Dimethylaminopropyl chloride

Indazoles can be considered as either azaindoles or azaisoindoles depending on the reader s prejudice. Benzydamine (54) represents a drug with this heterocyclic nucleus. Alkylation of the amine of anthranilic acid methyl ester with benzyl chloride in the presence of sodium acetate gives 52. Treatment with nitrous acid leads to the nitrosoamine, which cyclizes spontaneously to the 3-ketoindazole system, 53. This intermediate forms an ether of its enol form on heating the sodium salt with 3-dimethylaminopropyl chloride. There is thus obtained benzydamine (54), a fairly potent nonsteroidal antiinflammatory agent with significant antipyretic and analgesic properties. 

Ullmann condensation of the sodium salt of p-chlorothiophe-nol (31) with 2-iodobenzoic (32) acid gives 33. Cyclization by means of sulfuric acid affords the thioxanthone, 34. Reaction with the Grignard reagent from 3-dimethylaminopropyl chloride affords the tertiary carbinol (35). Dehydration by means of acetic anhydride affords chlorprothixene as a mixture of geometric isomers, 36. (Subsequent work showed the Z isomer-chlorine and amine on the same side—to be the more potent compound.) Chlorprothixene is said to cause less sedation than the phenothiazines. ... 

Cyclization of 2-benzyloxybenzoic acid (66) by means of poly-phosphoric acid affords the dibenzoxepinone, 67. Condensation with the Grignard reagent from 3-dimethylaminopropyl chloride, followed by dehydration of the alcohol thus produced affords doxepin (68), presumably as a mixture of geometrical isomers. 

The mixture is heated at reflux for two hours with continual agitation and there is then added dropwise a solution of 2-methyl-3-dimethylaminopropyl chloride in an equal volume of Xylene. The mixture is then heated for fifteen hours, after which time it is cooled and decomposed by the cautious addition of ice water. The layers are separated and the aqueous layer extracted with ether. The combined organic layers are next extracted with 10% hydrochloric acid and the acidic extracts then rendered alkaline by the addition of ammonium hydroxide. The precipitated oil is extracted three times with chloroform. The chloroform extracts are dried and concentrated in vacuo, the residue being distiiled to yield the product. 

A mixture of 20 g (0.1 mol) of 1 -azaphenothiazine, 4.3 g (0.11 mol) of sodamide and 300 ml of dry toluene is stirred and refluxed for eight hours. A slow stream of dry nitrogen gas is used to sweep out the ammonia as formed. The mixture is cooled and 110 ml of a 1 M solution of 3-dimethylaminopropyl chloride in toluene is added dropwise, with stirring. Subsequently, the mixture is stirred and refluxed for fifteen hours, cooled, and concentrated in vacuo. The viscous residue is refluxed with 500 ml of chloroform and filtered hot. The chloroform filtrate is treated with activated charcoal and again filtered. The filtrate is concentrated and the residue distilled to give about 19.B g (69% yield) of product, an oil distilling at about 195 C to 19B°C (under 0.5 mm pressure of mercury). 

Iprindol (25) is yet another antidepressant drug that differs structurally from the classical tricyclic antidepressants. Condensation of phenylhydrazine and cyclooctanone by the Rogers-Corson modification of the Fischer indole synthesis affords the tricyclic intermediate, 24. The active hydrogen of 6,7,8,9,10-hexahydro-5H-cyclooct[b]indole (24) is removed by reaction with sodium metal in DMF and the resulting salt condensed with 3-dimethylaminopropyl chloride. There is thus obtained iprindol (25). ... 

In an initial step, dibenzo [a,d]cyclohepten-5-one is reacted with the Grignard reagent of 3-dimethylaminopropyl chloride and hydrolyzed to give 5-(3-dimethylaminopropyl)-dibenzo[a,d][l,4]cycloheptatriene-5-ol. Then 13 g of that material, 40 ml of hydrochloric acid, and 135 ml of glacial acetic acid is refluxed for 3 /2 hours. The solution is then evaporated to dryness in vacuo and added to ice water which is then rendered basic by addition of ammonium hydroxide solution. Extraction of the basic solution with chloroform and removal of the solvent from the dried chloroform extracts yields the crude product which when distilled in vacuo yields essentially pure 5-(3-dimethylaminopropylidene)-dibenzo[a,d][l,4]cycloheptatriene, BP 173°C to 177°C at 1.0 mm. 

To a solution of 3-dimethylaminopropyl magnesium chloride obtained by reacting 0.2 g of magnesium with 1.0 g of 3-dimethylaminopropyl chloride in 10 ml of tetrahydrofuran under a nitrogen atmosphere using dibromoethane as a catalyst, is dropwise added a solution obtained by dissolving 2.0 g of 11-... 

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