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

HRID 74740Notes

Reaction equation

HRID 74740 reaction equation
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](O)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:46][O:47][C@@H:48]([C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)[C@@H:49]([CH3:65])[C:50]([NH:52][C@H:53]([C:61]([O:63][CH3:64])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[S:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([N:67]3[CH2:68][CH2:69][CH2:70][C@H:66]3[C@H:48]([O:47][CH3:46])[C@@H:49]([CH3:65])[C:50]([NH:52][C@@H:53]([CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:61]([O:63][CH3:64])=[O:62])=[S:51])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=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 86685741L-Valinamide, N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanyl-N-[(1S,2S)-1-[(1R)-2-carboxy-1-methoxyethyl]-2-methylbutyl]-N-methyl-HCID 131731848methyl N-{(2R,3R)-3-methoxy-2-methyl-3-[(2S)-pyrrolidin-2-yl]propanethioyl}-L-phenylalaninate, hydrochloride salt

Product 1

HCID 89573045N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-2-methyl-3-thioxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of #32 (321 mg, 0.881 mmol, 1 eq.) in dichloromethane (5 mL, 0.1 M) and N,N-dimethylformamide (1 mL) were added #39 (484 mg, ≦0.769 mmol, 0.9 eq.), HATU (353 mg, 0.881 mmol, 1 eq.) and diisopropylethylamine (463 μL, 2.64 mmol, 3 eq.). After stirring for 18 hours, the mixture was diluted with dichloromethane, washed with water and with brine, dried over magnesium sulfate, filtered, and concentrated onto silica in vacuo. The residue was purified by silica gel chromatography (Gradient: 0% to 30% acetone in heptane) to give #43 (574 mg, 68% over two steps) as a white solid. LC-MS: m/z 956.6 [M+H+], retention time=4.49 minutes; 1H NMR (400 MHz, CD3OD), presumed to be a mixture of rotamers, characteristic signals: δ 7.80 (d, J=7.5 Hz, 2H), 7.64-7.72 (m, 2H), 7.16-7.35 (m, 7H), [5.43 (dd, J=11, 4.5 Hz) and 5.58 (dd, J=11.5, 4 Hz), total 1H], 3.72 and 3.75 (2 s, total 3H), 3.34 and 3.35 (2 s, total 3H), 3.26 and 3.29 (2 s, total 3H), 3.05 and 3.11 (2 br s, total 3H), 1.39 and 1.40 (2 s, total 3H), [1.24 (d, J=6.7 Hz) and 1.29 (d, J=6.4 Hz), total 3H].

Workup

  1. washwashed with water and with brine
  2. dry with materialdried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated onto silica in vacuo
  5. customThe residue was purified by silica gel chromatography (Gradient: 0% to 30% acetone in heptane)
  6. customto give #43 (574 mg, 68% over two steps) as a white solid
  7. additiona mixture of rotamers, characteristic signals
  8. customδ 7.80 (d, J=7.5 Hz, 2H), 7.64-7.72 (m, 2H), 7.16-7.35 (m, 7H), [5.43 (dd, J=11, 4.5 Hz) and 5.58 (dd, J=11.5, 4 Hz), total 1H], 3.72 and 3.75 (2 s, total 3H), 3.34 and 3.35 (2 s, total 3H), 3.26 and 3.29 (2 s, total 3H), 3.05 and 3.11 (2 br s, total 3H), 1.39 and 1.40 (2 s, total 3H), [1.24 (d, J=6.7 Hz) and 1.29 (d, J=6.4 Hz), total 3H]

Sources & evidence

ORD record
ord-204c2a233b284bcc9cd7810bdf5a7c0a
Source dataset
uspto-grants-2014_09
Patent number
US08828401B2

Reaction notes

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