NO141962B - SAFETY LIGHT FOR FITTING IN THE SUPPLY PIPE FOR HEATERS - Google Patents

Description

Process for the preparation of anticoccidially active l-(pyrimidinylmethyl)-piperazines and their acid addition salts.

The present invention relates to a

process for the production of new 1-(pyrimidinylmethyl)-piperazines, as well as acid addition salts thereof which can be used

in the treatment of the poultry disease

coccidiosis and to prevent this.

Coccidiosis is a common and widespread

poultry disease caused by several species of protozoan parasites of the genus Eimeria,

e.g. E. tenella, E. necatrix, E. acervuline,

E. maxima, E. hagani and E. brunetti. E. tenella is the cause of a serious and often fatal

infection in the ceca of chickens with significant

bleeding, accumulation of blood in the ceca and blood

in the stool. E. necatrix as well as others

species attack the small intestine of chickens

and causes coccidiosis in the intestine. Related species of coccidia, such as E. melagridis

and E. anedoides causes coccidiosis in

turkeys. When the disease is not treated,

will the severe forms of coccidiosis lead to

poor weight gain, reduced feeding efficiency and high mortality in poultry. Eradication or control of coccidiosis is therefore

of very great importance in poultry farming. The invention provides a method for synthesizing such piperazines.

The compounds produced according to

invention, and which has a high anticoccidial activity, can be represented by the formula

In the above structural formula, R and R2 mean lower alkyl radicals, R, means hydrogen, lower alkyl or lower alkenyl, and n means 0 or 1 or 2. The lower alkyl radicals R, R, and R., preferably contain 1-3 carbon atoms, and are for example methyl, ethyl, propyl, although other lower alkyl radicals such as butyl and amyl can be used if desired. Those substances in which the alkyl radical in the 2-position of the pyrimidine ring, so R, has 2 or 3 carbon atoms, seem to be the most satisfactory for preventing coccidiosis. R, in the above compounds can be hydrogen or a lower alkyl or alkenyl radical such as methyl, ethyl, propyl, allyl and isopropyl. Although the preferred compounds according to the invention are those where n is 0, the invention also includes substances according to formula I where one or two lower alkyl groups are bound to the carbon atoms in the piperazine ring.

Said 1-(4-amino-2-lower-alkyl-5-pyrimidinylrnethyl)-piperazines which are produced according to the invention easily form acid addition salts which can contain up to three moles of acid per moles of piperazine. Although the invention is not limited to special acid addition salts, when it comes to the treatment of coccidiosis it is preferred to use a non-toxic salt, for example salts of mineral acids such as the hydrochloride, hydrobromide, sulphate and phosphate and salts of organic acids, such as e.g. the citrate, tartrate and naphthalene disulfonates. If an excess of acid is used, the tri-acid salt will be formed, and if a theoretical deficit of acid is used, it will be possible to obtain mixtures of mono-, di- and tri-acid salts.

The compounds according to the invention are prepared by bringing a suitable piperazine into intimate contact with a 4-amino-2-lower-alkyl-5-halo-methyl-pyrimidine. Such halomethyl-pyrimidines are usually prepared synthetically in the form of the diacid addition salts, and it is convenient to use such salts as starting materials. For this reason, it is preferred to use an inorganic base or an excess of piperazine to neutralize the excess acid. The new compounds according to the invention are prepared by reacting equimolar amounts of the piperazine and pyrimidine reactants, and an excess of piperazine or inorganic base is thus not necessary if 4-amino-2-lower-alkyl-5-halomethyl-pyrimidine is used in the form of the free base.

The reaction is conveniently carried out in an inert solvent. If desired, an excess of the liquid piperazine can be used as a reaction medium. The reaction proceeds satisfactorily at room temperature, but higher or lower temperatures can be used without harmful consequences. When one mole of hydrogen bromide is formed as a reaction product, an acid addition salt is formed unless an excess of piperazine or an inorganic base is used, such as e.g. sodium or potassium carbonate to neutralize this acid. The resulting 1-(4-amino-2-lower)alkyl-5-pyrimidinylmethyl)piperazine is conveniently recovered by quenching the reaction mixture in water and extracting the pyrimidinylmethylpiperazine with an organic solvent such as chloroform, benzene or ether. It has been found that the free bases are easier to purify than the acid addition salts, and it is therefore a preferred embodiment of the process to make the mixture strongly alkaline after the reaction is complete and recover the 1-substituted piperazines in the form of the free base. They can be conveniently transferred to any desired acid additive by treatment with an excess of the acid in question in a suitable solvent, such as e.g. methanol, ethanol or ether.

According to another feature of the invention, the present 1-(4-amino-2-lower alkyl-5-pyrimidinylmethyl)-4-lower-alkyl-(or 4-lower-alkenyl)-piperazines can be obtained by first reacting piperazine with 4-amino-2-lower-alkyl-5-halomethylpyrimidine, whereby one obtains 1-(4-amino-2-lower-alkyl-5-pyrimidinylmethyl)piperazine, and treating this with an alkylating agent, such as e.g. a lower alkyl or lower alkenyl halide.

