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Chemical Structure| 104266-90-2
Chemical Structure| 104266-90-2
Structure of 104266-90-2 * Storage: {[proInfo.prStorage]}
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Product Details of [ 104266-90-2 ]

CAS No. :104266-90-2 MDL No. :MFCD09817644
Formula : C15H19NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :JHGXEUXQJIKZMY-ZDUSSCGKSA-N
M.W : 261.32 Pubchem ID :11108107
Synonyms :

Calculated chemistry of [ 104266-90-2 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.47
Num. rotatable bonds : 5
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 76.44
TPSA : 46.61 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.79 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.41
Log Po/w (XLOGP3) : 2.97
Log Po/w (WLOGP) : 2.24
Log Po/w (MLOGP) : 2.25
Log Po/w (SILICOS-IT) : 2.58
Consensus Log Po/w : 2.49

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.23
Solubility : 0.152 mg/ml ; 0.000582 mol/l
Class : Soluble
Log S (Ali) : -3.61
Solubility : 0.0639 mg/ml ; 0.000244 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.55
Solubility : 0.0742 mg/ml ; 0.000284 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.89

Safety of [ 104266-90-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 104266-90-2 ]

* 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.

  • Downstream synthetic route of [ 104266-90-2 ]

[ 104266-90-2 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 503-74-2 ]
  • [ 90719-32-7 ]
  • (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 19h; Step1: (S)-4-Benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (65) To a solution of isovaleric acid (63, 10.0 g, 5.65 × 10 mmol) and (S)-4-benzyl-2-oxazolidinone (64, 7.40 mL, 6.78 × 10 mmol) in MeCN (100mL) were added DMAP (3.40 g, 2.79 × 10 mmol) and WSCHCl (12.0 g,6.28 × 10 mmol), and the mixture was stirred at room temperature for19 h. The reaction was quenched with saturated aqueous NaHCO3 solution.The mixture was extracted with toluene, and the organic layerwas washed with H2O, 1 M aqueous HCl solution, H2O and brine. Afterdrying over MgSO4 and filtration, the solvent was evaporated in vacuo togive the title compound 65 (15.0 g, quant.), which was applied to thenext step without further purification.1H-NMR (400 MHz, CDCl3) δ: 1.01 (d, J = 6.6 Hz, 3H), 1.03 (t, J =6.6 Hz, 3H), 2.17-2.28 (m, 1H), 2.75 (dd, J = 13.2, 9.6 Hz, 1H), 2.84(ddd, J = 44.9, 16.2, 6.9 Hz, 2H), 3.32 (dd, J = 13.2, 3.4 Hz, 1H),4.13-4.22 (m, 2H), 4.65-4.72 (m, 1H), 7.12-7.38 (m, 5H)
95% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Cooling with ice;
  • 2
  • [ 104266-90-2 ]
  • [ 128901-47-3 ]
  • [ 128948-72-1 ]
YieldReaction ConditionsOperation in experiment
With lithium diisopropyl amide 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h; Yield given. Multistep reaction;
With lithium diisopropyl amide THF, 0 deg C; Yield given. Multistep reaction;
With n-butyllithium; sodium chloride; diisopropylamine In tetrahydrofuran; hexane 1.iii EXAMPLE 1 (iii) A 1.6M solution of butyllithium in hexane (93.9 ml) was added dropwise over 30 minutes to a stirred solution of diisopropylamine (21.9 ml) in dry tetrahydrofuran (THF) (200 ml) at 0° C. under an atmosphere of argon. The temperature was maintained at 0° C. for 30 minutes and then the solution was cooled to -40° C. A solution of (4S)-4-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (31.3 g) (obtained as described in Tetrahedron. 1987, 44, 5525) in dry THF (70 ml) was added dropwise over 30 minutes. The solution was kept at -40° C. for 30 minutes and then the temperature was allowed to rise to 0° C. A solution of iodide (C) (39.0 g) in dry THF (75 ml) was added dropwise over 30 minutes, and then the solution was stirred at 0° C. for 1 hour. Saturated sodium chloride solution (250 ml) was added and the mixture was extracted with ether (3*250 ml). The extracts were washed with saturated sodium chloride solution (2*250 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluding with ethyl acetate/hexane (8:92 v/v), to give (4s)-4-benzyl-3-[(2S,4E)-6-cyclohexyl-2-isopropylhex-4-enoyl]oxazolidin-2-one (A) (34.5 g) as a clear oil; NMR: 0.8 -1.2(complex m, 12H), 1.6(m, 6H), 1.85(t, 1H), 2.0(m, 2H), 2.35(m, 2H), 2.6(m, 1H), 3.3(dt, 1H), 3.8(m, 1H), 4.1(d, 1H), 4.7(m, 1H), 5.4(m, 2H), 7.3(m, 5H); mass spectrum (+ve FAB), 398 (M+H+); 22 [α]436 +45.8 (c, 1.04, CHCl3).
  • 3
  • [ 104266-90-2 ]
  • [ 126191-05-7 ]
YieldReaction ConditionsOperation in experiment
Yield given. Multistep reaction;
Multi-step reaction with 2 steps 1: 1.) potassium hexamethyldisilazide (KHMDS) / 1.) THF, toluene, -78 deg C, 30 min, 2.) -78 deg C, 2 min 2: 82 percent / C5H5N / tetrahydrofuran / 13 h / 25 °C
  • 4
  • [ 104266-90-2 ]
  • [ 111525-68-9 ]
YieldReaction ConditionsOperation in experiment
77% With 2,4,6-Triisopropylbenzenesulfonyl azide; potassium hexamethylsilazane In tetrahydrofuran; toluene 1.) -78 deg C, 2 min, 2.) 25 deg C, 12 h;
Yield given. Multistep reaction;
Multi-step reaction with 2 steps 1: 1.) Bu2BOTf, R3N, 2.) NBS / 2.) CH2Cl2, -78 deg C, 75 min. 2: tetramethylguanidinium azide / CH2Cl2 / 10 h / 25 °C / var.: NaN3, DMF or DMSO, 0 deg C
Multi-step reaction with 2 steps 1: 1.) potassium hexamethyldisilazide (KHMDS) / 1.) THF, toluene, -78 deg C, 30 min, 2.) -78 deg C, 2 min 2: 6 percent / C5H5N / tetrahydrofuran / 13 h / 25 °C
Multi-step reaction with 2 steps 1: 1.) potassium hexamethyldisilazide (KHMDS) / 1.) THF, toluene, -78 deg C, 30 min, 2.) -78 deg C, 2 min 2: 91 percent / Me4N(1+)AcO(1-) / tetrahydrofuran / 13 h / 25 °C
Multi-step reaction with 2 steps 1: 1.) diisopropylethylamine, dibutylboryl triflate (n-Bu2BOTf), 2.) N-bromosuccinimide (NBS) / 1.) CH2Cl2, a.) -78 deg C, 15 min, b.) 0 deg C, 1 h, 2.) -78 deg C, 1.25 h 2: tetramethylguanidinium azide (TMGA) / CH2Cl2 / 9 h / 25 °C

  • 5
  • [ 90719-32-7 ]
  • [ 108-12-3 ]
  • (4S)-4-benzyl-3-(3-methylbutyryl)oxazolidin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: (S)-4-Benzyl-2-oxazolidinone With n-butyllithium; triphenylmethane In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: 3-methylbutanoyl chloride In tetrahydrofuran; hexane at -78 - 20℃; for 2.5h; Stage #3: With potassium carbonate In tetrahydrofuran; hexane; lithium hydroxide monohydrate
95% With triethylamine In dichloromethane at 0 - 10℃; for 0.5h; 5 EXAMPLE 5; Preparation of (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one, compound; 4-Dimethylaminopyridine (2.55 g, 21 .3 mmol) and triethylamine (46.9 ml, 340.8 mmol) in dichloromethane (100 ml) are added to a solution of (S)-(-)-4- benzyl-2-oxazolidinone (37.7g, 213 mmol) in dichloromethane (300 ml). Next, isovaleroyi chloride (33.75 ml, 207 mmol) in dichloromethane (50 ml) is added to the previously prepared mixture and cooled to 0 °C keeping the internal temperature below 10 °C. The reaction mixture is stirred for 30 minutes at 10 °C, then the formed salts are filtered. Water (100 ml) is added and the phases are separated. The organic phase is washed with water (100 ml) and brine (100 ml), dried over sodium sulphate and evaporated to dryness obtaining 53 g of a yellow oil, which solidifies over time (yield 95%).1 H NMR (300 MHz, CDCI3, 298K) δ 7.35-7.15 (m, 5H), 4.71 -4.61 (m, 1 H), 4.21 - 4.10 (m, 2H), 3.35-3.25 (dd, J = 13.2, J = 3.4 Hz.1 H), 2.85-2.72 (dd, J = 14.97 Hz, 6.8 Hz, 1 H), 2.80-2.67 (m, 2H), 2.29-2.12 (sept, J=13.2 Hz.1 H), 1 .03-0.98 (d, J = 6.8 Hz.3H), 0.98-0.95 (d, J = 6.8 Hz, 3H).13C NMR (75 MHz, CDCI3, 298K) δ 175.6, 171 .2, 154.4, 137.1 , 130.5, 130.2, 126.0, 82.1 , 66.1 , 45.6, 42.6, 41 .4, 34.0, 28.7, 27.3, 19.7.
