Ammonia → 6'-Bromo-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine

온도

74 °C

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 19 Step 3, 22.7 g, 57.7 mmol) and ammonia (7 M in MeOH, 180 mL, 1.26 mol) was put in a pressure reactor and heated to 74° C. overnight. The residue was allowed to reach r.t. and the mixture was concentrated. The residue was partitioned between 2 M citric acid (400 mL) and EtOAc (400 mL). Any insoluble material was filtered off and was determined to be unreacted starting material. The organic phase (org 1) was concentrated in vacuo to give additional unreacted starting material. To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The resulting organic phase (org 2) was saved. The residue from org 1, and the solid filtered off were combined and suspended in ammonia (7 M in MeOH, 180 mL, 1.26 mmol) and put in a pressure reactor and heated 100° C. overnight. The obtained solution was concentrated in vacuo. The residue was partitioned between 2 M citric acid (300 mL) and EtOAc (300 mL). To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The organic phase was combined with org 2 from above. Activated charcoal was added to the organic phase and the mixture was stirred for 30 min before it was filtered through diatomaceous earth. The organic phase was concentrated and dried in vacuo overnight to give a solid. To the solid was diisopropyl ether (125 mL) added and the mixture was refluxed overnight. The mixture was allowed to reach r.t. and the solid was filtered off to give the title compound (equivalent to Example 19 Isomeric Mixture 2 above) (15 g, 69% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 0.93 (m, 1 H) 1.1-1.25 (m, 2 H) 1.35-1.45 (m, 3 H) 1.81 (br. d, 2 H) 2.16 (s, 3 H) 2.87-3.03 (m, 3 H) 3.18 (s, 3 H) 6.59 (br. s., 2 H), 6.64 (d, 1 H), 7.25 (d, 1 H), 7.34 (dd, 1 H); ES+) m/z 376 [M+H]+.

1. customto reach r.t.
2. concentrationthe mixture was concentrated
3. customThe residue was partitioned between 2 M citric acid (400 mL) and EtOAc (400 mL)
4. filtrationAny insoluble material was filtered off
5. concentrationThe organic phase (org 1) was concentrated in vacuo
6. customto give additional
7. additionadded
8. filtrationThe residue from org 1, and the solid filtered off
9. customput in a pressure reactor
10. temperatureheated 100° C. overnight
11. concentrationThe obtained solution was concentrated in vacuo
12. customThe residue was partitioned between 2 M citric acid (300 mL) and EtOAc (300 mL)
13. additionadded
14. addition50% NaOH was added until pH ˜12
15. stirringthe mixture was stirred for 10 min
16. additionActivated charcoal was added to the organic phase
17. stirringthe mixture was stirred for 30 min before it
18. filtrationwas filtered through diatomaceous earth
19. concentrationThe organic phase was concentrated
20. customdried in vacuo overnight
21. customto give a solid
22. additionadded
23. temperaturethe mixture was refluxed overnight
24. customto reach r.t.
25. filtrationthe solid was filtered off

ORD 기록

ord-337ee12afcce435abaf03bcf90a8eddd

출처 데이터셋

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08865911B2