Hydrochloric Acid → tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate

HRID 2376071Notes

Reaction equation

HRID 2376071 reaction equation
C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[Mg+2].[Br-].[Br-].[Cl:19][C:20]1[C:21]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[N:22][CH:23]=[C:24]([CH:26]=O)[CH:25]=1.Cl>C1COCC1.CCOC(C)=O.CCN(CC)CC>[Cl:19][C:20]1[C:21]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[N:22][CH:23]=[C:24](/[CH:26]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:25]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 82241Magnesium BromideHCID 2734865Triethyl 2-fluoro-2-phosphonoacetateHCID 86603692tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-piperidinecarboxylate

Product 1

HCID 86603685tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
4 °C

Procedure

The mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (2.51 mL), MgBr2 (2.73 g), Et3N (1.89 mL) in THF (45 mL) was stirred at 3-5° C. for 1 hr and to the mixture was dropwise added a solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-piperidinecarboxylate (3.0 g) in THF (21 mL) at 3-5° C. The reaction mixture was stirred at same temperature for 2.5 hrs. The reaction mixture was poured into a mixture of AcOEt and ice-water and the mixture was adjusted to pH 3.5 with 1N-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of AcOEt and hexane (1:2 v/v) as an eluant. The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.38 g).

Workup

  1. stirringThe reaction mixture was stirred at same temperature for 2.5 hrs
  2. washThe separated organic layer was washed with water
  3. dry with materialdried over magnesium sulfate
  4. customevaporated in vacuo
  5. customThe residue was purified by column chromatography on silica gel using
  6. additiona mixture of AcOEt and hexane (1:2 v/v) as an eluant
  7. additionThe eluted fractions containing the desired product
  8. customwere collected
  9. customevaporated in vacuo

Sources & evidence

ORD record
ord-87ed787373c44882a6ee25a1867cdcf8
Source dataset
uspto-grants-2008_12
Patent number
US07465731B2

Reaction notes

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