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CAS No. : | 17016-83-0 | MDL No. : | MFCD00010847 |
Formula : | C6H11NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YBUPWRYTXGAWJX-RXMQYKEDSA-N |
M.W : | 129.16 | Pubchem ID : | 7157133 |
Synonyms : |
(S)-4-Isopropyl-2-oxazolidinone
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 37.23 |
TPSA : | 38.33 Ų |
GI absorption : | High |
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) : | -6.29 cm/s |
Log Po/w (iLOGP) : | 1.51 |
Log Po/w (XLOGP3) : | 1.12 |
Log Po/w (WLOGP) : | 0.37 |
Log Po/w (MLOGP) : | 0.41 |
Log Po/w (SILICOS-IT) : | 0.83 |
Consensus Log Po/w : | 0.85 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.28 |
Solubility : | 6.77 mg/ml ; 0.0524 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.52 |
Solubility : | 3.92 mg/ml ; 0.0303 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.94 |
Solubility : | 14.7 mg/ml ; 0.114 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.22 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
99% | Stage #1: With triethylamine; lithium chloride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: at 0 - 20℃; for 1.5 - 2 h; |
Example 2: Preparation of (S)-4-isopropyl-3-propionyloxazolidin-2-one (3) <n="15"/>The compound (2) prepared in Example 1 (10Og) was dissolved in tetrahydrofuran (300mNo.), and cooled to 0°C . Lithium chloride (36g) was added, triethylamine (10Ig) was then slowly added, and the resulting mixture was stirred for 30 min. Propionic acid anhydride (106g) was slowly added over a 30 min. time period. The reaction mixture was slowly warmed to room temperature, and stirred for 1-1.5 h. The reaction solution was cooled, IN aqueous sodium chloride solution (300mNo.) was added, and the mixture was stirred for 30 min. Ethyl acetate (300mf) was added, the phases were separated, and extracted once again by ethyl acetate (300m.pound.). After washing with 1.5 N hydrochloric acid (300m.pound.), the organic phase was washed once again with aqueous sodium chloride solution (300mNo.), dried, filtered and distilled to produce the title compound (142g, Yieldpercent). 1H NMR (300MHz, CDCl3) δ 4.4 (m, IH), 4.3-4.2 (m, 2H), 2.97 (m, 2H), 2.3 (m,IH), 1.2 (t, 3H), 0.93 (dd, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94%Chromat. | With oxygen; copper dichloride; In water; at 100℃; under 30003.0 Torr; for 4h;Autoclave; Green chemistry; | General procedure: In a typical experiment the glass vial was charged with a dou-bled distilled water solution (5.0 mL) of substrate (amine or aminol) (4 mmol), catalyst (CuCl2, 0.40 mmol), which appeared transparentand deep blue colored. The vial was introduced into the autoclave which was sealed, purged and charged with O2(0.6 MPa) and CO upto a total pressure of 4 MPa. Under these conditions, the substrate should be deemed the limiting reagent, also taking into account the head space of the autoclave and the stoichiometry of the carbony-lation process [Eq. (1)].The mixture was heated at 100C and allowed to react for 4 h.After this time, the autoclave was cooled at room temperature and then the residual gas was evacuated Identification of reaction products was performed via GC-MS bycomparison of their MS spectra with those reported in the litera-ture (and with the help of NIST database). A complete list of massspectral data of the major reaction products, including by-products,was reported into the supplementary material section. Quantitativeanalysis of reaction mixture was accomplished by GC-MS usingbutanone as an external standard. Conversions and yields were reported in Tables 1-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With n-butyllithium In tetrahydrofuran; hexane 1.) -78 deg C, 15 min, 2.) -78 deg C, 30 min; | |
95% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78 - 25℃; Inert atmosphere; Stage #2: propionyl chloride In tetrahydrofuran at -78 - 25℃; Inert atmosphere; | |
95% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h; Inert atmosphere; Stage #2: propionyl chloride In tetrahydrofuran; hexane at -78 - 20℃; for 2.5h; Inert atmosphere; |
92% | With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.333333h; | |
92% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: propionyl chloride In tetrahydrofuran; hexane at -78 - 20℃; | General procedure for the synthesis of propionylated oxazolidinones [1] General procedure: To a suspension of oxazolidinone (1.0 eq.) in anhydrous tetrahydrofuran a 2.5 M solution of n-butyllithium in hexane (1.0 eq.) was added dropwise at -78 °C. After stirring for 30 min at -78 °C propionylchloride (1.0 eq) was added dropwise at -78 °C. After stirring for 35 minutes at -78 °C and for 135 min at room temperature the reaction mixture was poured on an ice-water mixture and was extracted with diethylether (3 x 150 mL). The combined organic phases were washed with sat. sodiumhydrogencarbonate solution (1 x 50 mL) and sat. NaCl-solution (1 x 50 mL), were dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (10-15 % EtOAc in cyclohexane) of the crude product gave the desired propionylated oxazolidinone. |
89% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -75℃; for 0.75h; Inert atmosphere; Stage #2: propionyl chloride In tetrahydrofuran; hexane at -73℃; for 0.666667h; Inert atmosphere; | |
89% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5h; Stage #2: propionyl chloride In tetrahydrofuran; hexane at -78℃; for 1h; | 48 Example 48. Synthesis of compound 114 To a solution of (S) -4-isopropyloxazolidin-2-one (5.00 g, 38.7 mmol, 1.0 eq. ) in anhydrous THF (200 mL) at -78 was added n-BuLi (2.5 M in hexanes, 17.0 mL, 1.2 eq. ) in 30 min under N2. The mixture was stirred at -78 for 1 h, and then propionyl chloride (4.0 mL, 42.58 mmol, 1.1 eq. ) was added dropwise. After the mixture was stirred at -78 for another 1 h, TLC analysis indicated the reaction completed. Saturated ammonium chloride solution (250 mL) was added and extracted with EtOAc (3 × 100 mL) . The combined organic layers were washed with 1N NaOH solution (200 mL) and brine (300 mL) , dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (7: 1 hexanes/EtOAc) to give compound 114 as a colorless oil (6.36 g, 89%yield) . MS ESI m/z calcd for C9H16NO3[M+H]+186.10, found 186.10.1H NMR (400 MHz, CDCl3) δ 4.48 -4.39 (m, 1H) , 4.27 (t, J = 8.7 Hz, 1H) , 4.21 (dd, J = 9.1, 3.1 Hz, 1H) , 3.06 -2.82 (m, 2H) , 2.38 (dtd, J = 14.0, 7.0, 4.0 Hz, 1H) , 1.17 (t, J = 7.4 Hz, 3H) , 0.90 (dd, J = 17.0, 7.0 Hz, 6H) . |
89% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5h; Inert atmosphere; Stage #2: propionyl chloride In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; | 48 Example 48. Synthesis of compound 114 Under the protection of nitrogen, (S)-4-isopropyloxazolidin-2-one (5.00g, 38.7mmol) was dissolved in dry tetrahydrofuran (200mL). The temperature was lowered to -78 °C, n-butyllithium (2.5M n-hexane solution, 17.0 mL) was added dropwise into the reaction flask within 30 minutes, and the reaction was carried out at -78 °C for 1 hour. Then add propanoyl chloride (4.0mL, 42.58mmol) dropwise. After the addition is complete, react at -78 °C for 1 hour. TLC monitors the completion of the reaction. Pour the reaction solution into a saturated saline solution (250mL). Extract with ethyl acetate (3×100mL), combine the organic phases, wash once with 1N NaOH solution (200mL), wash once with saturated saline solution (300mL), dry with anhydrous sodium sulfate, and filter. Spin to dryness and purify with a silica gel column (7:1 petroleum ether/ethyl acetate) to obtain 6.36 g of a colorless oil with a yield of 89%. |
87% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at 1 - 70℃; for 1h; Inert atmosphere; Stage #2: propionyl chloride In tetrahydrofuran; hexane at -70℃; for 1h; | |
86% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h; Inert atmosphere; Stage #2: propionyl chloride In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; | |
83% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.333333h; Stage #2: propionyl chloride In tetrahydrofuran; hexane for 0.5h; | |
81% | ||
80% | With lithium diisopropyl amide In tetrahydrofuran; n-heptane at -78℃; for 1h; | |
79% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78 - -30℃; for 0.5h; Stage #2: propionyl chloride In tetrahydrofuran at -30 - 20℃; for 20h; | |
With n-butyllithium 1.) THF, hexane, -78 deg C, 0.5 h, 2.) 0 deg C, 3 h; Yield given. Multistep reaction; | ||
With n-butyllithium Yield given. Multistep reaction; | ||
With n-butyllithium In tetrahydrofuran at -78℃; | ||
With n-butyllithium | ||
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium Stage #2: propionyl chloride Further stages.; | ||
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78℃; Stage #2: propionyl chloride at -78℃; | ||
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium Inert atmosphere; Stage #2: propionyl chloride Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With oxygen In 1,2-dimethoxyethane at 60℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With n-butyllithium In diethyl ether; hexane Ambient temperature; | |
85% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With sodium hydride In tetrahydrofuran at 10 - 20℃; for 1h; Inert atmosphere; Stage #2: chloroacetyl chloride In tetrahydrofuran at 0 - 30℃; for 2h; Inert atmosphere; | General Procedure for preparation of 6a-c General procedure: Sodium hydride (2.2 g, 92.9 mmol) and tetrahydrofuran (100 ml) were added in a round bottom flask at room temperature under nitrogen atmosphere. Then this mixture was cooled to 10-20 °C. To the cold mixture, 4-isopropyloxazolidin-2-one (77.4 mmol) added portion wise in 4-5 min interval. Reaction mixture was stirred at 10-20 °C for 1h. Then chloroacetyl chloride (16.2 g, 143 mmol) was added slowly to the reaction mixture at 0-10 °C. After complete addition, temperature raised to 20-30 °C and stirred for 2h. Progress of the reaction monitored on thin layer chromatography. Then after completion of reaction water (30 ml) was added slowly to the reaction mixture and extracted reaction mixture twice with ethyl acetate (50ml). Organic layer was concentrated on the laboratory rotavapor under reduced pressure at 40-45 °C to afford 6a. (12.4 g, Yield 85 %). (S)-3-(2-chloroacetyl)-4-isopropyloxazolidin-2-one (6a); 1H NMR (500 MHz, CDCl3): δ, 0.90-0.96 (d, 6H), 2.41-2.47 (m, 1H), 4.29-4.31 (q, 1H), 4.34-4.39 (q, 1H), 4.47-4.50 (m, 1H), 4.71-4.79 (q, 2H) ; 13C NMR (125 MHz, CDCl3): 166.0, 153.7, 64.1, 58.7, 43.7, 28.1, 17.8, 14.6; IR (neat), ν/cm-1: 2961, 1742, 1445, 1260, 1060, 910; Anal. calcd for C8H12ClNO3: C, 46.73; H, 5.88; N, 6.81. Found: C, 46.70; H, 5.94; N, 6.78. |
85% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Schlenk technique; Stage #2: chloroacetyl chloride at -78 - 20℃; for 8h; Inert atmosphere; Schlenk technique; |
65% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78 - -20℃; for 0.5h; Stage #2: chloroacetyl chloride In tetrahydrofuran; hexane at -78 - 20℃; for 4h; | |
45% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With sodium hydride In tetrahydrofuran at 0 - 20℃; for 5h; Schlenk technique; Inert atmosphere; Stage #2: chloroacetyl chloride In tetrahydrofuran at 0 - 20℃; for 15h; Schlenk technique; Inert atmosphere; | |
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With sodium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: chloroacetyl chloride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | Step I: Synthesis of 3-(2-chloroacetyl)oxazolidin-2-ones (a-c) A suspension of NaH (60%) (253 mg, 6.33 mmol, 1.1 equiv.), previously washed with pentane, in 15 mL of dryTHF was stirred under nitrogen and cooled at 0 °C. Oxazolidinone (5.75 mmol, 1 equiv.) was added dropwise,and the reaction was warmed to room temperature. The mixture was stirred for 5 hours at room temperature and0.5 mL of chloroacetyl chloride (0.78 mL, 9.78 mmol, 1.7 equiv.) was added at 0 °C. The solution was furtherstirred for 15 h at room temperature. The mixture was filtered and evaporated under reduced pressure. Theresidue was diluted in CH2Cl2, washed with NaHCO3, dried over MgSO4, filtered and concentrated. The crudeproduct 3 was used without further purification. | |
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: chloroacetyl chloride In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; lithium chloride In dichloromethane at 20℃; for 1h; | |
97% | With n-butyllithium 1.) THF, -78 deg C, 15 min; 2.) THF, -78 deg C, 30 min then 0 deg C, 15 min; | |
95% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 1h; |
85% | With 18-crown-6 ether; sodium hydride In tetrahydrofuran at 20℃; | |
1.5 g | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With thionyl chloride In tetrahydrofuran for 0.333333h; Cooling; Stage #2: Cinnamoyl chloride In tetrahydrofuran at -30 - 20℃; | 8 4.3. General procedure of chiral cinnamic acid amides 2a-l General procedure: n-Butyllithium (1.15mL, 1.0equiv, 2.3M in hexanes) was added to a cooled until -75°C solution of the corresponding oxazolidinone (2.6mmol) in anhydrous THF (12mL), then the resulting solution was warmed to -30°C and stirred for 20min. At the same temperature, a solution of cinnamoyl chloride (1.0equiv) in anhydrous THF (7mL) was added dropwise and then allowed to rise to at room temperature and left overnight with continuous stirring. After work-up with 10% NH4Cl (15mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×25ml). The combined organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude products were purified by chromatography or crystallized from appropriate solvents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: n-octanoic acid chloride In tetrahydrofuran at -78 - -10℃; for 2.33333h; Inert atmosphere; | 4.1.1 (R)-4-Isopropyl-3-octanoyloxazolidin-2-one (R)-4 General procedure: n-BuLi (2.89M, 7.12mL, 20.6mmol) was added dropwise over 15min to a cold (-78°C), stirred solution of (R)-4-isopropyloxazolidin-2-one 3 (2.5g, 19.6mmol) in dry THF (80mL), and the mixture was stirred at -78°C for 30min. Octanoyl chloride (3.67mL, 21.5mmol) was then added dropwise, and the resulting mixture was stirred at -78°C for 20min, then warmed to -10°C for 2h. The mixture was quenched with 1M aqueous K2CO3 (100mL) and warmed to room temperature. The crude products were extracted with hexanes (2×100mL), and the combined hexane extracts were washed with water and brine, dried, and concentrated. The residue was purified by flash chromatography on silica gel (50g). Elution with hexane/EtOAc (9:1) afforded 4.93g (19.3mmol, 98%) of (R)- 4. |
