DE1087616B - Process for the preparation of ª ‡ -amino-ª ‰ -oxy-carboxylic acid amides with an analgesic effect - Google Patents

Description

In the German patent specification 963 776 a-amino - /? - oxybutyric acid anilides are described which have good anti-inflammatory properties. Furthermore, it has already been proposed that ß-oxybutyric acid tert-alkylamides with a very good analgesic effect.

It has now surprisingly been found that a-amino / J-oxy-carboxamides of the general formula

CH ₃ -CH-CH-CO-NH-

OH NH ₉

-R

wherein R is an aliphatic hydrocarbon radical with a tertiary bonded to the nitrogen atom Carbon atom means having very good analgesic properties. Subject of the present Invention is the preparation of such compounds by adding acetoacetic acid amides of the general formula

CH ₃ -CO-CH ₂ -CO-NH-R,

wherein R is an aliphatic hydrocarbon radical with a tertiary bonded to the nitrogen atom Carbon atom means treated in a manner known per se with nitrous acid or in the α-position substituted by an arylazo group and in the nitrosation products or in the arylazo compounds the nitroso or arylazo group and the keto group are reduced.

An embodiment of the method according to the invention is that in a known per se Way acetoacetamides of the formula given are nitrosated and the nitrosation products of reduction subject t. The preparation of the acetoacetic acid amides required as starting materials can be carried out in a known manner Manner, for example by reacting the corresponding amines with diketene. as Starting materials come into consideration, for example: acetoacetic acid tert-butylamide, acetoacetic acid - 2 - methyl - butyl- (2) -amide, acetoacetic acid -3- methyl-pentyl- (3) - amide, acetoacetic acid - 3 - ethyl pentyl - (3) - amide, Acetoacetic acid-4-ethyl-heptyl- (4) -amide.

To nitrosate the α-carbon atom, it is advantageous to dissolve the /? - ketocarboxamide in Glacial acetic acid and nitrosated by adding a concentrated aqueous solution of sodium nitrite. Man can also the / J-ketocarboxamide in an organic Dissolve solvents and the nitrosation by adding sodium nitrite and mineral acids make. Lower aliphatic alcohols, for example, are particularly suitable as organic solvents Methanol, in question. Processes for production are used as mineral acids

of analgetiscti effective

α-amino-ß-oxy-carboxamides

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M., Brüningstr. 45

Dr. Gustav Ehrhart, Bad Soden (Taunus),

Dr. Ingeborg Hennig, Kelkheim (Taunus),

Dr. Karl Schmitt, Frankfurt / M.-Unterliederbach,

Dr. Ernst Lindner, Frankfurt / M.-Höchst,

and Heinrich Ott, Eppstein (Taunus),

have been named as inventors

preferably sulfuric acid or hydrochloric acid is used.

An advantageous embodiment for the further implementation of the intermediates obtained Isonitroso compounds into the desired a-amino - /? - oxy-carboxamides represents the procedure given below, which can be carried out with good yields: The isonitroso compounds are treated first with reducing agents in such a way that only the isonitroso group in the amino group is converted. In this case, nascent, for example, are used as reducing agents Hydrogen - the z. B. of base metals such as zinc, iron or tin, in the presence of dilute Acids, can be obtained - sodium hydrosulfite or tin chloride into consideration. The reduction of Keto group in the α-amino - /? - keto compounds obtained to the secondary alcohol group is then carried out in a special reaction. Included it can be of advantage if the amino group in the α position is intermediately protected by acylation. Acylating agents are acid derivatives, for example acid halides and acid anhydrides, e.g. B.

