Dimethylformamide → Methyl (2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-([(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate

HRID 1010486Notes

Reaction equation

HRID 1010486 reaction equation
[OH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26](OC)=[O:27])[CH2:3]1.O[C@@H:31]1[CH2:36][NH:35][C@H:34]([C:37]([OH:39])=O)[C@@H:33](C(OC)=O)[CH2:32]1.C1(N2CCNCC2)C=CC=CC=1.F[P-](F)(F)(F)(F)F.[N:63]1([O:72][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=[O:86].C(N(CC)C(C)C)(C)C.C(Cl)Cl.ClC(OC)=O>CN(C1C=CN=CC=1)C>[OH:72][NH:63][C:26]([C@H:4]1[CH2:3][C@H:2]([O:1][C:36]([N:35]2[CH2:31][CH2:32][CH2:33][C@H:34]2[CH2:37][OH:39])=[O:86])[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@@H:5]1[C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19]1)=[O:13])=[O:27]

Participants

10

Reactant 8

HCID 6228DimethylformamideHCID 6344DichloromethaneHCID 6586Methyl chloroformateHCID 70961-PhenylpiperazineHCID 81531Diisopropylethylamine2×HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 67304346dimethyl(2S,3S,5S)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylateHCID 67304506(2S,3S,5S)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid

Product 1

HCID 86598252Methyl (2S,3S,5S)-3-[(hydroxyamino)carbonyl]-5-([(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylateYield 85.7%

Reagents, catalysts & solvents 1

HCID 142844-(Dimethylamino)pyridineCatalyst

Procedure

Part 1 dimethyl (2S,3S,5S)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate: To a mixture of (2S,3S,5S)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid (1.10 g, 0.00541 mol), 1-phenyl-piperazine, (0.910 mL, 0.00595 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.63 g, 0.00595 mol) in N,N-dimethylformamide (6.00 mL, 0.0775 mol) was added N,N-diisopropylethylamine (1.04 mL, 0.00595 mol) at 0 Celsius. The reaction was stirred at rt for 3 h. To the reaction mixture was added methylene chloride (40.00 mL, 0.6240 mol), cat. amount of DMAP, N,N-diisopropylethylamine (2.36 mL, 0.0135 mol), followed by methyl chloroformate (0.836 mL, 0.0108 mol) at 0 Celsius. The resulting reaction mixture was stirred at rt overnight. After quenched with water, the mixture was 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 (1.88 g, 85.7%). MS (ESI): (M+H)+=406.2.

Workup

  1. customThe resulting reaction mixture
  2. stirringwas stirred at rt overnight
  3. customAfter quenched with water
  4. extractionthe mixture was extracted with ethyl acetate
  5. washThe combined organic layers were washed with brine
  6. customdried
  7. concentrationconcentrated
  8. customto dry
  9. customThe residue was purified on silica gel
  10. washeluting with 0 to 100% EtOAc in hexane

Sources & evidence

ORD record
ord-07488b675ede43b9b2c7e1e159ed396c
Source dataset
uspto-grants-2011_07
Patent number
US07973041B2

Reaction notes

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