CS203970B2 - Method of producing novel heterocyclyl-oxy-hydroxy-amino-propanes - Google Patents

Abstract

1465946 Propanolamine derivatives CIBA GEIGY AG 13 Feb 1974 [20 Feb 1973 31 Jan 1974] 6518/74 Heading C2C Compounds of the general formula (I) (Het=optionally substituted pyridazinyl, pyrimidinyl, pyrazinyl or substituted pyridyl, R 1 = H or CH 3 and R 2 =C 1-7 alkyl, optionally substituted phenyl-(C 1-7 , alkyl), carboxy-(C 1-7 , alkyl) or functionally modified carboxy-(C 1-7 alkyl), provided that Het does not represent pyrazin-2 or 3-yl substituted at the 3- or 2-position respectively by C 1-5 alkyl or unsubstituted phenyl when R 1 R 2 CH 3 C- is C 3-6 alkyl or unsubstituted phenyl (C 3-6 ) alkyl, their condensation products with aldehydes, ketones and carbonic acid, and their N-oxides and salts are prepared by reacting (a) Het-O-CH 2 CHX 1 CH 2 Z 1 or an N-oxide thereof with Z 2 CCH 3 R 1 R 2 (one of Z 1,2 =NH 2 , the other=reactive esterified OH and X 1 =OH, or X 1 +Z 1 =O and Z 2 =NH 2 ), (b) Het-Z (Z= nucleophilically removable radical) with HOCH 2 CHOHCH 2 NHCCH 3 R 1 R 2 or the condensation product with an aldehyde, ketone or carbonic acid or (c) 3-hydroxypyridine with ZCH 2 CHX 1 CH 2 NHCCH 3 R 1 R 2 (Z = reactive esterified OH and X 1 = OH, or Z + X 1 = O) or the corresponding azetidine, optionally followed by introduction, modification or removal of substituents, conversion to a different compound of formula (I), isomer separation and/or salt formation. The preparation of starting materials for processes (a) and (b) and 2-allyloxy-3-morpholinopyrazine, 2-allyloxy-3-dimethylaminopyrazine, 2- allyloxy - 3 - isopropylaminopyrazine, 3 - chloro- 2-[2<SP>1</SP>,2<SP>1</SP>-dimethyl-1<SP>1</SP>,3<SP>1</SP>-dioxolanyl-(4<SP>1</SP>)]methoxypyridine, 3 - chloro - 2 - (2<SP>1</SP>,3<SP>1</SP> - dihydroxypropoxy)pyridine, 3 - (2<SP>1</SP>,3<SP>1 </SP>- dihydroxypropoxy)- 2 - methoxypyridine, 2 - [2<SP>1</SP>,2<SP>1</SP> - dimethyl- 1<SP>1</SP>,3<SP>1</SP> - dioxolanyl - (4<SP>1</SP>)] - methoxypyrimidine, 2 - (2<SP>1</SP>,3<SP>1</SP> - dihydroxypropoxy)pyrimidine, 5- hydroxymethyl-, chloromethyl-, cyanomethyl- and # - aminoethyl - 2,3 - dichloropyridine, 3 - benzylamino - 1,2 - propanediol, 3-benzyl - 5 - hydroxymethyl - 2 - phenyloxazolidine, 2 - (3<SP>1</SP> - benzylamino - 21 - hydroxypropoxy) - 3 - methylpyridine, 2 - hydroxy - 3 - chloropyridine - 5 - carboxylic acid, 5 - hexylcarbamoyl - 2,4(6) - dichloropyrimidine, 5 - (# - methoxyethyl)uracil, 5 - (# - methoxyethyl) - 2,4(6) - dichloropyrimidine, 5 - methylthiomethyluracil, 5 - methylthiomethyl - 2,4(6)- dichloropyrimidine and 5-ethyl-4-hydroxypyrimidine is described. Some of the above compounds are #-adrenergic blocking agents and some are stimulants. They may be administered in the form of pharmaceutical and veterinary preparations containing them in association with a carrier.

Description

The present invention relates to a process for the preparation of novel heterocyclyloxyhydroxyaminopropanes of the formula I:

CH3

AND

Het-O-CH-CH (OH) -CH ₂ -NH-C-R2

I Ri (I) wherein

R 1 is hydrogen or methyl,

R 2 is a lower alkyl group having 1 to 7 carbon atoms or optionally lower alkyl; or (C1-C7) lower-alkoxy, trifluoromethyl or halogen substituted phenyl (lower) C1-C7 alkyl in the lower alkyl radical; and

Het pyridyl radical of formula

Rj Rft or its N-oxides, wherein:

R3 represents halogen, cyano, nitro, lower alkyl of 1 to 7 carbon atoms, lower alkoxy of 1 to 7 carbon atoms, optionally halogen, trifluoromethyl, lower alkyl of 1 to 7 carbon atoms, lower alkenyl of 2 to 7 carbon atoms, lower alkoxymethyl of 2 to 8 carbon atoms, lower alkoxy of 1 to 7 carbon atoms or lower alkenyloxy of 2 to 7 carbon atoms substituted phenyl, lower alkylaminocarbamoyl of 1 to 7 carbon atoms in the lower alkyl moiety, a lower alkoxycarbonylamino (lower) alkyl group having from 1 to 7 carbon atoms in each case in the lower alkoxy and lower alkyl moieties,

R 1 represents hydrogen, lower alkyl of 1 to 7 carbon atoms, hydroxy (lower) alkyl of 1 to 7 carbon atoms, lower α-alkylcarbamoyl of 1 to 7 carbon atoms in the lower alkyl moiety or lower alkoxycarbonylamino (lower) alkyl having 1 to 7 carbon atoms in the lower alkoxy and lower alkyl moieties;

Het represents a pyrazinyl group of the formula

where

R 5 represents hydrogen or a lower alkyl group having 1 to 7 carbon atoms,

R4 is hydrogen, halogen, lower alkenyloxy of 2 to 7 carbon atoms, lower alkoxy (lower) alkoxy of 1 to 7 carbon atoms in each lower alkoxy moiety, lower alkylthio of 1 to 7 carbon atoms, optionally halogen, trifluoromethyl, lower alkyl a phenylthio or morpholino group is not a lower alkoxy group having from 1 to 7 carbon atoms in the lower radicals, or

Het represents a pyrimidinyl group of the formula

where

R3 is hydrogen, lower alkyl of 1 to 7 carbon atoms, hydroxy, lower alkoxycarbonyl of 1 to 7 carbon atoms in lower alkoxy, lower alkenyloxy of 2 to 7 carbon atoms, lower alkylcarbamoyl of 1 to 7 carbon atoms in lower alkyl a lower alkoxy (lower) alkyl group having 1 to 7 carbon atoms in the lower alkoxy and lower alkyl moieties or lower alkylthiof lower) alkyl group having 1 to 7 carbon atoms in each of the lower alkyl moieties;

Rd represents hydrogen or a di (lower) alkylamino group having 1 to 7 carbon atoms in each of the lower alkyl moieties, or

Het represents a pyridazinyl group of the formula

let: suppress isoproterenol-induced tachycardia on isolated guinea pig heart muscle and isoproterenol-induced relaxation on guinea pig isolated trachea at concentrations ranging from 0.001 to 3 µg / ml, suppress tachycardia and isoproterenol-induced vasodilation on narcolized cat at an intravenous dose of 0.01 to 30 mg / dose kg iv These compounds belong either to the group of non-cardioselective β-receptor blockers, ie they block vascular β-receptors or trachea at similar or even lower doses or concentrations than β-receptor receptors, or belong to the group of so-called cardioselective blockers β-receptors, ie, they block the β-receptors of the heart already in the dose or concentration range, which still does not block any β-receptor of the blood vessels or the trachea. As an additional property, some of these compounds have so-called "intrinsic sympathominetic activity (ISA)", ie, that these compounds cause partial β-stimulation in addition to β-blockade (the main effect).

The main effect of unsubstituted pyrazine and pyrimidines resides in the stimulation of adrehergic / Z-receptors, which can be demonstrated, for example, in the heart as a positively inotropic and positively chronotropic effect. Said compounds increase the heart rate and myocardial contraction intensity in the isolated anterior ventricles of the heart at concentrations from 0.01 to 1 µg / ml and on a narcoitized cat by intravenous administration from 0.001 to 0.1 mg / kg iv at concentrations significantly higher than those required for β-stimulation, these compounds also possess the ability to block β-receptors. However ^, 2- (2'-hydroxy-3'-isopropylaimopropoxy) -pyrimidine and 2- (2'-hydroxy-3'-isopropylaminopropoxy) pyrazine differ quantitatively from known β-receptor stimulators in that they only reduce arterial blood pressure at a dose of 1 mg / kg iv, a dose range that is substantially lower than that required to increase myocardial shrinkage intensity and heart rate, and compounds with a concentration of 10 µg / ml exhibit no relaxing effect on the isolated guinea pig trachea. properties, these compounds may be termed β-receptor cardioselective stimulators.

The novel compounds can therefore be used for the treatment of cardiovascular diseases.

For example, .alpha.3 -receptor blockers can be used to treat angina pectoris, hypertonia and cardiac rhythm disorders. Cardioselective agents have the advantage over non-cardioselective agents that at the doses required to block the β-receptor of the heart, blockade of β-receptors of other organs should be expected Risk of undesirable side effects such as seizures where

R 3 is hydrogen, halogen, C 1 -C 7 lower alkoxy or morpholino, as well as their salts, in particular their therapeutically useful acid addition salts.

The novel compounds have valuable pharmacological properties. The main effect of substituted pyridines, pyrazines and pyrimidines is to block adrenergic β-receptors, which can be shown to inhibit the effects of known

The stimulators, β-receptors in the various organs of the bronchial muscles are therefore very small. Unlike cardioselective agents, non-cardioselective agents block either the β-receptors of all organs approximately equally strongly, or preferably in certain organs (such as in blood vessels).

Β-receptor stimulators can be used as cardiotonics to treat cardiac muscle weakness (alone or in combination with other preparations such as cardiac glycosides). Compared to known β-receptor stimulators, these compounds have the following advantages: based on pharmacologically proven cardioselectivity, myocardial shrinkage intensity can be expected to increase without undesirable decrease in blood pressure. In addition, an insignificant increase in heart rate should be taken into account, since reflective tachycardia which occurs as a result of a decrease in blood pressure is eliminated.

Furthermore, the novel compounds can also be used as valuable products for the production of other useful substances, in particular pharmaceutically active compounds.

In the foregoing and the following part, the lower radical is in particular a radical having from 1 to 7 carbon atoms, in particular from 1 to 4 carbon atoms.

Lower alkyl radicals having 1 to 7 carbon atoms, in particular 1 to 4 carbon atoms, are, for example, methyl, ethyl, n-propyl, isopropyl or unbranched, or any butyl, pentyl, hexyl or heptyl radical attached or branched.

Optionally substituted phenyl (lower) alkyl radicals are lower alkyl radicals having 1 to 7 carbon atoms, in particular 1 to 4 carbon atoms, which are substituted at any point with optionally substituted phenyl groups. Suitable substituents for the phenyl radical are, in particular, lower alkyl groups, lower alkoxy groups, trifluoromethyl groups and halogen atoms. Examples which may be mentioned are 3-phenyl-n-propyl, and in particular benzyl and 2-phenylethyl.

