3-Pyridinemethanol → (r)-2-(3-Chloro-4-(3-pyridinylmethoxy)benzyl)morpholine

HRID 2252997Notes

Reaction equation

HRID 2252997 reaction equation
C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1

Participants

5

Reactant 3

HCID 75103-PyridinemethanolHCID 5363146Diisopropyl azodicarboxylateHCID 67073025n-Boc-(r)-2-(3-chloro-4-hydroxybenzyl)morpholine

Product 1

HCID 11623874(r)-2-(3-Chloro-4-(3-pyridinylmethoxy)benzyl)morpholine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (53 mg, 0.16 mmol), was dissolved in dichloromethane (4 mL) with 3-pyridinyl carbinol (35 mg, 0.32 mmol) shaken at room temperature for 20 mins and diisopropylazodicarboxylate (65 mg, 0.32 mmol) added in one portion. dichloromethane (6 mL) was added to solvate the polymer. The reaction mixture was shaken for 24 hrs then filtered. Polymer supported toluenesulfonyl chloride (0.18 g, 2.82 mmol/g) and MP-carbonate (0.39 g, 2.62 mmol/g) were added to the liquor and the mixture shaken for 6 hrs. The reaction was filtered and evaporated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo and the residue purified by preparative HPLC to yield the desired morpholine example 44 as a colorless oil (9 mg).

Workup

  1. stirringThe reaction mixture was shaken for 24 hrs
  2. filtrationthen filtered
  3. additionwere added to the liquor
  4. stirringthe mixture shaken for 6 hrs
  5. filtrationThe reaction was filtered
  6. customevaporated under a high flow of nitrogen
  7. dissolutionThe crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL)
  8. stirringshaken for 3 hrs at room temperature
  9. additionThe reaction mixture was added directly to an SCX-2 column (2 g)
  10. washwashed with dichloromethane (2 mL×2) and methanol (2 mL×2)
  11. washThe SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL)
  12. concentrationCombined ammonia washes were concentrated in vacuo
  13. customthe residue purified by preparative HPLC

Sources & evidence

ORD record
ord-bc038a64811f471395f6e7bafc8b93f4
Source dataset
uspto-grants-2008_01
Patent number
US07323466B2

Reaction notes

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