CS199575B2 - Method of preparing l-1-/4'-hydroxyphenoxy/-2-hydroxy-3-isopropyl aminopropane - Google Patents

Description

The present invention relates to a process for the preparation of the novel L-1- (4‘-hydroxyphenoxy) -2-hydroxy-3-isopropylamino-propane of the formula I

(O)

The Fischer projection of the compound of formula I is:

BOY

I (L) and corresponds to the S-form in Cahn-Ingold-Prelog's Jiomenklatura:

The novel compound has valuable pharmacology properties, in particular an effect on adrenergic (3-receptors), thus specifically stimulating cardiac (S-receptors), in particular positively inotropically and chronotropically to an isolated guinea pig chamber at a concentration of 0.005 to 0.5 µg / ml and As indicated by experiments on anesthetized cats, the novel compound does not act at the indicated doses, which are clearly positive inotropic and chronotropically effective, at all or only a minimal decrease in arterial blood pressure, which stimulates them. specifically cardiac β-receptors compared to β-receptors in blood vessels, and thus distinguishes it qualitatively from isoprotcrenol, which equally strongly stimulates β-ireceptors of the heart and blood vessels. Since pressure drop leads to tachycardia, it can be assumed that when used in humans at doses that are equally potent. causing a positive inotropic effect, the

CH-0

I. · »

TCHyc-CH-NH-Cu-OH (S) tachycardia than isoproterenol.

It is also particularly advantageous that the novel compound is substantially longer active in narcotized cats than isoproterenol and further that a clear effect is also obtained after an intraduodenal application of 0.05 mg / kg.

Thus, the novel compound can be used as a positively inotropically active agent, particularly for the treatment of cardiac muscle disorders, either alone or in combination with other preparations such as cardiac glycosides. Administration can be carried out in the form of suitable fairmacological preparations in an oral dose of 1 to 25 mg per dose or intravenously in an amount of 1 to 20 µg / kg per dose or infusion, in an amount of 0.2 to 2.0 (Ug / ml). kg / minute.

L-1- (4‘-Hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane according to the present invention is prepared in a known manner by reducing the Schiff base of formula II with hydrogen in the presence of palladium on carbon catalyst.

OP

A rs;

3A (ID or Formula III

OH and _HO _ / "yo-C« _{x f} CH-N = C (CH) »(l) 'or formula III to the corresponding cyclic tautomer of formula IV

HIM

NH

O-CHrCH -CH,

AND

ÍSJ

CPj CP ₃ (IV) wherein the compounds of formulas III and IV may also be present side by side. This reduction is carried out in a conventional manner, for example with hydrogen in the presence of a hydrogenation catalyst, a noble metal catalyst, for example palladium on carbon (5%).

Depending on the reaction conditions and the starting materials, the end product is obtained either in free form or in acid salt form, which are also within the scope of the invention. Thus, for example, basic, neutral or mixed salts can be obtained as well as their gaming, raonQ, sesqui- or polyhydrates. The acid salts of the novel compound can be converted into the free compound in a known manner, for example, with basic agents such as alkali or ion exchangers. On the other hand, the free base obtained can form salts with inorganic or organic acids. In particular, those acids which are suitable for the formation of therapeutically useful salts may be used to prepare acid salts. Such acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, fumaric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic acid, acetic acid, propionic acid, acid succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid or pyruvic acid, benzoic acid, anthranilic acid, p-hydroxybenzoic acid, sulfuric acid or emonic acid, methanesulfonic acid, ethanesulfonic acid , hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid or sulfanilic acid.

These and other salts of the novel compound, such as picrate, can also be used to purify the free base by converting the free base into a salt, separating it and liberating the base again from the salt. Due to the close relationship between the new compound in free form and in the form of its salts, in the above and the following description, the free compound is analogously understood to mean corresponding salts, if appropriate.

The invention also relates to those embodiments of the process starting from reactants which are optionally in the form of a salt.