The hydroxy (lower) alkyl moiety preferably has from 1 to 7 carbon atoms in the lower alkyl moiety, preferably 1 to 4 carbon atoms, and is, for example, 3-hydroxypropyl, 2-hydroxypropyl, 1-methyl-2-hydroxyethyl or unbranched or bonded at any point or branched hydroxybutyl, hydroxypentyl. hydroxyhexyl, hydroxyheptyl and especially hydroxymethyl and 2-hydroxyethyl.

The lower alkenyl radical preferably has 2 to 7 carbon atoms, and in particular 2 to 4 carbon atoms, such as vinyl, 2-methylmethyl, methallyl and especially allyl.

Suitable substituents for the optionally substituted phenyl moiety are halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkoxymethyl, lower alkoxy and lower alkenyloxy. Thus, optionally substituted phenyl is primarily phenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, tolyl, methoxymethylphenyl, methoxyphenyl, ethoxyphenyl, and allyloxyphenyl.

Lower alkoxy groups preferably contain 1 to 7 carbon atoms, in particular 1 to 4 carbon atoms, such as, for example, ethoxy, propoxy, isopropoxy, straight or branched butyloxy, pentyloxy, hexyloxy or heptyloxy bonded at any point.

The lower alkoxyph lower alkyl group contains lower alkoxy groups in the lower alkyl moiety preferably having 1 to 7 carbon atoms, in particular 1 to 4 carbon atoms, such as isopropyl or n-propyl, straight or branched, butyl, pentyl, hexyl bonded in any position or heptyl, especially ethyl, and especially methyl. The lower alkyl moiety carrying the lower alkoxy moiety preferably has 1 to 7 carbon atoms, especially 1 to 4 carbon atoms. For example, lower alkoxy (lower alkyl) is methoxymethyl, 2-ethoxyethyl, 3-methoxy-n-propyl, 3-ethoxy-n-propyl, 4-methyl, n-n-butyl or especially 2-methoxyethyl and ethoxymethyl.

Lower alkenyloxy groups are preferably groups having 2 to 7 carbon atoms, in particular 3 or 4 carbon atoms, such as methallyloxy or especially allyl alkoxy.

Lower alkoxy (lower) alkoxy in the lower alkyl moieties always has 1 to 7 carbon atoms, in particular 1 to 4 carbon atoms, and, for example, methoxymethoxy, ethoxymethoxy, 2-methoxyethoxy, 4-methoxy-n-butoxy, and in particular 3-methoxy- n-propoxy.

Lower alkylthio groups are preferably groups having 1 to 7 carbon atoms, in particular 1 to 4 carbon atoms, such as ethylthio, n-propylthio, n-butylthio, isopropylthio, or especially methylthio.

Lower alkylthio (lower jalkyl group in the lower alkyloyl moieties each has 1 to 7 carbon atoms, in particular 1 to 4 carbon atoms) and is, for example, methylthiomethyl, ethylthlomethyl, 3-methylthiopropyl, 4-methylthiobutyl and in particular 2-methylthioethyl, 2-ethylthioethyl or 2- (n-propylthio) ethyl.

Di (lower) alkylamino groups are preferably groups having 1 to 7 carbon atoms, in particular 1 to 4 carbon atoms in each of the lower alkyl moieties. The two lower alkyl radicals are independent of one another and together with the nitrogen atom form radicals such as, for example, dimethylamino, methylethylamino, diethylamino, dipropylamino, dibutylamino, or in particular dimethylamino.

The lower alkoxycarbonylamino group in the lower alkyl portion has lower alkoxy groups preferably having 1 to 7 carbon atoms, and in particular having 1 to 4 carbon atoms, and is, for example, n203970

propoxycarbonylamino, n-butoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, and in particular methoxycarbonylamino and ethoxycarbonylamino. Thus, by way of example, acylamino (lower) alkyl radicals are, in particular, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl and 2-ethoxycarbonylaminoethyl.

Optionally substituted phenylthio is, for example, phenylthio or halo, trifluoromethyl, lower alkyl or lower alkoxy substituted phenylthio is therefore preferably phenylthio, chlorophenylthio, bromophenylthio, trifluoromethylphthyllthio. methylphenylthio, methoxyphenylthio, or ethoxyphenylthio.

A lower alkoxycarbonyl group is a group which preferably has from 1 to 7 carbon atoms in the lower alkyl moiety, and in particular 1 to 4 carbon atoms, and is primarily a methoxycarbonyl group and an ethoxycarbonyl group.

Halogen is fluorine, bromine and especially chlorine.

The N- (lower alkylaminocarbonyl) group preferably has 1 to 7 carbon atoms in the lower alkyl moiety, especially 1 to 4 carbon atoms, and is therefore primarily methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, n-butylaminocarbonyl, tert-butylamtnoicarbonyl or N-hexylaminocarbonyl.

According to the invention, the novel compounds are prepared in a manner known per se by hydrolyzing the compound of the formula II,

«1 (II) in which

Het has the above meaning,

X is optionally lower alkyl of 1 to 7 carbon atoms or phenyl substituted methylene, furthermore carbonyl or thiocarbonyl, or a salt of such a compound.

In the general formula (II), X represents in particular a substituted methylene group. Possible substituents of the methylene group are any organic radicals, and for the hydrolytic cleavage it does not matter which kind of substituent is present on the methylene radical. Suitable substituents for the methylene group are, in particular, a lower alkyl radical or a phenyl radical.

The hydrolysis is carried out in a conventional manner, for example in the presence of hydrolyzing agents, for example in the presence of acidic agents such as aqueous mineral acids such as sulfuric acid or hydrohalic acid, or in the presence of basic agents such as alkali metal hydroxides such as sodium hydroxide.

The starting materials of the formula II can also be used in the form of their salts.

Depending on the reaction conditions and the starting materials, the end products and their N-oxides are obtained in free form or in the form of their acid addition salts, which are also within the scope of the invention. Thus, for example, basic, neutral or mixed salts, optionally also their hemihydrates, monohydrates, sesquihydrates or polyhydrates, can be obtained. The acid addition salts of the novel compounds or their N-oxides can be converted into the free compound in a manner known per se, for example by treatment with basic agents such as alkalis or ion exchangers. On the other hand, the free bases obtained or their N-oxides can form salts with organic or inorganic acids. In particular, acids suitable for the formation of therapeutically useful salts are used in the preparation of acid addition salts. Such acids include, for example: hydrohalic, sulfuric, phosphoric, nitric, perchloric, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric acids , lemon, ascorbic, maleic, fumaric or pyruvic; phenylacetic acid, benzoic, anthranllic, p-hydroxybenzoic, salicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic; halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanil or cyclohexylamine sulfonic.

These or other salts of the novel compounds, such as picrates or perchlorates, can also serve to purify the free bases obtained by converting the free bases into; the salts are separated and the base is liberated again. As a result of the close relationship between the novel compounds in free form and in the form of their salts, in both the preceding and the following parts, the free compounds are to be understood in terms of meaning and purpose.

The novel compounds can be obtained in the form of optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, also in the form of a mixture of isomers (racemic mixtures), depending on the starting materials and processes employed.

The mixtures of the isomers obtained (racemic mixtures) can be separated into the two stereoisomeric (diastereomeric) pure racemates, for example by chromatography and / or fractional crystallization, based on the physicochemical differences of the individual components.

The racemates obtained can be decomposed into diastereomers by known methods, for example by recrystallization from optically active solvents, by microorganisms or by reaction with an optically active acid which forms salts with the racemic compound and by separation of the salts thus obtained, for example antipodes can be released by the action of suitable agents. Particularly useful optically active acids are, for example, the D- and L-forms of tartaric, di-o-toluyltartaric, malic, mandelic, camphorsulfonic, glutamine, aspartic or quinic acids. Preferably, the more effective of both antipodes is isolated.

For carrying out the reactions according to the invention, it is expedient to use starting materials which lead to the groups of reaction products mentioned above, and in particular to the specially described or particularly emphasized final materials.

The starting materials can be obtained by known methods by reacting, for example, (R3) (R4) -2-halopyridine or (R3) (R4) -halopyridine or (R3) -halopyridazine or (R3) (R4) -halopyrimidine with a compound of formula (III) ₂

O-N-CR _z

in which

R1, R2, R3, R4 and X are as defined above.

The starting materials may also be present in the form of optical antipodes.

The novel compounds or their N-oxides can be used as medicaments, for example in the form of pharmaceutical preparations which contain these compounds alone or in the form of their salts in admixture with a pharmaceutical, organic or inorganic, solid or liquid carrier which is suitable, for example, for enteral or parenteral administration. Suitable substances for the preparation of such formulations are those which do not react with the novel compounds, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, acacia, polyalkylene glycols, vaseline, cholesterol or other known drug carriers. . The pharmaceutical preparations can be used, for example, in the form of tablets, dragees, capsules, suppositories, ointments, creams or in liquid form in the form of solutions (for example, elixirs or syrups), suspensions or emulsions. These preparations are optionally sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for influencing the osmotic pressure or buffers. They may also contain other therapeutically valuable substances. Those preparations which can also be used in veterinary medicine are obtained by conventional methods.

The daily dose is about 40 to 150 mg, in the case of warm-blooded about 75 kg body weight.

The following example illustrates the invention but does not limit it in any way. Temperatures are given in degrees Celsius.

Example 1

а) 4.9 g of 5-hydroxymethyl-3-isopropyl-2-phenylcxazolidine are added to a suspension of 0.5 g of sodium hydride in 40 ml of ethylene glycol dimethyl ether. The reaction mixture was stirred at 40-50 ° C for 2 hours, then 2.9 g of 2-chloro-6-methoxypyridine was added and the reaction mixture was heated under reflux for 14 hours. The solution of 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-6-methoxypyridine thus obtained was hydrolyzed with 20 ml of 2N hydrochloric acid for 2 hours while standing at room temperature. The solution was then evaporated in vacuo and the residue partitioned between 30 ml of water and 50 ml of ether. The aqueous phase was made strongly alkaline with concentrated sodium hydroxide and extracted three times with 100 ml of ethyl acetate each time. After drying and evaporation gave 2- ^{(3-isopropylamino-2-hydroxypropoxy)} -6-methoxypyridine, the neutral fumarate melts at 140-141 ° (recrystallized from methanol-acetone).

Example 2

10.7 g of 2-chloro-3-morpholinyl-5-methylpyrazine and 16.6 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine are dissolved in 130 ml of hexamethylphosphoric triamide. To this solution, 3.6 g of a 50% suspension of sodium hydride in paraffin oil was added over 30 minutes at 0-5 °. The reaction mixture was then stirred at 0-5 ° C for 1 hour and at room temperature for 24 hours. The reaction mixture is then poured onto 500 ml of ice-water and shaken into ether. The ether extracts were washed with water and evaporated in a water pump vacuum. The residue is taken up in 200 ml of 1N sulfuric acid and stirred at room temperature for 15 hours. The reaction mixture was then shaken with ether. The acidic aqueous phase was basified with concentrated sodium hydroxide and then shaken with ether. The ether extracts were washed with water, dried over sodium sulfate and evaporated in a water pump vacuum. The residue is crystallized from a mixture of ether and pentane to give 2- (3 &apos; -isopropylamino-2 &apos; -hydrogen-3-morpholinyl-5-methylpyrazine), m.p. 77 DEG-78 DEG.

The fumaric acid prepared by treatment with fumaric acid crystallizes from a mixture of methanol and ether, m.p. 183-184 °.

