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CAS No. : | 282735-66-4 | MDL No. : | MFCD09751026 |
Formula : | C16H15NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LTPOSIZJPSDSIL-CVEARBPZSA-N |
M.W : | 253.30 | Pubchem ID : | 11322747 |
Synonyms : |
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.19 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 76.2 |
TPSA : | 38.33 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.03 cm/s |
Log Po/w (iLOGP) : | 2.23 |
Log Po/w (XLOGP3) : | 2.55 |
Log Po/w (WLOGP) : | 1.59 |
Log Po/w (MLOGP) : | 2.38 |
Log Po/w (SILICOS-IT) : | 2.91 |
Consensus Log Po/w : | 2.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.35 |
Solubility : | 0.113 mg/ml ; 0.000444 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.0 |
Solubility : | 0.252 mg/ml ; 0.000995 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.25 |
Solubility : | 0.00143 mg/ml ; 0.00000565 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.86 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; at 70℃; for 5h;Molecular sieve; | Under argon, to a 100 mL flask with stir bar was added (2S.3R)-2,3,5,6-tetrahydro-2,3-diphenyl-l,4-oxazin-6-one (1.0 g, 3.96 mmol), 3-E-(3- bromo)-benzylidene-6-bromo-l,3-dihydro-indol-2-one (4.75 mmol), 2 g freshly activated 4 A molecular sieves, 3,3-dimethyl-butyraldehyde (4.75 mmol) and toluene (50 mL). The mixture was heated to 7O0C and kept at that temperature for 5 hours. The mixture was cooled to room temperature and the molecular sieves were filtered off. The solvent was removed in vacuo and the residue was purified by chromatography to yield the 1,3-dipolar product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; at 70℃; for 5h;Molecular sieve; | Under argon, to a 100 mL flask with stir bar was added (2S.3R)-2,3,5,6-tetrahydro-2,3-diphenyl-l,4-oxazin-6-one (1.0 g, 3.96 mmol), 3-E-(2- fluoro-3-chloro)-benzylidene-6-chloro-l ,3-dihydro-indol-2-one (4.75 mmol), 2 g freshly activated 4A molecular sieves, 3,3-dimethyl-butyraldehyde (4.75 mmol) and toluene (50 mL). The mixture was heated to 7O0C and kept at that temperature for 5 hours. The mixture was cooled to room temperature and the molecular sieves were filtered off. The solvent was removed in vacuo and the residue was purified by chromatography to yield the 1,3-dipolar product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In toluene; at 80℃; for 18h; | Example 8 Preparation of chiral(2'R,3'S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid methyl ester; To a mixture of <strong>[282735-66-4](5R,6S)-5,6-diphenylmorpholin-2-one</strong> (3.4 g, 13.4 mmol, ArkPharminc) in toluene (80 mL) was added E/Z-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one (3.5 g, 11.3 mmol) prepared in Example 2, 3,3-dimethylbutyraldehyde (1.3 g, 13.4 mmol, Aldrich). The reaction mixture was stirred at 80 C. for 18 h. The mixture was filtered through a short pad of celite. The pad was washed with additional toluene. The filtrates were combined, and concentrated. The residue was purified by chromatography (10-25% EtOAc inhexanes) to give desired 1,3-dipolar product chiral(3S,3'S,4'R,6'R,8'S,8a'R)-6-chloro-8'-(3-chloro-2-fluorophenyl)-6'-neopentyl-3',4'-diphenyl-3',4',8',8a'-tetrahydrospiro[indoline-3,7'-pyrrolo[2,1-c][1,4]oxazine]-1',2(6'H)-dione as a yellow foam (Yield, 5.7 g, 66%). |
