Hydrochloric Acid → 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(2,2,2-trifluoroethylamino)propan-1-one dihydrochloride

HRID 532795Notes

Reaction equation

HRID 532795 reaction equation
[ClH:1].Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH2:31][NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:28]([O-])=[O:29])=[CH:23][CH:22]=1.[K+].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.CCOCC>[ClH:20].[ClH:1].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([CH2:31][NH:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:28]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:29])=[CH:25][CH:26]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66617976Potassium 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoateHCID 66618034(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride

Product 1

HCID 866187412-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(2,2,2-trifluoroethylamino)propan-1-one dihydrochlorideYield 110.8%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 6228DimethylformamideSolvent

Procedure

A solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 98 umol) and potassium 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (31.2 mg, 98 umol) in DMF (1.0 mL) was treated with DIEA (36 uL, 205 umol) and HBTU (41 mg, 107 umol), respectively, at room temperature. The mixture was allowed to stir for 18 hours to completion, and the solution was partitioned between ethyl acetate and water. The aqueous portion was extracted twice, and the organics were combined. The organic portion was washed with water (3×), then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9:1 ethyl acetate:MeOH) to afford the pure free-base as a colorless oil. This material was dissolved in ether (1.0 mL), then treated with excess 2.0M HCl in ether. The suspension was concentrated in vacuo to afford the pure 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(2,2,2-trifluoroethylamino)propan-1-one dihydrochloride (31 mg, 99%) as a white solid. LCMS (APCI+) m/z 498.2 [M+H]+.

Workup

  1. customat room temperature
  2. customthe solution was partitioned between ethyl acetate and water
  3. extractionThe aqueous portion was extracted twice
  4. washThe organic portion was washed with water (3×)
  5. custombrine, separated
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by chromatography (silica gel eluted with 9:1 ethyl acetate:MeOH)
  10. customto afford the pure free-base as a colorless oil
  11. concentrationThe suspension was concentrated in vacuo

Sources & evidence

ORD record
ord-90490c5fe1ed41b2b9d3a2a2e7d236cf
Source dataset
uspto-grants-2014_10
Patent number
US08853199B2

Reaction notes

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