Trifluoroacetic acid → 2-((1-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone

Temperature

25 °C

Tetrabutylammonium chloride (0.33 eq.) and 35% sodium hydroxide solution (3 ml) were added at 0° C. to a cold solution of (1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methanol (0.47 mmol) in toluene (3 ml). tert-butyl bromoacetate (1.5 eq.) was added dropwise at 0° C. to this cold reaction mixture. The mixture was then stirred for 90 min. at 25° C. until the reaction was complete (TLC monitoring). The mixture was extracted with ethyl acetate (50 ml), and the organic phase was washed with water until the pH value was neutral. Extraction with saturated sodium chloride solution was then carried out, and the organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (20% ethyl acetate in hexane). Yield: 66% Step (iv): Trifluoroacetic acid (13 eq.) was added at 0° C. to a solution of tert-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)acetate (1 eq.) in dichloormethane (10 ml/mmol), and the mixture was stirred for 2 h at 25° C. The reaction mixture was then concentrated in vacuo, and the crude product was used in the next synthesis step without being purified further. Step (v): To a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydro-quinolin-2-yl)methoxy)acetic acid (1 eq.) in dichloromethane (5 ml/mmol) there was added at 0° C. diisopropylethylamine (2.5 eq.), followed by N-hydroxybenzotriazole (HOBt) (1 eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.5 eq.). The resulting reaction mixture was stirred for 15 min. at 25° C. It was then cooled to 0° C., and 1-(1-methylpiperidin-4-yl)piperazine (1.2 eq.) was added. The reaction mixture was stirred for 16 h at 25° C. until the reaction was complete. It was diluted with dichloromethane (30 ml) and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (2% methanol in dichloromethane). Yield: 60%; MS, m/z 585.3 (MH+)

1. extractionThe mixture was extracted with ethyl acetate (50 ml)
2. washthe organic phase was washed with water until the pH value
3. extractionExtraction with saturated sodium chloride solution
4. dry with materialthe organic phase was dried (Na2SO4)
5. concentrationconcentrated in vacuo
6. customThe crude product was purified by column chromatography (20% ethyl acetate in hexane)
7. stirringthe mixture was stirred for 2 h at 25° C
8. concentrationThe reaction mixture was then concentrated in vacuo
9. customthe crude product was used in the next synthesis step
10. customwithout being purified further
11. customThe resulting reaction mixture
12. stirringwas stirred for 15 min. at 25° C
13. temperatureIt was then cooled to 0° C.
14. stirringThe reaction mixture was stirred for 16 h at 25° C. until the reaction
15. extractionextracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution
16. dry with materialThe organic phase was dried (Na2SO4)
17. concentrationconcentrated in vacuo
18. customThe crude product was purified by column chromatography (2% methanol in dichloromethane)

ORD record

ord-a8c9033566f74a009daaa47daf4322e5

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08435978B2