Water → 1,1-Dimethylethyl (3R)-3-[({7-[1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]-1,6-naphthyridin-5-yl}amino)methyl]-3-fluoro-1-piperidinecarboxylate

HRID 473321Notes

Reaction equation

HRID 473321 reaction equation
Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([NH:12][CH2:13][C@:14]2([F:27])[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[N:3]=1.[CH3:28][C:29]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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]>[CH3:28][C:29]([N:32]1[CH:36]=[C:35]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[C:4]([NH:12][CH2:13][C@:14]3([F:27])[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[N:3]=2)[CH:34]=[N:33]1)([CH3:31])[CH3:30]

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 532171091-tert-butyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 866768011,1-Dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate

Product 1

HCID 682099451,1-Dimethylethyl (3R)-3-[({7-[1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]-1,6-naphthyridin-5-yl}amino)methyl]-3-fluoro-1-piperidinecarboxylateYield 99.9%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of 1,1-dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (1.300 g, 3.29 mmol) in 1,4-dioxane (10 ml) was added 1-(1,1-dimethylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.906 g, 3.62 mmol), caesium carbonate (2.145 g, 6.58 mmol), tetrakis(triphenylphosphine)palladium (0) (0.114 g, 0.099 mmol) and water (2 ml). The reaction mixture was heated in the microwave at 130° C. for 2 h. LCMS shows main peak of product with no starting material. The reaction mixture was filtered through 10 g celite and partitioned between ethyl acetate and water (100 ml×2). The organic layer was washed with brine (100 ml), evaporated the solvent and dissolved in minimum amount of DCM. This was loaded on to a 100 g silica column and purified on SP4 eluting with 20-90% ethyl acetate in cyclohexane over 22 CVs. Appropriate fractions were collected and the solvent was evaporated. The product was dried on high vacuum overnight to give the title compound as a yellow crystalline solid (1.586 g).

Workup

  1. filtrationThe reaction mixture was filtered through 10 g celite
  2. custompartitioned between ethyl acetate and water (100 ml×2)
  3. washThe organic layer was washed with brine (100 ml)
  4. customevaporated the solvent
  5. dissolutiondissolved in minimum amount of DCM
  6. custompurified on SP4
  7. washeluting with 20-90% ethyl acetate in cyclohexane over 22 CVs
  8. customAppropriate fractions were collected
  9. customthe solvent was evaporated
  10. customThe product was dried on high vacuum overnight

Sources & evidence

ORD record
ord-f919839822254ff89579365b8f54cbed
Source dataset
uspto-grants-2014_01
Patent number
US08633319B2

Reaction notes

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