82% | With n-butyllithium; triethylamine In tetrahydrofuran at -78℃; | |
82% | With n-butyllithium; triethylamine In tetrahydrofuran at -78℃; Inert atmosphere; |
With n-butyllithium 1.) THF, -78 deg C to -20 deg C, 30 min, 2.) THF, -78 deg C to r.t.; Yield given. Multistep reaction; | ||
With n-butyllithium 1.) THF, hexane, -78 deg C, 25 min, 2.) THF, hexane, -78 deg C, 2.5 h; Multistep reaction; | ||
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran Inert atmosphere; Stage #2: n-octanoic acid chloride In tetrahydrofuran Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1h; | |
91% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: isopentanoyl chloride In tetrahydrofuran; hexane at -78 - 20℃; | 2.A Step A Step A A solution of (4S)-(-)-4-isopropyl-2-oxazolidinone (19.85 g, 0.154 mol) in 400 mL of THF at -78°C under N2 is treated dropwise with n-butyl lithium (64.5 mL, 0.161 mol, 2.5 M solution in hexanes) resulting in the formation of solid. The mixture is stirred at -78°C for 30 minutes, then treated with dropwise addition of iso-valeryl chloride (20.6 mL, 0.169 mol). The reaction is allowed to warm to room temperature slowly overnight. The sample is concentrated and then partitioned between EtOAc and saturated KH2PO4 solution. The organic extract is washed with brine, dried (MgSO4), and the resultant yellow oil is chromatographed (MPLC, silica gel, 10% EtOAc in hexanes) to give 29.8 g (91%) of (S)-4-isopropyl-3-(3-methyl-butyryl)-oxazolidin-2-one as a light yellow oil. |
With n-butyllithium 1.) THF, hexane, -78 deg C, 15 min, 2.) 0 deg C, 1 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | [0351] Method A: nBuLi (1.6 M in hexanes, 7.6 ml, 12.2 mmol, 1.5 eq) was added slowly to a stirred solution of (S)-4-isopropyloxazolidin-2-one (Aldrich, 1.5 g, 11.6 mmol, 1 eq) in 20 ml anhydrous THF at -78 C. After 10 min 3-phenylpropanoyl chloride (Aldrich, 1.9 ml, 2.15 g, 12.8 mmol, 1.1 eq) was added dropwise. The reaction was warmed to 0 C. After 1 h the reaction was quenched with saturated aqueous NH4C1. The reaction was stirred at 0 C to room temperature overnight. The reaction was partitioned between water/EtOAc, and the layers were separated. The organic layer was washed with water (x2), brine (xl), and dried over Na2S04. The inorganics were filtered off, and the solvent was removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 2.73 g (10.44 mmol, 90% yield) of (S)-4-isopropyl-3-(3-phenylpropanoyl)oxazolidin-2-one. | |
80% | [0061] An oven-dried 500 milliliter (mL) Schlenk flask was cooled under nitrogen gas (N2)and then charged with (S)-4-isopropyloxazolidin-2-one (7.05 grams (g), 54.6 millimoles (mmol))and anhydrous THF (300 mL). After sealing with a rubber septum, the resulting colorless solutionwas cooled to -78 C in a dry ice/acetone bath and treated with a solution of n-BuLi (2.5 Molar (M)in hexanes , 24.0 mL, 60.0 mmol). The reaction mixture was stirred at -78 C for 30 minutes (mm)and treated with via syringe with 3-phenylpropanyl chloride (8.80 mL, 59.2 mmol). The resultingyellow solution was stirred for 2.5 hours (h) at -78 C, the cold bath was removed, a solution of saturated aqueous ammonium chloride (NH4C1, 100 mL) was added, and the resulting white suspension was allowed to stir at room temperature for 10 mm. The crude reaction mixture was extracted with ethyl acetate (EtOAc, 3 xl 00 mL), and the combined organic extracts were washed with saturated aqueous sodium chloride solution (NaC1, brine, 100 mL), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated by rotary evaporation. The crude concentrate was purified via column chromatography (silica gel (Si02), 1-30% acetone in hexanes) to give the title compound (11.4 g, 80%) as a white solid: mp 59 - 62 C; ?H NMR (400 MHz, CDC13) oe 7.33 -7.16 (m, 5H), 4.44-4.39 (m, 1H), 4.24 (dd,J= 9.1, 8.1 Hz, 1H), 4.19 (dd, J= 9.1, 3.2 Hz, 1H),3.32 (ddd, J= 16.9, 8.6, 6.7 Hz, 1H), 3.22 (ddd, J= 16.9, 8.0, 7.2 Hz, 1H), 3.06 - 2.92 (m, 2H),2.35 (pd, J= 7.0, 3.9 Hz, 1H), 0.90 (d, J= 7.0 Hz, 2H), 0.84 (d, J= 7.0 Hz, 2H); ?3C NMR (101MHz, CDC13) oe 172.40, 154.06, 140.49, 128.56, 128.46, 126.24, 63.40, 58.45, 37.07, 30.45, 28.39,17.97, 14.64; ESIMS m/z 262 ([M+H]j. | |
With n-butyllithium; sodium hydrogencarbonate; In tetrahydrofuran; hexane; water; | REFERENCE EXAMPLE 19 (S)4-(1-Methylethyl)-3-(1-oxo-3-phenylpropyl)-2-oxazolidinone To a solution of 2.5 g of (4S)4-isopropyl-2-oxazolidinone in 60 ml of dry tetrahydrofuran under argon, cooled to -78 C. was added 8 ml n-butyllithium (2.5M in hexane). The suspension was allowed to warm slowly to 0 C. and then cooled to -78 C. (total time 50 minutes). To the well stirred suspension was added dropwise 3.3 ml of 3-phenylpropionyl chloride. The resulting solution was stirred at -78 C. for 2 hours and at 0 C. for 0.5 hour. To the solution was added 20 ml of saturated sodium bicarbonate and mixture concentrated under reduced pressure. The suspension was diluted with 20 ml of water and extracted with 150 ml of ethyl acetate. The extract was washed with brine, dried (Na2 SO4) and the solvent removed to give 5.67 g of colorless oil. This oil crystallized on standing and the crystals were triturated with hexane to give 5.0 g of crystals; [alpha]D26 +71+-1 (c, 1.182, CHCl3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate at 125 - 126℃; for 6h; | |
87% | With sodium ethanolate In ethanol at 95 - 125℃; for 8h; | |
85% | With potassium carbonate at 20 - 130℃; for 5h; | 1 Example 1: Preparation of (S)-4-isoporpyloxazolidin-2-one (2)The starting material L-Valinol (15Og) was added to diethylcarbonate (227mNo.), and potassium carbonate (2Og) was then added while the mixture was stirred at room temperature. The reaction solution was refluxed for 5 h at 120~130°C . The reaction solution was cooled to 0°C, 1.5N hydrochloric acid (450mNo.) and ethyl acetate (450mNo.) were added, and the resulting two phases were separated. The aqueous phase was extracted twice with ethyl acetate (450m£), and the organic phase was washed with aqueous sodium chloride solution (450mNo.), phase-separated, dried, filtered and distilled. Isopropylether (225m£) was added to produce crystals to which n-hexane (225ml) was added. The mixture was stirred for 1 h at 0 °C , which was then filtered and dried to produce the title compound (17Og, Yield 85%).1H NMR (300MHz, CDCl3) δ 4.4 (t, IH), 4.1 (m, IH), 3.6 (q, IH), 1.7 (m, IH), 0.98 (dd, 6H) |
84% | With sodium ethanolate; potassium carbonate at 129℃; for 6h; Inert atmosphere; | |
83% | With potassium carbonate for 3h; Reflux; | |
82% | ||
80% | With potassium carbonate at 130℃; for 3h; | |
80% | With potassium carbonate In ethanol at 130 - 135℃; for 1h; | |
76% | With potassium carbonate at 140℃; for 4h; | |
61% | With potassium carbonate at 100℃; for 6h; | |
With sodium ethanolate at 95 - 125℃; for 8h; | ||
With potassium carbonate | ||
With sodium methylate 1.) toluene, reflux, 2.) 110 deg C; Yield given. Multistep reaction; | ||
9.59 g | With potassium carbonate at 145℃; | |
1 Step 1 Step 1 4-(S)-(1-Methylethyl)-2-oxazolidinone The title compound was prepared according to Evans, Mathre and Scott (J. Org. Chem., 50, 1830 (1985)) from (S)-(+)-2-amino-3-methyl-1-butanol and diethyl carbonate in the presence of K2 CO3. | ||
32.5 Step 5 Step 5 4-(S)-(1-Methylethyl)-2-oxazolidinone The title compound was prepared according to Evans, Mathre and Scott (J. Org. Chem., 50, 1830 (1985)) from (S)-(+)-2-amino-3-methyl-1-butanol and diethyl carbonate in the presence of K2 CO3. | ||
32.5 4-(S)-(1-Methylethyl)-2-oxazolidinone Step 5 4-(S)-(1-Methylethyl)-2-oxazolidinone The title compound was prepared according to Evans, Mathre and Scott (J. Org. Chem., 50, 1830 (1985)) from (S)-(+)-2-amino-3-methyl-1-butanol and diethyl carbonate in the presence of K2 CO3. | ||
With potassium carbonate at 140 - 145℃; Dean-Stark; | ||
29.9 g | With potassium carbonate at 135℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78 - -20℃; Stage #2: pent-4-enoyl chloride In tetrahydrofuran; hexane at -78 - 20℃; | |
With n-butyllithium 1.) hexane, THF, -50 deg C, 30 min, 2.) hexane, THF, -78 deg C, 30 min; Yield given. Multistep reaction; | ||
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: pent-4-enoyl chloride In tetrahydrofuran; hexane at -78℃; for 0.5h; |
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Stage #2: pent-4-enoyl chloride In tetrahydrofuran; hexane at -70℃; for 0.5h; | 5; 7.1 Tetrahydrofuran (2 L) solution of 108 g of (S)-4-isopropyl-oxazolidin-2-one was cooled in a dry ice bath at -70°C, 345 mL of 2.66 M n-butyllithium-hexane solution was added thereto, and the reaction liquid was stirred at -70°C for 30 minutes. Next, 102 mL of 4-pentenoyl chloride was added thereto at -70°C, the reaction liquid was stirred for 30 minutes, and water was added thereto to stop the reaction. This was extracted with ethyl acetate, the organic layer was washed with aqueous saturated sodium deuteride solution, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to obtain a crude product of the entitled compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With oxygen In 1,4-dioxane at 100℃; for 3h; | |
91% | With air; oxygen; potassium iodide; palladium(II) iodide In methanol at 100℃; for 15h; | |
72% | With dichloro bis(acetonitrile) palladium(II); copper(l) iodide; oxygen In acetonitrile for 6h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25h; Inert atmosphere; Stage #2: (E)-2-methylbut-2-enoyl chloride In tetrahydrofuran; hexane at -78℃; for 0.75h; | N-(2’-Methyl-2’E-pentenoyl)-4S-isopropyl-1,3-oxazolidin-2-one (A).1 General procedure: Butyllithium (2.5 M in hexane, 15.6 mL, 39.1 mmol, 1.01 equiv) was added dropwise to a solution of (S)-(+)-4-isopropyl-1,3-oxazolidin-2-one2 (5.00 g, 38.7 mmol) in anhydrous THF (70.0 mL) at -78 °C under argon. The resulting mixture was stirred for 15 min and a freshly distilled 2-methyl-2E-pentenoyl chloride (5.13 g, 38.7 mmol) in dry THF (30 mL) was added via syringe at -78 °C. The reaction was stirred for an additional 45 min at -78 °C and then warmed to ambient temperature. Saturated aqueous ammonium chloride (50 mL) was added and the resulting mixture stirred for 30 min. The solvent was removed under reduced pressure and the remaining aqueous phase transferred to a separation funnel. The aqueous phase was extracted with DCM (2×100 mL), the combined organics were washed with 3.0 M NaOH (25 mL), water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified with flash chromatography using hexanes/ethyl acetate 0-20% as a gradient to give 96% (8.37 g) of A as a white solid. |
61% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -60 - 0℃; Inert atmosphere; Schlenk technique; Stage #2: (E)-2-methylbut-2-enoyl chloride In tetrahydrofuran; hexane at -60 - 20℃; Inert atmosphere; Schlenk technique; | |
With n-butyllithium 1) THF, hexane, -78 deg C; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 3h; | |
0.4 g | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium hydroxide In dimethyl sulfoxide at 15 - 20℃; | General procedure for the synthesis of alkyl bromide (1a-1f) General procedure: In a round bottom flask dimethyl sulfoxide (50 ml) was added, followed by 1,3 dibromopropane (61.7 g, 306 mmol) and powdered potassium hydroxide (4.47 g, 80 mmol).[13] The reaction mixture was cooled to 15-20 C. To the cooled reaction mixture, was added (S)-4-phenyloxazolidin-2-one (10 g, 61.3 mmol) in 4 to 5 lots at an interval of 5 min each. The reaction mixture was stirred further at 15-20 C for 3-4h. Water (150 ml) was then added to the reaction mixture and it was extracted in dichloromethane (200 ml). The organic layer was concentrated on laboratory rotary evaporator. The resultant residue was purified on silica gel column using cyclohexane/ethyl acetate to get (1a) as colorless oil. Yield: 13.1 g (75%). 1b-1f were prepared in the same manneras 1a. |
57% | With potassium hydroxide In dimethyl sulfoxide at 20℃; for 4h; | |
With potassium hydroxide In dimethyl sulfoxide for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: 4-Methylpentanoic acid With pivaloyl chloride; triethylamine In tetrahydrofuran at 0℃; Inert atmosphere; | |
70% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 4-Methylpentanoic acid With pivaloyl chloride; triethylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #3: In tetrahydrofuran; hexane at 20℃; for 2h; | |
Stage #1: 4-Methylpentanoic acid With triethylamine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; | 21 4.1.21. (S)-4-Isopropyl-3-{3-(thiophen-2-yl)propanoyl}oxazolidin-2-one 30 General procedure: To 2-thiophene-propionic acid 28 (5.23 g, 33.5 mmol) in THF (60 mL) were added Et3N (5.6 mL, 40 mmol) and isobutylchloroformate (5.0 mL, 36.8 mmol) at 0 °C. After stirring for 30 min, the mixture was added to the lithio-(4S)-4-isopropyl-2-oxazolidinone, prepared by dropwise addition of n-BuLi (14.2 mL, 36.8 mmol, 2.6 mol/L in hexane) to (4S)-4-isopropyl-2-oxazolidinone (4.76 g, 36.8 mmol) in THF (60 mL) at -78 °C, and the mixture was stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO3 and the whole was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 5:1) to yield 30 (3.68 g, 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; O-(2,4-diphenylphosphenyl)-hydroxylamine In tetrahydrofuran; hexane at -78 - 20℃; | ||
With O-(4-nitrobenzoyl) hydroxylamine; potassium hydride In 1,4-dioxane at 20 - 60℃; | ||
