CS228139B2 - Production of o-substituted derivatives of 3//-hyanidols - Google Patents

Description

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of O-substituted 3- (+) -cyanidanol derivatives of general formula I

where

R 10 is C 1 -C 4 alkyl optionally substituted by C 1 -C 4 alkoxy, C 3 -C 6 alkoxyethoxy or benzoyl optionally substituted by halogen, C 2 -C 5 alkenyl, benzyl optionally substituted by alkyl or alkoxy a C 1 -C 4 radical on the aromatic ring, a C 1 -C 4 aliphatic carboxylic acid residue or a C 1 -C 4 alkyl ester ester thereof, characterized in that the tetraalkalic salt 3- ( +) -cyanidol with a reactive alcohol ester of the general formula

HO-Ri where

R1 is as defined above.

When R1 is lower alkyl of 1 to 4 carbon atoms, it is primarily methyl or ethyl. This radical is optionally further substituted by C 1 -C 4 alkoxy, preferably methoxy or C 1 -C 6 alkoxy or C 3 -C 6 alkoxyethoxy, in particular methoxyethoxy.

When R1 is lower alkyl of 2 to 5 carbon atoms, it is primarily allyl, methallyl,

2-butenyl or

2-pentenyl.

Among the possible meanings of R 1, allyl, methallyl, ethylallyl,

2-Butenyl,

2-pentenyl, methoxymethyl;

ethoxymethyl, methoxyethoxymethyl, acetonyl, propionylmethyl, cinamyl, phenacyl,;

benzyl,

2-Methylbenzyl,

4-methylbenzyl,

4-tert-butylbenzyl,,

4-methoxybenzyl,

4-ethoxybenzyl.

Compounds containing salt-forming groups, for example, free carboxyl groups, may be in free form or in the form of their salts. When the compound contains a free carboyl group, these are, for example, metal salts, in particular alkali metal salts, for example sodium or potassium salts, alkaline earth metal salts, for example magnesium or calcium salts, or ammonium salts, for example ammonia or organic bases such as lower trialkylamines, for example trimethylamine or triethylamine, are in particular non-toxic pharmaceutically usable salts. These salts can be obtained, for example, by treating the free compound with a hydroxide or carbonate of the selected metal, ammonia or one of the amines mentioned, or using appropriate ion exchangers or organometallic compounds.

Compounds containing basic groups may also form acid addition salts. This is also particularly the case with non-toxic pharmaceutically usable salts which are formed, for example, with inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric acids, in addition organic carboxylic or sulfonic acids, for example aliphatic, cycloaliphatic, cycloaliphatic-aliphatic , aromatic, arylaliphatic, heterocyclic or heterocyclicaliphatic such as acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, phenylacetic, benzoic, 4-aminobenzoic, anthranylic, 4-hydroxybenzoic, salicylic, , embonic or nicotinic, methanesulfonic acid, ethynsulfonic acid, 2-hydroxyethanesulfonic acid, ethylsulfonic acid, phenylsulfonic acid, p-ethylphenylsulfonic acid, naphthalenesulfonic acid, sulfanyl or cyclohexylsulfamic acid. Salts of these species can be obtained, for example, by treating free compounds containing basic groups with acid or appropriate anion exchangers.

The reactive ester is in particular an ester with a strong inorganic acid, in particular with a hydrohalic acid, for example hydrochloric or hydrobromic acid or an organic sulfonic acid, preferably a lower alkanesulfonic acid, for example methanesulfonic or ethanesulfonic acid or with benzenesulfonic acid optionally substituted on the benzene by methyl or atom. chlorine or bromine, for example p-toluenesulfonic acid or p-bromobenzenesulfonic acid.