The 2-chloro-3-morpholinyl-5-methylpyrazine used as starting material can be prepared as follows:

16.3 g of 2,3-dichloro-5-methylpyrazine and 100 ml of morpholine are heated at 100 DEG C. for 6 hours. The reaction mixture is then diluted with 200 ml of ether and shaken again with water. The ether phase is dried over sodium sulphate and evaporated in a water pump vacuum. The residue was distilled in a water pump vacuum. There was thus obtained 2-chloro-3-morpholinyl-5-methylpyrazine having a boiling point of 166-167 ° / 2000 Pa.

Example 3

In an analogous manner to that described in Example 2, 8.5 g of 2-chloro-3-allyloxy-pyrazine afforded 2- (3 &apos; -isopropylamino-2 &apos; -hydroxypropoxy) -2-allyloxypyrazine.

A fumarate is prepared from this by treatment with fumaric acid, which crystallizes from a mixture of methanol and acetone. Mp 149-150 °.

Example 4

A solution of 31 g of crude 3-tert-butyl-5- (3-cyanopyridin-2-yloxymethyl) -2-phenyloxazolidine in 50 ml of 2N hydrochloric acid solution is left for 3 to 4 hours at 20-30 °, then extracted with 100 ml. The resulting oil was extracted with ethyl acetate and the solvent was evaporated to give 1-tert-butylamino-3- (3-cyanopyridin-2-yloxy) -2-propanol. neutral fumarate, which melts at 228-230 ° after recrystallization from a mixture of methanol, dioxane and water.

The starting material is prepared as follows:

To a solution of 24.4 g of 3-tert-butyl-5-hydroxymethyl-2-phenyloxazolidine in 100 ml of dimethylformamide was added portionwise 4.2 g of a sodium hydride suspension. The reaction mixture was stirred at 40 ° for 1 hour, cooled to 20 °, and then 12.0 g of 2-chloronicotinic acid nitrile was added in 3 portions. The reaction mixture was heated to 60 °. The mixture was stirred for 2-3 hours, evaporated in vacuo, water (30 ml) was added and ether (200 ml) was extracted. The crude 3-tert-butyl-5- (3-cyanopyridin-2-yloxymethyl) -2-phenyloxazolidine obtained is further used in the crude state by evaporation of the ether solution.

Example 5

7.4 g of 2- (3'-isopropyl-2'-phenyloixazolidin-5'-у 1] methoxy-4-phenylpyridine are hydrolyzed analogously to Example 4 to give

2- (3 &apos; -isopropylamino-2 &apos; -hydroxypropoxy) -4-phenylpyridine, the neutral fumarate of which melts at 171-173 [deg.] (After recrystallization from a mixture of methanol and acetone).

Example 6

6.8 g of crude 2- (34sopropyl-2'-phenyloxazolidin-5'-yl) methoxy-5-nitropyridine were hydrolyzed analogously to Example 4, followed by pH adjustment to 9 with saturated sodium carbonate solution and the product further isolated as in Example 4. 2- (2'-Isopropylamino-2'-hydroxypropoxy) -5-nitropyridine, m.p. 117-123 after recrystallization from isopropyl alcohol, is obtained.

Example 7 g of crude 2- (3'-isopropyl-2'-phenyl-axazolidin-5'-yl) methoxy-3-methylpyridine, dissolved in 150 ml of ethanol, is hydrolyzed by treatment with 30 ml of 6N hydrochloric acid for 3 hours at a temperature of 20 ^of a reaction mixture is worked up analogously to Example 4. There was thus obtained 2- (3'-isopropylamino-2'-hydroixypropoxy) -3-methyl-Pyridin which distilled by Kugelrohr at 130-140 ° / 4 mbar and the fumarate melts at 153-155 ° (after recrystallization from methanol / acetone).

Example 8 g of 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-5-methylaminocarbonylpyridine is dissolved in 200 ml of ethanol and hydrolyzed with 30 ml of 6N hydrochloric acid for 3 to 3 hours. 4 hours at 20 °. The reaction mixture was worked up analogously to Example 4. 2- (3'-Isopropylamino-2'-hydroxypropoxy) -5-methylaminocarbonylpyridine, m.p. 118-120 °, was obtained.

Example 9

4.2 g of a 55% sodium hydride dispersion are introduced into 150 ml of dimethyloxyethane and a solution of 24.3 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine in 50 ml of dimethoxyethane is added dropwise with stirring and nitrogen introduction. The reaction mixture was stirred at 45 ^[ deg.] C. for 1.5 hours. After addition of 19.96 g of 3-chloro-6-morpholinopyridiazine, the reaction mixture is heated at reflux for 24 hours, then acidified at 20 ° with 15% hydrochloric acid and stirred for 2 hours. At 40 ° the dimethoxyethane was evaporated in vacuo and the residue was extracted with ether. The acidic phase was made basic with 5N sodium hydroxide and extracted with chloroform. The extract was washed with saturated sodium chloride solution, filtered through cotton wool and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography (eluent: chloroform / methanol 9: 1).

After recrystallization from methylene chloride / ether, the obtained 3- (3 &apos; -isopropylamino-2 &apos; -hydroxypropoxy) -6-morpholinopyridiazine melts at 112 DEG-113 DEG.

Example 10

12.5 g of 2- (3 &apos; -isopropyl-2 &apos; -phenyloxazolidin-5 &apos; -yl) methoxypyrimidine are dissolved in 60 ml of 1N sulfuric acid solution. The reaction solution is heated at reflux for 1 hour, cooled, the precipitated benzaldehyde is extracted with ether, the separated aqueous phase is treated with a solution of barium hydroxide in an amount necessary to neutralize the sulfuric acid and filtered. The filtrate was evaporated in vacuo. The oil obtained is distilled in a collar flask. After a small amount of precursor, 2- (3 &apos; -isopropylamino-2 &apos; -hydroxypropoxy) pyridine is obtained in the form of a colorless oily distillate at 140 [deg.] / 6.7 Pa.

The starting material is prepared as follows:

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-oxazolidinium was added while stirring at room temperature for 2 hours. 5.7 g of 2-chloropyrimidine dissolved in 20 ml of dimethoxyethane are then added. The mixture was stirred at room temperature for 2 hours and then heated at reflux for 17 hours. The mixture is then filtered to remove the precipitated inorganic salt. The filtrate was evaporated in vacuo and the remaining 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxypyrimidine was isolated as an oil.

Example 11

The following compound can be prepared in an analogous manner to that described in Examples 4 to 10:

[3- (34sopropylamino-2'-hydroxypropoxy) -2- (n-butylaminocarbonyl)] pyridine, m.p. 65-67 °.

Example 12

The following compounds can be prepared in an analogous manner to that described in Examples 9 to 10:

1) 3- (3'-isopropylamino-2'-hydro'xypropoxy) -6-methoxypyridazine, m.p. 115-116 °;

2) 3- ^{(3-isopropylamino-2'hydroxypropoxyJ-6-chloropyridazine,} mp 98-99 °.

3) 3- (3-isopropylamino ^T 2'-hydroxy propoxyjpyridazin, mp 91-93 °.

Example 13 g of crude 2 - [(3'-tert-butyl-2'-phenyloxazolidin-5'-yl) methoxy] -3-ethoxyl-6-methylpyridine are dissolved in 150 ml of 2N sulfuric acid and the solution is stirred for 2 hours at 20 ° to 30 °. The solution was extracted with 50 ml of ether, the aqueous phase was separated and basified with concentrated sodium hydroxide solution. Extraction of the alkaline phase with methylene chloride and evaporation of the solvent afforded 25 g of a yellow oil which was distilled in a collar flask at 110 to 115 ° / 2.7 Pa. The 3-ethoxy-2- (3'-tert-butylamino-2'-hydroxypropoxy) -6-methylpyridine thus obtained affords neutral fumarate with half an equivalent amount of fumaric acid, m.p. 169-170 ° (from methanol / acetone). ).

The starting material can be produced as follows:

To a solution of 17.1 g of 3-ethoxy-2-chloro-6-methylpyridine and 25.8 g of 5-hydroxymethyl-3-t-b) Utyl-2-phenyloxazolidine in 300 ml of hexamethylphosphoric anhydride were added within 1 1/2 hours. at 0 to 5 °, 4.8 g of a 55% sodium hydride dispersion are added in portions. The reaction mixture is then stirred at 20-30 ° for 2 hours and at 70 ° for 16 hours, then poured into ice water and extracted with about 500 ml of 2 - [(3'-tert-butyl-2'-phenyloixazolidine) ether. -5'-yl) methoxy] -3-ethoxy-6-methylpyridine. The crude product remaining after evaporation of the ether is further used as such.

Example 14

To a solution of 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-4-methylpyridine (34 g) in ethanol (200 ml) was added 4N hydrochloric acid (60 ml) and the reaction mixture was allowed to stand overnight. at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in about 200 mL of water. This solution was extracted with ether (100 mL). The aqueous phase was separated, basified strongly with concentrated potassium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained which is distilled in a collar flask at 120-130 ° / 13.3 Pa. The 2- (3'-isopropylamino-2'-hydroxypropoxy) -4-methylenopyridine thus obtained is mixed with half an equivalent amount of fumaric acid dissolved in methanol, the solution is evaporated in vacuo and then acetone is added. Thus ^one crystallized neutral fumarate, mp 136-139 °.

The starting material is prepared as follows:

To a solution of 27.5 g of 5-hydroxymethyl-3-isopropyl-2-phenyloxazolidine in 100 ml of dimethylformamide was added cautiously in portions at 20-40 ° 4.8 g of a 55% sodium hydride dispersion and stirred. 1 to 2 hours at 203970 ° C. 12.7 g of 2-chloro-4-methylpyridine are then added and the reaction mixture is stirred for 2 hours at 80 °. After evaporation of the solvent in vacuo, the residue is taken up in ether, the solution is washed with water and the ether solution is dried over magnesium sulphate and evaporated in vacuo. There was thus obtained crude 2- [3 ' -isopropyl-2 &apos; -phenyloxazolidin-5 &apos; -yl] methoxy-4-methylpyridine.

Example 15

To a solution of 2- (3 ' -isopropyl-2 &apos; -phenyloxazolidin-5-yl) methoxy-5-methylpyridine (40 g) in ethanol (200 ml) was added 4N hydrochloric acid (60 ml) and allowed to stand overnight. The solvent is evaporated in vacuo and the residue is dissolved in about 200 ml of water. The aqueous solution was extracted with ether (100 mL). The aqueous phase was separated, basified strongly 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 flask at 120-130 mm Hg. The 2- (3 &apos; -isopropylamino-2 &apos; -hydroxypropoxy) -5-methylpyridine thus obtained crystallizes and has a melting point of 2 DEG-67 DEG. To this product was added half equivalent amount of fumaric acid dissolved in methanol, the solution was evaporated in vacuo and acetone was added. Thus, a neutral fumarate with a melting point of 149 to 151 ° crystallizes.

