반응 #219684

반응 방정식

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 33.0%

(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-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamidine

수율 33.0%

용매

methanol

N,N-dimethylformamide

반응 조건

후처리

1. 1
   workup.STIRRINGwith stirring
2. 2
   온도The mixture was heated to 100° C.
3. 3
   workup.WAITheld for 54 hr
4. 4
   workup.STIRRINGwith stirring
5. 5
   온도Mixture was cooled to room temperature
6. 6
   여과Mixture was filtered
7. 7
   기타Filtrate was purified by reverse phase prep HPLC (acetonitrile-water-ammonium acetate)
8. 8
   기타Acetonitrile was removed from the fractions by roto-vap
9. 9
   workup.ADDITIONRemaining aqueous was diluted with water
10. 10
    여과Solids were filtered off
11. 11
    세척washed with water
12. 12
    workup.WAITAir was pulled through the filter cake for 2 hours
13. 13
    기타Solids were collected
14. 14
    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 (130 mg, 390.7 μmol) 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 (100 mg, 407.1 μmol). Mixture stirred at room temperature for 40 minutes. 3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (125 mg; 472.1 μmol) was added to the vessel with stirring. The mixture was heated to 100° C. and held for 54 hr with stirring. Mixture was cooled to room temperature and then diluted with methanol. Mixture was filtered. Filtrate was purified by reverse phase 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 2 hours. Solids were collected and then dried in vacuo. Title compound was obtained as tan solid in 33% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.62 (s, 1 H) 11.79 (s, 1 H) 8.35 (s, 1H) 7.73 (s, 1 H) 7.66 (d, J=7.94 Hz, 1H) 7.53 (d, J=7.93 Hz, 1H) 7.44 (t, J=7.63 Hz, 1 H) 7.25-7.33 (m, 2 H) 7.16 (t, J=7.48 Hz, 1 H) 5.59-5.71 (m, 1 H) 5.40 (d, J=17.40 Hz, 1 H) 4.90 (d, J=17.70 Hz, 1 H) 4.59-4.77 (m, 1 H) 4.27 (d, J=13.12 Hz, 2H) 4.00-4.15 (m, 1 H) 3.33-3.42 (m, 1 H) 3.03-3.26 (m, 4 H) 1.86-1.98 (m, 2) 1.54-1.71 (m, 2 H). High resolution MS m/e (M+H)+=611.1890.

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