65% | In toluene;Molecular sieve; Reflux; | Step 2 To a solution of compound 3 (6.25 g, 21 mmol) in toluene (75 ml) was added compound 4 (5.43 g, 21 mmol), compound 5 (2.15 g, 21 mmol) and 4 A molecular sieves (4 g). The reaction mixture was heated at reflux overnight and filtrated. The filtrate was evaporated and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=9:1 to 5:1) to give compound 6 (8.78 g, 65% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; for 6h;Inert atmosphere; Reflux;Product distribution / selectivity; | 121 (3R,3'R,4'S,6'S,8'R,8a'S)-6-chloro-8'-(3-chloro-2-fluorophenyl)-6'-neopentyl-3',4'-diphenyl 3',4',8',8a'-tetrahydrospiro[indoline-3,7'-pyrrolo[2,1-c][1,4]oxazine]-1',2(6'H)-dione To a suspension of 496 mg (1.61 mmol) of (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one in toluene under argon, were added 408 mg (1.61 mmol) of (5S,6R)-5,6-diphenylmorpholin-2-one and 213 muL (1.61 mmol) of 3,3-dimethyl-butyraldehyde. The reaction mixture was heated at reflux temperature for 6 hours, upon which it was cooled down to room temperature and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on a 70 g silica cartridge (15-40 mum silica gel ; eluting solvent : cyclohexane /ethyl acetate 90 /10 v/v; flow: 50 mL /min). 0.58 g of (3R,3'R,4'S,6'S,8'R,8a'S)-6-chloro-8'-(3-chloro-2-fluorophenyl)-6'-neopentyl-3',4'-diphenyl 3',4',8',8a'-tetrahydrospiro[indoline-3,7'-pyrrolo[2,1-c][1,4]oxazine]-1',2(6'H)-dione was obtained as an amorphous yellow solid. LC- MS: tR (min)=1.81 ; [M+H]+: m/z 643[M-H]-: m/z 641 (WATERS UPLC-SQD apparatus; Ionization: electrospray in positive mode and/or negative mode (ES+/-); Chromatographic conditions: Column: ACQUITY BEH C18 1.7 mum-2.1×50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 50 C.; Flow: 0.8 ml/min ; Gradient (2.5 min): from 5 to 100% of B in 1.8 min ; 2.4 min : 100% of B ; 2.45 min : 100% of B ; from 100 to 5% of B in 0.05 min ; Retention time=tR (min); referred to herein as ?Method C?) ; 1H NMR (400 MHz, DMSO-d6): 0.39 (s, 9H); 1.30 (dd, J=4.0 and 15.2 Hz, 1H); 1.93 (dd, J=6.3 and 15.2 Hz, 1H); 3.49 (dd, J=4.0 and 6.3 Hz, 1H); 4.47 (d, J=11.2 Hz, 1H); 5.04 (d, J=4.2 Hz, 1H); 5.08 (d, J=11.2 Hz, 1H); 6.53 (d, J=8.1 Hz, 1H); 6.66 to 6.76 (m, 3H); 6.96 (m, 2H); 7.10 to 7.26 (m, 9H); 7.34 (t broad, J=7.9 Hz, 1H); 7.62 (t broad, J=7.9 Hz, 1H); 10.71 (s broad, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Molecular sieve 4 A; | Example 16Isomerization StudiesGeneral InformationExperiments involving moisture and/or air sensitive components were performed in oven-dried glassware under an atmosphere of nitrogen. Commercial solvents and reagents were used without further purification with the following exception: THF was freshly distilled from sodium wire.Flash chromatography was performed using silica gel (type H) from TM chemicals, Inc. Columns were typically packed as slurry and equilibrated with hexane prior to use. Analytical thin layer chromatography (TLC) was performed using Merck 60 F254 precoated silica gel plate (0.2 mm thickness). Subjected to elution, plates were visualized using UV radiation. Further visualization was possible by staining with basic solution of potassium permanganate or acidic solution of phosphomolybdic acid, followed by heating with heating gun.Compounds were purified by HPLC using a Waters Sunfire C18 reverse phase semipreparative HPLC column (19 mm×150 mm) using solvent A (water, 0.1% of TFA) and solvent B (CH3CN, 0.1% of TFA or MeOH, 0.1% of TFA) as eluents with a flow rate of 10 mL/min on a Waters Delta 600 instrument. Analytical reverse phase HPLC was conducted using Waters 2795 Separation module.Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectroscopy were performed on a Bruker Advance 300 NMR spectrometer. Chemical shifts of 1H NMR spectra are reported as delta in units of parts per million (ppm) downfield from SiMe4 (delta 0.0) or relative to the signal of chloroform-d (delta=7.26, singlet), methanol-d4 (delta=3.31, quintuplet) and DMSO-d6 (delta=2.50, quintuplet). Multiplicities were given as: s (singlet); d (doublet); t (triplet); q (quartet); dd (doublet of doublets); ddd (doublet of doublets of doublets); dt (doublet of triplets); m (multiplets) and etc. The number of protons for a given resonance is indicated by nH. Coupling constants are reported as J values in Hz. Carbon nuclear magnetic resonance spectra (13C NMR) are reported as delta in units of parts per million (ppm) downfield from SiMe4 (delta 0.0) or relative to the signal of chloroform-d (delta=77.23, triplet), MeOH-d4 (delta=49.20, septuplet) and DMSO-d6 (delta=39.52, septuplet).Low resolution ESI mass spectrum analysis was performed on Thermo-Scientific LCQ Fleet mass spectrometer.Compounds 1-10 were prepared according to Scheme 10 and Table 4 using methods previous described (See, e.g., Ding, K. et al., J. Am. Chem. Soc. 127:10130-10131 (2005); Ding, K. et al., J. Med. Chem. 49:3432-3435 (2006); Yu, S. et al., J. Med. Chem. 52:7970-7973 (2009); Shangary, S., Proc. Natl. Acad. Sci. 105:3933-3938 (2008); U.S. Pat. No. 7,759,383) as a mixture of isomers. Isomer A was identified as the predominant isomer following CAN oxidation in most cases. Applicants have found that dissolving the mixture of isomers obtained from CAN oxidation in a solvent or a mixture of solvents and allowing the reaction mixture to mature for a period of time under various conditions provides a mixture of isomers having Isomer B as the predominant isomer. In some cases, Isomers C and D were isolated in pure or substantially pure form. Likewise, compounds 11 and 12 were prepared according to Scheme 11 and Table 5.The procedure for isomerization used in this study was as follows: approximately 30 mg product obtained from CAN oxidation (pre-purified by flash column chromatography) was placed in a round bottom flask equipped with magnetic stirring bar. Acetonitrile (2.4 mL) was added to dissolve the product. To the acetonitrile solution was added water (2.0 mL) and 0.5 mL NaHCO3 (saturated) solution to give a pH of approximately 8. The reaction mixture was allowed to stir at