95% With 4-dimethylaminopyridine In dichloromethane; lithium hydroxide monohydrate at 0 - 10℃; for 0.5h; 5 EXAMPLE 5
Preparation of (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one, Compound (XV)
4-Dimethylaminopyridine (2.55 g, 21.3 mmol) and triethylamine (46.9 ml, 340.8 mmol) in dichloromethane (100 ml) are added to a solution of (S)-(-)-4-benzyl-2-oxazolidinone (37.7 g, 213 mmol) in dichloromethane (300 ml). Next, isovaleroyl chloride (33.75 ml, 207 mmol) in dichloromethane (50 ml) is added to the previously prepared mixture and cooled to 0° C. keeping the internal temperature below 10° C. The reaction mixture is stirred for 30 minutes at 10° C., then the formed salts are filtered. Water (100 ml) is added and the phases are separated. The organic phase is washed with water (100 ml) and brine (100 ml), dried over sodium sulphate and evaporated to dryness obtaining 53 g of a yellow oil, which solidifies over time (yield 95%). 1H NMR (300 MHz, CDCl3, 298K) δ 7.35-7.15 (m, 5H), 4.71-4.61 (m, 1H), 4.21-4.10 (m, 2H), 3.35-3.25 (dd, J=13.2, J=3.4 Hz.1H), 2.85-2.72 (dd, J=14.97 Hz, 6.8 Hz, 1H), 2.80-2.67 (m, 2H), 2.29-2.12 (sept, J=13.2 Hz.1H), 1.03-0.98 (d, J=6.8 Hz.3H), 0.98-0.95 (d, J=6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3, 298K) δ 175.6, 171.2, 154.4, 137.1, 130.5, 130.2, 126.0, 82.1, 66.1, 45.6, 42.6, 41.4, 34.0, 28.7, 27.3, 19.7.
95% Stage #1: (S)-4-Benzyl-2-oxazolidinone With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 3-methylbutanoyl chloride In tetrahydrofuran; hexane at -78℃; for 2h;
95% With 4-dimethylaminopyridine; triethylamine In toluene at 0℃; 1 The preparation of embodiment 1 compound SM2 1mol S-4-benzyl-2-oxazolidinone, 0.2mol dimethylaminopyridine,0.5mol triethylamineAfter mixing with 15mL of toluene, it was prepared into solution A-1 and placed in the storage bottle A,1.5mol of isovaleryl chloride was mixed with 5mL of toluene and placed in storage bottle B,Set the reaction temperature to 0 °C,The materials in the A and B bottles were respectively pumped into the microchannel reactor with two plunger type metering pumps at a flow rate of 1:2, and the residence time was 20 seconds, and the liquid products were collected.HPLC monitored the completion of the reaction, and the reaction solution was quenched with 1% aqueous sodium hydroxide solution after flowing out.After entering the post-processing system, after extraction,After drying, after removing the organic solvent,SM2 was obtained with a purity of 99.5% and a yield of 95%.
94% Stage #1: (S)-4-Benzyl-2-oxazolidinone With n-butyllithium In tetrahydrofuran at -30 - -25℃; for 1.5h; Inert atmosphere; Stage #2: 3-methylbutanoyl chloride In tetrahydrofuran at -25℃; for 1.5h; Inert atmosphere;
93% With lithium hexamethyldisilazane In tetrahydrofuran
92% With n-butyllithium In tetrahydrofuran at -78℃; for 0.25h;
91% With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; 8 To a stirred solution of (ri)-4-benzyloxazolidin-2-one 75 (300 g, 1.69 mol) in CH2CI2 (2.1 L) under inert atmosphere were added 4-dimethylaminopyridine (20.6 g, 0.16 mol), triethylamine (256.7 g, 2.54 mol) followed by solution of 3-methylbutanoyl chloride (224.4 g, 1.86 mol) in CH2CI2 (900 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (2 L) and extracted with CH2CI2 (2 x 1 L). The combined organic extracts were washed with sat. sodium bicarbonate solution (1.0 L), water (1.0 L), 2.0 N aq HC1 solution (1 L), and brine (1 L). The organic solution was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was dissolved in n-hexane (1.5 L), cooled to 0 °C, and stirred for 1 h to obtain a solid. The solid was filtered and dried under vacuum to afford S)-4-benzyl-3-(3-methylbutanoyl) oxazolidin-2-one 76 (402 g, 1.54 mol, 91%) as an off-white solid. NMR (500 MHz, DMSO-^e) d 7.37-7.16 (m, 5H), 4.74-4.57 (m, 1H), 4.32 (t, J= 8.7 Hz, 1H), 4.17 (dd, J= 8.7, 2.9 Hz, 1H), 3.06-2.98 (m, 1H), 2.96-2.89 (m, 1H), 2.82- 2.73 (m, 1H), 2.69-2.58 (m, 1H), 2.13-2.07 (m, 1H), 0.98-0.92 (m, 6H).
91% With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; Step 1: (S)-4-Benzyl-3-(3-methylbutanoyl) oxazolidin-2-one (2): To a stirred solution of (S)-4-bcnzyloxazolidin-2-onc 1 (300 g, 1.69 mol) in CH2C12 (2.1 L) under inert atmosphere were added 4-dimethylaminopyridine (20.6 g, 0.16 mol), triethylamine (256.7 g, 2.54 mol) followed by solution of 3-methylbutanoyl chloride (224.4 g, 1.86 mol) in CH2C12 (900 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After complete consumption of starting material (by TLC); the reaction mixture was quenched with water (2 L) and extracted with CH2C12 (2 x 1 L). The combined organic extracts were washed with saturated aq. sodium bicarbonate solution (1.0 L), water (1.0 L), 2.0 N aq. HC1 solution (1 L), brine (1 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was solidified by dissolve it in hexane (1.5 L) and stirred for 1 h at 0 °C. The obtained solid was filtered and dried under vacuum to afford (.V)-4-benzyl-3- (3-methylbutanoyl) oxazolidin-2-one 2 (402 g, 1.54 mol, 91%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ 7.37-7.16 (m, 5H), 4.74-4.57 (m, 1H), 4.32 (t, J= 8.7 Hz, 1H), 4.17 (dd, J= 8.7, 2.9 Hz, 1H), 3.06-2.98 (m, 1H), 2.96-2.89 (m, 1H), 2.82-2.73 (m, 1H), 2.69-2.58 (m, 1H), 2.13-2.07 (m, 1H), 0.98-0.92 (m, 6H).
