DE2749279A1 - NEW 1,3-BENZODIOXIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

Dr. l ~. Zumcsoiri ücn. - Dr. E. Ar i; _; -im ■ - ·. ^r! r. ":. Κο ·· '-;".;·; / ..:,:, ·; ■ (.; ·:;? Dipl.-Phys. R. Holib ^ jer - LDipl.-ing .: ". IZlir- ^ cc -'- - ': ··. ·. · ■ D .. F .; ^ » ^ vi ^ l ^ in jun.

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New 1,3-bonzodioxiri derivatives, processes

to their manufacture and containing them

pharmaceutical compositions

The present invention relates to products of the Formula I ':

wherein

R ¹ ^ is a hydrogen atom, an alkyl radical having 1 to 5 carbon atoms, a 2,3-dihydroxypropcmyl radical, a (2,2-dimethyl-1,3-dioxolan-4-yl) -raethyl radical or a dialkylaminoalkyl radical, the alk. yl radicals contain 1 to 4 carbon atoms, means

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η alkyl! 5 carbon atoms means

denotes a hydrogen atom, an All lenstoffatomen or a phenyl radical,

R is a hydrogen atom or an alkyl radical with 1 to R. a hydrogen atom, an alkyl radical with 1 to 5 con

R. and R ₅ , which can be the same or different, represent a hydrogen atom or a halogen atom,

in racemisehen or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline earth, aluminum, ammonium and amine salts of the products of the formula I ¹ , in which R 'represents a hydrogen atom, and the addition salts with acids of the products of the formula I ¹ , in which R ¹ ^ is a dialkylaminoalkyl radical.

The invention relates in particular to the products of general formula I:

R ^ and R ₂ , which are identical or different, represent a hydrogen atom or an alkyl radical having 1 to 5 carbon atoms,

Ro is a hydrogen atom, an alkyl radical with 1 to 5 col ·. or a phenyl radical means and

R ₄ and R ₅ , which can be the same or different, represent a hydrogen atom or a halogen atom,

in racemic or optically active forms or in the form of mixtures of these isomers and the alkali, alkaline earth, aluminum, ammonium and amine salts of the products of the formula I. wherein R ^ means a hydrogen atom.

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The invention relates in particular to:

the products which are defined by the above general formulaΊ, in which in this formula IR ^ and R2, which may be the same or different, denote a hydrogen atom or a methyl radical, R ^ denotes a hydrogen atom, a methyl radical or a phenyl radical, R ^ denotes a hydrogen atom and R ₅ denotes a hydrogen atom or a chlorine atom, in the racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline earth, aluminum, ammonium and amine salts of these products of the formula I, wherein R _{1 represents} a hydrogen atom;

the products as defined by the above general formula I, in which in this formula I R. denotes a hydrogen atom or a methyl radical, R ~ denotes a hydrogen atom, R denotes a hydrogen atom, a methyl radical or a phenyl radical, R. denotes a hydrogen atom and R ₅ denotes a chlorine atom, in the racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline earth, aluminum, ammonium and amine salts of these products of the formula I, in which R. Means hydrogen atom.

The invention relates in particular to the products mentioned in the examples in their racemic and optically active forms.

It relates primarily to isomers A in the form of the examples are obtained, the products with the following designations:

6-chloro-4-methyl-4-phenyl- [4h] -1,3-benzodioxin-2-carboxylic acid methyl ester,

6-chloro-4- (3-chlorophenyl) -4-methyl- [4H] -I, 3-benzodioxin-2-carboxylic acid methyl ester,

6-chloro-4-methyl-4-phenyl- [4h] -1,3-benzodioxin-2-carboxylic acid ethyl ester,

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The term "alkyl of 1 to 5 carbon atoms" can e.g. a methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, Designate tert-butyl or pentyl radical.

The term "halogen atom" may, for example, be chlorine, bromine or Denote fluorine atom.

The term "mixtures of these isomers" means a mixture of racemic isomers or a mixture of optical active isomers, regardless of the ratio present.

In particular, they can be mixtures in any ratio of the racemic isomers, or mixtures in any ratio of the two optical antipodes and mixtures in any ratio of the two diastereomeric optically active products Act.

The alkali or alkaline earth salts of the products of the formula I, where R ^ is a hydrogen atom, for example be the sodium, potassium, lithium or calcium salts.

The amine salts of the products of the formula I in which R _{1 is} a hydrogen atom are the salts of customary amines. The usual amines include the monoalkylamines, such as methylamine, ethylamine, propylamine, the dialkylamines, such as dimethylarain, diethylamine, di-n-propylamine, and the trialkylamines, such as triethylamine. One can especially mention the piperidine, the morpholine, the piperazine and the pyrrolidine

The addition salts with acids can be, for example, the salts which with hydrochloric acid, hydrobromic acid, hydrogen iodide acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, Maleic acid, fumaric acid, succinic acid, tartaric acid, the alkylraonosulphonic acids such as methanesulphonic acid, the Ethanesulfonic acid, propanesulfonic acid, and alkyl disulfonic acids, such as α, ß-ethane disulphonic acid.

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6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid, 6-chloro-2,4-dimethyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid,

Sodium 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylate,

6-chloro-4- (3-chlorophenyl) -4-methyl- [4h] -1,3-benzodioxin-2-carboxylic acid and

the d- and 1-isomers of 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid.

In particular one can mention:

the piperidine salts of the two diastereomeric racemates A and B of 6-chloro-4-methyl-4-phenyl- [4H] -l, 3-benzodioxin-2-carboxylic acid,

the d- and 1-isomers of the two diastereomeric racemates A and B of 6-chloro-4-methyl-4-phenyl- [4h] -1,3-benzodioxone-2-carboxylic acid

as well as in their racemic or optically active forms:

6-chloro-4-methyl-4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester, the 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid 2,3-dihydroxypropanyl ester and

6-chloro-4-methyl-4-phenyl- [4H] -l, 3-benzodioxin-2-carboxylic acid 2- (diethylamino) ethyl ester

as well as their addition salts with acids.

The term "isomer A" denotes one or the other of the two diastereomeric racemic forms of the products of formula I, which have two asymmetric carbon atoms.

According to the invention, the products of the above general formula I and the alkali, alkaline earth, aluminum, ammonium and amine salts of the products of formula I wherein R ^ is

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Hydrogen atom means produced by a process which is characterized in that a product of the formula II:

II

wherein R ₃ , R ₄ and R _{5 are} as defined above with an alkali metal salt of a product of formula III:

Cl

C-COOH

III

in which R _{2 is} as defined above, reacts in the presence of a basic condensing agent and an alkali metal "salt of an acid corresponding to a product of the formula I is obtained, in which R _{1 is} a hydrogen atom, which salt is optionally treated with an acid to form the corresponding acid of the formula I, which acid is optionally converted into a salt or esterified in order to obtain the corresponding salt or the corresponding ester, and that, moreover, the products of the formula I in racemic or optically active forms or in the form of mixtures of these isomers isolated.

Under the preferred conditions for practicing the invention, the manufacturing process described above will be found carried out in the following way:

The alkali metal salt of the product of formula III can in particular be a sodium, potassium or lithium salt.

The basic condensation agent can in particular an alkali metal alcoholate, such as sodium methylate, sodium ethylate or sodium

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tert-butoxide; an alkali hydride such as sodium hydride or potassium hydride; an alkali amide such as sodium amide, potassium amide, or lithium amide; as well as sodium.

The reaction of the product of formula II with the product of formula III is carried out in an organic solvent medium such as e.g. benzene, toluene, xylene, ethyl ether, dioxane, dimethylformamide, tetrahydrofuran, phosphorus trisamide, or in the medium carried out a mixture of these solvents.

You can especially in the presence of a serving as a catalyst Compounds of the crown ether type, such as dibenzo-18-crown-6, dicyclohexyl-18-crown-6 or 18-crown-6, if appropriate in a mixture with an organic solvent such as dioxane.

The reaction can be carried out at a temperature from -10 ° C. to the reflux temperature of the reaction mixture can be carried out.

The product of the formula II is used with the basic condensing agent before it is allowed to react with the product of formula III.

The products of the general formula I in which R is an alkyl radical with 1 to 5 carbon atoms means, if they are prepared by esterification of the corresponding acid, by reacting an alcohol of the formula

R ₁ OH

where R. is an alkyl radical with 1 to 5 carbon atoms, with this acid, preferably in an acidic medium.

For example, in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, or in the presence of an acidic Resin work.

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The esters of the general formula I in which R ^ is an alkyl radical with 1 to 5 carbon atoms can also be prepared by transesterification.

The products of the formula I in which R ^ is a methyl radical can also be prepared by reacting diazomethane with the product of the formula I in which R _- . a hydrogen atom means to be produced in the medium of an organic solvent.

The esters of the general formula I can also be prepared in a customary manner, starting from a functional derivative of the corresponding Acid of formula I, such as the acid chloride, can be prepared. The functional derivatives of the acids of the formula I are produced using conventional methods.

The alkali, alkaline earth, aluminum, ammonium and amine salts of the products of formula I above, wherein R. is hydrogen atom means can be prepared by reacting appropriate bases with these products of the formula I.

The base can, for example, be a mineral or organic base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, Calcium hydroxide, aluminum hydroxide, sodium ethylate, potassium ethylate, Ammonia or an amine such as methylamine, ethylamine, Propylamine, dimethylamine, diethylamine, di-n-propylamine, Triethylamine, piperidine, morpholine, piperazine or pyrrolidine.

The reaction is preferably carried out in a solvent or a mixture of solvents, such as water, ethyl ether, Ethanol, acetone or ethyl acetate.

The invention also relates to a process for the preparation of products of the above formula I and their alkali, Alkaline earth, aluminum, ammonium and amine salts, which is characterized in that a product of the formula II:

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2 7 A 9 2 7 9

II

wherein R ₃ , R ₄ and R ₅ are as defined above, with an alkali metal salt of a product of the formula III ¹ :

^R 2

^Y \ I

^ C-COOH III '

wherein Y is a bromine or iodine atom and Rp is the above has given meaning, reacts in the presence of a basic condensing agent and optionally the synthesis continues as above.

The preferred conditions for performing this procedure are identical to those described above.

The invention relates in particular to a process for the preparation of products of the formula I as defined above, in which R 'is a 2,3-dihydroxypropanyl radical, a (2,2-diraethyll, 3-dioxolan-4-yl) methyl radical or a dialkylaminoalkyl radical, whose alkyl parts contain 1 to 4 carbon atoms, where Rp, R ₃ , R ₄ and R ^ are as defined above, in the racemic or optically active forms or in the form of mixtures of these isomers, and of addition salts with acids of the products of the formula I ', in which R * is a dialkylaminoalkyl radical which is characterized in that an acid of the formula I in which R. is a hydrogen atom or a functional derivative of this acid is mixed with an alcohol of the formula

R ' _a OH

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wherein R ^1. * is a (2,2-dimethyl-1,3-dioxolan-4-yl) methyl radical or a dialkylaminoalkyl radical, the alkyl parts of which contain 1 to 4 carbon atoms, treated, optionally the product of the formula I ^{1 obtained} , in which R ¹ ^ is a dialkylaminoalkyl radical, treated with an acid to form the salt therefrom, optionally the product of the formula I obtained, in which R ¹ ^ is a (2,2-dimethyl-1,3-dioxolan-4-yl ) -methyl radical, treated with a hydrolysis agent in order to obtain the corresponding product of the formula I ¹ , in which R ¹ ^ is a 2,3-dihydroxypropanyl radical, and that the products of the formula I or their salts can also be seen in the racemis or optically active forms or in the form of mixtures of these isomers.

Under the preferred conditions for carrying out this procedure, one operates in the following manner:

The functional derivative of the acid of formula I can be, for example, an ester or an acid halide.

The functional derivative is prepared in the usual way, starting from the acid of the formula I.

The reaction is preferably carried out in the medium of an organic solvent such as benzene, toluene, xylene and ethyl ether, carried out.

The reaction of the salt formation of the products of the formula I, in which R ¹ ^ is a dialkylaminoalkyl radical, is carried out in the customary manner.

The hydrolysis reaction is carried out by acid hydrolysis, and the acid used may be, for example, hydrochloric acid.

According to the invention, the products of the above general formula I in which R ₄ and R _{5 represent} a hydrogen atom can also be prepared by a process which is characterized in that a product of the formula I in which R ₄ or R _r

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or R ₄ and R _{5 represent} a chlorine atom, subject to the action of hydrogen in the presence of a catalyst and obtain the corresponding product of the formula I in which R ^ and R ^ represent a hydrogen atom.

Under the preferred conditions for practicing the invention the procedure just described is carried out in the following way:

The catalyst can in particular be palladium.

You work in an alkaline environment. The base used can, for example, be triethylamine, trimethylamine, dimethylaniline or pyridine be.

One works in the medium of an organic solvent, such as ethanol, methanol or isopropanol.

The products of the above formula I or I ¹ have at least one asymmetric carbon atom (carbon in the 2-position) and can have a second of these (carbon in the 4-position) with certain meanings of the substituents R ₃ and R ^.

The product of the formula II used as starting material for the preparation of the products of the formula I or I ¹ according to the invention may not have an asymmetric carbon atom with certain meanings of the substituents R ^ and R ^.

