Acetic Anhydride → HCID 66833631, compound

HRID 579566Notes

Reaction equation

HRID 579566 reaction equation
[ClH:1].Cl.[NH2:3][C:4]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C=O)C.Cl>[ClH:1].[NH2:3][C:4]([CH:15]1[CH2:16][CH2:17][N:18]([C:28](=[O:30])[CH3:29])[CH2:19][CH2:20]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6]

Participants

6

Reactant 3

HCID 7918Acetic AnhydrideHCID 8471TriethylamineHCID 66833181HCID 66833181, compound

Product 1

HCID 66833631HCID 66833631, compoundYield 53%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirring solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (Example 26-A, Step 1, 250 mg, 0.618 mmol) in dry DMF (13 mL) under nitrogen was added triethylamine (0.69 mL, 4.95 mmol) to give a white slurry. The resultant slurry was treated with acetic anhydride (0.131 mL, 1.39 mmol), added dropwise, and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was then diluted with ice water (10 mL) and 3 N HCl (5 mL) prior to extraction with ethyl acetate (2×25 mL). The aqueous layer was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 2% A for 2 min, 2% to 20% A over 23 min, then 20% to 100% A over 1 min.] Product fractions were pooled and concentrated, and the residue was taken up in 0.25N HCl (3 mL)/acetonitrile (8 mL) and concentrated. The residue was once again treated with 0.25N HCl (3 mL)/acetonitrile (8 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-[1-acetylpiperidin-4-yl]hexanoic acid hydrochloride (110 mg, 53%) as a white solid. 1H NMR (D2O, 400 MHz) δ 4.38 (bt, J=12 Hz, 1H), 3.92 (bt, J=12 Hz, 1H), 3.03 (m, 1H), 2.55 (m, 1H), 2.11 (m, 1H), 2.00 (s, 3H), 1.87-1.78 (m, 3H), 1.55 (m, 1H), 1.50-1.00 (m, 6H), 0.68 (t, J=7.2 Hz, 2H). ESI+ MS found for C13H25BN2O5 m/z 583.3 (2M−18+H), 565.6 (2M−2×18+H), 283.4 (M−18+H), 265.3 (M−2×18+H); ESI− MS m/z 581.6 (2M−18−H), 299.4 (M−H), 281.4 (M−18−H).

Workup

  1. customto give a white slurry
  2. additionadded dropwise
  3. extractionto extraction with ethyl acetate (2×25 mL)
  4. concentrationThe aqueous layer was concentrated under reduced pressure
  5. customto give the crude product which
  6. customwas purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column
  7. wait2% A for 2 min
  8. wait2% to 20% A over 23 min
  9. wait20% to 100% A over 1 min.] Product fractions were pooled
  10. concentrationconcentrated
  11. concentrationconcentrated
  12. additionThe residue was once again treated with 0.25N HCl (3 mL)/acetonitrile (8 mL)
  13. concentrationconcentrated
  14. customdried under high vacuum overnight

Sources & evidence

ORD record
ord-0f887dc7a5734698b6c91bf76b221231
Source dataset
uspto-grants-2015_05
Patent number
US09040703B2

Reaction notes

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