Acetic Acid → HCID 58054384, compound

HRID 1892968Notes

Reaction equation

HRID 1892968 reaction equation
[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([Cl:19])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:20][S:21]([C:24]3[S:25][C:26]([Cl:29])=[CH:27][CH:28]=3)(=[O:23])=[O:22])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:54](O)(=[O:56])[CH3:55].C(N(CC)C(C)C)(C)C>CN(C=O)C.CO.CS(C)=O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12]([NH:20][S:21]([C:24]1[S:25][C:26]([Cl:29])=[CH:27][CH:28]=1)(=[O:22])=[O:23])=[N:11][N:10]2[CH2:9][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][C:54](=[O:56])[CH3:55])[CH:8]=[CH:7][CH:6]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66664458HCID 66664458, compound

Product 1

HCID 58054384HCID 58054384, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 22036561Dimethyl sulfoxide methanolSolvent

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. custompartitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate
  2. customThe organic layer was separated
  3. washwashed with brine-water (1:1)
  4. customevaporated in-vacuo
  5. customto yield a yellow oil, which
  6. custompurified by Mass Directed AutoPreparative HPLC (Sunfire C18 column 150 mm×30 mm i.d
  7. customat ambient temperature
  8. washeluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B
  9. wait0.1% v/v solution of formic acid in acetonitrile) over 25 min
  10. customAppropriate fraction was evaporated in-vacuo

Sources & evidence

ORD record
ord-37c1427909a64ad484d6452f87791e55
Source dataset
uspto-grants-2013_08
Patent number
US08507543B2

Reaction notes

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