Citric Acid → N-Butyloxycarbonyl-3-[3-(3-methylimidazolidine-2,5-dione-1-ylmethyl)-phenyl]-5-iso-butylthiophene-2-sulfonamide

HRID 562557Notes

Reaction equation

HRID 562557 reaction equation
[CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=2)[C:3]1=[O:32].B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:49]([O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:50].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:52]([O:51][C:49]([NH:27][S:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:4]2[C:5](=[O:7])[CH2:6][N:2]([CH3:1])[C:3]2=[O:32])[CH:10]=1)(=[O:26])=[O:25])=[O:50])[CH2:53][CH2:54][CH3:55]

Participants

7

Reactant 5

HCID 311Citric AcidHCID 25135Boron TrichlorideHCID 61140Butyl chloroformateHCID 110190202-(Pyrrolidin-1-yl)pyridineHCID 670039673-[3-(3-methylimidazolidine-2,5-dione-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide

Product 1

HCID 11957071N-Butyloxycarbonyl-3-[3-(3-methylimidazolidine-2,5-dione-1-ylmethyl)-phenyl]-5-iso-butylthiophene-2-sulfonamideYield 80%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 3-[3-(3-methylimidazolidine-2,5-dione-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (42.1 mg, 0.088 mmol; see step (a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water, and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (26.1 mg, 0.176 mmol) and butyl chloroformate (112.0 μL, 0.88 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (3:97) as eluent and then with LCMS (30-100% CH3CN in water) to give the title compound in 80% yield, over two steps, (36.6 mg, 0.702 mmol).

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. additionWater (5 mL) was added to the residue
  3. extractionthis was then extracted with EtOAc
  4. washThe combined organic phase was washed with water, and brine
  5. dry with materialdried (over anhydrous MgSO4)
  6. concentrationconcentrated in vacuo
  7. dissolutionTo the crude product dissolved in pyridine (1.5 mL)
  8. stirringthe reaction mixture was stirred overnight
  9. extractionwas then extracted with EtOAc
  10. dry with materialdried (over anhydrous MgSO4)
  11. concentrationconcentrated in vacuo
  12. customthe residue purified by flash chromatography

Sources & evidence

ORD record
ord-75643446876743d1811ec9f92965bc38
Source dataset
uspto-grants-2011_11
Patent number
US08067418B2

Reaction notes

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