DE1016712B - Process for the preparation of ª ‡ -amino-ª ‰ -oxybutyric acid amides - Google Patents

Description

Process for the preparation of α-amino-β-oxybutyric acid amides It has been found that α-amino-β-oxybutyric acid amides of the general formula which are characterized by good analgesic and sedative properties with surprisingly low toxicity, are obtained in good yields if α-amino-β-oxybutyric acid amides of the general formula are used where R, hydrogen or an alkyl radical with a maximum of 4 carbon atoms and R2 an optionally substituted phenyl radical or R1 and R2 together with the connected nitrogen atom mean members of a heterocyclic ring system, reacted with formaldehyde in the presence of formic acid or catalytically hydrogenated in the presence of formaldehyde.

As a-amino-ß-oxybutyric acid amides, for example: a Amino-ß-oxybutyric acid-anilide, a Aminoß-oxybutyric acid-p-phenetidide, a.-Amino-ß-oxybutyric acid-p-anisidide, a-Amino-ß-oxybutyric acid-N-methylp-phenetidide, a-Amino-ß-oxybutyric acid-N-ethyl-p-phenetidide, a-Amino-ß-oxybutyric acid-m-anisidide, a-Aminoß-oxybutyric acid-N-isopropyl-anilide, a-Amino-ß-oxybutyric acid-N-n-butyl-p-anisidide, a-Amino-ß-oxybutyric acid-N-isobutyl-anilide, a Amino-ß-oxybutyric acid-o-anisidide, a-Amino-ß-oxybutyric acid-p-toluidide, a-Aminoß-oxybutyric acid xylidide, a-Amino-ß-oxybutyric acid-N-propyl-p-phenetidide, a-Amino-ß-oxybutyric acid- (p-carbethoxy-anilide), a-Amino-ß-oxybutyric acid (1,2,3,4-tetrahydroquinolide) and a-amino-ß-oxybutyric acid (1, 2, 3, 4-tetrahydro-6-methoxy-quinolide).

These starting materials can be obtained, for example, in the way that correspondingly substituted acetoacetamides are treated with nitrous acid and in the α-isonitroso-β-keto-carboxamides obtained both the isonitroso group as well as the keto group reduced in the usual way.

Formaldehyde is expediently used in an aqueous solution. One can but also in the presence of inert solvents, for example benzene or toluene or xylene, work. Furthermore, aliphatic alcohols and cyclohexane are also used as Suitable for solvents. Also paraformaldehyde in the presence of inert solvents can be used.

In the case of reduction by means of formic acid, it can be useful the reaction by heating to moderately elevated temperatures, advantageously to the Boiling temperature of the solvent used to carry out and the reaction mixture for some time to heat on the steam bath.

The process according to the invention gives crystalline compounds which, depending on the substituents present, are more or less soluble in water. They represent valuable remedies and in particular have a good analgesic and sedative effect with remarkably low toxicity. As a result of the associated They are superior to known compounds for a wide therapeutic range. For example corresponds to the analgesic effect of a-dimethylaminoß-oxybutyric acid-p-phenetidids, from which a 111% aqueous solution can be prepared, that of the known practically water-insoluble N-acetyl-p-phenetidines. In addition, it has a-dimethylamino-ß-oxybutyric acid-p-phenetidide a sedative component and continues to show an anti-inflammatory effect, the which corresponds to the above known compound.

When used as a medicinal product, however, the considerably lower toxicity of α-dimethylamino-β-oxybutyric acid-p-phenetidide is of decisive importance compared to the above known compound. For oral administration to the mouse, the Dos is. let. at least 3 g / kg, while that of the more well-known. Compound is 1.5 g / kg. For the rat the same data are 9 g / kg and 5 gfkg. Studies of chronic toxicity in cats showed that three out of four animals tolerated twenty-seven feedings with 0.25 g of a-dimethylamino-ß-oxybutyric acid-p-phenetidide per kg without any problems; only one animal died after fourteen feedings. The application of the same dose of the known compound led to death in almost all animals after three to four feedings.

