CS201042B2 - Method of producing etherified hydroxy-benzo-diheterocyclic compounds - Google Patents

Description

The invention relates to a process for the preparation of atherified hydroxybenzodiheterocyclic compounds of the general formula 1

OH

H in which

R ₁ represents a C 3 -C 5 alkyl radical which is optionally branched on the carbon atom to which this radical is attached, optionally further C 1 -C 3 alkoxy of up to 7 carbon atoms, or a C 3 -C 5 phenylalkyl radical substituted with a methylenedioxy radical in the alkyl moiety and alkyl

AND

R ₂ represents one of the groups -NH-, -O-CH ₂ -, -CH ₂ -O-, -N- with up to 7 carbon atoms, -CH ₂ -NH-, CO-NH-, -O- or -NH -CO-, or a salt thereof, in particular a pharmaceutically acceptable, non-toxic acid addition salt thereof.

The alkyl radical R 1 preferably contains 3 to 5 carbon atoms and is predominantly an isopropyl or tert-butyl radical, or also a sec-butyl or 2-methyl-2-butyl radical.

In particular, the substituted alkyl radical R1 is an optionally substituted phenylalkyl radical. Substituted phenyl contains lower alkoxy or methylenedioxy as substituents, these substituents being present one to three times and may be the same or different.

Thus, the substituted alkyl radical R 1, in particular in the phenyl radical optionally, for example as mentioned above, is substituted on the carbon atom to which this radical is attached optionally branched phenylalkyl radical, as in the phenyl radical optionally, for example as mentioned, substituted 1-phenyl- 2-propyl or 4-phenyl-2-butyl, in addition also 2-phenylethyl, wherein the substituted phenyl may be substituted by alkoxy or methylenedioxy.

An alkyl radical, unless specifically defined above for R, is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methyl-2 -butyl or neopentyl.

Alkoxy is, for example, methoxy, ethoxy, n-propyloxy, n-butyloxy or isobutyloxy.

Salts of the compounds of formula 1 are in particular acid addition salts, and in particular pharmaceutically usable, non-toxic acid addition salts, which are suitable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or suitable organic aliphatic, cycloaliphatic, aromatic, arallphatic or heterocyclic carboxylic acids 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, pyruvic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, phenylacetic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, 4-chlorobenzeneulide phonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylaminosulfonic acid.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, the free compounds and salts according to the meaning and expediently also include the corresponding salts or free compounds, if appropriate.

The novel compounds may exist in the form of racemates or in the form of antipodes.

The novel compounds have valuable pharmacological properties, in particular they have potent and long-lasting beta-receptor blocking effects which can be demonstrated by appropriate pharmacological experiments (see, for example, Meier et al., Arzneimittelforschung, Vol. 20, p. 1890 (1970)) . Thus, the novel compounds exhibit isoproterenol-induced tachycardia suppression on isolated guinea pig heart muscle (Langendorff) at a concentration ranging from about 0.001 µg / ml to about 1 µg / ml, and isoproterenol-induced tachycardia and vasodilation on anesthetized cat over a dose range of about 0.0003 mg / kg up to about 0.3 mg / kg when administered intravenously. The novel compounds can therefore be used as beta-raceptor blockers, for example in the treatment of cardiac rhythm disorders (arrhythmias) and coronary heart diseases such as Angina pectoris, as well as agents for lowering blood pressure in the treatment of hypertonia. In addition, these compounds still have cardiac stimulating activity which can be demonstrated in an isolated guinea pig atrium in the form of an increase in heart rate and myocardial counter-stroke in a concentration range of about 0.003 to about 3 µg / ml. This type of effect can be further demonstrated in anesthetized cat by increasing the heart rate and maximum rate of blood pressure increase (dP / dt) in the left ventricle over a dose range of about 0.0003 to about 0.3 mg / kg intravenously. Compounds with such cardiac stimulating activity therefore affect heart function less than substances that do not have these additional properties.

In addition, some of these compounds exhibit alpha-receptor blocking properties, which manifest themselves, for example, in an isolated congested mesenterial rat bed at concentrations ranging from about 0.03 to about 3 µg / ml by suppressing noradrenaline-induced vasoconstriction. For example, the blood pressure lowering effect may be favorably influenced by this component of action.

