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CAS No. : | 599-04-2 | MDL No. : | MFCD00005392 |
Formula : | C6H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SERHXTVXHNVDKA-BYPYZUCNSA-N |
M.W : | 130.14 | Pubchem ID : | 439368 |
Synonyms : |
D-(-)-Pantolactone
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 31.03 |
TPSA : | 46.53 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) : | -6.77 cm/s |
Log Po/w (iLOGP) : | 1.31 |
Log Po/w (XLOGP3) : | 0.46 |
Log Po/w (WLOGP) : | -0.07 |
Log Po/w (MLOGP) : | 0.0 |
Log Po/w (SILICOS-IT) : | 0.78 |
Consensus Log Po/w : | 0.5 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.94 |
Solubility : | 15.1 mg/ml ; 0.116 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.01 |
Solubility : | 12.8 mg/ml ; 0.0987 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.54 |
Solubility : | 37.6 mg/ml ; 0.289 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.17 |
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: |
* 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 |
---|---|---|
71% | Milling | 3-Aminopropionic acid (4.45 g, 0.05 mol), calcium oxide (1.68 g, 0.03 mol) were added to a 100 mL ball mill, Sodium chloride (12.26 g),Then add two iron balls with a diameter of 30 mm.Perform a mechanical ball mill for 30 min (frequency 30 Hz) The reaction mixture is reacted. to(6.50 g, 0.05 mol), sodium chloride (13 g), ball mill Rate 30 Hz, after 30 min, add the previous step after the ball mill solid powder. Ball mill frequency 30 Hz, time 30 min, take The reaction mixture was removed and the product was dissolved in methanol (85 mL), filtered and concentrated to crystallize. The product was filtered and dried to give a white powder Vitamin B5 (8.45 g, yield 71percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.3 g | for 3 h; Reflux | 55.5 g of sodium β-alaninate,Pantolactone 65 grams,Dissolved in 350 ml of absolute ethanol,Heated to reflux for 3 hours,Filtered while still hotThe reaction vessel was washed with 50 ml of ethanol,After the washing solution was filtered and the reaction mixture was combined,The filtrate was placed at 0 for 5 days,Filter, wash the solid with a little ethanol,Drying to constant weight at room temperature under reduced pressure,Got 76.3 grams of white crystalline powder,Which is the sodium D-pantothenate crystal described in GB565976. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; C38H79N3O16*CH4O3S; hydrogen; (C5H9)2POCH2C4H5ONP(C5H9)2; In toluene; at 25℃; under 750.075 Torr; for 2h;Catalytic behavior; | A rhodium catalyst precursor [Rh(COD)Cl]2, a chiral bisphosphine ligand 3 (R1 = Boc), a polyether alkylguanidinium salt ionic liquid [ (PG), CH3 (EO) 16TMG] SO3CH3, <strong>[13031-04-4]ketopantolactone</strong> and benzene, the molar ratio of 3 to Rh is 1.1: 1, the mass ratio of ionic liquid to rhodium catalyst precursor is 500: 1, the ratio of <strong>[13031-04-4]ketopantolactone</strong> to Rh The molar ratio is 100: 1, the volume ratio of benzene to ionic liquid is 4: 1, the atmosphere is replaced with nitrogen or argon for 4-6 times, and then pressurized with hydrogen to 5.0MPa, the reaction is carried out at 50 for 4 hours and then rapidly cooled After hydrogen was vented, the benzene was removed under reduced pressure and extracted twice with methyl tert-butyl ether. The volume ratio of methyl tert-butyl ether to benzene was 1: 1. The system was split into two phases and was isolated by simple phase separation The upper methyl tert-butyl ether phase containing D-pantolactone was analyzed by gas chromatography. The conversion of <strong>[13031-04-4]ketopantolactone</strong> was 77.6%, and the ee value of D-pantolactone was 60.7%. The reaction conditions and procedures were the same as in Example 1 except that the solvent was changed to toluene, the molar ratio of <strong>[13031-04-4]ketopantolactone</strong> to Rh was 200: 1, the pressure of hydrogen was 0.1 MPa, the reaction temperature was 25 C, and the reaction time was 2h. Analysis by gas chromatography showed that the conversion rate of <strong>[13031-04-4]ketopantolactone</strong> was 97.5% and that of D-pantolactone was 92.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In ethanol; at 160℃; for 3.0h;Microwave irradiation; | Step 1 : (R)-2, 4-Dihydroxy-N-(3-hydroxy-propyl)-3, 3-dimethyl-butyramideTo a solution of D-pantolactone (0.5 g, 1 eq) in dry EtOH (5 mL) in a microwave vial were added 3-amino-propan-1-ol (0.53 mL, 1.5 eq), Et3N (0.54 mL, 1 eq) and irradiated with MW radiation at 160C for 3 h. After this time, the reaction mixture wasconcentrated and purified by silica gel column chromatography to afford the product as a white solid (800 mg, 95%).1H NMR (400 MHz, DMSO d6): delta 7.70 (t, J = 4.0 Hz, 1 H), 5.32 (d, J = 4.0 Hz, H), 4.48-4.42 (m, 2H), 3.68 (d, J = 8.0 Hz, 1 H), 3.40 (dd, J = 4.0, 8.0 Hz, 2H), 3.31-3.26 (m, 1 H), 3.19-3.07 (m, 3H), 2.56-2.52 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H). |
at 60℃; for 5.0h; | Preparation of Panthenol:A 1 l four-neck flask was initially charged with 150 g of 3-aminopropanol. While stirring, 260 g of D-pantolactone were added slowly at room temperature. After the addition had ended, the reaction mixture was heated to 60 C. and stirred for a further 5 hours. The D-pantolactone used was washed twice beforehand with methyl tert-butyl ether (MTBE) and then dried.The crude panthenol obtained by the reaction of 3-aminopropanol and D-pantolactone was subsequently degassed and distilled.The degassing was performed in a thin-film evaporator at a pressure of 0.027 mbar, a bottom temperature of 80 C. and a lamellar speed of 280 rpm. After the degassing, the apparatus was cleaned by repeatedly purging with demineralized water and 2-propanol with subsequent drying under reduced pressure.Subsequently, the degassed panthenol was distilled. The distillation was performed in the same apparatus in which the degassing had already been undertaken. The bottom temperature was 120 C., the pressure 0.027 mbar and the lamellar speed 800 rpm.In the internal condenser, at a cooling coil temperature of 60 C., panthenol was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 4-amino-n-butyric acid With sodium hydroxide In water Stage #2: (R)-Pantolacton at 130℃; for 17h; Inert atmosphere; | |
89% | With triethylamine In methanol at 65℃; for 24h; Inert atmosphere; | |
53% | With diethylamine In methanol at 60℃; |
With sodium methylate | ||
With diethylamine In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: glycine With sodium hydroxide In water Stage #2: (R)-Pantolacton at 130℃; for 17h; Inert atmosphere; | |
With calcium methylate In methanol | ||
With triethylamine In methanol at 65℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With lithium aluminium tetrahydride In tetrahydrofuran Heating; | |
88% | Stage #1: (R)-Pantolacton With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 4h; Stage #2: With sulfuric acid; sodium sulfate In tetrahydrofuran; water | |
82% | Stage #1: (R)-Pantolacton With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Stage #2: With sodium hydroxide; water In tetrahydrofuran at 0℃; | 11 Example 11 (2R)-3,3-Dimethylbutane-1,2,4-triol (11) Adopting procedures or variations thereof, according to Blakemore et al., J. Org. Chem. 2005, 70, 5449-5460, Mandel et al., Org. Lett. 2004, 6, 4801-4803, and/or Lavallee et al., Tetrahedron Lett. 1986, 27, 679-682, a dry 1,000 mL three-necked flask equipped with a magnetic stirring bar, addition funnel, and reflux condenser topped with rubber septa was charged under a nitrogen atmosphere with 7.8 g (60.0 mmol) of D-pantolactone. The material was dissolved in 100 mL of anhydrous tetrahydrofuran (THF) and the solution was cooled to ca. 0° C. (ice bath). 65 mL (38.5 mmol) of a one molar (1M) solution of lithium aluminum hydride (LAH) in THF was added dropwise at this temperature and the reaction mixture was stirred overnight with gradual warming to room temperature. (Note: To ensure complete global reduction of the lactone several authors recommend heating the reaction mixture to reflux for ca. two hours after the overnight reaction to complete the reduction.) The reaction mixture was again cooled to ca. 0° C. (ice bath) and 4.23 mL of water, 8.46 mL of an aqueous solution of sodium hydroxide (10 wt-%), and 4.23 mL of water were carefully added (Note: Initial vigorous evolution of hydrogen[gas]) and the resulting colorless precipitate was filtered off. The filter residue was washed with dichloromethane (DCM) and the combined filtrates were dried over anhydrous magnesium sulfate (MgSO4). After filtration and evaporation of the solvents under reduced pressure using a rotary evaporator, 6.6 g (82% yield) of the title compound (11) was obtained as a slightly yellow, viscous liquid that was of sufficient purity to be used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ=0.768 (s, 3H), 0.777 (s, 3H), 3.15 (d, J=10.4 Hz, 1H), 3.21 (d, J=10.0 Hz, 1H), 3.22-32 (m, 2H), 3.44-3.52 (m, 1H), 4.20-4.40 (br. m, 3H) ppm. MS (ESI) m/z: 135.03 (M+H)+, 132.89 (M-H)-. The analytical data were consistent with the proposed structure and with the data given in the literature. |
58% | With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 2h; | |
With lithium aluminium tetrahydride | ||
With lithium aluminium tetrahydride In tetrahydrofuran | ||
With lithium aluminium tetrahydride In tetrahydrofuran 0 deg C, reflux, 5 h, room t.; | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; | ||
51.0 g | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 4h; | |
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; | ||
With lithium aluminium tetrahydride; sodium sulfate 1.) THF, reflux; Yield given. Multistep reaction; | ||
Multi-step reaction with 3 steps 1: 96 percent / EtNiPr2 / CH2Cl2 / 20 h / 40 °C 2: 88 percent / LiAlH4 / tetrahydrofuran / 12 h / 20 °C 3: 98 percent / p-toluenesulfonic acid / methanol / 12 h / 20 °C | ||
Multi-step reaction with 3 steps 1: 88 percent / TsOH*H2O / CH2Cl2 / 0.25 h / Ambient temperature 2: LiAlH4 / diethyl ether / 3 h / Ambient temperature 3: TsOH*H2O / methanol / 4 h / Ambient temperature | ||
With lithium aluminium tetrahydride In diethyl ether | ||
