Dichloromethane → tert-butyl 4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3,6-dihydropyridine-1(2H)-carboxylate

HRID 1972906Notes

Reaction equation

HRID 1972906 reaction equation
[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19](Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH:41]=2)O1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([C:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=3)[N:20]2[N:21]=[CH:22][N:23]=1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 585299415-(2-benzyl-2H-indazol-6-yl)-7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine

Product 1

HCID 58529584tert-butyl 4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3,6-dihydropyridine-1(2H)-carboxylateYield 69%

Reagents, catalysts & solvents 3

HCID 24290Palladium ChlorideCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
75 °C

Procedure

To a stirred suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (660 mg, 1.57 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (see Eastwood, P. R. Tetrahedron Lett 2000, 41, 3705 for preparation) (730 mg, 2.36 mmol), and 1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II)-complex with dichloromethane (115 mg, 0.16 mmol) in degassed DME (12 mL) was added aqueous Na2CO3 solution (2 M, 2.4 mL). The reaction was heated (75° C.) for 17 h and was then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL). The layers were separated and the organic layer was washed with brine, dried (Na2SO4), and concentrated to dryness. The crude residue was purified by ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 564 mg (69%) of the desired product, which was approximately 50% pure. ES-MS m/z 522.12 [M+H]+, HPLC RT (min) 3.20.

Workup

  1. temperaturewas then cooled to rt
  2. customThe mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL)
  3. customThe layers were separated
  4. washthe organic layer was washed with brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated to dryness
  7. customThe crude residue was purified by ISCO® chromatography

Sources & evidence

ORD record
ord-5a3cac6980524e6f903ba6dc09806564
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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