Water → N-{[(3S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-yl]Methyl}-N-{[(2S)-8-methyl-2,3-dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]methyl}amine

HRID 1593634Notes

Reaction equation

HRID 1593634 reaction equation
[C:1](#N)[CH2:2][CH2:3]C.[F:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH2:14][CH2:13][C@H:12]([CH2:20][NH2:21])[CH2:11][C:10]2=1.[C:22](=[O:25])([O-])[O-:23].[K+].[K+].S([C:32]1[CH:38]=CC(Br)=C[CH:33]=1)(O)(=O)=[O:29].[N:39]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:40]=1[CH3:41].[OH2:50]>CC(O)C>[C:22]([OH:23])(=[O:25])/[CH:1]=[CH:2]\[C:3]([OH:29])=[O:50].[F:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH2:14][CH2:13][C@H:12]([CH2:20][NH:21][CH2:33][C@@H:32]3[O:23][C:45]4=[C:44]5[C:49](=[CH:48][CH:47]=[C:46]4[O:50][CH2:38]3)[N:39]=[C:40]([CH3:41])[CH:42]=[CH:43]5)[CH2:11][C:10]2=1

Participants

8

Reactant 5

HCID 962WaterHCID 8008ButyronitrileHCID 11430Potassium CarbonateHCID 573556791-[(3S)-6-Fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]methanamineHCID 131726686HCID 131726686, compound

Product 2

HCID 444266Maleic AcidHCID 11995928N-{[(3S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-yl]Methyl}-N-{[(2S)-8-methyl-2,3-dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]methyl}amineYield 73%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
95 °C

Procedure

Butyronitrile (1.71 kg) was charged to a (5.0 L) cylindrical reactor equipped with an overhead stirrer, temperature controller, thermocouple, and reflux condenser (reactor A). To the reaction vessel, under nitrogen was charged sequentially, {[(3S)-6-Fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]methyl}-amine (180 g, 0.82 mole) (Example 92), potassium carbonate (110.5 g. 0.8 mole) and quinaldine brosylate (400.8 g, 0.9 mole) (prepared according to the procedure described in U.S. Pat. No. 6,693,197 B1). The slurry was heated with stirring under positive nitrogen pressure to 95±5° C. for 27 h. After completion of the reaction, the mixture was cooled to 22±5° C. Water (1100 mL) was charged and stirred for 10 min. The layers are separated and the aqueous layer discarded. Ammonium chloride solution was added and stirred. The layers are separated and the organic phase was washed once more with ammonium chloride solution (2% aqueous, 1100 mL). The layers were separated and the organic phase warmed to 40±5° C. in reactor A. A solution of maleic acid (119 g, 1.02 moles) in 2-propanol (0.7 L) was prepared by warming to 40±5° C. in a separate (2-L) reactor (reactor B). The warm maleic acid solution was added slowly to the butyronile solution in reactor A maintaining the temperature between 40 to 45° C. The solution was slowly cooled 20 to 25° C. and stirred for 16 h when solids separated out. The solids were filtered through a funnel lined with polypropylene and washed with 2-propanol (0.60 L). The wet solids from the funnel were transferred to ethanol (grade 2B, 2.5 L) in reactor A and warmed to 40 to 45° C. with stirring for 30 min. The slurry was cooled to 22 to 25° C. and stirred for an additional 2 h. The solids were filtered through a funnel lined with polypropylene and washed with ethanol (grade 2B, 1.7 L). The solid was dried under vacuum (<20 mm Hg) at 40° C. to give 330 g of maleic acid salt of N-{[(3S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-yl]Methyl}-N-{[(2S)-8-methyl-2,3-dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]methyl}amine (73% yield). Purity by HPLC is 97.4% (diastereomer content 2.1%), MW 431 (LC/MS).

Workup

  1. customequipped with an overhead stirrer
  2. temperaturetemperature controller, thermocouple, and reflux condenser (reactor A)
  3. additionTo the reaction vessel, under nitrogen was charged sequentially
  4. temperatureThe slurry was heated
  5. customAfter completion of the reaction
  6. temperaturethe mixture was cooled to 22±5° C
  7. stirringstirred for 10 min
  8. customThe layers are separated
  9. additionAmmonium chloride solution was added
  10. stirringstirred
  11. customThe layers are separated
  12. washthe organic phase was washed once more with ammonium chloride solution (2% aqueous, 1100 mL)
  13. customThe layers were separated
  14. temperaturethe organic phase warmed to 40±5° C. in reactor A
  15. temperatureby warming to 40±5° C. in
  16. customa separate (2-L) reactor (reactor B)
  17. additionThe warm maleic acid solution was added slowly to the butyronile solution in reactor A maintaining the temperature between 40 to 45° C
  18. customwas slowly cooled 20 to 25° C.
  19. stirringstirred for 16 h when solids
  20. customseparated out
  21. filtrationThe solids were filtered through a funnel
  22. washwashed with 2-propanol (0.60 L)
  23. customThe wet solids from the funnel were transferred to ethanol (grade 2B, 2.5 L) in reactor
  24. temperatureA and warmed to 40 to 45° C.
  25. stirringwith stirring for 30 min
  26. temperatureThe slurry was cooled to 22 to 25° C.
  27. stirringstirred for an additional 2 h
  28. filtrationThe solids were filtered through a funnel
  29. washwashed with ethanol (grade 2B, 1.7 L)
  30. customThe solid was dried under vacuum (<20 mm Hg) at 40° C.

Sources & evidence

ORD record
ord-e468063bc3e44474b5b905e8206c46c7
Source dataset
uspto-grants-2007_11
Patent number
US07297704B2

Reaction notes

Loading…