Ethylenediamine → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide

HRID 246178Notes

Reaction equation

HRID 246178 reaction equation
[OH:1][C@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][C@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6]

Participants

5

Reactant 3

HCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 712859342-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide

Product 1

HCID 712857432-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amideYield 48.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide (30 mg, 0.055 mmol) and TFA (0.3 ml, 3.9 mmol) were combined with dichloromethane (1 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.26 ml, 3.9 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 11 mg (47%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 12.85 (br. s., 1H), 9.16 (s, 1H), 8.78 (dd, J=8.9, 5.5 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.65 (dd, J=9.6, 2.1 Hz, 1H), 7.15 (td, J=9.2, 2.5 Hz, 1H), 5.17 (d, J=4.2 Hz, 1H), 4.20-4.33 (m, 1H), 4.15 (s, 3H), 3.98-4.09 (m, 1H), 3.59 (dd, J=9.8, 6.8 Hz, 1H), 3.50 (dd, J=9.4, 6.4 Hz, 1H), 3.27 (s, 3H), 1.13 (d, J=6.4 Hz, 3H).

Workup

  1. customto give an orange solution
  2. concentrationthen concentrated under reduced pressure
  3. dissolutionThe resultant crude solid was dissolved in dichloromethane (1 mL)
  4. stirringThe reaction mixture was stirred at room temperature for 18 h
  5. concentrationthen concentrated
  6. customthe residue was precipitated with water
  7. stirringThe suspension was stirred for 1 h
  8. filtrationthe crude solid collected by filtration
  9. customThe crude solid was purified by trituration (hot dichloromethane/heptane)

Sources & evidence

ORD record
ord-ce1d47e0f1d44be88c1436e28ac69479
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

Loading…