Hydrochloric Acid → n-({3-[(3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-hydroxy-1h-indazol-1-yl)methyl]phenyl}methyl)-3-morpholinecarboxamide formate salt

To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (43.8 mg, 0.071 mmol) in anhydrous DMF (1 mL) was added at room temperature morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (Fluorochem) (14.95 mg, 0.065 mmol) followed by N,N-diisopropylethylamine (0.034 ml, 0.19 mmol) and finally a solution of N-(1-{[3-(aminomethyl)phenyl]methyl}-4-hydroxy-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide formate salt (for a preparation see Intermediate 15) (32 mg, 0.065 mmol) in anhydrous DMF (1 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was 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 colourless oil. LCMS (System B) RT=2.91 min, ES+ve m/z 662/664 (M+H)+ for 1,1-dimethylethyl 3-{[({3-[(3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-hydroxy-1H-indazol-1-yl)methyl]phenyl}methyl)amino]carbonyl}-4-morpholinecarboxylate. This was suspended in anhydrous dichloromethane (2 mL) and treated with a solution of hydrogen chloride in 1,4-dioxane (4M, 0.162 mL, 0.646 mmol). The reaction mixture was still a suspension, therefore methanol was added dropwise until the reaction was in solution. The mixture was stirred at room temperature for 1 hour, and a further portion of hydrogen chloride solution (4M, 0.162 mL) was added to the reaction mixture and stirred for 90 min. Yet another portion of hydrogen chloride solution (4M, 0.162 mL) was added to the reaction mixture and stirred for 90 min. The reaction mixture was evaporated in-vacuo to yield a colourless oil. The residual oil was dissolved in MeOH:DMSO (1 mL) and purified by MDAP Sunfire C18 column, 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) (25 min run). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a colourless oil (17 mg, 43%). LCMS (System B) RT=1.62 min, ES+ve m/z 562/564 (M+H)+.

1. customThe reaction mixture was partitioned 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 colourless oil
6. stirringThe mixture was stirred at room temperature for 1 hour
7. stirringstirred for 90 min
8. stirringstirred for 90 min
9. customThe reaction mixture was evaporated in-vacuo
10. customto yield a colourless oil
11. customDMSO (1 mL) and purified by MDAP Sunfire C18 column
12. washeluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B
13. custom(25 min run)
14. customevaporated in-vacuo

ORD-Eintrag

ord-f7f122484bae4ed38f4029f958a1d01c

Quelldatensatz

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08304446B2