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

HRID 473322Notes

Reaction equation

HRID 473322 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][O:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.[OH-].[K+]>COCCOC.O.C(O)C>[F:27][C@@:14]1([CH2:13][NH:12][C:4]2[N:3]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH2:30][O:29][CH3:28])[CH:35]=3)[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1

Participants

7

Reactant 3

HCID 14797Potassium HydroxideHCID 671939951-(methoxymethyl)-4-(4,4,5,5-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 682098891,1-Dimethylethyl (3R)-3-fluoro-3-{[(7-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,6-naphthyridin-5-yl)amino]methyl}-1-piperidinecarboxylateYield 105%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
130 °C

Procedure

To 1,1-dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (650 mg, 1.646 mmol) in DME (5 ml), water (2.5 ml), ethanol (5.00 ml) was added 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.03 g 4.33 mmol), potassium hydroxide (3.95 ml, 3.95 mmol, 1M aqueous solution) and PEPPSI (112 mg, 0.165 mmol). The reaction was refluxed at 130° C. under nitrogen for 4 nights. LCMS showed main peak as product. The reaction mixture was filtered through celite and the solvent removed. The residue was dissolved in DCM and loaded onto a 25 g silica column and purified on the SP4 eluting with a 50-100% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and the solvent removed to give a yellow oil which was dried under high vacuum overnight to give the title compound as a yellow solid/film (813 mg).

Workup

  1. filtrationThe reaction mixture was filtered through celite
  2. customthe solvent removed
  3. dissolutionThe residue was dissolved in DCM
  4. custompurified on the SP4
  5. washeluting with a 50-100% ethyl acetate in cyclohexane gradient
  6. customthe solvent removed
  7. customto give a yellow oil which
  8. customwas dried under high vacuum overnight

Sources & evidence

ORD record
ord-c847e876ff014da78fbc17833462ec4b
Source dataset
uspto-grants-2014_01
Patent number
US08633319B2

Reaction notes

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