Ethylenediamine → 2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

HRID 245978Notes

Reaction equation

HRID 245978 reaction equation
[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[CH2:29][CH2:28][C:27]([CH3:32])([CH3:31])[CH2:26][C:25]=5[N:24]([CH3:33])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[CH2:29][CH2:28][C:27]([CH3:31])([CH3:32])[CH2:26][C:25]=5[N:24]([CH3:33])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]

Participants

5

Reactant 3

HCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 712888955-(2-trimethylsilanyl-ethoxymethyl)-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

Product 1

HCID 712857022-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amideYield 55%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 5-(2-trimethylsilanyl-ethoxymethyl)-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (40 mg, 0.068 mmol) in CH2Cl2 (3 mL) was added TFA (1.5 mL, 19.5 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (3 mL) and ethylenediamine (0.3 mL, 4.44 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h then quenched with water and extracted with CH2Cl2 (3×). The combined organics were concentrated to a yellow oily solid. Trituration with EtOAc/Et2O gave 17 mg (55%) of 2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as an off-white solid. MS (M+H)+=461; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.94 (d, J=2.0 Hz, 1H), 8.34-8.44 (m, 2H), 4.46-4.74 (m, 3H), 4.10-4.21 (m, 1H), 4.02 (dd, J=9.9, 6.4 Hz, 1H), 3.78-3.86 (m, 1H), 3.77 (s, 3H), 2.98-3.08 (m, 1H), 2.85-2.94 (m, 1H), 2.45 (s, 2H), 1.52 (t, J=6.4 Hz, 2H), 1.29-1.39 (m, 3H), 1.03 (s, 6H).

Workup

  1. concentrationthen concentrated
  2. dissolutionThe residue was redissolved in CH2Cl2 (3 mL)
  3. stirringThe reaction mixture was stirred at room temperature for 0.5 h
  4. customthen quenched with water
  5. extractionextracted with CH2Cl2 (3×)
  6. concentrationThe combined organics were concentrated to a yellow oily solid

Sources & evidence

ORD record
ord-a9ae9dd641604337838b74ec18dc2306
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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