US2438091A - Aspartic acid esters and their preparation - Google Patents

Description

Patented Mar. 16, 1948 ASPARTIC ACID ESTERS AND THEIR PREPARATION Kathryn L. Lynch, Stamford, Comm, assignmto American .Cyanamid Company, New York,

N. Y., a corporation of Maine No Drawing.

Application September 6, 1943, Serial No. 501,417

Claims. -(CL 260-482) This invention relates to N-substituted aspartic acid esters and to their preparation. The invention includes the new compounds themselves, the novel method by which they are prepared and also compositions containing them.

I have found that primary alkyl and primary alkoxyalkyl amines may be caused to react with certain maleic acid esters to be hereinafter described to yield N-alkyl and N-alkoxyalkyl substituted aspartic acid esters having the general formula:

the

in which R and R1 are members of the group consisting of hydrogen and alkyl radicals of from 1 to 3 carbon atoms, R2 and Rs are alkyl radicals of from 1 to 18 carbon atoms and R4 is a member of the group consisting of alkyl and alkoxyalkyl radicals. The alkyl radicals, R2 and R3, may be interrupted, terminated or substituted with various types and kinds of substituent groups.

Many of the compounds of this class, particularly those which have in the R2, R3 and R4 positions a long chain hydrophobe group and a short chain group are cationically surface active in the form of their acid salts and possess wetting, foaming and detergent properties. The hydrophobe group may be a long chain alkyl or alkoxyalkyl group of about six or more carbon atoms and may be positioned at any of R2, R3 or R4 in the general formula above.

Although the compounds of the present invention may be used in the form of their acid salts as surface active agents, they are of greatest value as intermediates in the preparation of a class of superior wetting agents and detergents described and claimed in my copending application, Serial No. 501,851, filed September 10, 1943.

When used as intermediates in this process at least one of the groups R2, R3 or R4 should be a hydrophobe alkyl or alkoxyalkyl radical having four or more carbon atoms. Of course, one or two of the groups R2, R: or R4 may be a short chain alkyl. or alkoxyalkyl radical provided that the requisite number of carbon atoms is present in the molecule to give a portion thereof having hydro- 2 phobic properties sumciently strong to orient themolecule at an oil-water interface. In order that this condition may be met the total number of carbon atoms in R2, R3 and R4 should be at least twelve.

The compounds vary in physical character from oily liquids to hard wax-like materials. The compounds are in general colorless but some are pale yellow to light brown in color. Those compounds of low molecular weight are soluble in water and very readily soluble in aqueous solutions of acids. As the length of the substituent chains increases, however, the compounds become more dimcultly soluble in water but may. be dissolved in aqueous acids, mineral spirits, alcohols, and other organic solvents.

Although it would be expected in a reaction involving a maleic acid ester with a primary amine that the ester groups would be hydrolyzed with the formation of amides, I have found that by following the procedure to be described hereinafter the primary amine may be caused to react at the double bond of the maleic acid ester to form N- substituted aspartic acid esters directly in substantially quantitative yield. As a result of my studies of the reaction I have discovered that when a primary amine is mixed with a maleic acid ester of the type described hereinafter a number of difl'erent reactions may occur simultaneously at different rates depending upon the temperature of the reaction mass and the relative proportions of the reactants. At temperatures within the range of 10-100 C. the principal reaction involves the addition of the primary. amine at the double bond of the maleic acid ester with the formation of N-substituted aspartic acid esters. A second and concurrent reaction involves the conversion of unreacted maleic acid ester to the corresponding fumaric acid ester. The third, a much slower reaction, involves the reaction of the primary amine with the fumaric acid ester. A fourth reaction involves the reaction of the aspartic acid ester with itself to form undesirable by-products such as diketo piperazine derivatives. This latter reaction occurs principally at elevated temperatures and upon heating the reac tion mixture for long periods of time.

During the early stages of the reaction the addition of the primary mine to the maleic acid ester is rapid, an approximately 50% yield of diethyl I through replacement of the ester groups.

N-octadecyl aspartate being obtained in 80 minutes upon reacting octadecyl amine with diethyl maleate at 20 C. At higher temperatures the reaction proceeds even faster. The conversion of the maleate ester to the fumarate ester is also fairly rapid during the early stages of the reaction. Since as stated'before the reaction of the primary amine with the fumarate ester is quite slow, it will be seen that the evenual completion of the.reaction to form N-substituted aspartic acid esters depends to a considerable'extent upon 'the amount of fumarate ester formed. As high temperatures favor the conversion of the maleic acid ester to the fumaric acid ester more than they favor the reaction of the primary amine with maleic acid ester it is desirable that the reaction be conducted at low temperatures, preferably less than about 50 C., in the early stages of the reaction. This is desirable in order to secure the formation of N-substituted aspartic acid esters from the maleic acid ester in as high yields as possible, while the maleic acid ester remains as such in the reaction mixture. After holding the reaction mixture at relatively low temperatures until the maleic acid ester has either reacted with the primary amine or has been converted to the corresponding fumaric acid ester, the tempera.- ture may be raised thereby allowing the reaction of the' primary amine and the fumaric acid ester to proceed more rapidly with the formation of N-substituted aspartic acid esters.

