CS235344B2 - Method of 1,3-benzodioxol-4-ether new derivatives production - Google Patents

Abstract

The invention relates to a process for the production of new ones 1,3-benzodioxole-4-ether ether derivatives formulas which are both pharmaceutically useful or may serve as intermediates for the synthesis of pharmacologically active compounds on the other hand they are raw materials for the production of agrotechnical chemicals; \ tor. \ t AND The imi themselves can be, and besides, hydroytic cleavage of the dioxolene ring allow for the availability of new pyrogallol derivatives hard to get.

Description

The invention relates to a process for the preparation of novel pyrogallol ether derivatives of the general formula I

O - C - (CH ₂ ) _{n -} R g (I), where

X, I and Z

R ^{8 K} 4 * ^which 4 are identical or different, represent hydrogen or a methyl group, which are also identical or different, denote hydrogen, chlorine, bromine, iodine or nitro, is 0, 1 or 2 and denotes hydrogen, oxiranyl, mono or dihydroxyalkyl of up to 3 carbon atoms, N- (dihydroxyalkyl) quinohydroxyalkyl of up to 7 carbon atoms, kerboxyl, carbethoxy, carbamoyl, the nitrogen of which is methyl-substituted or may be present in the pirazine ring, cyano, Δ ² -imidazolino-2- with an alkyl, amidoxime, N-isopropylidenoxylmethyl or dimethylacetal group, with the proviso that R @ 1 to H @ 1 cannot simultaneously represent a hydrogen atom, and salts thereof with inorganic or organic acids or bases.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of the above-mentioned novel pyragollol ether derivatives, comprising the preparation of a 1,3-benzodioxole-4-hydroxy compound of formula 11 (IX),

OH where

R, Rg, X, Y and Z are as defined above, or their phenolate, preferably in an inert solvent or solvent mixture, are reacted with compounds of formula III

AC- (CH ₂ ) _n -R ₆ (III), wherein

R p R n and n are as defined above,

R 8 has the same meaning as or is CH-GN-α

A is a halogen atom, a sulfonyloxy group, or when R 1 and R 2 are hydrogen, n is zero and R 8 is a -CH-CN group, it is a double bond with the adjacent carbon atom.

optionally in the resulting derivatives of formula I one R @ 1 group is converted into another group K @ 1 and, when X and / or X and / or Z is hydrogen, the resulting compounds of formula I are optionally treated with halogenation and / or nitrating agent.

The novel compounds which can be prepared by the process 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 otherwise difficult to obtain nucleosubstituted pyrogallol derivatives.

The compounds of formula (I) also have pharmaceutically useful properties or can serve as intermediates for the synthesis of pharmacologically active compounds. The derivatives of the general formula I iodinated on the core are useful for the production of X-ray contrast media. Possibilities of deployment of such compounds in human medicine help to recognize that the 1,3-benzodioxozole ring does not cleave in human tests (Pestic. Sci. 12, 638,

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

The starting materials of formula (II) are known in the art or can be prepared by methods known per se. The compound of formula (II) wherein R 1 and R ₂ are methyl, and X, X and Z are hydrogen, is used in large quantities as an intermediate to produce insecticides (Chem. Abstr. H, 38941 m (1969); 72110u (1973)) (£ g, 105250u (1976); £ g,

192700c (1976); (£ 51598 (1977)).

The following examples illustrate the invention in greater detail without restricting it. Temperature data is always expressed in degrees Celsius.

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

He did

To a solution of 10 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in 50 ml of methanol was added dropwise with stirring 10.8 g of a 30% solution of sodium methoxide in methanol. 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 was stirred at room temperature until no starting product was detectable by thin layer chromatography (silica gel 60 F 254, solvent system: chloroform / methanol 9: 1), then evaporated on a rotary evaporator and the residue was taken up in chloroform. The filtered chloroform solution was shaken twice with 1 N sodium hydroxide solution and three times with water, dried over sodium sulfate and evaporated. The 2,2-dimethyl-4- (ethoxycarbonylmethoxy) -1,3-benzodioxole, initially obtained as an oil, crystallized on standing and melted at 46-48 °.

*

Example 2

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

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. Sodium salt melts at 256-260 ⁰ dec.

Example 3

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

Example 4 '

The product of Example 3 can also be prepared as follows: 2,2-Dimethyl-4-hydroxy-5,7-dichloro-1,3-benzodioxole is reacted as described in Example 1 to give 2,2-dimethyl-4-ol. - (ethoxycarbonylmethoxy) -5,7-dichloro-1,3-benzodioxel, m.p. 82-84 °.

