Diisopropylethylamine → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-amide

HRID 245941Notes

Reaction equation

HRID 245941 reaction equation
C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30]([OH:32])=O)=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:72][C@@H:73]([C:75]1[O:76][CH:77]=[C:78]([CH2:80][OH:81])[N:79]=1)[CH3:74]>CN(C=O)C>[OH:81][CH2:80][C:78]1[N:79]=[C:75]([C@H:73]([NH:72][C:30]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[C:14]5[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=5)[N:17]([CH3:20])[N:16]=4)[N:22]=3)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[CH:28]=2)=[O:32])[CH3:74])[O:76][CH:77]=1

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 712796202-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acidHCID 71280113[2-((R)-1-amino-ethyl)-oxazol-4-yl]-methanol trifluoroacetate

Product 1

HCID 712881882-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-amideYield 66%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

In a round-bottomed flask, [2-((R)-1-amino-ethyl)-oxazol-4-yl]-methanol trifluoroacetate (crude from Step 5) was dissolved in DMF (1.5 ml) and N,N-diisopropylethylamine (0.70 ml, 4.0 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (140 mg, 0.32 mmol was added followed by HATU (133 mg, 0.35 mmol). The reaction was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-100% EtOAc) to afford 118 mg (66%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-amide as a light brown foam.

Workup

  1. customthen quenched with water
  2. extractionextracted with diethyl ether (2×)
  3. washThe combined organic layers were washed twice with water and once with brine
  4. dry with materialthen dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-100% EtOAc)

Sources & evidence

ORD record
ord-5f84d375075d4774b522662358bd3dec
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

Loading…