DE1114821B - Process for the preparation of aliphatic ª-aminocarboxylic acids - Google Patents

Description

GERMAN

PATENT OFFICE

G 29578 IVb / 12 q

REGISTRATION DATE: 30 A P R I L 1960

NOTICE THE REGISTRATION AND ISSUE OF THE EDITORIAL. OCTOBER 12, 1961

The production of aminoacetic acid from monochloroacetic acid and aqueous ammonium hydroxide according to the following equation

Cl-CH ₂ -COOH + 2NH ₃

- ». NH ₂ -CH ₂ -COOH + NH ₄ Cl

is known. Here the need is always emphasized to be one compared to the theoretical set to use a very large excess of ammonium hydroxide in order to achieve good yields.

Orten and Hill (Journ. Of Amer. Chem. Soc, 53 [1931], p. 2797) propose 1 mol of monochloroacetic acid to act on an aqueous solution containing 60 moles of gaseous ammonia. The aminoacetic acid yield in this case is 64% pure product.

W. Tobic and G. Ayres (Journ. Amer. Chem. Soc, 64 [1942], p. 725) report a yield of 75 to 77% of the theoretical value a slightly improved procedure using the same excess of ammonium hydroxide.

The undesired formation of derivatives which are multiply substituted on the nitrogen, ie of acids of the formulas NH (CH ₂ -COOH) ₂ and N (CH ₂ -COOH) ₃ , as well as the formation of glycolic acid prevent higher yields.

Using ammonium carbonate solutions instead of pure ammoniacal ones In solutions, the number of moles of ammonia can be reduced from 60 to 10, thus improving the final yield. According to Cheronis and Spitzmuller (Journ. Of Org. Chem., 6 [1941], p. 373) one obtains hence a theoretical yield of 84% per cent when using these working conditions.

Auger (Bull. Soc. Chim. Series [3], vol. 21, p. 6) sets ethyl chloroacetate or, better, sodium chloroacetate to hexamethylenetetramine and provides produce an addition product of the following formula:

(CHg) ₆ N ₄ - CH ₂ Cl - COOK

(s. also Grignard, Traite de Chemie Organique, Vol. 13, p 583, Ed Masson ^r). Auger then decomposes this addition product by boiling with alcoholic hydrogen chloride to formaldehyde and ethyl aminoacetate. The ethyl ester is hydrolyzed and then converted into the copper salt. Achieved in this way Auger yield 7I ⁰ Zo pure product.

G. and Anneliese Hillmann ((Z. Physiol. Chem., 283 [1948], p. 71) use the intermediate stage of the addition product, which they produce by the boiling chlorine process
of aliphatic α-aminocarboxylic acids

Applicant:

Henri Martin Guinot,

Versailles, Seine-et-Oise,

and Societe de Produits Chimiques

Industrieis SPC L,
La Plaine Saint-Denis, Seine (France)

Representative: Dr. W.Beil, A. Hoeppener

and Dr. H. J. Wolff, lawyers,

Frankfurt / M.-Höchst, Antoniterstr. 36

Claimed priority:
France of June 19 (No. 798 045)
and December 31, 1959 (No. 814 681)

Henri Martin Guinot, Versailles, Seine-et-Oise

(France),
has been named as the inventor

Decompose hydrogen alcohol. Under these conditions they achieved a 92% yield.

It has now been found that you can produce aminoacetic acid with almost theoretical yield if only small amounts of hexamethylenetetramine are used without an excess of ammonia. The deposition of the addition product according to the Auger process is unnecessary.

It has also been found that working under similar conditions gives good yields α-amino acids, which are higher homologues of aminoacetic acid, can produce, in particular that a-alanine and dl-valine by choosing from the corresponding ct-haloalkanoic acids, especially the α-chlorinated and a-brominated acids goes out.

According to a particular embodiment of the invention are employed in an aqueous medium chloro ammonium acetate with hexamethylenetetramine in a ratio of less than 1 mole of the latter substance to 2 moles of the former by, in the presence of so much ammonia that the _pH value of the medium

109 708/405

is held at 4 to 8. This gives an aqueous solution of aminoacetic acid, which is then crystallized State can deposit.