90% Stage #1: (S)-4-Benzyl-2-oxazolidinone With n-butyllithium In tetrahydrofuran at -78℃; for 0.25h; Stage #2: 3-methylbutanoyl chloride at -78 - 0℃;
90% Stage #1: (S)-4-Benzyl-2-oxazolidinone With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Stage #2: 3-methylbutanoyl chloride In tetrahydrofuran at 0℃; Inert atmosphere; 2 A solution of (S) -4-benzyl-oxazolidine-2-one (6.13g, 0. 035 [pi] o1) was added to the reaction flask under nitrogen atmosphere ,Dry tetrahydrofuran 90ml,Stirring. Potassium tert-butoxide (5. 03 g, 0.049 mol) was added at 0 ° C to afford Stirring was continued for 2 hours at low temperature and isovaleryl chloride (4.8 g, 0.039 mol) was added dropwise at 0 ° C,Of tetrahydrofuran solution 10ml, the temperature at 0 ° C or so, after the completion of the drop,TCL detection reaction is complete. 20 ml of saturated ammonium chloride solution was added dropwise, and the solvent was distilled off under reduced pressure.The residue was extracted with dichloromethane, 60 ml each, extracted three times and the organic phases were combined.Organic phase by adding lmol / L NaOH 60ml extraction, organic phase and then saturated with saline 60ml wash to neutral,Dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and evaporated to an oil. To this was added 60 ml of hexane,A large number of white solid precipitation, filtration, vacuum drying, (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidine-2-one as a white needles (8.lg, 90% yield), m.p. 49-50 ° C. Optical rotation measured data:[[alpha]]15D+54.8°(C1.0CHCl3), The data reported in the literature: [[alpha]]25D+55.8°(C1.0CHCl3)
84% Stage #1: (S)-4-Benzyl-2-oxazolidinone With sodium hydride In tetrahydrofuran at -15 - 20℃; Stage #2: 3-methylbutanoyl chloride In tetrahydrofuran at -15 - 20℃; Stage #3: With lithium hydroxide monohydrate; Sodium hydrogenocarbonate In tetrahydrofuran 3 Example 3: Preparation of (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one [Show Image] To a cold suspension (-15 °C) of sodium hydride (7.12 g, 178 mmol; ∼60% oil suspension) in anhydrous THF (600 mL) (S)-4-benzyloxazolidin-2-one (30.0 g, 169.3 mmol) was added portionwise. The reaction mixture was allowed to reach room temperature during 2 h and stirring was continued for 20 h, after the mixture was recooled to -15 °C once more. 3-Methylbutanoyl chloride (23.48 g, 24.00 mL, 194.7 mmol) was added dropwise and the mixture was allowed to reach room temperature during 2 h, and sitirring was continued for additional 3 h. The reaction was quenched by addition of saturated aqueous solution of NaHCO3 (300 mL) and the mixture was stirred at room temperature for 30 min. The product was extracted with CH2Cl2 (3 × 400 mL). The combined organic layers were washed with saturated aqueous Na2CO3 solution (2 × 300 mL) and brine (300 mL), and dried over anhydrous Na2SO4. After removal of the solvents under reduced pressure the oily residue was recrystallized from Et2O/petrolether 1:10 (408 mL) to yield, in two crops, 37.19 g (84%) of (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one as colourless crystals. 1H NMR (300 MHz, CDCl3) δ: 1.03 (d, 3H), 1.04 (d, 3H), 2.24 (m, 1H), 2.75 (dd, 1H) 2.73-2.95 (m, 1H), 3.32 (dd, 1H), 4.14-4.23 (m, 2H), 4.66-4.74 (sym m, 1H), 7.22-7.38 (m, 5H).
31.2 g Stage #1: (S)-4-Benzyl-2-oxazolidinone With n-butyllithium In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Stage #2: 3-methylbutanoyl chloride In tetrahydrofuran; hexane at 23℃; for 1.16667h; Inert atmosphere; Cooling;
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
9.5 g With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 10℃; for 0.5h; 1 [00165] 4,4-Dimethylaminopyridine (0.5 g) and triethylamine (8.8 mL) in dichloromethane (20 mL) were added to a solution of (S)-(-)-4-benzyl-2-oxazolidinone (9) (7 g, 40 mmol) in dichloromethane (100 mL). Isovaleroyl chloride (5 g, 41.4 mmol) in dichloromethane (15 mL) was added to the previously prepared mixture and cooled to 0°C keeping the internal temperature below 10°C. The reaction mixture was stirred for 30 minutes at 10°C. Water (100 mL) was added and the phases were separated. The organic phase was washed with a saturated aqueous NaHCO3 solution (50 mL), water (50 mL), HC1 (2N, 30 mL), water (50 mL) and brine (50 mL), dried over Na2SO4 and evaporated to dryness to give compound 10 (9.5 g) as a yellow oil.

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  • 6
  • [ 38792-42-6 ]
  • [ 104266-90-2 ]
  • [ 191664-12-7 ]
YieldReaction ConditionsOperation in experiment
81% With titanium tetrachloride; triethylamine In dichloromethane at 0℃; for 60h;
With titanium tetrachloride; triethylamine Yield given;
  • 7
  • [ 556-56-9 ]
  • [ 104266-90-2 ]
  • [ 240821-65-2 ]
YieldReaction ConditionsOperation in experiment
88% With lithium diisopropyl amide In tetrahydrofuran at -78 - 25℃; for 3h;
88% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Stage #2: allyl iodid In tetrahydrofuran at -78 - 25℃; for 3h;
80% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Stage #2: allyl iodid at -78 - 20℃;
72% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: allyl iodid In tetrahydrofuran at -45℃; Stage #3: With hydrogenchloride In tetrahydrofuran; water 4.b (b) Alkylation with allyl iodide: To a solution of lithium diisopropylamide (23 mL, 46 mmol; 2 M in THF) in anhydrous THF (120 mL), stirred at -78 °C under argon, a solution of (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (10.0 g, 38.27 mmol) in anhydrous THF (10 mL) was added and the mixture was stirred for 1.5 h. To the resulting mixture allyl iodide (10.30 g, 61.32 mmol) was added dropwise and stirring was continued for another 30 min. The resulting mixture was warmed to -45 °C at which it was stirred for 15 h. The reaction was quenched by the addition of 1 M aqueous HCl solution (100 mL) and the product was extracted with ethyl acetate (3 × 250 mL). The combined organic layers were successively washed with ice-cold 1 M aqueous HCl solution (100 mL), saturated aqueous Na-HCO3 solution (2 × 100 mL), and brine (2 × 100 mL), and dried over anhydrous Na2SO4. After removal of the solvents under reduced pressure 11.952 g of crude product were obtained which were further purified by radial chromatography on silica gel (petrolether/ethyl acetate = 10:1) to afford 8.302 g (72%) of alkylation product as a colourless oil. 1H NMR (300 MHz, CDCl3) δ: 0.98 (d, 6H), 1.98 (m, 1H), 2.35-2.54 (m, 2H), 2.64 (dd, 1H), 3.31 (dd, 1H), 3.83-3.90 (sym m, 1H), 4.12-4.17 (m), 4.65-4.73 (m, 1H), 5.02 (d, 1H), 5.09 (ddt 1H), 5.76-5.90 (m, 1H), 7.22-7.36 (m, 5H).

  • 8
  • [ 5292-43-3 ]
  • [ 104266-90-2 ]
  • [ 134807-37-7 ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With n-hexyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.75h; Inert atmosphere; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In tetrahydrofuran; hexane at -78 - 20℃; for 4h; Inert atmosphere; diastereoselective reaction;
85% With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 6h;
77% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In tetrahydrofuran at -78 - 20℃; for 12h;
50% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With n-hexyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.75h; Inert atmosphere; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In tetrahydrofuran; hexane at -78 - 20℃; for 4h; 6 EXAMPLE 6; Preparation of (S)-ie f-butyl-3-((S)-4-benzyloxazolidin-2-on-3-yl)-carbonyl-4- methyl-pentanoate, compound (XVI) in which Z = terf-butyl.; A solution of hexyllithium 2.3 M in hexane (18.3 ml, 42.1 mmol) is added at 0 °C and under nitrogen to a solution of diisopropylamine (5.19 ml, 42.1 mmol) in anhydrous tetrahydrofuran (10 ml). After 15 minutes the solution is cooled to -78 °C and a solution of (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (compound (XV), 10 g, 38.3 mmol), in THF (5 ml) is added dropwise. After 45 minutes at -78 °C, terf-butylbromoacetate (10.7 ml, 72.7 mmol) is added. The temperature is raised to 20 °C in 4 hours, then a saturated solution of ammonium chloride (50 ml) is added, the tetrahydrofuran is evaporated and the suspension thus obtained is extracted twice with ethyl acetate (2 x 100 ml). The combined organic phases are washed with 0.5N HCI, brine and are dried over sodium sulphate. After evaporating the solvent in a rotary evaporator, 16.48 g of raw product are obtained (orange-coloured solid), which is purified by flash chromatography (8:2 cyclohexane/ethyl acetate), obtaining 6.1 g of product as white solid (yield 50%). Alternatively the product can be purified by crystallizing the raw reaction product from isopropanol.1 H NMR (300 MHz, CDCI3, 298K) δ 7.37-7.20 (m, 5H), 4.70-4.60 (m, 1 H), 4.20- 4.08 (m, 3H), 3.35-3.25 (dd, J = 13.5 Hz, 3.1 Hz.1 H), 2.85-2.75 (dd, J = 28.9, 10.1 Hz, 1 H), 2.75-2.65 (dd, J = 13.8, 10.1 1 Hz, 1 H), 2.47-2.37 (dd, J = 16.8 Hz, 3.1 Hz, 1 H), 2.01 -1 .91 (m, 1 H), 1 .45-1 .35 (s, 9H).1 .05-0.95 (d, J = 6.7 Hz, 3H), 0.95-0.85 (d, J = 6.7 Hz, 3H).13C NMR (75 MHz, CDCI3, 298K) δ 176.8, 173.1 , 154.4, 137.1 , 130.5, 130.2, 178.3, 81 .6, 66.9, 57.0, 45.4, 38.5, 34.6, 31 .1 , 29.2, 21 .7, 19.5.
50% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With n-hexyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.75h; Reflux; Stage #2: bromoacetic acid <i>tert</i>-butyl ester 6 EXAMPLE 6
Preparation of (S)-tert-butyl-3-((S)-4-benzyloxazolidin-2-on-3-yl)-carbonyl-4-methyl-pentanoate, Compound (XVI) in which Z=tert-butyl
A solution of hexyllithium 2.3 M in hexane (18.3 ml, 42.1 mmol) is added at 0° C. and under nitrogen to a solution of diisopropylamine (5.19 ml, 42.1 mmol) in anhydrous tetrahydrofuran (10 ml). After 15 minutes the solution is cooled to -78° C. and a solution of (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (compound (XV), 10 g, 38.3 mmol), in THF (5 ml) is added dropwise. After 45 minutes at -78° C., tert-butylbromoacetate (10.7 ml, 72.7 mmol) is added. The temperature is raised to 20° C. in 4 hours, then a saturated solution of ammonium chloride (50 ml) is added, the tetrahydrofuran is evaporated and the suspension thus obtained is extracted twice with ethyl acetate (2*100 ml). The combined organic phases are washed with 0.5N HCl, brine and are dried over sodium sulphate. After evaporating the solvent in a rotary evaporator, 16.48 g of raw product are obtained (orange-coloured solid), which is purified by flash chromatography (8:2 cyclohexane/ethyl acetate), obtaining 6.1 g of product as white solid (yield 50%). Alternatively the product can be purified by crystallizing the raw reaction product from isopropanol. 1H NMR (300 MHz, CDCl3, 298K) δ 7.37-7.20 (m, 5H), 4.70-4.60 (m, 1H), 4.20-4.08 (m, 3H), 3.35-3.25 (dd, J=13.5 Hz, 3.1 Hz.1H), 2.85-2.75 (dd, J=28.9, 10.1 Hz, 1H), 2.75-2.65 (dd, J=13.8, 10.11 Hz, 1H), 2.47-2.37 (dd, J=16.8 Hz, 3.1 Hz, 1H), 2.01-1.91 (m, 1H), 1.45-1.35 (s, 9H).1.05-0.95 (d, J=6.7 Hz, 3H), 0.95-0.85 (d, J=6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3, 298K) δ 176.8, 173.1, 154.4, 137.1, 130.5, 130.2, 178.3, 81.6, 66.9, 57.0, 45.4, 38.5, 34.6, 31.1, 29.2, 21.7, 19.5.
1.52 g With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 3.5h; Step2: tert-Butyl (S)-3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-4-methylpentanoate (66) The compound 65 (2.00 g, approx. 7.7 mmol) was dissolved in THF(20 mL). To the solution, 1.0 M LiHMDS in THF (8.43 mL, 8.43 mmol)was added at 78 C. tert-Butyl bromoacetate (1.66 mL, 1.15 × 10mmol) was added to the reactant mixture, and then the mixture wasstirred at room temperature for 3.5 h. The mixture was quenched withaqueous NH4Cl solution and extracted with AcOEt, and the organic layerwas washed with aqueous NaHCO3 solution and brine, and dried overMgSO4. After filtration and concentration, the residue was crystallize inCHCl3-n-hexane. The precipitated solid was collected by filtration,washed with n-hexane, and dried to give the title compound 66 (1.52 g,53% yield, 2 steps).1H-NMR (400 MHz, DMSO-d6) δ: 0.80 (d, J = 6.8 Hz, 3H), 0.92 (d, J= 6.8 Hz, 3H), 1.39 (s, 9H), 1.89-2.00 (m, 1H), 2.45 (dd, J = 16.5, 3.7Hz, 1H), 2.64 (dd, J = 16.5, 11.6 Hz, 1H), 2.85 (dt, J = 13.4, 8.0 Hz, 1H),2.99 (dd, J = 13.4, 3.0 Hz, 1H), 4.00 (ddd, J = 11.6, 3.7, 3.0 Hz, 1H),4.14 (dd, J = 8.8, 2.5 Hz, 1H), 4.32 (t, J = 8.0 Hz, 1H), 4.65 (tt, J = 8.0,2.5 Hz, 1H), 7.23-7.33 (m, 5H)

  • 9
  • [ 104266-90-2 ]
  • [ 106-95-6 ]
  • [ 240821-65-2 ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; for 3h; Inert atmosphere; Stage #2: allyl bromide In tetrahydrofuran at -78 - 20℃; Inert atmosphere;
94% With lithium hexamethyldisilazane In tetrahydrofuran at -78℃;
83% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.16667h; Stage #2: allyl bromide In tetrahydrofuran at -78 - -45℃; for 8.5h; Stage #3: With ammonium chloride In tetrahydrofuran; water stereoselective reaction;
78% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: allyl bromide In tetrahydrofuran; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone at -78 - 10℃; Stage #3: With ammonium chloride In tetrahydrofuran; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; water 4.a : Preparation of (S)-3-((S)-2-isopropylpent-4-enoyl)-4-benzyloxazolidin-2-one [Show Image] (a) Alkylation with allyl bromide: To a solution of lithium diisopropylamide (23 mL, 46 mmol; 2 M in THF) in anhydrous THF (120 mL), stirred at -78 °C under argon, a solution of (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (10.0 g, 38.27 mmol) in anhydrous THF (10 mL) was added and the mixture was stirred for 1.5 h. Then allyl bromide (16.22 g, 134.07 mmol) and DMPU (16 mL) were successively added dropwise. The resulting mixture was continued to stir at -78 °C for 2 h and then allowed to reach -45 °C at which it was stirred for 4 h. The mixture was allowed to warm to 10 °C during 12 h. The reaction was quenched by the addition of saturated aqueous NH4Cl solution (100 mL) and the product was extracted with ethyl acetate (3 × 250 mL). The combined organic layers were successively washed with ice-cold HCl (1 M, 100 mL), saturated aqueous NaHCO3 solution (2 × 100 mL), and brine (2 × 100 mL), and then dried over anhydrous Na2SO4. After removal of the solvents under reduced pressure 14.46 g of crude product were obtained which were further purified by radial chromatography on silica gel (petrolether/ethyl acetate = 10:1) to afford 8.994 g (78 %) of alkylation product as a yellowish oil
Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0℃; for 0.5h; Stage #2: allyl bromide In tetrahydrofuran; toluene at -78 - 20℃; for 2h; To a stirred solution of (S)-4-benzyl-3-(3-methylbutyryl)-2-oxazolidinone (13.0 g, 50 mmol), which is prepared according to Rueger et a/ Tetrahedron Letters (2000), 41 (51), 10085-10089, in dry THF at -78 0C is added LiHMDS (55 mL, 1.0 M in toluene, 55 mmol) and the solution is stirred at 0 0C for 30 minutes before cooling down to -78 0C. AIIyI bromide (4.0 mL, 55 mmol) is then added and the mixture is stirred at room temperature for 2 hours. The products are extracted with EtOAc, washed with saturated aqueous NH4CI, water and saturated aqueous NaCI, dried (MgSO4) and evaporated to give a yellow oil which is purified by flash chromatography on silica gel eluting with 10% EtOAc/hexane to give IVA as a colourless oil. 1H NMR (400.13 MHz, CDCI3) δ 0.91 (d, 6H, J = 6.8 Hz), 1.8-2.0 (m, 1 H), 2.2-2.5 (m, 2H), 2.57 (dd, 1 H1 J = 13.3, 10.1 Hz), 3.25 (dd, 1 H, J = 13.3, 3.2 Hz), 3.7-3.9 (m, 1 H), 4.0-4.1 (m, 2H), 4.5-4.7 (m, 1H), 4.95 (d, 1 H, J = 10.2 Hz), 5.02 (dq, 1 H, J = 17.1 , 1.5 Hz), 5.7-5.8 (m, 1 H), 7.1-7.3 (m, 5H) ppm.
