JPS5829059B2 - Poultry feed composition and its manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a poultry feed composition containing a novel heterocyclic pyrimidine compound useful for the prevention and treatment of coccidiosis, and a method for producing the composition.

This new compound is effective in limiting coccidiosis when fed in relatively small amounts to poultry and other animals.

Coccidiosis is a common and widespread disease of poultry, caused by several species of Eimeria parasites.
For example, E. tenera (E.

tenella), E. J. J. Trix (E.

necatrix), E. acervulina (E.

acervulina), E. maxima (E.
maxima), E, hagani
), E. brunetti
) etc.

E. tenella (E. tenella) is a severe and often fatal cause of the cecum in chickens, a condition manifested by extensive bleeding, accumulation of blood in the cecum, and transfer of blood into the feces. It is due to cause.

E. necatrix and several other species attack the small intestine of chickens and cause what is known as enteric coccidia.

E. melagridis
) and E. adenoides
) and other coccidia-related organisms are the microorganisms that cause turkey coccidia disease.

If left untreated, coccidiosis can become rampant, causing weight loss, reduced feeding capacity, and high bird mortality.

Therefore, the elimination and control of coccidia is of great importance for the poultry farming industry.

Several pyrimidine compounds have high activity against protozoa that cause coccidiosis, including known anti-coccidiosis-resistant protozoa.

One object of the present invention is to provide poultry feed compositions containing such compounds.

Another object is to provide a method for making these compositions.

Yet another object is to provide animal feed, supplementary feed, and water-soluble compositions containing these pyrimidine compounds.

Other objects will become apparent from the following description of the invention.

According to the invention, 5-methyl(heterocyclic)-
2-Lower alkyl-4-amino-pyrimidine compounds (including compounds in which the heterocyclic ring substituent is substituted with at least one methyl group).

) was found to be highly effective in the treatment and prevention of coccidiosis.

They are especially various Eimeria
It is of value in the treatment and control of diseases caused by 'resistance' species.

The term ``1-resistance'' applies to a class of parasites that are not expected to be controlled by many commercially available anticoccidial agents.

Although these parasites appear to be identical to known species,
As far as susceptibility to commercially available anticoccidial agents is concerned, it is considered that the number has increased to 6.

The compositions of the present invention are effective anticoccidial agents against a variety of species and also control one or more "resistance 1" species.

The compound which is the active ingredient of the present invention has the following formula.

In the formula, R' is alkyl having 1 to 3 carbon atoms, 1 to
Perfluoro-alkyl with 3 carbon atoms, ■・1-
difluoroethyl or 2-2-2-)lifluoroethyl, and X is an anion.

b and C are integers such that b moles of positively charged cations are neutralized by C moles of anions X.

The term "perfluoroalkyl+1" refers to a fully fluorinated alkyl group, such as pentafluoroethyl, n-hebutafluoropropyl or trifluoromethyl.

In addition to these R' groups which are desired embodiments of the invention, other substituents such as methoxymethyl or cyclopropylmethyl and other substituents mentioned in this method may be used in the formula: R is hydrogen or methyl, and the dotted line indicates that only one alpha methyl group can be attached to the ring.

More fully herein below, these anticoccidial compounds combine 2-R'-4-amino-5-halomethyl-pyrimidine or 2-R'-4-amino-5-alkoxymethyl-pyrimidine with a bicyclic heterocyclic ring base. It is produced by reacting with

It is well understood that when R in the compounds R and E (both pyrrolopyridine) is hydrogen, they can exist in the form of typical deprotonated tertiary bases as shown below.

In other words, it is.

Depending on the pH of the physiological solvent, the equilibrium could possibly be unbalanced due to the reformation of the quaternary Q form and the tertiary base 1.

However, both were separately identified in our laboratory.

It is clear that other positional isomers or homologs of the above-mentioned compounds can be easily synthesized and possess anticoccidial activity.

Specifically speaking in bicyclic systems, there are two or more methyl substituents, one of which is in the alpha position relative to the ring nitrogen atom, and the others are in favorable positions unless the other is alpha. It is possible.

Three examples of these compounds are as follows.

All the compounds with the above structural formulas can be easily synthesized and extracted.
It will be clear that the quaternary halide hydrohalide salt (this compound) may be used as a chloride or bromide.

The V and E/ types mentioned above are exceptions to this.

Among many compounds, quaternary halides are most easily formed when R' is pentafluoroethyl, but halide hydrohalide salts can be isolated using excess hydrogen halide during the isolation step.

In the compound which is a good active ingredient of the present invention, the nitrogen-containing heterocyclic base is cheno[2,3-C]pyridine, cheno[3,2-C]
C]pyridine and furo[3.2-C]pyridine.

The dotted lines indicate that a methyl group can be in both positions or neither, but not in both positions at the same time.

