Dichloromethane → 1-(2-{5-Chloro-4-[7-(5-chloro-2-fluoropyridin-4-yl)-benzo[b]thiophen-2-yl]pyrimidin-2-ylamino}ethyl)imidazolidin-2-one

HRID 422111Notes

Reaction equation

HRID 422111 reaction equation
Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][NH:23][C:22]4=[O:26])[N:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[C:29](B(O)O)=[CH:30][C:31]([F:34])=[N:32][CH:33]=1.ClCCl.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.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]>[Cl:17][C:16]1[C:11]([C:9]2[S:8][C:7]3[C:2]([C:29]4[C:28]([Cl:27])=[CH:33][N:32]=[C:31]([F:34])[CH:30]=4)=[CH:3][CH:4]=[CH:5][C:6]=3[CH:10]=2)=[N:12][C:13]([NH:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])=[N:14][CH:15]=1

Participants

9

Reactant 5

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 44754822(5-Chloro-2-fluoropyridin-4-yl)boronic acidHCID 666739751-{2-[4-(7-Bromo-benzo[b]thiophen-2-yl)-5-chloro-pyrimidin-2-ylamino]-ethyl}-imidazolidin-2-one

Product 1

HCID 248228771-(2-{5-Chloro-4-[7-(5-chloro-2-fluoropyridin-4-yl)-benzo[b]thiophen-2-yl]pyrimidin-2-ylamino}ethyl)imidazolidin-2-one

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

In a microwave vial, combine 1-{2-[4-(7-bromo-benzo[b]thiophen-2-yl)-5-chloro-pyrimidin-2-ylamino]-ethyl}-imidazolidin-2-one (500 mg, 1.1 mmol), 5-chloro-2-fluoropyridine-4-boronic acid (578 mg, 3.3 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (90 mg, 0.11 mmol), 2-(di-tert-butylphosphino)biphenyl (20 mg, 0.066 mmol) and sodium carbonate (350 mg, 3.3 mmol) in THF (3 mL) and water (1.5 mL). Bubble nitrogen through the mixture for 5 min. Heat the mixture to 100° C. for 10 min. Concentrate the organic layer to dryness in vacuo. Slurry the resulting solid into dichloromethane/methanol and purify by column chromatography (1% 2 N ammonia/methanol solution in dichloromethane to 10% 2 N ammonia/methanol solution in dichloromethane) to afford the title compound. For further purification, dissolve the product in DMSO and purify by reverse phase column chromatography (50% acetonitrile in water (with 0.03% HCl) to 95% acetonitrile in water (with 0.03% HCl) to afford the title compound (146 mg, 26%). MS (ES) m/z 503 [M+1]+.

Workup

  1. concentrationConcentrate the organic layer to dryness in vacuo
  2. custompurify by column chromatography (1% 2 N ammonia/methanol solution in dichloromethane to 10% 2 N ammonia/methanol solution in dichloromethane)

Sources & evidence

ORD record
ord-a03bbb2f0bb24b2b8a7ee3dd85f7e578
Source dataset
uspto-grants-2012_01
Patent number
US08101628B2

Reaction notes

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