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

HRID 81372Notes

Reaction equation

HRID 81372 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. 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.44-8.33 (m, 2H), 7.94 (t, J=8.2 Hz, 4H), 7.76 (s, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.20 (s, 2H), 3.83 (m, 1H), 3.80 (s, 3H), 3.46 (hept, J=6.8 Hz, 1H), 3.25 (td, J=11.4, 2.1 Hz, 2H), 2.66-2.54 (m, 1H), 1.79 (br dd, 2H), 1.36-1.22 (m, 2H), 1.19 (d, J=6.8 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 167.57, 151.76, 141.07, 137.58, 135.75, 129.16, 128.53, 126.57, 126.41, 125.69, 124.52, 102.13, 65.83, 54.22, 52.60, 49.19, 33.18, 15.20.

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-690dc2eca84c4f8db64f0b5cf2f12915
Source dataset
uspto-grants-2014_09
Patent number
US08846686B2

Reaction notes

Loading…