Stage #1: (R)-Pantolacton With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Reflux; Stage #2: With water; sodium hydroxide In tetrahydrofuran | 112.A (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (3.21 g, 24.7 mmol) was added to 30 mL THF and cooled to 0 0C. Lithium aluminum hydride (24.7 mL, 24.7 mmol) was added slowly and the reaction was warmed to ambient temperature and heated for 6 hours at reflux, during which a heterogeneous mixture of white solids formed. The reaction was cooled to ambient temperature, and 1 mL water was added, followed by the addition of 1 mL of a 15% NaOH aqueous solution (w/v) and 3 mL of water, and the reaction was stirred overnight. The reaction was passed through Celite and filtered, rinsed with copious amounts of ethyl acetate, then dried over Na2SO4. The mixture was filtered, the filtrate was concentrated, and excess water was azeotroped with toluene-DCM (1-1). The residue was dried under high vacuum for 1 hour to yield 2.4 g of the desired product as a clear thick oil. | |
Stage #1: (R)-Pantolacton With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux; Stage #2: With water In tetrahydrofuran at 0℃; | 29.A To a stirred suspension of lithium aluminium hydride (3.00 g, 79.1 mmol) in dry THF (100 mL) at 0° C. was added a solution of (R)-pantolactone (10.30 g, 79.14 mmol) in THF (100 mL). The mixture was stirred overnight at room temperature and was then heated to reflux for a further 2 h. The mixture was cooled to 0° C. and the reaction was quenched with saturated aqueous Na2SO4until a white solid precipitated. The solid was filtered off, the filter cake was washed with THF (2×60 mL) and the filtrate was concentrated under reduced pressure to give the title compound as a pure colorless oil. | |
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux; Inert atmosphere; | ||
With lithium aluminium tetrahydride In diethyl ether Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;5% alumina-supported platinum catalyst; cinchonidine; In toluene; at 17℃; under 30003.0 Torr;Product distribution / selectivity; | Examples 1-4 [00041] The process of the present invention as set forth in FIG. 1 is typically initiated by dissolving the alpha ketocarbonyl compound and the modifier in vessel (1). The resulting solution contains from about 0.1 wt % to about 100 wt % of the alpha ketocarbonyl compound and from about 1×10-5 wt % to about 0.5 wt % of modifier. [00042] The mass flow is started at the reaction temperature, for example, at 17 C. or 20 C. (Examples 1 and 2, respectively). The above solution containing an alpha ketocarbonyl compound and a modifier is pumped into the fixed bed reactor (2) and contacted with hydrogen to start the hydrogenation reaction. Before catalytic runs, the reactor is flushed with nitrogen. [00043] Subsequently, the content of vessel (1) is continuously pumped into the fixed bed reactor. The solution flow rate is preferably from about 0.1 to about 50 ml/minute, the preferred flow of the alpha ketocarbonyl compound is 2×10-5-2×10-2 mol/gcat/minute. More preferably, the solution flow rate is preferably from about 2.5 to about 10 ml/minute, and the flow of the alpha ketocarbonyl compound is from about 2×10-4-3×10-3 mol/gcat/minute. [00044] The modifier flow rate is preferably from about 2×10-9 to about 2×10-4 mol/gcat/minute, such as, for example, from about 2×10-8 to about 7×10-6 mol/gcat/minute. [00045] Hydrogen is continuously fed into the fixed bed reactor via flow line (3) containing a compressor (4) and a pressure control system (5). The inert gas, e.g. nitrogen, is fed into the reactor (2) via line (7). [00046] The hydrogen flow rate into the reactor is metered and monitored by a rotameter. Suitable hydrogen flow rates are from about 0.0001 mol/minute (2.4 ml/minute) to about 1 mol/minute (24000 ml/minute), for example, from about 5×10-6 to about 10 mol/gcat/minute. [00047] The hydrogenation reaction can be carried out at a relatively low temperature ranging between about -20 C. and about 100 C., the preferred temperature range is from about -10 C. to about 50 C., such as for example from about 0 C. to about 20 C. [00048] The pressure in the reactor is suitably adjusted to between about 2 bar and about 150 bar, preferably from about 40 bar to about 100 bar. [00049] The effluent from the hydrogenation reaction zone is fed over a two-step expansion module (6) to a separator where the alpha hydroxy carbonyl compound is recovered. [00050] The process set forth in FIG. 2 is initiated by dissolving the alpha ketocarbonyl compound and the modifier in vessel (1) or by adding a solution containing the modifier to a liquid alpha ketocarbonyl compound. The resulting solution has the following concentration: [00051] about 0.1 wt % to about 100 wt % of alpha ketocarbonyl compound; and [00052] about 1×10-6 wt % to about 0.5 wt % of modifier. [00053] The reactor vessel (2) is charged with a supercritical solvent via flow line (3) containing a compressor (4) and a pressure control system (5). [00054] The organic flow is started at a reaction temperature of, for example, about 50 C. (Example 3) or 36 C. (Example 4). The solution set forth above is pumped into the fixed bed reactor (2) and contacted with hydrogen to start the hydrogenation reaction. [00055] Subsequently, the content of vessel (1) is continuously pumped into the fixed bed reactor with the same solution flow rate as in the process according to FIG. 1. [00056] The flow rate of the supercritical co-solvent is preferably from about 50 ml/minute to about 5000 ml/minute. [00057] When using a liquid alpha ketocarbonyl compound, the supercritical co-solvent is used with a flow rate of about 50 ml/minute to about 5000 ml/minute. [00058] The modifier flow rate is preferably from about 2×10-11 to about 2×10-4 mol/gcat/min. [00059] Hydrogen is continuously fed into the fixed bed reactor via flow line (7) containing a pressure control system (5). The hydrogen flow rate into the reactor was metered and monitored by a rotameter. [00060] Suitable hydrogen flow rates are from about 0.0001 mol/minute (2.4 ml/minute) to about 1 mol/minute (24000 ml/minute) such as for example from 5×10-6 to about 10 mol/gcat/minute. [00061] The hydrogenation reaction can be carried out at a relatively low temperature ranging between about 20 C. to about 100 C., preferably from about 30 C. to about 60 C., such as for example from about 35 C. to about 50 C. The pressure is suitably adjusted to between about 2 bar to about 150 bar, preferably about 40 bar to about 100 bar. | |
With hydrogen;5% alumina-supported platinum catalyst; cinchonidine; In ethane; toluene; at 50℃; under 75007.5 Torr;Product distribution / selectivity; | Examples 1-4 [00041] The process of the present invention as set forth in FIG. 1 is typically initiated by dissolving the alpha ketocarbonyl compound and the modifier in vessel (1). The resulting solution contains from about 0.1 wt % to about 100 wt % of the alpha ketocarbonyl compound and from about 1×10-5 wt % to about 0.5 wt % of modifier. [00042] The mass flow is started at the reaction temperature, for example, at 17 C. or 20 C. (Examples 1 and 2, respectively). The above solution containing an alpha ketocarbonyl compound and a modifier is pumped into the fixed bed reactor (2) and contacted with hydrogen to start the hydrogenation reaction. Before catalytic runs, the reactor is flushed with nitrogen. [00043] Subsequently, the content of vessel (1) is continuously pumped into the fixed bed reactor. The solution flow rate is preferably from about 0.1 to about 50 ml/minute, the preferred flow of the alpha ketocarbonyl compound is 2×10-5-2×10-2 mol/gcat/minute. More preferably, the solution flow rate is preferably from about 2.5 to about 10 ml/minute, and the flow of the alpha ketocarbonyl compound is from about 2×10-4-3×10-3 mol/gcat/minute. [00044] The modifier flow rate is preferably from about 2×10-9 to about 2×10-4 mol/gcat/minute, such as, for example, from about 2×10-8 to about 7×10-6 mol/gcat/minute. [00045] Hydrogen is continuously fed into the fixed bed reactor via flow line (3) containing a compressor (4) and a pressure control system (5). The inert gas, e.g. nitrogen, is fed into the reactor (2) via line (7). [00046] The hydrogen flow rate into the reactor is metered and monitored by a rotameter. Suitable hydrogen flow rates are from about 0.0001 mol/minute (2.4 ml/minute) to about 1 mol/minute (24000 ml/minute), for example, from about 5×10-6 to about 10 mol/gcat/minute. [00047] The hydrogenation reaction can be carried out at a relatively low temperature ranging between about -20 C. and about 100 C., the preferred temperature range is from about -10 C. to about 50 C., such as for example from about 0 C. to about 20 C. [00048] The pressure in the reactor is suitably adjusted to between about 2 bar and about 150 bar, preferably from about 40 bar to about 100 bar. [00049] The effluent from the hydrogenation reaction zone is fed over a two-step expansion module (6) to a separator where the alpha hydroxy carbonyl compound is recovered. [00050] The process set forth in FIG. 2 is initiated by dissolving the alpha ketocarbonyl compound and the modifier in vessel (1) or by adding a solution containing the modifier to a liquid alpha ketocarbonyl compound. The resulting solution has the following concentration: [00051] about 0.1 wt % to about 100 wt % of alpha ketocarbonyl compound; and [00052] about 1×10-6 wt % to about 0.5 wt % of modifier. [00053] The reactor vessel (2) is charged with a supercritical solvent via flow line (3) containing a compressor (4) and a pressure control system (5). [00054] The organic flow is started at a reaction temperature of, for example, about 50 C. (Example 3) or 36 C. (Example 4). The solution set forth above is pumped into the fixed bed reactor (2) and contacted with hydrogen to start the hydrogenation reaction. [00055] Subsequently, the content of vessel (1) is continuously pumped into the fixed bed reactor with the same solution flow rate as in the process according to FIG. 1. [00056] The flow rate of the supercritical co-solvent is preferably from about 50 ml/minute to about 5000 ml/minute. [00057] When using a liquid alpha ketocarbonyl compound, the supercritical co-solvent is used with a flow rate of about 50 ml/minute to about 5000 ml/minute. [00058] The modifier flow rate is preferably from about 2×10-11 to about 2×10-4 mol/gcat/min. [00059] Hydrogen is continuously fed into the fixed bed reactor via flow line (7) containing a pressure control system (5). The hydrogen flow rate into the reactor was metered and monitored by a rotameter. [00060] Suitable hydrogen flow rates are from about 0.0001 mol/minute (2.4 ml/minute) to about 1 mol/minute (24000 ml/minute) such as for example from 5×10-6 to about 10 mol/gcat/minute. [00061] The hydrogenation reaction can be carried out at a relatively low temperature ranging between about 20 C. to about 100 C., preferably from about 30 C. to about 60 C., such as for example from about 35 C. to about 50 C. The pressure is suitably adjusted to between about 2 bar to about 150 bar, preferably about 40 bar to about 100 bar. | |