The reaction of such a product of the formula II with a product of the above formula III or III ^f leads, according to the invention, to the achievement of a product of the formula I or I »with a single asymmetric carbon atom in racemic form, which is then converted into its optical antipodes according to the art known methods, such as, for example, the formation of salts with the aid of optically active bases, can cleave.

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The product of the formula II used can contain an asymmetric carbon atom. It can be seen in the racemic form or used in optically active form.

The product of the formula I or I ¹ , which is obtained starting from such a product of the formula II, contains two asymmetric carbon atoms. It is therefore in various isomeric forms which can be obtained in separate form by methods known from the art.

The racemates or the diastereomeric optically active products (which could be denoted by the prefix eis or trans) can be separated, for example by selective crystallization, can be obtained by countercurrent distribution or by column chromatography.

These racemates can moreover according to known in the art Methods, such as the formation of salts with the help of optically active bases, are separated into their optical enantiomers will.

The various isomeric forms obtained in this way can also if desired, mixed to give the desired mixture.

The products of the general formula I, and in particular I, in the racemic or optically active forms or in the form of mixtures of these isomers and their alkali, alkaline earth, aluminum, Ammonium and amine salts and optionally their addition salts with acids have interesting pharmacological properties Properties. In particular, they show a pronounced hypolipemic Activity. They reduce the plasmatic content of lipids: triglycerides and cholesterol.

These properties justify the use of the products according to the above formula I ¹ , and in particular I, as medicaments in the racemic or optically active forms or in the form of mixtures of these isomers and of them

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pharmaceutically acceptable alkali, alkaline earth, aluminum, ammonium and amine salts when R ^ or R 'denote a hydrogen atom, as well as of the addition salts with pharmaceutically acceptable acids of the products of the formula I ¹ , in which R · denotes a dialkylaminoalkyl radical.

Among the products of the formula I ', and in particular I, and the salts, the products of the formula I can be mentioned, in particular in their racemic or optically active forms or in the form of mixtures of these isomers, in which R ₁ and R ~ are identical or different can be, denote a hydrogen atom or a methyl radical, R denotes a hydrogen atom, a methyl radical or a phenyl radical, R ₄ denotes a hydrogen atom and R, - denotes a hydrogen atom or a chlorine atom, as well as the products of the formula I in which R ₁ is Denotes hydrogen atom or a methyl radical, R "and R * denote a hydrogen atom, R ₃ denotes a hydrogen atom, a methyl radical or a phenyl radical and Rr denotes a chlorine atom, as well as the alkali, alkaline earth, aluminum, ammonium and amine salts of the products of the formula I, in which R _{1 is} a hydrogen atom.

Among the products of the above formulas I ¹ and I can be mentioned in particular the isomers A described in the examples and, above all, their isomers A described and defined above «

The entirety of the products defined above are used in human therapy, especially in the treatment of acute or chronic hyperlipemia, cardiac insufficiencies of atheromatic origin and chronic anxiety states, very much valuable medicines.

The usual dose, according to the product used, the patient and the disease in question varies, for example 0.05 to 1 g per day in the adult when administered orally be.

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The present invention also relates to pharmaceutical compositions, which are characterized in that they have at least one of the aforementioned products or as an active ingredient Contain salts.

These compositions are prepared for administration by the digestive tract or by the parenteral route can be. They can be solid or liquid and are in pharmaceutical forms, usually in used in human medicine, such as simple or sugar-coated Tablets, gelcaps, granules, suppositories and injectables. They are made using the usual methods.

The active ingredient (s) can usually be incorporated into these pharmaceutical compositions for excipients such as talc, gum arabic, lactose, starch, magnesium stearate, Cocoa butter, aqueous or non-aqueous carriers, fatty substances of animal or vegetable origin, paraffin derivatives, Glycols, various wetting, dispersing or emulsifying agents and preservatives.

Finally, the present invention relates as new industrial products which can be used for the preparation of the products of the formulas I and I ¹ , the following products in their racemic or optically active forms:

S-chloro-a-hydroxy-a-methyl-a-phenylbenzolmethanol, the products of the formula II ¹ .:

¹¹¹ A

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where R ' ₄ denotes a chlorine atom or a fluorine atom, R ¹ ^ denotes a chlorine atom, R' ₃ denotes an alkyl radical having 2 to 4 carbon atoms, where R ' _{3 can} also denote a methyl radical when R' denotes a fluorine atom.

Most of the products of the formula II are known.

The products of the formula II, which are not known and in which R ₃ denotes a hydrogen atom, can be obtained by reducing the corresponding benzophenone derivatives of the formula A:

for example with the aid of a mixed hydride, being prepared in the medium of an organic solvent is working.

The products of the formula II, which are not known and in which R ₃ denotes an alkyl radical having 1 to 5 carbon atoms or a phenyl radical, can be obtained by reacting an organomagnesium derivative of the formula

R ₃ -Mg-HaI

wherein Hal is a chlorine or bromine atom and R _{3 has} the meaning given above, can be prepared with a corresponding benzophenone derivative of the above formula A in an organic solvent medium. Such a procedure is illustrated below in the experimental section.

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The following examples illustrate the invention without restricting it.

example 1

6-chloro-4-methyl-4-phenyl-r4Hi-1,3-benzodioxin ~ 2-carboxylic acid (Mixture of the two diastereomeric raceroates)

Mix 8.1 g of sodium amide and 100 ml of toluene with stirring, add dropwise, while stirring, one by dissolving 24.9 g of 5-chloro-2-hydroxy-o-methyl-a-phenylbenzene-methanol in 250 ml Toluene solution is added, the mixture is refluxed for 4 1/2 hours, the mixture is brought to room temperature back, add 18 g of potassium dichloroacetate in small fractions with stirring, add 20 ml of hexamethylphosphoric trisamide to, reflux for 5 hours, cool the mixture until it has reached room temperature, slowly add 10 ml of ethyl acetate and then 250 ml of water dropwise. The aqueous phase is recovered and the organic phase is extracted again 3 χ 100 ml of water and combine the various aqueous extracts, which are washed with 3 χ 100 ml of ether. You acidify them aqueous extraction phase containing the potassium salt of the expected product by introducing sulfur dioxide into and extracted 4 χ with 100 ml of ether. The essential extraction phase is washed with 3 × 50 ml of water. One dries the organic Phase over magnesium sulphate, treated with activated charcoal and the solvent is evaporated off in vacuo. 24 g of crude product are obtained, which are obtained from 100 ml of a cyclohexane / ßenzene mixture Oo / 10) crystallizes, the crystals obtained are dried and receives 15.2 g of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid. F = 142 ° C.

Analysis: (C ₁₆ H ₁₃ ClO ₄ )

Calculated; C 63.06 H 4.30 Cl 11.63 % Found: 63.3 4.4 11.5%

The starting material for the production of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid 5-chloro-2-hydroxy-a-methyl-a-phenylbenzenemethanol used can be applied to the

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can be produced in the following way:

14 g of magnesium turnings are dispersed with stirring in 100 ml of anhydrous ether, a solution obtained by dissolving 76 g of methyl iodide in 200 ml of anhydrous ether is added dropwise with stirring, refluxed for 1 hour, cooled to a temperature of 15 to 20 ° C , then adds a solution obtained by dissolving 59 g of 5-chloro-2-hydroxybenzophenone in 250 ml of anhydrous benzene at this temperature, partially distils off the ether and then refluxes again for 2 hours. The mixture is then cooled to a temperature of 5 to 10 ^° C. and 250 ml of 3N hydrochloric acid are added dropwise.

It is decanted and the organic phase is recovered and the aqueous phase is washed with 2 × 100 ml of benzene.

The organic extraction phase is then washed with water with a saturated sodium bicarbonate solution and finally with 2 × 50 ml of water. One dries the organic Phase over magnesium sulfate, then the solvent is evaporated in vacuo and 58.9 g of crystals are obtained, which are dissolved in petroleum ether (Bp. 60 to 80 ° C) takes up, and receives 53 g of 5-chloro-2-hydroxy-α-methyl-a-phenylbenzene methanol. F = 106 ° C.

Analysis: (C ₁₄ H ₁₃ ClO ₂ )

Calculated: C 67.61 H 5.27 Cl 14.26% Found: 67.8 5.4 14.2 %

Example 2

The isomers A and B of 6-chloro-4-methyl-4-phenyl- ("4H ~ l-1,3-benzodioxin-2-carboxylic acid methyl ester

A solution of 2.25 g of diazomethane in 150 ml of methylene chloride is prepared here, this solution cools down to 5 ° C., a solution that was obtained by adding dropwise thereto at 5 ° C. . Dissolve 3.3 g of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid in the form of the mixture obtained in Example 1

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of the two diastereomeric racemates in 75 ml of methylene chloride. The mixture is stirred for 1 hour at room temperature and then the solution is left for 24 hours. 10 ml of acetic acid are then added and the solvent is then evaporated off in vacuo. Is recovered 4.2 g of 6-chloro-4-methyl-4-phenyl- [4H] -I ₁ 3-benzodioxin-2-carbonsäuremethylester in the form of the mixture of the two diastereomeric Raceraate.

The residue obtained is subjected to column chromatography on silica, eluting with a mixture of ethyl ether and petroleum ether ( boiling point 60 to 80 ° C.) (20/80), and 1 g of isomer A of 6-chloro-4-methyl- 4-phenyl- [4H] -1, 3-bensodioxin-2-carboxylic acid methyl ester. F = 114 to 115 ° C.

Analysis; (C ₁₇ H ₁₅ ClO ₄ )

Calculated: C 64.06 H 4.74 Cl 11.12 % Found: 63.9 4.7 11.4 %

MNR spectrum (basic frequency of the equipment used: 60 Hz)

CH ₃ at 117 Hz

COOCH ₃ at 232 Hz

Hydrogen in position 2 at 311 Hz

aromatic protons from 410 to 445 Hz

0.6 g of isomer B of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester is also obtained. F = 102 ° C.

Analysis; (C ₁₇ H ₁₅ ClO ₄ )

Calculated: C 64.06 H 4.74 Cl 11.12 % Found: 64.0 4.8 11.3 %

MNR spectrum (basic frequency of the equipment used: 60 Hz)

CH ₃ at 125 Hz

COOCH ₃ at 228 Hz

Hydrogen in the 2-position at 341 Hz

aromatic protons from 405 to 455 Hz

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i 27A3279

Example 3 Isomer A of 6-chloro-4-methyl- ^

2-carboxylic acid

14 g of isomer A of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester are mixed, that in Example 2 at the end of a second implementation of the one described in Example 2 Procedure obtained, 2.8 g of potassium hydroxide biscuits, 32 ml of water and 160 ml of methanol, stirred for 22 hours at room temperature, added 320 ml of water, washed the aqueous Phase with 2 × 160 ml ether, then acidify the aqueous solution with a 2N hydrochloric acid solution, extract the obtained precipitate with 3 χ 320 ml of ether, washes the organic Extraction phase with 2 × 160 ml of water, dry over magnesium sulfate and bring to dryness. 13 g of crystals are obtained. 3.9 g of this are crystallized from 100 ml of an ethyl acetate / cyclohexane mixture (2θ / 8θ) around and dry. 3.3 g of isomer A of 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid are obtained. F = 175 to 176 ° C.

Analysis: (C ₁₆ H ₁₃ ClO ₄ )

Calculated: C 63.06 H 4.30 Cl 11.63% Found: 63.3 4.6 11.3 %

NMR spectrum (fundamental frequency: 60 Hz)

CH ₃ at 117 Hz

Hydrogen in position 2 at 313 Hz
COOH at 468 Hz
-aromatic protons from 412 to 443 Hz

Example 4

Isomer B of e-chloro ^ -methyl ^ -phenyl-MHi-l ^ -benzodioxin-2-carboxylic acid

5.3 g of isomer B of 6-chloro-4-methyl-4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylic acid methyl ester are mixed, that in Example 2 at the end of a second implementation of the one described in Example 2 Procedure was obtained, 10 ml of water, 1.2 g of potassium

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hydroxyd cookies and 50 ml of methanol, stirred for 20 hours Room temperature, add 200 ml of water, wash the aqueous phase with 2 × 80 ml of ether, then acidify the aqueous solution with a 2N hydrochloric acid solution, extracted with 3 χ 100 ml ether, combine the extracts, wash the extract with 2 χ 80 ml water, dry the ethereal phase over magnesium sulfate, the solvent is evaporated off in vacuo and 4.8 g of crystals are obtained, which are obtained from a cyclohexane / ethyl acetate mixture (8o / 2O) recrystallizes, dries and receives 4.4 g of isomer B of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid. F «171 ° C.

Analysis; (C ₁₆ H ₁₃ O ₄ Cl).

