DE2515622A1 - PROCESS FOR THE PREPARATION OF BETA-HYDROXYAMINO ACIDS - Google Patents

Description

Process for the preparation of β-hydroxy amino acids

The invention relates to a process for the preparation of ß-hydroxyamino acids, whereby one of alkali-sensitive Precursors of ό-hydroxyoxo compounds and the Implementation using the Strecker reaction.

It is known that the β-hydroxy amino acids are very important in pharmacy and also for the preparation of compounds can serve, from which food for humans or animals can be produced.

For example, serine is an important amino acid that is used in the pharmaceutical industry as an intermediate product Production of o-phospho-dl-serine and cycloserine can be used «,

An economical serine synthesis would also make it possible to use this amino acid as an intermediate in the enzymatic process Generation of 1-tryptophan to use the one for the human and animal diet is fundamental amino acid. The same goes for Treonin.

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The process according to the invention for the preparation of β-hydroxyamino acids from the alkali-sensitive precursors of ^ L-hydroxyoxo compounds with the help of the Strecker reaction is characterized in that the starting material is a Selects a compound that matches one of the following general formulas:

ROCO
R ₁ -C-

OCOR C-R,

COR

ROCO

R ₁ -C- L

Rp R-Z

OH

OCOR

-R ₅ COR /

- 3 -

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wherein R .., R ₂ , R *, Ri, R ₁ - and Rg, which can be the same or different, each represent an alkyl, aralkyl, aryl or cycloalkyl radical or a hydrogen atom, while R represents an alkyl , Aryl, aralkyl or cycloalkyl radical and X represents a halogen atom or the group -OCOR-.

The precursors of du-hydroxyoxo compounds corresponding to the above general formulas are relatively low Costs available, so that the process according to the invention can be carried out more economically than the known Synthesis of the ß-hydroxyamino acids mentioned above used intermediates.

As mentioned above, the β-hydroxyamino acids are formed according to the invention with the help of the Strecker reaction, preferably according to the modified Zelinsky-Stadnikoff implementation, and can either immediately and without prior hydrolysis of the alkali-sensitive precursors of cL -hydroxy- ' oxo compounds carried out because the hydrolysis of these derivatives in situ under the alkaline conditions of the Strecker reaction even enters.

According to another embodiment, however, the hydrolysis can also be carried out in a separate first stage, after which the further conversion then takes place with the aid of the Strecker reaction without isolating the hydrolysis products. It can do that It is up to a person skilled in the art to choose the best conditions to achieve a good yield of end products.

The cL-hydroxyoxo compounds corresponding to the above general formulas can, if they are not commercially available, be produced in a relatively simple manner. Corresponding procedures have already been worked out.

The method according to the invention is illustrated below using the example the production of dl-serine explained. As a starting material served either glycolaldehyde or its precursor, such as

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Monochlorethylene oxide, vinyl acetate epoxide, monoacetoxyacetaldehyde, 2,2-diacetoxyethanol, monochlorethylene carbonate, monoacetoxyethylene carbonate, Vinylene carbonate, 2,5-dichlorodioxane and 2,5-diacetoxydioxane. The working conditions are running out the individual examples.

example 1

The example explains the production of dl-serine with the help the Zelinsky-Stadnikoff reaction from glycolaldehyde or its precursors.

20 mmol of the starting material to be taken from the following overlooked below (in the case of 2,5-dichloro- and 2,5-diacetoxydioxane only 10 mmol), dissolved in 15 ml of methyl alcohol (if the starting material was water-soluble, in 15 ml of water) added "a solution of 1.30 g (20 mmol) of potassium cyanide" and 1.18 g (22 mmol) of ammonium chloride in 10 ml of concentrated ammonia (about 30 successfully), while stirring, was being cooled so far that the (temperature 20 to 25 Did not exceed ^{0 C,}

The mixture was then stirred for a further 18 to 20 hours at 30 to 35 ⁰ C, after which it was acidified with 11 ml concentrated hydrochloric acid and was dried at 6O ⁰ C under vacuum. The residue was taken up in 11 ml of concentrated hydrochloric acid and 11 ml of water and refluxed for 3 to 5 hours; After drying in vacuo, the residue was taken up in 10 ml of anhydrous ethyl alcohol and the insoluble salts were filtered off. The alcoholic solution was brought to a pH value of 6 with triethylamine or ammonia and dl-serine separated on cooling, which was separated off and, if necessary, recrystallized from ethyl alcohol-water.

