Diisopropylethylamine → methyl N-[(2R,3R)-3-{(2S)-1-[(3R,4S,5S)-4-{[N-(3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-dimethylpropanoyl)-L-valyl] (methyl)amino}-3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl}-3-methoxy-2-methylpropanoyl]-L-phenylalaninate

HRID 2282870Notes

Reaction equation

HRID 2282870 reaction equation
[CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[CH:46]1[C:58]2[CH:57]([CH2:59][O:60][C:61]([NH:63][CH2:64][C:65]([CH3:70])([CH3:69])[C:66](O)=[O:67])=[O:62])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50]=2[CH:49]=[CH:48][CH:47]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:55]1[C:56]2[CH:57]([CH2:59][O:60][C:61]([NH:63][CH2:64][C:65]([CH3:70])([CH3:69])[C:66]([NH:37][C@H:36]([C:35]([N:34]([CH3:42])[C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:6])=[O:45])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:67])=[O:62])[C:58]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]=2[CH:52]=[CH:53][CH:54]=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 450244313-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-2,2-dimethylpropanoic acidHCID 86685744methyl N-{(2R,3R)-3-methoxy-3-[(2S)-1-{(3R,4S,5S)-3-methoxy-5-methyl-4-[methyl(L-valyl)amino]heptanoyl}pyrrolidin-2-yl]-2-methylpropanoyl}-L-phenylalaninate

Product 1

HCID 86685747methyl N-[(2R,3R)-3-{(2S)-1-[(3R,4S,5S)-4-{[N-(3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-dimethylpropanoyl)-L-valyl] (methyl)amino}-3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl}-3-methoxy-2-methylpropanoyl]-L-phenylalaninateYield 78%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirring solution of #114 (200 mg, 0.316 mmol, 1.00 eq.) in 2 mL of dichloromethane, #124 (107 mg, 0.316 mmol, 1.00 eq.) was added followed by Hunig's base (0.167 mL, 0.948 mmol, 3.00 eq.) and HATU (149 mg, 0.379 mmol, 1.20 eq.). The reaction was allowed to stir at room temperature for ˜12 hours. The reaction was concentrated to a smaller volume, taken up in 10 mL of ethyl acetate, and washed two times with 5 mL of 1M HCl, and once with 5 mL of brine. The organic layer was dried over sodium sulfate and decanted. Organics where concentrated in vacuo and the crude material was taken up in dichloromethane. The precipitate was filtered. The organic layer was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-50% acetone in heptane) producing #125 (235 mg, 78%) as a white solid. LC-MS (Protocol Q): m/z 954.2 [M+H+] retention time=2.28 minutes.

Workup

  1. concentrationThe reaction was concentrated to a smaller volume
  2. washwashed two times with 5 mL of 1M HCl
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. customdecanted
  5. concentrationOrganics where concentrated in vacuo
  6. filtrationThe precipitate was filtered
  7. concentrationThe organic layer was concentrated in vacuo
  8. customthe residue was purified by silica chromatography (Gradient: 0%-50% acetone in heptane)

Sources & evidence

ORD record
ord-9fde0421341a4a0cbc4cbab16d221862
Source dataset
uspto-grants-2015_09
Patent number
US09138486B2

Reaction notes

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