Process of producing n-formylaspartic anhydride

A process for producing N-formylaspartic anhydride, which comprises, grinding solid aspartic acid into fine particles; and then reacting said finely ground aspartic acid with formic acid and acetic anhydride.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a process of producing N-formylaspartic 
anhydride by reacting aspartic acid with formic acid and acetic anhydride. 
2. Description of the Background 
A process which is known for the production of N-formylaspartic anhydride 
involves the reaction of aspartic acid with a large excess of formic acid 
and acetic anhydride, after which an aromatic hydrocarbon and/or 
halogenated hydrocarbon is added to the reaction mixture. Product 
N-formylaspartic anhydride is then isolated from the medium. (Published 
Unexamined Japanese Patent Application 91210/76). Another process involves 
the reaction of aspartic acid with formic acid and acetic anhydride in 
essentially stoichiometric amounts. However, a substantially longer 
reaction time of 48 to 60 hours is required (Published Unexamined Japanese 
Patent Application 46279/84). 
However, the above described processes are not satisfactory from the 
industrial viewpoint, because the mother liquor which remains can only be 
treated with difficulty because of the use of formic acid in large excess 
amounts, or because an aromatic hydrocarbon and/or halogenated solvent is 
employed, or because a very prolonged reaction time is required, even 
though formic acid and acetic anhydride are used as reactants in 
stoichiometric amounts. A need therefore continues to exist for a method 
of preparing N-formylaspartic anhydride in improved yields and shorter 
reaction times. 
SUMMARY OF THE INVENTION 
Accordingly, one object of the present invention is to provide a method of 
preparing N-formylaspartic anhydride in improved yields at short reaction 
times. 
Briefly, this object and other objects of the present invention as 
hereinafter will become more readily apparent can be attained in a method 
of preparing N-formylaspartic anhydride by grinding solid aspartic solid 
into fine particles, and then reacting the finely ground aspartic acid 
with formic acid and acetic anhydride. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
As a result of extensive investigations which have been conducted to 
overcome the above described problems and in order to provide an 
industrially satisfactory process for producing N-formylaspartic 
anhydride, it has now been discovered that N-formylaspartic anhydride can 
be produced in a short period of time in high yields if solid aspartic 
acid, prior to its reaction with formic acid and acetic anhydride, is 
ground into fine particles. This procedure obviates any necessity of using 
an aromatic hydrocarbon and/or halogenated hydrocarbon solvent even when 
acetic anhydride is only used in small amounts. 
An important feature of the present invention then is that aspartic acid, 
which may be either a racemic mixture or in one of its optically active 
forms, is ground into fine particles. By initially grinding the aspartic 
acid, the advantages which are provided are that N-formylaspartic 
anhydride can be produced in shortened periods of time in high yields. 
Moreover, formic acid and acetic anhydride can be used in the reaction in 
small amounts. 
The aspartic acid which is employed, can be obtained by a conventional 
process such as by neutralizing a solution obtained by the enzyme 
catalyzed reaction of fumaric acid. Upon crystallizing aspartic acid from 
such a solution, the acid has a particle size larger than 75 microns in 
amounts of 80% or more as shown in Table 1. Subsequently, the particulate 
aspartic acid is ground into particles of fine size in a device such as a 
mortar. The ground aspartic acid is then sieved into a number of particle 
size ranges. 
TABLE 1 
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Particle Size Distribution of Aspartic Acid 
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74 microns.gtoreq. 
74-100 100-150 150-300 
300 .ltoreq. 
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19.1% 13.2 16.8 20.4 20.5 
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Samples of aspartic acid of the different particle size ranges shown above 
were reacted under the conditions shown in Example 1 in order to examine 
the relationship between the particle size of the crystals and the yield 
of N-formylaspartic anhydride. As shown in Table 2, the results reveal 
that as the particle size of aspartic acid crystals is reduced, 
N-formylaspartic anhydride is obtained in increasingly shorter periods of 
time in increasingly higher yields. 
The smaller the particle size of the crystals, the better the results 
obtained. Accordingly, the particle size of the aspartic acid should 
generally be smaller than 75 microns, preferably smaller than 50 microns, 
most preferably 10 microns. While the particle size, as stated above, 
should be less than 75 microns, the presence of aspartic acid particles 
having a size greater than 75 microns in small amounts (less than about 
10%) is not objectionable or detrimental. 
Aspartic acid in fine particle sizes can easily be obtained by any one of 
several different methods. For example, aspartic acid can be ground into 
fine particles by mechanical means such as by grinding crystals of 
aspartic acid with a griner, or by emulsifying a mixture of aspartric acid 
crystals, formic acid and acetic anhydride in a homogenizer, or the like. 
Another alternative is to pulverize aspartic acid with a wet grinder during 
the course of the reaction. 
Formic acid and acetic anhydride, which are used as reactants in the 
present process, may be incorporated in the reaction mixture in amounts of 
1 to 1.5-fold mols of formic acid and 2 to 2.5-fold mols of acetic 
anhydride, based on aspartic acid. 