Calculated: C 63.06 H 4.30 Cl 11.63 % Found: 63.1 4.4 11.7%

NMR spectrum (fundamental frequency: 60 Hz)

CH ₃ at 124 Hz

COOH at 329 Hz *

Hydrogen in the 2-position at 341 Hz

aromatic protons from 408 to 445 Hz

Example 5 -,

6-chloro-2,4-dimethyl-4-phenyl-r 4H1-1,3-benzodioxin-2-carboxylic acid (mixture of the two diastereomeric racemates)

Mix 8 g of sodium amide and 100 ml of toluene with stirring, add dropwise at room temperature a suspension which is obtained by dispersing 24.9 g of 5-chloro-2-hydroxy-a-methyl-aphenylbenzene-methanol was obtained in 250 ml of toluene, the reaction device is brought to reflux for 6 hours and the mixture is cooled until it is at room temperature, add 17 g of sodium dichloro-2,2-propionate in small portions, bring again Reflux for 6 hours, cool to room temperature and add 700 ml of water. It is acidified by adding an n-hydrochloric acid solution and make it alkaline again by adding a saturated sodium bicarbonate solution. You win that

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aqueous extraction phase, which is washed with 3 χ 100 ml of ether, acidify the aqueous extract by adding a 2N hydrochloric acid solution and extracted with 3 χ 100 ml of ether, combined the organic extracts, which are mixed with 3 χ 80 ml of water washes and dried over magnesium sulfate, then evaporated the solvent in vacuo and obtained 23 g of 6-chloro-2,4-dimethyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid. F = 181 ° C.

Analysis: (C ₇ H ₁₅ ClO ₄ )

Calculated: C 64.06 H 4.74 Cl 11.12% Found: 64.0 4.8 11.2 %

Example 6

Isomers A and B of 6-chloro-2,4-dimethyl-4-phenyl ~ r4Hi-1,3-benzodioxin-2-carboxylic acid methyl ester

23 g of 6-chloro-2,4-dimethyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid are mixed in the form of the mixture of the two diastereomeric racemates A and B, which were obtained in Example 5, 100 g resin Redex "CF" (strongly sulfonic acid cationic resin) and 250 ml methanol, reflux for 20 hours, cool to room temperature, suck off the resin, rinse it with solvent and concentrate the filtrate in vacuo. This gives 20 g of crude product which was chromatographed on a kg Siliciumdioxydsäule under a pressure of 1.5, eluting with a mixture of ethyl ether and petroleum ether (bp. 60 to 8O ⁰ C) (20/80), and obtains 1, 7 g of isomer A of 6-chloro-2,4-dimethyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid methyl ester. F =, 134 ° C.

Analysis: (C ₁₈ H ₁₇ ClO ₄ )

Calculated: C 64.96 H 5.15 Cl 10.65 % Found: 65.2 5.2 10.9 %

NMR spectrum (fundamental frequency: 60 Hz)

CH ₃ groups at 103 and 113 Hz

COOCH ₃ at "172 Hz

aromatic protons from 419 to 447 Hz

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It also yields 8.2 g of isomer B (as an oil) of 6-chloro-2,4-dimethyl-4-phenyl- [4H] -I ₁ 3-benzodioxin-2-carbonsäurfemethylesters.

Analysis; (C ₁₈ H ₁₇ ClO ₄ )

Calculated: C 64.96 H 5.15 Cl 10.65 % Found: 65.8 5.1 10.8 %

NMR spectrum (fundamental frequency: 60 Hz)

CH ₃ groups at 106 and 117 Hz

COOCH ₃ at 224 Hz

aromatic protons from 415 to 455 Hz

Example 7

Isomer A of 6-chloro-2 _< 4 »dimethyl-4 ~ phenyl-r4Hi-1,3-benzodioxin-2-carboxylic acid

1.6 g of isomer A of the 6-chloro-2,4-dimethyl-4-phenyl- [4H] -l, 3-benzodioxin-2-carboxylic acid methyl ester obtained in Example 6 are mixed, 20 ml of methanol, 2 ml of water and 0.56 g of potassium hydroxide chips, if the mixture is stirred for 48 hours at room temperature, 100 ml of water are added, the aqueous phase that is taken with it is recovered

Washes 3 χ 50 ml of ether, acidifies the aqueous solution by adding it a 2N hydrochloric acid solution and extracted with

4 χ 50 ml ether, combine the essential extracts, which are washed with 3 χ 50 ml water, and then dry over magnesium sulfate. The solvent is evaporated off in vacuo and 1.5 g of product are obtained which are recrystallized from 80 ml of cyclohexane, ' and receives 1.2 g of isomer A of 6-chloro-2,4-diraethyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid. F »184 ° C.

Analysis: (C ₁₇ ^H 15 O ₄ Cl) 4, 74 Cl 11 • , 12 % Calculated : C 64, 06 H. 4, 8th 11 ,1 % Found: 64, 1

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NMR spectrum (fundamental frequency: 60 Hz)

CH ₃ groups at 101.5 and 113 Hz ■

COOH at 342 Hz

aromatic protons from 412 to 442 Hz

Example 8

Isomer B of 6-chloro-2,4-dimethyl-4-phenyl-r4Hi-1,3-benzodioxin-2-carboxylic acid

8 g of isomer B of 6-chloro-2,4-dimethyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid methyl ester, obtained in Example 6, 80 ml of methanol, 8 ml of water and 2 are mixed , 8 g of potassium hydroxide biscuits, stirred for 24 hours at room temperature, added 150 ml of water and the aqueous phase was recovered, which was washed with 3 × 60 ml of ether. The aqueous solution is acidified by adding a 2N hydrochloric acid solution and extracted with 4 × 60 ml of ethyl ether. The ethereal extracts are combined and washed with 2 × 80 ml of water, then dried over magnesium sulfate and the solvent is evaporated off in vacuo. 7.2 g of product are obtained which are recrystallized from 80 ml of cyclohexane. It is dried and 4.5 g of isomer B of 6-chloro-2,4-dimethyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid are obtained. F = 125 ° C.

Analysis; (C ₁₇ H ₁₅ O ₄ Cl)

Calculated: C 64.06 H 4.74 Cl 11.12% Found: 64.2 5.0 11.2 %

NMR spectrum (fundamental frequency: 60 Hz)

CH ₃ groups at 104 and 119 Hz
aromatic protons from 417 to 455 Hz COOH at ^ 540 Hz

Example 9

6-chloro-4-phenyl-r4Hl-1,3-benzodioxin-2-carboxylic acid

Mix 10.35 g of sodium amide and 100 ml of toluene, add dropwise at room temperature with stirring a solution that was obtained by dissolving 30.1 g of 5-chloro-2-hydroxy-

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α-phenylbenzenemethanol in 200 ml of anhydrous toluene, stir 2 hours at room temperature, bring the mixture to reflux for 6 hours, cool the mixture to room temperature and add Add 22.3 g of potassium dichloroacetate to small portions, add 20 ml of hexamethylphosphoramide to, stir for 20 hours at room temperature, bring the mixture to toluene reflux for 4 hours, leave to room temperature return, add 20 ml of ethyl acetate and then slowly 250 ml of water .. The aqueous phase is recovered and extracted Again the organic phase with 3 × 100 ml of water and combined the various aqueous extracts, which are mixed with 3 × 100 ml Wash with ether. The aqueous extraction phase containing the potassium salt of the expected product is acidified by introducing it of sulfur dioxide, extracted with 3 × 100 ml of ether, combined the extracts, washed with 3 χ 100 ml of water, dried over magnesium sulfate, treated with activated charcoal, evaporated the Solvent in vacuo and receives 24 g of crude product, which is allowed to disintegrate in cyclohexanone, gives crystals which are obtained from 520 ml of a benzene / cyclohexane mixture (7/3) recrystallized, and receives 5.3 g of 6-chloro-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid. F = 194 ° C.

Analysis: (C ^ sH ^ C ¹⁰ ^

Calculated: C 61.97 H 3.81 Cl 12.20 %
Found: 62.2 3.9 12.1 %

NMR spectrum (fundamental frequency: 60 Hz)

Hydrogen in the 2- and 4-positions at 343.5 and 364 Hz COOH at * 514 Hz

aromatic protons from 398 to 442 Hz

Example 10 6-chloro-4 _t 4-diphenyl-r4Hi-l _< 3-benzodioxin-2-carboxylic acid

Mix 12.4 g of 5-chloro-2-hydroxy-a, a-diphenylbenzene methanol, 150 ml of toluene and 3.2 g of sodium amide, bring the mixture to reflux for 6 hours, cool to room temperature and add 6.8 g Add potassium dichloroacetate, reflux again for 6 hours, cool to room temperature and add 300 ml of water. Man

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slightly acidic by adding a η-hydrochloric acid solution and then make it alkaline by adding a saturated sodium bicarbonate solution. It is washed with 2 χ 100 ml of methylene chloride, then acidify by adding a 2N hydrochloric acid solution on, extracted with 3 χ 100 ml of ether, combined the essentials Extracts, washed with 2 × 80 ml of water, then dried over magnesium sulfate and treated with activated charcoal. After this Evaporation of the solvent in vacuo gives 7 g of product which is recrystallized from 300 ml of benzene. 4.6 g are obtained 6-chloro-4,4-diphenyl- [4H] -1,3-benzodioxin-2-carboxylic acid. F = 226 ° C.

Analysis; CC ₂₁ H ₁₅ O ₄ Cl)

Calculated: C 68.76 H 4.12 Cl 9.67%
Found: 69.1 4.3 9.5 %

NMR spectrum (fundamental frequency: 60 Hz)

Hydrogen in position 2 at 325 Hz

COOH at - 313 Hz

aromatic protons from 405 to 443 Hz

Example 11

Isomer A of 4-methyl-4-phenyl-Γ4Hl-1,3-benzodioxin-2-carboxylic acid methyl ester

1.3 g of palladium on activated carbon to 10%, 11.8 g of isomer A of 6-chloro-4-methyl-4-phenyl- [4H] -l, 3-benzodioxin-2-carboxylic acid methyl ester are brought into a hydrogenation cell, that in Example 2 at the end of a second implementation of the one described in Example 2 Procedure was obtained, 500 ml of ethanol and 10 ml of triethylamine and stir the suspension under a stream of hydrogen at room temperature. The catalyst is washed with methylene chloride, the filtrate is then concentrated in vacuo, the residue is taken up in 100 ml of water, and 50 ml of a 2N hydrochloric acid solution are added and extracted with 3 χ 150 ml of methylene chloride, combined the extracts, washed with 2 χ 100 ml of water, dries over calcium chloride, then, after treatment with activated charcoal, evaporates the solvent under vacuum and

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- vT- . 27A9279 25

holds 9.7 g of expected product.

A sample of this product was recrystallized from methanol. F. 124 ° C.

Analysis; i ^c ₁ 7 ^H ₁ g ° 4) Calculated: C 71.82 H 5.67 % Found: 72.1 5.8 %

NMR spectrum (fundamental frequency: 60 Hz)

Hydrogen in the 2-position at 312 Hz COOCH ₃ at 231 Hz with regard to phenyl geminal CH ₃ : 117 Hz aromatic protons from 410 to 450 Hz

Example 12 Isomer A of 4-methyl-4-phenyl-1,3-benzodioxin-2-carboxylic acid

9.7 g of the isomer obtained in Example 11 are mixed with stirring A of the 4-methyl-4-phenyl- [4H] -l, 3-benzodioxin-2-carboxylic acid methyl ester, 4 g of potassium hydroxide biscuits, 10 ml of water and 90 ml of methanol, left for 6 hours at room temperature with stirring, add 400 ml of water, wash the aqueous phase with 2 × 100 ml of methylene chloride, acidify the aqueous phase Addition of a 2N hydrochloric acid solution, extracted with 3 χ 150 ml of methylene chloride, the extracts are combined and washed with 2 χ 80 ml water, dry over calcium chloride, evaporate the solvent in vacuo and 8 g of product are obtained, which is recrystallized from an ethyl acetate / Cyelohexah-Geraisch (20/80), and wins 5.1 g of isomer A of 4-methyl-4-phenyl-1,3-benzodioxin-2-carboxylic acid. P «163 ° C.

Analysis: (C ₁₆ H ₁₄ O ₄ )

Calculated: C 71.10 H 5.22 * Found: * 71.1 5.3 %

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.26-27A9279

3?

Example 14

Isomer B of 4-methyl-4-phenyl-r4H] -l., 3-benzodioxin-2-carboxylic acid

10.2 g of the isomer B of 4-methyl-4-phenyl- [4H] -l, 3-benzodioxin-2-carboxylic acid methyl ester obtained in Example 13 are mixed, 4 g of potassium hydroxide, 10 ml of water and 90 ml of methanol, left for 16 hours at room temperature with stirring, add 500 ml of water, wash the aqueous phase with 2-80 ml of methylene chloride, acidify the aqueous phase by adding a 2N hydrochloric acid solution, extracted with 3 χ 100 ml methylene chloride, washes with 2 χ 80 ml water, dries over calcium chloride, evaporates the solvent in vacuo, gives 9 g of product, which is obtained from an ethyl acetate / Cyclohexane mixture (20/80) recrystallized, and obtained 6.7g of the expected product. F = 153 ° C.

Analysis: (C ₁₆ H ₁₄ O ₄ )

Calculated: C 71.10 H 5.22%
Found: 71.1 5.3 %

NMR spectrum (fundamental frequency: 60 Hz)

CH ₃ at 128 Hz

Hydrogen in position 2 at 348 Hz

aromatic protons from 410 to 460 Hz

Example 15

6-chloro-4,4-diphenyl- [4H] -1,3-benzodioxin-2-carboxylic acid methyl ester

11 g of the 6-chloro-4,4-diphenyl- [4H] -1,3-benzodioxin-2-carboxylic acid obtained in Example 10, 50 g of Redex ¹¹ CF "resin (strongly sulfonic acid cationic resin) and 200 are mixed by stirring ml of methanol, reflux for 16 hours, cool to room temperature, suction the resin off, wash it with ether and concentrate the filtrate in vacuo.