In this way, 3 - (+) - cyanidol derivatives are obtained in which all four hydroxy groups on the phenyl nuclei are substituted. Of these tetraethers, 5,7,3 ‘, 4‘-tetra-O-benzyl- (+) -3-cyanidol was prepared by the laboratory method of K. Weinges, D. Seiler, Liebigs Ann. Chem. 714 193-204 (1968). This method is based on the action of:

3- (+) -cyanidol in acetone or benzyl chloride solution in the presence of potassium iodide or potassium carbonate under nitrogen at reflux for several hours. It is a classical benzylation which is carried out in a conventional manner and, after isolation of the resulting product and crystallization from ethanol, results in the preparation of a mixture of 8-benzyl-5,7,3 ', 4'-tetra-O-benzyl-3- (+ j-cyanidol) and 5,7,3 ', 4'-tetra-O-benzyl- (-1-) -cyanidol, which derivative is finally isolated by column chromatography in 1 to 2% yield, indicating that the process is not industrially useful for obtaining the above derivative.

It has been shown that the compounds of formula (I) can be easily obtained in a novel manner in good yield. The process comprises reacting 3- (+) -cyanidol in an aprotic organic solvent with a higher dielectric constant with an alkali metal hydride or carbonate, followed by reacting the tetraalkalic salt of 3- (+) -cyanidol obtained above. with a reactive alcohol ester of the formula

HO — Ri where

R1 is as defined above using 3- (+) -cyanidol, an alkali metal hydride and a reactive ester in a ratio of 1: 4.25: 4.5, or 3- (+) -cyanidol, an alkali metal carbonate and reactive ester in a ratio of 1: 8: 6.

In particular, the alkali metal hydride is sodium hydride, which is preferably used in the form of an oil dispersion. Of the alkali metal carbonates, potassium carbonate is preferably used.

Among the aprotic solvents having a higher dielectric constant, mention may be made in particular of amides, for example dlmethylformamide, but also of sulfoxides, for example dimethylsulfoxide. However, the most preferred solvent is dimethylformamide, both for economic reasons but also because it can be removed by simple distillation at atmospheric pressure and because it is easier to use than dimethylsulfoxide. Moreover, it is important that the reaction medium is as anhydrous as possible. When dimethylformamide is dried using a molecular sieve and then the solution of 3- (+) cyanidol in dimethylformamide is dried in the same manner, the formation of undesired secondary products is substantially reduced, and this drying does not adversely affect the formation of the resulting products.

The reaction may be carried out in the presence of a quaternary ammonium salt, for example tetra-n-butylammonium hydrogen sulfate, which is used in an amount of 0.1 to 0.5 mol per 1 mol of 3- (+) -cyanidol or methyl ether, preferably 18-crown. -6, which is used in an amount of 0.5 mol per 1 mol of 3- (+) -cyanidol.

The reaction is carried out at a temperature of -25 to + 50 degrees Celsius. As is known, dimethylformamide decomposes already at room temperature when it comes into contact with basic compounds, thus decomposition can be avoided by carrying out the reaction at a temperature of -25 to +25 ° C, preferably -5 ° C. to 0 ° C. When the reaction is carried out in dimethylsulfoxide, there is no risk of decomposition and the reaction can be carried out at a temperature below 50 ° C, preferably at a temperature of 15 to 30 ° C, for example at room temperature.

In the process according to the invention, after formation of the alkali salt of 3- (+) -cyanidol, the salt is not stable in the medium of dimethylformamide and sodium hydrides even at low temperature and it is therefore necessary to immediately add etherification or esterification agent to the reaction mixture. If this is not the case, the yield of the reaction is reduced and, moreover, the purification of the resulting product is difficult. On the other hand, in case of early addition of the etherification or esterification agent at a low temperature, it is necessary to maintain this temperature for some time and then allow the temperature to rise slowly, for example to room temperature. After completion of the reaction, the reaction mixture may be allowed to stand for more than 15 hours without affecting the purification of the final product, its quality or its yield. It is also necessary to ensure energetic stirring of the reaction mixture during the reaction.

The progress of the reaction can be monitored by thin layer chromatography on silica gel using, for example, chloroform or dichloromethane as the solvent.