Acetyl chloride, propionyl chloride, benzoyl chloride, phenylacetic acid chloride or the corresponding acid anhydrides, in particular acetic anhydride, are suitable. It is not necessary in this procedure to use the intermediate α-amino compounds

009 588/418

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to isolate; you can carry out the addition of the acylation hydrogenation, for example Ka-

by means of catalysts of group VIII of the periodic table immediately after the end of the reduction,

the isonitroso group. In the case of the preference nickel catalysts are used

use of nascent hydrogen as a reduction ability; the Raney cata-

medium made of base metals with the help of 5 analyzers. Organic

Acids, it is advisable to use niche solvents, preferably lower aliphatic

the solution before adding the acylating agent with table alcohols, optionally in the presence of

To blunt sodium acetate. To be used for the same water. One works appropriately

α-Acylamino-acetic acid amides can also be used at room temperature or at a moderately elevated temperature

the way via the a-arylazo-acetic acid amide io temperatures, preferably at 50 to 80 ° C.

reach. The cleavage of the acyl group from the obtained

According to another embodiment of the process a-acylamino - ^ - oxy-carboxylic acid anilides, according to the invention, the conversion of the customary methods, for example by saponification of acetoacetic acid amides used as starting materials with mineral acids, preferably with water halide in a-arylazo compounds, is expediently carried out by Um- 15 Substance acids, in particular with hydrochloric acid, set with an aryldiazonium salt. or hydrobromic acid.
The solution required for the reaction of the one can the aryldiazonium salt leading to the nitrosation products can be varied, for example, from the embodiment of the process according to an aromatic amine, such as aniline, with the aid of the invention in such a way that without sodium nitrite in a known manner produce. The solution obtained by isolating the crlsonitrosoacetoacetic acid amide becomes a solution of the austet. In this case too, the ketocarboxamide compounds used as the starting material are bound, as already described above, with sodium drops, which are advantageously nitrosated, for example with sodium trium nitrite in the presence of acids, the acetate is truncated. The reaction mixture obtained used as a solvent is, however, suitably a mixture of water and low-viscosity directly reduman. By adding the acylating agent according to molecular aliphatic alcohols. The final reduction formed is in this case immediately the α-arylazo compound is generally obtained while the corresponding α-acylamino-acetic acid amide is obtained or shortly after the dropwise addition has ended Carry out arylazo compounds, the isolation of which from the solution in almost quantitative yield can likewise be bypassed by obtaining that in most cases they are indirectly processed in the following manner by reducing the resulting reaction mixture and the acylating agent immediately afterwards. will give. The reduction of the keto group in the so

An embodiment of the process for the conversion of ct-amino- or a-acylamino-acetic acid management of the ct-aryl amides obtained as intermediates to corresponding a-amino or a-acylazo - /? - ketocarboxamides in the desired amino /? - oxybutyric acid amides is, as above bea-amino - /? - oxy-carboxylic acid amide corresponds to the one written for, then carried out afterwards,
the further processing of the nitrosation products. A particularly advantageous production method described, which also exists with good speed for the process products, but can be carried out in the yields. The reduction of the keto- 40 simultaneous reduction of the α-isonitroso group in the obtained α-amino - /? - keto compounds group or arylazo group and the keto group in to the sec-alcohol group is, as well as for the Ni one operation. This reduction can, for example, disruption products described above, then carried out catalytically with the aid of metals in a particular reaction; expediently VIII. Group of the Periodic Table, preferably with it is also in this case, the α-position amino-45 nickel catalysts are made. To protect by-group intermediately by acylation. It is also possible, for example, to use noble metals or Raney catalysts, which are again not required, can be used in this procedure. As a solvent borrowed, the intermediate α-amino compounds can be isolated organic solvents, preferably niegen. If the reduction is not carried out in other aliphatic alcohols, optionally in the presence of the acylating agent, 50 degrees of water can be used. This is also carried out immediately after the end of the addition of the α-arylazo group, expediently at room temperature or moderately. In the case of elevated temperatures, preferably 50 to 80 ° C., the use of nascent hydrogen, which can also be used as a reducing agent with nascent water from base metals with the aid of acids, for example from sodium or aluminum If amalgam and alcohol or sodium borohydride are used, reduce the solution before adding the acylating agent. The reduction can also be blunted electrolytically with sodium acetate. That is feasible at the. Aromatic amine obtained after the catalyst has been cleaved, and the desired α-amino- / α-oxy-cardiesen reaction conditions are maintained directly, as expected, ebonic acid amide.

if acylated. This acylation product is generally used in the technical context more easily soluble than the desired process, one keeps particularly good yields and very pure rens product and is made by fractionated crystallization process products, if one has a solution of the tion separated from this. by nitrosating the acetoacetic acid amides as intermediate

