Reaktion #1865183

Reaktionsgleichung

6-amino-4-((2-methoxyethyl)amino)nicotinonitrile

intermediate 75

6-amino-4-((2-methoxyethyl)amino)nicotinonitrile

N-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)acetamide

intermediate 198

N-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)acetamide

di(1H-1,2,4-triazol-1-yl)methanone

→

title compound

N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((N-(2-(dimethylamino)ethyl)acetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Lösungsmittel

DMF

DMF

DMF

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturto warm to room temperature
2. 2
   workup.STIRRINGstirred for approximately 2 h
3. 3
   workup.STIRRINGto stir for 48 h at room temperature
4. 4
   Sonstigequenched
5. 5
   workup.ADDITIONby pouring it into aqueous NaHCO3
6. 6
   workup.ADDITIONThe reaction mixture was diluted with EtOAc, phases
7. 7
   Sonstigewere separated
8. 8
   Extraktionthe water phase was extracted with EtOAc and DCM
9. 9
   SonstigeThe combined organic phases were dried
10. 10
    Filtrationfiltered
11. 11
    Sonstigeevaporated
12. 12
    SonstigeThe crude product was purified by reversed phase preparative HPLC
13. 13
    Wascheneluting with a gradient of MeCN and water (RP 5, H2O/MeCN 70:30 to 40:60 in 25 min)
14. 14
    workup.ADDITIONFractions containing the product
15. 15
    Sonstigewere collected
16. 16
    workup.ADDITIONdiluted with water and basified with NaHCO3
17. 17
    EinengenThe mixture was concentrated
18. 18
    Extraktionextracted with DCM
19. 19
    Sonstigedried
20. 20
    Filtrationfiltered
21. 21
    Einengenconcentrated
22. 22
    Sonstigedried

Vorschrift

A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 631 mg, 3.28 mmol) in anhydrous DMF (4 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (539 mg, 3.28 mmol) and DMF (4 ml) cooled at 0° C. After stirring for 30 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h, after which a solution of N-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)acetamide (intermediate 198, 460 mg, 1.313 mmol) in DMF (4 ml) was added. The reaction mixture was continued to stir for 48 h at room temperature and quenched by pouring it into aqueous NaHCO3. The reaction mixture was diluted with EtOAc, phases were separated and the water phase was extracted with EtOAc and DCM. The combined organic phases were dried using Na2SO4, filtered and evaporated. The crude product was purified by reversed phase preparative HPLC eluting with a gradient of MeCN and water (RP 5, H2O/MeCN 70:30 to 40:60 in 25 min). Fractions containing the product were collected, diluted with water and basified with NaHCO3. The mixture was concentrated and extracted with DCM, dried using Na2SO4, filtered, concentrated and dried to yield the title compound as a colorless foamy solid. (UPLC-MS 3) tR 0.73 min, ESI-MS 569.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.6:0.4) δ 13.55 (s, 0.6H), 13.52 (s, 0.4H), 8.28 (s, 1H), 7.53 (s, 1H), 7.51 (s, 0.4H), 7.40 (s, 0.6H), 6.98-6.91 (m, 1H), 5.41 (s, 0.6H), 5.40 (s, 0.4H), 4.70 (s, 0.8H), 4.65 (s, 1.2H), 3.96-3.90 (m, 2H), 3.53 (t, 2H), 3.42-3.24 (m, 13H), 2.86 (t, 0.8H), 2.81 (t, 1.2H), 2.36 (t, 1.2H), 2.30 (t, 0.8H), 2.17-2.08 (m, 7.8H), 1.96 (s, 1.2H), 1.94-1.86 (m, 2H).

Quelle