Another important factor which enables me to obtain N-substituted aspartates of high purity and in good yield relates to the proportions of reactants used. I have found that the use of more than the theoretical quantity of primary alkyl or primary alkoxyalkyl amine necessary to react with the maleic acid esters at the double bond position results in the formation of amides Accordingly I employ an equal molecular proportion of the maleic acid ester or a slight excess thereof with each mole of primary amine.

From the foregoing it will be seen that my new method comprises the steps of reacting a primary alkyl amine or a primary alkoxyalkyl amine with at least a stoichiometric proportion of maleic acid ester at temperatures not in excess of about 100 C. Preferably I carry out the first phase of the reaction at temperatures not in excess of about 50 C. until substantially all of the maleic acid ester has reacted with the primary amine to yield the corresponding N-substituted aspartic acid ester. I then allow the mixture to react at temperatures not in excess of about 100 C. until substantially all of the primary amine has reacted with the fumarate ester formed from the maleic ester. This procedure avoids the formation of amides and all undesirable by-products which result from side reactions when the reaction is attempted at high temperature. As a result I obtain N-substituted aspartic acid esters of excellent purity with yields as high as theoretical.

The reaction may be carried out by simply mixing a suitable primary alkyl or primary alkoxy alkyl amine with a maleic acid ester and allowing the mixture to stand at room temperatures until reaction is complete. In most cases it is desirable, however, to carry out the reaction with the reactants dissolved in a suitable solvent such as an alcohol, mineral spirits, toluene, ethers, dioxane, etc. Since the reaction is,exothermic in character, it is generally advisable to add one of the reactants to the other slowly in small proportions to prevent an excessive rise in the tem- 4 perature of the reaction mixture. The reactionmixture is then allowed to stand until the reaction is substantially complete. Towards the end of the reaction period the reactants may be heated up to about C. for a short time to hasten completion of the reaction. As stated before, however, use of high temperatures for extended periods of time is to be avoided if a product of high purity is to be obtained.

The maleic acid esters which may be employed in the reaction described herein are those having the general formula:

in which R and R1 are members of the group consisting of hydrogen and alkyl radicals of from 1 to 3 carbon atoms, R: and R: are alkyl radicals of from 1 to 18 carbon atoms. The alkyl radicals, R: and R3, may be interrupted, terminated or substituted with various types and kinds of substituent groups. Specific examples of the maleic acid esters that may be employed in my invention are diethyl maleate, diamyl maleate, dibutyl maleate, dicapryl maleate, di (methyl amyl) maleate, d1 (ethyl hexyl) maleate, di-n-hexyl maleate, didecyl maleate, dioctyl ethyl maleate, di-hexylcitraconate, dicapryl pyrocinchonate, di-ethyl itaconate, h'exyl octyl maleate, diglycol maleate, dicyclohexyl maleate, di (2 cyclohexyl ethyl) maleate, and the like.

Primary alkyl and primary alkoxyalkyl amines which may be employed in my process include those such as butyl amine, amyl amine, octyl amine, dodecyl amine, octadecyl amine, methoxypropyl amine, ethoxypropyl amine, amoxypropyl amine, dodecoxypropyl amine and others of similar character.

The invention will now be illustrated in greater detail by means of the following specific examples. It should be understood that although these examples may describe in detail some of the more specific features of the present invention they are given primarily by way of illustration and the invention in its broader aspects in not to be limited thereto.

EXAMPLE 1 g. (1 mol) dimethyl maleate was added slowly with stirring to a solution of 265 g. (1 mol) of octadecyl amine in 500 cc. of tertiary butanol at 50 C. After standing at 28 C. for 10 hours the formation of dimethyl N-octadecyl aspartate was 91.2% complete. After standing 43 hours the reaction was 94.5% complete and after 65 hours was 96.2% complete.

EXAMPLEZ 900 g. (5 mols+5% excess) of diethyl maleate was added slowly with stirring to a solution of 1325 g. (5 mols) of technical octadecyl amine in 1500 cc. of tertiary butanol. After standing 17 hours at room temperature the condensation was 91.2% complete and after standing 50 hours it was 95.5% complete.

