Potassium Carbonate → 5-(2,4-difluorophenoxy)-1-isobutyl-6-(piperidin-4-ylmethoxy)-1H-indazole

HRID 2112182Notes

Reaction equation

HRID 2112182 reaction equation
[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2.C(OC([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][CH2:32]1)=O)(C)(C)C.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC.O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:37][CH:34]1[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]1)[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 1859152-NaphthylalanineHCID 106428511-(tert-Butoxycarbonyl)-4-((p-toluenesulfonyloxy)methyl)piperidineHCID 1361636625-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol

Product 1

HCID 426111405-(2,4-difluorophenoxy)-1-isobutyl-6-(piperidin-4-ylmethoxy)-1H-indazoleYield 39.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.06 g, 0.19 mmol) and 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.20 mmol) in DMF (3 mL) was added Nal (0.014 g, 0.009 mmol) and K2CO3 (0.08 g, 0.56 mmol). The reaction mixture was heated to 70° C. for 20 hours. The mixture was diluted with ether and water and the layers were separated. The aqueous layer was extracted with ether (2×) and the combined organic layers were washed with water and brine, and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and purified by reverse phase HPLC. The desired fraction was concentrated to 0.037 g that was then treated with HCl (4N in dioxane) for 7 hours. The solvent was removed under reduced pressure and the final product was dried under high vacuum to obtain 0.031 g solid (37% yield). MS (APCI+) m/z 416(M+1) detected.

Workup

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted with ether (2×)
  3. washthe combined organic layers were washed with water and brine
  4. dry with materialdried over Na2SO4
  5. concentrationThe crude mixture was concentrated under reduced pressure
  6. custompurified by reverse phase HPLC
  7. concentrationThe desired fraction was concentrated to 0.037 g that
  8. additionwas then treated with HCl (4N in dioxane) for 7 hours
  9. customThe solvent was removed under reduced pressure
  10. dry with materialthe final product was dried under high vacuum

Sources & evidence

ORD record
ord-5db3053aa1d4415390a3041fe30bc36e
Source dataset
uspto-grants-2009_04
Patent number
US07521447B2

Reaction notes

Loading…