HCID 86708885, compound → HCID 131730826, compound

HRID 1895786Notes

Reaction equation

HRID 1895786 reaction equation
[CH:1]([C:3]1[CH:4]=[C:5]([C@H:9]([NH:11][C:12]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:56])[C@@H:21]([NH:37][C:38](=[O:55])[C@@H:39]([NH:43][C:44](=[O:54])[C@H:45]([CH3:53])[C@H:46]([O:51][CH3:52])[CH2:47][CH2:48]C=C)[CH:40]([CH3:42])[CH3:41])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:24]=3)[NH:15]2)=[O:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[CH2:2]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[C:33]([Si:30]([CH3:32])([CH3:31])[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][CH:21]1[NH:37][C:38](=[O:55])[CH:39]([CH:40]([CH3:41])[CH3:42])[NH:43][C:44](=[O:54])[CH:45]([CH3:53])[CH:46]([O:51][CH3:52])[CH2:47][CH2:48][CH:2]=[CH:1][C:3]2[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=2)[CH:9]([CH3:10])[NH:11][C:12](=[O:13])[CH:14]2[NH:15][N:16]([CH2:17][CH2:18][CH2:19]2)[C:20]1=[O:56])([CH3:35])([CH3:36])[CH3:34]

Participants

4

Reactant 1

HCID 86708885HCID 86708885, compound

Product 1

HCID 131730826HCID 131730826, compoundYield 22.1%

Reagents, catalysts & solvents 2

HCID 11763533(1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene)(dichloro)((2-((propan-2-yl)oxy)phenyl)methylidene)rutheniumCatalystHCID 111,2-DichloroethaneSolvent

Conditions

Temperature
80 °C

Procedure

Hoveyda-Grubbs 2nd generation catalyst (22 mg, 0.035 mmol) was added to a stirred solution of (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((2R,3R)-3-methoxy-2-methyl-hept-6-enoylamino)-3-methyl-butyrylamino]-prop ionyl}-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(3-vinyl-phenyl)-ethyl]-amide (276 mg, 0.35 mmol) in 1,2-dichloroethane (135 mL) and the reaction mixture was heated at 80° C. under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, silica gel was added and the reaction mixture was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to neat ethyl acetate to afford (E)-2R,5S,11S,14S,17R,18R)-11-[3-(tert-butyl-dimethyl-silanyloxy)-benzyl]-14-isopropyl-18-methoxy-2,17-dimethyl-3,9,12,15,28-pentaaza-tricyclo[21.3.1.1*5,9*]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetraone (59 mg, 22%) as a gum. LCMS (m/z) 762 [M+H], Tr=5.01 min. A solution of (E)-(2R,5S,11S,14S,17R,18R)-11-[3-(tert-butyl-dimethyl-silanyloxy)-benzyl]-14-isopropyl-18-methoxy-2,17-dimethyl-3,9,12,15,28-penta-azaricyclo[21.3.1.1*5,9*]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetraone (59 mg, 0.077 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. under nitrogen. A solution of tetra-N-butylammonium fluoride (1 M in tetrahydrofuran, 0.12 mL, 0.123 mmol) was added and the reaction mixture was stirred at 0° C. for 10 minutes. Silica gel was added and the solvent was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:3 to neat ethyl acetate. The residue was triturated with ether and the resulting solid was collected, washed with ether and dried to afford the title compound (30 mg, 60%) as a white solid. 1H NMR (300 MHz, CD3CN) δ0.94 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.7 Hz, 3H), 1.30 (d, J=7.1 Hz, 3H), 1.45 (d, J=6.9 Hz, 3H), 1.55-2.20 (m, 9H), 2.62-2.68 (m, 2H), 2.81-2.98 (m, 2H), 3.26-3.38 (m, 2H), 3.45 (s, 3H), 3.96 (d, J=12.2 Hz, 1H), 4.17 (t, J=8.0 Hz, 1H), 4.34-4.39 (m, 1H), 4.80-4.90 (m, 1H), 5.50-5.56 (m, 1H), 5.85 (d, J=15.8 Hz, 1H), 6.01-6.08 (m, 1H), 6.66-6.69 (m, 1H), 6.86-7.30 (m, 10H), 8.15-8.25 (br s, 1H). LCMS (m/z) 648 [M+H], Tr=4.30 min.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. additionsilica gel was added
  3. customthe reaction mixture was evaporated
  4. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-daa63dc890144de0a4329643d0daa497
Source dataset
uspto-grants-2013_08
Patent number
US08513184B2

Reaction notes

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