tert-Butyl (2S)-2-methylpiperazine-1-carboxylate → (S)-Tert-butyl-4-{5-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-fluoropyridin-2-yl}-2-methylpiperazine-1-carboxylate

HRID 920134Notes

Reaction equation

HRID 920134 reaction equation
Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]2)=[CH:4][N:3]=1.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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].CCOC(C)=O.O>[C:26]([O:25][C:23]([N:18]1[CH2:19][CH2:20][N:21]([C:2]2[C:7]([F:8])=[CH:6][C:5]([C@H:9]3[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]3)=[CH:4][N:3]=2)[CH2:22][C@@H:17]1[CH3:16])=[O:24])([CH3:29])([CH3:27])[CH3:28]

Participants

9

Reactant 4

HCID 10081508tert-Butyl (2S)-2-methylpiperazine-1-carboxylateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 89311091(S)-2-Chloro-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-fluoropyridine

Product 1

HCID 71165120(S)-Tert-butyl-4-{5-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-fluoropyridin-2-yl}-2-methylpiperazine-1-carboxylateYield 63%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of 114 (1.60 g, 6.91 mmol) in toluene (21.1 mL) under an argon atmosphere was added (S)-tert-butyl 2-methylpiperazine-1-carboxylate (115, 1.38 g, 6.91 mmol, AK Scientific, Inc., Union City, Calif.), sodium tert-butoxide (0.73 g, 7.60 mmol, Sigma-Aldrich), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (i.e., “X-Phos,” 0.49 g, 1.04 mmol, Sigma-Aldrich). The mixture was degassed under argon and then tris(dibenzylideneacetone)dipalladium (Pd2(DBA)3, 0.63 g, 0.69 mmol, Sigma-Aldrich) was added to form a reaction mixture. The reaction mixture, heated in an oil bath maintained at temperature within the range of from 80° C. to 85° C., was stirred for 1.5 hours. Thereafter, the mixture was cooled to a temperature of about 25° C., poured onto cold water, and extracted with EtOAc. The organic layer was separated, washed with brine, and concentrated to an oil which was chromatographed on a silica gel column eluted with 10:90 EtOAc:hexanes and 20:80 EtOAc:hexanes to provide 1.71 g of 116 as a solid (63% yield). 1H NMR (CDCl3) δ: 1.25 (3H, d, J=6.80 Hz), 1.46 (3H, s), 1.48 (9H, s), 1.53 (3H, s), 2.89 (1H, dt, J=3.29, 13.59 Hz), 3.09 (1H, dd, J=3.73, 12.06 Hz), 3.23 (1H, dt, J=2.85, 13.59 Hz), 3.69 (1H, t, J=7.89 Hz), 3.83 (1H, d, J=12.72 Hz), 3.92 (1H, d, J=13.81 Hz), 4.01 (1H, d, J=12.90 Hz), 4.27 (1H, t, J=6.14 Hz), 4.31 (1H, brs), 5.01 (1H, t, J=7.24 Hz), 7.30 (1H, d, J=1.97 Hz), 7.95 (1H, s). LC/MS (M+1): m/z=396.

Workup

  1. customThe mixture was degassed under argon
  2. customto form a reaction mixture
  3. temperatureThe reaction mixture, heated in an oil bath
  4. temperaturemaintained at temperature within the range of from 80° C. to 85° C.
  5. extractionextracted with EtOAc
  6. customThe organic layer was separated
  7. washwashed with brine
  8. concentrationconcentrated to an oil which
  9. customwas chromatographed on a silica gel column
  10. washeluted with 10:90 EtOAc

Sources & evidence

ORD record
ord-eab6b87f02cd4e68a7250d07b36e88af
Source dataset
uspto-grants-2016_03
Patent number
US09273043B2

Reaction notes

Loading…