Nitrogen → 4-[3-(3-Methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester

HRID 870745Notes

Reaction equation

HRID 870745 reaction equation
Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.O.[CH3:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1B(O)O.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:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][N:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([C:33]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[O:27][CH3:26])=[CH:3][N:4]=3)[N:7]=2)[CH2:12][CH2:13]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]

Participants

9

Reactant 5

HCID 947Nitrogen2×HCID 6344DichloromethaneHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 467390183-Methoxypyridine-4-boronic acid hydrateHCID 68647817Tert-butyl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-1,4-diazepane-1-carboxylate

Product 1

HCID 898025774-[3-(3-Methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-[1,4]diazepane-1-carboxylic 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 tert-butyl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-1,4-diazepane-1-carboxylate (329.9 mg, 0.8 mmol), (3-methoxy pyridin-4-yl)boronic acid monohydrate [1072952-50-1] (153.6 mg, 1.0 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (384.1 mg, 1.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (69.2 mg, 0.1 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (25 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 6 h then cooled and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to afford a brown solid which was purified by preparative RP-HPLC to provide 4-[3-(3-methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as 79.5 mg of off white powder, mp. 115-116° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotomers present) 1.01 (s, 4H) 1.20 (s, 4H) 1.91 (s, 2H) 2.51 (dt, J=3.60, 1.86 Hz, 2H) 3.27-3.35 (m, 4H) 3.57 (br. s., 1H) 3.64 (s, 1H) 3.70 (br. s., 2H) 3.81 (d, J=16.67 Hz, 2H) 4.02 (s, 3H) 7.19 (d, J=9.85 Hz, 1H) 7.93 (s, 1H) 8.11 (d, J=8.59 Hz, 1H) 8.32 (d, J=5.05 Hz, 1H) 8.49-8.54 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm (rotomers present) 13.89, 22.03, 24.66, 24.75, 27.49, 27.74, 31.20, 44.27, 44.96, 45.60, 47.99, 48.26, 48.39, 56.31, 78.25, 78.41, 109.66, 109.87, 119.88, 120.03, 120.27, 124.50, 126.00, 126.08, 134.46, 135.39, 135.52, 136.92, 141.96, 150.98, 152.56, 152.65, 154.01, 154.34. LRMS (ESI) m/z 425.2 [(M+H)]+, calc'd for C22H28N6O3: 424.51.

Workup

  1. customcontained in a 50 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 (
  9. customThe phase separated
  10. extractionextract
  11. dry with materialwas dried (MgSO4)
  12. customevaporated
  13. customto afford a brown solid which
  14. customwas purified by preparative RP-HPLC

Sources & evidence

ORD record
ord-ce95f799f9aa47d88651e9eaa6ec49b7
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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