Diisopropylethylamine → N1-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]-N2,2-dimethylalaninamide formate

HRID 1874708Notes

Reaction equation

HRID 1874708 reaction equation
[C:1]([N:8]([CH3:15])[C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])([O:3]C(C)(C)C)=[O:2].ClC(N(C)C)=C(C)C.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH2:33][N:34]2[C:42]3[C:37](=[C:38]([O:43][CH3:44])[CH:39]=[CH:40][CH:41]=3)[C:36]([NH:45][S:46]([C:49]3[S:50][C:51]([Cl:54])=[CH:52][CH:53]=3)(=[O:48])=[O:47])=[N:35]2)[CH:30]=[CH:31][CH:32]=1.C(N(CC)C(C)C)(C)C>C1COCC1.CO.CS(C)=O>[CH:1]([OH:3])=[O:2].[Cl:54][C:51]1[S:50][C:49]([S:46]([NH:45][C:36]2[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])[N:34]([CH2:33][C:29]3[CH:28]=[C:27]([CH2:26][NH:25][C:11](=[O:13])[C:9]([CH3:10])([CH3:14])[NH:8][CH3:15])[CH:32]=[CH:31][CH:30]=3)[N:35]=2)(=[O:47])=[O:48])=[CH:53][CH:52]=1

Participants

7

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 27347522-{[(Tert-butoxy)carbonyl](methyl)amino}-2-methylpropanoic acidHCID 66632476N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride

Product 1

HCID 66619782N1-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]-N2,2-dimethylalaninamide formateYield 87%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 22036561Dimethyl sulfoxide methanolSolvent

Procedure

To a solution of N-Boc-N,2-dimethylalanine (174 mg, 0.801 mmol) in anhydrous THF (8 mL) was added dropwise at room temperature 1-chloro-N,N,2-trimethylpropenylamine (0.106 mL, 0.801 mmol) and the resulting mixture was stirred for 30 min. N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (200 mg, 0.4 mmol), followed by N,N-diisopropylethylamine (0.209 mL, 1.20 mmol) were then added and the reaction mixture was stirred at room temperature for 90 min (heterogeneous reaction). A further 8 mL of anhydrous tetrahydrofuran and 70 μL of N,N-diisopropylethylamine was added in order to try to improve solubility. The reaction mixture was stirred at room temperature for 30 min and then evaporated in-vacuo and partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a cream oil. The residue (286 mg) was dissolved in MeOH:DMSO (1:1) (3×1 mL) and purified by MDAP on (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 fractions were combined and evaporated in-vacuo to yield the title compound as a clear oil (211 mg, 87%). LCMS (System B) RT=1.75 min, ES+ve m/z 562/564 (M+H)+.

Workup

  1. additionwere then added
  2. stirringthe reaction mixture was stirred at room temperature for 90 min
  3. custom(heterogeneous reaction)
  4. stirringThe reaction mixture was stirred at room temperature for 30 min
  5. customevaporated in-vacuo
  6. custompartitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate
  7. customThe organic layer was separated
  8. customevaporated in-vacuo
  9. customto yield a cream oil
  10. custompurified by MDAP on (Sunfire C18 column 150 mm×30 mm i.d
  11. customat ambient temperature
  12. washeluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B
  13. wait0.1% v/v solution of formic acid in acetonitrile) over 25 min
  14. customevaporated in-vacuo

Sources & evidence

ORD record
ord-de724adfaab74d7686d8d3178e37c767
Source dataset
uspto-grants-2012_11
Patent number
US08304446B2

Reaction notes

Loading…