Diisopropylethylamine → 4-{2-Butyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoic Acid

HRID 341380Notes

Reaction equation

HRID 341380 reaction equation
C([S:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.Cl.C[O:49][C:50](=[O:71])[C:51]1[CH:56]=[CH:55][C:54]([CH2:57][N:58]2[C:62]([CH2:63][NH2:64])=[CH:61][N:60]=[C:59]2[CH2:65][CH2:66][CH2:67][CH3:68])=[C:53]([F:69])[C:52]=1[F:70]>CN(C=O)C>[CH2:65]([C:59]1[N:58]([CH2:57][C:54]2[CH:55]=[CH:56][C:51]([C:50]([OH:71])=[O:49])=[C:52]([F:70])[C:53]=2[F:69])[C:62]([CH2:63][NH:64][C:6](=[O:8])[C@@H:5]([SH:4])[CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:61][N:60]=1)[CH2:66][CH2:67][CH3:68]

Participants

6

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 14505484(S)-2-(Acetylthio)-4-methylpentanoic acidHCID 669685314-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acid methyl ester dihydrochloride salt

Product 1

HCID 529130354-{2-Butyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoic AcidYield 23.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

(S)-2-Acetylsulfanyl-4-methylpentanoic acid (205 mg, 1.1 mmol) was dissolved in DMF (8.1 mL, 104 mmol). HATU (409 mg, 1.1 mmol) and DIPEA (170 μL, 1.0 mmol) were added and the mixture was stirred at room temperature for 30 minutes. 4-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acid methyl ester dihydrochloride salt (401 mg, 1.0 mmol) was dissolved in DMF (1 ml) with DIPEA (170 μL, 1.0 mmol) and added to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction was then quenched with water, and the mixture extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude residue was then redissolved in 1:1 MeOH:NaOH (4 mL) and stirred at room temperature under nitrogen for 1 hour. The reaction was quenched with acetic acid and the mixture was concentrated. The product was purified by preparative HPLC (2-90%) to yield 108 mg of the title compound as a white solid. MS m/z: [M+H+] calcd for C22H29F2N3O3S, 454.19; found 454.2. 1H-NMR (DMSO): 8.44 (1H, t), 7.59 (1H, t), 7.25 (1H, s), 6.62 (1H, t), 5.56 (2H, s), 4.24 (2H, m), 3.14 (2H, q), 2.79 (2H, t), 2.72 (1H, d), 1.2-1.6 (7H, m), 0.78 (6H, d), 0.71 (3H, d).

Workup

  1. additionadded to the mixture
  2. stirringThe mixture was stirred at room temperature for 2 hours
  3. customThe reaction was then quenched with water
  4. extractionthe mixture extracted with EtOAc
  5. washwashed with saturated aqueous NaCl
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. dissolutionThe crude residue was then redissolved in 1:1 MeOH
  10. stirringNaOH (4 mL) and stirred at room temperature under nitrogen for 1 hour
  11. customThe reaction was quenched with acetic acid
  12. concentrationthe mixture was concentrated
  13. customThe product was purified by preparative HPLC (2-90%)

Sources & evidence

ORD record
ord-973f8f9166fc439ca0e969f6f6dea640
Source dataset
uspto-grants-2014_11
Patent number
US08895755B2

Reaction notes

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