Nitrogen → {3-[3-(4-Aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propyl}-methyl-carbamic acid isopropyl ester

HRID 870675Notes

Reaction equation

HRID 870675 reaction equation
[CH:1]([O:4][C:5](=[O:22])[N:6]([CH2:8][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)[CH3:7])([CH3:3])[CH3:2].Cl.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.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>[CH:1]([O:4][C:5](=[O:22])[N:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:29]3[CH:30]=[CH:31][C:26]([CH2:25][NH2:24])=[CH:27][CH:28]=3)=[CH:19][N:20]=2)[N:17]=1)[CH3:7])([CH3:3])[CH3:2]

Participants

9

Reactant 5

HCID 947Nitrogen2×HCID 6344DichloromethaneHCID 27343114-Aminomethylphenylboronic acid hydrochlorideHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 86696375[3-(3-Bromo-imidazo[1,2-b]pyridazin-6-ylamino)-propyl]-methyl-carbamic acid isopropyl ester

Product 1

HCID 86696376{3-[3-(4-Aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propyl}-methyl-carbamic acid isopropyl 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 [3-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-propyl]-methyl-carbamic acid isopropyl ester (601.4 mg, 1.6 mmol), (4-(aminomethyl)phenyl)boronic acid hydrochloride [75705-21-4] (366.3 mg, 2.0 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (1.1 g, 4.9 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with dichloromethane [95464-05-4] (138.7 mg, 0.2 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (12 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 (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) purified by preparative RP-HPLC. Purified chromatography fractions were combined and partitioned between aqueous saturated sodium bicarbonate and ethyl acetate. The organic extract dried (CaSO4) and evaporated to provide {3-[3-(4-aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propyl}-methyl-carbamic acid isopropyl ester as 19.4 mg of clear yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.12 (br. s., 2H) 1.17-1.28 (m, 4H) 1.84-1.98 (m, 2H) 2.90 (s, 2H) 3.10-3.21 (m, 1H) 3.32-3.43 (m, 3H) 3.88 (s, 2H) 4.78-4.87 (m, 4H) 6.69 (d, J=9.60 Hz, 1H) 7.45 (d, J=8.34 Hz, 2H) 7.61 (d, J=9.60 Hz, 1H) 7.69-7.75 (m, 1H) 8.12 (dd, J=8.21, 2.65 Hz, 2H). 13C NMR (100 MHz, METHANOL-d4) δ ppm 22.58, 37.39, 40.24, 46.39, 70.29, 110.81, 114.20, 125.95, 126.19, 127.75, 127.85, 128.87, 129.41, 129.65, 129.73, 130.34, 138.67, 141.99, 155.32. LRMS (ESI) m/z 397.3 [(M+H)]+, calc'd for C21H28N6O2: 396.50.

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. custompurified by preparative RP-HPLC
  13. customPurified chromatography fractions
  14. custompartitioned between aqueous saturated sodium bicarbonate and ethyl acetate
  15. extractionThe organic extract
  16. dry with materialdried (CaSO4)
  17. customevaporated

Sources & evidence

ORD record
ord-e45675eba5984e06a169d48c62596098
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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