With O-(4-nitrobenzoyl) hydroxylamine; sodium hydride In 1,4-dioxane at 20 - 60℃; for 25h; |
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With sodium hydride In 1,4-dioxane; mineral oil at 60℃; for 1h; Stage #2: In 1,4-dioxane; mineral oil at 20℃; for 6h; | ||
Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 3.5h; Inert atmosphere; Stage #2: With chloroamine In tetrahydrofuran; diethyl ether for 3h; Inert atmosphere; | (S)-3-amino-4-benzyloxazolidin-2-one (2). General procedure: Aqueous NH4OH (15 M, 4.7 mL, 0.071 mol) was added dropwise (ca. 10 min) to a stirred and cooled (-5°C) suspension of NH4Cl (3 g, 0.056 mol) in Et2O (110 mL). Commercial bleach (58 mL, 8.25% NaOCl) was then added dropwise (ca. 10 min) to keep the solution’s temperature below 0°C, and the mixture was stirred for an additional 15 min. The reaction mixture was transferred to a separating funnel, and the aqueous layer was discarded. The organic layer was washed with brine (1x35 mL), and then dried over CaCl2 for 1 h at -20 °C. The solution was filtered immediately prior to use to yield an ethereal solution of NH2Cl (approx. 0.15 M). Concentration of NH2Cl was measured using standard iodometric titration technique: Standard Method 4500-Cl B.2 KOtBu (1.296 g, 11.5 mmol) was added to a stirred solution of 17 (0.2064 g, 1.1647 mmol) in THF (11.7 mL) (Ar atmosphere). The mixture was stirred at rt for 3.5 hours. The NH2Cl generated above (11.7 mL, 1.7471 mmol) was then added dropwise over ca. 10 min, and the reaction mixture stirred for 3 h. The reaction quenched with 1M Na2S2O3 (5 mL). The aqueous phase was extracted with Et2O (2 x 20 mL), and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure to give 2 as a yellow oil. | |
With chloroamine; potassium <i>tert</i>-butylate In tetrahydrofuran Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With oxygen; triethylamine; copper dichloride In 1,2-dimethoxyethane at 60℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With iron(III) chloride hexahydrate; potassium carbonate; N,N`-dimethylethylenediamine In toluene at 90℃; for 12h; | |
78% | With 1,10-Phenanthroline; copper(II) sulphate hydrate; potassium carbonate In toluene at 90℃; Inert atmosphere; | |
68% | With potassium phosphate |
49% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | 12 General procedure 1 for the synthesis of ynamides (1a-1d, 1f-1m, 1o, 1p, 1r)10c and procedure 2 for (1e, 1n, 1q)14 General procedure: Procedure 1: To a solution of alkyne (9.80 mmol, 1.0 equiv) in acetone (10 mL) was added NBS (10.78 mmol, 1.1 equiv) and AgNO3 (0.98 mmol, 0.1 equiv). The resulting solution was stirred under nitrogen at room temperature for 4 h. After removing excess acetone the reaction was quenched with water and extracted with petroleum ether three times, dried over MgSO4, and concentrated under reduced pressure. The residue was eluted through a short silica column (petroleum ether) to obtain the bromoalkyne. To a dried flask was added 2-oxazolidone (4.8 mmol, 1.2 equiv), CuSO4·5H2O (100 mg, 0.4 mmol, 0.1 equiv), 1,10-phenanthroline (144 mg, 0.8 mmol, 0.2 equiv) and K2CO3 (1.38 g, 10.0 mmol, 2.5 equiv), bromoalkyne (4.0 mmol, 1.0 equiv) and this mixture was subsequently treated with anhydrous toluene (10 mL). The flask was charged with nitrogen, and the solution was heated at 80 °C overnight. After completion, the crude reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. Purification of the crude residue using silica gel flash column chromatography yielded the pure ynamides. | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 70℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85%; 78% | In the same way as the 2-phenylpropanoic acid (S)-53, oxazolidin-2-one (R,S)-syn-34 (0.2 g, 0.76 mmol), lithium hydroxide monohydrate (64 mg, 1.53 mmol) and hydrogen peroxide (0.43 mL, 3.53 M in H2O, 1.53 mmol) in THF/water (1:1; 3 mL) gave, the recovered 4-isopropyl-oxazolidin-2-one (S)-13 (76 mg, 78%) as a white solid; RF [ethyl acetate/ethanol (9:1)] 0.82; mp 71-73 C; inlMMLBox (c 2.6, CHCl3); numax (CHCl3)/cm-1 3455 (NH) and 1750 (CO); deltaH (400 MHz; CDCl3) 7.26 (1H, broad s, NH), 4.34 (1H, t, J 8.7, CHAHBO), 4.00 (1H, dd, J 8.7 and 6.4, CHAHBO) and 3.53 (1H, tdd, J 8.7, 6.7 and 6.4, CHN); 1.67-1.57 (1H, br octet, J 6.7, CH(CH3)2), 0.86 (3H, d, J 6.7, inlMMLBox) and 0.80 (3H, d, J 6.7, inlMMLBox); deltaC (100 MHz, CDCl3) 160.6 (CO), 68.4 (CH2O), 58.2 (CHN), 32.6 (CH(CH3)2), 17.7 (inlMMLBox) and 17.4 (inlMMLBox) (Found inlMMLBox, 147.1129; C9H15N2O2 requires inlMMLBox, 147.1128); and 2-phenylpropanoic acid (R)-53 (97 mg, 85%) as a colourless oil; RF [light petroleum spirit (bp 40-60 C)/diethyl ether (1:9)] 0.5; inlMMLBox (c 2.4, CHCl3); numax (CHCl3) cm-1 1710 (CO) (Found inlMMLBox, 151.0755; C9H11NO2 requires 151.0759). | |
78% | In the same way as the 2-phenylpropanoic acid (S)-6, oxazolidin-2-one (R,S)-syn-5 (0.2 g, 0.76 mmol), lithium hydroxide monohydrate (64 mg, 1.53 mmol) and hydrogen peroxide (0.43 mL, 3.53 M in H2O, 1.53 mmol) in THF/water (1:1; 3 mL) gave, the recovered 4-isopropyl-oxazolidin-2-one (S)-2 (76 mg, 78%) as a white solid; RF [ethyl acetate/ethanol (9:1)] 0.82; mp 71-73 C; inlMMLBox (c 2.6, CHCl3); numax (CHCl3) cm-1 3455 (NH) and 1750 (CO); deltaH (400 MHz; CDCl3) 7.26 (1H, broad s, NH), 4.34 (1H, t, J 8.7, CHAHBO), 4.00 (1H, dd, J 8.7 and 6.4, CHAHBO) and 3.53 (1H, tdd, J 8.7, 6.7 and 6.4, CHN); 1.67-1.57 (1H, br octet, J 6.7, CH(CH3)2, 0.86 (3H, d, J 6.7, inlMMLBox) and 0.80 (3H, d, J 6.7, inlMMLBox); deltaC (100 MHz, CDCl3) 160.6 (CO), 68.4 (CH2O), 58.2 (CHN), 32.6 (CH(CH3)2), 17.7 (inlMMLBox) and 17.4 (inlMMLBox) (Found inlMMLBox, 147.1129; C9H15N2O2 requires inlMMLBox, 147.1128); and 2-phenylpropanoic acid (R)-6 (97 mg, 85%) as a colourless oil; RF [light petroleum spirit (bp 40-60 C)/diethyl ether (1:9)] 0.5; inlMMLBox (c 2.4, CHCl3); numax (CHCl3) cm-1 1710 (CO) (Found inlMMLBox, 151.0755; C9H11NO2 requires 151.0759). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With sodium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: 1.3-chlorobromopropane In tetrahydrofuran Heating / reflux; | (4S)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one (103NLS94). Sodium hydride (60% suspension in oil, 288 mg, 7.2 mmol) was added to a solution of (S)-4-isopropyl-2-oxazolidinone (775 mg, 6.0 mmol) in dry tetrahydrofuran (50 mL) under argon atmosphere. The suspension was stirred for 15 min at rt, then [1-BROM-3-] chloropropane (1.18 mL, 12.0 mmol) was added dropwise over 30 min. The mixture was refluxed overnight, filtered and the filtrate evaporated [IRA] vacuo. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 0-4% methanol in dichloromethane afforded [(4S)-3-(3-CHLOROPROPYL)-4-ISOPROPYLOXAZOLIDINON-2-ONE] (824 mg, 67 %) as a colourless oil. |
67% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one; 1.3-chlorobromopropane With sodium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: 1.3-chlorobromopropane In tetrahydrofuran Heating / reflux; | 153 Sodium hydride (60% suspension in oil, 288 mg, 7.2 mmol) was added to a solution of (5)-4-isopropyl-2-oxazolidinone (775 mg, 6.0 mmol) in dry tetrahydrofuran (50 mL) under argon atmosphere. The suspension was stirred for 15 min at rt, then l-bromo-3-chloropropane (1.18 mL, 12.0 mmol) was added dropwise over 30 min. The mixture was refluxed overnight, filtered and the filtrate evaporated in vacuo. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 0-4% methanol in dichloromethane afforded (45)-3-(3-chloropropyl)-4- isopropyloxazolidinon-2-one (824 mg, 67 %) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 2.1 step one: Dissolve 129 g (1.0 mol) of S-isopropyloxazolidinone and 215 g (1.0 mol) of p-bromophenylacetic acid in 2000 mL of dichloromethane, add 207 g (1.1 mol) of DCC dehydrating agent, and stir at room temperature until TLC shows the reaction When complete, add a mixture of 50 mL of methanol and 50 mL of acetic acid, stir for 2 hours, and filter. The filtrate is concentrated to obtain 300 g of product. Yield: 92.0%. |
52% | With pivaloyl chloride; triethylamine In toluene at 110℃; for 42h; Heating / reflux; | 11.A Preparative Example 11; Step A; A solution of commercially available 4-bromophenyl-acetic acid (5.13 g), (4S)-(-)-4-isopropyl-2-oxazolidinone (3.08 g), pivaloyl chloride (3.4 mL) and NEt3 (7.6 mL) in dry toluene was stirred at 110° C. for 18 h. Then additional 4-bromophenyl-acetic acid (5 g), pivaloyl chloride (3.4 mL) and NEt3 (10 mL) was added and the mixture was refluxed for additional 24 h. The mixture was diluted with EtOAc, washed with 1N HCl, brine, 2N NaOH, saturated aqueous NH4Cl solution and brine, dried and purified by column chromatography (silica, cyclohexane/EtOAc 9:1 to 4:1) to afford the title compound (4.04 g; 52%) as colourless needles after crystallization from EtOAc/pentane. [MH]+=326/328. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: Hexanoyl chloride In tetrahydrofuran; hexane at -78 - 20℃; | |
92% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 1.25h; | |
91% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: Hexanoyl chloride In tetrahydrofuran; hexane at -78 - 20℃; for 1.25h; Inert atmosphere; |
62% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78 - 25℃; Inert atmosphere; Stage #2: Hexanoyl chloride In tetrahydrofuran at -78 - 25℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 23℃; for 15h; | 8 Preparation 8 According to the literature (Kruse et AL., J. Med. Chem. (1987), 30,486-494), a solution of 3, 5-difluorocinnamic acid (9.94 g, 53.9 mmol) in THF (100 ML) was hydrogenated over 10% Pd/C (1.50 g) at 50 psi of H2 pressure for 5 h at RT. The mixture was filtered and concentrated under reduced pressure to yield the 3- (3, 5- difluoro-phenyl) propionic acid (10.9 g, 100%). Oxalyl chloride (13 ml, 150 mmol) was slowly added to a solution of the acid (10.9 g, 53.9 mmol) in THF (220 ML) at 23 °C, followed by the addition of a catalytic amount of DMF (1 drop). After 90 min at RT, the volatiles were removed under reduced pressure and the resulting residue was twice coevaporated with dry benzene to yield 3- (3, 5-DIFLUOROPHENYL)-PROPIONYL CHLORIDE as a yellow oil (11.91 g, 100%). The acid chloride was used in the ensuing step without further purification. The acylation was carried out in analogy to the literature (Pettit et al. Synthesis (1996), 719-725). A solution of (S)- (-)-4-ISOPROPYL-2- oxazolidinone (6.46 g, 50 mmol) in THF (150 ML) was stirred under argon and cooled to-78 °C. n-BuLi (2.45 M in hexanes, 20.8 ML, 50.96 mmol) was added dropwise, followed by a solution of the previously prepared 3- (3, 5-DIFLUOROPHENYL)-PROPIONYL chloride in THF (8 ML). After warming the reaction to 23 GC over 15 h, the reaction was quenched with saturated aq. NH4CI (30 ml), followed by removal of the volatiles in vacuo. The slurry was extracted with CH2CI2 (2x), and the combined organic layers washed with 1 M NAOH (2x) and brine, dried (NA2SO4) and concentrated in vacuo. Purification of the residue by chromatography over SILICA GEL (15O30% EtOAc/hexanes) gave the product (14.27 g, 48 mmol, 96%). 1H NMR (400 MHz, CECI3) 8 6. 73 (m, 2 H), 6.59 (m, 1 H), 4.37 (m, 1 H), 4.17-4. 25 (m, 2 H), 3.24 (m, 1 H), 3.16 (m, 1 H), 2.93 (m, 2 H), 2.30 (m, 1 H), 0.86 (d, 3 H, J= 6.8 Hz), 0.80 (d, 3 H, J= 6.8 Hz); LCMS (Conditions A): tR = 4.47 min: 595 (2M+H) +, 298 (M+H) +. |
With n-butyllithium |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium In methanol; ethyl acetate; Diethyl carbonate | 1 Synthesis of N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-(2'-naphthyl)alanyl-L-alanine, 2-aminoethyl Amide (Compound 1) STR5 The following is an alternative method, which is a preferred method, for preparing compound 1(c) such that a greater ratio of the desired stereoisomer (R) is produced as compared to the undesired stereoisomer (S). The reaction steps and reference numerals for the respective compounds are shown in Reaction Scheme 10. By following the procedure of Newman, M. S.; Kutner, A. J. Am. Chem. Soc. 1951, 73, 4199, a solution of sodium methoxide was prepared by dissolving 1.29 g (0.056 mol) of sodium in 15 ml of anhydrous methanol, which was added to a slurry of 25 g (0.242 mol) of L-valinol in 500 ml of diethyl carbonate. The reaction mixture was then heated for 2 hours, with 200 ml of distillate collected in the temperature range of 75°-123° C. The distillate was discarded and the reaction mixture was allowed to cool to room temperature and stand overnight. The excess diethyl carbonate was removed from the reaction mixture in vacuo by rotary evaporation to give a residue. The residue was dissolved in 500 ml of ethyl acetate and washed with water (3*200 ml) and brine (200 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give a white solid. The solid was recrystallized from ethyl acetate-hexane to produce 23.2 g (74% yield) of (S)-4-isopropyl-2-oxazolidinone 12(a) as white needles. TLC of 12(a): Rf 0.50 (ethyl acetate-hexane 3:1); 1 H NMR (CDCl3) δ 0.90(d, J=6.7 Hz, 3H), 0.97(d, J=6.7 Hz, 3H), 1.72(m, 1H), 3.63(m, 1H), 4.10(dd, J=8.7, 6.4 Hz, 1H), 4.45(m, 1H), 7.32(bs, 1H); 13 C NMR (CDCl3) d 17.5, 17.8, 32.6, 58.3, 68.5, 160.7. |
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 20 °C 2: dimethyl carbonate / CH2Cl2 / 0.67 h / 20 °C | ||
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 20 °C 2: dimethyl carbonate / CH2Cl2 / 0.67 h / 20 °C |
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 20 °C 2: dimethyl carbonate / 1 h / 20 °C | ||
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 20 °C 2: dimethyl carbonate / CH2Cl2 / 9 h / 20 °C | ||
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 20 °C 2: dimethyl carbonate / CH2Cl2 / 1 h / 20 °C | ||
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 20 °C 2: dimethyl carbonate / 48 h / 50 °C | ||
Multi-step reaction with 4 steps 1.1: Et3N / tetrahydrofuran / Heating 2.1: NaH / tetrahydrofuran; various solvent(s) / 0.75 h / 0 °C 2.2: tetrahydrofuran; various solvent(s) / 0 °C 3.1: 72 percent / SnCl4 / CH2Cl2 / -78 °C 4.1: NaBH4 / tetrahydrofuran; H2O / 2 h / 20 - 25 °C | ||
