Trifluoroacetic acid → HCID 71625970, compound

HRID 1396417Notes

Reaction equation

HRID 1396417 reaction equation
Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29]C(=O)OC(C)(C)C.CN1C(=O)CCC1.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[NH:29][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=2)[CH:3]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 13387N-methyl-2-pyrrolidoneHCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protectedHCID 86689766HCID 86689766, compound

Product 1

HCID 71625970HCID 71625970, compoundYield 24.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
130 °C

Procedure

A pressure tube was charged with 6-chloro-4-(6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide (230 mg, 752 μmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (242 mg, 1.13 mmol) and NMP (4 mL). The yellow solution was stirred at 130° C. for 2.5 days. After that, the NMP was distilled off using a Kugelrohr apparatus under high vacuum to afford a light brown solid. The crude solid was dissolved in dichloromethane and MeOH and adsorbed on silica gel, then purified by flash column (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH over 40 min) to give a light brown solid. The crude product was dissolved in dichloromethane (2 mL) and TFA (740 mg, 500 μL, 6.49 mmol) was added. The mixture was stirred at room temperature for 4 h. After that, the TFA and the dichloromethane were removed in vacuo, the brown solid obtained dissolved in dichloromethane, adsorbed on silica gel and then purified by flash column (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH over 40 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropyl-5-methylpyridin-2-ylamino)pyridazine-3-carboxamide (70 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (br. s., 1H), 8.37 (br. s., 1H), 7.92 (s, 1H), 7.61 (br. s., 1H), 7.48 (d, J=8.34 Hz, 1H), 6.71 (d, J=8.08 Hz, 1H), 6.66 (d, J=8.08 Hz, 1H), 3.24 (dt, J=13.39, 6.70 Hz, 1H), 3.08 (d, J=2.53 Hz, 1H), 2.26 (s, 3H), 1.30-1.75 (m, 11H), 1.26 (dd, J=6.70, 1.39 Hz, 6H). LC-MS 384 [M+H]+.

Workup

  1. distillationAfter that, the NMP was distilled off
  2. customto afford a light brown solid
  3. custompurified by flash column (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH over 40 min)
  4. customto give a light brown solid
  5. stirringThe mixture was stirred at room temperature for 4 h
  6. customAfter that, the TFA and the dichloromethane were removed in vacuo
  7. customthe brown solid obtained
  8. custompurified by flash column (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH over 40 min)

Sources & evidence

ORD record
ord-514c833877814844a657a94e9de01feb
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

Loading…