1,4-Dioxane → HCID 178433184、化合物

HRID 241198ノート

反応式

HRID 241198 の反応式
Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6](C(OCC(C)C)=O)[C:7]([NH:9][CH2:10][CH2:11][F:12])=[N:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[C:31]([N:37]3[CH2:43][C:42]4[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH2:38]3)=[N:32][CH:33]=[N:34][C:35]=2[CH3:36])=[CH:25][CH:24]=1.O1CCOCC1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:12][CH2:11][CH2:10][NH:9][C:7]1[NH:6][C:5]2[CH:20]=[CH:21][C:2]([C:45]3[CH:46]=[CH:47][C:41]4[O:40][CH2:39][CH2:38][N:37]([C:31]5[C:30]([CH2:29][C:26]6[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=6)=[C:35]([CH3:36])[N:34]=[CH:33][N:32]=5)[CH2:43][C:42]=4[CH:44]=3)=[CH:3][C:4]=2[N:8]=1

参加物

8

反応物 4

HCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 66820119(4-{5-[(4-Fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acidHCID 86647855Isobutyl 5-bromo-2-(2-fluoroethylamino)-1H-benzo[d]imidazole-1-carboxylate

生成物 1

HCID 178433184HCID 178433184、化合物収率 25%

試薬・触媒・溶媒 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 962Water溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
95 °C

実験手順

Isobutyl 5-bromo-2-(2-fluoroethylamino)-1H-benzo[d]imidazole-1-carboxylate (76 mg, 0.21 mmol) and (4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 8 step 2) (100 mg, 0.25 mmol), and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.5 mg, 0.01 mmol) were taken into dioxane (1 mL) and water (200 uL) followed by addition of DIPEA (180 uL, 1.03 mmol) and the mixture was heated to 95° C. over 12 h. On cooling to room temperature the crude mixture was diluted with ethyl acetate and dried over anhydrous sodium sulfate then filtered through a bed of silica gel. The filtrate was concentrated and the residue taken into methanol (5 mL) and basified by addition of 5 drops of 50% aqueous sodium hydroxide. The methanol solution was stirred for 0.5 h at room temperature then concentrated. The residue was partitioned with isopropyl acetate and 1M aqueous sodium hydroxide. The organic phase was washed twice with additional 1M aqueous sodium hydroxide then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using 20:1 ethyl acetate:ethanol then 10% methanol in dichloromethane as eluent. Fractions containing pure material were concentrated and the residue triturated with ethyl ether. The suspension collected by filtration to give N-(2-fluoroethyl)-5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine (27.4 mg, 25% yield). 1H NMR (400 MHZ, DMSO-d6): 10.84 (br s, 1H), 8.50 (s, 1H), 7.34 (d, 1H), 7.26 (br s, 1H), 7.18 (d, 1H), 7.12 (d, 4H), 6.98-6.91 (m, 3H), 6.85 (s, 1H), 4.68 (m, 1H), 4.55 (m, 1H), 4.46 (s, 2H), 4.25 (br s, 2H), 4.01 (s, 2H), 3.77 (br s, 2H), 2.16 (s, 3H). MS (EI) for C30H28F2N6O: 528 (MH+).

後処理

  1. dry with materialdried over anhydrous sodium sulfate
  2. filtrationthen filtered through a bed of silica gel
  3. concentrationThe filtrate was concentrated
  4. additionbasified by addition of 5 drops of 50% aqueous sodium hydroxide
  5. concentrationthen concentrated
  6. customThe residue was partitioned with isopropyl acetate and 1M aqueous sodium hydroxide
  7. washThe organic phase was washed twice with additional 1M aqueous sodium hydroxide
  8. dry with materialthen dried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by silica gel chromatography
  12. additionFractions containing pure material
  13. concentrationwere concentrated
  14. customthe residue triturated with ethyl ether
  15. filtrationThe suspension collected by filtration

出典と根拠

ORDレコード
ord-f9d49e2d179e4b6ebd8dbad197cf86b2
出典データセット
uspto-grants-2014_02
特許番号
US08648066B2

反応ノート

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