Réaction #992723

Équation de réaction

cyclopropylsulfonamide

cyclopropylsulfonamide

29

17-[3-(4-cyclopropylthiazol-2-yl)-6-methoxy-isoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid

1,1′-carbonyldiimidazole

DBU

→

target compound 30

Rendement 58.4%

N-[17-[3-(4-cyclopropylthiazol-2-yl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide

Rendement 58.4%

Solvants

THF

Conditions de réaction

Traitement

1. 1
   Températurewas heated
2. 2
   Températureat reflux for 2 h under nitrogen
3. 3
   Autreone peak of the intermediate (RT=5.37)
4. 4
   Autrecan be isolated
5. 5
   Températureheated at 55° C. for 24 h
6. 6
   AutreThe solvent was evaporated
7. 7
   Autrethe residue partitioned between AcOEt ethyl acetate and acidic water (pH=3)
8. 8
   AutreThe crude material was purified by column chromatography (ethyl acetateAcOEt/CH2Cl2/pPetroleum ether, 1:1:1)
9. 9
   AutreThe residue was crystallized in diethyl ether
10. 10
    Filtrationfiltered
11. 11
    Autreto give the target compound
12. 12
    AutreThis material was triturated in 3 mL of water
13. 13
    Filtrationfiltered
14. 14
    Lavagewashed with water
15. 15
    Autredried overnight with the high vacuum pump

Mode opératoire

A mixture of 29 (91 mg, 0.14 mmol) and 1,1′-carbonyldiimidazole (CDI) (47 mg, 0.29 mmol) in dry THF (7 mL) was heated at reflux for 2 h under nitrogen. LCMS analysis shows one peak of the intermediate (RT=5.37). Optionally, the azalactone derivative, if desired, can be isolated. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (52 mg, 0.43 mmol) was added. Then, DBU (50 μL, 0.33 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, and then heated at 55° C. for 24 h. The solvent was evaporated, and the residue partitioned between AcOEt ethyl acetate and acidic water (pH=3). The crude material was purified by column chromatography (ethyl acetateAcOEt/CH2Cl2/pPetroleum ether, 1:1:1). The residue was crystallized in diethyl ether, filtered to give the target compound contaminated with the cyclopropylsulfonamide. This material was triturated in 3 mL of water, filtered, washed with water and dried overnight with the high vacuum pump to give 60 mg (57%) of the target compound 30 as a slightly yellow powder: m/z=734 (M+H)+, 1H-NMR (CDCl3): 10.94 (s, 1H), 8.08 (d, J=8.6 Hz, 1H), 8.00 (s, 1H), 7.12-7.15 (m, 2H), 6.91 (s, 1H), 6.35 (s, 1H), 5.74-5.77 (m, 1H), 5.63-5.69 (m, 1H), 5.06 (t, J=10.4 Hz, 1H), 4.60 (t, J=12.3 Hz, 1H), 3.93 (s, 3H), 3.35-3.42 (m, 2H), 3.04 (s, 3H), 2.89-2.96 (m, 2H), 2.52-2.52 (m, 2H), 2.37-2.45 (m, 2H), 2.10-2.32 (m, 2H), 1.61-1.93 (m, 4H), 1.3-1.51 (m, 4H), 0.90-1.30 (m, 8H).

Source