Trifluoroacetic acid → N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]cyclopropanesulfonamide

HRID 1661445Notes

Reaction equation

HRID 1661445 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1.C(O)(C(F)(F)F)=O.C(N(CC)CC)C>N1C=CC=CC=1.O.CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 2760919Cyclopropanesulfonyl chloride2×HCID 59339817(alphaS,betaR)-beta-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-alpha-methylbenzeneethanamine

Product 1

HCID 24953162N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]cyclopropanesulfonamideYield 34.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1049PyridineSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

(1R,2S)-1-[1-(4-Fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-amine (1a, 16 mg, 0.044 mmole) was dissolved in dry pyridine (2 mL) and cooled to 0° C. Cyclopropanesulfonyl chloride (16 μl, 0.056 mmole) was added and the mixture was stirred at room temperature for 45 mm. The progression of the reaction was followed by HPLC (R.P C-18, 20-90% gradient of CH3CN in water, 0.1% TFA). After 45 and 75 mm additional portions of cyclopropanesulfonyl chloride (5 and 6 μl respectively) were added. As the reaction proceeded very slowly, triethylamine (27 μl, 0.2 mmol) was added after a total of 2.5 h of stirring. The stirring was continued at ambient temperature for additional 18.5h and the reaction mixture was then partitioned between ethyl acetate and aqueous hydrochloric acid (1.7M). The organic phase was washed twice with aqueous hydrochloric acid (1.7M), then with water and finally with brine. Evaporation and flash chromatography (SiO2, gradient of 0-50% EtOAc in heptane) and finally lyophilization from dioxane gave the title compound (7 mg, 33%) containing 15 mol % of dioxane.

Workup

  1. stirringof stirring
  2. customthe reaction mixture was then partitioned between ethyl acetate and aqueous hydrochloric acid (1.7M)
  3. washThe organic phase was washed twice with aqueous hydrochloric acid (1.7M)
  4. customEvaporation and flash chromatography (SiO2, gradient of 0-50% EtOAc in heptane) and finally lyophilization from dioxane

Sources & evidence

ORD record
ord-d1f5f929583d46f88e048bb930617b72
Source dataset
uspto-grants-2011_10
Patent number
US08030340B2

Reaction notes

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