Lithium Hydroxide → 1-[(3-chlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid

HRID 44567

反応式

HRID 44567 の反応式
[CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH:28]=[CH:27][CH:26]=1

参加物

8

反応物 4

HCID 3939Lithium HydroxideHCID 11430Potassium CarbonateHCID 698381-(Bromomethyl)-3-chlorobenzeneHCID 178498372HCID 178498372、化合物

生成物 1

HCID 669762511-[(3-chlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid収率 13.38%

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
80 °C

実験手順

To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-chlorobenzene (0.190 mL, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and a gray solid was isolated. The aqueous layer was found to contain a significant amount of product and was evaporated. Both solid and residue were purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (5-50%) over 10 minutes. The appropriate fractions were collected and evaporated to procide the desired product (37.5 mg, 0.097 mmol, 13.38% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.93 (br. s., 3H) 3.05 (br. s., 4H) 3.77-3.85 (m, 4H) 5.55 (br. s., 2H) 6.88 (s, 1H) 7.09 (br. s., 1H) 7.20 (s, 1H) 7.31-7.39 (m, 3H). MS (ES+) m/e 385.8 [M+H]+.

後処理

  1. customThe resulting reaction mixture
  2. temperatureThe solution was cooled to room temperature
  3. extractionwas extracted with EtOAc
  4. washThe combined organic phase was washed with Brine
  5. concentrationconcentrated
  6. customThe residue was purified on Biotage Isolera purification system
  7. washeluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes
  8. customThe expected compound was collected
  9. customevaporated
  10. customto yield a tan solid
  11. stirringThe reaction was stirred at 50° C. for 2 h
  12. temperatureThe reaction was cooled to room temperature
  13. customthe organic solvent was removed in vacuo
  14. additionThe solution was diluted with water (20 mL)
  15. filtrationThe mixture was then filtered
  16. customa gray solid was isolated
  17. customwas evaporated
  18. customBoth solid and residue were purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (5-50%) over 10 minutes
  19. customThe appropriate fractions were collected
  20. customevaporated

出典と根拠

ORDレコード
ord-f34627b4ceb045a195b2c85dcbec66f8
出典データセット
uspto-grants-2013_09
特許番号
US08541411B2

関連ノート

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