DE1081896B - Process for the preparation of ª-amino-ª-hydroxycarboxylic acids - Google Patents

Description

GERMAN

For the production of the physiologically important α-amino / 3-hydroxycarboxylic acids, like serine, phenylserine, threonine, there are numerous synthetic routes, but mostly with unsatisfactory yields. In addition, the syntheses used so far are not general are applicable.

Of the known syntheses for α-amino - ^ - hydroxycarboxylic acids is the synthesis of serine according to King (Am. Soc, 69, p. 2738 [1947], USA, patent 2,530,065 [1950]) by aldol addition of formaldehyde to acetaminomalone ester and subsequent saponification of the Addition product is probably the most elegant. However, this synthesis is only limited to the production of serine, since other aldehydes than formaldehyde with acetaminomalone ester under the conditions given by King do not react: Kingsche fails even when replacing the formaldehyde with acetaldehyde Synthesis. In addition, the preparative modification of this is first in this King's serine synthesis The resulting acetylaminohydroxymethyhnalonic acid ester is very cumbersome: it is first saponified in an alkaline manner and then, without isolating the first saponification product, after acidification in acidic solution further to the serine, must then dissolve the serine hydrochloride hot with alcohol from the salt-rich evaporation residue, whereby at the same time esterification to the serine ester occurs, so that, in order to get to the free serine, it is now acidic again must be saponified.

It has now been found that using a generally applicable and preparatively simple process for the preparation
of α-amino-β-hydroxycarboxylic acids

Applicant:

Paint factories Bayer Aktiengesellschaft, Leverkusen-Bayerwerk

Dr. rer. nat. Heinrich Hellmann,
Dipl.-Chem. Helmut Piediota, Tübingen,

Dr. Hans Henecka and Dr. Helmut Timmler,

Wuppertal-Elberfeld,
have been named as inventors

feasible synthesis of a-amino-zS-hydroxycarboxylic acids obtained when acylaminomalonic acid monoester reacts in an alkaline medium with aldehydes and the

resulting a-acylamino-jS-hydroxycarboxylic acid

ester in a conventional manner in a-amino-ß-hydroxy-

carboxylic acids transferred.

The implementation according to the invention is illustrated by the following equation:

COOH

CH-COOR + R'CHO

NH acyl

(Alkali)

R '-CH (OH) -CH-COOR

NH acyl

R '-CH (OH) -CH-COOH

NH ₂

In this scheme, R denotes methyl or ethyl groups, R 'denotes hydrogen, any straight-chain or branched, saturated or unsaturated alkyl radicals, cycloalkyl radicals, aryl or aralkyl radicals, which in addition can be substituted as desired, or heterocyclic aryl radicals. Acyl means aliphatic or aromatic Acyl residues.

The aldol additions can be carried out in the presence or absence of solvents or diluents will. If one starts out from the free acylaminomalone ester acids, one works expediently in methyl or ethyl alcoholic solution in the presence of a molar amount of an organic tertiary Base, such as trimethylamine or triethylamine. But you can also use an aqueous or aqueous-alcoholic solution, possibly with the addition of further water-soluble solutions or Thinners, work, what especially then It is advantageous if the prior isolation of the free acylaminomalone ester is dispensed with and immediately works with the aqueous-alcoholic solution of the alkali salt, which is obtained when one alcoholic suspension of an acylaminomalonic acid dialkyl ester with that for saponification of a carbalkoxy group calculated amount of an alkali. The weakly alkaline reaction of the is essential Reaction solution that can be obtained by adding a small amount of an alkali metal hydroxide or an alkali metal carbonate can reach.

The addition according to the invention of aldehydes to salts of acylaminomalonester acids proceeds in such a way that that the decarboxylation of the anion of the acylaminomalonester acid is directly linked to the aldol addition is because the carbenate anion formed by decarboxylation is also used as the methylene component of the

009 5TO / 320

Aldol addition functions so that the transition state of the reaction can be formulated as follows:

coo®

\ R '-— CH CH-COOR

I!

O NH-acyl

On the other hand, if, according to King, the acetaminomalonic acid diethyl ester is used, for example, it is activated of this ester to the methylene component of the addition now primarily a proton withdrawal to the corresponding one Carbenate anion

COOR

H — C — COOR

NH acyl

- Η®

COOR

C — COOR

NH acyl

became necessary. Since such an activation occurs more difficult than the implementation according to the invention, is This makes it understandable that King's synthesis is limited to the particularly reactive formaldehyde is, but the reaction according to the invention is a generally applicable synthesis.