With 5 wt% platinum/alumina; hydrogen; (8R,9S)-cinchonine; In toluene; at -5℃; under 52505.3 Torr; | 4 mmol 2, 10 mg 5 wt.% Pt/Al2O3, 13.5 mumol modifier in 10 mL toluene, at -5 C and 70 bar. |
With O-phenylcinchonidine; 5% platinum on aluminium oxide; hydrogen; In toluene; at 20.84 - 23.84℃; under 750.075 Torr;Catalytic behavior; | General procedure: Hydrogenations were performed in an atmospheric batch reactor. The catalytic system including catalyst (25 mg) and 5 mL of solvent (toluene or toluene and AcOH mixture) was loaded into the reactor and purged three times with H2. The catalyst was stirred and pre-hydrogenated for 30 min. The calculated amount of modifier was injected and after 0.5-1 min 1 mmol (128 mg) of KPL was added and stirred in the presence of H2 for the required reaction time. Standard conditions were: 25 mg Pt/Al2O3, 5 mL solvent, [modifier] 0.1 mM/L, 0.1 MPa H2 pressure, 294-297 K, ~ 900 rpm (diffusion control free reaction), and 1 mmol (128 mg) of KPL. The product identification and the enantiomeric excess, ee% = |[R] - [S]| × 100 / ([R] + [S]) were monitored by gas chromatography (HP 6890 N GC-FID using 30 m long Cyclodex-B capillary column, head pressure 21.65 psi He, and column temperature 398 K. Retention times (min): 10.6 of (S)-PL, and 11.2 of (R)-PL. The reproducibility was ± 2%. | |
With 5% platinum on aluminium oxide; hydrogen; beta-isocinchonine; In toluene; at 20.84 - 23.84℃; under 750.075 Torr;Catalytic behavior; | General procedure: Hydrogenations were performed in an atmospheric batch reactor. The catalytic system including catalyst (25 mg) and 5 mL of solvent (toluene or toluene and AcOH mixture) was loaded into the reactor and purged three times with H2. The catalyst was stirred and pre-hydrogenated for 30 min. The calculated amount of modifier was injected and after 0.5-1 min 1 mmol (128 mg) of KPL was added and stirred in the presence of H2 for the required reaction time. Standard conditions were: 25 mg Pt/Al2O3, 5 mL solvent, [modifier] 0.1 mM/L, 0.1 MPa H2 pressure, 294-297 K, ~ 900 rpm (diffusion control free reaction), and 1 mmol (128 mg) of KPL. The product identification and the enantiomeric excess, ee% = |[R] - [S]| × 100 / ([R] + [S]) were monitored by gas chromatography (HP 6890 N GC-FID using 30 m long Cyclodex-B capillary column, head pressure 21.65 psi He, and column temperature 398 K. Retention times (min): 10.6 of (S)-PL, and 11.2 of (R)-PL. The reproducibility was ± 2%. | |
With hydrogen; In toluene; at 24.84℃; under 30003.0 Torr;Kinetics; | General procedure: Enantioselective hydrogenations reactions Hydrogenation reactions were performed in a stainless steel semibatch reactor coated with Teflon. Typically, 50 mL of solvent was used in all reactions at 40 bar of pressure, room temperature, stirring speed of 800 rpm, and molar ratio [substrate/metal] of 100. The solvent used for HD, EP and AP substrates was cyclohexane and toluene for KP. The experimental conditions used in this study were carefully selected to avoid mass transfer limitations. Analyses of reagents and products concentrations were determined usinga SHIMADZU GC-MS, model QP5050, equipped with a chiral column BetaDEX 225 (Supelco) of 30 m long and 0.25 mm of diameter. Carrier gas used was helium (99.995% of purity). Optical yields expressed as ee values, were calculated with the following equation: ee (%)= ([R]-[S])/([R]+[S])x100 (eq.3) eemax indicates the highest enantioselectivity value reached at the end of selected reaction, when reactant conversion was completed. | |
With Pt/Al2O3; hydrogen; (S)-2-(fluorodiphenylmethyl)pyrrolidine; In toluene; at 20℃; under 750.075 Torr; for 2h;Sealed tube; | General procedure: Hydrogenations of ketones at atmospheric H2-pressure wereperformed in a 50-mL three-necked glass reactor at RT and atatmospheric pressure under constant flow of molecular H2 with a volumetric flow rate of 10 mL min-1 (semi-batch hydrogenation). The third opening of the reactor was sealed with a septum which allowed for addition/removal of solutions containing modifier and ketone by the use of a syringe. The stirring rate was set to 500 rpm. Hydrogenations performed at 10 bar H2-pressure were carried out in a 60-mL Hastelloy steel jacketed-reactor connected to a multi-position valve (VICI) which allows for connecting the reactor to the hydrogen and nitrogen reservoirs, and to open it to the atmosphere.The H2-pressure was controlled with a constant pressure regulator (Brooks 5688 Series). The standard reaction temperature (298 K) in the jacket was controlled with a Haake Phoenix (Thermo) water bath. The stirring rate was set to 750 rpm. The general reaction procedure for all hydrogenations was the following: the pre-reduced catalyst (50 mg Pt/Al2O3) was transferred to the reactor und reduced again in situ in 5 ml solvent under constant H2flow for 1 h. Then, the reaction was initiated by addition of modifier and ketone premixed in 5 mL solvent. The conversion and enantioselectivity in the hydrogenation were determined by gas chromatography (GC), using an Agilent Technologies 7890A gas chromatograph equipped with a flame ionisation detector (FID). Samples were injected with a split ratio of20: 1 at an injector temperature of 250C. For GC separation, a chiral capillary column (CP-Chirasil-Dex CB, 25 m length, 0.25 mm internal diameter, 0.25 m film thickness) was used. For the analysis of KPL hydrogenations, the temperature programme started at 80C, increased to 140C at 10C min-1, increased to 180C at 20C min-1, and then held for 2 min. For the analysis of MBF hydrogenations, the temperature programme started at 120C,increased to 180C at 20C min-1, and then held for 2 min. For the analysis of TFAP hydrogenations, the temperature programmestarted at 120C, held for 1 min, increased to 130C at 1C min-1, held for 1 min, increased to 140C at 10C min-1, held for 1 min,increased to 150C at 1C min-1, held for 1 min, and then increased to 180C at 40C min-1. The FID was operated at 300C with con-stant flows of hydrogen as fuel gas (30 mL min-1) and air as oxidant(400 mL min-1). Nitrogen was used as a make-up gas (25 mL min-1)and helium as a carrier gas (constant flow: 1.623 mL min-1). The target analytes could be separated: KPL (retention time 5.84 min,elution temperature 138.4C, (S)-PL (7.38 min, 167.6C), and (R)-PL (7.51 min, 170.2C); MBF (retention time 6.09 min, elutiontemperature 145.5C, (R)-MM (7.38 min, 155.2C), and (S)-MM(7.51, 155.7C); TFAP (retention time 1.75 min, elution temperature 120.8C, (S)-PTFE (10.7 min, 130.0C), and (R)-PTFE (11.1 min,130.1C). Products were identified using enantiopure alcohol products. | |
With Pt/Al2O3; (5S)-2,2,3-trimethyl-5-(anthracen-9-ylmethyl)imidazolidin-4-one; hydrogen; In toluene; at 20℃; under 750.075 Torr; for 2h;Sealed tube;Catalytic behavior; | General procedure: Hydrogenations of ketones at atmospheric H2-pressure wereperformed in a 50-mL three-necked glass reactor at RT and atatmospheric pressure under constant flow of molecular H2 with a volumetric flow rate of 10 mL min-1 (semi-batch hydrogenation). The third opening of the reactor was sealed with a septum which allowed for addition/removal of solutions containing modifier and ketone by the use of a syringe. The stirring rate was set to 500 rpm. Hydrogenations performed at 10 bar H2-pressure were carried out in a 60-mL Hastelloy steel jacketed-reactor connected to a multi-position valve (VICI) which allows for connecting the reactor to the hydrogen and nitrogen reservoirs, and to open it to the atmosphere.The H2-pressure was controlled with a constant pressure regulator (Brooks 5688 Series). The standard reaction temperature (298 K) in the jacket was controlled with a Haake Phoenix (Thermo) water bath. The stirring rate was set to 750 rpm. The general reaction procedure for all hydrogenations was the following: the pre-reduced catalyst (50 mg Pt/Al2O3) was transferred to the reactor und reduced again in situ in 5 ml solvent under constant H2flow for 1 h. Then, the reaction was initiated by addition of modifier and ketone premixed in 5 mL solvent. The conversion and enantioselectivity in the hydrogenation were determined by gas chromatography (GC), using an Agilent Technologies 7890A gas chromatograph equipped with a flame ionisation detector (FID). Samples were injected with a split ratio of20: 1 at an injector temperature of 250C. For GC separation, a chiral capillary column (CP-Chirasil-Dex CB, 25 m length, 0.25 mm internal diameter, 0.25 m film thickness) was used. For the analysis of KPL hydrogenations, the temperature programme started at 80C, increased to 140C at 10C min-1, increased to 180C at 20C min-1, and then held for 2 min. For the analysis of MBF hydrogenations, the temperature programme started at 120C,increased to 180C at 20C min-1, and then held for 2 min. For the analysis of TFAP hydrogenations, the temperature programmestarted at 120C, held for 1 min, increased to 130C at 1C min-1, held for 1 min, increased to 140C at 10C min-1, held for 1 min,increased to 150C at 1C min-1, held for 1 min, and then increased to 180C at 40C min-1. The FID was operated at 300C with con-stant flows of hydrogen as fuel gas (30 mL min-1) and air as oxidant(400 mL min-1). Nitrogen was used as a make-up gas (25 mL min-1)and helium as a carrier gas (constant flow: 1.623 mL min-1). The target analytes could be separated: KPL (retention time 5.84 min,elution temperature 138.4C, (S)-PL (7.38 min, 167.6C), and (R)-PL (7.51 min, 170.2C); MBF (retention time 6.09 min, elutiontemperature 145.5C, (R)-MM (7.38 min, 155.2C), and (S)-MM(7.51, 155.7C); TFAP (retention time 1.75 min, elution temperature 120.8C, (S)-PTFE (10.7 min, 130.0C), and (R)-PTFE (11.1 min,130.1C). Products were identified using enantiopure alcohol products. | |
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; C38H79N3O16*CH4O3S; C2HF3O2*C6H11NO3; hydrogen; In benzene; at 50℃; under 37503.8 Torr; for 4h;Catalytic behavior; | A rhodium catalyst precursor [Rh(COD)Cl]2, a chiral bisphosphine ligand 3 (R1 = Boc), a polyether alkylguanidinium salt ionic liquid [ (PG), CH3 (EO) 16TMG] SO3CH3, <strong>[13031-04-4]ketopantolactone</strong> and benzene, the molar ratio of 3 to Rh is 1.1: 1, the mass ratio of ionic liquid to rhodium catalyst precursor is 500: 1, the ratio of <strong>[13031-04-4]ketopantolactone</strong> to Rh The molar ratio is 100: 1, the volume ratio of benzene to ionic liquid is 4: 1, the atmosphere is replaced with nitrogen or argon for 4-6 times, and then pressurized with hydrogen to 5.0MPa, the reaction is carried out at 50 for 4 hours and then rapidly cooled After hydrogen was vented, the benzene was removed under reduced pressure and extracted twice with methyl tert-butyl ether. The volume ratio of methyl tert-butyl ether to benzene was 1: 1. The system was split into two phases and was isolated by simple phase separation The upper methyl tert-butyl ether phase containing D-pantolactone was analyzed by gas chromatography. The conversion of <strong>[13031-04-4]ketopantolactone</strong> was 77.6%, and the ee value of D-pantolactone was 60.7%. The reaction conditions and procedures were the same as in Example 1 except that the solvent was changed to toluene, the molar ratio of <strong>[13031-04-4]ketopantolactone</strong> to Rh was 200: 1, the pressure of hydrogen was 0.1 MPa, the reaction temperature was 25 C, and the reaction time was 2h. Analysis by gas chromatography showed that the conversion rate of <strong>[13031-04-4]ketopantolactone</strong> was 97.5% and that of D-pantolactone was 92.2%. | |
