DE1445111A1 - Process for the preparation of new piperazine compounds - Google Patents

Description

Process for the production of new Plperaainverbindimgen.

For this application, the priority will be from October 3rd, 1966 from United States patent application Serial Ho. 65,924 to claim

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The invention relates to a process for the production of new chemical compounds which are suitable for the treatment of poultry disease and for the prevention of the same.The invention encompasses the new compounds are PiperaBinrerbindungen, and swMX 1- (PyridinylMethyl) -piperazines as well as the acid addition algae dereelben feed for Titre containing these new compounds

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Coccidiosis is a widespread disease caused by several species of protozoal parasites dee (Senns: Eijaeria, such as E. tenella, S.necatrii, E. acervulina, S.aaxtBa, E. hagani and Brunetti, E. tenella raft a severe and often fatal infection of the appendix, which manifests itself in profuse bleeding, analation of blood in the appendix and the appearance of blood in stool. E «neoatrix and certain other species attack and cause the small intestine of chickens The so-called intestinal coccidiosis. Related species of coooidia, such as Smel * »gridis and E.adenoides, are causative agents of coooidlosis in turkeys high mortality of the poultry The elimination or control of the Coocidioee is therefore of the greatest importance for poultry breeding.

It has been found that certain 1-ciyrimidinylmethyl) piperazines and acid addition salts thereof have a strong activity against protozoa which cause coocidiosis. The purpose of the invention is to provide such connections. Am Another purpose of this invention to provide a method for the synthesis of such piperazines "is Furthermore, the invention aims to Sohaffung of agents for the treatment of Ooooi-" Diose or prevention of the same, containing the novel Piperazinoverbindungen as an active ingredient ·

They are compounds produced according to the invention

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1- (4-Amitio-2-lower alkyl-5-pyrijai <iiny! Methyl) -piperazines, the Ptperasinring of which can be further substituted by a lower alkyl or a lower alkenyl, as well as acid addition salts of such piperaisines. This class of compounds _f having the following formula have a powerful Aktirität against Cocoidioae.

In the structural formula above, E and E ₂ mean lower alkyl radicals »H _{1 is} a hydrogen atom» a lower alkyl or a lower alkenyl and η is an integer τοη 0 to 2; Preferably, the lower alkyl groups contain B ₉ E ₁ and E ₂ each having 1 to 3 carbon atoms such as _t β.Bο methyl, ethyl and propyl; however, other lower alkyl groups, such as butyl and amyl graphs, can optionally also be used. Those substances in which the alkyl reet in the position Hr. 2 of the fjrrimidinringes, ie the Best E ₉ has 2 or 5 carbon atoms, seem most effective in Torbeugung against Cocoidiose to be "E ^ may be hydrogen, a lower Alkylreat or a lower Alkenylreet like. the methyl, ethyl, propyl, allyl or isopropyl radical,

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interpret · Although the preferred compounds according to the invention are those in which η has the value Hull, there are compounds of the above formula in which 1 or 2 lower alkyl

8098OR / 1 07R

groups attached to the carbon atom of the piperazine ring are also within the scope of the invention.

The 1- (4-amino-2-lower "alkyl" 5 "pyrimidinylmethyl) piperazines prepared according to the invention easily form acid addition salts which can contain up to 3 moles of acid per mole of piperazine. The invention is not limited to certain acid addition salts; for the treatment of coccidiosis, however, is preferably used a nieht "toxisehes salt · Examples are the salts with mineral acids such as hydrochloric acid or hydrogen bromide acid, sulfates and phosphates and organic acid salts" as citric acid, tartaric acid and Naphthalindlsulfonsäure ■ "Vena is a If excess acid is used, is the tri-acid salt formed? ytewL a theoretical deficit of acid is used, ρ is obtained. natural mixtures of min- ₉ di- and tri-acid salts »

The new compounds are produced according to the invention » by combining a suitable piperazine with a 4-amino-S-niodoalkyl'-S-hydrozyiaethylpyrimidine ester a strong inorganic acid such as hydrohalic acid brings ο as a pyriffiidine reactant participant ^ -Amino ^ -niedo alley 1-5-halogeHmethylpyrimidin preferred «, Such Halogeame thy! Pyrimidine are usually synthetic in the form of their divalent addition salts, and it It is advantageous to use such salts as starting materials. For this reason, the use of an inorganic

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Nice base or an excess of piperazine to neutralize the excess acid. The new connections are through. Reacting equimolar amounts of the piperazines and pyrimidines "prepared so that an excess of piperazine or an inorganic base is not required _s when the 4-amino-nieä 2 * alkyi-5-halogenmethylpyrisidin at 3 used © rm © a free base will*

