Ethanol → HCID 89648878, compound

HRID 2207678Notes

Reaction equation

HRID 2207678 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C@H:17]3[CH2:21][CH2:20][C@@:19]4([CH2:25][CH2:24][N:23]([CH3:26])[C:22]4=[O:27])[NH:18]3)[CH:12]=1)[NH:7][N:6]=[CH:5]2.N(C(OC(C)(C)C)=O)=NC(O[C:33](C)(C)[CH3:34])=O.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:33]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C@H:17]4[CH2:21][CH2:20][C@@:19]5([CH2:25][CH2:24][N:23]([CH3:26])[C:22]5=[O:27])[NH:18]4)[CH:12]=3)[CH:9]=2)[CH:5]=[N:6]1)[CH3:34]

Participants

6

Reactant 4

HCID 702EthanolHCID 11776TriphenylphosphineHCID 97268Di-tert-butyl azodicarboxylateHCID 89649481HCID 89649481, compound

Product 1

HCID 89648878HCID 89648878, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
800 °C

Procedure

To a Smith microwave vial was added (2R,5S)-2-[4-(5-fluoro-1H-indazol-6-yl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Example 186) (40 mg, 0.1100 mmol), di-tert-butyl azodicarboxylate (126.03 mg, 0.5500 mmol), ethanol (0.03 mL, 0.5500 mmol) and triphenyl phosphine (143.56 mg, 0.5500 mmol) in THF (1 mL). The reaction mixture was heated by microwave at 800° C. for 45 minutes. The reaction mixture was cooled and eluted on an SCX-2 cartrige (0.5 g) and washed with DCM followed by MeOH. The desired product was eluted off the cartridge with ammonia in MeOH (0.2M). Evaporation of solvents gave a colourless oil. The crude residue was purified by silica gel chromatography (silica 10 g) eluting with methanol (containing 10% 0.88 ammonia) in ethyl acetate (0-80%), to give the products as a mixture of isomers. These were separated by HPLC using a ChiralPak IA column and eluting with ethanol/n-heptane (20%:80%) to give (2R,5S)-2-[4-(1-ethyl-5-fluoro-indazol-6-yl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one as the major isomer;

Workup

  1. temperatureThe reaction mixture was cooled
  2. washeluted on an SCX-2 cartrige (0.5 g)
  3. washwashed with DCM
  4. washThe desired product was eluted off the cartridge with ammonia in MeOH (0.2M)
  5. customEvaporation of solvents
  6. customgave a colourless oil
  7. customThe crude residue was purified by silica gel chromatography (silica 10 g)
  8. washeluting with methanol (containing 10% 0.88 ammonia) in ethyl acetate (0-80%)
  9. customto give the products
  10. additionas a mixture of isomers
  11. customThese were separated by HPLC
  12. washeluting with ethanol/n-heptane (20%:80%)

Sources & evidence

ORD record
ord-1b055e91e3fc45309943113ceb667e31
Source dataset
uspto-grants-2016_06
Patent number
US09376436B2

Reaction notes

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