After removal of the reaction solvents by distillation, the residue is mixed with a suitable solvent for crystallization. Trichlorethylene, which is a particularly preferred solvent, can be used for crystallization. However, other solvents such as carbon tetrachloride, toluene, ethyl acetate, ethanol, isopropanol, or solvent mixtures such as carbon tetrachloride, n-hexane or acetone / methanol may also provide good results. Less preferred solvents are ethyl ether and n-hexane, as well as acetone, pyridine, chloroform, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or dichloromethane, in which they are soluble at room temperature.

Due to the close relationship between the compounds which can be produced by the process of the invention in free form and in salt form, it is believed that whenever a free compound is mentioned, especially in the case of a pharmacological effect, it is automatically a salt effect and vice versa.

The above processes are carried out in a known manner in the absence or preferably in the presence of diluents or solvents, if necessary cooling or heating at a higher pressure and / or in an inert gas atmosphere, for example under a nitrogen atmosphere.

The compounds obtained by the process of the invention can be used as intermediates for the preparation of 3- (+) cyanidol derivatives, O-substituted at the 3-position, as described in the Czechoslovak patent 228 112 by incorporating into the 3-position the compounds of formula I substituent and the OR groups are cleaved and replaced with hydroxy groups.

The invention will be illustrated by the following examples.

Example 1

In a 50 ml three-necked flask equipped with a 25 ml pressure-compensated ampoule, nitrogen inlet and ascending condenser with a calcium chloride tube, add 0.95 g of 55% sodium hydride dispersion in oil (0 (53 g of hydrides) and the mixture was dried by heating under a stream of nitrogen. After cooling, the mixture is still kept under a nitrogen atmosphere, while 10 ml of freshly distilled dimethylsulfoxide are added and the mixture is stirred at room temperature with a magnetic stirrer. A solution of 1.45 g of 3- (+) -cyanidanol in 15 ml of freshly distilled dimethylsulfoxide is then added dropwise via a stopper vial with stirring at room temperature. Hydrogen begins to evolve. 30 minutes after the addition of the 3 - (+) - cyanidanol solution is complete, a solution of 2.74 ml (2.99 g) of methoxyethoxymethyl chloride in 10 ml of freshly distilled dimethylsulfoxide is slowly fed through the vial. 30 minutes after completion of the addition, the reaction solution is poured into 150 ml of saturated sodium chloride water and the pH is adjusted to 7. A brown-black precipitate is formed which is extracted three times with 100 ml of toluene. The solutions thus obtained are combined and washed three times with 50 liters of water, then the toluene is evaporated. 2.88 g of an oily brown-red residue are thus obtained. The oily residue is extracted ten times with 100 ml of n-hexane at reflux. The solutions were combined and cooled to give 1.53 g of 5,7,3 *, 4‘-tetra-O-methoxyethoxymethyl-3- (+) -cyanidanol as a yellowish oil. This material decomposes at 150 ° C at 2.7 Pa.

Example 2

Under a nitrogen atmosphere with vigorous stirring, a suspension of 92.8 g of sodium hydride is prepared as a 50% dispersion in oil (51 g of hydride) in 1 liter of freshly distilled dimethylformamide. The suspension is cooled to -5 to 0 ° C by external cooling.

A solution of 145 g of 3- [+) cyanidanol in 2 liters of freshly distilled dimethylformamide is added to the cooled suspension so that the temperature of the suspension during the addition is -5 to 0 ° C, the addition takes about 1 hour. The resulting hydrogen was removed by flushing the reaction with nitrogen.

After the addition of the 3- (+) -cyanidanol was complete, the reaction was allowed to proceed at the above temperature for 15 minutes, after which time hydrogen gas was no longer evolved. Then, 267.5 ml (385 g) of benzyl bromide are introduced over a period of 1.5 hours so that the temperature of the reaction mixture is -5 to 0 ° C. This temperature is maintained for 30 minutes after the addition of benzyl bromide is complete, after which the temperature is allowed to slowly rise to room temperature.

Dimethylformamide was removed by distillation under vacuum at 60 ° C and the oily residue was mixed with 3 liters of trichlorethylene. The organic solution was washed three times with 3 liters of distilled water and then filtered to remove a small aqueous portion.