The reaction is advantageously carried out in an inert solvent. Optionally can be an excess of liquid piperazine used as Eeaktionsmedium., The imple & ung extends sufrie & ensteilend at Eaumtemperatur, but can £ emperaturen also at higher or lower are performed _t without the process dedurch adversely affected "Since as Reaktionsprocltifct 1 mole of hydrogen bromide formed creates a Säurea & ditionssalsSj if is not an excess of piperazine or © ine inorganic base such as Hatrixsai- or Kialiusaearbonat present Mm neutralize the acid au. The 1- (4-amino- "2-jaiQd.alkyl-5-pyrimidinylmethyl) -pipöraain is expediently prepared by introducing the mixture into water and extracting the pyrimidinyl methylpiperaaiüis with an organic solvent such as chloroform-B ^ asol or ether, "won, it has been found to make t that the free bases are easier to clean than keeping the Säureadditionssalsse, and it is therefore a preferred embodiment of the erfinduxigsgemässen process, the mixture after the reaction is strongly alkaline au

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and the 1-substituted piperasines in the form of the free base to gain »You can then easily add any acid addition salt you want be converted »by treating them with an excess of the acid in question in a suitable solvent, such as methanol, ethanol or ether, added.

According to a second feature of the invention, the 1 ~ (4 ~ amin0 «2-n ± ed _a alkyl-5 ~ pyrimidinylmethyl) -4 · - lower alkyl (© der 4-lower alkenyl) - piperazines are obtained by first reacting pipsrazine with a 4-amino-2-lower alkyl-5-halomethylpyrimidine to give a 1- (4-imino-2-lower alkyl-5-pyrimidinylmethyl) piperazine and the latter with an alkylating agent how a lower alkyl or alkeny can react halide «.

When used for the prevention of coccidiosis these compounds are normally gugeführtj the poultry as part of .futters but they can also be presented in solution or suspension in drinking water · A feature of the invention relates to new fuel mixtures ₉ a 1 - (4-amino 2 ~ lower. Alkyl-5-pyr imidinyl methy 1) -piperazine of the above formula or an acid addition salt of the same as an active ingredient against Coccidioee. Such agents contain the piperazine compound intimately distributed or mixed with an inert carrier or diluent, i.e. a diluent which does not react with the piperazine and can be administered to animals without danger. As an embossing agent or thinning agent used pan pre-

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assign a substance that is also part of the putter Comes into consideration.

A preferred feature of the invention are the so-called putter replacements, which contain the active ingredient in a relatively large proportion and are suitable for addition to poultry feed either immediately or after dilution or mixing with another component. Examples of carriers or diluents in this sense are solid, orally administrable carriers, such as dried distillery residues, shark flour, citrus flour, fermentation residues, ground oyster shells »attapulgus clay, wheat milling waste» soluble helasse components, ffiaiskobmehl, edible vegetable matter, soybean flour, roasted soy beans, peeled soybean Soy groats, crushed limestone and the like. The piperazines are thoroughly distributed in the inert carrier by grinding, stirring, tumbling or derglo. "Substance mixtures by selecting appropriate diluents and InderuTsg of the ratio of carrier to active agent can be of any Konsentration prepared j in which the active ingredient content is about 1 to 40 wt .- ^, preferably from about 2 to 25 wt _o - is $, are particularly suitable sum 2ueata with poultry feed. The active ingredient is normally distributed uniformly in or mixed with the diluent ; Under certain circumstances, however, it can also be adsorbed onto the carrier. Examples of typical feed additives that have a ' ^? ~ (4-amine '?' 2 '' lower alkyl-5-pyri-

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is used in a solid inert carrier shares included? are the following*

Yes-

Α «1« (4- ^ Pyyy)

4-ethylpiperazine. 5 »0

Wheat middle good 95 ₉ O

B ο 1 ~ i (4ppy pyyy)

4 »BietkyXpiperazine 10.0

Dried corn distillery residue © 90.0

Co 1 ->. (4-Amino-2 ~ ethyl ~ 5 -pyrimidinylaie thyl) -

4-propylpiperazine 35 »0

Loosely © molasses component © 65 »0

D »1- (4-amino» 2-n-propyl-5 »pyrimidiny imethyl) -

piperazine trihydr ο ciilorid 20 ₉ 0

Melekeiro flour 30.0

. 50 ₉ O

These and similar ^ © uttersueätz be prepared by mixing the active ingredient with d ^ m institution or institutions equal bulky.