More specifically, 6-((4-amino-2-ethyl-5-pyrimidinyl)-methyl]-7-methylcheno[2,3C]pyridinium chloride hydrochloride;
-amino-2-pentafluoroethyl-5-pyrimidinyl)-methyl]-2,7-dimethylthieno[2,3-C
] Pyridinium chloride hydrochloride; 6-((4-amino-2-ethyl-5-pyrimidinyl)-methylio5-methylcheno[2.3C]pyridinium furomite hydrobromide: 5((4-amino-2- ethyl-5-pyrimidinyl)-methyl2-4-methylcheno[3,2-C]pyridinium chloride hydrochloride;
-Improvir-5-pyrimidinyl)-methyl2-6-
Methylcheno[3,2-C]pyridinium bromide hydrobromide; 5-((4-amino-2-pentafluoroethyl-5-pyrimidinyl)-methyl]-4-methylcheno[3,2-C]pyridinium bromide ;5-((
4-amino-2-ethyl-5-pyrimidinyl)-methylio4-methylfurano[3.2-C]pyridinium bromide hydrobromide; 5-((4-amino-2-ethyl-
5-pyrimidinyl)-methyl2-6-methylfurano[3
・2-C]-pyridinium chloride hydrochloride; and 5
-((4-amino-2-1',1'-difluoroethyl-5-pyrimidinyl)-methylyo4-methylfurano [
3.2-C]Pyridinium chloride hydrochloride and the like are good compounds having the above-mentioned groups.

Other suitable groups of the compound which is the active ingredient of the present invention are those in which the nitrogen-containing heterocyclic base is IH-pyrrolo[2,3-C]pyridine or LH-pyrrolo[3,2-C]pyridine, or as mentioned above. Its tertiary base form is as follows.

This is respectively: The dotted line shows that the methyl group can be placed in either position or neither, but not both at the same time.

R is hydrogen or methyl. These valuable and desirable classes of specific compounds include 6-[4-amino-2
-ethyl-5-pyrimidinyl)-methyl]-7-methyl-IH pyrrolo-[2,3-C]pyridinium bromide hydrobromide; 6-((4-amino-2-propyl-5-
pyrimidinyl)-methyl]-1,7-cymethyl-IH-
Pyrrolo[2,3-C)pyridinium bromide hydrobromide; 6-((4-amino2-methyl-5-pyrimidinyl)-methyl]=5-methyl-1H-pyrrolo[2,3-
C] Pyridinium chloride hydrochloride; 6-((4-amino 2-pentafluoroethyl-3-pyrimidinyl)-methyl]-5-methyl-6H-pyrrolo-[2,3-C]pyridine; 5-((4- Amino-2-ethyl-5-pyrimidinyl)methylcou-4-methylIH-pyrrolo[3,2-
C] Pyridinium chloride hydrochloride or 6-((4-
Amino-2-ethyl-5-pyrimidinyl)-methyl]-
7-methyl-6H-pyrrolo[2.3-C]-pyridine and the like.

In the third preferred compound of the active ingredient of the present invention, the nitrogen-containing heterocyclic base is iminodi[l.2-a]pyridine or iminodi[1.5-a]pyridine, respectively; the dotted line is methyl It shows that a group can be placed in either position, but not both at the same time.

It is preferred that there is only one or no methyl group in compounds of type F.

A unique compound that falls into this category of good is 1-[(
4-Amino-2-ethyl-5-pyrimidinyl)-methylyoimidazo[1,2-a]pyridinium chloride hydrochloride; l-[(4-amino-2-ethyl-5-pyrimidinyl)-methylyo3-methyl-imitab( 1-2-a
) Pyridinium bromide hydrobromide: 2-[(4-
Amino-2-ethyl-5-pyrimidinyl)-methyl]-
3-Methyl-imidazo[1,5-a]pyridinium bromide hydrobromide or 2-((4-amino-2-ethyl-5-pyrimidinyl)-methylyo1-methyl-imidazo[1,5-a] Pyridinium chloride hydrochloride, etc.

Among all the good compounds mentioned above, the salt is in the form of chloride hydrochloride, bromide hydrobromide salt is also effective.

Among these good compounds, X is bromide or chloride.

Quaternary anions include many inorganic anions such as iosate, nitrate, sulfate, phosphate, etc., citric, tartaric, acetic, stearic, succinic, benzoic, phthalic, phenoxyacetic, embolic, acetic, 2-naphthalenesulfonic, etc. An anion of an organic acid such as an acid may also be used.

It may also be an anion of a polymer such as a polyphosphate or polystyrene sulfonate ion.

The nature of the anion is not dangerous, and many anions can be used unless they are significantly toxic to poultry.

There are many steps that can be used to synthesize the various compounds described herein.

Generally, a suitably substituted pyrimidine (hereinafter referred to as ■pyrimidine 11) and a methylated nitrogen-containing bicyclic base (hereinafter referred to as °'base+1) are reacted and condensed in one solvent system.

The starting materials, pyrimidine and base, are each known and described in the present method, and can be readily synthesized using the steps described in the present method.

A. Acid Ester Process A good process utilizes a suitable 5-hydroxymethylpyrimidine which is converted to an ester of a strong acid by reaction with a base.

The term strong acid ester refers to a 5-position ester of a pyrimidine made from a hydroxymethyl group and a strong inorganic acid such as a hydrohalic acid.

For example, 2-R14-amino-5-halomethylpyrimidine dihydrohalide, where the halogen is bromine or chlorine and R' is as described above, is reacted directly with a base.

