CS235344B2 - Process for the preparation of new 1,3-benzodioxole-4-ether derivatives - Google Patents

Abstract

The invention relates to a method for the production of new derivatives of 1,3-benzodioxole-4-ether of the general formula which, on the one hand, have pharmaceutically useful properties or can serve as intermediates for the synthesis of pharmacologically active compounds, on the other hand, are raw materials for the production of agrotechnical chemicals or they themselves can be and, in addition, by hydrolytic cleavage of the dioxolene ring, enable the availability of new pyrogallol derivatives, which are difficult to obtain by other processes.

Description

The invention relates to a process for the production of novel pyrogallolether derivatives of the general formula I

O —C—(CH ₂ ) _n _Rg (I), where

X, I and Z

Rj ^{8 K} 4* ^which 4 are the same or different, represent hydrogen or a methyl group, which are also the same or different, represent hydrogen, chlorine, bromine, iodine or nitro group, represents 0, 1 or 2 and represents hydrogen, an oxiranyl, mono or dihydroxyalkyl group with up to 3 carbon atoms, an N-(dihydroxyalkyl)aminohydroxyalkyl group with up to 7 carbon atoms, a carboxyl, carbethoxy, carbamoyl group, the nitrogen of which is substituted by methyl or may be contained in a pyrazine ring, a cyano group, a Δ ² -imidazolin-2-yl, amidoxime, N-isopropylidenoxyl ester or dimethyl acetal group, with the proviso that R, to Hj together cannot represent a hydrogen atom, as well as their salts with inorganic or organic acids or bases.

The subject of the invention is a process for the production of the above-mentioned new pyragololether derivatives, which consists in the 1,3-benzodioxole-4-hydroxy compounds of the general formula 11 (IX),

OH where

R, Rg, X, Y and Z have the above meanings, or its phenolate, preferably in an inert solvent or solvent mixture, are reacted with compounds of general formula III

AC-(CH ₂ ) _n -R ₆ (III), where

Rp R^ and n have the meanings given above,

Rg has the same meaning as or represents a group CH-GN- and

A represents a halogen atom, a sulfonyloxy group or, in the case where R1 and R2 represent hydrogen, n represents zero and R8 represents a -CH-CN group, it represents a double bond with an adjacent carbon atom.

optionally, in the derivatives of general formula I formed, one group in the meaning of the symbol R^ is converted into another group Kj and, in the case where X and/or X and/or Z represent hydrogen, the formed compounds of general formula I are optionally treated with a halogenating and/or nitrating agent.

The new compounds that can be prepared by the method according to the invention are valuable raw materials for the production of agrotechnical chemicals or are themselves agrotechnical chemicals, or can - after hydrolytic cleavage of the dioxolane ring - serve as starting materials for the preparation of otherwise difficult-to-obtain core-substituted pyrogallol derivatives.

Compounds of general formula 1 also have pharmaceutically useful properties or can serve as intermediates for the synthesis of pharmacologically active compounds. Derivatives of general formula I iodinated on the nucleus are useful for the production of X-ray contrast agents. The possibility of using such compounds in human medicine is facilitated by the fact that the 1,3-benzodioxazole ring does not cleave in human tests (Pestic. Sci« 12, 638,

645 (1981). Some pyrogallolethers, which also have two oxygen atoms attached ortho to the 1,3-benzodioxole ring, occur in nature (apiol, myristicin, noscapine) and have known pharmacological effects.

The starting materials of the general formula II are either known or can be prepared by methods known per se. The compound of the general formula II, where R1 and _R2 represent a methyl group, and X, X and Z represent hydrogen, is used in large quantities as an intermediate for the production of insecticides (Chem. Abstr. H, 38941 m /1969/; 72110u /1973/; g£, 105250u/1976/; g£,

192700c /1976/; g£, 51598j /1977/).

The following examples illustrate the invention in more detail without limiting it to them. Temperature data are always expressed in degrees Celsius.

According to the described process, the novel derivatives of general formula I listed in the following table can be prepared.