The reduction of the keto group in the ct-isonitroso-acetic acid-

the above-described procedures obtained a-acyl-65 amide either batchwise by injection

Amino-acetic acid amides can be used, for example, to form a suspension of the catalyst at 50 to

by means of sodium or aluminum amalgam in counter-100 atmospheres and, if necessary, at an elevated temperature

wait for alcohol to be carried out. You can hydrogenate or if you have a solution of the a-isonitroso

also with sodium borohydride and electrolytic / ^ - ketocarboxamides at 50 to 100 at and

work. With particular success, a catalytic 70, if necessary at elevated temperature by a continuous

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naturally working hydrogenation apparatus - it is more surprising that the present process

pumps, the catalyst in this solution having such good analgesic properties

pending or in lump form already in the appate.

rature is included. The particular advantage of the last example 1

mentioned embodiment of the method according to the 5 .. i_ ^ »^. ,. i. ^ ι · j

Invention, namely the simultaneous reduction in a-amino - ^ - oxy-butyric acid-tert-butylamide

one operation is that reaction a) 85 g of acetoacetic acid tert-butylamide is obtained

can guide so that the reduction of both isoni- by converting tert-butylamine and diketene in

The troso group and the keto group are as similar as possible - benzene, are dissolved in 240 ecm of glacial acetic acid; the lo-

done in good time. The same applies to the solution that is mixed drop by drop with a concentrated aqueous solution.

Simultaneous reduction of a solution of 40 g sodium nitrite added,

of a-arylazo group and ^ -keto group. The reaction temperature is 20 to 30 ° C

namely found that side reactions are held by con. After concentration under reduced pressure

Densation of 2 mol of a-amino - ^ - keto-carbonsäurederi- the residue is mixed with a little water and

vaten to give corresponding heterocyclic compounds. After drying and distilling off the

conditions can occur, as they are already several times in the ether 93 g a-Isonitroso-acetacetic acid-tert, -

Literature have been described (cf., for example, butylamide obtained in crystalline form.

J. Am. Chem. Soc. 60 (1938), p. 1328. b) a solution of 50 g of this Isonitrosoverbin-

The compounds obtained can be converted into corresponding salts by digestion in 11 methanol in the presence of a nickel reaction with inorganic and organic oxygen catalysts, added to kieselguhr, at 95.degree. Hydrogenated as inorganic in the pressure vessel. After absorbing the calculated acids, for example, halogenated water. Neten amount of hydrogen, which in a short time is finished with chemical acids such as hydrochloric acid and bromine, is filtered and the filtrate is concentrated under hydrochloric acid, sulfuric acid, phosphoric acid and reduced pressure. The residue becomes sulfamic acid. Examples of organic acids that may react with 2N hydrochloric acid up to a Congo acid reaction are formic acid and acetic acid. After filtration with charcoal, 2N sodium acid, oxalic acid, malonic acid, succinic acid, and lactic acid are made alkaline and then extracted with ether. The syrupy acid, malic acid, tartaric acid, citric acid, oxy-ether residue is mixed with alcoholic hydrochloric acid in ethanesulphonic acid, aceturic acid, phenyldimethylpyra- the crystalline hydrochloride of a-amino-zS-oxy-butzolone-methylaminomethanesulphonic acid, ethylenediamine-tert.-tert.-butylenediamine- 30 221 to Ν, Ν'-tetraacetic acid, benzoic acid and salicylic acid, 22 ° C (from alcohol) converted,
as well as their derivatives. Example 2

The products are valuable Agency for Therapeutic Products _{Λ. o} , .. ..,,. 1, ^ 1 -j
tel and have a relatively low toxicity very "-amino- ^ oxybutyric acid-tert-butylamide
good analgesic effect. For example, 35 a) Two solutions are prepared,
wise with 100 mg / kg of a-amino - /? - oxybutyric acid 3-solution I: 25 g of aniline are dissolved in 88 ecm of concentrated ethyl pentyl (3) amide hydrochloride with subeutaner trated hydrochloric acid and 265 ecm of water. The application of a clear analgesic effect on this solution is found at 0 ° C, a solution of 18.8 g of the mouse. There was an extension of the sodium nitrite in 55 ecm of water added dropwise.
Response time of on average 7.7 seconds to 40 Solution II: A solution of 120 g of sodium acetate on average 23.9 seconds. Known compounds in 200 ecm of water are combined with a solution of 42.5 g of compounds, namely - as the following lines show acetoacetic acid tert-butylamide in 1.21 alcohol - both comparable and different.