Excess base or, optionally, an organic solvent such as acetonitrile or an N-N-di-lower alkyl alkanoamide such as DMF, which is inert under the reaction conditions, is used as the reaction solvent.

The reaction temperature is not critical, and this step is preferably carried out at room temperature.

The product (usually a quaternary salt) crystallizes in a short time and is removed by conventional methods such as filtration or centrifugation.

This process is explained as follows.

Konouchi R is alkyl consisting of 1 to 3 carbon atoms, 1
Perfluoroalkyl consisting of ~3 carbon atoms, ■・1
-difluoroethyl or 22,2-trifluoroethyl, X' is a halogen such as chlorine or bromine, and Although it is conveniently used, 2-
Quaternary salification with other esters of R'-4-amino-5-hydroxymethylpyrimidine can be carried out.

Suitable esters are methylsulfinate or p-)
Esters of organic sulfinic acids or sulfonic acids such as luenesulfonate.

The reaction is carried out in such a way that good salts for coccidia treatment are obtained directly.

The quaternary salt removed from the synthesis reaction solvent can be conveniently substituted with other salts by conventional methods.

B. Ether decomposition process Another process utilizes the reaction of 2-ft-4-amino-5 methyl ether pyrimidine with a base in the presence of an excess of hydrohalic acid (halogen is chlorine or bromine). be.

This process can be structured as follows.

Among these, R' is an alkyl consisting of 1 to 3 carbon atoms,
perfluoroalkyl of 1 to 3 carbon atoms, 2.
2.2-) IJ fluoroethyl, 1,1-difluoroethyl, R2 is an alkyl of less than 9 carbon atoms, or an aralkyl radical, X/ is a pyIJ midine reaction with halo such as chlorine, bromine The thing (formula above) is 2
-R'-4-Amino-5-hydrocarboxylic dimethylpyrimidine hydrohalide salt.

The hydrocarbon radical forming the 5-position ether substituent (R2> in formula (1) is an alkyl or aralkyl radical, and 9
Preferably, it is a radical containing fewer than 1 carbon atoms.

Such R2 is preferably a lower alkyl group such as methyl, ethyl, isopropyl, furoyl, t-butyl or amyl, or benzyl.

Pyrimidine preferably has methoxymethyl or impropoxymethyl.

These compounds are generally known, are not specifically published, and can be readily prepared by methods utilizing known related compounds.

For example, Journal of the American Chemical Society (J.A.C.S.), 1052 (19
47) or see US Pat. No. 3,161,642 or US Pat. No. 2,350,265.

The base used is also in the form of a hydrohalide salt.

These pyrimidinyl methyl ethers are reacted with a base under the following reaction conditions.

The latter is as evident above.

Use an excess of base over the pyrimidine.

Satisfactory results are obtained when 1.5 to 10 moles of base are used per mole of pyrimidine.

As noted from the above ether decomposition step, in this step pyrimidinyl methyl ether (I[) is decomposed with a base hydrochloride to form the desired quaternary salt.

Although the two reactants are mixed as hydrochloride salts and allowed to react as described below, it is also possible to introduce the pyrimidine and the base as a free base to the reaction mixture, and to add hydrogen chloride to the reaction mixture. addition to form the original salt.

One form of the process comprises converting a 2-lower alkyl-4-amino-5-hydrocarboxylic dimethylpyrimidine into an excess of hydrogen halide (i.e., the amount necessary to convert all the pyrimidine and base to the corresponding hydrohalide). (excess amount)).

This used a 7.5-100 percent excess of acid (
(in excess of the amount required for salt formation).

This step is carried out at normal pressure and at an elevated temperature of 110 to 200°C.

The optimal reaction time depends on the temperature used.

At low temperatures, 10 to 12 hours or more is required, but at higher temperatures, satisfactory results can be obtained in 5 to 10 minutes or less.

If this process is carried out within a favorable temperature range, the quaternary salt will be approximately
Obtained in high yield in 8 hours.

Since the reaction mixture is heterogeneous at several stages of the process, mixing efficiency is a factor in large equipment.

The optimal reaction time increases with decreasing stirring efficiency.

The method is carried out in organic solvents and uses aromatic and aliphatic solvents.

Typical examples are toluene, xylene, secondary butylbenzene, tetrachloroethane, tetrachloroethylene, chlorobenzene, etc.

Since the process is carried out under reflux, it is convenient to use a solvent with a boiling point close to the favorable reaction temperature.

Of course, in order to satisfy the above-mentioned temperature conditions, a solvent having a boiling point of at least 110°C is preferable.

In addition, the solvent should be immiscible with water so that undesired reaction by-products such as lower alkanol and/or water are continuously removed from the reaction system to obtain the highest yields.

Several methods are suitable for removing low-boiling byproducts, including:

i.e. continuous distillation of organic solvent and replacement of it with fresh solvent.

Low-boiling substances exit, but organic solvents are distilled or refluxed in the reactor with a steam-cooled condenser.

This includes the use of commercially available effective automatic separators.

At the end of the reaction time, the reaction system is cooled and the product can be conveniently removed.
A sufficiently pure solid is separated from the organic solvent.

