DE2306001B2 - PYRIMIDE DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND POULTRY FEED COMPOSITIONS THEREOF - Google Patents

Description

(111)

-N

the remainder of the general formulas A to D

(A)

(B)

(C)

(D)

denotes in which R ¹ denotes a hydrogen atom or a methyl group and at the end of one dotted line there is a hydrogen atom and at the end of the other dotted line there is a methyl group.

2. 6- [4-Amino-2-ethyl-5-pyrimidinyl) methyl] -7-methylthieno- [2,3-c] pyridinium chloride.

3. Process for the preparation of pyrimidine derivatives according to claim 1, characterized in that that one in a known manner

\) a compound of the general formula

v'orin R ^{2 is} a C ₁ - to C ₈ -alkyl or aralkyl radical, is reacted in the presence of hydrogen chloride or hydrogen bromide with a base of the general formulas (A), (B), (C) or (D).

4. Poultry feed composition containing as active ingredient a pyrimidine derivative according to claim 1 or 2.

The invention relates to new pyrimidine derivatives substituted by heterocyclic radicals. which to Prevention and cure of coccidiosis properties.

Coccidia is a common and widespread one Poultry disease caused by several species of the genus Eimeria such as E. tenella, E. necatrix, E. acervulina, E. maxima, E. hagani and E. brunetti. E. tenella causes life-threatening Infection of the appendix of chickens. The symptoms of this infection are profuse bleeding, Accumulation of blood in the appendix and appearance of blood in the feces. E. necatrix and others Species attack the small intestine of the chicken and

cause the condition known as intestinal coccidiosis. Related species, such as E. n.elagridis and E. adenoides, cause coccidiosis in turkeys. The more severe forms of coccidiosis lead to poor weight gain, reduced fertility and high mortality in poultry. The elimination or control of coccidiosis is therefore extremely important in poultry farming.
The subject matter of the invention is defined in the claims.

In compounds according to the invention in which

-N ⁺

has the general formula (D) and R ^{1 represents} a hydrogen atom, the pyrrole pyridine radical can occur in the deprotonized tertiary base form of the formula (D '):

(D)

NIi,

N "V

r-Lj

-CH, X '

(11)

where X 'is a bromine or chlorine atom, or depending on the pH of the physiological medium The equilibrium can be in favor of either the quaternary form or the tertiary base form relocate. However, both forms can be identified separately in the laboratory.

All connections according to the invention can be used easily in the form of the quaternary halide hydrohalo-

: nide, the halide being able to produce chloride or bromide. There is an exception, as suspected, in the case of the compounds of the formula (D '). If rner R 'has a entafluoroethyl group, is most easily formed as a quaternary halide, although when using an excess of hydrogen halide during isolation also releases the quaternary halide hydroalide can isolate.

Among the compounds according to the invention, those in which R denotes an ethylresi are preferred, and Or compounds which one of the residues

(A ₁ )

(B ₁ )

CH,

-N

R ¹

(D ₁ )

contain.

For the preparation of the compounds according to the invention, compounds of the general formula I or III reacted with a base of the general formulas A, B. C or D. These raw materials are compounds are either known or can be readily prepared by conventional methods.

In the procedure according to the invention using a compound of the general formula 11 can be used as the reaction medium, an excess of the bicyclic base or, according to a modified Method, organic solvents which are inert under the reaction conditions, for example acetonitrile or a Ν, Ν-DinicdrigmoIekular-alkyl-alkanolamide, such as dimethylformamide. The reaction temperature is not critical; one leads the procedure is preferably carried out at about room temperature. After a short time the product crystallizes, which is usually the quaternary salt, and is made according to conventional methods, such as by Filter or centrifuge, isolated.

In addition, according to this procedure, 5-hydroxymethylpyrimidine can be introduced into a previously prepared _{reaction medium} in the form of a mixture of thionyl chloride and an NN-dialkylformamide and then the bicyclic base can be added. The latter can be either the free base or its hydrochloride act, (, s The reaction medium is prepared from slöchiomctriseheii proportions of the two components

See at low temperatures, i.e. from about -5 to IO C. The mixture is then heated and the base is added. After the addition of the base, hold reflux the reaction mixture for 1 to 2 hours, then cool it and isolate the product.

Another embodiment of this procedure consists in that a 5-halomethyl-4-amino-2-R'-pyrimidine with the bicyclic base in dimethyl sulfoxide within 30 minutes to 3 hours at temperatures of 40 to 135 "C - if necessary in the presence of an alkali halide, such as potassium bromide, then the reaction mixture with an aryl sulfonic acid, such as p-toluenesulfonic acid, added, the mixture is then heated under reflux for a few minutes, then cooled and finally isolates the product.

