Diisopropylethylamine → N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanyl-N-{(3R,4S,5S)-3-methoxy-1-[(2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)amino]propyl}pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

HRID 2282831Notes

Reaction equation

HRID 2282831 reaction equation
Cl.[CH3:2][O:3][C@@H:4]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)[C@@H:5]([CH3:17])[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:40][C:41]([CH3:66])([C:43]([NH:45][C@H:46]([C:50]([N:52]([C@@H:54]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:55]([O:60][CH3:61])[CH2:56][C:57](O)=[O:58])[CH3:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])[CH3:42])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:40][C:41]([CH3:66])([C:43]([NH:45][C@H:46]([C:50]([N:52]([C@@H:54]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:55]([O:60][CH3:61])[CH2:56][C:57]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:18]3[C@H:4]([O:3][CH3:2])[C@@H:5]([CH3:17])[C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:58])[CH3:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])[CH3:42])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 86685741L-Valinamide, N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanyl-N-[(1S,2S)-1-[(1R)-2-carboxy-1-methoxyethyl]-2-methylbutyl]-N-methyl-HCID 131731845(2R,3R)-3-methoxy-2-methyl-N-(2-phenylethyl)-3-[(2S)-pyrrolidin-2-yl] propanamide, hydrochloride salt

Product 1

HCID 89573376N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanyl-N-{(3R,4S,5S)-3-methoxy-1-[(2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)amino]propyl}pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamideYield 19.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of #24 (104 mg, 0.256 mmol, 1 eq.) in dichloromethane (10 mL, 0.094 M) were added #32 (156 mg, 0.256 mmol, 0.9 eq.), diisopropylethylamine (135 μL, 0.768 mmol, 3 eq.) and HATU (120 mg, 0.307 mmol, 1.2 eq.). After stirring for 18 hours, the mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (10 mL), washed with 1 M aqueous hydrochloric acid solution (2×5 mL) and with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was diluted with dichloromethane and filtered. The filtrate was concentrated under reduced pressure onto silica and purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #55 (44 mg, 19%) as a white solid. LC-MS: m/z 884.5 [M+2H+], retention time=1.04 minutes.

Workup

  1. concentrationthe mixture was concentrated in vacuo
  2. additionthe residue was diluted with ethyl acetate (10 mL)
  3. washwashed with 1 M aqueous hydrochloric acid solution (2×5 mL) and with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. additionThe residue was diluted with dichloromethane
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated under reduced pressure onto silica
  10. custompurified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-bb11c556c7cc4b6096b969c847d84d21
Source dataset
uspto-grants-2015_09
Patent number
US09138486B2

Reaction notes

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