Triethylamine → 3,4-Dihydro-1H-isoquinolin-2-carboxylicacid-7-methoxy-2-(4-pyridinylamino)-2,3,4,5-t etrahydro-1H-benzo[c]azepin-8-yl ester hydrochloride

HRID 612489Notes

Reaction equation

HRID 612489 reaction equation
Cl.[CH3:2][O:3][C:4]1[C:21]([OH:22])=[CH:20][C:7]2[CH2:8][N:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][N:24]1[C:33]([Cl:35])=[O:34].C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[ClH:35].[CH3:2][O:3][C:4]1[C:21]([O:22][C:33]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)=[O:34])=[CH:20][C:7]2[CH2:8][N:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 19595159[7-Methoxy-8-hydroxy-1,3,4,5-tetrahydrobenzo[c]azepin-2-yl]-4-pyridinylamine hydrochlorideHCID 218905713,4-Dihydroisoquinoline-2(1H)-carbonyl chloride

Product 1

HCID 701081153,4-Dihydro-1H-isoquinolin-2-carboxylicacid-7-methoxy-2-(4-pyridinylamino)-2,3,4,5-t etrahydro-1H-benzo[c]azepin-8-yl ester hydrochlorideYield 30.8%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of [7-methoxy-8-hydroxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-pyridin-4-yl amine hydrochloride (500 mg) in chloroform (10 mL) was added 1,2,3,4-tetrahydroisoquinoline-2-yl carbonyl chloride (362 mg) followed by triethylamine (0.75 mL). The reaction mixture was heated under reflux for 3 hrs, cooled to ambient temperature, diluted with dichloromethane (200 mL), and the mixture was washed with saturated sodium bicarbonate solution. The organic phase was separated, dried under anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel, eluting with chloroform:methanol (9:1). The appropriate fractions were collected and evaporated. The residue was dissolved in methanol and conc hydrochloric acid was added. The precipitate was collected and crystallized from ethyl acetate-petroleum ether to give 230 mg of product, mp >100° C. (dec).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureunder reflux for 3 hrs
  3. washthe mixture was washed with saturated sodium bicarbonate solution
  4. customThe organic phase was separated
  5. customdried under anhydrous magnesium sulfate
  6. filtrationfiltered
  7. concentrationthe filtrate was concentrated in vacuo
  8. customchromatographed over silica gel
  9. washeluting with chloroform:methanol (9:1)
  10. customThe appropriate fractions were collected
  11. customevaporated
  12. dissolutionThe residue was dissolved in methanol
  13. additionconc hydrochloric acid was added
  14. customThe precipitate was collected
  15. customcrystallized from ethyl acetate-petroleum ether

Sources & evidence

ORD record
ord-9af730d79a9042209f3c37811a25e6c4
Source dataset
uspto-grants-1999_12
Patent number
US06004977

Reaction notes

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