In particular, the invention relates to a process for the preparation of a compound of formula I in which R 1 represents a C 3 -C 4 alkyl group, or optionally 1 to 3 methoxy or methylenedioxy in the phenyl group substituted with a C 1 -C 3 phenylalkyl and alkyl group

R ₂ represents one of the groups -NH-, -O-CH ₂ -, -CH 2 -O-, -N- with up to 4 carbon atoms, -CH ₂ -NH-, -CO-NH-, -O- or - NH-CO-.

In particular, the invention relates to a process for the preparation of a compound of formula I wherein R 1 is isopropyl, tert-butyl, 1-phenylprop-2-yl, 2- (3,4-dimethoxyphenyl) ethyl or 2- (3,4-methylenedioxyphenyl) ethyl and R ₂ represents one of the groups -NH-, _-O-CH2 -, _-CH2-O-, CH 3 CH ₂ -CH ₂ -CH ₂ -CH-)

-N-, -N-CH ₂ -NH-, -CO-NH-, -0- or -NH-CO-.

In particular, the invention relates to processes described in the Examples for the preparation of the compounds of formula I therein.

The novel compounds of the formula (I) are prepared in a manner known per se by reacting them in a compound of the formula (II)

Xl OH

I I cm

R- | -N - CH ₂ -CH ₂ -O-CH

H in which

X 1 represents in the phenyl moiety optionally lower alkyl or lower alkoxy of up to 7 carbon atoms, hydroxy, halogen or nitro substituted phenyl (lower) alkyl of up to 7 carbon atoms in the alkyl moiety, and

R 1 and R ₂ have the above meanings, hydrogenolyses the residue X by treatment with hydrogen in the presence of a nickel or noble metal catalyst, whereupon the optionally obtained free compound of formula I is converted into a salt or the obtained salt is converted into a free compound and / or the racemate is optionally separated into antipodes.

The starting materials usable in the form of salts are, in particular, starting materials in the form of acid addition salts, in particular the corresponding salts with inorganic acids, for example mineral acids, as well as with organic acids.

The above reactions are carried out in a manner known per se, usually in the presence of a solvent or solvent mixture and, if necessary, with cooling or heating, for example in a temperature range of about -20 to about +150 ° C in an open or closed vessel; and in an atmosphere of an inert gas such as nitrogen.

The starting materials of the formula II can be prepared in a manner known per se, for example by reacting a compound of the formula III (III)

Ν '

Němž in which

Rg is as defined above, with a compound of formula IV R _R X (IV) wherein

R1 is as defined above and

X ® is hydrogen, or together with X 1 is a direct bond and one of X 1 and X 2 is a reactive esterified hydroxy group, and the other is -NH (X 1), wherein X 1 is as defined above, or X 8 and X 3 form together bond and

X 4 is -NH (Xj).

The reactions are carried out in a manner known per se.

The starting materials of the formula III in which X 8 and X 3 represent a direct bond can be prepared in a manner known per se and optionally in situ. Thus, the starting materials can be advantageously obtained by, for example, converting a phenolic group into an allyloxy group in 2,3-dinltrophenol, as a reaction with an allyl halide, for example allyl bromide, in the presence of a base such as potassium carbonate, followed by reaction of the intermediate with hydrogen peroxide. in the presence of potassium bicarbonate, or by reaction with a suitable inorganic or organic percarboxylic acid, for example 3-chloroperbenzoic acid, converts this group to 2,3-epoxypropyloxy and is converted, for example, by reaction of intermediate 8 and the formula of the formula

R.-NH, (IIIa) is converted to 3- (R 1 -amino) -2-hydroxypropyloxyacin. Then, both nitro groups in the 3- (3- (R) -amino) -2-hydroxypropyloxy) -1,2-dinitrobenzene thus obtained are reduced to amino groups, for example by treatment with catalytically activated hydrogen. By reaction with a suitable reactive carbonic acid derivative, for example with an appropriate ester, such as di (lower) alkyl carbonate, for example dimethyl or diethyl carbonate, or with a mixed anhydride, such as carbonic acid dihalide, for example phosgene or amide, for example urea or with N, N'-carbonyl diimidazole, a preferred starting material is obtained, which is preferably formed only in situ and is directly converted to the compound of formula I.