The product is washed with a suitable solvent such as acetonitrile, isopropanol or ether to remove residual reaction solvent.

When this process is carried out under the reaction conditions previously described, yields of over 80 percent of the desired product are obtained.

In most cases, yields are close to 90 percent of theory.

C0 other processes Modifications other than the above two methods are possible.

For example, 5-hydrocarbonoxymethylpyrimidine and 5
-Hydrocarboxylic dimethylpyrimidine hydrohalide without solvent, with excess base hydrohalide and heating temperature (
If necessary, the reaction can be carried out at reflux for 30 minutes to 10 hours under pressure.

If pyrimidine and a base are first used in a low boiling point solvent, the solvent is distilled off at a temperature below 00°C by passing hydrogen chloride gas, and then heated to the reaction temperature to produce the original hydrohalide. be able to.

In either case, the reaction product mixture can be dissolved in a solvent such as ethanol, propatool, etc. and then recrystallized according to conventional methods to obtain the product.

Another variation utilizes the reaction of a 5-hydroxymethylpyrimidine hydronolide with a base hydronolide.

This is done by reacting 5-hydroxymethyl 4-amino-2-R'-pyrimidine with a basic hydrohalide in an organic solvent such as benzene, toluene, or xylene at pH 3 to 6.5, and then intercepting it as before. is good.

Add aqueous acid if necessary.

The reaction is carried out at a heating temperature of about 160-170°C.

The key to the process is that the solvent and water can be distilled off from the reaction mixture and the water removed from the solvent and recycled to prevent concomitant ionization of the corrosive hydrohalic acid in the system.

Another possible variation of this method is 5-hydroxymethyl-
It involves reacting 4-amino-2-R'-pyrimidine with a base.

This is characterized by mixing thionyl chloride and N-N-dialkylformamide, and first adding 5-hydroxymethylpyrimidine to a previously prepared reaction system, and then adding drohalide on top of the base.

The base may be a free base or a basic hydrohalide.

The reaction system is prepared with stoichiometric amounts of the two components.

Keep the opening to which the pyrimidine is added at a low temperature (approximately -5°C to 10°C).

Then heat the mixture and add the base. This is followed by refluxing for 1-2 hours, then cooling the mixture and removing the product.

In addition, 5-(trilower alkylammonium)methyl-4-amino-2-R'-pyrimidine halide (particularly chloride) can be subjected to a substitution reaction with a base;
()'J lower alkylphosphonium)-methyl-4-
Amino-2f(-pyrimidine halides, especially chlorides) can be reacted in a similar manner.

Another similar method utilizes the reaction of a -(2-R'-4-amino-pyrimidin-5-yl)methyl-base tetrachlorozinc complex with ammonia.

Another modification is 5-halomethyl-4-amino 2-B! −
The reaction of the pyrimidine with the base is carried out in dimethyl sulfoxide at 40-135°C for 0.5-3.0 hours with the optional addition of an alkali metal halide salt such as potassium bromide, followed by p.
-) An arylsulfonic acid such as luenesulfonic acid is added to the reaction mixture, after which the mixture is refluxed for a few minutes before cooling and removing the product.

The method is clearly very similar to the acid ester method described above, and variations are also possible.

Other variations and modifications of these methods may be described by other researchers.

It is noted that similar condensation reactions are fully described in the literature.

Obviously, many methods not specifically mentioned herein using similar reactants can be used to make the new compounds of this invention.

When the active ingredient compounds of the present invention are used for the treatment and prevention of coccidiosis, they can be conveniently fed to poultry as a composition of animal feed.

However, they can also be given dissolved or suspended in drinking water.

According to one aspect of the invention, novel acids are provided in which the above-mentioned compounds are provided as active anticoccidial components.

These compositions feature a quaternary salt that is well dispersed or mixed with an inert carrier or diluent.

An inert carrier is one that is non-reactive with respect to the quaternary salt and can be safely administered to animals.

Suitably, the carrier or diluent is or approximates a component of animal feed.

A preferred form of the present invention is a composition containing a relatively large amount of Banto active ingredient, which can be applied directly to poultry feed or after intermediate dilution.
Alternatively, so-called supplementary feeds are suitable to be added to the mixing stage.

Examples of suitable carriers or diluents for such compositions include solid orally ingestible carriers.

Namely, dried grains of sake brewers, corn flour, citrus flour, fermentation residue, oyster shells, attapulgus soil, wheat, molasses melt, corn cob flour, edible vegetables, and roasted Soybean powder, soybean powder feed, antibiotic bacteria, ground soybean powder,
Such as crushed limestone.

This quaternary salt is prepared with a solid inert carrier by crushing, stirring, milling,
Diffuse and mix well using methods such as rotational mixing.

By choosing the appropriate diluent and varying the ratio of carrier to active ingredient, it is possible to prepare compositions of many desired concentrations.

Forms containing about 1 percent to 40 percent by weight (preferably 2 to 25 percent of active ingredient) are suitable for addition to poultry feed.

Compositions containing from 5 to 15 percent by weight of anticoccidial agent are particularly satisfactory.

