmol) was added dropwise over 5 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-HYDROXYPYRROLIDINE-1-CARBOXYLATE (10. 6g, 56. 7MMOL) and triethylamine (11. 8ML, 85MMOL) in dichloromethane (250mL) AT-10C. After stirring for 1 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (25: 75 to 50: 50), to give the title compound as an oil. |
|
With triethylamine; In dichloromethane; at -10 - 0℃; for 1.08333h; |
Methanesulfonyl chloride (5.26mL, 68mmol) was added dropwise over 5 minutes to a stirred solution of 1, 1-dimethylethyl (3R)-3-hydroxypyrrolidine-1-carboxylate (10.6g, 56. 7mmol) and triethylamine (11. 8mL, 85mmol) in dichloromethane (250mL) at-10C. After stirring for 1 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (25: 75 to 50: 50), to give the title compound as an oil. |
|
With triethylamine; In tetrahydrofuran; at 0 - 25℃; for 1h; |
STEP B(S)-tert-butyl 3-(acetylthio)pyrrolidine- 1-carboxylate. [Chem.98][0460] To a solution of (R)-tert-butyl 3-hydroxypyrrolidine- 1-carboxylate (STEP A, 2.25 g, 12.0 mmol) and triethylamine (2.53 mL, 18.0 mmol) in tetrahydrofuran (30 mL) was added methanesulfonyl chloride (1.12 mL, 14.4 mmol) in tetrahydrofuran (5 mL) at 0 C. After stirring at room temperature for 1 h, the precipitate was filtered off and the filtrate was concentrated in vacuo. |
|
With triethylamine; In ethyl acetate; at -10 - 20℃; for 0.5h; |
A mixture of xiv (20.0 g, 107 mol) and triethylamine (31 ml, 214 mmol) in ethyl acetate (200 ml) was cooled to -10 - -5 C with an ice/salt bath. To this mixture was slowly added mesylchloride (9.9 ml, 128 mmol) via a syringe. Immediately, a white precipitate started forming, stirring was continued for half an hour at room temperature. Then, water (100 ml) was added and the organic layer was separated and washed with 1 N aq. HCl solution (100 ml), 5% aq. NaHCO3 solution (100 ml), and finally with saturated aqueous NaCl solution (100 ml). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness, yielding 28.9 g (107 mmol) of a oil identified as xvii by 1H-NMR. This oil was dissolved in DMF (250 ml) and potassium thioacetate (16.2 g, 142 mmol) was added. The resulting mixture was stirred under a nitrogen atmosphere overnight at about 60 C. After 15 minutes, as solid started forming. The mixture was cooled to room temperature, and water (250 ml) plus TBME (250 ml) were added to the solidified mixture. The resulting mixture was stirred for 10 minutes and subsequently, the layers were separated. The aqueous layer was extracted with 250 ml TBME, and the combined TBME layers were washed with water (3 x 200 ml), saturated aqueous NaCl solution (200 ml), dried over sodium sulfate, filtered, and evaporated to dryness to yield 23.5 g (90%) of an orange oil identified as xix by 1H-NMR. |
|
With triethylamine; In dichloromethane; at 0℃; |
To (R)-fert-butyl 3-hydroxypyrrolidine-l-carboxylate (87 mg, 0.465 mmol) in DCM (2 mL) at 0 C was added methanesulfonyl chloride (58.5 mg, 0.51 1 mmol) and triethylamine (56.4 mg, 0.558 mmol). The cold bath was removed and the reaction was stirred for 30 minutes. The reaction was diluted with 5 mL DCM, washed with water and brine, dried (Na2S04) and concentrated to give final product (131 mg). |
|
With triethylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere; |
Step 1:(R)-Pyrrolidinol (43.56 g, 0.5 mol) was dissolved in dry CH2C12 (1 L) and cooled with ice- bath to 0 C. To the solution was added Et3 (139.4 mL, 1.0 mol), followed by dropwise addition of (Boc)20 (130.95 g, 0.6 mol) in CH2C12 (160 mL), and keep stirring at 0 C for 2h. To the reaction mixture of Boc-protection was added more of Ets (139.4 mL, 1.0 mol), and followed by dropwise addition of MsCI (42.74 mL, 0.55 mol). After 2 h at 0 C, it was treated with H20 (500 mL) for 10 min, separated, and the aqueous phase was extracted with CH2C12 (300 mL x 2). The combined organic layers was washed with brine (500mL), concentrated and purified by silica column chromatography to give N-Boc prortected mesylate 20 as an oily product (123g, 93%)1H NMR (CDC13, 400 MHz): δ 5.29 - 5.23 (m, 1H), 3.74 - 3.40 (m, 4H), 3.05 (s, 3H), 2.36 - 2.20 (m, 1H), 2.20 - 2.05 (m, 1H), 1.46 (s, 9H). |
|
With triethylamine; In chloroform; at 0 - 20℃; for 1.5h; |
(R)-N-Boc-3-pyrrolidinol (935 mg) was dissolved in chloroform (15 ml), and triethylamine (1.04 ml) and methanesulfonyl chloride (467 μl) were added thereto at 0C. After stirring at room temperature for 1.5 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, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.1 g). Physical properties: m/z[M+H]+ 266.1 |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; |
