Trifluoroacetic acid → 5-(4-Isopropylsulfonylphenyl)-3-[3-[4-[(tetrahydropyran-4-ylamino)methyl]phenyl]isoxazol-5-yl]pyrazin-2-amine

HRID 575914Notes

Reaction equation

HRID 575914 reaction equation
C(OC([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34](C(OC(C)(C)C)=O)[CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:29][CH:28]=3)[CH:23]=2)=[N:20][C:19]([C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH:57]([CH3:59])[CH3:58])(=[O:56])=[O:55])=[CH:50][CH:49]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl.CCO>[CH:57]([S:54]([C:51]1[CH:52]=[CH:53][C:48]([C:19]2[N:20]=[C:21]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)=[CH:29][CH:28]=4)[CH:23]=3)[C:16]([NH2:8])=[N:17][CH:18]=2)=[CH:49][CH:50]=1)(=[O:56])=[O:55])([CH3:59])[CH3:58]

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 86680729tert-butyl tert-butoxycarbonyl(3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate

Product 1

HCID 715370835-(4-Isopropylsulfonylphenyl)-3-[3-[4-[(tetrahydropyran-4-ylamino)methyl]phenyl]isoxazol-5-yl]pyrazin-2-amineYield 98%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Procedure

A suspension of tert-butyl tert-butoxycarbonyl(3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate (A-6) (410 g; 492 mmol) in CH2Cl2 (410 mL) is stirred at ambient temperature in a flask. TFA (841 g, 568 mL; 7.4 mol) is added while maintaining the reaction temperature between 20-25° C. The solution is stirred at ambient temperature for about 3 h when analysis shows reaction completion. The solution is cooled to about 5-10° C. and diluted with EtOH (3.3 L) while maintaining the temperature below 20° C. A 5.0 M aqueous solution of NaOH (1.77 L; 8.85 mol) is added while allowing the reaction temperature to rise from about 14° C. to about 42° C. The suspension is heated at 70-75° C. for 6 h while removing distillate. The suspension is allowed to cool to ambient temperature. The solid is collected by filtration and the filter-cake is washed with water (4×1.64 L). The filter-cake is washed with EtOH (2×820 mL) and dried to afford 5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-(((tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl) isoxazol-5-yl)pyrazin-2-amine (Compound I-1) (257 g; 98% yield, 99.5 area % purity by HPLC) as a yellow powder.

Workup

  1. temperaturewhile maintaining the reaction temperature between 20-25° C
  2. stirringThe solution is stirred at ambient temperature for about 3 h when analysis
  3. customreaction completion
  4. temperatureThe solution is cooled to about 5-10° C.
  5. temperaturewhile maintaining the temperature below 20° C
  6. customto rise from about 14° C. to about 42° C
  7. temperatureThe suspension is heated at 70-75° C. for 6 h
  8. customwhile removing distillate
  9. temperatureto cool to ambient temperature
  10. filtrationThe solid is collected by filtration
  11. washthe filter-cake is washed with water (4×1.64 L)
  12. washThe filter-cake is washed with EtOH (2×820 mL)
  13. customdried

Sources & evidence

ORD record
ord-72584e46226548fab090c8c293e588b6
Source dataset
uspto-grants-2015_05
Patent number
US09035053B2

Reaction notes

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