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CAS No. : | 118399-28-3 | MDL No. : | MFCD09839299 |
Formula : | C12H13NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BNIBNUOPVTZWRT-SNVBAGLBSA-N |
M.W : | 235.24 | Pubchem ID : | 697924 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 59.09 |
TPSA : | 64.63 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.95 cm/s |
Log Po/w (iLOGP) : | 1.58 |
Log Po/w (XLOGP3) : | 1.1 |
Log Po/w (WLOGP) : | 1.08 |
Log Po/w (MLOGP) : | 1.04 |
Log Po/w (SILICOS-IT) : | 1.41 |
Consensus Log Po/w : | 1.24 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.92 |
Solubility : | 2.81 mg/ml ; 0.0119 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.05 |
Solubility : | 2.1 mg/ml ; 0.00891 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.06 |
Solubility : | 0.206 mg/ml ; 0.000875 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.83 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32 % ee | With alpha-D-glucopyranose; glucose dehydrogenase (GDH-105); Baeyere-Villiger monooxygenase P1-C06; oxygen; NADPH In methanol; aq. phosphate buffer at 30℃; for 24 h; Enzymatic reaction | General procedure: Owing to the problems that both ketones 1k,l and their corresponding lactones 2k,l showed when analyzed by GC, as well as their poor solubility in diethyl ether or ethyl acetate, their enzymatic transformations were carried out in a bigger scale (3, 2 mL tubes) but maintaining identical reaction conditions. After 24 h, products were extracted with deuterated chloroform (2400 μL). The organic phases were dried over anhydrous sodium sulfate, filtered and conversion values were determined by 1H NMR experiments. Similarly, samples were evaporated and the residue re-dissolved in a mixture of hexane:ethanol 90:10 for HPLC analyses (see Tables S20-S21). In a typical experiment carried out in 1.5 mL tubes (total volume of 500 μL), the substrate 1a-j, m-v (10 mM) was dissolved in methanol (5 μL, 1percent v/v) and KPi buffer (100 mM, pH 9.0, 482 μL), containing glucose (20 mM), glucose dehydrogenase (GDH-105, 10 U, from stock solution of 1.275 U/μL), NADPH (0.2 mM, from a 20 mM stock solution) and the corresponding Baeyere-Villiger monooxygenase (2 mg). The mixture was shaken at 250 rpm at 30 °C for 24 h. The reaction was stopped by extracting with diethyl ether (2x400 μL) and centrifugedat 13,000 rpm in order to separate both phases and pellet the suspended protein. The organic phases were combined, dried over anhydrous sodium sulfate and analyzed by GC in order to determine the conversion values. Then, the solvent in GC samples was evaporated with a continuous flow of nitrogen, the residue redissolved in a mixture of hexane:ethanol 90:10 and the new sample filtered and analyzed by HPLC, leading to the measurement of the enantiomeric excess of the lactones. Control experiments in the absence of enzyme were performed for all substrates, not observing any reaction product after similar periods of time (Tables S1-S19). |
78 % ee | With alpha-D-glucopyranose; glucose dehydrogenase (GDH-105); Baeyere-Villiger monooxygenase P1-D08; oxygen; NADPH In methanol; aq. phosphate buffer at 30℃; for 24 h; Enzymatic reaction | General procedure: Owing to the problems that both ketones 1k,l and their corresponding lactones 2k,l showed when analyzed by GC, as well as their poor solubility in diethyl ether or ethyl acetate, their enzymatic transformations were carried out in a bigger scale (3, 2 mL tubes) but maintaining identical reaction conditions. After 24 h, products were extracted with deuterated chloroform (2400 μL). The organic phases were dried over anhydrous sodium sulfate, filtered and conversion values were determined by 1H NMR experiments. Similarly, samples