In the procedure according to the invention using a compound of the general formula III, the radical R ^{2 can be,} for example, a methyl, ethyl, propyl, isopropyl, tert-butyl, amyl or benzyl radical. Pyrimidines with a methoxymethyl or isopropoxymethyl radical are preferred. These compounds are known; Compounds which are not specifically described can easily be prepared by the methods used for the known, similar compounds; see for example Journ. Amer. Chem. Soc, 59, 1052 (1947), or U.S. Patent 3,161,642 or 2,350,265.

An excess of the bicyclic bases is used here . B, C or D over the pyrimidine. Satisfactory results are achieved if 1.5 to 10 moles of base are used per mole of pyrimidine.

You can mix the two reaction components in the form of the hydrohalides, but it is also possible, the pyrimidine and the bicyclic base to be introduced in the form of the free bases into the reaction mixture and the salts in situ by adding To produce hydrogen chloride or hydrogen bromide to the reaction mixture. Use an excess over that amount of chlorine or hydrogen bromide which is necessary for the conversion of the pyrimidine and the bicyclic Base in the hydrohalides is necessary. The excess of acid over the amount required for the formation of cream is 7.5 to 100%.

This process variant is at atmospheric pressure and at elevated temperatures, ie from about 110 to 200 ^'1 C is performed. The optimal reaction time depends to a large extent on the temperature used. Satisfactory results are achieved within 5 to 10 minutes at higher temperatures, while 10 to 12 hours or more are required at lower temperatures. When the process is carried out within the preferred temperature range, the quaternary salt will form in high yield in about 1 to 8 hours. The R ^r action mixture is heterogeneous in some stages of the process, so that the Giad the mixing can play a role in large-scale plants. The optimum reaction time increases with a decrease in the stirring efficiency.

This procedure is also carried out in an organic solvent medium. Numerous aromatic and aliphatic solvents can be used, e.g. B. toluene, xylene, sec-butylbenzene, Tetrachloroethane, Tclrachlorethylene or chlorobenzene. It is advisable to use a solvent with a boiling point close to the desired reaction temperature, so that one can use the

Process can perform under reflux. The solvent should have a boiling point of at least 110 C, so that the temperature conditions mentioned above are maintained. aside from that the solvent should not be miscible with water, since to achieve optimal: yields undesirable Reaction by-products, such as low molecular weight alkanols and / or water, constantly from the site the reaction should be discharged. Several are suitable for removing low-boiling by-products Methods such as continuous distillation of organic solvents and their replacement by fresh solvent, distillation, or refluxing through a vapor-cooled Liquefier, which allows the low-boiling material to be drawn off, the organic solvent however, returned to the reaction vessel, or the use of commercially available mechanical separation devices.

At the end of the reaction, the reaction product is expediently obtained by cooling the reaction medium and separating the essentially pure solid from the organic solvent. The product is freed from the remaining reaction solvent by washing with suitable solvents such as acetonitrile, isopropanol or ether. If this process is carried out under the reaction conditions described above, the desired products are obtained in yields of above 80% of theory. In many cases, the training _w achieve yields a value of 90% of theory.

You can also react the 5-hydrocarbyloxymethylpyrimidine or the 5-hydrocarbyloxymethylpyrimidine hydrohalide with an excess of the hydrohalogenide of the bicyclic base in the absence of a solvent, the components being refluxed for 30 minutes to 10 hours at an elevated temperature, preferably from 130 to 220 ° C, if necessary under pressure, heated. The hydrohalides can be optionally prepared in situ, by first entering the pyrimidine and the bicyclic base in a low boiling solvent and hydrogen halide gas passes, evaporating the solvent at a temperature below 10O ⁰ C and then heated to the reaction temperature. The product can be recovered by dissolving the reaction product in a solvent such as ethanol or propanol and then recrystallizing it using conventional methods.

When using the compounds according to the invention for the treatment and prevention of coccidiosis, fed this can be found in the feed or in the drinking water of the poultry. For this purpose, the invention Compounds thoroughly dispersed or thoroughly incorporated in an inert carrier or diluent mixed with such a carrier or diluent. The carrier or diluent is preferably a material which from the outset is a constituent part of the animal feed or is used as such Component can be added.

Preferred compositions according to the invention are the feed additives which are relatively high Contain amounts of active ingredients and those of the poultry feed either directly or after prior dilution or blending can be incorporated. Mixtures with an active ingredient content of about 1 up to about 40% by weight, preferably from 2 to 25% by weight, are particularly suitable as an additive for poultry feed.

