7-[1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]-N-{[(3S)-3-fluoro-3-piperidinyl]methyl}-1,6-naphthyridin-5-amine dihydrochloride → 7-(1-tert-butyl-1H-pyrazol-4-yl)-N-{[(3S)-3-fluoropiperidin-3-yl]methyl}-1,6-naphthyridin-5-amine

HRID 473334Notes

Reaction equation

HRID 473334 reaction equation
Cl.Cl.[CH3:3][C:4]([N:7]1[CH:11]=[C:10]([C:12]2[N:13]=[C:14]([NH:22][CH2:23][C@:24]3([F:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[C:15]3[CH:16]=[CH:17][CH:18]=[N:19][C:20]=3[CH:21]=2)[CH:9]=[N:8]1)([CH3:6])[CH3:5]>O>[CH3:6][C:4]([N:7]1[CH:11]=[C:10]([C:12]2[N:13]=[C:14]([NH:22][CH2:23][C@:24]3([F:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[C:15]3[CH:16]=[CH:17][CH:18]=[N:19][C:20]=3[CH:21]=2)[CH:9]=[N:8]1)([CH3:3])[CH3:5]

Participants

3

Reactant 1

HCID 866768037-[1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]-N-{[(3S)-3-fluoro-3-piperidinyl]methyl}-1,6-naphthyridin-5-amine dihydrochloride

Product 1

HCID 545754607-(1-tert-butyl-1H-pyrazol-4-yl)-N-{[(3S)-3-fluoropiperidin-3-yl]methyl}-1,6-naphthyridin-5-amine

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
75.5 °C

Procedure

7-[1-(1,1-Dimethylethyl)-1H-pyrazol-4-yl]-N-{[(3S)-3-fluoro-3-piperidinyl]methyl}-1,6-naphthyridin-5-amine dihydrochloride (1 wt) is dissolved/suspended in water (10 vol) and washed with ethyl acetate (2×5 vol). The acidic aqueous phase is basified with 32% NaOH (0.6 vol) to pH 10 and extracted with ethyl acetate (2×5 vol). The extracts are washed with 5% w/v sodium chloride in water (5 vol). The combined extracts are concentrated on the Buchi to a solid. The residue is suspended in n-butyl acetate (2.8 vol) and heated to 73-78° C. to complete dissolution. The solution is line filtered through a 5 μM domnick hunter filter, with a 0.2 vol line wash. The solution is cooled to 45-50° C. and seeded with the title compound (0.001 wt). The mixture is cooled to 40-45° C. and aged for 50 min. The slurry is diluted with TBME (3 vol) over 30 min at 40-45° C., and aged at 40-45° C. for 1 h. The slurry is cooled to 20-23° C. and aged for 16 h. The solid is filtered, washed with 1:1 v/v n-butyl acetate/TBME (1 vol) followed by TBME (2×2 vol) and dried in vacuo at 40±5° C. to constant probe temperature.

Workup

  1. washwashed with ethyl acetate (2×5 vol)
  2. extractionextracted with ethyl acetate (2×5 vol)
  3. washThe extracts are washed with 5% w/v sodium chloride in water (5 vol)
  4. concentrationThe combined extracts are concentrated on the Buchi to a solid
  5. dissolutiondissolution
  6. filtrationfiltered through a 5 μM domnick hunter
  7. filtrationfilter, with a 0.2 vol line
  8. washwash
  9. temperatureThe solution is cooled to 45-50° C.
  10. temperatureThe mixture is cooled to 40-45° C. and aged for 50 min
  11. additionThe slurry is diluted with TBME (3 vol) over 30 min at 40-45° C.
  12. temperatureThe slurry is cooled to 20-23° C. and aged for 16 h
  13. filtrationThe solid is filtered
  14. washwashed with 1:1 v/v n-butyl acetate/TBME (1 vol)
  15. customdried in vacuo at 40±5° C. to constant probe temperature

Sources & evidence

ORD record
ord-a69a8210cdef4b4a88695cbe44b8e499
Source dataset
uspto-grants-2014_01
Patent number
US08633319B2

Reaction notes

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