Acetic Anhydride → HCID 86722375, compound

HRID 718783Notes

Reaction equation

HRID 718783 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@H:20]5[CH2:25][C@:24]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C@:21]5([CH2:31][CH:32]=O)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:49]3[CH:48]=[C:47]4[CH2:50][CH2:51][CH2:52][C@@H:53]5[CH2:58][C@@:57]([OH:63])([C:59]([F:62])([F:61])[F:60])[CH2:56][CH2:55][C@@:54]5([CH2:64][CH:65]=O)[C:46]4=[CH:45][C:44]=3[CH:43]=[N:42]2)=[CH:37][CH:36]=1.Cl.NO.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@H:20]5[CH2:25][C@:24]([OH:30])([C:26]([F:28])([F:27])[F:29])[CH2:23][CH2:22][C@:21]5([CH2:31][C:32]#[N:41])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:49]3[CH:48]=[C:47]4[CH2:50][CH2:51][CH2:52][C@@H:53]5[CH2:58][C@@:57]([OH:63])([C:59]([F:61])([F:60])[F:62])[CH2:56][CH2:55][C@@:54]5([CH2:64][C:65]#[N:8])[C:46]4=[CH:45][C:44]=3[CH:43]=[N:42]2)=[CH:37][CH:36]=1

Participants

5

Reactant 3

HCID 7918Acetic AnhydrideHCID 443297Hydroxyamine hydrochlorideHCID 86722378HCID 86722378, compound

Product 1

HCID 86722375HCID 86722375, compoundYield 79%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
60 °C

Procedure

A solution of 2-((3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)acetaldehyde; compound with 2-((3S,4aS,12bR)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)acetaldehyde (41, R1=4-Fluorophenyl, R3=Trifluoromethyl) (320 mg, 0.695 mmol) in pyridine (10 mL) was treated with hydroxylamine hydrochloride (53 mg, 0.76 mmol) and the mixture was heated to about 60° C. for about 15 min, then cooled to rt. Acetic anhydride (0.33 mL, 3.47 mmol) was added dropwise then the mixture was heated to about 60° C. for about 3 h. The reaction was cooled and concentrated under reduced pressure. The residue was dissolved in EtOAc (25 mL) and washed with 2N aq. NaOH and 2N aq. HCl. The organic layer was dried over Na2SO4 and filtered. Silica gel (˜2 g) was added and the solvent removed under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 10-50% EtOAc in heptane as eluant. Product fractions were combined and concentrated under reduced pressure to yield 2-((3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)acetonitrile; compound with 2-((3S,4aS,12bR)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)acetonitrile (42, R1=4-Fluorophenyl, R3=Trifluoromethyl) as a foam (255 mg, 79%); LC/MS, method 4, Rt=1.69 min, MS m/z 458 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.29 (d, J=0.8 Hz, 1H), 7.99 (s, 1H), 7.83-7.75 (m, 2H), 7.61 (s, 1H), 7.44-7.36 (m, 2H), 5.93 (s, 1H), 3.37 (d, J=17.4 Hz, 1H), 3.28-3.27 (m, 1H), 3.10 (d, J=17.4 Hz, 1H), 3.05-2.94 (m, 1H), 2.41-2.29 (m, 1H), 2.26-2.16 (m, 1H), 2.10-2.01 (m, 1H), 2.01-1.92 (m, 1H), 1.87-1.55 (m, 6H), 1.42-1.29 (m, 1H).

Workup

  1. temperaturecooled to rt
  2. temperaturethe mixture was heated to about 60° C. for about 3 h
  3. temperatureThe reaction was cooled
  4. concentrationconcentrated under reduced pressure
  5. dissolutionThe residue was dissolved in EtOAc (25 mL)
  6. washwashed with 2N aq. NaOH and 2N aq. HCl
  7. dry with materialThe organic layer was dried over Na2SO4
  8. filtrationfiltered
  9. additionSilica gel (˜2 g) was added
  10. customthe solvent removed under reduced pressure
  11. customThe residue was purified on silica gel (12 g)
  12. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-724e66e5e7634e5e9465d4050884632a
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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