The yield was slightly different depending on the starting material, as can be seen from the following list:

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Output compound

Glycol aldehyde vinyl acetate epoxide 2,5-diacetoxydioxane 2,5-dichlorodioxane Monoacetoxyethylene carbonate Monochlorethylene carbonate vinylene carbonate

25th 15622 1A-4 6 316 Yield, ber. on dl-rSerin 70: ° / o 70: ok 70: 45: ok 55: P. 35: Io 45 '

Example 2

For the preparation of dl-serine from honochlorethylene oxide via glycolaldehyde, 1.57 g (20 mmol) of monochlorethylene oxide were added dropwise to 15 ml of water with stirring and cooling, and the mixture was stirred for a further 2 hours at room temperature. Then the hydrolysis to glycolaldehyde was complete, which was indicated by the disappearance of the monochlorethylene oxide. Iitrieren by the developed hydrochloric acid in a sample of the reaction mixture with excess of sodium hydroxide has been found that the hydrolysis had proceeded with a yield of 65 io.

The hydrolysis mixture was no longer added with stirring and cooling to a temperature of 20 to 25 than ⁰ O A solution of 1.30 g (20 mmol) of potassium cyanide ia 15 ml of 30 $ aqueous ammonia, .worauf for 18 to 20 hours at 30 until 35 ⁰ C was further stirred. After treatment with acid and anhydrous alcohol as in Example 1 resulted from the Monochloräthylenoxid a Serinausbeute of approximately 45 i> (in this "value is the 65? 6ige yield of the hydrolysis to be considered to glycolaldehyde, as is well known, the yield with the use of glycol aldehyde by Zelinsky -Stadnikoff is 70 % , as can be seen from the list above).

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Example 3

For the production of dl-serine from monochlorethylene carbonate Via glycolaldehyde, 2.45 g (20 mmol) of monochlorethylene carbonate were obtained gradually with stirring the stoichiometric amount (based on the hydrochloric acid evolving) one Base (for example, sodium or potassium carbonate or bicarbonate Or hydroxide) in 15 ml of water was added, with the undissolved portion being added if the base was sparingly soluble.

The addition took place over 30 to 60 minutes and re-wurde-.so'guliert that the temperature of the mixture preferably not exceeding 25 ⁰ C and with strong bases such as sodium or potassium hydroxide, 5 ⁰ C and the pH in the alkaline The range remained and preferably did not exceed a value of 8 to 9. After adding the base, stirring was continued for at least 3 hours at room temperature until a uniform phase had formed. The cessation of carbon dioxide evolution indicated that hydrolysis to glycolaldehyde was complete; the pH was then about 4 and was brought down to 7 with additional base.

In order to determine the yield, a titration using hydroxylamine chlorohydrate was carried out on a sample of the reaction mixture according to the method described by E. Hauser in "Methods of Organ. Chemistry" (Houben-Weyl), Stuttgart, 1953 »p. 458. Then a solution of the HydroIysegemisch ■ 1.30 g (20 mmol) of potassium cyanide and 1.18 g (22 mmol) of ammonium chloride was added in 10 ml of 30 $ aqueous ammonia under stirring while cooling so that the temperature of 20 to 25 ⁰ C did not exceed. After the mixture had been stirred for a further 18 to 20 hours at 30 to 35 ^° C., it was treated according to Example 1 with acid and anhydrous alcohol. The serine yield, based on the monochlorethylene carbonate, was 70 %.

claims 8643

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Claims (1)

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PKOTKCTPATENT MÜNOHXV 1A-46 316 Paternity claim Process for the production of ß-hydroxyamino acids, especially dl-serine _? from alkali-sensitive precursors of 'k, -hydroxyoxo compounds with the aid of the optionally modified Strecker reaction, characterized in that a compound according to one of the following general formulas is chosen as the starting material: iU C) α " COR ROCO OCOR COR 509842/1000 1A-46 316 where IL., Rp, R ,, R ₄ , R ₅ «to Rg, which can be the same or different, each represent an alkyl, aralkyl, aryl or cycloalkyl radical or a hydrogen atom, while R represents an alkyl, Aryl, aralkyl or cycloalkyl radical and X represents a halogen atom or the group -OGOR-. 509842/1000