Multi-step reaction with 4 steps 1.1: Et3N / tetrahydrofuran / Heating 2.1: NaH / tetrahydrofuran; various solvent(s) / 0.75 h / 0 °C 3.1: SnCl4 / CH2Cl2 / -78 °C 3.2: 67 percent / H2O / CH2Cl2 4.1: NaBH4 / tetrahydrofuran; H2O / 2 h / 20 - 25 °C | ||
Multi-step reaction with 2 steps 1: aq. NaHCO3 / 1.5 h / 20 °C 2: K2CO3 / 100 - 130 °C | ||
Multi-step reaction with 2 steps 1: 78 percent 2: 11 percent / selenium dioxide, pyridine / pyridine / 1 h / Heating | ||
Multi-step reaction with 5 steps 1.1: potassium carbonate / ethanol / 0.5 h / 0 - 50 °C / Inert atmosphere 2.1: <i>N</i>,<i>N</i>-dimethyl-aniline / dichloromethane / 1 h / 0 °C / Inert atmosphere 2.2: 0.67 h / 0 - 20 °C / Inert atmosphere 3.1: dirhodium(II) tetraacetate dihydrate / dichloromethane / -20 °C / Inert atmosphere 4.1: cobalt(II) chloride / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: lithium hydroxide; dihydrogen peroxide / water; tetrahydrofuran / 0.58 h / -40 - 0 °C | ||
Multi-step reaction with 5 steps 1.1: potassium carbonate / ethanol / 0.5 h / 0 - 50 °C / Inert atmosphere 2.1: <i>N</i>,<i>N</i>-dimethyl-aniline / dichloromethane / 1 h / 0 °C / Inert atmosphere 2.2: 0.67 h / 0 - 20 °C / Inert atmosphere 3.1: dirhodium(II) tetraacetate dihydrate / dichloromethane / -20 °C / Inert atmosphere 4.1: cobalt(II) chloride / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: lithium hydroxide; dihydrogen peroxide / water; tetrahydrofuran / 0.58 h / -40 - 0 °C | ||
Multi-step reaction with 5 steps 1.1: potassium carbonate / ethanol / 0.5 h / 0 - 50 °C / Inert atmosphere 2.1: <i>N</i>,<i>N</i>-dimethyl-aniline / dichloromethane / 1 h / 0 °C / Inert atmosphere 2.2: 0.67 h / 0 - 20 °C / Inert atmosphere 3.1: dirhodium(II) tetraacetate dihydrate / dichloromethane / 18 h / -20 °C / Inert atmosphere 4.1: cobalt(II) chloride / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: lithium hydroxide; dihydrogen peroxide / water; tetrahydrofuran / 0.58 h / -40 - 0 °C | ||
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 17 h / 0 - 20 °C 2: triethylamine / dichloromethane / 4 h / 0 - 20 °C / Inert atmosphere 3: sodium iodide / acetone / 17 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; ammonium chloride; In tetrahydrofuran; hexane; | PREPARATION 11 4(S)-Isopropyl-3-[3-(4-methoxyphenyl)-1-oxobutyl]-2-oxazolidinone 18.19 ml (29.1 mmoles) of butyllithium (as a 1.6M hexane solution) were added dropwise at -78 C. and under an atmosphere of nitrogen to a solution of 3.13 g (24.2 mmoles) of 4(S)-isopropyl-2-oxazolidinone in 50 ml of anhydrous tetrahydrofuran, and then the mixture was stirred for 30 minutes. At the end of this time, a solution of 5.43 g (29.1 mmoles) of <strong>[15893-42-2]3-(4-methoxyphenyl)propionyl chloride</strong> in 20 ml of anhydrous tetrahydrofuran was added dropwise to the resulting mixture over the course of 10 minutes. The mixture was then stirred for a further 1 hour, after which a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by medium pressure silica gel column chromatography (using a 1:3 by volume mixture of ethyl acetate and hexane as eluent), followed by recrystallization from diisopropyl ether, to give 5.63 g (yield 80%) of the title compound as white crystals, melting at 62.0-63.5 C. [α]D20 =+60.4 (C=1, chloroform). Elemental analysis: Calculated for C16 H21 NO4: C, 65.96%; H, 7.27%; N, 4.81%. Found: C, 65.98%; H, 7.25%; N, 4.75%. Mass spectrum (m/e): 291 (M+), 162, 134, 121. Infrared Absorption Spectrum (KBr) νmax cm-1: 1777, 1698. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; hexane; | EXAMPLE 12 (S)-4-(1-Methylethyl)-3-(1-Oxo-4-Pentenyl)-2-Oxazolidinone To a -78 C. solution of 5.0 g of 4-(1-methylethyl)-2-oxazolidinone in 80 ml of tetrahydrofuran is added, dropwise, 15.5 ml of 2.5M n-butyl lithium in hexane. After stirring for 30 minutes, a solution of 4.8 g of <strong>[928-50-7]4-pentenyl chloride</strong> in 30 ml of tetrahydrofuran is added, dropwise, and the resulting solution is stirred at -78 C. for 3.5 hours. The reaction is diluted with aqueous ammonium chloride and diethyl ether. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, 25% ethyl acetate/petroleum ether) to give 5.8 g of the desired product as a pale yellow oil. [alpha]D26 =+79 (methylene chloride). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 4-methyl-morpholine; n-butyllithium In tetrahydrofuran; diethyl ether; hexane | 2.a A. (a) 3-(3-Cyclopropyl-2-oxopropyl)-4(S)-(1-methylethyl)-2-oxazolidinone A solution of mixed anhydride was prepared by adding under a N2 atmosphere pivaloyl chloride (14.8 mL, 120 mmol) over a period of 5 min to a cooled solution (0°) of 4-pentenoic acid (12.3 mL, 120 mmol) and N-methylmorpholine (15.4 mL, 140 mmol). The mixture was stirred at 0° for 30 min. Meanwhile, a second solution was prepared by adding dropwise under a N2 atmosphere a 1.4M solution of butyllithium in hexane (71 mL, 100 mmol) to a stirred cooled solution (-78°) of (S)-4-(1-methylethyl)-2-oxazolidinone [12.9 g, 100 mmol, described by L. N. Pridgen et al., J. Org. Chem., 54, 3231 (1989)] in dry THF (300 mL) over a period of 45 min. (Note: The agitation was done by an overhead stirrer.) After stirring for 15 min at -78°, the latter solution was added by cannulation to the stirred solution of the mixed anhydride at -78° over a period of 20 min. The mixture was stirred for an additional 30 min at the same temperature. A saturated aqueous solution of NH4 Cl (50 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with H2 O (300 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3*). The combined organic phases were dried (Na2 SO4) and evaporated to dryness under reduced pressure to give an oily residue [i.e. 4(S)-(1-methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone]. The latter oil was dissolved in 175 mL of a 0.4M Et2 O solution of diazomethane. The resulting solution was cooled to 0°. Palladium(II) acetate (112 mg, 0.5 mmol) was added to the cooled solution. The solution bubbled vigorously. After the bubbling subsided, additional palladium(II) acetate (112 mg, 0.5 mmol) and the Et2 O solution of diazomethane (175 mL) were added and the ensuing bubbling was allowed to subside. The latter addition was repeated two more times. (The total amount of diazomethane solution added was 700 mL.) The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residual oil was purified by chromatography (SiO2, eluent: EtOAc-hexane, 1:4) followed by distillation (100° at 0.05 mm Hg) to give the desired N-(3-cyclopropyl-1-oxopropyl)-2-oxazolidinone derivative (20.0 g, 89%); 1 H NMR (CDCl3) δ4.41 (complex m,1H), 4.28 (d, J=9.1 Hz, 1H), 4.20 (dd, J=3.4 Hz,8.8 Hz, 1H), 3.05 (m,2H), 2.36 (m, 1H), 1.55 (q, J=7.3 Hz, 2H), 0.91 (d, J=7.2 Hz, 3H), 0.87 (d, J=7.1 Hz, 3H), 0.89 (m, 1H), 0.43 (m,2H), 0.08 (m,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 4-methyl-morpholine; n-butyllithium In tetrahydrofuran; diethyl ether; hexane | 5.a Preparation of N4 -(Cyclohexylmethyl)-N4 -(2-morpholino-2-oxoethyl)-N1 -[1(S)-(cyclohexylmethyl)-(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide (a) 3-(3-Cyclopropyl-1-oxopropyl)-4(S)-(1-methylethyl)-2-oxazolidinone A solution of mixed anhydride was prepared by adding, under N2, pivoloyl chloride (14.8 mL, 120 mmol) over a period of 5 min to a cooled solution (0°) of 4-pentenoic acid (12.3 mL, 120 mmol) and N-methylmorpholine (15.4 mL, 140 mmol). The mixture was stirred at 0° for 30 min. Meanwhile, a second solution was prepared by adding dropwise under N2 a 1.4M solution of butyllithium in hexane (71 mL, 100 mmol) to a stirred cooled solution (-78°) of (S)-4-(1-methylethyl)-2-oxazolidinone (12.9 g, 100 mmol) in dry THF (300 mL) over a period of 45 min. (Note: The agitation was done by an overhead stirrer.) After stirring for 15 min at -78°, the latter solution was added by cannulation to the stirred solution of the mixed anhydride at -78° over a period of 20 min. The mixture was stirred for an additional 30 min at the same temperature. A saturated aqueous solution of NH4 Cl (50 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with H2 O (300 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3*). The combined organic phases were dried (Na2 SO4) and evaporated to dryness under reduced pressure to give an oily residue [i.e. 4(S)-(1-methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone]. The latter oil was dissolved in 175 mL of a 0.4M Et2 O solution of diazomethane. The resulting solution was cooled to 0°. Palladium(II) acetate (112 mg, 0.5 mmol) was added to the cooled solution. The solution bubbled vigorously. After the bubbling subsided, additional palladium(II) acetate (112 mg, 0.5 mmol) and the Et2 O solution of diazomethane (175 mL) were added and the ensuing bubbling was allowed to subside. The latter addition was repeated two more times. (The total amount of diazomethane solution added was 700 mL.) The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residual oil was purified by chromatography (SiO2, eluent: EtOAc-hexane, 1:4) followed by distillation (100° at 0.05 mm Hg) to give the desired 3-(3-cyclopropyl-1-oxopropyl)-2-oxazolidinone derivative (20.0 g, 89%); 1 H NMR(CDCl3) δ4.41 (complex m,1H), 4.28 (d, J=9.1 Hz,1H), 4.20 (dd, J=3.4 Hz,8.8 Hz,1H), 3.05 (m,2H), 2.36 (m,1H), 1.55 (q, J=7.3 Hz,2H), 0.91 (d, J=7.2 Hz,3H), 0.87 (d, J=7.1 Hz,3H), 0.89 (m,1H), 0.43 (m,2H), 0.08 (m,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃; for 0.75h; | |
96% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.25h; Stage #2: 6-methyl-6-heptenoic acid chloride In tetrahydrofuran; hexanes at -78 - 0℃; for 0.75h; Stage #3: With ammonium chloride In tetrahydrofuran; hexanes; water | 2.c; 4 To a solution of (5)-4-isopropyl-2-oxazolidonone (1.56 g, 12.1 mmol, 1 equiv) in THF (40 ml) at -78 0C was added M-butyllithium (4.84 ml of a 2.5 M solution in hexanes, 12.1 mmol, 1 equiv). After 15 min acid chloride 8 (2.14 g, 13.3 mmol, 1.1 equiv) was added and the mixture was stirred for 30 min at -78 0C and for 15 min at 0 0C. Saturated aqueous ammonium chloride (10 ml) was added and the resulting slurry was concentrated in vacuo. The residue was diluted with ether and washed successively with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) gave imide 9 ( 2.94 g, 96%) as a colorless oil: [α]22D = +66.7 (c= 0.6, CHCl3); TLC R/= 0.40 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 4.68 (s, IH), 4.66 (s, IH), 4.43-4.40 (m, IH), 4.25 (t, J= 9.0 Hz, IH), 4.19 (dd, J= 3.0 Hz, 9.0 Hz, IH), 3.01- 2.83 (m, 2H), 2.38-2.32 (m, IH), 2.02 (t, J= 7.8 Hz, 2H), 1.69 (s, 3H), 1.67-1.61 (m, 2H), 1.51-1.46 (m, 2H), 0.90 (d, J= 7.2 Hz, 3H), 0.85 (d, J= 7.2 Hz, 3H); 13C NMR (IOO MHz, CDCl3) δ 173.5, 154.3, 145.8, 110.2, 63.6, 58.6, 37.7, 35.6, 28.6, 27.2, 24.3, 22.6, 18.2, 14.9; HRMS calcd for C4H23NO3 + Na+ 276.1576; found 276.1567 [M + Na+]. |
87% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With triethylamine; lithium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: propionic acid anhydride In tetrahydrofuran at 0 - 20℃; for 1.5 - 2h; | 2 Example 2: Preparation of (S)-4-isopropyl-3-propionyloxazolidin-2-one (3) The compound (2) prepared in Example 1 (10Og) was dissolved in tetrahydrofuran (300mNo.), and cooled to 0°C . Lithium chloride (36g) was added, triethylamine (10Ig) was then slowly added, and the resulting mixture was stirred for 30 min. Propionic acid anhydride (106g) was slowly added over a 30 min. time period. The reaction mixture was slowly warmed to room temperature, and stirred for 1-1.5 h. The reaction solution was cooled, IN aqueous sodium chloride solution (300mNo.) was added, and the mixture was stirred for 30 min. Ethyl acetate (300mf) was added, the phases were separated, and extracted once again by ethyl acetate (300m£). After washing with 1.5 N hydrochloric acid (300m£), the organic phase was washed once again with aqueous sodium chloride solution (300mNo.), dried, filtered and distilled to produce the title compound (142g, Yield%). 1H NMR (300MHz, CDCl3) δ 4.4 (m, IH), 4.3-4.2 (m, 2H), 2.97 (m, 2H), 2.3 (m,IH), 1.2 (t, 3H), 0.93 (dd, 6H) |
With 2-phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimidine; N-ethyl-N,N-diisopropylamine In chloroform-d1 at 50℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine; chlorophosphoric acid diphenyl ester In dichloromethane at -40 - 25℃; | |
90% | With tetrabutylammonium triphenyldifluorosilicate In dimethylsulfoxide-d6 at 150℃; for 12h; chemoselective reaction; | |
80% | With caesium carbonate In dimethylsulfoxide-d6 at 25 - 150℃; for 24h; Schlenk technique; | Typical procedure for oxazolidinone synthesis To a DMSO-d6 (1 mL) solution of cesium carbonate (33 mg, 0.1 mmol) was added (S)-1a (0.1114 mL, 1 mmol). A dried glass Schlenk tube containing the reaction mixture was frozen with liquid nitrogen (-196 °C) under vacuum for air removal, then purged with CO2 gas and thawed at 25 °C. A balloon (1 L) filled with CO2 was fitted to the glass tube. The glass tube was stirred at 150 °C for 24 h. Upon completion, the reaction mixture was subjected to 1H NMR for crude product yield determination, which calculated based on the ratio between product and internal standard (N,N-dimethylformamide). After that, DMSO-d6 was removed through distillation undervacuum conditions (6 mmHg, 50 °C); the syrupy product was then purified bycolumn chromatography on silica gel (hexane/ethyl acetate 3:1) to give the product (S)-4-isopropyloxazolidin-2-one (S)-2a as white solids with an isolated yield of 80% (103.3 mg, 0.80 mmol). |
75% | With tetramethylphenylguanidine; diphenyl phosphoryl azide In acetonitrile at -40 - 20℃; | |