With hydrogen;[Rh(nbd)(CF3COO)]2; C52H64FeO6P2; In toluene; at 25℃; under 15001.5 Torr; for 14h;Product distribution / selectivity; | The hydrogenations are carried out in 1.2 ml vials. Stirring is effected by intensive shaking.Solutions having a volume of about 0.5 ml and the compositions shown in Table 1 are prepared in the 1.2 ml vials under a nitrogen atmosphere in a glove box. The catalysts are prepared "in situ" by mixing 1 equivalent of the metal precursor with 1.3 equivalents of ligand in dichloroethane and subsequently distilling off the dichloro- ethane under reduced pressure. The substrate is dissolved in the hydrogenation solvent and added as a solution to the catalyst. These vials are fixed in a pressure- rated, heatable vessel, the vessel is closed, the desired temperature is set, the nitrogen atmosphere in the vessel is replaced by hydrogen under the desired pressure and the hydrogenation is started by switching on the shaker. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In methanol at 40℃; for 10h; | |
21% | Stage #1: β-alaninamide With potassium carbonate In ethanol at 25℃; for 0.5h; Stage #2: (R)-Pantolacton In ethanol at 80℃; for 10h; Inert atmosphere; | 97.1 Step 1: To a mixture of 3-aminopropanamide (4.79 g) in EtOH (100 mL) was added K2003 (10.62 g). The mixture was stirred at 25 00 for 30 mm and then (3R)-3-hydroxy-4,4-dimethyl-tetrahydrofuran-2-one (5 g) was added. The mixture was degassed and purged with N2 three times, and then stirred at 80°C for10 hours under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by column chromatography (5i02, ethyl acetate / methanol, 1:0 to 5:1) to give (2R)-N-(3-amino-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butanamide (1 .8 g, 21%) as a yellow oil. LOMS: 219.2 (M÷Hj |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; | |
99% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 3h; | |
97% | With 1H-imidazole In tetrahydrofuran at 20℃; for 24h; |
96% | With 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene on polystyrene.HL In dichloromethane at 20℃; for 10h; | |
95% | With dmap; triethylamine In dichloromethane for 24h; Ambient temperature; | |
95% | With dmap; triethylamine In dichloromethane | |
95% | With 1H-imidazole In N,N-dimethyl-formamide for 1h; Ambient temperature; | |
With 1H-imidazole | ||
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12h; | |
72% | With dmap; dicyclohexyl-carbodiimide In dichloromethane for 24h; Ambient temperature; | |
72% | With dmap; dicyclohexyl-carbodiimide In dichloromethane |
72% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dmap; 2`,3`-dideoxycytidine In dichloromethane for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine In dichloromethane at -78 - 23℃; for 3.5h; Inert atmosphere; | |
98% | With pyridine In dichloromethane at 20℃; for 19.0667h; Inert atmosphere; Cooling with acetone-dry ice; | A A. (R)-4,4-Dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate Pyridine (2.8 mL, 34.6 mmol) was added to (R)-pantolactone (3.507 g, 26.9 mmol) in dichloromethane (27 mL) under nitrogen and the reaction mixture was cooled in a dry ice /acetone bath. Then, trifluoromethanesulfonic anhydride (5 mL, 29.7 mmol) was added over ~4 minutes. After two hours, the reaction mixture was allowed to warm to room temperature and stirred for seventeen hours. The reaction mixture was diluted with dichloromethane (50 mL), washed with 10% aqueous citric acid solution (25 mL, 2X) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated. Diethyl ether was added and the mixture was reconcentrated to give (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (6.905 g, 26.3 mmol, 98 % yield) as a yellow-orange liquid. 1H NMR (400 MHz, CD3SOCD3) δ 1 .06 (s, 3 H), 1 .19 (s, 3 H), 4.19 (q, J = 9 Hz, 2 H), 5.95 (s, 1 H); LC-MS (LC-ES) M+H = 263. |
96% | In pyridine; dichloromethane at -78 - 20℃; for 1.16667h; Inert atmosphere; |
93% | With pyridine at 0 - 20℃; for 0.166667h; | |
92% | With pyridine In dichloromethane 1.) -78 deg C, 20 min, 2.) RT, 1 h; | |
65% | With 2,6-dimethylpyridine In dichloromethane at -78 - 20℃; for 2.5h; Inert atmosphere; | (3R)-4,4-Dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (8). To a solution of D-(-)-pantolactone (0.24 g, 1.84 mmol) in anhydrous CH2Cl2 (8 ml) under argon atmosphere at -20 oC was added 2.6-lutidine (0.54 ml, 4.61 mmol) then at -78 oC (0.72 ml, 4.29 mmol) of Tf2O. The reaction mixture was stirred at -78 oC for 30 minutes, then warmed to room temperature and stirred for 2 hours. The reaction mixture wasdiluted with CH2Cl2 and washed with H2O (3-5 ml). The organic layers were dried over MgSO4, filtered, and thesolvent was distilled off in vacuo. After purification of the residue by column chromatography on SiO2 (petroleum ether-ethyl acetate, 7:1 → 4:1), triflate 814 (0.32 g, 65%) was obtained. White solid, Mp 29-30 oC,20. [ α]D +4.0o (c 1.0, MeOH) (lit.14 Mp 29-30 oC, 20. [ ]D +3.8o (c 1.0, MeOH)). 1H NMR (500 MHz, Acetone-d6): δH 1.20(s, 3H, CH3), 1.36 (s, 3H, CH3), 4.26 (d, J 9.0 Hz, 1H, H5A), 4.31 (d, J 9.0 Hz, 1H, H5B), 5.73 (s, 1H, H3). 13C NMR (125MHz, Acetone-d6): δC 19.83 (CH3), 21.70 (CH3), 41.43 (C4), 76.31 (C5), 87.89 (C3), 119.47 (q, 1JCF 319 Hz, CF3),169.95 (C=O). IR, υ, cm-1: 1792, 1419, 1248, 1362, 1208, 1139, 1034, 996, 868. |
With pyridine at 0℃; for 2h; | ||
With pyridine In dichloromethane at -20℃; for 1h; | ||
10 g | With pyridine In dichloromethane at -78 - 20℃; for 1.5h; | N.110.a Example N-110, Step a Example N-110 Example N-110, Step a To a solution of (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (5 g) in DCM (5 mL) was added pyridine (3.73 mL). The reaction mixture was cooled to -78° C., and triflic anhydride (7.07 mL, 41.9 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for 30 min and warmed to rt and stirred for 1 hr. The reaction was diluted with EtOAc, washed with water, sat. NaHCO3, water, citric acid, water, and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yltrifluoromethanesulfonate (10 g) as a clear oil. LC/MS (Cond. N-1): [M+H]+ 263.17, RT=3.235 min. 1H NMR (400 MHz, CHLOROFORM-d) ppm 5.09 (1H, s), 4.04-4.20 (2H, m), 1.32 (3H, s), 1.23 (3H, s). |
10 g | With pyridine In dichloromethane at -78 - 20℃; for 1.5h; | N-110.a EXAMPLE N-110 RRN 200Step a [0525] (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (5 g) in DCM (5 mL) was added pyridine (3.73 mL). The reaction mixture was cooled to -78° C., and triflic anhydride (7.07 mL, 41.9 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for 30 min and warmed to rt and stirred for 1 hr. The reaction was diluted with EtOAc, washed with water, sat. NaHCO3, water, citric acid, water, and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (10 g) as a clear oil. LC/MS (Cond. N-1): [M+H]+ 263.17, RT=3.235 min. 1H NMR (400 MHz, CHLOROFORM-d) ppm 5.09 (1H, s), 4.04-4.20 (2H, m), 1.32 (3H, s), 1.23 (3H, s). |
10 g | With pyridine In dichloromethane at -78 - 20℃; for 1.5h; | N-110.a To a solution of (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (5 g) in DCM (5 mL) was added pyridine (3.73 mL). The reaction mixture was cooled to - 78 °C, and triflic anhydride (7.07 mL, 41.9 mmol) was added drop wise. The reaction mixture was stirred at - 78 °C for 30 min and warmed to rt and stirred for 1 hr. The reaction was diluted with EtOAc, washed with water, sat. aHC03, water, citric acid, water, and sat. NaCl, dried over anhydrous Na2S04, filtered and concentrated to yield (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (10 g) as a clear oil. LC/MS (Cond. N-l): [M+H]+263.17, RT = 3.235 min. NMR (400 MHz,CHLOROFORM-if) ppm 5.09 (1 H, s), 4.04 - 4.20 (2 H, m), 1.32 (3 H, s), 1.23 (3 H, s). |
With pyridine In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With trifluoroacetic acid In dichloromethane at 20℃; for 15h; | |
83% | With trifluorormethanesulfonic acid In hexane; dichloromethane for 1h; | |
With trifluorormethanesulfonic acid In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 40℃; for 20h; | |
95% | With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 0℃; for 24h; Reflux; | |
90% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 48h; Inert atmosphere; |
89% | With sodium hydride In tetrahydrofuran for 1h; Ambient temperature; | |
75% | With lithium diisopropyl amide In dichloromethane Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrogenchloride; triethylamine In dichloromethane | 7.1 Step 1 Step 1 To a mixture of 46.8 g (360 mmol) of (R)-(-)-pantoyllactone, 54.7 g (541 mmol) of triethylamine and 300 ml of methylene chloride, 41.2 g (455 mmol) of acryloyl chloride was added dropwise at -25° C., and the mixture was stirred at -20° to -25° C. for five hours. On ice cooling, 500 ml of 0.5N hydrochloric acid was added to the reaction mixture to separate an organic layer, and an aqueous layer was extracted with methylene chloride (150 ml*3). Organic layers were combined and washed with successive, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution (each 250 ml). The solution was dried over magnesium sulfate and filtered, and the solvent was distilled off to obtain 64.5 g of crude acrylic acid ester. The product was purified by silica gel column chromatography (hexane-ethyl acetate 3:1), and 61.3 g (333 mmol) of (R)-dihydro-3-propenoyloxy-4,4-dimethyl-2(3H)-furanone was obtained. Yield: 93%. The compound was identified by 1 H-NMR chart analysis. The data of 1 H-NMR (CDCl3) are shown in the following. 1 H-NMR: δ1.1 (s, 3H), 1.3 (s, 3H), 4.0 (s, 2H), 5.5 (s, 1H), 5.9-6.7 (m, 3H). |
88% | With triethylamine In dichloromethane at -24℃; for 4.5h; | |
82% | With triethylamine In dichloromethane at -24℃; for 4.5h; |
74% | With triethylamine In dichloromethane at -24℃; for 5h; | |
57% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -10℃; for 2h; | |
