US Patent 2155194
Preparation of Alpha-Alkylaminoacylophenones
Abstract:
Alpha-alkylaminoacylophenones were prepared exclusively by halogenating and acylophenone and reacting the resultant halo-compound with an excess of alkylamine. Thus, in the preparation of alpha-methylaminopropiophenone, the common procedure involved the bromination of propiophenone and reacting the halo-compound with excess of methylamine. In this patent, alkyl-N-halogenated amines are generated in order to avoid formation and use of the alpha-halo compounds above, which are lachrymators and vesicants. It is also advantageous in that excess alkylamine is not required, thereby limiting over-alkylation of the nitrogen. It has been found that alpha-alkylaminoacylophenones may be obtained in one step by reacting an acylophenone with an alkyl-N-halogenated amines in a suitable solvent and in the presence of an alkaline substance.
CH3NH2 + NaOH + Br2 à NaBr + CH3NHBr
C6H5COCH2R + R’ NHXà C6H5CO-CH-R-NH-R’+ HX
By the term “alkaline substance”, it is to be understood that the substance shall have an aqueous pH of higher value than the alkylaminoacylophenone being prepared. Such compounds include the hydroxides and carbonates of ammonia and the alkali metals, the oxides and hydroxides of the alkali-earth metals, the quat salt hydroxides and the alkylamines, proper.
Example Procedure:
A halogen (e.g. bromine) is added in small portions to a well-cooled aqueous or alcoholic solution of one mole of alkylamine and one mole of alkali-metal hydroxide (or two moles of alkylamine) until one mole of the halogen has been dissolved. The temperature of the solution must not exceed 10*C during this addition. One mole of acylophenone dissolved in a miscible solvent such as alcohol, is now added and the mixture is agitated at a temperature lower than 15*C while adding slowly a solution of one-mole-equivalent of an alkaline substance. After stirring for two hour, the reaction mix is neutralized to litmus with HCl acid, diluted with water and unreacted acylophenone is extracted with ether. From the aqueous residue ( which comprises a solution of alpha-methylaminopropiophenone hydrochloride) the free base may be obtained in the usual manner by alkalinization and extraction with an organic solvent.
Alternatively, an aqueous solution of alkyl-N-halo-amine and an alkaline substance (alkylamine) may be agitated with an acylophenone dissolved in a water-immiscible solvent, such as benzene, at a temperature not exceeding 25*C for two hours. By dissolving the reagents in mutually immiscible solvents, the strongly exothermic reaction is somewhat moderated and a simple means is provided for separating the final end-products of the reaction.
Example 1:
Bromine is added in small portions to a well-cooled solution of 35g of methylamine and 40g of caustic soda in one liter of 95% alcohol at –5*C until a total of 160g of (50.3ml) has been added. The temperature of the solution should never exceed 10*C during the addition. 135g of propiophenone is now added and the mixture is agitated while a cold solution of 40g of caustic soda in 50ml of water is added in a thin stream. After stirring for two hours at a temperature below 15*C, the alcohol is distilled off under vacuum and the residue is dissolved in two liters of 1N HCl acid. Unchanged propiophenone is extracted with two successive 250ml portions of ether and the residual acid-aqueous solution of alpha-methylaminopropiophenone HCl is neutralized to litmus with a concentrated solution of sodium carbonate. It may now submitted to reduction by hydrogenation at 3-4 atm in the presence of Pd/C, Pt/C or Raney Nickel.
Example 2:
Bromine is added to a well-cooled solution of 95g of methylamine in one liter of water at –5*C in small portions until a total of 160g (50.3ml) has been added. The temperature of the solution should never be allowed to exceed 10*C during the addition. 135g of propiophenone dissolved in one liter of benzene is now added and the mix is vigorously agitated for two hours with efficient external cooling to keep the temperature below 25*C. The components of the reaction mix are now allowed to stratify and the aqueous solution of methylamine hydrobromide is separated from the benzene solution alpha-methylaminopropiophenone. The latter is neutralized to litmus with a conc. alcoholic solution of hydrochloric acid and the crystalline precipitate that forms is removed by filtration. By solution in alcohol and reprecipitation with acetone, white crystals of alpha-methylaminopropiophenone hydrochloride that had; MP: 179*C.
Table 1
R / R’ / MP of HCl Salt in *C
H/Me/219
Do/Et/228
Me/Me/179
Do/Et/182
Do/n-Pro/182
Do/iso-Pro/212
Do/n-Butyl/159
Do/n-Amyl/154
Et/Me/191
Do/Et/196
n-Pro/Me/181
The products of these reactions can be catalytically hydrogenated to their respective ephedrines in near quantitative yields with Pt/C or Pd/C or Raney Nickel