Indomethacin → HCID 18768680, compound

HRID 1374875Notes

Reaction equation

HRID 1374875 reaction equation
[CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=O)[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].B(F)(F)F.CCOCC.[BH4-].[Na+]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:11][N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][CH2:23][OH:24])=[C:2]2[CH3:1])=[CH:14][CH:15]=1

Participants

5

Reactant 3

HCID 3715IndomethacinHCID 8000Boron trifluoride etherateHCID 4311764Sodium borohydride

Product 1

HCID 18768680HCID 18768680, compoundYield 49%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of indomethacin (10 g, 28 mmol) in THF (90 mL) was immersed in an ice bath to maintain an internal temperature of 10–15° C. To this solution was added BF3-Et2O (30 mL, 230 mmol) over 5 min, resulting in the formation of a precipitate. Sodium borohydride (4.2 g, 110 mmol) was added portionwise over 10 min resulting in vigorous effervescence. After gas evolution subsided the flask was stoppered and allowed to warm to room temperature. After 1 hour the pressure was vented through a needle. The heterogeneous mixture was stirred for 6 hours. The mixture was cooled in an ice bath and was quenched by adding saturated NaHCO3. To break the resultant emulsion the mixture was made acidic with 1N HCl and extracted with a 3:1 mixture of Et2O:Hexane (270 mL). The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was taken up in a 3:1 mixture of hot Hex:EtOAc (80 mL). Upon cooling to room temperature, crystals began to form. Crystallization was completed by cooling to −20° C. The solid was removed by filtration, washed with cold 3:1 Hex:EtOAc (2×25), Hexane (1×25) and dried in vacuo. This gave the title compound (4.5 g, 49%) as a white solid. mp 113–115° C. 1H-NMR (300 MHz, CDCl3) δ 7.24 (d, J=8.4 Hz, 2H), 7.06 (d, J=9.1 Hz, 1H), 7.03 (d, J=3.5 Hz, 1H), 6.87 (d, J=8.3 Hz, 2H), 6.78 (dd, J=2.4 and 8.7 Hz, 1H), 5.23 (s, 2H), 3.86 (s, 3H), 3.84 (t, J=6.5 Hz, 2H), 2.99 (t, J=6.5 Hz, 2H), 2.29 (s, 3H); mass spectrum (API-TIS) m/z 330 (MH+). Anal calcd for C19H20ClNO2: C, 69.19; H, 6.11; N, 4.25; Cl, 10.75. Found: C, 68.98; H, 6.30; N, 4.08; Cl, 10.60.

Workup

  1. temperatureto maintain an internal temperature of 10–15° C
  2. customresulting in the formation of a precipitate
  3. customresulting in vigorous effervescence
  4. temperatureThe mixture was cooled in an ice bath
  5. customwas quenched
  6. additionby adding saturated NaHCO3
  7. extractionextracted with a 3:1 mixture of Et2O
  8. washThe organic layer was washed with brine
  9. dry with materialdried over Na2SO4
  10. customevaporated
  11. additionThe residue was taken up in a 3:1 mixture of hot Hex
  12. temperatureUpon cooling to room temperature
  13. customto form
  14. customCrystallization
  15. temperatureby cooling to −20° C
  16. customThe solid was removed by filtration
  17. washwashed with cold 3:1 Hex
  18. dry with materialEtOAc (2×25), Hexane (1×25) and dried in vacuo

Sources & evidence

ORD record
ord-d7e81d93225245c583096a1a97990105
Source dataset
uspto-grants-2007_01
Patent number
US07166618B2

Reaction notes

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