NO122650B - - Google Patents

Description

Process for the production of therapeutically active,

quaternary compounds.

The invention relates to the production of therapeutically active compounds with formula

wherein n means an integer from 2 to 5, m means an integer from 1 to 4 and p means an integer from 0 to 2, Y means a direct bond or a methylene, 1,1-ethylene- or'1, 2-ethylene group, and

X<®>means an acid anion, as well as acid addition salts thereof.

i The compounds according to the invention are e.g. applicable

in the form of animal repellants that are suitable for raising poultry, especially to reduce yield losses that can be attributed to the poultry disease known as coccidiosis.

! Coccidiosis is a protozoan infection of the digestive tract, especially in young poultry, such as young hens, and can cause severe disruptions in poultry farming and large economic losses. The disease is caused by coccidiosis agents such as e.g. Eimeria Tenella, Eimeria acervulina, Eimeria adenoides, Eimeria agridis, Eimeria brunetti, Eimeria hagani, Eimeria maxima or Eimeria necatrix, as the infection takes a more acute course with certain organisms, such as Eimeria tenella, with others a more chronic course such as Eimeria acervulina, Eimeria brunetti, Eimeria hagani, Eimeria maxima or Eimeria necatrix.

The anion X<®> as well as the aforementioned acid addition salts can preferably be derived from therapeutically usable inorganic or organic acids, e.g. from hydrohalic acids, such as hydrochloric or hydrobromic acids, sulphurous, phosphoric, nitric or perchloric acids, as well as aliphatic, alicyclic, aromatic or heterocyclic carbonic or sulphonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic , malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid, p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid, methionine, tryptophan, lysine or aginine.

, 4-amino-2-cyclopropylmethyl-5-(2,4-dimethyl-pyridinium)-methyl-pyrimidine chloride and 4-amino-2-cyclopropylmethyl-5-(2-methylpyridinium)-methyl-pyrimidine chloride should be highlighted and the acid addition salts, especially the hydrochlorides thereof.

The new compounds are produced according to the invention by either

a) reacts a reactive ester or ether of a compound of formula

wherein R means a hydroxy group, a mercapto group, or a salt thereof with a compound of formula

or a salt thereof, or

b) converts one to the compound of formula I corresponding quaternary base or pseudobase in the quaternary salt and, if desired, converts

a formed free compound in its acid addition salt or a formed acid addition salt in the free compound or in another salt and/or a resulting quaternary salt in another quaternary salt.

A reactive ester of the aforementioned 5-R0-methyl starting material is e.g. the ester of a strong inorganic or organic acid, such as a hydrohalic, sulfuric, sulphonic or carbamic acid, e.g. hydrochloric, hydrobromic, sulfuric or lower alkylsulfuric acid, a lower alkane or benzosulfonic acid, such as methane-, ethane-, benzol- or p-toluenesulfonic acid, or an unsubstituted or N-substituted carbamic acid, such as N,N-dimethylcarbamic acid or N-phenyl-carbamic acid. Ethers of the aforementioned 5-R-methyl compounds are preferably lower alkyl or phenyl lower alkyl ethers, such as methyl, ethyl, isopropyl or benzyl ether. Preferably, reactive esters of 4-amino-5-RQ-methyl-2-N-pyrimidine starting material react in free form or in the form of their acid addition salts with the free heterocyclic compounds, while the corresponding reactive ethers react in free form with the acid addition salts of the heterocyclic reaction participants.

The quaternary bases or pseudobases may contain the hydroxy group as anion or as substituents of the heterocyclic, ammonium nitrogen-giving ring. They are transferred e.g. by treatment with an acid or an acidic reagent as a suitable ion exchanger in the quaternary salts.

