2-Amino-5-chlorophenol → HCID 90412941, compound

HRID 1526654Notes

Reaction equation

HRID 1526654 reaction equation
C([NH:9][C:10]1[O:11][C@@H:12]2[C@H:14]([C@@:15]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=3[F:30])[C:23]([O:25]C)=O)([CH:17]([F:19])[F:18])[N:16]=1)[CH2:13]2)(=O)C1C=CC=CC=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1O>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]2[N:31]=[C:23]([C:22]3[CH:27]=[CH:28][C:29]([F:30])=[C:20]([C@@:15]4([CH:17]([F:18])[F:19])[C@H:14]5[C@H:12]([CH2:13]5)[O:11][C:10]([NH2:9])=[N:16]4)[CH:21]=3)[O:25][C:33]=2[CH:34]=1

Participants

3

Reactant 2

HCID 915912-Amino-5-chlorophenolHCID 90415733HCID 90415733, compound

Product 1

HCID 90412941HCID 90412941, compoundYield 11%

Conditions

Temperature
170 °C

Procedure

A sealable vial was charged with methyl 3-((1S,5R,6S)-3-benzamido-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorobenzoate (0.100 g, 0.24 mmol), 2-amino-5-chlorophenol (0.086 g, 0.60 mmol) and polyphosphoric acid (0.50 mL). The reaction mixture was purged with nitrogen for 1 min and then heated to 170° C. for 1 h. The reaction mixture was allowed to cool to rt, neutralized with aqueous, saturated Na2CO3 solution and 1 N NaOH. The mixture was extracted three times with a solvent mixture of CHCl3:i-PrOH (3:1). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude was purified first by silica gel chromatography 0-100% EtOAc-hexane. The collected fractions were further purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 16 min. The fractions containing the desired product were combined and neutralized with solid Na2CO3. The aqueous phase was extracted with DCM and dried over Na2SO4. The filtrate was concentrated in vacuo to obtain the title compound as a beige solid (10.5 mg, 11% yield). MS m/z=408 [M+H]+. Calculated for C19H13ClF3N3O2: 407.8.

Workup

  1. customThe reaction mixture was purged with nitrogen for 1 min
  2. temperatureto cool to rt
  3. extractionThe mixture was extracted three times
  4. additionwith a solvent mixture of CHCl3:i-PrOH (3:1)
  5. dry with materialThe combined organic extracts were dried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe crude was purified first by silica gel chromatography 0-100% EtOAc-hexane
  8. customThe collected fractions were further purified by reverse-phase preparative HPLC
  9. customover 16 min
  10. additionThe fractions containing the desired product
  11. extractionThe aqueous phase was extracted with DCM
  12. dry with materialdried over Na2SO4
  13. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-9dd4309ac42f4a2aab108bfdfc393968
Source dataset
uspto-grants-2015_07
Patent number
US09085576B2

Reaction notes

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