The amount of hexamethylenetetramine used is therefore less than that used in the process of Auger was deemed necessary. You can still separate the aminoacetic acid directly, without having to use the intermediate stage of the addition product, which is of great interest to industry is. ίο

The chloroacetic acid ammonium can instead of as such also in the form of monochloroacetic acid and Ammonia can be used in appropriate amounts. You can also use hexamethylenetetramine in Use the appropriate amounts of ammonia and formaldehyde.

The reaction is expediently carried out at a temperature of at least 40 and at most 90.degree by.

A dilute aqueous solution can be used, but it is advantageous to use a medium which contains as little water as possible to work. Since the aminoacetic acid is highly soluble in water, you would have to add large amounts of alcohol later to precipitate them.

However, a dilute aqueous solution can be effectively used and the final one can be used Concentrate the aminoacetic acid solution, preferably under vacuum.

Finally, the aqueous medium can also contain ethyl alcohol. In this case, the aminoacetic acid begins fail in the course of implementation. One can then have a lower concentration of the Use reactants as if you were working with a purely aqueous medium.

The chloroacetic acid is converted to aminoacetic acid according to the following equation:

2 (CHJ ₀ N ₄ + 4 Cl - CH ₀ - COOH
+ 4NH ₃ + "12H ₂ O

40

4NH ₂ -CH ₂ -COOH + 4NH ₄ Cl

12 HCHO + 8NH,

+ 12HCHO 2 (CH ₂ ) ₆ N ₄ + 12H ₂ O

A relatively small amount of hexamethylenetetramine is therefore sufficient to set the reaction in motion and to carry it through to the end. Since the reaction takes place at a very weak alkaline or even slightly acidic _pH value, only very small amounts of glycolic acid and of acids which are substituted more than once on the nitrogen produced.

Instead of chloroacetic acid ammonium or monochloroacetic acid and ammonia one can also assume bromoacetic acid ammonium or monobromoacetic acid and ammonia. The yield is still very good, albeit less than the chlorinated compounds. The latter is in The practice is therefore given preference, especially since they are currently less expensive.

The process described is also applicable to the production of higher homologues of aminoacetic acid, however, provided that the starting substance only has a halogen atom in the position owns and none in another position, e.g. B. in the carboxyl group.

Thus / J-chloropropionic acid gives only insignificant amounts Quantities of yS-alanine, while the a-chloropropionic acid «-Alanine gives in 74% yield.

The aliphatic brominated acids can be used in the same strength as the chlorinated products will.

For the preparation of higher homologues can be assumed, bring them by adding ammonia to an approximately neutral _pH value, then heat up and so much ammonia release in particular of an aqueous dispersion of α-chloro or a-bromoalkanoic acid and hexamethylenetetramine to the to keep _pH value 4 to 8

In general, the amination according to the invention starts slowly at ordinary temperature one, by heating one can accelerate it strongly. The most favorable temperature is generally around 50 to 80 ° C.

example 1

An aqueous solution of 105 g is placed in a flask equipped with a stirrer, thermometer and a tube for feeding the reactants (0.75 mol) hexamethylenetetramine and 105 g water.

The following substances are introduced separately and simultaneously with stirring and cooling into this solution: 5 mol of chloroacetic acid, i.e. about 492.5 g of commercially available acid in 96% purity, dissolved in 164 g of water and 520 cm ^{3 of} aqueous ammonium hydroxide of 28 ° Be.

The monochloroacetic acid solution is allowed to flow in continuously so that admixing is complete in about 2 hours. Regulating the admixture of the ammonia solution so that the _pH value is kept the mixture at about the 6th For this purpose one can use an indicator in the absence of a p _H -Wertmessers, such as bromocresol purple, which is violet at a _pH value of 5 yellow and at a _pH value of 6.8.

As soon as the reactants have flowed into the solution of hexamethylenetetramine, the temperature rises on quickly and the solution becomes acidic. The temperature is maintained by cooling from the outside about 75 to 80 ° C and add more ammonia solution to maintain the required pjj value.

When all the reactants have been added, the temperature is allowed to drop below 65 ° C. and gradually adding 51% methanol, with constant stirring, during which the aminoacetic acid precipitates. One cools the mixture is filtered off and the crystals obtained are dried.