95 %Spectr. | With caesium carbonate In dimethyl sulfoxide at 150℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | (4S)-3-(3-methyl-3-phenyl-1-oxobutyl)-4-isopropyl-2-oxazolidinone (3) 3-Methyl-3-phenylbutanoic acid (2, 1.00 g, 5.61 mmol) was dissolved in 70 mL of THF and cooled to -78 C. Triethylamine (1.17 mL, 8.42 mmol) and trimethylacetyl chloride (0.760 mL, 6.17 mmol) were added to the reaction flask producing a white solid. The resulting mixture was warmed to 0 C. for 1 h and then cooled back down to -78 C. In a second flask butyllithium (6.84 mL, 1.6 M in hexanes, 10.9 mmol) was added dropwise with vigorous stirring to a solution of (4S)-(-)-4-isopropyl-2-oxazolidinone (1.45 g, 11.2 mmol) at -78 C. in THF (60 mL) producing a white precipitate. The resulting suspension of the lithiated oxazolidinone was added via cannula to the reaction flask. Stirring was continued for 2 h, water was added and the reaction mixture was warmed to room temperature, whereupon it was extracted three times with diethyl ether. The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo. The product was purified by radial chromatography (4 mm plate, 3:7 diethyl ether-pet. ether) affording compound 3 as a clear, colourless oil in 84% yield (1.37 g, 4.74 mmol). 1H-NMR (400 MHz, CDCl3) 7.38 (d, 2H, J=7.3 Hz, H-19 and H-15) 7.28 (t, 2H, J=7.3 Hz, H-18 and H-16), 7.16 (t, 1H, J=7.3 Hz, H-17), 4.22-4.18 (m, 1H, H-4), 4.05 (dd, 1H, J=9.0 and 2.8 Hz, 1H-5), 4.00 (t, 1H, J=9.0 Hz, 1H-5), 3.38-3.30 (m, 2H, H-10), 2.16-2.12 (m, 1H, H-6), 1.48 (s, 3H, H-13 or H-12), 1.47 (s, 3H, H-13 or H-12), 0.79 (d, 3H, J=7.1 Hz, H-8 or H-7), 0.71 (d, 3H, J=6.9 Hz, H-8 or H-7); Mass spectrum (EI) 289 (8, M.+), 119 (100, [C9H11]+). Optical rotation obtained was [α]D25+69.5 (c 1.16, CHCl3). | |
27 mg | In a THF solution (900 mL) of compound J1 (17.2 g)Triethylamine (23.7 mL) and pivaloyl chloride (15.3 mL) were added at -78 C. The temperature was raised to 0 C. and the mixture was stirred for 1 hour. Separately, n-butyllithium (1.64 mol / L hexane solution 89.8 mL) was added to a THF solution (760 mL) of (S) -isopropyloxazolidinone (19.5 g) at -78 C., and the mixture was stirred for 30 minutes.Lithium salts were prepared. The temperature of the above reaction solution was adjusted to -78 C., a lithium salt was added dropwise, the mixture was stirred for 1 hour, the temperature was raised to 0 C., the mixture was further stirred for 30 minutes, water was added, and the mixture was extracted with tert-butyl methyl ether.The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent; hexane: tert-butyl methyl ether).Compound J2 (27.0 g) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine In acetonitrile at 40℃; for 15h; Schlenk technique; Inert atmosphere; | |
80% | With potassium carbonate at 80℃; for 4.5h; | B.B2 B 2. Preparation of (S)-4-isopropyloxazolidin-2-one L-valinol (5 g, 48.5 mmol), anhydrous potassium carbonate (0.67 g, 4.85 mmol), and dimethyl carbonate (8.7 g, 96.7 mmoll) were added to a vessel. The mixture was heated to 80°C. The distillation receiver was cooled in an ice bath, and methanol (ca. 3.8 ml) was collected from the reaction mixture over 4.5 hrs. The oil bath was removed, when the distillation of methanol ceased. The light-yellow residue was cooled to ambient temperature, and diluted with 30 ml of ethyl acetate. The solution was transferred to a separation funnel, and washed with water (25 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated with rotary evaporator, to afford a white crystalline solid. The crude solid was added into a hot solution of 1: 1 ethyl acetate/hexane (20 ml), and filtered hot. The filtrate was allowed to come to r.t, and the solids crystallized from the solution to afford (S)-4-isopropyloxazolidin-2-one (A12a) (5.0 g, 80.0% yield). |
With potassium carbonate at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Stage #2: Benzyloxyacetyl chloride In tetrahydrofuran; hexane at -78 - 0℃; for 4h; Inert atmosphere; | |
93% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: Benzyloxyacetyl chloride In tetrahydrofuran for 1h; | 33.A Step A: (4S)-3-[2-(benzyloxy)acetyl]-4-(propan-2-yl)-1,3-oxazolidin-2-one To a solution of (S)-4-isopropyl-2-oxazolidinone (10 g, 77.4 mmol, 1 eq) in tetrahydrofuran (200 mL) was slowly added sodium hydride (60% dispersion; 3.72 g, 92.9 mmol, 1.2 eq) at 0 °C. After 1 h, benzyloxyacetyl chloride (12.8 mL, 81.3 mmol, 1.05 eq) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched by the dropwise addition of saturated aqueous ammonium chloride (20 mL) at 0 °C, and extracted with ethyl acetate (250 mL). The organic extract was washed successively with water (250 mL) and brine (2 x 250 mL), dried (magnesium sulfate) and concentrated in vacuo. The solids were suspended in heptane (250 mL) and stirred vigorously for 1 h, then filtered, washed with heptane (2 x 100 mL) and dried under vacuum to afford the desired product as a white powder (19.9 g, 71.7 mmol, 93%). LC/MS (C15H19NO4) 278 [M+H]+; RT 1.19 (LCMS-V-B1) 1H NMR (400 MHz, DMSO-d6) d 7.42- 7.35 (m, 4H), 7.34- 7.28 (m, 1H), 4.64 (d, 2H), 4.57 (d, J = 0.8 Hz, 2H), 4.42- 4.29 (m, 3H), 2.26- 2.15 (m, 1H), 0.85 (dd, J = 20.8, 6.9 Hz, 6H). |
85% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 23℃; for 1h; | (S)-3-(2-(benzyloxy)acetyl)-4-isopropyloxazolidin-2-one (8) A solution ofoxazolidine (3.9 g, 30.2 mmol) in THF (40 mL) was cooled to -63 °C and treatedn-butyllithum (19 mL, 1.6 M in hexanes). After the solution was stirred at -78°C for 10 min, benzyloxyacetyl chloride (3.3 g, 17.6 mmol) was added, and theresulting solution was warmed to 23 °C for an hour. Reaction mixture was quenchedwith saturated aqueous NaHCO3 (60 mL) and concentrated in vacuo toremove the organic solvents. The resulting aqueous residue was extracted withEt2O (150 mL), and the combined organic layers were washed withwater (80 mL ) and brine (80 mL ), and then dried over sodium sulfate,,filtered and concentrated. Purification of the residue by flash chromatography(gradient elution, 20% to 25% EtOAc/Hexanes) ) to afforded imide 8 aswhite solid (7.1 g, 85%) mp 85.5-86.3 °C; 1H NMR δ 7.32 (m, 5H), 4.69 (d, J = 1.8 Hz, 2H), 4.65 (s, 2H), 4.42 (m, 1H),4.30 (m, 1H), 4.22 (m, 1H), 2.41 (m, 1H), 0.91 (d, J = 7.2 Hz, 3H), 0.86 (d, J = 7.2 Hz, 3H); 13C NMR δ 170.1,154.0, 137.3, 73.5, 69.6, 64.5, 58.2, 28.3, 17.9, 14.7; IR (neat) 3264, 2961,1722, 1611, 1513; MS m/z: [M+H]+ Calcd for C15H19NO4;278.1; Found 278.4. |
70% | With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 4.5h; | |
68% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78℃; for 0.75h; Stage #2: Benzyloxyacetyl chloride In tetrahydrofuran-d8 at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 12h; | To a solution of 3-bromo-5-chloropyrazolo[l,5-a]pyrimidine (5.30 g,22.8 mmol) and (S)-4-isopropyloxazolidin-2-one (4.42 g, 34.2 mmol) in dry DMF (100 mL) at ambient temperature was added sodium hydride (0.821 g, 34.2 mmol) and the solution stirred for 12 hours. Saturated aqueous NH4C1 solution was added and the solids were collected by filtration. Purification of the crude material by column chromatography, eluting with 1% MeOH/dichloromethane afforded 5.30 g (71%) of (S)-3-(3-bromopyrazolo[l,5- a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one as a yellow solid. LCMS (APCI+) m/z 325, 327 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate In dimethyl sulfoxide at 120℃; for 16h; | 119 A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (600 mg, 1.7 mmol), (S)-4-isopropyl-2-oxazolidinone (322 mg, 2.5 mmol), copper(I) iodide (96 mg, 0.5 mmol), N, N-dimethylglycine hydrochloride (140 mg, 1.0 mmol) and potassium carbonate (923 mg, 6.7 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120°C for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2 x 150 mL), washed with water (2 x 50 mL) and saturated aqueous ammonium chloride solution (2 x 50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-((S)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl- l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (555 mg, 80%) as a white solid : LC/MS m/e calcd for C24H28N2O4 (M+H)+: 409.50, observed: 409.1. |
80% | With potassium carbonate In dimethyl sulfoxide at 120℃; for 16h; | 119 A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (600 mg, 1.7 mmol), (S)-4-isopropyl-2-oxazolidinone (322 mg, 2.5 mmol), copper(I) iodide (96 mg, 0.5 mmol), N,N-dimethylglycine hydrochloride (140 mg, 1.0 mmol) and potassium carbonate (923 mg, 6.7 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-((S)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (555 mg, 80%) as a white solid: LC/MS m/e calcd for C24H28N2O4 (M+H)+: 409.50, observed: 409.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 1B (4S)-4-(Propan-2-yl)-3-(5,5,5-trifluoropentanoyl)-1,3-oxazolidin-2-one To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at -78 C. was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 min. The reaction mixture was warmed to 0 C., and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, and then extracted with EtOAc (2*). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP SiO2 120 g). Concentration of appropriate fractions provided Preparation 1B (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 4.44 (1H, dt, J=8.31, 3.53 Hz), 4.30 (1H, t, J=8.69 Hz), 4.23 (1H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2H, m), 2.32-2.44 (1H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2H, m), 1.88-2.00 (2H, m), 0.93 (3H, d, J=7.05 Hz), 0.88 (3H, d, J=6.80 Hz). | ||
7.39 g | To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (45)-4-(propan-2-yl)-l,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at -78 C was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 min. The reaction mixture was warmed to 0 C, and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4C1, and then extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60%> solvent A/B=hexanes/EtOAc, REDISEP Si02 120g). Concentration of appropriate fractions provided Intermediate S-IH (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDC13) δ ppm 4.44 (1 H, dt, J=8.31, 3.53 Hz), 4.30 (1 H, t, J=8.69 Hz), 4.23 (1 H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 18h; Inert atmosphere; | Intermediate 31 : (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin Intermediate 31 : (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidinA solution of 2,4-difluoropyrimidine (3.5 mL, 41 mmol) and (S)-4-isopropyloxazolidin-2- one (5.3 g 41 mmol) in 30 mL DMF was cooled to 0 °C under N2 atmosphere. NaH (2.1 g of 60% suspension, 53 mmol) was slowly added. Bubbling exotherm observed. Internal temp was kept below 5 °C. After 5 minutes, cold bath was removed. Reaction mixture (a sandy suspension) was allowed to warm to room temp and stir 18 h. The reaction mixture was diluted with water (100 mL) and extracted with (3 x 75 mL) EtOAc. Organic layer was washed with 50 mL each water, and brine. Dried over Na2S04, and concentrated on silica gel in vacuo. Column chromatography (EtOAc/heptane 10 to 100% gradient) gave 3.1 g (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IV) as a crystalline white solid (33%). 1H NMR (400 MHz, CDCI3) δ 8.50 (dd, J = 5.8, 2.2 Hz, 1 H), 8.19 (dd, J = 5.8, 3.8 Hz, 1 H), 4.79 (dt, J = 8.1 , 3.5 Hz, 1 H), 4.48 - 4.34 (m, 2H), 2.64 (heptd, J = 7.0, 3.6 Hz, 1 H), 1 .01 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H). MS m/z 471.8 and 471 .8 (M + H)+. |
33% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 18h; Inert atmosphere; | 31 Intermediate 31 (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one A solution of 2,4-difluoropyrimidine (3.5 mL, 41 mmol) and (S)-4-isopropyloxazolidin-2-one (5.3 g 41 mmol) in 30 mL DMF was cooled to 0° C. under N2 atmosphere. NaH (2.1 g of 60% suspension, 53 mmol) was slowly added. Bubbling exotherm observed. Internal temp was kept below 5° C. After 5 minutes, cold bath was removed. Reaction mixture (a sandy suspension) was allowed to warm to room temp and stir 18 h. The reaction mixture was diluted with water (100 mL) and extracted with (3×75 mL) EtOAc. Organic layer was washed with 50 mL each water, and brine. Dried over Na2SO4, and concentrated on silica gel in vacuo. Column chromatography (EtOAc/heptane 10 to 100% gradient) gave 3.1 g (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IV) as a crystalline white solid (33%). 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=5.8, 2.2 Hz, 1H), 8.19 (dd, J=5.8, 3.8 Hz, 1H), 4.79 (dt, J=8.1, 3.5 Hz, 1H), 4.48-4.34 (m, 2H), 2.64 (heptd, J=7.0, 3.6 Hz, 1H), 1.01 (d, J=7.0 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H). MS m/z 471.8 and 471.8 (M+H)+. |
33% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 18h; Inert atmosphere; |
33% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; | |
33% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 18h; Inert atmosphere; | |
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; Inert atmosphere; | General procedure: 1h (850 mg, 6.38 mmol) and 2,4-difluoropyrimidine (740 mg,6.37 mmol) were added to DMF (10 mL) under N2 and the mixturewas cooled to 0 C. After adding sodium hydride (310 mg,7.75 mmol) and stirring for 30 min, the reaction mixture waswarmed to rt and stirred for 2 h. After the reaction was completed,the reaction mixture was poured into ice-H2O (30 mL) thenextracted with EtOAc. The organic phase was combined andwashed once with H2O (60 mL) and once with brine (60 mL). Theorganic layer was washed with H2O and saturated aqueous NaCland dried over Na2SO4. it was then concentrated and purified viaflash chromatography on silica gel to get 1.1 g (Yield 75.2%) of whitecrystalline solid (1g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Intermediate S-1H: (4S)-4-(Propan-2-yl)-3-(5,5,5-trifluoropentanoyl)-1,3-oxazolidin-2-one [0285] 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at -78 C. was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride, dissolved in THF (20 mL), was added via cannula over 15 min. The reaction mixture was warmed to 0 C., and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, and the mixture was extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP SiO2 120 g). Concentration of the appropriate fractions provided Intermediate S-1H (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 4.44 (1H, dt, J=8.31, 3.53Hz), 4.30 (1H, t, J=8.69 Hz), 4.23 (1H, dd, J=9.06, 3.02Hz), 2.98-3.08 (2H, m), 2.32-2.44 (1H, m, J=13.91, 7.02, 7.02, 4.03Hz), 2.13-2.25 (2H, m), 1.88-2.00 (2H, m), 0.93 (3H, d, J=7.05 Hz), 0.88 (3H, d, J=6.80 Hz). | |
