Formaldehyde → Methyl (2s,3s,5s)-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2h)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxylate

HRID 61447Notes

Reaction equation

HRID 61447 reaction equation
[C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13]([C@@H:15]3[C@@H:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][C@H:18]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:17][N:16]3[C:32](OC(C)(C)C)=O)=[O:14])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O1CCCC1.C(#N)C.C(N(CC)C(C)C)(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:32][N:16]1[CH2:17][C@@H:18]([O:25][C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[CH2:19][C@H:20]([C:21]([O:23][CH3:24])=[O:22])[C@H:15]1[C:13]([N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)=[O:14]

Participants

9

Reactant 7

HCID 712FormaldehydeHCID 6342AcetonitrileHCID 6422Trifluoroacetic acidHCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 1317319271-Tert-butyl 3-methyl (2s,3s,5s)-2-[(4-phenyl-3,6-dihydropyridin-1(2h)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-1,3-dicarboxylate

Product 1

HCID 67304754Methyl (2s,3s,5s)-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2h)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

1-tert-butyl 3-methyl(2S,3S,5S)-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-1,3-dicarboxylate (0.09 g, 0.0002 mol) was treated with trifluoroacetic acid (1.0 mL, 0.013 mol) at rt for 1 h. The mixture was then concentrated to dry. The crude secondary amine made above was dissolved in tetrahydrofuran (0.80 mL, 0.0099 mol) and acetonitrile (0.80 mL, 0.015 mol). The mixture was then treated with N,N-diisopropylethylamine (0.061 mL, 0.00035 mol) to adjust the pH to around 7. To the resultant mixture was then added 12.32 M of formaldehyde in water (0.071 mL) followed by sodium triacetoxyborohydride (180 mg, 0.00087 mol). After stirred at rt overnight, the mixture was concentrated to dry in vacuo, diluted with with aq. sodium bicarbonate, extracted with EtOAc. The combined organic layers were washed with brine, dried, and evaporated to dry in vacuo. The residue was exposured in high vacuum and then used directly in next step. MS (ESI): (M+H)+=436.1.

Workup

  1. concentrationThe mixture was then concentrated
  2. customto dry
  3. concentrationthe mixture was concentrated
  4. customto dry in vacuo
  5. additiondiluted with with aq. sodium bicarbonate
  6. extractionextracted with EtOAc
  7. washThe combined organic layers were washed with brine
  8. customdried
  9. customevaporated
  10. customto dry in vacuo

Sources & evidence

ORD record
ord-97ab42ada21e42039070e8262f9c00cf
Source dataset
uspto-grants-2016_09
Patent number
US09440958B2

Reaction notes

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