Ethylenediamine → 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide

HRID 246174Notes

Reaction equation

HRID 246174 reaction equation
[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH2:9][O:10][CH3:11])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:9][O:10][CH3:11])[CH2:4]1)#[N:2]

Participants

5

Reactant 3

HCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 712889482-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide

Product 1

HCID 712887042-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amideYield 60%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide (44 mg, 0.071 mmol) and TFA (1.8 ml, 23.4 mmol) were combined with dichloromethane (6 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 (4 mL) and ethylenediamine (0.30 ml, 4.4 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 21 mg (59%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as a white solid. MS: [M+H]+=492; 1H NMR (300 MHz, DMSO-d6) δ: 12.72 (br. s, 1H), 9.16 (s, 1H), 8.74 (d, J=8.7 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.50 (d, J=4.9 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 4.86-5.04 (m, 1H), 4.46-4.73 (m, 2H), 4.17-4.19 (m, 1H), 4.16-4.28 (m, 4H), 4.04-4.16 (m, 1H), 3.77-3.93 (m, 1H), 3.72 (dd, J=9.5, 4.9 Hz, 1H), 3.59-3.68 (m, 1H), 3.27 (app d, J=4.9 Hz, 3H).

Workup

  1. customto give an orange solution
  2. concentrationthen concentrated under reduced pressure
  3. dissolutionThe resultant crude solid was dissolved in dichloromethane (4 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-9607e240f47a48e494938248d162d1d7
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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