Hydrochloric Acid → (4S,7R)-1,7,8,8-tetramethyl-2-(4-methyl-naphthalen-1-yl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one

HRID 1438079Notes

Reaction equation

HRID 1438079 reaction equation
C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH3:41])=[CH:33][CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[CH3:27][N:29]1[C:10]2[C@@:9]3([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:18](=[O:19])[N:30]1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH3:41])=[CH:33][CH:32]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 312751,4-DioxaneHCID 57941306(1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride2×HCID 57941313N-methyl-N'-(4-methyl-naphthalen-1-yl)-hydrazinecarboxylic acid tert-butyl ester

Product 1

HCID 57941402(4S,7R)-1,7,8,8-tetramethyl-2-(4-methyl-naphthalen-1-yl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 37%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Triethylamine (0.18 mL, 1.29 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 160 mg, 0.75 mmol) in 1,2-dichloroethane (2 mL) over 1 min. A solution of N-methyl-N′-(4-methyl-naphthalen-1-yl)-hydrazinecarboxylic acid tert-butyl ester (74 mg, 0.26 mmol) in 1,2-dichloroethane (4 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 30 min. The reaction mixture was cooled. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h and allowed to cool. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 40-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with methanol and then diethyl ether. The residue was dried under high vacuum at 70° C. overnight to give (4S,7R)-1,7,8,8-tetramethyl-2-(4-methyl-naphthalen-1-yl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (33 mg, 37%) as a light brown solid. ES(+)-MS (M+H) 347.

Workup

  1. waitin an oil bath at 50° C. for 30 min
  2. temperatureThe reaction mixture was cooled
  3. temperaturethe mixture was heated in an oil bath at 100° C. for 1 h
  4. temperatureto cool
  5. washthe mixture was washed with 1:1 water/brine (20 mL)
  6. dry with materialdried (magnesium sulfate)
  7. filtrationfiltered
  8. customevaporated
  9. custompurified by flash chromatography
  10. washeluting with 40-100% ethyl acetate/hexanes
  11. customFractions homogeneous for the product were evaporated
  12. customThe residue was dried under high vacuum at 70° C. overnight

Sources & evidence

ORD record
ord-b9ec57e4e40644e2b519ff554e0c08b0
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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