NO139682B - ANALOGICAL PROCEDURE FOR PREPARING BETA-RECEPTOR-ACTIVE COMPOUNDS - Google Patents

Description

The invention relates to an analogous method for the preparation of β-receptor-active compounds of formula

in which

FL means hydrogen or methyl

R 2 means lower alkyl or phenyl lower alkyl R means the pyridyl radical with formula

or its N-oxides, wherein n is 1, 2 or 3,

R-j means halogen, nitro, cyano, lower alkyl, lower alkoxy, phenyl, amino lower alkyl, hydroxy, lower alkoxycarbonylamino lower alkyl, lower alkylaminocarbonyl or pyrrolidinocarbonyl, or in which R means the pyrazinyl radical of formula

or its N-oxides, wherein

Rjj means hydrogen, halogen, lower alkyl and

FU means hydrogen, halogen, lower alkoxy, lower alkoxy lower real oxy, lower alkenyloxy, lower alkylthio, morpholinyl, lower alkylamino, dilower alkylamino, phenylthio, hydroxypiperidyl or lower alkylpiperazinyl or in which R means the pyridazinyl residue of formula:

or its N-oxides, wherein

Rg means hydrogen and

R^ means hydrogen, lower alkoxy, halogen or morpholino, or in which R means the pyrimidinyl radical of formula

or its N-oxides wherein

Rg means hydrogen, dilower alkylamino, lower alkyl and Rg means hydrogen, hydroxy, lower alkoxy lower alkyl, lower alkylthio

or lower alkylthiolower alkyl, lower alkylaminocarbonyl or lower alkoxycarbonyl or allyloxy, as well as their therapeutically useful salts.

The invention further relates to N-oxides and end products of formula I, as well as their therapeutically usable salts. In the following, end products with formula I mean the compounds not oxidized in the hetero part, as well as the N-oxides.

The new compounds have valuable pharmacological properties. The main effect of the substituted pyridines, pyrazines or pyrimidines consists in a blockade of adrenergic receptors such as can be demonstrated as inhibition of effects of known /J-receptor stimulators in various organs: inhibition of isoproterenol tachycardia on isolated guinea pig heart and isoproterenol relaxation on isolated guinea pig trachea at concen-

tions from 0.001 to 3 ug/ml. Inhibition of isoproterenol-tachy-

cardia and vasodilatation in anesthetized cats by intravenous administration of 0.01 to 30 mg/kg i.v. The compounds mentioned either belong to the class of non-cardioselective β-receptor blockers, i.e. they block the β-receptors on the vessels, resp. in the trachea in similar or even smaller doses resp. concentrations than the /J-receptor in the heart or they belong to the class of so-called cardioselective /3-receptor blockers, i.e. they block the Ø receptors of the heart already in a dose- or concentration range which does not yet cause any blockade of the /3-receptors in the vessels or

in the trachea. As an additional property, some of these compounds have a so-called "intrinsic sympathominetic activity (IS^), i.e. these compounds cause, in addition to ^-blockade (main effect), a partial /j-stimulation. The main effect of unsubstituted pyrazine and pyrimidine consists in a stimulation of adrenergic /^-receptors which can be demonstrated, for example, on hearts as positive inotropic and positive chronotropic effects. The compounds mentioned increase in isolated guinea pig forecourts the heart rate and myocardial contraction force in concentrations from 0.01 to 10 jig/ml and in anesthetized cat by intravenous administration of 0.001 to 1 mg/kg i.v. In concentrations significantly higher than those required for a β-stimulation, these compounds also have β-receptor blocking properties. 2-(2'-Hydroxy-3'-isopropylaminopropoxy )pyrimidine and 2-(2'-hydroxy-3'-isopropyl-aminopropoxy)-pyrazine, however, qualitatively clearly differ from known γ3-receptor stimulators, since in anesthetized cats they first in a do look at 1 mg/kg i.v. lowers the arterial blood pressure, i.e. in a dose range that is clearly above what is required for an increase in myocardial contraction force and heart rate. On isolated guinea pig trachea, the compounds have a concentration of 10 µg/ml yet no relaxing effect. Because of this property, these compounds can be termed cardioselective β-receptor stimulators.

The new compounds can therefore be used to treat diseases of the heart and circulatory system. Island receptor blockers can e.g. find application in the therapy of angina pectoris, hypertension and heart rhythm disturbances. The cardioselective preparations bring, compared to the non-cardioselective ones, the advantage that in doses required for a blockade of the ^-receptors of the heart no blockade of the /^-receptor in other organs is yet to be expected. The risk of unwanted side effects such as triggering a bronchospasm is therefore very small. In contrast to the cardioselective blockers, the non-cardioselective agents block either

The yfl receptors in all organs, e.g. equally strong or preferentially in certain organs (such as in vessels).

The ^-receptor stimulators can be used as cardiotonics for the treatment of heart muscle insufficiency (alone or in combination with other preparations, such as cardiac glycosides, for example). In relation to known β-receptor stimulators, these compounds have the following advantages: Due to the pharmacologically proven cardioselectivity, it can be expected that the myocardial contraction force increases without there being at the same time an unwanted drop in blood pressure. Furthermore, an insignificant increase in the heart rate can only be expected, because the reflex tachycardia occurring as a result of a drop in blood pressure disappears. However, they can also be used as valuable intermediates for the production of other useful substances, especially pharmaceutically active compounds.

From the Norwegian explanatory documents no. 118,172 and 128,653, there is known derivative of 2-hydroxy-3-alkylaminopropane which derives from the phenoxy radicals which are substituted on the one hand with an alkoxy group, on the other hand with alkylcarbamoyl and alkyl

and alkoxy groups and further by halogen. Furthermore, such phenoxy-2-hydroxy-3-alkylaminopropane compounds are known from the Norwegian patents no. 122.07^, 123-647 and 125.445 which are substituted in the phenyl residue with alkanoylamino and alkyl residues, on the other hand with methylthio or with carbamoyl - and alkyl or alkanoylamino residues or with halogen. Finally, naphthyl-oxy-2-hydroxy-3-alkylamino-propanes substituted by hydroxyl or ether groups are known from Norwegian patent no. 115,028.

All compounds mentioned in the aforementioned literature citations are attributed to blocking effects on β-adrenergic receptors or γ9-sympatholytic properties.

In contrast, the compounds according to the invention concern such derivatives of 2-hydroxy-3-alkylaminopropane, which are derived from a heterocyclyloxy acid residue, namely from N-containing heterocycles. Such substances differ with regard to their effect on ^-receptors in relation to the known substances by a greater breadth of action, such as e.g. This means that both blocking and stimulating properties can be assigned to the same compound types. Such a result was not expected with regard to the state of the art and is therefore surprising.

In the following tables I to III, the compounds produced according to the invention are compared with respect to their Ø-receptor-blocking properties to known, highly effective compounds, namely 1-(4-acetamido-phenoxy)-3-isopropylamino- 2-propanol, 1-isopropylamino-3-(1-naphthoxy)-2-propanol known under the name PROPRANOLOL and 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol known under the name OXPRENOLOL. Hereby, the tables designated I, Ia and Ib list the compounds according to the invention which are only superior to PRACTOLOL, while the tables designated II and Ila contain such substances according to the invention which show a superiority both to PROPRANOLOL and also to OXPRENOLOL , in those with III

and Ill labeled tables finally show the superiority of further substances according to the invention, in relation to PROPRANOLOL, OXPRENOLOL and also PRACTOLOL.

Finally, in table IV, experimental data are given, due to which a superiority of the compounds according to the invention listed there is shown with respect to their /9-receptor-stimulating effect in relation to the comparable known effect

of ISOPROTERENOL.

Conclusions:

Corresponding to the data given in Tables I, Ia and Ib, the compounds given here have the same advantage, albeit to a different degree in relation to "PRACTOLOL", namely a higher potency with regard to blockade of cardiac β-receptors.

From the experimental data set out in Tables II and IIa, it appears that the compounds mentioned in relation to "PROPRANOLOL" and "OXPRENOLOL" have the advantage of a preferred blockade of the cardiac compared to the vascular β-receptors, i.e. they have, although in varying degrees, cardioselective properties.

The compounds listed in Tables III and Illa are superior to "PRACTOLOL" as well as "PROPRANOLOL" and "OXPRENOLOL" due to the experimental data given there. This superiority can be e.g. further characterize and specify as follows:

From the experimental data given in Table IV it appears that the two given compounds. with respect to their /9-receptor-stimulating action, a superiority can be demonstrated in relation to the comparable known action of "D,L-ISOPROTERENOL". The stimulating effect on cardiac /9-receptors manifests itself as an increase in heart rate and the maximum rate of increase of the pressure in the left ventricle (dP/dt max.), which applies as a measure of the positive inotropic effect, without the arterial blood pressure changing significantly, i.e. pharmacologically speaking, it concerns cardioselective β-receptor stimulators.

"ISOPROTERENOL", on the other hand, in doses that cause a comparable stimulation of the cardiac β-receptors, causes a clear pressure reduction, i.e. it has no cardioselective properties.

As will further appear from Table IV, the two compounds are much longer active than "D,L-ISOPROTERENOL", which is of course advantageous in a number of possible applications.

The new compounds are prepared in a manner known in and of themselves, being a compound of formula

in which R has the indicated meaning, -Z-^ and Z^ means , together epoxy or Z^ is hydroxy and Z2 means a .reactive group, is reacted with an amine of the formula:

wherein B.sub.1 and R.sub.2 have the above meaning.

Thus, e.g. a compound of formula IVa or the corresponding pyrazine N-oxide

or with formula IVb, or the corresponding pyridazine N-oxide or with formula IVc, or the corresponding pyrimidine N-oxide is reacted with a compound of formula V

wherein R^, R2 > R^, R^, Z^ and Z^ each time have the above meaning.

A reactive group is especially one with a strong inorganic or organic acid, above all a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or a strong organic sulphonic acid, such as for example benzenesulphonic acid, 4-bromobenzenesulphonic acid, 4-toluenesulphonic acid or methanesulphonic acid, esterified hydroxyl group , thus Z^ means especially chlorine, bromine or iodine.

This turnover is carried out in the usual way. When using a reactive ester as starting material, work is preferably carried out in the presence of a basic condensation agent and/or with an excess of amine. Suitable basic condensation agents are e.g. alkali hydroxides such as sodium or potassium hydroxide, alkali carbonates such as potassium carbonate and alkali alcoholates, e.g. alkali metal alkanolates such as sodium methylate, potassium methylate and potassium tertiary butylate.

Further; can a compound of formula VI

is alkylated with a compound wherein R and R^ have the above meaning, under reducing conditions," or a compound of formula VI is alkylated with a compound of formula or a reactive ester of this compound, wherein R, R^ and R^ have the stated meaning Thus, a compound of formula Vlaa or Vlab or Vlac can

in which Rj and has the above-mentioned meaning, is reacted with a compound of formula VII, or a corresponding oxo compound, in which

R 1 and R 2 have the above meaning. "<vv>\

This reaction is carried out in the usual way, preferably in the presence of a basic condensing agent and/or with an excess of amine. Suitable basic condensing agents are, for example, alkali alcoholates, especially sodium or potassium alkali alcoholates, e.g. sodium methylate or also alkali carbonate, such as sodium

or potassium carbonate.

Furthermore, a compound of formula VIII or Villa can

which on the one hand means a 3-hydroxypyridine or on the other hand a 5-hydroxypyrimidine and R^ has the meaning indicated each time for a pyridine residue and R^ has the meaning indicated each time for a pyrimidine residue, is reacted with a compound of formula:

wherein R-^ and R^ have the above meaning.

This turnover is carried out in the usual way. When using starting compounds of formula IX, an alkali hydroxide is preferably used as basic condensation agent, such as e.g. potassium or sodium hydroxide.

This reaction is carried out in the usual way, preferably in the presence of a solvent or at reduced temperature, room temperature or elevated temperature, if necessary in the presence of a condensing agent, especially a basic condensing agent.

Furthermore, a compound of formula X can:

wherein R, R^ and R^ have the indicated meaning in that in the case that R means pyridyl, R^ also means the tetrahydropyranyloxymethyl residue and X means the divalent residue of an aldehyde or ketone, the carbonyl group or the thiocarbonyl group, or a salt of such a compound hydrolyzed. The hydrolysis is carried out, for example, in a basic or preferably in an acidic medium, e.g. by means of mineral acids such as sulfuric acid or hydrohalic acid, or by means of alkali hydroxides such as sodium hydroxide.

Furthermore, an end product of formula I, in which R is substituted with a benzoyloxy or allyloxy group, can be converted by means of hydrogenolysis into an end product of formula I containing a hydroxy group in the group R.

The hydrogenolysis is carried out in the usual way, especially with the help of catalytically energized hydrogen, which e.g. by means of hydrogen in the presence of a hydrogenation catalyst, for example Raney-nickel or palladium-charcoal.

Furthermore, an end product of formula I, in which R contains one of the following hydrogenolytically cleavable groups: halogen and/or halogen-substituted phenyl or lower alkylthio, can be converted by means of hydrogenolysis into an end product of formula I, where instead of said groups hydrogen is bound .

The conversion can be carried out with hydrogen and the usual hydrogenation catalysts such as Raney-nickel or palladium-charcoal. The cleavage of an allyloxy group can also be carried out with a reducing compound, e.g. with rhodium tris-(triphenylphosphine) dichloride preferably in a lower alkanol, such as methanol or ethanol and preferably at an elevated temperature, for example at the reflux temperature of the solvent.

Furthermore, an end product of formula I, in which R has a nitro group, can be reduced to a primary amino group and the compound formed can, if desired, be converted into a corresponding acylamino compound by acylation.

This reduction takes place in the usual way, e.g. with catalytically energized hydrogen or preferably in a high-boiling solvent, such as e.g. dimethylformamide or dioxane. As a hydrogenation catalyst, the usual catalysts such as Raney nickel, palladium coal, platinum, etc. are mentioned. The compound containing the primary amino group is then transferred by acylation to a corresponding acyl amino group-containing end product of formula I.

The acylation takes place with a common acylating agent, such as a reactive derivative of a carboxylic acid, especially an optionally substituted benzoic acid or a lower alkane carboxylic acid, e.g. acetic acid, or an aryl lower alkane carboxylic acid, e.g. phenylacetic acid. Suitable for acylation is in particular the anhydride or ketene of one of the aforementioned acids or the mixed anhydride thereof with a strong inorganic acid, such as a halogen, especially chloro or hydrobromic acid or an organic acid or an activated amide or an activated ester of one of the aforementioned acids.

Activated esters are e.g. esters with an electron-withdrawing structure, such as esters of phenol, thiophenol, p-nitrophenol, cyanomethyl alcohol and the like. Activated amides are e.g. The N-acyl derivatives of pyrazoles, such as 3,4-dimethylpyrazole or imidazole, such as imidazole itself. Suitable acylating agents are also activated formic acid esters such as e.g. haloformic acid ester, especially chloroformic acid ester. Depending on the nature of the acylation components, it may be appropriate to use a condensation agent. Thus, the substituted carbodiimides favor the reaction of the acids, bases, such as tert.amines, e.g. trilower alkylamines, N,N-dilower alkylanilines or aromatic tertiary nitrogen bases, such as pyridine or quinoline or inorganic bases, such as alkali or alkaline earth hydroxides, carbonates or bicarbonates, e.g. sodium, potassium or calcium hydroxide or sodium, potassium or calcium (bi)carbonate, or acylations of the reaction of acid anhydrides, acid halides and activated formic acid esters.