Step 1) (R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate [0199] To a mixture of (R)-l-(tert-butoxycarbonyl)pyrrolidin-3-ol (lg, 5.3mmol) and Et3N(1.2mL) in DCM (15mL) was added MsCl(0.62mL) dropwise at 0C. The reaction was stirred at rt for 2h, then concentrated in vacuo. The residue was diluted with H20(35mL)and extracted with EtOAc (25mL x 3). The combined organic phases were washed with 1M KHSO4(20 mL) followed by H20 (20mL), dried over anhydrous Na2S04, and concentrated in vacuo to give the crude compound as yellow oil (1.4 g), which was used for the next step without further purification. |
|
With triethylamine; In dichloromethane; at 20℃; for 3h;Cooling with ice; |
R)-tert-Butyl 3-hydroxypyrrolidine-1-carboxylate 7b (375 mg, 2 mmol) was dissolved in 10 mL of dichloromethane in an ice bath, followed by addition of triethylamine (404 mg, 4 mmol) and methanesulfonyl chloride (274 mg, 2.40 mmol). The reaction solution was warmed up to room temperature and stirred for 3 hours. The resulting solution was added with 5 mL of water and extracted with dichloromethane (20 mLx3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate 7c (530 mg) as a yellow oil, which was directly used in the next step without further purification. |
|
With triethylamine; In dichloromethane; at 20 - 30℃; for 3h;Cooling with ice; Inert atmosphere; |
(R)-tert-Butyl 3-hydroxypyrrolidine-1-carboxylate 7b (375 mg, 2 mmol) was dissolved in 10 mL of dichloromethane in an ice bath, followed by addition of triethylamine (404 mg, 4 mmol) and methanesulfonyl chloride (274 mg, 2.40 mmol). The reaction solution was warmed up to room temperature and stirred for 3 hours. The resulting solution was mixed with 5 mL of water and extracted with dichloromethane (20 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate 7c (530 mg) as a yellow oil, which was directly used in the next step without further purification. |
| 1.1 g |
With triethylamine; In chloroform; at 0 - 20℃; for 1.5h; |
(R)-N-Boc-3-pyrrolidinol (935 mg) was dissolved in chloroform (15 ml), and triethylamine (1.04 ml) and methanesulfonyl chloride (467 μl) were added thereto at 0 C. After stirring at room temperature for 1.5 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, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.1 g). Physical properties: m/z[M+H]+ 266.1 |
| 1.1 g |
With triethylamine; In chloroform; at 0 - 20℃; for 1.5h; |
(R)-N-Boc-3-pyrrolidinol (935 mg) was dissolved in chloroform (15 ml), and triethylamine (1.04 ml) and methanesulfonyl chloride (467 μl) were added thereto at 0 C. After stirring at room temperature for 1.5 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, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.1 g). Physical properties: m/z [M+H]+ 266.1 |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 16h; |
(R)-3-hydroxypyrrolidin-1-carboxylic acid tert-butyl ester (1 g, 5.34 mmol) was dissolved in 18 mL of MC. Et3N(2.22 ml, 16.02 mmol) was added thereto at 0C, and MsCl (0.62 ml, 8.01 mmol) was then added thereto. The mixturewas stirred at room temperature for 16 hours. The reaction solution was diluted with water and extracted with MC. Theorganic layer was dried with anhydrous magnesiumsulfate and purified by column chromatography to obtain (R)-3-methanesulfonyloxypyrrolidin-1-carboxylic acid tert-butyl ester. At another flask, diethyl malonate (1.7 ml, 11.3 mmol)was dissolved in 10 ml of ethanol. NaOEt (21%wt, 4.2 ml, 11.3 mmol) was added thereto, and the mixture was stirredat 40C for 1 hour. The obtained (R)-3-methanesulfonyloxypyrrolidin-1-carboxylic acid tert-butyl ester (1.5 g, 5.65 mmol)was dissolved in 8 ml of ethanol and added thereto. The mixture was stirred at 80C for 16 hours. The reaction solutionwas adjusted to pH 2 by the use of 6N HCl aqueous solution and extracted with ether. The organic layer was dried withanhydrous magnesiumsulfate and purified by column chromatography to obtain the title compound (0.785 g, 44 %).1H-NMR (CDCl3) δ 4.21 (4H, m), 3.63 (1H, m), 3.47 (1H, m), 3.25 (2H, m), 3.01 (1H, m), 2.80 (1H, m), 2.06 (1H, m),1.62 (1H, m), 1.42 (9H, s), 1.26 (6H, m). |
| 82.2 g |
With triethylamine; In dichloromethane; for 2h;Inert atmosphere; |
a.The reactor was purged with nitrogen, and after stirring 380 g of dichloromethane and 38 g of triethylamine from the feed port for a few minutes, 58 g of the compound 1 was added from the feed port, and then 39 g of methylsulfonyl chloride was slowly added dropwise. The reaction was kept for 2 hours, washed with water and concentrated to obtain Compound 2, and the yield was 82.2 g. |
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