Ammonium Chloride → 1-(2-Ethoxyphenyl)-4-[2-(6-aminocarbonylisochroman-1-yl)ethyl]piperazine

HRID 1417848Notes

Reaction equation

HRID 1417848 reaction equation
C([Li])(C)(C)C.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH:23]2[C:32]3[C:27](=[CH:28][C:29](Br)=[CH:30][CH:31]=3)[CH2:26][CH2:25][O:24]2)[CH2:17][CH2:16]1)[CH3:7].[C:34](Cl)(=[O:38])C(Cl)=O.[Cl-].[NH4+:41]>C1COCC1.CN(C=O)C>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH:23]2[C:32]3[C:27](=[CH:28][C:29]([C:34]([NH2:41])=[O:38])=[CH:30][CH:31]=3)[CH2:26][CH2:25][O:24]2)[CH2:17][CH2:16]1)[CH3:7]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 65578Oxalyl chlorideHCID 154878371-(2-Ethoxyphenyl)-4-[2-(6-bromoisochroman-1-yl)ethyl]piperazineHCID 178418306HCID 178418306, compound

Product 1

HCID 154878391-(2-Ethoxyphenyl)-4-[2-(6-aminocarbonylisochroman-1-yl)ethyl]piperazine

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

A dry 25 ml round bottom flask is charged with THF (2 ml) and cooled to -78°. t-butyllithium in hexanes (1.6M, 1.18 ml, 2 mmol) is added at once via syringe and stirred for 5 min. A solution of 1-(2-ethoxyphenyl)-4-[2-(6-bromoisochroman-1-yl)-ethyl]piperazine (CXXVI, EXAMPLE 126) in THF (3 ml) is added via canula, and stirred for another 10 min. Dry carbon dioxide gas is bubbled through the reaction mixture for 10 min, while maintaining the dry ice/acetone cooling bath. The reaction mixture is warmed to 20°-25°. When the gas evolution stopped, oxalyl chloride (0.13 ml, 1.5 mmol) is added dropwise via syringe, followed by DMF (4 drops). After two hours of stirring, the reaction mixture is poured into ammonium chloride (40 ml), extracted two times with equal volumes of methylene chloride (which are combined), dried with sodium sulfate, filtered and concentrated. The concentrate is purified by flash chromatography (silica gel, 25 g; eluting with methanol/ethyl acetate (10/90) to give the impure product. The impurity is removed by triturating with methylene chloride and hexane to leave an oil which is converted into the hydrochloride salt using ethereal hydrochloric acid to give the title compound, mp 208°-210°; HRMS Calcd for C24H31N3O3 =409.2365, found=409.2364.

Workup

  1. temperaturecooled to -78°
  2. stirringstirred for another 10 min
  3. customDry carbon dioxide gas is bubbled through the reaction mixture for 10 min
  4. temperaturewhile maintaining the dry ice/acetone cooling bath
  5. temperatureThe reaction mixture is warmed to 20°-25°
  6. stirringAfter two hours of stirring
  7. extractionextracted two times with equal volumes of methylene chloride (which are combined)
  8. dry with materialdried with sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe concentrate is purified by flash chromatography (silica gel, 25 g
  12. washeluting with methanol/ethyl acetate (10/90)
  13. customto give the impure product
  14. customThe impurity is removed
  15. customby triturating with methylene chloride and hexane
  16. customto leave an oil which

Sources & evidence

ORD record
ord-e1f5aa72dfaa44ddb27a48d6ffaff945
Source dataset
uspto-grants-1999_03
Patent number
US05877317

Reaction notes

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