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CAS No. : | 68108-18-9 | MDL No. : | MFCD00273370 |
Formula : | C4H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IOGISYQVOGVIEU-VKHMYHEASA-N |
M.W : | 101.10 | Pubchem ID : | 155084 |
Synonyms : |
(4S)-4-Hydroxy-2-pyrrolidinone
|
Chemical Name : | (S)-4-Hydroxypyrrolidine-2-one |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H319 | 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 |
---|---|---|
100% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 16h; | Imidazole (93.73 g, 1 .26 mol) and tert-butyldimethylsilyl chloride (145.3 g, 0.96 mol) were added to a solution of (S)-4-hydroxy-2-pyrrolidone (92.8 g, 0.92 mol) in dimethylformaide (560 ml_). The mixture was then stirred at room temperature for 16 hours, after which time it was poured over ice and an aqueous solution of hydrochloric acid (0.2 M, 300 ml_) was added. The mixture was stirred at room temperature for 10 minutes, and then extracted with ethyl acetate (4 x 500 ml_). The combined organic extracts were washed with brine (1000 ml_), dried over sodium sulphate, filtered, and evaporated u n d er red u ced p ressu re to g ive (S )-4-(tert-butyl-dimethyl-silanyloxy)- pyrrolidin-2-one as a solid (200 g, 100%). |
97.4% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 6h; | (17 g, 100 mmol) of (S) -4-hydroxy-2-oxopyrrolidine and 17 g (250 mmol) of imidazole were dissolved in 120 ml of DMF,A DMF solution of tert-butyldimethylchlorosilane (18.1 g of t-butyldimethylchlorosilane, 120 mmol) At room temperature for 6 hours,The reaction solution was poured into ice water, extracted three times with ethyl acetate, washed three times with saturated brine,Concentrated under reduced pressure, and recrystallized from diethyl ether to give 20.98 g of the compound represented by the formula III protected by t-butyldimethylsilane in a yield of 97.4%. |
97.1% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 6.5h; | (S)-4-hydroxy-2-oxo-pyrrolidine 10.1 g (100 mmol), imidazole 13.6g (200mmol) was dissolved in 100ml DMF, followed by the dropwise addition of t-butyldimethylchlorosilane in DMF (Containing tert-butyldimethylchlorosilane 18.1 g, 120 mmol) at room temperature for 6.5 hours. The reaction solution was poured into ice water, Ethyl acetate was extracted three times, washed with saturated brine three times, concentrated under reduced pressure and recrystallized from diethyl ether to give 20.9 g of the compound represented by the formula III protected by t-butyldimethylsilane in a yield of 97.1%. |
92% | With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h; | To a solution of ()-4-hydroxypyrrolidin-2-one (cas: 68108-18-9, 5.0 g, 49.5 mmol) in DMF (20 mL) at 0- 5 C was added /cvV-butyl chi orodi m ethyl si 1 an e (8.9 g, 1.2 equiv.) and imidazole (8.4 g, 2.5 equiv.). The reaction mixture was allowed to warm to ambient temperature and stirred for 12 hours. Water (50 mL) was then added and the reaction mixture was stirred for 10 minutes. The white precipitate that was formed was filtered and washed with water (15 mL) and then dried under high vacuum to afford 1-258 (9.8 g, 92% yield). MS (ESI, pos. ion) m/z: 2l6. l(M+l). |
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; | 1.02 g of imidazole and 1.58 g of t-butyldimethylchlorosilane were added to a dimethylformamide (5 ml) solution of 1.01 g of (S)-4-hydroxy-2-pyrrolidone, and stirred overnight at room temperature. Water was added to the reaction liquid, and stirred with cooling with ice. The precipitated crystal was taken out through filtration and dried to obtain 2.07 g of the entitled compound as a colorless crystal. | |