The active compound is usually dispersed homogeneously into the diluent or, in some cases, adsorbed onto the carrier.

The optimal concentration of anticoccidial agents in these supplemental feeds depends on the degree of specific compounds used.

For feed manufacturers, supplementary feed costs about 450 yen per ton of finished feed? (approximately 1 pound) is conveniently employed, so that a good concentration of the present anticoccidial agent in the supplemental feed is, in part, the desired functional amount of the active ingredient in the finished feed.

In addition to being used alone in mixed feeds, the active ingredient of the present invention, the new compound, can be used in combination with other known anticoccidial agents.

In this case, a sufficient anticoccidial activity spectrum can be ensured even against resistant species.

Other anticoccidial agents, such as amprolium (amp
rolium), ethopabat
e), ni carbaz in
, robenzidene sulfaquinoxaline (5ulfaquinoxaline)
, primethamine, alklomide, sulfanidran, clopitot/1/(
clopidol), nitromide (nitrom)
1de), Zoalene, Roxarzane, Arsanilic acid, Enquinolate, Dec
oquinate), monensin
), nitrophenide
, furazolidone, nihydrazone, nitrofurazone (
n1 trophurazone), dintarium (d
imethalium), clothiamine (cloth
Iamine), etc., were selected for use in conjunction with this product.

The weight ratio of the compound which is the active ingredient of the present invention and the above-mentioned second anticoccidial agent is from 1:1 to 1=IO.

An example of a typical supplemental feed containing a pyridinium quaternary salt dispersed in a solid inert carrier is as follows.

A: 6-[(4-amino-2-ethyl-5-pyrimidinyl) methyl]-7-methylcheno[2,3-C]pyridinium chloride hydrochloride Wheat standard midl ings kg (pounds) 2.7 (6,0) 42.3 (94,0) B: 5-C ( methyl-5 methyl] [3.2 chlorai-4-amino-2-epirimidinyl) = 4-methylchenoC] pyridinium dohydrochloride Salt 4.5 (10,0) Corn Brewer's Dry Grain C: 2-((4 thyl-5 methyl) zo[l.5 muchloriamin-2-epirimidinyl)-3-methylimidaa]pyridinium hydrochloride 40. 5 (90,0) 9.0 (20,0) Corn embryo powder 13.5 (30,0>
Corn brewery dried grains 22.5 (50,0)
These and similar supplementary feeds are prepared by homogeneously mixing the product with a single or composite carrier.

Supplemental feeds of the type exemplified above are usually further diluted with materials such as corn flour or soybean flour before they are incorporated into animal feed.

This dilution is done to facilitate uniform distribution of the substance in the finished feed.

Finished feed contains sources of fat, protein, carbohydrates, minerals, vitamins, and other nutrients.

The amount of drug required to prevent coccidiosis in poultry will, of course, vary somewhat depending on the particular compound or compounds used.

The compounds of formula I above are effective in preventing disease when administered in amounts up to 0.05 percent of the weight of the feed.

Compounds that are good active ingredients of the present invention, namely 6-(
(,4-amino-2-lower alkyl-5-pyrimidinyl)methylcheno[2,3-C)pyridinium or 6-
((4-amino-2-lower alkyl-5-pyrimidinyl)methylyocheno[2,3-C]-pyridinium salt has a good preventive effect when administered at 0.01 to 0.05 percent of the total feed consumed. is obtained.

0.0 of this salt. Most satisfactory results are obtained when the poultry feed contains OO1-Q, 025 percent weight.

When the salt is used as a therapeutic agent, relatively large amounts are used.

Concentrations of 0.02 to 0.05 percent of feed can be advantageously administered for the treatment of coccidiosis outbreaks.

In order to eliminate as much as possible the many side effects that may occur with long-term administration of this compound 4m, it is best to use the lowest dose that will provide adequate control of coccidiosis.

Many of these quaternary salts can be very advantageously and successfully administered to birds in their drinking water.

This method is often used to treat poultry with coccidiosis, as they tend to eat less solid feed than normal crows.

Water-soluble quaternary salts may be added directly to drinking water.

Specifically, a water-soluble powder is prepared in which the anticoccidial agent is thoroughly mixed with a suitable carrier such as dextrose, sucrose, etc., which is added to the poultry drinking water as required.

Such water-soluble powders contain many good concentrations of anticoccidial agents, and suitably contain from 1 to 25 percent by weight of active ingredient.

Preparation Example 1 2-Pentafluoroethyl-4-amino-5-hydroxymethylpyrimidine 2-pentafluoroethyl-4-amino-5-hydroxymethylpyrimidine (A) is Barone
et al., Journal of Organic Chemistry (J, of org, Chem,) i±, 199
(1959) using pentafluoropropionamidine as the starting material.

When using heptafluorobutrylamidine, trifluoroacetamidine, and 3,3,3 trifluoropropionamidine by the Barone'3 process, 2-n-heptafluoropropyl 4-amino-5-hydroxymethyl is used, respectively. Pyrimidine, 2-trifluoromethyl-4-amino-5-hydroxymethylpyrimidine and 2-(l·1-difluoroethyl)-4-amino-5-hydroxymethylpyrimidine are obtained.