86% | To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) inDCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol)dropwise over 5 min and the solution was stirred until all bubbling subsided. Thereaction mixture was concentrated under reduced pressure to give pale yellow oil. To aseparate flask charged with a solution of ( 48)-4-(propan-2-yl)-I ,3-oxazolidin-2-one ( 4.I820 g, 32.4 mmol) in THF (IOO mL) at -78 oc was added n-BuLi (2.5M in hexane, 13.0 mL,32.5 mmol) dropwise via syringe over 5 min. After stirring for IO min, the above acidchloride dissolved in THF (20 mL) was added via cannula over I5 min. The reactionmixture was warmed to 0 C, and was allowed to warm to room temperature as the bathwarmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, and25 then extracted with EtOAc (2x). The combined organics were washed with brine, dried(Na2S04), filtered and concentrated under reduced pressure. The crude material waspurified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solventA/B=hexanes/EtOAc, REDISEP Si02 I20g). Concentration of appropriate fractionsprovided Intermediate S-IB (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCh) 8 ppm 4.44 (I H, dt, J=8.3I, 3.53 Hz), 4.30 (I H, t, J=8.69 Hz), 4.23 (I H, dd, J=9.06,3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (I H, m, J=13.9I, 7.02, 7.02, 4.03 Hz), 2.13-2.25(2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz). | |
86% | [00141] To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) inDCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol)dropwise over 5 min. The solution was stirred until all bubbling subsided. The reactionmixture was concentrated under reduced pressure to give a pale yellow oil. To a separateflask, charged with a solution of ( 48)-4-(propan-2-yl)-1 ,3-oxazolidin-2-one ( 4.18 g, 32.420 mmol) in THF (100 mL) at -78 oc was added n-BuLi (13.0 mL, 32.5 mmol, 2.5M inhexane) dropwise via syringe over 5 min. After stirring for 1 0 min, the above acidchloride, dissolved in THF (20 mL ), was added via cannula over 15 min. The reactionmixture was warmed to 0 oc and was allowed to warm to room temperature as the bathwarmed and stirred overnight. To the reaction mixture was then added saturated NH4Cl,25 and it was then extracted with EtOAc (2x). The combined organics were washed withbrine, dried (Na2S04), filtered and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography (hexanes/EtOAc) to provideIntermediate S-1G (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCh) 8 4.44 (1H, dt, J=8.31, 3.53 Hz), 4.30 (1 H, t, J=8.69 Hz), 4.23 (1 H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz). |
86% | Preparation A-i B: (4S)-4-(Propan-2-yl)-3 -(5,5,5 -trifluoropentanoyl)- 1,3 -oxazolidin-2- one [00143j To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 mm and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)- 1 ,3-oxazolidin-2-one (4.18g, 32.4 mmol) in THF (100 mL) at -78 C was added n-BuLi (2.5M in hexane) (13.0 mL,32.5 mmol) dropwise via syringe over 5 mm. After stirring for 10 mm, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 mm. The reaction mixture was warmed to 0 C, and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4C1, andthe mixture was then extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 120g). Concentration of appropriate fractions provided Preparation A-lB (7.39 g, 86%) as a colorless oil: ‘HNMR (400 MHz, CDC13) ö ppm 4.44 (1 H, dt, J8.31, 3.53 Hz), 4.30 (1 H, t, J8.69 Hz),4.23 (1 H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02,7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz). | |
86% | Intermediate S-i H: (4S)-4-(Propan-2-yl)-3 -(5,5,5 -trifluoropentanoyl)- 1,3 -oxazolidin-2- one[00146j To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 mm and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)- 1 ,3-oxazolidin-2-one (4.18g, 32.4 mmol) in THF (100 mL) at -78 C was added n-BuLi (2.5M in hexane) (13.0 mL,32.5 mmol) dropwise via syringe over 5 mm. After stirring for 10 mm, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 mm. The reaction mixture was warmed to 0 C, and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4C1, andthen extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 1 20g). Concentration of appropriate fractions provided Intermediate S-1H (7.39 g, 86%) as a colorless oil: ‘H NMR (400 MHz, CDC13)o ppm 4.44 (1 H, dt, J=8.31, 3.53 Hz), 4.30 (1 H, t, J=8.69 Hz), 4.23 (1 H, dd, J9.06,3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25(2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J6.80 Hz). | |
86% | To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) inDCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol)dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction5 mixture was concentrated under reduced pressure to give a pale yellow oil. To a separateflask charged with a solution of ( 48)-4-(propan-2-yl)-1 ,3-oxazolidin-2-one ( 4.18 g, 32.4mmol) in THF (100 mL) at -78 oc was added n-BuLi (13.0 mL, 32.5 mmol, 2.5M inhexane) dropwise via syringe over 5 min. After stirring for 1 0 min, the above acidchloride dissolved in THF (20 mL) was added via cannula over 15 min. The reaction10 mixture was warmed to 0 C, and was allowed to warm to room temperature as the bathwarmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, andthen extracted with EtOAc (2x). The combined organics were washed with brine, dried(Na2S04), filtered and concentrated under reduced pressure. The crude material waspurified by silica gel chromatography (hexanes/EtOAc) to provide Intermediate S IA15 (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCh) 8 4.44 (1 H, dt, J=8.31, 3.53Hz), 4.30 (1 H, t, J=8.69 Hz), 4.23 (1 H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93(3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -75 - -65℃; for 0.5h; Inert atmosphere; Stage #2: n-valeryl chloride In tetrahydrofuran at -75 - -65℃; for 1h; Inert atmosphere; | 3 Embodiment 3: (S)-4-isopropyl-3-pentanoyloxazol-2-one In a reaction flask, tetrahydrofuran (50 mL) was added, (S)-4-isopropyloxazol-2-one (5.0 g, 38.7 mmol) was added, and the temperature was cooled to -70° C.; under nitrogen gas protection, the internal temperature was maintained at -65-75° C., 2.5 M n-butyllithium (16.2 mL, 40.5 mmol, 1.05 eq) solution was added dropwise, after the addition, the reaction was conducted for half an hour at a maintained temperature; then the internal temperature was maintained at -65-75° C., valeryl chloride (5.1 g, 42.3 mmol, 1.09 eq) was added dropwise and reacted for 1 hour, and TLC was used to detect the disappearance of (S)-4-isopropyloxazol-2-one, and treatment was performed; then the temperature was raised to 0° C., 20 mL saturated aqueous ammonium chloride solution was added and quenched by butyl lithium to separate the phase. The organic phase was concentrated under a reduced pressure. The concentrate was dissolved in 50 mL methylene dichloride, washed with water twice (25 mL×2). The organic phase was dried over 10.0 g anhydrous sodium sulfate for 2 hours; filtered and concentrated under a reduced pressure to give the target product as a light yellow oily substance (8.0 g, yield 96.8%). (0088) 1H NMR (600 MHz, CDCl3) δ 4.44 (ddd, J=8.4, 3.9, 3.1 Hz, 1H), 4.26 (t, J=8.7 Hz, 1H), 4.20 (dd, J=9.1, 3.0 Hz, 1H), 2.99 (ddd, J=16.6, 8.7, 6.3 Hz, 1H), 2.86 (ddd, J=16.5, 8.6, 6.4 Hz, 1H), 2.37 (dtd, J=14.0, 7.0, 3.9 Hz, 1H), 1.69-1.58 (m, 3H), 1.39 (h, J=7.5 Hz, 2H), 0.96-0.90 (m, 7H), 0.88 (d, J=7.0 Hz, 3H). MS (ESI): m/z 214.1 [M+H]+. [α]D19 +75.0° (c=1.0 g/100 mL, CHCl3). |
6.51 g | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78 - -68℃; for 0.5h; Stage #2: n-valeryl chloride In tetrahydrofuran; hexane at -78 - 20℃; | S9A Intermediate S9A To a stirred solution of pentanoic acid (5.98 g, 58.6 mmol) in CH2C12 (100 mL) and 10 drops DMF was added oxalyl chloride (5.64 mL, 64.4 mmol) dropwise over 5 min and the solution stirred for 2.75h, at which time all bubbling subsided. The solution was concentrated in vacuo. In a separate flask, to a cold (-78 °C), stirred solution of (S)-4-isopropyloxazolidin-2-one (7.56 g, 58.6 mmol) in THF (280 mL) was added n- BuLi (2.5M in hexane, 23.42 mL, 58.6 mmol) dropwise via addition funnel over 20 min (temperature never exceeded -68 °C). After stirring 10 min, the above acid chloride dissolved in THF (50 mL) was added via addition funnel over 25 min. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture. The mixture was transferred to a separatory funnel and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated to an amber oil. Theresidue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hex/EtOAc, REDISEP Si02 120g, applied as a DCM solution) to afford ((S)-4-isopropyl-3-pentanoyloxazolidin-2-one (6.51 g, 52%) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 4.44 (1 H, ddd, J=8.16, 3.51, 3.39 Hz), 4.27 (1 H, t, J=9.00 Hz), 4.21 (1 H, dd, J=9.00, 3.01 Hz), 2.99 (1 H, ddd, J=16.60, 8.50, 6.50 Hz), 2.86 (1 H, ddd, J=16.60, 8.50, 6.78 Hz), 2.31-2.44 (1 H, m), 1.56-1.72 (2 H, m), 1.39 (2 H, sxt, J=7.43 Hz), 0.94 (3 H, t, J=7.28 Hz), 0.92 (3 H, d, J=7.03 Hz), 0.88 (3 H, d, J=6.78 Hz); HPLC: RT=2.497 min (CHROMOLITH SpeedROD 4.6 x 50 mm (4 min grad) eluting with MeOH/H2O/0.1% TFA, 4 mL/min, monitoring at 220 nm); purity = 100%. |
Yield | Reaction Conditions | Operation in experiment |
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76% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: C11H20O4 With triethylamine In tetrahydrofuran; hexane at -78℃; for 1.5h; | 2 A solution of n-BuLi (1.6 mL, 2.6 mmol, 1.6 M in hexane) was added dropwise to a stirred solution of 3 (310 mg, 2.4 mmol) in THF (5.0 mL) at -78 °C. The mixture was stirred at this temperature for 30 min. In a separate flask containing 4-methylvaleric acid (0.30 mL, 2.4 mmol) and THF (5.0 mL) were added Et3N (0.40 mL, 2.9 mmol) and isobutylchloroformate (0.34 mL, 2.6 mmol) at 0 °C. After stirring for 30 min, the lithio-(4S)-4-isopropyl-2-oxazolidinone was added at 78 °C and stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO3. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 6:1) to yield 4 (800 mg, 76%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 0.88 (d, J = 6.9 Hz, 3H), 0.91-0.94 (m, 9H), 1.52-1.65 (m, 3H), 2.31-2.42 (m, 1H), 2.80-2.91 (m, 1H), 2.94-3.05 (m, 1H), 4.20 (dd, J = 9.0, 3.3 Hz, 1H), 4.27 (t, J = 8.6 Hz, 1H), 4.41-4.46 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 14.6, 17.9, 22.2, 22.3, 27.6, 28.3, 33.2, 33.5, 58.3, 63.2, 154.0, 173.5. {α]D28+81 (CHCl3, c 1.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.3% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -50℃; for 0.5h; Inert atmosphere; Stage #2: (R,S)-2-Fluoropropanoyl chloride In tetrahydrofuran; hexane at -50℃; for 1h; | 3 Example 3: preparation of ( 4S)-3-(2-fluoropropanoyl)-4-isopropyloxazolidin-2-one (5) n-butyllithium (2.5 Min hexane, 75 mL, 187 mmol, 1.1eq) was added to a solution of4-(S)-4-isopropyl-2-oxazolidinone (22 g, 170 mmol, 1 eq) in dry THF (200 mL) at -50 'C under N2atomosphere. After 30 min 2-fuoropropanoyl chloride (17 mL, 153 mmol, 0.9 eq) was added, andthe solution was stirred for 1 hat -50 'C. After the starting material was completely consumed, thereaction was then quenched with a saturated solution ofNH4Cl (125 mL), extracted with MTBE(200 mL * 2), washed with brine and dried over MgS04• Solvents were removed under reducedpressure. The product was purified over silica (hexane/EtOAc= 10/1) and recovered as a brown oil(34 g, 83.3%). 1H-NMR(CDCl3, 400 MHz): 8 5.93 (dm, J = 48.8 Hz, 1 H), 4.19-4.17 (m, 3H), 2.35(dm, J = 52.8 Hz, 1 H), 1.55 (td, J = 23.6 Hz, 3 H), 0.85 (dq, J =18Hz, 6 H). |
48% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -60 - -50℃; for 0.5h; Stage #2: (R,S)-2-Fluoropropanoyl chloride In tetrahydrofuran at -50 - 20℃; for 4h; | C.C2 (4S)-3-(2-fluoropropanoyl)-4-isopropyloxazolidin-2-one (S)-4-Isopropyloxazolidin-2-one (3.8 g, 0.029 mol) and THF (75 ml) were charged to a vessel. The solution was cooled to -60 °C, then n-butyllithium solution 2.7 M (18 ml, 0.049 mol) was added dropwise, while maintaining the reaction temperature at temperature was then raised to 15~20°C within 3 hrs. followed by stirring at 15~20°C for further 60 min. Upon reaction completion, 10 % NH4C1 solution (30 ml) was charged and the reaction mixture was stirred for 30 min. Phases were separated and the aqueous phase was extracted with methyl tert-butylether (30 ml). The combined organic layers were washed with saturated NaCl solution (30 ml). The organic phase was dried with Na2S04, filtered and evaporated under reduced pressure to remove the solvents. The residue was purified by column chromatography (eluent: HE/EA=3/lv/v) to obtain (4S)-3-(2-fluoropropanoyl)-4-isopropyloxazolidin-2-one (2.9 g, 48 % yield) as a light yellow oil. 'H-NMR (CDCI3, 400 MHz): 56.00 (m, 1H), 4.39 (m, 3H), 2.43 (m, 1H), 1.61 (m, 3H), 0.91 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
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97% | To 2-thiophene-propionic acid 28 (5.23 g, 33.5 mmol) in THF (60 mL) were added Et3N (5.6 mL, 40 mmol) and isobutylchloroformate (5.0 mL, 36.8 mmol) at 0 C. After stirring for 30 min, the mixture was added to the lithio-(4S)-4-isopropyl-2-oxazolidinone, prepared by dropwise addition of n-BuLi (14.2 mL, 36.8 mmol, 2.6 mol/L in hexane) to (4S)-4-isopropyl-2-oxazolidinone (4.76 g, 36.8 mmol) in THF (60 mL) at -78 C, and the mixture was stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO3 and the whole was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 5:1) to yield 30 (3.68 g, 97%). [alpha]D28 +78 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): delta 7.12 (dd, J = 5.2, 1.2 Hz, 1H), 6.91 (dd, J = 5.2, 3.2 Hz, 1H), 6.86-6.85 (m, 1H), 4.44 (td, J = 8.1, 3.6 Hz, 1H), 4.26 (dd, J = 9.2, 8.0 Hz, 1H), 4.21 (dd, J = 9.2, 3.2 Hz, 1H), 3.41-3.25 (m, 2H), 3.24-3.19 (m, 2H), 2.41-2.33 (m, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): delta 171.7, 153.9, 143.0, 126.7, 124.8, 123.4, 63.4, 58.3, 37.2, 28.2, 24.3, 17.8, 14.5; HRMS (EI) Calcd for C13H17NO3S [M]+: 267.0929. Found: 267.0933. |
