| 100% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; |
A solution of 1,1 -dimethylethyl (3 S)-3 -hydroxy- 1 -pyrrolidinecarboxylate (166 mmol) and N,N-diisopropylethylamine (265 mmol) in dichloromethane (200 mL) at 0 C under nitrogen atmosphere was treated with methanesulfonyl chloride (199 mmol) in dichloromethane and allowed to warm to ambient over 1 h. Analysis by LCMS indicated the reaction was complete. The mixture was washed with 1M aq hydrochloric acid and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-5% methanol/dichloromethane) gave the title product in quantitative yield (166 mmol). .H NMR (400 MHz, CDC13) delta ppm 1.49 (s, 9 H) 2.08 - 2.21 (m, 1 H) 2.29 (br. s., 1 H) 3.07 (s, 3 H) 3.36 - 3.64 (m, 3 H) 3.65 - 3.75 (m, 1 H) 5.28 (tt, J=4.23, 2.08 Hz, 1 H). |
| 100% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; |
1 ,1 -Dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate(a) 1 ,1 -Dimethylethyl (3S)-3-[(methylsulfonyl)oxy]-1 -pyrrolidinecarboxylateA solution of 1 , 1 -dimethylethyl (3S)-3-hydroxy-1 -pyrrolidinecarboxylate (166 mmol) and N,N- diisopropylethylamine (265 mmol) in dichloromethane (200 ml.) at 0 C under nitrogen atmosphere was treated with methanesulfonyl chloride (199 mmol) in dichloromethane and allowed to warm to ambient over 1 h. Analysis by LCMS indicated the reaction was complete. The mixture was washed with 1 M hydrochloric acid and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flashchromatography (0-5% methanol/dichloromethane) gave the title product in quantitative yield (166 mmol). 1 H NMR (400 MHz, CDCI3) delta ppm 1 .49 (s, 9 H) 2.08 - 2.21 (m, 1 H) 2.29 (br. s., 1 H) 3.07 (s, 3 H) 3.36 - 3.64 (m, 3 H) 3.65 - 3.75 (m, 1 H) 5.28 (tt, J=4.23, 2.08 Hz, 1 H). |
| 100% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; |
To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.00 g, 5.35 mmol) andTEA (1.62 g, 16.1 mmol) in DCM (15 mL) was added MsCI (920 mg, 8.03 mmol) at 000under N2 The solution was warmed to room temperature and stirred for another 1 hour.The mixture was diluted with H20 (30 mL) and extracted with DCM (3 x 15 mL). Thecombined organic layers were washed with sat.NaHCO3 solution and brine, dried overNa2SO4 and concentrated under vacuum to give the desired product (1.5 g, yield 100%) asyellow oil.1H NMR (300 MHz, CDCI3): 6 5.28-5.25 (m, 1H), 3.73-3.43 (m, 4H), 3.05 (s, 3H), 2.36-2.09(m, 2H), 1.47 (s, 9H).LC-MS: [mobile phase: from 90% water (0.02% NH4OAc) and 10% CH3CN to 5% water (0.02% NH4OAc) and 95% CH3CN in 4 mm], Rt = 2.153 mm MS Calcd.: 265. MS Found: 210 [M-56+H]. |
| 95% |
With triethylamine; In dichloromethane; at 0 - 25℃; for 0.5h; |
To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (5.00 g, 26.7 mmol, CAS101469-92-5) in DCM (80 mL) was added TEA (8.11 g, 80.1 mmol) and MsCl (3.98 g, 34.7 mmol) at 0 C. The mixture was then stirred at 25 C. for 0.5 hr. On completion, the reaction mixture was washed with water (3×60 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (7.00 g, 95% yield) as light yellow oil. 1H NMR (400 MHz, CDCl3) delta 5.30-5.23 (m, 1H), 3.70-3.42 (m, 4H), 3.05 (s, 3H), 2.38-2.08 (m, 2H), 1.47 (s, 9H). |
| 94% |
With triethylamine; In ethyl acetate; at -5 - 20℃; for 1h; |
