Aluminium lithium hydride → HCID 66664458, compound

HRID 1892967Notes

Reaction equation

HRID 1892967 reaction equation
[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:20])[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:29][CH2:28][C:24]1[CH:23]=[C:22]([CH2:21][N:13]2[C:14]3[C:19](=[C:18]([Cl:20])[CH:17]=[CH:16][CH:15]=3)[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:8])=[O:9])=[N:12]2)[CH:27]=[CH:26][CH:25]=1

Participants

4

Reactant 2

HCID 21226445Aluminium lithium hydride2×HCID 58054433HCID 58054433, compound

Product 1

HCID 66664458HCID 66664458, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To an ice/water bath cooled solution of 5-chloro-N-{4-chloro-1-[(3-cyanophenyl)methyl]-1H-indazol-3-yl}-2-thiophenesulfonamide (for a preparation see Intermediate 42) (95 mg, 0.20 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen atmosphere was added dropwise over 1 min lithium aluminium hydride (1M solution in diethyl ether, 0.513 mL, 0.513 mmol). The reaction was stirred in the ice/water bath for 10 min, and then at room temperature for 30 min. Reaction re-cooled in the ice/water bath and a further portion of lithium aluminium hydride (1M solution in diethyl ether, 0.2 mL) was added dropwise over 1 min. Reaction stirred at room temperature for 1.5 h, then cooled (ice/water bath) and cautiously quenched with water (dropwise) until no more effervescence. The reaction mixture was then diluted with 1:1 methanol-dichloromethane in order to try to improve solubility and applied to a methanol pre-conditioned 20 g SCX-2 cartridge. The cartridge was washed with methanol and then eluted using 2M ammonia in methanol solution. The 2M ammonia in methanol fractions were combined and evaporated in-vacuo to yield N-(1-{[3-(aminomethyl)phenyl]methyl}-4-chloro-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide (68 mg, 0.15 mmol) as an off-white solid. This amine was dissolved in DMF (2 mL) and added to a mixture of HATU (99 mg, 0.16 mmol), acetic acid (8.3 μL, 0.14 mmol), N,N-diisopropylethylamine (0.076 mL, 0.44 mmol) in anhydrous DMF (1 mL). The reaction mixture was stirred at room temperature for 4 h, partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine-water (1:1), passed through a hydrophobic frit and evaporated in-vacuo to yield a yellow oil, which was dissolved in MeOH-DMSO (1:1) (1 mL) and purified by Mass Directed AutoPreparative HPLC (Sunfire C18 column 150 mm×30 mm i.d. 5 μm packing diameter at ambient temperature) eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) over 25 min. Appropriate fraction was evaporated in-vacuo to yield the title compound as a yellow oil (6.7 mg, %). LCMS (System B) RT=2.66 min, ES+ve m/z 509/511 (M+H)+.

Workup

  1. customReaction
  2. customReaction
  3. customcautiously quenched with water (dropwise) until no more effervescence
  4. additionThe reaction mixture was then diluted with 1:1 methanol-dichloromethane in order
  5. washThe cartridge was washed with methanol
  6. washeluted
  7. customevaporated in-vacuo

Sources & evidence

ORD record
ord-f7d036ba10834dd6a72827a352e27f1a
Source dataset
uspto-grants-2013_08
Patent number
US08507543B2

Reaction notes

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