Such fodder soups are usually carried on with substances? such as corn flour or so, diluted jabohnenmehl _f before they are added to the animal feed "In this processing, the intermediate stage, the concentration of the agent against Coociäioss from about I ₅ O to about 0 _g 1 wt is., · = ^ lowered * The * Yerdünmmg serves aur ErleicshteruK ^ ^ ⁰¹ "uniform distribution dee THAT CONDITION Toffs in the final Püttes ·. the finished Fütter contains ®iaa source of protein lettp _t carbohydrates, minerals, vitamins and other 5iährstoffβ.

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The amount of 1- (4-aminO "2-lower alkyl-5" pyrimidinylmethyl) piperazine required to control coccidiosis in poultry will of course vary somewhat with the particular compound used generally effective when si © be administered in concentrations of less than about 0.05 · Gewo = ^ of the chuck "the Invention" according to preferred compounds & »h _a that" where the Eest R in the above formula Ithyl- or propyl, the Heat R ₁ is a lower alkyl radical and the value of η "Bull will result in good results, be presented when about 0 to about 0.05 ₈ 0005 ^ turn of the entire feed ingested" In the interest of beaten results to the Poultry feed prior to identification «about 0.005 to 0 ₉ 025 Gqw«. - ■ $ at the pipe-

rag contains * 3> the connections can also be dissolved or suspended in the ν öi & a öeflügels and in this form they can be rich

The following examples are intended to explain the invention further, however, do not limit their scope ^

1- (4-Aaijao-2 = »methyl -5-pyrimidinyl methyl) 4 i

20 g 4 ~ amino «2 ^ metti / l ^ r> - brommethylpyi * imidine-dihydro- ' bromide in a reaction flask with 50 ml of H-Äethylpiperaein offset. A violent reaction takes place, and the mixture is heated with stirring to remove all the solids

rx Q.

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bringing into solution "Then it is heated for 3 hours on a steam bath and cooled to room temperature * Precipitation of ff ^ ethylpiperasin hydrobromide is filtered off and the Filtrai" nearly evaporated to dryness under vacuum. The Bücketand is dissolved in 5 ml of warm ethanol »to the solution 175 ml of ether are added, and this resulting low precipitation of M-Msthjlpiperazin-hydrobroiaid is abfiltrierto The Piltrat is again fskuum virtually evaporated in the Irockne and. The residue taken up in a small Volume ether dissolved "Mach addition of an equal Tolmaena 3n äthanolisohen hydrogen chloride au Ätlierlösung of a resinous solid thus obtained crystals separates the _s wirdc brought after decantation of the solvent by Erwaimea with a small amount of ethanol for crystallization of Dia

trihydroohloria are obtained by filtration. When recrystallized from a mixture of methanol and ether, the product gives a sehmel pimple from 212 to 216 ° C ₀

Example 2

. 1 ° »(4- Aiaino" 2 "ätJa yl« ^ "pyyimidinylffie thyl) -piper agin A, 35 g 4-Aialao« -2- »ethyl-5-broiimiethylpyriJttidin - dihydrobriaid become 50 g of piperazine hexahydrate in 300 The mixture is heated for a few minutes, until all the solids have dissolved, and then left to stand for 18 hours at room temperature, after which it is cooled approximately and any precipitate of piperazine hydrobroide is filtered off.

»10 ■

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The FiXtrat is concentrated ml to about 100 and 5 made with 2 * "" Aqueous sodium hydroxide solution strongly alkaline. The alkaline solution is extracted with 300 ml of chloroform and the chloroform extract separated and washed with 100 ml of water · Then, it is concentrated by evaporation of the chloroform solution to dryness _f wherein one as a solid body 1- (4 'amino-2-ethyl "5 ° pyrimidinylmethyl) -piperassin obtained which ron after recrystallization from hot benzene seem a melting point 167-169 ° C.

B. 1- (4-Amino »2-ethyl-5-pyrimidinylmethyl) -2,5-dimethylpiperazine is obtained according to the process in Section A if 23 g of 2,5-dimethylpiperazine are used instead of the piperaainhexahydrate used.