1- (4'-Hydroxyphenoxy) -2S-hydroxy-3-aminopropane can be prepared by the following sequence of reactions: 5,6-anhydro-1,2-O-isopropylidene-α-D-glucofuranose is reacted with hydroquinone monobenzyl ether to 1, 2-O-isopropylidene-6-O- (4-benzyloxyphenyl) -α-D-glucofuranose, from which 6-O- (4-benzyloxyphenyl) -D-glucose is prepared by acid hydrolysis, which is oxidized with sodium periodate and then reduced to yield the product Converts conventionally to 1- (4-benzyloxyphenoxy) -2S, 3-dihydroxypropane. 2-Ethoxy-2-methyl-4- (4-benzyloxyphenoxymethyl) -dioxolane is obtained from this compound by treatment with triethyl orthoacetic acid ester, which is treated with trimethylchlorosilane to give 1- (4-benzoyloxyphenoxy) -2R-acetoxy-1- chloropropane, which is converted to 1- (4-benzyloxyphenoxy) -2S, 3-epoxypropane and hydrogenolysis, for example hydrogen in the presence of palladium on carbon (5%) in an alkaline medium, by treatment with a base such as trimethylammonium bromide (1%) to 1 (4-hydroxyphenoxy) -2S, 3-epoxypropane, from which 1- (4-hydroxyphenoxy) -2S-hydroxy-3-araonopropane is obtained by reaction with ammonia.

. The novel compound can be used as a medicament, for example in the form of pharmaceutical preparations which contain the new compound or the corresponding salt in admixture with, for example, solid or liquid pharmaceutically acceptable organic carriers for enteral, for example oral or parenteral administration. Suitable materials for the formation thereof are those which do not react with the novel compound, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, polyalkylene glycol, vaseline, cholesterol or other known carriers. Suitable pharmaceutical preparations are, for example, tablets, dragees, capsules, suppositories, ointments, creams or liquid forms, such as solutions (for example infusion or syrup), suspensions or emulsions, optionally sterilized or containing auxiliaries such as preservatives, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers, as well as other therapeutically useful substances The preparations which are also useful in veterinary medicine are prepared in a conventional manner The daily dose in warm-blooded animals weighing about 75 kg is about 10 up to 100 mg per os, preferably about 20 to 40 mg per os.

The following example illustrates the invention in more detail without restricting it in any way. Temperatures are given in degrees Celsius. Example

A solution of 1.83 g of crude 1- (4'-hydroxyphenoxy) -2S-hydroxy-3-aminopropane in 30 ml of methanol was mixed with 1 ml of acetone and hydrogenated in the presence of 0.5 g of palladium on carbon (5ύο) as a catalyst to calculated consumption of hydrogen. Then the catalyst is filtered off and the filtrate is evaporated to dryness. Pp recrystallization of the residue from ethyl acetate gave 1-isopropylamino-2S-hydroxy-3- (4'-hydroxyphenoxypropane) mp 129-130 ° C. [α] D ²⁰ = ^-10 ° ( ^c = 0.940, methanol).

The hydrochloride prepared in a conventional manner has a mp of 125-126 ° C, 129-130 ° C. [Α] ²⁰ D = - 26 ° + 1 ° (c = 1, methanol).

The starting material can be prepared as follows:

a) To 120 ° C, a heated melt of 100 g of 5,6-anhydro-1,2-isopropylidene-α-D-glucofuranose and 100 g of hydroquinone monobenzyl ether is mixed with a few drops of pyridine, maintaining the internal temperature at 140 ° C by external cooling with lukewarm water. . After the exothermic reaction is complete, the reaction mixture is stirred for 30 minutes at 140 ° C and then cooled to 80 ° C. Add 500 ml of methanol and then water until turbidity is observed. After standing at 0 ° C for several hours, the precipitated crystals are filtered off and recrystallized from methanol. There was thus obtained 1,2-O-isopropylidene-6-O- (4'-benzyloxyphenyl) -α-D-glucofuranose mp 99-102 ° C _f = 0.25 by thin layer chromatography on silica gel in methylene chloride-methanol 15: 1 system. .

