DE1117600B - Process for the preparation of quaternary ammonium salts effective against nematodes - Google Patents

Description

GERMAN

PATENT OFFICE

W 20835 IVb / 12 q

REGISTRATION DATE: MARCH 21, 1957

NOTICE THE REGISTRATION AND ISSUE OF THE EDITORIAL: NOVEMBER 23, 1961

It was found that compounds of the general formula

CH _a

0- (CH ₂ VN-CH ₂ -

CH _a

(I)

in which R ^{1 is} hydrogen, chlorine, bromine or a methyl or nitro group, R ^{a is} hydrogen, chlorine, bromine, fluorine or a methyl group and A ~ is the anion of an acid, e.g. B. bromide, iodide or methosulfate, means, are effective against intestinal parasites that are closely connected to mucous membranes in body cavities. Examples of this are the Trichostrongyliden in sheep and cattle, ie parasites of considerable economic importance. The effectiveness of the compounds according to formula I was determined by comparative experiments with Nippostrongylus muris in rats. Likewise, the connections are z. B. effective against the intestinal parasites Aspiculuris tetraptera and Nematospiroides dubius in mice.

When administered to sheep, the effectiveness of various members of the series was determined namely against parasitic organisms such as Nematodirus sp., Ostertagia circumcincta, O. trifuracata, Cooperia curticei and Trichostrongylus axei. The effectiveness over the first four of those mentioned Parasite is of particular concern as against them certain phenothiazine supplements, like them often used in veterinary medicine have little effect.

The administration of the compounds under discussion here to animals such as sheep, cattle and the like is also advantageous in that it is practical by combating and eliminating those living in the intestines of the animals nematodes already in the host-guest relationship an increase for understandable reasons the wool or meat yield can be achieved.

But also for the control and elimination of intestinal and intestinal worms in human medicine the compounds according to formula have proven themselves.

The invention accordingly consists in a process for the preparation of quaternary ammonium salts of this general formula I effective against nematodes, in which R ^{1 is} hydrogen, chlorine, bromine, a methyl or nitro group, R ^{2 is} hydrogen, chlorine, bromine, fluorine or a methyl group and A ~ is an anion other than chloride, characterized in that a tertiary amine, which three of the

Method of manufacture

of effective against nematodes

quaternary ammonium salts

Applicant:

The Wellcome Foundation Limited, London

Representative: Dr. M. Eule, patent attorney,

Munich 13, Kurfürstenplatz 2

Claimed priority:

Great Britain of March 29, 1956 (No. 9896/56)
and January 24, 1957 (No. 2595/57)

Frederick Charles Copp, London,
has been named as the inventor

Contains nitrogen substituents desired in the end product, in a manner known per se with introduction of the fourth desired substituent is quaternized and optionally the salt thus obtained into the Salt of another anion is converted in a manner known per se.

According to the invention, for. B. proceed in such a way that a tertiary amine the Formula II with 1 mole (or a slight excess) of a methylating agent such as methyl iodide or dimethyl sulfate is quaternized; the compounds in question here can also be established are by the reaction of a secondary amine of the formula III with two or more moles the methylating agent in the presence of an acid binding agent such as sodium carbonate. Here is note that this reaction occurs with formation of the intermediate of the tertiary amine of formula II and therefore the simultaneous production of this latter amine and its quaternization equals. Both reactions can take place in a solvent such as acetone or methanol does not enter into the reaction.

0- (CHJi) ₂ -N-CH ₂

- (CH ₂ )., - NH-CH

R ² (III)

109 740/548

3 4

Optional methods of synthesis result from the following equations:

(a) ζ J- ° - ( ^CH ^ - N (CH ₃ ) _a + XCH ₂

(b) <V- O- (CHa) ₂ X + N (CH ₃ ) _{2 -CH}

In these formulas (a) and (b), X represents an appropriate whereupon the mixture is left on a steam reactive moiety for 5 hours, e.g. B. a halogen bath was heated. The precipitated benzylamine ~ (Chlorine, bromine or iodine) or methosulphate. * 5 hydrobromide was filtered off and with fresh

The reaction (a) can be washed by the presence of benzene. The filtrate was supported together with potassium iodide, since the desired wash liquor was shaken with 4N sodium hydroxide solution, quaternary compound I usually isolated as iodide. The aqueous layer was removed, the benzene layer was removed. Both reactions - (a) and (b) - were dried over solid potassium hydroxide, advantageously filtered in a suitable solution and evaporated; the residue would be made in the medium like benzene. The former vacuum distilled. The 1-benzylamino reaction obtained is rapid, while the latter requires 2-phenoxyethane as a colorless oil with a boiling point of heating for prolonged periods of time; You can point from 150 to 154 ° / 0.3mm.
also by heating the reagents together without the procedure according to 4 g of this base in 5 ml

The presence of a solvent. Dissolved 25 methanol, whereupon 5.3 g of finely powdered

