1,2-Dichloroethane → 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide

HRID 1898591Notes

Reaction equation

HRID 1898591 reaction equation
[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O.[NH2:29][C@H:30]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39]#[N:40])[CH2:35][CH2:34]1)=[O:32].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:39]([CH:36]1[CH2:37][CH2:38][N:33]([C:31]([C@H:30]([NH:29][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)=[O:13])[C:41]([CH3:43])([CH3:42])[CH3:44])=[O:32])[CH2:34][CH2:35]1)#[N:40]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 584385252-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acidHCID 673860481-((R)-2-amino-3,3-dimethyl-butyryl)-piperidine-4-carbonitrile trifluoroacetate

Product 1

HCID 584385322-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amideYield 59%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

In a flask were combined 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.6 g, 4.3 mmol), 1-((R)-2-amino-3,3-dimethyl-butyryl)-piperidine-4-carbonitrile trifluoroacetate (crude from step 2), EDC (1.89 g, 9.9 mmol) and HOBt (1.67 g, 9.9 mmol). DMF (40 mL) was added followed by i-Pr2NEt (5.2 mL, 30.1 mmol). The reaction mixture was stirred at room temperature for overnight and then concentrated. The residue was taken up in EtOAc and 10% citric acid and the organic layer washed with 10% citric acid, sat. NaHCO3, sat LiCl and brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (40%-100% EtOAc/hexanes) to give 1.46 g (59%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a beige foamy solid.

Workup

  1. customIn a flask were combined
  2. concentrationconcentrated
  3. wash10% citric acid and the organic layer washed with 10% citric acid, sat. NaHCO3
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated
  6. customThe residue was purified by silica gel chromatography (40%-100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-bf97ffb3ac894ec188dc7bef551ec670
Source dataset
uspto-grants-2013_08
Patent number
US08518945B2

Reaction notes

Loading…