Taking into account the associated with the better solubility improved absorbability of a-dimethylamino-ß-oxybutyric acid-p-phenetidide compared to the known compound, the advantages that the invention available compounds in terms of toxicity are even clearer. Example 1 a) 23.8 g of a-amino-β-oxybutyric acid-p-phenetidide, 13.5 g of formic acid and 16 g of 40% formaldehyde solution are heated on the steam bath for 1 hour, whereby vigorous evolution of carbon dioxide occurs. The one mixed with excess caustic soda Solution is etherified. After distilling off the ether, a-dimethylamino-ß-oxybutyric acid-p-phenetidide becomes obtained as an oil, which brought to crystallization after repeated boiling with water will. The melting point of the recrystallized from a mixture of toluene and petroleum ether Product is 99 °. The yield of the crystallized compound is 20 g.

b) 720 g of a-amino-ß-oxybutyric acid-p-phenetidide, 340 g of 100% formic acid, 540 cc of 40% aqueous formaldehyde solution and 3 liters of water are used together for 5 hours heated on the steam bath, with vigorous evolution of carbon dioxide. Afterward the reaction mixture becomes acidic to the Congo by adding dilute hydrochloric acid posed. After filtering and clarifying with animal charcoal, the filtrate is diluted with Caustic soda just made alkaline. You immediately get 648 g (80% of theory) a-Dimethylamino-ß-oxybutyric acid-p-phenetidide with a melting point of 98 °.

c) 147 g of a-amino-ß-oxybutyric acid-p-phenetidide, 68 g of 100% formic acid, 108 g of 40% aqueous formaldehyde solution and 300 cc of benzene together are about Heated under reflux on the steam bath for 3 hours. After cooling, the reaction mixture a mixture of 50 cc of concentrated hydrochloric acid and 400 cc of water was added. The aqueous layer is separated off from the 2-phase system and washed with dilute sodium hydroxide solution made alkaline. The α-dimethylarrmino-ß-oxybutyric acid-p-phenetidide falls with good yield. The melting point is after recrystallization from ethyl acetate at 98 °.

. d) The same compound can be obtained from a-amino-ß-oxybutyric acid-p-phenetidid can also be obtained by catalytic hydrogenation in the presence of formaldehyde. The yield is 50% of theory. Example 2 26.6 g of a-amino-ß-oxybutyric acid (p-carbäthoxy-anihd) are with 13.5 g of formic acid and 16 g of 40% formaldehyde solution for 1 hour on the Steam bath heated. After cooling and mixing with excess sodium hydroxide solution separates the a-dimethylamino-ß-oxybutyric acid (p-carbethoxy-anilide) in oily form, which is taken up in ether and after drying and distilling off the solvent crystallized. Melting point 85 ° after recrystallization from a mixture of ethyl acetate and petroleum ether. The yield is 20% of theory.

The production of the a-amino-ß-oxybutyric acid (p-carbethoxy-anilide) used as the starting material was carried out in the following way: By reacting diketene with ethyl p-amino-benzoate Acetoacetic acid (p-carbethoxyanilide) was obtained, which via the a-isonitroso-acetic acid (p-carbethoxy-anilide) by hydrogenation of the isonitroso compound into the a .amino-ß-oxybutyric acid (p-carbethoxy-anilide) was convicted.

Example 3 26.4 g of a-amino-ß-oxybutyric acid (6-methoxy-1, 2, 3, 4-tetrahydroquinolide) are with 13.5 g of formic acid and 16 g of 40% formaldehyde solution according to in example 1 specified regulation implemented. There are 20.5 g of a-dimethylamino-ß-oxybutyric acid (6-methoxy-1, 2, 3, 4-tetrahydroquinolide). Melting point 97.5 'after recrystallization from a mixture of ethyl acetate and petroleum ether.

The production of the a-amino-ß-oxybutyric acid (6-methoxy-1, 2, 3, 4-tetrahydroquinolids) was carried out in the following way: By reaction of 6-methoxy-1, 2, 3, 4-tetrahydroquinoline with diketene becomes acetoacetic acid- (6-methoxy-1, 2, 3, 4-tetrahydroquinolide) obtained, this by nitrosation and reduction in the isonitroso compound and the latter by hydrogenation into a-amino-ß-oxybutyric acid- (6-methoxy-1, 2, 3, 4-tetrahydroquinolide) transferred. Example 4 26.5 g of α-amino-β-oxybutyric acid (N-methyl-p-phenetidide) become mixed with 26.5 ccm of 40 °! 0 formaldehyde solution. The clear solution becomes 13 ccm 850/0 formic acid heated on the steam bath for 45 minutes. After cooling down and Adding excess potassium carbonate solution falls a-dimethylamino-ß-oxybutyric acid (N-methyl-p-phenetidide) in oily form and is absorbed into ether. After drying and evaporation of the After standing for a while, the solvent crystallizes. Yield 18 g; Melting point 82 °.

