DE1216314B - Process for the preparation of 1- [2-propyl-4-aminopyrimidyl- (5) -methyl] -pyridinium-monohalides and -halide-hydrohalides - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

C07d

German class: 12 ρ - 7/01

Number: 1216 314

File number: H 39356IV d / 12 ρ

Filing date: May 6, 1960

Opening day: May 12, 1966

The invention relates to a process for the preparation of 1 - [2 - propyl - 4 - aminopyrimidyl (5) methyl] pyridinium monohalides and halide hydrohalides. These compounds are extremely suitable, coccidiosis in poultry control and promote poultry growth.

The method according to the invention is characterized in that in a manner known per se a 4-amino-5-alkoxymethyl-2-propylpyrimidine with a low molecular weight alkoxy group with a picoline and a hydrogen halide and, if desired, the resulting l- [2-propyl-4-aminopyrimidyl- (5) methyl] pyridinium halide hydrohalide into a monohalide or another halide hydrohalide convicted.

The conversion of the obtained l- [2-propyl-4-aminopyrimidyl- (5) -methyl] -methylpyridinium-halo- Genid hydrohalides can be used in a manner known per se, for. B. by ion exchange carried out.

According to one embodiment of the process according to the invention, a 4-amino-5-alkoxymethyl-2-propylpyrimidine, whose lower alkoxy group z. B. may be a methoxy or ethoxy group, with a picoline, e.g. B. α- or y-picoline, in the presence a hydrogen halide, e.g. B. chlorine or hydrogen bromide implemented.

The reaction can be carried out by adding a solution of the pyrimidine component and the pyridine component in an inert organic solvent or diluent, e.g. B. xylene, at elevated temperatures, for example at 75 to 14O ⁰ C, introduces dry hydrogen halide.

The new pyridinium compounds obtainable according to the invention have good solubility in water and are effective against coccidiosis, a very common poultry disease that occurs in the form of severe intestinal infection occurs and is often fatal. This disease is due to various infection Protozoa of the genus Eimeria, e.g. B. Eimeria tenella. Combating this Disease is therefore economically significant for poultry farmers. The new pyridinium compounds are used as active ingredients for the prevention, containment and cure of coccidiosis and can dem Poultry, e.g. B. chickens or turkeys, together with inert carriers, normal food or be administered to the drinking water in prophylactically or therapeutically effective amounts. The new Pyridinium compounds also exert a growth-promoting effect on the poultry and are therefore Can also be used as a growth promoting agent.

Process for the preparation of l- [2-propyl-4-aminopyrimidyl- (5) -methyl] -pyridinium-
monohalides and halide hydrohalides

Applicant:

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel (Switzerland)

Representative:

Dipl.-Ing. Dipl.-Chem. Dr. phil. Dr. techn.
J. Reitstötter and Dr.-Ing. W. Bunte,
Patent Attorneys, Munich 15, Haydnstr. 5

Named as inventor:

Dr. Robert Sancier Aries,

Stamford, Conn. (V. St. A.)

V. St. v. America 9 November 1959

(851520),

dated December 11, 1959

(858 847)

It has also been found that the pyridinium compounds obtained according to the invention exert a potentiating effect on certain sulfonamides, such as sulfachinoxaline.
The prophylactic and curative effectiveness of the new pyridinium _{compounds against coccidiosis is not inhibited by the presence of normal amounts of vitamin B 1} in the feed and compound feed, as is the case with known coccidiosis agents.

The coccidiostatic effect of one of the new compounds, namely l- [2-propyl-4-aminopyrimidyl- (5) - methyl] - methylpyridinemmchloride - hydrochloride, was determined by the following experiment. Groups of twelve weighed 2 week old chicks were given a measured amount of the Compound feed containing active substance. Hours after the start of feeding the die

609 568/547

Feed containing the active substance was inoculated for each chick with 50,000 oocytes of Eimeria tenella. Comparison groups of twelve weighed 2-week chicks each were fed the same compound feed to which, however, no active substance was added and also vaccinated with 50,000 oocytes each. After an 8-day test period, the surviving animals became both of the groups nourished with feed containing active substances and those with feed free of active substances fed groups are killed, weighed and examined for pathological changes. The results are compiled in the following table:

Active ingredient
in the feed
° / o mortality
° / o Weight
increase
7 » Caecale
Damage NuU
0.05
0.0125 37
0
0 31
68
- 59 strength
very light
easy

In contrast, the well-known 1- [2-methyl-4-aminopyrimidyl- (5) -methyl] -2-methyl-3-jS-hydroxyethylpyridinium bromide hydrobromide ineffective at a concentration of 0.05%.

