DE2615974A1 - PROCESS FOR THE PREPARATION OF N-SUBSTITUTED ALPHA-AMINOCARBON ACIDS - Google Patents

Description

CLBA-GEIGY AG, CH-4002 Basel Dr. F Zumsteln senior-Dr. E. Assmann

Dr. R. Koenlgeberger - Dipl. - Phys. Π. Holzbauer DIpI.-InQ. Λ Klingseisen - Dr. ϊ ^:. rjiistein jun.

Patent Attorneys 8 Munich 2, Bräuhausstrafle 4.

Case 3-9854 / CGM 125 / -F
Germany

Process for the preparation of N-substituted α-aminocarboxylic acids

The present invention relates to a process for the preparation of 2-hydroxy- or 3-aminoalkylated ones on the nitrogen atom cc-aminocarboxylic acids.

2-Hydroxyalkylated a-aminocarboxylic acids are valuable Intermediate products for the production of heterocyclic compounds, e.g. morpholine derivatives, which in turn are valuable intermediates for medical preparations or for the production of metal complexes with two Free OH groups can serve as diols to chelate polymers e.g. polyester-based can be processed.

There are several well-known processes for the preparation of hydroxyalkylated α-amino acids. N-2-hydroxy methyl glycine can be made, for example, by

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one 1-hydroxy-2-aminoethane with either formaldehyde and Sodium cyanide converts and then hydrolyzed or with chloroacetic acid or its salts or esters. One Another possibility for production is the conversion of α-aminocarboxylic acids or their salts and esters with epoxides, for example in the American patent 3,214,413. These processes have the major disadvantage that the starting products and the desired product can enter into further reactions which, in addition to other products, also bishydroxyalkylated Provide amino acids, thereby increasing the yield you want Product can be lowered considerably.

Another disadvantage is that after these procedures on cc-carbon atom-branched N-hydroxyalkylated cc-aminocarboxylic acids are difficult to access. A production of representatives of these amino acids by hydrolysis of the corresponding oc-aminonitriles with only insufficient ones Yields are described in Kiprianow, Z. obsc. Chim. 2 (1932), pages 586 ff. It should also be taken into account here that the corresponding nitriles are difficult to synthesize in good yields.

The hydrolysis of hydantoins to cc-aminocarboxylic acids in the presence of metal hydroxides is generally known, cf. e.g. French patent 1,525,649 and E. Ware, Chem. Rev. _46, 3 (1958), 438 ff. However, it is also known that N-substituted hydantoins are only hydrolyzed to α-aminocarboxylic acids with difficulty and in low yields since the substitution, especially in the 1-position, obviously stabilizes hydantoins in such a way that that other reactions are increasingly possible.

The object of the present invention is to provide a method

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to show, with the substituted in particular on the cc-carbon atom hydroxy- or aminoalkylated cc-aminocarboxylic acids in high Yields can be made pure.

The present invention relates to a process for the preparation of cc-aminocarboxylic acids substituted on the nitrogen atom of formula I.

X— CH — CH —NH — CR ³ R ⁴ —COOH (I)

¹ I '2
R ¹ R ^

X hydroxyl or aminomethyl, R hydrogen, alkyl with 1-4 carbon atoms, or Phenyl,

2 1

Usually hydrogen and unless R is hydrogen is, also alkyl with 1-4 carbon atoms,

1 2

R and R together tetramethylene,

R and R are identical or different and are hydrogen, alkyl having 1 to 4 carbon atoms, cycloalkyl, optionally substituted phenyl or benzyl or together tetra- or pentamethylene

mean, characterized in that a hydantoin of the formula II

R ³ R
\ /

X-CH-CH-N N-CH-CH-X (II)

R ¹ R ² ^ QR ² R ¹

wherein R to R and X have the same meaning; as in formula I. have decomposed in aqueous solution and in the presence of a metal hydroxide and the resulting salt in the «-Amino acid of the formula I is transferred and the acid is isolated.

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1 2

As alkyl, R and R preferably contain 1 to 2 carbon atoms, R and R as cycloalkyl, preferably 5 or 6 ring members and substituted phenyl or benzyl with alkyl groups

2
1 to 4 carbon atoms, R is especially hydrogen

O /

and R and R are preferably the same. X is preferably hydroxyl

1 2
and when X is aminomethyl, R and R are preferred

Hydrogen! Only one of the radicals R and R is preferred
a hydrogen atom or both alkyl, cycloalkyl, phenyl, benzyl, tetra- or pentamethylene.

Examples for R ¹ to R ⁴ are:

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl, cyclohexyl, Methylcyclohexyl, cycloheptyl, ethylcyclohexyl, phenyl, Methylphenyl, n-butylphenyl, tert-butylphenyl,

Isopropylphenyl, octylphenyl, tert.-octylphenyl, .dodecylphenyl, Benzyl, methylbenzyl and octylbenzyl. Particularly

1 3 4
preferred radicals R, R, R are, in addition to hydrogen, methyl,

3 4
Isopropyl, ethyl, phenyl and R and R together penta-

1 2
methylene. R and R are particularly preferably hydrogen.

