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 575912ノート

反応式

HRID 575912 の反応式
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>[Br:26][C:27]1[N:28]=[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)[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]([CH3:38])([CH3:39])[CH3:37])=[N:31][CH:32]=1

参加物

6

反応物 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

生成物 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)carbamate収率 78.1%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 6344Dichloromethane溶媒

反応条件

温度
20 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-946633b026a84439b465cf329a81a9a9
出典データセット
uspto-grants-2015_05
特許番号
US09035053B2

反応ノート

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