Example 3

1 -> (4 "Amiiio ™ 2-ethyi ~ 5 ^o -pyrimi disaylstethyl) 4-ethylpiperazine

A vegetable. from 0 _P 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 to Rttekflussteiaperatur for 2 hours» Then the ethanol is evaporated and the The residue is made strongly alkaline with dilute aqueous sodium hydroxide solution * The aqueous solution is extracted with an equal volume of ether and the ether extract is evaporated to dryness in vacuo, giving practically pure ι- (4 ~ amino-2-ethyl-5-pyrimidiny! Methyl} ~ 4-ethylpiperazine; F - 90 ° C =

BATH ORIGINAL

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example 4th

1 - ( 4-AsBino = '2-.ätJayl »5-pyi ¹ imidinyl methyl) -

_mmm ^ 4-methylpiperazine

A solution of 9 g of N-methylpiperazine and 10 ml of acetonitrile is added to a suspension of 6 * 3 g of 4-ABino «2 ~ ethyl-5-chloromethylpyrimidine dihydrachloride in 50 ml of acetonitrile Leave to stand for hours at room temperature ο It is then diluted with 200 ml of water. Then 25 ml of concentrated ammonium hydroxide are added and the solution is extracted animal times with 100 ml of chloroform each time. The chloroform extracts are combined, acidified with dilute hydrochloric acid and evaporated to dryness in vacuo. The residue is obtained by recrystallizing the residue from a mixture of methanol and acetone. practically pure 1 "(4-amino-2-ethyl-5-pyrimidinylmethyl) -4 ^ra methylpiperazine trihydrochloride ι P" 250 at 253 ° Co

Similar results are obtained using the above procedure with 10 g of 4-amino-2-ethyl-5-bΓommethylpyrimidin-dihydrobromid and 9 g of K-methylpiperazine as starting material © carries out ο

1 - {4-Amino -2-n <-pr opy 1-5 ~ pyr imid iny Imethyl) 24dfch

A mixture of 31 g of i-Garbatliozj-J-meth.ylpiporezin and 31 g of lithium aluminum hydrod in 5 liters of ether is heated to air flow temperature for 12 hours. 550 ml of water are then added

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to «The ether is decanted and the aqueous solution», which contains the major part of the solid matter, washed with further portions of fresh ether. The ether solutions are then combined and the ether is evaporated. During the distillation, the residue yields pure 1 ₉ 3 ~ dimethylpiperazine $ Κρ * α = 60 to 62 ° C.

10 g of 4-Äraino-2 «n-propyl ° 5-bromomethylpyrimidine-dihydro- bromide are added to 50 μl of aeetonitrile. This solution 12 g of 1,3-dimethylpiperasine are added "The reaction mixture is shaken" until all the solids have dissolved are »and then left to stand for 12 hours at room temperature · Then dilute with 200 ml of water and 25 ml of concentrated Ammoniumhydroxydo The solution is four times with each 100 ml of chloroform extracted and the chloroform evaporated in vacuo. The residue is dissolved in ether, the ether solution is filtered and then concentrated. Crystals of

Example 6

1- (4-Am ± no-2 ~ ethyl »5-pyrimidinylme thyl) - 4- äthylpiperazin

74 g of H-ethylpiperazine are added with stirring to a suspension of 125 g of anhydrous sodium carbonate in 750 ml of acetonitrile. The mixture is mixed with 246 g of 4-amino-2-ethyl-.5 ~ bro5iimethylpy2 '^>imidine-' dihydrol) romide in the course of 1 hour. The mixture thus obtained is 18 hours

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stirred at room temperature and then carefully mixed with 500 ml of water «The clear solution obtained is in vacuo concentrated to drive off the acetonitrile · Die as residue remaining strongly alkaline solution is four times with each 250 ml of chloroform extracted «The chloroform extracts are combined and evaporated to dryness in vacuo. The solid residue is dissolved in 500 ml of ether and the ether solution treated with decolorizing charcoal. After filtering off the charcoal, the ether solution is concentrated to about 200 ml and mixed with the same volume of petroleum ether added «Bs crystallized practically pure 1 ~ (4-ioaino-2-ethyl-> 5 ~ pyrimidinylmethyl) < 4-ethylpiperasine from ^ which after recrystallization a mixture of ether and petroleum ether has a melting point of 90 to 91 ° C »

The above procedure is used to synthesize the following described 1 «(4-amine ©« 2 ~ low < > alkyl ° »5 = py2rimidinylm @ thyl) -4-lower-alkylpiperasine © applied »the reactions using 3 mol of the respective piperazine compound each Mol of the pyrisaidine compound are carried out?

(a) 4-Aaino "2-n-propyl-" 5 = "bromme thylpyrimidine-dihyäro" - When reacted with N <4, bromide gives diethylpiperazine 1 - (4 ~ Amino-2-n "propyl-5-pyrimidiny! Methyl) ~ 4-methylpiperazine» which has a melting point of 126 ° C after recrystallization from a mixture of chloroform and petroleum ether.