Depending on the process conditions and the starting materials used, the novel compounds are obtained in free form or in the form of their salts, which are also included within the scope of the invention, wherein the novel compounds or their salts may also be present as hemihydrates, monohydrates, sesquihydrates or polyhydrates . Salts of the novel compounds can be converted into the free compounds in a manner known per se. Thus, acid addition salts can be converted to the free compounds, for example by treatment with basic agents such as alkali metal hydroxides, carbonates or acid alkali metal carbonates or by ion exchange, and optionally metal salts such as alkali metal salts obtained according to the invention, for example agents, such as mineral acids, to the free compounds. On the other hand, in

The free compounds obtained can be converted into acid addition salts by known methods, for example by reaction with organic or inorganic acids, such as the abovementioned acids, in particular those suitable for the production of pharmaceutically usable salts.

These or other salts, in particular the acid addition salts of these novel compounds, such as picrates or perchlorates, can also be used to purify the free bases obtained, by converting the free compounds into salts, separating and purifying the salts and from the salts. again form the free compounds.

Depending on the choice of starting materials and processes, the novel compounds can be present as optical antipodes or racemates.

The racemates obtained can be decomposed into antipodes by known methods, for example by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active compound which forms a salt with the racemic compound, in particular the corresponding acid, and by different solubilities, to diastereomeric salts from which free antipodes can be released by treatment with suitable agents. Particularly useful as 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.

The invention also relates to those embodiments of the process in which the reactants are optionally used in the form of salts.

Suitably, for the reactions according to the invention, such starting materials are used which lead to the groups of fines mentioned in particular in the introductory part of the description and in particular to the specially described or emphasized fines.

The novel compounds can be used in the form of pharmaceutical preparations containing a pharmacologically effective amount of the active ingredient, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for enteral, for example oral or parenteral administration. Thus, tablets or gelatin capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose or / and glycine, and / or lubricants such as silica gel, talc, stearic acid or its salts such as magnesium or calcium salt of stearic acid, and / or polyethylene glycol. The tablets may also contain binding agents, for example magnesium aluminum silicate, starches such as corn starch, wheat starch rice starch or marzipan starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and optionally together with tablet disintegrating agents such as starches. , agar, alginic acid, or a salt thereof, such as sodium alginate and / or mixtures of effervescent agents, or adsorbents, colorants, flavorings, and sweeteners.

Furthermore, the new pharmacologically active compounds can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, which, as in the case of lyophilized preparations which contain the active ingredient alone or together with a carrier, for example mannitol, may be prepared before use. The pharmaceutical preparations may be sterilized and / or contain excipients such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical compositions which, if desired, may contain other pharmacologically active substances are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain from about 0.1% to 100%, in particular from about 0.1% to 100%. about 1% to about 50%, lyophilizates up to 100% of active ingredient.

The dose may be dependent on various factors such as the mode of administration, the species, the age and / or the individual condition. Daily dosages for oral administration are between about 1 mg and about 15 mg for a warm-blooded weight of about 70 kg.

The following examples serve to illustrate the invention; temperatures are given in degrees Celsius.

He did

A solution of 10.9 g of 5- (3- (N-benzyl-tert-butylamino) -2-hydroxypropoxy) -3,4-dihydro-1H-quinazolin-2-one in 220 ml of dimethylformamide was added with 1 g of palladium on carbon as a catalyst, it hydrogenates under normal conditions until the hydrogen uptake is complete. Filtration and evaporation of the filtrate gave crude 5- (3-tert-butylamino-2-hydroxypropyloxy) -3,4-dihydro-1H-quinazolin-2-one crystals, m.p. 204-205 ° C. After introducing 1 equivalent of hydrogen chloride into a solution of the compound in a mixture of 150 ml of isopropanol and 50 ml of methanol, the hydrochloride of melting point 274 DEG-275 DEG C. is obtained.