Concentration and simultaneous cooling to 5 ° C yielded 159 g of crystalline 5,7,3 ', 4'-tetra-O-benzyl-3- (+) -cyanidanol in 51% yield, white crystals of melting point. Mp 144-145 ° C. Example 3

Under similar conditions to Example 2, but using dimethylformamide previously dried on a ⁴ x ¹⁰ m, 2 mm molecular sieve while pre-drying a solution of 3- (+) -cyanidanol in dimethylformamide using the same molecular sieve yields 5,7,3 '. 4'-tetra-O-benzyl-3- (+ 1-cyanidanol in 55% yield).

Example 4

The procedure was analogous to Example 2 except that the benzyl bromide was replaced

2.25 moles of benzyl chloride. The reaction mixture was allowed to warm to room temperature and maintained at this temperature with stirring for 10 hours, after which dimethylformamide was distilled off. There was thus obtained 5,7,3 ‘, 4‘-tetra-O-benzy-3- (+) -cyanidanol in 57% yield. Example 1 a d 5

A suspension of 0.93 g of a 55% dispersion of sodium hydride in oil (0.51 g of hydride) in 10 ml of freshly distilled dimethylsulfoxide is kept under a nitrogen atmosphere, while a solution of 1.45 g of 3- (+ of cyanidanol in 20 ml of freshly distilled dimethylsulfoxide. Hydrogen evolves and is removed by passing nitrogen through the reaction mixture. After stirring at room temperature for 1 hour, hydrogen evolution ceased and the sodium salt of 3- (+) -cyanidanol partially settled on the walls of the reaction vessel. 2.68 ml (3.85 g) of benzyl bromide is then added dropwise to form an exothermic reaction. After 30 minutes, the reaction mixture becomes cloudy and stirred for an additional hour at room temperature, then poured dropwise into 300 ml of 10% cooled solution. The resulting precipitate was filtered off, dried in vacuo at 80 degrees Celsius and recrystallized from 40 ml of carbon tetrachloride to give 1.96 g of 5,7,3 ', 4'-tetra- O-benzyl-3- (+) cyanidanol.

Example 6

The procedure is analogous to Example 2, but using 416 g of α-bromo-o-xylene instead of benzyl bromide. The residue obtained after removal of dimethylformamide is dissolved in chloroform and the chloroform solution thus obtained is washed with distilled water, filtered and the solvent is evaporated. The residue was recrystallized from 6: 3 benzene / petroleum ether to give 5,7,3 ', 4'-tetra-O- (2-methylbenzyl) -3- (+) in 51% yield. -cyanidanol, m.p. 88-90 ° C.

Example 7

The procedure is as in Example 2, but using 416 g of α-bromo-p-xylene. The residue obtained after evaporation of dimethylformamide is dissolved in chloroform, and the chloroform solution thus obtained is washed with water, filtered and evaporated and the residue is recrystallized from carbon tetrachloride. In this way, 5,7,3 ‘, 4‘-tetra-O- (4-methylbenzyl) -3- (+ 1-cyanidanol) is obtained in 40% yield, m.p. 66-70 ° C.

Example 8

The procedure was analogous to Example 2 except that 562 g of 2-bromobenzyl bromide was used instead of benzyl bromide. The residue obtained after removal of dimethylformamide is dissolved in chloroform. The chloroform solution obtained was washed with water, filtered and evaporated. The residue was recrystallized from chloroform / carbon tetrachloride (40: 55, v / v) to give 5,7,3 ', 4'-tetra-O- (2-bromobenzyl) -3- (+ j) in 74% yield. -cyanidanol, m.p. 155-157 ° C.

Example 9

The procedure is analogous to Example 2, except that 181 g of dimethyl ether chloride is used instead of benzyl bromide and the residue obtained after removal of dimethylformamide is dissolved in chloroform, washed three times with water and then evaporated. Recrystallization is carried out first from n-hexane and then from a 1: 1 v / v mixture of methanol and water. In this way, 5,7,3 ‘, 4‘-tetra-O-methoxymethyl-3- (+) -cyanidanol with a melting point of 92-93 ° C is obtained in a yield of 40%.

