1,2-Dichloroethane → (S)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enamide

HRID 1391718Notes

Reaction equation

HRID 1391718 reaction equation
[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3].[CH2:31]([C@H:35]1[CH2:39][CH2:38][N:37]([C@@H:40]([CH2:44][CH:45]=[CH2:46])[C:41](O)=[O:42])[C:36]1=[O:47])[CH2:32][CH2:33][CH3:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH:29][C:41](=[O:42])[C@@H:40]([N:37]2[CH2:38][CH2:39][C@H:35]([CH2:31][CH2:32][CH2:33][CH3:34])[C:36]2=[O:47])[CH2:44][CH:45]=[CH2:46])[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)[CH2:6]1)[CH:2]=[CH2:3]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 58813133HCID 58813133, compoundHCID 59676141HCID 59676141, compound

Product 1

HCID 58813141(S)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enamideYield 78.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Step J (1): A mixture of (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol (51 mg, 0.122 mmol) from stepE(2), (S)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoic acid (31 mg, 0.128 mmol) from stepB(5), EDC (25 mg, 0.128 mmol), HOBt (17 mg, 0.128 mmol), and DIEA (108 μL, 0.610 mmol) were mixed in 2 mL of DMF and stirred at room temperature for 24 h. Purified using reverse phase preparatory HPLC to give 61 mg of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enamide as clear viscous residue (TFA salt). A 2 mg sample was free based by passage through basic alumina (activated, Brockmann I), using methanol as an eluant: LC-MS (M+H)+=640.6; 1H NMR (500 MHz, CDCl3) δ 7.27-7.37 (m, 1H), 6.78-6.93 (m, 2H), 6.69-6.80 (m, 2H), 6.55-6.67 (m, 1H), 5.81-6.08 (m, 1H), 5.52-5.72 (m, 1H), 5.31 (dd, J=17.09, 1.53 Hz, 1H), 5.18 (dd, J=10.38, 1.22 Hz, 1H), 4.91-5.14 (m, 2H), 4.65-4.86 (m, 1H), 4.49 (dd, J=9.77, 6.10 Hz, 1H), 3.97-4.22 (m, 3H), 3.75-3.87 (m, 3H), 3.34-3.55 (m, 1H), 2.99-3.33 (m, 2H), 2.84-3.00 (m, 1H), 2.53-2.86 (m, 4H), 2.19-2.52 (m, 2H), 2.00-2.19 (m, 1H), 1.69-1.93 (m, 2H), 1.42-1.72 (m, 5H), 1.17-1.40 (m, 5H), 0.98-1.15 (m, 1H), 0.79-0.96 (m, 3H).

Workup

  1. customPurified

Sources & evidence

ORD record
ord-d77b0a4f56c14dcc929cf3110d9700cf
Source dataset
uspto-grants-2008_03
Patent number
US07338974B2

Reaction notes

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