chemical configuration, the process produces- Under cooling and stirring, solution I becomes

nisse with regard to their analgesic properties 45 solution II dripped.

think. In the case of oral administration, for example, the dose

of 1 g / kg ß- oxy-butyric acid-p-phenetidide (see. Formed yellow precipitate sucked off, from the after

German patent specification 964 057) to a demand recrystallization from alcohol 66 g of a-phenylazo-

tion of the reaction time of 5 seconds to 19.8 sec-acetacetic acid-tert-butylamide can be obtained,

announce (mean values from 20 mice); at 50 b) 66 g of a-phenylazo-acetic acid tert-butylamide

Administration of 1.5 g / kg of the same compound in 11 methanol in the presence of Raney

the reaction time of 5.7 seconds was hydrogenated on nickel as a catalyst at 100.degree. To

25.9 seconds longer (average values of filtration and concentration of the filtrate is this

30 mice). In addition, the process has been mixed with water several times and then re-used.

products compared to this known compound 55 evaporates in order to

the great advantage of water solubility, so that sub-distant. The residue is finally treated with 2N salt

Cutaneous injections are possible, while the acid is mixed with the Congo acid reaction

known connection can only be applied per os. Filtered charcoal and concentrated under reduced pressure.

When comparing the known phe- engt. There are 35 g of a-amino / 5-oxybutyric acid-tert.-

nyldimethylpyrazolonmethylaminomethanesulfonsauren 60 but'ylamide hydrochloride with a melting point of 222 ° C

Sodium has been found to get 1g / kg of this (from alcohol),

known analgesic with subeutaner application Example 3

has about the same potency as 100 mg / kg. . ", ^ .. _fr , ,,,,. _{,, O} \ · λ \

"-Amino-oxy-butyric acid-3-ethyl-pentyl- (3) -amide" -Ammo- _/ S-oxy-butyric acid- (2-methyl-butyl- (2) -am ₁ d)

hydrochloride. The toxicity of the latter-mentioned 65 According to the precedence given in Example 1 a

vehicle license is, if administered intravenously, 30 g acetoacetic acid (2-methyl-butyl-

range 100 mg / kg (dos. let. min.). (2) -amid) converted into the isonitroso compound.

Those in the first paragraph of the description as known After hydrogenation in that described in Example 1b

mentioned a-amino - ^ - oxy-butyric acid anilide.

practically no analgesic properties. In order to obtain 70 thyl-butyl- (2) -amid), its hydrochloride

(produced according to Example 1b) has a melting point of 187 to 188 ° C (from alcohol).

Example 4
α-Amino - ^ - oxy-butyric acid (3-ethylpentyl- (3) -amide)

According to the procedure given in Example 1 a, 100 g of acetoacetic acid (3-ethylpentyl (3) amide) 110 g of the isonitroso compound were obtained. After hydrogenation in that described in Example 1b This results in the a-amino - /? - oxy-butyric acid (3-ethyl-pentyl- (3) amide). By converting to the hydrochloride in the manner described above, the hydrochlorides of the two isomeric forms are obtained (threo- or erythro-form) of a-amino - /? - oxybutyric acid (3-ethyl-pentyl- (3) amide) obtained, which are to be separated from each other by fractional crystallization from alcohol. The high melting point connection melts at 222 to 223 ° C, the low-melting form at 179 to 180 ° C. The analysis values both connections are the same; only the UR spectra differ.