The 4-amino-5-alkoxymethyl-2-propylpyrimidine used as starting materials having a low molecular weight alkoxy group can, as will be explained below, be prepared in a manner not claimed.

Butyramidine hydrochloride, which is produced by the action of hydrogen halide, a lower alkanol, such as Methanol or ethanol, and obtained from ammonia on butyronitrile, is mixed with an alkali metal salt, z. B. the sodium salt, a lower alkyl ester of a-alkoxymethyl - /? - hydroxyacrylic acid with lower alkoxy group obtained by reacting a lower alkyl acrylate, a lower alkyl formate and a lower alkali metal alkoxide, such as sodium methylate or ethylate, obtained is made to react. The resulting ^ hydroxy-S-alkoxymethyl ^ -propylpyrimidine is then carried out into the corresponding 4-amino-5-alkoxymethyl-2-propylpyrimidine. As a lower alkyl formate and lower alkyl acrylates can be used, for example, their methyl or ethyl esters.

Then you can, for example, for the preparation of l- [2-propyl-4-aminopyrimidyl- (5) -methyl] -2-methyl- or ^ -methylpyridinium chloride hydrochloride Prepare the necessary starting substance as follows: First, butyronitrile is made according to known Methods converted into butyramidine hydrochloride by treatment with hydrogen chloride and ammonia. On the other hand, methyl acrylate and methyl formate are condensed with sodium methylate the sodium salt of a-methoxymethyl-jS-hydroxyacrylic acid methyl ester which is then reacted with the butyramidine hydrochloride to form 4-hydroxy-5-methoxymethyl-2-propylpyrimidine to build. This compound is made by treatment with phosphorus oxychloride into the corresponding 4-chloro-5-methoxymethyl-2-propylpyrimidine convicted. The 4-chloro-5-methoxymethyl-2-propylpyrimidine is treated with concentrated aqueous ammonia at elevated pressure to give 4-amino-5-methoxymethyl-2-propylpyrimidine to build.

Another convenient way of working is that you can acrylonitrile with a lower alkanol, for. B.

Methanol or ethanol, reacted in the presence of a basic agent and the / 3-alkoxypropionitrile thus obtained with a lower alkyl formate. Since the lower alkyl formate, in particular Formic acid methyl esters, tend to break down with the formation of carbon monoxide and alkanol decompose, it is advantageous to carry out the reaction with the lower alkyl formate in the presence of Carry out carbon monoxide under pressure. This in

ίο «-Alkoxymethylß-hydroxyacrylonitrile obtained in the form of an alkali salt is treated with a lower alkylating agent, e.g. B. with a lower dialkyl sulfate, such as Dimethyl or diethyl sulfate, alkylated. The α-alkoxymethyl- / 5-alkoxyacrylonitrile thus obtained is, as described above, condensed with butyramidine.

For example, acrylonitrile is used with methyl formate in the route described above with formation of α-methoxymethyl-β-hydroxyacrylonitrile around. This implementation is using

ao of approximately equimolar amounts of the starting materials and using sodium methylate made in an inert organic diluent as a condensing agent. That Sodium methylate is preferably used in a light

Excess over the molar amount, e.g. B. in an amount of 1.1 moles used. As an inert organic Diluents can be aromatic or aliphatic hydrocarbons at 5 mm absolute Boiling pressure below 70 ° C, can be used. Examples of such diluents are benzene, toluene, hexane and heptane. The reaction takes place smoothly at room temperature. This is what happens under these conditions Sodium salt of a-methoxymethyl - ^ - hydroxyacrylonitrile.

For the reasons given above, it is advantageous to when the reaction between the acrylonitrile and the methyl formate in the presence of gaseous Carbon monoxide under a pressure of about 10 to 20 atmospheres, preferably about 14 atmospheres, is made. The sodium salt of α-methoxymethyl-β-hydroxyacrylonitrile is obtained by using carbon monoxide under pressure in higher yields.

The sodium salt obtained in this way is converted into α-methoxymethyl- / 3-methoxyacrylonitrile by methylation with dimethyl sulfate convicted. The dimethyl sulfate is advantageously used in one Amount of about 1 mole, preferably in a slight excess, e.g. B. from 1.1 to 1.2 moles, per mole of the Sodium salt.

