反応 #1265396

反応方程式

iodopentane

(2S)-2-hydroxy-4-methylpentanoic acid

NaH

water

→

compound 9

(2S)-pentyl 4-methyl-2-pentyloxypentanoate

溶媒

DMF

反応条件

後処理

1. 1
   workup.STIRRINGThe reaction mixture was stirred at rt for additional 16 h
2. 2
   その他the layers separated
3. 3
   抽出The aqueous layer was extracted with methylene chloride
4. 4
   洗浄the combined extracts were washed with sat'd NaHCO3
5. 5
   乾燥dried over magnesium sulfate
6. 6
   濃縮concentrated to a crude product
7. 7
   その他Upon further purification

実験手順

To a solution of (2S)-2-hydroxy-4-methylpentanoic acid 8 (1 g, 7.6 mmol) in 50 mL DMF at 0° C. was added NaH (0.6 g, 15.2 mmol) and stirred for 20 min, followed by the addition of iodopentane (1.5 g, 7.6 mmol). The reaction mixture was stirred at rt for additional 16 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a crude product. Upon further purification, compound 9 was obtained as an oil (80 mg, 4%). MS [M+H]+ 273. Step 2: Preparation of (2S)-4-methyl-2-pentyloxypentanoic acid 10. To a solution of (2S)-pentyl 4-methyl-2-pentyloxypentanoate 9 (80 mg, 0.3 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in 5 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give an yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford compound 10 (45 mg, 74%). MS [M+H]+ 203. Step 3: Preparation of (7S)-[(2S)-1-oxo-2-pentyloxy-(4-methylpentyl)]amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one, 12. To a solution of (2S)-4-methyl-2-pentyloxypentanoic acid 10 (45 mg, 0.22 mmol) in CH2Cl2/DMF (5:1, 15 mL) at 0° C. was added HOBT (40 mg, 0.26 mmol) and EDC (50 mg, 0.26 mmol). The mixture was stirred for 10 min then the amine 11 (52 mg, 0.22 mmol) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1 N HCl, sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a glassy solid compound 12 (80 mg, 86%). MS [M+H]+ 423.

出典