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NMR spectrum (fundamental frequency: 60 Hz)

CH ₃ at 119 Hz

Hydrogen in the 2-position at 316 Hz

COOH at 534 Hz

aromatic protons from 418 to 450 Hz

Example 13

Isomer B of 4-methyl-4 ~ phenyl-r4Hl-1,3-benzodioxin-2 ~ carbon- · acid methyl ester

1.3 g of palladium on activated carbon are placed in a hydrogenation cell to 10%, 12.8 g of isomer B of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester, which was obtained in Example 2 in a second implementation of the procedure described in Example 2, 10 ml of triethylarain and 200 ml Ethanol, initiates a continuous stream of hydrogen and stir the suspension at room temperature for about 2 hours. It is filtered, the catalyst is rinsed with methylene chloride, the piltrate evaporates in vacuo, the residue is taken up in 80 ml of water, and 70 ml of a 2N hydrochloric acid solution are added to, extracted with 3 100 ml of methylene chloride, combined the extracts and washed with 3 χ 50 ml of water, dried over Calcium chloride and the solvent evaporated in vacuo. 10.2 g of the expected product are obtained.

A sample of this product is recrystallized from methanol. P = 137 ° C.

Analysis; (^ 7H ₁₆ O ₄ )

Calculated: C 71.82 H 5.67 %
Found: 71.8 5.8 %

NMR spectrum (fundamental frequency: 60 Hz)

CH ₃ at 128 Hz

COOCH ₃ at 234 Hz

Hydrogen in the 2-position at 347 Hz

aromatic protons from 410 to 465 Hz

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The crude product obtained is taken up in 200 ml of ether and washed the organic phase with 100 ml of a 5% sodium bicarbonate solution and then with 2 × 100 ml of water. One dries the essential Phase over magnesium sulfate, treated with activated charcoal, the solvent is evaporated and 6.3 g of product is obtained recrystallized from 140 ml of cyclohexane. After drying, 5.1 g of the expected product are obtained. F = 172 ° C.

Analysis: (C ₂₂ H ₁₇ O ₄ Cl)

Calculated: C 69.38 H 4.50 Cl 9.31%
Found: 69.7 4.6 9.3%

Nuclear Magnetic Resonance Spectrum (fundamental frequency: 60 MHz) (deuterochloroform)

COOCH ₃ at 230 Hz

aromatic protons from 406 to 443 Hz hydrogen in the 2-position at 324 Hz

Example 16

Isomer A of e-chlorine- ^ 2-carboxylic acid ethyl ester

Stage A: isomer A of the e-

zodioxin-2-carboxylic acid chloride

4.9 g of the isomer obtained in Example 3 are mixed by stirring A of the 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid and 50 ml of anhydrous benzene, cools the suspension to a temperature of 10 ° C, then add dropwise 2.3 ml of triethylamine, then add dropwise at the same) Temperature a solution of 1.5 ml of thionyl chloride in 25 ml of anhydrous benzene, the solution is brought to reflux for 2 hours, cools to room temperature, sucks the precipitate and wins the expected product in solution.

Stage B: Isomer A of 6-chloro-4-methyl-4-phenyl-r4Hl-1,3-benzodioxin-2-carboxylic acid ethyl ester

Mix 3 ml of abs. Ethanol, 50 ml of anhydrous benzene and 2.3 ml of triethylamine are added dropwise at room temperature

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acid chloride solution obtained in stage A, left for 20 hours with stirring at room temperature, filtered off with suction and washed the precipitate of the triethylamine hydrochloride with cold benzene, the filtrate was washed with 2 x 40 ml of water, the organic dried Phase over calcium chloride, treated with activated charcoal, the solvent evaporates in vacuo, receives 2 g of crude product, which is recrystallized from 30 ml of hexane and, after drying, 4 g of the expected product are obtained. P a 92 C.

Analysis: (C ₁₈ H ₁₇ O ₄ Cl)

Calculated: C 64.97 H 5.15 Cl 1O, 65 % Found: 65.1 5.3 10.8 %

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

CH ₃ of C ₂ H ₅ at 72.5-79.5-87 Hz CH ₃ in the 4-position at 116 Hz

CH ₂ of C ₂ H ₅ at 247.5-255-262-269 Hz hydrogen in the 2-position at 308 Hz aromatic protons from 412 to 441 Hz

Example 17

Isomer A of sodium 6-chloro-4-methyl-4-phenyl-r4Hl ~ 1,3-benzodioxin-2-carboxylate

Mix 0.6 g of sodium hydroxide and 250 ml of abs. Ethanol, adds at room temperature 4.6 g of the isomer A of 6-chloro-4-methyl-4 ^ phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid obtained in Example 3 to, brings to the boil for 5 minutes, filtered, cools to room temperature, adds 500 ml of ether to the piltrate and leaves 16 hours at room temperature with stirring. It is filtered off and, after drying, 3.8 g of the expected product are obtained.

Analysis: C ₁₆ H ₁₂ O ₄ ClNa

Calculated: C 58.82 H 3.70 Cl 10.85 * Found: 58.5 3.8 10.7 %

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ho

Example 18

d- and 1-isomers of isomer A of 6-chloro-4-methyl-4-phenyl-J ~ 4Hl-1,3-benzodioxin-2-carboxylic acid

1) 1-isomer

Level A; ll ~ p-Nitrophenyl-2-amino-l _< 3-propanediolsal2 of the 1-isomer of isomer A of 6-chloro-4-methyl-4-phenyl-r4H] -l _< 3-benzodioxin-2-carboxylic acid , 2 g of the isomer A of 6-chloro-4-methyl-4-phenyl- [4H] -I, 3-benzodioxin-2-carboxylic acid, 16.2 g of llp-nitrophenyl-2-amino- 1,3-propanediol and 800 ml of ethyl acetate.

The mixture is brought to reflux and, after the salt formed has precipitated, the reflux is maintained for 5 minutes. Man brings to room temperature, sucks the resulting precipitate, rinses it with ethyl acetate, dries in vacuo and wins 10 g of crude product. [The mother liquors are kept for the separation of the crude d-isomer (see later).]

The 10 g of the crude product obtained are recrystallized from isopropanol and 6.4 g of the expected product are finally obtained. F = 218 ° C. [α] ^ ° = -84 ° + 2 ° (c = 1 56, ethanol).

A sample of this product is recrystallized from a little isopropanol. F = 218 ° C. [oc] p ° = -84.5 ° + 2 ° (c = 1%, ethanol).

Stage B: 1-isomer of isomer A of 6-chloro-4-methyl-4 - phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid

The purified salt obtained in step A above is suspended in 150 ml of η-hydrochloric acid, then extracted with 3 χ 75 ml of ether, the organic extraction phase was washed with 3 50 ml of water and dried over magnesium sulfate. The solvent is evaporated off in vacuo, giving 3.5 g of crude product which is crystallized from cyclohexane, 2.7 g of crystals are obtained, which are obtained by recrystallization Purifies from cyclohexane, and receives 2.3 g of crystals from

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F = 113 to 114 ° C, which melts at 128 ° C after recrystallization. It is crystallized again from 80 ml of cyclohexane and receives 1.8 g of the expected product of F = 113 C.

Starting from the mother liquors from the above recrystallizations, 0.5 g of the expected product is obtained. One collects this 0.5 g of product and the 1.8 g of the product obtained above, the 2.3 g of product crystallized out 50 ml of cyclohexane around, maintaining the reflux of the solvent for 20 minutes, and then receives 2 g of the expected Product. F = 140 ° C.

(The changes in the various reading melting points for the expected product are likely to occur the changes in the crystal structure.)

Analysis: (C ₁₆ H ₁₃ ClO ₄ )

Calculated: C 63.06 H 4.30 Cl 11.63 % Found: 63.2 4.4 11.6 %

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

CH ₃ at 116.5 Hz

Hydrogen in position 2 at 313 Hz, aromatic protons from 415 to 443 Hz OH at approx. 540 Hz

Rotation value

[aj £ ° ₌ _ ₁₅₇ ° + 2.5 ° (c «1%, ethanol 95 °)

2) d-isomer

Stage A: Crude d-isomer of isomer A of 6-chloro-4-methyl-4-phenyl-F 4h1-1.3-benzodioxin-2-carboxylic acid

The ethyl acetate mother liquors of the salt formation of the isomer A of 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid are taken with l-l-p-nitrophenyl ^ -amino-ljS-propanediol on.

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(Λ

2 7 Λ 9 2 7 9

The solution is concentrated in vacuo, 17.8 g of crude product are obtained, which is treated with 20 ml of 2N hydrochloric acid, extracted with 3 × 100 ml of ether, the organic phase was washed with 2 × 50 ml of water, dried over magnesium sulfate and constricts in a vacuum. 8.4 g of residue are obtained, which is mixed with 150 ml of a cyclohexane-ethyl acetate mixture (7θ / 3θ) picks up, and brings to reflux, leaves cool, the crystallizing racemic acid sucks off the remaining starting substance, the filtrate is concentrated in vacuo around one and receives 7 g of the expected crude product.

Level B; d-l-p-nitrophenyl-2-amino-1,3-propanediol salt of d-isomers of the e-

1,3-benzodioxin-2-carboxylic acid

The residue obtained above is taken up in 300 ml of ethyl acetate and 7.4 g of d-1-p-nitrophenyl-2-amino-1,3-propanediol are added to the solution.

The suspension is brought to reflux and, after the salt formed has precipitated out, allowed to cool to room temperature, The precipitate is filtered off with suction and rinsed with a little ethyl acetate. After drying, 11.4 g of the expected product are obtained from F = 200 ° C.

It is recrystallized from 1.1 l of isopropanol and 6.2 g of the expected product with a melting point of 218 ° C. are obtained 800 ml of isopropanol recrystallized, and 5 g of the expected product with a melting point of about 218.degree. C. were obtained.

Stage C; d-isomer of isomer A of 6-chloro-4-methyl-4-phenyl-r4Hi-1,3-benzodioxin-2-carboxylic acid

The salt obtained above is taken up in 150 ml of water, acidified with 2N hydrochloric acid and extracted with 2 χ 100 ml ether, wash the organic extraction phase with 2 χ 50 ml water, dry over magnesium sulfate and the solvent is evaporated off in vacuo. 2.9 g of crude product are obtained, which is in a mixture of ethyl ether and

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Petroleum ether (bp 60 to 80 ° C) (2θ / 8θ) absorbs.

Finally, after separation, 2.4 g of the expected product are obtained. F = 128 ° C. [cc] * ⁰ = + 153 ° ± 2.5 ° (c = 1%, ethanol).

This product is recrystallized from 100 ml of cyclohexane and 2 g of the expected product are obtained. F = 128 ° C. [a] _D = + 153 ° ± 2.5 ° (c * 1%, ethanol).

It is recrystallized again from 60 ml of cyclohexane and 1.7 g of the expected product are finally obtained. F »140 ° C.

(As for the 1-isomer, the present has d-isomer multiple melting points. This is likely due to changes in the crystalline structure.)

Analysis; (C ₁₁ -H ₁₃ ClO ₁ )

Calculated: C 63.06 H 4.30 Cl 11.63 % Found: 63.2 4.3 11.6 %

Nuclear Magnetic Resonance Spectrum: (Deuterochloroform) (Fundamental frequency: 60 MHz)

CH ₃ at 117 Hz

monosubstituted phenyl at 440 Hz aromatic protons from 413 to 440 Hz

OH at 485 Hz

Hydrogen in the 2-position at 312.5 Hz

Rotation value:

[a] £ ° = + 154.5 ° + 2.5 ° (c «1 X ₁ ethanol)

Example 19

6-chloro-4- (3-chlorophenvl) -4-tnethvl-r 4Hi-I «3- * benzodioxin-2-carboxylic acid (mixture of the djastereomeric racemates)

Mix 10 g of sodium amide and 200 ml of anhydrous with stirring Toluene, then add a suspension in small portions at room temperature, which by dissolving 28.3 g of l- [5-

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- ■ * - 27A9279 «A

Chlorine-2-hydroxyphenyl] -l- [3-chlorophenyl] -ethanol in 250 ml of toluene was obtained, and then takes the reaction mixture for 6 hours to reflux (1 g of sodium amide is added to the mixture). After cooling to room temperature, it is added in small portions 25 g of potassium dichloroacetate are added with stirring and the mixture is again refluxed for 6 hours. Upon return on 150 ml of water and then 150 ml of 2N hydrochloric acid are slowly added at room temperature. You win the organic one Phase and again extracted the aqueous phase with 2 × 100 ml of ether. The organic extraction phase is washed with 2 × 100 ml Water. The organic phase is extracted with a saturated sodium bicarbonate solution and then with 2 × 100 ml of water. Man Wash the aqueous extraction phase with 3 × 100 ml of ether and then slowly acidify the aqueous phase with a 2N hydrochloric acid solution at. The aqueous phase is then extracted with 3 × 150 ml of ether. The organic extraction phase is washed with 2 χ 75 ml water. They are treated with activated charcoal and dried over magnesium sulfate. The solvent is evaporated under vacuum and finally 29.3 g of the expected product are obtained.

