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3-(5-Fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one → 3-(5-Fluoropyrimidin-4-yl)-3-methyl-6-(1H-pyrazol-4-yl)isoindolin-1-one

HRID 1749383
Notes
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Reaction equation

HRID 1749383 reaction equation
[F:1][C:2]1[C:3]([C:8]2([CH3:39])[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:18]=[N:19][N:20](C5CCCCO5)[CH:21]=4)=[CH:14][CH:15]=3)[C:10](=[O:28])[N:9]2[C@@H](C2C=CC(OC)=CC=2)C)=[N:4][CH:5]=[N:6][CH:7]=1>FC(F)(F)C(O)=O.CO>[F:1][C:2]1[C:3]([C:8]2([CH3:39])[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:21]=[N:20][NH:19][CH:18]=4)=[CH:14][CH:15]=3)[C:10](=[O:28])[NH:9]2)=[N:4][CH:5]=[N:6][CH:7]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

4

Reactant 1

HCID 904078753-(5-Fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one2×

Product 1

HCID 862700183-(5-Fluoropyrimidin-4-yl)-3-methyl-6-(1H-pyrazol-4-yl)isoindolin-1-one

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6422Trifluoroacetic acidSolvent

Conditions

Temperature
77.5 °C

Procedure

Dissolve 3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one (65 g, 123 mmol) in trifluoroacetic acid (600 mL) and heat to 75-80° C. for 16 hours. Evaporate under reduced pressure and dilute with ethyl acetate (500 mL) and water (500 mL). Adjust the pH of the aqueous layer to 8-9 with aqueous 6 N NaOH, extract the aqueous layer with ethyl acetate (3×500 mL), combine the organic layers, wash with saturated aqueous sodium chloride, dry with sodium sulfate, filter, and evaporate under reduced pressure. Chromatograph the crude product on silica gel with 50-100% ethyl acetate/petroleum ether. Combine the product fractions and evaporate under reduced pressure to give a yellow foam (33 g, 87% crude). Repeat the reaction conditions with 3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one and combine the products (10 g, 18.9 mmol). Dissolve the combined products in methanol and stir with SiliaBond® Thiol (Silia MetS® Thiol) at 15-20° C. for 20 hours, filter, and evaporate under reduced pressure to give the title compound with 77% ee (38 g, 87%).

Workup

  1. customEvaporate under reduced pressure
  2. additiondilute with ethyl acetate (500 mL) and water (500 mL)
  3. extractionextract the aqueous layer with ethyl acetate (3×500 mL)
  4. washwash with saturated aqueous sodium chloride
  5. dry with materialdry with sodium sulfate
  6. filtrationfilter
  7. customevaporate under reduced pressure
  8. customevaporate under reduced pressure
  9. customto give a yellow foam (33 g, 87% crude)
  10. filtrationfilter
  11. customevaporate under reduced pressure

Sources & evidence

ORD record
ord-fb44b66a3fb74211bf60712c86f90e44
Source dataset
uspto-grants-2015_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09156824B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes