Hydrochloric Acid → 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid

HRID 596033Notes

Reaction equation

HRID 596033 reaction equation
[NH2:1][C:2]1[C:3]([C:23]2[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([F:36])[CH:24]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([O:14][Si](C(C)(C)C)(C)C)[C@@H:10]([F:22])[CH2:9]2)=[CH:6][N:7]=1.Cl.[OH-].[Na+]>CCO.O>[NH2:1][C:2]1[C:3]([C:23]2[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:36])[CH:24]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:22])[CH2:9]2)=[CH:6][N:7]=1

Participants

6

Reactant 3

HCID 313Hydrochloric Acid2×HCID 14798Sodium HydroxideHCID 123676826tert-Butyl 4-(3-amino-6-((1S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate

Product 1

HCID 1180458824-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
30 °C

Procedure

To a suspension of tert-butyl 4-(3-amino-6-((1 S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (685.0 g, 1318.0 mmol) in EtOH (3.6 kg) was added aqueous HCl (36%, 400.5 g, 3954.2 mmol). The reaction mixture was heated to 30° C. and stirred for 4 hours. The reaction temperature was lowered to 5° C. and a solution of NaOH (342.7 g, 8567.5 mmol) in water (1.6 kg) was added. The reaction mixture was heated to 30° C. and stirred at this temperature for 18 hours. The pH of the reaction mixture was adjusted to 5 using 4 N aqueous HCl to form a solid precipitation. After distillation of EtOH under vacuum at 40-50° C., water (2.5 kg) was added to the residue and the temperature was cooled to 5° C. within 1 hour. The suspension was filtere, the solid was collected and dried under vacuum (<100 mbar) at 50-60° C. for 24 hours to give 4-(3-amino-6-((1 S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid as a brown powder (460 g, HPLC purity at 230 nm was 98.2%, quantitative yield). Mp 226-228° C. ESI-MS (m/z): 350.1282 ([M+H]+, 100). HPLC (method A), retention time 5.93 min. 1H NMR (400 MHz, DMSO-D6): 13.32 (br. s, 1H), 8.00 (t, J=8 Hz, 1H), 7.99 (s, 1H), 7.70 (d, J=8 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 6.24 (br. s, 2H), 5.16 (br. s, 1H), 4.44-4.49, 4.30-4.35 (m, 1H), 3.50-3.60 (m, 1H), 2.79-2.84 (m, 1H), 2.20-2.25 (m, 1H), 1.92-1.99 (m, 1H), 1.72-1.83 (m, 2H), 1.50-1.60 (m, 1H), 1.36-1.46 (m, 1H).

Workup

  1. customwas lowered to 5° C.
  2. temperatureThe reaction mixture was heated to 30° C.
  3. stirringstirred at this temperature for 18 hours
  4. customto form
  5. customa solid precipitation
  6. distillationAfter distillation of EtOH under vacuum at 40-50° C.
  7. additionwater (2.5 kg) was added to the residue
  8. temperaturethe temperature was cooled to 5° C. within 1 hour
  9. customthe solid was collected
  10. customdried under vacuum (<100 mbar) at 50-60° C. for 24 hours

Sources & evidence

ORD record
ord-4d5c50f087b74bb68fec7b1307260514
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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