The starting material can be prepared as follows:

(a) A solution of 336 g of 1,3-dinitrobenzene and 174 g of allyl alcohol in 2 000 ml of dioxane is heated to 40 ° C and a solution of 196 g of potassium cyanide in 400 ml of water is added over about 10 minutes. The temperature rises to about 60 ° C. The reaction mixture was stirred at 80 ° C for 2 hours, then cooled to 10 ° C, filtered through diatomaceous earth and the filtrate was evaporated. The residue was dissolved in 2 L of ethyl acetate and the solution was washed 5 times with 1 L of water each time. The dark organic phase is clarified with activated carbon and silica gel. Evaporation of the solvent left a dark red, partially crystalline residue which crystallized from isopropanol to give 2-allyloxy-6-nitrobenzonitrile, m.p. 102-104 ° C. Further amounts of the same compound were obtained by chromatography on 2 kg of silica gel and eluting with toluene (fractions 17-35 per liter of toluene).

b) To a solution of 26.8 g of m-chloroperbenzoic acid (85%) in 1 liter of chloroform is added

22.5 g of 2-allyloxy-6-nitrobenzonitrile and the mixture was heated to 50 ° C over 3 hours. The reaction mixture is kept at this temperature for 24 hours, then cooled and the solution is washed with 100 ml of 1 M sodium sulfite solution each, then with 2 N hydroxide solution and finally with water. After drying over magnesium sulphate and evaporating the solution, a colorless crystalline residue is obtained, which is triturated with 20 ml of isopropanol, filtered off and dried in vacuo to give crude 2- (2,3-epoxypropoxy) -6-nitrobenzonitrile, m.p. 131-135 ° C, which is further used as a crude product.

o) A suspension of 23.4 g of 2- (2,3-epoxypropoxy) -6-nitrobenzonitrile and 34.6 g of N-benzyl-tert-butylamine in 550 ml of isopropanol is heated to reflux until the solution is formed. is heated under reflux for a further 8 to 10 hours. On cooling, 1- (N-benzyl-tert-butylamino) -3- (2-cyano-3-nitrophenoxy) -2-propanol crystallizes, m.p. 102 DEG-122 DEG C .; concentration of the filtrate yielded an additional amount of this compound.

d) In a flask equipped with a stirrer, reflux condenser and dropping funnel, 28.0 g of 1- (N-benzyl-tert-butylamino) -3- (2-cyano-3-nitrophenoxy) -2-propanol are heated to boiling in 350 ml. ethanol. After the addition of about 0.5 ml of Raney nickel suspension, a solution of 18.2 g of hydrazine hydrate in 20 ml of ethanol is added dropwise during the boiling so as to give rise to a strong gas leakage. The reaction mixture was then cooled, filtered through diatomaceous earth, and the filtrate was evaporated. The residual oil is crude 5- [2-hydroxy-3- (N-benzyl-tert-butylamino) propoxy] -anthranilamide and is processed further without further purification.

e) A solution of 27 g of 6- [2-hydroxy-3- (N-benzyl-tert-butylamino) propoxy] anthranilamide in 400 ml of tetrahydrofuran is added dropwise to a suspension of 8.3 g of lithium aluminum hydrides in 100 ml of tetrahydrofuran. An additional 8.0 g of lithium aluminum hydride was added to the mixture under stirring at reflux temperature, and the mixture was again heated to reflux for 60 to 65 hours. Under ice-cooling, excess lithium aluminum hydride is decomposed by addition of 17 ml of concentrated sodium hydroxide and 40 ml of water. The precipitate was filtered off, washed with 50 ml of tetrahydrofuran and the combined filtrates were evaporated. Crude 2-aminomethyl-3- [2-hydroxy-3- (N-benzyl-tert-butylamino) propoxy] aniline is obtained as an oil which, by dissolving in methanol and introducing hydrogen chloride until acidic, affords the hydrochloride, m.p. mp 265 ° C.