Preparation Example 2 2-Pentafluoroethyl-4-amino-5-bromomethylpyrimidine Hydrobromide 5 grams of 2-pentafluoroethyl-4-amino-5-hydroxymethylpyrimidine was dissolved in 30-32 percent hydrogen bromide. , dissolved in 30 ml of acetic acid solution.

The mixture is heated at 65° C. for 6 hours and then cooled to room temperature.

The resulting crystals are poured into 100 milliliters of ether, collected, thoroughly washed with fresh ether, and air dried to give the pyrimidine hydrobromide as a colorless solid.

6.6 grams (86 percent) melting point 167-169°
C (decomposition).

Preparation Example 3 Perfluoroalkylamidine Pentafluoropropionamidine is prepared by the following method: 80 grams of commercially available, inexpensive pentafluoropropionitrile are added to a dry ice-acetone condenser.
Concentrate in a little flask in a dry ice-acetone bath and add about 250 milliliters of liquid ammonia to the flask.

The cooling bath is removed and the mixture is heated to reflux for approximately 1 hour.

Next, ammonia is released and removed.

Amidine remains as colorless crystals. 75.2 grams (84
percent), melting point 48-50°C.

Other perfluoroalkylamidines can be synthesized in a similar manner from commercially available, inexpensive perfluoroalkyl nitriles.

Preparation example 4 3,3,3-trifluoropropionamidine A, 0°C
3.3. in 35.4 grams of absolute alcohol cooled to
3-Trifluoropropionitrile (A, I, S
By hchekot 1khim et al., zh.

Vses, Khim, 0bschchest, 13.
358 (1968).

) 76.3 grams of solution to 28. Add 1 duram of dry hydrogen chloride.

The reaction mixture is kept at O 0 C for 4 days. Ether (500 milliliters) is added and the reaction mixture is cooled to about -25°C.

The resulting crystalline 3,3,3-trifluoro-propionimide ethyl ester hydrochloride is collected and washed with ether.

B, 88.7 grams of 3.3.3-)') Fluoropropionimide ethyl ester hydrochloride in 200 g of ethanol
Add to a stirred solution containing 20 grams of ammonia per milliliter.

After 3 hours at room temperature, the reaction mixture is filtered and then concentrated under vacuum to a thick silolag.

The precipitate of 3,3,3-trifluoropropionamidine hydrochloride obtained by adding an equal amount of acetone is collected and washed with ether.

This material is then treated with equimolar sodium ethoxide in ethanol to yield the free amidine.

Preparation Example 5 2,2-Zinfluoropropionamidine A, ethyl pyruvate (116 grams) are placed in a 1 liter stainless steel hydrogenation vessel.

The container was cooled to -78°C, evacuated to 1⁻ and replaced with nitrogen gas three times.

Sulfur tetrafluoride is distilled into a cooled evacuated vessel.

This is then sealed and heated at 90°C for 10 hours.

The gaseous reaction components are allowed to escape and the liquid is poured into a solution of sodium fluoride in ether (125 milliliters).

The vessel is washed with ether, the combined ether solutions are distilled through a column at normal pressure, and the ethyl 2,2-difluoropropionate is isolated by vacuum distillation as a colorless liquid.

Boiling point 45-50°C (50mm). B, ethyl-2・2-
Difluoropropionate (18 grams) is dissolved in 70 milliliters of ethanol and cooled to 0°C.

The reaction mixture is then saturated with ammonia and left overnight at 0°C.

The mixture is filtered to remove insoluble material and the ethanol is distilled off in vacuo, leaving the 2,2-difluoropropionamide as colorless crystals.

A mixture of 100 grams of 2,2-difluoropropionamide and 200 grams of phosphorus pentoxide, melting point 65-66°G C, is placed in a distillation flask fitted with a condenser and receiver and cooled in a dry ice acetate tank. .

Slowly place the flask into an oil bath maintained at 200°C.

The 2,2-difluoropropionitrile produced as the reaction progresses is distilled off from the reaction mixture.

The crude nitrile is distilled at normal pressure. 06 Next, 2,2-difluoropropionamidine is converted into 2,2-difluoropropionitrile color, and the process for producing pentafluoropropionamidine 1'! Manufactured by the solid method.

Example 1 6-((4-amino-2-ethyl-5-pyrimidinyl)
methyl]-7-methylcheno[2,3-C-)hyridinium chloride hydrochloride 17.8 grams of 4-amino-2-ethyl-5-pyrimidinylmethylbromide hydrobromide and 8.94 grams of 7 -Methylcheno[2.3-C]pyridine is mixed in 50 milliliters of dry acetonitrile.

The reaction mixture is mechanically stirred at room temperature overnight.

The colorless precipitate formed is removed and washed with ether.

Recrystallize from methanol-acetone to give 16.5 grams (6
1.5 percent).

Identified as 6-4m(4-amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylcheno[2,3-C]pyridinium furomy)J hydrolide with a melting point of 249-250°C (decomposition).

Dissolve this bromide hydrobromide in 50 milliliters of concentrated hydrochloric acid.

Precipitate with 1.5 liters of acetone.

Repeat this process four times. A colorless crystalline solid is obtained.

