DE1218462B - Process for the preparation of alkylbenzyldimethylammonium iodine halides - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY GERMAN ^ TVQnSS PATENT OFFICE

EDITORIAL

Int. α .:

C07c

Number:
File number:
Registration date:
Display day:

German KL: 12 q- 1/02

W 32369IV b / 12 q
5th June 1962
June 8, 1966

The present invention relates to a process for the preparation of alkylbenzyldimethylammonium iodine halides the general formula

[C _K H ₂ " ₊₁ N (CH ₃ ) ₂ CH ₂ C ₆ H ₅ ] PC-J ₂ ]

in which η is an integer from 8 to 18 and preferably 12 or 14 and X is a halogen ion.

It has long been known that iodine is an extremely effective bactericidal agent, but his was Use severely limited in that it causes both irritation and discoloration of body tissues causes. Try to find preparations containing iodine that have excellent bactericidal properties of iodine without having the above disadvantages have not hitherto been in this field successful, although for various non-medical purposes, the solubilization of small amounts of iodine succeeded in water with large excesses of suitable nonionic surfactants. this is described, for example, in U.S. Patent 2,679,533. Those described in this patent However, preparations are not considered to be used in humans and animals for skin treatment and for oral lozenges Antiseptics suitable, they are mainly because of their great water solubility and their poor and strongly bitter taste unsuitable for oral administration.

However, poor water solubility is associated with an antiseptic compound applied to the skin should be desirable, and it is especially necessary in the case of antiseptic lozenges for the mouth or throat and other orally administered pharmaceutical preparations, since a proportionate one low but stable concentration of bactericides should be generated over a should last for a longer period of time.

The process according to the invention for the preparation of alkylbenzyldimethylammonium iodine halides consists in the fact that in a known manner a solution of iodine in an aqueous medium with a solution of an alkylbenzyldimethylammonium halide having 8 to 18 carbon atoms in the alkyl radical reacted and the resulting precipitate is isolated, washed and dried.

For economic reasons, it is preferred to choose the amount of iodine and quaternary compound to be practically equimolar. However, if this condition is not met, there is a further advantage of the process according to the invention is that a contamination of the process product by excess quaternary compound is removed when washing with water, while a contamination process for the production of
Alkylbenzyldimethylammonium iodine halides

Applicant:

Sterwin A. G., Zug (Switzerland)

Representative:

Dr. F. Zumstein, Dr. E. Assmann

and Dr, R. Koenigsberger, patent attorneys,

Munich 2, Bräuhausstr. 4th

Named as inventor:
Eric Richard Brown,
Ponteland, Newcastle-on-Tyne
(Great Britain)

Claimed priority:

Great Britain June 5, 1961 (20 206)

of the process product by excess iodine during drying, which can be brought about at only a slightly elevated temperature, for example below the melting point of the process product.
The products of the process show exceptional activity against a wide range of both gram-positive and gram-negative bacteria, even at low concentrations. They are not toxic, nor do they give rise to irritation or other undesirable side effects. They are therefore suitable as antiseptics, and because they have a mild and pleasant taste, they are particularly valuable for use as oral antiseptics.

Preferred alkylbenzyldimethylammonium iodine halides are those having a water solubility of about 0.002 g per 100 ml, i.e. those in which »means at least 10.

For reasons of economy in production, it is preferred that the starting compounds used are the chlorides,

The new compounds obtained according to the invention or mixtures thereof are bactericidal or bacterostatic action against another

609 578/550

Range of microorganisms, including those mentioned below: ""

Candida albicans 45348 (monilia albicans)

Escherichia coli 8134. ".,

Staphylococcus aureus 6571 (penicillin-sensitive) Staphylococcus aureus (penicillin-resistant ' ^% clinical strain). ■ ■ '"-.- ■■>.

Streptococcus haemolyticus 8198 '* "' Bacillus fusiformis 7582

The numbers given for the organisms listed above are those that correspond to them by the National "Collection öf" Type Cultures or by the Commonwealth Mycological Institute.

Tests to determine the bactericidal activity of this compound in vitro have shown that it against certain typical organisms quantitatively at least as well and in many cases clearly are better than iodine and the quaternary higher alkylbenzyldimethylammonium salt.

To show this are in the table below those obtained for the action of various novel compounds obtained according to the invention Results compared to that of iodine and the simple one quaternary compounds that are constituents of the corresponding new compounds, as well as the from some other iodine-containing preparations currently available on the market against three different ones Organisms specified. In the table are the various bactericides used in each case according to the following key - indicated if an abbreviation is necessary.

M. qüat. '' '= Myristylbenzyldimethylammonium

chloride;
Conn. (c) = myristylbenzyldimethylammonium

... iodine chloride; . .

"Roccal" I == a mixture of decyl, lauryl,

Myristyl, cetyl and staerylbenzyl

dimethylammonium chlorides, too

known as benzalkonium chloride

- · and 'in Great Britain as »ROC-

CAL «(registered trademark)

in trade;

Bezalkonium- = a mixture of the following veriodochloride compounds (a), (b), (c), (d) and (e)

corresponds to Roccal in the mixing ratio;

Preparation B = a polyvinylpyrollidone-iodine com- '■ -' ■■■■ · ■■■■ plexj'that contains 1% available iodine ---- '' ■ '■ ■ -'- ; '.'.- ■ _'. - .- .- Preparation W = 9.1 ^a / ₀ Polyethoxypolypropoxypoly- · ■ -. ..-.-. ethoxyethanol-iodine complex,

8.74% nonylphenoxypolyethoxy- - ^; ":. ' ethanol-iodine complex,

0.1% hydrogen chloride (contains 1.6% available iodine). · '■■■ · "■ ■": - ■■' - "-" ■■ '.' ■ " ^:

" The results shown in the following table are the phenol coefficients of the various bactericides / determined against the organisms listed using the FDA method, -" the ^: in "Official Methods of Analysis of the Association of Official Agricultural Chemists"; 9th edition, 1960, using a 10 ^ minute endpoint / -. ^;

Phenol coefficient

Bactericide
Iodine ........ λ., ...; ..; ./.;.

