Diisopropylethylamine → HCID 24831022, compound

HRID 446901Notes

Reaction equation

HRID 446901 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C@H:18]([NH:20][C:21](=[O:27])OC(C)(C)C)[CH3:19])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:28]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=C=O.CCN(C(C)C)C(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C@H:18]([NH:20][C:21]([NH:28][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[O:27])[CH3:19])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 27604933-IsocyanatopyridineHCID 59363286tert-Butyl (R)-1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethylcarbamate

Product 1

HCID 24831022HCID 24831022, compound

Reagents, catalysts & solvents 1

HCID 21863450Trifluoroacetic acid methylene chlorideSolvent

Procedure

(Step 2-i) tert-Butyl (R)-1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethylcarbamate (50 mg, 0.13 mmol) was dissolved in 5 mL TFA:CH2Cl2 (1:1) and left standing for 20 min. The solvent was removed under reduced pressure and CH2Cl2 was added and removed 4 times to remove residual TFA. The amine was dissolved in 1 mL NMP and 3-isocyanatopyridine (20 mg, 0.17 mmol) was added followed by the addition of DIEA (0.086 mL, 0.5 mmol). The reaction mixture was microirradiated at 100° C. for 10 min, loaded onto a preparative reversed-phase HPLC column, and the column eluted with a H2O/CH3CN 0.1% TFA gradient. Fractions containing pure product were combined and concentrated, 6M HCl was added, and the resulting solution concentrated to give the product, 1-((R)-1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-3-(pyridin-3-yl)urea, as the HCl salt (31 mg, 0.076 mmol, 58% yield): 1H NMR (500 MHz, DMSO-d6) 10.30 (s, 1H), 10.00 (s, 1H), 9.10 (d, J=2.2 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H), 8.31 (dd, J=1.2, 8.7 Hz, 1H), 8.16 (d, J=9.8 Hz, 1H), 7.94-7.89 (m, 2H), 7.76 (dd, J=1.5, 8.2 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.23 (d, J=9.9 Hz, 1H), 7.06 (dd, J=1.4, 8.0 Hz, 1H), 5.52 (t, J=7.3 Hz, 1H), 1.68 (d, J=7.0 Hz, 3H); MH+409.20.

Workup

  1. waitleft
  2. customThe solvent was removed under reduced pressure and CH2Cl2
  3. additionwas added
  4. customremoved 4 times
  5. customto remove residual TFA
  6. dissolutionThe amine was dissolved in 1 mL NMP
  7. waitThe reaction mixture was microirradiated at 100° C. for 10 min
  8. washthe column eluted with a H2O/CH3CN 0.1% TFA gradient
  9. additionFractions containing pure product
  10. concentrationconcentrated
  11. addition6M HCl was added
  12. concentrationthe resulting solution concentrated

Sources & evidence

ORD record
ord-ccf0305ead0d4a9b8d31af6d823a6d39
Source dataset
uspto-grants-2013_07
Patent number
US08481538B2

Reaction notes

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