[00243] To a cooled (-5 to-10C, ice/salt bath) solution of pyrrolidinol (xiv) (18.2 g, 98 mmol) and triethylamine (28 ml, 196 mmol) in ethylacetate (150 ml) was slowly added methanesulfonyl chloride (9.1 ml, 118 mmol) via a syringe. After completion of addition, the mixture was left stirring at room temperature for one hour. Water (100 ml) was added, and the layers were separated. The organic layer was washed with 1 N aq. HCl solution (100 ml), 5% aq. sodium bicarbonate solution (100 ml), and with saturated aqueous NaCl solution (100 ml). Then, the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure, yielding 24.3 g (92 mmol, 94%) of a yellow oil. This oil was dissolved in 150 <n="59"/>ml dry DMF, and potassium thioacetate (13.5 g, 119 mmol) was added. The resulting mixture was heated to 65 0C overnight under a nitrogen atmosphere, the solution started to solidify after about half an hour. After the mixture was cooled to room temperature, water (250 ml) and TBME (200 ml) were added. The layers were separated, and the aqueous layer was extracted with another portion of TBME (250 ml). The combined organic layers were washed with water (3x250 ml), and with brine (200 ml), dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Yield: 20.8 g (92%) of a yellow oil, identified as xvi by 1H- NMR. |
| 92% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; |
To a solution of the latter (10.0 g) and NEt3 (8.2 ml) in DCM (150 ml) at 0C, methanesulfonyl chloride (4.34 ml) was added. After stirring at RT for 3 h, the reaction mixture was poured into ice/water and extracted with DCM.The organic phase was washed with 5% aqueous NaHCO3, water and brine, was dried and was evaporated to dryness to give an oil which solidified after standing overnight in the refrigerator. The solid was triturated with Et2theta to give lambdaf-tert-butoxycarbonyl-3-(S)-pyrrolidinyl methanesulfonate (13.0 g, 92%) as a light yellow solid.1H-NMR (300 MHz, DMSO-d6, ppm from TMS): delta 5.23 (IH, m), 3.60-3.10 (4H, m), 3.23 (3H, s), 2.11 (2H, m), 1.39 (9H, s). |
| 92% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; |
To a solution ofN-tert-butoxycarbonyl-(S)-pyrrolidinol (A) (10.0 g) and triethylamine (8.2 mL) in CH2CI2 (150 mL) at 0 C, methanesulfonyl chloride (4.34 mL) was added. After stirring at room temperature for 3 h, the reaction mixture was poured into ice/water and extracted with CH2CI2. The organic phase was washed with 5% aqueous NaHC03, water, and brine, dried and evaporated to dryness to give an oil which solidified after standing overnight in the refrigerator. The solid was triturated with Et20 to give N-tert-butoxycarbonyl-(S)-3-pyrrolidinyl methansulfonate (13.0 g, 92%)M/52334-PCT 78 (Compound B) as a light yellow solid. 1H- MR (300 MHz, DMSO-d6, ppm from TMS): delta 5.23 (IH, m), 3.60-3.10 (4H, m), 3.23 (3H, s), 2.11 (2H, m), 1.39 (9H, s). |
| 92% |
|
To a solution of N-tert-butoxycarbonyl-(S)-pyrrolidinol (10.0 g) and triethylamine (8.2 mL) in CH2CI2 (150 mL) at 0 C, methanesulfonyl chloride (4.34 mL) was added. After stirring at room temperature for 3 h, the reaction mixture was poured into ice/water and extracted withCH2CI2. The organic phase was washed with 5% aqueous NaHCU3, water, brine, dried and evaporated to dryness to give an oil which solidified after standing overnight in the refrigerator. The solid was triturated with Et2theta to give N-tert-butoxycarbonyl-(S)-3-pyrrolidinyl methansulfonate (13.0 g, 92%) as a light yellow solid. 1H-NMR (300MHz, DMSO-de, ppm from TMS): delta 5.23 (IH, m), 3.60-3.10 (4H, m), 3.23 (3H, s), 2.11 (2H, m), 1.39 (9H, s). |
| 91% |
With triethylamine; In dichloromethane; at 28℃; for 1h; |