This ester, after saponification according to Example 2, affords the corresponding free acid of the melting point of 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 was heated to reflux until the starting material was no longer detectable by thin-layer chromatography (cf. Example 2). The residue obtained after evaporation of the solution is recrystallized from isopropyl ether; It consists of 2,2-dimethyl-4- (morpholino-methoxycarbonyl) -3-benzodioxole, m.p. 92-93 ° C.

Example 1 a d 6

To a solution of 6.3 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in 30 ml of acrylonitrile was added 2 drops of a 40% methanolic solution of benzyltrimethylaminium hydroxide, followed by heating to reflux with stirring until the chromatogram was thin. The layer (cf. Example 1) can no longer be detected other than traces of the starting material. The residue was dissolved in a mixture of ethyl acetate and water, filtered, the ethyl acetate phase was shaken with 1 N sodium hydroxide solution and again with water, dried over sodium sulfate and evaporated.

The oily residue, 2,2-dimethyl-4- (2'-cyanoethoxy) -1,3-benzodioxole, was used for the subsequent reaction with hydroxylamine.

For this purpose, with external cooling with water, 9 g of a 30% methanolic sodium methoxide solution are added dropwise with stirring to a solution of 3.5 g of hydroxylamine hydrochloride in 15 ml of methanol and the precipitated sodium chloride is filtered off with suction. The solution thus obtained was 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 an additional 15 minutes at reflux, the reaction was complete by thin layer chromatography (cf. Example 1).

The filtered solution was evaporated. The oily residue crystallized from isopropanol. It is 2,2-dimethyl-4- (2'-carbamidoximethoxy) -1,3-benzodioxole, m.p. 100-103 °.

Example 7

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

Example 1 ffd 8

To a solution of 2.2 g of hydroxylamine hydrochloride in methanol, to 15 ol for míphání dropwise at 2 ⁰ 5.7 g 30% solution of sodium methoxide in methanol. The filtrate was 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 refluxing ethanol. About 15 minutes after the addition was complete, the reaction mixture was 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- (carbamidoximethoxy) -5,7-dibromo-1,3-benzodioxole melts at 153-155 °.

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 was added 4.3 g of a 30% methanolic sodium methoxide solution and then the reaction mixture was evaporated under reduced pressure. . The residue was dissolved in 50 [mu] l ethanol and the resulting solution was heated to reflux after addition of 2.65 g of 3-chloro-1,2-propanediol until only a trace of the starting compound was seen in the thin-layer chromatogram (cf. Example 1). The solution, filtered through celite, is evaporated under reduced pressure, the residue is taken up in a mixture of chloroform and water, the chloroform phase is dried over sodium sulphate and evaporated. The residue crystallized from isopropanol after filtering the hot activated carbon solution. The resulting 2,2-dimethyl-4- (2 ', ^{3-dihydroxy-propoxy)} -5,7-diiodo-1,3-benzodioxole melts at 112-114.

He did

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

They did

From a solution of 1.7 g of 2,2-dimethyl-4- (carboxyethoxy) -5,7-diiodo-1,3-benzodioxole in 25 ml of freshly distilled dimethylformsmid, 1 ml of thionyl chloride is added dropwise with stirring. The next time a 33% solution of methylamine in absolute ethanol was added until the mixture reacted ally, the mixture was then allowed to stand overnight. The mixture was evaporated under reduced pressure and precipitated with saturated sodium chloride solution. The resulting precipitate was recrystallized from ethanol-water. The dried 2,2-dimethyl-4- (N-methylcarbomoylaethoxy) -5,7-diiodo-1,3-benzodioxole melts at 146-148 °.

Example 12

Following the procedure of Example 7 and e from 2,2-dimethyl-4-hydroxy-1,3-benzodioxole sodium salt, 2,2-dimethyl-4-cyanomethoxy-1,3-benzodioxole was obtained as an orange-colored oil.

g of this oil is heated to 100 DEG C. for 1 hour after addition of 0.1 g of sulfur in 20 ml of ethylenediamine. The evaporation residue is then dissolved in ethyl acetate, filtered several times after shaking with water and then extracted with 2N hydrochloric acid. The acidic aqueous phase is then made alkaline by addition of sodium hydroxide and shaken with chloroform. Evaporation of the chloroform solution, dried over sodium sulfate, gave a yellow powder. After recrystallization from isopropenol, the resulting 2,2-dimethyl-4- ( ^{2 2} -imidazol-2-ylmethoxy) -1,3-benzodioxole forms colorless leaves, m.p. 158-111 °.

