Triethylamine → 2-Methylalanyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[2-(cyclohepta-2,4,6-trien-1-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

HRID 74754Notes

Reaction equation

HRID 74754 reaction equation
C1C2C(COC([NH:18][C:19]([CH3:65])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:33]([O:59][CH3:60])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:57][CH3:58])[C@@H:43]([CH3:56])[C:44]([NH:46][CH2:47][CH2:48][CH:49]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=[CH:50]3)=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:33]([O:59][CH3:60])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:57][CH3:58])[C@@H:43]([CH3:56])[C:44]([NH:46][CH2:47][CH2:48][CH:49]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=[CH:50]1)=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:65])[NH2:18]

Participants

4

Reactant 2

HCID 8471TriethylamineHCID 89573340N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[2-(cyclohepta-2,4,6-trien-1-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

Product 1

HCID 715707242-Methylalanyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[2-(cyclohepta-2,4,6-trien-1-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamideYield 85.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of #65 (540 mg, 0.603 mmol, 1 eq.) in dichloromethane (10 mL, 0.06 M) was added triethylamine (10 mL) and the reaction mixture was stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #66 (347 mg, 85%) as a colorless solid. HPLC (Protocol A at 45° C.): m/z 674.5 [M+H+], retention time=7.015 minutes. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.03 (br d, J=9 Hz) and 8.05 (br d, J=9 Hz), total 1H], [7.77 (br dd, J=5.5, 5.5 Hz) and 7.98 (br dd, J=5.5, 5.5 Hz), total 1H], 6.54-6.65 (m, 2H), 6.10-6.19 (m, 2H), 5.11-5.19 (m, 2H), [4.48 (dd, J=9, 8 Hz) and 4.54 (dd, J=9, 7.5 Hz), total 1H], 3.94-4.04 (br m, 1H), 3.26 and 3.29 (2 s, total 3H), 3.17 and 3.19 (2 s, total 3H), 2.93 and 3.06 (2 br s, total 3H), 1.20 and 1.21 (2 s, total 3H), 1.12 and 1.13 (2 s, total 3H), [1.04 (d, J=6.8 Hz) and 1.07 (d, J=6.7 Hz), total 3H].

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. customthe residue was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane)

Sources & evidence

ORD record
ord-07a77d04307a42839a0758b23a6dff84
Source dataset
uspto-grants-2014_09
Patent number
US08828401B2

Reaction notes

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