Isopropanol → Elvitegravir

HRID 391238Notes

Reaction equation

HRID 391238 reaction equation
C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([O:26][CH3:27])=[C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[CH:13]=2)[N:8]([C@H:28]([C:32](C)(C)[O:33][SiH2]C(C)(C)C)[CH:29]([CH3:31])[CH3:30])[CH:7]=1)=[O:5])C.C(O)(C)C.[OH-].[Na+]>CCCCCCC>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:26][CH3:27])[N:8]([C@H:28]([CH2:32][OH:33])[CH:29]([CH3:31])[CH3:30])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]

Participants

5

Reactant 3

HCID 3776IsopropanolHCID 14798Sodium HydroxideHCID 131730268HCID 131730268, compound

Product 1

HCID 5277135ElvitegravirYield 99.6%

Reagents, catalysts & solvents 1

HCID 8900HeptaneSolvent

Conditions

Temperature
70 °C

Procedure

1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (900 mg) was added to isopropyl alcohol (3.6 mL), and 1N sodium hydroxide (3.6 mL) was added. After stirring at 70° C. for 3 hr, the completion of the reaction was confirmed by HPLC. The reaction mixture was cooled, and allowed to cool to room temperature. n-Heptane (5 mL) was added and, after stirring, the mixture was partitioned. The aqueous layer was washed with n-heptane (5 mL). 35% Hydrochloric acid (400 mg) was added to the aqueous layer, methylisopropylketone (10 mL) was added and, after stirring, the mixture was partitioned. The organic layer was washed successively with 8.5% aqueous sodium hydrogencarbonate solution (5 mL) (3 times), 0.5N hydrochloric acid (5 mL) containing sodium chloride (250 mg), and 10% brine (5 mL). After the washing, methylisopropylketone was evaporated under reduced pressure to give 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (680 mg, yield 99.3%) as a yellow-white solid.

Workup

  1. additionwas added
  2. temperatureThe reaction mixture was cooled
  3. temperatureto cool to room temperature
  4. stirringafter stirring
  5. customthe mixture was partitioned
  6. washThe aqueous layer was washed with n-heptane (5 mL)
  7. addition35% Hydrochloric acid (400 mg) was added to the aqueous layer, methylisopropylketone (10 mL)
  8. additionwas added
  9. stirringafter stirring
  10. customthe mixture was partitioned
  11. washThe organic layer was washed successively with 8.5% aqueous sodium hydrogencarbonate solution (5 mL) (3 times), 0.5N hydrochloric acid (5 mL)
  12. additioncontaining sodium chloride (250 mg), and 10% brine (5 mL)
  13. customAfter the washing, methylisopropylketone was evaporated under reduced pressure

Sources & evidence

ORD record
ord-b5a3191d86cc4c78a44cae1927775265
Source dataset
uspto-grants-2013_02
Patent number
US08383819B2

Reaction notes

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