Step 1 (S)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylateTo a cooled solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (15 g, 80.11 mmol) inDCM (150 mL) was added TEA (22.3 mL, 160.22 rnmol) and MsCl (7.44 mL, 96.13 mmol). Thereaction mixture was stirred at 28 C for I hr. The reaction mixture was diluted in DCM (100 mL),washed with 1 N HCI (100 mL), saturated NaHCO3 (100 mL) and brine (100 mL). The organiclayer was dried over anhydrous Na2SO4, filtered and concentrated to afford the desired product (19.4g, 91% yield) as ayellowoil. ?H NMR (400 MHz, CDCI3) oe 5.30-5.26 (m, lH), 3.68 3.43 (m, 4H), 3.05 (s, 3H), 2.27 -2.13 (m, 2H), 1.46 (s, 9H). |
| 89% |
With triethylamine; In toluene; at 25℃; for 1.16667h;Cooling with ice; |
Example 2: Production of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine The (S)-1-(tert-butoxycarbonyl)-3-pyrrolidinol (3.61 g) produced in Example 1 was dissolved in toluene (30 ml), and triethylamine (1.58 g) was added thereto. To the solution, methanesulfonyl chloride (1.64 g) was added dropwise on an ice bath over 10 minutes, and the mixture was stirred at 25C for 1 hour. To the reaction mixture, distilled water (15ml) was added in order to extract the target compound into the organic layer. The obtained organic layer was washed with distilled water (15 ml). The organic layer was concentrated under reduced pressure to obtain 4.10 g of the target compound as a brown oil (content amount: 74.6wt%, yield: 89%). 1H-NMR (CDCl3): delta (ppm) 1.47(s, 9H), 2.15(m, 1H), 2.27(m, 1H), 3.05(s, 3H), 3.42-3.78(m, 4H), 5.26(m, 1H) |
| 85% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere; |
a) 1,1 -dimethylethyl (35)-3 - [(methylsulfonyl)oxy] - 1 -pyrrolidmecarboxylateTo a 100 mL round bottom flask containing 1,1 -dimethylethyl (35)-3 -hydroxy- 1- pyrrolidinecarboxylate (20 g, 107 mmol) was added CH2C12 (300 mL) and Et3N (24 mL, 172 mmol). The solution was cooled to 0 C and MsCl (10 mL, 128 mmol) was added dropwise to the reaction. The reaction was stirred under nitrogen while the cooling bath was allowed to warm slowly to room temperature. After 3 h, analysis by LCMS indicated the reaction had progressed to completion. The mixture was diluted with CH2C12 (300 mL) and washed with 0.1 N aq. HC1 and then with brine. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. Purification of the crude oil by flash chromatography (0-5% MeOH/CH2Cl2) afforded the title compound (24 g, 85%).MS(ES)+ m/e 266.0 [M+H]+. |
| 79% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h; |
Intermediate 116 :(S)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-l-carboxylate; To a stirred solution of (S)-tert-butyl 3-hydroxypyrrolidine-l-carboxylate (4.38 g, 23.4 mmol) and N-ethyldiisopropylamine (6.11 mL, 35.1 mmol) in dichloromethane (94 mL) at 0 0C was added methanesulfonyl chloride (2.173 mL, 28.1 mmol). The mixture stirred at ambient temperature for 16 hours, evaporated in vacuo to a residue which was taken up in ethyl acetate (125 mL), washed with water, citric acid solution, brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica with <n="171"/>50% ethyl acetate in isohexane as eluant to give (S)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-l-carboxylate (4.92 g, 79 %). 1H NMR (CDCl3) delta: 1.4 (s, 9H), 2.0 - 2.2 (m, 2H), 3.0 (s, 3H), 3.4 - 3.6 (m, 4H) and 5.2 (dt, IH). |
| 70% |
With triethylamine; In dichloromethane; at 20℃;Cooling with ice; |
Example 22. N-(4-(4-amino-l-((R)-pyrrolidm-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3- yl)phenyl)-3-(trifluoromethyl)benzamide (AD72); Step l; OH ,s=oOBoc Boc[0205] (5)-l-(fcr-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate. A solution of (S)- tert-buty 3-hydroxypyrrolidine-l-carboxylate (1.0 g, 5.3 mmol) and triethylamine (2.77 mL, 20 mmol) in CH2Cl2 (20 niL) was cooled in an ice-water bath. To this, methanesulfonyl chloride (1.15 mL, 15 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3x 50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (S)-I- (te/-t-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.97 g, brown oil, 70% yield). |
