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

HRID 1675879Notes

Reaction equation

HRID 1675879 reaction equation
CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:15]=2[C@H:14]([CH3:34])[CH2:13]1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O.O>[CH3:34][C@H:14]1[C:15]2[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:18]=[N:17][C:16]=2[C:12](=[O:11])[CH2:13]1

Participants

8

Reactant 4

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 59580348(R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

Product 1

HCID 59580350(R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylateYield 82.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent4×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of DMSO (5.45 mL, 76.8 mmol) in DCM (50 m) was added dropwise by addition funnel to a −78° C. solution of oxalyl chloride (3.35 mL, 38.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 35 minutes. A solution of (5R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel. The reaction mixture was stirred for another 1 hour at −78° C., after which neat NEt3 (18.0 mL, 129 mmol) was added. The reaction mixture was then allowed to warm to room temperature, stirred 30 minutes, and then H2O was added. The mixture was extracted with DCM (3×200 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 65M): the column was flushed with ca. 800 mL 4:1 DCM:EtOAc, then gradient to 1:1 DCM:ethyl acetate until product eluting, then 1:4 DCM:EtOAc eluted product to give (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (7.5 g, 82.3% yield) as a brown foam. The foam was concentrated (3×) from DCM/hexanes, which gave a very light brown foam. HPLC>95% area. LC/MS (APCI+) m/z 333 [M+H]+.

Workup

  1. stirringThe reaction mixture was stirred for another 1 hour at −78° C.
  2. stirringstirred 30 minutes
  3. extractionThe mixture was extracted with DCM (3×200 mL)
  4. dry with materialthe combined extracts were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude was purified on silica gel (Biotage 65M)
  8. customthe column was flushed with ca. 800 mL 4:1 DCM
  9. washEtOAc, then gradient to 1:1 DCM:ethyl acetate until product eluting

Sources & evidence

ORD record
ord-1348eb9ca0b64ddd91b365ff616d5919
Source dataset
uspto-grants-2011_08
Patent number
US08003651B2

Reaction notes

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