Example 10

The procedure was analogous to Example 2 except that 272 g of allyl bromide was used instead of benzyl bromide. The dimethylformamide solution was poured into a mixture of water and crushed ice. A white precipitate formed, which was collected by centrifugation and then dissolved in chloroform. The chloroform solution is then washed three times with water and then evaporated. The residue is recrystallized from n-hexane. In this way 5,7,3 tetra, 4‘-tetra-O-allyl-3- (+) -cyanidanol is obtained in a yield of 28%;

78.5 to 80 ° C.

They did

The procedure was analogous to Example 2 except that 244 g of ethyl chloroformate was used instead of benzyl bromide. The dimethylformamide distillation residue was dissolved in chloroform and the chloroform solution was washed several times with water and then evaporated. The residue obtained is washed with a 15: 5 by volume mixture of methanol and water, whereupon impurities precipitate. The mixture is allowed to stand for several days in a cold environment and then distilled off to give 5,7,3 ', 4'-tetra-O-ethoxycarbonyl-3- (+} -cyanidanol in a yield of 52%, m.p. 68 ° C.

Example 12

A solution of 1.45 g of 3- (+ i-cyanidanol in 50 ml of anhydrous acetone) is prepared, 6.91 g of anhydrous potassium carbonate are added to the solution, and the mixture is heated to reflux under a nitrogen atmosphere. 6.26 g of p-bromophenacyl bromide in 30 ml of anhydrous acetone and the mixture was refluxed under mechanical stirring for 3 hours, after cooling the reaction mixture, the solid was filtered off and the solution was evaporated to dryness, the residue was dissolved in 50 ml of chloroform. and the chloroform solution was washed with water (3.times.50 ml), then the chloroform was evaporated to give 6.23 g of a yellowish powder residue which was dissolved in 1000 ml of ether, and the insoluble material was collected by filtration as well as a small portion of crystals. The ether solution was concentrated to 150 ml, yielding 2.9 g of 1fl in 53.8% yield after recrystallization from ethanol.

5,7,3 °, 4‘-tetra-O- (4-bromophenacyl) -3- (+) cyanidanol, m.p. 127-129 ° C.

Example 13

A 1 liter flask was fitted with a rotary stirrer, thermometer, silica gel tube condenser, nitrogen inlet, 250 mL vial fitted with a stopper, and the whole vial was dried overnight under vacuum at 100 ° C. The flask was heated on an oil bath maintained at a constant temperature. The flasks are then charged with 110 g of anhydrous potassium carbonate and 250 ml of anhydrous dimethylformamide under a stream of nitrogen. Then charged to the flask by a solution of 29.0 g of 3- (+) ol is obtained in 250 ml of anhydrous dimethylformamide, dried overnight using a molecular sieve and 10.4 ° ^_ ma 17.25 ml of benzyl bromide, diluted with 100 ml of anhydrous dimethylformamide. The reaction mixture was heated at 100 ° C for 5.5 hours with stirring under a stream of nitrogen. The resulting suspension is hot filtered, the filtrate is evaporated in vacuo on a rotary evaporator at 80 ° C, and the residue is dissolved in 250 ml of chloroform. The chloroform solution is filtered and transferred to a 1 liter stoppered flask and washed three times with 250 ml of water, dried over magnesium sulphate and evaporated to dryness.

