Lithium Hydroxide → HCID 86722487, compound

A flask with stir bar and nitrogen line was charged with (3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.15 g, 0.336 mmol), THF (3 mL) and sodium hydride (60 wt % in oil, 0.027 g, 0.672 mmol) then warmed to about 65° C. for about 15 min. The mixture was cooled to rt then benzyl 2-bromoacetate (0.096 g, 0.420 mmol) was added and the mixture was stirred for about 20 min. Benzyl 2-bromoacetate (0.096 g, 0.420 mmol) was added to the mixture then after about 20 min sodium hydride (60 wt % in oil, 0.027 g, 0.672 mmol) and another portion of benzyl 2-bromoacetate (385 mg, 1.68 mmol). The mixture was transferred to a microwave vial then it was heated in a microwave at about 130° C. for about 20 min. Water (1 mL) and lithium hydroxide (200 mg, 8.33 mmol) were added then the mixture was heated in microwave at about 130° C. for about 20 min. Acetic acid (1.5 mL) was added then the reaction mixture was purified without further manipulation in one portion by preparative reverse phase HPLC using a Hypersil HS C18 column (250 mm×21.2 mm, 8 μm particle size) with a gradient of 15-100% MeCN in 0.05 N aq. ammonium acetate pH 4.5 buffer. Product fractions were concentrated under reduced pressure then the material was suspended in water (˜3 mL), collected by filtration then dried to yield 2-(((3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-yl)oxy)acetic acid (18.3 mg, 10.80%); LC/MS, method 2, Rt=2.60 min, MS m/z 505 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.82-7.78 (m, 2H), 7.57 (s, 1H), 7.43-7.37 (m, 2H), 4.21 (s, 2H), 3.27-3.20 (m, 1H), 2.96-2.91 (m, 1H), 2.31-2.09 (m, 3H), 2.08-1.98 (m, 2H), 1.89-1.76 (m, 4H), 1.70-1.61 (m, 3H), 1.40-1.29 (m, 1H), 0.44 (t, J=7.2 Hz, 3H).

1. stirringthe mixture was stirred for about 20 min
2. temperatureit was heated in a microwave at about 130° C. for about 20 min
3. temperaturethe mixture was heated in microwave at about 130° C. for about 20 min
4. customthe reaction mixture was purified without further manipulation in one portion by preparative reverse phase HPLC
5. concentrationProduct fractions were concentrated under reduced pressure
6. filtrationcollected by filtration
7. customthen dried

ORD record

ord-e44f5b6ac249455db418c7216dd24437

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2