Phosphorus oxychloride → HCID 21404764, compound

HRID 596817Notes

Reaction equation

HRID 596817 reaction equation
[CH3:1][N:2]([CH3:19])[CH2:3][C:4]([C:6]1(O)[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[CH2:5].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:19][N:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]=1)=[CH2:5]

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 21404754HCID 21404754, compound

Product 1

HCID 21404764HCID 21404764, compound

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

The reaction of the keto group of the 6-alkoxy, and 6-cycloalkoxy 7-aza-1-tetralones with the lithium salt formed by adding butyl lithium to an appropriate halo substituted dimethylaminoalkene affords the corresponding N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-alkoxyisoquinol-8-yl]alk2-en-1-yl)amine, or the appropriate cycloalkyloxy derivative. Typically, 7-aza-6-methoxy-1-tetralone is contacted with a solution containing butyl lithium and 2-bromo-3-dimethylaminopropene to yield N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8 -hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-1yl)amine. The hydroxyl substituent is removed with a phosphorous oxyhalide, such as phosphorous oxychloride in pyridine or in concentrated sulfuric acid, to yield the N,N-dimethyl-N-(2-[5,6-dihydro-3-substituted-isoquinol-8-yl]alk-2-en-1-yl)amine. For example, N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine is contacted with phosphorous oxychloride in pyridine to obtain N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl-]prop-2-en-1-yl)amine. Quaternarization of the amines with an alkyl halide, e.g. methyl iodide, yields the quaternary salts, which are subsequently reacted with silver oxide and then with 2-(lower alkyl)cyclopentane-1,3-dione to yield the appropriate 5,6-dihydro-3-substituted-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)alk-1-en-2-yl]isoquinoline. In that manner, the aforementioned N,N-dimethyl-N-(2[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine is treated with methyl iodide to afford the corresponding trimethyl ammonium iodide. Subsequent treatment with silver oxide and 2-(lower alkyl)cyclopentane-1,3-dione produces 5,6-dihydro-3-methoxy-8-[3-( 2-methyl-1,3-dioxocyclopent-2-yl)prop-1-en-2-yl]isoquinoline. Cyclization of the diketones is effected conveniently with sulfuric acid to afford the corresponding dl-2-aza-3-substituted-11β-methylestra-1,3,5(10),8(14),9(11),15-hexaen-17-ones. Representative thereof is the formation of dl-2-aza-3-methoxy-11β-methylestra-1,3,5(10),8(14),9(11),15-hexaen17one upon contacting the aforementioned isoquinoine derivative with sulfuric acid.

Workup

  1. customThe hydroxyl substituent is removed with a phosphorous oxyhalide, such as phosphorous oxychloride in pyridine or in concentrated sulfuric acid
  2. customto yield the N,N-dimethyl-N-(2-[5,6-dihydro-3-substituted-isoquinol-8-yl]alk-2-en-1-yl)amine

Sources & evidence

ORD record
ord-87006552539c41d9b65e8206eb161c62
Source dataset
uspto-grants-1977_03
Patent number
US04012391

Reaction notes

Loading…