When the compounds according to the invention are used to combat coccidiosis, they are normally given to poultry as a component of the feed, although they can also be given dissolved suspended in the drinking water.

The following examples will further illustrate the invention: Example 1: 1-(4-amino-2-methyl-5-pyrimidinylmethyl)-4-methyl-piperazine. 20 g of 4-amino-2-methyl-5-bromomethyl-pyrimidine dihydrobromide are added to 50 ml of N-methyl-piperazine in a reaction flask. A vigorous reaction is obtained, and the mixture is stirred and heated so that the solids dissolve. The mixture is heated on a steam bath for 3 hours and cooled to room temperature. The precipitated N-methyl-piperazine hydrobromide is removed by filtration, and the filtrate is evaporated in vacuo almost to dryness. The residue thus obtained is dissolved in 5 ml of hot ethanol, 175 ml of ether is added to the solution, and the small amount of precipitate of N-methylpiperazine hydrobromide that is obtained is removed by filtration. The filtrate is re-evaporated substantially to dryness in vacuo, and the residue is dissolved in a small amount of ether. An equal volume of 3 N ethanolic hydrogen chloride is added to the ether solution, whereupon a gummy solid is separated, which, after decanting the solvent, is crystallized by heating in a small amount of ethanol. The thus obtained crystals of 1-(4-amino-2-methyl-5-pyrimidinylmethyl)-4-methylpiperazine trihydrochloride are isolated by filtration. After recrystallization from a mixture of methanol and ether, a product is obtained which melts at 212-216°C.

Example 2: 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-

piperazine.

A. 35 g of 4-amino-2-ethyl-5-bromo-methyl-pyrimidine dihydrobromide is added to 50 g of piperazine hexahydrate in 300 ml of ethanol. The mixture is heated for a few minutes until all solids dissolve and then allowed to stand at room temperature for 18 hours. The mixture is cooled, and any precipitate of piperazine hydrobromide is removed by filtration. The filtrate is evaporated to a volume of approx. 100 ml and made strongly alkaline with 2.5 N aqueous sodium hydroxide. The alkaline solution is extracted with 300 ml of chloroform, and the chloroform extract is separated and washed with 100 ml of water. The chloroform solution is then evaporated to dryness to give a solid consisting of 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-piperazine, m.p. 167—169° C after recrystallization from hot benzene.

B. 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-2,5-dimethylpiperazine is obtained by carrying out the method described under A. using 23 g of 2,5-dimethylpiperazine instead of the piperazine hexahydrate.

Example 3: 1-(amino-2-ethyl-5-pyrimidinylmethyl)-

4- ethylpiperazine.

A mixture of 0.55 g of 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-piperazine and 0.4 g of ethyl iodide in 10 ml of ethanol is heated for 2 hours under reflux. The ethanol is evaporated, and the residue is made strongly alkaline with dilute aqueous sodium hydroxide. This aqueous solution is extracted with an equal volume of ether, and the ether extract is evaporated to dryness in vacuo, yielding practically pure 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-4-ethylpiperazine, m.p. 90°C.

Example 4: 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-

4-methyl-piperazine.

A solution of 9 g of N-methylpiperazine and 10 ml of acetonitrile is added to a suspension of 6.3 g of 4-amino-2-ethyl-5-chloromethyl-pyrimidine dihydrochloride in 50 ml of acetonitrile. The reaction mixture is shaken vigorously for several minutes and is then allowed to stand at room temperature for 18 hours. It is then diluted with 200 ml of water. 25 ml of concentrated ammonium hydroxide are added, and the resulting solution is extracted four times with chloroform in portions of 100 ml. The chloroform extracts are combined and acidified with dilute hydrochloric acid, and the resulting acid solution is evaporated to dryness in vacuo. The residue thus obtained is crystallized from a mixture of methanol and acetone, whereby essentially pure 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-4-methyl piperazine trihydrochloride, sm. p. 250—253° C.

Similar results are obtained when the above method is carried out using 10 g of 4-amino-2-ethyl-5-bromo-methyl-pyrimidine-dihydrobromide and 9 g of N-methylpiperazine as starting materials.

Example 5: 1-(4-amino-2-n-propyl-5-pyrimidinylmethyl)-2,4-dimethylpiperazine.

A mixture of 31 g of 1-carbethoxy-3-methylpiperazine and 81 g of lithium aluminum hydride in 3 liters of ether is heated under reflux for 12 hours. At the end, add 350 ml of water. The ether is decanted, and the aqueous layer containing the largest amount of solids is washed with further portions of new ether. The ether solutions are combined, and the ether is evaporated. The residue is distilled, which gives essentially pure 1,3-dimethylpiperazine, boiling point 60-62° C/38

etc.