|
With pyridine;Product distribution / selectivity; |
A comparative sample of S-BMSP was obtained by using 3S-N-tert-butoxycarbonyl-3-hydroxypyrrolidine, methanesulfonyl chloride, and pyridine in accordance with a known process as described in [Non-Patent Document 1]. |
|
With triethylamine; In dichloromethane; at 0 - 30℃; |
To a stirred, 0 C. solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10.4 g, 55.5 mmol) and triethylamine (15.5 mL, 0.1111 mole) in CH2Cl2 (150 mL) was added dropwise methanesulfonyl chloride (5.2 mL, 0.06665 mole). When the addition was complete, the reaction mixture was allowed to warm to room temperature, then stirred overnight. The reaction mixture was concentrated under reduced pressure to give a residue that was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% hexane to 70:30 hexane/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to give (S)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate. 1H NMR (300 MHz, CD3OD) delta ppm 1.47 (s, 9H), 2.14-2.29 (m, 2H), 3.12 (s, 1H), 3.36-3.67 (m, 4H), 5.24-5.30 (m, 1H); MS (DCI/NH3) m/z 266 (M+H)+, 283 (M+NH4)+. |
|
With triethylamine; In dichloromethane; at 0℃; |
Example 90: (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine.; Step A: Preparation of 3-(4-chloro-2-formyl-phenoxy)-pyrrolidine-1 - carboxylic acid tert-butyl ester.; To (SJ-S-hydroxy-pyrrolidine-i-carboxylic acid tert-butyl ester (2.0 g, 10.9 mmol) in CH2CI2 (50 ml_) at 0 0C was added Et3N (1.4 g, 1.9 ml_, 13.4 mmol) and methanesulfonyl chloride (1.38 g, 0.94 ml_, 12.1 mmol). After 1 h, brine was added and the mixture extracted with CH2CI2 (2X). The combined organics were dried to give 3-methanesulfonyloxy-pyrrolidine-1 - carboxylic acid tert-butyl ester that was used without further purification.To this compound in DMF (50 ml_) was added 5-chloro-2-hydroxy- benzaldehyde (1.9 g, 12.1 mmol) and K2CO3 (1.8 g, 13.1 mmol). The reaction was heated at 90 0C for 2h, then cooled to rt and H2O was added. The mixture was extracted with EtOAc (2X). The combined organics were washed with brine and dried. Silica gel chromatography (10-50% EtOAc in hexanes) gave 1.85 g (52%) of the title compound. 1H NMR (CDCI3): 10.36 (s, 1 H), 7.81 (s, 1 H), 7.50 (s, 1 H), 6.90 (d, J = 8.9 Hz, 1 H), 5.00 (s, 1 H), 3.72-3.50 (m, 4H), 2.26-2.18 (m, 2H), 1.47 (s, 9H). |
|
With triethylamine; In tetrahydrofuran; at 0℃; for 1h; |
Triethylamine (9.67 mL) and methanesulfonyl chloride (5.12 mL) were added to tetrahydrofuran solution (100 mL) of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (11.8 g) under cooling with ice, followed by an hour's stirring under the same condition. Adding water, the reaction liquid was extracted with ethyl acetate twice. The organic layer was washed with 10% citric acid solution, saturated sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated to provide the title compound (16.8 g). |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; |
To a solution of N-tert-butoxycarbonyl-(S)-pyrrolidinol (10.0 g) and triethylamine (8.2 mL) in CH2C¾ (150 mL) at 0 C, methanesulfonyl chloride (4.34 mL) was added. After stirring at room temperature for 3 h, the reaction mixture was poured into ice/water and extracted with CH2CI2. The organic phase was washed with 5% aqueous NaHC03, water, brine, dried and evaporated to dryness to give an oil which solidified after standing overnight in the refrigerator. The solid was triturated with Et20 to give N-fert-butoxycarbonyl-(S)-3-pyrrolidinyl methansulfonate (13.0 g, 92%) (Compound A) as a light yellow solid. 'H-NMR (300 MHz, DMSO-dg, ppm from TMS): delta 5.23 (1H, m), 3.60-3.10 (4H, m), 3.23 (3H, s), 2.11 (2H, m), 1.39 (9H, s). |
|
With triethylamine; In dichloromethane; at 4℃; for 2h; |
To a solution of (S)-(+)-N-Boc-3-pyrrolidinol (2.67 mmol) and triethylamine (4.01 mmol) in methylene chloride (50 mL) was added methansulfonyl chloride (4.01 mmol) under ice-bath and the resulting mixture was further stirred at 4 C. After 2 h, the residue was diluted with methylene chloride (50 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (2:1 hexanes/ethyl acetate) to give E1. |
|
With triethylamine; In dichloromethane; for 3h;Cooling with ice; |
Mesylchloride (232.0 mul) was added to an ice-cooled solution of the (S)-1-N-Boc-3-hydroxypyrrolidine (374.0 mg) and triethylamine (556.0 mul) in dichloromethane (10.0 ml) The mixture was stirred at this temperature for 3 h. After this time the reaction mixture was diluted with dichloromethane, washed with 10% aq. KHSO4, 10% aq. K2CO3 and passed through a hydrophobic frit. The solvent was evaporated. The residue was combined with methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (333.3 mg) and potassium carbonate (276.0 mg) in DMF (7.0 ml) and heated at 80 C. overnight. EtOAc and water were added and the suspension was filtered. The filtrate was separated, the aqueous layer was discarded and the organic was washed with brine (2×). After drying the organic passed through a hydrophobic frit and the solvent was evaporated. The residue was triturated with MeOH and solids combined. The solids were washed with Et2O and dried.Yield: 311.0 mg |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 6h; |
Step-I: (S)-tert-Butyl 3-(methylsulfonyloxy)pyrrolidine-l-carboxylate (intermediate -1) [00333] To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-l-carboxylate (1.0 g, 5.34 mmol) in dichloromethane (20.0 mL) at 0 C, was added triethylamine (1.861 mL, 13.35 mmol) and subsequently methanesulfonyl chloride (0.541 mL, 6.94 mmol) as a neat liquid. The temperature of the mixture was gradually raised to room temperature. After being stirred for 6.0 h, the mixture was partitioned between saturated aqueous sodium bicarbonate solution and DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product as light-yellowish oil, which was used as such in the next reaction. NMR (400 MHz, chloroform-d) delta 5.21 - 5.29 (m, 1H), 3.40 - 3.73 (m, 4H), 3.04 (s, 3H), 2.05 - 2.35 (m, 2H), 1.43 - 1.49 (m, 9H). |
|
In tetrahydrofuran; at 0℃; for 1h; |
To 3.44 g (187 mmol) (S)-1-Boc-3-pyrrolidinol in 15 ml THF are added 1.70 mL (21.6 mmol) of methanesulfonyl chloride at 0 C. The reaction mixture is stirred for 1 h. Water is added and it is extracted with EtOAc (3*). The organic layer is washed with an aq. NaHCO3 solution and dried over MgSO4. The solvent is removed in vacuo. C10H19NO5S (M=265.3 g/mol). Rt (HPLC): 0.67 min (method B). |
|
In tetrahydrofuran; at 0℃; for 1h; |
To 3.44 g (187 mmol) (S)-1 -Boc-3-pyrrolidinol in 15 ml THF are added 1 .70 mL (21 .6 mmol) of methanesulfonyl chloride at 0C. The reaction mixture is stirred for 1 h. Water is added and it is extracted with EtOAc (3x). The organic layer is washed with an aq. NaHC03 solution and dried over MgS04. The solvent is removed in vacuo. C10H19N05S (M = 265.3 g/mol) Rt (HPLC): 0.67 min (method B) |
| 1.3 g |
With triethylamine; In chloroform; at 20℃; for 1.5h; |