In the first crystallization, 346 g of aminoacetic ^{acid with a purity of 98.5 10 10} % and containing less than 0.12% ammonium chloride are obtained. The yield is 92% of the theoretical yield. If the aqueous liquid is concentrated somewhat in vacuo before the methanol is admixed and the volume of the methanol is increased somewhat, a somewhat greater yield is achieved; however, the ammonium chloride content of the crude product has also increased.

Example 2

A concentrated hexamethylenetetramine solution is prepared by adding 360 g of an aqueous, 30% formaldehyde solution is saturated with gaseous ammonia.

This solution, the temperature of which is kept at 60 to 70 ° C. and which is vigorously stirred, is poured slowly a solution of 400 kg (4230 mol) of monochloroacetic acid in 1201 of water. Simultaneously directs

to the _pH value to keep the liquid at about 7 to gaseous ammonia. Cool and regulate the rate of addition of the chloroacetic acid in order to keep the temperature between 60 and 70 ° C. The reaction time is 6 hours. Then 100 l of water are added to the liquid and the mixture is kept at about 60 to 70 ° C. for a further hour.

The liquid is poured into a precipitation vessel equipped with a stirring and cooling device and then add 1401 water and 13001 methanol. The liquid is cooled while stirring and held at 15 to 20 ° C for 1 hour. It is filtered, washed twice with 200 l of methanol and dries. 290 kg (3875 mol) of aminoacetic acid of 99.5% purity are obtained, that is about one yield of 91.5%.

By recrystallizing from water with the addition of charcoal, a pure product is obtained from a 98% crystallization yield.

Example 3

The procedure of Example 1 is repeated, but using an amount 2 times less Hexamethylenetetramine, about 0.375 moles per 5 moles of monochloroacetic acid. The yield is 89 »/ ο.

Example 4

The procedure of Example 1 is repeated, but using 150 g of hexamethylenetetramine, that is to say about 1.07 moles per 5 moles of monochloroacetic acid. In this case the yield is approximately 94 to 95 "7ο of the theoretical value. You can use the hexamethylenetetramine unchanged from the Recover the filtrate from which the aminoacetic acid has separated out.

You can do this in the following way:

After the aminoacetic acid has been filtered off, the methanol is removed by distillation and added to the aqueous, boiling solution, enough sodium hydroxide to add to the ammonium chloride present in the solution decompose. The ammonia released can be recovered. Then the aqueous solution is im Concentrated vacuum until the sodium chloride begins to crystallize. You give 3 times the amount of Volume of the entire mixture of methanol increases, whereby after cooling the precipitation of almost the entire Sodium chloride takes place. A solution which is slightly brown in color is obtained by filtration and which contains almost the entire amount of hexamethylenetetramine initially used.

This solution, which has been brought back to its initial volume, becomes after adding only 14 g Hexamethylenetetramine is reused to reduce the losses incurred during the process balance.

As a result, the actual consumption of hexamethylenetetramine amounts to in several operations to less than 4 moles per 100 moles of monochloroacetic acid, the initial yield being about 94 to 95% of the theoretical value is kept constant.

In general, used in place of ¹ kn stallisierten hexamethylenetetramine aqueous solutions, which result from mixing of formaldehyde and ammonium hydroxide, wherein the respective amounts of the two reactants do not have to be accurately determined. You can also bring the formaldehyde solution as the lowest layer in the reaction vessel and then add the two solutions of ammonium chloroacetic acid and ammonium hydroxide in the required ratio. It is inexpedient to use the corresponding ίο alkali salts instead of chloroacetic acid ammonium.

After filtration of the aminoacetic acid, the hexamethylenetetramine can be removed from the ammonium chloride also separate by ion exchange resins.