The residue is dissolved in 750 ml of carbon tetrachloride at reflux. The brown residue was separated and crystallized with stirring at room temperature with intermittent cooling in the refrigerator. This gives 31.2 g of the title product, which is identical to the product of Example 37 and has a melting point of 144-145 ° C. Example 14

A 500 ml four-necked flask was equipped with an efficient mechanical stirrer, a 250 ml vial with a stopcock, a chloride tube and a nitrogen inlet stream, then 100 ml of anhydrous dimethylformamide was added and cooled to -3 ° C and then added. 9.28 g of a 55% sodium hydride dispersion in oil. A solution of 14.5 g of 3- (+) -cyanidanol in 200 ml of anhydrous dimethylformamide and 1.698 g of tetra-m-butylammonium hydrogen sulphate is then gradually added under vigorous stirring, and the mixture is then kept at 0 ° C for one hour with constant stirring. A solution of 25.9 ml of benzyl chloride in 25 ml of anhydrous dimethylformamide was added over 15 minutes, and the mixture was stirred at 0 ° C for 30 minutes, then the mixture was allowed to warm to room temperature while stirring. hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give a residue which was dissolved in 250 ml of chloroform. The chloroform solution is washed four times with 250 ml of distilled water, dried over magnesium sulphate and filtered again, then the chloroform is evaporated off under reduced pressure. The residue is washed with 50 ml of hexane and then dried to constant weight. The residue is dissolved in 500 ml of carbon tetrachloride, the solution is filtered hot and the filtrate is allowed to cool to room temperature, then concentrated to 350 ml and then to 150 ml to give a total of

23.6 g of 5,7,3 ‘, 4‘-tetra-O-benzyl-3- (+) cyanidanol identical to the product of Example 2.

Example 15

The procedure is analogous to Example 13, but after addition of a solution of 3- (+) cyanidanol in dimethylformamide,

13.22 g of 18-crown-6 and benzyl bromide are replaced with 69 ml of benzyl chloride. The reaction mixture was then heated with vigorous stirring to 60 ° C for 20 hours.

In this way 45.5 g of 5,7,3 ‘, 4‘-tetra-O-benzyl-3- (+) cyanidanol are obtained, which is identical to the product of Example 2. Example 16

The procedure is analogous to Example 15, but the 18-crown-6 is replaced

16.98 g of tetra-n-butylammonium hydrogen sulfate.

In this way, 44.5 g of 5,7,3 ‘, 4‘-tetra-O-benzyl-3- (+) -cyanidazole identical to the product of Example 2 are obtained.

Example 17

In a manner analogous to that described in the above examples, the following end products can be obtained:

3,5,7,3 ‘, 4‘-penta-O-methoxymethyl-3- (+) cyanidanol, m.p. 74.5-76 ° C;

3,5,7,3 ‘, 4‘-penta-O-allyl-3- (+) cyanidanol, m.p. 59-60 ° C;

5,7,3 ‘, 4‘-tetra-O-trimethylsilyl-3- (+) cyanidanol,

5,7,3 ‘, 4‘-tetra-O-benzyl-3-O- (N, N-dimethylamino-3-propyl) -3- (+) cyanidanol *, m.p. 50-52 ° C;

5,7,3 ', 4'-tetra-O-benzyl-3-O- (4,4-ethylenedioxy-4-fluorophenylbutyl) -3- (+) cyanidanol, m.p. 95, 5 to 96 ° C,

5,7,3 ‘, 4‘-tetra-O-benzyl-3-O- (2,3-dihydroxypropyl) -3- (+) cyanidanol, m.p. 64-65 ° C.

Claims (2)

A process for the preparation of O-substituted 3- (4-) cyanidanol derivatives of the general formula I wherein R 10 is C 1 -C 4 alkyl optionally substituted by C 1 -C 4 alkoxy, C 3 -C 6 alkoxyethoxy or benzoyl optionally substituted by halogen, C 2 -C 5 alkenyl, benzyl optionally substituted by alkyl or alkoxy a C 1 -C 4 radical on the aromatic ring, a C 1 -C 4 aliphatic carboxylic acid radical or a C 1 -C 4 alkyl esterified ester thereof, characterized in that the tetraalkalic salt 3- ( +) -cyanidol with a reactive alcohol ester of the general formula HO — Ri where R1 is as defined above. 2. A process according to claim 1, wherein the reactive alcohol ester of the formula HO-R1 is a benzyl halide.