Example

To a solution of 10 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in 50 ml of methanol, 10.8 g of a 30% solution of sodium methoxide in methanol are added dropwise while stirring. A solution of 12.55 g of ethyl bromoacetate in 15 ml of methanol is then added dropwise to the dark-colored mixture. The mixture is stirred at room temperature until no more starting product is detectable on a thin-layer chromatogram (silica gel 60 F 254, solvent system: chloroform/methanol 9:1), after which it is evaporated in a rotary evaporator and the residue is taken up in chloroform. The filtered chloroform solution is shaken twice with 1 N sodium hydroxide solution and three times with water, after which it is dried over sodium sulfate and evaporated. 2,2-Dimethyl-4-(ethoxycarbonylmethoxy)-1,3-benzodioxole, obtained initially as an oil, crystallizes on standing and then melts at a temperature of 46 to 48 °.

*

Example 2

To a solution of 11.3 g of the ester, prepared according to Example 1, in 100 ml of ethanol, 8 g of a 30% solution of sodium methoxide in methanol are added dropwise with stirring after adding 20 ml of water. After stirring for one hour, it is evident from the thin layer chromatogram (silica gel 60 F 254, solvent system; ethyl acetate/methanol/2N ammonium hydroxide = 25:8:3) that the reaction has proceeded completely. The solution is evaporated under reduced pressure and the residue is dissolved in water. When the aqueous solution is acidified with hydrochloric acid, a precipitate is separated, which is filtered off with suction, washed with water and dried under reduced pressure. Recrystallization from a mixture of chloroform and carbon tetrachloride gives 2,2-dimethyl-4-(carboxymethoxy)-1,3-benzodioxole with a melting point of 136 to 141 °.

The sodium salt of this compound can be prepared, for example, by reacting a methanolic solution of the free acid with an equivalent of sodium methoxide, evaporating the mixture and treating the residue with isopropyl ether. The sodium salt melts at 256-260 ^°C with decomposition.

Example 3

To a mixture of 4 g of carboxylic acid, prepared according to Example 2, B g of sodium bicarbonate and 100 ml of carbon tetrachloride, a solution of 4.5 g of chlorine in 100 ml of carbon tetrachloride is added dropwise with stirring at a temperature of -5 ⁰ after adding a crystal of iodine. The reaction is allowed to proceed at a temperature of 0 °, after which the reaction mixture is filtered. The precipitate formed is extracted hot with chloroform, the extract is combined with the filtrate obtained above and the mixture is evaporated under reduced pressure. The residue after evaporation is taken up with a mixture of chloroform and water, the resulting phases are separated from each other and the chloroform phase is evaporated. The crystalline residue is recrystallized from carbon tetrachloride, thereby obtaining 2,2-dimethyl-4-(carboxymethoxy)-5,7-dichloro-1,3-benzodioxole with a melting point of .43 to 145 °.

Example 4'

The product from Example 3 can also be prepared in the following way: 2,2-Dimethyl-4-hydroxy-5,7-dichloro-1,3-benzodioxole is reacted as described in Example 1 to give 2,2-dimethyl-4-(ethoxycarbonylmethoxy)-5,7-dichloro-1,3-benzodioxole with a melting point of 82 to 84 °.

This ester, after saponification according to Example 2, provides the corresponding free acid with the melting point given in Example 3.

Example 5

A mixture of 6.5 g of the ester prepared according to the procedure of Example 1, 8 g of morpholine, 6 ml of dimethylformamide and 20 ml of benzene is heated under reflux until the starting material can no longer be detected in the thin-layer chromatogram (compare Example 2). The residue obtained after evaporation of the solution is recrystallized from isopropyl ether; it consists of 2,2-dimethyl-4-(morpholinomethoxycarbonyl)-,,3-benzodioxole with a melting point of 92 to 93 °*

Example 1 and 6

To a solution of 6.3 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in 30 ml of acrylonitrile are added 2 drops of a 40% methanolic solution of benzyltrimethylaminium hydroxide, after which the mixture is heated under reflux with stirring until only traces of the starting material can be detected in the thin-layer chromatogram (compare Example 1). The residue after evaporation of the solution is dissolved in a mixture of ethyl acetate and water, the solution is filtered, the ethyl acetate phase is shaken with 1 N sodium hydroxide solution and again with water, then dried over sodium sulfate and evaporated.

The oily residue, which is 2,2-dimethyl-4-(2*-cyanoethoxy)-1,3-benzodioxole, is used for subsequent reaction with hydroxylamine.