The new compounds are obtained in free form, which contains a free 4-amino group, or in the form of their acid addition salts, depending on the conditions under which the process is carried out. Due to the close relationship between the new compounds in free form and in the form of their salts, in the foregoing and the following, the free compounds and salts are possibly also meant the corresponding salts or the free connections. Formed acid addition salts can be converted in a manner known per se into the free compounds, e.g. by treatment with mild alkaline agents, such as alkali metal carbonates or hydrogen carbonates, or in other salts, e.g. using suitable ion exchangers. Similar to the quaternary bases or pseudobases, free compounds formed by reaction with inorganic or organic acids, especially with those which are suitable for the formation of therapeutically usable salts, e.g. acids that give the anion X<®> are converted in the acid addition salt.

A quaternary ammonium group RQ can, by requaternization in a known manner, be transferred into the desired group R^, preferably with an excess of the corresponding heterocyclic base.

The above-mentioned reactions can be carried out at normal or elevated pressure according to known methods, in the presence or absence of diluents, especially those that are inert towards the reagents and aim to dissolve them, catalysts, condensation agents and/or inert atmosphere, at low temperatures, room temperature or preferably at elevated temperatures.

One can proceed from a compound formed as an intermediate product at one or other stage and carry out the remaining procedural steps, or interrupt the process at one or another stage or where the starting substances are formed under the reaction conditions or where the reaction components are used in the form of derivatives thereof , e.g. their salts. For example, the reactive ester of the 5"RQ-methyl compound, for example a sulphonic acid ester, is preferably formed under the reaction conditions, i.e. in the presence of the heterocyclic compound.

In the process, starting materials are preferably used which lead to the compounds mentioned at the outset as particularly valuable.

The starting materials are known, and if they are new, can be produced in a manner known per se. Thus allows e.g. 4-amino-5-hydroxymethyl-2-R-pyrimidine is prepared by reaction of an R-carboxylic acid amidine or a corresponding imidoester with a lower alkoxy-methylene-malodinitrile, reduction of the formed 4-amino-5~cyan-2-R- pyrimidine to corresponding 5-aminomethyl compound, e.g. with catalytically activated hydrogen, and converting this into the desired 5-hydroxymethyl compound, e.g. under the influence of nitric acid. The alcohol formed can be reactively esterified or etherified

according to known methods, e.g. by treatment with thionyl or phosphorus halide, a sulfuric or sulfonic acid halide, such as thionyl, sulfuryl, p-toluenesulfonyl, or p-bromobenzenesulfonyl chloride. A formed 4-amino-5-halomethyl-2-R-pyrimidine compound can then re-

is added with an anhydrous alcohol or mercaptan to the desired ether. The latter can e.g. is also produced by reaction of an acid addition salt of an R-carboxylic acid amidine with an etherified α-alkoxymethyl-8-

R -propionitrile.

o

The quaternary bases or pseudobases can be obtained by reduction of the corresponding oxo compounds, i.e. of cyclic amides, e.g. using complex light metal hydrides such as lithium aluminum hydride or sodium borohydride.

The production of the new compounds is described in more detail

in the following examples. The temperatures are indicated in degrees Celsius.

The ion exchangers used are described in Ullmann, Encyklopådia der technischen Chemie, volume 8' (1957), the resin designated Amberlite IRA 400 is a strongly basic ion exchanger based on quaternary ammonium ions as it e.g. is described in US patent no. 2,591,573.

Example 1.

A solution of 20.2 g of 4-amino-2-cyclopentyl-5-hydroxymethyl-pyrimidine hydrochloride in water is made basic with a saturated aqueous potassium carbonate solution and the organic material is extracted with n-butanol. The organic extract is evaporated to dryness and the formed 9.7 g of 4-amino-2-cyclopentyl-5-hydroxymethyl-pyrimidine, with m.p. 101-104°C, dissolve in 50 ml of 2,4-lutidine. The solution is mixed at room temperature in portions with 9.73 g of powdered o-toluenesulfonyl chloride, left for a few days at -15°C and then 5 days at room temperature, the product falling out. It is filtered off and washed with isopropanol and then recrystallized from a mixture of methanol and isopropanol, 4-amino-2-cyclopentyl-5-(2,4-dimethyl-pyridinium)-methyl-pyrimidine-chloride-hydrochloride with the formula crystallising at concentration to remove the methanol, m.p. 254-255°C.