If so desired, each can re anhydrous sodium carbonate and 14.5 g methyl iodide resulting salts were added to the salts in the usual manner. After half an hour of heating other suitable acids are converted. the mixture was filtered under reflux, and the

Remarkably, it was found that the filtrate was slowly added to ether. The effectiveness of these compounds differed with the indicated 30 N-benzyl-N: N-dimethyl-N-2-phenoxyäthylam structure is closely connected. It has been found that monium iodide in colorless crystals with a variant that depends on the general formula I melting point of 146 to 147 °.
differ, are either poisonous, e.g. B. chlorides,.

or - if, for example, R ¹ or R ^{2 is} alkoxy Example 2

Groups or higher alkyl groups than methyl 35 23 gl-Benzylamino-2-phenoxyethane were slow - show no effect. The same applies to a cooled mixture of 12 g of anhydrous substitution of the benzene rings in meta- or para-formic acid and 9.5 ml of 37% aqueous form. Certain compounds, which are added with those aldehydes. When heated on a structurally narrow steam bath according to the general formula I, gas was rapidly evolved. have already been described in the literature, 40 The heating was then continued for 14 hours but with all these compounds one had to continue, the solution was then cooled, 15 ml make sure that it either did not concentrate any for the present Hydrochloric acid was added and the uses showed appropriate effect or mixture was evaporated in vacuo. The return but was available for administration in therapeutic doses was dissolved in water, ammonia was used in the too toxic. For example, the sweat excess is added, and the precipitated oil was extracted with ether, described in Zerian Patent 256,345. The ethereal extract was phenoxyäthyldimethylbenzylammoniumchlorid dried over solid potassium hydroxide, filtered Nippostrongylus muris completely ineffective and shows and evaporated. The remaining 1- (N-benzyl against Nematospiroides dubius only had little effect. N-methylamino) -2-phenoxyethane was distilled in a vacuum. It was in no way predictable that by so 50; it had a boiling point of 116 to slight changes in the molecule completely different - 12270.04 mm.
like effects can be achieved. According to the procedure, 3 g of dimethyl sulfate were added

The compounds prepared according to the invention are a solution of 5 g of this base in 10 ml of acetone can be added in the form of tablets, suppositories or respectively. The mixture warmed up spontaneously, Suppositories, capsules or (if the compound is un- 55 and .es crystallized N-benzyl-N: N-dimethyl soluble is) in aqueous suspension, which suitable N-2-phenoxyäthylammoniummethylsulfat with a May contain suspending agents, presented melting point of 102 °. One used in place will. of the dimethyl sulfate, 3.7 g of methyl iodide were then obtained

The present invention is now to hand one the corresponding iodide; It was identical to the examples below, in which all temperatures are the product described in Example 1,
temperatures are given in degrees Celsius and -.

if necessary - also the production of example 3

Starting materials is described, the more detailed A solution of 10.0 g of 2-phenoxyethyl bromide and

to be purified. 6.8 g of N: N-dimethylbenzylamine in 10 ml of benzene

Example 1 ^{6s me (} % heated on a steam bath for 40 hours.

An oil slowly separated and crystallized

30 g of 2-phenoxyethyl bromide were then a solution. After cooling it became solid of 50 g of benzylamine in 50 ml of benzene added, the body filtered off, washed with fresh benzene

Claims (1)

