DE1164421B - Process for the preparation of salts of ª ‰ -aminocarboxylic acid halides - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Cl .:

Number:
File number:
Registration date:
Display day:

C07c

German KL: 12 q - 6/01

F 27292 IVb / 12 q
18th December 1958
March 5, 1964

It is known that lactams, such as butyrolactam or caprolactam, at low temperatures, for example at room temperature, using hydrogen chloride to provide lactam hydrochloride while they are on heating with hydrohalic acids in an aqueous medium into the hydrohalides of the corresponding Aminocarboxylic acids are converted. When heating the hydrochloride of the above Lactams, for example of caprolactam hydrochloride, form the esters of the with alcohols corresponding aminocarboxylic acids in the form of their hydrochlorides. This is obviously what it is a simple alcoholysis of the amide bond of the lactams.

It is also known that 3-methyl-1-ethyl- ¹ S propiolactam forms a compound with hydrogen chloride which was thought to be the corresponding lactam hydrochloride. The correctness of this view could be confirmed by reworking.

Testa and his coworkers have indicated that the 3-ethyl-3-phenyl-propiolactam (3-Ethyl-3-phenyl-2-azetidinone) on the action of hydrogen chloride in ether in the hydrochloric acid Salt of the corresponding aminocarboxylic acid chloride passes (Il Pharmaco, XIII, p. 156 and 162).

It has now been found that hydrohalides of hydrogen in the α-position are generally used bearing ß-aminocarboxylic acid halides obtained if one / S-lactams with hydrogen on the nitrogen atom and 2 hydrogen atoms or 1 hydrogen atom and an alkyl group on the α carbon atom in the absence of water, optionally dissolved in inert organic and / or inorganic diluents, treated with halogen-hydrogen. It has been shown that not only hydrogen chloride or hydrogen bromide, but also hydrogen fluoride and hydrogen iodide the reaction mentioned give. The implementation usually proceeds practically quantitatively and without disruptive side reactions, so that the very reactive hydrohalic acid salts der / 9-aminocarboxylic acid halides in high yield and is usually kept completely pure. You can therefore the carboxylic acid halides prepared in this way without Immediately process intermediate insulation and previous cleaning, which is the case with such sensitive substances means a great advantage.

Instead of the hydrogen halides mentioned, it is also possible to use substances which split off a hydrogen halide at the reaction temperature used. For example, processes for the production of salts
of / 3-Aniinocarbonsäurehalogeniden

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning, Frankfurt / M.

Named as inventor:

Dr. Paul Schlack, Offenbach / M.,

Dr. Gerhard Lohaus, Kelkheim

(Taunus) -Münster,

Dr. Roderich Graf, Hofheim (Taunus)

Potassium bifluoride or trimethylammonium bifluoride are used.

The process of the present invention applies generally to / S-lactams of general formula I.

R ₂

Ri

N-CO
H

in which Ri is hydrogen or an alkyl radical, R2 is hydrogen, an alkyl or aryl radical, R3 Hydrogen or an alkyl radical, Ri and R2 or R2 and R3 together also denote an alkylene radical.

Except for monovalent ^ -lactams, which correspond to the above general formula, can also those are used which have more than one ß-lactam ring, for example two / S-lactam rings, contain and the structure of the rest of the general formula given above with regard to the Corresponds to substituents on the nitrogen atom and on the a-carbon atom of the lactam rings.

As alkyl radicals for Ri, R2 and R3 can be straight-chain or branched alkyl radicals having 1 to 9, preferably 1 to 6 carbon atoms. as The aryl radical for R2 can, for example, be the phenyl radical or an indifferent substituent, such as Alkoxy, alkyl or halogen atoms, substituted aryl groups act.

