3-(1-((Tert-butoxy)carbonyl)piperidin-4-yl)propanoic acid → HCID 19081835, compound

HRID 963337Notes

Reaction equation

HRID 963337 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].CON(C)C(=O)[C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([NH2:38])=[CH:33][C:32]=1[O:39][CH3:40]>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1.O>[NH2:38][C:34]1[C:35]([Cl:37])=[CH:36][C:31]([C:16](=[O:18])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[C:32]([O:39][CH3:40])[CH:33]=1

Participants

7

Reactant 3

HCID 15125403-(1-((Tert-butoxy)carbonyl)piperidin-4-yl)propanoic acidHCID 2724682Lithium diisopropylamideHCID 190818494-Amino-5-chloro-N,2-dimethoxy-N-methylbenzamide

Product 1

HCID 19081835HCID 19081835, compoundYield 21.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 12679HexamethylphosphoramideSolvent2×

Conditions

Temperature
0 °C

Procedure

3-[1-(tert-Butoxycarbonyl)piperidin-4-yl]propionic acid (4.6 g, 18 mmol), prepared as in Example 1, was dissolved in HMPA (10 mL) and THF (10 mL), and this solution was added to a -20° solution of lithium diisopropylamide (60 mmol). The mixture was warmed to 0° C., stirred for 30 minutes, and then cooled to -40° C. N-Methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (4.9 g, 20 mmol), prepared as in Example 2, was dissolved in HMPA (10 mL) and THF (10 mL) and this solution was added to the mixture. The mixture was allowed to warm to 0° C. over 1 hour, then diluted with water, washed with ether, acidified with hydrochloric acid, and extracted into methylene chloride. The methylene chloride extract was concentrated in vacuo and the residue was heated in an oil bath to 140° C. for 30 minutes. The mixture was cooled, partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with 5% sodium hydroxide and then brine, dried over sodium sulfate, and evaporated. Purification by silica gel chromatography (40% ethyl acetate-hexane) gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(tert-butoxycarbonyl)piperidin-4-yl]-propan-1-one (1.5 g, 3.8 mmol), m.p. 133°-134° C.

Workup

  1. temperaturecooled to -40° C
  2. temperatureto warm to 0° C. over 1 hour
  3. washwashed with ether
  4. extractionextracted into methylene chloride
  5. extractionThe methylene chloride extract
  6. concentrationwas concentrated in vacuo
  7. temperaturethe residue was heated in an oil bath to 140° C. for 30 minutes
  8. temperatureThe mixture was cooled
  9. custompartitioned between water and ethyl acetate
  10. customThe ethyl acetate layer was separated
  11. washwashed with 5% sodium hydroxide
  12. dry with materialbrine, dried over sodium sulfate
  13. customevaporated
  14. customPurification by silica gel chromatography (40% ethyl acetate-hexane)

Sources & evidence

ORD record
ord-e17ddee7b4a746ca96f16ba981f01472
Source dataset
uspto-grants-1998_06
Patent number
US05763458

Reaction notes

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