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Chemical Structure| 897365-76-3
Chemical Structure| 897365-76-3
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Product Details of [ 897365-76-3 ]

CAS No. :897365-76-3 MDL No. :MFCD16038628
Formula : C15H8Cl2FNO Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 308.13 Pubchem ID :-
Synonyms :

Safety of [ 897365-76-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 897365-76-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 897365-76-3 ]

[ 897365-76-3 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 2987-16-8 ]
  • [ 897365-76-3 ]
  • [ 282735-66-4 ]
  • [ 897365-81-0 ]
YieldReaction ConditionsOperation 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).
  • 2
  • [ 74444-81-8 ]
  • [ 85070-48-0 ]
  • [ 897365-76-3 ]
YieldReaction ConditionsOperation in experiment
81% With piperidine; In methanol; at 20.0℃; for 3.0h; Step 1 To a stirred solution of oxindole 1 (4.19 g, 25 mmol) in methanol (50 mL) was added aldehyde 2 (3.96 g, 25 mmol) and piperidine (2.45 mL, 25 mmol). The reaction mixture was stirred at room temperature for 3 h and the yellow precipitate was collected, washed successively with methanol, hexanes, and ethyl ether and dried to give compound 3 (6.25 g, 81% yield).
  • 3
  • [ 56341-37-8 ]
  • [ 85070-48-0 ]
  • [ 897365-76-3 ]
YieldReaction ConditionsOperation in experiment
89% With piperidine; In methanol; at 50℃; for 3h; To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%).
  • 4
  • [ 1174006-94-0 ]
  • [ 85070-48-0 ]
  • [ 897365-76-3 ]
YieldReaction ConditionsOperation in experiment
89% With piperidine; In methanol; at 50℃; for 3h; Example 2 Preparation of intermediate E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one; To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%).
  • 5
  • [ 392332-35-3 ]
  • [ 85070-48-0 ]
  • [ 897365-76-3 ]
YieldReaction ConditionsOperation in experiment
89% With piperidine; In methanol; at 50℃; for 3h; To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%).
  • 6
  • [ 897365-76-3 ]
  • [ 1398570-16-5 ]
  • [ 623-33-6 ]
  • [ 1398571-15-7 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,3-bis(fluoromethyl)cyclobutan-1-one; glycine ethyl ester hydrochloride With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 70℃; for 1h; Molecular sieve; Stage #2: (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one In tetrahydrofuran; N,N-dimethyl-formamide at 70℃; for 32h; 57.1; 57.2 Glycine ethyl ester hydrochloride (6.98 g, 50 mmol) and the compound (6.70 g, 50.0 mmol) obtained in Step 2 of Reference Example 21 were dissolved in tetrahydrofuran (210 ml) and N,N-dimethylformamide (210 ml), triethylamine (7.6 ml, 54.5 mmol) and molecular sieves 4A (powder) (18.8 g) were added and the resulting mixture was stirred at 70° C. for 1 hour. (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) (14.0 g, 45.4 mmol) was added to the reaction mixture and the resulting mixture was stirred at 70° C. for 14 hours. Glycine ethyl ester hydrochloride (1.58 g, 11.4 mmol) and the compound (1.52 g, 11.4 mmol) obtained in Step 2 of Reference Example 21 were further added to the reaction mixture and the resulting mixture was further stirred at 70° C. for 18 hours. After cooling, insoluble matter was removed by filtration through celite and the filtrate was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=9:1→1:1 (v/v)] to give 5.31 g (22%) of the title compound.Step 2Ethyl (3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-3,3-bis(fluoromethyl)-2-oxo-1,2-dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3-indole]-5'-carboxylateThe racemate (5.31 g, 10.1 mmol) obtained in Step 1 above was fractionated and purified by chiral column liquid chromatography [fractionation conditions: CHIRALPAK IC, n-hexane:tetrahydrofuran=4:1 (v/v)] to give 2.33 g (44%) of the title compound.1H-NMR (400 MHz, CDCl3) δ: 1.19 (3H, t, J=7.1 Hz), 1.70 (1H, d, J=13.7 Hz), 1.83-1.89 (1H, m), 2.20 (1H, d, J=12.8 Hz), 2.42 (1H, dd, J=12.8, 2.7 Hz), 3.66-3.76 (1H, m), 3.77-3.96 (2H, m), 4.09-4.22 (2H, m), 4.45 (1H, d, J=9.5 Hz), 4.48 (1H, d, J=9.5 Hz), 4.54-4.78 (2H, m), 6.81 (1H, d, J=1.8 Hz), 6.96 (1H, td, J=8.0, 1.2 Hz), 7.13 (1H, dd, J=8.0, 2.1 Hz), 7.16-7.21 (1H, m), 7.36 (1H, br s), 7.40 (1H, dd, J=8.1, 2.0 Hz), 7.44-7.48 (1H, m).