For this purpose, 9 g of a 30% methanolic solution of sodium methoxide are added dropwise to a solution of 3.5 g of hydroxylamine hydrochloride in 15 ml of methanol while being cooled externally with water, and the precipitated sodium chloride is filtered off with suction. The solution thus obtained is added dropwise to a stirred and refluxed solution of 6.2 g of 2,3-diethyl-4-(2'-cyanoethoxy)-1,3-benzodioxole in 25 ml of ethanol. After a further 15 minutes of refluxing, the reaction is complete according to the thin-layer chromatogram (cf. Example 1).

The filtered solution is evaporated. The oily residue crystallizes from isopropanol. It is 2,2-dimethyl-4-(2*-carbamidoximethoxy)-1,3-benzodioxole with a melting point of 100 to 103 °.

Example 7

A solution of 10 g of the sodium salt of 2,2-dimethyl-4-hydroxy-5,7-dibromo-1,3-benzodioxole and 0.7 g of benzyltriethylammonium chloride in 40 ml of chloroacetonitrile is stirred under reflux until the thin-layer chromatogram (compare Example 1) indicates complete reaction. The reaction mixture is then evaporated under reduced pressure, the residue is dissolved in ethyl acetate and the resulting solution is shaken first with 1 N sodium hydroxide solution and then with water. The residue remaining after evaporation of the ethyl acetate solution is crystallized by standing in a refrigerator. After recrystallization from petroleum ether, the melting point of the resulting 2,2-diethyl-4-cyanoethoxy-5,7-dibromo-1,3-benzodioxole is 64 to 66 °.

Appendix 1 ffd 8

To a solution of 2.2 g of hydroxylamine hydrochloride in 15 ml of ethanol, 5.7 g of a 30% solution of sodium hydroxide in methanol are added dropwise at a temperature of .2 ⁰ with stirring. The filtrate of the resulting mixture is added dropwise, with stirring, to a solution of 7.4 β 2,2-dimethyl-4-cyanomethoxy-5,7-dibromo-1,3-benzodioxole in 25 ml of ethanol, heated to reflux. About 15 minutes after the end of the addition, the reaction mixture is evaporated in a rotary evaporator. The residue is treated with acetone and the resulting precipitate is recrystallized from isopropanol. The resulting 2,2-dimethyl-4-(carbamidoximemethoxy)-5,7-dibromo-1,3-benzodioxole melts at a temperature of 153 to 155 °.

Example 9

To a solution of 10 g of 2,2-dimethyl-4-hydroxy-5,7-diiodo-1,3-benzodioxole in 50 ml of methanol, 4.3 g of a 30% methanolic solution of sodium methoxide are added and the reaction mixture is then evaporated under reduced pressure. The residue is dissolved in 50 ml of ethanol and the resulting solution is heated under reflux after addition of 2.65 g of 3-chloro-1,2-propanediol until only traces of the starting compound are visible in the thin-layer chromatogram (compare Example 1). The solution, filtered through a celite filter aid, is evaporated under reduced pressure, the residue is taken up in a mixture of chloroform and water, the chloroform phase is dried over sodium sulfate and evaporated. The residue is crystallized from isopropanol after filtering the hot solution with activated carbon. The resulting 2,2-dimethyl-4-(2*,3 ^- dihydroxypropoxy)-5,7-diiodo-1,3-benzodioxole melts at a temperature of 112 to 114°C.

Example

The sodium salt of 5 g of 2,2-dimethyl-4-hydroxy-5,7-diiodo-1,3-benzodioxole is prepared in methanol by adding 2.15 g of a 30% methanolic solution of sodium methoxide and evaporating the mixture. The residue is dissolved in 30 ml of epichlorohydrin after adding 0.5 g of triethylbenzylammonium chloride and the solution is left to stand overnight. The residue after evaporation is then treated with hot ethyl acetate and the filtered solution is evaporated. This gives 5.6 g of 2,2-diethyl-4-(2',3*-epoxypropoxy)-5,7-diiodo-1,3-benzodioxole as a yellow oil. On a thin layer chromatogram (compare Example 2) it migrates slightly higher than the starting material and shows ee as the pure product. On standing the product crystallizes and then melts at a temperature of 64 to 67 °.