f) 5.3 g of methyl chloroformate were added dropwise to a solution of 16.2 g of 2-aminomethyl-3- [2-hydroxy-3- (N-benzyl-tert. butylamino) propoxy] aniline in a mixture of 150 ml of isopropanol and water each. The reaction mixture was stirred at room temperature for 2 hours and then evaporated. The residue is dissolved in 100 ml of water and the solution is extracted with 50 ml of ether, the aqueous phase is basified with concentrated ammonia and extracted 3 times with 200 ml of ethyl acetate each time. The residue obtained after evaporation of the organic phase is dissolved in 50 ml of methanol and the solution is refluxed with 4.86 g of sodium methoxide for 3 hours. The slowly crystalline precipitate formed is filtered off after cooling the reaction mixture on an ice bath to give 5- [3- (N-benzyl-tert-butylamino) -2-hydroxypropoxy] -3,4-dihydro-1H-quinazoline-2- m.p. 215-217 ° C.

Example 2

A solution of 7.0 g of 5- [3- (N-benzyl-tert-butylamino) -2-hydroxypropoxy] - (1H) (3H) -quinazoline-2,4-dione in 200 ml of 2-methoxyethanol is added after addition of 1 g The palladium on carbon catalyst (5%) hydrogenates under normal conditions until the calculated amount of hydrogen is consumed. Filtration and evaporation of the solvent left a crystalline residue which was stirred with 10 ml of isopropanol and then filtered to give 5- (tert-butylamino-2-hydroxypropoxy) - (1H) (3H) -quinazoline-2,4 mp 271-275 ° C. The hydrochloride melts at 298-305 ° C (dec.).

The starting material can be produced as follows:

(a) 16 g of crude 6- [3- (N-benzyl-tert-butylamino) -2-hydroxypropoxy] anthranilamide obtained by the procedure of Example 1d) are dissolved in 45 ml of glacial acetic acid and a solution of 7 is added. 45 g of potassium cyanate in 23 ml of water. As a result of the exothermic reaction, the internal temperature of the reaction mixture is increased to 41 ° C. The solution was stirred at room temperature for 4 hours, then poured into 200 ml of water and basified with 2N sodium carbonate solution. The precipitated crystals of 2- [3- (N-benzyl-t-butylamino) -2-hydroxypropoxy] -6-ureidobenzamide are filtered off and recrystallized from a small amount of isopropanol, m.p. (158 ° C), 163-167 ° C.

b) To a solution of 0.65 g of sodium in 100 ml of absolute ethanol was added 9.7 g of 2- [3- (N-benzyl-tert-butylamino) -2-hydroxypropoxy] -6-ureidobenzamide and the suspension was heated under stirring under with a reflux condenser until no more ammonia cleavage can be observed (after about 5 to 6 hours). The suspension is cooled, the crystals are filtered off and then washed with 20 ml of ethanol and then with water. After drying under vacuum at 90 ° C for 14 hours, the thus obtained 5- [3- (N-benzyl-tert-butylamino) -2-hydroxypropoxy] - (1 R) (3 H) -quinazoline-2,4-dione melts. at 190-192 ° C.

Example 3

3.7 g of 7- [3- (N-benzyl-tert-butylamino) -2-hydroxypropoxy] -2- (3H) -benzoxazolone are hydrogenated in 70 ml of methanol with the addition of 0.4 g of palladium on carbon catalyst as normal. conditions until the end of hydrogen consumption. After filtering off the catalyst, the filtrate was neutralized with a 5 N solution of hydrogen chloride in ethanol, evaporated and the residual oil was crystallized in acetone. 7- (3-tert-butylamino-2-hydroxypropoxy) -2 (3H) -benzoxazolone hydrochloride is obtained, which melts at 221-224 ° C after recrystallization from methanol-acetone.

The starting material ae can be produced as follows:

(a) To a solution of 140 g of o-allyloxyphenylacetate and 100 ml of acetyl chloride in 300 ml of freshly distilled tetrachloroethane is added, under stirring and cooling, in an ice-salt bath at -5 to -15 ° C in portions of 125 g of finely sprayed dried silver nitrate. The temperature of the reaction mixture is allowed to rise slowly to 20 ° C over 3 hours, then the mixture is filtered, the filtrate is washed with a saturated solution of urea in water and evaporated. A pale brown, oily residue is obtained which is chromatographed over 800 g of silica gel using toluene in 250 ml fractions. Fractions 1 to 4 are set aside. A boiling component of 2-allyloxy-3-nitroacetic acid phenyl ester is isolated from fractions 5 and 6 and from 7 to 11 at 25 to 135 ° C / 13.3 Pa.

