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

HRID 74777Notes

Reaction equation

HRID 74777 reaction equation
[CH3:1][O:2][C@@H:3]([C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C@@H:4]([CH3:23])[C:5]([NH:7][C@H:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44]([NH:46][C:47]([CH3:72])([C:49]([NH:51][C@H:52]([C:56]([N:58]([C@@H:60]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:61]([O:66][CH3:67])[CH2:62][C:63](O)=[O:64])[CH3:59])=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH3:48])=[O:45])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44]([NH:46][C:47]([CH3:72])([C:49]([NH:51][C@H:52]([C:56]([N:58]([C@@H:60]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:61]([O:66][CH3:67])[CH2:62][C:63]([N:25]3[CH2:26][CH2:27][CH2:28][C@H:24]3[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:23])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:6])=[O:64])[CH3:59])=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH3:48])=[O:45])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1

Participants

8

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 86685746tert-butyl N-{(2R,3R)-3-methoxy-2-methyl-3-[(2S)-pyrrolidin-2-yl]propanoyl}-L-phenylalaninate

Product 1

HCID 86685745N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-tert-butoxy-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamideYield 63.1%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirring solution of #121 (0.55 g, 1.0 mmol, 1.0 eq.) in 10 mL of dichloromethane and 1 mL of DMF, #32 (0.62 g, 1.0 mmol, 1.0 eq.) was added followed by HATU (0.42 g, 1.1 mmol, 1.1 eq.) and Hunig's base (0.72 mL, 4.1 mmol, 4.0 eq.). The reaction was allowed to stir at room temperature for approximately 21 hours. Reaction was reduced down, diluted with ethyl acetate, and then washed with 0.5 N HCl and brine. Organic layer was dried over sodium sulfate, filtered, and concentrated to a smaller volume before being concentrated down onto silica. Silica chromatography was then performed (Gradient: 0%-40% acetone in heptane) producing #122 (0.62 g, 62%) as a white solid. LC-MS (Protocol Q): m/z 982.3 [M+H+] retention time=2.44 minutes.

Workup

  1. customReaction
  2. washwashed with 0.5 N HCl and brine
  3. dry with materialOrganic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated to a smaller volume
  6. concentrationbefore being concentrated down onto silica

Sources & evidence

ORD record
ord-a150ec7d90d741119dce2425c190fca2
Source dataset
uspto-grants-2014_09
Patent number
US08828401B2

Reaction notes

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