bj Warm solution to 70 ° C 127.3 g of 1,2-O-isopropylidene-6-O- (4'-benzyloxyphenyl) -α-D-isopropylidene-6-O- (4'-benzyloxyphenyl) -1'-acetic acid 500 ml of water added dropwise with stirring, further stirred at 70 DEG C. for 14 hours and then evaporated to dryness under a water pump vacuum. The crystalline residue is recrystallized from 1 liter of glacial acetic acid to give 6-O-. (4'-benzyloxyphenyl) -D-glucose, 1.1.164 168 ° C, R _f = 0.61 on silica gel TLC in methanol. [a] ²⁰ = -62 ° ± 1 ° (methanol, c = 0.985).

c) A suspension of 36.2 g of the obtained 6-O- (4'-benzyloxyphenyl) -D-glucose in a mixture of 600 ml of methanol, 10 ml of glacial acetic acid and 60 ml of water is mixed with portions added over 15 minutes under external cooling and stirring. The reaction mixture was stirred at 25 ° C for 20 hours. After insoluble material was filtered off, the filtrate was evaporated to dryness, the residue was dissolved in chloroform, washed with water, dried over magnesium sulfate and the solvent evaporated in a water pump vacuum. Dissolve the residue in 150 ml of methanol and add dropwise to the cooled solution at -5 ° C over 45 minutes.

3.8 g of sodium borohydride in 150 ml of methanol and 40 ml of water. After standing for a further 15 hours at about 25 ° C, the reaction mixture was evaporated to dryness, the residue was dissolved in chloroform, washed with ice-cooled 2 N hydrochloric acid and water, and dried over magnesium sulfate, and the solvent was evaporated under water pump vacuum. The residue was recrystallized from chloroform to give 1- (4'-henzyloxyf) -2S, 3-dihydroxypropane mp 134-138 ° C, R _f = 0.32 silica gel TLC in the system methylene chloride-methanol 15: 1.

d) 13.7 g of 1- (4'-benzyloxyphenoxy) -2S, 3-dihydnoxypropane in 16.2 g of ortho-acetic acid triethyl ester and 0.1 ml of trifluoroacetic acid are suspended in a 100 ml round-bottom flask equipped with a magnetic stirrer and a CaCl 2 drying tube. Upon further stirring for 3 hours at room temperature, the reaction solution was basified with triethylamine, evaporated to dryness, finally under high vacuum to give 2-ethoxy-2-methyl-4- (4'-be). nzyloxyphenoxymethyl] -dioxolane, which is used as such.

e) 18.2 g of the crude product obtained are dissolved in 45 ml of methylene chloride and 8.2 trimethylchlorosilane is added. After standing at room temperature for 2 hours, the reaction is complete. The solution was then evaporated in vacuo to a high vacuum end leaving a colorless gum consisting of 1- (4 1--benzyloxyphenoxy) -2R-acetoxy-1-chloropropane.

f) Mix 16.2 g of this crude product in a 250 ml sulfation flask equipped with a stirrer and thermometer with 3.9 g tetrabutylammonium bromide and 120 ml methylene chloride.

After formation of the solution, 105 ml of 2 N sodium hydroxide and 12 ml of ethanol are added and the mixture is stirred vigorously for one hour.

The organic phase was separated and washed with 20 ml of distilled water. The combined aqueous phases are extracted twice more with 20 ml of methylene chloride, the combined methylene chloride extracts are evaporated and the residue is extracted with 40 ml of ether. The insoluble tetrabutylammonium salt is filtered off, washed twice with 10 ml of ether, the ethereal solutions are combined and washed twice with 10 ml of water each time, and the combined aqueous phases are extracted once more with 10 ml of ether. The ethereal solutions were combined, dried (MgSO4), filtered and evaporated. 1- (4‘-Benzyloxyphenoxy) -2S, 3-epoxypropane, m.p. 70 ° C / 8.6 Pa, was obtained as a crude product.

