1-Hydroxybenzotriazole → 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide

HRID 246206Notes

Reaction equation

HRID 246206 reaction equation
[Cl: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](O)=[O:22])=[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][C@@H:33]([CH2:35][OH:36])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[OH:36][CH2:35][C@H: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]([Cl: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]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:34]

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 80308(R)-(-)-2-Amino-1-propanolHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)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 acid

Product 1

HCID 712860912-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amideYield 56%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 20 mL scintillation vial, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (400 mg, 0.87 mmol), D-alaninol (131 mg, 1.75 mmol), HBTU (431 mg, 1.14 mmol), HOBt (153 mg, 1.14 mmol) and DIPEA (0.31 ml, 1.75 mmol) were combined with DMF (6 ml) to give a light yellow solution. After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc (50 mL) and washed with sat NaHCO3 (3×25 mL) and H2O (3×25 mL). The organic layer were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM with 0.1% NH4OH) to provide 250 mg (56%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide as an off-white solid. MS: (M+H)+=516.

Workup

  1. customto give a light yellow solution
  2. washwashed
  3. dry with materialThe organic layer were dried over Na2SO4
  4. concentrationconcentrated in vacuo
  5. customThe crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM with 0.1% NH4OH)

Sources & evidence

ORD record
ord-db95f7439a064b4b8f0d44ccf03a112f
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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