Furthermore, a final product of formula I can be obtained, in which R contains an amino lower alkyl group, which is converted by acylation into a corresponding lower alkoxycarbonylamino lower alkyl group.

The acylation takes place in the usual way with a suitable acylating agent, e.g. a corresponding acid halide, such as an acid chloride or corresponding anhydride or a corresponding haloformic acid ester, e.g. a chloroformate ester. In this way, a suitable solvent such as e.g. a mixture of a lower alkanol, e.g. isopropanol with water.

Furthermore, an end product of formula I, in which R contains a cyano group, can be converted to an aminomethyl group by reduction. Preferably, the reduction takes place by hydrogenation using catalytically energized hydrogen and in the presence of ammonia. The usual noble metal catalysts such as palladium-coal or platinum and, above all, Raney-nickel are used as hydration catalysts.

Furthermore, an end product of formula I, in which R is substituted with easily cleavable groups by reaction with a lower alkanol, lower alkanethiol or hydroxypiperidine can be converted into an end product of formula I, where R is substituted with lower alkoxy, lower alkylthio or a hydroxypiperidino group.

Appropriately, a basic condensation agent is used, such as e.g. nitrogen bases, alkali hydroxides, alkali carbonates or alkali alcoholates, such as e.g. pyridine, triethylamine, sodium hydroxide, potassium hydroxide, sodium methylate, potassium methylate, sodium ethylate or potassium ethylate.

Furthermore, N-oxidized end products of formula I cannot be oxidized to the corresponding N-oxides. The oxidation takes place with one of the usual oxidizing agents, such as organic peracids, for example peracetic acid, penbenzoic acid or m-chloroperbenzoic acid or with hydrogen peroxide, e.g. a hydrogen peroxide/glacial vinegar mixture. The reaction takes place at room temperature or elevated temperature. When perbenzoic acid or m-chloroperbenzoic acid is used, the reaction preferably takes place in a chlorinated hydrocarbon such as methylene chloride or chloroform.

Furthermore, mono- or di-N-oxide-containing end products of formula I are reduced to the corresponding non-oxidized compounds. The turnover can e.g. take place with sulfuric acid at room temperature or slightly elevated temperature with phosphorus oxychloride or above all by catalytic hydrogenation. As a hydrogenation catalyst, it is e.g. suitable noble metal catalysts such as platinum or palladium-charcoal, also Raney nickel.

The aforementioned reactions can optionally be carried out simultaneously or one after the other and in any order.

Depending on process conditions and starting materials, the final materials are obtained in free form or in the form of their acid addition salts, which are also covered by the invention. Thus, for example, basic, neutral or mixed salts, possibly also hemi-, mono-, sesqui- or polyhydrates thereof can be obtained. The acid addition salts of the new compounds can be transferred in the free compound in a manner known per se, e.g. with basic agents such as alkalis or ion exchangers. On the other hand, the free bases formed can form salts with organic or inorganic acids. For the production of acid addition salts, acids which are suitable for the formation of therapeutically applicable salts are used in particular. Examples of such acids should be mentioned: halogen-hydrogen acids, sulfuric acids, phosphoric acids, nitric acids, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid , tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid or pyruvic acid; phenylacetic acid, benzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylaminesulfonic acid.

These or other salts of the new compounds such as e.g. the picrates or perchlorates can also be used to purify the formed free bases, as one transfers the free bases into salts, separates these and releases the base from the salts again. Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the foregoing and the following, free compound is also to be understood possibly also the corresponding salts.

Depending on the choice of starting materials and working methods, the new compounds can exist as optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, also as isomer mixtures (racemate mixtures).

Formed isomer mixtures (racemate mixtures) can, due to the physico-chemical differences of the components, be divided into the two stereoisomeric (diastereomer) pure racemates in a known manner, for example by chromatography and/or fractional crystallization.

Formed racemates can be prepared according to known methods, for example by recrystallization from an optically active solvent with the help of microorganisms, or by reaction with an optically active acid that forms salts with the racemic compound and separation of the salts formed in this way, e.g. because of their different solubilities, are divided into the diastereomers, from which the antipodes can be liberated by the action of a suitable agent. Particularly common optically active acids are e.g. The D and L form of tartaric acid, di-O-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. It is advantageous to isolate the most effective of the two antipodes.

Expediently, for carrying out the reaction according to the invention, such starting substances are used which lead to the groups of end substances specifically mentioned at the outset and especially in the end substances specifically mentioned or highlighted.

The starting materials are known or can, if they are new, be obtained by methods known in and of themselves.

Thus, starting substances of formula IV can be obtained by reaction of a corresponding (R^) (Rjj)-pyrazinol or (R^)(R2t)-pyridazinol with epichlorohydrin obtained in the usual way. In the same way, (Rj)-pyridinols and (R-j) (R^-pyrimidinols can be reacted, if the hydroxy group is not each time in the 2-position. Starting substances with formula IV, which are derived from 2-pyridyl or 2-pyrimidinyl, can by reaction of a corresponding 2-chloropyridine or 2-chloropyrimidine with 2,2-dimethyl-4-hydroxymethyl-dioxolane is converted to the corresponding 2-(2',2*-dimethyl-1',3'-dioxolanoyl-( 41)]-methoxy-pyridine or -pyrimidine, which is then hydrolyzed with dilute mineral acid to the corresponding 2-(2<1>,3'-dihydroxy-propoxy)-pyridine or -pyrimidine, from which reaction with >methanesulfonyl chloride gives the corresponding 2-(3'-methanesulfonyloxy-2'-hydroxy-propoxy)-pyridine or -pyrimidine, to which optionally cyclization using tetrabutylammonium chloride in the presence of caustic soda is added, gives the corresponding 2-(2',3'-epoxy -propoxy)-pyridine Starting materials of formula VI can be obtained by reacting a starting material of formula IV with ammonia in a suitable solvent such as ethanol.

Starting substances of formula X can be obtained by reacting a (Rj) (Rjj)-halopyrazine or -pyridazine or -pyrimidine or -pyridine with a compound of formula in the presence of a basic condensing agent such as sodium hydride.

The starting materials can also be present as optical antipodes.

The new compounds may find use as pharmaceuticals, e.g. in the form of pharmaceutical preparations containing the compounds by their salts in admixture with an e.g. for enteral or parenteral application proper pharmaceutical, organic or inorganic, solid or liquid carrier material. For the formation of these, substances which do not react with the new compounds such as e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oil, benzyl alcohols, rubber, polyalkylene glycols, petroleum jelly, cholesterol or other known drug carriers. The pharmaceutical preparations can e.g. available as tablets, dragées, capsules, suppositories, ointments, creams or in liquid form as solutions (e.g. as elixirs or syrups), suspensions or emulsions. If necessary, they are sterilized and resp. or contains auxiliary substances such as preservatives, stabilisers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffers. They may also contain other therapeutically valuable substances. The preparations, which can also be used in veterinary medicine, are produced according to usual methods.

The daily dose is approx. 40-150 mg in the case of warm-blooded animals of approx. 75 kg body weight.

The invention will be explained in more detail with the help of some examples.

Example 1

39>7 g of 5-bromo-3-morphoblinyl-2-(3'-bromo-2'-hydroxy-propoxy)-pyrazine are heated with 41 g of isopropylamine in 500 ml of methanol for 15 hours at reflux. The reaction mixture is then evaporated in a water jet vacuum. The residue is distributed between 2N' hydrochloric acid and ether. The water phase is made alkaline with concentrated caustic soda and shaken out with ether. The combined ether extracts are dried over sodium sulphate and evaporated in a water jet vacuum. The crude base is obtained and from this with ethereal hydrochloric acid in methanol the product 5-bromo-3-morpholinyl-2-(3<1->isopropylamino-2'-hydroxy-propoxy)-pyrazine hydrochloride, melting point 202-203°C .

The starting material 5_bromo-3-morpholinyl-2-(3'-bromo-2'-hydroxy-propoxy)-pyrazine can be prepared as follows: la) 149 g of 2j3-dichloropyrazine are stirred with 300 g of morpholine and 400 ml of water for 16 hours at 40° C. The reaction mixture is shaken out with ether. The ether extracts are washed neutral with water, dried over sodium sulphate and evaporated in a water jet vacuum. The residue is distilled in a water jet vacuum. 2-Chloro-3-morpholinyl-pyrazine is obtained, b.p. l62-l65°C/15 Torr.

lb) 120 g of 2-chloro-3-morpholinyl-pyrazine and 70 g of allyl alcohol are dissolved in 640 ml of hexamethylphosphoric acid triamide. 8.8 g of sodium hydride are added to this solution at 0°C over the course of 30 minutes. Stirring is continued for 1 hour at 0°C, then stirring is continued to terminate the reaction for 1 hour at 30°C and 15 hours at room temperature. The reaction mixture is then poured into 2 liters of ice water. After the excess of sodium hydride has been decomposed, it is shaken out with ether. The ether extracts are washed neutral with water, dried over sodium sulphate and evaporated in a water jet vacuum. The residue is distilled under high vacuum, and 2-allyloxy-3-morpholinyl-pyrazine is obtained, b.p. 105-106°C/0.03 Torr.

lc) 32 g of 2-allyloxy-3-morpholinyl-pyrazine are dissolved in 350 ml of dimethylsulfoxide and 2.7 ml of water. 52 g of N-bromosuccinimide are added to this solution with stirring over the course of 30 minutes. The reaction temperature then rises to 35°C. You continue to stir for 30 minutes, dilute with approx. 500 ml of water and shake the reaction mixture out with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. 5-bromo-3-morpholinyl-2-(3'-bromo-2'-hydroxy-propoxy)-pyrazine is obtained.

. Example 2

71 g of 5-bromo-3-dimethylamino-2-(3'-bromo-2'-hydroxy-propoxy)-pyrazine are boiled with 71 g of isopropylamine in 1 liter of methanol for 15 hours at reflux. The reaction mixture is then evaporated in a water jet vacuum. The residue is distributed between 2N hydrochloric acid and ether. The water phase is made alkaline with concentrated caustic soda and shaken out with ether. The combined ether extracts are dried over sodium sulfate and evaporated in a water jet vacuum. The crude base is obtained and from this with fumaric acid in methanol-ether the product 5_bromo-3-dimethylamino-2-(3'-isopropylamino-2'-hydroxy)-pyrazine hydrogen fumarate, melting point 146-147°C.

The starting material 5-bromo-3-dimethylamino-2-(3'-bromo-2'-hydroxy-propoxy)pyrazine can be prepared as follows: 2a) To 350 ml of a 40% aqueous solution of dimethylamine, 74 g of 2,3-dichloro-pyrazine infused while stirring over 15 minutes. The reaction temperature is maintained by cooling at 30°C. After the exothermic reaction is over, stirring continues for 15 hours at room temperature. The reaction mixture is shaken out with ether. The ether extracts are washed neutral with water, dried over sodium sulphate and evaporated in a water jet vacuum. The residue is distilled in a water jet vacuum. 2-Chloro-3-dimethylamino-pyrazine is obtained, b.p. 100-102°C/10 Torr.

2b) 47 g of 2-chloro-3-dimethylamino-pyrazine and 35 g of allyl alcohol are dissolved in 300 ml of hexamethylphosphoric acid triamide. 14.4 g of sodium hydride are added to this solution at 0°C over 30 minutes. The mixture is then stirred for 1 hour at 0°C and 15 hours at room temperature. The reaction mixture is poured into 2 liters of ice water. After decomposition of the excess of sodium hydride, one shakes

out with ether. The ether extracts are washed to neutrality with water, dried over sodium sulphate and evaporated in a water jet vacuum. The residue is distilled under reduced pressure and 2-allyloxy-3-dimethyl-amino-pyrazine is obtained, b.p. 110-115°C/10 Torr.

2c) Dissolve 45 g of 2-allyloxy-3-dimethylaminopyrazine

in 600 ml of dimethylsulfoxide and 9 ml of water. 89 g of N-bromo-succinimide are added to this solution with stirring over the course of 30 minutes. With external cooling, the temperature is kept at 35°C. The mixture is stirred for 1 hour at room temperature, diluted with 2 liters of ice water and shaken out with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. 5-bromo-3-dimethylamino-2-(3'-bromo-2'-hydroxy-propoxy)-pyrazine is obtained.

Example 3

7.5 g of 5-bromo-3-morpholinyl-2-(3'-isopropylamino-2'-hydroxy-propoxy)pyrazine are dissolved in 80 ml of methanol and hydrogenated with 0.4 g of palladium charcoal (5%) at 20- 30°C under normal pressure. After 10 minutes, the reaction is finished with absorption of the calculated amount of hydrogen. The catalyst is then filtered off and evaporated in a water jet vacuum. The residue is distributed between water and ether. The water phase is made alkaline with concentrated caustic soda and shaken out with ether. The ether extracts are washed with water, dried

over sodium sulfate and evaporated in a water jet vacuum. 3-morpholinyl-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine is obtained, melting point 74-76°C. • The produced hydrochloride crystallizes from methanol-acetone, melting point 136-137°C.

Example 4

In an analogous manner as described in example 3, the compound 3-dimethylamino-2-( 3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine hydrochloride, melting point 130-131°C.

Example 5

53 g of 2-(3'-bromo-2'-hydroxy-propoxy)-3-chloro-pyrazine are refluxed with 59 g of isopropylamine in 500 ml of methanol,

for 15 hours. The reaction mixture is then evaporated in a water jet vacuum. The evaporation residue is shaken out between 2N hydrochloric acid and ether. The hydrochloric acid phase is made alkaline with concentrated caustic soda and shaken out with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. The residue crystallizes from ether. This gives 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, melting point 99-100°C.

The hydrochloride produced from this crystallizes from methanol-ether, melting point 183°C.

The starting material 2-(3'-bromo-2'-hydroxy-propoxy)-3-chloropyrazine can be prepared as follows: 5a) 59.6 g of 2,3-dichloropyrazine and 92.8 g of allyl alcohol are dissolved in 400 ml of dimethyl sulfoxide. 9.6 g of sodium hydride are added to this solution with stirring at 0-5°C for 30 minutes.

It is then stirred for 15 hours at room temperature. The reaction mixture is poured into 2 liters of ice water and shaken out with ether. The ether extracts are washed out with water, dried over sodium sulphate and evaporated in a water jet vacuum. The residue is distilled in high vacuum. 2-allyloxy-3-chloro-pyrazine is obtained, b.p. 42-44°C/0.03 Torr.

5b) 34 g of 2-allyloxy-3-chloro-pyrazine and 7.2 ml of water are dissolved in 500 ml of dimethyl sulphoxide. While stirring, 71 g of N-bromosuccinimide are added over the course of 30 minutes, whereby the temperature is kept at 30°C during cooling. Then stir for 30 minutes at room temperature.

temperature and dilute with 1 liter of water. The reaction mixture is shaken out with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. The crude 2-(3'-bromo-2'-hydroxy-propoxy)-3-chloro-pyrazine is obtained.

Example 6

In an analogous manner as in example 1, one obtains from 39.7 g of 5-bromo-3-morpholinyl-2-(3'-bromo-2'-hydroxy-propoxy)-pyrazine and 51 g of tert.butylamine the compound 5-bromo- 3-morpholinyl-2-(3'-tert.-butylamino-2'-hydroxy-propoxy.)-pyrazine, melting point 104-105°C.

Example 7

In an analogous manner to example 3, the product 3-morpholinyl-2-(3 '-tert.butylamino-2'-hydroxy-propoxy)-pyrazine hydrochloride, melting point 175-176°C.