7.85 grams (60 percent), melting point 249-25
6-((4-amino-2-ethyl-5-
pyrimidinyl)methyl]-7-methylcheno[2,3-
C] Identified as pyridinium chloride hydrochloride.

The compounds, 6[(4-amino-2-ethyl-5pyrimidinyl)methyl]-5-methylcheno[2,3-C]pyridinium chloride hydrochloride and 6[(4-amino-2-
Methyl-5-pyrimidinyl) methylcheno[2,3-C
] Pyridinium chloride hydrochloride was converted into 4-amino-2-ethyl-5- as a reactant according to the above reaction.
pyrimidinyl-methyl bromide hydrobromide and 5-
It can be produced using methylcheno[2.3-C,1-pyridine and 4-amino-2-methyl-5-pyrimidinyl-methylbromide hydrobromide and cheno[2.3C]pyridine.

Example 2 6-((4-amino-2-ethyl-5-pyrimidinyl)
Methyl]-2,7-dimethylthieno[2,3-C]pyridinium bromide hydrobromide 891 milligrams of 2-ethyl-4-amino-5-bromomethylpyridine hydrobromide was dissolved in 5 milliliters of dimethylformamide (DMF). When 1.95 g of 2,7-dimethylthieno[2,3-C]pyridine is added, a precipitate immediately forms.

Take the precipitate, wash it with DMF, and discard it.

The slurry was stirred overnight at room temperature, diluted with ether, and an off-white precipitate was removed.

This was washed with ether, the solid was dissolved in methanol,
Introduce hydrogen bromide gas.

The colorless product is isolated from methanol-isopropanol.

Product 6-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-2,7-dimethylthieno[2,3-
C] Pyridinium furomite hydrobromide at 270 miI
Take a J-gram.

Melting point 215-216°C (decomposition), 20 percent yield.

Example 3 6-[(4-amino-2-pentafluoroethyl-5-
pyrimidinyl)methyl]-7-methylcheno[2,3-
C]-pyridinium bromide and 6-((4-amino-2-pentafluoroethyl-5-pyrimidinyl)methyl)-7-methylcheno[2,3-C]pyridinium furomite hydrobromide 4-amino-2 -967 milligrams of pentafluoroethyl-5-methylbromopyrimidine hydrobromide salt are suspended in 15 milliliters of acetonitrile.

Propylene oxide (160 mg 2.75
(IJ mol) to dissolve the solid.

Next, 373 milligrams of 7-methylcheno [2.3
-C] Pyridine is added and the homogeneous reaction mixture is stirred for at least 2 days.

The colorless precipitate formed by diluting with ether was recrystallized with isopropanol to obtain 530 mg (46.5%), melting point 215-216°C, which was added to 6-4
Identified as (4-amino-2-pentafluoroethyl-5-pyrimidinyl)methylcheno[2.3-C]-pyrimidinium furomite.

The latter product is then dissolved in concentrated HBr water and sufficient acetone is added to precipitate the hydrobromide salt of this bromide.

Example 4 5,-((4-amino-2-ethyl-5-pyrimidinyl)methyl2-4-methylcheno[3.2C]pyridinium chloride hydrochloride 4-amino-2-ethyl-5-pyrimidinylmethylbromide hydrobromide 82.5 grams are suspended in 1000 milliliters of dry acetonitrile and 82.5 grams of 4-methylcheno[3.2-C]pyridine are added.

The reaction mixture is stirred at room temperature for two more days.

The resulting colorless precipitate was collected, washed with ether, and recrystallized with methanol-isopropanol to give a colorless solid 69.5
g, melting point 218-220°C (decomposition).

This was recrystallized again from methanol-isopropanol to give 52.1 grams (42%), melting point 229-23.
0 °C (decomposition) and 5-((4-amino 2-ethyl-
5-pyrimidinyl) methyl-4-methylthieno[3.2
-C) Identified as pyridinium furomite hydrobromide.

This bromide salt is then dissolved in 130 milliliters of concentrated hydrochloric acid and crystallized with acetone.

Repeat this process 5 times.

The result is 33,0 grams (33 percent), melting point 2
5-((4-Amino-2-ethyl-5-pyrimidinyl)methyl2-4-methylcheno[3.2-C]-pyridinium chloride hydrochloride is obtained at 29-230°C (decomposition).

Other compounds prepared according to the invention are listed in Table 1.

The condensation process used was as described in Examples 1-4 above.

In each case, 5-bromomethylpyrimidine and base are condensed in an inert solvent using about equivalent amounts at room temperature (about 25°C).

References to 11-base form 11 in the table refer to structural formulas A, B,
C, D, E, F, G, each of which is further quantified below.

Example 16 6-((4-amino-2-ethyl-5-pyrimidinyl)
Reflux 50 g of 2-ethyl-4-amino-5-methoxymethylpyrimidine, 50 g of 7-methylcheno[2.3C]pyridine and 500 ml of xylene. Place in a 2 liter flask equipped with a tube, stirrer, thermometer and gas inlet tube.

Hydrogen chloride gas is introduced in increments of 30 minutes at a rate sufficient to add 0.2 mole equivalents of pyrimidine to the mixture.