The α-methoxymethyl-iS-methoxyacrylonitrile is condensed with butyramidine hydrochloride in the presence of sodium methylate to form 4-amino-5-methoxymethyl-2-propylpyrimidine. Practically equimolar amounts of the three reaction components are required for this reaction. However, it is advantageous to use a small excess of sodium methylate.
The production of 4-amino-5-methoxymethyl-2-propylpyrimidine, which is not claimed here, according to the procedure described above is explained in more detail in Examples a and b below:

Example a

In a fully glass reaction apparatus with a capacity of 51, 691 g of dry,

5 6

With a salt water ^{bath to 5 0} C cooled butyro aqueous solution is filtered to remove oily nitrile 1000 g of particles saturated at room temperature.

Solution of hydrogen chloride in absolute ethanol. The solution is concentrated in vacuo to give it

given. The addition takes place with stirring in portions to reduce the volume by 25% and thus the of 100 g, keeping the temperature at 5 ° C to remove 5 volatile substances. The residue will and the temperature of the reaction mixture 10 ° C diluted with water to the original volume, can not be exceeded. After the whole of the ethano- whereupon the pH-value by means of strong hydrochloric acid to 5.5 Lische hydrogen chloride has been added is adjusted and then an excess of 200 ml stronger dry hydrogen chloride with hydrochloric acid is added over 3 hours.

at a rate of 100 g per hour into the xo Man, the liquid is _{blown in vacuo to 55 ° / 0 of} its reaction mixture, the temperature of the original volume being reduced, whereupon the temperature is kept at 5 ° C. The temperature-restricted solution is then allowed to cool to 25 ° C. and crystallize to rise to 15 to 25 ° C., whereupon the reaction is allowed to occur. The crystals are centrifuged and left to stand overnight with a mixture. In the morning the small amount of cold water is washed, whereupon the excess hydrogen chloride is removed by drying the product at 70 ° C in vacuo, the reaction mixture at 25 ° C in a vacuum of yield of ^ hydroxy-S-methoxymethyl ^ -propyl 10 mm Hg absolute pressure and this pyrimidine is 210 g.

Maintain vacuum for at least 2 hours - To 500 g ^ Hydroxy-S-methoxymethyl ^ -propyl-

receives. Then the reaction mixture to O ⁰ C in a flask pyrimidin are to 1,120 g phosphorus cooled. 20 oxychloride. The mixture is slowly increased to 80 ° C. An alcoholic ammonia solution is prepared, heated and at this temperature for 1 hour by keeping ammonia in absolute ethanol at 5 ° C. It is then cooled to 30.degree. C. and one introduced until the relative pressure is finally 0.7 kg / cm ^{2 of} vacuum from 50 mm of mercury. The ammonia solution is then reduced to 0 ^° C. After the reaction mixture has been cooled in this for 1 hour. The alcoholic ammonia solution is kept in a vacuum, it is slowly heated under the upright butyronitrile-hydrogen chloride reaction product, while maintaining the vacuum, in addition to removing excess phosphorus oxychloride from the imino ether hydrochloride. That

The reaction mixture is cooled to 30 ° C. and up

ητχ η rvrm r \ n xj υπ given 1500 g of crushed ice. The mixture will

C ₃ M ₇ C (JNJbI) - UC ₂ JtIs · JbLCl. : P. . . * · Ττ -πτ . ·. *

3o with ammonia water to a pH value of about

8.5 and then four times with 600 ml of chloro

is added. Alcoholic ammonia is added until extracted. The combined chloroform extracts, the excess hydrogen chloride is neutralized, are under a reduced pressure of about and the temperature is allowed to rise to about 60 ° C. After standing for 200 mm of mercury at 70 ° C. for no more than 1 hour, the product is distilled by a temperature rising to 35. The filter, which is kept at 60 to 65 ° C., is then filtered. The clear pressure on a 10 mm mercury column not over solution is concentrated in vacuo by reducing it to increasing value. The heated to about 115 ° C above 6O ⁰ C and the pressure finally at 10 mm solid product is collected as a forerun. The mercury is brought to the temperature of the main product distilled at 115 ° C in excess of the residue 70 ⁰ C was reached. The residue 40 to temperatures above and is collected until the mixture is cooled to 5O ⁰ C, followed by drops under agitation temperature. Are added in this manner 1800 g of heptane and 4-chloro-5-methoxymethyl-2-propyl-pyrimidine lowers the temperature below 510 g stirring to room temperature (25 ⁰ C). Received that.

