반응 #219685

반응 방정식

8-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride

N,N-Diisopropylethylamine

(R)-7-Amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one

diphenyl N-cyanocarbonimidate

→

Title compound

수율 34.0%

(R)-N-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-N′-cyano-4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamidine

수율 34.0%

용매

methanol

N,N-dimethylformamide

반응 조건

후처리

1. 1
   workup.STIRRINGwith stirring
2. 2
   온도The mixture was heated to 60° C.
3. 3
   workup.STIRRINGwith stirring for 54 hours
4. 4
   온도The mixture was warmed to 100° C.
5. 5
   workup.STIRRINGwith stirring
6. 6
   workup.WAITheld for 28 hours
7. 7
   기타Reaction
8. 8
   기타Mixture was purified by prep HPLC (acetonitrile-water-ammonium acetate)
9. 9
   기타Acetonitrile was removed from the fractions by roto-vap
10. 10
    workup.ADDITIONRemaining aqueous was diluted with water
11. 11
    여과Solids were filtered off
12. 12
    세척washed with water
13. 13
    workup.WAITAir was pulled through the filter cake for 1 hour
14. 14
    기타Solids were collected
15. 15
    기타dried in vacuo

실험 절차

(R)-7-Amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (115 mg, 345.6 mmol) was dissolved in N,N-dimethylformamide (5.0 mL). N,N-Diisopropylethylamine (200 μL, 1.1 mmol) was added to the mixture followed by diphenyl N-cyanocarbonimidate (94 mg, 382.7 μmol). Mixture stirred at room temperature for 40 minutes. 8-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (121 mg, 427.9 μmol) was added to the vessel with stirring. The mixture was heated to 60° C. and held with stirring for 54 hours. The mixture was warmed to 100° C. and with stirring held for 28 hours. Reaction was diluted with methanol. Mixture was purified by prep HPLC (acetonitrile-water-ammonium acetate). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was diluted with water. Solids were filtered off and washed with water. Air was pulled through the filter cake for 1 hour. Solids were collected and dried in vacuo. Title compound was obtained as tan solid in 34% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.61 (s, 1 H) 11.82 (s, 1 H) 8.35 (s, 1 H) 7.80 (s, 1 H) 7.52 (dd, J=16.48, 7.63 Hz, 2 H) 7.32-7.39 (m, 1 H) 7.29 (s, 1 H) 7.08-7.19 (m, 1 H) 5.57-5.76 (m, 1 H) 5.40 (d, J=18.01 Hz, 1 H) 4.90 (d, J=17.40 Hz, 1 H) 4.59-4.79 (m, 1 H) 4.27 (d, J=12.82 Hz, 2 H) 4.01-4.17 (m, 1 H) 3.32-3.41 (m, 1 H) 2.98-3.25 (m, 4 H) 1.78-2.00 (m, 2 H) 1.42-1.71 (m, 2 H). High resolution MS m/e (M+H)+=629.1788.

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