2-Chloro-l-dimethylaminopropane

Diphenylacetonitrile is condensed with 2-chloro-l-dimethylaminopropane to give 4-(dimethylamino)-2,2-diphenyl valeronitrile. It is then reacted with ethyl magnesium bromide and then hydrolyzed using HCI to give methadone hydrochloride. 

Ganellin and Ridley obtained a mixture of isomeric products by the action of 2-chloro-l-dimethylaminopropane on indole magnesium iodide. In this case both 3-(2-dimethylamino-l-methylethyl)... 

Dimethylamino)-2, 2-diphenylvaleronitrile may be prepared by the eondensation of the eyclized form of 2-chloro-l-dimethylaminopropane with diphenyl aeetonitrile in the presenee of sodamide togetherwithanundesiredequimolarproportionofanisomerienitrile.Theundesiredisomer isseparatedandrejected,whiletherightisomerissubjeetedtoGrignardReactionwithethylmagnesium bromide to yield an addition compound which on acidic hydrolysis forms the official compound. 

An alternate and more controlled approach to the synthesis of phenothiazines involves sequential aromatic nucleophilic displacement reactions. This alternate scheme avoids the formation of the isomeric products that are sometimes observed to form from the sulfuration reaction when using substituted aryl rings. The first step in this sequence consists of the displacement of the activated chlorine in nitrobenzene (30-1) by the salt from orf/io-bromothiophenol (30-2) to give the thioether (30-3). The nitro group is then reduced to form aniline (30-4). Heating that compound in a solvent such as DMF leads to the internal displacement of bromine by amino nitrogen and the formation of the chlorophenothiazine (30-4). Alkylation of the anion from that intermediate with 3-chloro-l-dimethylaminopropane affords chlorpromazine (30-5) [31]. 

A mixture of 10.0 g of 5.5-dimethylacridan, 2.0 g of pulverized sodium amide and 6.5 g of l-chloro-3-dimethylaminopropane in 50 ml of xylene is heated at reflux with stirring for one hour. To the cooled reaction mixture is added one volume of water. The organic layer is separated and extracted several times with diluted lactic acid. The acidic extracts are combined, washed with ether and neutralized by alkali. The crude 10-(3 -dimethylaminopropyl)-5,5-dimethylacridan is isolated by ether extraction and purified by distillation in a high vacuum. The yield is 6.4 g BP 170°-180°C/0.005mm. nD29 = 1.59 90. 

A 0.61 N solution (90 cc) of l-chloro-2-methyl-3-dimethylaminopropane in xylene is then added over 50 minutes and heating with reflux is continued for 20 hours. After cooling, the mixture is treated with water (40 cc) and N methanesulfonic acid (70 cc). The aqueous layer is washed with ether, treated with aqueous sodium hydroxide (density = 1.33 10 cc) and extracted with ether. 

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