Diisopropylethylamine → N2-(3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-dimethylpropanoyl)-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

HRID 2282851Notes

Reaction equation

HRID 2282851 reaction equation
[CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[CH:47]1[C:59]2[CH:58]([CH2:60][O:61][C:62]([NH:64][CH2:65][C:66]([CH3:71])([CH3:70])[C:67](O)=[O:68])=[O:63])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=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.CN(C)C=O>[CH:56]1[C:57]2[CH:58]([CH2:60][O:61][C:62]([NH:64][CH2:65][C:66]([CH3:71])([CH3:70])[C:67]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:68])=[O:63])[C:59]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1

Participants

7

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 86685731N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Product 1

HCID 86762711N2-(3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-dimethylpropanoyl)-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamideYield 60.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To #86 (100 mg, 0.152 mmol, 1 eq.) in dichloromethane (4 mL, 0.038 M) and N,N-dimethylformamide (0.5 mL) was added #93 (51.6 mg, 0.152 mmol, 1 eq.) followed by diisopropylethylamine (80.0 μL, 0.457 mmol, 3 eq.) and HATU (89.8 mg, 0.229 mmol, 1.5 eq.). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (6 mL) and was washed with 1 M aqueous hydrochloric acid solution (2×2 mL) and with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in dichloromethane (250 mL) and filtered; the filtrate was concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane) to provide #94 (90 mg, 60%) as a white solid. LC-MS: m/z 979.8 [M+H+], 1002.7 [M+Na+], retention time=1.15 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic product signals: δ [8.64 (br d, J=8.6 Hz) and 8.86 (br d, J=8.6 Hz), total 1H], 7.86-7.91 (m, 2H), [7.77 (d, J=3.3 Hz) and 7.79 (d, J=3.3 Hz), total 1H], 7.67-7.73 (m, 2H), [7.63 (d, J=3.3 Hz) and 7.65 (d, J=3.3 Hz), total 1H], 6.87-6.95 (m, 1H), [5.39 (ddd, J=11, 8, 4 Hz) and 5.52 (ddd, J=11.5, 9, 4 Hz), total 1H], [4.44 (dd, J=8.4, 8.4 Hz) and 4.55 (dd, J=8.4, 8.4 Hz), total 1H], 3.16, 3.20, 3.21 and 3.25 (4 s, total 6H), 2.96 and 3.06 (2 br s, total 3H), 0.69-0.77 (m, 3H).

Workup

  1. concentrationconcentrated in vacuo
  2. washwas washed with 1 M aqueous hydrochloric acid solution (2×2 mL) and with brine
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. filtrationfiltered
  7. concentrationthe filtrate was concentrated in vacuo onto silica
  8. custompurified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane)

Sources & evidence

ORD record
ord-72d6559ef03c42c193c0e8d385f4c1c6
Source dataset
uspto-grants-2015_09
Patent number
US09138486B2

Reaction notes

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