Tetrahydrofuran → tert-Butyl {4-[6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamate

HRID 1803891Notes

Reaction equation

HRID 1803891 reaction equation
[CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[C:17]([CH3:34])=[C:18]([CH3:33])[C:19]4[N:20]([C:22](I)=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:54]2[CH:59]=[CH:58][N:57]=[C:56]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH:55]=2)O1>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.ClCCl>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[C:17]([CH3:34])=[C:18]([CH3:33])[C:19]4[N:20]([C:22]([C:54]5[CH:59]=[CH:58][N:57]=[C:56]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:65])([CH3:64])[CH3:66])[CH:55]=5)=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 10796Cesium carbonateHCID 49760449tert-butyl N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamateHCID 594069656-(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-3-iodo-7,8-dimethylimidazo[1,2-b]pyridazine

Product 1

HCID 59406975tert-Butyl {4-[6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamateYield 72.4%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a solution of 3.60 g (6.34 mmol) of 6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-3-iodo-7,8-dimethylimidazo[1,2-b]pyridazine in 15 mL of a mixture of tetrahydrofuran and water (9:1) are added 6.2 g (19 mmol) of cesium carbonate and 2.4 g (7.6 mmol) of tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate. After sparging with a stream of argon for a few moments, 0.47 mg (0.57 mmol) of a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (PdCl2(dppf).CH2Cl2) is added and the reaction mixture is refluxed under argon for 5 hours. The mixture is then poured into 250 mL of water and the product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off to give a brown solid. The product is purified by chromatography on silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:05) to give 2.91 g of a beige-colored solid.

Workup

  1. additionis added
  2. temperaturethe reaction mixture is refluxed under argon for 5 hours
  3. extractionthe product is extracted with ethyl acetate
  4. dry with materialthe organic phase is dried over sodium sulfate
  5. filtrationfiltered
  6. customthe solvent is evaporated off
  7. customto give a brown solid
  8. customThe product is purified by chromatography on silica gel
  9. washeluting with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:05)

Sources & evidence

ORD record
ord-10214d87238948e2ac60e16d2d1227b7
Source dataset
uspto-grants-2013_01
Patent number
US08354405B2

Reaction notes

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