Acetic Acid → 2-(Trimethylacetylamino)-6-[(4-t-butoxycarbonylamino-1-piperidinyl)methyl]pyridine formic acid salt

HRID 992737Notes

Reaction equation

HRID 992737 reaction equation
[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=O)[N:7]=1)=[O:4].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:19][CH2:18]1.[C:30]([OH:33])(=[O:32])C.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[H][H].[OH-].[Na+].O1[CH2:56][CH2:55][CH2:54]C1>O>[CH:23]([OH:25])=[O:24].[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:30]([O:33][C:55]([CH3:54])([CH3:56])[CH3:34])=[O:32])[CH2:22][CH2:21]2)[N:7]=1)=[O:4]

Participants

9

Reactant 7

HCID 176Acetic AcidHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 12682914-Amino-1-Boc-piperidineHCID 5049666Sodium triacetoxyborohydrideHCID 9920710N-(6-formylpyridin-2-yl)-2,2-dimethylpropanamideHCID 178418361HCID 178418361, compound

Product 1

HCID 184131672-(Trimethylacetylamino)-6-[(4-t-butoxycarbonylamino-1-piperidinyl)methyl]pyridine formic acid salt

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a stirred solution of 2-(trimethylacetylamino)-6-formylpyridine (3.00 g, 14.6 mmol) in 1:1 ethyl acetatetetrahydrofuran (24 mL) was added 4-amino-N-Boc-piperidine (reference example 2, 3.38 g, 18.2 mmol) and acetic acid (1.16 mL, 20.3 mmol) at 15° C. Then, sodium triacetoxyborohydride (4.50 g, 20.1 mmol) was added in 4 portions to the above homogenous solution over a period of 1.5 h at room temperature. Then, additional of tetrahydrofuran (6 mL) was added. After stirred for 1 h at room temperature, water (3 mL) was added maintaining the temperature below 15° C. with an ice-water bath. The reaction mixture was stirred for 10 min (after evolution of hydrogen) and 1N NaOH (22 mL) was added at this temperature. The mixture was extracted with ethyl acetate (3×40 mL) and the ethyl acetate extract washed with brine (40 mL). Then, the resulting solution was concentrated under reduced pressure and re-dissolved in ethyl acetate (40 mL) and treated with formic acid (1 mL). Then, the solvent was switched with methyl t-butyl ether (30 mL) and hexane (50 mL) was added dropwise. After stirring for 1.5 h at room temperature, the solvent was decanted and the residual formate salt of reductive amination product was dried to give 4.9 g (90%) as a sticky material.

Workup

  1. temperaturemaintaining the temperature below 15° C. with an ice-water bath
  2. additionwas added at this temperature
  3. extractionThe mixture was extracted with ethyl acetate (3×40 mL)
  4. extractionthe ethyl acetate extract
  5. washwashed with brine (40 mL)
  6. concentrationThen, the resulting solution was concentrated under reduced pressure
  7. dissolutionre-dissolved in ethyl acetate (40 mL)
  8. additiontreated with formic acid (1 mL)
  9. additionwas added dropwise
  10. stirringAfter stirring for 1.5 h at room temperature
  11. customthe solvent was decanted
  12. dry with materialthe residual formate salt of reductive amination product was dried
  13. customto give 4.9 g (90%) as a sticky material

Sources & evidence

ORD record
ord-49b54c87b52e4f468a6c71ea4f81d0eb
Source dataset
uspto-grants-2002_10
Patent number
US06469172B2

Reaction notes

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