Lithium hydroxide, monohydrate → 7,8-Dihydro-2,3-bis(4-methylphenyl)pyrido[2,3-b]pyrazine-5(6H)-heptanoic acid

HRID 406184Notes

Reaction equation

HRID 406184 reaction equation
[C:1]1([CH3:35])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.O>[C:1]1([CH3:35])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1

Participants

5

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 66665782Ethyl 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate

Product 1

HCID 566444827,8-Dihydro-2,3-bis(4-methylphenyl)pyrido[2,3-b]pyrazine-5(6H)-heptanoic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

Ethyl 7-(2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) was dissolved in THF (94 ml) and lithium hydroxide monohydrate (7.79 g, 186 mmol) in water (94 ml) was added dropwise. The reaction mixture was warmed to 50° C. and stirred for 7.5 hours. The reaction mixture was concentrated in vacuo to remove the THF and diluted with water (500 ml). The pH of the aqueous layer was adjusted to pH 2 with 1 N HCl (100 ml) and extracted with EtOAc (3×500 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude solid was suspended in TBME/hexane (1:1, 100 ml) and rotated on the rotary evaporator (no vacuum) at RT until crystals formed. The solid was removed by filtration, washed with heptanes (50 ml) and dried at RT overnight. The solid was re-crystallized from a hot mixture of EtOH (211 ml) and water (159 ml). After seeding and stirring for 1 h at 5° C., the crystals were filtered off and the product dried overnight at 40° C. in a vacuum oven to afford the title compound; See Table 4 for characterising data.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. customto remove the THF
  3. additiondiluted with water (500 ml)
  4. extractionextracted with EtOAc (3×500 ml)
  5. washThe combined organic layers were washed with brine (200 ml)
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated in vacuo
  8. customrotated on the rotary evaporator (no vacuum) at RT until crystals
  9. customformed
  10. customThe solid was removed by filtration
  11. washwashed with heptanes (50 ml)
  12. customdried at RT overnight
  13. customThe solid was re-crystallized from a hot mixture of EtOH (211 ml) and water (159 ml)
  14. stirringstirring for 1 h at 5° C.
  15. filtrationthe crystals were filtered off
  16. customthe product dried overnight at 40° C. in a vacuum oven

Sources & evidence

ORD record
ord-44fd8d411f6a478ebf5e3ece854740a9
Source dataset
uspto-grants-2014_06
Patent number
US08754085B2

Reaction notes

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