Potassium Carbonate → 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 1593635Notes

Reaction equation

HRID 1593635 reaction equation
C(O)(=O)/C=C\C(O)=O.[F:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH2:17][CH2:16][C@H:15]([CH2:23][NH:24][CH2:25][C@@H:26]3[O:40][C:30]4=[C:31]5[C:36](=[CH:37][CH:38]=[C:29]4[O:28][CH2:27]3)[N:35]=[C:34]([CH3:39])[CH:33]=[CH:32]5)[CH2:14][C:13]2=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH2:17][CH2:16][C@H:15]([CH2:23][NH:24][CH2:25][C@@H:26]3[O:40][C:30]4=[C:31]5[C:36](=[CH:37][CH:38]=[C:29]4[O:28][CH2:27]3)[N:35]=[C:34]([CH3:39])[CH:33]=[CH:32]5)[CH2:14][C:13]2=1

Participants

4

Reactant 2

HCID 11430Potassium CarbonateHCID 69234176HCID 69234176, compound

Product 1

HCID 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 74.4%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
50.5 °C

Procedure

Ethanol (grade 2B, 8.0 L) was charged to a charged to a (22-L) reactor equipped with an overhead stirrer, temperature controller, thermocouple, and reflux condenser. 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 maleic acid salt, (800 g, 1.46 mole) (Example 93), was added to the reactor followed by solid potassium carbonate (325 mesh, 222 g, 1.6 mole). The slurry was heated with stirring under nitrogen at 49 to 52° C. for 1 h. The reaction mixture was allowed to cool to 20 to 24° C., stirred for 2 h and the solids were filtered through a funnel lined with polypropylene. The filter cake was washed with ethanol (grade 2B, 8.0 L). The combined ethanol filtrate and washes were concentrated to a volume of 2.8 to 3.0 L at 40 to 45° C. and 45-60 mm Hg. The concentrate was stirred for 20 h at 20-25° C. when solids separate out. Water (1 L) was added to the slurry and stirred for another 4 h at 20-25° C. followed by stirring for an additional 3 h at 10 to 15° C. The solids are filtered and the cake washed with a mixture of ethanol (grade 2B, 0.1 L) and water (0.7 L). The solid was dried under vacuum (<20 mm Hg) at 40° C. to give 469 g 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 (74% yield). Purity by HPLC is 98.5% (diastereomer content 1.1%), MW 431 (LC/MS).

Workup

  1. customequipped with an overhead stirrer
  2. temperaturetemperature controller, thermocouple, and reflux condenser
  3. temperatureThe slurry was heated
  4. temperatureto cool to 20 to 24° C.
  5. stirringstirred for 2 h
  6. filtrationthe solids were filtered through a funnel
  7. washThe filter cake was washed with ethanol (grade 2B, 8.0 L)
  8. concentrationThe combined ethanol filtrate and washes were concentrated to a volume of 2.8 to 3.0 L at 40 to 45° C.
  9. stirringThe concentrate was stirred for 20 h at 20-25° C. when solids
  10. customseparate out
  11. additionWater (1 L) was added to the slurry
  12. stirringstirred for another 4 h at 20-25° C.
  13. stirringby stirring for an additional 3 h at 10 to 15° C
  14. filtrationThe solids are filtered
  15. washthe cake washed with a mixture of ethanol (grade 2B, 0.1 L) and water (0.7 L)
  16. customThe solid was dried under vacuum (<20 mm Hg) at 40° C.

Sources & evidence

ORD record
ord-05c5007f788440c1808b94a0b0391f61
Source dataset
uspto-grants-2007_11
Patent number
US07297704B2

Reaction notes

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