The starting material can e.g. obtained in the following way:

A suspension of 55 g of sodium cyanide in 265 ml of dimethyl sulfoxide is mixed at 110-115°C with 105 g of cyclopentyl chloride, the reaction mixture is kept for 3 hours at 125°C, then cooled and diluted with 1000 ml of water, then extracted 4 times with methylene chloride . The organic solution is then extracted cold with 6-n hydrochloric acid, then washed with water and dried over anhydrous magnesium sulfate, filtered and evaporated. The cyclopentyl cyanide is distilled twice and recovered at 63°C at 15 mm Hg.

A solution of 18 g of cyclopentyl cyanide in 9.2 g of ethanol is treated at -20°C with 16.2 g of anhydrous hydrogen bromide and allowed to stand for 16 hours at -15°C. The crystalline precipitate is suctioned off, washed with a small amount of ether and dried in vacuo, the cyclopenta-carboxyimino-ethyl ether hydrobromide formed melts at 80-82°C.

A solution of 153.6 g of cyclopentanecarboxyimino-ethyl ether hydrobromide in 120 ml of ethanol is mixed with a saturated ethanolic ammonia solution, an excess of ammonia being present in the reaction mixture at the end of the addition. The reaction mixture is stirred for 18 hours at room temperature, then concentrated under reduced pressure and cooled. The crystalline guanidocyclopentane hydrobromide formed melts at 148°C. A solution of 12.3 g of sodium in 500 ml of anhydrous ethanol is mixed at 0 to -5°C during half an hour with a solution of 103>5 g of guanidocyclopentane hydrobromide in 250 ml of anhydrous ethanol. The reaction mixture is stirred for fifteen minutes and filtered to remove sodium bromide formed. The filtrate is then added during one hour at 0 to -5°C to a solution of 6554 g of ethoxymethylene-malodinitrile in 685 ml of anhydrous ethanol and the resulting mixture is stirred for 3 hours at this temperature and then filtered. The filter residue is washed with a small amount of ethanol, the vacuum-dried 4-amino-5-cyano-2-cyclopentyl-pyrimidine melts after recrystallization from isopropanol at 161-162°C. A mixture of 18.8 g of 4-amino-5-cyano-2-cyclopentyl-pyrimidine and 2 g of a 10# palladium-on-charcoal catalyst in 250 ml of 3-n hydrochloric acid is hydrated at approx. 3 atmospheric initial pressure to absorb 2 mole equivalents of hydrogen. During the reduction, Schiff's base is formed, which is hydrolysed to the aldehyde and this is further reduced to the hydroxymethyl compound. The catalyst is filtered off and the filtrate is evaporated to dryness. Traces of water are removed azeotropically with isopropanol, the precipitated ammonium chloride being continuously filtered off. The residue is recrystallized twice from isopropanol and 4-amino-2-cyclopentyl-5-hydroxymethyl-pyrimidine hydrochloride is thus obtained, which melts at 110-111°C. The structure of the compound is correct due to elemental analysis and nuclear resonance spectrum. ;Example 2. ;A solution of 35 g of 4-amino-2-cyclobutylmethyl-5-hydroxymethyl-pyrimidine in 250 ml of freshly distilled 2,4-lutidine is mixed in portions with stirring and at room temperature with 34.7 g of powdered p-toluenesulfonyl chloride. The reaction mixture is cooled for 48 hours at -15°C, then allowed to stand at room temperature for 4 days and the solid material is filtered off and washed with acetone. 