Sodium hydroxide--water (1/1/1) → Elagolix Sodium

HRID 1049113Notes

Reaction equation

HRID 1049113 reaction equation
C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][NH:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:12]1=[O:40])C.[OH-].[Na+:49].O>>[Na+:49].[F:26][C:19]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:16](=[O:17])[N:11]([CH2:10][C@H:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([O-:47])=[O:3])[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:12](=[O:40])[N:13]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:14]=1[CH3:27]

Participants

3

Reactant 2

HCID 23719242Sodium hydroxide--water (1/1/1)HCID 67105103Ethyl 4-(((1R)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl)-1-phenylethyl)amino)butanoate

Product 1

HCID 24785956Elagolix SodiumYield 78%

Conditions

Temperature
22.5 °C

Procedure

To a reactor was charged a stock solution of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid ethyl ester 4a (81.8 kg solution, containing ˜17.1 kg of 4a). A solution of NaOH/water (2.2 kg/70 L) was added and the reactor contents were stirred at 20-25° C. for five hours until reaction completion. The reactor contents were concentrated using vacuum distillation. Water (124 L) was added and the solution was passed through a 5 μm line filter. Methyl isobutyl ketone (120 L) was charged and the mixture heated to 55° C. Separate the layers and add methyl isobutyl ketone (120 L) to the aqueous layer at ambient temperature. Agitate the mixture and add 48% aqueous sodium hydroxide (33 kg). Separate the layers and wash the aqueous layer with methyl isobutyl ketone (51 L). Separate the layers and wash the combined methyl isobutyl ketone layers with an aqueous brine solution (15.4 kg NaCl/44 L water). Separate the layers and concentrate the organic layer to ˜2-3 volumes methyl isobutyl ketone. Filter the concentrated solution through a 0.2 μm filter. Charge the methyl isobutyl ketone solution to a well-agitated reactor containing heptane (171 L) cooled to 20° C. The mixture is stirred for two hours, filtered, and the cake is washed with heptane (10 L) to provide 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid sodium salt 5-1 as an off-white solid (13.2 kg, 78% yield). LCMS (ESI) m/z 632.2 (MH+)

Workup

  1. concentrationThe reactor contents were concentrated
  2. distillationvacuum distillation
  3. additionWater (124 L) was added
  4. filtrationfilter
  5. additionMethyl isobutyl ketone (120 L) was charged
  6. temperaturethe mixture heated to 55° C
  7. customSeparate the layers
  8. additionadd methyl isobutyl ketone (120 L) to the aqueous layer at ambient temperature
  9. stirringAgitate the mixture
  10. additionadd 48% aqueous sodium hydroxide (33 kg)
  11. customSeparate the layers
  12. washwash the aqueous layer with methyl isobutyl ketone (51 L)
  13. customSeparate the layers
  14. washwash the combined methyl isobutyl ketone layers with an aqueous brine solution (15.4 kg NaCl/44 L water)
  15. customSeparate the layers
  16. concentrationconcentrate the organic layer to ˜2-3 volumes methyl isobutyl ketone
  17. filtrationFilter the concentrated solution through a 0.2 μm
  18. filtrationfilter
  19. additionCharge the methyl isobutyl ketone solution to a well-agitated reactor
  20. additioncontaining heptane (171 L)
  21. temperaturecooled to 20° C
  22. stirringThe mixture is stirred for two hours
  23. filtrationfiltered
  24. washthe cake is washed with heptane (10 L)

Sources & evidence

ORD record
ord-6be5065abf104e8fa78bdf7fe05f1153
Source dataset
uspto-grants-2016_07
Patent number
US09382214B2

Reaction notes

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