Example 16

To a solution of 35 g of 2- (3'-isopropyl-2'-phenyloxazolin-5-yl) -5-methyl-6-methylpyridine in 200 ml of ethanol is added 60 ml of 4N hydrochloric acid. and the reaction mixture is allowed to stand at room temperature for 1 hour. The solvent was evaporated in vacuo and the residue was dissolved in about 200 ml of water. This solution is extracted with 100 ml of ether. The aqueous phase was separated, basified strongly with concentrated potassium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained which is distilled in a flask at 13075.3 Pa. To the 2- (3 &apos; -isopropylamino-2 &apos; -hydroxypropoxy) -6-methylpyridine thus obtained was added half equivalent amount of fumaric acid dissolved in methanol, the solution was evaporated in vacuo and acetone was added. Thus, a neutral fumarate with a melting point of 164 to 165 ° crystallizes.

Example 17

To a solution of 40 g of 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-3-ethoxypyridine in 200 ml of ethanol is added 60 ml of 4N hydrochloric acid and the reaction mixture is left at room temperature. room overnight. The solvent was evaporated in vacuo and the residue was dissolved in about 200 ml of water. This solution was extracted with ether (100 mL). The aqueous phase was separated, basified strongly with concentrated potassium hydroxide solution and extracted with ethyl acetate. After drying and evaporation of the solvent, a dark oil is obtained, which is distilled in a flask at 130-140 mbar. The thus obtained 2- (3 &apos; -isopropylamino-2 &apos; -hydroxypropoxy) -3-thiophosphoric acid is mixed with half an equivalent amount of fumaric acid dissolved in methanol, the solution is evaporated in vacuo and methyl ethyl ketone is added. A neutral fumarate with a melting point of 142 ° to 144 ° crystallizes.

For example.

A solution of 30 g of 2- (3'-isopropyl-2'-phenyloxazolidin-5-yl) methoxy-3-chloro-5- (methylaminocarbonyl) pyridine in 260 ml of 2N sulfuric acid was stirred at room temperature for 4 hours. This solution was extracted with ether (100 mL), the aqueous phase was separated, basified with concentrated potassium hydroxide solution and extracted with ethyl acetate, dried and evaporated to give a dark oil which crystallized from ether to give 2- (3'-isopropylamino). -2'-hydroxypropoxy) -3-chloro-5- (methylaminocarbonyl) pyridine melts at 130-132 ° C. To this product is added half of an equivalent amount of fumaric acid dissolved in methanol, and the solution is evaporated in vacuo, then by addition of of acetone crystallizes a neutral fumarate with a melting point of 133-136 °.

The starting material is prepared as follows:

a) Under stirring and cooling, to a solution of 16.0 g of 2,3-dichloro-5-methylaminocarbonylpyridine and 18.5 g of 5-hydroxymethyl-3-isopropyl-2-phenyloxazolidine in 250 ml of hexamethylphosphoric triamide is added 4 hours. 25 g of a 55% sodium hydride dispersion. The reaction mixture was stirred at room temperature overnight, then poured into 250 ml of ice-water and extracted three times with 200 ml of ether each time. The combined ether extracts were evaporated to give crude 2- (3 &apos; -isopropyl-2 &apos; -phenyloxazolidin-5 &apos; -ylmethoxy-3-chloro-5-methylaminocarbonylpyridine).

The starting material can be obtained through the following steps:

(b) A solution of 63 g of potassium chlorate in 750 ml of water is added dropwise at a temperature of 80 to 85 ° to a suspension of 210 g of 2-hydroxypyridine-5-carboxylic acid in 1.5 liters of concentrated hydrochloric acid. During the dropwise addition, a yellow solution is formed from which crystals slowly precipitate again. After dripping (1.5 to 2 hours). The reaction mixture was cooled in an ice bath and the crystallized 2-hydroxy-3-chloropyridine-5-carboxylic acid (m.p. 318-322 °) was filtered off.

c) To a suspension of 108 g of phosphorus pentachloride in 300 ml of toluene, 45 g of 2-hydroxy-3-chloropyridine-5-carboxylic acid are added with stirring over about 30 minutes. The reaction mixture was refluxed for 2 hours and then vigorously evaporated on a rotary evaporator under vacuum, finally at a bath temperature of 70-80 °. The crude 5,6-dichloronicotinic acid chloride thus obtained is further used in the crude state.

(d) A solution of 30 g of crude 5,6-dichloronicotinic acid chloride in 150 ml of chloroform is added dropwise to a solution of 50 g of methylamine in 250 ml of ethanol under stirring and cooling at 10 to 15 °. The reaction mixture was stirred at 20-30 ° for 2 hours and then evaporated in vacuo. The residue is taken up in ethyl acetate, the ethyl acetate solution is washed with 2N sodium carbonate solution, dried over magnesium sulphate and evaporated. The residue was recrystallized from a mixture of ethanol and ether. Thus obtained

2,3-dichloro-5-methylaminocarbonylpyridine melts at 134-138 °.

Example 19

A solution of 32 g of 2- (3'-isopropyl-2'-phenyloxazolidin-5-yl) methyl-5-chloro-Sn-hexylaminocarbonylpyridine in 260 ml of 2N sulfuric acid was stirred at room temperature for 4 hours. The aqueous phase was separated, strongly basified with concentrated potassium hydroxide solution, then extracted with ethyl acetate, dried and evaporated to give a dark oil which crystallized from ether to give 2- (34sopropylamino-2'-hydroxypropoxy-3-chloro). -5-n-hexylaminocarbonylpyridine melts at 131-132 DEG C. To this product is added half of an equivalent amount of fumaric acid dissolved in methanol, the solution is evaporated in vacuo and acetone is added to the residue to give a neutral fumarate, m.p. °.

The starting material is prepared as follows:

a) In analogy to Example 18a, using 15.6 g of 2,3-dichloro-5-n-hexylaminocarbonylpyridine, 13.6 g of 5-hydroxymethyl-3-isopropyl-2-phenyloxazolidine and 3.15 g. g of a 55% dispersion of sodium hydride in oil in 250 ml of hexamethylphosphoric triamide produces 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-3-chloro-5-n-hexylaminocarbonylpyridine.

The starting material can be prepared analogously to Example 18d.

b) Using 30 g of n-hexylamine, 2,3-dichloro-5-n-hexylaminocarbonylpyridine is obtained which melts at 87-89 ° after recrystallization from ether-n-hexane.

Example 1 a d 2 0

A solution of 28 g of 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-5-cyanopyridine in 260 mL of 2N sulfuric acid is allowed to stand at room temperature for 4 hours. This solution was extracted with ether (100 mL). The aqueous phase was separated, basified strongly with concentrated potassium hydroxide solution and then extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained which crystallizes from a mixture of methylene chloride and ether. The 2- (3 &apos; -isopropylamino-2 &apos; -hydroxypropoxy) -5-cyanopyridine thus obtained melts at 124 DEG-126 DEG.

Example 21

A solution of 25 g of crude 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-5- [2'-aminoethyl) pyridine in 150 ml of 4N sulfuric acid was reacted analogously to Example 35 and the corresponding the process is also processed. There was thus obtained crude 5- (2'-aminoethyl) -2- (3'-isopropylamino-2'-hydroxypropoxy) pyridine of a purity sufficient for further reactions to obtain the pure product by distillation in a flask flask at 140-150%. 0.7 Pa.

The starting material is prepared as follows:

(a) To a solution of 46,8 g of 5-hydroxymethyl-3-isopropyl-2-phenyloxazolidine in 300 ml of 1,2-dimethoxyethane, at a temperature of 20 to 40 °, 6,1 g of a 55% sodium hydride dispersion are carefully added in portions The mixture was stirred at 40 DEG C. for 1 to 2 hours. Then, 11.0 g of 5- (2'-aminoethyl) -2-chloropyridine was added and the reaction mixture was stirred at 80 ° C for 18 hours. After evaporation of the solvent in vacuo, the residue is taken up in ether, the ether solution is washed with water, dried over magnesium sulphate and evaporated in vacuo. This gives crude 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-5- (2'-aminoethyl) pyridine.

(b) The starting material may be produced as follows:

To a solution of 30.4 g of (6-chloro-3-pyridine) -acetonitrile in 90 ml of methanol was added; adding about 10 g of Raney nickel suspension dropwise at 50-60 ° a solution of 7.6 g of sodium borohydride in 25 ml of 8N sodium hydroxide solution. Cooling maintained the temperature at 50 to 60 °. After the dropwise addition, the reaction mixture was stirred for an additional 20 minutes at about 50 °. The reaction mixture was cooled, the nickel was filtered off and the filtrate was evaporated in vacuo.

The residual dark red oil was stirred with 15 g of solid potassium hydroxide for 1 hour and the resulting suspension was extracted with a total of 200 ml of dichloromethane. After drying and evaporation of the solvent, an oil is obtained which is isolated by distillation under high vacuum as a colorless oil of 5- (2 &apos; -ammoethyl) -2-chloropyridine at 76-80 [deg.] / 2.7 Pa.

Example 22

To a solution of 2- (3'-tert-butyl-2'-phenyloxazolidin-5'-yl) methoxy-3-ethoxy pyridine (24 g) in ethanol (100 ml) was added 4N hydrochloric acid (60 ml) and the reaction mixture was allowed to stand for 2 hours. The solvent is evaporated in vacuo and the residue is dissolved in about 100 ml of water, this solution is extracted with 100 ml of ether, the aqueous phase is separated off, basified with a strongly concentrated potassium hydroxide solution and extracted with ether. The 2- (3'-tert-butylamino-2'-hydroxypropoxy) -3-ethoxypyridine thus obtained is reacted with half the equivalent amount of fumaric acid dissolved in methanol. The solution obtained is evaporated in vacuo and butanone is added to the residue, a neutral fumarate having a melting point of 170 DEG-172 DEG C. crystallizes.

Example 23

5.2 g of 2 - [(3 &apos; -isopropyloxazolidin-2 &apos; -one-5 &apos; -yl) methoxyl] -4-phenylpyridine was refluxed in a mixture of 70 ml of ethanol and 20 ml of 2N sodium hydroxide solution for 16 hours. The reaction mixture was then evaporated in vacuo and the residue partitioned between ether (100 ml) and water (20 ml). The organic phase was separated and extracted with 40 ml of 2N hydrochloric acid. The acidic extract was basified with concentrated sodium hydroxide solution and the precipitated oil was extracted with ether. The 2- (2'-hydroxy-3'-isopropylaminopropoxy) -4-phenylpyridine thus isolated forms a neutral fumarate with a melting point of 171-173 °.

Example 24

To a solution of 48 g of 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-3-chloropyridine in 200 ml of ethanol was added 50 ml of 4N hydrochloric acid and the reaction mixture was allowed to stand at room temperature for 3 hours. . Dissolve the solvent in vacuo and dissolve the residue in about 200 mL of water. This solution was extracted with ether (100 mL). The aqueous phase was separated, basified strongly with concentrated potassium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent, an oil is obtained from which 2- (3'-isopropylamino-2'-hydroxypropoxy) -3-chloropyridine hydrochloride is isolated by addition of a solution of hydrochloric acid in methanol up to pH 2-3. from a mixture of methanol and acetone at 167-169 °.

Example 25

To a solution of about 35 g of 4- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-3-methylpyridine in 100 ml of ethanol was added 60 ml of 4N hydrochloric acid and the reaction mixture was allowed to stand at room temperature for 2 hours. rooms. The solvent was evaporated in vacuo and the residue was dissolved in about 100 ml of water. This solution was extracted with ether (100 mL). The aqueous phase was separated, basified strongly with concentrated potassium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent, a yellow oil is obtained which is distilled in a flask flask at 145 ° / 2.7 Pa. The 4- (3 &apos; -iso-propylamino-2 &apos; -hydroxypropoxy) -3-methylpyridine thus obtained is reacted with an equivalent amount of fumaric acid dissolved in methanol. The resulting solution was evaporated in vacuo and isopropyl alcohol was added to the residue. An acid fumarate crystallizes, having a melting point of 167-169 °.