Product is filtered on the centrifuge. The solid Into a stainless steel autoclave with a residue as far as possible by centrifugal 45 content of 51 are fugieren 625 ml of concentrated aqueous, and then in a vacuum dryer at 6O ⁰ C solution of ammonia, 90 g of 4-chloro-5-methoxymethylgetrocknet. This gives butyramidine-2-propylpyrimidine and finally 1800 ml of additional hydrochloride in a yield of 90% of the theoretically concentrated aqueous ammonia solution introduced, table value. The autoclave is sealed and heated to 90 ⁰ C. 100 g of sodium are dispersed in 1000 g of heated, 50 The supply of heat is then cut off. In Autovorgetrocknetem paraffin oil in a Stickstoffatmo- klav the temperature continues to rise to about 125 ⁰ C and sphere to form at about 140 ° C "sodium sand". the pressure within about ¹ _1/2 hours to 10.5 kg / cm ² . Then, still under nitrogen, 1000 g. After cooling, the contents of the autoclave are added to methanol in order to form sodium methylate. transferred to 3O ⁰ C in another vessel. After cooling the sodium methylate to 25 ° C., the autoclave is washed with 500 ml of water. A mixture of 167 g of methyl acrylate and wash water is added to the bulk of the reaction 261 g of methyl formate while cooling in a nitrogen mixture. The aqueous-ammoniacal substance atmosphere gradually added. 405 g of butyramidine are extracted with stirring to the reaction mixture obtained six times with 11 l of chloroform mixture each time, and the combined extracts are added under hydrochloride. The mixture is concentrated under a reduced pressure (about 200 mm Hg with absolute careful stirring 1200 ml of water (ice water under pressure) below 40 ° C. until the residue is 0 to 5 ° C.) and finally concentrated ammonia becomes stiff. Then the absolute pressure is added to 100 mm. The reaction mixture is reduced overnight and the temperature is increased to 70 ° C. After kept at ⁰ ° C. Allowing the layers of- removal of the volatile constituents of the back confusion will separate and the temperature to room was 65 to 30 ⁰ C cooled, whereupon sufficient xylene to increase temperature. The aqueous layer is separated off, carefully added to a filterable suspension, the oily layer is washed with water and made up. The suspension is nitrated, whereupon the washing water is added to the aqueous layer. The solid residue with a small amount of xylene

7 8

wash and finally dry at 50 ° C in a vacuum, dry the residue in the oven for 4 hours net is. The yield of 4-amino-5-methoxymethyl- at 60 ° C in vacuo. 68 g of 4-amino-5-me-2-propylpyrimidine are obtained is 77 g. thoxymethyl-2-propylpyrimidine, resulting in a yield

of about 75.1% of the theoretical value.

Example ^{b 5} The method according to the invention is described in

the following examples are explained in more detail: "

In one with a shaker, reflux condenser

and heating device equipped autoclave made of rust - Example 1

free steel with a content of 1.51 is produced

With constant stirring and under reflux, toluene is poured into a flask with a capacity of 51, which is equipped with a suspension of 23 g of sodium in 500 ml of dry reflux condenser and a stirrer. After ¹ _1/2 hours, the contents of the autoclave are cooled to 11 xylene, 250 ml of n-picoline and 200 g of 4-amino to room temperature, whereupon 5-methoxymethyl-2-propylpyrimidine is slowly added.
Stir 32 g of dry methanol are added, the mixture is heated to about 75 ° C, and it

160 g of dry chlorinated water are maintained at about 70 ° C with gentle refluxing, with stirring. After the sodium full gas is initiated. The mixture is then continuously dissolved, the mixture is cooled to room reflux temperature of about 140 ° C., heated during temperature (about 25 ° C.) and kept under reflux with stirring for 6 hours and then to 65 ° C. mixture of 48 g acrylonitrile and 67.5 g formic acid-cooled. The xylene solution is separated off and methyl ester is added to it. The autoclave is then closed with carbon 20% by volume aqueous isopropanol. It is rinsed with monoxide, then heated under a carbon dioxide, the mixture is placed under reflux pressure of 14 atmospheres for 1 hour and overflowed, 3 liters of isopropanol are added, the mixture is cooled and shaken overnight. In the morning the pressure is down to room temperature and then allowed to drop about 10 atmospheres overnight. After lifting the stand ^{at 15 0 C.} The mixture is then brought to about pressure, 150 g of dimethyl sulfate 25 are shaken at 5.degree. C., the mixture is added at this temperature over the course of 4 hours and the temperature is slowly increased, kept under constant pressure and then filtered. The solid residue is stirred within 4 hours to 50 ° C. The contents of the dried. The yield of 1- [2-propyl-4-amino autoclave is then cooled to 25 ° C. and carefully transferred pyrimidyl- (5) -methyl] -2-methylpyridinium chloride-hy in a separating funnel with a capacity of 21. Hydrochloride, which is a white crystalline powder (mp. The autoclave is washed with 200 ml of a 0.5 ° / ₀ igen 30 234 ° C with beginning decomposition), is 280 g. Caustic soda and gives the washing liquid to the

