Triethylamine → ethyl (2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylate

HRID 2376138Notes

Reaction equation

HRID 2376138 reaction equation
C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[Br-].[Mg+2].[Br-].CCN(CC)CC.[CH2:26]([N:33]1[CH2:37][CH2:36][C@@H:35]([NH:38][C:39]2[C:46]([Cl:47])=[CH:45][C:42]([CH:43]=O)=[CH:41][N:40]=2)[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.C(OCC)(C)=O.O>[CH2:26]([N:33]1[CH2:37][CH2:36][C@@H:35]([NH:38][C:39]2[N:40]=[CH:41][C:42](/[CH:43]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:45][C:46]=2[Cl:47])[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 82241Magnesium BromideHCID 2734865Triethyl 2-fluoro-2-phosphonoacetateHCID 866037486-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinaldehyde

Product 1

HCID 86603747ethyl (2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylateYield 81.6%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 22728543Water ethylacetateSolvent

Conditions

Temperature
7.5 °C

Procedure

To a mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (1.46 g) and magnesium bromide (1.33 g) in THF (20 ml) was added dropwise to a Et3N (0.92 ml) with stirring at 0-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at same condition for an hour. A solution of 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinaldehyde (1.36 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at 0-15° C. for 4 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (3:7). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylate (1.42 g).

Workup

  1. stirringthe reaction mixture was stirred at same condition for an hour
  2. stirringwas stirred at 0-15° C. for 4 hours
  3. washthe organic layer was washed with brine
  4. dry with materialdried over MgSO4
  5. customThe solvent was evaporated in vacuo
  6. customthe residue was chromatographed on silicagel
  7. washeluting with AcOEt-n-hexane (3:7)
  8. additionThe eluted fractions containing the desired product
  9. customwere collected
  10. customevaporated in vacuo

Sources & evidence

ORD record
ord-b9c2b3ff478e48b88254e7a7e2d311f1
Source dataset
uspto-grants-2008_12
Patent number
US07465731B2

Reaction notes

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