Water → HCID 86713275, compound

HRID 927894Notes

Reaction equation

HRID 927894 reaction equation
[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([O-:33])=[O:32])=[C:29]3[C:24]([CH:25]4[CH2:34][CH:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH2:4]1)[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([OH:33])=[O:32])=[C:29]3[C:24]([C@H:25]4[CH2:34][C@H:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:18])=[O:19])[CH2:4]1)[CH3:2]

Participants

5

Reactant 3

HCID 962WaterHCID 168937Lithium hydroxide, monohydrate2×HCID 86713276HCID 86713276, compound2×

Product 1

HCID 86713275HCID 86713275, compoundYield 45%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of methyl (1aR,7bS))-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 221, 0.071 g) and lithium hydroxide monohydrate (0.059 g) was suspended in dioxane (5 mL) and water (2 mL) and the mixture was stirred and heated at 100° C. for 25 hours. Further lithium hydroxide monohydrate (0.116 g) was added and the mixture was heated at 100° C. for a further 18 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and saturated with sodium chloride. The mixture was extracted with DCM and the organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18), eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-60% to give (1aR,7bS)-5-[2-(1-ethyl-piperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.032 g) as a white solid.

Workup

  1. temperaturethe mixture was heated at 100° C. for a further 18 hours
  2. temperatureAfter cooling
  3. customthe volatiles were removed in vacuo
  4. additionthe residue was acidified by addition of aqueous citric acid solution (10%) and saturated with sodium chloride
  5. extractionThe mixture was extracted with DCM
  6. dry with materialthe organic layer was dried (Na2SO4)
  7. filtrationfiltered
  8. customThe filtrate was evaporated to dryness
  9. customthe residue was purified by preparative HPLC (C18)
  10. washeluting with a mixture of acetonitrile and water
  11. additioncontaining 0.1% formic acid

Sources & evidence

ORD record
ord-aa152450b25946638af7b0696f6b17a1
Source dataset
uspto-grants-2016_03
Patent number
US09290472B2

Reaction notes

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