  • 7
  • [ 897365-76-3 ]
  • [ 4255-62-3 ]
  • [ 282735-66-4 ]
  • (3'S,4'R,7'S,8'S,8a'R)-6-chloro-8'-(3-chloro-2-fluorophenyl)-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(1H)-dione [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 8
  • [ 897365-76-3 ]
  • [ 630-19-3 ]
  • [ 282735-66-4 ]
  • [ 897365-81-0 ]
  • 9
  • [ 897365-76-3 ]
  • [ 4255-62-3 ]
  • [ 459-73-4 ]
  • ethyl (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With copper diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine In N,N-dimethyl acetamide at 20℃; for 22h; Inert atmosphere; 2 [Example 2] (3'-chloro-2-fluorophenyl) -4,4-dimethyl-2''-oxo-1 ', 4'- ', 2' '- Dihydrospiro [cyclohexane-1,2'-pyrrolidin-3', 3 '-indole] -5'-carboxylate To a solution of (3E / Z) -6-chloro-3- (3-chloro-2- fluorobenzylidene) -1,3-dihydro-2H-indol-2- one (WO2006 / 091646 ) (98.7 mg), (R) -BINAP (12.1 mg, 0.019 mmol), CuOAc (2.0 mg, 0.016 mmol) was added 4,4-dimethylcyclohexanone (61.4 mg, 0.48 mmol) (39.5 L, 0.39 mmol), triethylamine (6.8 L, 0.049 mmol) in N, N-dimethylacetamide (2.0 mL) was stirred at room temperature for 22 hours. To the reaction mixture was added ethyl acetate (2 mL), water (1 mL), 20% aqueous ammonium chloride solution (1 mL), and the organic layer was vigorously stirred. The aqueous layer was extracted twice with ethyl acetate (2 mL each), all the organic layers were combined and then washed three times with water (5 mL each). The resulting organic layer was concentrated under reduced pressure, ethyl acetate (6 mL) and silica gel (500 mg) were added to the residue, and the silica gel was filtered off. The filtrate was concentrated under reduced pressure, ethanol (1.0 mL) was added to the residue, water (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure at 40 ° C, whereby the title compound (137 mg, yield: 82%, 94% ee) was obtained as a solid.
  • 10
  • [ 897365-76-3 ]
  • [ 4255-62-3 ]
  • [ 459-73-4 ]
  • ethyl (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With copper (I) acetate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; triethylamine In N,N-dimethyl acetamide at 20℃; for 22h; Inert atmosphere; 2 Example 2 Ethyl (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate Example 2 Ethyl (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxylate To a mixture of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) (98.7 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of 4,4-dimethlcyclohexanone (61.4 mg, 0.48 mmol), glycine ethyl ester (39.5 μL, 0.39 mmol) and triethylamine (6.8 μL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 22 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2 mL each), and the organic layers were all combined and then washed with water three times (5 mL each). The organic layer obtained was concentrated under reduced pressure. To the residue, ethyl acetate (6 mL) and silica gel (500 mg) were added, and the silica gel was filtered off. The filtrate was concentrated under reduced pressure. To the residue, ethanol (1.0 mL) was added, then water (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The deposited solid was filtered and dried under reduced pressure at 40° C. to obtain the title compound (137 mg, yield: 82%, 94% ee) as a solid. 1H NMR (500 MHz, CDCl3): δ=0.67 (s, 3H), 0.91 (s, 3H), 1.10-1.19 (m, 2H), 1.17 (t, J=7.3 Hz, 3H), 1.25-1.33 (m, 1H), 1.44-1.72 (m, 3H), 1.87-2.01 (m, 1H), 3.16 (s, 1H), 4.07-4.21 (m, 2H), 4.52 (d, J=8.5 Hz, 1H), 4.83 (d, J=8.5 Hz, 1H), 6.74 (d, J=1.5 Hz, 1H), 6.81-6.86 (m, 1H), 7.06 (dd, J=8.3, 2.8 Hz, 1H), 7.10-7.16 (m, 1H), 7.37 (dd, J=8.3, 1.8 Hz, 1H), 7.48-7.54 (m, 1H), 7.81 (s, 1H).(0242) (Conditions for HPLC for Optical Purity Measurement) (0243) Column: CHIRALPAK OD-3R 4.6×150 mm, 3 μm (0244) Mobile phase: 10 mM phosphate buffer:MeCN=40:60 (0245) Flow rate: 1.0 min/min (0246) Column temperature: 40° C. (0247) Detection wavelength: 254 nm (0248) Injection quantity: 5 μL, (0249) Retention time: title compound=13.8 min, enantiomer=12.9 min
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