When the temperature rises to about 67℃, remove the gas introduction tube,
The mixture is heated to reflux for 2 hours.

(138°C). During this time, fresh xylene is added to replace the amount of liquid to be distilled off.

Add 25 more 7-methylcheno[2,3-C]pyridine
g and the mixture is refluxed for 40 minutes.

At the end of the reflux time, the reaction mixture is cooled to 65° C. and the xylene is decanted.

Add 50 milliliters of acetonitrile to this residue,
This mixture is stirred at room temperature for about 12 hours.

This was filtered and washed to form a solid substance 6 ((4-amino-2-
Ethyl-5-pyrimidinyl)methyl]-7-methylcheno[2.3-C]pyridinium chloride hydrochloride is obtained.

The melting point of the product is 249-250°C (decomposed).

In the above reaction, chlorobenzene is used as a solvent in place of xylene, and 7-methylcheno[2.3-C]pyridine, which is added second, is omitted.

Same product 6-((4-amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylcheno[2,3-C]
Pyrimidinium chloride hydrochloride is obtained.

Example 17 6-((4-amino-2-ethyl-5-pyrimidinyl)
Methyl]-7-methyl-i H-pyrrolo[2,3-C]
Pyridinium bromide and 6-((4-amino-2
-ethyl-5-pyrimidinyl)methyl)-7-methyl-
A solution of pyrimidinylmethylbromide hydrobromide (I) (10 grams) and pyrrolopyridine (■) (0.44 grams) in 6H-pyrrolo[2,3-C]pyridine dimethylformamide (6 milliliters) Add polyethylamine (420 milligrams).

The mixture is stirred at room temperature under a stream of nitrogen gas for 16 hours.

The reaction product partially crystallizes in the mixture.

Add ether to complete the separation.

Filter and air dry to obtain 1.6 grams of crude product.

For this purification, dissolve in chloroform/25 percent methanol (~5 ml) and adjust the pH of the solution to ~8 by adding a few drops of concentrated aqueous ammonia.

This solution was chromatographed on dry silica gel H in chloroform/25 percent methanol to give pure 6-((4-amino-2-ethyl-5-pyrimidinyl)methyl]-7-methyl-IH-pyrrolo[2・3
-C]pyridinium bromide (0.63 grams), melting point 235-237°C.

The above quaternary bromide (200 milligrams) was dissolved in methanol (2 milliliters), and a normal LiOH aqueous solution was added to adjust the pH to 8 and crystallize. ]-7-
Methyl-6H-pyrrolo[2,3-C]pyridine (100
milligrams), with a melting point of 192-194°C.

Conversely, adding one molar equivalent of hydrohalide acid to this base re-forms the quaternary halide.

Adding excess hydrohalide acid to both compounds forms the hydronolide salt of the quaternary halide.

The anticoccidial activity of the pyrimidinyl compound, which is the active ingredient of the present invention, is as follows.

(1) 5-((4-amino-2-ethyl-5-pyrimidyl)methyl]-6-methylcheno(3.2C)pyridinium bromide hydrobromide (2) 6-((4-amino-2- Ethyl-5-pyrimidyl)methyl]-7-methylcheno(2,3-C)pyridinium bromide hydrobromide (3) 6-((4-amino-2-ethyl-5-pyrimidinyl)methyl)-7- Methylcheno(2.C)pyridinium chloride hydrochloride (4) 6-((4-amino-2-ethyl-5-pyrimidinyl)methyl)-7-methylcheno(2.2-C)pyridinium permoate hydrate Product (5) 5-(4-aminodinylmethyl)-4 Ethylmethylcheno(3-pyrimi・2-C)pyridiniumfuromite hydrobromide (6) 5-(
4-amino-2-ethyl-5-pyrimidinylmethyl)-
4-Methylfuro(3,2-(:)pyridiniumfuromite hydrobromide

Claims (1)

[Claims] Formula 1: (wherein R' is alkyl or perfluoroalkyl having 1 to 3 carbon atoms; 1,1-difluoroethyl or 2,2,2-trifluoroethyl; X is an anion. b and C are integers, and b moles of positively charged cations are neutralized by C moles of anion X. is composed of the following various groups: where R is hydrogen or methyl, and the dotted line indicates that a methyl group or hydrogen can be placed on the condition that at least one alpha methyl group is present and both are not alpha methyl groups.) A poultry feed composition containing a compound as an anti-coccidial agent. Acid ester of 22-R'-4-amino-5-hydroxymethylpyrimidine (the acid is a hydrohalic acid,
The halogen is bromine or chlorine) and a bicyclic base are reacted with the formula: (wherein R' is alkyl or perfluoroalkyl having 1 to 3 carbon atoms,
difluoroethyl or 2,2,2-trifluoroethyl, where b and C are hydrogen or methyl such that b moles of positively charged cations are neutralized with c moles of chloride anion X, and the dotted line is at least 1
containing as an anticoccidial agent a compound characterized in that it produces a compound having 5 alpha-methyl groups, indicating that a methyl group or hydrogen can be placed on the condition that both are not alpha-methyl groups. Process for preparing poultry feed compositions.