Sodium Carbonate → 4-(2-(4-(6-Fluoropyridin-3-yl)phenoxy)ethyl)morpholine

HRID 1398004Notes

Reaction equation

HRID 1398004 reaction equation
[F:1][C:2]1[N:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.Br[C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(OC)(C)C>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 15413tert-Butyl methyl etherHCID 20538154-(2-(4-Bromophenoxy)ethyl)morpholineHCID 67202011HCID 67202011, compound

Product 1

HCID 441854204-(2-(4-(6-Fluoropyridin-3-yl)phenoxy)ethyl)morpholineYield 101%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolvent2×

Conditions

Temperature
80 °C

Procedure

A 72 L reactor equipped with reflux condenser, sparging tube, bubbler, and temperature probe was charged with 6-fluoropyridin-3-ylboric acid (2.84 kg, 1.24 equiv.), 4-(2-(4-bromophenoxy)ethyl)morpholine (4.27 kg, 1.0 equiv.), and DME (27 L). Agitation was started and sodium carbonate (4.74 kg, 3.0 equiv.) as a solution in DI water (17.1 L) was then charged to the reaction mixture. Argon was bubbled through the reaction mixture for 50 minutes. Under an argon atmosphere, tetrakis(triphenylphosphine)palladium (750 g, 0.04 equiv.) was added to the reaction mixture as a slurry in DME (1.0 L). The reaction mixture was heated to 75-85° C. and stirred overnight (17 h). The reaction mixture was cooled to between 18-22° C. DI water (26.681 kg) and MTBE (26.681 L) were charged to the reactor and stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with MTBE (2×26.7 L). The combined organics were extracted with 2M HCl (1×15.0 L, 3×21.8 L). The aqueous phase was then charged back to the reactor and ethyl acetate was added (26.7 L). The pH was adjusted to 6.2 using 6 M sodium hydroxide (26.7 L) while maintaining a temperature between 15-25° C. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×26.7 L). The combined organics were dried with magnesium sulfate and concentrated to give 4555 g of a residue (101% crude yield, 67.1% AUC by HPLC).

Workup

  1. customA 72 L reactor equipped
  2. temperaturewith reflux condenser
  3. customsparging tube
  4. customArgon was bubbled through the reaction mixture for 50 minutes
  5. temperatureThe reaction mixture was cooled to between 18-22° C
  6. stirringstirred for 5 minutes
  7. customThe phases were separated
  8. extractionthe aqueous phase was extracted with MTBE (2×26.7 L)
  9. extractionThe combined organics were extracted with 2M HCl (1×15.0 L, 3×21.8 L)
  10. additionThe aqueous phase was then charged back to the reactor and ethyl acetate
  11. additionwas added (26.7 L)
  12. temperaturewhile maintaining a temperature between 15-25° C
  13. customThe phases were separated
  14. extractionthe aqueous phase was extracted with ethyl acetate (2×26.7 L)
  15. dry with materialThe combined organics were dried with magnesium sulfate
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-c72d065b1c1242de96224188de03f0f6
Source dataset
uspto-grants-2014_12
Patent number
US08901297B2

Reaction notes

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