Example 2 6 g of crude 2 - [(3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxyl] -3-chloro-5 - [(tetrahydropyran-2'-yloxy) methyl] The pyridine is dissolved in 250 ml of 2N sulfuric acid, allowed to stand at room temperature for 4 hours, then extracted with 100 ml of ether, the aqueous phase is evaporated in vacuo to a volume of about 50 ml, and the residue is basified with concentrated sodium hydroxide solution. Extraction is carried out three times with 150 ml of methylene chloride each time, and the methylene chloride extracts are dried and the solvent is evaporated to give 3-chloro-2- (2'-hydroxy-3'-isopropylaminopropoxy) -5-hydroxymethylpyridine which distills in a flask flask at 170 to 18075.3 Pa as a colorless oil and forms a neutral fumarate, m.p. 205-207 ° (from methanol).

The starting material is prepared as follows:

a) 27 g of crude 2,3-dichloro-5 - [(tetrahydropyran-2-yloxy) methyl] pyridine with 25 g of 5-hydroxymethyl-3-isopropyl-2-phenyloxyazolidine and 4.5 g of a 55% hydride dispersion The reaction mixture was refluxed for 16 hours in 250 ml of 1,2-dimethoxyethane, and the reaction mixture was worked up in the usual manner. This yields crude 2- ((3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxy] -3-chloro-5-

- [(tetrahydropyran-2-yloxy) methyl] pyridine.

(b) The starting material may be prepared as follows:

2,3-Dichloro-5-hydroxymethylpyridine is converted to 2,3-dichloro-5 - [(tetrahydropyran-2-yloxy) methyl] pyridine (boiling point 115-123710.6 Pa) by treatment with 2,3-dihydropyran.

Example 2 7

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 hydrolysed with 120 ml of a 4N hydrochloric acid solution. for 3 hours at 20 ° in analogy to Example 14, and the reaction mixture is then worked up in an analogous manner. Distillation in a flask at 140 to 15075.3 Pa yielded 2- [2'-hydroxy-3'- (1-methyl-3-phenylpropylamino) propoxy] -3-methylpyridine as a pale yellow oil.

The starting material can be produced by the following process:

(a) 31.1 g of 2-phenyl-3- (1-phenyl-3-butyl) -5-hydroxymethyloxazolidine, dissolved in 150 ml of dimethylformamide, are reacted with a 55% dispersion of sodium hydride in an amount of 6.5 g and then with 34 4 g of 2-bromo-3-methylpyridine for 18 hours. This gave crude 3-methyl-3 - {[2-phenyl-3- (4-phenyl-3-butyl) oxazolidin-5-yl] methoxy} pyridine.

Example 28

In an analogous manner to that described in Example 2, 9.4 g [0.05 mol] of 2-chloro-3- (2'-methoxyethoxy) pyrazine of 3- (2'-methoxyethoxy) -2- (Z &lt; - &gt; isopropylamin-2'-hydroxypropyloxy) pyrazine. The fumarate produced from this compound by fumaric acid crystallizes from a mixture of methanol and acetone, m.p. 120-121 °.

2-Chloro-3- ^{(2-methoxyethoxy)} pyrazine used as starting material was prepared as follows:

14.9 g (0.1 mol) of 2,3-dichloropyrazine and 30 g (0.5 mol) of ethylene glycol monomethyl ether are dissolved in 150 ml of hexamethyltriamide. of phosphoric acid and at 0 to 5 °, 4.8 g (0.1 mol) of a 55% suspension of sodium hydride in paraffin oil are added in portions. The reaction mixture was then stirred at room temperature for 15 hours. The reaction mixture was then poured onto 1 liter of ice water and shaken with ether. The ether extracts were washed with water, dried over sodium sulfate and evaporated in a water pump vacuum. To give 2-chloro-3- (2'-methoxyetho.xy) pyrazine b.p. 7470.4 Pa, n _D ^22: 1.5118.

Example 2 9

A mixture of 0.3 g of 3 - [(3-isopropyloxazolidin-2-one-5-yl) methoxy] -6-methylpyridine-1-oxide, 30 ml of ethanol, 1.0 g of sodium hydroxide and 1 ml of water is heated for 6 hours with stirring to reflux. The precipitate was filtered off, the filtrate was evaporated in vacuo and dissolved in ethyl acetate. After drying and evaporation of the solvent, an oil is obtained which crystallizes from ether. After two additional crystallizations from ether, 3- (2'-hydroxy-3 ') melts

(isopropylaminopropoxy) -6-methylpyridine-1-oxide at 87-89 °.

The starting material can be produced as follows:

To a solution of 4.8 g of 3-isopropyl-5 - [(6-methylpyridin-3-yloxy) methyl] oxazolidin-2-one in 50 ml of dichloromethane, a solution of 4.1 g of m-chloroperbenzoic acid in 30 ml of dichloromethane and the mixture is allowed to stand overnight at room temperature. After dilution with 50 ml of dichloromethane, the reaction mixture is extracted with 20 ml of saturated potassium bicarbonate solution each, then the extracts are dried over sodium sulphate and evaporated in vacuo. The crystalline residue is recrystallized from a mixture of dichloromethane and ether. The thus obtained 3 - [(3-isopropyloxazolidin-2-one-5-yl) methoxy] -6-methylpyridine-1-oxide melts at 137-139 °.

Example 1 a d. 3 0

The following compounds were obtained in an analogous manner to that described in Example 2:

a) From 17.1 g of 2-chloro-3-ethylthlopyrazine, 3-ethylthio-2- (3'-tert-butylamino-2'-hydroxypropoxy) pyrazine is obtained, the hydrochloride of which melts after recrystallization from methanol / ether at 147-148. °.

b) from 15.6 g of 2-chloro-3-methylthiopyrazin.u gave 3-methylthio-2- ^{(3'-tert-butylamino-2?} -hydroxypropoxy) pyrazine, the neutral fumarate was recrystallized from isopropyl alcohol to 184 185 °.

c) 2- (3'-Isopropylamino-2'-hydroxypropoxy) -3-ethylthiopyrazine is obtained from 8.85 g of 2-chloro-3-ethylthiopyrazine, the neutral fumarate of which melts after recrystallization from methanol / ether at 158-160 °. .

Example 31

1.6 g of 5-allyloixy-2- ^{(3-isopropyl-2'-phenyl-oxazolidin-5'-yl)} methoxypyriimdmu was dissolved in 6 ml of IN hydrochloric acid. The solution is heated to boiling for 10 minutes, then cooled, the precipitated benzaldehyde is extracted with ether and 3 ml of 2N sodium hydroxide solution are added to the separated aqueous phase. The base which forms in an oily form is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulfate, filtered and the filtrate is evaporated under reduced pressure. The oily crude base obtained is dissolved in a small amount of acetone and a solution of 0.5 g of oxalic acid in 2 ml of acetone is added thereto, followed by crystallization of 5-allyloxy-2- (3'-isopropylamino-2'-hydroxypropoxy) pyrimidine hydrogen oxalate, which was recrystallized from methanol-acetone. 152 DEG-153 DEG.

5-A11у11ху-2- (3´-isopropyl-2´-phenyloxazolidin-5´-yl) methoxypyrimidine, which is used as starting material, can be produced as follows:

To a suspension of 0.13 g of sodium hydride in 5 ml of dimethoxyethane was added 1.2 g of 2-ynyl-3-isopropyl-5-hydroxymethyl-oxazolic alcohol, and the mixture was stirred at room temperature for 2 hours. 1.2 g of 5-allyloxy-2-methylsulfonylpyrimidine, which is dissolved in 20 ml of dimethoxyethane, are then added. The mixture was stirred at room temperature for 2 hours and then heated to reflux for 10 hours. The precipitated inorganic salt is then filtered off, the filtrate is evaporated in vacuo and the remaining oily 5-allyloxy-2- (3 &apos; -isopropyl-2 &apos; -phenyloxazolidin-5 &apos; -yl) methoxypyrimidine is further processed without further purification.

The 5-allyloxy-2-methylsulfonylpyrimidine used as starting material can be obtained as follows:

4.5 g of 5-hydroxy-2-methylthiopyrimide, 9.0 g of potassium carbonate and 3.9 g of allyl bromide are heated together in 50 ml of acetone under stirring and reflux.

4.5 hours to boil. The inorganic salts are filtered off and the filtrate is evaporated under reduced pressure. The residual oil is 5-allyloxy-2-methylthiopyrimidine from petroleum ether, m.p. 41-42 °.

3.5 g of 5-allyloxy-2-methylthiopyrimidine are dissolved in 30 ml of glacial acetic acid and 20 ml of 20% hydrogen peroxide are added to this solution. After 46 hours at 20 °, the solution is evaporated under reduced pressure at 20 °. The residue is crystallized from 5-allyloxy-2-methylsulfonylpyrimidine ether, m.p. 66 DEG.

Example 32

44.7 g of 2,3-dichloropyrazine and 70.5 g of 2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine are dissolved in 300 ml of hexamethylphosphoric triamide. 13.1 g of a 55% suspension of sodium hydride in paraffin are added to this solution at 0-5 ° with stirring over 1 hour. The reaction mixture was stirred at room temperature for 15 hours, then poured onto ice water and extracted with ether. The combined extracts are evaporated in a water-jet vacuum, the oily residue is taken up in 309 ml of 2N sulfuric acid solution, stirred for 2 hours at room temperature and then shaken into ether. The aqueous phase was basified with concentrated sodium hydroxide solution and extracted with a 1: 1 mixture of benzene and ether. The extracts in the benzene / ether mixture were washed with water, dried over sodium sulfate and evaporated in a water pump vacuum. The residue is recrystallized from a mixture of benzene and petroleum ether. There was obtained 3-chloro-2- (3-tert-butylamino-2-hydroxy-1-propyloxy) pyrazine, m.p. 105-106 °.

Example 33

5.4 g of 2-methylmercapto-4- (3'-isopropyl-2'-phenyloxazolidin-5'-yl] methoxypyrimidine are dissolved in 20 ml of 1N hydrochloric acid solution, which is heated at reflux for 10 minutes, then cooled, The precipitated benzaldehyde is extracted with ether and 10 ml of 2N sodium hydroxide solution are added to the separated aqueous phase, the oily base is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The oil obtained yields crystalline 2-methylmercapto-4- (6) - (3'-isopropylamino-2'-hydroxypropoxy) pyrimidine from carbon tetrachloride, m.p. 82-83 °.

The starting material is prepared as follows:

α] 35 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine were added to a suspension of 3.8 g of sodium hydride in 40 ml of dimethoxyethane and the mixture was stirred at room temperature for 2 hours. 23.5 g of 2-methylmercapto-4-chloropyrimidine dissolved in 40 ml of dimethoxyethane are then added dropwise. The mixture was then stirred at room temperature for 1 hour and then at reflux for 4 hours. The precipitated inorganic salt is then filtered off, the filtrate is evaporated in vacuo and the residual oil contains 2-methylmercapto-4- [3 &apos; -isopropyl-2 &apos; -phenyloxazolidin-5 &apos; -yl) methoxypyrimidine.