With lithium hexamethyldisilazane optical yield given as %de;

  • 10
  • [ 104266-90-2 ]
  • [ 444722-18-3 ]
YieldReaction ConditionsOperation in experiment
75% With sodium azide In ethanol at 40℃; for 8h;
  • 11
  • [ 104266-90-2 ]
  • [ 100-39-0 ]
  • [ 117037-09-9 ]
YieldReaction ConditionsOperation in experiment
91% With sodium hexamethyldisilazane In tetrahydrofuran at -40℃; for 4h;
  • 12
  • [ 75-77-4 ]
  • [ 104266-90-2 ]
  • [ 100-52-7 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With triethylamine; magnesium chloride In ethyl acetate at 23℃; for 24h;
  • 13
  • [ 104266-90-2 ]
  • [ 106-95-6 ]
  • [ 240821-65-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
60% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Stage #2: allyl bromide In tetrahydrofuran at -78 - 45℃; for 5h;
  • 14
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
  • [ 503004-07-7 ]
  • [ 503004-06-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Stage #2: dimethyl[(Z)-2-phenyl-2-(phenylsulfonyl)vinyl]selenonium tetrafloroborate In tetrahydrofuran at -78℃; for 2h; Further stages.;
  • 15
  • [ 104266-90-2 ]
  • [ 188836-56-8 ]
  • [ 503004-07-7 ]
  • [ 503004-06-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Stage #2: (Z)-diphenyl[(Z)-2-phenyl-2-(phenylsulfonyl)vinyl]selenonium trifluoromethanesulfonate In tetrahydrofuran at -78℃; for 2h; Further stages.;
  • 16
  • [ 3587-60-8 ]
  • [ 104266-90-2 ]
  • [ 470454-06-9 ]
YieldReaction ConditionsOperation in experiment
53% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With titanium tetrachloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 5℃; for 1h; Stage #2: Benzyloxymethyl chloride In dichloromethane at 0℃;
  • 17
  • [ 104266-90-2 ]
  • [ 400007-07-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: MgCl2; Et3N / ethyl acetate / 24 h / 23 °C 2: TFA / methanol
  • 18
  • [ 104266-90-2 ]
  • [ 325740-67-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1: 94 percent / LIHMDS / tetrahydrofuran / -78 °C 2: 88 percent / OsO4; NMMO / 2-methyl-propan-2-ol; acetone; H2O 3: NaIO4; RuCl3*H2O / CCl4; acetonitrile; H2O / 6 h 4: (COCl)2 / dimethylformamide; toluene / 1 h 5: NEt3 / CH2Cl2 6: 100 percent / H2 / Pd/C / ethyl acetate 7: (COCl)2 / toluene; dimethylformamide / 1 h 8: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 9: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr
Multi-step reaction with 5 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 1.17 h / -78 °C 1.2: 8.5 h / -78 - -45 °C 2.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride / dichloromethane / 27 h / Reflux 3.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / water; acetone / 21 h / 20 °C 4.1: tert.-butyl lithium / tetrahydrofuran; pentane / 1.83 h / -78 °C 4.2: 19 h / -78 °C 5.1: hydrogen; palladium on activated charcoal / methanol / 67 h / 2947.82 Torr
  • 19
  • [ 104266-90-2 ]
  • [ 324763-46-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1: 94 percent / LIHMDS / tetrahydrofuran / -78 °C 2: 88 percent / OsO4; NMMO / 2-methyl-propan-2-ol; acetone; H2O 3: NaIO4; RuCl3*H2O / CCl4; acetonitrile; H2O / 6 h 4: (COCl)2 / dimethylformamide; toluene / 1 h 5: NEt3 / CH2Cl2 6: 100 percent / H2 / Pd/C / ethyl acetate 7: (COCl)2 / toluene; dimethylformamide / 1 h 8: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 9: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr 10: NEt3 / CH2Cl2 11: 85 percent / NaN3; 15-crown-6; DMPU
Multi-step reaction with 8 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 1.17 h / -78 °C 1.2: 8.5 h / -78 - -45 °C 2.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride / dichloromethane / 27 h / Reflux 3.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide / water; acetone / 21 h / 20 °C 4.1: tert.-butyl lithium / tetrahydrofuran; pentane / 1.83 h / -78 °C 4.2: 19 h / -78 °C 5.1: hydrogen; palladium on activated charcoal / methanol / 67 h / 2947.82 Torr 6.1: triethylamine / dichloromethane / 2 h / -10 - 0 °C 7.1: lithium bromide / tetrahydrofuran / 23 h / Reflux 8.1: sodium azide / N,N-dimethyl-formamide / 48 h / 90 °C
  • 21
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: LDA / tetrahydrofuran / 1 h / -78 °C 1.2: 88 percent / tetrahydrofuran / 3 h / -78 - 25 °C 2.1: 96 percent / H2O2; LiOH; H2O / tetrahydrofuran / 5 h / 0 - 25 °C 3.1: 50 percent / LiAlH4 / diethyl ether / 2 h / 0 °C 4.1: 89 percent / DCC; DMAP / CH2Cl2 / 4 h / 25 °C 5.1: B-I-9-BBN / pentane; hexane / 2 h / -25 °C 5.2: 90 percent / AcOH / pentane; hexane / 1 h / 0 °C 6.1: 58 percent / TiCl4; Zn; TMEDA / PbCl2 / tetrahydrofuran; CH2Cl2 / 3.5 h / 25 °C 7.1: 44 percent / PhCMe2CH=Mo=N(2,6-(i-Pr)2C6H3)[OCMe(CF3)2]2 / pentane / 5 h / 25 °C 8.1: HCl; H2O / tetrahydrofuran / 2 h / 25 °C 8.2: PCC; SiO2 / CH2Cl2 / 3 h / 25 °C 9.1: CrCl2 / dimethylformamide / 3.5 h / 25 °C 9.2: 62 percent / AsPPh3 / Pd2(dba)3 / 1-methyl-pyrrolidin-2-one / 6 h / 70 °C
Multi-step reaction with 10 steps 1: 88 percent / LDA / tetrahydrofuran / 3 h / -78 - 25 °C 2: H2O2, LiOH, H2O / tetrahydrofuran / 5 h / 0 - 25 °C 3: LiAlH4 / diethyl ether / 2 h / 0 °C 4: 89 percent / DCC, DMAP / CH2Cl2 / 4 h / 25 °C 5: 1.) B-I-9-BBN, 2.) AcOH / 1.) pentane, -20 deg C, 2 h, 2.) pentane, 1 h 6: 58 percent / Zn, PbCl2, TiCl4, TMEDA / tetrahydrofuran / 3.5 h / 25 °C 7: 55 percent / 2,6-diisopropylphenylimidoneophylidene molybdenum bis(h; exafluoro-t-butoxide) / pentane / 4 h / 25 °C 8: HCl, H2O / tetrahydrofuran / 2 h / 25 °C 9: PCC, SiO2 / CH2Cl2 / 3 h / 25 °C 10: 1.) CrCl2, 2.) AsPh3 / 2.) Pd2dba3 / 1.) DMF, 3 h, 2.) NMP, 70 deg C, 6 h
  • 22
  • [ 104266-90-2 ]
  • [ 113543-44-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1.) Bu2BOTf, R3N, 2.) NBS / 2.) CH2Cl2, -78 deg C, 75 min. 2: tetramethylguanidinium azide / CH2Cl2 / 10 h / 25 °C / var.: NaN3, DMF or DMSO, 0 deg C
Multi-step reaction with 2 steps 1: 1.) diisopropylethylamine, dibutylboryl triflate (n-Bu2BOTf), 2.) N-bromosuccinimide (NBS) / 1.) CH2Cl2, a.) -78 deg C, 15 min, b.) 0 deg C, 1 h, 2.) -78 deg C, 1.25 h 2: tetramethylguanidinium azide (TMGA) / CH2Cl2 / 9 h / 25 °C
  • 23
  • [ 104266-90-2 ]
  • [ 125816-10-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr
  • 24
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide
  • 25
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: dioxane / 6 h / 100 °C
  • 26
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: 20 percent / 1 M dimethylaluminium chloride / hexane; CH2Cl2 / 6 h / Heating
  • 27
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: dioxane / 6 h / 100 °C
  • 28
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: 1 M dimethylaluminium chloride / hexane; CH2Cl2 / 6 h / Heating
  • 29
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: dimethylaluminium chloride / hexane; CH2Cl2 / 6 h / Heating
  • 30
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: dioxane / 6 h / 100 °C
  • 31
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: dioxane / 6 h / 100 °C
  • 32
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: dioxane / 6 h / 100 °C
  • 33
  • [ 104266-90-2 ]
  • [ 128901-37-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: 37 percent / dioxane / 6 h / 100 °C
  • 34
  • [ 104266-90-2 ]
  • [ 128948-63-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 1.) LDA / 1.) hexane, THF, -40 deg C, 0.5 h, 2.) 0 deg C, 1 h 2: 97 percent / N-bromosuccinimide / H2O; 1,2-dimethoxy-ethane / 0.17 h / 0 °C 3: NaN3, DMPU 4: 100 percent / H2 / 10percent Pd/C / ethanol / 20 °C / 760 Torr 5: 69 percent / 1-hydroxybenzotriazole hydrate (HOBT), 1-ethyl-3-<3-(dimethylamino)propyl>carbodiimide hydrochloride (EDC) / H2O; dimethylformamide 6: 31 percent / dioxane / 6 h / 100 °C
  • 35
  • [ 104266-90-2 ]
  • [ 640-68-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 1.) diisopropylethylamine, dibutylboryl triflate (n-Bu2BOTf), 2.) N-bromosuccinimide (NBS) / 1.) CH2Cl2, a.) -78 deg C, 15 min, b.) 0 deg C, 1 h, 2.) -78 deg C, 1.25 h 2: tetramethylguanidinium azide (TMGA) / CH2Cl2 / 9 h / 25 °C 3: 96 percent / lithium hydroxide / tetrahydrofuran; H2O / 0.5 h / 0 °C 4: 99 percent / H2 / 10percent Pd/C / H2O; acetic acid / 3 h / 760 Torr
  • 36
  • [ 104266-90-2 ]
  • [ 40224-49-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1.) diisopropylethylamine, dibutylboryl triflate (n-Bu2BOTf), 2.) N-bromosuccinimide (NBS) / 1.) CH2Cl2, a.) -78 deg C, 15 min, b.) 0 deg C, 1 h, 2.) -78 deg C, 1.25 h 2: tetramethylguanidinium azide (TMGA) / CH2Cl2 / 9 h / 25 °C 3: 96 percent / lithium hydroxide / tetrahydrofuran; H2O / 0.5 h / 0 °C
  • 37
  • [ 110-88-3 ]
  • [ 104266-90-2 ]
  • [ 150615-46-6 ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With titanium tetrachloride In dichloromethane at 0℃; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Inert atmosphere; Stage #3: 1,3,5-Trioxan Further stages;
64% With titanium tetrachloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2.5h; 1-5.15 Intermediate 15: [(R)-4-BENZVL-3- (2-HYDROXYMETHYL-3-METHVL-BUTANOYL)-OXAZOLIDINONE] [4-BENZYL-3- (3-METHYLBUTANOYL)-OXAZOLIDINONE] (14) * (26. 1g, 0.1mol) was stirred in dry [DICHLOROMETHANE (400ML)] at [0°C] under nitrogen as titanium tetrachloride (1. 0M solution in dichloromethane, 105ml, 0. [105MOL)] was added and the mixture, which contained a yellow precipitate, was stirred a further 15 minutes then [DIISOPROPYLETHYLAMINE (19ML, 0. 11MOL)] was added dropwise, maintaining the temperature below [5°C.] The resulting purple solution was stirred for 75 minutes then 1,3, 5-trioxane (9.9g, [0.] 11mol) in [DICHLOROMETHANE] (60ml) was added, and after a further 10 minutes, titanium tetrachloride (1. [OM] in DCM, 105ml, 0. [105MOL)] was added. The mixture was stirred for 2.5 hours at [0°C] then quenched by the addition of saturated ammonium chloride (500ml). Water (100ml) and [DICHLOROMETHANE] [(100ML)] were added, the aqueous phase extracted with a further 2 x [100ML DICHLOROMETHANE,] the combined organics dried over [NA2SO4] and evaporated. Recrystallisation from 30% [DICHLOROMETHANE/PETROLEUM] gave 18.7g (64%) of the title compound as a white solid. LCMS RT=2.94minutes [MH+ 292]
  • 38
  • [ 821-06-7 ]
  • [ 104266-90-2 ]
  • [ 173153-99-6 ]
YieldReaction ConditionsOperation in experiment
91% With N,N-dimethylpropenylurea; lithium hexamethyldisilazane at 30℃; for 0.0111111h; 2 The preparation of embodiment 2 compound SM3 Put 1mol SM2,0.3mol N,N-dimethylpropenyl urea was mixed and prepared into solution A-2 and placed in storage bottle C,0.2mol lithium bistrimethylsilylamide and 1.2molTrans-1,4-dibromo-2-butene is mixed and placed in storage bottle D,The reaction temperature was set to 30°C, and C,The material in bottle D is pumped into the microchannel reactor by two plunger metering pumps at a flow rate of 1:1.The residence time was 40 seconds, the liquid product was collected,HPLC monitored the completion of the reaction, and the reaction solution was quenched with 10% aqueous hydrochloric acid after flowing out.After entering the post-processing system, after extraction,After drying, after removing the organic solvent,SM3 was obtained with a purity of 96.5% and a yield of 91%.
88% Stage #1: (4S)-4-benzyl-3-(3-methylbutyryl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -50℃; for 1h; Inert atmosphere; Large scale; Stage #2: With N,N’-dimethylpropyleneurea In tetrahydrofuran at -50℃; for 2h; Inert atmosphere; Large scale; Stage #3: trans-1,4-dibromo-2-butene In tetrahydrofuran at -50 - 10℃; for 3.5h; Inert atmosphere; Large scale;
With N,N’-dimethylpropyleneurea; lithium hexamethyldisilazane In tetrahydrofuran at -75 - 0℃; for 20h; 81.g g) 2 (S), 7 (S) -Diisopropyl-oct-4-ene-dicarboxylic acid [bis (4 (S) -benzyl-oxazolidin-2-one)]-amide THE 3 (S)-ISOPROPYL-5 (S)-1(S)-AZIDO-3 (S)-ISOPROPYL-4-OXO-butyl-tetrahydrofuran-2-one used in step d) is prepared as follows: g) 2 (S), 7 (S) -Diisopropyl-oct-4-ene-dicarboxylic acid [bis (4 (S) -benzyl-oxazolidin-2-one)]-amide 48 ml of a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran are added dropwise, with stirring, AT-75°C,] within a period of one hour, to a solution of 11.5 g of 4 (S)- benzyl-3-isovaleroyl-oxazolidin-2-one in 32 ml of tetrahydrofuran. The mixture is stirred further for 2 hours at- [75°C] and for 20 minutes [AT-20°C,] and there are then added thereto 10 ml of 1, 3-dimethyl-3,4, 5,6-TETRAHYDRO-2- (1H)-pyrimidone (DMPU) and, within a period of 45 minutes, a solution of 4.28 g of 1, 4-dibromo-2-butene in 10 ml of tetrahydrofuran. The reaction mixture is stirred for a further 15 hours AT-20°C and is then brought to [0°C] within a period of one hour; 10 ml of saturated ammonium chloride solution are then added thereto at- [20°C] and, after 15 minutes, the mixture is brought to room temperature. The reaction mixture is then partitioned between dichloromethane and saturated sodium chloride solution/water=1 : 1. The organic phases are combined, dried over sodium sulfate and concentrated by evaporation, and the residue is purified by means of FC (hexane/ethyl acetate=4: 1), yielding the title compound: Rf (hexane/ethyl acetate=4: 1) =0.30 ; HPLC Rt =21.6 minutes; FAB-MS (M+H) [+] =575; m. p. [=110°-111°C.]