(b) 31.0 g of the compound obtained in (a) are dissolved in 200 ml of ethanol, 40 ml of a 10N solution of hydrogen chloride in ethanol are added and the mixture is refluxed for 2 hours. Evaporation of the solution, washing with water and distillation at 8 Pa gives 2-allyloxy-3-nitrophenol, which boils at 90 to 103 ° C / 8 Pa.

c) 10.0 g of 2-allyloxy-3-nitrophenol, 27 g of potassium carbonate and 54 ml of epichlorohydrin are stirred in 300 ml of acetone for 5 to 20 hours under reflux. After filtration of the reaction mixture and evaporation of the filtrate, crude 2-allyloxy-1- (2,3-epoxypropoxy) -3-nitrobenzene is obtained which can be further used as such.

d) 14 g of crude 2-yllyloxy-1- (2,3-epoxypropoxy) -3-nitrobenzene and 11.0 g of N-benzyl-tert-butylamine were refluxed in 70 ml of isopropanol for 7 hours. After neutralization with concentrated hydrochloric acid, 1- (2-allyloxy-3-nicotrophenoxy) -3- (N-benzyl-tert-butylamino) -2-propanol crystallizes as the hydrochloride which melts at 206 to 209 after recrystallization from methanol / isopropanol. ° C with gas evolution. The base is an oil.

e) A solution of 19.4 g of 1- (2-allyloxy-3-nitrophenoxy) -3- (N-benzyl-tert-butylamino) -2-propanol in a mixture of 350 ml of ethanol, 35 ml of water and 5 ml of triethylamine was added with 1 g of rhodium tris- (triphenylphosphine) chloride was stirred under reflux for 45 minutes. Filtration and evaporation gave crude 1- (N-benzyl-tert-butylamino) -3- (2-hydroxy-3-nitrophenoxy) -2-propanol as a dark red oil, which was used for the next reaction without further purification.

f) A solution of 16.1 g of crude 1- (N-benzyl-tert-butylamino) -3- (2-hydroxy-3-nitrophenoxy) -2-propanol in 150 ml of ethanol is reduced analogously to Example 1d) by 15 min. ml of hydrazine hydrate and Raney nickel to give 1- (N-benzyl-tert-butylamino) -3- (3-amino-2-hydroxyphenoxy) -2-propanol. The base forms a dark oil which is used for the next reaction without further purification. It crystallizes from ether in greenish crystals, m.p. 05-110 ° C.

(g) 14.5 g of 1- (N-benzyl-tert-butylemino) -3- (3-amino-2-hydroxyphenoxy) -2-propanol are dissolved in 140 ml of a 1: 1 mixture of isopropanol and water at a temperature of The mixture was stirred at room temperature for 5 to 20 ° C with vigorous stirring, 5.0 ml of methyl chloroformate was continued for 1.5 hours at room temperature, the reaction mixture was evaporated and the residue was dissolved in 50 ml of water. After extraction with 20 ml of ethyl acetate, the acidic aqueous phase is made alkaline with concentrated sodium hydroxide and extracted 3 times with 100 ml of methylene chloride each time. Evaporation of the organic phase yields a crude base from which crystallized 1- (N-benzyl-tert-butylamino) -3- (2-hydroxy-3-methoxycarbonylaminophenoxy) -2-propanol is isolated, m.p. 130-133 ° C.

(h) 6.4 g of 1- (N-benzyl-tert-butylamino) -3- (to the ice-cooled suspension of 1.0 g of a 50% dispersion of sodium hydride in 1,2 dimethoxyethane at 10 to 15 ° C are added in portions Of 2-hydroxy-3-methoxycarbonylaminophenoxy) -2-propanol and the mixture was heated under reflux for 1 hour. The reaction mixture was evaporated and the residue partitioned between glacial acetic acid (1.5 ml), water (10 ml) and ethyl acetate (100 ml). The aqueous phase is extracted again with 100 ml of ethyl acetate. The combined ethyl acetate extracts yielded after evaporation a crude base which was purified over neutral fumarate, m.p. 202-206 ° C.