Phenyldimethylpyrazolonmethylaminomethanesulfosaures a-amino- / oxybutyric acid- (3-ethylpentyl-

(3) -amide)

10.8 g of a-amino / 3-oxybutyric acid (3-ethylpentyl (3) amide) and 15.55 g of phenyldimethylpyrazolone methylaminomethanesulfonic acid are dissolved in 40 ecm of alcohol and filtered. After concentration under reduced pressure, 26 g phenyldimethylpyrazo lonmethylaniinomethansulfosaures a- amino butyric acid are -β oxy-3-äthylpentyl- (3) -amide as a white powder obtained hygro skopisches.

Maleic acid a-amino - ^ - oxybutyrate- (3-ethylpentyl- (3) -amide)

18.1 g of a-amino-yS-oxybutyric acid-3-ethylpentyl- (3) -amide and 9.7 g of maleic acid are dissolved in water. After concentration under reduced pressure the residue dissolved in hot alcohol. After cooling, a crystal slurry is formed. It will be 25.5 g Maleic a-amino - ^ - oxybutyric acid-3-ethyl-pentyl- (3) -amide obtained from melting point 132 to 133 ° C.

100 ecm of water dissolved at about 60 ° C. After filtering and cooling, a crystal slurry is obtained. There are 31 g of 2,5-dioxybenzoic acid a-amino - ^ - oxybutyric acid (3-ethylpentyl- (3) -amide) obtained from melting point 183 to 185 ° C.

Example 5
α-Amino-zS-oxy-butyric acid tert-butylamide

ίο 50 g of the a - isonitroso - acetic acid - tert prepared according to Example la. - butylamids are mixed with 150 ecm of glacial acetic acid and 50 ecm of acetic anhydride; 50 g of zinc dust are introduced into the reaction mixture in portions with stirring. After stirring for 1 hour at 40 ° C., 750 ecm of water are slowly added with continued stirring. After several hours of stirring, the mixture is filtered off with suction and the filtrate is extracted with methylene chloride. After drying and distilling off the solvent, the residue crystallizes. The melting point of the obtained a- acetylamino - acetic acid - tert. - butylamids is • 128 to 130 ° C (from ethyl acetate).

30 g of the compound obtained are reduced in 100 ecm of methanol and 10 ecm of water with sodium borohydride. After neutralization with dilute hydrochloric acid and shaking with methylene chloride, 25 g of et-acetamino- β- oxy-butyric acid-tert-butylamide with a melting point of 160 to 162 ° C. (from ethyl acetate) are obtained.

- 30 20 g of this compound are concentrated with 20 ecm Hydrochloric acid and 20 ecm of water heated on the steam bath for 30 minutes. After cooling, the reaction mixture becomes made alkaline with dilute sodium hydroxide solution and extracted with methylene chloride. To Drying and distilling off the solvent gives a residue which is obtained with alcoholic hydrochloric acid into the crystalline hydrochloride of a-amino - /? - oxy-butyric acid tert-butylamide is converted from melting point 221 to 222 ° C.

40

45

S alicylic acid a - amino - β - oxybutyric acid - (3 - ethylpentyl- (3) -amide)

17 g of a-amino-yg-oxybutyric acid (3-ethylpentyl- (3) -amide and 10.9 g of salicylic acid are dissolved in a little alcohol at about 40 ° C. After adding Water up to the beginning of cloudiness and cooling ice creates a crystal slurry. It will be 20.5 g salicylic acid a-amino - /? - oxybutyric acid (3-ethylpentyl- (3) -amide) obtained from melting point 148 to 149 ° C.

2,5 - Dioxybenzoic acid α - amino -β- oxybutyric acid- (3-ethylpentyl- (3) -amide)

23 g of a-amino ~ /? - oxybutyric acid (3-ethylpentyl- (3) amide) and 16 g of 2,5-dioxybenzoic acid are in

Claims (1)

PATENT CLAIM: Process for the preparation of analgesic α-amino - /? - oxy-carboxamides, thereby characterized in that one acetoacetamides of the general formula CH ₃ -CO-CH ₂ -CO-NH-R wherein R is an aliphatic hydrocarbon radical with a tertiary bonded to the nitrogen atom Carbon atom means treated with nitrous acid in a manner known per se or substituted in the α-position by an arylazo group and in the nitrosation products or in the arylazo compounds, the nitroso or arylazo group and the keto group, if appropriate gradually, reduced. © 009 588/418 8.60