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BATH ORIGINAL

(b) 4 ~

Chloride supplies when reacted with N-ethylpiperassine 1 «- (4-amino-2 ^ n-propyl-5-pyriaiidiiiylme1äiyl) -4 ~ ethylpiperazine, which after recrystallization from a mixture of Ether and petroleum ether have a melting point of 126 ° C

(c) 4-

when reacted with N-isopropylpiperazine

1- (4-Amino-2 «ethyl-5 ~ pyrimidinylmethyl) -4-isopropylpiperazine, which after recrystallization from a mixture of Ither and petroleum ether has a melting point of 82 to 84 ° C having,

(d) 4-imino ~ 2 »ethy 1-5-chlorinethylpyrimidine dihydrochloride delivers when converted with! «- n-P ^ opylpiperasin

4-n ~ propylpiperazine,

which after dom recrystallization aue pin. ©! » Mixture of ether and petroleum ether a S imitate Ispunkt v "A 85 to 86 ° G has"

A solution of 22 g 1- (4
methyXj-piperazine in: 00 al 95 tigern Ithancl is mixed with 10 ml of 3-chlorpropea and 10 g of Hatrtuiatd.earbonat · The mixture is heated to 50 ° C and then for 1 hour at room temperature etehen gelaseezio Hiarauf sets mem. 10 ml of water are added and the mixture is heated to 60 ° to 70 ° C. for 1 hour, then becomes

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the alcohol is evaporated * 50 ml of water are added, and the product is extracted with 500 ml of benzene. The benzene solution is dried over sodium sulfate, filtered and in vacuo evaporated to Srookne »As a Hucketand you get 1- (4-Amino2-ethyl ° '5 =' PyrlJBiäinylm @ thyl) «4-ellylpiperazine; F a 85 ° C. This compound is soluble in cold water.

When recrystallizing from a mixture of benzene and petroleum ether the melting point rises to 91 to 92 ° C.

In a similar way, 3-chloro becomes ~ 2 = ethylpropene with 1 - (4-amino ~ 2 "> ethyl ~ 5" pyrimidinyl methyl) piperazine to 1 - (4-amino = -2 "ethyl = .5 ^ pyrimidinylxB © thyl) =" 4- "methallylpiperaain implemented ο

BATH

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Claims (1)

Claims Claims Process for the preparation of compounds of the formula in which E and E ₂ lower alkyl groups »H ^ mean a hydrogen atom, a lower alkyl group or a lower alfcenyl group and η has a value from 0 to 2, characterized in that one is a 4-amiao-2 ° »nied, alkyl ~ 5-halogejiaethylpyrijaidiii with a ST-S ^ -Piperazia, where B ^ the above meaning Mat. 2 "Process for the preparation of τοη 1- (4-Amiao-2-ni" i.e. alkyl-5-P77imidinyIiaethyl) -4 ~ lower ₉ aLkylpiperas3in3n, characterized in that an addition is used as a hydrogen halide and a 4 ~ Aminp * 2-ni «D.alkyl» 5 '«- halomethylpyrimidini» with an N-lower alb: .ylpIperf «;. Iii converts. 5 · Process for manufacturing lux ton i
midijiylmetiiyl) -4 ~ äthylpiper £ i.'üin, characterized in that 809805/1076 a hydrohalide of 4-Amino-2-ethyl-5-halo-thy 1-pyrimidine reacts with ΙΓ-ethylpiperazine. 4ο process for the preparation of 1- (4-AminQ-2 "-propyl-5-pyrimidinyljaethyl) ~ 4 ~ äthylpiperaz: in _t characterized in that aan a hydrohalide Onea 4-Am no-± 2» propyl-5-'halogeBimethylpyrimidine old an N-lower alkylpiperazine converted * 5 * feed for poultry »characterized _s that ee a connection de? formula in the R and Rg lower alkyl groups * R ^ a water et of fat am, mean a lower alkyl group or a lower alkenyl group and η © in © n has a value from 0 to 2 © inechliesslish, or an acid additive of such a compound contains 6. Futterzueatz for poultry, based on a genieasbaren inert Slower "wherein _t> DAEA it comprises a compound of the formula - 18. 809805/1076 in which R and E ₂ lower ACyl groups »E ^ mean a hydrogen atom, a lower alkyl group or a lower alkenyl group and η has a value from 0 to 2 inclusive, or an acid addition of such a compound in amounts of about 1 to 40 wt. ^ contains 0 9 8 0 5; 1076