Triethylamine → 2-Chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenylethynyl}-benzoic acid methyl ester

HRID 1877425Notes

Reaction equation

HRID 1877425 reaction equation
Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:51])[C:42]1[CH:47]=[CH:46][C:45]([C:48]#[CH:49])=[CH:44][C:43]=1[Cl:50]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:39][O:40][C:41](=[O:51])[C:42]1[CH:47]=[CH:46][C:45]([C:48]#[C:49][C:2]2[CH:3]=[C:4]([Cl:31])[C:5]([O:6][C:7]3[C:12]([C:13]([N:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]([CH:25]5[CH2:26][CH2:27]5)[CH2:17][CH2:16]4)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:28][C:29]=2[Cl:30])=[CH:44][C:43]=1[Cl:50]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 59294468[2-(4-Bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanoneHCID 71306162Methyl 2-chloro-4-ethynylbenzoate

Product 1

HCID 592945182-Chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenylethynyl}-benzoic acid methyl esterYield 33.3%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
100 °C

Procedure

To a degassed suspension of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (100 mg, 0.19 mmol, 1.0 equiv; Example 163) in triethylamine (0.73 g, 1.0 mL, 7.21 mmol, 38.0 equiv; [CAS RN 121-44-8]) under Ar was added 2-chloro-4-ethynyl-benzoic acid methyl ester (120 mg, 0.62 mmol, 3.2 equiv), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmol, 0.1 equiv; [CAS RN 14221-01-3]) and copper(I) iodide (3.7 mg, 0.02 mmol, 0.1 equiv; [CAS RN 7681-65-4]). The reaction mixture was heated by microwave irradiation to 100° C. for 40 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) and eluting with a gradient of acetonitrile/water provided 40 mg (33%) of the title compound as a light brown powder. MS (ISP): 634.2 [M+H]+.

Workup

  1. customRemoval of the solvent mixture
  2. customunder reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column
  3. customequipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps
  4. washa Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) and eluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-194109a40b9e44d58a01a91ace56de45
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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