Hydrochloric Acid → N1-({3-[(3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-hydroxy-1H-indazol-1-yl)methyl]phenyl}methyl)-N2-methyl-D-alaninamide formic acid salt

To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (39.7 mg, 0.064 mmol) in anhydrous DMF (1 mL) was added at room temperature N-Boc-N-methyl-D-alanine (11.91 mg, 0.059 mmol), followed by N,N-diisopropylethylamine (0.0306 mL, 0.176 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) (29 mg, 0.059 mmol) in anhydrous DMF (1 mL). The reaction mixture was stirred at room temperature for 1 hour and then 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=3.01 min, ES+ve m/z 634/636 (M+H)+ for desired BOC protected product. This product was suspended in a solution of hydrogen chloride in 1,4-dioxane (4M, 0.5 mL) and methanol was added until the reaction was in solution. The mixture was stirred at room temperature for 18 hours and then evaporated in-vacuo to yield a colourless oil. The residual oil was dissolved in MeOH-DMSO (0.5 mL) and purified by MDAP) on OA MDAP on 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). The appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a colourless oil (15 mg, 44%). LCMS (System B) RT=1.63 min, ES+ve m/z 534/536 (M+H)+

1. customwas 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. additionwas added until the reaction
7. stirringThe mixture was stirred at room temperature for 18 hours
8. customevaporated in-vacuo
9. customto yield a colourless oil
10. custompurified by MDAP) on OA MDAP on Sunfire C18 column
11. washeluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B
12. custom(25 min run)
13. customevaporated in-vacuo

ORD 기록

ord-e3d2f54b2c4c48debb82d085d1f53ef7

출처 데이터셋

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08304446B2