Dimethylformamide → dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate

HRID 535051Notes

Reaction equation

HRID 535051 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.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C(Cl)Cl.Cl[C:72]([O:74][CH3:75])=[O:73]>>[OH:1][C@H:2]1[CH2:7][N:6]([C:72]([O:74][CH3:75])=[O:73])[C@H:5]([C:8]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)=[O:10])[C@@H:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3]1

Participants

8

Reactant 7

HCID 6228DimethylformamideHCID 6344DichloromethaneHCID 6586Methyl chloroformateHCID 70961-PhenylpiperazineHCID 81531Diisopropylethylamine2×HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 67305204(2S,3S,5R)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid

Product 1

HCID 67304460dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylateYield 83%

Procedure

To a mixture of (2S,3S,5R)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid (3.140 g, 0.01545 mol), 1-phenyl-piperazine (2.597 mL, 0.01700 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (7.518 g, 0.01700 mol) in N,N-dimethylformamide (10.00 mL, 0.1291 mol) was added N,N-diisopropylethylamine (3.230 mL, 0.01854 mol) at 0 Celsius. After stirred at rt overnight the reaction mixture was diluted with methylene chloride (90.0 mL, 1.40 mol) and then cooled to 0 Celsius. To the mixture was added N,N-diisopropylethylamine (5.38 mL, 0.0309 mol) followed by methyl chloroformate (2.39 mL, 0.0309 mol). The mixture was stirred at rt for 2 h and then concentrated to dry. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to dry. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the titled compound (5.20 g, 83.0%). MS (ESI): (M+H)+=406.1.

Workup

  1. temperaturecooled to 0 Celsius
  2. stirringThe mixture was stirred at rt for 2 h
  3. concentrationconcentrated
  4. customto dry
  5. additionThe residue was diluted with water
  6. extractionextracted with ethyl acetate
  7. washThe combined organic layers were washed with brine
  8. customdried
  9. concentrationconcentrated
  10. customto dry
  11. customThe residue was purified on silica gel
  12. washeluting with 0 to 100% EtOAc in hexane

Sources & evidence

ORD record
ord-3751ef92034547da8825716f0bc237c4
Source dataset
uspto-grants-2014_10
Patent number
US08853243B2

Reaction notes

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