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CAS No. : | 40499-83-0 | MDL No. : | MFCD00005256 |
Formula : | C4H9NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 87.12 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 27.11 |
TPSA : | 32.26 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.32 cm/s |
Log Po/w (iLOGP) : | 1.2 |
Log Po/w (XLOGP3) : | -0.69 |
Log Po/w (WLOGP) : | -1.04 |
Log Po/w (MLOGP) : | -0.57 |
Log Po/w (SILICOS-IT) : | 0.52 |
Consensus Log Po/w : | -0.12 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.05 |
Solubility : | 98.8 mg/ml ; 1.13 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.49 |
Solubility : | 268.0 mg/ml ; 3.07 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.13 |
Solubility : | 64.4 mg/ml ; 0.74 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.25 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With formic acid In tetrahydrofuran for 5 h; Heating / reflux | In a 100 ml flask, 2 g (R)-3-Hydroxy pyrrolidine, 25 ml THF, 0.49 g paraformaldehyde and 1.5 g formic acid (90percent) were added. The mixture was stirred under reflux for 5 hours (until all solid disappeared), then cooled at 0° C. and added with 10 ml of NaOH solution (10 N) to adjust the pH to about 10. The organic layer was separated and dried over MgSO4. After filtering the dried solution and removing the solvent (THF), an oily product (1.5 g, 92percent) of (R)3 was obtained. 1H NMR (CDCl3, 300 MHz): 1.50-1.60 (m, 1H), 1.98-2.10 (m, 1H), 2.25 (s, 3H), 2.25-2.40 (m, 2H), 2.50-2.60 (m, 1H), 2.61-2.70(m, 1H), 3.80(brs, 1H), 4.20-4.30(m, 1H). |
85.6% | Stage #1: With sodium tetrahydroborate In methanol; water at 10 - 20℃; for 2.33333 h; Stage #2: With hydrogenchloride In methanol; water for 0.333333 h; |
15 g (0.172 mol) of (3R)-pyrrolidin-3-ol (commercially available) were dissolved in 240 ml of MeOH. This solution was cooled to 10-15°C, and formaldehyde (124.5 mi of a 36 percent solution in water, diluted with 125 ml of MeOH) and NaBH4 (16.27 g, 0.43 mol) were added in small portions, alternativately during 1h, maintaining the temperature at 10-15°C. After 20 min the mixture was warmed to room temperature and the reaction continued for 1 hour. The reaction mixture was acidified with HCI 2N, stirred during 20 minutes and neutralised with solid NaHCO3. MeOH and most of the water were evaporated and the residue was diluted with a small quantity of water, basified with solid K2C03 and exhaustively extracted with CHC13. The organic phases were combined and dried over Na2SO4. CHCl3 was evaporated to give an oil which was purified by Kugelrohr distillation at reduced pressure (0.2-0. 3 mbar, 50-60°C oven) to give 14.91 g (85.6 percent) of the title product. 'H-NMR (CDCI3) :. No. 1.60-1. 80 (m, 1H), 2.10-2. 40 (m, 5H), 2.40-2. 70 (m, 2H), 2.75-2. 95 (m, 1H), 4.20-4. 40 (m, 1H), 4.40-4. 50 (bs, 1H, OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In acetonitrile at 0 - 20℃; for 24 h; Inert atmosphere | Step 1: In a 500 mL oven-dried round-bottomed flask charged with (R)-3-pyrrolidinol (5.15 g, 58 mmol) was added dry CH3CN (200 mL) to give a light brown solution under N2. Then Et3N (16.2 mL, 0.12 mol) was added dropwise. This was cooled to 0 °C and then CbzCl (48 mL, 83 mmol) was added dropwise. The temperature was allowed to warm up to rt gradually. After stirring for 24 h, solvent was removed in vacuo. The residue was treated with DCM and DI water. Organic layer was separated and the aqueous layer was extracted with DCM once. The combined organic layer was dried ( a2S04) and concentrated in vacuo. The crude material was purified by S1O2 column chromatography eluting with Hexane: EtOAc = 1 : 1 to provide the desired alcohol 1 (12.6 g, 98percent).1H NMR (CDCI3, 400 MHz): δ 7.37 - 7.30 (m, 5H), 5.14 (s, 2H), 4.52 - 4.46 (m, 1H), 3.60 - 3.41 (m, 4H), 2.01 - 1.95 (m, 2H), 1.61 (br s, 1H). |
83% | With triethylamine In dichloromethane at 0℃; for 2 h; Inert atmosphere | To a solution of (R)-pyrrolidin-3-ol (10 g, 114.8 mmol) and NEt3 (18.3 mL, 131.2 mmol) in CH2C12(120 mL) under N2 atmosphere stirred in an ice/water bath, was added Cbz-Cl (15.6mL, 109.31 mmol) dropwise. The reaction was stirred in the ice/water bath for 2 h. The reaction was worked up by the addition of CH2C12 (25 mL), and iN aqueous solution of HC1 (100 mL). The organic phase was separtated, washed with saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mL), dried over Na2504 and the solvent was removed in vacuo. The yellowish residue was dissolved in EtOAc and filtered through a silica gel pad, washing with more EtOAc until no more product was washed out. The solvent was evaporated to afford a light yellowish oil as the title compound (20. 19g, 83percent). LC/MS (Rt = 1.49 mi +ESI m/z: MH+ = 222.3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine In dichloromethane at 20℃; for 12 h; | To a solution of pyrrolidin-3-ol (10.45 g, 120.1 mmol) in dichloromethane (300 mL) was added benzyl chloroformate (24.6 g, 144 mmol) and triethylamine (24.3 g, 240.2 mmol). The resulting solution was stirred at room temperature for 12 hours. After concentrating the reaction, the remaining material was partitioned between ethyl acetate (100 mL) and water (60 mL). The layers were separated. The organic layer was washed with water (60 mL), aqueous saturated sodium chloride solution (60 mL), dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to give benzyl 3-hydroxypyrrolidinyl-1-carboxylate (15.2 g, 57percent) as a colorless gum. LCMS m/z = 222.1 [M+H]+. |
49% | for 20 h; | Prβparatlon 16; S-Hydroxy-pyrrolldlne-i-carboxyllc acid benzyl ester; 3-Pyrrolidiπol (6.99g, 68.9 mmol), benzyl chloroformata (10.66 mL, 75.8 mmol) and CH2CI2 (200 mL) were stirred for 2Oh then washed with water and brine, dried (MgSO4) and concentrated to give a thick yellow oil. Chromatography, flushing first with 20percent EtOAc/ hexaπes then eluting with 30percent MeOH/EtOAc, afforded 7.4Og (49percent) of the title compound: NMR (CDCI3) δ 7.35-7.26 (m, 5H), 5.11 (s, 2H), 4.46 (br s, 1H), 3.60-3.38 (m, 4H)1 2.00-2.82 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydroxide In tetrahydrofuran; water at 20℃; for 3 h; | To the solution of pyrrolidin-3-ol (1.0 g, 11 mmol) in THF (5 mL) and 1M NaOH (5 mL) was added dibenzyldicarbonate (3.3, 11 mmol) at room temperature. The reaction mixture was stirred for 3 h then the THF removed under reduced pressure. The residue was dissolved in DCM (50 mL) and washed successively with saturated NaHCO3 (2.x.20mL) and saturated NaCl (2.x.20 mL). The solution was dried over Na2SO4, decanted and concentrated. Benzyl 3-hydroxypyrrolidine-1-carboxylate (1.1 g, 47percent) was isolated by prep. HPLC YMC ODSA 30.x.100 mm, 20-100percent MeOH/H2O (0. 1percent TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.93 min. LCMS: 1.21 min [M+1] 222.06 (2 min gradient, MeOH/H2O 0.1percent TFA). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In dimethyl sulfoxide; at 136℃; for 7h; | Example 31a; 7V-(2-Amino-5-(5-chlorothiophen-2-yl)phenyl)-4-(3-morpholinopyrrolidin-l-yl)benzamide(271); Ste 1 : tert-Butyi 4-(3-hvdroxypyrrolidin-l-yl)benzoate (266); [0900] A mixture of fluoride 97 (2.24 g, 11.4 mmol), pyrrolidin-3-ol (1.37 g, 15.8 mmol) and potassium carbonate (2.24 g) was suspended in dimethyl sulfoxide (5 mL) and stirred at 136 0C for 7 h. The reaction mixture was cooled to room temperature, diluted with DCM, washed with H2O, dried over MgSO4, filtered and concentrated to provide title compound 266 (3.93 g, 100%). <n="152"/>[0901] LRMS: 263.3 (calc) 264.1 (obs) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In acetonitrile; at 0 - 20℃; for 24h;Inert atmosphere; | Step 1: In a 500 mL oven-dried round-bottomed flask charged with (R)-3-pyrrolidinol (5.15 g, 58 mmol) was added dry CH3CN (200 mL) to give a light brown solution under N2. Then Et3N (16.2 mL, 0.12 mol) was added dropwise. This was cooled to 0 C and then CbzCl (48 mL, 83 mmol) was added dropwise. The temperature was allowed to warm up to rt gradually. After stirring for 24 h, solvent was removed in vacuo. The residue was treated with DCM and DI water. Organic layer was separated and the aqueous layer was extracted with DCM once. The combined organic layer was dried ( a2S04) and concentrated in vacuo. The crude material was purified by S1O2 column chromatography eluting with Hexane: EtOAc = 1 : 1 to provide the desired alcohol 1 (12.6 g, 98%).1H NMR (CDCI3, 400 MHz): delta 7.37 - 7.30 (m, 5H), 5.14 (s, 2H), 4.52 - 4.46 (m, 1H), 3.60 - 3.41 (m, 4H), 2.01 - 1.95 (m, 2H), 1.61 (br s, 1H). |
95% | In tetrahydrofuran; water; | (a) N-Benzyloxycarbonyl-(R)-3-hydroxypyrrolidine. To a stirred mixture of (R)-3-hydroxypyrrolidine (4.35 g, 50 mmol) in THF (50 mL) and aqueous sodium carbonate (10.6 g, 100 mmol in 50 mL water) cooled to 0 C. was added a solution of benzyl chloroformate in THF (60 mmol, 8.6 mL in 10 mL THF) over a period of 5-10 min. After stirring at 0 C. for 2 h, the reaction mixture was diluted with 200 mL water and extracted with methylene chloride (3*100 mL). The combined extracts were washed with 1N sulfuric acid (3*75 mL) followed by brine solution (3*50 mL). This extract was then dried over anhydrous sodium sulfate and the solvent evaporated to give a light yellow oil (10.5 g, 95% yield) which was used for the next reaction without any purification. |
95% | In tetrahydrofuran; water; | (a) N-Benzyloxycarbonyl-(R)-3-hydroxypyrrolidine To a stirred mixture of (R)-3-hydroxypyrrolidine (4.35 g, 50 mmol) in THF (50 mL) and aqueous sodium carbonate (10.6 g, 100 mmol in 50 mL water) cooled to 0 C. was added a solution of benzyl chloroformate in THF (60 mmol, 8.6 mL in 10 mL THF) over a period of 5-10 min. After stirring at 0 C. for 2 h, the reaction mixture was diluted with 200 mL water and extracted with methylene chloride (3*100 mL). The combined extracts were washed with 1N sulfuric acid (3*75 mL) followed by brine solution (3*50 mL). This extract was then dried over anhydrous sodium sulfate and the solvent evaporated to give a light yellow oil (10.5 g, 95% yield) which was used for the next reaction without any purification. |
83% | With triethylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere; | To a solution of (R)-pyrrolidin-3-ol (10 g, 114.8 mmol) and NEt3 (18.3 mL, 131.2 mmol) in CH2C12(120 mL) under N2 atmosphere stirred in an ice/water bath, was added Cbz-Cl (15.6mL, 109.31 mmol) dropwise. The reaction was stirred in the ice/water bath for 2 h. The reaction was worked up by the addition of CH2C12 (25 mL), and iN aqueous solution of HC1 (100 mL). The organic phase was separtated, washed with saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mL), dried over Na2504 and the solvent was removed in vacuo. The yellowish residue was dissolved in EtOAc and filtered through a silica gel pad, washing with more EtOAc until no more product was washed out. The solvent was evaporated to afford a light yellowish oil as the title compound (20. 19g, 83%). LC/MS (Rt = 1.49 mi +ESI m/z: MH+ = 222.3). |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.16667 - 3.66667h;Product distribution / selectivity; | Description 1Benzyl (3R)-3-hydroxy-1-pyrrolidinecarboxylate (D1)Method A; Benzyl chloroformate (27.4ml) was added to a stirred solution of (R)-3-pyrrolidinol(obtainable from Lancaster 19499; 16g) and triethylamine (26.7ml) in dry DCM (250 ml) at 00C over 10min under an inert atmosphere. The mixture was allowed to warm to room temperature and stirred for a further 2h. The solvent was evaporated and the residue partitioned between EtOAc (250ml) and aqueous 0.5M HCI (80ml). The organic layer was separated, washed with saturated sodium hydrogen carbonate solution (50ml) and brine (50ml), dried (MgSO4) and evaporated to give the title compound (D1) as a pale orange oil (39g). LCMS electrospray (+ve) 244 (MNa+); Method B Benzyl chloroformate (90ml of 95% purity) was dissolved in DCM (100 ml) and added dropwise to a stirred, ice-bath cooled, solution of (R)-3-pyrrolidinol (obtainable commerically from Lancaster; 5Og) and triethylamine (84ml) in DCM (700 ml) over 40min under argon. The mixture was allowed to warm to room temperature and stirred for a further 3h. The mixture was transferred to a separating funnel and washed with 0.5M aqueous HCI (100 ml) and saturated sodium hydrogen carbonate solution (100ml). The organic layer was dried (MgSO4) and evaporated to afford the title compound (D1) as a pale orange oil (126.1g). LCMS electrospray (+ve) 244 (MNa+) | |
With triethylamine; In dichloromethane; at 5 - 20℃; for 2.5h; | A 22-L, 3-neck, round bottom flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 425 g (4.88 mol) of (3R)-3- HYDROXYPYRROLIDINE, 8 L of dichloromethane, and 1 L (7.17 mol) of triethylamine. The solution was cooled to 5-10 C with an ice bath and then 1000 g (5.86 mol) of benzyl chloroformate was added dropwise over a period of about 1.5 h keeping the reaction temperature <20 C. The reaction mixture was stirred for an additional hour in the ice bath, then the bath was removed and the reaction mixture was allowed to warm to ambient temperature overnight. The mixture was poured into a large extractor containing-15 L of saturated aqueous sodium bicarbonate solution. The aqueous phase was back-extracted with two 2-L portions of dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to give an orange oil. The crude material was taken up in dichloromethane, applied to a 5-kg column of silica gel prepacked in 50% ethyl acetate/hexane, and eluted sequentially with 8 L of 50%, 16 L of 75%, then 100% ethyl acetate/hexane to provide the title compound as a yellow oil which crystallized upon standing. | |
With triethylamine; In dichloromethane; at 0 - 20℃; | INTERMEDIATE 1 (3S)-3-Fluoropyrrolidine hydrochloride Step A: Benzyl (3R)-3-hydroxypyrrolidine-1-carboxylate; A 22-L, 3-neck, round bottom flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 425 g (4.88 mol) of (3R) -3-hydroxypyrrolidine, 8 L of dichloromethane, and 1 L (7.17 mol) of triethylamine. The solution was cooled to 5 - 10 C with an ice bath and then 1000 g (5.86 mol) of benzyl chloroformate was added dropwise over a period of about 1.5 h keeping the reaction temperature below 20 C. The reaction mixture was stirred for an additional h in the ice bath, then the bath was removed and the reaction mixture was allowed to warm to ambient temperature overnight. The mixture was poured into a large extractor containing about 15 L of saturated aqueous sodium bicarbonate solution. The aqueous phase was back-extracted with two 2-L portions of dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to give an orange oil. The crude material was taken up in dichloromethane, applied to a 5-kg column of silica gel prepacked in 50% ethyl acetate/hexane, and eluted sequentially with 8 L of 50%, 16 L of 75%, then 100% ethyl acetate/hexane to provide the title compound as a yellow oil which crystallized upon standing. | |
