Diisopropylethylamine → HCID 178481750, compound

HRID 246785Notes

Reaction equation

HRID 246785 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](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.Cl.[NH2:33][CH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[OH:38][C@@H:36]1[CH2:37][C@H:34]([NH:33][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=2)=[O:22])[CH2:35]1.[OH:38][C@H:36]1[CH2:37][C@H:34]([NH:33][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=2)=[O:22])[CH2:35]1

Participants

8

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 533084663-Aminocyclobutanol hydrochlorideHCID 712796202-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid

Product 2

HCID 178481750HCID 178481750, compoundYield 48%HCID 178481751HCID 178481751, compoundYield 35%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (250 mg, 0.57 mmol), 3-aminocyclobutanol hydrochloride (98 mg, 0.79 mmol) and DMF (2.8 mL). N,N-diisopropylethylamine (266 mg, 0.36 mL, 2.06 mmol) was added followed by HATU (237 mg, 0.62 mmol). The yellow solution was stirred at room temperature overnight (a precipitate was formed). The reaction mixture was diluted with water and petroleum ether. The suspension was filtered. The solid was washed with water and a little petroleum ether. The resulting off-white powder was dried under high vacuum. The mixture of cis- and trans-product (265 mg off-white powder) was submitted for further separation by SFC chromatography (KROMASIL OD 3×25 cm, 25% MeOH/CO2+0.1% Triethylamine) to afford 139 mg (48%) 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclobutyl)-amide as an off-white solid and 102 mg (35%) 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-hydroxy-cyclobutyl)-amide as an off-white solid.

Workup

  1. customwas formed)
  2. filtrationThe suspension was filtered
  3. washThe solid was washed with water
  4. customThe resulting off-white powder was dried under high vacuum
  5. additionThe mixture of cis- and trans-product (265 mg off-white powder)
  6. customwas submitted for further separation by SFC chromatography (KROMASIL OD 3×25 cm, 25% MeOH/CO2+0.1% Triethylamine)

Sources & evidence

ORD record
ord-8aa638b4ca7744a6930d6705c230e414
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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