Citric Acid → HCID 71113201, compound

HRID 716829Notes

Reaction equation

HRID 716829 reaction equation
[NH2:1][C@:2]([CH3:26])([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][O:17][C:16]3([CH3:23])[CH3:22])=[CH:8][CH:7]=1)=[O:4].C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[CH3:23][C:16]1([CH3:22])[C:15]2[CH:14]=[C:13]([O:12][C:9]3[CH:8]=[CH:7][C:6]([N:5]4[C:3](=[O:4])[C@:2]([CH2:24][CH3:25])([CH3:26])[NH:1][C:32]4=[O:33])=[CH:11][CH:10]=3)[CH:21]=[CH:20][C:19]=2[CH2:18][O:17]1

Participants

5

Reactant 3

HCID 311Citric AcidHCID 682631,1'-Carbonyldiimidazole3×HCID 71113010HCID 71113010, compound2×

Product 1

HCID 71113201HCID 71113201, compound

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent3×

Procedure

(2R)-2-amino-N-[4-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]phenyl]-2-methyl-butanamide (Intermediate 71, 140 mg, 0.39 mmol) was dissolved in ethyl acetate (2 mL) and the resulting solution was added drop wise to a suspension of CDI (1.4 equiv) in ethyl acetate (0.5 mL). The resulting suspension was stirred overnight. A new solution of CDI was freshly prepared (60 mg in 0.5 mL of ethyl acetate) and added drop wise to the mixture. A third portion of CDI (50 mg) was added and the reaction mixture was left stirring over week-end at room temperature. The mixture was treated with 10% w/w aqueous citric acid solution, two layers were separated and the organic layer washed with water and brine, then dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate from 80:20 to 60:40 as eluent. The fractions containing the product were combined, evaporated to dryness and further purified by crystallization from ethyl acetate/n-heptane. The slurry was stirred for 2 hours, and then the solid collected, washed with n-heptane and dried under vacuum. The residue was re-purified by flash chromatography on silica gel using dichloromethane/methanol from 100:0 to 90:10. The fractions containing the product were combined, evaporated to dryness and the residue further purified by crystallization from methyl tertbutyl ether/n-heptane to afford the title compound (47 mg) as white solid.

Workup

  1. additionthe resulting solution was added drop
  2. additionadded drop wise to the mixture
  3. waitthe reaction mixture was left
  4. stirringstirring over week-end at room temperature
  5. customwere separated
  6. washthe organic layer washed with water and brine
  7. dry with materialdried over Na2SO4
  8. customevaporated to dryness
  9. customThe residue was purified by flash chromatography on silica gel
  10. additionThe fractions containing the product
  11. customevaporated to dryness
  12. customfurther purified by crystallization from ethyl acetate/n-heptane
  13. stirringThe slurry was stirred for 2 hours
  14. customthe solid collected
  15. washwashed with n-heptane
  16. customdried under vacuum
  17. customThe residue was re-purified by flash chromatography on silica gel
  18. additionThe fractions containing the product
  19. customevaporated to dryness
  20. customthe residue further purified by crystallization from methyl tertbutyl ether/n-heptane

Sources & evidence

ORD record
ord-e53d2a43313a4a378fd70f32a51484a0
Source dataset
uspto-grants-2015_11
Patent number
US09193704B2

Reaction notes

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