Patent GB-779317-A (GB)
Title: New compounds comprising substituted piperazinediones and acid and alkali metal salts thereof, and the preparation thereof
IPC: C07D241/08
Filed: 1955-09-29
Abstract: The invention comprises substituted piperazinediones of the formula: <FORM:0779317/IV(b)/1> in which R1 is hydrogen or a lower alkyl (1 to 6 carbon atoms), carboakloxy, carboaralkyloxy or acyl radical, R2 is hydrogen or a lower alkyl radical, R3 and R4 are hydrogen or lower alkyl radicals (one being hydrogen and one being lower alkyl) and R5 and R6 are hydrogen or phenyl (one being hydrogen and one phenyl) and acid and alkali metal salts thereof.  One group of such compounds of the formula: <FORM:0779317/IV(b)/2> can be prepared by treating a -(a 1-carbethoxybenzylamino) propionitrile with a mineral acid in the presence of a lower alkyl alcohol and condensing the resulting a -(a 1-carbethoxybenzylamino) propionamide in the presence of an alkali metal lower alkoxide to obtain 3-methyl5-phenyl-piperazinedione and if desired treating this compound with a lower alkyl or acyl chloride whereby the hydrogen atoms in the N1 and N4 positions are selectively replaced by alkyl or acyl radicals, and finally if desired reacting the products with acids or bases to form salts.  This group of compounds can be separated into racemic pairs of compounds, one pair being soluble in and the other pair being precipitated by hydrochloric acid.  Another group of compounds, the 3-ethyl-3-phenyl-2,6-piperazinediones, may be prepared by condensing glycine ethyl ester with propiophenone and hydrogen cyanide to form a -carbethoxymethylamino-a -phenylbutyronitrile, hydrolysing with mineral acid to the corresponding carboxyamide, reacting this with methyl alcohol under esterifying conditions to give a -(carbomethoxymethylamino) - a  - phenylbutyramide hydrochloride, condensation of which in the presence of sodium methoxide gives 3-ethyl-3-phenyl-2,6-piperazinedione. Other alcoholates or alkali metal amides can also be used.  In examples: (1) a  - (a 1 - carbethoxybenzylamino) - propionitrile hydrochloride is reacted with methanol to give a -(a 1-carbethoxybenzylamino) propionamide hydrochloride, treatment of which with sodium methoxide in ethanol gives 3-methyl-5-phenyl - 2,6 - piperazinedione; (2) and (3) the product of Example (1) dissolved in normal hydrochloric acid is treated with 12N HCl to give a precipitate consisting largely of one racemate ("Racemate B") and a filtrate containing the other racemate ("Racemate A"); (4) and (5) Racemate A and Racemate B, respectively, are reacted with carbobenzyloxy chloride to give the corresponding 4-carbobenzyloxy - 3 - methyl - 5 - phenyl - 2,6 - piperazinediones; (6) 4-carbobenzyloxy-3-methyl-5 - phenyl - 2,6 - piperizinedione is methylated in the 1-position by reaction with methyl iodide in the presence of sodium methoxide; (7) the product of (6) is decarbobenzyloxylated by treatment with hydrogen and a platinum catalyst to give 1,3-dimethyl-5-phenyl-2,6-piperazinedione hydrochloride; (8) 4-dichloroacetyl-3 - methyl - 5 - phenyl - 2,6 - piperazinedione is prepared from the product of Example (3) (Racemate B) and dichloracetyl chloride; (9) a  - (carboethoxymethylamino) - a - phenylbutyronitrile hydrochloride (from the reaction of glycine ethyl ester, propiophenone and liquid hydrogen cyanide) is treated with hydrochloric acid to give a -(carboxymethylamino)-a -phenylbutyramide, which with methanol and hydrochloric acid gives a -(carbomethoxymethylamino) - a  phenylbutyramide hydrochloride.  This compound treated with methanol in the presence of sodium methoxide gives 3-ethyl-3-phenyl - 2,6 - piperazinedione; (10) the product of Example (9) treated with carbobenzyloxy chloride gives 4-carbobenzyloxy-3-ethyl-3-phenyl - 2,6 - piperazinedione; the product of Example (9) treated in acetic acid with formaldehyde and hydrogen in the presence of platinum oxide gives 3-ethyl-4-methyl-3-phenyl-2,6 - piperazinedione; (12) 3 - ethyl - 3 - phenyl-2,6-piperazinedione is methylated at the 1-position with methyl iodide in the presence of sodium methoxide; (13) 3-ethyl-3-phenyl-2,6-piperazinedione with phenoxyacetyl chloride gives 3 - ethyl - 4 - phenoxyacetyl - 3 - phenyl-2,6-piperazinedione. A list of other compounds corresponding to the first general formula above is given.