Trifluoroacetic acid → HCID 178468257, compound

HRID 2096108Notes

Reaction equation

HRID 2096108 reaction equation
C[O:2][C:3](=[O:31])[C:4]([OH:30])([CH3:29])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.[OH:39][C:40]1[CH:44]=[C:43]([C:45](O)=[O:46])[O:42][N:41]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.O.[OH-].[Li+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:28][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:6]([CH2:5][C:4]([OH:30])([CH3:29])[C:3]([OH:2])=[O:31])[NH:7][C:45]([C:43]3[O:42][N:41]=[C:40]([OH:39])[CH:44]=3)=[O:46])=[CH:17][CH:18]=2)[CH:27]=[CH:26][CH:25]=1

Participants

12

Reactant 7

HCID 6422Trifluoroacetic acidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrateHCID 181649HOAtHCID 681809013-[N'-t-Butoxycarbonyl-N-(3'-fluorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid methyl esterHCID 178524642HCID 178524642, compound

Product 1

HCID 178468257HCID 178468257, compoundYield 0%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolvent3×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

3-[N′-t-Butoxycarbonyl-N-(3′-fluorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid methyl ester (100 mg, 231 mmol, 1.0 eq.) was dissolved in DCM (2.0 mL). TFA (2.0 mL) was added and the mixture was stirred at room temperature until the reaction was complete (˜45 minutes). The mixture was then concentrated. 3-Hydroxyisoxazole-5-carboxylic acid (38.8 mg, 300 mmol, 1.3 eq.) and 1 HOAt (40.9 mg, 300 μmol, 1.3 eq.) were dissolved in DMF (2 mL) of DMF, then EDCI (53.2 μL) was added followed by DIPEA (121 μL) and the mixture was stirred for 30 minutes. To this was added the concentrated mixture from above in DMF (2 mL) and the resulting mixture was stirred at room temperature until the reaction was complete (˜2.5 hours). The mixture was then dissolved in THF (2.0 mL), followed by the addition of lithium hydroxide monohydrate (97.0 mg, 2.3 mmol) in water (2.0 mL. The resulting mixture was stirred at room temperature until the reaction was complete (˜1 hour). The reaction was quenched by addition of AcOH, then the solution was concentrated. The crude product was purified by preparative HPLC (10-70% MeCN/water) to yield the title compound (43 mg; purity 99%). MS m/z [M+H]+ calc'd for C21H20FN3O6, 430.13; found 430.4.

Workup

  1. custom(˜45 minutes)
  2. concentrationThe mixture was then concentrated
  3. stirringthe mixture was stirred for 30 minutes
  4. stirringthe resulting mixture was stirred at room temperature until the reaction
  5. custom(˜2.5 hours)
  6. stirringThe resulting mixture was stirred at room temperature until the reaction
  7. custom(˜1 hour)
  8. customThe reaction was quenched by addition of AcOH
  9. concentrationthe solution was concentrated
  10. customThe crude product was purified by preparative HPLC (10-70% MeCN/water)

Sources & evidence

ORD record
ord-1d552435aa7e499cb4411020e16c2413
Source dataset
uspto-grants-2013_05
Patent number
US08449890B2

Reaction notes

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