4-amino-2-cyclobutylmethyl-5-(2,4-dimethyl-pyridinium)-methyl-pyrimidine chloride hydrochloride of the formula; ; melts after recrystallization from anhydrous ethanol at 240-242°C. ;The starting material is obtained in the following way:;A mixture of 23.6 g of lithium aluminum hydride in 500 ml of ether is mixed with stirring with a solution of 50 g of cyclobutane-carbonic acid in 500 ml of ether, allowing it to boil slightly under reflux during the addition. The mixture is refluxed for a further 3 hours, then cooled in an ice bath and mixed with 71.6 ml of a 15% aqueous sodium hydroxide solution, working under a nitrogen atmosphere. The inorganic precipitate is filtered off and washed with ether, the filtrate and the ether washing liquid are combined and evaporated. The residue is distilled and cyclobutyl methanol is collected at 142-143°C. 36.2 g of the product is dissolved in 250 ml of anhydrous ether and cooled to -70°C, then treated with 14.8 ml of phosphorus tribromide in 20 ml of ether, the temperature is maintained with stirring for 2 hours at -65 to ~70°C and brought then slowly to room temperature. After dilution with 10 ml of water, the mixture is shaken and the separated ether solution is extracted twice with a saturated aqueous sodium carbonate solution. The washing liquid is then washed with ether. The combined ether extracts are dried over magnesium sulphate and evaporated, the residue is distilled and the desired cyclobutyl methyl bromide is collected at 134-136°C. . A suspension of 10.5 g of sodium cyanide in 76.4 ml of dimethyl sulphoxide is heated to 50°C and then mixed dropwise over 10 minutes. while stirring with 28.5 g of cyclobutyl methyl bromide, the resulting mixture is heated for 2 hours at 70°C, then cooled to room temperature and diluted with 150 ml of water. It is extracted 5 times with ether, the ether extract is extracted 2 times with cold 6-n hydrochloric acid and 2 times with water, then dried over magnesium sulfate and evaporated. The residue is distilled and the cyclobutyl acetonitrile is collected at 78°C and 38 mm Hg. A solution of 11.6 g of cyclobutylacetonitrile in 5>6 g of ethanol is treated at -30°C to -40°C with 9.9 g of anhydrous hydrobromic acid and the reaction mixture is allowed to stand for 16 hours, at -15°C. The crystalline product is filtered off and dried under reduced pressure over phosphorus pentoxide, the desired cyclobutyl-acetimino-ethyl ester hydrobromide melts at 79-81°C; A solution of the product thus formed in 10 ml of anhydrous ethanol is treated with a slight excess of a saturated ethanolic ammonia solution. The reaction mixture is stirred for 16 hours at room temperature and then concentrated to a small volume. The crystalline product formed is filtered off, washed with ether and dried in vacuum, the cyclobutyl acetamidine hydrobromide thus formed melts at 152-156°C. A solution of 2.3 g of sodium in 100 ml of anhydrous ethanol is mixed, at 0°C, over the course of one hour with a solution of 18.4 g of cyclobutyl-acetamidine hydrobromide in 100 ml of anhydrous ethanol. The mixture is stirred cold for 15 min. and the formed sodium bromide is filtered off. The filtrate is then added during one hour at 0°C to -15°C to 12 g of ethoxymethylene-maodinitrile in 110 ml of ethanol and the reaction mixture is stirred for 4 hours at 0°C. The solid product formed is filtered off, washed with a small amount of cold anhydrous ethanol and dried in vacuo, the desired 4-amino-5-cyano-2-cyclobutylmethyl-pyrimidine melting at 179-181°C. ;A mixture of 18.8 g of 4-amino-5-cyano-2-cyclobutylmethyl-pyrimidine and approximately 5 g of Raney nickel in 250 ml of methanol and 50 ml of liquid ammonia is hydrated at approx. 