5 6 and from a mixture of propanol (2) and ethyl ammonium iodide with a melting point of 166 to acetate recrystallized. N-benzyl-N: N-di-167 ° was obtained. methyl-N-2-phenoxyethylammonium bromide as an example 9 colorless solid with a melting point from 144.5 to 146 °. 5 7.5 g o-chlorobenzyl bromide and 6 g potassium iodide. Example 4 were added to a solution of 4.5 g of 1-dimethylamino- 2-phenoxyethane in methanol is added. That As in Example 1, the mixture was refluxed from 2-phenoxy for 30 minutes ethyl bromide and o-methylbenzylamine 1-o-methyl and filtered; Ether was added to the filtrate. benzylamino-2-phenoxyethane produced and after io it was a rather resinous product. This the procedure of Example 2, paragraph 1, into which was filtered off and recrystallized from propanol (2), l- (N-methyl-N-o-methylbenzylamino) -2-phenoxyethane to pure N-o-chlorobenzyl-N: N-dimethyl-N-2-with converted to a boiling point of 128 ° / 0.06 mm. phenoxyäthylammoniumjodid with a melting case the quaternization according to the procedure reacted to give a point of 122 to 123 °, this base gently with methyl iodide in acetone solution 15 and thereby gave N: N-dimethyl-N-o-methylbenzyl example 10 N-2-phenoxyethylammonium iodide with a melting- As in Example 9, 1-dimethylamino point from 144 to 145 °. 2-o-methylphenoxyethane with o-chlorobenzylbrqmide reacted in the presence of potassium iodide to Example 5 _ao No-chlorobenzyl-N: N-dimethyl-N- (2-o-methylphene to give l-benzylamino-2-o-methylphenoxyethane with an oxyethylammonium iodide; it crystallized Boiling point of 200 to 204719 mm was similar from propanol- (2) with a melting point of 176 Way made from 2-o-Methylphenoxyäthylbromid to 177 ° from. and benzylamine and converted to the 1- (N-benzyl example 11 N-methylamino) -2-o-methylphenoxyethane with a 25 Boiling point of 198 ° / 16mm. With methyl iodide from l-dimethylamino-2-phenoxyethane and o-fluoro this base according to the N-benzyl-N: N-dimethylbenzyl bromide process was N-o-fluorobenzyl-N: N-dimethyl-N- (2-omethylphenoxyethyl) - ammonium iodide with N-2-phenoxyethylammonium bromide with a melting point of 153 to 154 °. Melting point of 142 to 144 ° obtained and analogous 30 with o-bromobenzyl bromide the N-o-bromobenzyl example 6 N: N-dimethyl-N-2-phenoxyethylammonium bromide. with a melting point of 101 to 102 °. 1 - ο - methylbenzylamino - 2- ο - methylphenoxyethane with a boiling point of 144 to 148 ° / 0.3 mm, Example 12 prepared in a similar manner from 2-o-methylphenoxy-35 ethyl bromide and o-methylbenzylamine and vice versa 250 g of 2-o-nitrophenoxyethyl bromide and 450 ml converts to l- (N-methyl-N-o-methylbenzylamino) - a 50% solution of dimethylamine in methanol 2-o-methylphenoxyethane with a boiling point of were in an autoclave for 2 hours at 80 ° 138 to 140 ° / 0.1 mm. Reacted with one another according to the method with methyl. The reaction iodide reacted, this base resulted in N: N-dimethyl mixture was then evaporated, the residue with N-o-methylbenzyl-N- (2-o-methylphenoxyethyl) -am- ammonia made basic in excess and that Monium iodide with a melting point of 182 to deposited oil extracted with ether. The residue 183 °. from the evaporation of this essential extract was treated with excess 2N hydrochloric acid Example 7 45 and evaporated the resulting solution. Man received l-dimethylamino-2-o-nitrophenoxyethane hydro- l-Benzylamino-2-o-chlorophenoxyethane with a chloride obtained from ethanol with a melting point Boiling point from 138 to 144 ° / 0.05 mm was crystallized in from 174 to 175 °, similarly prepared from benzylamine and this hydrochloride was made with aqueous ammonia 2-o-Chlorophenoxyäthylbromid and converted in 50 treated in excess to the free base. erdas l- (N-Benzyl-N-methylamino) -2-o-chlorophenoxy hold, which in the usual way with ether ethane with a boiling point of 144 to 148 ^o / 0.07 mm. isolated and dissolved in 500 ml of acetone. Implemented according to the process with methyl iodide, resulted in the process, reacted with 115 g of benzyl chloride, this base N-benzyl-N- (2-o-chlorophenoxyethyl) -N: crystallized N-benzyl-N: N-dimethyl-No-nitrophen-N- dimethylammonium iodide with a melting point of 55 oxyäthylammoniumchlorid from. This chloride was from 119 to 120 °. filtered off after 72 hours with fresh acetone washed and immediately dried in vacuo. Since that Example 8 Salt is deliquescent, it was dissolved in 700 ml of water and with a solution of 170 g of potassium iodide in l-o-chlorophenoxy-2-o-methylbenzylaminoethane 60 200ml water treated to the corresponding iodide with a boiling point of 146 to 150 ° / 0, 1 mm was to be obtained, which results from the aqueous mixture in prepared in a similar manner from 2-o-chlorophenoxy crystals with a melting point of 140 to 141 ° ethyl bromide and o-methylbenzylamine and quickly parted, converts to the l-o-chlorophenoxy-2- (N-methyl- N-o-methylbenzylamino) ethane with a boiling point of 65. from 146 to 15070.2 mm. According to the procedure with Reacted methyl iodide, this gave BaseN- (2-o-chloro process for the preparation of against Nema- phenoxyethyl) - N: N-dimethyl-N-ο-methylbenzyl- deadly effective quaternary ammonium salts the general formula CH _a -0- (CHs) ₂ -N-CH ₂ -A " in which R ^{1 is} hydrogen, chlorine, bromine, a methyl or nitro group, R ^{2 is} hydrogen, chlorine, bromine, fluorine or a methyl group and A ^{- is} an anion other than chloride, characterized in that a tertiary amine, which is three of the im End product contains desired nitrogen substituents, is quaternized in a manner known per se with introduction of the fourth desired substituent and, if appropriate, the salt thus obtained is converted into the salt of another anion in a manner known per se. Considered publications:
German Patent No. 627 880;
British Patent No. 703,477;
Swiss Patent No. 258 716;
U.S. Patent No. 2,734,918;
Comptes rendus, 1955, p. 2155. 109 740/548 11.61