Example 8

7j.5 g of 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine and 3.2 g of sodium methylate are boiled in 150 ml of methanol for 10 hours at reflux. The reaction mixture is then evaporated in a water jet vacuum. The evaporation residue is distributed between 2N hydrochloric acid and ether. The acidic, aqueous phase is made alkaline with concentrated

caustic soda and shake out with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. The crude base is obtained and from this with ethereal hydrochloric acid in methanol the compound 3-methoxy-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine hydrochloride, melting point 152-153°C.

Example 9

In a similar way as in example 1, from 37 g of 5-bromo-3-isopropylamino-2-(3'-bromo-2'-hydroxy-1-propoxy)-pyrazine the compound 5-bromo-3-isopropylamino-2- (3'-isopropylamino-2'-hydroxy-1-propoxy)-pyrazine, mp 108-109°C, crystallized from ether.

In the same way as in example 1, the starting material 5-bromo-3-isopropylamino-2-(3'-bromo-2'-hydroxy-propoxy)-pyrazine can be prepared in the following way: 9a) From 149 g (1.0 mol ) 2,3-dichloro-pyrazine and 1.4 liters of aqueous, 40 percent solution of isopropylamine gives 2-chloro-3-isopropylamino-pyrazine, b.p. 120-121°C/12 Torr.

9b) From 86 g of 2-chloro-3-isopropylamino-pyrazine, 2-allyloxy-3-isopropylamino-pyrazine is obtained, b.p. 121-123°C/12 Torr.

9c) From 39 g of 2-allyloxy-3-isopropylamino-pyrazine

5-bromo-3-isopropylamino-2-(3'-bromo-2'-hydroxy-propoxy)-pyrazine is obtained.

Example 10

In a similar way as in example 3, the compound 3-isopropylamino-2-(3'- isopropylamino-2'-hydroxy-propoxy)-pyrazine dihydrochloride, melting point 198-200°C.

Example 11

10.7 g of 2-chloro-3-morpholinyl-5-methyl-pyrazine and 16.6 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine are dissolved in 130 ml of hexamethylphosphoric acid triamide. 356 g of a 50% suspension of sodium hydride in paraffin oil are added to this solution while stirring at 0-5°C over the course of 30 minutes. The mixture is then stirred for 1 hour at 0-5°C and 24 hours at room temperature. The reaction mixture is poured into 500 ml of ice water and shaken out with ether. The ether extracts are washed with water and evaporated in a water jet vacuum. The residue is taken up in 200 ml IN sulfuric acid and stirred for 15 hours at room temperature. The reaction mixture is then shaken out with ether. The acidic water phase is made alkaline with concentrated caustic soda and shaken with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. The residue crystallizes from ether-pentane. 2-(3'-isopropylamino-2'-hydroxy-propoxy)-3-morpholinyl-5-methyl-pyrazine is obtained, melting point 77-78°C.

The hydrogen fumarate prepared with fumaric acid crystallizes from methanol-ether, melting point 183-184°C.

The starting material 2-chloro-3-morpholinyl-5-methyl-pyrazine

can be produced in the following way:

16.3 g of 2,3-dichloro-5-methyl-pyrazine and 100 ml of morpholine are heated for 6 hours at 100°C. The reaction mixture is diluted with 200 ml of ether and shaken out again with water. The ether phase is dried over sodium sulphate and evaporated in a water jet vacuum. The residue is distilled in a water jet vacuum. 2-Chloro-3~morpholinyl-5-methyl-pyrazine is obtained, b.p. 166-167°C/15 Torr.

Example 12

In a similar manner as described in example 3, 4.9 g of 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine is obtained from 2-(3'-isopropylamino-2'-hydroxy-propoxy )-pyrazine. The pumarate prepared with fumaric acid crystallizes from isopropanol, melting point 136-137°C.

Example 13

In a similar way as in example 11, one obtains from

8.5 g of the 2-chloro-3-allyloxy-pyrazine compound 2-(3'-isopropylamino-2'-hydroxy-propoxy)-3-allyloxy-pyrazine.

The fumarate prepared with fumaric acid crystallizes from methanol-acetone, melting point 149-150°C.

Example 14

A solution of 150 g of 3-chloro-2-(2',3'-epoxy-propoxy)-pyridine in 100 ml of isopropanol is added to 20 g of isopropylamine and heated further for 3 hours under reflux. The reaction mixture is evaporated in vacuo, dissolved in 300 ml of ethyl acetate and extracted with 100 ml of 2N hydrochloric acid. The hydrochloric acid extract is made alkaline with 30 ml of concentrated caustic soda and extracted with 3 x 100 ml of ethyl acetate. The organic phases are washed with 10 ml of sol, combined and dried over magnesium sulfate. 2-(3'-isopropylamino-2'-hydroxy-propoxy)-3-chloro-pyridine is obtained, which is recrystallized from ether-petroleum ether and melts at 71-73°C. The hydrochloride melts at 167-169°C (methanol-acetone).

The starting material 3-chloro-2-(2',3'-epoxy-propoxy)-pyridine can be prepared in the following way:

l4a) to a 'Suspension of 16.5 g of sodium hydride i

600 ml of 1,2-dimethoxyethane is added dropwise to 108 g of 2,2-dimethyl-4-hydroxy-methyl-dioxolane in such a way that the reaction is kept under control. Stir for 1 hour at a bath temperature of 50-60°C. To the gel-like suspension formed, 100.0 g of 2,3-dichloropyridine is added in portions under reflux. The reaction mixture, which once again becomes thin, is stirred after the addition has been completed for 3 hours under reflux. The solvent is evaporated in vacuo and the residue is distributed between 2 liters of ether and 200 ml of water. The ether phase is dried over magnesium sulfate. The evaporation residue after evaporation of the ether is distilled in high vacuum and gives 3~chloro-2-(2',2'-dimethyl-1',3'-dioxolanyl-(4')1-methoxy-pyridine which boils at 95-100°C /0.01 Torr.

14b) A solution of 157 g of 3-chloro-2-(2',2'-dimethyl-1*,3'-dioxolanyl-(4'))-methoxypyridine in 100 ml of ethanol is added to 320 ml of 2N hydrochloric acid and stirred for 2 hours at room temperature. After evaporation of the ethanol, the product is dissolved in as little water as possible (approx. 100 ml), washed with 100 ml of ether and the water phase made alkaline with concentrated caustic soda. The separating oil is extracted with 3 x 200 ml of ethyl acetate. Each extract is washed with 20 ml of sol, dried and evaporated. -The 3-chloro-2-(2',3'-dihydroxy-propoxy)-pyridine formed boils at 142-145°C/0.015 Torr.

14c) To a solution of 40.6 g of 3-chloro-2-(2',3'-dihydroxy-propoxy)-pyridine in 100 ml of pyridine, 25.2 g of methanesulfonic acid chloride are added while stirring and cooling at 0-5°C drop by drop over the course of 1 hour. The reaction mixture is further stirred for 5 hours at room temperature and then poured into 200 ml of ice water. The oil that separates is isolated as in example lb). The crude 3-chloro-2-(3'-methanesulfonyloxy-2'-hydroxy-propoxy)-pyridine is obtained, which is processed further without purification.

14d) 67 g of crude 3-chloro-2-(3'-methanesulfonyloxy-2'-hydroxy-propoxy)-pyridine, 400 ml of methylene chloride, 240 ml of IN caustic soda and 5 g of tetrabutylammonium chloride are stirred for 15 hours at room temperature. The methylene chloride phase is separated, washed with 2 x 40 ml of water, dried and evaporated. From the evaporation residue, the desired 3-chloro-2-(2',3'-epoxy-propoxy)-pyridine is isolated by distillation as a pale yellow oil, b.p. 115-130°C/0.03 Torr.

Example 15

22 g of crude 2-methoxy-3-(3'-methanesulfonyloxy-2'-hydroxy-propoxy)-pyridine, 50 ml of isopropylamine and 150 ml of isopropanol are heated for 16 hours at reflux. After working up in analogy to example 14, 3-(3'-isopropylamino-2'-hydroxy-propoxy)-2-methoxy-pyridine is obtained which, after recrystallization from ether-pentane, melts at 50-65°C. After reaction with half the equivalent amount of fumaric acid, the neutral fumarate with melting point 146-147°C is obtained (recrystallized from acetone).

The starting material 2-methoxy-3-(3'-methanesulfonyloxy-2'-hydroxy-propoxy)-pyridine is prepared as follows: 15a) 26 g of 3-(1',3'-dioxolan-2'-on-yl-( 4')N-Methoxy-2-nitro-pyridine is heated with a solution of 7.5 g of sodium in 500

ml of absolute methanol for 15 hours at reflux. The resolution

cooled, neutralized with 2N hydrochloric acid and evaporated in vacuo. The residue is boiled off with 500 ml of chloroform, the solution is filtered and evaporated. The evaporation residue gives the crude 3~ (2',3'-dihydroxy-^v >v propoxy)-2-methoxy-pyridine as a yellowish oil.

15b) 14.8 g of 3-(2*,3'-dihydroxy-propoxy)-2-methoxy-pyridine is dissolved in 100 ml of anhydrous pyridine and added at -10

to -15°C dropwise and with stirring 9.0 g of methanesulfonic acid chloride. The reaction mixture is further stirred for 3 hours at -10°C. The pyridine is then evaporated in a rotary evaporator as completely as possible at 10 Torr, and the crude 2-methoxy-3-(3'-methanesulfonyloxy-2'-hydroxy-propoxy)-pyridine formed is further reacted without purification, with isopropylamine.

Example 16

A solution of 6.5 g of 2-(3'-isopropyl-2'-phenyloxa-zolidinyl-(5'))-methoxy-6-methoxy-pyridine in 40 ml of ethylene glycol dimethyl ether and 10 ml of ethanol is added to 20 ml 2N hydrochloric acid and stirred for 2 hours at room temperature. The solution is evaporated in vacuo and the residue is distributed by shaking between 30 ml of water and 50 ml of ether. The water phase is made strongly alkaline with concentrated caustic soda and extracted with 3 x 100 ml of ethyl acetate. After drying and evaporation, 2-(3'-isopropylamino-2'-hydroxy-propoxy)-6-methoxy-

pyridine, and the neutral fumarate of this compound melts at 140-141°C (recrystallized from methanol/acetone).

Example 17

7.4 g of 2-C3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-4-phenyl-pyridine is hydrolyzed as in example 16 and gives 2-(3'-isopropylamino-2'-hydroxy -propoxy)-4-phenyl-pyridine, whose neutral fumarate melts at 171-173°C (recrystallized from methanol/acetone).

Example 18

6.8 g of crude 2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-5-nitropyridine are hydrolyzed in the same way as in example 16, adjusted to pH 9 with saturated soda solution and the product is isolated further as in example 16. 2-(3'-isopropylamino-2'-hydroxy-propoxy)-5~nitropyridine with melting point 117-123°C (recrystallized from isopropanol) is obtained.

Example 19

33 g of crude 3-(2',3'-epoxy-propoxy)-6-methylpyridine,

350 ml of isopropanol and 75 ml of isopropylamine are heated for 12 to 14 hours at reflux. The preparation takes place as in example 14. The prepared 3-(3'-isopropylamino-2'-hydroxy-propoxy)-6-methyl-pyridine boils in a bubble tube at 135-150°C/0.2 Torr. The neutral fumarate of the compound melts at 171-173°C (recrystallized from methanol/acetone).

The starting material 3-(2',3'-epoxy-propoxy)-6-methyl-pyridine is prepared as follows:

19a) 22 g 6-methyl-3-pyridinol, 50 g potassium carbonate

■and 80 ml of epichlorohydrin are heated in 500 ml of acetone with stirring and reflux for 18 to 20 hours. Undissolved matter is filtered off and the filtrate is evaporated at 30-40°C bath temperature, in vacuum.

The produced 3-(2<1>,3'-epoxy-propoxy)-6-methyl-pyridine is processed further without purification.

Example 20

a) 4.9 g of 5-hydroxy-methyl-3-isopropyl-2-phenyl-oxazolidine is added to a suspension of 0.5 g of sodium hydride in 40 ml of ethylene glycol dimethyl ether. The reaction mixture is stirred for 2 hours at 40-50°C, 2.9 g of 2-chloro-6-methoxypyridine is added and boiled for 14 hours at reflux. The solution of 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'j)-methoxy-6-methoxy-pyridine can, as indicated in example 16, be hydrolyzed without isolating the product. In an analogous way, one can also prepare the following compounds: b) 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5' )3-methoxy-4-phenyl-pyridine from 2-bromo-4-phenyl-pyridine. c) 2- C3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-5-nitropyridine from 2-chloro-5~nitro-pyridine. d) 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-3-methyl-pyridine from 2-chloro-3-methyl-pyridine. e) 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-5-methylaminocarbonyl-pyridine from 6-chloro-N-methylnicotinic acid amide.

The starting material for example 20e) can be prepared as follows: In a suspension of 126 g of phosphorus pentachloride in 300 ml of toluene, 42 g of 6-hydroxynicotinic acid are dripped over the course of 1 hour. The reaction mixture is heated to boiling for 3 hours and evaporated under reduced pressure. The crude, crystalline evaporation residue is dissolved in 200 ml of chloroform and dripped under ice-cooling into 300 ml of a 16-prose solution of methylamine in absolute ethanol. After the addition, stir for 3 hours. One filters and evaporates at reduced pressure. The evaporation residue is dissolved in ethyl acetate, washed with 2N sodium carbonate solution and recrystallized from ethanol-ether. The isolated 6-chloro-N-methylnicotinic acid amide melts at 149-151°C.

Example 21

40 g of crude 2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5')J-methoxy-3-methylpyridine dissolved in 150 ml of ethanol are hydrolyzed with 3.0 ml of 6N hydrochloric acid for 3 hours at 20°C and worked up as in example 16. In this way, 2-(3'-isopropylamino-2'-hydroxy-propoxy)-3-methylpyridine is obtained, which is distilled in a bubble tube at 130-140°C7 0.03 Torr and the fumarate is found to melt at 153 -155°C (recrystallized from methanol-acetone).

Example 22

22 g of 2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-5-methyl-aminocarbonyl-pyridine are dissolved in 200 ml of ethanol and hydrolysed with 30 ml of 6N hydrochloric acid for 3-4 hours at 20 °C, and worked up as in example 16. 2-(3'-isopropylamino-2'-hydroxy-propoxy)-5-methylaminocarbonylpyridine is obtained which melts at 118-120°C.

Example 23

25 g of crude 3-(2?,3'-epoxy-propoxy)-2-pyrrolidinocarbonyl-pyridine dissolved in 350 ml of isopropanol is boiled with 150 ml of isopropylamine for 3 hours at reflux. After evaporation and work-up of the residue in analogy with example 14, 3-(3'-isopropylamino-2'-hydroxy-propoxy)-2-pyrrolidinocarbonylpyridine is obtained which melts at 108-111°C (recrystallized from ethyl acetate-ether).

The starting material is obtained by reacting 2-pyrrolidinocarbonyl-3-hydroxypyridine with epichlorohydrin as described in example 19a).

Example 24

4.2 g of sodium hydride dispersion (55%) is mixed with 150 ml of dimethoxyethane and a solution of 24.3 g of 2-phenyl-3~isopropyl-5-hy-

hydroxymethyl-oxazolidine in 50 ml of dimethoxyethane. Stir for 1.5 hours at 45°C. After adding 19.96 g of 3-chloro-6-morpholino-pyridazine, the reaction mixture is heated for 24 hours at reflux, acidified at 20°C with hydrochloric acid (15%) and stirred thoroughly for 2 hours. At 40°C, the dimethoxyethane is evaporated in vacuum and the hydrochloric acid residue is extracted with ether. The acidic phase is set alkaline

with 5N caustic soda and extracted with chloroform. The extract is washed with saturated sodium chloride solution and filtered through cotton wool, evaporated in vacuo and the residue purified by chromatography on silica gel (eluent: chloroform/methanol = 9/1).

