Tetrahydrofuran → (R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

HRID 1675878Notes

Reaction equation

HRID 1675878 reaction equation
O[Li].O.C([O:7][CH:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[C@H:10]([CH3:30])[CH2:9]1)(=O)C.C1COCC1.[NH4+].[Cl-]>O>[OH:7][CH:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[C@H:10]([CH3:30])[CH2:9]1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 25517Ammonium ChlorideHCID 168937Lithium hydroxide, monohydrateHCID 59580360(R)-tert-butyl 4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

Product 1

HCID 59580348(R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylateYield 56.4%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

LiOH—H2O (6.577 g, 156.7 mmol) was added to a 0° C. solution of (5R)-tert-butyl 4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (23.6 g, 62.69 mmol) in 2:1 THF:H2O (320 mL). The reaction mixture was stirred 10 minutes and then warmed to room temperature. LC/MS looked same at 3 and 4.5 hours. The reaction mixture was cooled to 0° C., and saturated NH4Cl was added. The reaction mixture was stirred for 5 minutes, and most of the THF was removed by rotary evaporation. The mixture was extracted with EtOAc (3×250 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on Biotage 65M: 4:1 DCM:ethyl acetate, then gradient to 1:1 to 1:4 DCM:ethyl acetate. Once product eluting, then ethyl acetate flushed through column, then 30:1 DCM:MeOH eluted rest of product (8.83 g), mixed fractions re-flashed with Biotage 40M using same conditions to give another 2.99 g which give a combined yield of (5R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (11.82 g, 56.38% yield) as a brown foam. LC/MS (APCI+) m/z 335.1 [M+H]+.

Workup

  1. customlooked same at 3 and 4.5 hours
  2. temperatureThe reaction mixture was cooled to 0° C.
  3. stirringThe reaction mixture was stirred for 5 minutes
  4. custommost of the THF was removed by rotary evaporation
  5. extractionThe mixture was extracted with EtOAc (3×250 mL)
  6. dry with materialthe combined extracts were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. washOnce product eluting
  10. customethyl acetate flushed through column
  11. addition30:1 DCM:MeOH eluted rest of product (8.83 g), mixed fractions
  12. customto give another 2.99 g which

Sources & evidence

ORD record
ord-d04ecc4a0b744562a951ae155afebbf2
Source dataset
uspto-grants-2011_08
Patent number
US08003651B2

Reaction notes

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