With triethylamine; In dichloromethane; at 0 - 20℃; | A 22-L, 3-neck, round bottom flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 425 g (4.88 mol) of (3R) -3-hydroxypyrrolidine, 8 L of dichloromethane, and 1 L (7.17 mol) of triethylamine. The solution was cooled to 5 - 10 C with an ice bath and then 1000 g (5.86 mol) of benzyl chloroformate was added dropwise over a period of about 1.5 h keeping the reaction temperature <20 C. The reaction mixture was stirred for an additional hour in the ice bath, then the bath was removed and the reaction mixture was allowed to warm to ambient temperature overnight. The mixture was poured into a large extractor containing -15 L of saturated aqueous sodium bicarbonate solution. The aqueous phase was back-extracted with two 2-L portions of dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to give an orange oil. The crude material was taken up in dichloromethane, applied to a 5-kg column of silica gel prepacked in 50% ethyl acetate/hexane, and eluted sequentially with 8 L of 50%, 16 L of 75%, then 100% ethyl acetate/hexane to provide the title compound as a yellow oil which crystallized upon standing. | |
With triethylamine; In dichloromethane; at 5 - 20℃; | A 22-L, 3-neck, round bottom flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 425 g (4.88 mol) of (3R)- 3-hydroxypyrrolidine, 8 L of dichloromethane, and 1 L (7.17 mol) of triethylamine. The solution was cooled to 5-10 C with an ice bath and then 1000 g (5.86 mol) of benzyl chloroformate was added dropwise over a period of about 1.5 h keeping the reaction temperature below 20 C. The reaction mixture was stirred for an additional hour in the ice bath, then the bath was removed and the reaction mixture was allowed to warm to ambient temperature overnight. The mixture was poured into a large extractor containing approximatelyl5 L of saturated aqueous sodium bicarbonate solution. The aqueous phase was back-extracted with two 2-L portions of dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to give an orange oil. The crude material was taken up in dichloromethane, applied to a 5-kg column of silica gel prepacked in 50% ethyl acetate/hexane, and eluted sequentially with 8 L of 50%, 16 L of 75%, then 100% ethyl acetate/hexane to provide the title compound as a yellow oil which crystallized upon standing. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine; In dichloromethane; at 20℃; for 12h; | To a solution of pyrrolidin-3-ol (10.45 g, 120.1 mmol) in dichloromethane (300 mL) was added benzyl chloroformate (24.6 g, 144 mmol) and triethylamine (24.3 g, 240.2 mmol). The resulting solution was stirred at room temperature for 12 hours. After concentrating the reaction, the remaining material was partitioned between ethyl acetate (100 mL) and water (60 mL). The layers were separated. The organic layer was washed with water (60 mL), aqueous saturated sodium chloride solution (60 mL), dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to give benzyl 3-hydroxypyrrolidinyl-1-carboxylate (15.2 g, 57%) as a colorless gum. LCMS m/z = 222.1 [M+H]+. |
49% | In dichloromethane; for 20h; | Prbetaparatlon 16; S-Hydroxy-pyrrolldlne-i-carboxyllc acid benzyl ester; 3-Pyrrolidi?ol (6.99g, 68.9 mmol), benzyl chloroformata (10.66 mL, 75.8 mmol) and CH2CI2 (200 mL) were stirred for 2Oh then washed with water and brine, dried (MgSO4) and concentrated to give a thick yellow oil. Chromatography, flushing first with 20% EtOAc/ hexa?es then eluting with 30% MeOH/EtOAc, afforded 7.4Og (49%) of the title compound: NMR (CDCI3) delta 7.35-7.26 (m, 5H), 5.11 (s, 2H), 4.46 (br s, 1H), 3.60-3.38 (m, 4H)1 2.00-2.82 (m, 2H). |
8.87 g (81%) | In potassium hydroxide; | A. A solution of 4.29 g (48.9 mmol) of 3-hydroxypyrrolidine in 30 mL of 2N potassium hydroxide was cooled to 0 C. and 10.2 mL of benzyl chloroformate were added with stirring. The reaction was stirred for four hours at 0 C. and then extracted with ethyl acetate (3*100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacua. The residue was chromatographed on silica gel with 70/30 hexanes/ethyl acetate. The correct fractions were combined and concentrated in vacuo to give 8.87 g (81%) of benzyl 3-hydroxypyrrolidine-1-carboxylate as a viscous clear oil. Rf=0.11 in 50/50 hexanes/ethyl acetate Mass Spectrum (FD+): M+221; IR (CHCl3, cm-1): 913, 977, 993, 1100, 1117, 1175, 1236, 1360, 1427, 1454, 1498, 1694, 2884, 2954, 3013, 3020, 3436 (broad), 3610; UV (C2 H5 OH) lambdamax =205 (epsilon=9112), 264 (epsilon=142); 1 H NMR (300 MHz, CDC13) delta: 1.91-2.05 (m-, 2H); 3.00 (broad s, 1H); 3.39-3.61 (m, 4H); 4.41 (s, 1H); 5.12 (s, 2H); 7.30-7.43 (m, 5H). |
8.87 g (81%) | In potassium hydroxide; | A. A solution of 4.29 g (48.9 mmol) of 3-hydroxypyrrolidine in 30 mL of 2N potassium hydroxide was cooled to 0C and 10.2 mL of benzyl chloroformate were added with stirring. The reaction was stirred for four hours at 0C and then extracted with ethyl acetate (3 x 100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel with 70/30 hexanes/ethyl acetate. The correct fractions were combined and concentrated in vacinoto give 8.87 g (81%) of benzyl 3-hydroxypyrrolidine-1-carboxylate as a viscous clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 20℃; for 16.0h; | 5.8 g (66.5 mMol) 3-Pyrrolidinol und 6.7 g (67 mMol) Triethylamin werden in 80 ml Methylenchlorid gelst und tropfenweise mit einer Lsung von 15.3 g (70 mMol) Di-tert.Butyl-dicarbonat in 40 ml Methylenchlorid versetzt. Nach 16 Stunden bei Raumtemperatur wird mit Wasser verrhrt, die organische Phase wird getrocknet und eingedampft. Ausbeute: 12.4 g (100 % der Theorie), Rf-Wert: 0.75 (Kieselgel; Essigester/Methanol = 9:1) |
100% | In isopropyl alcohol; at 20℃; for 2.0h; | Compound 208a: 3-Hydroxy-pyrrolidine-i-carboxylic acid tert-butyl ester: A solution of 3-hydroxypyrrolidine (1.5 g, 17.2 mmol, 1.0 eq) and BOC anhydride (3.76 g, 17.2 mmol, 1.0 eq) in IPA (20 ml) was stirred at room temperature for 2 hours and the solvent removed to give the title compound as a tan solid (3.73 g, 17.2 mmol, 100 % corrected). 1H NMR shows product in ca. 90% purity. |
99% | With potassium carbonate; In tetrahydrofuran; water; | Example 12; 2-(3-Benzvloxvpvrrolidin-l-yl)-3-methvl-6-pvridin-4-yl-3H- pvrimidin-4'one (Compound No. D2); l-(tert-Butoxvcarbonvl)-3-hvdroxvpyrrolidine; A solution of di-tert-butyl dicarbonate (14.17 g, 64.9 mmol) in tetrahydrofuran (10 ml) and 10% aqueous potassium carbonate (30 ml) was added to a solution of 3-hydroxypyrrolidine (5.38 g, 61.8 mmol) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate = 1/3) to afford l-(tert-butoxycarbonyl)-3-hydroxypyrrolidine (11.43 g, 99%). |
98% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 3.5h; | Pyrrolidin-3-ol (1.09 g, 12.5 mmol) was dissolved in dichloromethane (20 mL), cooled to 00C in an ice bath. Triethylamine (1.93 mL, 13.8 mmol), di-fert-butyl dicarbonate (3.06 g, 13.8 mmol) and dimethylaminopyridine (153 mg, 1.25 mmol) were added. The reaction mixture was allowed to warm up to room temperature while stirring. Progress of the reaction was monitored by TLC (silica gel, hexane: EtOAc (1:1, v/v) stained by nihydrin and upon completion (approximately 3.5 hours) 1 M NaOH aqueous solution (10 mL) was added. The mixture was stirred vigorously for 5-10 minutes and the organic layer was separated, washed with saturated sodium bicarbonate (twice), saturated ammonium chloride and brine, dried over MgSO4, concentrated. Product was purified from the residue by flash column chromatography (50% hexanes / ethyl acetate) to give fert-3-hydroxy-pyrrolidine- 1 -carboxylate (2.3 g, 98%) as a white solid. |
98% | A 3 L, four-necked, round-bottomed flask, was equipped with a mechanical stirrer, 1 L addition funnel, K-type thermocouple, cooling bath and nitrogen inlet. A stirred solution of DL-pyrrolidinol (140.0 g, 1.61 mol), triethylamine (228 g, 314 mL, 2.25 mol), and MeOH (1500 mL) was aged under nitrogen at 15-20 C. in a cold water bath for 20 minutes. Neat di-t-butyl dicarbonate (528.0 g, 2.42 mol) was added drop-wise, adding ice to the cooling bath to maintain an internal temperature below 30 C. After the addition was complete, the batch was stirred at 15-25 C. overnight. The mixture was concentrated under reduced pressure to a residue, which was purified by passage through silica gel (230-400 mesh, 1000 g) packed with 50% by volume ethyl acetate-hexane (2000 mL). The product was eluted with ethyl acetate (8000 mL), taking 250 mL fractions. Pure fractions were pooled and concentrated in vacuo to give the title compound as an off white solid (294 g, 98% yield). | |
97% | With triethylamine; In dichloromethane; at 0 - 20℃; for 16.0h; | PREPARATION 60 < 3- [5-Chloro-2- (3-oxopropyl)-phenoxy]-pyrrolidine-l-carboxylic acid ter-t butyl ester Slowly add di-tert-butyl dicarbonate (5.5 g 25.29 mmol) to a solution of 3- hydroxypyrrolidine (2 g, 23 mmol) and triethylamine (6.45 mL, 45.98 mmol) in 30 mL of anhydrous dichloromethane under nitrogen at 0 C. Stirr the reaction mixture at ambient temperature for 16 h. After dilution with CH2C12, wash the organics with dilute acetic acid, saturated NaHCO3 and water. Dry over MgS04, filter and concentrate to afford the carbamate as an orange solid (4. 18 g, 97%). |
97% | With triethylamine; In dichloromethane; at 5 - 20℃; | Ste 1: tert- Butyl 3-hydroxypyrrolidine-l-carboxylateTo a solution of 3-pyrrolidinol (1.82 g, 20.87 mmol) and triethylamine (6.4 mL, 45.92 mmol) in dichloromethane (104 mL) was added di-tert-butyldicarbonate (5.01 g, 22.96 mmol) in portions at 5 C. After stirring at room temperature for 16 h the reaction mixture was washed with HCI 0.1N, saturated NaHC03 solution and brine then dried over Na2S04. The combined organic layers were concentrated under reduced pressure to give the title compound (3.78 g, 97%) as a dark orange oil.*H NMR (DMSO-c/6, 300 MHz) : delta (ppm) : 4.95-4.84 (m, 1H), 4.30-4.13 (m, 1H), 3.35-3.01 (m, 4H), 1.92-1.64 (m, 2H), 1.39 (s, 9H). |
95% | With triethylamine; In dichloromethane; at 0 - 20℃; for 16.5h; | To 3- hydroxypyrrolidine (10.0 g, 114.8 mmol)and triethylamine (12.8 g, 17.6 mL) in methylene chloride (225 mL)at 0 0C was added dropwise over 30 min di-tert-butyldicarbonate (25.3 g, 115.9 mmol). The mixture was warmed to rt and stirred for 16 h. The organic material was then washed with saturated ammonium chloride, dried via passage through a cotton plug, and concentrated. The residue was chromatographed through silic gel eluting with ca. 1 :1 hexanes/ethyl acetate to provide the title compound in the amount of 20.4 g (95%). 1 H NMR (500 MHz, CDCI3) 1.42 (s, 9H), 1.80-1.98 (m, 2H), 2.20-2.27 (d, J = 2.3 Hz, 1 H), 3.27-3.30 (m, 1 H); 3.32-3.50 (m, 3H), 4.39-4.43 (m, 1 H). |
95% | With dmap; triethylamine; In dichloromethane; at 20℃; for 5.0h; | A mixture of 3-hydroKypyrrolidine (2.0 g, 23 mmol), triethylamine (3.8 mL, 28 mmoL), di-tert-butyl dicarbonate (5.2 g, 24 mmol) and N, N-dimethylaminopyridine (140 mg, 1.1 mmol) in CH2C12 (180 mL) was stirred at ambient temperature. After 5 h, the reaction mixture was diluted with H2O (50 mL) . The aqueous layer was separated and extracted with CH2C12 (25 mL). The combined organic .layers were washed with saturated NaCl (40 mL), dried (Na2S04) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 90: 10 CH2Cl2/MeOH) gave ter(at)-butyl 3-hydroxypyrrolidine-1- carboxylate (4.1 g, 95%): ¹H NMR (300 MHz, CDC13) 81.46 (9H, s), 1.92-2.04 (2H, s), 2.11-2.17 (lH, s), 3.30-3.49 (4H, s), 4.44- 4.45 (1H, m).To an ice-cold solution of tert-butyl 3- ... hy(at)(at),(at)(at)r(at)p(at)(at)(at),(at),1(at)(at)li(at),e,(at)tlv'- (at)(at)arboxylate (1. 0 g, 5.5 mmol), N- hydroxyphthalimide (0.90 g, 5.5 mmol) and triphenylphosphine (1.4 g, 5.5 mmol) in THF (30 mL) was added a solution of diethyl azodicarboxylate (0.96 mL, 6.1 mmol) in THF (5 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 3 days, most of the THF was removed under reduced pressure. The residue was partitioned between CH2C12 (40 mL) and H20 (30 mL) . The organic layer was separated and washed with saturated NaCl (20 mL), dried (Na2S04) and concentrated under reduceci pressure. Purification by column chromatography (silica gel, 75: 25 hexanes/EtOAc to 50:50 hexanes/EtOAc) gave tert-butyl 3-[(1,3-dioxo-1,3-dihydro-2H- isoindol-2-yl) oxy] pyrrolidine-1-carboxylate (0.96 g, 52%): ¹H NMR (300 MHz, CDC13) 81.49 (9H, s), 1.97-2.20 (1H, s), 2.25- 2.31 (1H, m), 3.53-3.78 (4H, m), 4.95-5.00 (lH, m), 7.75-7.87 (4H, m) .To an ice-cold solution of tert-butyl 3-[(1,3-dioxo-1,3- dihydro-2 H-isoindol-2-y1)oxy]pyrrolidine-1-carboxylate (0.96 g, 2.8 mmol) in CH2C12 (16 mL) and MeOH (4 mL) was added methylhydrazine (0.70 mL, 13 mmol) dropwise. The stirred reaction mixture was allowed to slowly warm to ambient temperature. After 2 h, the reaction mixture was concentrated under reduced pressure. To the residue was added CH2C12 (20 mL) and with the aid of sonication a solid formed and was collected by vacuum filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 75:25 hexanes/EtOAc to 25: 75 hex<anes/EtOAc) to afford tert-butyl 3- (aminooxy)pyrrolidine-1-ca rboxylate (440 mg, 76%) : ¹H NMR (500 MHz, CDC13) 8 1.46 (9H, s), 1.82-1.98 (lH, m), 2.04-2.10 (lH, m), 3.31-3.65 (4H, m), 4.24-4.27 (lH, m), 5.37. |
93% | With triethylamine; In dichloromethane; at 25℃; for 16.0h; | [00685] To a solution of 227-lb (0.7 g, 8.0 mmol, 0.6 uL, 1.0 eq) in DCM (10.0 mL) were added TEA (1.2 g, 12.0 mmol, 1.6 mL, 1.5 eq) and Boc20 (2.1 g, 9.6 mmol, 2.2 mL, 1.2 eq). The mixture was stirred at 25 C for 16 h. TLC (Petroleum ether : ethyl acetate = 3 : 1) indicated 227-lb was consumed completely and many new spots formed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by column chromatography (Si02) to give 227-la (1.4 g, 7.5 mmol, 93% yield). |
90% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 48.0h; | 3-Pyrrolidinol (4.66 g, 53 mmol) was dissolved in 90 mL of DCM. Dimethylaminopyridine (0.65 g, 5.3 mmol)and TEA (8.1 mL, 58.3 mmol) were added thereto. The reaction solution was cooled to 0C, and di-tert-butyl dicarbonate(12.84 g, 58.8 mmol) was added thereto. The mixture was stirred at room temperature for 48 hours. 1 M NaOH aqueoussolution (53 mL, 53 mmol) was added thereto, and the mixture was stirred for 10 minutes. After addition of water, thereaction solution was extracted with DCM and dried with MgSO4. The organic layer was purified by column chromatographyto obtain the title compound (8.98 g, 90 %).1H-NMR (CDCl3) delta 4.45 (1H, m), 3.46 (3H, m), 3.33 (1H, m), 1.97 (2H, m), 1.42 (9H, s) |