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

CH ₃ at 117 and 125.5 Hz

Hydrogen in the 2-position at 315.5 and 346 Hz, aromatic protons from 412 to 455 Hz COOH at 588 Hz

The starting material for the preparation of 6-chloro-4- (3-chlorophenyl) -4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid l- [5-chloro-2-hydroxyphenyl] -l- [3-chlorophenyl] -ethanol used can be prepared in the following way:

11 g of magnesium powder are dispersed in 100 ml with stirring anhydrous ether, add dropwise at room temperature and with stirring one by dissolving 64 g of methyl iodide in 100 ml anhydrous ether obtained solution. Maintain a gentle reflux of the solvent during the addition and continues the reflux for 1 hour, leads to room temperature

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back and then adds a solution of 31.7 g of (5-chloro-2-hydroxyphenyl) - (3-chlorophenyl) methanone dropwise over 25 minutes in 100 ml of anhydrous ether and 150 ml of anhydrous benzene.

The ether is distilled, 250 ml of anhydrous benzene are added and the solution is then refluxed for 4 hours.

The mixture is cooled to room temperature and hydrolyzed while maintaining this temperature with the aid of an ice bath, with an n-hydrochloric acid solution.

The organic phase is recovered and the aqueous phase is extracted again Phase with 2 χ 80 ml ether, washes the organic extraction phase with 3 χ 80 ml of water, the organic phase is dried over magnesium sulfate and then the solvent is evaporated Vacuum.

31.5 g of expected product are then obtained, which is recrystallized from 750 ml of cyclohexane.

Finally, 25.5 g of the expected product are obtained. P = 125 ° C.

Analysis; (C ₁₄ H ₁₂ O ₂ Cl ₂ )

Calculated: C 59.38 H 4.27 Cl 25.04 % Found: 59.2 4.3 24.9 %

That used as a starting material for the preparation of the above 1- [5-chloro-2-hydroxyphenyl] -1- [3-chlorophenyl] ethanol [5-chloro-2-hydroxyphenyl] - [3-chlorophenyl] methanone can can be produced as follows:

Stage A: 4-chlorophenyl 3-chlorobenzoate

5.87 g of 4-chlorophenol and 46.1 g of triethylamine are mixed with stirring and 250 ml of anhydrous benzene, cools to 10 ° C., a solution of 80 g of 3-chlorophenylcarboxylic acid chloride is added dropwise in 100 ml of anhydrous benzene, leaves one night with stirring at room temperature, filtered, sucks the Nieder-

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hit the triethylamine hydrochloride, the filtrate wins and brings to dryness. 122 g of crude product are obtained, which is obtained from 200 ml of a mixture of ethyl ether and petroleum ether (Bp. 60 to 80 ° C) (2θ / 8θ) crystallized.

116 g of the expected product are obtained. F = 72 C.

Analysis: (C 3HgCl ₂ O ₂ )

Calculated: C 58.45 H 3.02 Cl 26.55% Found: 58.5 3.0 26.2 %

Level B: Γ 5-chloro-2-hydroxyphenyl] - [3-chlorophenyl 1-methanone

64.5 g of 4-chlorophenyl 3-chlorobenzoate, which was obtained in the previous stage, and 32 g of aluminum chloride are mixed with stirring, the mixture is gradually heated to 160 ° C. with stirring and left at this temperature for 30 minutes Return to room temperature, the crude product obtained is taken up in methylene chloride, the organic solution is slowly hydrolyzed at the beginning with 250 ml of n-hydrochloric acid, the organic phase is decanted, then the aqueous phase is extracted with 2 × 70 ml of methylene chloride, the organic extraction phase is washed with 3 × 70 ml of water, the organic phase is dried over calcium chloride and the solvent is then evaporated off under vacuum. Finally obtained 60 g of crude product which was a mixture of ethyl ether and petroleum ether (bp. 60 to 8O ⁰ C) crystallized (20/80). It is filtered off with suction, dried and 41.3 g of the expected product are obtained.

A sample of this product is recrystallized from cyclohexane. F = 72 ° C.

Analysis: (C ₁₃ HgCl ₂ O ₂ )

Calculated: C 58.45 H 3.02 Cl 26.55% Found: 58.4 3.2 26.6 %

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Example 20

Isomers A and B of 6-chloro-4- (3-chlorophenyl) -4-methyl-Γ4η1-1,3-benzodioxin-2-carboxylic acid methyl ester

29.3 g of 6-chloro-4- (3-chlorophenyl) -4-methyl- [4H] -1, 3-benzodioxin-2-carboxylic acid are mixed with stirring in the form of the mixture of the two diastereomeric racemates obtained in Example 19, 300 ml of methanol and 30 g of strongly sulfonic acid cationic resin, brought to reflux with stirring for 20 hours, cooled to room temperature, the resin is filtered off with suction, rinsed with methanol and the filtrate is concentrated in vacuo. 20 g of crude product are obtained, which is carried out over a silica column under pressure and while eluting with a mixture of ethyl ether and petroleum ether (Bp. 60 to 80 ° C) (20/80) chromatographed, and obtained after fractionation and evaporation of the solvent:

9.5 q of the expected isomer A, of which 4 g are purified by recrystallization from methanol: 3.2 g of the expected isomer A are obtained in purified form, mp = 112 ° Cj

Calculated: C 57.97 H 3.72 Cl 20.13 % Found: 57.9 4.0 19.8%

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 90 MHz)

CH ₃ at 172 Hz

COOCH ₃ at 345 Hz

Hydrogen in the 2-position at 461.5 Hz, aromatic protons from 623 to 660 Hz

and 8.4 q of the expected isomer B in the form of the crude product.

Analysis: (C ₁₇ H ₁₃ O ₄ Cl ₂ )

Calculated: C 57.97 H 3.72 Cl 20.13 % Found: 58.2 4.0 20.1 %

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Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 90 MHz)

CH ₃ at 184 Hz

COOCH ₃ at 343.5 Hz

Hydrogen in position 2 at 509 Hz

aromatic protons from 612 to 674 Hz

Example 21

Isomer A of 6-chloro-4- (3-chlorophenyl) -4-methyl-r4H'l-l _< 3-benzodioxin-2-carboxylic acid

6.5 g of isomer A of 6-chloro-4- (3-chlorophenyl ) -4-methyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester, which was obtained in Example 20, 2.8g potassium hydroxide cookies, 10 ml of water and 100 ml of methanol, the mixture is stirred for 16 hours at room temperature, 200 ml of water are added, and the mixture is washed the aqueous solution with 2 × 50 ml ether, the aqueous solution acidified with a 2N hydrochloric acid solution, extracted wash the aqueous phase with 3 80 ml ether, wash the organic extraction phase with 2 χ 50 ml water, dry the ethereal phase Phase over magnesium sulfate, the solvent is evaporated off in vacuo and 6.1 g of product obtained from 100 ml of cyclohexane recrystallized. 3.6 g of the expected product are obtained. F = 131 ° C.

Analysis; (C ₁₆ H ₁₂ O ₄ Cl ₂ )

Calculated: C 56.66 H 3.57 Cl 20.90 % Found: 56.7 3.7 20.6 %

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

CH ₃ at 174.5 Hz

Hydrogen in position 2 at 466.5 Hz, aromatic protons = peaks from 625 to 665 Hz

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Example 22

Isomer B of 6-chloro-4- (3-chlorophenvl) -4-methyl-r4Hl-1,3-benzodioxin-2-carboxylic acid

5.3 g of that obtained in Example 20 are mixed with stirring Isomers B of 6-chloro-4- (3-chlorophenyl) -4-methyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester, 2.4 g of potassium hydroxide biscuits, 10 ml of water and 100 ml of methanol, the mixture is stirred one night at room temperature, add 250 ml of water, then wash the aqueous phase with 2 χ 80 ml of ether, acidify the aqueous solution with a 2N hydrochloric acid solution on, the aqueous phase extracted with 3 80 ml of ether, the organic phase was washed with 2 χ 50 ml of water, dried the ethereal phase over magnesium sulphate, concentrated in vacuo and 5.3 g of the expected product are obtained, which can be obtained from 110 ml of a cyclohexane / ethyl acetate mixture (80/30) recrystallized. 4 g of the purified expected product are obtained. F = 177 ° C.

Analysis: (C ₁₆ H ₁₂ O ₄ Cl ₂ )

Calculated: C 56.66 H 3.87 Cl 20.90 % Found: 56.8 3.8 20.9 %

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 90 MHz)

CH ₃ at 185.5 Hz

Hydrogen in the 2 position at 510 Hz

aromatic protons from 610 to 673 Hz

Example 23

6-chloro-4-r (l-methyl) -äthyl1-4-phenyl-r4Hi-l, 3-benzodioxin-2-carboxylic acid (mixture of the two diastereomeric racemates)

Mix with stirring 8.1 g of 50% sodium hydride in oil, 60 ml of anhydrous dioxane and 360 mg of dibenzo-18-crown-6 from in "Synthesis", 1976, page 168, adds by leaving the solution at room temperature for 10 minutes a solution of 3.66 ml of dichloroacetic acid in 60 ml of anhydrous dioxane is added with stirring, then added at room temperature

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a solution of 8.7 g of 5-chloro-a - [(l-methyl) ethyl] -2-hydroxyoc-phenylbenzene methanol in 30 ml of anhydrous dioxane, the suspension is heated to 90 to 100 ° C. for 10 hours, Bring to room temperature, add 500 ml v / water dropwise while cooling with an ice-water bath, wash the aqueous phase with 2 200 ml of ether, extract the ethereal phase with 3 χ 100 ml of 2N sodium hydroxide, acidify the aqueous phase 2N hydrochloric acid and extracts the free acid with 3 χ 150 ml ether, wash the ethereal phase with 3 χ 100 ml water, extract the acid formed in the form of the sodium salt by extraction of the ethereal phase with a saturated sodium bicarbonate solution, then with 3 χ 100 ml of water, wash the aqueous extraction phase with 2 χ 80 ml of ether, acidify by adding 2N hydrochloric acid the acid released in this way is extracted with 3 χ 150 ml of ether, the organic extraction phase is washed with 3 χ 80 ml Water, dries and treated with activated charcoal, brings to dryness and receives 8.8 g of the expected product in the form of an oil.

NMR spectrum (deuterochloroform) (basic frequency of the apparatus:

60 MHz) hydrogen in the 2-position at 323 Hz (the isomer A

corresponding peak)

Hydrogen in the 2-position at 335 Hz (the isomer B

corresponding peak)

^CH 3 _X

the two CH ₃ residues ^ - ^CH ~ ^{of 4} ^ ^ xs ^{69 Hz}

CH ₃

CH ₃
the hydrogen of the residue ^ CH- from 100 to 190 Hz

aromatic protons from 410 to 465 Hz OH at 490 Hz

That used as the starting material for the above manufacture 5-chloro-a - [(l-methyl) ethyl] -2-hydroxy-a-phenylbenzene methanol was made in the following way:

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21.4 g of magnesium turnings and 200 ml of anhydrous are mixed by stirring Ether and 2 ml isopropyl bromide.

The mixture is stirred until the expected magnesium compound is formed, and then added dropwise so that a lighter Reflux is maintained at room temperature a solution of 110.8 g of isopropyl bromide in 400 ml of anhydrous ether to. After the addition is complete, reflux is continued for 2 hours. 58.2 g of [(5-chloro-2-hydroxy) -phenyl] -phenylmethanone are also mixed and 600 ml of anhydrous benzene and then add 520 ml of the dropwise at room temperature solution of the magnesium compound prepared above.

The ether is distilled off and gradually replaced by benzene. The reflux is continued for 6 hours.

After cooling to room temperature, the reaction mixture is poured into 1 liter of an ice-cold 10% ammonium chloride solution. The organic phase is decanted and the aqueous phase is extracted with 2 × 150 ml of ether. You collect the organic ones Phases, washes them with 3 χ 100 ml of water, dries, treated with activated charcoal and evaporate the solvent under vacuum. 74 g of crude product are obtained which are placed on a silica column chromatographed while eluting with methylene chloride. After fractionation, 18 g of crude product are obtained is taken up in 50 ml of cyclohexane. 8.7 g of the expected product are obtained. P * 114 ° C.

A sample of this product is purified by recrystallization from cyclohexane. F «118 ° C.

Analysis; (C ₁₈ H ₁₇ O ₂ Cl)

Calculated: C 69.43 H 6.19 Cl 12.81% Found: 69.7 6.2 12.8%

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27A9279

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency of the apparatus used: 60 MHz)

the two CH ^ groups of the (1-methyl) ethyl radical at 48-55 Hz

and 63-70 Hz / CH- at ^ 165 Hz (multiplet).

OH of the methanol at 165 Hz

OH of the 2-hydroxy residue at 537 Hz

aromatic protons from 395 to 455 Hz

Example 24

Isomer A of 6-chloro-4-f (1-methyl) -ethyll-4-phenyl-r4H] -l, 3-benzodioxin-2-carboxylic acid methyl ester

Level A; Isomer A of 6-chloro-4 ~ r (1-methyl) ethyl 1-4-phenylr4Hl-1,3-benzodioxin-2-carboxylic acid chloride

8.8 g of 6-chloro-4 - [(1-methyl) ethyl] -4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid are mixed with stirring, which was obtained in Example 23, and 100 ml of anhydrous benzene, add while maintaining from room temperature to 3.7 ml of triethylamine, 3.8 ml of thionyl chloride and 25 ml of anhydrous benzene, brings the The mixture is refluxed for 3 hours, cooled to room temperature, filtered off with suction, the precipitate was washed with a little anhydrous Benzene and recover the piltrate, which contains the expected product.

