(Diethylamino)sulfur trifluoride → tert-butyl 4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

HRID 82404Notes

Reaction equation

HRID 82404 reaction equation
O[C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.CCN(S(F)(F)[F:31])CC>C(Cl)Cl>[F:31][C@@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1

Participants

4

Reactant 2

HCID 123472(Diethylamino)sulfur trifluorideHCID 59580343tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

Product 1

HCID 66844899tert-butyl 4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylateYield 61%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-20 °C

Procedure

tert-Butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.190 g, 3.558 mmol) was dissolved in methylene chloride (55 mL) and cooled to −20° C. The solution was treated with DAST (1.410 mL, 10.68 mmol) and stirred at −20° C. for 1 hour. The reaction was quenched with ice and then warmed to ambient temperature. The mixture was diluted with saturated NH4Cl and separated. The aqueous phase was extracted with methylene chloride (2×), and the combined organics were dried over Na2SO4 and concentrated to a dark oil. This oil was chromatographed on SiO2 (Biotage 40S, load with methylene chloride) then eluted with 2.5% MeOH/DCM then 3.5% MeOH/DCM. The mixed fractions were concentrated, and the material was re-chromatographed on SiO2 (Biotage 40S, load with DCM) and eluted with 2 hexane/EtOAc. The product was collected as a dark oil to give tert-butyl 4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.725 g, 61%). LCMS (APCI+) m/z 337.0 [M+H]+; Rf 3.13 min.

Workup

  1. customThe reaction was quenched with ice
  2. temperaturewarmed to ambient temperature
  3. additionThe mixture was diluted with saturated NH4Cl
  4. customseparated
  5. extractionThe aqueous phase was extracted with methylene chloride (2×)
  6. dry with materialthe combined organics were dried over Na2SO4
  7. concentrationconcentrated to a dark oil
  8. customThis oil was chromatographed on SiO2 (Biotage 40S, load with methylene chloride)
  9. washthen eluted with 2.5% MeOH/DCM
  10. concentrationThe mixed fractions were concentrated
  11. customthe material was re-chromatographed on SiO2 (Biotage 40S, load with DCM)
  12. washeluted with 2 hexane/EtOAc
  13. customThe product was collected as a dark oil

Sources & evidence

ORD record
ord-2207c91d75f14e77a50f4d5ac803404a
Source dataset
uspto-grants-2014_09
Patent number
US08846681B2

Reaction notes

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