375 mg | With triethylamine In dichloromethane at -24℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In dichloromethane for 12h; | (3R)-4,4-Dimethyl-2-oxotetrahydrofuran-3-yl methanesulfonate (5). To a solution of D-(-)-pantolactone (1.0 g,7.68 mmol) in anhydrous CH2Cl2 (15 ml) was added Et3N (1.59 ml, 11.53 mmol), then MsCl (0.83 ml, 10.76 mmol).The reaction mixture was stirred for 12 h, then washed with H2O (2×10 ml). The combined organic layers weredried over MgSO4, filtered, and the solvent was removed under reduced pressure. After purification of theresidue by column chromatography on SiO2 (petroleum ether-ethyl acetate, 9:1 → 4:1) mesylate 5 was obtainedin 91% (1.45 g) yield as a white solid. Mp 54-55 oC, [α ]D+16o (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): δH 1.17(s, 3H, CH3), 1.27 (s, 3H, CH3), 3.28 (s, 3H, CH3), 4.05 (d, J 9.1 Hz, 1H, H5A), 4.10 (d, J 9.1 Hz, 1H, H5B), 4.99 (s, 1H,H3). 13C NMR (125 MHz, CDCl3): δC 19.56 (CH3), 22.18 (CH3), 39.74 (CH3), 40.31 (C4), 76.24 (C5), 81.41 (C3), 171.37(C=O). IR (vmax, cm-1): 1781, 1480, 1350, 1183, 1070, 979, 852. Anal. calcd for C7H12O5S (208.23): C, 40.38; H,5.81; S, 15.40. Found: C, 40.49; H, 5.70; S, 15.51. |
88% | With pyridine at 0 - 20℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With ammonia Inert atmosphere; | |
99% | With ammonia In methanol at 20℃; for 24h; | |
95% | at 20 - 60℃; for 6h; |
91% | With ammonia at -60 - 20℃; | |
86% | In dichloromethane; water at 10℃; for 3h; | D-Pantoic acid amide (2, D-2,4-dihydroxy-3,3-dimethylbutanamide). Gaseous ammonia was passed over a period of 3 h through a mixture of 240 mL of methylene chloride, 120 g of D-(-)-pantolactone, and 4 mL of water under stirring at 10°C. Large colorless crystals separated from the mixture during the subsequent 24 h. Yield 81-86%, mp 98°C. IR spectrum, ν, cm-1: 3476-3194 (NH, OH), 2976, 2967,2937, 2924, 2880, 2851 (C-H), 1684 (C=O). 1H NMR spectrum (400 MHz, acetone-d6), δ, ppm: 0.89 s (3H,CH3), 0.95 s (3H, CH3), 3.41 d.d (2H, CH2, 2J =10.9 Hz), 3.91 br.s (1H, CH), 6.77 br.s (2H, NH2), 7.06br.s (~1.2H, OH, partially exchangeable). Found, %:C49.30; H 8.51; N 9.09. C6H13NO3. Calculated, %: C48.97; H 8.90; N 9.52. |
With ammonia at 0℃; for 14h; | 1 0124] Step-1: Synthesis of Compound 2: [0125] To the compound 1 was added neat liquid ammonia and stirred the reaction mixture at 0° C. for 14 h. TLC indicated complete conversion of starting material. Then the liquid ammonia was evaporated and the crude intermediate 2 was used for next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; triethylamine In dichloromethane at 0℃; for 0.5h; | |
90.59% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 55℃; | |
37% | In ethanol at 120℃; for 2h; Microwave irradiation; | G General procedure G: Pantolactone opening General procedure: General procedure G: Pantolactone openingA microwave vial was charged with compound of Formulae (Vb) (1 eq), D or L- pantolactone (1.5 eq) and EtOH (20 vol) and heated at 120°C under microwave radiations for 2 h. After completion of the reaction the solvent was removed under reduced pressure and purified by silica gel column chromatography to get the title compound. |
at 55℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With silver(l) oxide In acetonitrile at 58℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With silver(l) oxide In N,N-dimethyl-formamide at 0 - 20℃; for 72h; Darkness; | 22.1 Step 1: (R)-3-(Benzyloxy)-4,4-dimethyldihydrofiiran-2(3H)-one Benzyl bromide (5 mL, 42 mmol, 1.1 eq) was added over 5 mins at 0 °C to a mixture of D- pantolactone (5 g, 38 mmol, 1 eq) and silver oxide (13 g, 58 mmol, 1.5 eq) in DMF (25 mL). The flask was protected from light with aluminium foil and the reaction mixture was stirred for 3 days atRT. A TLC (25% AcOEt in heptanes) showed full conversion. The reaction mixture was diluted with AcOEt and was filtered through a pad of Celite. The solids were washed with AcOEt until no product could be detected in the filtrate by TLC. TBME was added to the filtrate and the latter was washed with brine (2x) and water (l x). The organic layer was dried over sodium sulfate, filtered and concentrated to dryness. The crude oil was purified by ISCO and (A)-3-(benzyloxy)-4,4- dimethyldihydrofuran |
87% | With silver(l) oxide In N,N-dimethyl-formamide at 0 - 20℃; for 22h; Inert atmosphere; | |
86% | With silver(l) oxide In N,N-dimethyl-formamide at 0 - 20℃; for 22h; |
83% | With silver(l) oxide In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With phosphomolybdic acid hydrate; silica gel In tetrahydrofuran at 20℃; for 12h; | |
84% | With iron(III) p-toluenesulfonate hexahydrate In methanol for 27.5833h; Reflux; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine In dichloromethane at -20 - 23℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine In ethanol at 160℃; for 0.5h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine In dichloromethane at 20℃; for 2h; | Compound 7a; TEA ("triethylamine") (4.3 mL, 30.6 mmol) was added to a solution of (R)- (-)-Pantolactone (1.991 g, 15.3 mmol), purchased from Aldrich, and bis(4- nitrophenyl)carbonate in DCM (77 mL) and the reaction was stirred at r.t. for 2h. The reaction mixture was concentrated and then diluted with ethyl acetate, washed four times with an aqueous NaOH solution (IN), once with a solution of saturated NaHCO3, and once with brine before it was dried over Na2SO4 and concentrated. The crude residue was purified using silica gel chromatography (10-30 % ethyl acetate in hexane) to give Compound 7a (3.83 g, 12.4 mmol, 81%). Mass spectrum: (M+H)+ = 310.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.4% | In dichloromethane at 20℃; for 2.25h; | 9.ad ad) Transacetalisation if (R)-(-)-pantolactone with methyl-2,3-dideoxy-4,6-O- methylene-c D-erythro-hex-2-enopyranoside with BF3. Et0 as a Lewis-acid catalyst; R- (-)-Pantolactone (0.95 g, 7.30 mmol) and methyl-2,3-dideoxy-4, 6-O-methylene-a-D- erythro-hex-2-enopyranoside (0.527 g, 3.07 mmol) were dissolved in anhydrous dichloromethane (20 mL). BF3. Et2O (10 pL) was added to this mixture at room temperature. Since after 90 minutes no reaction had taken place, another aliquot of BF3. Et20 (300 uL, 2.37 mmol) was added and the reaction mixture stirred for 45 minutes at room temperature. The solution went dark. The reaction mixture was quenched with solid sodium hydrogencarbonate (5.0 g, 59.5 mmol) and in intervals a total of 50 mL water was added. This mixture was stirred for 30 minutes at room temperature and more dichloromethane (25 mL) was added to facilitate extraction. The extract was dried (Na2S04) and the solvents removed by rotary evaporation to give a crude brownish product. This residue was chromatographed on silica gel the a-adduct (0.285 g, 36.4%), (see figure 2) IH-NMR (CDCl3, 200 MHz): 5=6. 107 (d, J=10. 3 Hz, 1H), 5. 836 (ddd, J=10. 3,2. 4,2. 4 Hz, 1H), 5.434 (dd, J=0. 9,0. 9Hz, 1H), 5.059 (d, J=6. 2 Hz, 1H), 4.678 (d, J=6. 2 Hz, 1H), 4. 148 (s, 1H), 4. 108 (dd, J=9. 8,4. 2 Hz, 1H), 4.020 (d, J=8. 8 Hz, 1H), 3.924 (d, J=8. 8 Hz, 1H), 3.899 (dm, J=9. 8 Hz, 1H), 3.751 (ddd, J=10. 1,10. 1,4. 3 Hz, 1H), 3.549 (dd, J=10. 1,10. 1 Hz, 1H), 1.189 (s, 3H), 1.102 (s, 3H). 13C (CDC13, 50 MHz): 8=175. 06 (C=O), 130.73, 126.33 (2x-CH=), 94.02 (O-CH2-O), 93.76 (a-O-CH-O), 78. 50 (CH-O), 76.25 (CH2), 74.99 (O-CH-), 69.01 (-CH20-), 64.34 (O-CH-), 39.96 (C), 22.79, 19.51 (2x CH3). Added note: The most visible, distinguishable change in 1H-NMR with either the addition or the so-called back-reaction of pantolactone are the methyl-groups which in pantolactone are wider spaced at 8=1. 235 and 1.080 (A=0. 155) vs with the adducts 5=1. 189 and 1.102 (A=0. 087) [CDCl3] ; The methylene-protons or methine-proton are not as dramatic in chemical shift : 1H-NMR (CDCl3, 200 MHz): 8=4. 109 (s, 1H), 4.031 (d, J=9. 0 Hz, 1H), 3. 938 (d, J=9. 0 Hz, 1H), 2.3 (OH), 1.235 (s, 3H), 1.080 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 120 - 150℃; for 2h; | 11.A Reference 1 1; Synthesis of (Λ)-2-hydroxy-3,3-dimethyl-4-(naphthalen-2-ylsulfonyl)butanoic acid; Step A: Synthesis of (i?)-2-hydroxy-3,3-dimethyl-4-(naphthalen-2-ylthio)butanoic acid; A mixture of naphthalene-2-thiol (1.3828 g, 8.6 mmol), (/?)-3-hydroxy-4,4-dimethyl- dihydrofuran-2(3H)-one (1.0199 g, 7.8 mmol) and potassium carbonate (2.3851 g, 17 mmol) in DMF (10.0 mL) was stirred under microwave at 120 0C for 1 h, and then at 150 °C for 1 h. To the reaction mixture was added IN HCl aq. (200 mL) and the product was extracted with AcOEt (100 mL x 2). The combined organic phase was washed with IN HCl aq. (200 mL) EPO and sat'cLNaCl. The solvent was removed under reduced pressure and chromatographed on silica (Et2θ -> Et2θ/AcOH = 50/1). The semi- purified product was re-chromatographed on silica (CH2CI2 "^ CH2Cl2/MeOH/AcOH =100/5/2) to yield the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol;Product distribution / selectivity; | 100 g of the dried methanolic Na-beta-Ala solution (321.8 mmole) were reacted with 41.9 g (321.8 mmole) of R-pantolactone to obtain a solution of Na-D-pantothenate.The work-up including an ion-exchange from sodium to calcium was carried out according to methods known to a person skilled in the art.Calpan product: 79.64 g, 163.93 mmole. Yield: 93.6 %.Analysis:Calcium pantothenate 98.09 w/w%Calcium pantoate 0.59 w/w%Calcium pant-beta-Ala-beta-Ala 0.02 w/w%Water ad lthetatheta w/w%; Preparation of C alpan100 g of the dried methanolic Na-beta-Ala solution (323.4 mmole) were reacted with 42.1 g (323.4 mmole) of R-pantolactone to obtain a solution of Na-D-pantothenate.The work-up including an ion-exchange from sodium to calcium was carried out according to methods known to a person skilled in the art.Calpan product: 76.78 g, 160.68 mmole. Yield: 92.9 %Analysis:Calcium pantothenate 99.73 w/w%Calcium pantoate 0.25 w/w%Calcium pant-beta-Ala-beta-Ala 0.08 w/w%Water ad lthetatheta w/w%; Preparation of Calpan100 g of the dried methanolic Na-beta-Ala solution (303.3 mmole) were reacted with 39.5 g (303.3 mmole) of R-pantolactone to obtain a solution of Na-D-pantothenate.The work-up including an ion-exchange from sodium to calcium was carried out according to methods known to a person skilled in the art.Calpan product: 79.19 g, 160.06 mmole. Yield: 94.3 %Analysis:Calcium pantothenate 96.32 w/w%Calcium pantoate 0.14 w/w%Calcium pant-beta-Ala-beta- Ala 0.16 w/w% (significantly higher than in Ex. 4 and 5)Water ad lthetatheta w/w%; Preparation of Calpan110.5 g of the dried methanolic Na-beta-Ala solution (237.4 mmole) were reacted with 31.2 g (237.3 mmole) of R-pantolactone to obtain a solution of Na-D-pantothenate.The work-up including an ion-exchange from sodium to calcium was carried out according to methods known to a person skilled in the art. <n="15"/>Calpan product: 56.71 g, 110.00 mmole,. Yield: 83.2 %Analysis:Calcium pantothenate 92.72 w/w%Calcium pantoate 3.06 w/w% (significantly higher than in Ex. 4, 5, 7) Calcium pant-beta-Ala-beta-Ala 0.19 w/w% (significantly higher than in Ex. 4 and 5) Water ad lthetatheta w/w% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In methanol; water at 25℃; for 3h; Inert atmosphere; | |