Particularly suitable acylaminomalonic acid monoesters are the formyl or acetylaminomalonic acid monomethyl or monoethyl ester, without the success of the reaction on the compounds mentioned as Reaction component is limited; for example, corresponding benzoylaminomalonic acid monoesters can also be used use.

A particular characteristic of the reaction according to the invention is its generality with regard to the aldehyde component. Suitable aldehydes are, for example, applicable aliphatischeAldehyde such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde or isobutyraldehyde, unsaturated aldehydes such as crotonaldehyde, higher fatty aldehydes, such Önanthal oderHexadienal, alieyclische aldehydes such as hexahydrobenzaldehyde or 2,5-Endomethylen- / l ³ -tetrahydrobenzaldehyd, aromatic aldehydes, such as benzaldehyde / naphthaldehyde, heterocyclic aldehydes, such as furfural or pyridine aldehydes, which can also be substituted as desired.

The reaction according to the invention proceeds at a satisfactory rate even at ordinary temperature. However, it is entirely possible, for example when using aldehydes which can be aldolized, even with lower aldehydes To work temperature, as it is also possible to increase the reaction rate according to the invention Reaction at higher temperature, d. H. at 30 to about 100 ° C.

The α-amino - ^ - hydroxycarboxylic acids R - CH (OH) - CH (NH ₂ ) - COOH formed according to the invention when using aldehydes R - CHO can occur in two diastereomeric forms. By appropriate choice of the respective solvate system, the predominant development of the desired shape can be influenced. The most favorable solvate system for a particular implementation according to the invention must be determined in each case by means of special experiments. Since the more detailed reaction conditions can be varied within wide limits, it is possible to determine conditions under which an α-amino-γS-hydroxycarboxylic acid which can be prepared according to the invention is formed primarily in the desired diastereomeric form.

The α-amino-β-hydroxycarboxylic acids which can be prepared by the process according to the invention are as such immediately pharmaceutically usable; they also provide valuable intermediate products for synthesis of remedies.

example 1
5

17.5 g (0.1 mole) are suspended in 20 g (0.4 mol) of a 40 ° / ₀ aqueous formaldehyde solution and treated portionwise with 10 g (0.1 mol) of triethylamine Acetaminomalonsäure-monomethylester. After brief shaking, the suspended ester dissolves with warming and slight evolution of gas. It is then left to stand at room temperature for 24 hours.

The light yellow solution is then evaporated in vacuo on a water bath to a clear syrup, the one dissolves in 50 ecm of concentrated aqueous hydrochloric acid and reflux for 1 hour. The solution turns brownish. It is then saved in Vacuum evaporated on the water bath to a brownish syrup, which is heavily interspersed with crystals.

ao After dissolving in a little water and adding concentrated ammonia to _pH 8 to 9, it is evaporated in vacuo on a water bath to a light brown crystal mass. This is redissolved in a little water and boiled for 20 minutes with the addition of animal charcoal. It is then filtered off and the dark brown filtrate is carefully injected with ethanol while still warm until the excretion of a brownish-yellow, crystalline substance can be seen. It is cooled to -20 ° C for 30 minutes, filtered off with suction, the crystalline filter residue is washed once with very little cold water, twice with a lot of absolute ethanol and finally twice with absolute ether.

The yield of pale yellowish colored, crystalline DL-serine is 7.2 g, corresponding to 72% of the Theory. The product is pure according to paper chromatography. With silver nitrate there are only traces of ionogenic chlorine to prove.

Example 2

17.5 g (0.1 mol) of acetaminomalonic acid monomethyl ester are suspended in 20 g (about 0.5 mol) of acetaldehyde and 10.0 g (0.1 mol) of triethylamine are added in portions. The reaction mixture warms up at the same time, and the suspended half-ester goes into solution.

After standing for 60 hours at room temperature, the solution has turned dark brown. Triethylamine and excess acetaldehyde are evaporated off in vacuo on a water bath, twice the volume of concentrated aqueous hydrochloric acid is added to the remaining dark brown syrup and the mixture is refluxed for 1 hour. Is evaporated to a dark brown oil then in vacuo on a water bath, which is dissolved in a little water and treated with concentrated aqueous ammonia until the p _H. 8

The oil, obtained by re-evaporation in vacuo on a water bath, is dissolved in a little Water. After adding animal charcoal, the solution is boiled for 20 minutes, filtered and slowly with a large excess of absolute ethanol added. From the clear, red-brown solution separate at 16 hours Crystals stand out under cooling. One sucks off and the filter residue is washed twice with absolute Ethanol, then once with absolute ether.

