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

HRID 75400Notes

Reaction equation

HRID 75400 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 (6.58 g, 157 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 for 10 minutes, and then warmed to room temperature. LC/MS looked the same at 3 hours and 4.5 hours. The reaction mixture was cooled to 0° C., and then saturated NH4Cl was added to the mixture. The 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 the product was eluting, then ethyl acetate was flushed through the column. Then 30:1 DCM:MeOH eluted the rest of the product (8.83 g). The mixed fractions were re-flashed with Biotage 40 M using the same conditions to give another portion (2.99 g), which gave 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 foam. LC/MS (APCI+) m/z 335.1 [M+H]+.

Workup

  1. customsame at 3 hours
  2. custom4.5 hours
  3. temperatureThe reaction mixture was cooled to 0° C.
  4. stirringThe mixture was stirred for 5 minutes
  5. custommost of the THF was removed by rotary evaporation
  6. extractionThe mixture was extracted with EtOAc (3×250 mL)
  7. dry with materialthe combined extracts were dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. washOnce the product was eluting
  11. customethyl acetate was flushed through the column
  12. washThen 30:1 DCM:MeOH eluted the rest of the product (8.83 g)
  13. customto give another portion (2.99 g), which

Sources & evidence

ORD record
ord-d217004fab8a42dd9a9e8ff432c665c1
Source dataset
uspto-grants-2014_09
Patent number
US08835434B2

Reaction notes

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