room temperature for approximately 3 days. The percentage of isomers was determined using analytical HPLC. Further purification was performed on semi-preparative or preparative reverse phase HPLC using MeOH (0.1% TFA) and water (0.1% TFA) as mobile phase.Isomerization of Isomer A to Isomer B can also be carried out under acidic conditions, e.g., MeCN-H2O, CF3CO2H (pH<1), room temperature, 3 days; ethyl acetate, acetic acid, 60 C., 3 h, or neutral conditions e.g., MeOH or MeOH-H2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | In toluene; at 70℃; for 120h;Molecular sieve; Inert atmosphere; | <strong>[282735-66-4](5R,6S)-5,6-diphenylmorpholin-2-one</strong> (506 mg, 2.00 mmol), 4,4-dimethylcyclohexanone (252 mg, 2.00 mmol), and molecular sieves 4A (powder) (2 g) were added to a toluene (20 ml) solution of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) (616 mg, 2.00 mmol) under nitrogen atmosphere and the resulting mixture was stirred under heating at 70 C. for 5 days. After cooling, insoluble matter was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with 1N hydrochloric acid and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=9:1?6:1 (v/v)] to give 194 mg (14%) of the title compound as a yellow amorphous solid.1H-NMR (400 MHz, CDCl3) S: 0.19 (3H, s), 0.52 (3H, s), 0.94-1.00 (3H, m), 1.29-1.41 (3H, m), 1.80 (1H, d, J=11.0 Hz), 2.27 (1H, d, J=14.2 Hz), 4.61 (1H, d, J=11.0 Hz), 4.86 (1H, d, J=2.7 Hz), 5.35 (1H, d, J=11.4 Hz), 6.23 (1H, d, J=8.2 Hz), 6.60 (1H, dd, J=8.2, 1.8 Hz), 6.72-6.78 (2H, m), 6.88 (1H, d, J=1.8 Hz), 7.07-7.26 (11H, m), 7.67 (1H, s), 7.77 (1H, t, J=6.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With copper(II) sulfate; In toluene; for 24h;Reflux; Inert atmosphere; | <strong>[282735-66-4](5R,6S)-5,6-diphenylmorpholin-2-one</strong> (2.62 g, 10.3 mmol), 4,4-dimethylcyclohexanone (1.30 g, 10.3 mmol), and anhydrous copper sulfate (16.4 g, 103 mmol) were added to a toluene (80 ml) solution of the compound (2.67 g, 8.60 mmol) obtained in Reference Example 1 and the resulting mixture was heated to reflux for 24 hours under nitrogen atmosphere. After cooling, insoluble matter was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with 1N hydrochloric acid solution and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=9:1?6:1 (v/v)] to give 5.1 g (90%) of the title compound as a yellow amorphous solid.1H-NMR (400 MHz, CDCl3) delta: 0.20 (3H, s), 0.55 (3H, s), 0.90-1.08 (3H, m), 1.21-1.32 (1H, m), 1.33-1.47 (2H, m), 1.76-1.86 (1H, m), 2.26-2.36 (1H, m), 4.65 (1H, d, J=11.2 Hz), 4.88 (1H, d, J=3.2 Hz), 5.36 (1H, d, J=11.2 Hz), 6.52 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=8.2 Hz), 6.71-6.78 (2H, m), 7.06-7.24 (10H, m), 7.25-7.32 (1H, m), 7.74-7.83 (1H, m), 9.00 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With boron trifluoride diethyl etherate; In tetrahydrofuran; at 70℃; for 168h;Molecular sieve; Inert atmosphere; | A boron trifluoride-diethyl ether complex (0.038 ml, 0.30 mmol) and molecular sieves 4A (powder) (3 g) were added to a tetrahydrofuran (30 ml) solution of the compound (873 mg, 3.00 mmol) obtained in Reference Example 