were evaporated and the residue re-dissolved in a mixture of hexane:ethanol 90:10 for HPLC analyses (see Tables S20-S21). In a typical experiment carried out in 1.5 mL tubes (total volume of 500 μL), the substrate 1a-j, m-v (10 mM) was dissolved in methanol (5 μL, 1percent v/v) and KPi buffer (100 mM, pH 9.0, 482 μL), containing glucose (20 mM), glucose dehydrogenase (GDH-105, 10 U, from stock solution of 1.275 U/μL), NADPH (0.2 mM, from a 20 mM stock solution) and the corresponding Baeyere-Villiger monooxygenase (2 mg). The mixture was shaken at 250 rpm at 30 °C for 24 h. The reaction was stopped by extracting with diethyl ether (2x400 μL) and centrifugedat 13,000 rpm in order to separate both phases and pellet the suspended protein. The organic phases were combined, dried over anhydrous sodium sulfate and analyzed by GC in order to determine the conversion values. Then, the solvent in GC samples was evaporated with a continuous flow of nitrogen, the residue redissolved in a mixture of hexane:ethanol 90:10 and the new sample filtered and analyzed by HPLC, leading to the measurement of the enantiomeric excess of the lactones. Control experiments in the absence of enzyme were performed for all substrates, not observing any reaction product after similar periods of time (Tables S1-S19). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 4 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water |
To a stirred slurry of sodium borohydride (8.38 g, 0.223 mol) in THF (290 ml) at O0C was added a solution of 0100 (46 g, 0.185 mol) in THF (290ml) over a period of 3 h. After stirring at room temperature for 1 h, the reaction mixture was carefully acidified to pH 2 with 6 N HCl and then concentrated to approximately one-fourth the volume under reduced pressure. The resulting solution was diluted with water and extracted with four portions of ether, and then the combined organic extracts were concentrated under reduced pressure to a heterogeneous residue. The yellow residue was taken up in toluene (200 ml), containing p-TsOH (200 mg), and then water was azeotropically removed by using a Dean-Stark apparatus. After the mixture refluxed for 5 h, the toluene was removed under reduced pressure to afford a viscous residue, which gave 0101 (37 g, 85percent) as a white crystals upon triturated with ether. LCMS: 236 [M+l]+; 1H NMR (DMSO-J6): δ 2.39 (dd, IH, J1 = 3.6 Hz, J2 = 18.0 Hz), 2.86 (dd, IH, J1 = 8.1 Hz, J2 = 17.7 Hz), 4.11 (dd, IH, J1 = 3.6 Hz, J2 = 9.3 Hz), 4.319 (m, IH), 4.43 (dd, IH, J1 = 6.0 Hz, J2 = 9.0 Hz), 5.05 (s, 2H), 7.365 (m, 5H), 7.88 (d, IH, J= 4.5 Hz). |
57% | Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 2 h; Stage #2: With hydrogenchloride; ethanol In tetrahydrofuran for 12 h; Heating / reflux |
A stirred suspension NaBH4 (5.8 g, 154 mmol) in THF (100 mL) was cooled to 0 0C, treated dropwise with a solution of compound c (32 g, 128 mmol) in 50 mL of THF, allowed to warm to room temperature, and stirred for 2 hours, The resulting mixture was treated with concentrated HCl (26.2 mL) and ethanol (26.2 mL), heated to reflux for 12 hours, allowed to cool to room temperature, poured into brine and the layers were separated. The aqueous layer was extracted with EA and the combined extracts were dried, filtered, concentrated and purified by silica provide the desired product d (17 g, yield: 57percent) MS (ESI) m/e (M-I-H+): 236; 1H-NMR (CDCl3, 400 MHz): δ 7.33- 7.28 (m, 5H), 5.32 (m, IH), 5.09 (s, 2H), 4.49 (br s, 2H), 4.22 (m, IH), 2.84 (dd, J = 7.6 18Hz, IH), 2.45 (dd, J= 2.8 17.6Hz, IH). |
51% | Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 2 h; Stage #2: With hydrogenchloride In tetrahydrofuran; ethanol; water for 12 h; Heating / reflux |
