Triethylamine → tert-butyl (5-bromo-3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate

HRID 81370Notes

Reaction equation

HRID 81370 reaction equation
Cl[C:2](=[N:24][OH:25])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Br:26][C:27]1[N:28]=[C:29]([C:48]#[CH:49])[C:30]([N:33]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:31][CH:32]=1.CCN(CC)CC>C(Cl)Cl.O>[C:44]([O:43][C:41](=[O:42])[N:33]([C:30]1[C:29]([C:48]2[O:25][N:24]=[C:2]([C:3]3[CH:23]=[CH:22][C:6]([CH2:7][N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:5][CH:4]=3)[CH:49]=2)=[N:28][C:27]([Br:26])=[CH:32][N:31]=1)[C:34]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:40])([CH3:45])([CH3:46])[CH3:47]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 58070394tert-butyl N-(5-bromo-3-ethynylpyrazin-2-yl)-N-[(tert-butoxy)carbonyl]carbamateHCID 86680728tert-butyl 4-(chloro(hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate

Product 1

HCID 86680727tert-butyl (5-bromo-3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamateYield 78.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
20 °C

Procedure

A solution of tert-butyl 4-(chloro(hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4-i) (1.60 kg, 4.34 mol) and tert-butyl N-(5-bromo-3-ethynylpyrazin-2-yl)-N-tert-butoxycarbonylcarbamate (Compound A-4-ii) (1.73 kg, 4.34 mol) in CH2Cl2 (12.8 L) is stirred at 20° C. Et3N (483 g, 665 mL; 4.77 mol) is added and the reaction temperature maintained below 30° C. The suspension stirred at 20° C. to complete the reaction then diluted with water (8.0 L) and agitated. The phases are separated and the organic phase is washed with water (8.0 L) and then concentrated. i-PrOAc (1.6 L) is added and the mixture and heated at 50° C. Heptane (4.0 L) was slowly added then the suspension is allowed to cool to ambient temperature and stirred overnight. Additional heptane (7.2 L) is added to the suspension and it is stirred for 1 h. The solid is collected by filtration. The filter-cake is washed with heptane (2×1.6 L) and dried to afford tert-butyl(5-bromo-3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate (A-5) (2.478 kg; 78%, 97.8 area % purity by HPLC) as a fine, tan powder. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.31 (m, 3H), 4.42 (br m, 3H), 4.03-3.82 (m, 2H), 3.38 (br s, 2H), 1.60 (m, 4H), 1.36 (s, 27H).

Workup

  1. temperaturethe reaction temperature maintained below 30° C
  2. customthe reaction
  3. stirringagitated
  4. customThe phases are separated
  5. washthe organic phase is washed with water (8.0 L)
  6. concentrationconcentrated
  7. additioni-PrOAc (1.6 L) is added
  8. temperaturethe mixture and heated at 50° C
  9. additionHeptane (4.0 L) was slowly added
  10. temperatureto cool to ambient temperature
  11. stirringstirred overnight
  12. additionAdditional heptane (7.2 L) is added to the suspension and it
  13. stirringis stirred for 1 h
  14. filtrationThe solid is collected by filtration
  15. washThe filter-cake is washed with heptane (2×1.6 L)
  16. customdried

Sources & evidence

ORD record
ord-3ff8b3e90bad4ac8b6702238f1aae7b4
Source dataset
uspto-grants-2014_09
Patent number
US08846686B2

Reaction notes

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