After recrystallization from methylene chloride/ether, the produced 3-(3'-isopropylamino-2'-hydroxy-propoxy)-6-morpholino-pyridazine melts at 112-113°C.

Example 25

12.5 g of 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5')J-methoxy-pyrimidine is taken up in 60 ml of 1N sulfuric acid. It is heated to boiling for half an hour, cooled, -extracted benzaldehyde with ether, to the separated water phase add the required amount of barium hydroxide solution to neutralize the sulfuric acid, and filter. The filtrate is evaporated in vacuo. The oil formed is distilled in a bubble tube. After a short course, the product 2-(3'-isopropylamino) is obtained -2'-hydroxy-propoxy)-pyrimidine as a colorless oily distillate at 140°C70.05 Torr. The hydrogen oxalate melts -.at 181-182°C (from acetone).

Example 26

13.3 g of 2-(3'-para-toluenesulfonyloxy-2'-hydroxy-propoxy)-pyrimidine is dissolved in 100 ml of isopropanol and 22 ml of isopropylamine and allowed to stand for 48 hours at room temperature. The volatile components are distilled off in a vacuum, the oil residue is taken up in acetone and a solution of 4 g of oxalic acid is added. 2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrimidine hydrogen oxalate is obtained, which is recrystallized from methanol-acetone, melting point 181-182 C.

The starting material 2-(3'-para-toluenesulfonyloxy-2'-hydroxy-propoxy)-pyrimidine can be prepared as follows: 26a) To a suspension of 1.2 g of sodium hydride in 50 ml of dimethoxyethane, 6.6 g of 2,2-dimethyl -1,3-dioxolane-4-methanol and stir for 2 hours at room temperature. 5.7 g of 2-chloropyrimidine are added. The reaction mixture is heated for 2 hours at reflux and evaporation in a vacuum. The residue is distilled in a ball tube. After a short distillation process, 2-(2',2'-dimethyl-1',3'-dioxolane-(4'))-methoxypyrimidine is obtained as a colorless oil at 200°C/19 Torr.

26b) 16 g of 2-(2',2'-dimethyl-1',3'-dioxolane-(4 *)J-methoxy-pyrimidine is heated with 20 ml of water and 2 ml of 2N sulfuric acid for 15 minutes by boiling. It is cooled , adds the necessary amount of barium hydroxide solution to neutralize the acid, and filters. The filtrate is evaporated and the remaining oil is distilled in a bubble tube, which gives 2-(2',3'-dihydroxy-propoxy)-pyrimidine as a colorless oily distillate with bp l80-190°C/ 0.4 Torr.

26c) To a solution of 11.8 g of 2-(2',3'-dihydroxy-propoxy)-pyrimidine in 18 ml of pyridine that has been cooled to -10°C, 13.6 g of para-toluene sulfochloride in within 15 minutes. The reaction mixture is allowed to stand for 15 hours at 0°C.

Ice is added and, while stirring, 20 ml of 6M hydrochloric acid. Then extract with 2 x 150 ml of methylene chloride. The extracts are washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated. 2-(3'-para-toluenesulfonyloxy-2'-hydroxy-propoxy)-pyrimidine is obtained as a yellow oil.

Example 27

By analogy with examples 14-23, the following compound can then be prepared: 3-(3'-isopropylamino-2'-hydroxy-propoxy)-2-(n-butylaminocarbonyl)pyridine, melting point 65-67°C.

Example 28

In a similar manner as described in Examples 24-26

the following compounds can also be synthesized:

1) 3-(3'-isopropylamino-2'-hydroxy-propoxy)-6-methoxy-pyridazine, melting point 115-116°C, 2) 3-(3'-isopropylamino-2'-hydroxy-propoxy)-6 -chloro-pyridazine, melting point 98-99°C, 3) 3-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridazine, melting point 91-93°C.

Example 29

40 g crude 2-((3'-tert.butyl-2'-phenyl-oxazolidinyl-

(5')N-Methoxy]-3-ethoxy-6-methyl-pyridine is stirred in 150 ml of 2N sulfuric acid for 2 hours at 20-30°C. The solution is extracted with 50 ml of ether, the aqueous phase is separated and made alkaline with concentrated caustic soda. The extraction of the alkaline phase with methylene chloride and evaporation of the solvent gives 25 g of a yellow oil, which bubble tube distills at 110-115°C/0.02 Torr. The thus formed 3-ethoxy-2-(3'-tert.butylamino-2'-hydroxy-propoxy)-6-methyl-pyridine with half the equivalent amount of fumaric acid gives a neutral fumarate of melting point 169-170°C (from methanol -acetone).

The starting material can be obtained in the following way:

A solution of 17.1 g of 3-ethoxy-2-chloro-6-methyl-pyridine and 25.8 g of 5-hydroxymethyl-3-tert.butyl-2-phenyloxazolidine in 300 ml of hexamethylphosphoric anhydride is mixed during ±{ hour at 0- 5°C with 4.8 g sodium hydride dispersion (55%) in portions. The reaction mixture is then stirred for 2 hours at 20-30°C and 16 hours at 70°C, then poured onto ice water and 2-([3'-tert.butyl-2'-phenyl-oxazolidinyl-(5')J- methoxy-3-ethoxy-6-methyl-pyridine is extracted with about 500 ml of ether.The crude product remaining after evaporation of the ether is further used as such.

Example 30

A solution of 34 g of 2-(3'-isopropyl-2'-phenyl-oxa-zolidinyl-(5'))-methoxy-4-methyl-pyridine in 200 ml of ethanol is added to 60 ml of 4N hydrochloric acid and set aside overnight at room temperature. The solvent is evaporated in a vacuum and the residue is dissolved in approx.

200 ml of water. The solution is extracted with 100 ml of ether. The water phase is separated, made strongly alkaline with concentrated potassium hydroxide and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained which is distilled in a bubble tube at 120-130°C7o,l Torr. Half the equivalent amount of fumaric acid dissolved in methanol is added to the 2-(3'-isopropylamino-2'-hydroxy-propoxy)-4-methylpyridine produced, the solution is evaporated in vacuo and acetone is added. The neutral fumarate with a melting point of 136-139°C is obtained.

Example 31

A solution of 40 g of 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-5-methyl-pyridine in 200 ml of ethanol is added to 60 ml of 4N hydrochloric acid and allowed to stand overnight at room temperature . The solvent is evaporated in a vacuum and the residue is absorbed for approx. 200 ml of water. This solution is extracted with 100 ml of ether. The water phase is separated, made alkaline with concentrated caustic soda and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained which is distilled in a bubble tube at 120-130°C/0.1 Torr. The formed 2-(3'-isopropylamino-2<*->hydroxy-propoxy)-5-methyl-pyridine crystallizes with a melting point of 62-67°C.

Half the equivalent amount of fumaric acid dissolved in methanol is added, the solution is evaporated and acetone is added. The precise

tral fumarate crystallizes out with a melting point of 149-151°C.

Example 32

A solution of 35 g of 2-(3'-isopropyl-2'-phenyl-oxa-zolidinyl-(5'))-methoxy-6-methyl-pyridine in 200 ml of ethanol is added to 60 ml of 4N hydrochloric acid and allowed to stand at room temperature for 1 hour. The solvent is evaporated in a vacuum and the evaporation residue is dissolved in approx. 200 ml of water. The solution is extracted with 100 ml of ether. The water phase is separated, made strongly alkaline with concentrated potash,

and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained, which distils in the ball tube

res at 130°C/0.04 Torr. The prepared 2-(3'-isopropylamino-2'-hydroxy-propoxy)-6-methyl-pyridine is added to half the equivalent

lean amount of fumaric acid dissolved in methanol, the solution is evaporated under vacuum and acetone is added. The neutral fumarate, melting point 164-165°C, is crystallized in this way.

Example 33

A solution of 40 g of 2-(3'-isopropyl-2'-phenyl-oxazo-lidinyl-(5')}-methoxy-3-ethoxy-pyridine in 200 ml of ethanol is added to 60 ml of 4N hydrochloric acid and allowed to stand overnight at room temperature . The solvent is evaporated in vacuo and the residue is dissolved in approx. 200 ml of water. This solution is extracted with 100 ml of ether. The water phase is separated, made strongly alkaline with concentrated potassium hydroxide and extracted with ethyl acetate. After drying and evaporation of the solvent, you get a dark oil which is distilled in the ball tube at 130-140°C/0.03 Torr. The formed 2-(3'-isopropylamino-2'-hydroxy-propoxy)-3-ethoxy-pyridine is added to half the equivalent amount of fumaric acid dissolved in methanol, the solution is evaporated in vacuo and methyl ethyl ketone is added.It crystallizes out the neutral fumarate, melting point 142-144°C.

ri / Example 34

A solution of 30 g of 2-(,3'-isopropyl-2'-phenyl-oxa-zolidinyl-(5')J-methoxy-3-chloro-5-(methylaminocarbonyl)-pyridine in 260 ml of 2N sulfuric acid is stirred in 4 hours at room temperature. This solution is extracted with 100 ml of ether. The aqueous phase is separated, made strongly alkaline with concentrated potassium hydroxide and extracted with ethyl acetate. After drying and evaporation of the solvent, a dark oil is obtained which crystallizes from ether. The formed 2 -(3'-isopropylamino-2'-hydroxy-propoxy)-3-chloro-5~(methylaminocarbonyl)-pyridine melts at 130-132° C. Half the equivalent amount of fumaric acid dissolved in methanol is added, the solution is evaporated in vacuo and acetone is added The neutral fumarate crystallizes out with a melting point of 133-136°C.

Example 35

A solution of 32 g of 2-f 3 '-isopropyl-2'-phenyl-oxa-zolidinyl- (51 ) 1-methoxy-3-chloro-5-n-hexylaminocarbonyl-pyridine in 260 ml of 2N sulfuric acid is stirred for 4 hours at room temperature. This solution is extracted with 100 ml of ether. The water phase is separated, made strongly alkaline with concentrated potassium hydroxide and extracted with ethyl acetate. After drying and evaporation of the solvent, a dark oil is obtained which crystallizes from ether. The 2-(3'-isopropylamino-2'-hydroxy-propoxy-3-chloro-5~n-hexylaminocarbonyl-pyridine produced melts at 131-132°C. Half the equivalent amount of fumaric acid dissolved in methanol is added, the solution is evaporated in vacuum and acetone is added.The neutral fumarate is obtained by crystallization, melting point 170-172°C.

Example 36

A solution of 28 g of 2-(3'-isopropyl-2'-phenyl-oxa-zolidinyl-(5')]-methoxy-5-cyano-pyridine in 260 ml of 2N sulfuric acid

leave for 4 hours at room temperature. This solution is extracted with 100 ml of ether. The water phase is separated, made strongly alkaline with concentrated potassium hydroxide and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained which is crystallized from methylene chloride-ether. The formed 2-(3'-isopropylamino-2'-hydroxy-propoxy)-5-cyano-pyridine melts at 124-126°C.

Example 37

12.5 g of 2-(3'-isopropylamino-2'-hydroxy-propoxy)-5-cyano-pyridine are dissolved in 100 ml of methanol. The solution is added to 5-7 g of ammonia and hydrogenated by adding 3 g of Raney nickel at 70-80°C and 40 atm. starting pressure until hydrogen is no longer absorbed. The catalyst is filtered off, the solvent is evaporated and the residue is distilled in a bubble tube at 140°C70.01 Torr.

5-Aminoethyl-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine is obtained as a pale yellow oil.

Example 38

28.7 g of 2-(3'-isopropylamino-2'-hydroxy-propoxy)-5-nitro-pyridine are dissolved in 300 ml of methanol and hydrogenated by adding 3 g of Raney nickel at room temperature and atm. pressure to absorb a theoretical amount of hydrogen. The catalyst is filtered from under a nitrogen atmosphere and the filtrate is evaporated. The prepared crude 5-amino-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine is dissolved in 150 ml of dichloromethane and 14.3 ml of acetic anhydride is added dropwise while stirring. The solution is thereby heated exothermically to reflux. After adding the anhydride dropwise, the reaction mixture is stirred further for 20-30 minutes. After shaking out the solution with 90 ml of 2N sodium carbonate solution, the organic phase is extracted with a total of 200 ml of 2N hydrochloric acid, the acidic, aqueous extract is treated with activated carbon Approx. 10 g) and evaporated in a vacuum. The produced dark oil is taken up in the smallest amount of water and made alkaline with concentrated caustic soda. By extraction with dichloromethane, the crude base is isolated. From butanone, 5-acetamido-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine with a melting point of 138-141°C is crystallized. The compound forms a hydrochloride with a melting point of 204-206°C (from methanol-acetone).

Example 39

A solution of 25 g of crude 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-5-(2'-aminoethyl)-pyridine in 150 ml of 4N sulfuric acid is reacted analogously to example 34 and worked up further.

The crude 5-(2'-aminoethyl)-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine is obtained, which is sufficiently pure for further reactions. The pure product is obtained by ball tube distillation at 140-150 C7 0.005 Torr.

Example 40

12.4 g of 5-(2'-aminoethyl)-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine dissolved in a mixture of 45 ml isopropanol and 45 ml water, added dropwise and with stirring, at a temperature of 20-35°C, 5.4 ml of chloroformic acid methyl ester with possible cooling with ice water. The reaction mixture is stirred for a further hour at room temperature, evaporated in vacuo and the evaporation residue dissolved in 30 ml of water. This solution is extracted with 20 ml of ethyl acetate and the acidic water phase is made alkaline with concentrated caustic soda. The separated oil is extracted with dichloromethane. After drying the solution over magnesium sulfate and evaporation

of the solvent gives 2-(3'-isopropylamino-2'-hydroxy-propoxy)-5~(2'-methoxycarbonyl-aminoethyl)-pyridine which, after recrystallization from a little butanone, melts at 97J99°C.

Example 41

Using 8.9 nil chloroformic acid n-butyl ester i

instead of 5.4 ml chloroformic acid methyl ester, in analogy with example 40, 5-(2'-n-butoxycarbonylaminoethyl)-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine is obtained, which after crystallization from butanone melts at 93-95°C and forms a neutral fumarate with a melting point of 145-147°C.