When the reaction of the present invention is carried out in the presence 
of oxides, hydroxides or salts of various metals as catalysts, it is 
sufficient that the formic acid and acetic anhydride reactants are 
normally employed in stoichiometric amounts, i.e., 1 to 1.1-fold molar 
amounts of formic acid and 2 to 2.1-fold molar amounts of acetic 
anhydride. Suitable metal compounds which can be used as catalysts include 
oxides or hydroxides of various metals such as the alkali metals including 
lithium, sodium, potassium, and the like; the alkaline earth metals 
including magnesium, calcium, and the like; the copper group elements 
including copper, and the like; the zinc group elements including zinc, 
and the like; the boron group elements including aluminum, and the like; 
the iron group elements including iron, and the like; or salts of the 
metals derived from various acids such as, for example, the carbonates, 
carboxylates such as acetate, and the like, hydrochlorides (chlorides), 
hydrobromides (bromides), nitrates, phosphates, sulfates, and the like. 
(Published Unexamined Japanese Patent Application 175484/84). 
There is no particular limitation to the amount of catalyst employed in the 
reaction. However, the amount of catalyst used is such that it does not 
adversely affect subsequent steps. The amount of catalyst may vary 
somewhat depending upon the kind of compound employed as a catalyst. When 
magnesium acetate is used as the catalyst as shown in Example 2, the 
amount employed is 0.005-fold mols based on L-aspartic acid. It has been 
observed that magnesium acetate is effective even in extremely small 
amounts. The optimum amount of any given compound employed as a catalyst 
in industrial scale operation can be easily determined by one skilled in 
the art by preliminary experiments prior to actually conducting full scale 
operations. The catalyst usually is added to the reaction system at the 
initiation of the dehydration reaction. Alternatively, the catalyst may be 
added to the system during the course of the reaction. 
A preferred embodiment of the process is to conduct the reaction while 
subjecting the materials within the reactor to ultrasonic waves. 
N-formylaspartic anhydride can be obtained in higher yield by this 
technique. The frequency of the ultrasonic waves should be greater than 10 
KHz. In fact, the greater the better. However, a sufficient effect can be 
achieved even when using a conventional ultrasonic wave cleaner which 
emits waves at a frequency of 20 to 50 KHz. 
With regard to the reaction temperature, the same should range between 
100.degree. C. and 10.degree. C., preferably between 80.degree. C. and 
20.degree. C.; this is from the viewpoint of minimizing racemization of 
the product as much as possible. 
As discussed above, use of the process of the present invention provides 
for the production of N-formylaspartic anhydride in shorter periods of 
time in high yields even when formic acid and acetic anhydride are used in 
small amounts. 
Having generally described this invention, a further understanding can be 
obtained by reference to certain specific examples which are provided 
herein for purposes of illustration only and are not intended to be 
limiting unless otherwise specified.

EXAMPLE 1 
To a solution prepared by adding 42.9 g (0.42 mols) of acetic anhydride to 
13.8 g (0.30 mols) of formic acid was added 26.6 g (0.2 mols) of 
L-aspartic acid having a particle size of 150 to 300 microns. While 
stirring, the reaction was carried out while maintaining the temperature 
at 45.degree. C. Sampling of the reaction was conducted with the passage 
of time in order to measure the rate at which N-formylaspartic anhydride 
is formed. 
The analysis of N-formylaspartic anhydride is performed as follows: 
N-formylaspartic anhydride is reacted with methanol to form the .alpha.- 
and .beta.-methyl ester compounds. The ester compounds are quantitatively 
determined by high speed liquid chromatography, from which data, the yield 
of N-formylaspartic anhydride can be calculated. 
The highest yields and reaction times obtained were 87.5% and 24 hours for 
the above-described reaction. 
Similar runs were carried out employing L-aspartic acid of varying particle 
sizes. The results are shown in Table 2 below. 
TABLE 2 
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Particle Size, Yield and Reaction 
Time of Aspartic Acid 
Particle Size Reaction 
of L-Asp Time Yield 
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150-250.mu. 24 hrs. 87.5% 
35-75.mu. 12 90.6 
2-10.mu. 8 91.7 
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EXAMPLE 2 
To a solution prepared by adding 64.3 g (0.63 mols) of acetic anhydride to 
15.2 g (0.33 mols) of formic acid was added 39.9 g (0.3 mols) of 
L-aspartic acid having a particle size of 35 to 75 microns. Then 0.322 g 
(0.0015 mols) of magnesium acetate tetrahydrate was added to the mixture. 
While stirring, the reaction was carried out for 8 hours while maintaining 
the temperature of the reaction medium at 45.degree. C. The yield of 
N-formylaspartic anhydride was 92.1%. 
EXAMPLE 3 
The procedure of Example 2 was repeated with the reaction being conducted 
for 8 hours. The reaction medium was irradiated with ultrasonic waves from 
an ultrasonic wave generator (manufactured by Sharp Co., Ltd., Model 
UTB-152, frequency of 28 KHz, output of 150 W). The yield of 
N-formylaspartic anhydride was 95.7%. 
Having now fully described the invention, it will be apparent to one of 
ordinary skill in the art that many changes and modifications can be made 
thereto without departing from the spirit or scope of the invention as set 
forth herein.