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

HRID 61455Notes

Reaction equation

HRID 61455 reaction equation
[OH:1][C@@H:2]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=O)[C@@H:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3]1.Cl.[C:16]1([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:38]=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C(#N)C.O1CCCC1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[OH:1][C@@H:2]1[CH2:7][N:6]([CH3:38])[C@H:5]([C:8]([N:25]2[CH2:24][CH:23]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26]2)=[O:10])[C@@H:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3]1

Participants

11

Reactant 9

HCID 712FormaldehydeHCID 6228DimethylformamideHCID 6342AcetonitrileHCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 27238604-Phenyl-1,2,3,6-tetrahydropyridine hydrochlorideHCID 5049666Sodium triacetoxyborohydrideHCID 67304506(2S,3S,5S)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid

Product 1

HCID 67304114Methyl (2s,3s,5s)-5-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2h)-yl)carbonyl]piperidine-3-carboxylateYield 85%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A mixture of (2S,3S,5S)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid (0.309 g, 0.00152 mol), 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (0.357 g, 0.00182 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.807 g, 0.00182 mol) in N,N-dimethylformamide (2.50 mL, 0.0323 mol) was stirred at rt for 5 min, then treated with N,N-diisopropylethylamine (0.636 mL, 0.00365 mol) at rt for 2 h. The reaction mixture was diluted with acetonitrile (5.0 mL, 0.096 mol) and tetrahydrofuran (5.0 mL, 0.062 mol). To the mixture was added 12.32 M of formaldehyde in Water (0.41 mL) followed by sodium triacetoxyborohydride (1.1 g, 0.0051 mol). After stirred at rt overnight, the mixture was concentrated to dry, then diluted with aq. sodium bicarbonate, extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to dry. The residue was applied on silica gel, eluting with 0 to 100% EtOAc in hexane, to yield the methyl amine compound (0.31 g, 85%). MS (ESI): (M+H)+=358.1.

Workup

  1. stirringAfter stirred at rt overnight
  2. concentrationthe mixture was concentrated
  3. customto dry
  4. additiondiluted with aq. sodium bicarbonate
  5. extractionextracted with EtOAc
  6. washThe combined organic layers were washed with brine
  7. customdried
  8. concentrationconcentrated
  9. customto dry
  10. washeluting with 0 to 100% EtOAc in hexane

Sources & evidence

ORD record
ord-982aa7269799479685fa4e1f1ce92310
Source dataset
uspto-grants-2016_09
Patent number
US09440958B2

Reaction notes

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