They applied

From a solution of 1.7 g of 2,2-dimethyl-4-(carboxyoethoxy)-5,7-diiodo-1,3-benzodioxole in 25 ml of freshly distilled dimethylformamide, 1 ml of thionyl chloride is added dropwise with stirring. Next, a 33% solution of methylamine in absolute ethanol is added until the mixture reacts alkylally, and the mixture is then left to stand overnight. The mixture is then evaporated under reduced pressure and precipitated with saturated sodium chloride solution. The resulting precipitate is recrystallized from a mixture of ethanol and water. Dried 2,2-dimethyl-4-(N-methylcarbamoylethoxy)-5,7-diiodo-1,3-benzodioxole melts at a temperature of 146 to 148 °.

Example 12

By the procedure of Example 7 ae, 2,2-dimethyl-4-cyanomethoxy-1,3-benzodioxole is obtained from the sodium salt of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in the form of an orange-colored oil.

g of this oil is heated for 1 hour at 100° after adding 0.1 g of sulfur in 20 ml of ethylenediamine. The residue after evaporation of the reaction mixture is then dissolved in ethyl acetate, the resulting solution is filtered, shaken several times with water and then extracted with 2 N hydrochloric acid. The acidic aqueous phase is then made alkaline by adding sodium hydroxide and shaken with chloroform. Evaporation of the chloroform solution, dried with sodium sulfate, gives a yellow powder. After recrystallization from isopropenol, the resulting 2,2-dimethyl-4-(A ² -imidazolin-2-ylmethoxy)-1,3-benzodioxole forms colorless flakes which melt at a temperature of 158 to 151°.

Example 13 g of sodium salt of 2,2-diethyl-4-hydroxy-5,7-dibromo-1,3-benzodioxole is stirred for 2 hours at 100°C after addition of 0.4 g of benzyltriethylammonium chloride in 10 ml of butyl bromide. The residue after evaporation of the reaction mixture is then dissolved in ethyl acetate, the resulting solution is washed with 1 N sodium hydroxide solution and water and then evaporated. The remaining yellowish oil consists of 2,2-dimethyl-4-butoxy-5,7-dibromo-1,3-benzodioxole, * 1.546 8. The R _f value of this compound on silica gel 60 F 254 using the solvent system: chloroform/methanol (9:1) is 0.82.

Example 14

A solution of 10 g of 2,2-dimethyl-4-(2',3*-epoxypropoxy)-5,7-diiodo-1,3-benzodioxole, which can be prepared according to the procedure of Example 10, in 50 ml of ethanol ee is heated to reflux with 2.2 g of 2-amino-2-ethyl-1,3-propanediol until the reaction is complete according to the thin layer chromatogram (compare Example 2). The residue after evaporation is then dissolved in ethyl acetate, the resulting solution is shaken first with water, then with 2 N hydrochloric acid, whereby ee precipitates an oil, which is dissolved again by adding water. The acidic aqueous solution is treated with activated carbon, filtered, made alkaline with sodium hydroxide and shaken with chloroform. Evaporation of the chloroform solution, dried over sodium sulfate, gives an oil as a residue, which is dissolved in ethyl acetate. By adding an alcoholic solution of hydrochloric acid to the ethyl acetate solution, a crystalline product is precipitated. This product melts after recrystallization from isopropanol or acetonitrile at a temperature of 205 to 208 ⁰ and consists of 2,2-dimethyl-4-[3'-(^,^-dihydroxymethylethylemino)-2'-hydroxypropexyl]-5,7-diiodo-1,3-benzodioxole hydrochloride.

Example 15

To a solution of 10 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in 20 ml of methanol, 10.83 g of a 30% solution of sodium methoxide in methanol are added dropwise with stirring and the whole is evaporated. The residue is redissolved in 15 ml of chloroacetaldehyde dimethyl acetal and, after adding 1 g of tetrabutylammonium bromide, the mixture is heated to reflux for several days until the reaction is almost complete according to the thin-layer chromatogram (silica gel 60 F 254, solvent ratio: cyclohexane/acetone “3:1).

The residue after evaporation of the reaction mixture is then dissolved in ethyl acetate, the resulting solution is washed with dilute sodium hydroxide solution, dried over sodium sulfate, filtered after addition of activated carbon and evaporated. The resulting oil is distilled (boiling point 155 to 157 ⁰ at a pressure of 1,596 kPa). 2,2-dimethyl-4-(2',2*-dimethoxyothexy)-1,3-benzodioxole is obtained. Thin layer chromatography (see above) shows an Rf value of 0.44, the starting material has an _Rf value of 0.30. The ^nf value of the obtained dimethyl acetal is 1.497 1.