The compounds of the invention make up in doses less than about 0.05% by weight of the fertilizer effective disease control. In doses of about 0.01-0.05% by weight of the feed the compounds of the invention give good prophylactic results.

The following table shows the superiority of the compounds according to the invention:

Look-up table c

Attempt no.

link

l'rozenlgehal! Active ingredient
in poultry feed called the one
useful effect
can be determined against

Eimciia
lenclla

1 inicria
accrvulina

H ₂ NH ₂ Π ',

I ^c <1 '

N / " ^N N ^A

Cl HCl

0.0030

0.0030

H ₂ NH ₂ CII,

V ₂ W,

Cl IKI

6 - [(4-Amino-2-ethyl-5-pyrimidinyl) -methyl | - 7-methylthieno [2,3-pyridinium chloride-liyclrochloride O. (MK) 2

0.0015

Fortset / unj;

Try no connection

l'ro / .cnlgchall active ingredient in Gcflügclfutlcr. with the one useful effect detectable isl against

Kimcria tcncllu

Eimcria accrvulina

H ₂ NH ₂ CH ₃

I c I

C ₂ H,

-S

Br HBr

5 - [(4-Amino-2-ethyl-5-pyrimidinyl) methyl] -4-methylthieno [3,2-c] pyridinium bromide hydrobromide 0.0004

0.003

H ₂ N

C ₂ H ₅ -

H, CH.,

- O

Br HBr

5 - [(4-Amino-2-ethyl-5-pyrimidinyl) -methyl] -4-methylfuro [3,2-c] pyridinium bromide hydrobromide 0.0008

0.006

H ₂ N

, _N

BrHBr

6 - [(4-Amino-2-ethyl-5-pyrimidinyl) methyl] -

7-methyl-1 H-pyrrolo [2.3-c] pyridinium bromide hydrobromide 0.0008

0.0015

example 1

6 - [(4-Amino-2-ethyl-5-pyrimidinyl) -methyl] -7-methylthieno [2,3-c] pyridinium bromide hydrobromide and chloride hydrochloride

17.8 g of 4-ammo-2-ethyl-5-pyrimidinylmethylbiomide hydrobromide and 8.94 g of 7-methylthieno [2,3-c] pyridine are mixed in 50 ml of anhydrous acetonitrile. The reaction mixture is stirred mechanically at room temperature overnight. The colorless precipitate is isolated and washed with ether. After crystallization from methanol and acetone, 16.5 g (yield 61.5%) of a substance with a melting point of 249 to 250 ° C (Zers-K which is 6 - [(4-amino-2-ethyl-5-pyrimidmy! ) - methyl] - 7 - methytthieno [2.3 - c] -pyridintumbromid-hydrobromid is identified.

The bromide hydrobromide is dissolved in 50 ml of concentrated hydrochloric acid and it is precipitated with 1.5 l of acetone. This procedure is repeated four times. Finally, 7.85 g (yield 60% ) of a colorless, crystalline, solid substance of "F 249 to 25 (TC (decomp.), Soft as 6 ^ (4-Am" o-2-ethy I - 5-p> Tnnkimyl | -raethyl] -7-methylthieno (2L3 - *:] · Dvridinium chloride hydrochloride is identified.

Example 1 2

6 - [(4-Amino-2-pentafluoroethyl-5-pyrirnidinyl) -

methy]] - 7-methylthieno [2,3-c] pyridinium bromide

and 6 - [(4-Amino-2-pentafluoroethyl-5-pyrimidinyl) methyl] -7-methylthieno [2,3-c] pyridinium bromide

* ° hydrobromide

967 mg of 2-peotafluoroethyl-4-amino are suspended 5-bromomethylpyrimidine hydrobronaid in 15 ml of acetonitrile and adds 160 mg (2.75 mmol) of propylene oxide Dissolution of the solid substance added. Then 373 mg of 7-methylthieno [23-c] pyridine are added and stir the homogeneous reaction mixture over there; Weekend. The colorless precipitate formed is mi Ether diluted, isolated and recrystallized as isopropanol

te bsiert. 530 rag (yield 46%) of product are obtained

from F. 215 to 216 C. which as 6 - [(4-Ammo-2-pen tafiuoräthyl-5-pyrirnidinyi) -raethyl] -7-methylthieno [13-c] pyridinium bromide is identified.