935 mg of (S)-(-)-N-Boc-3-pyrrolidinol was dissolved in 15 ml of chloroform, and 1.04 ml of triethylamine and 467 mul of methanesulfonyl chloride were added thereto under ice cooling. The mixture was stirred for 1.5 hours at room temperature, subsequently ethyl acetate and water were added thereto, and an organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of ammonium chloride, and water, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and thus 1.3 g of the title compound was obtained as a colorless oily substance. Physical property value: m/z [M+H]+ 266.1 |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 0.333333h;Inert atmosphere; |
Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of argon, were placed a solution of(S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3g, 16.02 mmol) and TEA (6.70 ml, 48.1 mmol) in DCM (30 ml)) under argon atmosphere. This was followed by the addition of Ms-Cl (1.498 ml, 19.23 mmol) dropwised at 0C. The resulting mixture was stirred under argon atmosphere at ambient temperature for 20 mm. The reaction was quenched with ice water (100 ml) and extracted with EtOAc (3 x 100 ml).The combined organic layers were washed with brine (1 x 200 ml),dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to afford the title compound which was used directly in next step without further purification:LCMS (ESI) calc?d forC,0H,9N055. |
| 1.3 g |
With triethylamine; In chloroform; at 20℃; for 1.5h;Cooling with ice; |
(Step 1) Synthesis of (S)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (S)-(-)-N-Boc-3-pyrrolidinol (935 mg) was dissolved in chloroform (15 mL). To the solution, triethylamine (1.04 mL) and methanesulfonyl chloride (467 muL) were added under ice cooling. The mixture was stirred at room temperature for 1.5 hours, and then, ethyl acetate and water were added thereto to separate an organic layer. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride, and water and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.3 g of the title compound as a colorless oil. Physical property value: m/z [M+H]+ 266.1 |
| 1.3 g |
With triethylamine; In chloroform; at 20℃; for 1.5h;Cooling with ice; |
935 mg of (S)-(-)-N-Boc-3-pyrrolidinol was dissolved in 15 mL of chloroform, and 1.04 mL of triethylamine and 467 muL of methanesulfonyl chloride were added thereto under ice cooling. The mixture was stirred for 1.5 hours at room temperature, subsequently ethyl acetate and water were added thereto, and an organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of ammonium chloride, and water, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and thus 1.3 g of the title compound was obtained as a colorless oily substance. Physical property value: m/z [M+H]+ 266.1 |
|
With triethylamine; In toluene; at -10 - 20℃; for 1.33333h; |
(3S)-3-hydroxypyrrolidin-1-carboxylic acid tert-butyl ester (1.5 g, 8 mmol) was dissolved in 16 mL of tolueneand cooled to -10C. TEA (1.7 mL, 12 mmol) and methanesulfonyl chloride (0.8 mL, 10.1 mmol) were slowly addedthereto. The mixture was stirred at room temperature for 80 minutes, and solids were filtered. The filtrate was washedwith sodium bicarbonate aqueous solution, dried with MgSO4 and concentrated under reduced pressure to obtain (3S)-3-methylsulfonyloxypyrrolidin-1-carboxylic acid tert-butyl ester. 27 mL of EtOH and malonic acid ethyl ester (2.62 g, 16.4mmol) were prepared in another flask, and sodium (0.37 g, 16 mmol) was added thereto little by little. The mixture wasstirred at room temperature for 30 minutes. (3S)-3-methylsulfonyloxypyrrolidin-1-carboxylic acid tert-butyl ester wasadded thereto, and the mixture was stirred for 16 hours under reflux. The reaction solution was cooled to room temperatureand adjusted to pH 4 by the addition of water and 1N HCl aqueous solution. The reaction solution was extracted with MTBE to obtain the title compound (2.08 g, 79 %).1H-NMR (CDCl3) delta 4.22 (2H, q), 3.64 (1H, m), 3.50 (1H, m), 3.28 (2H, m), 3.03 (1H, m), 2.81 (1H, m), 2.08 (1H, m), 1.63(1H, m), 1.45 (9H, s), 1.27 (6H, t) |