Example34

Tablets containing 50 mg of active ingredient are prepared in the usual manner with the following composition:

Ingredients

2- (З'-t-butylamino-2'-hydroxy-

propoxy) -3-morpholinopyrazine 50 mg wheat starch 59 mg milk sugar 70 mg colloidal silicic acid 10 mg talc 10 mg magnesium stearate 1 mg 200 mg

Production

2- (3 &apos; -T-Butylamino-2 &apos; -hydroxypropoxy) -3-morpholinopyrazine is mixed with a portion of wheat starch, milk sugar and colloidal silicic acid and passed through a sieve to give a powder mixture. Another portion of the wheat starch is granulated using a five-fold amount of water in a water bath, and the powder mixture is bent with this erasable starch until a slightly plastic mass is formed.

The plastic mass is passed through a sieve with a mesh width of about 3 mm, dried and the resulting dry granulate is sieved again. The remaining wheat starch, talc and magnesium stearate are then admixed and the tablets are compressed with a notch of 200 mg.

The daily dose is 1/2 to 4 tablets, in the case of warm-blooded, weighing about 75 kg of body weight, the corresponding dose of active ingredient can also be administered in the form of a single tablet, which then has the appropriate composition.

Example 35

In an analogous manner to that described in Example 2, from 2-chloro-3-phenylthiopyrazine (11.1 g, 0.05 mol) and 2-phenyl-3-isopropyl-5- (13.2 g, 0.06 mol) were added. hydroxymethyloxazolidine gave 3-phenylthio-2- (3'-isopropylamino-2'-hydroxypropyloxy) pyrazine, m.p. 70-71 ° (from ether / petroleum ether).

The fumarate produced from this compound crystallizes from isopropyl alcohol, m.p. 167-169 °.

Example 36

In an analogous manner to that described in Example 2, from 10.7 g (0.05 mol) of 2-chloro-3-morpholinyl-5-methylpyrazine and 15.5 g (0.05 mol) of 2-phenyl-3- (1-phenyl-3-butyl) -5-hydroxymethyloxazolidine affords 2- [3'- (1-phenyl-3-butylamino) -2'-hydroxypropoxy] -3-morpholinyl-5-methylpyrazine and therefrom by treatment with 2 25 g of fumaric acid are obtained fumarate crystallizing from a mixture of methanol and acetone, m.p. 134-136 °.

Example 37

In an analogous manner to that described in Example 2, from 2-phenyl-3-isopropyl-5- (2-phenyl-3-isopropyl-5-) (8.2 g, 0.05 mol) was added. hydroxymethyloxazolidine and 3.4 g of a 50% suspension of sodium hydride in paraffin oil gave 2-chloro-3- (3'-isopropylamino-2'-hydroxypropyloxy) -5-methylpyrazine, m.p. 109-110 °, from benzene. Fumaric acid crystallizes from methanol / ether and has a melting point of 164-165 °.

Example 38

8.5 g of 5- (N-hexylcarbamoyl) -2- (3 &apos; -isopropyl-2 &apos; -phenyloxazolidin-5 &apos; -yl) methoxypyrimidine are dissolved in 25 ml of 1N hydrochloric acid. The solution is heated to boiling for 10 minutes, then cooled, the precipitated benzaldehyde is extracted with ether and 13 ml of 2N sodium hydroxide are added to the separated aqueous phase. The base which is formed as an oil is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulphate, filtered. and evaporated under reduced pressure. The residue is crystallized from petroleum ether. 5- (N-hexylcarbamoyl) -2- (3-isopropylamino-2 &apos; -hydroxypropoxy) pyrimidine is obtained as crystals (colorless), m.p. 114 DEG-115 DEG. The hydrogen oxalate of this compound crystallizes from acetone and melts at 149-150 °.

The starting material is prepared as follows:

(a) 9.7 g of 5- (N-hexylcarbamoyl) -2,4 (6) -dichloropyrimidine are heated in 100 ml of 50% ethanol with 20 g of zinc dust with stirring for 1 1/2 hour to boiling. Thereafter, the reaction mixture is filtered while hot, the filter residue is washed with ethanol and the filtrate is distilled under reduced pressure, preferably completely free of ethanol. The oil which precipitated from the aqueous solution was extracted with ethyl acetate, the extract was washed with water, dried over sodium sulfate and evaporated. The residual oil was chromatographed on 50 g of silica gel using a 1: 1 mixture of benzene and ether as eluent. Fractions containing product were combined. After distilling off the solvent, 5- (N-hexylcarbamoyl) -2-chloropyrimidine is obtained in the form of a colorless oil, which yields crystals from petroleum ether, m.p.

b) 8.2 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine were added to a suspension of 0.88 g of sodium hydride ¹ in 20 ml of dimethoxyethane and the mixture was stirred at room temperature for 2 hours. 9.0 g of 5- (N-hexylcarbamoyl) -2-chloropyrimidine, which is dissolved in 30 ml of dimethoxyethane, are then added dropwise. The mixture was stirred at room temperature for 18 hours. Then precipitated inorganic salt removed by filtration, the filtrate was evaporated in vacuo and the residual oil containing 5- (N-hexylcarbamoyl) -2- (3'-isopropyl-propyl ^and 2'-phenylmethyl-5'loxazolidin 1-yl] methoxypyrimidine.

The starting material can be produced as follows:

c) To a solution of 22.6 g of 2,4 (6) -dichloropyrimidine-5-carboxylic acid chloride in 150 ml of diethyl ether, 20.2 g of n-hexylamine is added dropwise at -10 ° with stirring for 1 hour, and the mixture stirred at 0 ° for 1 hour. The precipitate formed is filtered off. 5- (N-hexylcarbamoyl) -2,4 (6) -dichloropyrimidine was obtained as a colorless oil from the filtrate by distillation of the ether.

Example 39

9.0 g of 2-dimethylamino-5-ethoxycarbonyl-4 (6) - ^{(3'-isopropyl-2} -fenyloxazolidin-5'-yl) methoxypyrimidine was dissolved in 45 ml of IN hydrochloric acid. The reaction solution is heated to boiling for 10 minutes, cooled, the precipitated benzaldehyde is extracted with ether and 23 ml of 2N sodium hydroxide are added to the separated aqueous phase. The base precipitated oil was extracted with ethyl acetate, the extract washed with water, dried over ^sodium: sulfate, filtered and evaporated under reduced pressure. The oil obtained is dissolved in a small amount of acetone and a solution of 2.9 g of oxalic acid in acetone is added. 2-Dimethylamino-5-ethoxycarbonyl-4 (6) - (3'-isoproplamino-2'-hydroxypropoxy] pyrimidine oxalate is obtained, which is recrystallized from methanol / acetone, m.p. 155-156 °.

The starting material is prepared as follows:

and 4.8 g of 2-phenyl-3-isopropylhydroxymethyloxazolidine were added to a suspension of 0.53 g of sodium hydride in 20 ml of dimethoxyethane and the mixture was stirred at room temperature for 2 hours. 5.0 g of 2-dimethylamino-4-chloro-5-ethoxycarbonylpyrimidine dissolved in 30 ml of dimethoxyethane are then added dropwise. The mixture was then stirred at room temperature for 18 hours, finally at 80 ° C for 1 hour. Thereafter, the precipitated salt is filtered off, the filtrate is evaporated in vacuo and the remaining residue contains 2-dimethylamino-5-ethoxycarbonyl-4- (3'-isopropyl-2'-phenylethyl) methyl. .beta.-pyrimidine.

The starting material can be produced as follows:

b) A suspension of 16 g of 2-dimethylamino-4-hydroxy-5-ethoxy-4-hydroxy-5-carboxylic acid in 100 ml of phosphorous oxychloride was heated under stirring for 1/2 hour. It is then filtered while hot and the filtrate is evaporated under reduced pressure. 200 g of ice are added to the oily residue. 200 ml of methylene chloride are then added and 30% sodium hydroxide solution is added under cooling with ice until a pH of 8 is reached. The precipitated inorganic salts are then 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-ethoxycarbonylpyrimidine is obtained in the form of a yellowish oil which can be used further without purification.

Example 40

7.0 g of 5- (2-methoxyethyl) -2- (3 &apos; -isopropyl-2 &apos; -phenyloxa-zdidin-5 &apos; -yl) methoxypyrimide-iodide are dissolved in 24 ml of 1N hydrochloric acid. Heat the solution to boiling for 10 minutes, then heat. After cooling, the precipitated benzaldehyde was extracted with ether and 12 ml of 2N sodium hydroxide was added to the separated aqueous phase. The oily base is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The oil obtained is dissolved in a small amount of isopiropylalcohol and then the solvent is distilled off as far as possible. The resulting rupee is diluted with acetone and then crystallized

5- (2-Methoxy-2- (3 &apos; -oxide-2-hydroxypropoxy) pyrimidine hydrofumarate, m.p. 103-104 ° C after recrystallization from methanol / acetone).

The starting material is prepared as follows:

a-) To a suspension of 0.48 g of sodium hydride in 10 ml of dimethoxyethane was added 4.1 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazclidine and the mixture was stirred at room temperature for 2 hours and then 3.4 g was added. Of 5- (2-methoxyethyl) -2-chloro-pyrimidine, dissolved in 10 ml of dimethoxyethane. The mixture was stirred at room temperature for 2 hours and then heated to boiling for 3 hours. The precipitated inorganic salt is then filtered off, the filtrate is evaporated in vacuo and the residual oil contains 5- (2-methoxyethyl) -2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxypyrimidine.

The starting material can be produced as follows:

b) 6.0 g of 5- (2-methylsulfonyloxyethyl) uracil was suspended in 100 ml of absolute methanol and heated to 120-130 ° C in a pressure vessel for 1 hour. After cooling to room temperature, the crystals obtained are filtered off and washed with methanol. There is obtained 5- (2-methoxyethyl) uracil, m.p. 232-234 °.

c) A suspension of 10.3 g of 5- (2-methoxyethyl) uracil in 50 ml of phosphorus oxychloride was heated at reflux for 2 hours. The resulting solution was freed from excess phosphorus oxychloride by distillation under reduced pressure, and the resulting oil was poured onto 200 g of ice. Then ^1, the product extracted into ether, washed with water and sodium bicarbonate solution, dried over · sulfate and evaporated. The oil obtained is taken up in hot hexane, filtered to remove insoluble impurities and the solvent is distilled off under reduced pressure. 5- (2-methoxyethyl) -2,4 (G-dichloropyrimidine) is obtained in the form of a colorless oil which can be used further without purification.

d) 8.7 g of 5- (2-methoxyethyl) -2,4 (6) -dichlorogyrimidine are heated in 100 ml of 50% ethanedane with 20 g of zinc powder with stirring for 1 1/2 hour to reflux. Then the mixture is filtered while hot, the residue on the filter is washed with ethan and the filtrate is distilled off under reduced pressure, as much as possible, free of ethanol. The oil precipitated from the aqueous solution was extracted with ethyl acetate, the extract was washed with water, dried over sodium sulfate and evaporated. The residual oil is chromatographed on 50 g of silica gel (60 Merk) using a 1: 1 mixture of benzene and ethyl acetate as eluent. The fractions containing the reaction product were combined. After distilling off the solvent, 5- (2-methoxy-ethyl) -2-chloropyrimidine is obtained in the form of a colorless oil which yields crystals from petroleum ether, m.p. 25-26 °.