  • 39
  • [ 821-06-7 ]
  • [ 104266-90-2 ]
  • [ 919995-31-6 ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; for 4h; Inert atmosphere; Stage #2: (E)-1,4-dibromobutene In tetrahydrofuran at -78 - 20℃; Inert atmosphere;
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0℃; 6 To a solution of 5.6 g of N-isovaleroyl-(S)-4-benzyl-oxazolidin-2-one in 12 ml of toluene are added, at 00C, first of all 23.5 ml of a 1 -molar solution of bis-trimethylsilyl-lithium amide in tetrahydrofuran, then 5.7 g of dimethylpropylene urea. The solution obtained is added dropwise at 00C to a solution of 6 g of trans -1 ,4-dibromobut-2-ene in 10 ml of toluene. After stirring, the mixture is acidified with diluted hydrochloric acid, separated, and the organic solution concentrated. The crude product is purified by chromatography on a column of silica gel (eluant: hexane/ethyl acetate 85:15).
  • 40
  • [ 104266-90-2 ]
  • [ 88086-58-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
78% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Li-compound was added over a period of 65 min; Stage #2: 1,3-chloroiodopropene In tetrahydrofuran at 0℃; for 20h;
  • 41
  • [ 104266-90-2 ]
  • [ 88086-58-2 ]
  • [ 324519-70-2 ]
YieldReaction ConditionsOperation in experiment
78% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 2.08333h; Stage #2: 1,3-chloroiodopropene In tetrahydrofuran at -78 - 0℃; for 20h; Stage #3: With water; ammonium chloride In tetrahydrofuran B3 Beispiel B3 Eine Lösung von 290 g 4S-Benzyl-3-(3-methyl-butyryl)-oxazolidin-2-one in 0,58 l Tetrahydrofuran wird auf -78 °C gekühlt und während 65 Minuten 1,14 l 1 M Lithiumhexamethyldisilazid (in Tetrahydrofuran) zugetropft. Das Gemisch wird noch 1 Stunde bei -78 °C nachgerührt und anschliessend mit der vorbereiteten Lösung von trans-1-Chloro-3-iod-propen in Tetrahydrofuran versetzt. Man lässt die Temperatur auf 0 °C steigen und rührt noch weitere 20 Stunden nach. Das Reaktionsgemisch wird mit 500 ml 10%-iger Ammoniumchloridlösung versetzt und mit Diethylether extrahiert (2x 1 l). Die organischen Phasen werden mit Wasser (1x 1 l) gewaschen, mit Natriumsulfat getrocknet und eingedampft. Aus dem Rückstand wird mittels Flashchromatographie (SiO2 60F / Essigsäureethylester/Hexan 5:1) die Titelverbindung B3 als leicht oranges Oel erhalten (582 g, 78 %). 1H-NMR (400 MHz, CDCl3, δ) : 0,85 (m, 6H), 2,02(m, 1H), 2,3 - 2,55 (m, 2H), 2,75 (m, 1H), 3,30 (m, 1H), 3,88 (m, 1H), 4,18 (m, 2H), 4,70 (m, 1H), 5,80 - 6,10 (m, 2H), 7,15 - 7,40 (m, 5H) ppm. Herstellung von trans- 1-Chlor-3-iod-propen: Eine Lösung von 184,7 g trans-1,3-Dichlorpropen in 0,58 l Tetrahydrofuran wird mit 266,1 g Natriumiodid versetzt und unter Lichtausschluss während 30 Minuten bei Raumtemperatur gerührt. Das Gemisch wird klarfiltriert und das Filtrat direkt eingesetzt.
  • 42
  • [ 104266-90-2 ]
  • [ 89358-30-5 ]
  • [ 1187941-31-6 ]
YieldReaction ConditionsOperation in experiment
77% With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; optical yield given as %de;
Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With sodium hexamethyldisilazane In tetrahydrofuran; hexane at -78℃; for 1.25h; Inert atmosphere; Stage #2: benzyl (2E)-4-bromobut-2-en-1-yl ether In tetrahydrofuran; hexane at -78 - -40℃; for 5h; Inert atmosphere; diastereoselective reaction; 1 6.1.1. (2R,4E)-6-(Benzyloxy)-2-methylhex-4-enoic acid (12c) General procedure: A solution of sodium bis(trimethylsilyl)amide in n-hexane (1.03 M, 164 mL, 169 mmol) was added to a solution of 11c (32.9 g, 141 mmol) in THF (330 mL) under N2 atmosphere and at -78 °C over 45 min, and the mixture was stirred at the same temperature for 30 min. Then, a solution of benzyl (2E)-4-bromobut-2-en-1-yl ether (35.5 g, 148 mmol) in THF (80 mL) was added to the above solution over 30 min, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was raised to -40 °C and further stirred for 4 h. Saturated NH4Cl aqueous solution (100 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with water (500 mL), followed by extraction with AcOEt. Then, the organic layer was washed with water and brine, and dried over anhydrous MgSO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, n-hexane/AcOEt = 7:1-2:1) to obtain (4S)-4-benzyl-3-[(2R,4E)-6-(benzyloxy)-2-methylhex-4-enoyl]-1,3-oxazolidin-2-one (37.9 g, 69%, 99% ee) as a colorless liquid.
  • 43
  • [ 18866-73-4 ]
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran; toluene at -70 - 0℃; Inert atmosphere; Stage #2: cis-1,4-dibromo-2-butene In tetrahydrofuran; toluene at -70 - 20℃; Inert atmosphere; 1 Preparation of cis-2(S),7(S)-diisopropyl-octe-4-enedioic acid (IIb) from VIIIa Example 1 Preparation of cis-2(S),7(S)-diisopropyl-octe-4-enedioic acid (IIb) from VIIIa To a solution of 4(S)-benzyl-3-isovaleroyl-oxazolidin-2-one (12 g, THL 2000, 41, 10085), dissolved in THF (80 ml), under inert atmosphere cooled to -70° C. 1M-solution of lithium hexamethyldisilazide in toluene (LiHMDS, 50 ml) was slowly added dropwise under stirring at -70° C. within a period of ca. 1 hr. After stirring at the same temperature for 1 hr the reaction mixture was wormed to 0° C., then again cooled down to -70° C. and cis-1,4-dibromo-but-2-ene (4.5 g) in THF (10 ml) was slowly added, the reaction mixture shortly stirred at -70° C., then warmed to it and stirred for 7 hrs and finally poured on mixture of ice water and saturated sodium chloride solution (400 ml, 1:1). The aqueous phase was extracted 3 times with ethylacetate (3*200 ml), the combined organic phases washed once with saturated sodium bicarbonate solution (200 ml), dried with sodium sulphate, filtered and the filtrate evaporated under vacuum providing compound (IIa) as cis-2(S),7(S)-diisopropyl-oct-4-enedioic acid [bis((4(S)-benzyl-oxazolidin-2-one)]amide as a single diastereomer: crude 9.2 g (77% isolated yield) as a yellow semi crystalline oil. To stirred solution of the crude compound (IIa) (9.2 g), dissolved in a mixture of THF (100 ml) and water (30 ml), at 0° C. 35% aqueous hydrogen peroxide (30 ml) followed by 5 M aqueous solution of LiOH (70 ml) were added. After stirring for 1 hr at 0° C. the solution was warmed to rt and stirred over night. After addition of 0.5 M aqueous solution of Na2SO3 (70 ml) and water (70 ml) the aqueous phase was washed 3 times with MTBE to recover the chiral auxiliary. The aqueous phase was then acidified with conc.-HCl to pH 1, extracted 3 times with MTBE (3*200 ml), the combined organic phases dried over MgSO4, filtered and the filtrate concentrated under reduced pressure providing the title compound (IIb) (cis-2(S),7(S)-2,7-diisopropyloct-4-enedioic acid) as a single diastereomer as white crystals crude 3.9 g (95% isolated yield): Anal. calculated for C14H24O4: C, 65.60; H, 9.44; O 24.97. Found: C, 65.53; H, 9.38; O 24.88.