Example 5

52.2 g of α-chloropropionic acid (0.48 mol), 14 g of hexamethylenetetramine (0.10 mol) and 30 cm ^{3 of} water are placed in a flask equipped with a stirrer. The mixture is neutralized with a 28% ammonium hydroxide solution until the color changes from bromocresol. This requires 31 cm ^3. The mixture is heated to 70 ° C. and about as much ammonia gas is introduced that the dye remains in the transition zone. The reaction is complete as soon as it is determined volumetrically with the aid of silver nitrate that all of the chlorine in the original acid has converted into the ionic state. The implementation takes 3½ hours. After the end of the heating and after slight cooling, 20 cm ^{3 of} water and 500 cm ^{3 of} methanol are added. The mixture can crystallize after cooling. After filtering, washing and drying the precipitate, 31.6 g of α-alanine are obtained, which corresponds to a yield of 74%.

Example 6

The following substances are introduced into one with a stirrer provided piston:

45 g of a-bromoisovaleric acid (0.248 mol),
9 g hexamethylenetetramine (0.064 mol),
12 cm ^{3 of} water.

The solution is neutralized by introducing ammonia gas into the stirred solution until the bromocresol turns purple. The mixture is heated to 55 ° C. and gradually a 28% ammonium hydroxide solution to keep the solution at a _pH value of 6 to 6.5. The implementation takes 26 hours. Towards the end of the reaction, the temperature is gradually increased to 70 ° C. 20 cm ^{3 of} water are added and, after the solution has cooled, 250 cm ^{3 of} methanol are added. After crystallization, filtration, washing and drying, 19.7 g of dl-valine are obtained, that is about a yield of 68.2% of the theoretical yield (0.169 mol).

The process can also be carried out continuously without reducing the yield and the speed implementation is noticeably faster. It has been found that the speed of the Amination depends much more on the reaction temperature than is evident from the above examples.

If, for example, are added to an aqueous solution of chlorine ammonium acetate and hexamethylenetetramine an aqueous ammonium hydroxide solution at such a rate that the _pH value

of the mixture remains approximately neutral, it is found that the chloroacetic acid is completely aminated the conversion times change with the temperature as follows:

At a temperature of 16 ° C it takes at least 400 hours to complete the reaction;

100 hours are required at 20 ^{° C .;}

at 30 ^c C 21 hours are required;

at 35 ° C, IOV2 hours are required; at 42 ° C, 4 ^3/4 hours are required;

at 50 ° C 2 hours are required;

at 70 ° C, 1 hour is required;

at 75 ° C, 20 minutes are required.

15th

At temperatures above 75 ° C, the reaction proceeds as if the formaldehyde complex compound were suddenly activated much more strongly and as if an implementation could be achieved in a few minutes, the yield being 92%.

One embodiment is in a zone that is continuous with reactants is charged to maintain a temperature of at least 75 ° C and the mean residence time to adjust in this zone to the required value, so that the degree of conversion of aminated Acid clearly reaches its maximum, the reaction mixture being withdrawn from this zone to the extent that it is becomes how it is introduced into them.

In order to maintain the temperature in the reaction zone, it is advisable to move it to a larger one Main stream and split into a smaller circulating stream. This circulating stream receives a cooling device with a larger heat exchanger and a drive device that leads the circulating flow back into the mixture.

The degree of conversion into aminated acid is determined by the continuous supply of the α-halocarboxylic acid certainly. Therefore, the amount of ammonium hydroxide required for amination becomes not completely introduced into this reaction zone. You put the rest into the discharge that comes from this Zone comes to the conversion of the a-halocarboxylic acid, which has not yet been implemented.

The drawing shows a schematic representation for a continuous process.

The vessels 1, 2 and 3 each containing a solution of chloro-acetic acid ammonium, a solution obtained by neutralizing an aqueous 3O ° / o formaldehyde solution with ammonia gas to a p _H -Wert7 and finally an aqueous ammoniacal solution with 14 moles of ammonia per liter.

The ammonium chloroacetic acid and the formaldehyde solution are passed through the coils 4 and 5, which are immersed in a heated to 80 ° C water bath 6, the two solutions also on heated to approximately the same temperature. They are then combined in a mixer 7 and carried out into a reaction vessel 8 equipped with a stirrer 9, where they are thoroughly mixed. The preheating either solution is not essential; you can do the two solutions too Pour cold into the reaction vessel, where the correct temperature prevails.

The reaction soon starts in the vessel 8 and the liquid immediately becomes acidic. Keeping the _pH value in the mixture, by adding at the required speed, the ammonia solution contained in the vessel 3 (pipe 10).