Level B; Isomer A of 6-Οι1ογ-4-Γ (1-methyl) -ethyl] -4-phenylr4H] -l, 3-benzodioxin-2-carboxylic acid methyl ester

Mix 50 ml of anhydrous benzene and 4 ml of anhydrous benzene with stirring Methanol and 3.7 ml of triethylamine, add the filtrate obtained above in step A dropwise at room temperature, stir the mixture for 50 hours at room temperature, suck off and wash the precipitate with a little benzene, the filtrate wins, washes with 2N sodium hydroxide solution and then with water until a neutral pH is achieved. One dries the organic Phase, treated with activated charcoal, brings to dryness and receives 7.3 g of crude product, which is crystallized from methanol,

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sucks off, dries the crystals obtained and wins 4.5 g of the expected product obtained by recrystallizing twice purifies from methanol. 1.8 g of purified expected product are obtained. P = 114 to 115 ° C.

Analysis: (C ₁₉ H ₁₉₄

Calculated: C 65.80 H 5.52 Cl 10.22 % Found: 65.8 5.6 10.2% NMR spectrum (deuterochloroform) (fundamental frequency: 90 MHz) the two CH ₃ groups of (1-methyl ) ethyl residue at 74 and 77Hs

-CH- of the (l-methyl) ethyl radical from'187 to 239 Hz COOCH ₃ at 351 Hz

Hydrogen in the 2-position at 479 Hz

aromatic protons from 616 to 681 Hz

Example 25

6-chloro-4 - [(1,1-dimethyl) -äthvl1-4-phenyl-f 4Hi-1.3-benzodioxin-2-carboxylic acid (mixture of the two diastereomeric racemates)

12.8 g of 50% sodium hydride in oil, 100 ml of anhydrous dioxane and 600 mg of dibenzo-18 crown are mixed with stirring, then a solution of 5.82 ml of dichloroacetic acid in 100 ml of dioxane is added dropwise while maintaining room temperature Suspension at room temperature, a solution of 14.1 g of 5-chloro-α- (1,1-dimethyl) -ethyl-2-hydroxy-α-phenylbenzenemethanol in 100 ml of dioxane is added dropwise, the mixture is then heated to 80 for 6 hours ⁰ C, cools to room temperature and while maintaining this temperature by means of an ice water bath, 400 ml of water are added, the aqueous phase is extracted with 600 ml of ether, extracted with 3 × 100 ml of O, ln sodium hydroxide, and the aqueous extraction phase is acidified with 2N hydrochloric acid on, extracted with 3 χ 150 ml of ether, the organic extraction phase was washed with 3 χ 100 ml of water, the acid extracted in the form of the sodium salt with the aid of a saturated sodium bicarbonate solution and then with

3 χ 100 ml of water and collect the aqueous extracts.

The aqueous phase is washed with 3 × 100 ml of ether and acidified aqueous phase with 2N hydrochloric acid, extracted with

4 χ 150 ml ether, washes the ethereal phase with 3 χ 1OO ml

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Water, the ethereal phase dries over magnesium sulphate, treated with activated charcoal, brought to dryness and obtained 9.1 g of the expected product in crude form.

MNR spectrum (Deuterochlorοform) (basic frequency of the apparatus:

60 MHz) hydrogen in position 2 at 317 Hz (isomer A) hydrogen in position 2 at 340 Hz (isomer B) (1,1-dimethyl) ethyl at 63 and 65 Hz
aromatic protons from 415 to 4 72 Hz OH at 52 7 Hz

That used as the starting product in the above production 5-chloro-a- (1,1-dimethyl) -ethyl-2-hydroxy-a-phenylbenzenemethanol was made as follows:

40.2 g of (5-chloro-2-hydroxyphenyl) phenylmethanone and 400 ml of anhydrous ether, 192 g of a tert-butyllithiutene solution in pentane are added dropwise at room temperature, and the mixture is stirred 2 hours at room temperature, distill off the ether by gradually replacing it with 600 ml of anhydrous benzene, brings the solution to benzene reflux for 16 hours, cools to room temperature, poured onto 1 l of an ice-cold 10% ammonium chloride solution, removes the organic phase by decanting, extracts the aqueous phase with 2 × 100 ml ether, the organic phase was washed with 2 × 70 ml of water, dried over magnesium sulfate, treated with activated charcoal, brought to the Dry and obtain 50 g of crude product (in the form of an oil), which is chromatographed on a silica column, whereby one eluted with methylene chloride, and obtained by fractionation 14.1 g of product from which a sample is recrystallized from cyclohexane. F = 146 ° C.

Analysis: (C ₁₇ H ₁₉ O ₂ Cl)

Calculated: C 70.22 H 6.59 Cl 12.19 % Found: 70.5 6.7 11.9%

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5S

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

OH of the 2-hydroxy residue at 530 Hz

OH of the methanol at 175 Hz

[l, l-Dimethyl) ethyl] residue at 75 Hz

aromatic protons of the phenyl radical in the α-position of the

Methanol from 420 to 455 Hz other aromatic protons from 400 to 455 Hz

Example 26

Isomer A of 6-Οί1ογ-4-Γ (! «! - dimethyl) -äthyl1-4-phenyl- [4Hi-1,3-benzodioxin ^ 2-carboxylic acid methyl ester

Level A; 6- € 3ί1ογ-4-Γ (1 «! - dimethyl) -äthyl1-4-phenyl-r4Hl-l, 3-

benzodioxin-2-carboxylic acid chloride (mixture of racemates)

9.1 g of the mixture of the diastereomeric racemates are mixed 6-chloro-4 - [(1,1-diraethyl) ethyl] -4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid, prepared as indicated in Example 25) and 100 ml of anhydrous benzene.

3.7 ml of triethylamine are then added gradually, while maintaining room temperature, and then dropwise a solution of 6.2 g of thionyl chloride in 25 ml of anhydrous benzene is added, the mixture is refluxed for 3 hours and cooled to room temperature off, sucks off and washes the precipitate with anhydrous benzene, the filtrate is recovered and the solution is concentrated Vacuum until a solution volume of 30 ml is obtained.

Level B; Isomer A of 6-chloro-4- (1,1-dimethyl) -äthyl1-4-

phenyl-Γ 4h1-1 «3-benzodioxin-2-carboxylic acid methyl ester

3 ml of methanol, 50 ml of anhydrous benzene and 3.7 ml of triethylamine are mixed with stirring, and the mixture is cooled to 15 to 20 ° C., added dropwise at this temperature the solution obtained above in step A, to which 30 ml of anhydrous benzene are added was, stirred for 16 hours at room temperature, filtered off and washed the precipitate with anhydrous benzene.

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The filtrate is concentrated in vacuo and 6.5 g of crude product are obtained which is carried out on a silica column while eluting with a mixture of ethyl ether and petroleum ether (b.p. 60 to 80 C) (2θ / δΟ) chromatographed, and obtained after fractionation and then evaporating off the solvent, the expected crude product, which is crystallized from 20 ml of methanol, and is obtained after drying, the expected product. F = 85 C.

To alyse:

Calculated: C 66.57 H 5.87 Cl 9.82 % Found: 66.5 6.0 10.0%

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

(1,1-Dimethyl) ethy1 at 6 2 Hz

COOCH., At 117 Hz

Hydrogen in position 2 at 338 Hz aromatic protons: peaks from 412 to 468 Hz

Example 2 7

6-fluoro-4-methyl-4-p1ienyl-r4Hl-1,3-benzodioxin-2-carboxylic acid (Mixture of diastereomeric racemates)

Mix 25 g of sodium hydride, 350 cm, under an argon atmosphere anhydrous dioxane and 1.55 g of dibenzo-18-crown-6, adds

3 rend an hour a solution of 16.5 cm dichloroacetic acid

3
in 150 cm of dioxane and then at the end of the reaction for one hour at 22 ° C. a solution of 31 g of cc-phenyl-a-methyl- (5-fluoro-2-hydroxy) -phenylmethanol in 150 cm of anhydrous dioxane is heated approx. 80 C, stirred for 6 hours at 80 to 85 ° C, cooled, poured onto a mixture of ice and water, extracted with ether, acidified the aqueous phase, extracted the aqueous phase with ether, washed the ethereal phase with water who extracted the essential? Phase with sodium bicarbonate, washed with methylene chloride, acidify the alkaline phases, extracted with methylene chloride, washed with water, dried over magnesium sulfate and brought to dryness in vacuo. 29.5 g of the expected crude product (in the form of an oil) are obtained.

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NMR spectra

ε *

Hydrogen in the 2-position at 310 Hz and CH ₃ at 117 Hz (peak corresponding to the dsm isomer A of the acid obtained)

Hydrogen in the 2-position at 339 Hz and CH ₃ at 126 Hz (the peak corresponding to the isomer B of the acid obtained)

aromatic protons from 400 to 450 Hz OH at 505 Hz

That used as the starting product in the above production α-Phenyl-α-methyl- (5-fluorine-2-hydroxy) -phenyltanol was made as follows:

13.3 g are mixed under an argon atmosphere while stirring

Magnesium shavings and 50 cm of anhydrous ether, then

3 3

slowly dissolve a solution of 34.7 cm of methyl iodide in 250 cm of anhydrous Ether and then heated to reflux for 1 hour. 220 cm of the resulting solution of the magnesium compound are then added a solution of 30 g of a-phenyl- (5-fluoro-2-hydroxy) -phenylmethanone

in 150 cm of anhydrous benzene, the ether is distilled by adding it is completely replaced by anhydrous benzene, then stirred for 4 hours at approx. 78 ° C, cooled, poured onto an ammonium chloride solution, extracted with ether, washed with water, dried over magnesium sulfate and brought to dryness in vacuo. Man receives 32 g of the expected product in raw form.

A sample of this product is recrystallized from cyclohexane. F = 122 ° C.

Analysis: ^ ^c - ₁ / i ⁱⁱ - ₁ 22

Calculated: C 72.40 H 5.64 F 8.18% Found: 72.4 5.6 8.2 %

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Example 2 8

Isomer A of 6-fluoro-4-methyl-4-phenyl-r 4Ii] -I, 3-benzodioxin-2-cjrboxylic acid methyl ester

29.5 g of the mixture of the racemates of 6-fluoro-4-methyl-4-phenyl- [4H] -l, 3-benzodioxin-2-carboxylic acid obtained in Example 2 7 are mixed, 300 cm of methanol and 130 g of acidic resin, brought to reflux and left under reflux for 24 hours. Man cools down, treated with activated charcoal, filtered, rinsed with methanol, brought to dryness, takes up with ether, washes the

3
ethereal phase with 3 × 200 cm bicarbonate and then with water / water, dry over magnesium sulfate, bring in a vacuum

3 to dryness and receives 23.8 g of crude product, which is taken up in 200 cm of methanol. 5 g of product are obtained from 20 cm Recrystallized methanol. 4.4 g of the expected product are obtained. F = 95 ° C.

Analysis: (C ₁₇ H ₁₅ FO ₄ )

Calculated: C 67.64 H 5.00 F 6.28 %
Found: 67.7 5.0 6.2%

NMR spectrum (deuterochloroform) (frequency of the apparatus: 90MHz,)

CH ₃ at 171 Hz COOCH ₃ at 345 Hz

Hydrogen in the 2-position at 463 Hz

aromatic protons: peaks from 615 to 6 80 Hz

Example 29

Isomer A of 6-chloro-4-methyl-4-phenyl-r4H] -1,3-benzodioxin-2-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester

Stage A: chloride of isomer A of 6-chloro-4-methyl-4-phenylf4H 1-1,3-benzodioxin-2-carboxylic acid

4.9 g of the isomer A of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid are mixed with stirring, that was obtained in Example 3, and 50 ml of anhydrous benzene, cools to about "10 C, is added dropwise at this temperature 1.66 g of triethylamine and then adds at this temperature

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Si

temperature a solution of 2.5 g of thionyl chloride in 25 ml of anhydrous benzene and then brought to reflux for 2 hours. The suspension is cooled to room temperature off, sucks off the precipitate and wins the filtrate, which contains the expected product.

Stage B: Isomer A of 6-chloro-4-methyl-4-phenyl- [4Hl-l, 3-

benzodioxin-2-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester

2.25 g of (2,2-dimethyl-1,3-dioxolan-4-yl) -methanol are mixed by stirring, 50 ml of water-free benzene and 2.3 ml of triethylamine and add the above in step A dropwise at room temperature collected filtrate too. The mixture is stirred for 20 hours at room temperature. It is filtered and the filtrate is washed with a 10% sodium carbonate solution and then washes with water until neutral pH.

The benzene phase is dried over calcium chloride and treated with activated charcoal, the solvent evaporates in vacuo and 4.5 g of crude product is obtained, which is passed on a silica column chromatographed, eluting with methylene chloride. After fractionation, 2 g of the expected crude product are obtained in the form of a colorless gummy substance.

