Triethylamine → 9H-fluoren-9-ylmethyl N-[(E)-3-[(6aS)-3-[3-[[(6aS)-2-methoxy-8-[4-(4-methylpiperazin-1-yl)phenyl]-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-2-methoxy-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]prop-2-enyl]carbamate

HRID 1057071Notes

Reaction equation

HRID 1057071 reaction equation
FC(F)(F)S(O[C:7]1[CH2:8][C@H:9]2[C:15](=[O:16])[N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:13]3[CH:25]=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]4[C:37]([O:81][CH3:82])=[CH:38][C:39]5[C:45](=[O:46])[N:44]6[CH:47]=[C:48](/[CH:50]=[CH:51]/[CH2:52][NH:53][C:54]([O:56][CH2:57][CH:58]7[C:70]8[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=8[C:64]8[C:59]7=[CH:60][CH:61]=[CH:62][CH:63]=8)=[O:55])[CH2:49][C@H:43]6[C:42](=[O:71])[N:41]([CH2:72][O:73][CH2:74][CH2:75][Si:76]([CH3:79])([CH3:78])[CH3:77])[C:40]=5[CH:80]=4)[C:27]([O:29][CH3:30])=[CH:28][C:12]=3[C:11](=[O:83])[N:10]2[CH:84]=1)(=O)=O.[CH3:87][N:88]1[CH2:93][CH2:92][N:91](OB(C2C=CC=CC=2)O)[CH2:90][CH2:89]1.C(N([CH2:108][CH3:109])CC)C>C1(C)C=CC=CC=1.C(O)C.O>[CH3:82][O:81][C:37]1[C:36]([O:35][CH2:34][CH2:33][CH2:32][O:31][C:26]2[C:27]([O:29][CH3:30])=[CH:28][C:12]3[C:11](=[O:83])[N:10]4[CH:84]=[C:7]([C:109]5[CH:108]=[CH:9][C:8]([N:91]6[CH2:90][CH2:89][N:88]([CH3:87])[CH2:93][CH2:92]6)=[CH:7][CH:84]=5)[CH2:8][C@H:9]4[C:15](=[O:16])[N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])[C:13]=3[CH:25]=2)=[CH:80][C:40]2[N:41]([CH2:72][O:73][CH2:74][CH2:75][Si:76]([CH3:78])([CH3:77])[CH3:79])[C:42](=[O:71])[C@@H:43]3[CH2:49][C:48](/[CH:50]=[CH:51]/[CH2:52][NH:53][C:54](=[O:55])[O:56][CH2:57][CH:58]4[C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][C:64]=5[C:65]5[C:70]4=[CH:69][CH:68]=[CH:67][CH:66]=5)=[CH:47][N:44]3[C:45](=[O:46])[C:39]=2[CH:38]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 89464103(4-Methylpiperazin-1-yl)phenylboronic acidHCID 90407815[(6aS)-3-[3-[[(6aS)-8-[(E)-3-(9H-fluoren-9-ylmethoxycarbonylamino)prop-1-enyl]-2-methoxy-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-2-methoxy-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl] trifluoromethanesulfonate

Product 1

HCID 1317364549H-fluoren-9-ylmethyl N-[(E)-3-[(6aS)-3-[3-[[(6aS)-2-methoxy-8-[4-(4-methylpiperazin-1-yl)phenyl]-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-2-methoxy-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]prop-2-enyl]carbamateYield 54%

Reagents, catalysts & solvents 1

HCID 86587398Ethanol toluene waterSolvent

Procedure

Mono triflate 13 (0.100 g, 0.0802 mmol, 1.0 eq.), (4-methylpiperazin-1-yl)phenylboronic acid, pinacol ester (0.023 g, 0.0762, 0.95 eq.) and triethylamine (0.051 mL, 0.369 mmol, 4.6 eq.) were solubilised in a mixture of Toluene/Ethanol/H2O [6:3:1] (4 mL) under a nitrogen atmosphere. The reaction was flushed with nitrogen for 5 minutes and palladium-tetrakistriphenylphosphine (0.9 mg, 0.000802 mmol, 0.01 eq.) was added. The reaction was then subjected to microwave irradiation at 80° C. for 5 minutes. The above reaction was repeated 3 times on 0.100 g scale. The combined reaction mixtures were concentrated under reduced pressure, and the solid residue was partitioned between H2O (180 mL) and ethyl acetate (180 mL). The aqueous layer was extracted with ethyl acetate (2×180 mL) before the combined organics were washed with brine (180 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude mixture was purified by flash chromatography (silica gel, 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH) to afford the desired product as a yellow solid (0.220 g, 54%). LC/MS (2.833 min (ES+)), m/z: 1272.53 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, 2H, J=7.5 Hz), 7.60 (d, 2H, J=7.3 Hz), 7.43-7.39 (m, 3H), 7.35-7.30 (m, 6H), 6.95 (m, 1H), 6.90-6.87 (m, 1H), 6.34 (d, 1H, J=15.7 Hz), 5.67-5.57 (m, 1H), 5.50 (dd, 2H, J=10.1, 3.3 Hz), 4.86 (m, 1H), 4.75 (dd, 2H, J=10.1, 5.6 Hz), 4.54 (m, 2H), 4.44 (d, 2H, J=6.8 Hz), 4.31-4.21 (m, 6H), 3.96-3.87 (m, 9H), 3.81-3.73 (m, 3H), 3.71-3.62 (m, 3H), 3.31-3.20 (m, 5H), 3.10 (m, 1H), 2.87 (m, 1H), 2.58 (m, 4H), 2.43 (m, 2H), 2.36 (s, 3H), 0.97 (m, 4H), 0.01 (s, 18H).

Workup

  1. customThe reaction was flushed with nitrogen for 5 minutes
  2. customirradiation at 80° C. for 5 minutes
  3. customThe above reaction
  4. customThe combined reaction mixtures
  5. concentrationwere concentrated under reduced pressure
  6. customthe solid residue was partitioned between H2O (180 mL) and ethyl acetate (180 mL)
  7. extractionThe aqueous layer was extracted with ethyl acetate (2×180 mL) before the combined
  8. washorganics were washed with brine (180 mL)
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe resulting crude mixture was purified by flash chromatography (silica gel, 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH)

Sources & evidence

ORD record
ord-7018258254554ae59b4f493bdc6b6ddb
Source dataset
uspto-grants-2016_07
Patent number
US09399073B2

Reaction notes

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