M.Quat. · ..

Conn. (c)

"Roccal"

Benzalkonium iodine chloride. · ..-.- ..
PreparationB, ..- ". ... \ . ■". . ·. ^: X'J. .V PreparationW ...; ..; -; -. - ..-. .;.: ..

The effectiveness of the compounds according to the invention as bactericides was confirmed by Ih-vivo tests. The following technique was used as a measure of the skin sterilization: First, the hands of a test group were washed, then each palm was brought into contact with solidified nutrient agar for 30 seconds, and the agar was then incubated in a Petri dish for 48 hours at 37 ° C. Colonies. To count. Using this method, fewer colonies were produced when washing with a 1% solution of myristylbenzyldimethylammomum iodine chloride in acetone than after washing with 8% chloroxylenol solution according to the British Pharmacopoeia. '■' ^? ■ ^!

The effectiveness of the new compounds according to the invention for combating infections of the mouth and throat would be tested / that 5 mg amounts thereof were formulated in the form of lozenges and payments 'of' microorganisms alif cultures of the mouth or - Rachenflöf a ~ one = ^; Number of Streptococcus '*'
:: Haemolyticus;
.. (NCTC 8198K

Staphylödcus Bacillus . -Aureus- . Fusiformis (NCTC 6571) _:. - (NCTC 7582) 260 · - 23 ■ ~. , 630 - 210 · - 660 210 • 42Ü-. : - ■■ :. .-. ·: ■ 440 ';;.

300
420
680

-400
440:

, 350
350

various test persons before and after sucking such a Pästillö were carried out. These studies - showed a marked decrease in the count of cultures 'derived from mouth rinses made even 2 hours after the administration of a single throat lozenge'. Immediately after "administration, the reduction in the number of cultures derived from throat swabs" is "of the order of 90% .. ■; - · ■ - ■■ ■ -.- ■ '' ■ "■" · - ■■ :. -., '. Example 1

Production of myristylbenzyldimethyl

■ .- ammonium iodine chloride _: - _,

0.6 'g pure - crystalline' Myristylbenzyldimethyl · - ammonium chloride are dissolved in '95 ml of water To this solution, a distinction is made · ^{andauerndem;.} A solution stirring slowly von 0; 42g of iodine in 5 mL of aqueous 95 ⁰ / ⁱ oigernÄthaüol . inflicted It ^forms; immediately crystallized a golden brown Niederschlag'der quickly and

is eliminated. The reaction mixture is left to stand for 1 hour and then filtered through a glass frit No. 3. The product isolated in this way is washed with a little water, as far as possible by vacuum filtration dried and then left to air dry overnight.

This gives a yield of 0.994 g of the desired Myristylbenzyldimethylammoniumj odchlorids (97.5% of theory), mp = 70 ⁰ C.

The product can be dissolved by dissolving in a little ethanol and pouring into water or by slowly crystallizing be recrystallized from ethanol or chloroform. It has the shape of golden brown Crystals.

By replacing the myristylbenzyldimethylammonium chloride with the stoichiometric amount of corresponding decyl, lauryl, cetyl or stearyl derivatives can the corresponding Alkylbenzyldimethylammoniumjodchloride, their physical Constants given later can be obtained in a similar manner.

Example 2

Production of mixed iodine halides
2 ml of an aqueous 30% solution of a mixture of lauryl, myristyl, cetyl and stearylbenzyldimethylammonium chloride, known as benzalkonium chloride, is added to 92 ml of water. A solution of 0.43 g of iodine in 5 ml of aqueous 95% strength ethanol is slowly added to this solution with stirring. To obtain a golden-brown precipitate which crystallized by cooling the solution to lstündigem 4 ⁰ C. The isolation was performed as described in Example 1 to give 0.930 g (90% of theory) of a mixed product, mp = 40 to 42 ⁰ C, is obtained.
According to Example 1, the following were produced:

(a) Decylbenzyldimethylammonium iodine chloride

(Mp = 48 ° C, solubility = 0.003 g / 100 ml water at 2O ⁰ C);

(b) Laurylbenzyldimethylammonium iodine chloride

(Mp = 60 ° C, solubility = 0.002 g / 100 ml water at 20 ⁰ C);

(c) myristylbenzyldimethylammonium iodine chloride

(M.p. = 70 ° C, solubility = 0.002 g / 100 ml water at 20 ° C);

(d) cetylbenzyldimethylammomum iodine chloride

(Mp = 75 ° C, solubility = 0.001 g / 100 ml water at 20 ⁰ C);

(e) stearylbenzyldimethylammomum iodine chloride

(F. = 8O ⁰ C, solubility = 0.001 g / 100 ml of water at 2O ⁰ C).

Claims (1)

Claim: Process for the preparation of ACylbenzyldimethylammonium iodine halides, characterized in that in per se known Way a solution of iodine in an aqueous medium with a solution of an alkylbenzyldimethylammonium halide reacted with 8 to 18 carbon atoms in the alkyl radical and the resulting precipitate isolated, washed and dried will. Considered publications:
U.S. Patent No. 2,679,533. 609 578/550 5.66 © Bundesdruckerei Berlin