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

HRID 473332Notes

Reaction equation

HRID 473332 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.C(N(C(C)C)CC)(C)C.O>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

6

Reactant 4

HCID 962WaterHCID 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
110 °C

Procedure

A mixture of 5,7-dichloro-1,6-napthyridine (1 eq, 1 wt), 1,1-dimethylethyl (3R)-3-(aminomethyl)-3-fluoro-1-piperidinecarboxylate (1.1 eq, 1.28 wt), and diisopropylethylamine (2 eq, 1.75 vol) in NMP (6 vol) is stirred at 110±5° C. for 17 h. The solution is cooled to 70-75° C. and water (6 vol) added over 47 min at 65-75° C. The mixture is aged at 65-75° C. for 50 min, then cooled to 45° C. to give a slurry. The mixture is slowly cooled to 20-25° C. then aged for 2.25 h. The solid is collected under suction. The filter cake is washed with 1:2 v/v NMP/water (2 vol) then water (2×4 vol) and dried in vacuo at 40±5° C. As the solid still contains significant NMP (16.2% w/w) it is reslurried in 1:1 v/v NMP/water (7.3 vol). The slurry is heated to 65° C. and stirred at 65-66° C. for 1 h. The slurry is cooled to 20-25° C. and aged for 3 days. The solid is collected under suction. The filter cake is washed with 1:2 v/v NMP/water (2 vol) then water (2×4 vol) and dried in vacuo at 40±5° C.

Workup

  1. temperatureThe solution is cooled to 70-75° C.
  2. waitThe mixture is aged at 65-75° C. for 50 min
  3. temperaturecooled to 45° C.
  4. customto give a slurry
  5. temperatureThe mixture is slowly cooled to 20-25° C.
  6. waitthen aged for 2.25 h
  7. customThe solid is collected under suction
  8. washThe filter cake is washed with 1:2 v/v NMP/water (2 vol)
  9. dry with materialwater (2×4 vol) and dried in vacuo at 40±5° C
  10. temperatureThe slurry is heated to 65° C.
  11. stirringstirred at 65-66° C. for 1 h
  12. temperatureThe slurry is cooled to 20-25° C. and aged for 3 days
  13. customThe solid is collected under suction
  14. washThe filter cake is washed with 1:2 v/v NMP/water (2 vol)
  15. dry with materialwater (2×4 vol) and dried in vacuo at 40±5° C.

Sources & evidence

ORD record
ord-329f8fc6a8c04f71b1168ce326f70311
Source dataset
uspto-grants-2014_01
Patent number
US08633319B2

Reaction notes

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