Acetic Anhydride → HCID 67468474, compound

HRID 2204267Notes

Reaction equation

HRID 2204267 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:29]3[C:30]([CH:33]=O)=[CH:31][CH:32]=[C:28]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:35]=1.Cl.[NH2:37]O.C([O-])(=O)C.[Na+].CC(OC(C)=O)=O.C([O-])(O)=O.[Na+]>C(O)C.O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:29]3[C:30]([C:33]#[N:37])=[CH:31][CH:32]=[C:28]3[C:8]3([CH2:9][CH2:10][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:12][CH2:13]3)[O:7][C:6]=2[CH:35]=1

Participants

9

Reactant 5

HCID 7918Acetic AnhydrideHCID 443297Hydroxyamine hydrochlorideHCID 516892Sodium BicarbonateHCID 517045Sodium AcetateHCID 58550852HCID 58550852, compound

Product 1

HCID 67468474HCID 67468474, compound

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
95 °C

Procedure

To a solution of 7-chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro-[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (310 mg, 0.61 mmol) in ethanol (1.5 mL) was added an aqueous solution of hydroxylamine hydrochloride (190 mg, 2.7 mmol) and sodium acetate (380 mg, 4.6 mmol) in water (1.5 mL). The mixture was heated at 95° C. for 2 hours. The reaction mixture was cooled to 25° C., water was added and the white precipitate that formed was collected by filtration, washed thoroughly with water and dried by azeotrope with toluene. The solid was dissolved in Ac2O (1.1 mL, 12 mmol) and was heated at 140° C. for 3.5 hours. The mixture was cooled to 25° C., poured into ice, diluted with dichloromethane (30 mL), and neutralized with NaHCO3 (2 g). The organic phase was separated, and the aqueous phase further extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried, filtered, concentrated to a yellow oil that was purified by column chromatography (silica gel, 5-30% AcOEt in hexanes) to yield 7-chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro[benzo-[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile. 1H NMR (400 MHz, CDCl3) δ 8.06 (t, J=10.1 Hz, 1H), 7.70 (s, 1H), 7.64 (dd, J=8.6, 1.6 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.10 (dd, J=8.7, 2.2 Hz, 1H), 7.03 (dd, J=10.4, 6.3 Hz, 2H), 6.13 (d, J=4.0 Hz, 1H), 4.61 (s, 1H), 3.96 (d, J=20.2 Hz, 3H), 3.89-3.06 (m, 3H), 2.16-1.81 (m, 4H). ESI-MS m/z calc. 501.9, found 502.0 (M+1)+; Retention time: 2.17 minutes (3 min run).

Workup

  1. temperatureThe reaction mixture was cooled to 25° C.
  2. customthe white precipitate that formed
  3. filtrationwas collected by filtration
  4. washwashed thoroughly with water
  5. dry with materialdried by azeotrope with toluene
  6. temperaturewas heated at 140° C. for 3.5 hours
  7. temperatureThe mixture was cooled to 25° C.
  8. additionpoured into ice
  9. customThe organic phase was separated
  10. extractionthe aqueous phase further extracted twice with dichloromethane
  11. washwashed with brine
  12. customdried
  13. filtrationfiltered
  14. concentrationconcentrated to a yellow oil that
  15. customwas purified by column chromatography (silica gel, 5-30% AcOEt in hexanes)

Sources & evidence

ORD record
ord-554fd2dd95944ec2b0835efd9a00cf89
Source dataset
uspto-grants-2016_06
Patent number
US09365588B2

Reaction notes

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