EXAMPLE 21B benzyl (3R)-5-oxotetrahydro-3-furanylcarbamate A suspension of NaBH4 (2.71 g, 71.5 mmol) in THF (50 mL) was cooled to 0° C., treated dropwise with a solution of EXAMPLE 21A (16.21 g, 65.0 mmol) in THF (50 mL), allowed to warm to room temperature, and stirred for 2 hours. The resulting mixture was treated with concentrated HCl (13.1 mL) and ethanol (13.1 mL), heated to reflux for 12 hours, allowed to cool to room temperature, poured into brine (100 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated with diethyl ether (50 mL) for 2 hours, cooled overnight, and the solid collected by filtration to provide the desired product (7.81 g, 51percent). |
50% | With sodium tetrahydroborate In tetrahydrofuran at 20℃; for 1 h; | 0.9 g (3.6 mmol) of anhydride 25 in THF (8 ml) is added dropwise to a stirred slurry of 0.138 g (3.6 mmol) of sodium borohydride in THF (7 ml) at 0° C. After stirring at ambient temperature for 1 hour, the reaction mixture is carefully acidified to pH 2 with 6N HCl and is then concentrated to approximately a quarter of its volume under reduced pressure (water suction). The residue is diluted with water and extracted with 4 portions of ethyl acetate and then the combined organic extracts are concentrated under reduced pressure. The crude product is purified by flash chromatography (1/1: EtOAc/hexanes). The fractions comprising the substance with an Rf value of 0.4 are combined and concentrated to produce the compound (R)-26 in the form of a white solid (50percent) having a melting point of 101-102° C. [α]D+49.2° (c 1, CHCl3). MS (CI, Isobut.): m/z 236 (M+1). Infrared (KBr): 1558, 1674-1694 (O-CO-N), 1780 (lactone CO), 3307.4 (NH) cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With toluene-4-sulfonic acid In toluene for 3 h; Dean-Stark conditions; Reflux | (R)-3-(Benzyloxycarbonylamino)-4-hydroxybutanoic acid (INTERMEDIATE 2, 27.7 g, 109.38 mmol) was dissolved in toluene (648 ml). p-Toluenesulfonic acid (367 mg, 2.13 mmol) was added to the solution and the resulting mixture was heated at reflux under Dean-Stark conditions for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Diethyl ether (200 ml) was added, and formation of crystals was observed upon standing. The crystals were filtered in vacuo. The mother liquors were concentrated in vacuo and additional diethyl ether (40 ml) was added. More crystals appeared which were filtered in vacuo. Both sets of crystals combined to give the title product (22.8 g, yield: 83percent).1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.49 (dd, 1H) 2.76-2.94 (m, 1H) 4.24 (d, 1H) 4.42-4.61 (m, 2H) 5.03-5.24 (m, 3H) 7.27-7.46 (m, 5H).LCMS: (ESI) m/z 234 [M-H]+.Optical Rotation:Concentration: 0.155 g/dLLamp: SodiumWavelength: 589 nmTemperature: 20° C.Path length: 10 cm Cell volume: 1 ml Solvent: CH2Cl2 [α]=+46 |
18.9 g | With toluene-4-sulfonic acid In toluene for 6 h; Dean-Stark; Reflux | 3. Synthesis of intermediate 4 (0354) (0355) [00126] To the crude residue of 3 was added toluene (150 mL) and p-TsOH (150 mg). (0356) The mixture was refluxed for 6 hours equipped with a Dean-Stark apparatus. The solvent was removed in vacuo and Et20 (200 mL) was added. The mixture was stirred at room (0357) temperature for 2 hours and then filtered to afford 4 (18.9 g, 77percent for 2 steps) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32 % ee | With alpha-D-glucopyranose; glucose dehydrogenase (GDH-105); Baeyere-Villiger monooxygenase P1-C06; oxygen; NADPH In methanol; aq. phosphate buffer at 30℃; for 24 h; Enzymatic reaction | General procedure: Owing to the problems that both ketones 1k,l and their corresponding lactones 2k,l showed when analyzed by GC, as well as their poor solubility in diethyl ether or ethyl acetate, their enzymatic