Dimethylformamide → HCID 68210096, compound

HRID 1908041Notes

Reaction equation

HRID 1908041 reaction equation
[CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C1COCC1>[C:31]([C:1]1[N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]2=[CH:3][CH:2]=1)#[N:30]

Participants

5

Reactant 3

HCID 6228DimethylformamideHCID 70918Chlorosulfonyl isocyanateHCID 58550745HCID 58550745, compound

Product 1

HCID 68210096HCID 68210096, compoundYield 76.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-75 °C

Procedure

To tert-butyl spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (54.6 g, 160.5 mmol) in THF (500 mL) at −75° C. was added chlorosulfonyl isocyanate (17.5 mL, 200.6 mmol) in THF (100 mL) dropwise over a 30 minutes period keeping the temperature below −70° C. and the mixture was stirred at −75° C. for 1 hr. To this mixture was added DMF (37.3 mL, 481.5 mmol) dropwise at −75° C. and the mixture was warmed to ambient temperature, stirring for a total of 2 h. The mixture was quenched with 1 L of 1N NaOH and transferred to a separatory funnel with 500 mL of methyl-tert-butyl ether. The aqueous phase was separated and extracted with an additional 500 mL of methyl-tert-butyl ether. The combined organic phases were washed twice with 500 mL of brine, dried over MgSO4, filtered and concentrated in vacuo to yield a crude mixture that was purified by column chromatography with a 0-100% EtOAc/hexane gradient to yield tert-butyl 1-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (45 g, 76%) as an oil that crystallized upon standing. ESI-MS m/z calc. 365.2. found 266.2 (M-Boc+1)+. Retention time: 2.43 minutes (3 min run).

Workup

  1. customthe temperature below −70° C.
  2. temperaturethe mixture was warmed to ambient temperature
  3. stirringstirring for a total of 2 h
  4. customThe mixture was quenched with 1 L of 1N NaOH
  5. customtransferred to a separatory funnel with 500 mL of methyl-tert-butyl ether
  6. customThe aqueous phase was separated
  7. extractionextracted with an additional 500 mL of methyl-tert-butyl ether
  8. washThe combined organic phases were washed twice with 500 mL of brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customto yield a crude mixture that
  13. customwas purified by column chromatography with a 0-100% EtOAc/hexane gradient

Sources & evidence

ORD record
ord-2d9496e6584f4dc28326069984414705
Source dataset
uspto-grants-2013_12
Patent number
US08598164B2

Reaction notes

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