Example 4

A solution of 3.22 g of 5- (3-benzylisopropylamino-2-hydroxypropoxy) -1,2,3,4-tetrahydro-2,3-dioxoquinoxazoline hydrochloride hemihydrate in 60 ml of water is added with 2.0 g of palladium on carbon as a catalyst (5%) hydrogenated at room temperature at 50 psi. After about 5 hours, the calculated amount of hydrogen is consumed. The reaction mixture was separated from the catalyst by filtration and the filtrate was completely evaporated in a water pump vacuum to give 5- (3-isopropylamino-2-hydroxypropoxy) -1,2,3,4-tetrahydro-2,3-dioxoquinoxazoline hydrochloride. mp 290-294 ° C (dec.).

Recrystallization from methanol / ether gave a melting point of 293-295 ° C (dec.).

The starting material can be prepared as follows:

(a) A solution of 5.3 g of 4- (2,3-epoxypropoxy) benz-2,1,3-thiadiazole and 3 δ g of N-benzylisopropylamine in 100 ml of isopropanol is refluxed for 4 hours. The reaction mixture was evaporated in a water-jet vacuum, the residue was dissolved in ether and taken up in 2N hydrochloric acid. The combined extracts in hydrochloric acid were basified with concentrated ammonia and extracted with ether. The combined ether extracts were washed with water, dried over sodium sulfate and evaporated in a water pump vacuum to give 4- (3-benzylisopropylamino-2-hydroxypropoxy) benz-2,1,3-thiadiazole as a yellow oil.

b) To a solution of 8.7 g of 4- (3-benzylisopropylamino-2-hydroxypropoxy) benz-2,1,3-thiadiazole in 110 ml of glacial acetic acid, 12.8 g of zinc powder are added in 3 portions at room temperature. . After stirring at room temperature for about 3 hours, the reaction mixture was separated by filtration from excess zinc powder and completely evaporated in a water pump vacuum. The residue was mixed with 5½ sodium hydroxide and extracted with methylene chloride. The combined methylene chloride extracts were washed with water, dried over sodium sulphate and evaporated in a water pump vacuum to give 3- (3-benzylisopropylamino-2-hydroxypropoxy) -1,2-phenylenediamine, m.p. 60-63 ° C.

c) 8 g of 3- (3-benzylisopropylamino-2-hydroxypropoxy) -1,2-phenylenediamine are stirred with 40 ml of oxalic acid dimethyl ester for 15 hours at 00 ° C. The precipitated crystals were filtered off and washed with ether. The obtained crystals were dissolved in 50 ml of methanol and stirred with 5 ml of 2 N sodium hydroxide for 2 hours at 60 ° C. The resulting suspension was acidified with 2N hydrochloric acid and the methanol was evaporated in vacuo, the clear hydrochloric acid solution was neutralized with sodium bicarbonate solution and the precipitated crystals were filtered off. The crystalline product is 5- (3-benzylisopropylamino-2-hydroxypropoxy) -2,3,4-tetrahydro-2,3-dioxoquinoxazoline, m.p. 263 DEG-267 DEG C. (decomposition). The hydrochloride produced using methanolic hydrogen chloride crystallizes from a mixture of water and acetone as a hemihydrate, m.p. 250 DEG-252 DEG C. (decomposition).

Example 5

The following compounds were prepared using analogous procedures to those described in Examples 1 to 4 using the corresponding starting materials:

(a) 4- (3-tert-butylamino-2-hydroxypropyloxy) benzimidazol-2-one in the form of its hydrochloride, m.p. 250 DEG-260 DEG C. (gradual decomposition);

b) 8- (3-tert-butylamino-2-hydroxypropyloxy) -2,3-dihydro- (4H) -benz [5,6] oxazin-3-one in the form of the hydrochloride, m.p. 82-183 ° C;

c) 7- (3-tert-butylamino-2-hydroxypropyloxy) -4H-1,3-benzoxazin-2 (1H) -one in the form of the hydrochloride, m.p. 243-244 ° C;