Analysis: (C ₂₂ H ₂₃ O ₆ Cl)

Calculated: C 63.08 H 5.53 Cl 8.46 %
Found: 62.0 5.5 8.9%

NMR spectrum (deuterochloroform) (basic frequency of the apparatus:

60 MHz), the CH ₃ groups of the 2,2-Dimethyldioxolans at - 81 to 82 Hz

CH ₃ in position 4 at 115 Hz
COO-CH ₉ -CH-CH ₅ from 215 to 260 Hz
0 0

aromatic protons from 411 to 441 Hz

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Example 30

Hydrochloride of the isomer A of 6-chloro-4-methyl-4-phenyl-r4Hil, 3-benzodioxin-2-carboxylic acid 2- (diethylamino) ethyl ester

A mixture is brought under a nitrogen atmosphere with stirring from 6.2 g of isomer A of the 6-chloro-4-methyl-4-phenyl- [4H] -l, 3-benzodioxin-2-carboxylic acid methyl ester obtained as indicated in Example 16, 100 ml of anhydrous toluene and 2.6 g of diethylaminoethanol and a small amount of sodium hydride Reflux. The mixture is refluxed for 3 hours, cooled, 5 ml of a 4N hydrochloric acid solution in ether are added 200 ml of anhydrous ether are added, filtered, washed with ether, dried and 3.7 g of product are obtained, which are then poured into 20 ml at 60 ° C Absorbs isopropanol, treated with activated charcoal, cooled, added 50 ml of ether, filtered, dried and obtained 2.7g of the expected Product. F = 110 ° C.

Analysis: (C ₂₂ H ₂₇ Cl ₂₁

Calculated: C 60.00 H 6.18 Cl 16.10 N 3.18 % Found: 59.6 6.4 15.9 3.4%

Example 31

6-chloro-4-ethy3.-4-phenyl-r 4h1-1.3-benzodioxin-2-carboxylic acid (Mixture of the two diastereomeric racemates)

- 3

250 cm of liquid ammonia, which has been condensed, is mixed with approx. 100 mg of ferric nitrate and 4.8 g of sodium, while stirring, which is added in small portions, then adds a solution of 26.2 g of 5-chloro-ethyl-2-hydroxy-a-phenylbenzenemethanol at -28 to -30 ° C. in the course of 1 1/2 hours in 200 cm of anhydrous toluene, increases the temperature and drives off the free ammonia, heated to reflux for 3 hours, adds 100 cm Toluene and at 50 ° C. 18 g of potassium dichloroacetate are added, the mixture is refluxed for one night and 9 g of potassium dichloroacetate are added, and the mixture is stirred reflux for another 2 hours, cool, pour into water, remove the organic phase, acidify the aqueous phase and extracted with ether, the ethereal phase washes with it

extracts the Ä

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3 × 500 cm of water, the ethereal phase extracted with

3 3

3 χ 300 cm sodium bicarbonate, washes with 2 χ 500 cm ether, acidify the aqueous phase with concentrated hydrochloric acid, extract with 3 × 500 cm ether, wash with water, dries over magnesium sulfate, brings to dryness in vacuo and receives 27 g of the expected crude product.

The S-chloro-oc-ethyl - ^ - hydroxy-a-phenylbenzenemethanol used as the starting material for the preparation of the product of Example 31 can be prepared as indicated in Example 23, but using ethyl iodide instead of isopropyl bromide. F = 85 ° C.

Example 32

Isomers A and B of 6-chloro-4-ethyl-4-phenyl-r4Hi-1,3-benzodioxin-2-carboxylic acid methyl ester

For the preparation and isolation of the two diastereomeric racemates A and B of 6-chloro-4-ethyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester, starting from a mixture of isomers A and B of the corresponding acids, the mixture obtained in Example 31 and the same Technique as described in Example 20.

Starting from 26 g of the mixture of isomers A and B, which was obtained in Example 31, the following were obtained:

4.5 q of the expected isomer A, which is recrystallized from methanol under reflux; 3.5 g of the expected isomer A are obtained in purified form, mp = 128 ° C .;

Analysis: (C ₁₈ H ₁₇ ClO ₄ )

Calculated: C 64.96 H 5.15 Cl 10.65 % Found: 65.0 5.2 10.4 %

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Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

Ethyl in the 4-position at 44 - 51 - 58 Hz, 110 to 160 Hz COOCH ₃ at 232 Hz

Hydrogen in position 2 at 314 Hz

aromatic protons of the 1,3-benzodioxin nucleus from 415 to 450 Hz Phenyl at the 4-position at 445 Hz

and 4 q of the expected isomer B, F = 108 C.

Example 33

6-chloro-4- (4-chlorophenyl) -4-methyl-f 4Hl-1,3-benzodioxin-2-car bonsäure (mixture of the two diastereomeric racemates)

250 cm of dioxane and 1.6 g of dibenzo-18-crown-6 are mixed with stirring and 25 g of sodium hydride, then adds over 45 minutes

3 3

ute a solution of 16 cm dichloroacetic acid in 100 cm dioxane, then add a solution at 30 ° C. over the course of one hour of 36.6 g of 5-chloro-2-hydroxy-a-methyl-a- (4-chlorophenyl) -benzenemethanol in 150 cm of dioxane, heated to 80 C for 5 hours, cooled, poured onto a mixture of ice and water,

3
extracted with 3 × 500 cm ether, acidified the aqueous phase with concentrated hydrochloric acid, extracted with

3 × 500 cm ether, extracts the ethereal phase with sodium bicarbonate, acidify the aqueous phase and extract with

4 χ 300 cm ether, washes with water, dries over magnesium sulfate, brings to dryness in vacuo and receives 40 g of the expected crude product.

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

Hydrogen in position 2 at 309 Hz

CH ₃ at 116 Hz

This corresponds to the one expected of the isomers (isomer A) hydrogen in the 2-position at 340 Hz

CH ₃ at 124 Hz

This corresponds to the expected other isomer (isomer B) aromatic protons from 405 to 445 Hz OH at 510 Hz

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That used as the starting material for the above manufacture 5-chloro-2-hydroxy-a-methyl-o- (4-chlorophenyl) benzene methanol can be made as follows:

Mix with magnetic stirring and under an argon atmosphere:

3 13.5 g of 2-hydroxy-5-chloroacetophenone and 130 cm of anhydrous ether, cool from the outside with an ice-water bath, bring in drop by drop while maintaining an internal temperature between 10 and 20 ° C: 330 cm of an essential, freshly made and filtered solution of the 1-chloro-4-bromobenzene magnesium compound with a titer of 0.46 mol / l, the stirring being maintained at room temperature for one night. One cools them yellow suspension with ice and dropwise 125 cm of ice-cold aqueous 2N hydrochloric acid, decanted off, the organic phase was washed with water, dried over sodium sulfate, treated with activated charcoal, filtered off with suction and brought in a vacuum to dryness, the residue is dissolved in 100 cm of cyclohexane and allowed to crystallize with stirring, and the precipitate is sucked off off, paste it with a little cyclohexane, dry it in the oven and get 19.3 g of the expected product. F = 130 ° C.

Analysis: i ^c ^ 4 ^H i2 ° 2 ^C1 2 ^

Calculated: C 59.38 H 4.27 Cl 25.04% Found: 59.7 4.3 -24.7 %

Example 34

Isomer A of 6-chloro-4- (4-chlorophenyl) -4-methyl-r4Hi-1,3-benzodioxin-2-carboxylic acid methyl ester

40 g of the mixture of the diastereomeric racemates of 6-chloro-4- (4-chlorophenyl) -4-methyl- [4H] -l _t 3-benzodioxin-2-carboxylic acid, the mixture obtained in Example 33, 400 cm of methanol and 180 g of strongly sulfonic acid resin, stirred for 18 hours under reflux, cooled, filtered off with suction, washed four times with 300 cm of ether, brought to dryness in vacuo, the residue taken up in 500 cm of ether, washed with 3 × 300 cm of sodium bicarbonate and then with 4 × 500 cm of water, dried over magnesium sulfate, brought to dryness in vacuo and obtained 35.5 g of product. Man treated

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the product obtained with 100 cm of methanol, left one night at room temperature, filtered off with suction, washed with ice-cold methanol, 10 g of product is obtained, which is recrystallized from 60 cm of methanol, left at room temperature for one night and obtained 9.1 g of the expected isomer A. F = 108.degree.

Analysis: (C ₁₇ H ₁₄ Cl ₂ O ₄ )

Calculated: C 57.81 H 4.0 Cl 20.0 %
Found: 58.0 4.0 19.9 %

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

CH ₃ at 115 Hz

COOCH ₃ at 231 Hz

Hydrogen in position 2 at 308 Hz

aromatic protons from 412 to 442 Hz

Example 35

6-chloro-4-methyl-4-phenyl-r4Hi-1,3-benzodioxin-2-carboxylic acid (Mixture of the two diastereomeric racemates)

4 g of sodium amide and 50 ml of anhydrous toluene are mixed, and a solution of 9.95 g of 5-chloro-2-hydroxy-α-methyl-α-phenylbenzene-methanol is added dropwise at room temperature in 150 ml of anhydrous toluene and bring the equipment to reflux for 6 hours, cools to room temperature, brings in 10.25 g of potassium dibromoacetate and refluxes again for 6 hours. One cools down and takes up in 200 ml of water, decanted off, the organic phase extracted with 2 × 80 ml of water, the aqueous phase was washed with 2 χ 80 ml of ether and acidify the aqueous solution with 40 ml of 2N hydrochloric acid.

A precipitate is formed, which is mixed with 3 χ 100 ml of ether extracted. The organic phases are washed with 2 80 ml of water and the expected acid is extracted 3 χ with 50 ml of a saturated aqueous 5% sodium bicarbonate solution.

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The aqueous extraction phase is washed with 3 × 80 ml of ether and the alkaline solution is acidified with 90 ml of a 2N hydrochloric acid solution at. The expected acid is extracted with 4 × 100 ml of ether. The organic phase is washed with water, dries over magnesium sulfate in the presence of activated charcoal, removes the solvent in vacuo and receives 7.85 g of crude product, that is taken up in hexane. The crystals obtained are filtered off with suction and dried, giving 6 g of the expected product receives. F - 144 ° C.

Nuclear Magnetic Resonance Spectrum (deuterochloroform) (fundamental frequency: 60 MHz)

CH ₃ at 117 Hz

Hydrogen in position 2 at 312 Hz (corresponding to isomer A)

CH ₃ at 125.5 Hz

Hydrogen in position 2 at 342.5 Hz (corresponding to isomer B)

aromatic protons from 405 to 450 Hz OH at <* 350 Hz

Example 36

6-chloro-4-methyl-4-phenyl-r 4h1-1 «3-benzodioxin-2-carboxylic acid (Mixture of the two diastereomeric racemates)

3 *

10 cm of dioxane and 1.35 g of 50 % sodium hydride are mixed in Oil. 60 mg of dibenzo-18-crown-6 are added at 15 ° C. and then

3 3

0.61 cm of dichloroacetic acid and 10 cm of dioxane within 5 minutes to.

1.25 g of 2-hydroxy-5-chlora-methylbenzhydrol are brought in at about 20 ° C. in 10 minutes and 5 cm of dioxane.

The mixture is then heated to about 80 ° C. for 6 hours, then cooled to about 20 ° C., 2 cm of methanol is added, poured into ice water and extracted 3 χ with ethyl acetate and washes 5 χ with ice-cold 0.1N sodium hydroxide solution. The aqueous phases are combined, acidify it with a 2N hydrochloric acid solution pH 1, extracted 3 χ with methylene chloride, dried and brought to dryness, whereby the expected crude product is obtained.

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(o (e

Example 37

Piperidine salt of the isomer A of 6-chloro-4-methyl-4-phenylr4H] -1, 3-benzodioxin-2-carboxylic acid

The mixture of the two diastereomeric racemates of 6-chloro-4-methyl-4-phenyl- [4h] -1,3-benzodioxin-2-carboxylic acid obtained above in Example 36 is dissolved in 4 cm ethyl acetate and add 0.8 cm piperidine at 10 C. The expected piperidine salt crystallizes from scratching. After 15 minutes, it is filtered off with suction, washed with ethyl acetate and ether and dried at 20 ° C in vacuo and receives 855 mg of the expected product.

The crystallization mother liquor is collected and diluted with methylene chloride, washed with ice-cold n-hydrochloric acid, dries and brings to dryness, takes the return

3 3

got up with 12 cm of methylene chloride and adds 0.6 cm of boron trifluoride etherate to, leaves 1/2 hour at 20 ° C, poured onto ice, washed twice with water, extracted back with methylene chloride, dries and brings to dryness, takes up in 2 cm ethyl acetate and 0.4 cm piperidine, lets crystallize and isolated 545 mg of the expected product. Another operation carried out in the same way, starting from the crystallization mother liquor (isomerization with boron trifluoride, addition of piperidine) leads to the recovery of more 130 mg of the expected product. A total of 1.53 g of the expected product was thus obtained. F = - 165 C.

Example 38 .