Reaction between diethyl maleate and octadecyl amine to form diethyl N-octadecyl aspartate was caused to take place at different temperatures and the course of the reaction followed by taking samples of the reaction mixture from time to time. The results of this series of experiments 75 are given in the following table.

Tm: Aspartate formatiorh-percent completion Time Temperature 1 Hour 1% Hours 3 Hours Per cent Per cent From the above it will be seen that the reaction proceeds rapidly in the earlier stages but requires a considerable period of time for completion even at the higher temperatures. At low temperatures, the reaction will go to approximately 98% of completion if given suilicient time for reaction.

EXAMPLE 3 50 g. of diglycol maleate was added to 66 g. of technical octadecyl amine dissolved in 250 cc. of tertiary butanol. The reaction mixture was kept at 895 C. for 2% hours at the end of which time the formation of diglycol noctadecyl aspartate was 82.5% complete. The reaction mixture was allowed to stand at 895 C. for 29.5 hours and then at 25 C. for 48 hours at which time the reaction was 96% complete. The product was an almost colorless pasty mass.

EXAMPLE 4 51.2 parts of diamyl maleate was stirred with 20.6 parts of ethoxypropyl amine at 26 C. The temperature of the reaction mass rose to 47 C. as the mixture was being stirred. Within 10 to 15 minutes diamyl N-ethoxypropyl asparate had been formed to such an extent that the product was soluble in dilute hydrochloric acid to give a foaming and wetting solution. The product was a colorless oil-like liquid.

EXAMPLE 20 parts. by weight of diisopropyl maleate was added slowly with stirring to 28 parts by weight or technical octadecyl amine dissolved in 39 parts by weight of tertiary butanol. The mixture was allowed to stand at room temperature for 113 hours at the end of which time the formation of diisopropyi n-octadecyl asp'artate was 95% complete.

EXAMPLE c 14.6 parts by weight of butyl amine was added to 68 parts by weight of dioctyl maleate at 24 C. In less than 2 minutes the temperature of the reaction mass had risen to 64 C. A clear colorless oil was obtained which was slightly soluble in dilute hydrochloric acid to give aqueous solutions having wetting and foaming properties.

ELE 7 57.6 g. (0.4 mol) of dimethyl maleate was dissolved in 150 cc. of ethanol. 51.6 g. (0.4 mol) of octyl amine was then added to the solution while keeping the temperature of the reaction mass below 49 C. by cooling. After allowing the mixture to stand at 28 C. for one hour dimethyl fumarate separated from the liquid as a solid. The mixture was filtered and 13 g. of dimethyl fumarate was obtained. The filtrate containing dimethyl N-octyl aspartate was very soluble in dilute hydrochloric acid solution to give a slightly roaming and wetting solution.

EXAMPLE 9 To a solution of 23 g. (0.2 mol) of n-heptylamine in 30 ml. of t-butanol was added 46 g. (0.2 mol) of dibutyl maleate and the mixture allowed to stand at room temperature. The reaction was more than 99% complete in seventy hours. The t-butanol was then removed by heating under reduced pressure until the temperature of the residual liquid rose to -100 C. There was obtained 69 g., a 99% yield of dlbutyl N-nheptylaspartate.

\EXAMPLE 10 To a solution of 15 g. (0.2 mol) of n-butylamine in 30 ml. of t-butanol was added 68 g. (0.2 mol) of di-n-octyl maleate and the mixture allowed to stand at room temperature. In seventytwo hours reaction had taken place to the extent of and was more than 99% complete in ninety hours. The t-butanol was then removed by heating the solution under reduced pressure until the temperature of the residue rose to 90-100 C. The yield was 82 g., a 99% yield of theoretical of di-n-octyl N-n-butylaspartate.

EXABTPLE 11 To 34 g. (0.08 mol) of di-undecyl maleate was added 25 ml. of t-butanol solution containing 0.08 mol of methylamine and the mixture was allowed to stand at room temperature. The reaction was more than 99% complete in sixtyseven hours. The t-butanol was evaporated by heating under reduced pressure until the temperature of the *residual liquid reached 110 C. After cooling, the yellow oily liquid was filtered to remove a small amount of white solid which separated. The yield was 30 g., a 82% yield of di-undecyl N-methylaspartate.

To 43 g. (0.2 mol) of n-tetradecylamine dissolved in 50 ml. of t-butanol was added 35 g. (0.2 mol) of diethyl maleate and the solution was allowed to stand at room temperature. The reaction was more than 99% complete in sixty-eight hours. The t-butanol was evaporated under reduced pressure with heating until the temperature of the liquid residue rose to 90-100" C.

There was obtained 77 g., a 98% yield of diethyl N-n-tetradecylaspartate.

