Piperidine → HCID 67254421, compound

HRID 1916157Notes

Reaction equation

HRID 1916157 reaction equation
[O:1]=[C:2]1[C@H:10]([NH2:11])[CH2:9][CH2:8][C@H:7]2[N:3]1[C@@H:4]([C:12]([O:14]C)=[O:13])[CH2:5][CH2:6]2.[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17].C([O-])(O)=O.[Na+].N1CCCCC1.CCN(C(C)C)C(C)C>CC(C)=O.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>[O:1]=[C:2]1[C@H:10]([NH:11][C:16]([O:18][CH2:19][CH:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH2:9][CH2:8][C@H:7]2[N:3]1[C@@H:4]([C:12]([OH:14])=[O:13])[CH2:5][CH2:6]2

Participants

9

Reactant 5

HCID 8082PiperidineHCID 81531DiisopropylethylamineHCID 134122N-(9-Fluorenylmethoxycarbonyloxy)succinimideHCID 516892Sodium BicarbonateHCID 67254898HCID 67254898, compound

Product 1

HCID 67254421HCID 67254421, compound

Reagents, catalysts & solvents 3

HCID 180AcetoneSolventHCID 6228DimethylformamideSolvent2×HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateSolvent

Procedure

Amino acids were purchased from Advanced Chemtech (Louisville, Ky.), and used as the following derivatives: N-Fmoc-D-Ala-OH.H2O, N-Fmoc-D-Leu-OH, N-Fmoc-D-Glu(O-t-Bu)-OH, N-Fmoc-D-Pro-OH, N-Fmoc-D-Tyr(O-t-Bu), N-Fmoc-D-Arg(Pmc)-OH. (R)-β-hydroxy-N-(Fmoc)valine was prepared from (R)-β-hydroxy-N-(Boc)valine (Dettwiler et al., 2003) by removal of the Boc group (1:1 TFA (trifluoroacetic acid)/CH2Cl2), protection with Fmoc-OSu and NaHCO3 in aqueous acetone (Capatsanis et al. 1983), followed by purification by chromatography over silica gel (1:1:98 MeOH/HOAc/CHCl3) and lyophilization from aqueous acetonitrile (78% yield). (3R,6R,9R)-2-Oxo-3-[N-(Fmoc)amino]-1-azabicyclo[4.3.0]-nonane-9-carboxylic acid was prepared from (3R,6R,9R)-methyl 2-oxo-3-amino-1-azabicyclo[4.3.0]-nonane-9-carboxylate (in turn prepared (Lombart et al. 1996) from D-glutamic acid) by Fmoc-protection with Fmoc-OSu and NaHCO3 in aqueous acetone (Capatsanis et al. 1983), followed by selective hydrolysis of the methyl ester (Pascal et al. 1998). Peptide synthesis was performed on a 0.1 mmol scale (200 mg resin), and conducted by deprotection with piperidine in DMF (10 ml/g resin, 20% v/v, 1×2 min, 1×3 min, 1×10 min) followed by washing with DMF (10 ml/g resin, 5×1 min). Fmoc protected amino acid (0.5 mmol, 500 mol %) dissolved in a solution of TBTU in DMF (0.25 M, 2 ml) was added to the resin. After agitation of the resin (5 min), DIEA (0.6 mmol, 600 mol %) was added, and agitation continued for 1 h. The resin was washed with DMF (10 ml/g resin, 5×1 min), and coupling efficiency determined using the Kaiser test. The resin was agitated using a mechanical vortex apparatus during coupling, rinsing and deprotection sequences. Rp-HPLC analysis was performed on an Alltech C18 column (dimensions 250 mm×4.6 mm) using acetonitrile/water/TFA mixtures, where solvent A=water/0.1% TFA and solvent B=MeCN/0.1% TFA (see below). The flow rate was 0.5 ml/min, and detection was performed at 214 nM.

Workup

  1. washby washing with DMF (10 ml/g resin, 5×1 min)
  2. additionwas added to the resin
  3. washThe resin was washed with DMF (10 ml/g resin, 5×1 min)
  4. washrinsing

Sources & evidence

ORD record
ord-cf811395455a41afa2b6299ad75877a9
Source dataset
uspto-grants-2013_12
Patent number
US08618054B2

Reaction notes

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