Trifluoroacetic acid → N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)-4-((5R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide

HRID 388315Notes

Reaction equation

HRID 388315 reaction equation
FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][N:14]([CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:15]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.Cl[C:49]1[C:50]2[C@H:57]([CH3:58])[CH2:56][CH:55]([OH:59])[C:51]=2[N:52]=[CH:53][N:54]=1>C(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:30][CH2:31][N:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:49]3[C:50]4[C@H:57]([CH3:58])[CH2:56][CH:55]([OH:59])[C:51]=4[N:52]=[CH:53][N:54]=3)[CH2:21][CH2:22]2)=[O:16])=[CH:37][CH:38]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 67135067tert-butyl 4-(N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylateHCID 86654856(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

Product 1

HCID 25171407N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)-4-((5R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamideYield 21%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-(N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate (88 mg, 0.19 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 3 hours, and then concentrated in vacuo. The residue was dissolved in n-butanol (1 mL). N,N-diisopropylethylamine (0.11 mL, 0.6 mmol) was added to the solution. Then, (5R)-4-chloro-6,7-dihydro-5-methyl-5H-cyclopenta[d]pyrimidin-7-ol (37 mg, 0.20 mmol) was added to the solution. The reaction mixture was heated at 80° C. for 16 hours. The mixture was then diluted with H2O (1 mL), and extracted with DCM (2×5 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by preparative HPLC to give N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)-4-((5R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide (19.9 mg, 21%). MS (APCI+) [M+H]+ 501.3. 1H NMR (CDCl3, 400 MHz) 8.46 (s, 1 H), 7.34 (d, J=8.4 Hz, 4 H), 7.13 (d, J=8.4 Hz, 4 H), 5.50 (t, J=8 Hz, 1 H), 5.28 (dd, J=3.6, 8.4 Hz, 1 H), 4.45 (s, 4 H), 4.14-4.04 (m, 4 H), 3.94-3.81 (m, 4 H), 3.51-3.42 (m, 8 H), 3.20-3.00 (m, 16 H), 2.73-2.64 (m, 2 H), 2.40-2.20 (m, 4 H), 2.05-1.98 (m, 1H), 1.86-1.78 (m, 1 H), 1.33 (d, J=7.2 Hz, 3 Hz), 1.28 (t, J=7.2 Hz, 12 H), 1.21 (d, J=6.8 Hz, 3 Hz).

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionThe residue was dissolved in n-butanol (1 mL)
  3. temperatureThe reaction mixture was heated at 80° C. for 16 hours
  4. extractionextracted with DCM (2×5 mL)
  5. dry with materialThe combined organics were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by preparative HPLC

Sources & evidence

ORD record
ord-7537be1e591343ef8956deae85b821c0
Source dataset
uspto-grants-2013_02
Patent number
US08377937B2

Reaction notes

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