Diisopropylethylamine → 3-(1-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-azetidine-1-carboxylic acid tert-butyl ester

HRID 245982

Reaction equation

HRID 245982 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH2:14])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([C:35]3[N:36]=[C:37]4[C:43]([C:44](O)=[O:45])=[CH:42][N:41]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:38]4=[N:39][CH:40]=3)=[N:30][N:31]2[CH3:34])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH:14][C:44]([C:43]2[C:37]3[C:38](=[N:39][CH:40]=[C:35]([C:29]4[C:28]5[C:32](=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=5)[N:31]([CH3:34])[N:30]=4)[N:36]=3)[N:41]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:42]=2)=[O:45])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 712796712-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acidHCID 71279891Tert-butyl 3-(1-aminoethyl)azetidine-1-carboxylate

Product 1

HCID 712802663-(1-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-azetidine-1-carboxylic acid tert-butyl esterYield 94.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-(1-amino-ethyl)-azetidine-1-carboxylic acid tert-butyl ester (crude from step 3, 63 mg, 0.31 mmol) in DMF (2 mL) were added N,N-diisopropylethylamine (69 μL, 0.39 mmol), 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.26 mmol), and HATU (110 mg, 0.29 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 30% to 60% EtOAc/hexanes to afford 158 mg (94%) of 3-(1-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-azetidine-1-carboxylic acid tert-butyl ester as a white foam. 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.23 (s, 1H), 8.36 (t, J=4.3 Hz, 2H), 8.18 (d, J=9.1 Hz, 1H), 7.52 (s, 1H), 7.24-7.29 (m, 1H), 5.73 (s, 2H), 4.57-4.68 (m, 1H), 4.18 (s, 3H), 3.87-4.08 (m, 3H), 3.79 (dd, J=8.7, 6.0 Hz, 1H), 3.55-3.65 (m, 2H), 2.73 (br. s., 1H), 1.39 (s, 9H), 1.36 (d, J=6.8 Hz, 6H), 0.89-1.01 (m, 2H), −0.03 (s, 9H).

Workup

  1. customthen quenched with water
  2. extractionextracted with EtOAc (3×)
  3. washThe combined organics were washed with water (3×) and brine
  4. dry with materialthen dried over MgSO4
  5. concentrationconcentrated
  6. customThe residue was purified by silica gel chromatography with 30% to 60% EtOAc/hexanes

Sources & evidence

ORD record
ord-c5ab8f0c4d994d6bb3be14c864133dab
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Linked notes

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