3 atmospheres initial pressure for theoretical uptake of hydrogen. The catalyst is filtered off, the filtrate is evaporated and the oily residue is dissolved in anhydrous ethanol and transferred by adding an ethanolic hydrochloric acid solution to a positive Congo red reaction in the hydrochloride. The precipitate formed is filtered off and washed with anhydrous ethanol, 4-amino-5-aminomethyl-2-cyclobutylmethyl-pyrimidine-dihydrochloride melts at 259-262°C. ;A solution of 24.3 g of sodium nitrite in 1000 ml of water is added to 82.5 g of 4-amino-5_aminomethyl-2-cyclobutylmethyl-pyrimidine-dihydrochloride in 1100 ml of water, the addition is carried out over 2 hours at 50-55°C . The resulting reaction mixture is stirred for 6 hours at this temperature, then filtered, concentrated under reduced pressure and made cold basic with a saturated aqueous sodium carbonate solution. The solid precipitate is filtered off, washed with a small amount of cold water and stirred. 4-amino-2-cyclobutylmethyl-5-hydroxymethyl-pyrimidine melts after recrystallization from acetic acid ethyl ester at 137°C. ;Example 3.;9.2 g of 4-amino-2-cyclobutylmethyl-5-hydroxymethylpyrimidine is dissolved in 75 ml of 2-picoline and mixed at room temperature with stirring with 9.1 g of p-toluenesulfonyl chloride, the reaction mixture is kept for 2 days at -15 °C and 4 days at room temperature. The reaction mixture is filtered and the residue is washed with acetone. After recrystallization from anhydrous ethanol, the formed 4-amino-2-cyclobutylmethyl-5-(2-methyl-pyridinium)-methyl-pyrimidine-chloride-hydrochloride melts with the formula; ; Example 4.j<1>;jjA solution of 2.2 g of 4-amino-2-cyclopentyl-5-hydroxymethyl-pyrimidine in 12 ml of redistilled 2-picoline is mixed with stirring with 2.15 g of p-toluenesulfonyl chloride. The reaction mixture is allowed to stand for 36 hours at room temperature and is then diluted with ether, a gum-like precipitate forming which crystallizes on tearing]. The excess 2-picoline is removed by decanting off the excess liquid, the precipitate is dissolved in isopropanol and precipitated with ether. The precipitation is repeated a further 3 times. The solid material is finally dissolved in 100 ml of 0.06-n hydrochloric acid and the solution is poured through an ion exchange resin in chloride form (Amberlite ÆRA 400). The eluate is evaporated on a steam bath and thus 4-amino-2-cyclopentyl-5-(2-methyl-pyridinium)-methylpyrimidine chloride-hydrochloride is obtained! , with formula ; ; Example 5. 1,;j;A solution of 18.5 g of 4-amino-2-cyclopropyl-methyl-5-hydroxy-methyl-pyrimidine in 100 ml of 2-picoline is mixed with 19.9 g of p-toluenesulfonyl chloride. The reaction mixture is allowed to stand for 4 days at room temperature and is then diluted with ether, a precipitate forming. The above solution is decanted off, the residue is dissolved in isopropanol and the product is precipitated with ether, the precipitation is repeated 4 times, until no more 2-picoline can be determined. The solid material is dissolved in 100 ml of water and the solution is poured through a column containing an ion exchanger (Amberlite IRA ;400) in chloride form. The aqueous filtrate is evaporated under reduced pressure and the mra sidfuar a 'soomlkredess ta4l-almisineroe-2s -fcrya kloepn rboplaynld-minetg yalv -5m-e(t2a-nmoetl oğl -pyrisoipdrinopiuamno-1;;methyl)-pyrimidine-chloride-hydrochloride with formula; ; which melts at 225.5 - 226.5°C. ;The starting material is prepared in the following way:;To a suspension of 4l.l g of lithium aluminum hydride in;;300 ml of anhydrous ether, a solution of 100 g of cyclopropanecarbonic acid in 300 ml of ether is added while stirring so that the solvent is boiled gently, stirred for 8 hours and boiled under reflux. The reaction mixture is then diluted with 500 ml of ether, and 130 ml of a 15% aqueous sodium hydroxide solution is stirred in under ice cooling, the mixture is filtered and the residue is washed with ether, the filtrate is dried and evaporated. The residue is distilled and