Isomer A der 6-Crilor-4-me \ & yl-4-vheriyl- \ AYi] -I ^ 3> 2-carboxylic acid

The 1.53 g of piperidine salt obtained above in Example 37 are taken up in a mixture of methylene chloride and η-hydrochloric acid, washed, dried and treated with activated charcoal, concentrated by adding cyclohexane up to a volume of 3 cm, filtered off with suction, washed with Cyclohexane, dries at 40 ⁰ C in a vacuum and receives 1.1 g of the expected product. F = 175 ° C. This product is identical to the isomer A obtained in Example 3.

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-se.

Example 39

Tablets were made with the following formulation:

6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid (in the form of isomer A) 300 mg

Excipient quantum satis for one tablet with

a final weight of 500 mg

(Components of the excipient: lactose, starch, talc, Magnesium stearate)

Example 40

Gel capsules of the following formulation were made:

6-C3ilor-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid methyl ester (in the form of isomer A) 25 mg

Excipient quantum satis for a gel capsule with

a final weight of 500 mg

(Components of the excipient: talc »magnesium stearate, Aerosi1)

Example 41

Make tablets of the following formulation:

Isomer A as in Example 21 obtained 300 mg

Excipient quantum satis for one tablet with

a final weight of 500 mg

(Components of the excipient: talc, magnesium stearate, aerosil)

Example 42

Gel capsules of the following formulation were made:

d-isomer as in Example 18 obtained 250 mg

Excipient quantum satis for a gel capsule with a

Final weight of \ 500 mg

(Components of the excipient: talc, magnesium stearate, aerosil)

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Pharmacological investigation

1) Determination of acute toxicity

The acute toxicity was determined in groups of 5 mice weighing 18 to 22 g. The product was in suspension in carboxymethyl cellulose administered by the intraperitoneal route.

The animals were kept under observation for one week.

The lethal dose 50 (LD ₅₀ ) was determined and the following results were obtained:

product of example ^LD 50 in mg / kg 1 130 3 150 16 Isomer A ζ 800 17th Isomer A * 200 18th Isomer A
lr shape * 250 20th Isomer A <1000 21 Isomer A £ 150 each

2) Determination of the hypolipemic effect

The study was carried out on groups of 8 male rats from the Sprague Dawley S.P.F. with a weight of carried out approx. 200 g.

The animals are given a diet which contains 50% sucrose and which is enriched with 1% cholesterol. you will be

809819/0 878

Treated for 10 days with the product to be investigated, which is suspended in water mixed with carboxymethyl cellulose administered through an esophageal tube.

The animals are fasted 16 hours after the last administration of the product, after which they are fed Abdominal puncture blood is taken, and the determinations of the are carried out on the blood taken via sodium heparinate Triglycerides, cholesterol and total lipids the following methods:

Determination of triglycerides;

(Semi-automatic determination) Technique by G. Kessler and H. Lederer, Automation in Analytical Chemistry, New York, 341 (1965) modified by J.R. Claude and F. Corre, Ann. Biol. Clin. 26_, 3-4, 451 (1968).

Determination of cholesterol;

Technique by J. Levine, Symposium Technicon 1967, Volume I, 25, which was adapted to the Auto-Analyzer I-System.

Nephelometric determination of total lipids;

Semi-automatic determination of H.C. Girard, J. Canal,

J. Delattre and J. Peynet, Technicon Symposium 1970, Paris.

The changes (expressed as a percentage) in the levels of triglycerides, cholesterol and total lipids were determined after administration of different doses of the product to be examined to the treated animals in comparison to the comparison animals.

The following results were obtained:

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ΊΟ-

Product of example Cans
mg / kg /
Day Change in% of the contents of cholesterol Total lipids 1 5 Triglycerides -22 -26 3 2 -11 -36 -38 16 isomer A 2 -12 -17 -25 17 isomer A 2 -32 -43 -47 "Ο isomer A
¹⁸ 1-form 2 -57 -47 -53 20 isomer A 1 -53 -36 -32 21 isomer A 1 -13 -11 -25 -62

8098 19/0878

Claims (24)

Claims 1., products of the general formula I ¹ : wherein R * is a hydrogen atom, an alkyl radical with 1 to 5 carbon atoms, a 2,3-dihydroxypropanyl radical, a (2,2-dimethyl-1,3-dioxolan-4-yl) methyl radical or a dialkylaminoalkyl radical whose alkyl radicals contain 1 to 4 carbon atoms, means, R ₂ denotes a hydrogen atom or an alkyl radical having 1 to 5 carbon atoms, R _{3 is} a hydrogen atom, an alkyl radical with 1 to 5 carbon atoms or a phenyl radical and R ₄ and R ₅ , which can be the same or different, represent a hydrogen atom or a halogen atom, in the racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline earth, aluminum, ammonium and amine salts of the products of the formula I *, in which R ¹ .. denotes a hydrogen atom, and the addition salts with Acids of the products of the formula I *, in which R ' * denotes a dialkylaminoalkyl radical. 2. Products of general formula I: 809819/0878 ORIGINAL INSPECTED worxn
R "and R Around (ι) ~, which can be the same or different, a hydrogen atom or an alkyl radical with 1 to 5 carbon atoms mean a hydrogen atom, an alkyl radical with 1 to 5 carbon atoms or a phenyl radical and ₅ , which can be the same or different, denote a hydrogen atom or a halogen atom, in the racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline earth, Aluminum, ammonium and amine salts of the products of formula I, in which means a hydrogen atom. 3. Products of general formula I according to claim 2, characterized in that in the formula IR ₁ and R ~, which may be the same or different ', represent a hydrogen atom or a methyl radical, R ^ is a hydrogen atom, a methyl radical or a Phenyl radical, R ₄ denotes a hydrogen atom and R ₅ denotes a hydrogen atom or a chlorine atom, in the racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline earth, aluminum, ammonium and amine salts of these products of the formula I, in which R _{1 is} a hydrogen atom. 4. Products of general formula I according to claim 2, characterized in that in this formula IR _{1 is} a hydrogen atom or a methyl radical, R _{2 is} a hydrogen atom, R ^ is a hydrogen atom, a methyl radical or 809819/0878 denotes a phenyl radical, R ₄ denotes a hydrogen atom and R ₅ denotes a chlorine atom, in the racemic or optically active forms or in the form of mixtures of these isomers and the alkali, alkaline earth, aluminum, ammonium and amine salts of these products of the formula I wherein R ^ is a hydrogen atom. 5. Products of the formula I according to claim 2 in the raceraisehen or optically active forms or in the form of mixtures of these isomers with the following designations: 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid; 6-chloro-2,4-dimethyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid; 6-chloro-4-phenyl- [4H] -1, 3-benaodioxin-2-carboxylic acid; 6-chloro-4,4-diphenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid; 4-methyl-4-phenyl-1,3-benzodioxin-2-carboxylic acid; 6-Chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester. 6. Products of the formula I ¹ * according to claim 1 in the racemic or optically active forms or in the form of mixtures of these isomers with the following designations: 6-chloro-4,4-diphenyl- [4h] -1,3-benzodioxin-2-carboxylic acid methyl ester; . 6-chloro-4-methyl-4-phexryl- [4H] -1, 3-benzodioxin-2-carboxylic acid ethyl ester; Sodium 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate; the piperidine salts of the two diastereomeric racemates A and B 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid; 809819 / 087S the d- and 1-isomers of the two diastereomeric racemates A and B of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid; 6-chloro-4- (3-chlorophenyl) -4-methyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester; 6-chloro-4- (3-chlorophenyl) -4-methyl- [4H] -1, 3-benzodioxin-2-carboxylic acid; 6-chloro-4 - [(1-methyl) ethyl] -4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylic acid methyl ester; 6-chloro-4 - [(1,1-dimethyl) ethyl] -4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester; 6-fluoro-4-methyl-4-phenyl- [4H] -I ₁ 3-benzodioxin-2-carboxylic acid methyl ester; 6-chloro-4-ethyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester; 6-chloro-4- (4-chlorophenyl) -4-methyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester; 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester; 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid 2,3-dihydroxy-propanyl ester; 6-Qilor-4-methyl- * - 4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid 2- (diethylamino) ethyl ester as well as their addition salts with acids. 7. Isomer A of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid methyl ester · 8. Isomer A of 6-chloro-4- (3-chlorophenyl) -4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid methyl ester. 9. Isomer A of 6-chloro-4-methyl-4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylic acid ethyl ester. 809819/0878., _ _L1NSPE CTB » 10. Products of the formula I according to claim 2 with the following designations: Isomer A of 6-chloro-4-methyl-4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid; Isomer A of 6-chloro-2,4-dimethyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid. 11. Products of the formula I according to claim 2 with the following Bez ei chnung s: Isomer A of sodium 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate; Isomer A of 6-chloro-4- (3-chlorophenyl) -4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid; the d- and 1-isomers of isomer A of 6-chloro-4-methyl-4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid. 12. Process for the preparation of the products of the general formula I according to claim 2 in their racemic or optical active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline earth, aluminum, ammonium and Amine salts of the products of formula I in which R ^ is hydrogen atom means, characterized in that a product of the formula II: wherein R ₃ , R ₄ and R _{5 are} as defined in claim 2 with an alkali metal salt of a product of formula III 809819/0878 Cl ^R 2 ^ - COOH (III) Cl wherein R "is as defined in claim 2, in the presence a basic condensing agent and an alkali metal salt of a product of the formula I corresponding Acid in which R. is a hydrogen atom, which Salt is optionally treated with an acid in order to obtain the corresponding acid of the formula I, which Acid is optionally converted into a salt or esterified to give the corresponding salt or the corresponding To obtain esters, and that, if appropriate, the products of the formula I in their racemic or optically active forms or isolated in the form of mixtures of these isomers. 13. The method according to claim 12, characterized in that the product of formula II according to claim 12 with a Alkali salt of a product of formula III ': Y? 2 C - COOH (III ¹ ) wherein Y is a bromine or iodine atom and R _{2 has} the meaning given in claim 12, treated in the presence of a basic condensing agent and, if appropriate, the synthesis continues as in claim 12. 14. A process for the preparation of the products of the general formula I according to claim 1, wherein R '^ is a 2,3-dihydroxypropanyl radical, a (2,2-dimethyl-1 _t 3-dioxolan-4-yl) -raethyl radical or a dialkylaminoalkyl radical , the alkyl radicals of which contain 1 to 4 carbon atoms, wherein R ₂ , Ro, R ₄ and Rr are as defined in claim 1, in the racemic or optically active forms or in the form of mixtures of these isomers, as well as the addition salts with acids of the products of the formula I ¹ , wherein R ¹ ^ is a dialkylaminoalkyl radical, characterized in that 809819/0878 that an acid of the formula I ₁ as obtained according to claim 12 or 13, in which R ₁ denotes a hydrogen atom, or a functional derivative of this acid with an alcohol of the formula wherein R 'is a (2,2-dimethyl-1,3-dioxolan-4-yl) methyl radical or a dialkylaminoalkyl radical, the alkyl radicals of which contain 1 to 4 carbon atoms, treats the product of the formula I', in which R * ^ denotes a dialkylaminoalkyl radical, optionally treated with an acid in order to form the salt therefrom, or optionally the product of the formula I ^{1 obtained} , in which R ·., a (2,2-dimethyl-1,3-dioxolan-4-yl ) -methyl radical, treated with a hydrolysis agent in order to obtain the corresponding product of the formula I · in which R ¹ ^ is a 2,3-dihydroxypropanyl radical, and that, moreover, the products of the formula X * or their salts in the raceric or optically active forms or in the form of mixtures of these isomers. 15. A process for the preparation according to claim 12 of products of the formula I according to claim 2, wherein R ₄ and R _{5 represent} a hydrogen atom, characterized in that a product of the formula I in which R ₄ or R ₅ or R ₄ and R _{5 represents} a chlorine atom, is subjected to the action of hydrogen in the presence of a catalyst and the corresponding product of the formula I is obtained, in which R ₄ and R _{5 represent} a hydrogen atom. 16. Pharmaceutical compositions, characterized in that they contain at least one of the compounds of the Formula I * or at least one of its pharmaceutically acceptable salts according to Claim 1. 17. Pharmaceutical compositions, characterized in that they contain at least one of the compounds of the active ingredient Formula I or at least one of its pharmaceutically acceptable 809819/0878 containable salts according to claim 2. 18. Pharmaceutical compositions, characterized in that they contain at least one of the compounds of the Formula I or at least one of its pharmaceutically acceptable salts according to Claim 3, 4, 5 or 10. 19. Pharmaceutical compositions, characterized in that they contain the compound according to claim 7 as active ingredient. 20. Pharmaceutical compositions, characterized in that they contain the compound according to claim 8 as active ingredient. 21. Pharmaceutical compositions, characterized in that they contain the compound according to claim 9 as active ingredient. 22. Pharmaceutical compositions, characterized in that they contain at least one of the compounds of formula I ¹ or at least one of their pharmaceutically acceptable salts according to claim 6 or 11 as active ingredient. 23. 5-Oilor-2-hydroxy-a-methyl-a-phenylbenzenemethanol in racemic form or optically active form. 24. The compounds of the formula H ' _A - 8098 19/0878 in the racemisehen or optically active forms, in which R ' _{4 is} a chlorine atom or a fluorine atom, R ¹ C is a chlorine atom and R' _{3 is} an alkyl radical having 2 to 4 carbon atoms, where R * ~ can also represent a methyl radical if R ^first means a fluorine atom. 809819/0878