Yield | Reaction Conditions | Operation in experiment |
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96% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25h; Inert atmosphere; Stage #2: (E)-2-methyl-2-pentenoyl chloride In tetrahydrofuran; hexane at -78℃; for 0.75h; | N-(2’-Methyl-2’E-pentenoyl)-4S-isopropyl-1,3-oxazolidin-2-one (A).1 Butyllithium (2.5 M in hexane, 15.6 mL, 39.1 mmol, 1.01 equiv) was added dropwise to a solution of (S)-(+)-4-isopropyl-1,3-oxazolidin-2-one2 (5.00 g, 38.7 mmol) in anhydrous THF (70.0 mL) at -78 °C under argon. The resulting mixture was stirred for 15 min and a freshly distilled 2-methyl-2E-pentenoyl chloride (5.13 g, 38.7 mmol) in dry THF (30 mL) was added via syringe at -78 °C. The reaction was stirred for an additional 45 min at -78 °C and then warmed to ambient temperature. Saturated aqueous ammonium chloride (50 mL) was added and the resulting mixture stirred for 30 min. The solvent was removed under reduced pressure and the remaining aqueous phase transferred to a separation funnel. The aqueous phase was extracted with DCM (2×100 mL), the combined organics were washed with 3.0 M NaOH (25 mL), water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified with flash chromatography using hexanes/ethyl acetate 0-20% as a gradient to give 96% (8.37 g) of A as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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1: 70% 2: 11% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; | 23 Intermediate III-5: (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one Example 23 Intermediate III-5: (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one A solution of (S)-4-phenyloxazolidin-2-one (3.0 g, 23.2 mmol) and 2,4-dichloropyrimidine (4.10 g, 27.5 mmol) in DMF (40 mL) was treated with NaH (60% in oil, 0.97 g, 24.3 mmol). The resulting mixture (yellow to red cloudy solution) was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc (200 mL), washed with saturated aqueous NH4Cl (75 mL) and brine (2*100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on an ISCO chromatography system (on a SiO2 column: eluted with 0 to 50% Hexanes/EtOAc gradient) to obtain the desired product III-5 as white solid (3.91 g, 70% yield) along with the other isomer III-5a (0.59 g, 11%). III-5: 1H NMR (300 MHz, CDCl3): δ ppm 8.46 (d, J=6.0 Hz, 1H), 8.18 (d, J 6.0 Hz, 1H), 4.80-4.75 (m, 1H), 4.42-4.34 (m, 2H), 2.66-2.54 (m, 1H), 0.99 (d, J=7.1 Hz, 3H), 0.87 (d, J=7.1 Hz, 3H). LCMS (method 3): Rt 11.62 min, m/z 242.1 [M+H]+. III-5a: 1H NMR (300 MHz, CDCl3): δ ppm 8.57 (d, J=5.2 Hz, 1H), 7.07 (d, J=5.2 Hz, 1H), 4.75-4.65 (m, 1H), 4.40-4.29 (m, 2H), 2.60-2.47 (m, 1H), 0.96 (d, J=6.9 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H). LCMS (method 3): Rt 9.90 min, m/z 242.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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68% | With pivaloyl chloride In toluene at 115℃; for 16h; | (S)-3-(2-(3,4-dimethoxyphenyl)acetyl)-4-isopropyloxazolidin-2-one (7). To a solution of (S)-4-isopropyloxazolidin-2-one (5.0 g, 38.76 mmol) and 3,4-Dimethoxy- phenylacetic acid (10.2 g,52.04 mmol) in dry toluene (250 mL) at 80°C was added PivCl (7.2 mL, 60.78 mmol) and the mixture was refluxed at 115°C for 16h. The reaction was quenched with 1M HCl and the aqueous layer was extracted with CH2Cl2, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (PE-EtOAc, 4:1) to afford 7 (5.3 g,68 %) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.91 -6.79 (m, 1H), 4.47 - 4.40 (m, 0H), 4.29 (dd, J = 20.6, 11.7 Hz, 1H),4.22 - 4.13 (m, 1H), 3.86 (t, J = 5.2 Hz, 2H), 2.39 - 2.29 (m, 0H), 0.88(d, J = 7.0 Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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1: 90% 2: 0.89 g | With methanol; lithium borohydride In diethyl ether at 20℃; for 1.5h; Inert atmosphere; Cooling with ice; | (-)-(S)-2-Methylhexan-1-ol (19) (Scheme 7) To an ice-cooled solution of the 3-(2-methylhexanoyl)oxazolidin-2-one (18; C13H23NO3, 241.33 g/mol, 1.82 g, 7.54 mmol, 1 equiv) and MeOH (32.04 g/mol, 0.79 g/mL, 0.9 mL, 711 mg, 22.19 mmol, 3 equiv) in Et2O (75 mL) was added LiBH4 (21.78 g/mol, 0.49 g, 22.6 mmol, 3 equiv). The cooling bath was removed and the mixture was stirred atr.t. for 1.5 h. The reaction mixture was diluted by the addition of sat. aq Na/K tartrate (40 mL) and subsequently stirred at r.t. for 30 min. The biphasic mixture was then partitioned in a separatory funnel andthe aqueous layer was extracted with Et2O (4 × 30 mL). The combined organic phases were dried (MgSO4) and carefully concentrated at reduced pressure (40 °C/700 mbar). The residue was purified by Kugelrohr distillation (100 °C/20 mbar) to yield, as the distillate, the colorless liquid alcohol 19 (C7H16O, 116.20 g/mol, 0.79 g, 6.8 mmol, 90 %) and residual (S)-4-isopropyloxazolidin-2-one (C6H11NO2, 129.16 g/mol, 0.89 g, 6.89 mmol, 91 %); Rf = 0.31 (hexanes-EtOAc, 5:1); [α]25D -13.1 (c 1.0, CHCl3) {Lit.47 [α]D25 -14.2 (c 0.31, MeOH), Lit.48 [α]D19-11.6 (c 7.59, Et2O)}. IR (film): 3700-3100, 3000-2850, 1465, 1260 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 6.9 Hz, 3 H), 0.89 (d, J = 6.5Hz, 3 H), 1.04-1.12 (m, 1 H), 1.19-1.40 (m, 6 H), 1.53-1.62 (m, 1 H), 3.39 (dd, J = 10.5, 6.5 Hz, 1 H), 3.48 (dd, J = 10.5, 5.8 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 14.0, 16.5, 22.9, 29.1, 32.7, 35.6, 68.3. HRMS (EI): m/z calcd for [C7H16O]+: 116.1196; found: 116.1177. |
Yield | Reaction Conditions | Operation in experiment |
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87% | <strong>[42288-04-0]3-(3-bromophenyl)-3-methylbutanoicacid</strong> (Compound D12, 7.7 g, 29.94 mmol) was dissolved in 170 ml of THF and cooled to -20 C. Triethylamine (8.3 ml, 59.89 mmol) and trimethylacetyl chloride (3.7 ml, 29.94 mmol) were added to the reaction flask producing a white precipitate. The resulting mixture was stirred at -20 C for 1 h under N2 atm, after which LiCl (1.27 g, 29.94 mmol) and (4S)-(-)-4-isopropyl-2oxazolidinone (3.87 g, 29.94 mmol) were added sequentially and the resulting reaction mixture was stirred at -20 oC for 2 h and overnight at rt under N2 atm. Water was added and the reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash column chromatography (silica gel, hexane:EtOAc, 4:1) affording compound D13 as a clear, colorless oil in 87% yield (9.5 g, 25.79 mmol).1H NMR (400 MHz, CDC13) delta 7.52-7.50 (m, 1H), 7.36-7.31 (m, 2H), 7.21-7.18 (m, 1H), 4.25-4.21 (m, 1H, H-4), 4.17-4.09 (m, 2H), 3.42-3.31 (m, 2H, H-10), 2.22-2.10 (m, 1H), 1.50 (s, 3H), 1.49 (s, 3H), 0.86 (d, 3H, J = 6.80 Hz), 0.77 (d, 3H, J=6.80 Hz) [00323] Preparation of compound D14 |
Yield | Reaction Conditions | Operation in experiment |
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74.1% | With sodium hydride In N,N-dimethyl-formamide at 0℃; for 4h; | 3.1.1. Synthesis of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (3) To a mixture of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) and (S)-4-isopropyl-oxazolidin-2-one (867 mg, 6.71 mmol) in 7 mL anhydrousDMF, a solution of NaH (322 mg, 13.43 mmol) in DMF was addeddropwise under ice bath. The mixture was stirred for 4 h at 0 °C till itscompletion monitored by TLC. The reaction mixture was poured intoice water and the organic layer was collected with EtOAc, washed withsaturated NaHCO3 solution and dried with anhydrous Na2SO4.Purification of the crude product by rapid column chromatography(Petroleum: EtOAc=15:1, v:v) to afford the intermediate 3 as whitesolid (1.2 g, yield 74.1%). 1H NMR (500 MHz, CDCl3)δ 8.52 (d, J=5.8 Hz, 1H), 8.23 (d, J=5.8 Hz, 1H), 4.94-4.77 (m, 1H), 4.50-4.26(m, 2H), 2.72-2.55 (m, 1H), 1.04 (d, J=7.0 Hz, 3H), 0.93(d,J=7.0 Hz, 3H). |
73% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; | 1.1 (1) Synthesis of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one In an ice bath, NaH (60% in mineral oil, 520 mg, 13.0 mmol) was added in batches to a solution of (S)-4-(S)-4-isopropyloxazolidin-2-one (1.50 g, 11.6 mmol) and 2,4-dichloropyrimidine (1.90 g, 12.8 mmol) in DMF. The resulting yellow suspension was stirred overnight at room temperature. Then the mixture was poured into water (150 mL) and extracted with EtOAc (70 mL*3). The combined organic layer was washed with brine (70 ml), dried over MgSO4 and concentrated. The crude product was purified by column chromatography (petroleum ether: EtOAc = 5:1) to obtain the title compound (2.05 g, yield 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 6.0 Hz, 1H), 8.18 (d, J = 6.0 Hz, 1H), 4.81-4.77 (m, 1H), 4.43-4.34 (m, 2H), 2.64-2.56 (m, 1H), 0.99 (d, J = 7.2 Hz, 3H), 0.88 (d, J = 7.2 Hz, 3H) |
62% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h; |
40.4% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 12.0833h; Inert atmosphere; | (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (8) A solution of (S)-4- isopropyloxazolidin-2-one (a) (5.3 g, 41 mmol) and 2,4-dichloropyrimidine (b) (6.1 g, 41 mmol) in 30 mL DMF was cooled to 0 °C under N2 atmosphere. NaH (2.1 g of 60% suspension, 53 mmol) was slowly added to the solution. After 5 min, cold bath was removed. Reaction mixture was allowed to warm to room temperature and stirred 12 h. The reaction mixture was diluted with water and extracted with EtOAc. Organic layer was washed water, and brine. Combined organic layers were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography provided (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (8) as a white solid (4 g, 40.4 %). MS m/z 242.09 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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46% | With pivaloyl chloride; triethylamine In toluene at 80℃; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
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82% | Stage #1: valeric acid With pivaloyl chloride; potassium hydrogencarbonate In 2-methyltetrahydrofuran at 5℃; for 5h; Inert atmosphere; Stage #2: (4S)-4-isopropyl-1,3-oxazolidin-2-one With lithium chloride In 2-methyltetrahydrofuran at 10 - 15℃; for 10h; | 9 Example 9Synthesis of (S) -4- isopropyl-3-pentanoyl-oxazolidin-2-one (compound 4c) To the reaction flask was added 1 liter 2-methyltetrahydrofuran, pentanoic acid (Compound 1a, 1.2 eq.), Potassium bicarbonate (188.4 g, 2.7 eq), nitrogen was cooled to 5 .Specter pivaloyl chloride was slowly added dropwise 100.8 (compound 3a, 1.2 equiv).Kept under stirring for 5 5 hours, anhydrous lithium chloride (38.4 g, 1.3 eq).(S) -4- isopropyl - oxazolidin-2-one (compound 2c, 90 g) was formulated into a solution of 2-methyl tetrahydrofuran, was slowly added dropwise to the reaction solution.NATURAL warmed to 10 ~ 15 ), stirring was continued for 10 hours.Filtered, the filtrate was added potassium bicarbonate solution, and sufficiently stirred, the solvent was evaporated under reduced pressure and extracted with a solvent.The organic layer was washed with dilute hydrochloric acid, saturated brine, dried, filtered, and solvent removal, to obtain 122 g of colorless oil (S) -4- isopropyl-3-pentanoyl-oxazolidin-2-one (compound 4c , purity 92%, yield 82%). |
Yield | Reaction Conditions | Operation in experiment |
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320 mg | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 80℃; for 16.3333h; Inert atmosphere; | 10 Synthesis of (45)-3-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-dl pyrimidin-4-yl]-4- (propan-2-yl)-1,3-oxazolidin-2-one 4,6-dichloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 1.83 mmol), (45)-4-(propan-2-yl)-1,3-oxazolidin-2-one (260.09 mg, 2.01 mmol), Pd2(dba)3 (50.29 mg, 0.05 mmol), Xantphos (31.78 mg, 0.05 mmol), K3P04 (777.19 mg, 3.66 mmol) were weighed out in an Ace pressure tube. Toluene (5 ml) was added and the mixture was “degassed” by bubbling a stream of nitrogen through it for 10 minutes. The mixture was then heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature, then partitioned between DCM (10 ml) and water (10 ml) . The aqueous phase was further extracted with DCM (10 x 2m1) and the combined organic layers dried (Na2504)and concentrated. The crude material was purified by Biotage Isolera flash column chromatography (SiC2 25 g) eluting with10-50% EtCAc in heptane gradient to give 320 mg of required product as a mixture of diastereoisomers. LCMS MH+ 281.9 RT 1.26 System 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With n-butyllithium; pivaloyl chloride; triethylamine In tetrahydrofuran; hexane at -78℃; Inert atmosphere; | To a solution of 14 (10 g, 46.5 mmol) in dry THF (400 mL) at -78 C under argon atmosphere was added triethylamine (14 mL, 102.3 mmol), and then dropped gradually pivaloyl chloride (6 mL, 51.2 mmol). The mixture was stirred 15 min at -78 C and then warmed to 0 C. The reaction was stirred for 1 h at 0 C. To a solution of (S)-4-isopropyloxazolidin-2-one (15, 9 g, 69.8 mmol) in dry THF (400 mL) was dropped n-BuLi (2.5 mol/L in hexanes, 28 mL, 69.8 mmol ) at -78 C under argon. The mixture was stirred for 10 min at -78 C, to which was dropped the above-prepared solution. After stirring for 2 h at -78 C, the reaction was warmed to room temperature and stirred overnight. The reaction solution was quenched by adding saturated NH4Cl solution, and then was extracted by EtOAc (3 × 400 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA 6:1) to afford 16 (10.9 g, 72%) as a yellow oil. [α]32D : +59.6 (c 2.25, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 0.94 (s, 9H), 1.44 (s, 9H), 2.49 (q, J = 6.4 Hz, 2H), 3.30 (m, 2H), 4.23 - 4.32 (m, 2H), 4.51 (dd, J =7.2, 1.6 Hz, 1H), 4.66 ( br, 1H), 7.06 (m, 1H), 7.32 (d, J = 15.2 Hz, 1H); 13C NMR (100 MHz CDCl3) 25.5, 28.3, 29.6, 33.2, 35.8, 39.0, 60.8, 65.2, 122.3, 147.4, 154.5, 155.7, 165.0. IR (KBr): ν 3374, 2966, 1781, 1694, 1638, 1520, 1368, 1251, 1186, 1070, 980, 852, 783, 759, 715cm-1. HRMS (ESI) calcd for C16H26N2NaO5 [M + Na]+ 349.1739, found 349.1734. