Dichloromethane → 4-bromo-benzoic acid 2-((3R,4R)-3-hydroxy-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethyl ester

HRID 60375

反応式

HRID 60375 の反応式
[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH3:33])[N:19]4[N:18]=3)=[C:12]([O:34][CH3:35])[CH:11]=2)[C@@H:6]([OH:36])[CH2:5]1.C(N(CC)CC)C.C(Cl)Cl.[Br:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1>>[OH:36][C@@H:6]1[C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH3:33])[N:19]4[N:18]=3)=[C:12]([O:34][CH3:35])[CH:11]=2)[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:52](=[O:53])[C:51]2[CH:55]=[CH:56][C:48]([Br:47])=[CH:49][CH:50]=2)[CH2:5]1

参加物

5

反応物 4

HCID 6344DichloromethaneHCID 8471TriethylamineHCID 685154-Bromobenzoyl chlorideHCID 86288905(3R,4R)-1-(2-hydroxyethyl)-4-[3-methoxy-4-[[7-(2-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl]amino]phenyl]piperidin-3-ol

生成物 1

HCID 865817254-bromo-benzoic acid 2-((3R,4R)-3-hydroxy-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethyl ester収率 60%

実験手順

To a mixture of (3R,4R)-1-(2-hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol (Example 16b; 40.00 mg, 0.082 mmol) and triethylamine (12 uL, 0.09 mmol) in methylene chloride (0.400 mL, 6.24 mmol) was added 4-bromo-benzoyl chloride, (19 mg, 0.086 mmol) at 0° C. The reaction was stirred overnight allowing the cooling bath/reaction to slowly warm to room temperature. The volatile were evaporated and the crude residue was further dried on high vacuum, The product was isolated by preparative reverse phase hplc (Gilson) and the free base was released by using a strong cation exchange resin column (Strata, from Phenomenex) to give 33 mg (60% yield) of 4-bromo-benzoic acid 2-((3R,4R)-3-hydroxy-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethyl ester. 1H NMR (CDCl3): 8.70 (br s, 1H), 8.35 (d, J=8.1 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.47 (br s, 1H), 7.46-7.40 (m, 1H), 7.12 (app t, J=7.5 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.02 (d, J=4.7 Hz, 1H), 6.85 (d, J=4.7 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 6.76 (br s, 1H), 4.50 (app t, J=5.8 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.80 (m, 1H), 3.31 (m, 1H), 3.04 (br d, J=11.3 Hz, 1H), 2.90 (app t, J=5.8 Hz, 2H), 2.35 (m, 1H), 2.26 (m, 1H), 2.15 (app t, J=10.2 Hz, 1H), 1.86 (m, 2H), 1.67 (br s, 1H).

後処理

  1. customthe cooling bath/reaction
  2. customThe volatile were evaporated
  3. dry with materialthe crude residue was further dried on high vacuum
  4. customThe product was isolated by preparative reverse phase hplc (Gilson)

出典と根拠

ORDレコード
ord-291b81896417482899e1561d2719602a
出典データセット
uspto-grants-2016_09
特許番号
US09440984B2

関連ノート

読み込み中…