cyclopropyl methanol is recovered at 122-126°c'. n^<5>s .1.4299. A solution of 89.1 g of cyclopropyl methanol is dissolved in 350 ml of anhydrous ether, the solution is cooled to -70°C and 40.8 g of phosphorus tribromide is added dropwise with stirring over the course of \ hour. During 16 hours, the temperature of the mixture is allowed to rise to room temperature and then mixed with 12 ml of water, and the organic layer is separated, washed with saturated aqueous sodium carbonate solution and water, dried and evaporated. The residue is distilled and the cyclopropylmethyl bromide is recovered at 102-110°C n^5 = 1.4752. A suspension of 51.9 g of sodium cyanide in 377 ml of dimethyl sulfoxide is mixed with 126.5 g of cyclopropyl methyl bromide, the temperature being kept between 55-60°C. The temperature is then raised to 70°C for two hours, the mixture is cooled, diluted with 500 ml of water and extracted with ether. The extract is washed with water<p>g 25 ml of n-hydrochloric acid, dried and evaporated and the residue is distilled, the cyclopropyl acetonitrile is recovered at 142-147°C, n^<5>= 1.4218. Into a solution of 101 g of cyclopropylacetonitrile in 61.4 g of anhydrous ethanol, chlorine hydrogen gas is introduced until 48.3 g of this has been taken up. After the mixture has stood overnight, the formed precipitate is filtered off at -20°C, washed with water and dried under reduced pressure. The hygroscopic cyclopropyl acetimino ethyl ether hydrochloride is thus obtained. ;To the solution of 173.1 g of cyclopropyl-acetiminoethyl-ether hydrochloride in 100 ml of anhydrous ethanol, 130 ml of 6.3_n ethanolic ammonia is quickly added while stirring and cooling. The reaction mixture is allowed to stand for 16 hours at room temperature, the filtrate is filtered and concentrated to half the volume, after which, after ice-cooling and rubbing, crystallization is formed. The cyclopropyl-acetamidine hydrochloride formed is filtered off, washed with anhydrous ether and dried under reduced pressure. The solution of 136.6 g of cyclopropyl acetamidine hydrochloride in 700 ml of anhydrous ethanol is added to the solution formed by 23.6 g of sodium and 950 ml of anhydrous ethanol over the course of 1 hour with stirring at 15°C. After adding filter cellulose, the mixture is filtered through a glass internutsch and the filtrate is added to the solution of 130 g of ethoxymethylenemalodinitrile in 130 ml of anhydrous ethanol during 1/4 hour at -5 to -10°C. The mixture is stirred for 3 hours at this temperature, the residue is filtered and washed with cold anhydrous ethanol and dried in a vacuum at 50°C. One thus obtains 4-amino-5-cyano-2-cyclopropyl-methyl-pyrimidine, m.p. 181-182.5°C. The suspension of 17.4 g of 4-amino-5-cyano-2-cyclopropyl-methyl-pyrimidine and 2.5 g of a 10% palladium-on-charcoal catalyst in 200 ml of glacial acetic acid is saturated with anhydrous hydrogen chloride and is hydrated at an initial pressure of 10.2 atmospheres, after approx. 6 hours, the theoretical amount of hydrogen has been absorbed. The mixture is diluted with water, filtered and the filtrate is evaporated under reduced pressure. Isopropanol is added to the residue, which is distilled again to remove water and acetic acid. Finally, the residue is heated on a steam bath for one hour under reduced pressure and recrystallized from a mixture of isopropanol and methanol, thus obtaining 4-amino-5-aminomethyl-2-cyclopropylmethyl-pyrimidine dihydrochloride with m.p. 228.5-229°C. ;To a solution of 75>8 g of 4-amino-5-aminomethyl-2-cyclo-propylmethyl-pyrimidine dihydrochloride in 1000 ml of water, at 55°C, during 2 1/4 hours with stirring, the solution of 23 g sodium nitrite in 100 ml