Ammonia → HCID 74220987, compound

HRID 718871Notes

Reaction equation

HRID 718871 reaction equation
[CH2:1]([C@:3]12[CH2:27][CH2:26][C@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[H-].[Na+].Br[CH2:36][C:37]([O:39]CC)=O.CO.[NH3:44]>CN(C=O)C>[CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([O:28][CH2:36][C:37]([NH2:44])=[O:39])([C:29]([F:32])([F:31])[F:30])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]=2[CH:16]=1)[CH3:2]

Participants

7

Reactant 5

HCID 222AmmoniaHCID 887MethanolHCID 7748Ethyl bromoacetate3×HCID 24758Sodium hydride3×HCID 86722486HCID 86722486, compound

Product 1

HCID 74220987HCID 74220987, compoundYield 18%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

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) (0.230 g, 0.515 mmol)], DMF (3 mL) and sodium hydride (60 wt % in oil, 12.0 mg, 0.30 mmol). The mixture was stirred at rt for about 20 min then cooled to about 0° C. Ethyl 2-bromoacetate (0.086 g, 0.515 mmol) was added then the mixture was allowed to warm to rt for about 12 h. Sodium hydride (60 wt % in oil, 20 mg, 0.500 mmol) was added then after about 15 min ethyl 2-bromoacetate (0.120 g, 0.719 mmol) was added dropwise over about 1 h. Sodium hydride (60 wt % in oil, 20 mg, 0.50 mmol) was added then after about 10 min ethyl 2-bromoacetate (0.120 g, 0.719 mmol) was added dropwise over about 10 min. The mixture was concentrated under reduced pressure, dissolved in 7 M ammonia in MeOH (5 mL, 35.0 mmol) transferred to a microwave vial and heated in a microwave at about 130° C. for about 1 h. The reaction mixture was purified without manipulation in one portion by preparative reverse phase HPLC using a Hypersil HS C18 column (250 mm×21.2 mm, 8 um 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 lyophilized 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)acetamide (0.046 g, 18%); LC/MS, method 2, Rt=2.82 min, MS m/z 504 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=0.7 Hz, 1H), 7.84 (s, 1H), 7.83-7.77 (m, 2H), 7.57 (s, 1H), 7.45-7.37 (m, 2H), 7.33 (s, 1H), 7.20 (s, 1H), 4.02 (d, J=14.7 Hz, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.27-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.26-1.97 (m, 5H), 1.94-1.80 (m, 4H), 1.79-1.56 (m, 3H), 1.40-1.30 (m, 1H), 0.44 (t, J=7.3 Hz, 3H).

Workup

  1. stirringThe mixture was stirred at rt for about 20 min
  2. temperatureto warm to rt for about 12 h
  3. concentrationThe mixture was concentrated under reduced pressure
  4. temperatureheated in a microwave at about 130° C. for about 1 h
  5. customThe reaction mixture was purified without manipulation in one portion by preparative reverse phase HPLC
  6. concentrationProduct fractions were concentrated under reduced pressure

Sources & evidence

ORD record
ord-87d5d53decbd4607a959c550a499c911
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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