Of ß-lactams that are used for the method of the present Invention are suitable, are for example: propiolactam, /? - methyl - /? - butyro-

409 537/552

lactam, ß-methyl-jS-yalerolactam, a-methyl-ß-methyl hydrocarbons, such as cyclohexane, aromatic / S-butyrolactam, ß-ethyl-jö-valerolactam, / S-methyl hydrocarbons, such as benzene, halogenated ^ alipha-

/? - caprolactam, yJ-phenyl-zS-propiolactam and the table hydrocarbons, such as ethylene chloride or

jS-Lactam of l-amino-cyclohexyl-l-acetic acid. Be Tetrachlbräthan, halogenated aromatic carbon

particularly suitable and, due to their reactivity, 5 hydrogens such as chlorobenzene, saturated acyclic ones

valuable are the ß-lactams with a methylene ether, such as diethyl ether, cyclic ethers, such as dioxane,

group in α-position. On suitable / S-lactamver phenol ethers such as anisole, esters such as ethyl acetate

bonds with more than one ß-lactam ring or ethylene carbonate, sulfones, such as methylethyl

for example the dilactam, which is replaced by umsulfone, or alkylene sulfones, such as tetramethylene sulfone,

Setting of dipentene with carbonyl sulfamic acid io dialkyl amides, such as dimethylformamide or liquid

chloride is obtained, and also the corresponding sulfur dioxide can be used. Mixtures too

manufacturable Dilactam from Dimethallyl called. from the above-mentioned organic solutions

The reaction temperature may be in wide forward, move, optionally with an inorganic limits, namely between about -20 solvent such as the above-mentioned and +80 ⁰ C. However, undesirable secondary 15 sulfur dioxide may be applicable, the reactions produced according to the invention the quantities of optionally angewandtem Verß-Aminocarbonsäurehalogenide by intermolecular diluent can vary within wide limits, to avoid lare condensation reaction is carried out frequently, it is recommended that the diluent is advantageously between about -15 and +25 ⁰ C. in about 3 to ten-fold However, the amount by weight, based on the conversion, is not necessarily tied to the temperature ranges specified for the lactam used. The ß-aminocarboxylic acid halides formed for the purpose of obtaining salts other than the hydrochloride of the ß-lactams used at a temperature suitable Thus, after the formation of carboxylic acid halides or their salts, the end of the cleavage reaction, the salt-forming halides and, furthermore, the solubility of these compounds can be hydrogenated by adding an equivalent in the selected reaction medium. Amount of another strong organic or

When the hydrohalides formed displace the / 9-amino-inorganic acid. You can do this carboxylic acid halides suitable acids from the reaction mixture also precipitate at the same time as the halogen, so they are to introduce unwanted secondary hydrogen into the reaction mixture, Changes largely protected. It is therefore essential that the acids in the water expedient to be added to this fact when choosing free state. For example of the solvent or diluent can be used as such acids: Butansichtigen, if particularly sensitive carbo-1-sulphonic acid, xylene monosulphonic acid, tetrahydro acid halides should be produced. React- 35 naphthalenesulfonic acid, trichloroacetic acid, trifluorotion usually takes place very quickly, what acetic acid or concentrated sulfuric acid in Absich it shows that it depends on the dependency on the diluent used. Type and amount of dilution applied, according to the method of the present assessment the hydrohalide of the formed /? - Amino- discovery compounds which can be prepared can be very carboxylic acid halides when introducing the halogen 40 versatile as acylating agent in the preparative Hydrogen often immediately or in a short time aborganic chemistry, for example at Herscheidet, in the production of pharmaceutical preparations.

The effect of the mentioned halogen water ends. Furthermore, they can be used for the production of high-grade substances under atmospheric pressure or under molecular polycondensation products, elevated pressure. The use of 45 t> · ■ 1 1 excess pressure has the advantage that undesirable side reactions are prevented. Since the jS-methyl-.beta.-butyro-lactam inclination into a solution of 0.1 mole to side reactions with increasing temperature-in anhydrous benzene is introduced at 0 ⁰ C temperature increases, the application of a certain 0.22 mole of hydrogen chloride is a. The hydrochloride overpressure at higher reaction temperatures 50 of the / i-amino-jS-methyl-butyric acid chloride separates sometimes indicated. In addition, the use in colorless crystals can be found in the very good extent of hydrogen halide under excess pressure at the yield of 92% of theory, based on the use of the comparatively less reactive lactam. The salt does not have any sharp hydrogen halides, such as the melting point of water fluorine, but decomposes according to precursors, which is advantageous. For those cases in which the sintering has gone between 110 and 120 ⁰ C. Use of hydrogen halide under an _{anal of the hydrochloride} . certain overpressure seems favorable, range in

generally lower overpressures, for example from Calculated N 8.15 / 0, Cl 41.1 / 0;

about 0.05 to 2 atmospheres. The hydrogen halides found N 8.4%, Cl 39.4%.