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 21h; | (S)-4-Hydroxypyrrolidin-2-one (101 g) was dissolved in N,N-dimethylformamide (400 mL), imidazole (102 g) and t-butyldimethylchlorosilane (158 g) were added thereto at 0 C., and stirring was conducted at room temperature for 21 hours. The reaction liquid was added to water, and the precipitated white solid was collected by filtration and washed with water to give the title compound (210 g) as a white solid.1H-NMR (CDCl3) δ (ppm): 0.02 (6H, s), 0.81 (9H, s), 2.16-2.22 (1H, m), 2.42-2.50 (1H, m), 3.14-3.18 (1H, m), 3.49-3.54 (1H, m), 4.46-4.52 (1H, m), 5.76 (1H, br.s).ESI/MS (m/z): 216 (M+H)+. | |
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | (S)-4-hydroxy-2-pyrrolidone S20 (500 mg, 4.95 mmol) was dissolved in DMF (50 mL), and tertbutyldimethyl silyl chloride (894.5 mg, 5.93 mmol, 1.2 equiv) and imidazole (673.4 mg, 9.89 mmol,2equiv) were added under the protection of nitrogen at 0 C and stirred for 30 minutes at roomtemperature. The mixture was poured into H2O, filtered, collected, and dried to obtain 4-tert-butyldimethylsiloxane -2-pyrrolidone S21 white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.1% | EXAMPLE 2 Synthesis of (S)-4-Hydroxy-2-pyrrolidone (One-pot Reaction) In a 200 ml autoclave were charged 40 g of the product obtained in Reference Example 1 (containing 35.9 g (0.129 mol) of ethyl 4-benzyloxycarbonylamino-3-oxobutanoate), 120 ml of ethanol, and 0.179 g (0.204 mmol) of [RuCl(benzene)((R)-BINAP)]Cl in a nitrogen stream, and asymmetric hydrogenation was conducted at 50 C. and at a hydrogen pressure of 30 atm for 17 hours (conversion: 98.2%; optical purity: 93.8% e.e.). Thereafter, 1.68 g of wet 5% palladium-on-carbon was put therein, and hydrogenolysis was carried out at 25 C. and at a hydrogen pressure of 4 to 6 atm for 4.5 hours. The reaction mixture was stirred at 60 C. for 8 hours and then at room temperature for 7 hours to carry out cyclization. To the reaction mixture was added 0.5 g of activated carbon, followed by stirring at 50 C. for 1 hour. To the mixture was added 20 ml of ethanol, and the mixture was filtered. The methanolic filtrate was crystallized by stirring at -10 C. for 1.5 hours, followed by filtration to obtain 10.4 g of the title compound in a yield of 80.1%. Melting point: 158 to 162 C. Optical purity: 100% e.e. | |
77.3% | Thereafter, 1.68 g of wet 5% palladium-on-carbon was put therein, and hydrogenolysis was carried out at 25 C. and at a hydrogen pressure of 4 to 6 atm for 4.5 hours. The reaction mixture was stirred at 60 C. for 8 hours and then at room temperature for 7 hours to carry out cyclization. To the reaction mixture was added 0.5 g of activated carbon, followed by stirring at 50 C. for 1 hour. To the mixture was added 20 ml of ethanol, and the mixture was filtered. The methanolic filtrate was crystallized by stirring at -15 C. for 1.5 hours, followed by filtration to obtain 10.1 g of the title compound in a yield of 77.3%. Melting point: 158 to 162 C. Optical purity: 100% e.e. | |
70.6% | 18 ml of methanol was added to the primary mother liquor weighing 7.1 g to perform crystallization in the same manner as above thereby producing 2.35 g of secondary crystals. The primary and secondary crystals were added up to find that the title compound amounted to 9.2 g and the yield was 70.6%. Melting point: 158-162C Chemical purity: 100% Optical purity: 100% e.e. 1H-NMR: δppm (400 MHz, D2O) 2.26 (1H, dd, J=2Hz, 18Hz), 2.75 (1H, dd, J=6.4Hz, 17.6Hz), 3.32 (1H, dd, J=1.6Hz, 11.6Hz), 3.7 (1H, dd, J=5.2Hz, 11.6Hz), 4.59-4.62 (1H, m) |
63.0% | 6 ml of methanol was added to the primary mother liquor weighing 2.41 g to perform crystallization in the same manner as above thereby producing 0.71 g of secondary crystals. The primary and secondary crystals were added up to find that the title compound amounted to 2.95 g and the yield was 63.0%. | |
