Dichloromethane → HCID 58292916, compound

HRID 511514Notes

Reaction equation

HRID 511514 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].OB(O)[C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[CH2:35]([O:34][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([C:44]4[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:31][CH2:32][CH3:33])=[O:37])[CH3:36]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 3121834-Carboxyphenylboronic AcidHCID 58293036HCID 58293036, compound

Product 1

HCID 58292916HCID 58292916, compoundYield 27%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate (20.0 mg, 0.0304 mmol), 4-(Dihydroxyboryl)benzoic acid (10.1 mg, 0.0608 mmol), potassium carbonate (12.6 mg, 0.0911 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (2.48 mg, 0.00304 mmol), 1,4-dioxane (0.6 mL) and water (0.15 mL) were mixed and heated in microwave at 100° C. for 30 minutes. The crude mixture was passed through Thiol-SPE cartridge to remove Pd and was subsequently purified by MDP to obtain the title compound (5.7 mg, 27% yield). 1H NMR (400 MHz, DMSO-d6) δ=1.13 (t, J=7.1 Hz, 6 H), 3.08 (s, 3 H), 3.34 (d, J=21.5 Hz, 2 H), 3.75 (s, 3 H), 3.85-4.02 (m, 4 H), 4.67 (s, 2 H), 6.94 (d, J=8.1 Hz, 1 H), 7.08 (br. s., 1 H), 7.43 (br. s., 1 H), 7.58 (d, J=8.6 Hz, 1 H), 7.75 (m, J=8.3 Hz, 2 H), 8.02 (m, J=8.6 Hz, 2 H), 8.42 (s, 1 H), 9.20 (s, 1 H), 13.05 (s, 1 H). MS (ES+): m/z 700.25 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).

Workup

  1. customto remove Pd
  2. customwas subsequently purified by MDP

Sources & evidence

ORD record
ord-699b3c7658d34a08a98a3c2e25c66ead
Source dataset
uspto-grants-2015_08
Patent number
US09096624B2

Reaction notes

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