The hydroxyalkylated hydantoins of the formula II are known compounds which are obtained, for example, by reacting epoxides with hydantoins. Representatives of these compounds and processes for their preparation are described, for example, in the German OffenlegungsSchriften 1 812 003, 1 912 026 and 1 966 743. Japanese Patent 276,504 describes the preparation of N-bis-oc-aminopropylhydantoins by adding acrylonitrile to hydantoins.
Among the metal hydroxides are in particular the water-soluble hydro-

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xide preferred, especially the alkaline earth and alkali metal hydroxides, especially barium hydroxide. Further suitable hydroxides are zinc and cadmium hydroxide, aluminum hydroxide or chromium hydroxide, strontium hydroxide, calcium hydroxide, Sodium hydroxide, potassium hydroxide.

In addition to the aminocarboxylic acid salts, ethanolamine and CO ₉ or a metal carbonate are formed in the reaction. It has been found that high yields are achieved in reasonable times, especially when an excess of metal hydroxide, in particular barium hydroxide, is used. The excess can be up to 100 % (based on the stoichiometric amount of barium hydroxide), preferably up to 50%.

The reaction is generally conducted at temperatures from about 80 ⁰ C and below the decomposition temperature of the hydantoin of the formula II, preferably at 100 to 200 ⁰ C and at Kormaloder overpressure, preferably 1 performed atm to 15, wherein said known for such reactions facilities such as shaking autoclave or stirred flask or. boiler can be used.

The conversion of the salt obtained into the amino acid takes place according to known methods by neutralizing the reaction mixture. It has proven to be advantageous

to neutralize with carbon dioxide after the reaction has ended, especially if sparingly soluble metal carbonates are formed, which can be conveniently filtered off. The aqueous solution can then be evaporated to dryness to remove the water and the alkanolamine formed, and the crude product can then be recrystallized for purification, for example from alkanol / water mixtures. However, it is also possible to use acids to

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neutralize, e.g. those that form sparingly soluble salts with the metal ions of the hydroxide. When using barium hydroxide e.g. sulfuric acid is suitable.

Alternatively, the desired amino acid from the aqueous reaction solution after neutralization and after filtering off insoluble components also precipitates by adding a precipitant such as acetone or alcohols such as ethanol and from the other products be separated.

With the inventive method, the nitrogen atoms surprisingly high yields are achieved in spite of substitution and it may be assumed that _s hydroxyalkylated hydantoins are activated to monohydroxy or aminoalkylated "amino carboxylic acids are obtained upon hydrolysis by a single reaction. A particular advantage of the process according to the invention is that it is easy to prepare hydroxy- or aminoalkylated α-aminocarboxylic acids which are mono- or disubstituted _{on the α-carbon β atom.}

The following examples explain the invention in more detail. Percentages (X) indicated herein are percentages by weight. The acid numbers were determined by titration with NaOH.

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Example 1: Preparation of N-ß-hydroxyethyl-a-amino-

cyclohexanecarboxylic acid

24.3 g of 3-Dih3 ^ droxyäthyl-5,5-pentamethylene hydantoin are mixed with 46 g of Ba (OH) ₉ χ 8 H ₉ O and 300 ml of water in a pouring

^ - in

telautoklaven held for 3 hours at 160 ⁰ C. CO2 is introduced into the cooled reaction mixture until pH 7 is reached, the precipitated BaCOn is suctioned off and washed several times with water. The filtrate becomes dry
concentrated and recrystallized from methanol / water (5/1).

Yield: 15.8 g = 94% of theory. Th. (Papers)

Mp: 282-285 ° C (subl.)
Acid number: calculated 299.5
found 305

The IR and NMR spectra agree with the structure of the desired Product.

Example 2: Preparation of N-β-hydroxyethyl-1-methyΙα -aminoproρionic acid

78 gl, 3-dihydroxyethyl-5,5-dimethylhydantoin are with
185 g of Ba (OH) ₂ × 8 H ₂ O and 300 ml of water were kept in a shaking autoclave at 160 ^° C. for 3 hours. _{CO 9 is introduced} into the cooled reaction mixture until pH 7 is reached, and the BaCO- precipitated is filtered off with suction and washed several times with water. The filtrate becomes dry
concentrated and recrystallized from ethanol / water (8/1).

Yield: 42.7 g = 80.7% of theory. Th. (Needles)
Mp: 285-288 ° C (subl.)

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Acid number: calculated 380.9
found 392

The IR and Ni-IR spectra agree with the structure of the product specified above.

