Diisopropylethylamine → (S)-3-[4-(1H-indazol-5-ylsulfanyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 503944Notes

Reaction equation

HRID 503944 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[C:62]([O:66][C:67]([N:69]1[CH2:73][CH2:72][C@@H:71]([C:74]2[CH:79]=[CH:78][C:77]([SH:80])=[CH:76][CH:75]=2)[CH2:70]1)=[O:68])([CH3:65])([CH3:64])[CH3:63].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:62]([O:66][C:67]([N:69]1[CH2:73][CH2:72][C@@H:71]([C:74]2[CH:79]=[CH:78][C:77]([S:80][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][N:6]=[CH:5]4)=[CH:76][CH:75]=2)[CH2:70]1)=[O:68])([CH3:65])([CH3:63])[CH3:64]

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 7619295-bromo-1H-indazoleHCID 59428410(S)-3-(4-mercapto-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 86586342KHSO4 Na2SO4

Product 1

HCID 66877589(S)-3-[4-(1H-indazol-5-ylsulfanyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 62.5%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

5-Bromo-1H-indazole (200.9 mg, 1.02 mmol), Pd2(dba)3 (115.9 mg), Xantphos (145.9 mg) and DIPEA (0.188 mL) were added to a solution of (S)-3-(4-mercapto-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (285 mg, 1.02 mmol) in 1,4-dioxane (4 mL) under argon atmosphere. The reaction mixture was heated at 100° C. for 18 hours, then cooled to 5° C. and a solution of 10% KHSO4/Na2SO4 was added. The mixture was filtered, the filter cake was washed with EtOAc, and the filtrate was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/EtOAc, 7/3) to give 252 mg (62% yield) of (S)-3-[4-(1H-indazol-5-ylsulfanyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.

Workup

  1. temperaturecooled to 5° C.
  2. filtrationThe mixture was filtered
  3. washthe filter cake was washed with EtOAc
  4. extractionthe filtrate was extracted with EtOAc
  5. washThe combined organic extracts were washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. customevaporated under reduced pressure
  9. customThe resulting crude material was purified via flash chromatography (hexane/EtOAc, 7/3)

Sources & evidence

ORD record
ord-1814ea894cdd4aeaaffa745ca44204e5
Source dataset
uspto-grants-2010_08
Patent number
US07776910B2

Reaction notes

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