89% | With sodium hydrogencarbonate; In 1,4-dioxane; water; | A. rac-tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate To a solution of 3-pyrrolidinol (3.144 g, 3.00 mL, 36.09 mmol) in 1,4-dioxane (50 mL) and water (50 mL) was added di-tert-butyl dicarbonate (8.664 g, 39.70 mmol) and sodium bicarbonate (10.612 g, 126.3 mmol). The mixture was stirred at room temperature for 18 h to afford a white suspension in a yellow solution. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (2*50 mL). The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate as a pale yellow oil (6.039 g, 89%). 1H NMR (DMSO-d6, 400 MHz) delta 1.51 (s, 9H), 1.84-2.05 (m, 2H), 2.28 (d, 1H), 3.33-3.48 (m, 4H), 4.43 (s, 1H). |
89% | With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 18.0h; | [1225] To a solution of 3-pyrrolidinol (3.144 g, 3.00 mL, 36.09 mmol) in 1,4-dioxane (50 mL) and water (50 mL) was added di-tert-butyl dicarbonate (8.664 g, 39.70 mmol) and sodium bicarbonate (10.612 g, 126.3 mmol). The mixture was stirred at room temperature for 18 h to afford a white suspension in a yellow solution. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate as a pale yellow oil (6.039 g, 89%). 1H NMR (DMSO-d6, 400 MHz) delta 1.51 (s, 9H), 1.84-2.05 (m, 2H), 2.28 (d, 1H), 3.33-3.48 (m, 4H), 4.43 (s, 1H). |
86% | In dichloromethane; | (a) Synthesis of tert-butyl 3-hydroxypyrrolidine-1-carboxylate A solution of di-tert-butyl carbonate (13.8 g, 63.1 mmol) in dichloromethane was added to a solution of 3-pyrrolidinol (5 g, 57.4 mmol) in dichloromethane (50 mL), and the resulting mixture was allowed to stand overnight. After the solvent was distilled off under reduced pressure, the residue was purified by a silica gel chromatography to obtain tert-butyl 3-hydroxypyrrolidine-1-carboxylate (9.23 g, 86%). |
85.6% | With N-ethyl-N,N-diisopropylamine; In 1,3-dioxane; water; at 0 - 20℃; for 5.0h; | To 831 muL (10 mmol) of 3-hydroxypyrrolidine were added 50 mL of a solution containing 25 mL of H2O and 25 mL of dioxane, 2.62 gm (12 mmol) of di-t-butyl dicarbonate, and 2.1 mL (12 mmol) of DIEA at ice-bath temperature. The reaction mixture was slowly warmed to room temperature and allowed to stir at room temperature for 5 h. After 5 h, solvents were removed in vacuo. To the residue were added 100 mL of H2O and 100 mL of ethyl acetate. After removing the aqueous layer, the organic layer was washed with H2O (2 x 50 mL) and concentrated under reduced pressure. The crude product was purified by flash chromatography (2 : 1, hexane : ethyl acetate) to obtain 1.6 gm (85.6 %) of a clear oil: 1H NMR (300 MHz, CD3OD) delta 4.35 (1H, m), 3.41 - 3.25 (4H, m), 1.95 (2H, m), 1.46 (9H, s). |
80% | With triethylamine; In tetrahydrofuran; at 20℃; | To a solution of 3-hydroxypyrrolidine (8.71 g, 100 mmol) in tetrahydrofuran (200 mL) were added at room temperatureDi-tert-butyl dicarbonate (21.6 g, 100 mmol) and triethylamine (20.2 g, 200 mmol) were added and the reaction was continued with stirring overnight. After the reaction was concentrated, ethyl acetate was added, washed with water and saturated brine and dried. The resulting residue was concentrated by column chromatography (petroleum ether: ethyl acetate = 4: 1) to give the title compound (15 g, 80% ). |
79% | With triethylamine; In dichloromethane; at 0 - 20℃; | 3-pyrrolidinol (10 g, 0.12 mole) in 75 ml anhydrous methylene chloride and triethylamine (24.24 g, 0.24 mole) were combined under nitrogen. Cool with an ice bath & add dropwise diterbutyldicarbonate (31.39 g 0.144 mole) in 40 mL anhydrous methylene chloride keeping temperature below +15 C. Stir at room temperature over the weekend. Add ice and acidify with a saturated citric acid solution. Extraction with methylene chloride gave 22.69 g of crude product as an oil. Flash chromatography over silica gel with 20% to 75% ethyl acetate in hexane provided the purified title compound (17.7 g, 79%) as an oil. Mass Spec ESI+, M+1=188.4 (MW=187.237) 1H NMR (300 MHz CDCl3) delta 1.46 (9H, s); 1.56 (2H, s); 1.924 to 2.006 (2H, m); 3.367 to 3.505 (3H, m); 4.449 to 4.465 (1H, m). |
79% | With triethylamine; In tetrahydrofuran; at 20℃; for 2.0h; | a) (/?S)-terf-Butyl 3-hydroxypyrrolidine-1-carbox lateTo a solution of (RS)-3-hydroxypyrrolidine (1.00 g, 11.5 mmol, 1.0 eq) in THF (20 mL) was added Et3N (1.91 mL, 13.8 mmol, 1.2 eq) followed by a solution of di-ferf-butyl dicarbonate (3.30 mL, 14.9 mmol, 1.3 eq) in THF (10 mL) at 0C, and the mixture was allowed to stir at RT for 2 h. The mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous citric acid (30 mL). The organic layer was dried (Na2S0 ) and concentrated under reduced pressure and purification by silica gel chromatography (10% MeOH/CHCI3) gave a gum (1.7 g, 79%); 1H NMR (400 MHz, CDCI3) delta ppm 4.53 (s, 1 H), 3.47-3.33 (m, 4H), 2.01- 1.92 (m, 3H), 1.46 (s, 9H); m/z (APCI)+: 132 [M-'Butyl]+. |
With triethylamine; In tetrahydrofuran; water; at 20℃; for 3.0h; | The 1-tert-butoxycarbonyl-3-hydroxypyrrolidine can be prepared in the following way: A solution of 2.78 cm3 of triethylamine and 3.27 g of di-tert-butyl dicarbonate is added to 0.848 cm3 of 3-hydroxypyrrolidine in a mixture of 30 cm3 of tetrahydrofuran and 9.6 cm3 of water. The reaction medium is stirred at a temperature in the region of 20 C. for 3 h, and is then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up with water and ethyl acetate. The solution is stirred for 5 min, and is then separated by settling out. The aqueous phase is extracted three times with ethyl acetate. The organic phases are pooled, dried over magnesium sulfate, filtered through an Iena filter and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1.823 g of 1-tert-butoxycarbonyl-3-hydroxypyrrolidine in the form of colorless crystals. m/z 188 (MH+), m/z 132 [MH+-tBu]. | |
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 18.0h; | 3-Hydroxy-pyrrolidine-l-carboxylic acid ter-butyl ester; Di-tert-butyl-dicarbonate (764 g, 350 mmol) as a solution in 1,4-dioxane (100 ml) is added to 3-hydroxy-pyrrolidine 1 (23.43 g, 269 mmol) in a mixture of water/1, 4-dioxane (350 ml, 1: 1 v/v) and sodium hydrogen carbonate (68 g, 807 mmol) and the mixture stirred at room temperature for 18 hours. After which the organic layer is separated, dried (using MgS04), filtered and evaporated to give the title compound as a thick colourless oil. | |
31.9 g (91%) | In tetrahydrofuran; | (i) 3-Hydroxy-pyrrolidine-1-carboxylic Acid Tert-Butyl Ester A solution of <strong>[40499-83-0]pyrrolidin-3-ol</strong> (16.25 g, 186.5 mmol) and di-tert-butyl-dicarbonate (40.7 g, 186.5 mmol) in dry THF (50 ml) under nitrogen was stirred over night. Concentration at reduced pressure and purification by flash chromatography on silica (EtOAc:heptane, 7:3) gave 31.9 g (91%) of the subtitle compound. 1H-NMR (400 MHz, DMSO-d6): delta 4.87 (d, 1H, J 3.4 Hz), 4.21 (bs, 1H), 3.31-3.22 (m, 3H), 3.10 (d, 1H, J=11.5 Hz), 1.83 (m, 1H), 1.72 (m, 1H), 1.39 (s, 9H). APCI-MS: m/z 132 [MH+-56] |
1.6 gm (85.6%) | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water; ethyl acetate; | Step (a) 1-t-Butoxycarbonyl-3-hydroxypyrrolidine To 831 muL (10 mmol) of 3-hydroxypyrrolidine were added 50 mL of a solution containing 25 mL of H2O and 25 mL of dioxane, 2.62 gm (12 mmol) of di-t-butyl dicarbonate, and 2.1 mL (12 mmol) of DIEA at ice-bath temperature. The reaction mixture was slowly warmed to room temperature and allowed to stir at room temperature for 5 h. After 5 h, solvents were removed in vacuo. To the residue were added 100 mL of H2O and 100 mL of ethyl acetate. After removing the aqueous layer, the organic layer was washed with H2O (2*50 mL) and concentrated under reduced pressure. The crude product was purified by flash chromatography (2:1, hexane:ethyl acetate) to obtain 1.6 gm (85.6%) of a clear oil: 1H NMR (300 MHz, CD3OD) delta 4.35 (1H, m), 3.41-3.25 (4H, m), 1.95 (2H, m), 1.46 (9H, s). |
With potassium carbonate; In tetrahydrofuran; tetrahydrofuran-water; hexane; ethyl acetate; | EXAMPLE 1 Preparation of t-Butyl 3-Hydroxy-1-pyrrolidine-carboxylate A stirred solution of 3-pyrrolidinol (5.0 g 57 mmol) and potassium carbonate (8.23 g, 60 mmol) in a mixture of THF/H2O is treated with a solution of di-t-butyl dicarbonate (12.5 g, 57 mmol) in THF over a 15 minute period at room temperature, stirred for 20 h at room temperature and diluted with EtOAc. The organic phase is separated, washed with H2O, dried over Na2SO4 and concentrated in vacuo. The resultant residue is dissolved in EtOAc/hexane and filtered through a thin layer of silica gel. The silica gel layer is washed with EtOAc. The combined filtrates are concentrated in vacuo to give the title product as a white solid, 8.5 g, mp 52-54 C., identified by NMR and mass spectral analyses. | |
In tetrahydrofuran (150 ml)-ethanol; | 1) Synthesis of tert-butyl 3-oxopyrrolidine-1-carboxylate To a solution of 25.63 g (0.2942 M) of 3-pyrrolidinol in tetrahydrofuran (150 ml)-ethanol (50 ml) was added 70.6 g (0.324 M) of di-tert-butyl dicarbonate dropwise at room temperature and the mixture was stirred at room temperature for 1 hour. The solvent was then distilled off under reduced pressure to provide crude t-butyl 3-hydroxypyrrolidine-1-carboxylate. | |
With triethylamine; In dichloromethane; acetonitrile; for 16.0h; | To a mixture of 3-hydroxypyrrolidine (11.17 mmol, 134.3 mmol) and triethylamine (23.4 mL) in dichloromethane/acetonitrile (150 mL, 4:1) was added di-tert-butyl dicarbonate (1.1 eq., 32.24 g). The mixture was stirred for 16 hours, partitioned between ethyl acetate and 1 N HCl, and the aqueous layer was extracted with ethyl acetate (2*25 mL). The combined organic extracts were washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The material was used in the next step without purification. MS (CI) m/z 205 [M+NH4]+. | |
With triethylamine; In dichloromethane; acetonitrile; for 16.0h; | Example 70A 3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester To a mixture of 3-hydroxypyrrolidine (11.17 mmol, 134.3 mmol) and triethylamine (23.4 mL) in dichloromethane/acetonitrile (150 mL, 4:1) was added di-tert-butyl dicarbonate (1.1 eq., 32.24 g). The mixture was stirred for 16 hours, partitioned between ethyl acetate and 1 N HCl, and the aqueous layer was extracted with ethyl acetate (2*25 mL). The combined organic extracts were washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The material was used in the next step without purification. MS (CI) m/z 205 [M+NH4]+. | |
In tetrahydrofuran; at 20 - 30℃; for 3.0h; | The mixture was cooled to 20 to 30 C, and a mixed solution of di-t-butyl dicarbonate and tetrahydrofuran was added dropwise to the flask at a rate of 5 ml / min. After completion of the dropwise addition, the reaction was carried out for 3 hours, followed by extraction with chloroform three times. The obtained organic layers were dried over anhydrous magnesium sulfate and then evaporated to dryness. After drying the chloroform, adding petroleum ether, freezing crystallization, and filtering to obtain 1-BOC-3-hydroxypyrrolidine. | |
10.4 g (98%) | In dichloromethane; | 1) 1-(t-butoxycarbonyl)-3-hydroxypyrrolidine Scale: 5.0 g, 57.0 mmol A solution of 3-hydroxypyrrolidine (5.0 g, 57.0 mmol) in CH2Cl2 (125 ml) was added to an ice-cold solution of di-t-butyl dicarbonate (13.15 g, 60 mmol) in CH2Cl2 (125 ml). After stirring overnight the solvents were evaporated and the residue purified by column chromatograph, on silica, eluding with CH2Cl2, then Et2O, then EtOAc, givina the product as a white solid. Yield 10.4 g (98%). Rf=0.23 (Et2O) 1H-NMR (250 MHz, CDCl3): delta=1.42 (s, 9H), 2.0 (m, 3H), 3.4 (m, 3H), 4.4 (m, 1H). MS (CI+): m/e 188 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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97% | With sodium hydrogencarbonate; In 1,4-dioxane; water; at 87℃; for 10.0h;Heating / reflux; | [0140] 2 g of 1-fluoro-4-nitrobenzene (0.0155 mol), 1.3 g of sodium hydrogen carbonate (0.0155 mol) and 15 ml of a dioxane/water mixture (8/2) were placed in a three-necked flask. 1.35 g of 3-pyrrolidinol (0.0155 mol) was rapidly added to this mixture. The heterogeneous mixture was heated at reflux (87 C.) for 10 hours. The reaction mixture was then poured into ice-water; a yellow precipitate was obtained, which was filtered off and rinsed with water. After drying under vacuum in the presence of P2O5, 2.95 g of a yellow solid are obtained (97% yield). [0141] 1H NMR (DMSO-d6, 200 MHz, ppm) in accordance with the expected product: 8.04 (d, J=9 Hz, 2H); 6.58 (d, J=9 Hz, 2H); 5.06 (d, J=3.6 Hz, 1H); 4.41 (m, 1H); 3.45 (m, 3H); 3.20 (m, 1H); 2.04 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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18.6% | EXAMPLE 614-lsopropyl-lambda/-{2-methyl-6-r(1-propylpyrrolidin-3-yl)oxylpyridin-3- vDbenzenesulfonamide (2E)-but-2-enedioate61.1 2-Methyl-3-nitro-6-(pyrrolidin-3-yloxy)pyridine6-Methyl-5-nitropyridin-2-ol (5 g) was dissolved in tetrahydrofuran and DL-3- pyrrolidinol (2.83 g) and triphenylphosphine (12.76 g) were added. Di-tert-butyl (E)-diazene-1 ,2-dicarboxylate (11.21 g) dissolved in tetrahydrofuran (15 ml_) was added dropwise over 15 min. The reaction mixture was stirred at room temperature for 50 h. The reaction mixture was concentrated in vacuo. The remaining residue was suspended in dichloromethane and trifluoroacetic acid (7.55 ml_) was added dropwise. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated in vacuo, redissolved in dichloromethane and extracted several times with 1 N hydrochloric acid. The combined aqueous extracts were treated with 1 N NaOH to pH 10 and extracted with ethyl acetate (3x). The combined ethyl acetate extracts were successively washed with water and brine and dried (sodium sulfate). After concentration in vacuo, the crude product was purified by flash chromatography (silica, dichloromethane, 1-10% methanol gradient). Yield: 1.5 g (18.6%, pale yellow oil). |
Yield | Reaction Conditions | Operation in experiment |