The aforementioned product is then η

6s concentrated aqueous hydrobromic acid dissolved

The solution becomes with a to the Ausfafleag of the bromide

hydrobromids sufficient amount of acetone verseui

The starting product 2-pentafluoroethylene | -4-amino

5-Bromomethylpyrimidine hydrobromide is obtained as follows:

80 g of commercially available pentafluoropropionilril are condensed in a dry ice / Acelon condenser and I-I flasks immersed in a dry ice / acelon bath. You fill the flask with about 250 ml of liquid ammonia, remove the cooling bath and allow the mixture to reflux for 1 hour. The ammonia is then allowed to draw off. Pentafluoropropionamidine remains in the form of a colorless, crystalline, solid substance (75.2 g: yield 84%) with a melting point of 48 to 50 ° C

2 - Pcnlafluoroethyl - 4 - amino - 5 - hydroxymethylpyrimidine can be made from pentafluoropropionamidine

10

according to the procedure of Barone et al .. Journ. Org Chem. Vol. 24 (1959). P. 199.

5 g of 2-pentafluoroethyl-4-amino-5-hydroxymethylpyrimidine are dissolved in 30 ml of a 30 to 32% bromine hydrogen solution in acetic acid. The resulting mixture it is heated to 65 ° C. for 6 hours and then cooled to room temperature. This creates a Precipitation, which is poured into KK) ml of ether, filtered off, Wash thoroughly with fresh ether and air dry. 2-Pcnlafluoroethyl-4-amino-5 is obtained - Bromomethylpyrimidine - hydrobromide (6.6 g; Yield 86%) in the form of a colorless, solid substance from F 167 to 169 C (decomposition).

example

5 - [(4-Amino-2-ethyl-5-pyrimidinyl | -methyl] -4-methylthieno [3.2-c] pyridinium bromide hydrobromide and chloride hydrochloride

82.5 g of 4-amino-2-ethyl-5-pyrimidinylmethylbromide hydrobromide are suspended in I I anhydrous acetonitrile. 82.5 g of 4-methylthieno- [3,2-c] pyridine are then added and the reaction mixture is stirred for 2 days at room temperature. The resulting colorless Precipitation is isolated, washed with ether and recrystallized from methanol / isopropanol. You get 69.5 g of a colorless, solid substance from F. 218.5 to 220 C (dec.). After repeated recrystallization from methanol / isopropanol, this gives 52.1 g (yield 42%) of a product with a melting point of 229 to 230 C (decomp.), Which is 5 - [(4-amino-2-ethyl-5-pyrimidinyl> · methyrj -4-methylthieno [3,2-c] pyridinium bromide hydrobromide is identified.

The aforementioned bromide is then dissolved in 130 ml of concentrated HCl and treated with acetone Brought precipitation. This procedure is carried out five times. Finally, 33 g (yield 33%) 5 - [(4-Amino-2-ethyi-5-pyrimidinyl) methyl] -

4-methylthieno [3,2-c] pyridinium chloride hydrochloride from F. 229 to 230 C (decomp.).

Further compounds prepared according to the invention are listed in the table. It becomes that prominent For the examples 1 to 3 described

Densation method applied. In any case it will be the 5-bromomethylpyrimidine and the bicyclic base in an inert solvent in about equimolar amounts Portions condensed at room temperature (about 25 C). The term "base type" in the table

is refers to formulas A, B, C and D

example

^Vcrblndu "S base type

6 - [(4-Amino-2-n-propyI-5-pyrimidinyl) methyl] - A

7-methylthieno [2.3-c] pyridinium bromide hydrobromide 5 - [(4-Amino-2-ethyi-5-pyrimidinyl) methyl] - B

6-methylthieno [3,2-c] pyridinium bromide hydrobromide 5 - [(4-Amino-2-pentafluoroethyl-5-pyrimidinyl} -methyl] - B 4-methylthieno [3,2-c] pyridinium bromide hydrobromide 5 - [(4-Amino-2-ethyl-5-pyrimidinyl) methyl] - C

4-methylfuro [3,2-c] pyridinium bromide hydrobromide 6 - [(4-Amino-2-ethyl-5-pyrimidinyl) methyl] - D

7-meth.y 1- 1 H-pyrrolot23-c] pyridjiniuiBbronii <i £ 6- (4-Ainmo-2-äüiyl-5-pyrimidmyl) -metliyi3- D

1,7-dimetay! -l H-pyrroloC23-c] pyridinium brorrudhydrobroniid

6- [14-ainino-2-ethyi-5-pyrinndinyl) -niethyl] - D '

