CS199574B2 - Method of preparing l-1-/4'-hydroxyphenoxy/-2-hydroxy-3-isopropyl aminopropane - Google Patents

Description

The invention relates to a process for the preparation of L-1- (4 ' -hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropanone of formula I (L)

HIM

O-CH _Z CH (OH) CH,

NH-CH 2 CH 2 (I)

Fischer, the projection of the compound of formula I is:

BOY

AND

CH 2 NH-CH 2 CH 2 (L) and corresponds to the S-form in the Cahn-Ingold-Prelog nomenclature:

cr-o-A-OH * - H - (CH 2 NH-CH 2 OH (S))

The novel compound has valuable pharmacological properties, in particular an effect on adrenergic O-receptors. Thus, it specifically stimulates cardinal β-receptors. In particular, it acts positively inotropically and chronotropically on an isolated guinea pig chamber at a concentration of 0.005 to 0.5 µg / ml, and in anesthetized cats at a dose of 0.001 to 0.1 mg / kg intravenously. As can be seen from experiments on narcotized cats, the new compound at the indicated doses, which are clearly positively intrinsic and chronotropic, does not at all or only at least decrease blood pressure in the arteries, it stimulates them specifically with cardiac μ-receptors compared to β-receptors. and is distinguished qualitatively from isoproterenol, which equally strongly stimulates β-receptors of the heart and blood vessels. Since the pressure drop leads to tachycardia, it can be calculated that when used in humans at doses that are equally potent inotropic, tachycardia may be substantially lower than that of isoproterenol.

It is also particularly outstanding that the new compound is substantially longer active in narcotized cats than isoproterenol and that even after an intraduodenal administration of 0.05 mg / kg, a clear effect is obtained.

Thus, the novel compound can be used as a positively inotropic active agent, particularly for treating 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 pharmacological 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 by infusion, in an amount of 0.2 to 2.0 µg / kg / minute.

According to the invention, L-1- (4 ' -hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane can be prepared in a manner known per se by preparing a compound of formula II

(L) (II) is reacted with a compound of formula III

Y2-CH (CH3) 2 (III), wherein one of Y1 and Y2 is a primary amino group and the other is a reactive esterified hydroxy group and X1 is hydroxyl or Y1 together with X1 is an epoxy group, in the latter case the absolute epoxide configuration corresponds to S- and Y 2 is the primary amino group.

The reactive esterified hydroxy group is in particular a hydroxyl group esterified with a strong inorganic or organic acid, in particular a hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or a strong organic acid such as a strong aromatic sulfonic acid such as benzenesulfonic acid, 4-bromobenzenesulfonic acid acid or 4-toluenesulfonic acid. So Yi respectively. Y2 is particularly preferably chlorine, bromine or iodine.

The reaction is carried out in a conventional manner. When using the reactive ester as the starting material, the reaction is preferably carried out in the presence of a basic condensing agent and / or an excess of the amine can be employed. Suitable base condensing agents are, for example, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as potassium carbonate, and alkali metal alcoholates such as sodium methylate, potassium ethylate and potassium tert-butylate.

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 as well as their gaming, mono-, sesqui- or polyhydrates can be obtained. 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, 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, salicylic acid or emonic acid, methanesulfonic acid, 'thansulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid or sulfamic 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 in which the reaction components are in the form of a salt.

The starting compounds are known or, if new, can be prepared by known methods.

Thus, the compound of formula II in the S form, where X 1 and Y 1 together form an epoxy group, can be prepared by the following reaction sequence: 5,6-anhydro-1,2-O-isopropylidene-α-D-glucofuranose is reacted by reaction with monobenzyl ether of hydroquinone to form 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 followed by reduction The product obtained is converted to 1- (4-benzyloxyphenoxy) -2S-3-dihydroxypropane in a conventional manner.

Reaction with triethyl ortho-acetic acid affords 2-ethoxy-2-methyl-4- (4'-benzyloxyphenoxymethyl) -dioxolane from which, by treatment with trimethylchlorosilane, 1- (4-benzoyldoxyphenoxy) -2R-acetoxy-1-chloropropane is obtained. then by reaction with a base, for example trimethylammonium bromide, is converted to 1- (4-benzyloxyphenoxy) -2S-3-epoxypropane in an alkaline medium and is converted to 1- (4'-hydroxyphenyl) by hydrogenolysis, for example with hydrogen in the presence of palladium on carbon (5%). enoxy) -2S-3-epoxypropane.

The starting material of formula II, wherein X 1 is hydroxyl and Y 1 is a reactive esterified hydro group, for example chlorine, is prepared as follows.

