DE1076700B - Process for the production of locally anesthetically effective anilides - Google Patents

Description

GERMAN

Patent application C 16197 IVb / 12q describes the preparation of anilides of the general formula

Method of manufacture
of local anesthetic anilides

Addition to patent application C 16197 IVb / 12 q
(Interpretation document 1 068 720)

R ₄

-N-CO-R ₁ -SR ₂ -Am I.

where R ₁ and R _{2 are} a branched or unbranched alkylene group, Am is a mono- or dialkylated amino group, the pyrrolidino or piperidino radical, R ₄ and R _{5 are} lower alkyl, alkoxy groups or halogen, where the benzene nucleus Y can also be further substituted, described. Such anilides have valuable anesthetic properties.

It has now been found that anilides of the general formula

Applicant:

CILAG-Chemie Aktiengesellschaft,
Schaffhausen (Switzerland)

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schnüed-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority:
Switzerland from July 6, 1956 and February 15, 1957

-N-CO-R ₁ -SR ₂ -Am II

in which R ₁ , R ₂ and Am have the abovementioned meaning and R _{3 represents} chlorine, bromine or the methoxy group, likewise have a strong local anesthetic effect.

The new substances according to the invention can be produced as already described in the main patent application by reacting anilines of the general formula

-NH,

III

or their reactive derivatives with acids of the general formula

HOOC-R ₁ -SR ₂ -Am

IV

or their reactive derivatives according to the methods customary for amide formation.

So you can, for example, anilines of the formula III or their salts with acids of the formula IV in the presence of dehydrating agents such as phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride.

Dr. Henry Martin, Zurich,

and Dipl.-Chem. Hans Müller, Schaffhausen (Switzerland), have been named as inventors

In addition, the isocyanates or carbamic acid halides which can easily be prepared from the anilines, the Phosphazo compounds, the phosphoric or arsenic anilides under appropriate conditions with the acids of formula IV to react.

Instead of the free acids IV, their functional derivatives can also be used to form anilide will. For example, halides, esters, anhydrides, mixed anhydrides can be used.

The method described above can also be modified in such a way that instead of Acids of the formula IV acids or their reactive functional derivatives used in place of the basic group Am contain a radical which is easily converted into one of the desired basic groups can be.

Such a radical can for example consist of a halogen atom or a radical reacting analogously, ζ. B. an alkyl or arylsulfonyloxy radical. These can, if appropriate, by reacting with ammonia or amines in the presence of basic condensing agents, converted into an amino or substituted amino group will.

909 758/511

3 4

Such a residue can, for example, also be a carbonylic acid: sulfuric acid, hydrochloric acid,

be group that with the help of ammonia or amines hydrobromic acid, phosphoric acid; than organic

and reducing agents into an amino or substituted acid: acetic acid, glycolic acid, citric acid, succinic

Amino group can be converted. acid, fumaric acid, maleic acid, dioxymaleic acid,

You can get valuable anuides if you use 5 methanesulphonic acid, ethanesulphonic acid, hydroxyethane

2-chloroaniline, 2-bromoaniline or 2-methoxyaniline with sulfonic acid.

Diethylairnnoäthylmercapto-acetic acid, diethylamino- BeisDiel 1
ethyl mercapto propionic acid, diethylaminoethyl

mercapto-butyric acid or the corresponding di- 134 g o-chloroanulin and 92 g thioglycolic acid propylamino-, dibutylamino-, pyrrolidino-, piperidino- ίο heated to boiling point in 600 ecm xylene for 14 hours. That converts alkyl mercapto compounds. The water that is split off is separated off in the separator. Instead of the disubstituted aminoalkyl mercapto- Now the xylene becomes acidic under reduced pressure Monosubstituted aminoalkyl can also be distilled and the residue with 2N sodium hydroxide solution mercapto acids are used to build, e.g. B. mixed. The aqueous alkaline solution is used for Monoäthylaminoäthylmercapto-acetic acid, Monoäthyl- 15 removal of starting amine with ether several times aminopropylmercapto-acetic acid, monobutylamino- extracted and then acidified. The acidic solution propyl mercapto acetic acid. is now extracted with ether and the essential The method described above, in a solution with sodium hydrogen carbonate solution and water Washed anilide formation from preformed acid and an aniline. After the ether has dried, it is can now also be carried out in stages. 20 evaporates and the residue from dilute acetic acid For example, you can recrystallize according to the above. 120 g of mercaptoacetic acid are thus obtained Methods Anilides of the general formula (2-chloroanilide) with a melting point of 59 to 60 ° C.

11.5 g of sodium are in 400 ecm abs. Dissolved ethanol

■ y ³ and to a solution of 50.4 g of mercaptoacetic acid (2-

25 chloranilide) in 500 ecm abs. Allowed ethanol to flow in.

-CO-R ₁ —X 'V Now a solution of 36g dimethylaminoethyl

chloride hydrochloride in 600 ecm abs. Ethanol added dropwise. The mixture is turbinated on the water bath for 2 hours at 20 ^° C. and then for a further 2 ¹ Z _{4 hours.} ,,. ". _TT,. ,, ,, 30 After cooling, the precipitated sodium gains and then with compounds of the general _{cMorid filtered off with suction, the filtrate md} ^ _n vacuo vaporized.

common formula _{The residue} is taken up in 2N hydrochloric acid,

X 'R ₂ VI Am di ^e solution nitrated with charcoal and the filtrate washed with 2 n-

Caustic soda made alkaline. The alkaline solution

continue to implement; in both formulas 35 is extracted with ether, the ethereal solution with

R ₁ , R ₂ , R ₃ and Am have the meaning already mentioned, washed with water, dried over sodium sulfate and

during one of the symbols X 'a reactive then vaporizes. The residue, a slightly yellowish one