The yield of crystalline, almost colorless Rohthreonin is 6.3 g, corresponding to 53 ° / ₀ of theory, based on Acetaminomalonsäure-monomethylester. Except for very small traces of glycine, the product is pure according to paper chromatography. Ionic chlorine can only be detected in traces with silver nitrate.

Microbiological testing determined that ethanol was added. Immediately noticeable gas evolution is that the product obtained in this way to 95%, and the solution changes color to dark green to from DL-allothreonine and 5 ° / ₀ of DL-threonine dark yellow.

consists. Over the course of 16 hours, the contents of the

Example 3 ** reaction vessel to a yellow crystal cake which

floating in absolute ether, sucked off and two-

17.5 g (0.1 mol) acetaminomalonic acid-momomethyl- is washed times with absolute ether. The yield ester is mixed with 11.6 g (0.2 mol) of propionaldehyde and 10.0 g (0.1 mol) of triethylamine of N-acetyl-p-nitrophenylserine ethyl ester. The semi-drying in vacuo over calcium chloride 4.2 g, deester dissolves with weak evolution of gas. According to io speaking 70.2 per _cent of theory. The product can be left to stand for 24 hours at room temperature, is recrystallized well from water-ethanol and shows a vacuum on the water bath to a yellow syrup and then a melting point of 147.5 to 148 ° C. It is steamed with 50 ecm of concentrated aqueous no melting point depression, mixed with that according to GW hydrochloric acid and refluxed for 1 hour. Moersch et al, J. Amer. Former Soc, 74, p. 565 (1952), It is evaporated in vacuo on a water bath to give an erythro-N-acetyl-p-nitrophenylserine ethyl dark brown syrup made with concentrated aqueous ester with a temperature of 158 ° C therefore displaced in the main rigem ammonia to p _H 9 and again in from the erythro compound.
Evaporated to dryness in vacuo on a water bath
will. After dissolving the crystalline, from brown smear C ₁₃ H ₁₆ N ₂ O ₆ (296.3).

permeated residue in 60 ecm of water is calculated as C 52.70%, H 5.44%, N 9.46 ⁰ I;

Boiled with animal charcoal for 20 minutes, nitrided and found that C 52 ^ 0%! H 5.90%! N 9.71%!

The filtrate is mixed with 85 ecm of absolute alcohol while it is still hot.

After standing under cooling overnight, example 6 separates

the 2-hydroxy-norvaline formed in this way is crystalline.

It is suctioned off, washed twice with a little absolute 25,217 g (1 mol) of acetaminomalonic acid dimethyl ester or alcohol and then once with absolute ether. suspended in 500 ecm of ethanol (absolute). Under The yield is 5.8 g (43.6% of theory). Melting point stirring becomes a solution of at room temperature 231 ° C decomposes. 56 g potassium hydroxide solution (1 mol) in 300 ecm ethanol (absolute) inside

CH NO (13315) was added dropwise halfway over 2 hours. The mixture is stirred for 24 hours

^Β _π ^η , ³ , ' r ^ ΛΓ-4 ^ _ηί -r-rannni "r ₍ n po". 3 ° at room temperature and then drips to the

Calculated C 45.10% H 8.33% N 10.52%; _{AcetLinomalonsäure} monomethylester stood one

& ^{found C 45} > ²⁸ ° / o> ^H Z- ⁴⁶⁰ Io- N 10.990 / ,. _{Solution of 150 g of 4} _ _{nitrobenzaldehyde (1 mol} f _{m 750 ccm}

If the propionaldehyde is replaced by the equivalent dimethylformamide within 1 hour ^{, if the amount of butyraldehyde (14.4 g) is stirred for x} / ₂ hours, 7.6 g are obtained analogously and a solution of 138 g potassium 2-hydroxynorleucine ( 51.3% of theory) of the mp 228 ° C 35 carbonate in 400 ecm of water within 1 hour. Man (out of water). lets stir for 48 hours at room temperature, sucks

from the deposited precipitate (potassium _{hydrocarbo-C 6} H ₁₃ NO ₃ (147.17). _na t) and the solvent evaporates in vacuo.