As the reaction develops heat (about 25 calories per mole), part of the liquid is withdrawn from the vessel and conducted by means of a pump 11 through a cooler 12 which is equipped with plates and has an exchanger for a small liquid content. The rate of circulation of the liquid through the cooler is regulated so that a temperature of 85 ° C. is maintained in the reaction vessel 8, which temperature is monitored by means of the thermometer t.

The capacity of the entire vessel 8 and the recycle stream including the cooler 12 becomes so calculated that the three liquids introduced together for 4 to 5 minutes at this temperature stay at 85 ° C.

At a lower reaction temperature, the residence time in the reaction zone must be appropriate to be extended; at a temperature of 75 ° C e.g. B. the capacity of the entire solutions would be like this be increased that a residence time of the liquid mixture of 20 minutes in the vessel 8 is necessary were.

The liquid then leaves the vessel 8 by means of an overflow and enters a mixer 13 equipped with a stirrer Vessel 12, or the required ammonium hydroxide is added via tube 14 to to achieve complete implementation of the monochloroacetic acid.

Finally, the solution flows from the vessel 12 into a vessel 16 equipped with a stirrer 17 from where it is mixed with 2 to 3 times its volume of methanol. This methanol comes off a vessel 15. The aminoacetic acid which crystallizes out is obtained in a filter system 18 while the stock liquid, which comes directly from the vessel 16, and the filtrate in a vessel 19 for the purpose Distillation can be collected.

The continuous process and apparatus described above can be used in the manufacture other acids aminated in the α-position can be used.

You can also use ammonia gas instead of aqueous ammonia solution to carry out the reaction to effect. This procedure makes it possible to work with more concentrated solutions, if required but a stronger cooling.

Claims (12)

Patent claims: 1. A process for the preparation of aliphatic α-aminocarboxylic acids from aliphatic α-Μοηο-halocarboxylic acids and hexamethylenetetramine, characterized in that 2MoI of an aliphatic halocarboxylic acid is reacted in an aqueous medium with less than 1 mol of hexamethylenetetramine in the presence of so much ammonia that the aqueous mixture is converted a _pH value 4-8 has. 2. The method according to claim 1, characterized in that the reaction is carried out at a Performs a temperature of at least 40 and at most 90 ° C. 3. The method according to claim 1 and 2, characterized in that there is an aqueous medium is used that contains ethyl alcohol. 4. The method according to claim 1 to 3, characterized in that the aliphatic α-monohalocarboxylic acid Chloroacetic acid or ammonium chloroacetic acid is used. 5. The method according to claim 1 to 4, characterized in that instead of hexamethylenetetramine Ammonia and formaldehyde used as raw material. 6. The method according to claim 1 to 5, characterized in that there is an aqueous dispersion an α-chloro or α-bromoalkanoic acid having at least three carbon atoms as a starting material used. 7. The method according to claim 1 to 6, characterized in that after implementation has been completed the reaction product by adding a diluent with methanol, ethanol or Acetone or a mixture of these substances separates. 8. The method according to claim 1 to 7, characterized in that to recover the Hexamethylenetetramine, the organic solvent is distilled off, the ammonium chloride with Sodium hydroxide decomposes, the solution is concentrated and the sodium chloride is separated out Add a solvent in which the sodium chloride is insoluble. 9. The method according to claim 1 to 7, characterized in that to recover the Hexamethylenetetramine after separation of the aminoacetic acid the solution with an ion exchange resin treated. 10. Continuous process according to one of the preceding claims, characterized in that that one in a zone which is continuously supplied with the reactants, a Maintains temperature of at least 75 ° C and the mean residence time in this zone sets the value corresponding to a maximum of the conversion of the α-halocarboxylic acid. 11. The method according to claim 10, characterized in that in the discharge which the Leaves reaction zone, introduces so much additional ammonia that the conversion of the a-halocarboxylic acid, which has not yet reacted, takes place. 12. The method according to claim 10 or 11, characterized in that one from the reaction zone continuously withdraws part of the liquid, this part a heat exchange submits with a cooling liquid and returns it to the zone and thereby the temperature holds at least 75 ° C. 1 sheet of drawings © 109 708/405 10.61