Diisopropylethylamine → 1,1-Dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate

HRID 473318Notes

Reaction equation

HRID 473318 reaction equation
Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:13][CH2:14][C@:15]1([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([NH:13][CH2:14][C@:15]2([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]2)[N:11]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 122042335,7-Dichloro-1,6-naphthyridineHCID 68210002tert-Butyl (R)-3-(aminomethyl)-3-fluoropiperidine-1-carboxylate

Product 1

HCID 866768011,1-Dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
100 °C

Procedure

To 5,7-dichloro-1,6-naphthyridine (5.01 g, 25.2 mmol) and 1,1-dimethylethyl (3R)-3-(aminomethyl)-3-fluoro-1-piperidinecarboxylate (5.32 g, 22.90 mmol) in NMP (20 ml) was added DIPEA (8.00 ml, 45.8 mmol) and the mixture was stirred at 100° C. for 72 h under nitrogen. The reaction was cooled and partitioned between ethyl acetate and water (200 ml each). The aqueous was washed with ethyl acetate. The combined organics were washed with water and the solvent was removed. The residue was dissolved in DCM and loaded onto a 100 g silica SNAP column and purified on the SP4 eluting with 0-50% ethyl acetate in cyclohexane over 17 CVs. Appropriate fractions were combined and the solvent was removed to give the title compound as a pale orange solid which was dried under high vacuum for 2 h (7.61 g).

Workup

  1. temperatureThe reaction was cooled
  2. custompartitioned between ethyl acetate and water (200 ml each)
  3. washThe aqueous was washed with ethyl acetate
  4. washThe combined organics were washed with water
  5. customthe solvent was removed
  6. dissolutionThe residue was dissolved in DCM
  7. custompurified on the SP4
  8. washeluting with 0-50% ethyl acetate in cyclohexane over 17 CVs
  9. customthe solvent was removed

Sources & evidence

ORD record
ord-26504d44e3254af3a4a85fe74888d429
Source dataset
uspto-grants-2014_01
Patent number
US08633319B2

Reaction notes

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