Reaction of 4-hydroxyphenyl-N-D-glucopyranoside with 10-behzyl-2S-anhydro-D-glycerin affords 4- (3-benzyloxy-2S-hydroxypropoxy) phenyl-4-D-glucopyranoside in a conventional manner. of acetic acid is converted to 4- (2S-acetoxy-3-benzyloxypropoxy) phenyl-2,3,4,6-tetra-O-acetyl- [beta] -D-glucopyranoside followed by hydrogenation in the presence of palladium on carbon to 4- (2S-acetoxy-3-hydroxypropoxy) phenyl-2,3,4,6-tetra-O-acetyl- [beta] -D-glucopyranoside. From this, 4- (2R-acetoxy-3-methanesulfonyloxypropoxy) phenyl-2,3,4,6-tetra-O-acetyl-5-D-glucopyranoside is obtained from which it is reacted with a strong base, for example a strongly basic ion exchange resin affords 442S-3-epoxypropoxyphenyl-S-D-glucopyranoside, which hydrolysis with concentrated hydrochloric acid affords 1- (4-hydroxyphenoxy) -2S-hydroxy-3-chloropropane.

The novel compound can be used as a medicament, for example, in the form of pharmaceutical preparations which contain the novel 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. those substances that do not react with the novel compound, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzoyl alcohol, gum, polyalkylene glycol, petrolatum, cholesterol or other known carriers are contemplated. Suitable pharmaceutical preparations are 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 conventional manner. about 10 to 100 mg per os, preferably about 20 to 40 mg per os.

The following examples illustrate the invention in more detail without restricting it in any way. Temperatures are given in degrees Celsius.

Example 1

0.33 g of 4- (2S-3-epoxypropoxy) -phenyl- [3-D-glucopyranoside] was treated with 1 ml of ice-cold concentrated hydrochloric acid and hydrogen chloride gas was introduced into the mixture for 15 minutes while cooling with ice / sodium chloride. . The reaction mixture was then allowed to stand at 20 ° C for 20 hours, evaporated to dryness in vacuo, and the residue was digested with 3 X 20 mL of methylene chloride. The combined methylene chloride extracts were dried over sodium sulfate, evaporated in vacuo to give crude 1- (4-hydroxyphenoxy) -2S-hydroxy-3-chloropropane.

[α] _π ^2θ = +4 '^> + 1 ° (c = 1 methanol).

A solution of 0.2 g of the obtained crude 1- (4 ' -hydroxyphenoxy) -2S-hydroxy-3-chloropropane in 20 ml of ethanol is treated with 0.11 g of isopropylamine and the solution is heated under reflux for two hours. After evaporation of the solvent to dryness, the oily residue is mixed with 30 ml of water and 30 ml of ethyl acetate. The organic phases are dried over sodium sulphate and evaporated to dryness in vacuo. The obtained 1-isopropylamino-2S-hydroxy-3- (4 ' -hydroxyphenoxy) propane is recrystallized from ethyl acetate; 1.1.129 to 130 °.

[α] D ²⁰ = -1 ° d from 1 (c = 0.940 methanol). Hydrochloride mp 125-126 ° C, 129-130 degrees Celsius, [α] _D ²⁰ = -26 °, 1 (= 1, methanol). .

The starting material used 4- (25-3-epoxypropoxy) phenyl- [beta] -D-glucopyranoside is prepared as follows:

a) A solution of 100 g of 4-hydroxyphenyl- [beta] -D-glucopyranoside and 60.5 g of 10-benzyl-2S-anhydro-D-glyerine in 366 ml of 0.1 N sodium hydroxide and 740 ml of acetonitrile was heated for 50 hours. to reflux under a nitrogen atmosphere. The solvent was then distilled off under a water pump vacuum and the residue was dissolved in 1 liter of water. The crystallized product was filtered off and dried to give 4- (3-benzyloxy-2S-hydroxy xypropoxy ^l) phenyl-0-D-glucopyranoside 1.1 Mp 146-147 ° C.

Rf = 0.45 on silica gel thin layer chromatography in methylene chloride-methanol 3: 1 [α] _D 20 = -34 ° + ₁ (methanol, c = 1.027).

b) A solution of 123 g of 4- (3-benzyloxy-2S-hydroxypropoxy) -phenyl-β-D-glucopyranoside in 1400 ml of pyridine is reacted with 270 ml of acetic anhydride at 25 ° for 16 hours, then poured into 3000 ml of ice water. After standing for two hours, the crystalline product is filtered off, washed three times with 500 ml of water each, dried and recrystallized from 700 ml of ethanol, whereby 4- (2S-acetoxy-3-benzyloxypropoxy) -phenyl-2,3,4,6 is obtained. -tetra-O-acetyl- [beta] -D-glucopyranoside mp 93-96 [deg.] C., Rf = 0.37 on silica gel thin layer chromatography in methylene chloride-ethyl acetate 85:15.