|
|
Et3N (5.58 mL, 40 mmol) was added to a solution of (S) tert-butyl 3- hydroxypyrrolidine-1-carboxylate (3 g, 16.02 mmol) in dry DCM (35 mL). The solution was cooled to 0 C, stirred for 10 mm and then, methanesulfonyl chloride (2.1 mL, 27.24 mmol) was added and the reaction mixture was stirred at 0 C. After 1 h the reaction mixture was allowed to warm to rt and stirred for 0.5 h. The mixture waspoured into ice-water and diluted with DCM. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as a crude yellow oil (4.25 g) that was used in the next step without further purification.1H NMR (400 MHz, CDC13) O ppm 1.49 (s, 9 H) 2.08-2.21 (m, 1 H) 2.29 (br. s., 1 H)3.07 (s, 3 H) 3.36 - 3.64 (m, 3 H) 3.65 - 3.75 (m, 1 H) 5.28 (tt, J=4.23, 2.08 Hz, 1 H)) |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 0.166667h; |
To the above alcohol (g, 10.7 mmol), Et3N (2.15g, 21 mmol), in CH2Cl2 (50 mL) at 00C was added MsCl (1.46 g, 12.8 mmol), were allowed to stirr for 10 inutes room temperature Then the reaction mixture was diluted with diluted with CH2Cl2 (50 mL) and the organic layer washed with brine (2x50 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated.Purification of the resulting crude by flash silica gel chromatography provided the dimesolate compound (2.9 g) as an oil. |
|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 3h; |
tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (3.0g, 16.02mmol, 1eq) was added a reaction flask was added THF (30mL) solution was cooled to 0 deg.] C, was added triethylamine (3.24 g of , 32.04mmol, 2eq), was slowly added methanesulfonyl chloride (2.2g, 19.23mmol, 1.2eq), slowly warmed to room temperature for 3 hours, complete reaction was monitored by TLC, the reaction solution was suction filtered, the filtrate was concentrated under reduced pressure to give a pale as a yellow oil tert-butyl (S)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate, cast without purification step |
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With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; |
To a solution of (S)-Boc-3-pyrrolidinol (8.42 g, 45 mmol) in DCM (150 mL) at 0 C was added triethylamine (9.5 mL, 68.2 mmol) followed by methanesulfonyl chloride (4 mL, 50.8 mmol) The reaction mixture was stirred at 0 C for 30 min, then warmed to rt for 30 min, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo, yielding the crude product, which was used directly for the next step without further purification. |
| 1.3 g |
With triethylamine; In chloroform; at 20℃; for 1.5h;Cooling with ice; |
(S)-(-)-N-Boc-3-pyrrolidinol (935 mg) was dissolved in chloroform (15 mL). To the solution, triethylamine (1.04 mL) and methanesulfonyl chloride (467 muL) were added under ice cooling. The mixture was stirred at room temperature for 1.5 hours, and then, ethyl acetate and water were added thereto to separate an organic layer. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride, and water and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.3 g of the title compound as a colorless oil. Physical property value: m/z[M+H]+ 266.1 |
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