Example 3: Preparation of N-β-hydroxyäthyI-1,1-diphenyΙα-aminoacetic acid

10.2 g of 3-dihydroxyethyl-5,5-diphenylhydantoin are ^{kept at 160 °} C. for _{5 hours in a shaking autoclave with 15 g of Ba (OH) 2} × 8 H ₂ O and 75 ml of water. The reaction mixture is concentrated to dryness and about 150 ml of dilute sulfuric acid are added. The precipitated barium sulfate is filtered off with suction, washed several times with water and the filtrate is neutralized with sodium bicarbonate, the product precipitating out.

Yield: 7.1 g = 87.3% of theory

Mp: 262-264 ° C (after recrystallization, from dilute Hydrochloric acid)

Acid number: calculated 207.
found · 197

Example-4: Preparation of N-ß-hydroxyethyl-1-isopropyl-2-methyl-1-aminobutyric acid

22.8 gl, 3-dihydroxyethyl-5,5-isopropylidene-hydantoin be. ^{that was kept at 160 °} C. for 7 hours with 48 g of Ba (OH) ₂ 8 H ₂ O and 250 ml of water. _{CO 2} is passed into the cooled reaction mixture until pH 7 is reached, and the BaCOo which has precipitated is filtered off with suction and washed several times with water. The pale yellow filtrate is decolorized with activated charcoal and

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finally concentrated to dryness. The colorless crude product is recrystallized from ethanol / water (9/1).

Yield: 12.5 g = 79% of theory mp: 295-29 ° C. (subl.)

IR and NMR spectra confirm the assumed structure.

Example 5: Preparation of N-7-aminopropyl-oc.-amino-

cyclohexanecarboxylic acid.

14.1 g of 1,3-diaminopropyl-5,5-pentamethylene hydantoin are kept in a shaking autoclave at 160 ° C. for 6 hours _{with 25.4 g of Ba (OH) 2} × 8 H _{3 O and 75 ml of water.} After cooling, the reaction mixture is diluted with approx. 200 ml of water and adjusted to pH 8-9 _{by passing in CO 2.}

The precipitated barium carbonate is filtered off with suction, washed with water and the filtrate is concentrated to dryness. Of the The residue is washed with acetone, filtered off with suction and dried.

Yield: 8.7 g = 87% of theory. Th.

Mp: 220-23O ⁰ C (decomposition)

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Claims (14)

Patent claims 1. Process for the preparation of substituted on the nitrogen atom cc-aminocarboxylic acids of the formula I. X-CH-CH-NH-CR ³ R ^ -COOH (I) I ₁ I ₂
R ¹ R ^Z wherein . X hydroxyl or aminomethyl, R is hydrogen, alkyl with 1-4 carbon atoms, or Phenyl, 2 1 R is hydrogen and unless R is hydrogen is, also alkyl with 1-4 carbon atoms, 12th R and R together tetramethylene, R and R are identical or different and are hydrogen, alkyl with 1-4 C atoms, cycloalkyl, if appropriate substituted phenyl or benzyl or together denote tetra- or pentamethylene, characterized in that a hydantoin of the formula II R ³ R ⁴ ₀ X-CH-CH-N N-CH-CH-X (II) I ₁ I ₂ \ _c / I ₂ I ₁ R ¹ R ^Z £ R ^Z R- 14th
in which R to R and X have the same meaning as in formula I, decomposed in aqueous solution and in the presence of a metal hydroxide and the resulting salt is converted into the α-amino acid of formula I and the acid is isolated. 609844/1189 2. The method according to claim 1, characterized in that 12 ι that R and R as alkyl have 1 to 2 carbon atoms, R 4th
and R as cycloalkyl have 5 or 6 ring members and the phenyl or benzyl radical is substituted by alkyl radicals having up to 4 carbon atoms. 3. The method according to claims 1 to 2, characterized in that 2
indicates that R is hydrogen. 4. The method according to claims 1 to 3, characterized in that R and R ^{1- are the} same. 5. The method according to claims 1 to 4, characterized in that that R is hydrogen, methyl, ethyl or phenyl. 6. The method according to claims 1 to 5, characterized in that that R and R hydrogen and in particular methyl, ethyl, isopropyl or phenyl and together mean pentamethylene. 7. The method according to claims 1 to 6, characterized in that that X is hydroxyl .. 8. The method according to claim 1, characterized in that 1 2 that X is aminomethyl and R and R are hydrogen, 9. The method according to claims 1 to 8, characterized in that that the metal hydroxide is an alkaline earth hydroxide. 609844/1189 10. The method according to claim 9, characterized in that it is decomposed in the presence of barium hydroxide. 11. The method according to claim 10, characterized in that that an excess of barium hydroxide is used. 12. Process according to claims 1 to 11, characterized in that the reaction temperature is ^{at least 80 ° C.} 13. The method according to claims 9 to 11, characterized in that, indicates that for the isolation of the α-aminocarboxylic acid of formula I neutralized the reaction mixture with carbon dioxide and the precipitated barium carbonate is filtered off. 14. The method according to claims 1 to 13, characterized in that that the reaction is carried out at normal or elevated pressure. 609844/1189