2-(Dicyclohexylphosphino)-2'-methylbiphenyl → N-((4-aminocyclohexyl)methyl)-6-(1H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-amine

HRID 2280110Notes

Reaction equation

HRID 2280110 reaction equation
Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH:41]([NH:44]C(=O)OC(C)(C)C)[CH2:40][CH2:39]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.CC(C)([O-])C.[Na+]>COCCOC.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:44][CH:41]1[CH2:42][CH2:43][CH:38]([CH2:37][NH:36][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][N:9]=3)[N:7]=2)[CH2:39][CH2:40]1

Participants

8

Reactant 4

HCID 27349382-(Dicyclohexylphosphino)-2'-methylbiphenylHCID 2756045tert-butyl N-[4-(aminomethyl)cyclohexyl]carbamateHCID 23676156Sodium t-butoxideHCID 866659333-(6-bromopyridin-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine

Product 1

HCID 178507611N-((4-aminocyclohexyl)methyl)-6-(1H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-amineYield 31.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6344DichloromethaneSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

To a stirred solution of 3-(6-bromo-2-pyridyl)-1-trityl-pyrazolo[5,4-b]pyridine (100 mg, 0.1933 mmol) and tert-butyl N-[4-(aminomethyl)cyclohexyl]carbamate (52.97 mg, 0.232 mmol) in DME (1.5 mL) was added Palladium acetate (4.340 mg, 0.01933 mmol) followed by dicyclohexyl-[2-(o-tolyl)phenyl]phosphane (7.046 mg, 0.01933 mmol) and sodium t-butoxide (27.87 mg, 0.2900 mmol). The reaction mixture was allowed to stir at 120 degrees in the microwave for 2 hours at which time consumption of the SM was observed. The mixture was diluted with DCM and filtered through a 2.5 g celite cartridge, combined washings were evaporated down to a smaller volume (5 ml) and the resultant solution was cooled to 0 degrees (with the aid of an ice bath) and treated with triethylsilane (0.4 mL, excess) followed by TFA (0.8 mL, excess). The reaction was allowed to stir at 0 degrees for 3 hours at which time LCMS analysis showed presence of product. The mixture was evaporated to dryness, taken up in DMSO and purified by the Fractionlynx system. Relavant fractions were collated together and filtered through a NaHCO3 cartridge to give the free base. The washings were evaporated to dryness, taken up in a small amount of MeCN/water and freeze-dried to give the required product as a white solid (19.5 mg, 31%).

Workup

  1. filtrationfiltered through a 2.5 g celite cartridge
  2. customwere evaporated down to a smaller volume (5 ml)
  3. temperaturethe resultant solution was cooled to 0 degrees (with the aid of an ice bath) and
  4. additiontreated with triethylsilane (0.4 mL, excess)
  5. stirringto stir at 0 degrees for 3 hours at which time LCMS analysis
  6. customThe mixture was evaporated to dryness
  7. custompurified by the Fractionlynx system
  8. filtrationfiltered through a NaHCO3 cartridge
  9. customto give the free base
  10. customThe washings were evaporated to dryness
  11. customfreeze-dried

Sources & evidence

ORD record
ord-74d2e7f636ab4f219851ffed30c0583c
Source dataset
uspto-grants-2015_09
Patent number
US09137973B2

Reaction notes

Loading…