Hydrochloric Acid → HCID 71767991, compound

HRID 1054894Notes

Reaction equation

HRID 1054894 reaction equation
C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:25])=[C:11]([C:14]3[C:15]([O:23][CH3:24])=[N:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.CC(C)=O.CO>[Cl:25][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7]2)=[CH:12][C:11]=1[C:14]1[C:15]([O:23][CH3:24])=[N:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 90421732HCID 90421732, compound

Product 1

HCID 71767991HCID 71767991, compoundYield 178%

Reagents, catalysts & solvents 3

HCID 180AcetoneSolventHCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of Intermediate 6-chloro-5-(6-dimethylamino-2-methoxy-pyridin-3-yl)-1H-indole-3-carboxylic acid methyl ester (45.0 g, 130 mmol) in 1:1 tetrahydrofuran:methanol (1250 mL) at 50° C. was added 2 N NaOH (1250 mL). After 60 h, the reaction was cooled to <5° C. and with stirring, 6 N HCl (417 mL) was added dropwise until pH 6-7. The solution was divided in half and each was diluted with ethyl acetate (1.5 L) and the layers separated. The aqueous layers were back extracted with ethyl acetate (2×600 mL). All organics were combined and washed with sat. aq. NH4Cl (1 L) and brine (1 L), and dried over MgSO4, filtered and concentrated in vacuo to give crude material. Several batches of crude material were combined (117 g) and acetone (3.5 L) was added. This was refluxed to dissolve all solids and then partially concentrated to ˜1.5 L and slowly cooled to lead to solids crashing out. These solids were suspended in heptanes (˜500 mL) and stirred at 80° C. for 48 h. Solids were collected by filtration and suction dried for 15 h to afford desired product (80.0 g) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ=12.03 (br. s., 1 H) 11.86 (br. s., 1 H) 8.04 (d, J=2.73 Hz, 1 H) 7.83 (s, 1 H) 7.55 (s, 1 H) 7.32 (d, J=8.20 Hz, 1 H) 6.21 (d, J=8.20 Hz, 1 H) 3.76 (s, 3 H) 3.07 (s, 6 H); MS (ES+) 346.1 (M+H)+.

Workup

  1. temperaturethe reaction was cooled to <5° C.
  2. customthe layers separated
  3. extractionThe aqueous layers were back extracted with ethyl acetate (2×600 mL)
  4. washwashed with sat. aq. NH4Cl (1 L) and brine (1 L)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give crude material
  9. additionwas added
  10. temperatureThis was refluxed
  11. dissolutionto dissolve all solids
  12. concentrationpartially concentrated to ˜1.5 L
  13. temperatureslowly cooled
  14. stirringstirred at 80° C. for 48 h
  15. filtrationSolids were collected by filtration and suction
  16. customdried for 15 h

Sources & evidence

ORD record
ord-03bed366ef8a4ab19b3ee86b6b479bf0
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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