To a solution of 18 g. (0.2 mol) of -y-methoxypropylamine in 300 ml. of t-butanol was added 57 g. (0.2 mol) of di-n-hexyl maleate and the mixture allowed to stand at room temperature. In seventy-two hours, the reaction was more than 99% complete. The t-butanol was evaporated by heating under reduced pressure until the temperature of the residual liquid rose to 90-100 C. There was obtained 75 g., a 100% yield, of di-n- 7 hexyl N-methoxypropylaspartate, a slightly yellow oily liquid To a solution of 50 g. (0.27 mol) of n-dodecylamine in 40 ml. of t-butanol was added 89 g. (0.27 mol) of dimethyl maleate. The mixture was allowed to stand at room temperature. The addition was found to be more than 99% comlete in sixty-nine hours. The t-butanol was evaporated by heating under reduced pressure until the temperature of the liquid residue rose to 90-l00 C. There was obtained 87 g., a 98% yield, of dimethyl N-n-dodecylaspartate.

EXAIMPLE 15.

To 81 g. (0.47 mol) of diethylmaleate was added at once 148 m1. of a t-butanol solution containing 0.47 mol of methylamine with cooling in a water bath. There was a noticeable heat of reaction. The addition was 91% complete in one hour. and in nineteen hours at room temperature, the addition was more than 99% complete. The t-butanol was evaporated under reduced pressure with heating until the residue reached a temperature of 100-110 C. There was obtained 93 g., a 98% yield, of diethyl N-methylaspartate.

The surface active characteristics of the products of the last flve examples are given in the table below in terms of their wetting power as measured by the standard Draves test. The wetting power is expressed as the number of seconds required for a 5.5 g. gray cotton skein attached to a 1.5 g. hook to sink in a designated concentration of the surface active agent in water. The

compounds were tested in the form of their 1131- drochloride salt.

As will be seen from the above results the compound diethyl N-methyl aspartate has no wetting power whatever. The reason being that it has no hydrophobe groups as do the other compounds shown above. As stated before the compounds must have a total of at least 12 carbon atoms in the groups R2, R: and R4, if they are to have surface active properties.

The last four compounds in the table, that is the products of Examples 11 to 14, inclusive, also showed a remarkable lowering of the surface tension of water when dissolved therein. As measured by the Du Nuoy tensiometer at 30 0., these four compounds at a concentration of 0.5% lowered the surface tension of distilled water from 71 dynes per centimeter to an average of about 34 dynes whereas diethyl N-methyl aspartate had no appreciable eifect on the surface tension at the same concentration. This latter compound also failed to give foaming solutions at all congeneral formula:

12 0 H-d-l-O-m in which R and R1 are members of the group consisting of hydrogen, and alkyl radicals having 1 to 3 carbon atoms, R: and R: are alkyl radicals of from 1 to 18 carbon atoms and R4 is a member of the group consisting of alkyl and alkoxyalkyl radicals. the total number of carbon atoms in Ra. R: and R4 being at least twelve.

2. Diallwl N-alkyl aspartates having surface active properties said compounds having at least 12 carbon atoms in the alkyl groups thereof.

3. Dialkyl N-alkoxyalkyl aspartates having surface active properties said compound having at least 12 carbon atoms in the alkyl groups thereof.

4. A method of preparing dialkyl esters of N- suhstituted aspartic acid which comprises mixing substantially equal molecular quantities of a primary amine of the group consisting of primary alkyl amines containing at least 4 carbon atoms and primary allromalkyl amines containing at least 4 carbon atoms with a dialkyl ester of maleic acid, allowing the mixture to react at temperatures not in excess of about 50 C. until substantially all of the maleic acid present has reacted with the primary amine, and then heating the mixture at temperatures of 50-100 C. to complete the reaction between the remaining primary amine and the fumarate ester formed from the maleic ester.

5. A method of preparing dialkyl esters of N- substituted aspartic acid which comprises mixing substantially equal molecular quantities of a primary alkyl amine containing 4 to 18 carbon atoms and a dialkyl ester of maleic acid, allowing the mixture to react at temperatures not in excess of about 50 C. until substantially all of the maleic acid ester present has reacted with the primary amine and then heating the mixture at temperatures of 50-100 C. to complete the reaction between the remaining primary amine and the fumarate ester formed from the maleic ester.

KATHRYN L. LYNCH.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,017,537 Hoifmann Oct. 15, 1935 2,200,220 Reppe May 7, 1940 2,317,378 Harris Apr. 27, 1943 2,324,712 Lynch July 20, 1943 OTHER REFERENCES Korner and Menozzi: Gazetta Chimica Italiana," vol. 19, pages 422, 426. 431 (1889)