97% | In methanol at 20℃; for 3h; Inert atmosphere; | (R)-2,4-Dihydroxy-N-3,3-trimethylbutanamide (40)S9 To a solution of D-pantolactone (2.00 g, 15.3 mmol) in MeOH (6 mL) was added N-methylamine (40% aqueoussolution, 1.6 mL, 20.6 mmol). The reaction was stirred at RT for 3 h. The reaction was concentrated in vacuo togive 40 (2.40, 97%) as a colourless oil; Rf 0.45 (5% MeOH/CH2Cl2); [α]D20 +49.6 (c 1.0, MeOH); 1H NMR (600 MHz,CDCl3) δ 7.04 (1H, d, J = 4.5 Hz, NH), 4.73 (1H, br, OH), 4.00 (1H, s, H5), 3.50 - 3.43 (2H, m, H2), 2.81 (3H, d, J= 4.5 Hz, H8), 0.96 (3H, s, H4) and 0.89 (3H, s, H4); 13C NMR (150 MHz, CDCl3) δ 177.8 (C6), 75.8 (C5), 71.1(C2), 39.4 (C3), 25.4 (C8), 21.2 (C4) and 20.5 (C4); HRMS calc’d for C7H16NO3 expected 162.1130, found162.1133. The data is in good agreement with the literature values.S9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine In dichloromethane at 20℃; | 4.1. General procedure for the preparation of α-halo ester 1 General procedure: A chiral alcohol (1.0 equiv) was treated with racemic α-bromo carboxylic acid (1.0 equiv), DCC, and DMAP (or α-chloro acid chloride and Et3N) in CH2Cl2 and stirred at room temperature for 3-10 h. The precipitate was filtered off and the organic phase was washed with water. The organic phase was dried over MgSO4, filtered, and concentrated to provide the crude product that was purified by column chromatography on silica gel. α-Halo esters 1b-d, 1j-m, and 1n were prepared by previously reported procedure in Refs. [4], [5], [7] and [8]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine In dichloromethane at 20℃; | 4.1. General procedure for the preparation of α-halo ester 1 General procedure: A chiral alcohol (1.0 equiv) was treated with racemic α-bromo carboxylic acid (1.0 equiv), DCC, and DMAP (or α-chloro acid chloride and Et3N) in CH2Cl2 and stirred at room temperature for 3-10 h. The precipitate was filtered off and the organic phase was washed with water. The organic phase was dried over MgSO4, filtered, and concentrated to provide the crude product that was purified by column chromatography on silica gel. α-Halo esters 1b-d, 1j-m, and 1n were prepared by previously reported procedure in Refs. [4], [5], [7] and [8]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; dicyclohexyl-carbodiimide In dichloromethane for 3h; | 64a N,N'-Dicyclohexylcarbodiimide (1.8 g, 8.6 mmol) is added to a stirred solution of alpha- Bromo-4-Fluorophenylacetic acid (2.0 g, 8.6 mmol), D-(-)-Pantolactone (1.1 g, 8.6 mmol) and 4-Dimethylaminopyridine (100 mg, 0.8 mmol) in DCM and the reaction mixture is stirred 3 hours. The precipitate is filtered out and the filtrate is concentrated under reduced pressure; the residue is purified by Silica gel flash chromatography, using Hexane/EtOAc 8:2 as eluent, to obtain the title compound (2.6 g, 86% yield). UPLC-MS (Method 1): Rt = 1.34 min MS (ES+): m/z = 345-347 [M+H]+ . |
51% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 4.1. General procedure for the preparation of α-halo ester 1 General procedure: A chiral alcohol (1.0 equiv) was treated with racemic α-bromo carboxylic acid (1.0 equiv), DCC, and DMAP (or α-chloro acid chloride and Et3N) in CH2Cl2 and stirred at room temperature for 3-10 h. The precipitate was filtered off and the organic phase was washed with water. The organic phase was dried over MgSO4, filtered, and concentrated to provide the crude product that was purified by column chromatography on silica gel. α-Halo esters 1b-d, 1j-m, and 1n were prepared by previously reported procedure in Refs. [4], [5], [7] and [8]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With triethylamine In dichloromethane at 20℃; | 4.1. General procedure for the preparation of α-halo ester 1 General procedure: A chiral alcohol (1.0 equiv) was treated with racemic α-bromo carboxylic acid (1.0 equiv), DCC, and DMAP (or α-chloro acid chloride and Et3N) in CH2Cl2 and stirred at room temperature for 3-10 h. The precipitate was filtered off and the organic phase was washed with water. The organic phase was dried over MgSO4, filtered, and concentrated to provide the crude product that was purified by column chromatography on silica gel. α-Halo esters 1b-d, 1j-m, and 1n were prepared by previously reported procedure in Refs. [4], [5], [7] and [8]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In dichloromethane at 20℃; | 4.1. General procedure for the preparation of α-halo ester 1 General procedure: A chiral alcohol (1.0 equiv) was treated with racemic α-bromo carboxylic acid (1.0 equiv), DCC, and DMAP (or α-chloro acid chloride and Et3N) in CH2Cl2 and stirred at room temperature for 3-10 h. The precipitate was filtered off and the organic phase was washed with water. The organic phase was dried over MgSO4, filtered, and concentrated to provide the crude product that was purified by column chromatography on silica gel. α-Halo esters 1b-d, 1j-m, and 1n were prepared by previously reported procedure in Refs. [4], [5], [7] and [8]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium tetrahydroborate In methanol at 0℃; | |
93% | With sodium cyanoborohydride In methanol Cooling with ice; | 8-10 Dissolve (R)-P-1 (317.8mg, 1.8mmol) with an optical purity of 99%ee in 5mL methanol, place the reaction flask in an ice water bath, and slowly add to the reaction solution in batches under stirring Sodium cyanoborohydride (137.6mg, 2.19mmol), continue to stir until the reaction is over, slowly quench the reaction with 5% dilute hydrochloric acid, extract three times with ethyl acetate, combine the ethyl acetate phases, wash with a small amount of saturated brine, no After drying with sodium sulfate and concentration under reduced pressure, it was quickly purified by silica gel column chromatography to obtain 218 mg of (R)-pantoic acid lactone with a yield of 93% and 99% ee. |
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / diethyl ether / 20 °C 1.2: Saturated solution 2.1: toluene-4-sulfonic acid / diethyl ether / 20 °C |
With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; (R)-N-(2-hydroxyethyl)pyrrolidine-2-carboxamide; sodium formate In water; <i>tert</i>-butyl alcohol at 40℃; for 1h; Inert atmosphere; | 3a-3f General procedure for transfer hydrogenation ethyl (R)-2-hvdroxy-3,3-dimethyl-4-ox- obutanoate to yield (R)-2-hvdroxy-3,3-dimethyl-Y-butyrolactone General procedure: The preformed transition metal catalyst or the transition metal salt and the ligand were added to a solution of ethyl (R)-2-hydroxy-3,3-dimethyl-4-oxobutanoate (from exam ple 2) in watertert-butanol (2:1). The mixture was degassed, sodium formate (5 eq.) was added and the mixture was stirred at the desired temperature for the stated time. The reaction mixture extracted with MTBE or dichloromethane and the combined or ganic phases were dried, filtered and concentrated in vacuo |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | In diphenylether at 130 - 220℃; for 24h; | 3 Procedure II - (One pot synthesis): (R,Z)-alyl 3-(2,4-di hyd roxy-3, 3- dimethylbutanarnido)acrylate (4) (Scheme 4) A mixture 'of amine 2 (250 mg, 1.3 mmol) and D (-) - pantolactone (340 mg, 2.6 mmol) in diphenyl ether (15 mL) were heated to 130°C for 24 h and the progress of the reaction was monitored through .TLC. After considerable amount of pantolactone was consumed with no in the reaction, the temperature of the reaction mixture was further raised to 220°C for 20 min. After the completion of reaction (TLC monitoring), the crude reaction mixture was cooled to room temperature 27°C and purified by silica gel column chromatography eluting with methanol : DC (3 : 97) to yield 202 mg (61%) of 4 as a brown colored mass. |
61% | In diphenylether at 130 - 220℃; for 24.3333h; | 3.II 10045] Procedure II (One pot synthesis): (R,Z)-allyl 3-(2, 4-dihydroxy-3,3-dimethylbutanamido)acrylate (4) (Scheme4) 10045] Procedure II (One pot synthesis): (R,Z)-allyl 3-(2, 4-dihydroxy-3,3-dimethylbutanamido)acrylate (4) (Scheme4)10046] A mixture of amine 2 (250 mg, 1.3 mmol) and D(-)-pantolactone (340 mg, 2.6 mmol) in diphenyl ether (15 mE) were heated to 130° C. for 24 hand the progress of the reaction was monitored through TEC. Afier considerable amount of pantolactone was consumed with no further improvement in the reaction, the temperature of the reaction mixture was further raised to 220° C. for 20 mi Afier the completion of reaction (TEC monitoring), the crude reaction mixture was cooled to room temperature 27° C. and purified by silica gel column chromatography eluting with methanol:DCM (3:97) to yield 202 mg (61%) of 4 as a brown colored mass. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With camphor-10-sulfonic acid In dichloromethane at 23℃; for 24h; Reflux; | 1.15 4.1.15 (4R)-5,5-Dimethyl-4-hydroxymethyl-2-phenyl-1,3-dioxane (22) To a mixture of 21 32 (371 mg, 2.77 mmol, 1.0 equiv) and benzaldehyde dimethyl acetal (548 mg, 3.04 mmol, 1.1 equiv) in CH2Cl2 (300 mL) was added camphorsulfonic acid (50 mg, 0.28 mmol, 0.1 equiv) at 23 °C. The reaction mixture was refluxed for 24 h, then saturated NaHCO3 aqueous solution was added to adjust the pH to 7. The mixture was extracted with EtOAc, and the combined organic extracts were washed with saturated aqueous NaCl, dried (NaSO4), and concentrated. Purification by flash chromatography (6:1 petroleum ether-EtOAc) afforded the title compound (500 mg, 85%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 6.8 Hz, 2H), 7.43-7.33 (m, 3H), 5.51 (s, 1H), 3.69-3.60 (m, 5H), 1.14 (s, 3H), 0.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.4, 129.2, 128.4, 126.4, 102.2, 86.0, 79.0, 61.6, 31.7, 21.5, 19.3; MS (ESI+) calcd for C13H19O3 [M+H]+ 223.1, found 223.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydrogencarbonate In dichloromethane at 85℃; for 48h; | 4.1 tert-butyl(R)-3 -(2,4-dihydroxy-3 ,3 -dimethylbutanamido)propanoate 3-(tert-butoxy)-3- xopropan-l-aminium chloride (1.0 eq) was treated with a saturated aqueous solution, of NaHC03 and extracted with DCM. The combined organic extracts were dried over MgS04, and then the solvent was evaporated under reduced pressure to afford the free amino acid. This compound was treated with (3R)- 4,4-dimethyl-3-oxidanyl-oxolan-2-one (1.0 eq) and heated with stirring at 85 °C. This mixture melted giving a pale yellow oil that after 48 h was cooled and taken up in the minimum amount of DCM and purified by flash chromatography column on Si02 using Petroleum Ether / EtOAc as eluent to furnish the title compound (88%) as a colorless oil. 1H-NMR (400 MHz, CDC13, 300 K) δ 7.18 (bs, 1H), 4.03 (s, 1H), 3.60-3.49 (m, 4H), 2.51-2.48 (t, J = 5.8 Hz, 2H), 1.47 (s, 9H), 1.04 (s, 3H), 0.93 (s, 3H). UPLC tR 1.17 min; MS (ES4) m/z 276 [M+Hj+. |