Example 13 g of 2,2-diaethyl-4-hydroxy-5,7-dibromo-1,3-benzodioxole sodium salt was stirred for 2 hours at 100 ml after addition of 0.4 g of benzyltriethylammonium chloride in 100 ml of butyl bromide. then dissolved in ethyl acetate, washed with 1 N sodium hydroxide solution and water and then evaporated. The remaining pale yellow oil composed of 2,2-dimethyl-4-butoxy-5,7-dibromo-l., 3-benzodioxole, * 1546 8. The value of R _f the compound is not 60 F 254 silica gel 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 as described in Example 10, in 50 ml of ethanol is heated to boiling under with 2.2 g of 2-amino-2-ethyl-1,3-propanediol until the reaction according to the thin-layer chromatogram (cf. Example 2) is complete. The evaporation residue is dissolved in ethyl acetate, the solution is shaken first with water and then with 2 N hydrochloric acid, whereupon an oil is formed which is redissolved by the addition of water. The acidic aqueous solution was treated with activated carbon, filtered, basified with sodium hydroxide and shaken with chloroform. Evaporation of the chloroform solution, dried over sodium sulfate, yielded an oil which was dissolved in ethyl acetate. Addition of an alcoholic solution of hydrochloric acid to the ethyl acetate solution of the solution precipitates a crystalline product. This product melts after recrystallization from isopropanol or ecetonitrile at 205-208 ^° and consists of 2,2-dimethyl-4- [3 '- (N, 4-dihydroxymethylethylemino) -2'-hydroxypropexyl] -5,7-diiodide hydrochloride -1,3-benzodioxole.

Example 15

To a solution of 10 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in 20 ml of methanol was added dropwise with stirring 10.83 g of 30% sodium methoxide solution in methanol and evaporated. The residue is dissolved in 15 ml of chloroacetaldehyde dimethylacetal and after addition of 1 g of tetrabutylammonium bromide, the mixture is heated under reflux for several days until the reaction is thin-layer chromatographed (eilica gel 60 F 254, solvent solvent: cyclohexane / acetone) 3: 1) almost finished.

The evaporation residue is then dissolved in ethyl acetate, the solution is washed with dilute sodium hydroxide solution, dried over sodium sulfate, filtered and evaporated after addition of activated carbon. The resulting oil was distilled (b.p. 155-157 ⁰ under a pressure of 1,596 kPa). To give 2,2-Dimethyl-4- (2 ', 2 * -dimethoxyothexy) -1,3-benzodioxol.Ní ehromatograau TLC (see above) showed an Rf 0.44, starting material R _f value my " 0.30. The n- ⁴ value of the dimethylacetal obtained is 1.497 l.

Example 16

If ee used 7.6 g of 2-amino-1,3-propanediol (serinol) in place of 2-amino-2-methyl-1,3-propanediol instead of 2-amino-2-methyl-1,3-propanediol, the hydrochloride 2 was obtained in an otherwise identical procedure, 2-dimethyl-4- [3 '- (1,3-dihydroxyisopropylamino) -2'-hydroxypropoxy] -5,7-diiodo-1,3-benzodioxole, which melts at recrystallization from acetonitrile / methanol 190-195 °.

Example 1 a d 17

To a suspension of 10 g of 2,2-dimethyl-4- (carbomethoxy) -1,3-benzodioxole, which can be prepared according to Example 2, in 150 ml of methylene chloride, 3.3 g of acetonoxime are added under stirring, and the solution is added dropwise. 9.2 g of Ν, Ν-dicyclohexylcarbodiimide in ml0 ml of methylene chloride;

After 30 minutes, the reaction was complete by thin layer chromatography (silica gel 60 F 254, solvent: cyclohexane / acetone = 1: 1). The evaporation residue is dissolved in isopropyl ether, the precipitate which precipitates overnight is filtered off with suction and the filtrate is evaporated. The crystalline residue is recrystallized from isopropyl ether. The acetone-O- (2,2-dimethyl-1,3-benzodioxol-4-dioxyacetyl) oxime thus formed melts at 73-75 ° C.

Table

Novel pyrogallol ethers of general formula 1

(AND)

X Y OF n ^fi 5 Melting point ° C R ,, , K ₂ = CH 3 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 NOH 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 (with decomposition) H

X AND OF n ^R 5 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.