Calculated C 48.96%, H 8.90%, N 9.52%; The tough, dark brown residue is about 300 ecm

found C 48.93%, H 8.91%, N 9.75%. 40 Ethanol poured over it and left to stand for 16 hours. That

product that has crystallized out is filtered off with suction, in a little

Example 4 Dissolved water, the solution is clear nitrided and diluted with

Hydrochloric acid, adjusted to p _H 2 to 3. The here-

7.0 g (0.04 mol) of acetaminomalonic acid monomethyl precipitated product is sharply suctioned off. It melts crude ester with 4.0 g (0.04 mol) of freshly distilled 45 with decomposition at 188 to 190 ° C, after a single benzaldehyde and with 4.0 g (0.04 mol) of triethylamine dissolving from water 190 to 191 ° C with decomposition. The solvent used was an absolute yield of 20 ecm: 125 g = 46.5% of theory.
Ethanol added. After merging the CHON (268)

Components could be observed slight evolution of gas- ¹ ^ ^12. , ⁶ «,", · "-" _{,, ·, ^ ^ n} ,

_{eighth 5} o Calculated ...... C 49.25%, H 4.51%, N 10.45%;

After standing for days at room temperature found C 49.42%, H 4.61%, N 10.38%.

were triethylamine and alcohol in vacuo on the Instead of dimethylformamide can also do the same

Evaporated water bath. The remaining yellowish oil amount of alcohol to be used as a solvent

solidified to a still within 24 hours. The compound thus obtained is that

greasy crystals, from which by recrystallization 55 D.L-threo-N-acetyl-p-nitrophenylserine. The one on usual

from methanol-water is 4.8 g of a solid substance which can be prepared from this ethyl ester with a melting point of 187 ° C

Melting point 134 to 136 ° C could be obtained. Identical in terms of melting point and mixed melting point

Analysis data agreed with those of N-acetyl-phenyl with that obtained according to G. Ehrhart, vol. 86, p. 485 (1953).

serine ethyl ester. In a mixture with authentic ten N-acetyl-p-nitrophenylserine ethyl ester.

N-acetyl-phenylserine ethyl ester is not a melting point of 60

watching depression. Example 7

¹ ^ ₁ ¹⁷ 1 , ^ mAAn, π s C ^ _n , - »τ r- rn _n ■ 21.7 ε Acetanünomalonsäurediethylester (0.1 mol) are

^Be 5 ^ec ^ ^et C 62.14% H 6.82% N 5.57%; _the ^ | _{Q ccm absobltem} ^ ₀ J ₁₀₁ Donated and 'under

found ^{C 62} · ^Ο3 ° / o> ^{H 6} - ⁹³ ° / o. N 5.53. «/ ,. _{65 bd Zimmertem stirring} with a solution of p _erature

p g

Example 5 5.6 g of potassium hydroxide in 30 cc of absolute alcohol

offset within 2 hours. Then 3.8 g (0.02 mol) of acetaminomalonic acid monoethyl ester are stirred for a further 24 hours at room temperature. then with 3.0 g (0.02 mol) of p-nitrobenzaldehyde, 2.0 g are added to the resulting solution of acetamino- (0.02 Mol) triethylamine and with 10 ccm of absolute 70 malonic acid monoethyl ester, which is weakly alkaline

should act, a solution of 15 g of 4-nitrobenzaldehyde (0.1 mol) in 75 ecm of dimethylformamide drop within ¹ Z ₂ hours. The mixture is stirred for 48 hours at room temperature, the separated bicarbonate is filtered off with suction, the solvent is evaporated off in vacuo and the residue is triturated with water, whereupon the D, L-threo-N-acetyl-p-nitrophenylserine ethyl ester crystallizes. After redissolving from a little methanol: mp 186 to 187 ° C. Yield: 10 g = 54 ° / ₀ of theory. Identical in terms of melting point and mixed melting point to the N-acetyl-p-nitrophenylserine ethyl ester mentioned in the examples.

Example 8

A mixture of 18.9 g (0.1 mol) acetaminomalonic acid monomethyl ester, 50 ecm alcohol and 10.7 g (0.1 mol) pyridine-4-aldehyde are mixed with 10 g (0.1 mol) while stirring at room temperature Triethylamine mixed. The batch remains at room temperature for 16 hours. After evaporation of the solvent, the reaction product crystallizes on standing in the refrigerator. Yield: 19 g = 75% of theory N-acetyl _J 5- [pyridyl- (4)] - serinäthylester, mp 130 ° C.

Claims (1)

Claim: Process for the preparation of α-amino-io-hydroxycarboxylic acids, characterized in that acylaminomalonic acid monoesters are reacted with aldehydes in an alkaline medium and the α-acylamino- ^ - hydroxycarboxylic acid esters formed are converted into α-amino-zS-hydroxycarboxylic acids in a conventional manner convicted. © 009 510/320 5.