84.5% | With triethylamine In 1,4-dioxane at 65℃; for 72h; | 1.3; 2.3; 3.3 Synthesis of Compound-3 [0112] (D)-(-)-pantolactone (25.0 g, 192.30 mmol), β-alanine tert-butyl ester HCl (25.0 g, 137.66 mmol) and Et3N (22.0 mL, 168.0 mmol) in dioxane (250 mL) was heated at 65° C. for 3 days. The reaction mixture was cooled to RT, filtered the salt, filtrate was evaporated in vacuo and purified by column chromatography to afford compound 3 (32.0 g, 116.0 mmol) as light yellow syrup. Rf: 0.3 (80% EtOAc/Hexane); LCMS (M+H): 276.2; Yield: 84.5% |
84.5% | With triethylamine In 1,4-dioxane at 65℃; for 72h; | 1 Synthesis of compound - 3 A solution of (D)-(-)-pantolactone (25.0 g, 192.30 mmol), β-alanine tert -butyl ester HC1 (25.0 g, 137.66 mmol) and Et3N (22.0 mL, 168.0 mmol) in dioxane (250 mL) was heated at 65 °C for 3 days. The reaction mixture was cooled to RT, filtered the salt, filtrate was evaporated in vacuo and purified by column chromatography to afford compound 3 (32.0 g, 116.0 mmol) as light yellow syrup. Rf: 0.3 (80% EtOAc/Hexane); LCMS (M+H): 276.2; Yield: 84.5%. |
84.5% | With triethylamine In 1,4-dioxane at 65℃; for 72h; | 3 Synthesis of compound - 3: A solution of (D)-(-)-pantolactone (25.0 g, 192.30 mmol), β-alanine tert -butyl ester HC1 (25.0 g, 137.66 mmol) and Et3N (22.0 mL, 168.0 mmol) in dioxane (250 mL) was heated at 65 °C for 3 days. The reaction mixture was cooled to RT, filtered the salt, filtrate was evaporated in vacuo and purified by column chromatography to afford compound 3 (32.0 g, 116.0 mmol) as light yellow syrup. Rf: 0.3 (80% EtOAc/Hexane); LCMS (M+H): 276.2; Yield: 84.5%. |
84.5% | With triethylamine In 1,4-dioxane at 65℃; for 72h; | 3 Synthesis of Compound-3: A solution of (D)-(-)-pantolactone (25.0 g, 192.30 mmol), f3-alanine tert-butyl ester HCl (25.0 g, 137.66 mmol) and Et3N (22.0 mL, 168.0 mmol) in dioxane (250 mL) was heated at 65° C. for 3 days. The reaction mixture was cooled to RT, filtered the salt, filtrate was evaporated in vacuo and purified by column chromatography to afford compound 3 (32.0 g, 116.0 mmol) as light yellow syrup. Rf: 0.3 (80% EtOAc/Hexane); LCMS (M+H): 276.2; Yield: 84.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid In dichloromethane at 20℃; for 19h; Inert atmosphere; | PMB-Protected (R)-Pantolactone 15 To a solution of (R)-pantolactone (13; 130.14 g/mol, 1.65 g, 12.68 mmol, 1.1 equiv) and 2-(4-methoxybenzyloxy)-3-nitropyridine18 (14; 260.25 g/mol, 3.06 g, 11.76 mmol, 1 equiv) in CH2Cl2 (80 mL) was added (+)-CSA (232.30 g/mol, 0.14 g, 0.60 mmol, 0.05 equiv) at r.t. After being stirred for 19 h, the orange reaction mixture was diluted with sat. aq NaHCO3 and the aqueous layer was extracted with CH2Cl2 (3 ×). The combined organic layers were dried (MgSO4) and concentrated. Purification of the residue by chromatography (cyclohexane-EtOAc, 50:1 to 10:1) delivered the title compound 15 (250.29 g/mol, 2.02 g, 8.07 mmol, 69% from 14) as a white solid; mp 69 °C; Rf = 0.46 (cyclohexane-EtOAc, 2:1); [α]D20 +94.8 (c 1.33, CHCl3) {Lit.16 [α]D20 +99.9 (c2.00, CHCl3)}. IR (KBr): 2965 (m), 2935 (m), 2840 (m), 1785 (s), 1610 (s), 1515 (s), 1465 (m), 1300 (w), 1250 (s), 1175 (m), 110 (s), 1035 (s), 1010 (m), 820 cm-1 (w). 1H NMR (400 MHz, CDCl3): δ = 1.07 (s, 3 H), 1.11 (s, 3 H), 3.71 (s, 1 H), 3.81 (s, 3 H), 3.85 (d, J = 8.8 Hz, 1 H), 3.99 (d, J = 8.8 Hz, 1 H), 4.69 (d, J = 11.8 Hz, 1 H), 4.95 (d, J = 11.8 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 2 H),7.31 (d, J = 8.8 Hz, 2 H). 13C NMR (101 MHz, CDCl3): δ = 19.4, 22.4, 40.4, 55.4, 72.1 (CH2), 76.5 (CH2), 80.0, 113.9, 129.4, 129.9, 159.6, 175.6. Anal. Calcd for C14H18O4: C, 67.2; H, 7.3. Found: C, 67.3; H, 7.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With ammonium hydroxide; calcium(II) chloride at 28℃; for 8h; Microbiological reaction; Resolution of racemate; Enzymatic reaction; | |
26 % ee | With (S)-(–)-benzotetramisole; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78℃; for 94h; Molecular sieve; Resolution of racemate; enantioselective reaction; | |
40.98519 % ee | With missing linker defects in a Zn-terephthalato-L-lactato-DMF homochiral metal-organic framework (0.85LacDMF) In acetonitrile at 20℃; for 24h; Resolution of racemate; |
With CHIRALPAK IG In hexane; isopropanol at 25℃; Resolution of racemate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium chloride; calcium oxide;Milling; | 3-Aminopropionic acid (4.45 g, 0.05 mol), calcium oxide (1.68 g, 0.03 mol) were added to a 100 mL ball mill, Sodium chloride (12.26 g),Then add two iron balls with a diameter of 30 mm.Perform a mechanical ball mill for 30 min (frequency 30 Hz) The reaction mixture is reacted. to(6.50 g, 0.05 mol), sodium chloride (13 g), ball mill Rate 30 Hz, after 30 min, add the previous step after the ball mill solid powder. Ball mill frequency 30 Hz, time 30 min, take The reaction mixture was removed and the product was dissolved in methanol (85 mL), filtered and concentrated to crystallize. The product was filtered and dried to give a white powder Vitamin B5 (8.45 g, yield 71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.3 g | In ethanol; for 3.0h;Reflux; | 55.5 g of sodium beta-alaninate,Pantolactone 65 grams,Dissolved in 350 ml of absolute ethanol,Heated to reflux for 3 hours,Filtered while still hotThe reaction vessel was washed with 50 ml of ethanol,After the washing solution was filtered and the reaction mixture was combined,The filtrate was placed at 0 for 5 days,Filter, wash the solid with a little ethanol,Drying to constant weight at room temperature under reduced pressure,Got 76.3 grams of white crystalline powder,Which is the sodium D-pantothenate crystal described in GB565976. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Stage #1: glycine ethyl ester hydrochloride With diethylamine In methanol; dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: (R)-Pantolacton In methanol; dichloromethane at 60℃; for 20h; Inert atmosphere; | 1.3.17 Synthesis of compound 9a In a pressure vessel (20 mL), glycine methyl ester hydrochloride (4.60 mmol, 1.5 equiv.) and diethylamine (7.70 mmol, 2.5 equiv.) were dissolved in dry DCM (10 mL) and methanol (3 mL) and stirred at 0°C for 15 minutes. D-Pantolactone (3.1 mmol, 1.0 equiv.) was next added to the solution and the mixture was stirred at 60°C for 20 hours. The reaction mixture was next loaded directly on silica gel and purified with a gradient of 0-100% EtOAc in hexanes, followed by 0-50% MeOH in EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: methyl 3-aminopropanoate hydrochloride With diethylamine In methanol at 0℃; for 0.25h; Inert atmosphere; Stage #2: (R)-Pantolacton In methanol at 60℃; for 20h; Inert atmosphere; | 1.3.18 General protocol 5 for the synthesis of compounds 9b and 10 General procedure: In a pressure vessel (5 mL), the desired ester (1.08-1.69 mmol, 1.1 equiv.) and diethylamine (1.47-2.31 mmol, 1.5 equiv.) were dissolved in dry methanol (3 mL) and stirred at 0°C for 15 minutes. The desired lactone (0.98-1.54 mmol, 1.0 equiv.) was next added to the solution and the mixture was stirred at 60°C for 20 hours. The reaction mixture was next loaded directly on silica gel and the product was purified with a gradient of 0-100% EtOAc in hexanes, followed by 0-50% MeOH in EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: methyl 3-aminopropanoate hydrochloride With diethylamine In methanol at 0℃; for 0.25h; Inert atmosphere; Stage #2: (R)-Pantolacton In methanol at 60℃; for 20h; Inert atmosphere; | 1.3.18 General protocol 5 for the synthesis of compounds 9b and 10 General procedure: In a pressure vessel (5 mL), the desired ester (1.08-1.69 mmol, 1.1 equiv.) and diethylamine (1.47-2.31 mmol, 1.5 equiv.) were dissolved in dry methanol (3 mL) and stirred at 0°C for 15 minutes. The desired lactone (0.98-1.54 mmol, 1.0 equiv.) was next added to the solution and the mixture was stirred at 60°C for 20 hours. The reaction mixture was next loaded directly on silica gel and the product was purified with a gradient of 0-100% EtOAc in hexanes, followed by 0-50% MeOH in EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Stage #1: methyl γ-aminobutyrate hydrochloride With diethylamine In methanol; dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: (R)-Pantolacton In methanol; dichloromethane at 115℃; for 2h; Microwave irradiation; Inert atmosphere; | 1.3.19 Synthesis of compound 9c In a pressure vessel (20 mL), methyl aminobutyrate hydrochloride (4.60 mmol, 1.5 equiv.) and diethylamine (7.70 mmol, 2.5 equiv.) were dissolved in dry DCM (10 mL) and methanol (3 mL) and stirred at 0°C for 15 minutes. D-Pantolactone (3.1 mmol, 1.0 equiv.) was next added to the solution and the mixture was stirred at 115°C in a microwave reactor for 2 hours. The reaction mixture was then loaded directly on silica gel and purified with a gradient of 0-100% EtOAc in hexanes, followed by 0-50% MeOH in EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With diethylamine; In tetrahydrofuran; at 60℃; for 16h;Inert atmosphere; | In a pressure vessel (5 mL), -alanine benzyl ester 4-toluenesulfonate salt (1.42 mmol, 1.0 equiv.) and diethylamine (8.11 mmol, 5.7 equiv.) were dissolved in dry THF (2 mL). D-Pantolactone (3.33 mmol, 2.3 equiv.) was next added to the solution. The reaction mixture was stirred at 60C for 16 hours. The reaction mixture was next loaded directly onto silica gel and purified using a gradient of 0-100% EtOAc in hexanes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.7% | With hydrogenchloride In water at 20℃; for 0.5h; | 8.A; 8.B A: Dissolve 7.5 g of D-pantosodium salt in 10 ml of water, adjust the pH to 1-2 (including 2) with concentrated hydrochloric acid,stirat room temperaturefor 30 minutes, extract with ethyl acetate, and use anhydrous magnesium sulfate for the organic layer. After drying, filtration and distillation under reduced pressure to give a solvent,D-(-)-panic acid lactone 5.4 g, yield 94.7%, and an enantiomeric excess of 98.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | With hydrogenchloride In water at 20℃; for 0.5h; | 8.C; 8.D Or D: a D- pantoic acid potassium salt 15 g dissolved in 20 ml of water, concentrated hydrochloric acid was added to adjust the PH to 1-2 (including 2), oftenstirred temperature for 30 minutes, extracted with ethyl acetate, the organic layer was dried over anhydrous After drying over magnesium sulfate and distilling the solvent,11.1 g ofD-(-)-pantolactone was obtained, the yield was 96.9%, and the enantiomeric excess was 97.