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99% | With triethylamine; In isopropyl alcohol; at 70℃; for 0.5h;Microwave irradiation; | Step 1 A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (5.00 g, 14.7 mmol), <strong>[40499-83-0]pyrrolidin-3-ol</strong> (2.55 g, 29.3 mmol), and triethylamine (4.09 mL, 29.3 mmol) in 2-propanol (32 mL) was heated in the microwave for 30 minutes at 70 C. in two vials. The reaction mixtures were combined and concentrated. The crude product was purified by flash chromatography using a Horizon purification system in three batches (2*40M and 1*40S columns) eluding with chloroform/methanol (0.1-8%). The resulting solid was dissolved in chloroform containing 0.1% methanol (810 mL) and washed with water and 1:1 water:brine, dried (MgSO4), filtered and concentrated to afford 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]<strong>[40499-83-0]pyrrolidin-3-ol</strong> (5.08 g, 99%). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.93-1.99 (m, 1H) 2.02-2.07 (m, 1H) 3.49-3.57 (m, 1H) 3.61-3.73 (m, 3H) 4.39-4.50 (m, 1H) 5.04-5.15 (m, 1H) 5.90 (s, 2H) 7.53 (dd, J=8.34, 4.29 Hz, 1H) 7.76 (dd, J=8.72, 1.89 Hz, 1H) 7.93 (s, 1H) 8.00 (d, J=8.59 Hz, 1H) 8.22 (s, 1H) 8.36 (d, J=8.34 Hz, 1H) 8.89 (dd, J=4.17, 1.64 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In acetonitrile; at 120℃; for 0.5h;Microwave; | mixture of (3i?)-3-pyrrolidinol (620 mg), <strong>[607380-28-9]2,6-dichloro-5-aminoquinoline</strong> (WO2005009968) (500 mg) and triethylamine (0.66 mL) in acetonitrile (3 mL) was heated with stirring in a microwave at 1200C for 30 minutes. The products were concentrated in vacuo and purified by chromatography (SiO2, dichloromethane:methanol:7N NH3 in methanol 97:3:0.2 as eluant) to yield the sub-title compound as a solid (490 mg).1HNMR (300 MHz, d6-DMSO) delta 8.30 (IH, d), 7.26 (IH, d), 6.82-6.69 (2H, m), 5.78 (2H, s), 4.95 (IH, d), 4.44-4.36 (IH, m), 3.65-3.39 (4H, m), 2.10-1.97 (IH, m), 1.95-1.85 (IH, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 80℃; | Step 1 : A solution of C13 (9.87 g; 57.5 mmol) in 2-propanol (100 mL) was treated with DIIPEA (16 mL; 86.25 mmol) followed by 3-pyrrolidinol (5.26 g; 60.38mmol). The reaction mixture was stirred at 8O0C overnight. The reaction mixture was concentrated and the resultant slurry mixture was treated with ethyl acetate (40 mL). The resultant precipitate was collected by filtration, rinsed with ethyl acetate (2 x 75 mL) and dried to provide 1-(5-methyl- <n="99"/>7H-pyrrolo[2,3-d]pyrimidin-4-yl)<strong>[40499-83-0]pyrrolidin-3-ol</strong> (C55). Yield: 10.58 g, 84 %. LRMS (M+): 219.1; tR (LCMS polar): 0.5 min. |
Yield | Reaction Conditions | Operation in experiment |
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95% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 12h; | [0167] In a three necked flask, 38.78 g of 5-fluoro-2-nitrotoluene (0.25 mol), 41.4 g of potassium carbonate (0.3 mol) and 200 ml of N-methylpyrrolidinone were mixed. 26.13 g of 3-pyrrolidinol (0.3 mol) were added to this mixture. The heterogeneous mixture was agitated at ambient temperature for 12 hours. The reacting mixture was then poured on ice water. A yellow powder was then obtained. The powder was then filtered off and rinsed with water. After drying under vacuum with P2O5, 55.56 g of a yellow solid were obtained (yield) (95%). [0168] RMN 1H (400 MHz-DMSO) ppm 8.01 (d, 1H); 6.50-6.46 (m, 2H); 5.04(m,1H); 4.42 (m, 1H) 3.50-3.42 (m, 3H); 3.24-3.21 (m, 1H); 2.56 (s, 3H); 2.15-1.90 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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94% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 3.0h; | 2,2-Diphenyl-benzo [1, 3] [DIOXOLE-5-CARBOXYLIC] acid benzotriazol-1-yl ester (87 mg, 0.2 mmol), the appropriate amine [(22] mg, 0.25 mmol) and ethyldiisopropylamine (32 mg, 0.25 mmol) were dissolved in acetonitrile (2 ml) and stirred at room temperature for 3 hours. Water (20 ml) was added and the reaction was stirred at room temperature for 1 hour. The precipitate was filtered off, washed with water and dried in high vacuum to yield the product as a crystalline white solid.From 2,2-diphenyl-benzo [1, 3] dioxole-5-carboxylic [ACIDBENZOTRIAZOL-1-YL] ester (87 mg, 0.2 mmol) and 3-pyrrolidinol (22 mg, 0.25 mmol), the title compound was obtained as a white crystalline solid (73 mg, 94 %). m. p.: [106-107C.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Combine l-chloro-2-methoxy-4-nitro-benzene (10 g, 53.3 mmol) and (3R)-3- pyrrolidinol (9.3 g, 106.6 mmolj. Heat the mixture to 100 C overnight. Cool the mixture and dissolve in CH2Cl2 (200 mL) and wash with IN NaOH (100 mL). Wash the extract with brine (3 x 50 mL). Dry the organic layer with Na2SO4, filter, and concentrate to give the intermediate pyrrolidinol as a crude dark reddish wet solid (12.17 g, 95%). MS (ES+) 239.1 (M+l)+.Dissolve the crude (R)-l-(2-methoxy-4-nitro-phenyl)-pyrrolidin-3-ol (10.9 g, 45.5 mmol) in dry pyridine (50 mL) and chill to 0 C. Add chloro-triisopropyl-silane (19.8 mL, 91 mmol) dropwise and then heat to 80 C overnight. Remove the pyridine via reduced pressure and then wash the crude material with NaHSO3 solution and extract with EtOAc (3 x 100 mL). Combine the organic solutions, then dry and concentrate to give the crude product. Purify over a silica plug with hexanes (300 mL) and flush with 10% EtOAc in hexanes (800 mL) to give the title compound as a reddish oil (17.85 g, 99%). MS (ES+) 395.2 (M+l)+. 1H NMR (400 MHz, CDCl3): delta 7.81 (dd, J= 8.8, 2.2 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 6.45 (d, J = 88 Hz, 1H), 4.57-4.52 (m, 1H), 3.84 (s, EPO <DP n="57"/>3H), 3.84-3.78 (m, 1H), 3.72-3.64 (m, 1H), 3.61-6.53 (m, 1H), 3.45 (dd, J = 11.0, 2.2 Hz, 1H), 2.06-1.92 (m, 2H), 1.04-1.01 (m, 21H). | |
95% | at 100℃; | Preparation 66; (R)-l-(2-Methoxy-4-nitro-phenyl)-3-triisopropylsilanyloxy-pyrrolidine; Combine l-chloro-2-methoxy-4-nitro-benzene (10 g, 53.3 mmol) and (R)-3- pyrrolidinol (9.3 g, 106.6 mmol). Heat the mixture to 100 0C overnight. Cool the mixture and dissolve in CH2Cl2 (200 mL) and wash with 1 N NaOH (100 mL). Wash the extract with brine (3 x 50 mL). Dry the organic layer with Na2SO4, filter, and concentrate to give the intermediate pyrrolidinol as a crude dark reddish wet solid (12.17 g, 95%). MS (ES+) 239.1 (M+l)+. |
91% | A mixture of 1-chloro-2- (methyloxy)-4-nitrobenzene (9.35 g, 0.050 mol) and (3R)-3-pyrrolidinol (8.7 g, 0.100 mol) was warmed to 100 C overnight. The reaction mixture was allowed to come to ambient temperature, diluted with methylene chloride (200 mL) and sodium hydroxide (1 N, 200 mL), then extracted three times with brine, dried, filtered, and concentrated to give (3R)- 1- [2- (methyloxy)-4-nitrophenyl]-3-pyrrolidinol (10.8 g, 0.045 mol, 91%). 1H NMR (300 MHz, DMSO-d6) 6 7.80 (d, 1 H), 7.60 (s, 1 H), 6.60 (d, 1 H), 4.98 (m, 1 H), 4.35 (m, 1 H), 3.80 (s, 3H), 3.40-3. 80 (m, 4H), 1.95 (m, 2H). LCMS m/z 239 (M+H). |
37.2% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 130℃; for 3h;Sealed tube; | EXAMPLE 53 (R)-2-(4-Chlorophenyl)-5-(4-(3-hydroxypyrrolidin- 1 -yl)-3-methoxyphenyl)-4,5- dihydropyrrolo[3,4-c]pyrazol-6(2H)-one, TFA; Example 53 A. (i?)-l-(2-Methoxy-4-nitrophenyl)pyrrolidin-3-ol; [00254] A mixture of l-chloro-2-methoxy-4-nitrobenzene (500 mg, 2.67 mmol) and (i?)-pyrrolidin-3-ol (325 mg, 3.73 mmol), and DIEA (0.454 ml, 2.60 mmol) in acetonitrile (1 mL) was heated at 130 0C in a sealed tube for 3h. After cooling down to room temperature, the obtained crude product was further purified by ISCO automated chromatography (12 g, CH2Cl2/Me0H, 100:0 to 92:8 gradient) to give Example 52A (236 mg, 37.2 %) as an orange foam. LCMS (ES): m/z 239.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 90 - 100℃; | To 0.76 g (4 mmole) of 5- (2, 2-Dimethyl-propyl)-2-fluoro-benzonitrile in 15 mL of DMF was added 1.11 g (8 mmole, 2 eq. ) of potassium carbonate and 0.43 mL (5.2 mmole, 1.3 eq. ) of 3-pyrrolidinol and heated to 90-100 C overnight. The reaction was monitored by HPLC/MS, Rt = 1.349 min (method [2]), m/e = 259.2/281. 2. The reaction was allowed to cool to r. t. , and quenched with ice/water/DCM, extracted and washed with brine, dried, concentrated, and purified by flash column to give 0.82 g of 5-(2,2-Dimethyl-propyl)-2-(3-hydroxy-pyrrolidin-1- yl)-benzonitrile (80% yield). Structure was confirmed by NMR. TLC (30% EtOAc/Hexane). Rf = 0.16 where s. m. at Rf = 0.84. LCMS m/e=259.2 (M+H), Rt (retention time, minutes) =1.349 (method [2]). |
80% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60 - 100℃; | 5-(2,2-dimethyl-propyl)-2-(3-hydroxy-pyrrolidin-1-yl)-benzonitrile To 0.76 g (4 mmole) of 5-(2,2-dimethyl-propyl)-2-fluoro-benzonitrile in 15 mL of DMF was added 1.11 g (8 mmole, 2 eq. ) of potassium carbonate and 0.43 mL (5.2 mmole, 1.3 eq. ) of 3-pyrrolidinol and heated to 90-100 C overnight. The reaction was monitored by HPLC/MS, Rt = 1.349 min (method [2]), m/e = 259.2/281. 2. The reaction was allowed to cool to r. t. , and quenched with ice/water/DCM, extracted and washed with brine, dried, concentrated, and purified by flash column to give 0.82 g of 5-(2, 2-dimethyl-propyl)-2-(3-hydroxy-pyrrolidin-1-yl)-benzonitrile (80% yield). Structure was confirmed by NMR. TLC (30% EtOAc/Hexane). Rf = 0.16 where s. m. at Rf = 0.84. LCMS m/e=259. 2 (M+H), Rt (retention time, minutes) =1.349 (method [2]). |
80% | With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 100℃; | Step 1. Preparation of 5-(2,2-Dimethyl-propyl)-2-(3-hydroxy-pyrrolidin-1-yl)-benzonitrile To 0.76 g (4 mmol) of 2-fluoro-5-neopentylbenzonitrile in 15 mL of DMF was added 1.11 g (8 mmol, 2 eq.) of potassium carbonate and 0.43 mL (5.2 mmol, 1.3 eq.) of 3-pyrrolidinol and heated to 90-100 C. overnight. The reaction was monitored by HPLC/MS, Rt=1.349 min, m/e=259.2/281.2. The reaction was allowed to cool to room temperature and quenched with ice/water/DCM. It was then extracted and washed with brine, dried, stripped of solvent and purified by flash column to give 0.82 g of 5-(2,2-Dimethyl-propyl)-2-(3-hydroxy-pyrrolidin-1-yl)-benzonitrile (80% yield). TLC (30% EtOAc/Hexane). Rf=0.16 where s. m. at Rf=0.84. LCMS m/e=259.2(M+H), Rt (retention time, minutes)=1.349. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | With potassium carbonate;potassium iodide; In acetonitrile; at 20℃; for 72h; | 0.5 g (0.0057 mol) of (3R)-pyrrolidin-3-ol (commercially available) were dissolved in 15 ml of acetonitrile. To this solution were added 1.32 g (0.0065 mol) of (2- bromoethoxy) benzene, 0.095 g (0.00057 mol) of KI and 1.57 g (0.0114 mol) of K2C03. This mixture was stirred during 72 h at room temperature. The solid was filtered and the solvent was evaporated to dryness. CHCI3 was added to the residue and the solution obtained was washed with water and brine, dried over Na2SO4 and the solvent was evaporated to obtain 1.43 g of an oil. This product was purified by chromatography on silica gel eluting with chloroform/methanol/NH40H (90: 10: 1). The yield was 1.08 g of the title compound (91. 5 %). MS [M+1] + : 208 'H-NMR (CDCI3) : No. 1.80 (m, 1H), 2.20 (m, 1H), 2.40 (m, 1H), 2.65 (m, 1H), 2.75-3. 10 (m, 4H), 4.10 (t, 2H), 4.35 (m, 1H), 6.95 (m, 3H), 7.30 (m, 2H). (3R)-1-(2-phenoxyethyl)pyrrolidin-3-ol is described in WO 9625417 A1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 17h; | a) To a stirred solution of (RS)-3-pyrrolidinol (0.51 g, 5.85 mmol) in THF (12 ml) was added at 0 C. (ice water bath) commercially available <strong>[69812-29-9]2-acetamido-4-methylthiazole-5-sulfonyl chloride</strong> (1.0 g, 3.93 mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield (RS)-1-(2-acetamido-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (0.82 g, 68%) as a white solid. MS (ISP) 306.3 [(M+H)+]; mp 241 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With formic acid; In tetrahydrofuran; for 5h;Heating / reflux; | In a 100 ml flask, 2 g (R)-3-Hydroxy pyrrolidine, 25 ml THF, 0.49 g paraformaldehyde and 1.5 g formic acid (90%) were added. The mixture was stirred under reflux for 5 hours (until all solid disappeared), then cooled at 0 C. and added with 10 ml of NaOH solution (10 N) to adjust the pH to about 10. The organic layer was separated and dried over MgSO4. After filtering the dried solution and removing the solvent (THF), an oily product (1.5 g, 92%) of (R)3 was obtained. 1H NMR (CDCl3, 300 MHz): 1.50-1.60 (m, 1H), 1.98-2.10 (m, 1H), 2.25 (s, 3H), 2.25-2.40 (m, 2H), 2.50-2.60 (m, 1H), 2.61-2.70(m, 1H), 3.80(brs, 1H), 4.20-4.30(m, 1H). |
85.6% | 15 g (0.172 mol) of (3R)-pyrrolidin-3-ol (commercially available) were dissolved in 240 ml of MeOH. This solution was cooled to 10-15C, and formaldehyde (124.5 mi of a 36 % solution in water, diluted with 125 ml of MeOH) and NaBH4 (16.27 g, 0.43 mol) were added in small portions, alternativately during 1h, maintaining the temperature at 10-15C. After 20 min the mixture was warmed to room temperature and the reaction continued for 1 hour. The reaction mixture was acidified with HCI 2N, stirred during 20 minutes and neutralised with solid NaHCO3. MeOH and most of the water were evaporated and the residue was diluted with a small quantity of water, basified with solid K2C03 and exhaustively extracted with CHC13. The organic phases were combined and dried over Na2SO4. CHCl3 was evaporated to give an oil which was purified by Kugelrohr distillation at reduced pressure (0.2-0. 3 mbar, 50-60C oven) to give 14.91 g (85.6 %) of the title product. 'H-NMR (CDCI3) :. No. 1.60-1. 80 (m, 1H), 2.10-2. 40 (m, 5H), 2.40-2. 70 (m, 2H), 2.75-2. 95 (m, 1H), 4.20-4. 40 (m, 1H), 4.40-4. 50 (bs, 1H, OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | 1. Synthesis of 1-(6-methoxy-5-nitropyridin-2-yl)pyrrolidin-3-ol 2 g (0.0106 mol) of <strong>[40851-91-0]6-chloro-2-methoxy-3-nitropyridine</strong>, 25 ml of ethanol and 1.9 g of 3-pyrrolidinol are charged to a fully equipped round-bottomed flask. The mixture is brought to 50 C. for one hour with stirring and the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2 g of yellow powder are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | (a) 3-Hydroxy-pyrrolidine-1-carboxylic acid benzyl ester. 