0 3 9 7 0 '

Example 41

4.9 g of 5-methylthiomethyl-2- (2-isopropyl-2-phenyloxazolidin-5-yl) methoxypyrimidine are dissolved in 25 ml of 1N hydrochloric acid. The solution is heated to boiling for 10 minutes, then cooled, the precipitated benzaldehyde is extracted with ether and 13 ml of 2N sodium hydroxide are added to the separated aqueous phase: The oil precipitated base is extracted with ethyl acetate, the ethyl acetate extract is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The oil obtained is dissolved in a small amount of isopropyl alcohol and a solution of 0.7 g of fumaric acid in 10 ml of isopropanol is added thereto, followed by crystallization of 5-methylthi-methyl-2- (3 &apos; -isopropylamino-2 &apos; -hydroxypropyl) pyrimidine hydrogen fumarate. Melting point 142-143 ° after recrystallization from isopropyl alcohol.

The starting material is prepared as follows:

3.1 g of 2-phenyl-3'-isopropyl-5-hydroxy-oxy-ethyloxazolidine were added to a suspension of 0.33 g of sodium hydride in 10 ml of dimethoxyethane, and the mixture was stirred at room temperature for 2 hours. 2.4 g of 5-methylthiomethyl-2-chloropyrimidine dissolved in 10 ml of dimethoxyethane are then added. The mixture was stirred at room temperature for 2 hours and then heated to reflux for 3 hours. The precipitated inorganic salt is then filtered off, the filtrate is evaporated in vacuo and the residual oil contains 5-methylthiomethyl-2- (3 &apos; -isopropyl-2 &apos; -phenyloxazolidin-5 &apos; -yl) methoxypyrimidine.

The starting material can be prepared as follows. as follows:

b) To a solution of 14 g of 5-hydroxymethyluracil in 80 ml of lriflurric acid is added po; for 1 hour until saturation of methylmercaptan while maintaining the temperature at 25 °. The reaction mixture is then left to stand for 2 hours, the solvent is evaporated off under reduced pressure and the residue is crystallized from glacial acetic acid. It is obtained

5-methylthiomethylaracil in the form of colorless crystals of m.p. 239 DEG-241 DEG.

cj A suspension of 9.4 g of 5-methylthiomethyluracil in 100 ml of phosphorus pentachloride was heated to boiling under stirring for 2 hours, then the mixture was filtered while hot and the filtrate was 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 with sodium bicarbonate solution, dried over sodium sulphate and evaporated. There was thus obtained 5-methylthirmethyl-2,4 (6) -dichloropyrimidine as a yellow oil which could be used without further purification.

(d) 6,6 g of 5-methylthiomethyl-2,4 (6) -d'chloropyrimidine in 60 ml of 50% ethanol are heated with 15 g of zinc powder with stirring for 1 1/2 hour to boiling. Thereafter, the mixture is filtered while hot, the filter residue is washed with ethanol and the filtrate is preferably freed of ethanol completely by distillation under reduced pressure. The oil which separated from the aqueous solution was extracted with ethyl acetate, the extract was washed with water, dried over sodium sulfate and evaporated. The residual oil is chromatographed on 50 g of silica gel (60 Merek), eluting with benzene / ethyl acetate (1: 1). Fractions containing the desired product were combined. Distillation of the solvent gave 5-methylthiomethyl-2-chloropyrimidine. which gives crystals from petroleum ether having a melting point of 56-57 °.

Example 42

20.5 g of 5-ethyl-4- (6 '- (3'-isopropyl-2'-enenyxazolidin-5'-yl) methoxypyrimidine are dissolved in 75 ml of 1N hydrochloric acid and the solution is heated at reflux for 10 minutes. After cooling, the precipitated benzaldehyde is extracted with ether and 38 ml of 2N sodium hydroxide are added to the separated aqueous phase, the oil which forms as an oil is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulphate, filtered and evaporated. The oil obtained from cyclohexane is 5-ethyl-4 (6) - (3'-isopropyrimino-2'-hydroxypropoxy) pyrimidine as colorless crystals, m.p. 56-58 °. in isopropanol melts at 136-137 °.

The starting material is produced as follows:

(a) To a suspension of 1.5 g of sodium hydride in 20 ml of dimethoxyethane was added 13.9 g of 2-cynyl-3-isopropyl-5-hydroxymethyl-xxazolidine, and the mixture was stirred at room temperature for 2 hours. 9.0 g of 4-chloro (6) -chloropyrimidine dissolved in 50 ml of dimethoxyethane are then added at 0 °. The reaction mixture was then stirred at room temperature for 18 hours and then at 80 ° for 1 hour. The precipitated inorganic salt is filtered off, the filtrate was evaporated in vacuo, the residual oil contains alpha eththy 1-4 (6) - ^{(3'-isrprrpyl-2} - phenyloxazolidine-5'-yl) methoxypyrimidine.

The starting material can be produced as follows:

(b) To a suspension of 52 g of 5-ethyl 1-4 (6) -hydroxy-2-mercaptropyrimidine in 600 ml of water at 70-80 °, stirring portionwise over 1 hour, 140 g of Raney nickel are added and the mixture is heated for 4 hours. hours to reflux. The hot nickel formed is then filtered off, rinsed with hot water and the filtrate is evaporated completely under reduced pressure. The residual yellow oil crystallizes on cooling, filtering and washing the product with acetone. and the ether gives 5-ethyl-4-hydroxypyrimidine. Melting point 95-97 ° (after burning at 87-88 °).

c) To a mixture of 12.5 ml of N, N-diethylaniline and 50 ml of phosphorus oxychloride, 10 g of 5-ethyl-4 (6) -hydroxypyrimidine are added and the mixture is heated to 100-110 ° with stirring for 2 hours. The excess phosphorus oxychloride was then removed by distillation under reduced pressure and the residue was poured onto 100 g of ice. The product was extracted with ether, the ether extract was washed with water and sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residual oil, after distillation in vacuo, affords 5-ethyl-4-chloropyrimidine, boiling point 95-98 ° / 3.333 Pa as a colorless oil.

EXAMPLE 4 3 g of crude 2- (3'-tert-butyl-2'-phenyloxazolidin-5'-yl) methoxy-5-cyanopyridine are stirred with 100 ml of 2N hydrochloric acid for 3-4 hours at 20 ° C. to 30 °. The reaction mixture was washed with ether (100 ml), basified with concentrated sodium hydroxide solution and the oil extracted twice with ethyl acetate (100 ml). Washing with saturated aqueous sodium chloride solution, drying over magnesium sulfate and evaporation of ethyl acetate gave crude 2- [3'-tert-butylamino-2'-hydroxypropoxy) -5-cyanopyridine which melts at 132-134 ° after recrystallization from a small amount of ethyl acetate. . It forms a neutral fumarate with a melting point of 220-221 °.

The starting material can be produced as follows:

To a solution of 33.2 g of 3-tert-butyl-5-hydroxymethyl-2-phenyloxazolidine in 200 ml of 1,2-dimethoxymethane at 20-30 ° with stirring is added 4.5 g of a 55% sodium hydride dispersion and then the mixture Stir for 2 hours at 40 °. 13.0 g of 2-chloro-5-cyanopyridine are added to the obtained suspension, and the reaction mixture is then heated under reflux for 12-14 hours. The reaction mixture was evaporated and the residue was partitioned 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 to give crude 2- (3'-tert-butyl-2'-phenyloxazolidin-5'-yl) methoxy-5- cyanpyridine.

Example 44

In an analogous manner to that described in Example 10, 5-hydroxy-4 (6) - (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxypyrimidine is obtained from 5-hydroxy-4 (6) - (3'-Isopropylamino-2'-hydroxypropoxy] pyrimidine, the acid oxalate of which melts after recrystallization from methanol / acetone at 165-166 ° (dec.).

Example 45

In an analogous manner to that described in Example 2, starting from 2-chloropyrazine and 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine followed by hydrolysis of 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) methoxypyrazine. which was obtained as an intermediate, to afford 2- ^{(3-isopropylamino-2-hydroxypropoxy)} pyrazine fumarate which was recrystallized from isopropanol at 136-137 °.

Example 46

In an analogous manner to that described in Example 4, the following compounds were obtained:

a) 3-isopropyl-5-hydroxymethyl-2-phenyl-oxazolidine and 2-chloro-5- (2'-methoxykarbonylaminoethyl) -pyridine and subsequent hydrolysis of 2- ^{(3-isopropyl-2'-phenyl-oxazolidin-5'-yl)} meth oxy -5-methoxykarbonylaminoethylpyridinu obtained as intermediate, 2- (3'-isopropylamino-2'hydroxypropoxy) -5- ⁽² -methoxykarbonylaminoethyljpyridin after recrystallization from a small amount of butanone melts at 97-99 °.

b) From 2-chloro-5- (2'-n-butoxycarbonylaminoethyl) pyridine and 3-isopropyl-5-hydroxymethyl-2-phenyloxazolidine followed by hydrolysis of 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) ) methoxy-5- (2'-n-butoxycarbonylaminoethyl) pyridine, which was obtained as: an intermediate, gave 2- (3'-isopropylamino-2'-hydroxypropoxy) -5- (2'-n-butoxycarbonylaminoethyl) pyridine , which melts at 93-95 ° after recrystallization from butanone. The neutral fumarate melts at 145-147 °.

c) From 3-isopropyl-5-hydroxymethyl-2-phenyloxazolidine and 2,3-dichloro-5- (2'-methoxycarbonylaminoethyl) pyridine followed by hydrolysis of 2- (3'-isopropyl-2'-phenyloxazolidin-5'-yl) ) methoxy-3-chloro-5- (2'-methoxycarbonylaminoethyl) pyridine, which was obtained as an intermediate, gave 2- (3'-isopropylamino-2'-hydroxypropoxy) -3-chloro-

-5- (2 &apos; -methoxycarbonylaminoethyl) pyridine, which melts at 99-101 DEG after recrystallization from ether; the neutral fumarate melts after recrystallization from ethanol at 179-180 °.

d) From 3-isopropyl-5-hydroxymethyl-2-phenyloxazolidine and 2,3-dichloro-5- (2'-ethoxycarbonylaminoethyl) pyridine followed by hydrolysis as: an intermediate of the obtained 2- (3'-isopropyl-2'-phenyloxazolidine- 5'-yl) methoxy-3-chloro-5- (2'-ethoxycarbonylaminoethyl) pyridine gives 2- (3'-isopropylamino-2'-hydroxypropoxy) -3-chloro-5- (2'-ethoxycarbonylaminoethyl) pyridine which melts at 120 to 122 °; the neutral fumarate melts after recrystallization from ethanol-acetone at 149-151 °.

e) From 3-isopropyl-5-hydroxymethyl-2-phenyl-oxazolidine and 2-chloro-5-methoxycarbonylaminoethylpyridine, followed by hydrolysis, as an intermediate obtained: 2- (3'-

Isopropyl 1-2'-phenyloxazolidin-5'-yl) methose affords 2- (3'-isopropylamin-2'-hydroxypropoxy) -5-methoxycarbonylaminomethylpyridine which melts at 96-97 ° after recrystallization from ether. The neutral fumarate melts at 138-140 °.

f) From 3-isopropyl-5-hydroxymethyl-2-phenyloxazolidine and 2-chloro-5-n-butoxycarbonyl-amine-4-methyl-piperidine and subsequent hydrolysis as an intermediate of the obtained 2- (3'-bispropyl-2'-phenylcxazolidine). 5'-yl) methoxy-5-n-butoxycarbonylaminomethylpyridine affords 2- (3'-isopropylamino-2'-hydroxypropoxy] -5-n-butoxycarbonylaminomethylpyridine which melts at 85-87 ° after recrystallization from dichloromethane / ether. (south of 79 °).

