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-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

HRID 2282840Notes

Reaction equation

HRID 2282840 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)=[O: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>[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])=[O: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

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 118704819(S)-methyl 2-((2R,3R)-3-methoxy-2-methyl-3-((S)-pyrrolidin-2-yl)propanamido)-3-phenylpropanoate hydrochloride

Product 1

HCID 89573209N-[(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-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

According to general procedure D, from #32 (353 mg, 0.488 mmol, 1 eq.) in dichloromethane (10 mL, 0.04 M), amine #67 (271 mg, ≦0.588 mmol, 1.3 eq.), HATU (223 mg, 0.586 mmol, 1.2 eq.) and diisopropylethylamine (238 μL, 1.71 mmol, 3.5 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 40% acetone in heptane), affording #68 (404 mg, 88% over two steps) as a solid. LC-MS: m/z 940.7 [M+H+], 962.7 [M+Na+], retention time=1.04 minutes; HPLC (Protocol C): retention time=9.022 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.25 (br d, J=8 Hz) and 8.48 (br d, J=8 Hz), total 1H], 7.89 (d, J=7.4 Hz, 2H), 7.67-7.75 (m, 2H), 7.38-7.44 (m, 2H), 7.31-7.36 (m, 2H), 7.14-7.24 (m, 5H), 4.43-4.69 (m, 3H), 4.17-4.26 (m, 3H), 3.91-3.99 (br m, 1H), 3.63 and 3.65 (2 s, total 3H), 3.19 and 3.24 (2 s, total 3H), 3.14 and 3.15 (2 s, total 3H), 2.90 and 2.99 (2 br s, total 3H), 1.36 and 1.37 (2 br s, total 3H), 1.30 and 1.32 (2 s, total 3H), [1.02 (d, J=6.8 Hz) and 1.06 (d, J=6.6 Hz), total 3H].

Workup

  1. customwas purified by silica gel chromatography (Gradient: 0% to 40% acetone in heptane)
  2. customaffording #68 (404 mg, 88% over two steps) as a solid
  3. additiona mixture of rotamers, characteristic signals
  4. custom[8.25 (br d, J=8 Hz) and 8.48 (br d, J=8 Hz), total 1H], 7.89 (d, J=7.4 Hz, 2H), 7.67-7.75 (m, 2H), 7.38-7.44 (m, 2H), 7.31-7.36 (m, 2H), 7.14-7.24 (m, 5H), 4.43-4.69 (m, 3H), 4.17-4.26 (m, 3H), 3.91-3.99 (br m, 1H), 3.63 and 3.65 (2 s, total 3H), 3.19 and 3.24 (2 s, total 3H), 3.14 and 3.15 (2 s, total 3H), 2.90 and 2.99 (2 br s, total 3H), 1.36 and 1.37 (2 br s, total 3H), 1.30 and 1.32 (2 s, total 3H), [1.02 (d, J=6.8 Hz) and 1.06 (d, J=6.6 Hz), total 3H]

Sources & evidence

ORD record
ord-3ab747df19f3425fab0224e065cf07b1
Source dataset
uspto-grants-2015_09
Patent number
US09138486B2

Reaction notes

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