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

HRID 1811990Notes

Reaction equation

HRID 1811990 reaction equation
C([Li])CCC.[F:6][C:7]1[N:12]=[CH:11][C:10]([C@H:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[CH:9][CH:8]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][N:15]([C@@H:13]([C:10]2[CH:9]=[C:8]([B:28]([OH:33])[OH:29])[C:7]([F:6])=[N:12][CH:11]=2)[CH3:14])[CH2:20][CH2:19]1)=[O:22])([CH3:26])([CH3:25])[CH3:27]

Participants

5

Reactant 3

HCID 21531Triisopropyl borateHCID 68517711(R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 66600472(R)-5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acidYield 81.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

n-Butyllithium (2.5 M in hexanes, Aldrich; 20.0 mL, 50.0 mmol) was added (dropwise over 20 min) to a solution of (R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (10.0 g, 32.3 mmol) in THF (150 mL) at −78° C., and the resulting mixture was stirred at −78° C. for 20 min. Triisopropyl borate (15.0 mL, 65.2 mmol) was then added (dropwise over 10 min), followed by additional THF (20 mL) to rinse solidified triisopropyl borate from the side of the flask. The resulting mixture was stirred at −78° C. for 15 min, and the cooling bath was then removed. The reaction mixture was stirred for 1 h, and 1 N aq. NaOH (100 mL) and water (40 mL) were then sequentially added. The resulting mixture was stirred for 10 min, and the organic layer was separated. The organic layer was extracted with 1 N aq. NaOH (40 mL), and the aqueous layers were then combined and pH-adjusted with 5 N aqueous HCl to a final pH of about 5. The resulting mixture was extracted with EtOAc (3×200 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (R)-5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (9.27 g, 81% yield) as a white solid. 1H NMR (400 MHz, d4-MeOH) δ 8.39 (br. s., 1H), 8.26 (d, J=6.5 Hz, 1H), 4.54-4.63 (m, 1H), 3.31 (br. s., 4H; masked by MeOH), 3.13 (br. s., 4H), 1.80 (d, J=6.8 Hz, 3H), 1.45 (s, 9H). 19F NMR (377 MHz, d4-MeOH) δ −60.93 (br. s., 1 F). m/z (ESI, +ve) 354.2 (M+H)+.

Workup

  1. washto rinse solidified triisopropyl borate from the side of the flask
  2. stirringThe resulting mixture was stirred at −78° C. for 15 min
  3. customthe cooling bath was then removed
  4. stirringThe reaction mixture was stirred for 1 h
  5. addition1 N aq. NaOH (100 mL) and water (40 mL) were then sequentially added
  6. stirringThe resulting mixture was stirred for 10 min
  7. customthe organic layer was separated
  8. extractionThe organic layer was extracted with 1 N aq. NaOH (40 mL)
  9. extractionThe resulting mixture was extracted with EtOAc (3×200 mL)
  10. dry with materialthe combined organic extracts were dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-b055511eae6b4e38b672a0de8ceec50a
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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