Diisopropylethylamine → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-1,3-dimethyl-butyl)-amide

HRID 246185Notes

Reaction equation

HRID 246185 reaction equation
[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][CH:33]([CH3:39])[CH2:34][C:35]([CH3:38])([OH:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CCOC(C)=O.C(#N)C>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][CH:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:23])[CH3:39]

Participants

7

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 125420854-Amino-2-methylpentan-2-olHCID 712796202-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid

Product 1

HCID 712857852-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-1,3-dimethyl-butyl)-amideYield 63%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (98 mg, 0.22 mmol), 4-amino-2-methylpentan-2-ol [prepared according to US 2003/0171584 A1] (27 mg, 0.23 mmol), and HATU (89 mg, 0.23 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.2 mL, 1.12 mmol). The yellow reaction mixture was stirred at room temperature overnight then diluted with EtOAc and washed with water (3×). The organic layer was combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-90% EtOAc) to afford 75 mg (63%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-1,3-dimethyl-butyl)-amide as an off-white solid. MS: [M+H]+=541.

Workup

  1. washwashed with water (3×)
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated
  4. customThe residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-90% EtOAc)

Sources & evidence

ORD record
ord-4739737c6b6141ac81a6be044089f8a6
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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