ethyl 3-[4-(tributylstannanyl)-1H-1,2,3-triazol-1-yl]propyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate → (10S)-10-ethoxy-14-methoxy-N-methyl-10-oxo-20-(trifluoromethyl)-9-oxa-3,4,5,16,18,22,25,28-octaza-10lambda5-phosphapentacyclo[21.2.2.212,15.12,5.117,21]hentriaconta-1(25),2(31),3,12,14,17,19,21(28),23,26,29-undecaene-24-carboxamide;(10R)-10-ethoxy-14-methoxy-N-methyl-10-oxo-20-(trifluoromethyl)-9-oxa-3,4,5,16,18,22,25,28-octaza-10lambda5-phosphapentacyclo[21.2.2.212,15.12,5.117,21]hentriaconta-1(25),2(31),3,12,14,17,19,21(28),23,26,29-undecaene-24-carboxamide

HRID 2279895Notes

Reaction equation

Br[C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:57]=[CH:56][C:27]([CH2:28][P:29](=[O:55])([O:33][CH2:34][CH2:35][CH2:36][N:37]4[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[N:39]=[N:38]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:58][CH3:59])[N:14]=2)=[CH:4][CH:3]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:31]([O:30][P@@:29]1(=[O:55])[CH2:28][C:27]2[CH:56]=[CH:57][C:24](=[C:25]([O:58][CH3:59])[CH:26]=2)[NH:23][C:15]2=[N:14][C:13](=[C:18]([C:19]([F:20])([F:21])[F:22])[CH:17]=[N:16]2)[NH:12][C:5]2[CH:4]=[CH:3][C:2](=[N:7][C:6]=2[C:8]([NH:9][CH3:10])=[O:11])[C:40]2=[CH:41][N:37]([N:38]=[N:39]2)[CH2:36][CH2:35][CH2:34][O:33]1)[CH3:32].[CH2:31]([O:30][P@:29]1(=[O:55])[CH2:28][C:27]2[CH:56]=[CH:57][C:24](=[C:25]([O:58][CH3:59])[CH:26]=2)[NH:23][C:15]2=[N:14][C:13](=[C:18]([C:19]([F:20])([F:21])[F:22])[CH:17]=[N:16]2)[NH:12][C:5]2[CH:4]=[CH:3][C:2](=[N:7][C:6]=2[C:8]([NH:9][CH3:10])=[O:11])[C:40]2=[CH:41][N:37]([N:38]=[N:39]2)[CH2:36][CH2:35][CH2:34][O:33]1)[CH3:32]

Participants

Conditions

Temperature: 100 °C

Procedure

A mixture of ethyl 3-[4-(tributylstannanyl)-1H-1,2,3-triazol-1-yl]propyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 64A, 0.331 mmol assumed) and Pd(PPh3)2Cl2 (11.6 mg, 0.0166 mmol) in 1,4-dioxane (8 mL) was evacuated and refilled with nitrogen (3×), then heated at 100° C. for 5 h. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (ISCO system: MeOH/DCM-EtOAc (1:1)=0-15%) to give the desired product as a white solid, (51 mg, 24% yield over 2 steps). 1H NMR (CDCl3, 400 MHz): δ 10.86 (s, 1H), 8.53 (s, 1H), 8.48 (m, 1H), 8.36 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.79 (br s, 1H), 7.56 (d, J=7.8 Hz, 1H), 6.66 (s, 1H), 6.25 (d, J=8.4 Hz, 1H), 4.66-4.77 (m, 2H), 4.05-4.11 (m, 2H), 3.89-3.97 (m, 2H), 3.84 (s, 3H), 3.09 (dd, J=21.2, 2.2 Hz, 2H), 3.04 (d, J=5.0 Hz, 3H), 2.36-2.49 (m, 2H), 1.28 (t, J=7.1 Hz, 3H). MS (ESI): m/z 648.69 [M+H]+. UPLC: tR=1.08 min (UPLC-SQD: analytical—2 min).

Workup

customwas evacuated
additionrefilled with nitrogen (3×)
concentrationThe mixture was concentrated under reduced pressure
customthe residue was purified by silica gel chromatography (ISCO system: MeOH/DCM-EtOAc (1:1)=0-15%)

Sources & evidence

ORD record: ord-402b30cf54a04280b7f997902527ae81
Source dataset: uspto-grants-2015_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09133224B2

Reaction notes

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