2-Aminopyridine → HCID 178511624, compound

HRID 1943486Notes

Reaction equation

HRID 1943486 reaction equation
Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CC(C)([O-])C.[K+].[C@H:35]1([NH2:42])[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1>C1COCC1.CO>[NH2:41][C@H:38]1[CH2:39][CH2:40][C@H:35]([NH:42][C:6]2[CH:7]=[C:2]([NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[C:3]3[N:4]([C:9]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[F:21])=[O:13])=[CH:10][N:11]=3)[N:5]=2)[CH2:36][CH2:37]1

Participants

7

Reactant 4

HCID 104392-AminopyridineHCID 23665647Potassium tert-butoxideHCID 596244958-Bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamideHCID 178511674HCID 178511674, compound

Product 1

HCID 178511624HCID 178511624, compoundYield 5.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 8028TetrahydrofuranSolvent2×

Procedure

A suspension of 5A (20 mg, 0.061 mmol) in THF (1 mL) was treated with pyridin-2-amine (11.54 mg, 0.123 mmol). A solution of potassium t-butoxide (0.123 mL, 0.123 mmol) in THF was added and the reaction was stirred at room temperature. After two hours the solvent was removed under a stream of nitrogen. (trans)-cyclohexane-1,4-diamine (200 mg, 1.751 mmol) was added and the reaction mixture was heated to 160° C. for 3 hours. The solution was cooled to room temperature and diluted with MeOH. The solid residue was filtered and dried. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=28.731 minutes) was isolated and lyophilized to dryness to afford 6-((trans-4-aminocyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (1.5 mg, 4.25%). HPLC Rt=3.343 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=462.1.

Workup

  1. customAfter two hours the solvent was removed under a stream of nitrogen
  2. temperaturethe reaction mixture was heated to 160° C. for 3 hours
  3. temperatureThe solution was cooled to room temperature
  4. filtrationThe solid residue was filtered
  5. customdried
  6. customThe crude reaction product
  7. custompurified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm)
  8. customThe product (retention time=28.731 minutes) was isolated

Sources & evidence

ORD record
ord-2653485f4edc49e6b8fcb3cb7e8c698f
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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