3-Hydroxy-pyrrolidine (10 g, 115 mmol, 1.0 equiv) was dissolved in 2 N NaOH (100 mL) and the mixture was cooled to 0 C. Benzylchloroformate (21 g, 126 mmol, 1.1 equiv) was added dropwise over a 45 min period. After addition, the reaction was stirred at room temperature for 4 h at which time the pH was adjusted to 7-8 using concentrated HCl. The product was extracted with 3*100 mL of CH2Cl2. The organic extracts were combined and dried over Na2SO4, decanted and concentrated in vacuo to yield the desired product as a light yellow oil (24.1 g, 95%) that was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; potassium hydroxide; N-benzyl-trimethylammonium hydroxide; | EXAMPLE 5 This example shows the synthesis of 4-hydroxypyrrolidine. A 500 mL flask equipped with an addition funnel, reflux condenser, nitrogen inlet, and magnetic stirrer was charged with pyrrole (116 g) and benzyltrimethylammonium hydroxide (Triton B, 11.6 mL). Acrylonitrile (116 mL) was added over a period of about 1 hr by means of an addition funnel, keeping the temperature below 40 C. with an ice bath. The solution was warmed to room temperature and stirred for an additional hour. A solution of KOH (116 g) in approximately 150 mL of water was prepared and added to the reaction solution. The resulting two-phase mixture was heated to reflux; after 1 hr at reflux, the mixture had become homogeneous and it was cooled to room temperature. Concentrated HCl (~50 mL) was added to neutralize the base and the product was extracted into 2*300 mL of ethyl ether. The nearly colorless ether solution was dried over magnesium sulfate and the solvent was removed by rotary evaporation. Kugelrohr distillation afforded 92.1 g of colorless oil, 3-pyrrolylpropionic acid 1 which solidified upon standing. STR8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In aqueous hydrofluoroboric acid; diethyl ether; dimethyl sulfoxide; | EXAMPLE 27 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-hydroxy-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [Steps (A2), (A3)+(A4)] A suspension of 0.50 g (0.0015 mole) of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XXXII) (prepared as described in Preparation 3) in 10 ml of 42% aqueous hydrofluoroboric acid was stirred at 90-100 C. for 3 hours, and then poured into water to precipitate a crystalline substance. This crystalline substance was collected by filtration to afford 0.55 g of the chelate (IV) as a colorless powder. The whole of this chelate was dissolved in 2.5 ml of dimethyl sulfoxide, and 0.52 g (0.006 mole) of 3-hydroxypyrrolidine was added to the resulting solution. The mixture was then allowed to stand at room temperature overnight. At the end of this time, the reaction mixture was poured into 250 ml of diethyl ether to precipitate yellow crystals, which were collected by filtration. The whole of these crystals was dissolved in a mixture of 150 ml of 80% aqueous ethanol and 25 ml of triethylamine, and the solution was heated under reflux for 4 hours. The solution was then cooled to room temperature, insoluble material was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure to yield a crystalline substance, which was washed with ethanol. The crude crystals thus obtained were recrystallized from a mixture of methanol and water to afford 0.35 g of 1-cyclopropyl-6-fluoro-8-methoxy-7-(3-hydroxy-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as pale brown needles melting at 253-254 C. Mass Spectrum: m/e 362 (M+), 318 (M+ -CO2). Elemental analysis: Calculated for C18 H19 FN2 O5: C, 59.67%; H, 5.25%; N, 7.73%. Found: C, 59.74%; H, 5.30%; N, 7.72%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 2 The procedure of Example 1 was repeated except that 4 g of <strong>[84367-31-7](R)-<strong>[84367-31-7]4-chloro-3-hydroxybutyronitrile</strong></strong> obtained in Reference Example 2 was used to give 2.23 g of (R)-3-pyrrolidinol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | Preparation 78 tert -Butyl (3 S)-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate Triethylamine (8.7ml, 62.4mmol) was added to a solution of (3R)-3-pyrrolidinol (5.16g, 41.7mmol) in dichloromethane (30ml), and the solution stirred for 10 mins. Di-tert-butyl dicarbonate (9.11g, 41.7mmol) was added and the reaction stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate, and the layers separated. The organic phase was washed with 1N citric acid, water, and brine, then dried over MgSO4, and evaporated under reduced pressure to give a pale yellow oil, 7.14g. This intermediate alcohol was dissolved in dichloromethane (100ml), triethylamine (6.4ml, 45.9mmol) added and the solution cooled in an ice-bath. Methanesulphonyl chloride (3.25ml, 41.9mmol) was added slowly, and the reaction stirred for 2 hrs. The reaction mixture was washed with 1N citric acid, saturated NaHCO3solution, brine, the dried over Na2SO4and evaporated under reduced pressure to afford the title compound as an oil, (9.36g, 85%). 1H NMR (CDCl3, 300MHz) delta: 1.40 (s, 9H), 2.03-2.28 (m, 2H), 2.99 (s, 3H), 3.36-3.60 (m, 4H), 5.18 (m, 1H). LRMS: m/z = 283 (M+18)+ | |
With triethylamine; In dichloromethane; | Preparation 78 tert-Butyl (3S)-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate Triethylamine (8.7 ml, 62.4 mmol) was added to a solution of (3R)-3-pyrrolidinol (5.16 g, 41.7 mmol) in dichloromethane (30 ml), and the solution stirred for 10 mins. Di-tert-butyl dicarbonate (9.11 g, 41.7 mmol) was added and the reaction stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate, and the layers separated. The organic phase was washed with 1N citric acid, water, and brine, then dried over MgSO4, and evaporated under reduced pressure to give a pale yellow oil, 7.14 g. This intermediate alcohol was dissolved in dichloromethane (100 ml), triethylamine (6.4 ml, 45.9 mmol) added and the solution cooled in an ice-bath. Methanesulphonyl chloride (3.25 ml, 41.9 mmol) was added slowly, and the reaction stirred for 2 hrs. The reaction mixture was washed with 1N citric acid, saturated NaHCO3 solution, brine, the dried over Na2SO4 and evaporated under reduced pressure to afford the title compound as an oil, (9.36 g, 85%). 1H NMR (CDCl3, 300 MHz) delta: 1.40 (s, 9H), 2.03-2.28 (m, 2H), 2.99 (s, 3H), 3.36-3.60 (m, 4H), 5.18 (m, 1H). LRMS: m/z=283 (M+18)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In isopropyl alcohol; at 100℃; | To a mixture of racemic 3-pyrrolidinol (48 mg, 0.55 mmol) and 4-chloroquinoline (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred overnight at 100 C. After cooling to rt, it was concentrated in vacuo. The residue was partitioned between aqueous K2CO3 and DCM. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 105 mg (100%) of crude 1-quinolin-4-yl-<strong>[40499-83-0]pyrrolidin-3-ol</strong> (34a) which was used as such for the next step. The crude 34a (11 mg, 0.05 mmol) was dissolved in anhydrous THF and stirred at RT while a 1.0 M solution of NaHMDS in THF (0.1 mL, 0.1 mmol) was added to it followed by (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a. The mixture was stirred at RT for 30 min and then at 80 C. for 30 min. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K2CO3 and EtOAc. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the crude product which was purified by Preparative TLC (silica gel; 5% MeOH/DCM) to yield 6.9 mg (37%) of pure (4-isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester. 1H NMR (300 MHz, CDCl3): delta 8.49 (d, 1H), 8.18 (d, 1H), 8.07 (d, 1H), 7.63 (m, 1H), 7.39 (m, 1H), 7.31-7.24 (m, 2H), 7.16 (m, 2H), 6.82 (bs, 1H), 6.48 (d, 1H), 5.53 (m, 1H), 4.16-4.08 (m, 1H), 4.02-3.90 (m, 1H), 3.86-3.70 (m, 2H), 2.92-2.80 (m, 1H), 2.40-2.2 (m, 2H), 1.21 (d, 6H). LC/MS (ESI): calcd mass 375.2, found 376.2 (MH)+. |
100% | EXAMPLE 34; (4-Isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester (Compound No. 34); To a mixture of racemic 3-pyrrolidinol (48 mg, 0.55 mmol) and 4-chloroquinoline (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred overnight at 100 C. After cooling to rt, it was concentrated in vacuo. The residue was partitioned between aqueous K2CO3 and DCM. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 105 mg (100%) of crude 1-quinolin-4-yl-<strong>[40499-83-0]pyrrolidin-3-ol</strong> (34a) which was used as such for the next step. The crude 34a (11 mg, 0.05 mmol) was dissolved in anhydrous THF and stirred at RT while a 1.0 M solution of NaHMDS in THF (0.1 mL, 0.1 mmol) was added to it followed by (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a. The mixture was stirred at RT for 30 min and then at 80 C. for 30 min. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K2CO3 and EtOAc. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the crude product which was purified by Preparative TLC (silica gel; 5% MeOH/DCM) to yield 6.9 mg (37%) of pure (4-isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester. 1H NMR (300 MHz, CDCl3): delta 8.49 (d, 1H), 8.18 (d, 1H), 8.07 (d, 1H), 7.63 (m, 1H), 7.39 (m, 1H), 7.31-7.24 (m, 2H), 7.16 (m, 2H), 6.82 (bs, 1H), 6.48 (d, 1H), 5.53 (m, 1H), 4.16-4.08 (m, 1H), 4.02-3.90 (m, 1H), 3.86-3.70 (m, 2H), 2.92-2.80 (m, 1H), 2.40-2.2 (m, 2H), 1.21 (d, 6H). LC/MS (ESI): calcd mass 375.2, found 376.2 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20 - 100℃; for 0.2h; | EXAMPLE 25; (6-Cyclobutoxy-pyridin-3-yl)-carbamic acid 1-thieno[3,2-d]pyrimidin-4-yl-pyrrolidin-3-yl ester; a. 1-Thieno[3,2-d]pyrimidin-4-yl-pyrrolidin-3-ol 4-Chloro-thieno[3,2-d]pyrimidine (0.985 g, 5.78 mmol) was added to a mixture of racemic 3-pyrrolidinol (0.527 g, 6.06 mmol), DIPEA (1.10 mL, 6.31 mmol), and DMSO (1.5 mL). The mixture was stirred at ?rt? for 2 min, during which time it spontaneously warmed and became a nearly homogeneous solution. The reaction was then stirred at 100 C. for 10 min, and the resulting homogeneous dark reddish-brown solution was allowed to cool to rt and then shaken with water (?17 mL) before extracting with EtOAc (1×20 mL). The organic layer was washed with 4M NaCl (1×20 mL), dried (Na2SO4), and concentrated to give ?150 mg of title compound. Additional title compound was obtained as follows: The aqueous layers were combined (?40 mL) and extracted with EtOAc (1×300 mL), and the organic layer was dried (Na2SO4) and concentrated to give a powder. The two organic extract-derived powders were combined to give 911 mg of the title compound (71%). 1H NMR (400 MHz, DMSO-d6) delta 8.38 (s, 1H), 8.18 (d, 1H), 7.39 (d, 1H), 5.12 (br s, 1H), 4.43 (br s, 1H), 4.05-3.68 (br m, 4H), 2.12-1.90 (m, 2H). |
71% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20 - 100℃; for 0.2h; | 4-Chloro-thieno[3,2-d]pyrimidine (0.985 g, 5.78 mmol) was added to a mixture of racemic 3-pyrrolidinol (0.527 g, 6.06 mmol), DIPEA (1.10 mL, 6.31 mmol), and DMSO (1.5 mL). The mixture was stirred at "rt" for 2 min, during which time it spontaneously warmed and became a nearly homogeneous solution. The reaction was then stirred at 100 C. for 10 min, and the resulting homogeneous dark reddish-brown solution was allowed to cool to rt and then shaken with water (~17 mL) before extracting with EtOAc (1*20 mL). The organic layer was washed with 4M NaCl (1*20 mL), dried (Na2SO4), and concentrated to give 150 mg of title compound. Additional title compound was obtained as follows: The aqueous layers were combined (~40 mL) and extracted with EtOAc (1*300 mL), and the organic layer was dried (Na2SO4) and concentrated to give a powder. The two organic extract-derived powders were combined to give 911 mg of the title compound (71%). 1H NMR (400 MHz, DMSO-d6) delta 8.38 (s, 1H), 8.18 (d, 1H), 7.39 (d, 1H), 5.12 (br s, 1H), 4.43 (br s, 1H), 4.05-3.68 (br m, 4H), 2.12-1.90 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 3h; | To the solution of pyrrolidin-3-ol (1.0 g, 11 mmol) in THF (5 mL) and 1M NaOH (5 mL) was added dibenzyldicarbonate (3.3, 11 mmol) at room temperature. The reaction mixture was stirred for 3 h then the THF removed under reduced pressure. The residue was dissolved in DCM (50 mL) and washed successively with saturated NaHCO3 (2×20mL) and saturated NaCl (2×20 mL). The solution was dried over Na2SO4, decanted and concentrated. Benzyl 3-hydroxypyrrolidine-1-carboxylate (1.1 g, 47%) was isolated by prep. HPLC YMC ODSA 30×100 mm, 20-100% MeOH/H2O (0. 1% TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.93 min. LCMS: 1.21 min [M+1] 222.06 (2 min gradient, MeOH/H2O 0.1% TFA). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; | Step 1. 1-Benzylpyrrolidin-3-ol. To a solution of (R)-pyrrolidine-3-ol (0.24 g, 2.75 mmol) and benzyl bromide (0.56 g, 3.28 mmol) in DMF (10 ml) was added K2CO3 (0.49 g, 3.54 mmol, 1.3 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight before it was diluted with EtOAc (80 ml). The organic layer was washed with water (3*50 ml), brine (50 ml), dried over Na2SO4 and concentrated on a rotavap to give the desired product 167 as a yellow oil 0.15 g, 32%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 23℃; for 15h; | A solution of 33.43 mmol of (R)-(+)-3-pyrrolininol in 30 ml_ of CH2CI2 is added to a solution of 33.43 mmol of C-(bis-benzothazol-1 -yl)-methylene amine [28992-50-9] in 180 ml_ of CH2CI2. The reaction mixture is stirred at RT for 15 h, washed with aqueous 10% NaHCO3 (2 x 75 ml_), dried over Na2SO4, filtered and evaporated to afford the title compound as an orange oil. LC-MS: 232 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.2% | (3R)-pyrrolidin-3-ol (28 gm) and potassium carbonate (89 gm) in anhydrous acetonitrile (200 ml) was stirred at room temparature for 10 minutes and the mixture was heated to reflux for 2 hrs. The benzofuran derivative was added dropwise to the above mixture and refluxed for 6 hrs. After the reaction completion, the reaction mixture was filtered and concentrated under reduced pressure .The residue was taken in methylene dichloride, washed with Aq.HCl followed by washing with saturated pot.carbonate solution. The MDC layer was dried over Sodium sulphate and concentrated to furnish white solid of the desired compound. Dry Weight : 53.3 g Yield : 78.2 percent HPLC purity : 98 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | 3-pyrrolidinol (2 mL, 24.7 mmol) and potassium carbonate (4.8 g) were dissolved in DMF (5 mL), and <strong>[66684-58-0]3,4,5-trifluoronitrobenzene</strong> (2.6 mL) was slowly added and stirred under argon at room temperature overnight. The mixture was treated with cold water and the product was separated as a solid. This solid was filtered, washed with water and dried at 60°C under vacuum to give 5.4 g (Yield = 89percent) of title compound. HPLC (t, percent): 7.71 min, 100 percent. MS(ESI) m/z = 245 (M+1) 1H NMR (400 MHz, delta, ppm, DMSO): 1.87 (2H, m), 3.45 (1H, m), 3.69 (1H, m), 3.85 (2H, m), 4.33 (1H, m), 5.05 (1H, m), 7.86(2H, dd, J = 2.8, 9.6 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃;Reflux; | 4-tert-Butyl-2,6-dimethylphenylsulfur trifluoride (6.0 mmol) was taken in aTeflon vessel and dissolved in 20 ml of dry dichloromethane. Triethylamine (12.1 mmol) was added at room temperature followed by the addition of a solution of (+/-)-3-pyrrolidinol (6.0 mmol) in 5 ml of dry dichloromethane. The reaction mixture was refluxed for 10 hours. After cooling to room temperature, the reaction mixture was poured in aqueous sodium carbonate solution. The mixture was extracted with dichloromethane, and the organic layer was separated and dried on magnesium sulfate. After filtration, the filtrate was evaporated to dryness and the residue was column-chromatographed on silica gel using a 2:1 mixture of ether and hexane to give l-(4-tert-butyl-2,6-dimethylphenylsulfinyl)-3-fluoropyrrolidine (I- 44): Yield 72%. 19F NMR showed that the product was a 1:0.66 mixture of two stereoisomers. 19F-NMR (CDCl3) delta - 173.28 (m) and -174.44 (m) in an integral ratio of 1:0.66; 1H-NMR (CDCl3) delta 1.27 (s, 9H), 2.10-2.20 (m, 2H), 2.53 (s, 6H), 3.10-3.70 (m, 4H), 4.90-5.50 (m, IH), 6.98 (s, 2H); 13C-NMR (CDCl3) major isomer: delta 19.98, 31.17, 34.48, 43.95, 53.43, (d, J = 23.8 Hz), 92.97 (d, J = 178.4 Hz) 127.48, 134.63, 137.44, 153.32, minor isomer: delta 19.98, 31.13, 34.48, 46.24, 51.60 (d, J = 23.8 Hz), 93.22 (d, J = 178.4 Hz) 127.48, 134.94, 137.35, 153.32. Elemental analysis calculated for C16H24FNOS: C, 64.61%; H,8.13%; N, 4.71%. Found; C, 64.08%; H, 8.21%; N, 4.53% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In dichloromethane; at 20℃; | To a mixture of 3-pyrrolidinol (32 muL, 0.39 mmol) and triethylamine (50 muL, 0.4 mmol) in DCM (2.0 mL) at 0 C. was added <strong>[65001-21-0]5-bromopyridine-3-sulfonyl chloride</strong> (50 mg, 0.19 mmol) [Combi-Blocks, ST-7824] in a single portion. The reaction mixture was stirred overnight while coming to room temperature. The reaction was quenched with sat. NaHCO3 (2 mL). The organic layer was removed, and the aqueous layer was extracted with DCM (2×2 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography (25-100% EtOAc in DCM) afforded a white solid (39.0 mg, 65%). LCMS for C9H12BrN2O3S (M+H)+: calculated m/z=307.0, 309.0; found 306.9, 308.9. |