Separating funnel. The contents of the funnel are swirled carefully - Example 2

folds up and lets him sit down. The aqueous layer

is carefully peeled off and discarded. The funnel man works in the same way ₅ as in example 1,

is content-ml two more times with 200 of a 0.5 ° / ₀ by weight 35 is used, however, 250 ml of sodium hydroxide solution for the last reaction stage and then three times with 200 ml of water, y-picoline in place of 250 ml of a-picoline. Washes are obtained in order to remove excess dimethyl sulfate and then 280 g of l- [2-propyl-4-aminopyrimidyl- (5) -water-soluble constituents. The wet thyl] -4-methylpyridinium chloride hydrochloride in the form of a toluene layer is then distilled in a white crystalline powder; MP 246 carefully dried to vacuum at 40 ° C or below, 40 248 ° C (decomposition).

whereby first the water and then the toluene ent- Both the product obtained according to Example 1 as

gives way. The remaining oil is then distilled at an absolute pressure of 5 mm of mercury at a product produced according to Example 2. Nitrogen values which are satisfactory during the analysis and which correspond to the formulas specified for the distillate that passes over to 80 ° C,
discarded. The one at 88 to 102 ° C at a pressure of 45

5mm mercury column distilling fraction Example 3

consists of «-methoxymethyl-jS-methoxyacrylonitrile. It

a small amount of residue remains. The in a equipped with reflux condenser and agitator

Yield of a-methoxy-methyl-ZJ-methoxyacrylonitrile armed flask of 21 contents are 400 ml of xylene, is 61g, i.e. about 52%; based on the 50 100 ml of a-picoline and 80 g of 4-amino-5-methoxymethyl compound Acrylonitrile. 2-propylpyrimidine heated. This mixture is on

11.5 g of sodium are dissolved in 265 ml of methanol. heated to about 75 ° C., and 64 g As soon as the sodium has completely dissolved, dry hydrogen chloride gas is passed in. Then will 61.3 g of dry butyramidine hydrochloride and then the mixture to the reflux temperature of about 64.1 g of α-methoxymethyl-β-methoxyacrylonitrile are added. 55 140 ° C heated for 6 hours under reflux

This mixture is held back for 3 hours and then cooled to 65 ° C, whereupon the Flow temperature (about 71 ° C) heated and then separated for the purpose of xylene solution. The xylene solution will be complete removal of the methanol in vacuo, 400 ml of 83 percent by volume aqueous isopropanol concentrated. The remaining oil is set for 2 hours, whereupon the mixture undercuts for 1 hour which is heated with 125 g of a 50% strength sodium hydroxide solution in a 60 reflux, 1.21 isopropanol added heated boiling water bath. The mixture will be on and the mixture slowly to room temperature-room temperature cooled and then cooled four times at each temperature and then kept at 15 ° C overnight 150 ml of chloroform extracted. The combined chloro- will. The mixture is then cooled to 5 ° C, Form extracts are placed on a water bath and kept at this temperature for 4 hours steams. 500 ml of xylene are added to the residue and the mixture is finally filtered. The solid residue is concentrated the mixture dries to a volume of about 110 ml. 113 g of l- [2-propyl-4-aminopyriein are obtained, whereupon the concentrate is brought to room midyl- (5) -methyl] -2-methylpyridinium chloride hydrotemperature overnight is cooled. The pulp and chloride are filtered off in the form of a fluffy, white crystalline

Powder; Mp. About 234 ° C (with the beginning of decomposition).

Claims (1)

Claim: Process for the preparation of 1- [2-propyl-4 - aminopyrimidyl - (5) - methyl] pyridinium monohalides and halide - hydrohalides, characterized in that in a 4-amino-5-alkoxymethyl-2-propylpyrimidine known per se with a low molecular weight alkoxy group with a picoline and a hydrogen halide implements and, if desired, that 10 obtained 1- [2-propyl-4-aminopyrimidyl (5) methyl] pyridinium halide hydrohalide converted into a monohalide or another halide hydrohalide. Considered publications:
U.S. Patent No. 2,587,262;
"Reports of the German Chemical Society", ίο Vol. 80, 1947, pp. 502 to 505; Journal of the American Chemical Society, Vol. 71, 1949, pp. 2231-2233. When the registration is announced, there are two priority documents and a declaration of transfer have been laid out. 609 568/547 5.66 © Bundesdruckerei Berlin