of water, the mixture is then kept for 6 hours at 54°C and 16 hours at room temperature. It is then treated with charcoal after adding filtration cellulose, filtered and the filtrate is concentrated under reduced pressure to a volume of 500 ml. The concentrate is cooled to 5°, neutralized with saturated sodium carbonate solution to pH 7.5 - 8.0 and extracted with n-butanol, the extract is dried and concentrated under reduced pressure until crystallization begins. After adding ether, the mixture is filtered, the residue is washed with ether, thus obtaining 4-amino-2-cyclopropylmethyl-5-hydroxymethyl-pyrimidine, m.p. 143-146°C. ;The transfer of 4-amino-5-aminomethyl-2-cyclopropyl-methyl-pyrimidine dihydrochloride in 4-amino-2-cyclopropylmethyl-5-hydroxymethyl-pyrimidine can also be carried out in the following way: To a solution of 26.6 g 4 -amino-5-aminomethyl-2-cyclopropylmethyl-pyrimidine dihydrochloride in 400 ml of water, the solution of 7.5 g of sodium nitrite in 400 ml of water is placed over the course of 3 hours, the temperature being kept at 50-55°C. The homogeneous solution is stirred for 17 hours at this temperature, during which time the pH is gradually adjusted to approx. 7.5-8 with saturated sodium carbonate solution. The mixture is evaporated to dryness and the yellow residue is extracted with 4 portions of boiling 90% aqueous acetone. The organic solution is evaporated to a small volume and the remaining water is removed azeotropically with ethanol. The mixture is filtered, the filtrate is acidified with ethanolic hydrochloric acid to a pH of approx. 4 and dilute with ether. After a short period of time, the precipitated yellow precipitate is filtered off, ground in a mortar with ether, filtered off and dried in a vacuum at 50°C. The formed 4-amino-2-cyclopropylmethyl-5-hydroxymethyl-pyrimidine hydrochloride is dissolved in the minimal amount of water required for dissolution and solid potassium carbonate is added to the solution while cooling and stirring until an oily layer separates. It is then extracted with n-butanol until the latter extract is colourless. The combined extracts are dried over potassium carbonate, filtered and evaporated under reduced pressure. The residue is expelled with ether, filtered off, washed with ether and dried in vacuum at 50°C. 4-amino-2-cyclopropylmethyl-5-hydroxymethyl-pyrimidine is thus obtained. ;Example 6. ;A solution of 2.2 g of 4-amino-2-cyclopropylmethyl-5-hydroxymethyl-pyrimidine in 15 ml of freshly distilled 2,4-lutidine is mixed with 2.24 g of p-toluenesulfonyl chloride and the mixture is allowed to stand for 4 days at room temperature. It is then diluted with ether, whereupon a precipitate forms, from which the above solution is decanted. The residue is dissolved in isopropanol and the product is precipitated 4 times with ether, after which the smell of 2,4-lutidine disappears. The formed crystalline product is dissolved in 100 ml of water and the solution is passed through a column with an ion exchange resin present in chloride form (Amberlite IRA 400). The aqueous eluate is concentrated under reduced pressure and the precipitate formed is recrystallized from a mixture of methanol and isopropyl alcohol. ^1. One thus obtains 4-amino-2-cyclopropylmethyl-5-(2,4-dimethyl-pyridinium)-methyl-pyrimidine-chloride-hydrochloride with ; which melts at 250.5 - 251°C during decomposition. ;Example 7 . A solution of 19 g of 4-amino-2-cyclopropyl-methyl-5-hydroxymethyl-pyrimidine in 100 ml of 2,4-lutidine is cooled and mixed in portions with 20.4 g of p-toluenesulfonyl chloride. The mixture is filtered and the filtrate is left for 18 hours at -20°C and 5 days at room temperature and; then diluted