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydride In N,N-dimethyl-formamide at 0℃; for 2h; | 1 Chemistry 4.1.1 3-(6-Chloropyrazin-2-yl)-4-isopropyloxazolidin-2-one (I) To a solution of 2,6-dichloropyrazine (100 mg, 0.671 mmol) and (S)-4-isopropyloxazolidin-2-one (86.7 mg, 0.671 mmol) in 5 mL DMF was slowly added with a solution of NaH (35 mg, 1.34 mmol) in 1 mL DMF at an ice bath. The mixture was stirred at 0 °C for about 2 hours. After the completion of the reaction monitored by TLC, the mixture was added dropwise to ice water. Then the mixture was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over anhydrous Na2SO4 and evaporated to afford the white crude product. Purification of the crude product with flash column chromatography (PE: EA = 8:1, v:v) gave 150 mg of I as a white solid, yield 92%. 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.52 (s, 1H), 4.69-4.67 (m, 1H), 4.49-4.46 (m, 2H), 2.38-2.33 (m, 1H), 0.92-0.78 (dd, J = 6.0 Hz, J = 9.0 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: tert-butyl (S)-4-(4-(1-((4,6-difluoropyrimidin-2-yl)amino)ethyl)benzyl)piperazine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.0166667h; Stage #2: (4S)-4-isopropyl-1,3-oxazolidin-2-one In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | 60 Preparation 60 tert-Butyl 4-(4-((S)- 1 -((4-fluoro-6-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)benzyl)piperazine- 1 -carboxylate Sodium hydride (61 mg, 1.53 mmol, 60% in mineral oil) is added to a solution oftert-butyl (S)-4-(4-( 1 -((4,6-difluoropyrimidin-2-yl)amino)ethyl)benzyl)piperazine- 1-carboxylate (550 mg, 1.27 mmol) in DMF at (6 mL) 0 °C. After 1 minute, (S)-4-isopropyloxazolidin-2-one (180 mg, 1.39 mmol) is added and the mixture is stirred for 1hour at 0 °C followed by warming to room temperature and stirring overnight. Thereaction mixture is then quenched with water and is extracted with EtOAc. The EtOAc extract is washed with 5% aqueous LiC1 (2x), dried (Na2504), filtered, and concentrated to give a residue which is purified by silica gel chromatography eluting with a gradient of 30-50% EtOAc/hexanes to give the title compound a solid (500 mg, 0.92 mmol, 73%).ES/MS (mlz): 543 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium hydroxide In dimethyl sulfoxide at 15 - 20℃; | General procedure for the synthesis of alkyl bromide (1a-1f) General procedure: In a round bottom flask dimethyl sulfoxide (50 ml) was added, followed by 1,3 dibromopropane (61.7 g, 306 mmol) and powdered potassium hydroxide (4.47 g, 80 mmol).[13] The reaction mixture was cooled to 15-20 C. To the cooled reaction mixture, was added (S)-4-phenyloxazolidin-2-one (10 g, 61.3 mmol) in 4 to 5 lots at an interval of 5 min each. The reaction mixture was stirred further at 15-20 C for 3-4h. Water (150 ml) was then added to the reaction mixture and it was extracted in dichloromethane (200 ml). The organic layer was concentrated on laboratory rotary evaporator. The resultant residue was purified on silica gel column using cyclohexane/ethyl acetate to get (1a) as colorless oil. Yield: 13.1 g (75%). 1b-1f were prepared in the same manneras 1a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In diethyl ether; hexane at -78℃; for 1h; Stage #2: [3]furyl-acetyl chloride In diethyl ether; hexane at -78 - 20℃; for 1h; | To a stirring solution of (S)-4-isopropyl-2-oxazolidinone (1.02 g, 7.93 mmol) in Et2O (35 mL) was added n-BuLi (1.64 M in hexane, 4.9 mL, 8.03 mmol) at -78 °C. After stirring for 1 h, the crude acid chloride in Et2O (15 mL) was added to the mixture at -78 C and stirring was continued for 1 h at room temperature. The reaction was quenched with saturated NH4Cl solution and aqueous layer was extracted three times with Et2O. Combined organic layer was washed with saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/Et2O = 1:1) to afford 7 (1.50 g, 80%) as colorless needles: mp = 80-82 °C; 1H NMR (400 MHz, CDCl3): δ 7.43 (1H, s), 7.38 (1H, t, J = 2.0 Hz), 6.39 (1H, s), 4.44 (1H, ddd, J = 3.2 Hz, 4.4 Hz, 8.8 Hz), 4.28 (1H, t, J = 8.8 Hz), 4.21 (1H, dd, J = 3.2 Hz, 8.8 Hz), 4.18 (1H, d, J = 16.0 Hz), 4.04 (1H, d, J = 16.0 Hz), 2.36 (1H, dsept, J = 4.4 Hz, 7.2 Hz), 0.90 (3H, d, J = 7.2 Hz), 0.82 (3H, d, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): δ 170.63, 153.96, 142.85, 140.97, 116.86, 111.47, 63.33, 58.46, 31.78, 28.21, 17.89, 14.51; IR (KBr) νmax 1763, 1703, 1378, 1275, 1218 cm-1; HRMS (ESI) m/z calcd. for C12H15NNaO4 [M+Na]+ 260.0893, found 260.0895; [a]D28 = +86.6 (c 1.28, CHCl3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | With 2-chloro-1-methylpyridinium p-toluenesulfonate; triethylamine In dichloromethane at 20℃; for 4h; | 4 Example 4 Add 10 ml of dichloromethane, 500 ml of triethylamine (3.6 mol), and isopropyl oxazolidinone 129 g to a 5-liter four-necked bottle.(1 mol), 80 g (1.1 mol) of acrylic acid, and 300 g (1 mol) of 2-chloropyridine methyl p-toluenesulfonate 1000 ml of dichloromethane was added dropwiseThe alkane solution was added and stirred at 20 ° C for 4 hours. TLC showed the reaction was complete. The mixture was extracted with water and washed with water and saturated brine.The organic phase was dried over anhydrous sodium sulfate, concentrated and recrystallized to give product 170 g, yield: 92.9%, HPLC purity >99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.3% | With 2-chloro-1-methylpyridinium p-toluenesulfonate; triethylamine In dichloromethane at 20℃; for 5h; | 3 Example 3 Add 10 ml of dichloromethane, 500 ml of triethylamine (3.6 mol), and isopropyl oxazolidinone 129 g to a 5-liter four-necked bottle.(1 mol), propionic acid 80 g (1.1 mol), 300 g (1 mol) of 2-chloropyridine p-toluenesulfonic acid methyl ester salt in 1000 ml of dichloromethaneThe solution was added and stirred at 20 ° C for 5 hours. TLC showed the reaction was complete, and the mixture was extracted with water and washed with water and saturated brine.The organic phase was dried over anhydrous sodium sulfate, concentrated and then recrystallised to afford product 180 g, yield 97.3%, HPLC purity >99% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In acetonitrile; at 20℃; for 1h;Sealed tube; | <strong>[16369-05-4]valinol</strong> (258.0 mg, 2.5 mmol) was dissolved in acetonitrile (3 mL) in a 50 mL reaction flask.The reaction flask was sealed with a rubber stopper and CF3SO3CF3 (109.0 mg, 0.5 mmol)Dissolved in 2mL of acetonitrile and into the reaction bottle with a syringe.The mixed liquid was stirred at room temperature for 1 h, and after completion of the reaction, the reaction was quenched with 5 drops of water.The solvent was removed under reduced pressure using petroleum ether:Ethyl acetate = 5:1 (v / v) as the eluent, column chromatography to give the product:4-isopropyloxazolidin-2-one(White solid, 118.4 mg), Yield: 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With iodine In 1,4-dioxane at 110℃; for 24h; Sealed tube; stereoselective reaction; | 2. Experimental details and characterization data for all compounds General procedure: A sealed tube was charged with the mixture of chiral oxazolidin-2-ones 1 (0.5 mmol), paraformaldehyde 2a (2.0 mmol) and styrene 3 (1.0 mmol) or allylbenzene (1.0 mmol), I2 (20 mol%)and then stirred in dioxane (3.0 mL) at 110 °C under air atmosphere for indicated time. Evaporation of the solvent followed by purification on silica gel column using petroleum ether/EtOAc (V/V 1:6) as eluent gave the corresponding product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.1% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acryloyl chloride In tetrahydrofuran; hexane at -78 - 0℃; for 0.5h; Inert atmosphere; | 1 (S, E) -3- (3- (2,3-dihydrobenzo [b] [1,4] dioxan-6-yl) acryloyl) -4-isopropyl Synthesis of 2-yl-2-one (Compound 4) Add S-isopropyl-2-oxazolidinone (1292g, 1mol), 4L tetrahydrofuran to the reaction kettle,The temperature of nitrogen was reduced to -78 ° C, and n-hexane solution of butyl lithium (420mL, 1.05mol, specification 2.0mol / L) was added dropwise.-78 ° C for 30 minutes.(E) -3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acryloyl chloride (247.1g, 1.1mol) was added dropwise, and the dropwise addition was maintained at -78 -70 , dripping is completed,The temperature was naturally raised to 0 ° C for 30 minutes. Saturated aqueous ammonium chloride solution to quench the reaction (5L),Extracted with ethyl acetate (1L * 2), combined organic phases, washed with saturated brine (3L),The organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure.The residue was added with ethyl acetate: n-hexane = 1:10 (volume ratio, 1.5L) to beat,Suction filtration yielded 291.7 g of product with a yield of 92.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With triethylamine; lithium chloride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: 5-hexenoyl chloride In tetrahydrofuran | 4; 5 Example 4 In a 2000ml four-neck flask, add 1000ml of tetrahydrofuran, 42.5g of anhydrous lithium chloride, 150g of triethylamine, and 129g of Evens prosthetic group. After stirring at room temperature for 15 minutes, add 200g of 5-hexenoyl chloride in 200ml of tetrahydrofuran solution. , Stir until the reaction is complete after TLC detection, add water and ethyl acetate to extract, dry and concentrate. Intermediate 209g was obtained with a yield of 92.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1,1,1,2-tetrafluoroethane; dinitrogen pentoxide at 5 - 20℃; for 1h; Autoclave; | Synthesis of 3-Nitrooxazolidin-2-ones 2; General Procedure General procedure: A steel autoclave containing substrate 1 (5 mmol) was filled with liquidTFE at r.t. to one third of volume and cooled to 5 °C. DNP (0.59 g,5.5 mmol for 1a-e; 1.18 g, 11.0 mmol for 1f,g; 4.86 g, 45.0 mmol for1g′) was placed into an auxiliary dosing vessel, which was then closedand filled with the same fluid to half. The obtained DNP solution was slowly added to the autoclave. The dosing vessel was twice washed with the fluid (one third of volume) to transfer residual DNP into the autoclave. The reaction mixture was stirred at 0.6 MPa and ambienttemperature for 1 hour, then water (2 mL) was added to the reactor todecompose the excess of the nitrating agent. The fluid was removed by decompression. The autoclave was opened and ice water (20 mL)was added to the residue. The resulting mixture was neutralized withsodium hydrocarbonate aqueous solution and extracted with EtOAc(3 × 10 mL). The combined organic extracts were dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure (50Torr) to afford nitro compounds 2. The yields are given in Table 1 and Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With (+)-1,2-bis((2S,5S)-2,5-diphenylphospholanyl)ethane; hydrogen; nickel diacetate In 2,2,2-trifluoroethanol at 80℃; for 24h; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27 g | Triethylamie in a THF solution (900 mL) of compound J1 (17.2 g) at -78 C. (23.7 mL) and pivaloyl chloride (15.3 mL) were added. The temperature was raised to 0 C. and the mixture was stirred for 1 hour. Separately, in a THF solution (760 mL) of (S) -isopropyloxazolidinone (19.5 g), N-Butyllithium (1.64 mol / L hexane solution 89.8 mL) was added at -78 C. and stirred for 30 minutes to prepare a lithium salt. Bring the previous reaction solution to -78 C and After dropping the lithium salt and stirring for 1 hour, The temperature was raised to 0 C., the mixture was further stirred for 30 minutes, water was added, and the mixture was extracted with tert-butyl methyl ether. Wash the organic layer with saturated saline , Dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent; hexane: tert-butyl methyl ether) to obtain compound J2 (27.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In dichloromethane at 0℃; for 0.5h; | 2.1.2. General procedure for the synthesis of sulfamoyloxy- oxazolidinones C(1-10) General procedure: A solution of oxazolidinone (1 equiv) in anhydrous CH 2 Cl 2 (5 mL) was added to a stirring solution of chlorosulfonylisocyanate (CSI) (1.1 equiv) in (5 mL) of anhydrous CH 2 Cl 2 at 0 °C dropwise over a period of 30 min. The resulting solution was transferred to a mixture of primary or secondary amine (1.0 equiv) in CH 2 Cl 2 (5 mL) in the presence of triethylamine (1.3 equiv). The solution was stirred at 0 °C for less than 1.5 h. The reaction mixture was washed with HCl 0.1 N and water, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography; or (9/1) mixture of diethyl ether and ethanol was added to the reactionmixture and pure product was crystallized to 6 °C overnight to give sulfamoyloxazolidinone-carboxamides in excellent yields. |
In dichloromethane at 0℃; for 0.5h; | 3.3. General procedure General procedure: A solution of oxazolidin-2-one (1 eq) in anhydrous CH 2 Cl 2 (10 mL) was added dropwise to a stirring solution of chlorosulfonyl isocyanate (CSI) (1 eq) in anhydrous CH 2 Cl 2 (10 mL) at 0 °C over 30 min. The resulting solution (carbamate) was transferred to a mixture of bis(2-chloroethyl)amine hydrochloride (1 eq) in CH 2 Cl 2 (10 mL) in the presence of triethylamine (2 eq). The solution was stirred at 0 °C for 2 h, and then neutralized by adding a solution of aqueous HCl 0.1 M to pH = 7. The organic layer was extracted, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo . The residue was purified by silica gel chromatography (CH 2 Cl 2 :MeOH/95:05) to give the final product in good yields. |
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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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