d) 4- (3-tert-butylamino-2-hydroxypropyloxy) -3-n-butylbenzimidazol-2-one in the form of the hydrochloride, m.p. 226-227 ° C;

e) 4- (3-isopropylamino-2-hydroxypropyloxy) benzimidazol-2-one in the form of hydrochloride, m.p. 231-232 ° C;

f) 4- (3-tert-butylamino-2-hydroxypropyloxy (-3-methylbenzimidazol-2-one) in the form of the hydrochloride, m.p. 246 DEG-243 DEG C. (dec.);

g) 4- [3- (1-phenylpropyl-2-amino) -2-hydroxypropyloxy] -benzimidazol-2-one in the form of a fumarate (1: 1), m.p. 186-188 ° C;

h) 4- [3- (2- (3,4-dimethoxyphenyl) ethylamino) -2-hydroxypropyloxy] benzimidazol-2-one in the form of hydrochloride, m.p. 230-232 ° C;

i) 4- [3- (2- (3,4-methylenedioxyphenyl) ethylamino) -2-hydroxypropyloxy] benzimidazol-2-one in the form of hydrochloride, m.p. 249-251 ° C; the compound turned south at 243 ° C.

Claims (8)

SUBJECT OF THE INVENTION A process for the preparation of etherified hydroxybenzodiheteroeyl compounds of the general formula I wherein: R @ 1 represents a C3 -C5 alkyl group optionally branched at the carbon atom to which it is bound, optionally C1 -C7 alkoxy or C3 -C5 phenylalkyl substituted by a methylenedioxy group; alkyl moieties, and alkyl Rg is one of the groups -NH-, -O-CHg-, -CH ₂ -0-, -N-, with up to 7 carbon atoms-CH₂-NH-, -CO-NH-, -0- or -NH-CO or a salt thereof, characterized in that the compound of formula (II) in which: X ₁ represents a phenylalkyl group having up to 7 carbon atoms in the alkyl moiety, which group in the phenyl moiety is optionally substituted by a lower alkyl group or a lower alkoxy group each having up to 7 carbon atoms, a hydroxy group, a halogen or a nitro group, Rj and Rg have the meanings given above, hydrogenolyzes the residue Xj by treatment with hydrogen in the presence of a nickel catalyst or a noble metal catalyser, whereupon the optionally obtained free compound of formula 1 is converted into a salt or the obtained salt is converted into a free compound and / splits into antipodes. 2. The process according to claim 1, wherein the starting material is used in the form of a salt. Process according to one of Claims 1 to 2, characterized in that the hydrogenolysis is carried out in the presence of palladium on carbon catalyst. 4. A process according to any one of claims 1 to 3, wherein the starting material is a compound of formula (II) wherein X is benzyl and Hj and Rg are as defined above. Process according to one of Claims 1 to 4, characterized in that a compound of the general formula II is used as starting material in which R 1 represents an alkyl group having 3 to 4 carbon atoms or in the phenyl moiety optionally 1 to 3 methoxy or methylenedioxy substituted phenylalkyl having 1 to 3 carbon atoms in the alkyl portion of alkyl and Rg represents one of the groups -NH-, -O-CHg-, -CHg-Ο-, -N- with up to 4 carbon atoms, -CHg-NH-CO -NH-, -O- or -NH-CO-, and X is as defined above. Process according to one of Claims 1 to 4, characterized in that the compounds of the general formula II in which R 1 is an isopropyl group, a tert-butyl group, a 1-phenyl-2-propyl group, - (3,4-dimethoxyphenyl) ethyl or 2- (3,4-methylenedioxyphenyl) ethyl and R8 is one of -NH-, CH ₃ CH-CH₂-CH₂-CH -O-CHg-, -CHg-Ο-, -N-, -N-, -CHg-ΝΗ-, -CO-HH-, -O- or -NH-CO- and X is as defined above. Process according to one of Claims 1 to 4, characterized in that 4- (3-N-benzyl-tert-butylamino) -2-hydroxypropyloxybenzimidazol-2-one is used as starting material. 8. A process according to any one of claims 1 to 7, wherein the compound of formula I is converted to a pharmaceutically acceptable non-toxic acid addition salt.