3,3-Dimethylbutanal → HCID 68749601, compound

HRID 1192023Notes

Reaction equation

HRID 1192023 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]\[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[F:20])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:21]1([C@@H:27]2[NH:32][CH2:31][C:30](=[O:33])[O:29][C@@H:28]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH:43]=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C@@:6]3([C@H:43]([CH2:42][C:41]([CH3:46])([CH3:45])[CH3:40])[N:32]4[C@H:31]([C:30](=[O:33])[O:29][C@H:28]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C@@H:27]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C@H:12]3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[F:20])[C:5]2=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 763353,3-DimethylbutanalHCID 10354905(5S,6R)-5,6-diphenyl-2-morpholinoneHCID 57987043HCID 57987043, compound

Product 1

HCID 68749601HCID 68749601, compoundYield 56%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

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 μL (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 μm 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 μm-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, 9 H); 1.30 (dd, J=4.0 and 15.2 Hz, 1 H); 1.93 (dd, J=6.3 and 15.2 Hz, 1 H); 3.49 (dd, J=4.0 and 6.3 Hz, 1 H); 4.47 (d, J=11.2 Hz, 1 H); 5.04 (d, J=4.2 Hz, 1 H); 5.08 (d, J=11.2 Hz, 1 H); 6.53 (d, J=8.1 Hz, 1 H); 6.66 to 6.76 (m, 3 H); 6.96 (m, 2 H); 7.10 to 7.26 (m, 9 H); 7.34 (t broad, J=7.9 Hz, 1 H); 7.62 (t broad, J=7.9 Hz, 1 H); 10.71 (s broad, 1 H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux temperature for 6 hours
  3. concentrationconcentrated to dryness under reduced pressure
  4. customThe residue was purified by flash chromatography on a 70 g silica cartridge (15-40 μm silica gel; eluting solvent: cyclohexane/ethyl acetate 90/10 v/v; flow: 50 mL/min)

Sources & evidence

ORD record
ord-6789c4101ba94f29995d999a27cfd9fa
Source dataset
uspto-grants-2014_03
Patent number
US08680132B2

Reaction notes

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