Acetic Acid → 1-(5,7,8,9-Tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2'-[1,3]dioxolan]-1-yl)ethanone

HRID 718815Notes

Reaction equation

HRID 718815 reaction equation
[CH3:1][C:2]1[C:16]([NH:17][C:18](=[O:20])[CH3:19])=[CH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3([CH2:14][C:4]=2[CH:3]=1)[O:13][CH2:12][CH2:11][O:10]3.CC([O-])=O.[K+].CC(O)=O.C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.C(O[N:61]=O)CC(C)C.C([O-])(O)=O.[Na+]>FC1C=CC(N2C3C(=CC=C(CCCC(O)=O)C=3)C=N2)=CC=1.C(Cl)(Cl)Cl>[O:10]1[CH2:11][CH2:12][O:13][C:9]21[CH2:14][C:4]1[CH:3]=[C:2]3[C:16](=[CH:15][C:5]=1[CH2:6][CH2:7][CH2:8]2)[N:17]([C:18](=[O:20])[CH3:19])[N:61]=[CH:1]3

Participants

10

Reactant 7

HCID 176Acetic AcidHCID 7918Acetic Anhydride2×HCID 8053Isoamyl Nitrite2×HCID 2855718-Crown-6HCID 516892Sodium Bicarbonate2×HCID 517044Potassium AcetateHCID 86722424N-(3-Methyl-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2'-[1,3]dioxolan]-2-yl)acetamide

Product 1

HCID 867224251-(5,7,8,9-Tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2'-[1,3]dioxolan]-1-yl)ethanoneYield 48.1%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 867223224-(1-(4-fluorophenyl)-1H-indazol-6-yl)butanoic acidSolvent

Procedure

In a 20 L 3 necked flask, N-(3-Methyl-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-[1,3]dioxolan]-2-yl)acetamide (78) (900 g, 3.27 mol) was dissolved in chloroform (10 L). KOAc (634 g, 6.54 mol), HOAc (382 mL, 6.54 mol), acetic anhydride (655 mL, 6.54 mol), 18-crown-6 (130 g, 523 mmol) and isoamylnitrite (1.30 L, 13.4 mol) were respectively added. The mixture was heated to reflux for about 3 h. Acetic anhydride (900 mL, 9.54 mol) and isoamylnitrite (1.80 L, 13.4 mol) were added and the mixture was heated to reflux overnight. The reaction mixture was cooled to rt and then carefully poured into sat. aq. NaHCO3 (80 L). The pH was carefully adjusted to basic with NaHCO3. The layers were separated and the aq. phase was extracted with DCM (2×15 L). The combined organic layers were concentrated under reduced pressure. tert-Butyl methyl ether (1500 mL) was added and the resulting slurry was stirred for about 1 h. The precipitate was collected by filtration to afford 1-(5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolan]-1-yl)ethanone (79) (450 g, 48% yield) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 8.38 (s, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 3.95 (m, 2H), 3.82 (m, 2H), 3.16 (s, 2H), 2.96 (m, 2H), 2.64 (s, 3H), 1.84 (m, 2H), 1.62 (m, 2H).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for about 3 h
  3. temperaturethe mixture was heated
  4. temperatureto reflux overnight
  5. customThe layers were separated
  6. extractionthe aq. phase was extracted with DCM (2×15 L)
  7. concentrationThe combined organic layers were concentrated under reduced pressure
  8. additiontert-Butyl methyl ether (1500 mL) was added
  9. filtrationThe precipitate was collected by filtration

Sources & evidence

ORD record
ord-5df592074e2a41ed9edfa7535d8a94b4
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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