Then the crude product was dissolved in methanol (1 Lit.) and to it 5% palladium-carbon (10 g) was added. The mixture was stirred for 17 hours at room temperature under a hydrogen atmosphere. After the reaction was over, palladium-carbon was filtered off and the solvent was distilled off under vacuo. The resulting product was recrystallized from acetone-water to give (S)-4-hydroxy-2-pyrrolidone (99 g, 0.98 mol, yield:84%) as a colorless crystalline solid. Optical purity:98.3% ee, Specific rotation:[α]D22 -57.6(c=1.00, H2 O). | ||
After completion of the ring-closing reaction, methanol was distilled off under reduced pressure and the resulting crude crystals were recrystallized from ethanol (10 ml) to obtain colorless crystals. Yield: 1.40 g (83.4%). Melting point: 156.2-157.6 C. NMR (500 MHz. D2 O, δ ppm): 4.62 (1H, m), 3.72 (1H, dd, J=5.4 11.7 Hz), 3.33 (1H, dd, J=1.3 11.7 Hz), 2.77 (1H, dd, J=6.4 17.7 Hz), 2.27 (1H, dd, J=1.9 17.7 Hz). [α]D25-58.5 (c=1.01, H2 O). IR (KBr, cm-1): 3242, 3135, 1674, 1303, 968, 682. | ||
EXAMPLE 2 Production of (S)-4-hydroxy-2-pyrrolidinone A 28% methanol solution of sodium methoxide (40 mg, 0.2 mmol as NaOMe) was added to a methanol solution (25 ml) of ethyl (S)-4-amino-2-hydroxybutyrate (1.32 g, 9.0 mmol) and the mixture was stirred at room temperature for 2 hours. After completion of the ring-closing reaction, methanol was distilled off under reduced pressure and the resulting crude crystals were recrystallized from ethanol to obtain colorless crystals. The yield was 0.71 g (79%) and the melting point was 156.6-157.9 C. The NMR data, IR data, and behavior during the HPLC analysis using an optical resolution column of the thus-obtained colorless crystals were identical with those obtained in Example 1. | ||
(2) Synthesis of (S)-4-Hydroxy-2-pyrrolidone In a 200 ml autoclave were charged 33.5 g of the product obtained in (1) (containing 28.16 g (0.1 mol) of ethyl (3S)-4-benzyloxycarbonylamino-3-hydroxybutanoate), 100 ml of methanol, and 1.68 g of wet 5% palladium-on-carbon, and hydrogenolysis was conducted at 25 C. under a hydrogen pressure of 4 to 6 atm for 3.5 hours. The reaction mixture was filtered, and methanol was evaporated under reduced pressure to obtain 18.95 g (liquid) of a crude aminohydroxy-ester. A 17 g portion of the crude product was weighed out, and 85 ml of methanol was added thereto, followed by stirring at 60 C. for 8 hours and then at room temperature for 7 hours to conduct cyclization. One gram of activated carbon was added to the reaction mixture, and the mixture was stirred at 50 C. for 1 hour, followed by filtration. For the filtration, 20 ml of methanol was used. The methanolic filtrate was crystallized by stirring at -15 C. for 1.5 hours. The crystals were collected by filtration and washed with ethyl acetate/methanol (4/1) to obtain 6.03 g of first crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 140h; | Part F An amide from the table below (1.2 eq) was added to a test tube containing 8 mg (0.4 eq) of copper iodide, 42 mg of potassium phosphate, and a magnetic stir bar. A solution of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H imidazo[4,5-c][1,5]naphthyridin-1- yl] -2-methylpropan-2-ol (38 mg, 1.0 eq) in 1,4-dioxane (1.0 mL) was added to the test tube and the test tube was purged with nitrogen. A solution of N,N- dimethylethylenediamine (4.4 μL) in 1,4-dioxane (25 μL) was added to the test tube and the test tube was purged with nitrogen. The test tube was capped and the reaction mixture was stirred at 110 C for 140 hours. The reaction mixture was filtered and then concentrated by vacuum centrifugation. The compounds were purified as described in Examples 15 - 30. The table below shows the amide used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. |