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

HRID 473333Notes

Reaction equation

HRID 473333 reaction equation
[Cl:1][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(OC(C)(C)C)=O)[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-].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[ClH:1].[ClH:1].[CH3:28][C:29]([N:32]1[CH:36]=[C:35]([C:2]2[N:3]=[C:4]([NH:12][CH2:13][C@:14]3([F:27])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]3)[C:5]3[CH:6]=[CH:7][CH:8]=[N:9][C:10]=3[CH:11]=2)[CH:34]=[N:33]1)([CH3:31])[CH3:30]

Participants

7

Reactant 3

HCID 516892Sodium BicarbonateHCID 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 866768037-[1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]-N-{[(3S)-3-fluoro-3-piperidinyl]methyl}-1,6-naphthyridin-5-amine dihydrochloride

Reagents, catalysts & solvents 3

HCID 178454861HCID 178454861, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
20 °C

Procedure

1,1-Dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (1 wt), 1-(1,1-dimethylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.76 wt), sodium bicarbonate (0.64 wt) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.00825 wt) are dissolved/suspended in 1,4-dioxane (8 vol) and water (2 vol). The mixture is heated to reflux and stirred for 3 h. The mixture is cooled to 20±3° C. to form a suspension. The solid is filtered off under vacuum. The filtrate is concentrated to 2 vol via vacuum distillation. Toluene (10 vol) is added. The solution is washed with water (5 vol) then stirred with Silicycle Si-Thiol derivatised silica gel (1 wt) at 60-65° C. for 2 h. The mixture is filtered at 60-65° C. and the cake washed with toluene (2 vol). The organic filtrate is then heated to 60-63° C. and 4M hydrogen chloride in 1,4-dioxane (2.9 vol) added over 30 min. The mixture is stirred at 60-63° C. for 5 h. The resulting slurry is cooled to 20±3° C. and aged for 15.5 h. The solid is filtered off under suction and washed with toluene (2×2 vol). The product is dried in vacuo at 40±3° C. to constant probe temperature.

Workup

  1. temperatureThe mixture is heated
  2. temperatureto reflux
  3. customto form a suspension
  4. filtrationThe solid is filtered off under vacuum
  5. concentrationThe filtrate is concentrated to 2 vol via vacuum distillation
  6. additionToluene (10 vol) is added
  7. washThe solution is washed with water (5 vol)
  8. stirringthen stirred with Silicycle Si-Thiol
  9. customat 60-65° C.
  10. customfor 2 h
  11. filtrationThe mixture is filtered at 60-65° C.
  12. washthe cake washed with toluene (2 vol)
  13. temperatureThe organic filtrate is then heated to 60-63° C.
  14. addition4M hydrogen chloride in 1,4-dioxane (2.9 vol) added over 30 min
  15. stirringThe mixture is stirred at 60-63° C. for 5 h
  16. temperatureThe resulting slurry is cooled to 20±3° C. and aged for 15.5 h
  17. filtrationThe solid is filtered off under suction
  18. washwashed with toluene (2×2 vol)
  19. customThe product is dried in vacuo at 40±3° C. to constant probe temperature

Sources & evidence

ORD record
ord-801904268e954e708f8073ad15dec9e6
Source dataset
uspto-grants-2014_01
Patent number
US08633319B2

Reaction notes

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