  • 44
  • [ 3587-60-8 ]
  • [ 104266-90-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With titanium tetrachloride In dichloromethane at -5 - 1℃; for 1h; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at -5℃; for 1h; Stage #3: Benzyloxymethyl chloride In dichloromethane at 0℃; for 4h; diastereoselective reaction;
  • 45
  • [ 104266-90-2 ]
  • [ 887143-15-9 ]
  • [ 1415986-74-1 ]
YieldReaction ConditionsOperation in experiment
84% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With titanium tetrachloride In dichloromethane at 0℃; Inert atmosphere; Stage #2: With triethylamine In dichloromethane at 0℃; Inert atmosphere; Stage #3: N,N-dibenzyliminium trifluoroacetate salt In dichloromethane at -80℃; for 16h; Inert atmosphere; diastereoselective reaction;
  • 46
  • [ 104266-90-2 ]
  • [ 870-63-3 ]
  • [ 1639215-20-5 ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; for 3h; Inert atmosphere; Stage #2: prenyl bromide In tetrahydrofuran at -78 - 20℃; Inert atmosphere;
  • 47
  • [ 134807-37-7 ]
  • [ CAS Unavailable ]
  • [ 134807-38-8 ]
  • [ 104266-90-2 ]
YieldReaction ConditionsOperation in experiment
1: 85% 2: 79% With n-hexyllithium In tetrahydrofuran; hexane at -10 - 0℃; for 6h; Inert atmosphere;
  • 48
  • [ 18866-73-4 ]
  • [ 104266-90-2 ]
  • [ 1310055-48-1 ]
YieldReaction ConditionsOperation in experiment
88% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -50℃; for 1h; Inert atmosphere; Stage #2: With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran at -50℃; for 0.5h; Inert atmosphere; Stage #3: cis-1,4-dibromo-2-butene In tetrahydrofuran at -50℃; for 1h; Inert atmosphere; 1 Example 1 Under N2 protection,500mL three flask, compound 4 (26.83g, 102.7mmol) was dissolved In 80mL ofanhydrous THF a low temperature (-50 ° C) was added dropwise with 1.0M LiHMDS(110mL, 110 mmol), After the addition was complete, -50 ° C under stirring for1h, and then added dropwise 1,3-dimethyl-3,4,5,6-tetrahydro-2- Pyrimidone(DMPU) (28.95g, 225.8mmol), the addition was complete the mixture was stirredat -50 ° C under 0.5h After the addition of cis-2-butene-1,4-dibromo-5 (8.78g,41.0mmol) in 18mL anhydrous THF, Stirred for 1h at -50 ° C, the naturallywarmed to 0 ° C, kept at 0 ° C 1h, then rose to 5-10 ° C insulation 1.5h, TLCplate track points to the end of the reaction. With 50mL of saturated solutionof NH4Cl quench the reaction, Rotary evaporation to remove THF, (30mL × 3) theaqueous phase was extracted with ethyl acetate, the combined EA phases werewashed with 1M (50mL × 4) EA dilute HCl rinse with about three times, driedover anhydrous MgSO4, spin-dry, drain the solvent, The crude product wasrecrystallized from methanol. To give a white crystalline solid was 20.72g,namely the title compound 2.3, Yield 88%.
  • 49
  • [ 104266-90-2 ]
  • [ 74-88-4 ]
  • [ 2071637-31-3 ]
YieldReaction ConditionsOperation in experiment
68% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With n-butyllithium; diisopropylamine In tetrahydrofuran at -80℃; for 1h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at -78 - 20℃; for 5h; Inert atmosphere; diastereoselective reaction;
  • 50
  • [ 104266-90-2 ]
  • [ 75-03-6 ]
  • [ 2543891-87-6 ]
YieldReaction ConditionsOperation in experiment
36% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.83333h; Stage #2: ethyl iodide In tetrahydrofuran at -78 - 20℃; for 22h; 8 To a stirred solution of LiHMDS (1.724 mL, 1.14 mol) in THF (2.1 L) under inert atmosphere was added (ri)-4-benzyl-3-(3-methylbutanoyl) oxazolidin-2-one 76 (300 g, 1.14 mol) in THF (900 mL) portion wise over period of 20 min at -78 °C. The mixture was stirred for 1.5 h. Ethyl iodide (712.6 g, 4.59 mol) was added at -78 °C. The reaction mixture was stirred for 2 h at - 78 °C and then stirred at about -5 °C for 4 h. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with sat. ammonium chloride solution (3 L) and extracted with EtOAc (2 x 1 L). The combined organic extracts were washed with 1.0 M aq HC1 solution (500 mL) and saturated sodium bicarbonate solution (500 mL). The organic solution was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 2% EtO Ac/Hexane) to afford (S)- 4-benzyl-3-(fV)-2-ethyl-3-methylbutanoyl) oxazolidin-2-one 77 (120 g, 36%) as a colorless oil. 'H NMR (500 MHz, DMSO-^e) d 7.34-7.18 (m, 5H), 4.72-4.68 (m, 1H), 4.30 (t, J= 8.4 Hz, 1H), 4.15 (dd, J= 8.7, 2.7 Hz, 1H), 3.54-3.50 (m, 1H), 3.05 (dd, J= 13.4, 3.4 Hz, 1H), 2.91-2.86 (m, 1H), 1.98-1.72 (m, 1H), 1.69-1.51 (m, 2H), 0.89-0.79 (m, 9H).
36% Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 2.66667h; Inert atmosphere; Stage #2: ethyl iodide In tetrahydrofuran at -78 - 20℃; for 22h; Inert atmosphere; Step 2: (S)-4-Benzyl-3-((S)-2-ethyl-3-methylbutanoyl) oxazolidin-2-one (3) To a stirred solution of LiHMDS ( 1.724 mL, 1.14 mol) in THF (2.1 L) under inert atmosphere was added (S)-4-benzyl -3 -(3-methylbutanoyl) oxazolidin-2-one 2 (300 g, 1.14 mol) in THF (900 mL) portionwise over the period of 10 min at -78 °C. After stirring for 1.5 h at same temperature, ethyl iodide (712.6 g, 4.59 mol) was added to the reaction mixture and maintained for 2 h at -78 °C. Then, the reaction mixture was further stirred for 4 h at 0 °C and for 16 h at room temperature. After complete consumption of starting material (by TLC); the reaction mixture was diluted with saturated aq. ammonium chloride solution (3 L) and extracted with EtOAc (2 x 1 L). The combined organic extracts were washed with 1.0M aq. HC1 solution (500 mL), saturated sodium bicarbonate solution (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica-gel flash column to afford (.V)-4-benzyl-3-((S)-2 -ethyl -3-methylbutanoyl) oxazolidin-2-one 3 (120 g, 0.41 mol, 36%) as colorless oil. 1H NMR (500 MHz, DMSO-d6): δ 7.34-7.18 (m, 5H), 4.72-4.68 (m, 1H), 4.30(t, J= 8.4 Hz, 1H), 4.15 (dd, J= 8.7, 2.7 Hz, 1H), 3.54-3.50 (m, 1H), 3.05 (dd, J= 13.4, 3.4 Hz, 1H),2.91-2.86 (m, 1H), 1.98-1.72 (m, 1H), 1.69-1.51 (m, 2H), 0.89-0.79 (m, 9H).
0.75 g Stage #1: (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.5h; Inert atmosphere; Stage #2: ethyl iodide In tetrahydrofuran at -78 - 20℃; Inert atmosphere; 1 [00166] To a solution of NaHMDS (6 mL, 6 mmol; 1 M in THF) in anhydrous THF (20 mL) was added a solution of compound 10 (1.3 g, 5 mmol) in anhydrous THF (10 mL) at -78°C under N2. The mixture was stirred for 1.5 hr at -78°C and then iodoethane (3.12 g, 20 mmol) was added dropwise. The resulting mixture was stirred at -78°C for 2 h and then allowed to reach - 5°C and stirred for 4 h. The mixture was allowed to warm to room temperature overnight. The reaction was quenched by the addition of saturated aqueous NH4CI solution (30 mL) and the product was extracted with ethyl acetate (3x50 mL). The combined organic layers were successively washed with ice-cold HC1 (1 M, 20 mL), saturated aqueous NaHCO3 solution (2x30 mL), and brine, and then dried over anhydrous Na2SO4. The crude mixture was purified by flash chromatography on silica gel to afford compound 11 (0.75 g) as a yellow oil.
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