Piperazine → HCID 44253238, compound

HRID 1942120Notes

Reaction equation

HRID 1942120 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:20]=[CH:21][C:22]3[C:27](=[O:28])[NH:26][C:25]4([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[C:23]=3[N:24]=2)=[CH:14][CH:13]=1.[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCCC1.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:35]1([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[N:20]=[CH:21][C:22]4[C:27](=[O:28])[NH:26][C:25]5([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)[C:23]=4[N:24]=3)=[CH:14][CH:13]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1

Participants

8

Reactant 4

HCID 4837PiperazineHCID 2733832Lithium Hexamethyldisilazide2×HCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl2×HCID 58233774HCID 58233774, compound

Product 1

HCID 44253238HCID 44253238, compound

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
100 °C

Procedure

Lithium bis(trimethylsilyl)amide, (1.0M solution in tetrahydrofuran, 1.68 ml, 1.68 mmol) under an atmosphere of N2 was added to a solution of 2′-((4-bromophenyl)amino)spiro[cycloheptane-1,7′-pyrrolo[3,4-d]pyrimidin]-5′(6′H)-one (136) (0.217 g, 0.560 mmol), and piperazine (0.145 g, 1.68 mmol) in anhydrous toluene (3 ml). After degassing the solution with nitrogen, S-Phos (0.092 g, 0.224 mmol) and tris(dibenzylideneacetone)-dipalladium (0) (0.051 g, 0.056 mmol) were added and the reaction was heated at 100° C. for 2 hrs. Additional lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (1.68 ml, 1.68 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.051 g, 0.056 mmol), and S-Phos were added (0.092 g, 0.224 mmol) and the reaction was heated at 100° C. for another 1 hr before it was cooled to 20° C. The reaction was quenched with methanol and concentrated under vacuum. The residue was triturated with DCM and solids removed by filtration. The filtrate was concentrated under vacuum and purified by preparative HPLC eluting with a gradient of 20% MeCN-60% MeCN/H2O/0.1% TFA. The fractions containing the product were combined and concentrated under vacuum. Trituration with methanol gave 2′4((4-(1-piperazinyl)phenyl)amino)spiro[cycloheptane-1,7′-pyrrolo[3,4-d]pyrimidin]-5′(6′H)-one (131) as a white solid (26 mg, crude). 1H NMR (500 MHz, DMSO-d6) δ ppm 10.02 (1H, s), 8.75 (1H, s), 8.73 (2H, br. s.), 8.62 (1H, s), 7.68 (2H, d, J=8.5 Hz), 6.99 (2H, d, J=9.2 Hz), 3.28-3.32 (4H, m), 3.21-3.28 (4H, m), 1.92-2.02 (2H, m), 1.77-1.86 (2H, m), 1.55-1.77 (8H, m); LCMS-ESI (POS), M/Z, M+1: Found 393.2.

Workup

  1. additionwere added
  2. temperaturethe reaction was heated at 100° C. for another 1 hr before it
  3. temperaturewas cooled to 20° C
  4. customThe reaction was quenched with methanol
  5. concentrationconcentrated under vacuum
  6. customThe residue was triturated with DCM and solids
  7. customremoved by filtration
  8. concentrationThe filtrate was concentrated under vacuum
  9. custompurified by preparative HPLC
  10. washeluting with a gradient of 20% MeCN-60% MeCN/H2O/0.1% TFA
  11. additionThe fractions containing the product
  12. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-c3ddc94e12674b8ab930d00c3041d003
Source dataset
uspto-grants-2013_03
Patent number
US08389533B2

Reaction notes

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