[ _.alpha. ] _D @ ²⁰ = -22 DEG + 1 DEG (chloroform, c = 0.967).

c) A solution of 144 g of 4- (2S-acetoxy-3-benzyloxypropoxy) -phenyl-2,3,4,6-tetra-O-acetyl- [beta] -D-glucopyranoside in 1500 ml of methanol is hydrogenated with 14 g of 5% palladium on carbon at normal pressure. The catalyst was filtered off and the solvent was distilled off under water pump vacuum. Crystallization from ether-petroleum ether gave 4- (2S-acetoxy-3-hydroxypropoxy] -phenyl-2,3,4,6-tetra-O-acetyl- [beta] -D-glucopyranoside, m.p. C. Rf = 0.22 by thin layer chromatography on silica gel in methylene chloride-ethyl acetate 85:15;

[?] _D ²⁰ = -29 ⁰ ± 1 ° (chloroform, c = 1.141).

(d) A solution of 116 g of 4- (2S-acetoxy-3-hydroxypropoxy) -phenyl-2,3,3,6,6-tetra-O-acetyl- (3-D-glucopyranoside) in 700 ml of pyridine is cooled with ice 17.4 ml of methanesulfonyl chloride were added dropwise over one hour and the reaction mixture was allowed to stand at 25 [deg.] C. for five hours, and the reaction mixture was poured into 5 liters of ice water, the product crystallized. 800 ml of hot ethanol to give 4- (2R-acetoxy-3-methanesulfonyloxypropoxy) -phenyl-2,3,4,6-tetra-O-acetyl- [beta] -D-glucopyranoside mp 110-115 degrees Celsius Rf = 0.20 on TLC silica gel in methylene, · methyl chloride-ethyl acetate 85: 15. _[QR] 20 _{D ==} _28 ° ± 1 ° (chloroform, c = 1.223).

(e) A suspension of 103 g of 4- (2R-acetoxy-3-methanesulfonyloxypropoxy) -phenyl-2,3,4,6-tetra-O-acetyl-4-D-glucopyranoside in 3 liters of absolute methanol is mixed with 250 g of freshly regenerated and absolute methanol freshly washed Dowex 1 (OH ^- ) 50-100 mesh ion exchange resin and stirred at 25 ° C for 30 minutes. The ion exchanger is filtered off and washed with 500 ml of methanol. The filtrate was evaporated in a water pump vacuum to about 300 mL and 1 L of ether was added with stirring. The crystallized product was filtered off and recrystallized from a mixture of ethanol and ether to give 4- (2S-3-epoxypropoxy) -phenyl -? - D-glucopyranoside, mp 134-136 ° C. Rf = 0.37, by thin layer chromatography on silica gel in methylene chloride-methanol 3: 1.

[?] _D 20 = -44 ^{and 0} + i, [ «] H = -168 ₈ ^{20 D +} 1 ° (c = 1.703, methanol).

Example 1 a d 2

A solution of 1.85 g of crude 1- (4'-hydroxyphenoxy) -2S-3-epoxypropane in isopropanol was added dropwise at 20 ° C to a mixture of 5 ml of isopropylamine and 5 ml of isopropanol, and the reaction mixture was stirred at 20 ° C for one hour. hour at 50 ° C. After evaporation of the reaction solution, the solid residue is partitioned between 25 ml of ether and 20 ml of 1N hydrochloric acid and the phases are separated. The ether phase is re-extracted with 1 N hydrochloric acid and the combined aqueous phases are evaporated in vacuo. The pH was adjusted to 9-10 by the addition of concentrated ammonia, precipitating crude 1-isopropylamino-2S-hydroxy-3- (4-hydroxyphenoxy) propane, which was recrystallized from ethyl acetate, mp 129-130 ° C.

[α] ²⁰ _ο = -1, ⁰ ± 1 ° (c = 0.940, methanol).

The starting material can be prepared as follows:

(a) A melt heated to 120 ° C consisting of 100 g of 5,6-anhydro-1,2-O-isopropylidene-α-D-glucofuranose and 100 g of hydroquinone monobenzyl ether is mixed with a few drops of pyridine and kept at internal temperature by external cooling with lukewarm water. below 140 ° C. After the exothermic reaction is complete, the reaction mixture is stirred for another 30 minutes at 140 ° C, cooled to 80 ° C and 500 ml of methanol are added followed by water until the initial turbidity. After standing at 0 ° C for several hours, the precipitated crystals are filtered off and recrystallized from methanol. Yield l, 2-0-isopropylidene-6-0- (4'-benzyloxyphenyl) -ad-glucofurano se t, t. ^IC 99 to 1O2 ^C. Rf = 0.25 on silica-gel TLC in methylene chloride -methanol 15: 1.

b) A heated solution of 127.3 g of 1,2-O-isopropyllden-6-O- (4'-benzyloxyphenyl) -. alpha.-D-glucofuranose in 800 ml of glacial acetic acid was added dropwise to 500 ml with stirring. The mixture was stirred at 70 ° C for 14 hours and evaporated in a water pump vacuum. The crystalline residue was recrystallized from 1 liter of glacial acetic acid to give 6-O- (4-benzyloxyphenyl) -D-glucose mp 164-168 ° C. _Rf = 0.61, by thin layer chromatography on silica gel in methanol.

