Cesium carbonate → tert-butyl 4-[(6-{[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-2-cyanopyridin-3-yl]amino}pyridin-2-yl)methyl]piperazine-1-carboxylate

HRID 1504870Notes

Reaction equation

HRID 1504870 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[NH2:25][C:26]1[N:31]=[C:30]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:29]=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[C:20]([O:19][C:18]([NH:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:4]1[CH:3]=[C:2]([NH:25][C:26]2[N:31]=[C:30]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH:29]=[CH:28][CH:27]=2)[C:7]([C:8]#[N:9])=[N:6][CH:5]=1)=[O:24])([CH3:23])([CH3:22])[CH3:21]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 58552896Tert-butyl 4-((6-aminopyridin-2-yl)methyl)piperazine-1-carboxylateHCID 86716545tert-butyl (1S,2R)-2-(5-bromo-6-cyanopyridin-3-ylamino)cyclohexylcarbamate

Product 1

HCID 86731739tert-butyl 4-[(6-{[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-2-cyanopyridin-3-yl]amino}pyridin-2-yl)methyl]piperazine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
100 °C

Procedure

To a flask containing tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (120 mg, 0.30 mmol), tert-butyl 4-[(6-aminopyridin-2-yl)methyl]piperazine-1-carboxylate (89 mg, 0.30 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (29 mg, 0.061 mmol), Pd2(dba)3 (28 mg, 0.031 mmol) and cesium carbonate (198 mg, 0.609 mmol) was added degassed dioxane (3 mL), and the reaction mixture was heated to 100° C. After 16 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography on silica gel (0-60% ethyl acetate/hexanes, linear gradient) afforded tert-butyl 4-[(6-{[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-2-cyanopyridin-3-yl]amino}pyridin-2-yl)methyl]piperazine-1-carboxylate. MS ESI calc'd for C32H47N8O4 [M+H]+ 607. found 607. 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.77 (s, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.52 (s, 1H), 6.94-6.82 (m, 2H), 6.60 (d, J=7.8 Hz, 1H), 6.40 (d, J=7.6 Hz, 1H), 3.74-3.60 (m, 2H), 3.52-3.36 (m, 2H), 3.36-3.24 (m, 4H), 2.34 (s, 4H), 1.75-1.40 (m, 8H), 1.36 (s, 9H), 1.25 (s, 9H).

Workup

  1. additionwas added
  2. customdegassed dioxane (3 mL)
  3. temperaturethe reaction mixture was cooled to room temperature
  4. additiondiluted with ethyl acetate and water
  5. customthe organic layer was separated
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customPurification by chromatography on silica gel (0-60% ethyl acetate/hexanes, linear gradient)

Sources & evidence

ORD record
ord-3eccd4bda9b34967824977d7bb2808c1
Source dataset
uspto-grants-2015_12
Patent number
US09216173B2

Reaction notes

Loading…