with ether. The gum-like precipitate is expelled; with ether and recrystallized from a mixture of isopropanol. and ether. A solution of 40.3 g of the crystalline material in 3.00 ml of water, containing 5 ml of 0.006 N hydrochloric acid, is treated with activated carbon, filtered and the filtrate is passed through a column with an ion exchange resin in chloride form (Amberlite IRA 400). The column is washed with 500 ml of water, the combined eluates are treated again with activated carbon, filtered and evaporated under reduced pressure. Isopropanol is added to the residue, which is distilled off to azeotropically remove remaining water. The thus dried residue is suspended in acetone and the suspension is filtered. The residue is washed with acetone and recrystallized from a 1:1 mixture of methanol and isopropanol. One thus obtains 4-amino-2-cyclopropyl-methyl-5-(2,4-dimethyl-pyridinium)-methyl-pyrimidin-chloride hydrochloride, m.p. 250.5 - 251 oC during cleavage, which is identical to the product formed according to example 6. Example 8. A suspension of 2.7 g of 4-amino-5-chloromethyl-2-cyclopropylmethyl-pyrimidine hydrochloride in 20 ml of 2,4-lutidine is heated for 4 days on a steam bath, then cooled and diluted with ether. The supernatant solution is decanted off and the residue is boiled with isopropanol. After cooling, it is filtered and the residue is washed with isopropanol and recrystallized from a mixture of methanol and isopropanol. The formed 4-amino-2-cyclopropyl-methyl-5-(2,4-dimethyl-pyridinium)-methyl-pyrimidine-chloride-hydrochloride melts at 252°C during cleavage and is identical to that in the method according to example 6 and 7 formed product. ;The starting material can be obtained in the following way:;A solution of 5.8 g of 4-amino-2-cyclopropylmethyl-5-hydroxymethyl-pyrimidine in 10 ml of dimethylformamide is mixed with stirring and cooling to a temperature below 5°C dropwise with 2.45 ml of thionyl chloride. After stirring for two hours while cooling in an ice bath, the reaction mixture is allowed to stand for 18 hours at 0°C, then diluted with ether and the precipitate filtered off. This is triturated with ether and acetone and recrystallized from a mixture of isopropanol and ether, 4-amino-5-chloromethyl-2-cyclopropylmethyl-pyrimidine hydrochloride melts at 191-195°C with decomposition.*

Claims (1)

1. Process for the preparation of therapeutically active compounds with formula wherein n means an integer from 2 to 5, m means an integer from 1 to 4 and p means an integer from 0 to 2, Y means a direct bond or a methylene, 1,1-ethylene or 1,2 -ethylene group and X <®> means an acid anion and acid addition salts thereof, characterized by either) reacting a reactive ester or ether of a compound of formula wherein RQ means a hydroxy or mercapto group, or a salt of which with a compound of formula or b) converts a quaternary base or pseudobase corresponding to the compound of formula I into the quaternary salt and, if desired, transfers a formed free compound into its acid addition salt or a formed acid addition salt into the free compound or into another salt and/or converts a resulting quaternary salt in another quaternary salt. 2.. Method according to claim 1, characterized in that one reacts a reactive ester or ether of a 4-amino-2-cyclopropylmethyl-5-R0 -niethylpyrimidine, in which RQ means a hydroxy or mercapto group or a salt thereof with 2 ,4-lutidine or a salt thereof. 3. Process according to claim 1, characterized in that one reacts a reactive ester or ether of a 4-amino-2-cyclopropylmethyl-5-R0-niethyl-pyrimidine in which R means a hydroxy or mercapto group, or a salt thereof with 2- picolin or a salt thereof.