[ _.alpha. ] _D @ 20 = -62 DEG + 1 DEG (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 in portions over 15 minutes with external cooling and stirring. 64 g of sodium meta-periodate and the reaction mixture was stirred at 25 ° C for 20 hours. The insoluble material was filtered off, the filtrate was evaporated to dryness, the residue was dissolved in chloroform, washed with water, dried over magnesium sulphate and the solvent evaporated in a water pump vacuum. The residue was dissolved in 150 ml of methanol and added dropwise over 45 minutes

199-5 ° C cooled solution of 3.8 g of sodium borohydride in 150 ml of methanol and 40 ml of water. After standing for an additional 15 hours at about 25 ° C, the reaction mixture was evaporated to dryness, the residue was dissolved in chloroform, washed with ice-cold 2 N hydrochloric acid, and dried over sodium sulfate, and the solvent was evaporated in a water pump vacuum. The residue was recrystallized from chloroform to give 1- (4'-benzyloxyphenoxy) -2S, 3-dihydroxypropane, mp 134-138 ° C. R _F = 0.32 on silica-gel TLC in the system methylene chloride-methanol 15: 1st

(d) In a 100 ml round-bottomed flask equipped with a magnetic stirrer and CaCl2 drying tube, 13.7 g of 1- (4'-benzyloxyphenoxy) -2S, 3-dihydroxypropane are suspended in 16.2 g of ortho-acetic acid triethyl ester and 0.1 ml is added. ml of trifluoroacetic acid. Under stirring, a slightly endothermic reaction results in a clear solution. After stirring for another 3 hours at room temperature, the reaction solution was basified with triethylamine, evaporated to dryness, finally under high vacuum to give crude 2-ethoxy-2-methyl-4- (4'-benzyloxyphenoxymethyl) -dioxolane, which as such process further.

e) 18.2 g of the crude product obtained are dissolved in 45 ml of methylene chloride and 8.2 g of trimethylchlorosilane are added. After standing at room temperature for 2 hours, the reaction is complete. The solution was evaporated in vacuo, finally under high vacuum to give a colorless

4 oil which contains crude 1- (4 ' -benzyloxyphenoxy) -2R-acetoxy-1-chloropropane.

(f) 3.9 g of tetrabutylammonium bromide and 120 ml of methylene chloride are mixed in a sulphation flask equipped with a stirrer and a thermometer. After dissolution, 105 ml of 2 N sodium hydroxide solution and 12 ml of ethanol are added and the mixture is stirred vigorously for one hour.

The organic phase is separated and washed with 20 ml of distilled water. The combined aqueous phases are extracted twice with 20 ml of methylene chloride each, the combined methylene chloride extracts are evaporated and the residue is extracted with 40 ml of ether. The insoluble tetrabutylammonium salt was filtered off and washed twice with ether, the ether extracts were combined and washed twice with 10 ml of water each time, and the combined aqueous phases were again extracted once with 10 ml of ether. The ethereal solutions were combined, dried (MgSO4), filtered and evaporated to give crude crude.

1- (4 ' -benzyloxyphenoxy) -2S, 3-epoxypropane m.p. 70 DEG C./6.6 Pa.

g) 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 uptake of the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated in vacuo at room temperature to give 1- (4'-hydroxyphenoxy) -2S, 3-epoxypropane which was used as such.

Claims (4)

Process for the preparation of L- (4'-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane of formula I (L) (I) and its acid salts, characterized in that the compound of formula II (U (ID forged hydroxy group and Xi) is hydroxyl or Y 1 together with X 1 forms an epoxy group, in the latter case the absolute configuration of the epoxide corresponds to the S-form and Y 2 is the primary amino group, or a salt of one of these compounds is reacted; converted to an acid salt. 2. The process of claim 1 wherein the compound of formula (II) wherein X1 is hydroxyl and Y1 is a reactive esterified hydroxyl group is reacted with an excess of isopropylamine. 3. A process according to claim 2, wherein Y1 is a chlorine, bromine or iodine atom. is reacted with a compound of formula III Y 2 —CH (CH 3) 2 (III), wherein one of Y 1 and Y 2 is a primary amino group and the other is a reactive ester 4. A process according to any one of claims 1 to 3, wherein the compound of formula I in free base form is converted to a therapeutically useful acid salt.