4-Chlorophenylboronic acid → 18-[4-(4'-Chloro-4-methoxybiphenyl-2-ylmethoxy)phenyl]-17-cyclohexyl-1,4,11-triazatricyclo[11.5.2.016,19]icosa-13(20),14,16(19),17-tetraene-3,12-dione

HRID 523311Notes

Reaction equation

HRID 523311 reaction equation
C([O-])(O)=O.[Na+].Br[C:7]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:8]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:34]3[C:35]4[CH:36]=[C:22]([C:23](=[O:38])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:37])[CH2:33]3)[CH:21]=[CH:20][C:19]=4[C:18]=2[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:13][CH:12]=1.[Cl:51][C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([C:7]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:8]=2[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:34]4[C:35]5[CH:36]=[C:22]([C:23](=[O:38])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:37])[CH2:33]4)[CH:21]=[CH:20][C:19]=5[C:18]=3[CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:13][CH:12]=2)=[CH:54][CH:53]=1

Participants

6

Reactant 3

HCID 742994-Chlorophenylboronic acidHCID 516892Sodium BicarbonateHCID 4412925918-[4-(2-Bromo-5-methoxybenzyloxy)phenyl]-17-cyclohexyl-1,4,11-triaza-tricyclo[11.5.2.016,19]icosa-13(20),14,16(19),17-tetraene-3,12-dione

Product 1

HCID 5954908518-[4-(4'-Chloro-4-methoxybiphenyl-2-ylmethoxy)phenyl]-17-cyclohexyl-1,4,11-triazatricyclo[11.5.2.016,19]icosa-13(20),14,16(19),17-tetraene-3,12-dione

Reagents, catalysts & solvents 2

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
73 °C

Procedure

A saturated solution of NaHCO3 (1 mL) was added to a solution of 9 (20 mg, 0.029 mmol), 4-chlorobenzeneboronic acid (11 mg, 0.068 mmol) and bis(triphenyl-phosphine)palladium (II) chloride (4 mg, 0.0063 mmol) in dimethoxyethane (DME; 6 mL). The resulting solution was heated at 73° C. for 8 h. Then, the reaction mixture was successively cooled down to room temperature, partitioned between water and ethyl acetate, dried (Na2SO4) and evaporated. Purification by column chromatography (CH2Cl2/methanol, 97:3) afforded the target product contaminated with impurities. The product was further purified by trituration in methanol, then filtered off to give the target product 10: m/z=704 (M+H)+. NMR (DMSO-d6): δ (ppm) 1.23-1.33 (m, 6H), 1.42-1.53 (m, 8H), 1.67-1.77 (m, 2H), 1.87-2.02 (m, 2H), 2.80 (m, 1H, CH cyclohexyl), 3.15 (m, 4H, 2×CH2NHCO), 3.83 (s, 3H, OCH3), 4.44 (s, 2H, CH2CONH), 5.00 (s, 2H, CH2O), 7.04-7.09 (m, 3H), 7.23 (d, J=2.6 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.40-7.47 (m, 7H), 7.76 (d, J=8.4 Hz, 1H), 7.93 (s, 1H), 8.30 (broad s, 1H, NH), 8.51 (broad s, 1H, NH).

Workup

  1. temperatureThen, the reaction mixture was successively cooled down to room temperature
  2. custompartitioned between water and ethyl acetate
  3. dry with materialdried (Na2SO4)
  4. customevaporated
  5. customPurification by column chromatography (CH2Cl2/methanol, 97:3)
  6. customafforded the target product
  7. customThe product was further purified by trituration in methanol
  8. filtrationfiltered off

Sources & evidence

ORD record
ord-6716ae019c554e79b31de847b5056d56
Source dataset
uspto-grants-2016_05
Patent number
US09334282B2

Reaction notes

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