Diisopropylethylamine → 5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide

HRID 2204478Notes

Reaction equation

HRID 2204478 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]2[CH2:15][C@H:14]([C:16]3[N:20]4[C:21]5[CH:27]=[CH:26][N:25]([S:28]([C:31]6[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=6)(=[O:30])=[O:29])[C:22]=5[N:23]=[CH:24][C:19]4=[N:18][N:17]=3)[C:13]2([CH3:39])[CH3:38])(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:40]([NH:43][C@@H]1C[C@H](C(O)=O)C1(C)C)(=O)C.CCN(C(C)C)C(C)C.BrC1C=CC(S(Cl)(=O)=O)=NC=1.C([Zn]C#N)#N>CN(C=O)C.[OH-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)CCl>[C:40]([C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]2[CH2:15][C@H:14]([C:16]3[N:20]4[C:21]5[CH:27]=[CH:26][N:25]([S:28]([C:31]6[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=6)(=[O:30])=[O:29])[C:22]=5[N:23]=[CH:24][C:19]4=[N:18][N:17]=3)[C:13]2([CH3:39])[CH3:38])(=[O:9])=[O:10])=[N:6][CH:7]=1)#[N:43]

Participants

10

Reactant 5

HCID 81531DiisopropylethylamineHCID 11183048(1S,3R)-3-acetamido-2,2-dimethylcyclobutane-1-carboxylic acidHCID 445580975-Bromopyridine-2-sulfonyl chlorideHCID 580103065-bromo-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamideHCID 178514179HCID 178514179, compound

Product 1

HCID 580102855-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamideYield 14%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 111,2-DichloroethaneSolventHCID 6228DimethylformamideSolventHCID 14798Sodium HydroxideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 5-bromo-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide (0.69 g, 1.1 mmol, prepared using A from (1S,3R)-3-acetamido-2,2-dimethylcyclobutanecarboxylic acid [Tetrahedron: Asymmetry 2008, 19, 302-308] and Preparation #9 with EDC, C with DIEA, JJ, N from 5-bromopyridine-2-sulfonyl chloride [Chem Impex]) in degassed DMF (1.5 mL) was added dicyanozinc (0.321 g, 2.74 mmol) followed by Pd(Ph3P)4 (0.063 g, 0.055 mmol, Strem). The reaction was heated at about 80° C. for about 16 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature before it was diluted with aqueous NaOH (1N, 10 mL) and extracted with EtOAc (25 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (12 g) eluting with a gradient of 1-10% MeOH in DCM to give 5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide (0.09 g, 14%) as a tan solid: LC/MS (Table 2, Method a) Rt=2.14 min; MS m/z: 577 (M+H)+.

Workup

  1. temperatureto cool to ambient temperature before it
  2. extractionextracted with EtOAc (25 mL)
  3. washThe organic layer was washed with brine (20 mL)
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe product was purified by silica gel chromatography (12 g)
  8. washeluting with a gradient of 1-10% MeOH in DCM

Sources & evidence

ORD record
ord-e3dfe318017f405e9f91783e2e9c6781
Source dataset
uspto-grants-2016_06
Patent number
US09365579B2

Reaction notes

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