Triisopropyl borate → 5-(1-(4-(Tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid

HRID 1621848Notes

Reaction equation

HRID 1621848 reaction equation
[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>O1CCCC1>[C:19]([O:18][C:16]([N:13]1[CH2:12][CH2:11][N:10]([CH:8]([C:5]2[CH:4]=[C:3]([B:28]([OH:33])[OH:29])[C:2]([F:1])=[N:7][CH:6]=2)[CH3:9])[CH2:15][CH2:14]1)=[O:17])([CH3:21])([CH3:20])[CH3:22]

Participants

5

Reactant 3

HCID 21531Triisopropyl borateHCID 68515831Tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 666004735-(1-(4-(Tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acidYield 57.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (8.41 g, 27.2 mmol) in tetrahydrofuran (100 mL) was chilled to −78° C. in a dry ice/acetone bath. Then n-butyllithium (1.6 M in hexanes; Aldrich; 18.69 mL, 29.9 mmol) was added via cannula into the mixture. The deep red solution was stirred at the same temperature for 1 h, then triisopropyl borate (7.50 mL, 32.6 mmol) was added into the mixture. The resulting mixture was stirred at the same temperature (−78° C.) for 30 min, then the ice bath was removed. After the reaction mixture warmed up to room temperature, the tan mixture was quenched with 1 N NaOH(aq) (50 mL) and stirred 10 min. The separated aqueous layer was collected and the round-bottomed flask was rinsed with 1 N NaOH(aq) (2×10 mL). The aqueous layer was carefully acidified with 10% HCl until acidic (about pH 5 to 6) and the resulting cloudy mixture was extracted with 3:1 dichloromethane/methanol (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave 5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (5.507 g, 15.59 mmol, 57.4% yield) as tan solid. 1H NMR (400 MHz, d6-DMSO) δ 7.79-8.70 (m, 2H) 3.66 (t, J=6.36 Hz, 1H) 3.34 (s, 4H) 2.56 (s, 3H) 2.39 (s, 4H) 1.26-1.51 (m, 12H). m/z (ESI, +ve ion) 354.2 (M+H)+.

Workup

  1. stirringThe resulting mixture was stirred at the same temperature (−78° C.) for 30 min
  2. customthe ice bath was removed
  3. customthe tan mixture was quenched with 1 N NaOH(aq) (50 mL)
  4. stirringstirred 10 min
  5. customThe separated aqueous layer was collected
  6. washthe round-bottomed flask was rinsed with 1 N NaOH(aq) (2×10 mL)
  7. extractionthe resulting cloudy mixture was extracted with 3:1 dichloromethane/methanol (3×20 mL)
  8. dry with materialThe combined organic extracts were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-064f4b62b971489aa64b664e34107fe8
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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