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

HRID 1726690Notes

Reaction equation

HRID 1726690 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]N[C@H:34]([C:37](O)=O)[C@@H:33](C(OC)=O)[CH2:32]1.C1(N2CCNCC2)C=CC=CC=1.[F:56][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.C(N(CC)C(C)C)(C)C.C(Cl)Cl.ClC(OC)=O>>[F:56][C:37]1[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=1)[O: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:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([NH:63][OH:72])=[O:27])[CH2:3]1

Participants

9

Reactant 8

HCID 6228DimethylformamideHCID 6344DichloromethaneHCID 6586Methyl chloroformateHCID 70961-PhenylpiperazineHCID 81531Diisopropylethylamine2×HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 67304460dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylateHCID 67305204(2S,3S,5R)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid

Product 1

HCID 86598247Methyl(2S,3S,5S)-5-(3-fluorophenoxy)-3-[(hydroxyamino)carbonyl]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1-carboxylateYield 83%

Procedure

Part 7. dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate: 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-66522b28143941a1b99336fb462ee6f9
Source dataset
uspto-grants-2009_02
Patent number
US07491724B2

Reaction notes

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