transformations were carried out in a bigger scale (3, 2 mL tubes) but maintaining identical reaction conditions. After 24 h, products were extracted with deuterated chloroform (2400 μL). The organic phases were dried over anhydrous sodium sulfate, filtered and conversion values were determined by 1H NMR experiments. Similarly, samples were evaporated and the residue re-dissolved in a mixture of hexane:ethanol 90:10 for HPLC analyses (see Tables S20-S21). In a typical experiment carried out in 1.5 mL tubes (total volume of 500 μL), the substrate 1a-j, m-v (10 mM) was dissolved in methanol (5 μL, 1percent v/v) and KPi buffer (100 mM, pH 9.0, 482 μL), containing glucose (20 mM), glucose dehydrogenase (GDH-105, 10 U, from stock solution of 1.275 U/μL), NADPH (0.2 mM, from a 20 mM stock solution) and the corresponding Baeyere-Villiger monooxygenase (2 mg). The mixture was shaken at 250 rpm at 30 °C for 24 h. The reaction was stopped by extracting with diethyl ether (2x400 μL) and centrifugedat 13,000 rpm in order to separate both phases and pellet the suspended protein. The organic phases were combined, dried over anhydrous sodium sulfate and analyzed by GC in order to determine the conversion values. Then, the solvent in GC samples was evaporated with a continuous flow of nitrogen, the residue redissolved in a mixture of hexane:ethanol 90:10 and the new sample filtered and analyzed by HPLC, leading to the measurement of the enantiomeric excess of the lactones. Control experiments in the absence of enzyme were performed for all substrates, not observing any reaction product after similar periods of time (Tables S1-S19). |
78 % ee | With alpha-D-glucopyranose; glucose dehydrogenase (GDH-105); Baeyere-Villiger monooxygenase P1-D08; oxygen; NADPH In methanol; aq. phosphate buffer at 30℃; for 24 h; Enzymatic reaction | General procedure: Owing to the problems that both ketones 1k,l and their corresponding lactones 2k,l showed when analyzed by GC, as well as their poor solubility in diethyl ether or ethyl acetate, their enzymatic transformations were carried out in a bigger scale (3, 2 mL tubes) but maintaining identical reaction conditions. After 24 h, products were extracted with deuterated chloroform (2400 μL). The organic phases were dried over anhydrous sodium sulfate, filtered and conversion values were determined by 1H NMR experiments. Similarly, samples were evaporated and the residue re-dissolved in a mixture of hexane:ethanol 90:10 for HPLC analyses (see Tables S20-S21). In a typical experiment carried out in 1.5 mL tubes (total volume of 500 μL), the substrate 1a-j, m-v (10 mM) was dissolved in methanol (5 μL, 1percent v/v) and KPi buffer (100 mM, pH 9.0, 482 μL), containing glucose (20 mM), glucose dehydrogenase (GDH-105, 10 U, from stock solution of 1.275 U/μL), NADPH (0.2 mM, from a 20 mM stock solution) and the corresponding Baeyere-Villiger monooxygenase (2 mg). The mixture was shaken at 250 rpm at 30 °C for 24 h. The reaction was stopped by extracting with diethyl ether (2x400 μL) and centrifugedat 13,000 rpm in order to separate both phases and pellet the suspended protein. The organic phases were combined, dried over anhydrous sodium sulfate and analyzed by GC in order to determine the conversion values. Then, the solvent in GC samples was evaporated with a continuous flow of nitrogen, the residue redissolved in a mixture of hexane:ethanol 90:10 and the new sample filtered and analyzed by HPLC, leading to the measurement of the enantiomeric excess of the lactones. Control experiments in the absence of enzyme were performed for all substrates, not observing any reaction product after similar periods of time (Tables S1-S19). |
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