Example 42

In a similar way as in example 40, 14.1 g of 5-(2'-aminoethyl)-3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy')-pyridine is obtained instead of 5- (2'-aminoethyl)-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine the product 3~chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-5-(2' -methoxycarbonylaminoethyl)-pyridine with melting point 99-101°C (from ether). The product forms a neutral fumarate with a melting point of 179-180°C (from ethanol). The starting material can be produced as follows:

a) The crude 5,6-dichloronicotinic acid chloride obtained from

279 g of 2-hydroxy-5-pyridinecarboxylic acid, is reduced with 185 g of sodium borohydride in 3.2 liters of water as described by P.E. Ziegler and J.G. Sweeny, J. Org. Chem. 34., 3545 (1969) to 2,3-dichloro-5-hydroxymethylpyridine, melting point 72-75°C. b) The 2,3-dichloro-5-hydroxy-methyl-pyridine is reacted in a known manner with thionyl chloride to 5-chloromethyl-2,3-dichloro-pyridine,

and this is reacted further without purification, with sodium cyanide (e.g.

as described by L.A. Carlson and colleagues in Acta Pharm. Suecica 9, 4ll (1972). The 5,6-dichloro-pyridine-3-acetonitrile produced melts after recrystallization from ether at 72-75°C.

c) 85>5 g of (5,6-dichloro-3-pyridine)-acetonitrile in 200 ml of methanol is, in analogy to example 40a), reduced by 18.5 S

sodium borohydride in 65 ml of concentrated caustic soda and 20 g of Raney nickel. From this crude product, 5-(2'-aminoethyl)-2,3-dichloropyridine is obtained by distillation in bubble tubes at 95-115°C bath temperature and 0.08 Torr.

d) 44 g of 5-(2'-aminoethyl)-233-dichloro-pyridine and 55 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine dissolved in 500 ml

1,2-dimethoxyethane is added under ice-cooling at 0-10°C, portion wise 12 g of sodium hydride dispersion (55%)■ The reaction mixture is then stirred for 2 hours at room temperature and 16 hours under reflux. The work-up gives the crude 5-(2'-aminoethyl)-3-chloro-2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-pyridine which is hydrolyzed without further purification in analogy to example 37 to 5-(2'-aminoethyl)-3-chloro-2-(3'-isopropylamino-2*-hydroxy-propoxy)-pyridine (boiling point 165-185°C/0.06 Torr).

Example 43

6 g of 5-aminoethyl-2-(2'-hydroxy-3'-isopropylamino-propoxy)-pyridine dissolved in 25 ml of isopropanol and 25 ml of water is, as described in example 40, reacted with 2.3 ml of chloroformic acid methyl ester and worked up, giving 2-(2'-Hydroxy-3'-isopropylamino-propoxy)-5-methoxy-carbonyl-aminomethyl-pyridine with melting point 96-97°C (from ether). The neutral fumarate melts at 138-140°C.

Example 44

Analogously to example 43, by using 3.7 ml of chloroformic acid n-butyl ester instead of the -methyl ester, 2-(2'-hydroxy-3'-isopropylamino-propoxy)-5_(n-butoxycarbonyl-aminomethyl)-pyridine with melting point 85-87°C (sinters at 79°C), after recrystallization from dichloromethane ether.

Example 45

A solution of 24 g of 2-(3'-tert.butyl-2'-phenyl-oxa-zolidinyl-(5')}-methoxy-3-ethoxy-pyridine in 100 ml of ethanol is added to 60 ml of 4N hydrochloric acid and allowed to stand for 2 hours at room temperature. The solvent is evaporated in vacuo and the residue is dissolved in 100 ml of water. The solution is extracted with 100 ml of ether. The water phase is separated, made strongly alkaline with concentrated potassium hydroxide and extracted with ether. After drying and evaporation of the solvent, a dark oil which is distilled in a bubble tube at 130°C/ 0.03 Torr. The 2-(3'-tert.butylamino-2'-hydroxy-propoxy)-3-ethoxy-pyridine produced is added to half the equivalent amount of fumaric acid, dissolved in methanol , the solution is evaporated in vacuo and butanone is added. The neutral fumarate crystallizes with a melting point of 170-172°C, crystal transformation at 161-163°C.

Example 46

19.5 g of crude 3-(2',3'-epoxy-propoxy)-2-nitro-pyridine, dissolved in 300 ml of isopropanol, is boiled with 100 ml of isopropylamine for 4 hours at reflux. After working up as described in example 14, 3-(2'-hydroxy-3'-isopropylamino-propoxy)-2-nitro-pyridine is obtained which melts at 99-101°C after crystallization from ether.

The starting material is obtained in the following way:

a) 28 g of 2-nitro-3-pyridinol, 200 ml of epichlorohydrin and 60 g of potassium carbonate are boiled with stirring in 500 ml of acetonitrile for 8 hours at reflux. Filtration and evaporation of the reaction mixture gives crude 3-(2',3_'-epoxy-propoxy)-2-nitro-pyridine as a yellow oil.

Example 47

5.2 g of 2-((3'-isopropyl-oxazolidin-2'-on-5'-yl)-methoxy]-4-phenyl-pyridine is boiled in a mixture of 70 ml of ethanol and 20 ml of 2N caustic soda for 16 hours at reflux. The reaction mixture is evaporated in vacuo, distributed between 100 ml of ether and 20 ml of water, the organic phase is separated and extracted with 40 ml of 2N hydrochloric acid. The hydrochloric acid extract is made alkaline with concentrated caustic soda and the separated oil is extracted again with ether The isolated 2-(2'-hydroxy-3'-isopropylamino-propoxy)-4-phenyl-pyridine forms a neutral fumarate with a melting point of 171-173°C.

Example 48

A solution of 48 g of 2-^3'-isopropyl-2'-phenyl-oxa-zolidinyl-(5'))-methoxy-3-chloro-pyridine in 200 ml of ethanol is added to 60 ml of 4N hydrochloric acid and allowed to stand for 3 hours at room temperature. The solvent is evaporated in a vacuum and the residue is absorbed for approx. 200 ml of water. The solution is extracted with 100 ml of ether. The water phase is separated, made strongly alkaline with concentrated potassium hydroxide and extracted with methylene chloride. After drying and evaporation of the solvent, an oil is obtained which, by adding a hydrochloric acid solution of methanol to pH 2-3, can be isolated as the hydrochloride of 2-(3'-isopropylamino-2'-hydroxy-propoxy)-3 -chloro-pyridine. It melts on recrystallization from methanol-acetone at 167-169°C.

Example 49

A resolution of approx. 35 g of 4-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-3-methyl-pyridine in 100 ml of ethanol are added to 60 ml of 4N hydrochloric acid and allowed to stand for 2 hours at room temperature. The solvent is evaporated off in a vacuum and the residue is dissolved in approx.

100 ml of water. This solution is extracted with 100 ml of ether. The water phase is separated, made strongly alkaline with concentrated potassium hydroxide and extracted with methylene chloride. After drying and evaporation of the solvent, a yellow oil is obtained which is distilled in a ball tube at 145°C/0.02 Torr. The resulting 4-(3'-isopropylamino-2'-hydroxy-propoxy)-3-methyl-pyridine is added to the equivalent amount of fumaric acid, dissolved in methanol, the solution is evaporated in vacuo and isopropanol is added. The acid fumarate with a melting point of 167-169°C is crystallized out.

Example 50

5.3 g of 5~(2'-aminoethyl)-3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine is reacted in analogy to example 40 with 2.2 g of chloroformic acid ethyl ester in a mixture of 25 ml of isopropanol and 25 ml of water, and after recrystallization from acetone ether gives 5-(2'-ethoxy-carbonylamino-ethyl)-3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine with a melting point of 120-122 C. It forms a neutral fumarate with a melting point of 149-151°C (ethanol-acetone).

Example 51

32 g of crude 2-[(3'-isopropyl-2'-phenyl-oxazolidin-5'-yl)-methoxy)-3-chloro-5-(tetrahydropyran-2'-yloxy)-methyl]-pyridine are dissolved in 250 ml of 2N sulfuric acid, the solution is allowed to stand for 4 hours at room temperature and extracted with 100 ml of ether. The water phase is evaporated in vacuum to approx. 50 ml, made alkaline with concentrated caustic soda and extracted with 3 x 150 ml methylene chloride. After drying and evaporation of the solvent, 3-chloro-2-(2'-hydroxy-3'-isopropylamino-propoxy)-5-hydroxy-methyl-pyridine is obtained, which is distilled in a bubble tube at 170-180°C/0.04 Torr and gives a colorless oil, which forms a neutral fumarate with a melting point of 205-207°C (from methanol).

Example 52

A solution of 45 g of crude 3-methyl-2-{(2-phenyl-3-(4-phenyl-2-butyl)-oxazolidin-5-yl)-methoxy]-pyridine in 200 ml of ethanol is hydrolyzed with 120 ml of 4N hydrochloric acid for 3 hours at 20°C and up- . is worked on. Carbon tube distillation at 140-150°C/0.04 Torr yields 2-(2<1->hydroxy-3'-(1-methyl-3-phenyl-propylamino)-propoxyJ-3-methyl-pyridine as a pale yellow oil.

The starting material can be produced in the following way:

a) 31.1 g of 2-phenyl-3-(1-phenyl-3-butyl)-5-hydroxy-methyl-oxazolidine, dissolved in 150 ml of dimethylformamide, is reacted with

6.5 g of sodium hydride dispersion (55%) and then with 34.4 g of 2-bromo-3-methylpyridine for 18 hours. The crude 3-methyl~3-|(2-phenyl-3-(4-phenyl-3-butyl)-oxazolidin-5-yl)-methoxy]-pyridine is obtained.

Example 53

A mixture of 61 g of 6-methyl-3-pyridinol, 5.5 g of 1-isopropyl-3-azetidinol, 0.3 g of potassium hydroxide and 25 ml of benzyl alcohol is stirred under a nitrogen atmosphere for 16 hours in a bath maintained at 150°C . After cooling, the reaction mixture is diluted with 150 ml of ether and extracted with 30 ml of 4N hydrochloric acid. The water phase is separated, made alkaline with concentrated caustic soda and extracted with 100 ml of methylene chloride. From this crude product, 3-(3'-isopropylamino-2'-hydroxy-propoxy)-6-methylpyridine is obtained by bubble tube distillation at 130-140°C bath temperature and 0.04 Torr. It is identical in properties to the product produced according to example 19.

Example 54

14.8 g of 3-benzyloxy-2-(2'-hydroxy-3'-isopropylamino-propoxy)-6-methyl-pyridine, dissolved in 150 ml of dioxane, is hydrogenated by adding 1.5 g of palladium-charcoal catalyst. After absorption of the theoretical amount of hydrogen, the hydrogenation stops. The catalyst is filtered off, the filtrate is evaporated and the remaining oil is added to a solution of 2.6 g of fumaric acid in approx. 50 ml of methanol. This solution is filtered, evaporated in vacuo to a

oil and 50 ml of isopropanol is added to the residue. The neutral fumarate of 2-(2*-hydroxy-3'-isopropylamino-propoxy)-6-methyl-3-pyridinol with a melting point of 198-200°C is crystallized.

Example 55

By catalytic debenzylation of 6-benzyloxy-2-(2'-hydroxy-3'-isopropylamino-propoxy)-pyridine analogous to example 54, 6-(2'-hydroxy-3'-isopropylamino-propoxy)-2-pyridinol with melting point 177-178°C (from methanol-ether).

The starting material can be produced in the following way:

a) 2,6-dichloropyridine is reacted with 1 equivalent of sodium benzylate in dimethylformamide to 2-benzyloxy-6-chloro-pyridine (bp. 95-100°C/0.01 Torr). b) 2-benzyloxy-6-chloro-pyridine is usually transferred to 2-benzyloxy-6-(2'-hydroxy-6'-isopropylamino-propoxy)-pyridine (bp. 140-150°C70.02 Torr in ball tube, melting point 57-64°C).

Example 56

By catalytic debenzylation of 3-benzyloxy-2-(2'-hydroxy-3'-isopropylamino-propoxy)-pyridine analogously to example 55, 2-(2'-hydroxy-3'-isopropylamino-propoxy)-3-pyridinol is obtained.

The starting material can be obtained from 3-benzyloxy-2-nitro-pyridine in the usual way.

Example 57

A solution of 31 g of crude 3-tert.butyl-5-(3-cyano-pyridin-2-yloxymethyl)-2-phenyl-oxazolidine in 50 ml of 2N hydrochloric acid is allowed to stand for 3-4 hours at 20-30°C, then extract with 100 ml of ether and make the aqueous phase alkaline with 30 ml of concentrated caustic soda. The precipitated oil is extracted with ethyl acetate and the solvent is then evaporated, after which 1-tert.butyl-amino-3-(3-cyano-pyridin-2-yloxy)-2-propanol is obtained. It forms a neutral fumarate which, after recrystallization from methanol-dioxane-water, melts at 228-230°C.

The starting material can be obtained in the following way:

A solution of 24.4 g of 3-tert.butyl-5-hydroxy-methyl-2-phenyl-oxazolidine in 100 ml of dimethylformamide is mixed in portions with 4.2 g of the sodium hydride suspension. The reaction mixture is stirred for one hour at 40°C, cooled to 20°C and then mixed in 3 portions with 12.0 g of 2-chloronicotinic acid nitrile. The reaction mixture is thereby heated to 60°C, stirred for 2-3 hours, evaporated in vacuo, mixed with 30 ml of water and extracted with 200 ml of ether. The crude 3-tert-butyl-5-(3-cyano-pyridin-2-yloxy-methyl)-2-phenyl-oxazolidine formed by evaporation of the ether solution is further used crude.

Example 58

A solution of 4.8 g of 3~isopropyl-5-((6-methyl-pyridin-3-yloxy)methyl)-oxazolidin-2-one in 50 ml of dichloromethane is added with stirring over the course of 10 minutes to a solution of 4, 1 g of m-chloroperbenzoic acid in 30 ml of dichloromethane and leave overnight at room temperature. After dilution with 50 ml of dichloromethane, the reaction mixture is extracted with 20 ml of saturated potassium bicarbonate solutions, dried over sodium sulphate and evaporated in vacuo. The crystalline residue is recrystallized from dichloromethane ether. The 3-((3-isopropyl-oxazolidin-2-on-5-yl)-niethoxy-6-methyl-pyridine-1-oxide produced melts at 137-139°C.

Example 59

After adding 4 ml of a 2N solution of hydrochloric acid in methanol, 12 ml of acetone over 30 minutes, with stirring. The reaction mixture is stirred overnight at room temperature, then evaporated in vacuo and acidified with 2N hydrochloric acid. The water solution is shaken out once with 30 ml of ether. The hydrochloric acid phase is separated and made alkaline with concentrated caustic soda. 2-(2'-hydroxy-3'-isopropylamino-propoxy)-3-methyl-pyridine is isolated by extraction with ethyl acetate and is identical to the product described in example 21.

The starting material can be produced in the following way:

a) Glycerol glycide and benzylamine are converted in a known manner to 3-benzylamino-1,2-propanediol (bp. 160-170°C/0.01 Torr), b) 3-benzylamino-1,2-propanediol is transferred with benzaldehyde by azeotropic distillation with benzene in otherwise known manner to 3-benzyl-5-hydroxymethyl-2-phenyl-oxazolidine (bp. 168-171°C/0.005 Torr). c) With 2 bromo-3-methyl-pyridine and 3-benzyl-5-hydroxy-methyl-2-phenyl-oxazolidine, 2-(3 '-benzyl-amino-2'-hydroxy-propoxy)- 3-methyl-pyridine. This melts after recrystallization from ethyl acetate-cyclohexane at 77-82°C. d) Catalytic debenzylation of a solution containing 28.3 g of 2-(3'-benzylamino-2'-hydroxy-propoxy)-3-methyl-pyridine in 300 ml of ethyl acetate while adding a total of 12 g of palladium/charcoal (5%) leads to 2-(3'-amino-2'-hydroxy-propoxy)-3-methylpyridine with bp. 120-130°C7 0.07 Torr, in ball tube.

Example 60

27 g of crude 2,3-dichloro-5-/"(tetrahydropyran-2-yloxy)-methyl7-pyridine is boiled with 25 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine and 4.5 g of sodium hydride dispersion (55% ) in 250 ml of 1,2-dimethoxyethane for 16 hours at reflux, and worked up in the usual way. The crude 2-[(3'-isopropyl-2'-phenyl-oxazolidin-5'-yl)-methoxy7-3 -chloro-5-(tetrahydropyran-2-yloxy)-methylpyridine.