5.1 g of 1- (4 (-benzyloxyphenoxy) -2S, 3-epoxypropane was dissolved in 200 ml of methanol and hydrogenated in the presence of 0.1 g of palladium on carbon (5%) at 15-20 ° C. After the calculated amount of hydrogen had been consumed, the catalyst was filtered off and the filtrate was evaporated in vacuo at room temperature. The crude 1- (4'-hydroxy-phenoxy-2S, 3-epoxy-propane) was used as such.

h) A solution of 3.3 g of 1- (4'-hydroxyphenoxy) -2S, 3-epoxypropane in 20 ml of ethanol is added dropwise to 40 ml of concentrated aqueous ammonia over 30 minutes and then the solution is allowed to stand for 4 hours at 50 ° in a sealed flask. C. After cooling to room temperature, the solution was filtered and evaporated to dryness in vacuo. 1- (4‘-Hydroxyphenoxy) -2S-hydroxy-3-aminopropane was obtained as a crude product.

Claims (2)

199375 7 After formation of the solution, 105 ml of 2 N sodium hydroxide and 12 ml of ethanol are added and the mixture is stirred vigorously for one hour. The organic phase was separated and washed with 20 billion distilled water. The combined aqueous phases are extracted twice more with 20 ml of methylene chloride, the combined methylene chloride extracts are evaporated and the residue is extracted with 40 ml of ether. The insoluble tetrabutylammonium salt is filtered off, washed twice with 10 ml of ether, the ethereal solutions are combined and twice The mixture was washed with 10 ml of water each time and the combined aqueous phases were extracted once more with 10 ml of ether. The ethereal solutions were combined, dried (MgSO4), filtered and evaporated. 1- (4‘-Benzyloxyphenoxy) -2S, 3-epoxypropant was obtained as a crude product. mp 70 ° C / 8.6 Pa. gj 5.1 g of 1- (4‘-benzyloxyphenoxy) -2S, 3-epoxypropane are dissolved in 200 ml of methanol and hydrogenated in the presence of 0.1 g of palladium carbon (5%) at 15-20 ° C. After the calculated amount of hydrogen has been consumed, the catalyst is filtered off and the filtrate is evaporated under vacuum at room temperature. H) A solution of 3.3 g of 1- (4'-hydroxyphenoxy) -2S, 3-epoxypropane in 20 ml of ethanol is obtained. The reaction mixture was added dropwise to 40 ml of concentrated aqueous ammonia over 30 minutes and the solution was then allowed to stand at 50 ° C for 4 hours in a sealed flask. After cooling to room temperature, the solution was filtered and evaporated to dryness in vacuo. 1- (4‘-Hydroxyphenoxy) -2S-hydroxy-3-aminopropane is obtained as a crude product. A process for preparing L- (4'-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane of the formula I (L) HO fO-CH 2 CH (OH) -CH 2 NH-CH (CH * (I) and its acid salts characterized in that, as a catalyst, it reduces the Schiff base with hydrogen in the presence of palladium on carbon of the formula II OH (S) HO - (-) - CH - CH - CH = N - CH (CH 2 (U) or of formula III (L) HO - (-) - O-CH 2 CH-CH 2 C (CH * 4 (III)) or formula IIImer of formula IV corresponding to the cyclic tauto (S) HO Where the compounds of the formulas III and IV may also be present side-by-side or a corresponding salt of one of these compounds, optionally liberating the base or free base of the obtained salt base is converted to salt by acid. 2. The process of claim 1, wherein the free compound of formula I is converted to a therapeutically useful acid salt. Severography; p., plant 7, Most