Remainder, e.g. B. halogen, and the other sulfur together oil, weighs 48.5 g; it represents the / S-dimethylaminoethyl

with a hydrogen atom or another slightly mercapto-acetic acid (2-chloramlide). The hydro-

means removable residue. 40 chloride of the compound can be made with the help of essential

According to this process, for example, a hydrochloric acid can be produced. It melts from ethanol--

Haloalkanecarboxylic acid anilide recrystallized according to the aforementioned ether, at 122 to 123 ° C.
Process and produce this with an unsubstituted

or substituted aminoalkanethiol or an alkane salt Example 2
such a reaction. On the other hand, 45

you also prepare a thiolalkanecarboxylic acid anilide In the same way as described in Example 1,

and this with an aminoalkyl halide in the presence is obtained from mercaptoacetic acid (2-chloroanilide) and

Basic condensation agent to convert to diethylaminoethyl chloride hydrochloride in alcoholic

bindings of the same type to arrive. Solution in the presence of sodium methylate the / S-di-

In the formed anüiden of the formula 50 äthylamrnoäthyhriercapto-acetic acid- (2-chloranilid), the

finally in the Am group, if it boils unsubstituted below 0.04 mm at 150 to 152 ° C,
or is simply substituted, one or two more

Substituents by reacting the anilide with alky- Example 3
lating agents are introduced. Under alkylating

Agents, are said to be both reactive esters of alkanols, 55 from 60.5 g of mercaptoacetic acid (2-chloranilide) and

Alkenols and alkynols as well as corresponding aldehydes 51g pyrrolidinoethyl chloride hydrochloride in the presence

or ketones and reducing agents are understood. of sodium ethylate solution (from 13.8 g of sodium and

The group Am can moreover, as mentioned at the beginning, 500 ecm abs. Ethanol produced) one gains 76.7 g

also be quaternary, being the quaternary ammonium pyrrolidinoethyl mercapto acetic acid (2 - chloroanilide).

group by heating in the presence or absence of a 60 whose hydrochloride melts, from methanol-ether

high-boiling solvent can dequaternize, recrystallize, at 125 to 126 ° C.
as well as if one or more of the substituents

can be split off by hydrogenation (benzyl groups or example 4
substituted benzyl groups) are the quaternary

Ammonium group by catalytic hydrogenation into the 65. The anilide described in Example 2 can also be used in

can convert tertiary or secondary amino group. in the following way:

The anilides of the initially mentioned 20 g of chloroacetic acid (2-chloroanilide) (made from

Formula can advantageously be used in the form of their salts with chloroacetic acid chloride and 2-CMoranüin in acetone, in

inorganic or organic acids can be isolated. Presence of sodium acetate, m.p. = 71 ° C) are with

Inorganic acids that can be used to form salts are 70 12.9 g of diethylaminoethanethiol in 60 ecm of chlorobenzene

10

heated to boiling. After IV ₂ hours, two layers have formed. The solvent is evaporated off in vacuo, the residue is treated with sodium hydroxide solution and extracted with ether. After drying, the ether solution is evaporated and the residue is distilled in a high vacuum. 22.7 g of diethylaminoethyl mercapto-acetic acid (2-chloroanilide), which boils below 0.08 mm at 173 to 175 ° C., are obtained.

Example 5

20 g of chloroacetic acid (2-chloroanilide) are in 60 ecm Chlorobenzene heated to boiling with 18.5 g of di-n-butylaminoethane thiol for 30 minutes. Added after cooling one with 100 ecm of ether and after some time sucks off the formed crystals. These are made from ethanol Ether recrystallized, 33 g of the hydrochloride des / 3-di-n-butylaminoäthyknercapto-acetic acid- (2-chloranilides) receives. This melts at 128 to 129 ° C and dissolves easily in water, methanol, acetone and chloroform, little in ether and petroleum ether.

In the same way as described in the examples, the following can be obtained:

/ 3-piperidinoethyl mercapto - acetic acid - (2 - methoxyanilide); Melting point of the hydrochloride: 114 to 116 ⁰ C;

j3-diethylaminoethyhnercaptoacetic acid (2-methoxyanilide); Melting point of the hydrochloride: 123 to 125 ⁰ C.

Claims (3)

Patent claims: 1. Further development of the process according to patent application C 16197 IVb / 12q for production of locally anesthetically effective anilides of the general formula N-CO-R ₁ -SR ₂ -Am II wherein R ₁ and R _{2 are} a branched or unbranched alkylene group, Am is a mono- or dialkylated amino group, the pyrrolidino or piperidino radical, R _{3 is} chlorine, bromine or the methoxy group, characterized in that anilines of the general formula R » , -NH, or salts or reactive derivatives of such anilines with acids of the general formula HOOC-R ₁ -SR ₂ -Am IV or their reactive derivatives according to the methods customary for amide formation or anilines of the formula III with acids which, instead of the basic group Am, can be converted into the basic group Contain the remainder, after which this remainder is then converted into the anilides formed converted into the basic group and the anilides formed, if desired, converted into their salts. 2. Embodiment of the method according to claim 1, characterized in that the acid anilides general formula -N-CO-R ₁ -X ' with compounds of the general formula X '—R ₂ -Am reacted, where in both formulas R ₁ , R ₂ , R ₃ and Am have the meaning already mentioned, while one of the symbols X 'denotes a reactive, removable radical and the other represents sulfur together with a hydrogen atom or another easily removable radical. 3. Embodiment of the method according to claim 1 and 2, characterized in that in the anilides formed in Am further alkyl, alkenyl or alkynyl radicals with the aid of introducing such radicals Introducing agents or, if Am is a quaternary amino group, Am by Entquaternization and / or hydrogenation converted into a tertiary or secondary amino group. © 909 758/511 2.60