The starting material can be prepared as follows: 2,3-dichloro-5-hydroxymethyl-pyridine is transferred in a known manner with 2,3-dihydropyran to 2,3-dichloro-5-/'(tetrahydropyran-2-yloxy)-methyl/-pyridine , (bp. 115-123°C/0.08 Torr.)

Example 6l

While stirring and cooling, a solution of 16.0 g of 2,3-dichloro-5-methylaminocarbonyl-pyridine and 18.5 g of 5-hydroxy-methyl-3-isopropyl-2-phenyl-oxazolidine in 250 ml of hexamethylphosphoric acid triamide, 4, 25 g of sodium hydride dispersion (55%) within 1 hour. The reaction mixture is stirred overnight at room temperature, poured into 250 ml of ice water and extracted with 3 x 200 ml of ether. The combined ether extracts are evaporated and give the crude 2-Z"3'-isopropyl-2'-phenyl-oxazolidinyl-(5')J-methoxy-3-chloro-5-methylaminocarbonyl-pyridine, which is the starting material for example 12.

The starting material can be produced over the following steps:

a) To a solution of 210 g of 2-hydroxypyridine-5-carboxylic acid in 1.5 liters of concentrated hydrochloric acid, at 80-85°C, a

solution of 63 g of potassium chlorate in 750 ml of water. During the instillation, a yellow solution is formed, from which crystals are eventually separated. After the addition (1J-2 hours), the reaction mixture is cooled in an ice bath and the crystallized 2-hydroxy-3-chloro-pyridine-5-carboxylic acid is filtered off (melting point 318-322°C).

b) To a suspension of 108 g of phosphorus pentachloride i

300 ml of toluene is stirred for approx. 30 minutes 45 g

2-hydroxy-3-chloro-pyridine-5-carboxylic acid. The reaction mixture is boiled for 2 hours under reflux and is then thoroughly evaporated in the rotary evaporator in vacuum, finally at a bath temperature of 70-80°C. The crude 5>6-dichloronicotinic acid chloride produced in this way is further used in its crude state.

c) To a solution of 50 g of methylamine in 250 ml of ethanol, while stirring and cooling at 10-15°C, a solution of 30 g of crude 5,6-dichloronicotinic acid chloride in 150 ml of bromoform is added dropwise. The reaction mixture is stirred for 2 hours at 20-30°C and then evaporated in vacuo. The evaporation residue is taken up in ethyl acetate, washed with 2N soda solution, dried over magnesium sulphate and evaporated. The evaporation residue is recrystallized from ethanol-ether. The 2,3-dichloro-5-methylaminocarbonylpyridine produced melts at 134-138°C.

Example 62

A solution of 46.8 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine in 300 ml of 1,2-dimethoxyethane is carefully added 6.1 g of sodium hydride dispersion (55%) in portions at 20-40°C , and after the foaming has stopped, continue stirring for 1-2 hours at 40°C. H.0 g of 5~(2'-aminoethyl)-2-chloro-pyridine is then added and the reaction mixture is stirred for 18 hours at 80°C. After evaporation of the solvent in vacuum, the evaporation residue is taken up in ether, washed with water, the ether solution is dried over magnesium sulfate and evaporated in vacuum. The crude 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5')J-methoxy-5-(2'-aminoethyl)-pyridine is obtained, which is the starting material for example 39. The starting material can be prepared as follows: After adding approx.

10 g of Raney-nickel suspension, a solution of 7.6 g of sodium borohydride in 25 ml of 8N caustic soda, at 50-60°C. During cooling, the temperature is kept at 50-60°C. After the addition, the reaction mixture is further stirred for 20 minutes at approx. 50°C. It is then cooled, filtered from the nickel and the filtrate is evaporated in a vacuum. The remaining dark red oil is stirred with 15 g of solid potassium hydroxide for 1 hour and the resulting suspension is extracted with a total of 200 ml of dichloromethane. After drying and evaporation of the solvent, an oil is obtained which, on distillation in high vacuum, gives 5-(2'-aminoethyl)-2-chloro-pyridine with b.p. 76-80°C/0.02 Dry as a colorless oil.

Example 63

A solution of 27.5 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine in 100 ml of dimelylformamide is carefully added at 20-40°C in portions to 4.8 g of sodium hydride dispersion (55%),

and after the foaming has ceased, stirring is continued for 1-2 hours at 40°C. 12.7 g of 2-chloro-4-methylpyridine are then added and the reaction mixture is stirred for 2 hours at 80°C. After evaporation of the solvent in vacuum, the evaporation residue is taken up in ether, washed with water, the ether solution is dried over magnesium sulfate and evaporated in vacuum. The crude 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5')}-methoxy-4-methyl-pyridine is obtained, which is the starting material for example 30.

In an analogous manner, the following starting products can be prepared: 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5')J-methoxy-5-methyl-pyridine, 2-f3'-isopropyl-2'-phenyl- oxazolidinyl-(5'))-methoxy-3-ethoxy-pyridine, 2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5')]-methoxy-6-methyl-pyridine, 2-(3' -isopropyl-2'-phenyl-oxazolidinyl-(5')]-methoxy-5-cyanopyridine, 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-3-chloropyridine, 4 - 3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-3-methylpyridine.

Example 64

In analogy to example 60, by using 15.6 g of 2,3-dichloro-5-n-hexylaminocarbonyl-pyridine, 13.6 g of 5-hydroxy-methyl-3-isopropyl-2-phenyl-oxazolidine and 3, 15 g of sodium hydride dispersion (55% in oil) in 250 ml of hexamethylphosphoric acid triamide prepare 2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5')J-methoxy-3-chloro-5-n-hexyl-amino -carbonyl-pyridine, which is the starting material for e.g. 36.

The starting material can be prepared in analogy with example 6lc).

By using 30 g of n-hexylamine, 2,3-dichloro-5-n-hexylamino-carbonylpyridine is prepared which, after recrystallization from ether/n-hexane, melts at 87-89°C.

Example 65

In a similar manner to that described in example 11, the compound 3-(2'-methoxyethoxy)-2-(3 '-isopropylamino-2'-hydroxy-propyl-oxy)-pyrazine. The pumarate produced from this with fumaric acid crystallizes from methanol-acetone, melting point 120-121°C.

Starting material a 2-chloro-j5-(2'-methoxyethoxy)-pyrazine

can be produced as follows:

Dissolve 14.9 g (0.1 mol) of 2,3-dichloropyrazine and 30 g (0.5 mol) of ethylene glycol monomethyl ether in 150 ml of hexamethyl-phosphoric acid triamide and add at 0-5°C in portions 4.8 g (0. 1 mol) 50 percent suspension of sodium hydride in paraffin oil. It is then stirred for 15 hours at room temperature. The reaction mixture is poured into 1 liter of ice water and shaken out with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. The residue is distilled in high vacuum. One obtains 2-chloro-3_ (2'-methoxy-sethoxy)pyrazine, b.p. 74°C70.003 Torr, n<22> = 1.5118.

Example 66

In a similar way as described in example 8, from 7.5 g (0.03 mol) of 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propyloxy)-pyrazine, 2.8 g (0.045 mol) ethyl mercaptan and 2.4 g (0.045 mol) sodium methylate in 150 ml of methanol after refluxing for 30 hours the crude base, and of this with 1.74 g of fumaric acid 3'-tyl-thio-2-(3'-isopropylamino- 2'-Hydroxy-propyloxy)-pyrazine fumarate, melting point 158-160°C, crystallized from methanol-ether.

Example 67 .

9.8 g (0.04 mol) of 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propyloxy)-pyrazine is heated with 12.1 g (0.12 mol) of 4-hydroxypiperidine for 1 hour at 130°C. After cooling, the reaction mixture is taken up in chloroform-ether 1:3 and washed with 2N caustic soda and water. The organic phase is dried over sodium sulfate and evaporated in a water jet vacuum. 3-(4'-Hydroxy-1'-piperidyl)-2-(3'-isopropylamino-2'-hydroxy-propyloxy)-pyrazine, melting point 88-91°C from ether-pentane is obtained. The cyclamate produced from this with cyclohexylaminosulfonic acid crystallizes from acetone, melting point 90-92°C.

Example 68

In an analogous manner as described in example 66, one obtains from 9.8 g (0.04 mol) 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propyloxy)-pyrazine and 12.0 g (0. 12 mol) ■ N-methylpiperazine 3-(4-methyl 1-1-^piperazinyl)-2-(3'-isopropylamino-2'-hydroxy-propyloxy)-pyrazine, melting point 62-64°C, from petroleum ether. The fumarate produced from this with fumaric acid crystallizes from methanol, melting point 200-201°C.

Example 69

In a similar manner as described in example 11, one obtains from 10.7 g (0.05 mol) 2-chloro-3-morpholinyl-5-myl-pyrazine and 15.5 g (0.05 mol) 2-phenyl- 3-(1-phenyl-3-butyl)-5-hydroxymethyl-oxazolidine 2-(3(1-phenyl-3-butylamino)-2'-hydroxy-propyloxy)-3-morpholinyl-5-methyl-pyrazine and of this with 2.25 g of fumaric acid fumarate from methanol/acetone, melting point 134-136°C.

Example 70

Analogous to the description in example 11, one obtains from 11.1 g (0.05 mol) 2-chloro-3-phenylthio-pyrazine and 13.2 g (0.06 mol) 2-phenyl-3-isopropyl-5- hydroxymethyl-oxazolidine, the compound 3-phenyl-thio-2-(3'-isopropylamino-2'-hydroxy-propyloxy)-pyrazine with melting point 70-71°C, crystallized from ether-petroleum ether.

The fumarate produced from this crystallizes

from isopropanol, melting point 167.169°C.

The starting material 2-chloro-3-phenylthio-pyrazine can be prepared in the following way:

To a solution of 10.8 g (0.2 mol) sodium methylate

in 200 ml of ethanol, 22 g (0.2 mol) of thiophenol and 29.8 g (0.2 mol) of 2,3-dichloropyrazine are successively dissolved dropwise, and the mixture is stirred for 1 hour. The reaction mixture is cooled to 0°C, the precipitated reaction product is filtered off and washed with ethanol and water. After drying, 2-chloro-3-phenylthio-pyrazine is obtained, melting point 100-111°C.

Example 71

In a similar way as described in example 11, from 8.2 g (0.05 mol.) 2,3-dichloro-5-methyl-pyrazine, 11 g (0.05 mol) 2-phenyl-3-isopropyl -5-hydroxymethyl-oxazolidine and 3.4 g of a 50% suspension of sodium hydride in paraffin oil, the compound 2-chloro-3-(3'-isopropylamino-2'-hydroxy-propyloxy)-5-methyl-pyrazine, melting point 109-110 °C, crystallized from benzene. The fumarate produced from this with fumaric acid crystallizes from methanol-ether, melting point 164-165°C.

Example 72

As described in example 3, 5.2 g (0.02 mol) of 2-chloro-3-(3'-isopropylamino-2<*->hydroxy-1-propyloxy)-5-methyl-pyra-K* lr zin the compound 3~(3<1->isopropylamino-2'-hydroxy-propyloxy)-5-methyl-pyrazine, melting point 78-r79°C, crystallized from ether-petroleum ether. The hydroclide produced from this compound crystallizes from methanol-acetone, melting point 125°C.

Example 73

To a suspension of 1.2 g of sodium hydride in 50 ml of dimethoxyethane, 11.0 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine are added and stirred for 2 hours at room temperature. 5>7 g of 2-chloropyrimidine dissolved in 20 ml of dimethoxyethane are then added. Stir for 2 hours at room temperature and then heat for 17 hours under reflux. The formed inorganic salt is filtered off, the filtrate is evaporated in vacuo and the remaining oil 2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxypyrimidine is isolated> which is the starting material for example 25.

Example 74

8.5 g of 5-(N-hexylcarbamoyl)-2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5')J-methoxypyrimidine are taken up in 25 ml of 1N hydrochloric acid.

Heat to boiling for 10 minutes, cool, extract the precipitated benzaldehyde with ether and add the separated water

the phase 13 ml 2N caustic soda. An oily base is separated which is extracted with vinegar, the extract is washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The evaporation residue is crystallized from petroleum ether. 5-(N-hexylcarbamoyl-2-(3'-isopropylamino-2'-hydroxypropoxy)-pyrimidine is obtained as colorless crystals with a melting point of 114-115°C. The hydrogen oxalate produced from this in acetone melts at 149-150° C.

Example 75

8.2 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine are added to a suspension of 0.88 g of sodium hydride in 20 ml of dimethoxyethane and the mixture is stirred for 2 hours at room temperature. 9.0 g of 5-(N-b.hexylcarbamoyl)-2-chloropyrimidine dissolved in 30 ml of dimethoxyethane are then added dropwise. Moon then stirs for 18 hours at room temperature.

The precipitated inorganic salt is filtered off, the filtrate is evaporated

in vacuo and the remaining oil contains 5-(N-hexylcarbamoyl)-2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5*))-methoxypyrimidine, which

is starting material for e.g. 74. The starting material can be prepared as follows: To a solution of 22.6 g of 2,4(6)-dichloro-pyrimidine-

5-carbonic acid chloride in 150 ml of diethyl ether is added dropwise at -10°C

and, with stirring, 20.2 g of n-hexylamine over the course of 1 hour, and stirring is continued for 1 hour at 0°C. It is then filtered from the precipitated bottom drop. After distillation of the filtrate, the ether 5-(N-hexylcarbamoyl)-2,4(6)-dichloropyrimidine is obtained as a colorless oil.

9.7 g of 5-(N-hexylcarbamoyl)-2,4(6)-dichloropyrimidine are heated in 100 ml of 50 percent ethanol with 20 g of zinc dust while stirring for 1| hour by refluxing. It is filtered off hot, rinsed with ethanol and the filtrate is freed from most of the ethanol by distillation under reduced pressure. The oil that is separated

of the water phase is extracted with vinegar, the extract is washed with water, dried over sodium sulphate and evaporated. The remaining oil is chromatographed on 50 g of silica gel 60 from Merck with benzene ether (1:1). The fractions containing the product are combined. After distilling off the solvent, 5~(N-hexylcarbamoyl)-2-chloropyrimidine is obtained as a colorless oil which gives crystals crystallized from petroleum ether, melting point 101-102°C.

Example 76

9.0 g of 2-dimethylamino-5-carbethoxy-4(6)-f3'-isopropyl-2'-phenyloxazolidinyl-(5'))-methoxypyrimidine are taken up in 45 ml of 1N hydrochloric acid. Heat to boiling for 10 minutes, cool, extract the precipitated benzaldehyde with ether and add 23 ml of 2N caustic soda to the separated water phase. The base which separates as an oil is extracted with vinegar, the extract is washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The oil formed is dissolved in a little acetone and a solution of 2.9 g of oxalic acid in acetone is added. 2-dimethylamino-5-carbethoxy-4(6)-(3'-isopropylamino-2*-hydroxypropoxy)-pyrimidine oxalate is obtained, which is recrystallized from methanol-acetone, melting point 155-156°C.