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.94% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). (R)-Acetic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (3a), pale yellow oil, yield: 94.94%, HPLC purity: 96.9% (tR=3.18 min), 1HNMR (400 MHz, DMSO-d6): 5.53 (s, 1H, CH), 4.11 (d, J=4.4 Hz, 1Ha,OCHaHb), 4.02 (d, J=4.4 Hz, 1Hb, OCHaHb), 2.13 (s, 3H, CH3), 1.09 (s,3H, CH3), 0.99 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): 173.17, 170.0 (C]O), 75.8, 75.2, 40.2, 22.3, 20.7, 20.0. HRMS (TOF-MS): Calcd for [C8H12O4+H]+ 173.0808, Found 173.0811. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.5% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.5% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.1% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.69% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.66% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.94% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.51% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.86% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.12% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.28% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.19% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.21% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.83% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.03% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.39% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.99% | With dmap; triethylamine In dichloromethane at 0 - 5℃; | 4.2. General procedure for the synthesis of compounds 3a-3s General procedure: A solution of dry dichloromethane (10.0 mL) containing the substituted acyl chloride 2 (12.0 mmol) was added dropwise to the solution of dichloromethane (20.0 mL) containing D-(-)-pantolactone (1, 10.0 mmol, 1.30 g), 4-dimethylaminopyridine (1.0 mmol, 0.12 g) and triethylamine (12.0 mmol, 0.95 g). The reaction mixture was stirred overnight at 0-5 °C, and the reaction process was monitored by TLC. After completion of the reaction, the solvent was then removed under reduced pressure to give a residue which was extracted with ethyl acetate (3×50 mL). The solution was dried over anhydrous MgSO4 and concentrated under vacuum to obtain a slurry residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give products 3a-3s in yields of 57.19-94.94% (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine In ethanol for 16h; Reflux; | 1 Synthesis of [(S)-2-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-1-methyl-ethyl]-carbamic acid benzyl ester (6): Synthesis of [(S)-2-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-1-methyl-ethyl]-carbamic acid benzyl ester (6): Procedure: To a stirred solution of ((S)-2-Amino-1-methyl-ethyl)-carbamic acid benzyl ester (4) (26 g, 124.8 mmol) in EtOH (150 mL) were added D-(-)-Pantolactone (5) (48.7 g, 374.5 mmol) and Et3N (60.9 mL, 436.9 mmol). Reaction mixture was refluxed for 16h. Reaction mixture was concentrated under reduced pressure to get crude mass which was purified by column chromatography (silica gel, 100-200 mesh) using 3% MeOH in DCM to afford [(S)-2-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-1-methyl-ethyl]-carbamic acid benzyl ester (6) (31.2 g, 74%) as colorless sticky gum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: (R)-Pantolacton; 3-amino propanoic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene In methanol at 70℃; Stage #2: N-methyl-2-(tritylthio)ethan-1-amine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; acetonitrile at 20℃; for 72h; | 20.4 Step 4: (R)~2,4~Dihydroxy~3,3~dimethyI~N~(3~(methyl(2~(tritylthio)ethyl)ammo)-3- oxopropyljbutan amide b-alanine (481 mg, 5 4 mmol, 1 eq) and DBU (807 pL, 5.4 mmol, 1 eq) were stirred in methanol (10 mL) at 70 °C until the mixture became homogeneous. Then D-panto lactone (702,36 mg, 5.4 mmol, 1 eq) was added and the reaction mixture was stirred overnight at 70 °C. The mixture was concentrated to dryness and stripped with acetonitrile (2x). The sticky residue presumed to contain 3-[( ?)-2,4-dihydroxy-3,3-dimethylbutyrylamino]propionic acid was taken in acetonitrile (40 mL) then added to the above methylamine (1.8 g, 5.4 mmol, 1 eq). EDO (1.14 g, 5.94 mmol, 1 eq), HQBt (730 mg, 5.4 mmol, 1 eq) and DIPEA (1.9 mL) were added and the resulting reaction mixture was stirred for 3 days at room temperature. The reaction was quenched with brine and the product was extracted with AcOEt (3 x). The organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by automated silica gel chromatography (0-5% MeOH in DCM) and (i?)-2,4-dihydroxy-3,3-dimethyl-A7-(3-(methyl(2- (tritylthio)ethyi)amino)-3-oxopropyl)butanamide was isolated as a clear sticky oil (2.028 g, 70% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In neat (no solvent) at 20℃; for 72h; | 21.1 Step 1: ( R)~N~(2~Cyanoethyi)-2 , 4-dihydroxy-N, 3, 3-trimethylbutanamide 3 -(Methyl aminojpropanenitriie (3.88 g, 4.31 mL, 46.1 mmol, 2 eq) was added to a neat mixture of D-pantolactone (3.00 g, 23.1 mmol, 1 eq) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l ,2- ajpyrimidine (TBD) (321 mg, 2.31 mmol, 0.1 eq) and the mixture was stirred for 3 days at room temperature. The crude mixture was purified by automated silica gel chromatography (0-5% MeOH in AcOEt) to afford (i?)-A-(2-cyanoethyl)-2,4-dihydroxy-iV, 3, 3-trimethylbutanamide (2.1 g, 43% yield) as a colorless oil. (4155) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium tetrahydroborate In ethanol Cooling with ice; | 12 Dissolve (R)-P-2 (160.2mg, 1.0mmol) in 5mL ethanol, place the reaction flask in an ice-water bath, and slowly add sodium borohydride (45.4mg, 45.4mg, 1.2mmol), continue to stir until the reaction is complete, slowly quench the reaction with 5% dilute hydrochloric acid, extract three times with ethyl acetate, combine the ethyl acetate phases, wash with a small amount of saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure , Quickly purified by silica gel column chromatography to obtain 113mg (R)-pantoate lactone, the yield is 87%, 99%ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With camphor-10-sulfonic acid In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; | 4.1.1. (3R)-3-(4-methoxybenzyloxy)-4,4-dimethyltetrahydrofuran-2-one (12) 4-Methoxybenzyl alcohol (9.8 g, 71 mmol) in ether (60 mL) wasadded to a suspension of sodium hydride (60% in mineral oil, 0.56 g,14 mmol) in ether (75 mL) at rt and the mixture stirred for 30 minbefore cooling to 0 C. Trichloroacetonitrile (7.8 mL, 78 mmol) wasadded and the reaction mixture stirred at rt overnight thenconcentrated under reduced pressure. Light petroleum (90 mL)wasadded, followed by methanol (0.6 mL). The suspension was filteredthrough Celite and concentrated under reduced pressure to givethe acetimidate as a yellow-orange oil (17.1 g, 60.5 mmol, 85%); dH (300 MHz, CDCl3) 3.84 (3H, s, OCH3), 5.30 (2H, s, CH2), 6.94 and 7.40(each 2H, d, J 8.8, ArH) and 8.39 (1H, s, NH).(R)-Pantolactone (11) (5.0 g, 38 mmol) was added to the acetimidate(14.4 g, 50.9 mmol) in DCM (50 mL) and the solution cooledto 0 C. Camphorsulfonic acid (1.16 g, 4.99 mmol) was added portionwiseand the reaction mixture was allowed to warm to rt. Thewhite suspension was stirred overnight before the addition ofsaturated aqueous sodium bicarbonate (125 mL). The suspensionwas filtered through Celite and the aqueous phase was extractedwith DCM (100 mL). The organic extracts were washed with saturatedaqueous sodium bicarbonate (90 mL), dried (MgSO4) andconcentrated under reduced pressure. After trituration with DCM,chromatography of the residue (ether:light petroleum 1:10) gavethe title compound 12 [12] (5.39 g, 21.6 mmol, 56%) as white needles,Rf 0.23 (ethyl acetate:light petroleum 1:4), m.p. 59.7e63.1 C;[a]D20 89.3 (c 6.45, CH2Cl2) (Found:M Na, 273.1093. C14H18O4NarequiresM, 273.1098); nmax/cm1 3310, 2960,1780,1758,1512,1247,1111, 1031, 997, 984, 828 and 813; dH (CDCl3, 400 MHz) 1.08 and 1.12(each 3H, s, 4-CH3), 3.72 (1H, s, 3-H), 3.82 (3H, s, OCH3), 3.86 and3.99 (each 1H, d, J 8.7, 5-H), 4.70 and 4.96 (each 1H, d, J 11.8, ArHCH)and 6.90 and 7.31 (each 2H, d, J 8.7, ArH); dC (CDCl3, 100 MHz) 19.3,23.2, 40.3, 55.2, 72.0, 76.3, 79.9, 113.8, 129.2, 129.7, 159.4 and 175.5;m/z (ES) 273 (M 23, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 2,6-dimethylpyridine In dichloromethane at 20℃; for 96h; Inert atmosphere; | (R)-4,4-Dimethyl-3-((triisopropylsilyl)oxy)dihydrofuran-2(3H)-one (S1) To a stirred solution of 14 (5.05 g, 38.8 mmol) in DCM (38.8 mL) was added 2,6-Lutidine (26.6 mL, 233 mmol) and TIPSOTf (31.2 mL, 116 mmol) at 0°C under N2 atmosphere. The stirring mixture was allowed warm to room temperature and stirred for 4 days. The reaction mixture was then quenched with MeOH (4.70 mL), and stirred for 1h, and quenched with saturated aq. NH4Cl (100 mL). Resulted two layers were separated,and the aqueous phase was extracted with DCM (100 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under pressure to afforda crude product. The residue was purified by silica gel chromatography (hexane/EtOAcOOTIPSOS1TIPSOTf, 2,6-LutidineDCM, r.t, 4 d, quant.OOHOD-pantolactone (14)= 20:1) to afford S1 (13.9 g, quant.) as a colorless oil; Rf = 0.74 (hexane/EtOAc = 2/1); [α]20D = +21.2 (c 1.00, CHCl3); IR (Diamond Prism) (ν cm -1): 2938, 2866, 1793, 1658,1462, 1123, 1008, 876, 831, 677; 1H NMR (500 MHz, CD2Cl2) δ (ppm): 4.17 (s, 1H),3.98 (d, J = 9.2 Hz, 1H), 3.87 (d, J = 8.6 Hz, 1H), 1.25-1.18 (m, 6H), 1.13-1.05 (m, 21H);13C NMR (125 MHz, CD2Cl2) δ (ppm):175.8, 75.7, 41.5, 31.0, 23.3, 19.2, 18.1(3C),18.0(3C), 12.6(3C); HRMS-ESI (m/z): [M+Na]+ calcd for C15H30O3SiNa 309.1862;found 309.1854. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 48h; | 3.2.1. General Procedure A for Steglich Esterification A mixture of methacrylic acid (1.0 equiv.) alcohol (1.0 equiv.), EDC (1.1 equiv.) andDMAP (5 mol %) in dry DCM was stirred at rt until complete consumption of the startingacid or alcohol. The reaction mixture was washed with sat. aqueous citric acid (3x50 mL)and sat. aqueous NaHCO3 (3 50 mL), dried (Na2SO4) and concentrated in vacuo. Theresidue was purified by flash column chromatography (FCC) with an appropriate eluentas indicated. |
Tags: 599-04-2 synthesis path| 599-04-2 SDS| 599-04-2 COA| 599-04-2 purity| 599-04-2 application| 599-04-2 NMR| 599-04-2 COA| 599-04-2 structure
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