Claims (18)

1. A process for the preparation of novel heterocyclyl-oxyhydroxyaminopropanes of the formula I, CH3 AND Het —O — CH2 —CH (OH) —CH2 — NH-C — R2 AND Rt (I) wherein is R 1 is hydrogen or methyl, R 2 is a lower alkyl group having 1 to 7 carbon atoms or optionally lower alkyl groups or lower alkoxy groups having 1 to 7 carbon atoms each, a trifluoromethyl group or a halogen-substituted phenyl (lower) alkyl group having 1 to 7 carbon atoms in the lower alkyl radical; Het a pyridyl radical of formula or N-oxides thereof, wherein: R3 represents halogen, cyano, nitro, lower alkyl of 1 to 7 carbon atoms, lower alkoxy of 1 to 7 carbon atoms, optionally halogen, trifluoromethyl, lower alkyl of 1 to 7 carbon atoms, lower alkenyl of 2 C 7-C 7 nižší, C,-C nižší nižší lower alkoxymethyl, C 1-C nižší nižší lower alkoxy or C 2-C nižší nižší lower alkenyloxy, phenyl substituted with C nižší-C alky lower alkylaminocarbamoyl, a lower alkoxycarbonylamino (lower) alkyl group having 1 to 7 carbon atoms in each case in the lower alkoxy and lower alkyl moieties, R a represents hydrogen, a lower alkyl group having 1 to 7 carbon atoms, a hydroxy (lower) asylum group having 1 to 7 carbon atoms, a lower alkylcarbamoyl group having 1 to 7 carbon atoms in the lower alkyl moiety or a lower alkoxycarbonylamino (lower) alkyl group; C1-C7 in each lower alkoxy and lower alkyl moiety; Het means a pyrazinyl group of the formula "О" where R3 represents hydrogen or a lower alkyl group having 1 to 7 carbon atoms, R4 is hydrogen, halogen, lower alkenyloxy having 2 to 7 carbon atoms, lower alkenyloxy having 1 to 7 carbon atoms in each lower alkoxy moiety, lower alkylthio having 1 to 7 carbon atoms, optionally halogen, trifluoromethyl; . a phenylthio or morpholino group substituted by a lower alkyl group or by a lower alkoxy group having from 1 to 7 carbon atoms in the lower radicals, or Het represents a pyrimidinyl group of the formula wherein R3 is hydrogen, lower alkyl of 1 to 7 carbon atoms, hydroxy, lower alkenylcarbonyl of 1 to 7 carbon atoms in lower alkoxy, lower alkenyloxy of 2 to 7 carbon atoms, lower alkylcarbonyl of 1 to 7 carbon atoms in the lower alkyl moiety, lower alkoxy (lower) alkyl groups of 1 to 7 carbon atoms in the lower alkoxy and lower alkyl moieties, or lower alkyl (lower alkyl) of 1 to 7 carbon atoms in each of the lower alkyl moieties, R 4 is hydrogen or di (lower) alkylamino having 1 to 7 carbon atoms in each of the lower alkyl moieties, or Het represents a pyridazinyl group of the formula wherein R 3 is hydrogen, halogen, C 1 -C 7 lower alkoxy or morpholino, and salts thereof, characterized in that a compound of formula (II) is hydrolyzed in which: R1, R'2, Het and the corresponding symbol R3 and Rd are as defined above, X is optionally lower alkyl of 1 to 7 carbon atoms or phenyl substituted methylene, further carbonyl or thiocarbonyl, or a salt of such a compound, whereupon the obtained compound of formula I or its salt is converted into a therapeutically useful acid addition salt or the resulting mixture of isomers is separated into pure isomers, or the racemate obtained is separated into optical antipodes, 2. The process according to item 1 for the preparation of the novel heterocyclyloxyhydroxyaminopropanes of the general formula I, [I] N-Het-O-CH2-CH (OH) -CH2-NH-C-R ₂₁ Ri in which it means R 1 is hydrogen or methyl, R2 is a lower alkyl group having 1 to 7 carbon atoms or optionally lower alkyl groups or lower alkoxy groups having 1 to 7 carbon atoms each, a trifluoromethyl group or a halogen substituted phenyl (lower) alkyl group having 1 to 7 carbon atoms in the lower alkyl radical; Het a pyridylated radical of the formula or N-oxides thereof, wherein: R3 is halogen, cyano, nitro, lower alkyl of 1 to 7 carbon atoms, lower alkoxy of 1 to 7 carbon atoms, optionally halogen, trifluoromethyl, lower alkyl of 1 to 7 carbon atoms, lower alkenyl of 2 to 7 carbon atoms, lower alkoxymethyl of 2 to 8 carbon atoms, lower alkoxy of 1 to 7 carbon atoms or lower alkenyloxy of 2 to 7 carbon atoms in the lower residues substituted phenyl, lower alkylaminocarbamoyl of 1 to 7 carbon atoms in the lower alkyl a lower alkoxycarbonylamino [lower] alkyl group having 1 to 7 carbon atoms in the lower alkoxy and lower alkyl moieties, Rd is hydrogen, lower alkyl of 1 to 7 carbon atoms, hydroxyf lower) alkyl of 1 to 7 carbon atoms, lower alkylcarbamoyl of 1 to 7 carbon atoms in the lower alkyl moiety or lower alkoxycarbonylamino (lower) alkyl group of 1 to 7 In each case lower carbon alkoxy and lower alkyl moieties, or Het represents a pyrazinyl group of the formula wherein R3 represents hydrogen or a lower alkyl group having 1 to 7 carbon atoms, R 4 is hydrogen, halogen, lower alkenyloxy (2 to 7 carbon atoms, lower alkoxy (lower) (C 1 -C 7) alkoxy in each lower alkoxy moiety, lower alkylthio (C 1 -C 7), or morpholino; * or Het represents a pyrimidinyl group of the formula wherein R3 is hydrogen, lower alkyl of 1 to 7 carbon atoms, hydroxy, lower alkenyloxy of 2 to 7 carbon atoms, lower alkoxy (lower) alkyl of 1 to 7 carbon atoms in the lower alkoxy and lower alkyl moieties, R a represents hydrogen or a di (lower) alkylamino group having 1 to 7 carbon atoms in each of the lower alkyl moieties, or ^: ??? Het represents a pyridazinyl group of the formula O ^r where R 3 represents hydrogen, halogen, a lower alkoxy group having 1 to 7 carbon atoms or a morpholino group, and salts thereof, characterized in that a compound of the formula ^: R 1, R 2, Het and the corresponding symbols R 5 and R 1 are as defined above, X is optionally lower alkyl of 1 to 7 carbon atoms or phenyl substituted methylene, further carbonyl or thiocarbonyl, or a salt of such a compound, whereupon the obtained compound of formula I or its salt is converted into a therapeutically useful acid addition salt or the resulting mixture of isomers is resolved into the pure isomers, or the resulting racemate is resolved into optical antipodes. 3. A process according to claim 1, wherein the hydrolysis is carried out in the presence of acidic agents. 4. A process according to claim 1, wherein the hydrolysis is carried out in the presence of basic agents. 5. The process of claim 1 wherein the hydrolysis is carried out in the presence of aqueous mineral acids. 6. The process according to claim 1, wherein the hydrolysis is carried out in the presence of alkali metal hydroxides. 7. A process according to claim 2 wherein the hydrolysis is carried out in the presence of acidic agents. 8. A process according to claim 2, wherein the hydrolysis is carried out in the presence of basic agents. 9. The process according to claim 2, wherein the hydrolysis is carried out in the presence of aqueous mineral acids. 10. A process according to claim 2, wherein the hydrolysis is carried out in the presence of alkali metal hydroxides. 11. The process of item 2 for the preparation of 2- [3'-isopropylamino-onhydroxypropoxy) -3-chloropyridine as well as its selers, characterized in that 2- (3'-isopropyl-2'-phenyloixazolidine-5) is used. 1-yl) methoxy-3-chloropyridine is hydrolyzed with a 4N hydrochloric acid solution and the compound obtained is optionally converted into a therapeutically useful acid addition salt. 12. The process of item 2 for the preparation of 2- (3'-isopropylamino-2'-hydroxypropoxy) -3-ethoxypyridine as well as its salts, characterized in that 2- (3'-isopropyl-2'-phenyloazolidine- The compound is hydrolyzed with a 4N hydrochloric acid solution and the compound obtained is optionally converted into a therapeutically useful acid addition salt. 13. A process according to claim 2 for the preparation of 2- (3'-tert-butylamino-2'-hydroxypropoay) -3-ethoaypyridide, and salts thereof, characterized in that 2- (3'-tert-butyl-2) is obtained. 1-Phenyl-oxazolidin-5-yl) methoxy-3-ethoxypyridine is hydrolyzed with 4N hydrochloric acid solution and the resulting compound is optionally converted into a therapeutically useful acid addition salt. 14. The process of item 2 for producing 1-tert-butylamino-3- (3-cyanopyridin-2-yloxy) -2-propanol, as well as its. a salt, characterized in that 3-tert-butyl-5- (3-cyanopyridine-2-nitro-1-yl) -2-phenyloxazole is hydrolyzed with a 2N hydrochloric acid solution and optionally converted to a therapeutically useful acid addition salt. 15. A process according to item 2 for the preparation of 2- (3'-isopropylamino-2'-hydroxypropoxy) pyrazine, as well as salts thereof, characterized in that 2- (3'-isopropyl-2'-phenyloazazolidine-5) is obtained. ^, yl) methoaypyrazlh hydrolysed with sulfuric acid and the compound obtained is optionally converted into a therapeutically useful acid addition salt. 16. The method according to claim 2 for the production of 2- (3'-isopropylamino-2'-j hydroayproρoxy pyrimidine and its salts, characterized in that the ss 2- ^{(3-isopropyl-2--fenyloxazolidin} 5'yljmethoxypyrimidin hydrolyzed with 1N sulfuric acid and the compound obtained is optionally converted into a therapeutically useful acid addition salt. 17. The method according to claim 2 for the production of 2- ^{(3'-isopropylamiho-2} -hydroaypropoxy] -5- (2'-1 j methoxykarbohylamlnQethy pyridine and its salts, characterized in that the 2- (3'- 1-Isopropyl-2'-phenyloazolidin-5'-yl] methoxy-5- (2'-methoayocarbonylaminomethyl) pyridine is hydrolyzed by treatment with 2N hydrochloric acid and the compound obtained is optionally converted into a therapeutically useful acid addition salt. amino; (ethyl) pyridine hydrolyzes by treatment 2N hydrochloric acid solution and the obtained compound are optionally converted into a therapeutically useful acid addition salt. 18. The process of item 2 for the preparation of 2- (3'-isopropylamino-2'-hydroxypropoxy) -3-chloro-5- [2'-ethoxycarbonylaminoethyl] pyridine, as well as the salts thereof, characterized in that 2 - (3'-Isopropyl-2'-phenyloxazolidin-5'-yl) methoxy-3-chloro-5- (2'-ethoxycarbonyl-