Example 77

To a suspension of 0.53 g of sodium hydride in 20 ml of dimethoxyethane, 4.8 g of 2-phenyl-3-isopropyl-5-hydroxy-methyl-oxazolidine are added and stirred for 2 hours at room temperature. 5.0 g of 2-dimethylamino-4-chloro-5-carbethoxypyrimidine, dissolved in 30 ml of dimethoxyethane, are then added dropwise. Stirring continues for 18 hours at room temperature, then one hour at 80°C. The precipitated salt is filtered off, the filtrate is evaporated under vacuum and the remaining oil contains 2-dimethylamino-5-carbethoxy-4-(3'-isopropyl-2 1-phenyloxazolidinyl-(5*))-methoxypyrimidine* which is the starting material for example 76 The starting material can be prepared as follows: A suspension of 16 g of 2-dimethylamino-4-hydroxy-5-carbethoxy-pyrimidine in 100 ml of phosphorus oxychloride is heated for half an hour while stirring at reflux. One filters hot and the filtrate is evaporated under reduced pressure. The oily residue is added to 200 g of ice. 200 ml of methylene chloride is added and, under ice cooling, 30 per cent caustic soda is added until pH 8. The precipitated inorganic salts are filtered off and washed with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and evaporated. 2-Dimethylamino-4-chloro-5-carbethoxypyrimidine is obtained as a yellowish oil which can be used further without purification.

Example 78

13>0 g of 3-chloro-2-(3-tert.butylamino-2-hydroxy-1-propyl-oxy)-pyrazine, 3.6 g of methyl mercaptan and 4.05 g of sodium methylate in 850 ml of methanol are boiled for 30 hours under backflow. After processing corresponding to example 8, 11.9 g of crude base is obtained and from this the calculated amount of fumaric acid 3-methylthio-2-(3-tert.butylamino-2-hydroxy-1-propyloxy)-pyrazine fumarate (2:1), which is recrystallized from isopropanol; melting point l84-l85°C.

Example 79

7.0 g of 5-(2-methoxyethyl)-2-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5' )J-methoxypyrimidine is taken up in 24 ml of 1N hydrochloric acid. It is heated while boiling for 10 minutes, cooled , extract the precipitated benzaldehyde with ether and add to the separated aqueous phase 12 ml of 2N caustic soda. The base separates as an oil and is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oil formed is dissolved in a little isopropanol, a solution of 2.3 g of fumaric acid in 30 ml of isopropanol is added and the solvent is then mostly distilled off. The resulting syrup is diluted with acetone and 5-(2-methoxyethyl)-2-(3'-isopropylamino-2'-hydroxy- propoxy )-pyrimidine hydrogen fumarate crystallizes out, melting point 103-104°C, after recrystallization from methanol-acetone.

Example 80

To a suspension of 0.48 g of sodium hydride in 10 ml of dimethoxyethane, 4.1 g of 2-phenyl-3-isopropyl-5-hydroxy-methyl-oxazolidine is added and stirred for 2 hours at room temperature. 3.4 g of 5-(2-methoxyethyl)-2-chloropyrimidine dissolved in 10 ml of dimethoxyethane are then added. Stir for 2 hours at room temperature and then heat for 3 hours while boiling. Precipitated inorganic salts are filtered off, the filtrate is evaporated in vacuo and the remaining oil contains 5-(2-methoxyethyl)-2-(3'-isopropyl-2'-phenyl-oxazolidi-nyl)-(5'))-methoxy -pyrimidine.

Starting material f can be produced as follows:

6.0 g of 5-(2-methylsulfonyloxyethyl)-uracil are suspended

in 100 ml of absolute methanol and the suspension is heated in a pressure vessel for one hour at 120-130°C. After cooling to room temperature, the formed crystals are filtered off and washed with methanol. You get 5-(2-methoxyethyl)-extacid, melting point 232-234°C.

A suspension of 10.3 g of 5-(2-methoxyethyl)-uracil i

50 ml of phosphorus oxide chloride is heated for 2 hours while boiling. The resulting solution is freed by distillation under reduced pressure of excess phosphorus oxychloride and the resulting oil is poured onto 200 g of ice. The product is extracted with ether, the extract is washed with water and sodium bicarbonate solution, dried over sodium sulfate and evaporated. The oil formed is dissolved in hot hexane, undissolved impurities are filtered and the product is freed from solvent by distillation under reduced pressure. 5-(2-Methoxyethyl)-2,4(6)-dichloropyrimidine is obtained as a colorless oil which can be used further without purification.

8.7 g of 5-(2-methoxyethyl)-2,4(6)-dichloro-pyrimidine are heated in 100 ml of 50 percent ethanol with 20 g of zinc dust while stirring for 1.5 hours until boiling. One filters from hot, separates with ethanol and frees the filtrate from most of the ethanol by distillation under reduced pressure. The oil that precipitates from the aqueous solution is extracted with vinegar, the extract is washed with water, dried over sodium sulfate and evaporated. The remaining oil is chromatographed on 50 g of silica gel 60, from Merck, with benzene-acetic ester (1:1). The fractions containing the product are combined, and after distilling off the solvent, 5~(2-methoxyethyl)-2-chloropyrimidine is obtained as a colorless oil, which crystallizes from petroleum ether with a melting point of 25-26°C.

Example 81

4.9 g of 5-methylthiomethyl-2-(3'-isopropyl-2'-phenyl-oxazolidinyl- (5' )3-methoxypyrimidine are dissolved in 25 ml 1N hydrochloric acid. Heat to boiling for 10 minutes, cool, extract

the precipitated benzaldehyde with ether and add to the separated water phase 13 ml of 2N caustic soda. The separated oil is extracted with vinegar, the extract is washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The oil formed is dissolved in a little isopropanol and a solution of 0.7 g of fumaric acid in 10 ml of isopropanol is added, after which 5-methylthiomethyl-2-(3'-isopropylamiho-2'-hydroxy-propoxy)-pyrimidine hydrogen fumarate crystallizes out, melting point 142-143°C, from isopropanol.-Example 82

To a suspension of 0.33 g of sodium hydride in 10 ml of dimethoxyethane is added 3.1 g of 2-phenyl-3-isopropyl-5-hydroxy-methyl-oxazolidine and stirred for 2 hours at room temperature. 2.4 g of 5-methylthiomethyl-2-chloropyrimidine, dissolved in 10 ml of dimethoxyethane, are then added. The mixture is stirred for 2 hours at room temperature and then heated for 3 hours at reflux. Precipitated inorganic salts are filtered off, the filtrate is evaporated in vacuo and the remaining oil contains 5-methylthiomethyl-2-C3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-pyrimidine, which is the starting material for e.g. 81 The starting material can be produced as follows:

To a solution of 14 g of 5-hydroxymethyluracil i

80 ml of trifluoroacetic acid is introduced over the course of an hour until saturation, and a temperature of 25°C is maintained. The mixture is then allowed to stand for 2 hours, the solvent is evaporated under reduced pressure and the evaporation residue is crystallized from glacial acetic acid. 5-methyl-thiomethyluracil is obtained as colorless crystals with a melting point of 239-241°C. A suspension of 9.4 g of 5-methylthiomethyluracil in 100 ml of phosphorus oxychloride is heated for 2 hours with stirring to boiling, filtered hot and the filtrate evaporated under reduced pressure. 200 g of ice are added to the oily residue, the product is extracted with ether, the extract is washed with water and sodium bicarbonate solution, dried over sodium sulphate and evaporated. 5-methylthiomethyl-2,4(6)-dichloropyrimidine is obtained as a yellow oil, which is used further without purification. 6.6 g of 5-methylthiomethyl-2,4(6)-dichloropyrimidine is heated by boiling in 60 ml of 50 per cent ethanol together with 15 g of zinc dust, for 1J hour with stirring. It is filtered off hot, rinsed with ethanol and the filtrate is freed of most of the ethanol by distillation under reduced pressure. The oil that precipitates from the aqueous solution is extracted with vinegar, the extract is washed with water, dried over sodium sulphate and evaporated. The remaining oil is chromatographed on 50 g "silica gel 60", Merck, with benzene-acetic ester (1:1). The fractions containing the product. are combined and after distilling off the solvent, 5-methylthiomethyl-2-chloropyrimidine is obtained which, crystallized from petroleum ether, gives crystals with a melting point of 56-57°C.

Example 83

20.5 g of 5~ethyl-4(6)-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5'))-methoxypyrimidine are taken up in 75 ml of 1N hydrochloric acid. It is heated to boiling for 10 minutes, cooled, the precipitated benzaldehyde is extracted with ether and 38 ml of 2N caustic soda is added to the separated water phase. The base which separates as an oil is extracted with acetic acid, the extract is washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The oil formed crystallizes from cyclohexane 5-ethyl-4(6)-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrimidine as colorless crystals with a melting point of 56-58°C. The hydrogen fumarate crystallized from isopropanol melts at 136-137°C.

Example 84

To a suspension of 1.5 g of sodium hydride in 20 ml of dimethoxyethane is added 13.9 g of 2-phenyl-3-isopropyl-5-hydroxy-methyl-oxazolidine and stirred for 2 hours at room temperature. 9.0 g of 5-ethyl-4(6)-chloropyrimidine, dissolved in 50 ml of dimethoxyethane, are then added at 0°C. Stirring is continued for 18 hours and then one hour at 80°C. Inorganic salts are filtered off, the filtrate is evaporated in vacuo and the remaining oil then contains 5-ethyl-4(6)-, C3'-isopropyl-2'-phenyl-oxazolidinyl-(5'X)-methoxypyrimidine, which is the starting material for e.g. . 83. The starting material can be prepared as follows: A suspension of 52 g of 5-ethyl-4(6)-hydroxy-2-mercapto-pyrimidine in 600 ml of water is heated at 70-80°C with stirring and

140 g Raney nickel is added in portions over the course of 1 hour, after which it is boiled under reflux for 4 hours. The nickel catalyst from

filtered hot, rinsed with hot water and the filtrate evaporated completely under reduced pressure. The remaining yellow oil crystallizes on cooling and after filtration and washing with acetone and ether gives 5-ethyl-4-hydroxypyrimidine with melting point 95-97°C (after sintering at 87-88°C).

10 g of 5-ethyl-4(6)-hydroxypyrimidine is added to a mixture of 12.5 ml of N,N-diethylaniline and 50 ml of phosphorus oxychloride and heated with stirring for 2 hours at 100-110°C. The excess of phosphorus oxychloride is then removed by distillation under reduced pressure and the residue entirely on 100 g of ice. The product is extracted with ether, the extract is washed with water and sodium bicarbonate solution, dried over sodium sulfate and evaporated. The remaining oil gives, after distillation in vacuum, 5-ethyl-4-chloropyrimidine, boiling point 95-98°C/25 Torr, as a colorless oil.

Example 85

10 g of crude 3-(2,3-epoxy-propoxy)-6-methyl-pyridine-1-oxide are heated in 200 ml of isopropanol with 25 ml of isopropylamine for 6 hours at reflux. The reaction mixture is then evaporated in vacuo, taken up in 300 ml of ethyl acetate and extracted with 30 ml of saturated potassium bicarbonate solution. The oil formed crystallizes from ether and gives 3-(2'-hydroxy-3'-isopropylamino-propoxy)-6-methyl-pyridine-1-oxide with melting point 87-89°C.

The starting material can be produced in the following way:

a) To a solution of 10 g of crude 3-(2,3-epoxy-propoxy)-6-methyl-pyridine in 100 ml of dichloromethane is placed under

stirring a solution of 12.2 g of m-chloroperbenzoic acid in 100 ml of dichloromethane during approx. 10 minutes by dripping, and the temperature in the solution gradually rises to 32°C. The reaction mixture is stirred for 30 minutes, then 40 ml of saturated potassium bicarbonate solution is added, dried and evaporated in vacuo. The 3-(2,3-epoxy-propoxy)-6-methyl-pyridine-1-oxide formed is further processed in a crude state.

Example 86

A mixture of 0.3 g of 3-(.(3-isopropyl-oxazolidin-2-on-5-yl)methoxy}-6-methyl-pyridin-1-oxide, 30 ml of ethanol, 1.0 g of sodium hydroxide and 1 ml of water is heated for 6 hours under reflux and stirring. The precipitate is filtered off, the filtrate is evaporated in vacuo and dissolved in ethyl acetate. After drying and evaporation of the solvent, an oil is obtained which is crystallized from ether. After two further crystallizations from ether, 3- (2'-Hydroxy-3'-isopropylamino-propoxy)-6-methyl-pyridine-1-oxide at 87-89°C.

Example 87

To a suspension of 3.8 g of sodium hydride in 40 ml

dimethoxyethane, 35 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine are added and stirred for 2 hours at room temperature. 23.5 g of 2-methylmercapto-4-chloropyrimidine, dissolved in 40 ml of dimethoxyethane, are then added dropwise. It is then stirred for one hour at room temperature and for 4 hours

by refluxing. Precipitated inorganic salts are filtered off, the filtrate is evaporated in vacuo and from the remaining oil 2-methylmercapto-4-(3'-isopropyl-2'-phenyl-oxazolidinyl-(5')J-methoxy-pyrimidine is obtained.

Example 88

5.4 g of 2-methylmercapto-4-(3'-isopropyl-2'-phenyl-oxa-zolidinyl-(5*))-methoxypyrimidine are taken up in 20 ml of 1N hydrochloric acid. It is heated to boiling for 10 minutes, cooled, the precipitated benzaldehyde is extracted with ether and 10 ml of 2N caustic soda is added to the separated water phase. The base is separated as an oil and extracted with vinegar, the extract is washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The oil crystallized from tetrachloromethane yields 2-methylmercapto-4(6)-(3'-isopropylamino-2'-hydroxy-propoxypyrimidine with melting point 82-83°C).

Example 89

Dissolve 2.57 g of 2-methylmercapto-4(6)-(3'-isopropylamino-2'-hydroxypropyloxy)-pyrimidine in 20 ml of 0.5N hydrochloric acid, add 10 g of water-moistened Raney nickel and heat for 6 hours while stirring at 60°C. It is ensured, by adding diluted hydrochloric acid at intervals, that the reaction mixture maintains a pH of 5-6 at all times. At the end, the nickel sludge is filtered off and washed with water. The filtrates are combined, made alkaline with dilute potash and saturated with potassium carbonate. Extraction with acetic acid, drying the extract over sodium sulphate, filtration and evaporation of the filtrate in a vacuum gives the crude product as a colorless oil. This

is dissolved in 5 ml of methanol together with 0.9 g of oxalic acid while heating. On cooling, 4(6)-(3<1->isopropylamino-2-hydroxy-propoxy)-pyrimidine-hydrogen-oxalate is obtained, which is obtained pure by recrystallization from methanol, melting point 164-165°C.

Example 90

3.2 g of crude 1-(5-pyrimidinyloxy)-2,3-epoxypropane are dissolved in 50 ml of isopropanol and heated after the addition of 15 ml of isopropylamine for 18 hours under reflux to boiling. The reaction mixture is then evaporated under vacuum, the residue is taken up in 25 ml of acetone, heated to boiling and mixed with 25 ml of acetic acid. The solution is then decanted from undissolved resins and then evaporated under vacuum. The evaporation residue is dissolved in acetone and mixed with a solution of 1.8 g of oxalic acid in 10 ml of acetone. Crystals separate which, after recrystallization from methanol-acetone, give 5-(3-isopropylamino-2-hydroxypropoxy)-pyrimidine hydrogen oxalate of melting point 166-167°C.

The 1-(5-pyrimidinyloxy)-2,3-epoxypropane used as starting material can be prepared as follows: 8.6 g of 5-hydroxypyrimidine and 21 g of potassium carbonate are mixed in 300 ml of acetone while stirring with 9 ml of epichlorohydrin and then heated to 40 hours under reflux to boil. The precipitate is then suctioned off, the filter residue is washed with acetone and the filtrate is evaporated in a vacuum. A brown oil, consisting of crude 1-(5-pyrimidinyloxy)-2,3-epoxy-propane, is obtained as an evaporation residue, which can be further used without purification.