Intermediate 26: 1 -[(5-bromopyridin-3-yl)sulfonyl]pyrrolidin-3-olTEA (0.32 ml_, 2.29 mmol) was added to a suspension of 5-bromo pyridine-3- sulfonyl chloride (370 mg, 1.26 mmol) in dichloromethane at O0C. The reaction mixture was stirred for 10 min at 00C before the addition of a solution of 3- pyrrolidinol (100 mg, 1.147 mmol) in DCM. Reaction mixture was then stirred at RT overnight under nitrogen atmosphere. It was then washed successively with saturated sodium bicarbonate, water and brine. Organic layer was separated and dried over sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography on basic alumina (HCC^MeOH) to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 16h;Inert atmosphere; | Reference Example 54 1-[2-fluoro-4-(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of <strong>[40161-54-4]1-bromo-2-fluoro-4-(trifluoromethyl)benzene</strong> (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (137 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 mL) was stirred under an argon gas atmosphere at 85C for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 - 65:35) to give the title compound (2.82 g, yield 66%) as a gray solid. 1H-NMR (300 MHz, CDCl3) delta:1.63 (d, J = 4.5 Hz, 1 H), 1.96 - 2.22 (m, 2 H), 3.40 - 3.57 (m, 2 H), 3.61 - 3.81 (m, 2 H), 4.51 - 4.66 (m, 1 H), 6.64 (t, J = 9.1 Hz, 1 H), 7.15 - 7.25 (m, 2 H). |
66% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 85℃; for 16h;Inert atmosphere; | A solution of <strong>[40161-54-4]1-bromo-2-fluoro-4-(trifluoromethyl)benzene</strong> (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (137 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 ml) was stirred under an argon gas atmosphere at 85 C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-65:35) to give the title compound (2.82 g, yield 66%) as a gray solid.1H-NMR (300 MHz, CDCl3) delta: 1.63 (d, J=4.5 Hz, 1H), 1.96-2.22 (m, 2H), 3.40-3.57 (m, 2H), 3.61-3.81 (m, 2H), 4.51-4.66 (m, 1H), 6.64 (t, J=9.1 Hz, 1H), 7.15-7.25 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 16h;Inert atmosphere; | Reference Example 55 1-[2-fluoro-5-(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of <strong>[68322-84-9]2-bromo-1-fluoro-4-(trifluoromethyl)benzene</strong> (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (193 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 mL) was stirred under an argon gas atmosphere at 85C for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 - 65:35) to give the title compound (2.12 g, yield 49%) as a brown oil. 1H-NMR (300 MHz, CDCl3)delta:1.67 (d, J = 4.3 Hz, 1 H), 1.96 - 2.23 (m, 2 H), 3.35 - 3.49 (m, 2 H), 3.56 - 3.76 (m, 2 H), 4.49 - 4.65 (m, 1 H), 6.79 - 6.88 (m, 1 H), 6.88 - 6.96 (m, 1 H), 6.97 - 7.10 (m, 1 H). |
49% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 85℃; for 16h;Inert atmosphere; | A solution of <strong>[68322-84-9]2-bromo-1-fluoro-4-(trifluoromethyl)benzene</strong> (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (193 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 ml) was stirred under an argon gas atmosphere at 85 C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-65:35) to give the title compound (2.12 g, yield 49%) as a brown oil.1H-NMR (300 MHz, CDCl3) delta: 1.67 (d, J=4.3 Hz, 1H), 1.96-2.23 (m, 2H), 3.35-3.49 (m, 2H), 3.56-3.76 (m, 2H), 4.49-4.65 (m, 1H), 6.79-6.88 (m, 1H), 6.88-6.96 (m, 1H), 6.97-7.10 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 18.0h;Inert atmosphere; | Reference Example 1 1-[3,5-bis(trifluoromethyl)phenyl]<strong>[40499-83-0]pyrrolidin-3-ol</strong>; A solution of 3,5-bis(trifluoromethyl)phenyl bromide (21.1 g), 3-hydroxypyrrolidine (6.53 g), tris(dibenzylideneacetone)dipalladium(0) (1.47 g), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.99 g) and sodium tert-butoxide (10.6 g) in toluene (140 mL) was stirred under an argon gas atmosphere at 100C for 18 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 95:5 - 70:30) to give the title compound (13.2 g, yield 61%) as colorless crystals. 1H-NMR (300 MHz, CDCl3)delta:1.82 (br, 1 H), 2.08 - 2.25 (m, 2 H), 3.30 - 3.34 (m, 1 H), 3.39 - 3.46 (m, 1 H), 3.52 - 3.60 (m, 2 H), 4.64 - 4.68 (m, 1 H), 6.85 (s, 2 H), 7.11 (s, 1 H). |
61% | With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃; for 18.0h;Inert atmosphere; | A solution of 3,5-bis(trifluoromethyl)phenyl bromide (21.1 g), 3-hydroxypyrrolidine (6.53 g), tris(dibenzylideneacetone)dipalladium(0) (1.47 g), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.99 g) and sodium tert-butoxide (10.6 g) in toluene (140 ml) was stirred under an argon gas atmosphere at 100 C. for 18 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 95:5-70:30) to give the title compound (13.2 g, yield 61%) as colorless crystals.1H-NMR (300 MHz, CDCl3) delta:1.82 (br, 1H), 2.08-2.25 (m, 2H), 3.30-3.34 (m, 1H), 3.39-3.46 (m, 1H), 3.52-3.60 (m, 2H), 4.64-4.68 (m, 1H), 6.85 (s, 2H), 7.11 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 16h;Inert atmosphere; | Reference Example 53 1-[4-fluoro-3-(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of <strong>[393-37-3]4-bromo-1-fluoro-2-(trifluoromethyl)benzene</strong> (10 g), 3-hydroxypyrrolidine (3.56 g), palladium(II) acetate (462 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.57 g) and cesium carbonate (26.8 g) in toluene (220 mL) was stirred under an argon gas atmosphere at 90C for 16 hr. After cooling to room temperature, the reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The filtrate and washing were combined and the solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 - 25:75) to give the title compound (5.91 g, yield 58%) as a pale-yellow oil. 1H-NMR (300 MHz, CDCl3) delta:1.72 (d, J = 3.4 Hz, 1 H), 2.00 - 2.29 (m, 2 H), 3.25 (d, J = 10.2 Hz, 1 H), 3.33 (td, J = 8.8, 3.6 Hz, 1 H), 3.40 - 3.59 (m, 2 H), 4.63 (br. s, 1 H), 6.54 - 6.70 (m, 2 H), 7.05 (t, J = 9.4 Hz, 1 H). |
58% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 90℃; for 16h;Inert atmosphere; | A solution of <strong>[393-37-3]4-bromo-1-fluoro-2-(trifluoromethyl)benzene</strong> (10 g), 3-hydroxypyrrolidine (3.56 g), palladium(II) acetate (462 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.57 g) and cesium carbonate (26.8 g) in toluene (220 ml) was stirred under an argon gas atmosphere at 90 C. for 16 hr. After cooling to room temperature, the reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The filtrate and washing were combined and the solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20-25:75) to give the title compound (5.91 g, yield 58%) as a pale-yellow oil.1H-NMR (300 MHz, CDCl3) delta: 1.72 (d, J=3.4 Hz, 1H), 2.00-2.29 (m, 2 H), 3.25 (d, J=10.2 Hz, 1H), 3.33 (td, J=8.8, 3.6 Hz, 1H), 3.40-3.59 (m, 2H), 4.63 (br. s, 1H), 6.54-6.70 (m, 2H), 7.05 (t, J=9.4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 16h;Inert atmosphere; | Reference Example 71 1-[3-fluoro-5-(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (10.0 g), 3-hydroxypyrrolidine (3.58 g), palladium(II) acetate (461 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.56 g) and cesium carbonate (26.7 g) in toluene (222 mL) was stirred under an argon gas atmosphere at 90C for 16 hr. After cooling to room temperature, the reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The filtrate and washing were combined and the solution was washed with water and saturated brine. This was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 98:2 - 20:80) to give the title compound (10.65 g, yield quant.) as a brown oil. 1H-NMR (300 MHz, CDCl3)delta:1.73 (br. s, 1 H), 2.05 - 2.28 (m, 2 H), 3.27 (d, J = 10.6 Hz, 1 H), 3.38 (td, J = 8.9, 3.4 Hz, 1 H), 3.45 - 3.59 (m, 2 H), 4.55 - 4.70 (m, 1 H), 6.35 (dt, J = 11.7, 2.3 Hz, 1 H), 6.52 (s, 1 H), 6.60 (d, J=8.7 Hz, 1 H). |
100% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 90℃; for 16h;Inert atmosphere; | A solution of <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (10.0 g), 3-hydroxypyrrolidine (3.58 g), palladium(II) acetate (461 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.56 g) and cesium carbonate (26.7 g) in toluene (222 ml) was stirred under an argon gas atmosphere at 90 C. for 16 hr. After cooling to room temperature, the reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The filtrate and washing were combined and the solution was washed with water and saturated brine. This was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 98:2-20:80) to give the title compound (10.65 g, yield quant.) as a brown oil.1H-NMR (300 MHz, CDCl3) delta: 1.73 (br. s, 1H), 2.05-2.28 (m, 2H), 3.27 (d, J=10.6 Hz, 1H), 3.38 (td, J=8.9, 3.4 Hz, 1H), 3.45-3.59 (m, 2H), 4.55-4.70 (m, 1H), 6.35 (dt, J=11.7, 2.3 Hz, 1 H), 6.52 (s, 1H), 6.60 (d, J=8.7 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 16h;Inert atmosphere; | Reference Example 52 1-[4-fluoro-2-(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of <strong>[40161-55-5]1-bromo-4-fluoro-2-(trifluoromethyl)benzene</strong> (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (193 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 mL) was stirred under an argon gas atmosphere at 85C for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 - 65:35) to give the title compound (3.58 g, yield 84%) as a yellow oil. 1H-NMR (300 MHz, CDCl3)delta:1.88 - 2.03 (m, 2 H), 2.14 - 2.30 (m, 1 H), 3.00 - 3.17 (m, 2 H), 3.33 - 3.41 (m, 1 H), 3.41 - 3.52 (m, 1 H), 4.48 (br. s, 1 H), 7.08 - 7.23 (m, 2 H), 7.28 - 7.37 (m, 1 H). |
84% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 85℃; for 16h;Inert atmosphere; | A solution of <strong>[40161-55-5]1-bromo-4-fluoro-2-(trifluoromethyl)benzene</strong> (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (193 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 mL) was stirred under an argon gas atmosphere at 85 C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-65:35) to give the title compound (3.58 g, yield 84%) as a yellow oil.1H-NMR (300 MHz, CDCl3) delta: 1.88-2.03 (m, 2H), 2.14-2.30 (m, 1H), 3.00-3.17 (m, 2H), 3.33-3.41 (m, 1H), 3.41-3.52 (m, 1H), 4.48 (br. s, 1H), 7.08-7.23 (m, 2H), 7.28-7.37 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 16h;Inert atmosphere; | Reference Example 57 1-[2,4-bis(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of <strong>[327-75-3]1-bromo-2,4-bis(trifluoromethyl)benzene</strong> (4.45 g), 3-hydroxypyrrolidine (1.2 g), palladium(II) acetate (156 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (846 mg) and cesium carbonate (13.6 g) in toluene (74 mL) was stirred under an argon gas atmosphere at 85C for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 - 65:35) to give the title compound (3.28 g, yield 79%) as a brown oil. 1H-NMR (300 MHz, CDCl3)delta:1.66 (d, J = 4.2 Hz, 1 H), 1.97 - 2.25 (m, 2 H), 3.24 - 3.54 (m, 2 H), 3.64 - 3.88 (m, 2 H), 4.49 - 4.70 (m, 1 H), 6.94 (d, J = 9.1 Hz, 1 H), 7.56 (dd, J=8.7, 1.9 Hz, 1 H), 7.82 (s, 1 H) . |
79% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 85℃; for 16h;Inert atmosphere; | A solution of <strong>[327-75-3]1-bromo-2,4-bis(trifluoromethyl)benzene</strong> (4.45 g), 3-hydroxypyrrolidine (1.2 g), palladium(II) acetate (156 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (846 mg) and cesium carbonate (13.6 g) in toluene (74 ml) was stirred under an argon gas atmosphere at 85 C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-65:35) to give the title compound (3.28 g, yield 79%) as a brown oil.1H-NMR (300 MHz, CDCl3) delta: 1.66 (d, J=4.2 Hz, 1H), 1.97-2.25 (m, 2H), 3.24-3.54 (m, 2H), 3.64-3.88 (m, 2H), 4.49-4.70 (m, 1H), 6.94 (d, J=9.1 Hz, 1H), 7.56 (dd, J=8.7, 1.9 Hz, 1H), 7.82 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; for 16.0h;Inert atmosphere; | Reference Example 30 1-[2,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of <strong>[7617-93-8]2,5-bis(trifluoromethyl)phenyl bromide</strong> (4.45 g), 3-hydroxypyrrolidine (1.2 g), palladium(II) acetate (0.16 g), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.87 g) and cesium carbonate (13.6 g) in toluene (74 mL) was stirred under an argon gas atmosphere at 80C for 16 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10 - 75:25) to give the title compound (3.79 g, yield 91%) as an orange oil. 1H-NMR (300 MHz, CDCl3)delta:1.72 (d, J = 4.9 Hz, 1 H), 1.95 - 2.10 (m, 1 H), 2.10 - 2.24 (m, 1 H), 3.21 - 3.43 (m, 2 H), 3.60 - 3.78 (m, 2 H), 4.48 - 4.65 (m, 1 H), 7.01 - 7.16 (m, 1 H), 7.16 - 7.23 (m, 1 H), 7.63 - 7.74 (m, 1 H). |
91% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane; toluene; at 80℃; for 16.0h;Inert atmosphere; | A solution of <strong>[7617-93-8]2,5-bis(trifluoromethyl)phenyl bromide</strong> (4.45 g), 3-hydroxypyrrolidine (1.2 g), palladium(II) acetate (0.16 g), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.87 g) and cesium carbonate (13.6 g) in toluene (74 mL) was stirred under an argon gas atmosphere at 80 C. for 16 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-75:25) to give the title compound (3.79 g, yield 91%) as an orange oil.1H-NMR (300 MHz, CDCl3) delta: 1.72 (d, J=4.9 Hz, 1H), 1.95-2.10 (m, 1 H), 2.10-2.24 (m, 1H), 3.21-3.43 (m, 2H), 3.60-3.78 (m, 2H), 4.48-4.65 (m, 1H), 7.01-7.16 (m, 1H), 7.16-7.23. (m, 1H), 7.63-7.74 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 16h;Inert atmosphere; | Reference Example 70 1-[3-chloro-5-(trifluoromethyl)phenyl]pyrrolidin-3-ol ; A solution of <strong>[928783-85-1]1-bromo-3-chloro-5-(trifluoromethyl)benzene</strong> (5.0 g), 3-hydroxypyrrolidine (1.85 g), palladium(II) acetate (217 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.2 g) and cesium carbonate (18.8 g) in toluene (96 mL) was stirred under an argon gas atmosphere at 85C for 16 hr. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 - 10:90) to give the title compound (4.11 g, yield 80%) as a brown oil. 1H-NMR (300 MHz, CDCl3)delta:1.65 (d, J = 3.8 Hz, 1 H), 2.00 - 2.29 (m, 2 H), 3.19 - 3.32 (m, 1 H), 3.38 (td, J = 8.7, 3.4 Hz, 1 H), 3.45 - 3.60 (m, 2 H), 4.58 - 4.72 (m, 1 H), 6.61 (s, 1 H), 6. 63 - 6.68 (m, 1 H), 6.88 (s, 1 H). |
80% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 85℃; for 16h;Inert atmosphere; | A solution of <strong>[928783-85-1]1-bromo-3-chloro-5-(trifluoromethyl)benzene</strong> (5.0 g), 3-hydroxypyrrolidine (1.85 g), palladium(II) acetate (217 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.2 g) and cesium carbonate (18.8 g) in toluene (96 mL) was stirred under an argon gas atmosphere at 85 C. for 16 hr. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20-10:90) to give the title compound (4.11 g, yield 80%) as a brown oil.1H-NMR (300 MHz, CDCl3) delta: 1.65 (d, J=3.8 Hz, 1H), 2.00-2.29 (m, 2 H), 3.19-3.32 (m, 1H), 3.38 (td, J=8.7, 3.4 Hz, 1H), 3.45-3.60 (m, 2H), 4.58-4.72 (m, 1H), 6.61 (s, 1H), 6.63-6.68 (m, 1H), 6.88 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 16.0h;Inert atmosphere; | Reference Example 62 1-[3-(thiomorpholin-4-ylcarbonyl)-5-(trifluoromethyl)phenyl]<strong>[40499-83-0]pyrrolidin-3-ol</strong>; A solution of 4-[3-bromo-5-(trifluoromethyl)phenyl]carbonyl}thiomorpholine (5.0 g) obtained in Reference Example 61, 3-hydroxypyrrolidine (1.35 g), palladium(II) acetate (158.5 mg), (+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (884 mg) and cesium carbonate (13.8 g) in toluene (71 mL) was stirred under an argon gas atmosphere at 90C for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 50:50 - 0:100) to give the title compound (5.56 g, yield quant.) as a pale-yellow solid. 1H-NMR (300 MHz, CDCl3)delta:1.94 (d, J = 4.2 Hz, 1 H), 2.01 - 2.27 (m, 2 H), 2.57 (br. s, 2 H), 2.73 (br. s, 2 H), 3.22 - 3.33 (m, 1 H), 3.33 - 3.46 (m, 1 H), 3.46 - 3.58 (m, 2 H), 3.66 (br. s, 2 H), 4.01 (br. s, 2 H), 4.57 - 4.72 (m, 1 H), 6.65 (s, 1 H), 6.75 (s, 1 H), 6.84 (s, 1 H) . |
100% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 90℃; for 16.0h;Inert atmosphere; | A solution of 4-[3-bromo-5-(trifluoromethyl)phenyl]carbonyl}thiomorpholine (5.0 g) obtained in Reference Example 61, 3-hydroxypyrrolidine (1.35 g), palladium(II) acetate (158.5 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (884 mg) and cesium carbonate (13.8 g) in toluene (71 mL) was stirred under an argon gas atmosphere at 90 C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 50:50-0:100) to give the title compound (5.56 g, yield quant.) as a pale-yellow solid.1H-NMR (300 MHz, CDCl3) delta: 1.94 (d, J=4.2 Hz, 1H), 2.01-2.27 (m, 2 H), 2.57 (br. s, 2H), 2.73 (br. s, 2H), 3.22-3.33 (m, 1H), 3.33-3.46 (m, 1H), 3.46-3.58 (m, 2H), 3.66 (br. s, 2H), 4.01 (br. s, 2H), 4.57-4.72 (m, 1H), 6.65 (s, 1H), 6.75 (s, 1H), 6.84 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; toluene; at 80℃; for 16.0h;Inert atmosphere; | Reference Example 64 1-{3-[(1-oxidothiomorpholin-4-yl)carbonyl]-5-(trifluoromethyl)phenyl}<strong>[40499-83-0]pyrrolidin-3-ol</strong>; A solution of 4-[3-bromo-5-(trifluoromethyl)phenyl]carbonyl}thiomorpholine 1-oxide (2.99 g) obtained in Reference Example 63, 3-hydroxypyrrolidine (774 mg), palladium(II) acetate (91 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (504 mg) and cesium carbonate (7.9 g) in a mixed solvent of toluene (40 mL) and DMF (15 mL) was stirred under an argon gas atmosphere at 80C for 16 hr. After cooling to room temperature, the reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol 100:0 - 80:20) to give the title compound (2.10 g, yield 69%) as a white solid. 1H-NMR (300 MHz, CDCl3)delta:1.87 (d, 1 H), 2.06 - 2.27 (m, 2 H), 2.96 (br. s, 4 H), 3.30 (d, J = 10.6 Hz, 1 H), 3.41 (td, J = 8.7, 3.4 Hz, 1 H), 3.47 - 3.62 (m, 2 H), 3.77 (br. s, 1 H), 4.12 (br. s, 2 H), 4.57 (br. s, 1 H), 4.62 - 4.74 (m, 1 H), 6.68 (s, 1 H), 6.79 (s, 1 H), 6.86 (s, 1 H). |
69% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In N,N-dimethyl-formamide; toluene; at 80℃; for 16.0h;Inert atmosphere; | A solution of 4-[3-bromo-5-(trifluoromethyl)phenyl]carbonyl}thiomorpholine 1-oxide (2.99 g) obtained in Reference Example 63, 3-hydroxypyrrolidine (774 mg), palladium(II) acetate (91 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (504 mg) and cesium carbonate (7.9 g) in a mixed solvent of toluene (40 ml) and DMF (15 ml) was stirred under an argon gas atmosphere at 80 C. for 16 hr. After cooling to room temperature, the reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol 100:0-80:20) to give the title compound (2.10 g, yield 69%) as a white solid.1H-NMR (300 MHz, CDCl3) delta: 1.87 (d, 1H), 2.06-2.27 (m, 2H), 2.96 (br. s, 4H), 3.30 (d, J=10.6 Hz, 1H), 3.41 (td, J=8.7, 3.4 Hz, 1H), 3.47-3.62 (m, 2H), 3.77 (br. s, 1H), 4.12 (br. s, 2H), 4.57 (br. s, 1H), 4.62-4.74 (m, 1H), 6.68 (s, 1H), 6.79 (s, 1H), 6.86 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 16.0h;Inert atmosphere; | Reference Example 60 N-[3-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl]-N-methylacetamide; A solution of N-[3-bromo-5-(trifluoromethyl)phenyl]-N-methylacetamide (6.37 g) obtained in Reference Example 59, 3-hydroxypyrrolidine (1.7 g), palladium(II) acetate (219 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.2 g) and cesium carbonate (19 g) in toluene (100 mL) was stirred under an argon gas atmosphere at 85C for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 34:66 - 0:100) to give the title compound (5.02 g, yield 85%) as a pale-yellow solid. 1H-NMR (300 MHz, CDCl3)delta:1.92 (s, 3 H), 2.01 - 2.31 (m, 3 H), 3.25 (s, 3 H), 3.27 - 3.34 (m, 1 H), 3.34 - 3.46 (m, 1 H), 3.46 - 3.61 (m, 2 H), 4.66 (br. s, 1 H), 6.46 (s, 1 H), 6.70 - 6.74 (m, 2 H). |
85% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 85℃; for 16.0h;Inert atmosphere; | A solution of N-[3-bromo-5-(trifluoromethyl)phenyl]-N-methylacetamide (6.37 g) obtained in Reference Example 59, 3-hydroxypyrrolidine (1.7 g), palladium(II) acetate (219 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.2 g) and cesium carbonate (19 g) in toluene (100 ml) was stirred under an argon gas atmosphere at 85 C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 34:66-0:100) to give the title compound (5.02 g, yield 85%) as a pale-yellow solid.1H-NMR (300 MHz, CDCl3) delta: 1.92 (s, 3H), 2.01-2.31 (m, 3H), 3.25 (s, 3H), 3.27-3.34 (m, 1H), 3.34-3.46 (m, 1H), 3.46-3.61 (m, 2 H), 4.66 (br. s, 1H), 6.46 (s, 1H), 6.70-6.74 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 16.0h;Inert atmosphere; | Reference Example 67 N-[3-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl]-N-methylmethanesulfonamide; A solution of N-[3-bromo-5-(trifluoromethyl)phenyl]-N-methylmethanesulfonamide (7.19 g) obtained in Reference Example 66, 3-hydroxypyrrolidine (1.71 g), palladium(II) acetate (221 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.23 g) and cesium carbonate (19.3 g) in toluene (100 mL) was stirred under an argon gas atmosphere at 85C for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 33:67 - 0:100) to give the title compound (5.45 g, yield 82%) as a brown amorphous form. 1H-NMR (300 MHz, CDCl3)delta:1.91 (br. s, 1 H), 2.06 - 2.30 (m, 2 H), 2.86 (s, 3 H), 3.26 - 3.34 (m, 1 H), 3.32 (s, 3 H), 3.34 - 3.62 (m, 3 H), 4.59 - 4.70 (m, 1 H), 6.66 (s, 1 H), 6.75 (s, 1 H), 6.80 (s, 1 H) . |
82% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 85℃; for 16.0h;Inert atmosphere; | A solution of N-[3-bromo-5-(trifluoromethyl)phenyl]-N-methylmethanesulfonamide (7.19 g) obtained in Reference Example 66, 3-hydroxypyrrolidine (1.71 g), palladium(II) acetate (221 mg), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.23 g) and cesium carbonate (19.3 g) in toluene (100 ml) was stirred under an argon gas atmosphere at 85 C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 33:67-0:100) to give the title compound (5.45 g, yield 82%) as a brown amorphous form.1H-NMR (300 MHz, CDCl3) delta: 1.91 (br. s, 1H), 2.06-2.30 (m, 2H), 2.86 (s, 3H), 3.26-3.34 (m, 1H), 3.32 (s, 3H), 3.34-3.62 (m, 3H), 4.59-4.70 (m, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 6.80 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | at 80℃; | To commercially available <strong>[57381-51-8]2-fluoro-4-chlorobenzonitrile</strong> 15a (1 g, 6.4 mmol) was added 3-pyrrolidinl -ol (2equiv., 1 g) and the solution was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 1.2 g of a white solid. Yield = 85% 'HNMR (DMSO, 200 MHz) delta 1.91 (2H, m), 3.54 (4H, m), 4.37 (1H, b), 5.06 (1H, bd, J = 3.4 Hz), 6.72 (2H, m), 7.50 (1H, d, J = 8.2 Hz) |
85% | In ethyl acetate; | Preparation of 4-chloro-2-(3-hydroxypyrrolidin-1-yl)benzonitrile 16ai (scheme 8) To commercially available <strong>[57381-51-8]2-fluoro-4-chlorobenzonitrile</strong> (1 g, 6.4 mmol) was added 3-pyrrolidinl-ol (2equiv., 1 g) and the solution was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 1.2 g of a white solid. Yield = 85% 1HNMR (DMSO, 200 MHz) delta 1.91 (2H, m), 3.54 (4H, m), 4.37 (1H, b), 5.06 (1H, bd, J = 3.4 Hz), 6.72 (2H, m), 7.50 (1H, d, J = 8.2 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.1% | With caesium carbonate;copper(l) iodide; L-proline; In dimethyl sulfoxide; at 95℃; for 5.5h;Inert atmosphere; Sealed tube; | Example 24; 4-(3 -(6-Chloro- 1 -oxoisoindolin-2-yl)-2-methylphenyl)-7-(3 -hydroxypyrrolidin- 1 -yl)-9H- -b]indole-1-carboxamide; 1. 1 -( 1 H-Indol-6-yl)pyrrolidin-3 -olH; To a pressure tube containing a light orange, homogeneous solution of 6- bromo-1H-indole (1.01 g, 5.15 mmol) in DMSO (8.58 mL) purged with nitrogen were added <strong>[40499-83-0]pyrrolidin-3-ol</strong> (4.49 g, 51.5 mmol), cesium carbonate (3.36 g, 10.30 mmol), copper(I) iodide (0.098 g, 0.515 mmol) and (S)-pyrrolidine-2-carboxylic acid (0.652 g, 5.67 mmol). The pressure tube was sealed and stirred at 95 C for 5.5 hr. The reaction was cooled to room temperature and immersed in an ice-water bath. Ice water (20 mL) was added, and the mixture was stirred for 10 min. It was extracted with EtOAc (4x75 mL), and the organic layers were combined, dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120g column eluting with 20-100% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.5215 g, 2.58 mmol, 50.1% yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With lithium carbonate; In dimethyl sulfoxide; at 100℃; for 3h; | A suspension of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (10.0 g, 64.3 mmol), pyrrolidin-3-ol 9 (5.60 g, 64.3 mmol), and lithium carbonate (7.12 g, 96.4 mmol) in DMSO (100 mL) was stirred at 100 C for 3 h. The mixture was diluted with H2O. The precipitated compound was collected by filtration, air-dried, and recrystallized from hexane-EtOAc to give 4 (9.56 g, 67%) as light brown crystals, mp 130.5-131 C. 1H NMR (300 MHz, CDCl3) delta: 1.68 (1H, d, J = 4.0 Hz), 2.00-2.30 (2H, m), 3.25-3.36 (1H, m), 3.37-3.49 (1H, m), 3.49-3.64 (2H, m), 4.55-4.80 (1H, m), 6.41 (1H, dd, J = 8.8 and 2.4 Hz), 6.56 (1H, d, J = 2.4 Hz), 7.42 (1H, d, J = 8.8 Hz). MS (ESI) m/z 223 [(M+H)+]. Anal. Calcd for C11H11ClN2O: C, 59.33; H, 4.98; N, 12.58; Cl, 15.92. Found: C, 59.38; H, 4.93; N, 12.53; Cl, 15.78. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | Intermediate 46 A 1 - [(4-Aminopyrrolo [2, 1 -fj [ 1 ,2,4]triazin-7-yl)methyl]pyrroiidin-3-ol 3-Pyrrolidinol (1.56 g, 1 7.9 mmol) and 37% formalin solution (1.45 g, 1 7.9 mmol) were dissolved in acetic acid ( 75 mL) and stirred at room temperature for 10 min. To this solution was added a solution of pyrrolo[2, 1 -fj [ 1 ,2,4]triazin-4-amine (2.0 g, 14.9 mmol) in acetic acid (75 mL), and the mixture was stirred at 60C for 4 h. After evaporation, the residue was taken up in 200 mL of 1 N aqueous potassium carbonate solution and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative 1 1 PLC (method 4) to give 390 mg (1 1% of th.) of the title compound. LC-MS (method 4): Rt = 0.22 min; MS (ESIpos): m/z (%) = 234.2 (20) [M+H]+, MS (ESIneg): m/z (%) = 223.0 (100) [M-H]~ .H NMR (400 MHz, <¾-DMSO): delta (ppm) = 1.50 (br. m, H I ). 1.94 (m, 11 1 ). 2.34 (dd, 1H), 2.44 (dd, 1H), 2.60 (dd, 1H), 2.71 (dd, 1H), 3.84 (dd, 2H), 4.15 (br, 1H), 4.65 (d, 1H), 6.52 (d, 1H), 6.83 (d, i l l ). 7.61 (br, 21 . ). 7.82 (s, 1 1 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.1 g | To a solution of tert-butyl 4- [ (Z) - (2-oxo-4-thioxo-l, 3- thiazolidin-5-ylidene) methyl] piperidine-l-carboxylate (6.75 g) in ethanol (60 mL) was added 3-pyrrolidinol (1.66 mL) , and the mixture was stirred at 80°C for 4 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give a mixture. To a solution of the obtained mixture in ethylacetate (10 mL) was added 4M hydrogen chloride/ethyl acetate solution (20 mL) , the mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reducedpressure. To a solution of the obtained residue in N,N- dimethylformamide (50 mL) were added triethylamine (5.55 mL) and 2, 4-bis (trifluoromethyl) benzaldehyde (3.62 g) . Thereaction mixture was stirred at room temperature for 30 min under a nitrogen atmosphere, and sodium triacetoxyborohydride (8.44 g) was added. The mixture was stirred at roomtemperature for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (2.10 g) . XH NMR (300 MHz, CDC13) delta 1.46-2.33 (9H, m) , 2.84 (2H, d, J = 11.3 Hz), 3.56-4.06 (7H, m) , 4.51-4.85 (lH,.m), 6.22-6.53 (1H, m) , 7.77 (1H, d, J = 8.7 Hz), 7.88 (1H, s) , 7.97 (1H, d, J = 7.4 Hz) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In N,N-dimethyl-formamide; at 125℃; for 24h;Inert atmosphere; | a) 6-(3-hvdroxypyrrolidin-1 -vDnicotinamide To a solution of <strong>[6271-78-9]6-chloronicotinamide</strong> (0.16 g, 1 mmol) and pyrrolidin-3-ol (0.87g, 1 mmol) in DMF (5 ml) was added K2C03 (0.41 g, 3mmol). The resulting solution was stirred under nitrogen at 125 C for 24 h, and then allowed to cool to ambient temperature. The reaction mixture was then filtered and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated to afford the title compound (0.145g, 70%) as a yellow solid. [LCMS RtA=1 23 min, [M+H]+ =208.1]. |
70% | With potassium carbonate; In N,N-dimethyl-formamide; at 125℃; for 24h;Inert atmosphere; | a) 6-(3-hydroxypyrrolidin-1-yl)nicotinamide To a solution of <strong>[6271-78-9]6-chloronicotinamide</strong> (0.16 g, 1 mmol) and pyrrolidin-3-ol (0.87 g, 1 mmol) in DMF (5 ml) was added K2CO3 (0.41 g, 3 mmol). The resulting solution was stirred under nitrogen at 125 C. for 24 h, and then allowed to cool to ambient temperature. The reaction mixture was then filtered and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated to afford the title compound (0.145 g, 70%) as a yellow solid. [LCMS RtA=1.23 min, [M+H]+=208.1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium tris(acetoxy)borohydride; In dichloromethane; at 20.0℃; for 5.0h; | To a slurry of intermediate No. 2 (440 mg, 2.0 mmol) and (R)-pyrrolidin-3-ol (250 mg, 1.5 equiv.) in 30 mL of dichloromethane, was added NaBH(OAc)3 (1.3 g, 3 equiv.) at room temperature. The reaction was stirred for 5 hour at room temperature and then quenched with iiV-NaOH. It was extracted with ethyl acetate and washed twice with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (heptane/ethyl acetate) to afford desired intermediate as a pale yellow solid (468 mg, 80 %). A round bottomed flask was charged with (R)-l-((l-(2-chloropyrimidin-4-yl)- 3-methyl-iH-pyrazol-4-yl)methyl)pyrrolidin-3-ol (268 mg, 1.6 mmol), 3-chloro-l- cyclopropyl-iH-indol-5-amine (430 mg, 1.3 equiv.), potassium carbonate (0.66 g, 3.0 equiv), palladium acetate (18 mg, 0.05 equiv.), Xantphos (0.1 equiv.) and 50 mL of anhydrous dioxane. After being degassed by nitrogen bubbling, the reaction mixture was heated at 100 C for 5 hours. Volatiles were removed in vacuo and then the resulting residue was extracted with dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (DCM/MeOH) to give 519 mg (70 %) of the desired Compound 142 as a pale yellow solid. MS (ESI) m/z 464 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In Isopropyl acetate; at 70℃; for 14h; | Stage 9.6: (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate DIPEA (105.3 g, 142.2 mL, 814.4 mmol) was added to a solution of <strong>[78686-77-8]methyl-5-bromo-6-chroronicotinate</strong> (85 g, 339.5 mmol) and (R)-pyrrolidin-3-ol (54.2 g, 441.2 mmol) in isopropyl acetate and the RM was stirred at 70 C. for 14 h. The solvent was evaporated off under reduced pressure to give a the residue which was dissolved in toluene (850 mL), washed with water (127 mL) and brine (127 mL) and concentrated under reduced pressure until precipitation commenced. n-Heptane (340 mL) was slowly added to the stirred mixture at 22 C., which was then cooled to 0 C. and the product was filtered, washed with a toluene/n-heptane mixture (1:1.5) and dried to give the title compound as a yellow solid. HPLC (Condition 7) tR=8.54 min, LC-MS (Condition 8) tR=4.62 min, m/z=300.9/302.9 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) delta ppm 1.77-1.99 (m, 2H), 3.57 (d, J=11.54 Hz, 1H), 3.72 (ddd, J=11.11, 7.97, 3.26 Hz, 1H), 3.78 (s, 3H), 3.81-3.90 (m, 2H), 4.26-4.39 (m, 1H), 4.99 (br. s, 1H), 8.11 (d, J=2.01 Hz, 1H), 8.56 (d, J=1.76 Hz, 1H). | |