4, <strong>[282735-66-4](5R,6S)-5,6-diphenylmorpholin-2-one</strong> (760 mg, 3.00 mmol), and 4,4-dimethylcyclohexanone (379 mg, 3.00 mmol) under nitrogen atmosphere and the resulting mixture was stirred under heating at 70 C. for 7 days. After cooling, insoluble matter was removed by filtration through celite and the filtrate was washed with brine and then dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=4:1?1:1 (v/v)] to give 1.18 g (60%) of the title compound as a pale yellow amorphous solid.1H-NMR (400 MHz, CDCl3) delta: 0.54 (3H, s), 0.67 (3H, s), 0.80-0.92 (1H, m), 1.15-1.41 (4H, m), 1.71-1.82 (1H, m), 1.82-1.94 (1H, m), 2.15-2.26 (1H, m), 4.42 (1H, d, J=10.7 Hz), 4.81 (1H, d, J=3.7 Hz), 5.03 (1H, d, J=10.7 Hz), 6.60-6.68 (2H, m), 6.78-6.84 (2H, m), 6.85-6.89 (1H, m), 6.91-6.98 (2H, m), 7.06-7.31 (9H, m), 7.47 (1H, s), 8.14 (1H, d, J=5.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; toluene; for 3h;Reflux; | Compound 3 (19.5 mmol), <strong>[282735-66-4](5R,6S)-5,6-diphenylmorpholin-2-one</strong> (4) (23.4 mmol), and ketone 5 (39 mmol) were dissolved in THF (7.5 mL) and toluene (75 mL) and refluxed for 3 hours. After cooling to room temperature, the reaction was filtered. The solution was concentrated and purified by column chromatography to give the product (30-50% yield) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With boron trifluoride diethyl etherate; In tetrahydrofuran; at 70℃; for 168h;Molecular sieve; Inert atmosphere; | [Step 2] (3'S,4'R,7'S,8'S,8a'R)-6'-chloro-8'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-tetrahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-c][1,4]oxazine-7',3'-indole]-1',2'(1'H)-dione A boron trifluoride-diethyl ether complex (0.15 ml, 1.20 mmol) and 4A molecular sieves (powder) (3 g) were added to a tetrahydrofuran (30 ml) solution of the compound (1.86 g, 6.00 mmol) obtained in Step 1, <strong>[282735-66-4](5R,6S)-5,6-diphenylmorpholin-2-one</strong> (1.67 g, 6.60 mmol), and 4,4-dimethylcyclohexanone (0.83 g, 6.60 mmol) under a nitrogen atmosphere and the resulting mixture was stirred under heating at 70C for 7 days. After cooling, insoluble matter was removed by filtration through celite and the filtrate was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate = 4:1 ? 1:1 (v/v)] to give 3.39 g (84%) of the title compound as a solid. 1H-NMR (400 MHz, CDCl3) delta: 0.21 (3H, s), 0.53 (3H, s), 0.89-1.08 (3H, m), 1.28-1.43 (3H, m), 1.73-1.81 (1H, m), 2.23-2.33 (1H, m), 4.58 (1H, d, J=11.0 Hz), 4.86 (1H, d, J=3.2 Hz), 5.31 (1H, d, J=11.0 Hz), 6.25 (1H, d, J=8.3 Hz), 6.67 (1H, dd, J=8.3, 1.8 Hz), 6.72-6.77 (2H, m), 6.93 (1H, d, J=1.8 Hz), 7.04-7.17 (6H, m), 7.18-7.25 (3H, m), 7.79 (1H, t, J=4.6 Hz), 7.99 (1H, s), 8.29 (1H, d, J=5.0 Hz). MS (APCI) m/z: 670 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With boron trifluoride diethyl etherate; In tetrahydrofuran; at 70℃; for 168h;Molecular sieve; Inert atmosphere; | A boron trifluoride-diethyl ether complex (0.15 ml, 1.20 mmol) and 4A molecular sieves (powder) (3 g) were added toa tetrahydroffiran (30 ml) solution of the compound (1.86 g, 6.00 mmol) obtained in Step 1, (5R,65)-5,6-diphenylmor- pholin-2-one (1.67 g, 6.60 mmol), and 4,4-dimethylcyclo- hexanone (0.83 g, 6.60 mmol) under a nitrogen atmosphere and the resulting mixture was stirred under heating at 70 C.for 7 days. After cooling, insoluble matter was removed by filtration through celite and the filtrate was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=4: 1 -4 1:1 (v/v)] to give 3.39 g (84%) of the title compound as a solid.?H-NMR (400 MHz, CDC13) oe: 0.21 (3H, s), 0.53 (3H, s),0.89-1.08 (3H, m), 1.28-1.43 (3H, m), 1.73-1.81 (1H, m),2.23-2.33 (1H, m), 4.58 (1H, d, J=1 1.0Hz), 4.86 (1H, d, J=3.2Hz), 5.31 (1H, d, J=11.0 Hz), 6.25 (1H, d, J=8.3 Hz), 6.67(1H, dd, J=8.3, 1.8Hz), 6.72-6.77 (2H, m), 6.93 (1H, d, J=1 .8Hz), 7.04-7.17 (6H, m), 7.18-7.25 (3H, m), 7.79 (1H, t, J=4.6 Hz), 7.99 (1H, s), 8.29 (1H, d, J=5.0 Hz).MS (APCI) mlz: 670 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
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16% | In toluene; at 70℃;Molecular sieve; Inert atmosphere; | 3-Benzylidene-1,3-dihydro-indol-2-one compounds 3a/3b/3c, (0.475 mmol), 3-methyl-butyraldehyde (0.0509 ml, 0.475 mmol), and <strong>[282735-66-4](2S,3R)-2,3,5,6-tetrahydro-2,3-diphenyl-1,4-oxazine-6-one</strong> (0.1 g, 0.396 mmol) were dissolved in toluene in the presence of 2 g of freshly activated molecular sieves (4A) followed by stirring overnight at 70C under argon atmosphere. After completion of the reaction, the solvent was evaporated in vacuo and the major crude product was purified by silica gel column chromatography (hexanes/ EtOAc, 5:1). Compound 6a (yield 16%), compound 6b (yield 9%), and compound 6c (yield 5%). (3R,3'S,4'R,6'S,8'S,9'R)-3',4',8'-triphenyl-6'-(2-methylpropyl)-3',4',8',9'-tetrahydro-1'H,6'H-spiro[2,3-dihydro-indole-3, 7'-pyrrolo[2,1-c][1,4]oxazine]-1',2(1H)-dione (Compound 6a). 1H-NMR (400 MHz, CDCl3) delta (ppm): 7.64 (1H, s, NH), 7.34-6.94 (18H, m, HAr), 6.91 (1H, t, 3JHH= 8.0, 7.6 Hz, 6-HAr), 6.56 (1H, d, 3JHH = 8.0 Hz, 7-HAr), 6.63 (1H, t, 3JHH = 8.0, 7.2 Hz, 5-HAr), 6.23 (1H, d, 3JHH = 7.2 Hz, 4-HAr), 6.35 (1H, d, 3JHH = 4.0 Hz, 3'-H), 4.80 (1H, d, 3JHH = 4.4 Hz, 4'-H), 4.39 (1H, d, 3JHH = 10.8 Hz, 9'-H), 4.25 (1H, d, 3JHH = 10.8 Hz, 8'-H), 3.20 (1H, dd, 3JHH = 10.0, 4.0 Hz, 6?-H), 2.07-2.0 (1H, m, 6'H-iBu(-CH2)), 1.75-1.68 (1H, m, 6?HiBu(-CH2)), 1.05-1.04 (1H, m, 6'H-iBu(-CH)), 0.80 (3H, d, 3JHH = 6.8 Hz, 6'H-iBu(-CH3)), 0.47 (3H, d, 3JHH = 6.0 Hz, 6'H-iBu(-CH3)); COSY proton-proton correlations [deltaEta/deltaEta]: 6.91/6.56 [6-HAr/7-HAr], 6.91/6.63 [6-HAr/5-HAr], 6.63/6.23 [5-HAr/4-HAr], 6.35/4.80 [3'-H/4'-H], 4.39/4.25 [8a?-H/8'-H], 3.20/2.07-2.0 [6'-Heq/CH2], 3.20/1.75-1.68 [6'-H/CH2], 2.07-2.0/1.75-1.68 [CH2/CH2]; 13C-NMR (400 MHz, CDCl3) delta(ppm): 129.8, 128.1, 127.7, 126.9, 125.7, 125.0, 122.0, 109.2, 83.7, 66.1, 60.5, 60.3, 56.0, 36.5, 24.9, 23.8, 21.6; MS (ESI) m/z: 543 [M+H]+; Anal. (C36H34N2O3-0.5 H2O) requires C, 78.37; H, 6.40; N, 5.07; found C, 78.22, H, 6.62, N, 5.04. |
Tags: 282735-66-4 synthesis path| 282735-66-4 SDS| 282735-66-4 COA| 282735-66-4 purity| 282735-66-4 application| 282735-66-4 NMR| 282735-66-4 COA| 282735-66-4 structure
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