Example 91

0.65 g of 5-allyloxy-2-(3'-isopropylamino-2-hydroxy-propoxy)-pyrimidine and 0.092 g of rhodium-tris-(triphenylphosphine)-dichloride are dissolved in 20 ml of 90 percent ethanol. After adding 0.05 ml of triethylamine, the reaction solution is heated to boiling for 4 hours. The reaction mixture is then evaporated under reduced pressure, the residue is extracted several times with each time 10 ml of hot acetone, the acetone extracts are heated with 0.5 g of activated carbon to boiling and filtered hot through diatomaceous earth ("Hyflo"). The filtrate is concentrated to a volume of 5 ml and mixed with a solution of 0.3 g of oxalic acid in acetone. Upon extraction, 5-hydroxy-2-(3'-isopropylamino-2-hydroxy-propoxy)-pyrimidine hydrogen oxalate crystallizes,

which is recrystallized from methanol-acetone. Melting point l65-l66°C during decomposition.

Example 92

lj6 g of 5-allyloxy-2-(3'-isopropyl-2'-phenyloxazolidin-yl-(5')J-methoxypyrimidine is taken up in 6 ml of 1N hydrochloric acid. It is heated to boiling for 10 minutes, cooled, the separated benzaldehyde is extracted with ether and mixes the separated water phase with 3 ml of 2N caustic soda. The oily base that separates is extracted with vinegar, the extract is washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily crude base formed is dissolved in a little acetone and mixed with a solution of 0.5 g of oxalic acid in 2 ml of acetone, whereupon 5-allyloxy-2-(3'-isopropylamino-2'-hydroxypropoxy)-pyrimidine hydrogen oxalate crystallizes out, which is recrystallized from methanol-acetone. Melting point 152-153 °C.

The 5-allyloxy-2-[3'-isopropyl-2'-phenyloxazolidinyl-(5'))-methoxypyrimidine used as starting material can be prepared in the following way: For a suspension of 0.13 g of sodium hydride in 5 ml of dimethoxyethane, one has 1.2 g -2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine and stir for 2 hours at room temperature. 1.2 g of 5-allyloxy-2-methylsulfonyl-pyrimidine, dissolved in 20 ml of dimethoxyethane, are then added. Stir for another 2 hours at room temperature and then heat for 10 hours until boiling. The precipitated inorganic salt is then filtered off, the filtrate is evaporated under vacuum and the remaining oily 5_allyloxy-2-[3'-isopropyl-2'-phenyloxazolidinyl-(5'))-methoxypyrimidine is further processed without further purification.

The 5-allyloxy-2-methyl-sulfonyl-pyrimidine used as starting material can be obtained in the following way: 4.5 g of 5-hydroxy-2-methylthiopyrimidine, 9.0 g of potassium carbonate and 3.9 g of allyl bromide are heated together in 50 ml of acetone stirring and refluxing for 4£ hours until boiling. Inorganic salts are filtered off and the filtrate is evaporated under reduced pressure. The remaining oil gives from petroleum ether 5-allyloxy-2-methylthio-pyrimidine, melting point 41-42°C.

3.5 g of 5-allyloxy-2-methylthiopyrimidine are dissolved in

30 ml of glacial acetic acid and mix with 20 ml of 20 percent hydrogen peroxide.

After 46 hours at 20°C, the solution is evaporated under reduced pressure at 20°C. The residue gives after crystallization from ether 5-allyloxy-2-methylsulfonyl-pyrimidine, melting point 66°C.

Example 93

0/195 g of crude 1-(2-methylthio-5-pyrimidinyloxy)-2j3-epoxypropane is dissolved in 10 ml of isopropanol and after the addition of 1.5 ml of isopropylamine is heated for 18 hours under reflux to boiling and the reaction mixture is then evaporated under vacuum. The evaporation residue is dissolved in acetone, filtered clear and the filtrate is mixed with a solution of 0.1 g of oxalic acid in 0.5 ml of acetone. Upon extraction, 5-(3'-isopropylamino-2'-hydroxypropoxy)-2-methylthio-pyrimidine hydrogen oxalate crystallizes, which is recrystallized from

methanol-acetone, melting point 196-197°C.

The 1-(2-methylthio-5-pyrimidinyloxy)-2,3-epoxypropane used as starting material can be prepared as follows: 1.42 g of 5-hydroxy-2-methylthiopyrimidine and 2.1 g of potassium carbonate are mixed in 30 ml of acetone under stirring with 0.9 ml of epichlorohydrin and then heated for 40 hours under reflux to boiling. It is then suctioned off, the filter residue is washed with acetone and the filtrate is evaporated under vacuum. A brown oil, consisting of crude 1-(2-methylthio-5-pyrimidinyl-oxy)-2,3-epoxy-propane, is obtained as an evaporation residue, which can be further used without purification.

Example 94

13.0 g of 3-chloro-2-(3-tert.butylamino-2-hydroxy-1-propyloxy)-pyrazine, 4.65 g of ethyl mercaptan and 4.05 g of sodium methylate in 250 ml of methanol are boiled for 30 hours under reflux. After work-up corresponding to example 8, 14.0 g of crude base is obtained and from this with ethereal hydrochloric acid 3~ethylthio-2-(3-tert.butylamino-2-hydroxyl-propyloxy)-pyrazine hydrochloride, which is recrystallized from methanol-ether. Melting point 147-148°C.

Example 95

44.7 g of 2,3-dichloropyrazine and 70.5 g of 2-phenyl-3-tert.-butyl-5-hydroxymethyl-oxazolidine are dissolved in 300 ml of hexamethylphosphoric acid triamide. 13 sl g of a 55 percent suspension of sodium hydride in paraffin are introduced into this solution at 0-5°C with stirring over the course of 1 hour. The reaction mixture is then stirred for 15 hours at room temperature. is then poured Then ice water and extirpated with

ether. The combined ether extracts are evaporated in a water jet vacuum,

the oily residue is taken up in 300 ml of 2N sulfuric acid, stirred for 2 hours at room temperature and then shaken out with ether.

The aqueous phase is made alkaline with concentrated caustic soda and

shake with benzene-ether (1:1). The benzene-ether extracts are washed with water, dried over sodium sulfate and evaporated in a water jet vacuum.

The residue is recrystallized from benzene-petroleum ether; 3-chloro-2-(3-tert.butylamino-2-hydroxy-1-propyloxy)-pyrazine is obtained with melting

point 105-106°C.

Example 96

33 g of crude 2-(3'-tert.butyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-5-cyanopyridine are stirred with 100 ml of 2N hydrochloric acid 3-4

hours at 20-30°C. The reaction mixture is washed with 100 ml of ether,

the aqueous phase is made alkaline with caustic soda and the separated oil is extracted twice with 100 ml of ethyl acetate each time. After washing with saturated aqueous sodium chloride solution, drying over magnesium sulfate and evaporation of ethyl acetate, the crude 2-(3'-tert.butylamino-2'-hydroxy-propoxy)-5-cyano-pyridine is obtained, which after recrystallization from a little ethyl acetate melts at 132-134°C,

it forms a neutral fumarate with a melting point of 220-221°C.

The starting material can be obtained in the following way:

A solution of 33.2 g of 3-tert.butyl-5-hydroxy-methyl-2-phenyl-oxazolidine in 200 ml of 1,2-dimethoxyethane is mixed at 20-30°C with stirring with 4.5 g of sodium hydride dispersion (55

percentage) and then stirred for 2 hours at 40°C. 13.0 g of 2-chloro-5-cyano-pyridine is added to the resulting suspension and the reaction mixture is then boiled for 12-14 hours while stirring and returning

run. The reaction mixture is then evaporated and the residue is distributed between 200 ml of ether and 100 ml of water. The ether phase is separated, washed with 50 ml of water, dried over magnesium sulphate and evaporated, where-

after which crude 2-(3'-tert.butyl-2'-phenyl-oxazolidinyl-(5'))-methoxy-5-cyano-pyridine is obtained as an oil.

Claims (12)

1. Analogy method for the preparation of β-receptor-active compounds of formula wherein means hydrogen or methyl, R 2 means lower alkyl or phenyl lower alkyl, R means the pyridyl residue of formula or its N-oxides, in which n means 1, 2 or 3 R-j means halogen, nitro, cyano, lower alkyl, lower alkoxy, phenyl, aminolower alkyl, lower alkylamino, hydroxy, lower alkoxycarbonylaminolower alkyl, lower alkylaminocarbonyl or pyrrolidinocarbonyl, .. or in which R means the pyrazinyl residue with formula or its N-oxides in which R^ means hydrogen, halogen, lower alkyl, Rjj means hydrogen, halogen, lower alkoxy, lower alk- oxylaverealoxy, loweralkenyloxy, loweralkylthio-, morpholinyl, loweralkylamino, diloweralkylamino, phenylthio, hydroxypiperidyl or loweralkylpiperazinyl, or in which R means the pyridazinyl radical of formula: or its N-oxides in which Rg means hydrogen and Ry means hydrogen, lower alkoxy, halogen or mbrfolino, or in which R means the pyrimidinyl residue with formula: or its N-oxides, in which Rg means hydrogen, dilower alkylamino, lower alkyl and Rg means hydrogen, hydroxy, lower alkoxy lower alkyl, lower alkylthio or lower alkylthio lower alkyl, lower alkylaminocarbonyl, lower alkoxycarbonyl or allyloxy, as well as their therapeutically usable salts, characterized in that a) a compound of formula wherein R has the indicated meaning, Z-. and Z2 together means epoxy or Z^ means hydroxy and Z^ means a reactive group is reacted with an amine of the formula:- in which and R^ has the above meaning, or b) a compound of formula is alkylated with a compound of formula: where R and R2 have the above meaning under reducing conditions or c) a compound of formula VI is alkylated with a bond with formula or a reactive ester of this compound where R, R^ and R^ have the above meaning or d) a compound of formula which on the one hand means a 3-hydroxypyridine or on the other hand a 5-hydroxypyrimidine, and R^ each time has the meaning indicated for a pyridine residue and Rg has the meaning indicated each time for a pyrimidine residue. in which R^ and R^ have the above-mentioned meaning or e) a compound of formula wherein R, R^ and R2 have the indicated meaning, in that for the case that R means pyridyl, R3 also means the tetrahydropyranyloxymeth<y>1 residue and X means a divalent residue of an aldehyde or ketone, the carbonyl group or the thiocarbonyl group or a salt of such a compound is hydrolyzed, or f) an end product of formula I, in which R is substituted with a benzoyloxy or allyloxy group is converted by hydrogenolysis into an end product of formula I containing a hydroxy group in the group R, or g) an end product of formula I, in which R contains one of the following hydrogenolytically cleavable groups: halogen and/or halogen-substituted phenyl or lower alkylthio, is converted by means of hydrogenolysis into a final product of formula I, in which hydrogen is bonded instead of said groups, h) an end product of formula I, in which R contains a nitro group, this is reduced to primary amino groups and the compound formed is converted, if desired, by acylation into a corresponding acylamino compound or i) an end product of formula I, in which R contains an amino lower alkyl group, this is converted by acylation into a corresponding lower alkoxycarbonyl amino lower alkyl group or k) an end product of formula I, in which R contains a cyano group, this is converted by reduction to an aminomethyl group or 1) an end product of formula I, in which R is substituted with easily cleavable groups is converted by reaction with a lower alkanol, lower alkanethiol, lower alkyl piperazino or hydroxypiperidine into an end product of formula I, where R is substituted with lower alkoxy, lower alkylthio or a hydroxypiperidino group, or m) optionally formed non-N-oxidized end products of formula I are oxidized to the corresponding N-oxides, or formed mono-, resp. di-N-oxides of the end product of formula I are reduced to the non-N-oxidized end product, and if desired, a formed salt is transferred into the free compound of formula I or another free compound into a therapeutically usable salt of formula I. 2. Process for the production of 3-methylthio-2-(3'-tert.butylamino-2'-hydroxy-propyloxy)-pyrazine according to claim 1, characterized in that 3-chloro-2-(3'-tert.-butyl -amino-2'-hydroxy-propyloxy)pyrazine is reacted with methylmercaptan, and if desired, the compound formed is transferred into a therapeutically applicable acid addition salt. 3. Process for the preparation of 3-ethylthio-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine according to claim 1, characterized in that 3-chloro-2-(3'-isopropylamino-2'-hydroxy -propyloxy)-pyrazine is reacted with ethyl mercaptan, and if desired, the compound formed is transferred into a therapeutically applicable acid addition salt. 4. Process for the preparation of 3-ethylthio-2-(3'-tert-butylamino-2'-hydroxy-propyloxy)-pyrazine according to claim 1, characterized in that 3-chloro-2-(3'-tert-butyl -amino-2'-hydroxy-propyloxy)-pyrazine is reacted with ethyl mercaptan, and if desired, the compound formed is transferred into a therapeutically applicable acid addition salt. 5. Process for the production of 2-(3'-isopropylamino-2'-hydroxy-propoxy)-3-chloro-pyridine according to claim 1, characterized in that 2-Cb'-isopropyl-2'-phenyl-oxazolidinyl-(5 )7~Methoxy-3-chloro-pyridine is hydrolysed with the aid of dilute mineral acid, and if desired, the compound formed is transferred into a therapeutically applicable acid addition salt. 6. Process for the production of 2-(3'-isopropylamino-2'-hydroxy-propoxy)-3-ethoxy-pyridine according to claim 1, characterized in that 2-(3'-isopropyl-2'-phenyl-oxazolidinyl- ( 5'))-Methoxy-3-ethoxy-pyridine is hydrolysed with the aid of dilute mineral acid and, if desired, the compound formed is transferred into a therapeutically applicable acid addition salt. 7. Process for the production of 2-(3'-tert.butyl-amino-2'-hydroxy-propoxy)-3-ethoxy-pyridine according to claim 1, characterized in that 2-[3'-tert.butyl-2' -phenyl-oxazolidinyl-(5'))-methoxy-3-ethoxy-pyridine is hydrolyzed with the aid of dilute mineral acid} and, if desired, the compound formed is transferred into a therapeutically applicable acid addition salt. 8. Process for the production of 1-tert.butylamino-3-(3-cyan-pyridin-2-yloxy)-2-propanol according to claim 1, characterized in that 3-tert.butyl-5-(3-cyan-pyridin-2 -yloxymethyl)-2-phenyl-oxazolidine is hydrolysed with the aid of dilute mineral acid and, if desired, the compound formed is transferred into a therapeutically applicable acid addition salt. 9. Process for the production of 2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine according to claim 1, characterized in that in 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy) -pyrazine, chlorine is replaced with hydrogen using catalytically activated hydrogen and, if desired, the compound formed is transferred into a therapeutically applicable acid addition salt. 10. Process for the production of 2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrimidine according to claim 1, characterized in that 2-f3'-isopropyl-2'-phenyloxazolidinyl-(5')]-methoxy- pyrimidine is hydrolysed with the aid of dilute mineral acid and, if desired, the compound formed is transferred into a therapeutically applicable acid addition salt. 11. Process for the production of 5-(2'-n-butoxy-carbonylaminoethyl)-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine according to claim 1, characterized in that 5-(2'-aminoethyl )-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine is reacted with chloroformic acid n-butyl ester, and if desired, the compound formed is transferred into a therapeutically usable acid addition salt. 12. Process for the production of 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-5-(2'-methoxycarbonylamino-ethyl)-pyridine according to claim 1, characterized in that 5-(2' -aminoethyl)-3~chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine is reacted with chloroformic acid methyl ester and, if desired, the compound formed is transferred into a therapeutically usable acid addition salt.