Example 16

If, in the procedure of Example 14, 7.6 g of 2-amino-1,3-propanediol (serinol) is used instead of 2-amino-2-methyl-1,3-propanediol, 2,2-dimethyl-4-(3'-(1,3-dihydroxyisopropylamino)-2'-hydroxypropoxy)-5,7-diiodo-1,3-benzodioxole hydrochloride is obtained using the same procedure, which, after recrystallization from a mixture of acetonitrile and methanol, melts at a temperature of 190 to 195°.

Example 17

To a suspension of 10 g of 2,2-dimethyl-4-(carboxymethoxy)-1,3-benzodioxole, which can be prepared according to the procedure of Example 2, in 150 ml of methylene chloride, 3.3 g of acetone oxime are added with stirring, over which a solution of 9.2 g of N,N-dicyclohexylcarbodiimide in 0.0 ml of methylene chloride is added dropwise;

After 30 minutes, the reaction is complete according to the thin layer chromatogram (silica gel 60 F 254, solvent system: cyclohexane/acetone = 1:1). The residue after evaporation of the reaction mixture is dissolved in isopropyl ether, the precipitate that forms overnight is filtered off with suction and the filtrate is evaporated. The crystalline residue is recrystallized from isopropyl ether. The acetone-0-(2,2-dimethyl-1,3-benzodioxole-4-doxyacetyl)oxime thus formed melts at a temperature of 73 to 75 *·

Table

New pyrogallol ethers of general formula 1

(AND)

X Y From n ^fi 5 Melting point °C R,, , K ₂ = CHj Kp R* = H Br H Br 0 COOH 175 to 178 J B J 0 COOH 198 to 200 Cl H H 0 COOH 118 to 120 no ₂ H ' H 0 COOH 123 to 125 H H no ₂ 0 COOH 165 to 167 FOOT H H H 0 < NH ₂ 13.0 to 134 H H H 0 /—\ CO.NN—CH ₃ 106 to 108 H H H 0 choh.ch ₂ oh 68 to 70 Cl H H 0 Jn.MCI 195 to 205 (under decomposition) H

X I From n ^R5 Melting point °C ^R 1. ' ^R 2' ^R 3 ¹ = CH ₃ Br H Br 0 COOH 161 to 164 J H J 0 COOH 190 to 193

SUBJECT OF THE INVENTION

Claims (1)

A process for the preparation of the novel 1,3-benzodioxazole-4-ether derivatives of the general formula I wherein R 1, R 8, and R _4, which are the same or different, are hydrogen or methyl, X, Y and Z, which are the same or different, are hydrogen, chlorine, bromine, iodine or nitro, U is 0, 1 or 2 and R1 represents hydrogen, oxiranyl, mono or dihydroxyalkyl of not more than 3 carbon atoms, N- (dihydroxyalkyl) eminohydroxyalkyl of not more than 7 carbon atoms, carboxyl, ketrbethoxy, carbamoyl group whose nitrogen is methyl substituted or may be present in the pirazine ring, cyano, Δ ² -imidazolin-2-yl, amidoxime, N-isopropylidenoximester or dimethylacetal. with the proviso that R @ 1 to R @ 2 cannot simultaneously represent a hydrogen atom and salts thereof with inorganic or organic acids or bases, characterized in that the 1,3-benzodioxole-4-hydroxy compounds of general formula (IX) (II) are: OH where R 1, S ₂ > X, Ϊ and Z, as defined above, or a phenol ether thereof, preferably in an inert solvent or solvent mixture, are reacted with compounds of formula III A - C - (CH _{2) n} - R wherein ^S 3 ^R * 4 ^{8 B} «« her abovementioned meaning, R 8 has the same meaning as R 6 or is CH-CH- a A represents a halogen atom, a sulfonyloxy group or, when R1 and R1 are hydrogen, and represents zero and R8 represents a -CH-CH group, represents a double bond with an adjacent carbon atom, optionally converting one group in the resulting derivatives of formula I and in the case where X and / or Y and / or Z is hydrogen, the resulting compounds of formula I are optionally treated with a halogenating and / or nitrating agent.