7-methyl-6H-pyrrok> [23-c] pyridtti

yield Melting point ro 44 269-270 (decomp.) 72 270-271 (dec.) 32 191-192 (decomp.) 30th 228-230 (dec.) 41 235-237 (decomp.) 19th 256-258 (Zere) 30th 192-194 (Zere. 1

example

6 - [(4-Ainino-2-ethyl-5-pyrinüdinyIhrnethyl] -7-methvfthirao [23-cjpyridiniunichlorid-

hydrochloride

50 g of 2-Ayyi-4-anHao-5-Q} eti3Oxyn] etfayi- »ydiaidia are placed. 50 g of 7-MeAyith3eao [23-c3pyridjn and 500 ml of xyiol al emem oat a re-cooler. Führer, TherniOBieter and GaseiolaBrohr aasgestatteen 24-KoSiea. Yes, this mixture is passed

to during 301 Miniaea Cbl _OTW assemo% as with a sufficient amount of ferf «^^ - - ·

used

Replacing the Gasetnfaflrohrdami Bat a Desta-

2 stands aster

25 g 7-methyl

11 12

40 minutes under reflux. At the end of the reflux methanol (about 5 ml) dissolves. Adjust the pH

Period, the reaction mixture is cooled to 65 C of the solution by adding a few drops of water

away. decanted the xylene and mixed the residue concentrated ammonia to about 8. the

with 50 ml of acetonitrile. The resulting mixture becomes solution over dry filled silica gel H

Stirred for about 12 hours at room temperature and S in chloroform / 25% methanol chromatographs.

filtered. The solid 6 - [(4-amino-2-ethyl) obtained in this way gives pure 6 - [(4-amino-2-ethyl-5-pyrimidinyl) -

5-pyrimidinyl) methyl] -7-methyIthieno [2,3-c] pyridimethyl] - 7 - methyl -1 H - pyrrolo [2,3 - c] pyridinium

Niuinchlorid-hydroehlorid is washed. The probomide (0.63 g) has a mp of 255 to 237 ° C.

duct has an F. from 249 to 250 C (decomp.). Dissolve 200 mg of the aforementioned qualernary

The reaction described above can also be carried out using bromide in 2 ml of methanol, which provides the solution

using chlorobenzene instead of In aqueous LiOH to a pH of 8

Xylene can be carried out as a solvent; which and lets the product crystallize out of the solution,

/ further addition of 7 - methylthieno [2,3 - pyridine This gives 100 mg of 6 - [(4-amino-2-ethyl-5-pyridine

stops doing this. The same product is obtained, i.e. midinyl) methyl] -7-methyl-6H-pyrrolo [2,3-c] pyridine

6-t <4-Amino-2-ethyl-5-pyrimidinyl) -methyl] -7-methyl-"5 with a melting point of 192 to 194 ° C.

thieno [2,3-c] pyridinium chloride hydrochloride. By adding 1 mol of halogenated water to the base

acidic, conversely, one obtains the quaternary

Example 12 Nary Halide.

6 - [(4-Amino-2-ethyl-5-pyrimidinyl) methyl] -

7-methyl-IH-pyrrolo [2,3-c] pyridinium bromide and ²⁰ preparations

6-r (4-Amino-2-ethyl-5-pyrimidinyl) -methyl] - _w . ,,. -, .. ",,,. ,

7-methyl-6H-pyrrolo [2,3-c] yridin _P, ^M * ⁿ mixed dteerfindungsgemaße compound

j vj L AVJ evenly with the carrier materials m the following

One carries 420 mg of diisopolyethylamine in amounts:

Solution of 1 g of the pyrimidinylmethyl bromide hydro-25

bromide (I) and 0.44 g of pyrrolopyridine (II) in 6 ml of ^A · 6 - [(4-Amino-2-ethyl-5-pyrimidinyl-

Dimethylformamide. The mixture is stirred methyl] -7-methylthieno [2,3-c] pyridi-

16 hours at room temperature in a nitrogen chloride hydrochloride 2.7 kg

the atmosphere. The reaction product crystallizes wheat standard feed meal 42.6 kg

partly from the mixture of; for complete removal 30 B. 5 - [(4-Amino-2-ethyl-5-pyrimidinyl) -

ether is added to the separation. After filtration and methyl] -4-mcthy1thieno [3,2-c] pyridi-

Drying in air gives 1.6 g of crude product, 4.5 kg of sodium chloride hydrochloride

which is used for cleaning in chloroform / 25% dried grain pulp 40.8 kg

Claims (1)

l ',) a compound of the general form * Claims: 1. Pyrimidine derivatives of the general formula (D in which R denotes an ethyl, n-propyl or pentafluorethyl radical, X denotes a chlorine or bromine ion, b and c denote such integers that the positive charge of b moles of the cation is neutralized by r moles and NH,