A-amino-β-oxybutyric acid (N-methyl-p-phenetidide) was prepared in the following way: N-methyl-p-phenetidine is converted into acetoacetic acid (N-methyl-p-phenetidide) with diketene and this after Nitrosation converted in the usual way into the isonitroso compound of acetoacetic acid (N-methyl-p-phenetidide), from which the a-amino-ß-oxybutyric acid (N-methyl-p-phenetidide) is formed by hydrogenation. Example 5 21.5 g of α-amino-β-oxybutyric acid (Nn-butyl-p-anisidide) are briefly heated with 21.5 cc of 40% formaldehyde solution and 21.5 cc of water while shaking. An oil forms that solidifies again after a few minutes. After adding 11 cc of 85% formic acid, the mixture is heated on the steam bath for a further 30 minutes. After adding water and filtration, it is made alkaline with potassium carbonate solution. The precipitated oil (crude yield 22.5 g) solidifies immediately. After recrystallization from cyclohexane, α-dimethylamino-β-oxybutyric acid (Nn-butyl-p-anisidide) with a melting point of 101 'is obtained.

The production of a-amino-ß-oxybutyric acid (N-n-butyl-p-anisidide) took place in the following way acetoacetic acid (N-n-butyl-p-anisidide), obtained from N-n-butyl-p-anisidine and diketene, gives after nitrosation the isonitrosoacetoacetic acid- (N-n-butyl-p-anisidide), which by hydrogenation into the a-amino-ß-oxybutyric acid (N-n-butyl-p-anisidide) is convicted.

EXAMPLE 6 35 g of α-amino-β-oxybutyric acid (p-chloroanilide) are refluxed for 1 hour with 21 g of formic acid, 35 cc of water and 25.4 g of 400/0 aqueous formaldehyde solution. The initially cloudy solution clears after cooling and is made alkaline with dilute sodium hydroxide solution. The separated oil soon solidifies and is sucked off. After recrystallization from a mixture of ethyl acetate and petroleum ether, α-dimethylamino-β-oxybutyric acid (p-chloroanilide) with a melting point of 90 to 91 'is obtained. The yield is 650/0 of theory of crystallized compound.

The preparation of the starting compound was carried out as described below Ways: Acetoacetic acid (p-chloroanilide), obtained from p-chloroaniline and diketene, gives after nitrosation, the a-isonitrosoacetoacetic acid (p-chloroanilide) of the melting point 177 to 178 °, which by hydrogenation into the a-Aminoß-oxybutyric acid (p-chloroanilide) is converted from melting point 126 to 127 '. Example 7 109 g of a-amino-ß-oxybutyric acid (3-chloro-4-methylanilide) are mixed with 450 cc of water, 51.5 g of 100% formic acid and 82 g of 40% aqueous Formaldehyde solution heated on the steam bath for 4 to 5 hours. After cooling it will 37 cc of concentrated hydrochloric acid are added to the reaction mixture, with largely Solution occurs. After dilution with 1.5 l of water, it is filtered with sodium hydroxide solution made alkaline, whereupon after standing in ice 88 g of a-dimethylamino-ß-oxybutyric acid (3-chloro-4-methyl-anilide) can be obtained. Melting point 101 to 102 ° after recrystallization from a mixture from ethyl acetate and petroleum ether.

Claims (1)

PATENT CLAIM: Process for the preparation of α-amino-ß-oxybutyric acid amides of the general formula characterized in that one uses α-amino-ß-oxybutyric anilides of the general formula where R, hydrogen or an alkyl radical with a maximum of 4 carbon atoms and R2 an optionally substituted phenyl radical or Ri and R, together with the connected nitrogen atom, mean members of a heterocyclic ring system, reacted with formaldehyde in the presence of formic acid or catalytically hydrogenated in the presence of formaldehyde.