Nitrogen → {2-[3-(5-Acetyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethyl}-methyl-carbamic acid tert-butyl ester

HRID 870702Notes

Reaction equation

HRID 870702 reaction equation
[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18](Br)=[CH:19][N:20]=2)[N:17]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[CH3:24].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.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>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:29]3[S:30][C:26]([C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=3)=[CH:19][N:20]=2)[N:17]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]

Participants

9

Reactant 5

HCID 947Nitrogen2×HCID 6344DichloromethaneHCID 4143377(5-Acetylthiophen-2-yl)boronic acidHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 86696401[2-(3-Bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester

Product 1

HCID 86696404{2-[3-(5-Acetyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethyl}-methyl-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

To a mixture of [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester (285.5 mg, 0.8 mmol), (5-acetylthiophen-2-yl)boronic acid [206551-43-1] (157.3 mg, 0.9 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (354.8 mg, 1.5 mmol), and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (63.4 mg, 0.1 mmol) contained in a 25 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (12.5 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 17 h then cooled and partitioned between brine and ethyl acetate. The phase separated extract was dried (MgSO4), evaporated, flash chromatographed (silica gel eluted with 100% ethyl acetate) and crystallized (ethyl acetate/heptane) to provide {2-[3-(5-acetyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethyl}-methyl-carbamic acid tert-butyl ester as 121.3 mg of yellow powder, mp. 174-175° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotamers present) 1.11 (br. s., 6H) 1.39 (br. s., 3H) 2.54 (s, 3H) 2.87 (br. s., 2H) 2.92 (br. s., 1H) 3.32 (s, 1H) 3.52 (br. s., 3H) 3.62 (br. s., 1H) 7.78-7.85 (m, 2H) 7.96 (d, J=4.29 Hz, 1H) 8.14 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 26.95, 28.16, 28.50, 34.07, 46.09, 78.50, 113.14, 123.02, 124.18, 126.13, 130.89, 134.37, 137.71, 138.38, 141.77, 154.32, 155.43, 191.11. LRMS (ESI) m/z 416.2 [(M+H)]+, calc'd for C14H20BrN6O2: 415.52.

Workup

  1. customcontained in a 25 mL round bottomed flask
  2. customThe reaction
  3. custompot was fitted to a reflux condenser
  4. customlowered into an ambient temperature
  5. stirringThe rapidly stirred
  6. customreaction
  7. temperaturethen cooled
  8. custompartitioned between brine and ethyl acetate
  9. customThe phase separated
  10. extractionextract
  11. dry with materialwas dried (MgSO4)
  12. customevaporated
  13. customflash chromatographed
  14. wash(silica gel eluted with 100% ethyl acetate)
  15. customcrystallized (ethyl acetate/heptane)

Sources & evidence

ORD record
ord-f1c4ed7c2cf840d6b2a9bcb9d162f2a4
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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