is expediently allowed in a molar amount or in 60 The reaction proceeds analogously if one starts

act in a small excess, based on the point of hydrogen chloride used, of hydrogen iodide

Lactam. The application of halogen leaves.

hydrogen in a substantially above molar. . However, the amount exceeding the ratio does not result in any disadvantages. 6 ₅ In a solution of 0.1 mole of O-phenyl-ß-propio-AIs inert organic or inorganic lactam in dry dioxane, for example aliphatic temperature hydrogen chloride in small molar hydrocarbons, such as hexane, cycloaliphatic excess can be introduced with room thinners . The formed ^ -amino- ^ - phenyl-

Propionic acid chloride hydrochloride remains in solution and becomes practically quantitative with absolute ether Yield fell.

Analysis:

Calculated Cl 15.35%;

found Cl 15.6%.

Example 3

IO

In a solution of 0.1 mol / S-phenyl-zS-propiolactam The equimolecular amount of hydrogen bromide is introduced into 70 ml of benzene at 8 to 10 ° C. The / ^ amino-ß-phenyl-propionic acid bromide hydrobromide * 5 is formed immediately in a very good yield as an almost colorless, crystalline mass.

Example 4

In a solution, cooled to 0 ° C., of 0.1 mol of jS-methyl-jS-butyrolactam and 0.1 mol of anhydrous p-xylene monosulfonic acid in 100 ml of benzene passes 1.2 mol of hydrogen chloride are added, the xylene sulfonate des / 3-amino-jS-methyl-butyric acid chloride deposited in the form of colorless crystals. The water-soluble salt melts between 196 and 200C.

Analysis of p-xylene monosulfonate:

Calculated N 4.35%;

found N 4.52%.

Analysis of the xylene sulfonate of the aminocarboxylic acid mentioned:

Calculated N 4.52%;

found N 4.65%.

Example 5

/ S-methyl-ß-caprolactam is tenfold Amount of benzene reacted with hydrogen chloride at 0 ° C. As a result of the substitution by a higher one The resulting / S-amino - ^ - methyl-caproic acid chloride remains dissolved in the hydrocarbon residue. The latter is precipitated by adding dry ether.

Example 6

In 0.1 mol / 9-methyl-ß-butyrolactam one passes hydrogen fluoride at 0 ° C for 2 hours. Then the batch is placed under a hydrogen fluoride atmosphere left to stand for a further 12 hours at room temperature. After this time, about 40% of the lactam into the jS-amino-jS-methyl-butyric acid fluoride hydrofluoride converted. The fluoride is a colorless, very hygroscopic salt. The rest of the lactam can be almost completely recovered.

Analysis:

Calculated N 10.08%;

found N 9.98%.

Claims (5)

Patent claims: 1. A process for the preparation of salts of ß-aminocarboxylic acid halides, characterized in that that one on compounds with one or more jS-lactam rings, where the nitrogen atoms of these lactam rings are hydrogen and the a-carbon atoms of these lactam rings carry either 2 hydrogen atoms or 1 hydrogen atom and an alkyl group, in the absence of water, optionally in the presence of an inert organic and resp. or inorganic diluent with hydrogen halide at temperatures between about -15 and + 25 ° C. 2. The method according to claim 1, characterized in that as compounds with a / i-lactam ring / S-lactams of the general formula I R ₂ R ₁ N - CO
H in which Ri is hydrogen or an alkyl radical, R2 is hydrogen, an alkyl or an aryl radical, R3 is hydrogen or an alkyl radical, Ri and Ra or R2 and R3 each together represent an alkylene radical, is used. 3. The method according to claim 1 and 2, characterized in that the hydrogen halides allowed to act under increased pressure, preferably between about 0.05 and 2 atmospheres. 4. The method according to claim 1 to 3, characterized in that the hydrogen halides in the presence of other strong anhydrous organic or inorganic acids in quantities up to 1 mol, based on the ^ -lactam used, can act. 5. The method according to claim 1 to 4, characterized in that the organic and or or inorganic anhydrous diluents, aliphatic hydrocarbons, cycloaliphatic Hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, saturated acyclic ethers, cyclic ethers of the dioxane type, phenol ethers, dialkyl sulfones, alkylene sulfones, dialkyl carboxamides and or or liquid sulfur dioxide is used. 409 537/552 2.64 © Bundesdruckerei Berlin