10 g of 4-amino-2-n-propyl-5-bromo-methylpyrimidine dihydrobromide are added to 50 ml of acetonitrile. 12 g of 1,3-dimethylpiperazine are added to this solution. The reaction mixture is shaken so that solids dissolve, after which it is allowed to stand at room temperature for 12 hours. It is then diluted with 200 ml of water and 25 ml of concentrated ammonium hydroxide. The solution is extracted with 4 x 100 ml of chloroform, and the chloroform is removed in vacuo. The residue is dissolved in ether, the ether solution is filtered and evaporated, which gives crystals of 1-(4-amino-2-n-propyl-5-pyrimidinylmethyl)-2,4-dimethylpiperazine.

Example 6: 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-4-ethylpiperazine.

74 g of N-ethylpiperazine are added, with stirring, to a suspension of 125 g of anhydrous sodium carbonate and 750 ml of acetonitrile. 246 g of 4-amino-2-ethyl-5-bromo-methylpyrimidine dihydrobromide are added to the resulting mixture over the course of one hour. The resulting mixture is stirred at room temperature for 18 hours, after which carefully

add 500 ml of water. The clear solution obtained is evaporated in vacuo, whereby the acetonitrile is removed. The strongly alkaline residual solution is then extracted with 4 x 250 ml portions of chloroform. The chloroform extracts are combined and evaporated to dryness in vacuo.

The remaining solid is dissolved in 500

ml of ether, and the ether solution is treated with bleaching charcoal. This is removed by filtration, the ether is evaporated to a volume of approx. 200

ml and treated with the same volume of petroleum ether. There, mainly pure 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-4-ethylpiperazine crystallizes out, which after recrystallization from a mixture of ether and petroleum ether melts at 90-91°C.

The method described above is used for synthesizing the below-described 1-(4-amino-2-lower-alkyl-5-pyrimidinylmethyl)-4-lower-alkyl-pipera-

zines, the reactions being carried out using three molar equivalents of the piperazine reactant for each molar equivalent of the pyrimidine reactant: (a) 4-amino-2-n-propyl-5-bromo-methyl-pyrimidine dihydrobromide is reacted with N-methylpiperazine, giving 1-(4-amino-2-n-propyl-5-pyrimidinylmethyl)-4-methylpiperazine, sm. at 126° C after recrystallization from a mixture of chloro-

form and petroleum ether.

(b) 4-amino-2-n-propyl-5-chloromethyl-pyrimidine dihydrochloride is reacted with N-ethylpiperazine to give 1-(4-amino-2-n-2-n-propyl-5-pyrlmidinylmethyl) - 4-ethylpiperazine, sm. at 126° C after recrystallization

tion from a mixture of ether and petrol-

ether.

(c) 4-amino-2-ethyl-5-chloromethylpyrimidine dihydrochloride is reacted with N-isopropylpiperazine to give 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-4-isopropylpiperazine, sm. p. 82—84° C after recrystallization from a mixture of ether and petroleum

ether.

(d) 4-amino-2-ethyl-5-chloromethyl-pyrimidine dihydrochloride is reacted with N-n-propylpiperazine to give 1-(4-amino-2-ethyl-5-pyrimidinyl-methyl)-4-propyl-

piperazine, sm. p. 85—86° C after recrystallization from a mixture of ether and petroleum

ether.

Example 7:

l-( 4- amino- 2- ethyl- 5- pyrimidinyl-

methyl) - 4- allylpiperazine.

10 ml of 3-chloro-propene and 10 g of sodium bicarbonate are added to a solution of 22 g of 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-piperazine in 100 ml of 95% ethanol. The mixture is heated to 50° C and then allowed to stand at room temperature for 18 hours.

10 ml of water is added, and the mixture is heated for one hour at 60-70° C. The alcohol is then evaporated, 50 ml of water is added,

and the product is extracted with 500 ml of bone

zen. The benzene solution is dried over sodium sulfate, filtered and evaporated to dryness

hot in vacuo, giving a residue of 1-(4-amino-2-ethyl-5-pyrimidinylmethyl)-4-allylpiperazine, m.p. at 85° C. This is up-

soluble in cold water. After recrystallization from a mixture of benzene and petroleum ether, the product melts at 91-92° C.

In a similar way, 3-chloro-2-methylpropene is reacted with l-(4-amino-2-ethyl-5-pyrimidinylmethyl)-piperazine, whereby one obtains l-(4-amino-2-ethyl-5-pyrimidinylmethyl)-4 -methallylpiperazine.

Claims (2)

1. Process for the preparation of anticoccidally active l-(pyrimidinylmethyl)-piperazines with the formula where R and R2 are lower alkyl groups, R means hydrogen, lower alkyl and lower alkenyl, and n can be 0,1 or 2, as well as their acid addition salts, characterized by reacting 4-amino-2-lower-alkyl-5- halomethyl-pyrimidine with a compound of the formula where R, has the same meaning as above, or, if desired, when R, is hydrogen, introduces a lower alkyl or alkenyl group instead of the hydrogen atom by alkylation in a manner known per se and, if desired, converting the compounds into their acid addition salts. 2. Method according to claim 1, characterized in that one reacts a halogen hydrogen acid addition salt of 4-amino-2-lower-alkyl-5-halomethyl-pyrimidine with N-lower-alkyl-piperazine.