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 140℃; for 1h; | [00548] Methyl-5-bromo-6-chroronicotinate (1 g, 4 mmol) and (R)-pyrrolidin-3-ol (418 mg, 4.8 mmol) were dissolved in iPrOH (4 mL). DIPEA (0.9 mL, 5.2 mmol) was added and the RM mixture was heated at 140C for 1 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2S04 and the solvent was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (RediSep Silica gel column, n-hexane / EtOAc, from 50% to 80% EtOAc) to afford the title compound as a brown-yellow oil. HPLC (Condition 4) tR = 4.11 min, UPLC-MS (Condition 7) m/z = 301 [M+H . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 20h; | General procedure: (a) (S)-pyrrolidin-3-ol, 22, (500mg, 5.75mmol), <strong>[34941-90-7]2,4-difluoropyridine</strong> (793mg, 6.9mmol) and DIPEA (0.5mL) in DMF (5mL) was heated at 60C for 20h. The mixture was poured into 1N NaOH solution (100mL), extracted with ethyl acetate (2X). Combined extracts were washed with brine, dried over magnesium sulfate, and concentrated to give (S)-1-(4-fluoropyridin-2-yl)pyrrolidin-3-ol 23 (512mg, 49% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With triethylamine; In N,N-dimethyl-formamide; at 150℃; for 1h;Sealed tube; Microwave irradiation; | PREPARATION x2: (R)-1-(5-bromo-6-methylpyridin-2-yl)pyrrolidin-3-ol [0150] 3-Bromo-6-chloro-2-methylpyridine (350 mg, 1.695 mmol), (i?)-pyrrolidin-3-ol (148 mg, 1.695 mmol), Et3N (0.709 mL, 5.09 mmol) and DMF (4 mL) were mixed in an 8 mL tube equipped with a magnetic stir bar to give an orange solution. The tube was sealed and the mixture was heated in a microwave to 150C for 1 hour. The reaction mixture was subsequently partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated. The aqueous layer was back-extracted with EtOAc (20 mL) and the combined organic layers were concentrated to yield a brown syrup. The residue was purified via flash chromatography (12 g column), eluting with 0-80% EtOAc in heptanes. The pure fractions were combined and concentrated to give the title compound as a clear liquid (144 mg, 33.0%). MS [M+H]+ calc'd for Ci0Hi3BrN2O, 257.03; found 257.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1.5h;Microwave irradiation; | To a solution of <strong>[444120-94-9]2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (239 mg, 1 mmol) in NMP (2 mL) was added pyrrolidin-3-ol (174 mg, 2 mmol) and DIPEA (500 uL, 3 mmol), then the mixture was sealed in a microwave tube and heated in microwave reactor at 180 C. for 1.5 hours. TLC and LC-Ms showed the reaction had completed and the desired compound was detected. The reaction mixture was poured into 30 mL of H2O, and extracted with n-BuOH, washed with water and brine, concentrated and purified on TLC(CH2Cl2:MeOH=10:1) to give a white solid. MS(mlz): 209 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In 1,4-dioxane; 1-methyl-pyrrolidin-2-one; at 150℃; for 18h;Sealed tube; | [00227j Step 1: 6-Amino-2-chloronicotinonitrile (0.100 g, 0.65 1 mmol) was taken in a sealed tube and dissolved in dioxane (3 mL) and NMP (0.2 mL). To that was added (R)pyrrolidin-3-ol (0.05 7 g, 0.651 mmol) and NMP (0.2 mL) and the set up was heated at 150 C for 18 h. The solvents were evaporated from the reaction mixture and the crudewas dissolved in water and made basic by adding NaHCO3 and was extracted with DCM(3 x 15 mL). The combined organic layer were dried and evaporated to get the product(80 mg, 42% yield) which was directly in the next reaction. LCMS 205.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.6% | With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In toluene; at 50℃; for 1.0h;Inert atmosphere; | Example 28 4-(3-(3-Fluoro-4-((pyrrolidin-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidi n-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 -(trifluoromethyl)benzonitrile 1e (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of pyrrolidine-3-ol (12 mg, 0.14 mmol), 1,1'-(azodicarbonyl)dipiperidine (47 mg, 0.19 mmol), 5 mL of methylbenzene and tri-n-butylphosphine (38 mg, 0.19 mmol) successively. The reaction solution was warmed up to 50C and stirred for 1 hour. The reaction solution was concentrated under the reduced pressure, and the residue was purified by thin layer chromatography with elution system A to obtain the title compound 4-(3-(3-fluoro-4-((pyrrolidin-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidi n-1-yl)-2-(trifluoromethyl)benzonitrile 28 (45 mg, yield 77.6%) as a white solid. |
77.6% | With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In toluene; at 50℃; for 1.0h; | 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1e (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of pyrrolidine-3-ol (12 mg, 0.14 mmol), 1,1'-(azodicarbonyl)dipiperidine (47 mg, 0.19 mmol), 5 mL of methylbenzene, and tri-n-butylphosphine (38 mg, 0.19 mmol), successively. The reaction solution was warmed up to 50 C. and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with elution system A to obtain the title compound 4-(3-(3-fluoro-4-((pyrrolidin-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 28 (45 mg, yield 77.6%) as a white solid. MS m/z (ESI): 493.2 [M+1]; 1H NMR (400 MHz, CDCl3): delta 8.00-7.96 (m, 2H), 7.85-7.82 (m, 1H), 7.17-7.04 (m, 3H), 3.54-3.35 (m, 5H), 2.27-2.18 (m, 2H), 1.60 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
REFERENCE EXAMPLE 600 Preparation of (3R)-1-(3,4-dichlorophenyl)pyrrolidine-3-ol (3R)-pyrrolidine-3-ol was reacted with <strong>[1435-49-0]1,2-dichloro-4-fluorobenzene</strong> in the same manner as Reference Example 590 to yield the titled compound. MS (ESI) m/z: 232/234 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydrogensulfite; In water; at 120 - 130℃; for 72.0h; | General procedure: A steel bomb was charged with 6-bromo-2-naphthol (14), a secondary amine, sodium bisulfite, and water. The mixture was stirred at 120 C-130 C for 72 h. Upon cooling the reaction mixture was diluted with water, the product was extracted with CH2Cl2 or EtOAc, and the organic layer was washed with 5% NaOH solution, followed by washing with brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation. The crude product was purified by crystallization to give the corresponding naphthylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | Step" : 2-(3-hvdroxypyrrolidin-1-yl)isonicotinonitrile (2a) In a 100ml flask equipped with a magnetic stir bar and condenser was placed 2-chloro- isonicotinonitrile (1500 mg, 10.8 mmol), DMF (15 ml), 3-pyrrolidinol (1.3 ml, 16.2 mmol) and potassium carbonate (2300 mg, 21.7 mmol). The reaction was heated to 60C for 3 hours then partially concentrated to remove DMF, diluted with EtOAc and water, separated, extracted 1X with EtOAc, washed four times with brine, dried over sodium sulfate, filtered, then concentrated under reduced pressure (1770mg, 86% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Potassium carbonate (0.722 g, 5.22 mmol) was added to a stirred solution of <strong>[22532-61-2]<strong>[22532-61-2]2-bromo-6-hydroxybenzaldehyd</strong>e</strong> (0.875 g, 4.35 mmol) and 1-bromo-3-chloropropane (0.857 mL, 8.71 mmol) in DMF (10 mL) and heated at 65 C. overnight. The reaction mixture was cooled to rt and diluted with ether and washed with water, brine, dried (Na2SO4), concentrated and purified by silica gel chromatography (0-10% EtOAc/hexane) to yield a mixture of 2-bromo-6-(3-chloropropoxy)benzaldehyde and 2-bromo-6-(3-bromopropoxy)benzaldehyde in 7:3 ratio as a clear viscous oil (1.1 g). (0665) Neat DAST (0.491 mL, 3.72 mmol) was added to a cold (-20 C.) stirred solution of 2-bromo-6-(3-chloropropoxy)benzaldehyde (0.43 g, 1.549 mmol) and EtOH (0.063 mul, 1.085 mumol) in an. DCM (5 mL) and the mixture was allowed to warm rt and stirred overnight. Reaction mixture was diluted with water and quenched with ice and neutralized with satd. NaHCO3. Organic layer washed with water, brine, dried (MgSO4), concentrated and purified by silica gel flash column chromatography (=FCC) (0-10% EtOAc-hexanes) to afford a mixture of 1-bromo-3-(3-chloropropoxy)-2-(difluoromethyl)benzene and 1-bromo-3-(3-bromopropoxy)-2-(difluoromethyl)benzene in 7:3 ratio as a clear oil (0.394 g, 1.315 mmol, 85% yield) which was dissolved in DMF (3 mL) and added (R)-pyrrolidin-3-ol (0.174 g, 2.0 mmol), potassium carbonate (0.3 g, 2.2 mmol) and sodium iodide (30 mg, 0.2 mmol) and heated at 65 C. for 12 h. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (Na2SO4), concentrated and purified by silica gel FCC (0-20% MeOH-DCM) to yield (R)-1-(3-(3-bromo-2-(difluoromethyl)phenoxy) propyl)pyrrolidin-3-ol (0.42 g, 91%) as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca.75 mg | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 90 - 92℃; for 12h;Inert atmosphere; | To a mixture of the starting material 7H (150 mg, 0.38 mmol) and dioxane (8 mL) were added (R)-pyrrolidin-3-ol (100 mg, 1.1 mmol, 3 eq) and DIEA (147 mg, 1.14 mmol, 3 eq) at room temperature. The mixture was then stirred at 90-92 C. under nitrogen for 12 h. LC-MS analysis showed the product peak. The mixture was not a clear solution. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure, and the resultant residue was suspended in 50 mL acetonitrile, and centrifuged at 4000 rpm for 15 min. The pellet was then suspended in cooled 80% acetonitrile, and centrifuged at 4000 rpm for 15 min. The pellet was re-suspended in cooled 80% acetonitrile, and centrifuged at 4000 rpm for 15 min. The supernatants were combined and concentrated to dryness to afford the target compound XI (H-30) (?75 mg) as an off-white solid. LC-MS: 445 (M+H); 1H NMR (DMSO-d6): 11.40 (s, 1H. NH), 9.83 (s, 1H, NH), 8.19 (s, 1H), 7.40 (m, 1H), 7.24 (m, 2H), 5.80 (s, 1H), 4.98 (s, 1H), 4.35 (s, 1H), 2.53 (s, 3H), 2.20 (s, 2H), 2.12 (s, 2H), 1.85 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In toluene; at 90℃; for 3.0h; | Intermediate III1g (1.78 mmol) was dissolved in 35 ml of toluene, and 3-hydroxypyrrolidine 2.05 mmol was added.Potassium carbonate 2.05 mmol, stirred at 90 C for 3 h, the desired product was obtained.The obtained mixed solution is evaporated to dryness, and the mixture is reconstituted in dichloromethane, and 100 g of 100-200 mesh silica gel is added and mixed well, after the solvent is evaporated,The crude product-silica gel powder mixture was purified by column chromatography (200-300 mesh silica gel powder as stationary phase, petroleum ether: ethyl acetate = 1:1 as mobile phase).The pure product of the product 22-O-[2-(3-hydroxypyrrolidinylacetamido)phenyl]thioacetyl methane (Compound 21) was obtained.The yield was 83%. |
55% | With potassium carbonate; In acetonitrile; at 70℃; for 3.0h; | General procedure: A solution of compound 6 (1 g, 1.78 mmol) in acetonitrile(10 mL) and K2CO3 (0.48 g, 3.48 mmol), piperazine derivatives(2 mmol) was added, the solution was stirred at 70 C for 3 h. Aftercompletion of the reaction, water (50 mL) and CHCl3 (30 mL) wasadded to the solution, the mixture is transferred to the separationfunnel after mixing, the organic phase was washed with NaCl solution(15% w/v) for twice after vibrating sufficiently and staticallystratified, then dried (Na2SO4) and concentrated under reducedpressure to give the crude product. The crude product was purifiedby silica gel column chromatography to give a pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.9% | In ethanol; water;Reflux; | Dissolve 266.33 mg of magnolol (1 mmol) and 87 mg (1 mmol) of (R) -3-pyrrolidinol with ethanol,Add 37% aqueous formaldehyde (75 muL, 1 mmol),Heat to reflux, spot the plate to monitor the progress of the reaction,After the reaction is completed, the solvent is spun off directly, and the sample is passed through a column (petroleum ether-ethyl acetate = 5/1) to obtain 219 mg of a beige powdery solid with a yield of 59.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
390 mg | With tris-(dibenzylideneacetone)dipalladium(0); (R)-(+)-2,2?-bis(diphenylphosphino)-1,1?-binaphthalene; caesium carbonate; In toluene; for 1h;Reflux; | (1) A mixture of <strong>[1130165-74-0]ethyl 4-bromo-3-fluorobenzoate</strong> (500 mg), tris(dibenzylideneacetone)dipalladium (0) (94 mg), (R)-(+)-(1,1'-binaphthalene-2,2'-diyl)bis(diphenylphosphine) (189 mg), cesium carbonate (1.98 g), (R)-pyrrolidin-3-ol (353 mg), and toluene (5 mL) was stirred for 1 hour under heating and refluxing. The reaction mixture was cooled to room temperature and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; 70%-30% n-hexane/ethyl acetate] to obtain ethyl (R)-3-fluoro-4-(3-hydroxypyrrolidin-1-yl)benzoate (390 mg) as a brown oily substance. MS (ESI nm/z): 254 (M+H) RT (min): 1.41 |
Tags: 40499-83-0 synthesis path| 40499-83-0 SDS| 40499-83-0 COA| 40499-83-0 purity| 40499-83-0 application| 40499-83-0 NMR| 40499-83-0 COA| 40499-83-0 structure
[ 104706-47-0 ]
(R)-3-Hydroxypyrrolidine hydrochloride
Similarity: 0.96
[ 122536-94-1 ]
(S)-3-Hydroxypyrrolidine hydrochloride
Similarity: 0.96
[ 104706-47-0 ]
(R)-3-Hydroxypyrrolidine hydrochloride
Similarity: 0.96
[ 122536-94-1 ]
(S)-3-Hydroxypyrrolidine hydrochloride
Similarity: 0.96
[ 104706-47-0 ]
(R)-3-Hydroxypyrrolidine hydrochloride
Similarity: 0.96
[ 122536-94-1 ]
(S)-3-Hydroxypyrrolidine hydrochloride
Similarity: 0.96
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P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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