Dimethylcarbamoyl Chloride → HCID 178484727, compound

HRID 1943404Notes

Reaction equation

HRID 1943404 reaction equation
[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:53][N:54]([CH3:58])[C:55](Cl)=[O:56]>C(Cl)Cl>[CH3:53][N:54]([CH3:58])[C:55]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1)=[O:56]

Participants

5

Reactant 3

HCID 6598Dimethylcarbamoyl ChlorideHCID 81531DiisopropylethylamineHCID 178490937HCID 178490937, compound

Product 1

HCID 178484727HCID 178484727, compoundYield 45.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide 5C (41.5 mg, 0.051 mmol) and DIEA (0.045 mL, 0.256 mmol) in CH2Cl2 (1 mL) at room temperature was added dimethylcarbamic chloride (4.94 μL, 0.054 mmol), slowly, via syringe. The reaction was stirred overnight at room temperature. Volatiles were removed via a stream of nitrogen and TFA (0.5 mL) was added. The mixture was then heated at 60° C. in an oil bath for 4 h. The reaction was then cooled to room temperature and the TFA was removed under reduced pressure. The resulting crude material was diluted with 1 mL of THF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=56.165 min. 6-((trans-4-((dimethylcarbamoyl)amino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide, 2TFA (18 mg, 45.2% yield) was obtained as a white foam. LC/MS, m/z 533.1 (M+1). HPLC Rt=4.200 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.31 (1H, s), 9.82 (1 H, s), 8.73 (1H, d, J=2.47 Hz), 8.51 (1H, t, J=6.05 Hz), 8.44 (1H, d, J=5.22 Hz), 8.34 (1H, d, J=3.85 Hz), 8.12 (1H, s), 7.97 (1H, s), 7.68-7.80 (1H, m), 7.50 (1H, d, J=8.52 Hz), 7.17-7.26 (1H, m), 7.02 (1H, dd, J=6.74, 5.36 Hz), 5.84-5.93 (1H, m), 3.77-3.87 (1H, m), 3.40 (1H, d, J=6.05 Hz), 2.78 (6H, s), 2.06 (2H, s), 1.80 (2H, s), 1.34 (4H, d, J=12.10 Hz).

Workup

  1. customVolatiles were removed via a stream of nitrogen and TFA (0.5 mL)
  2. additionwas added
  3. temperatureThe mixture was then heated at 60° C. in an oil bath for 4 h
  4. temperatureThe reaction was then cooled to room temperature
  5. customthe TFA was removed under reduced pressure
  6. additionThe resulting crude material was diluted with 1 mL of THF
  7. custompurified via preparatory HPLC
  8. customB=100, gradient time 60 min, flow rate 25 mL/min

Sources & evidence

ORD record
ord-bbd5cd2c37984b92aadba9525028277c
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

Loading…