CH625517A5 - Processes for the preparation of new 1,3-benzodioxin derivatives - Google Patents

Description

The subject of the present invention is processes for preparing the products of general formula:

Formula at the top of the next column.

in which R '[represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a 2,3-dihydroxypropanyl radical, a radical (2,2-dimethyl l, 3-dioxolan-4-yl) methyl or a dialkoylaminoalkyl radical whose radicals

(! ')

R

COOR

alkyls contain from 1 to 4 carbon atoms, R2 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical, and R4 and R5, identical 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, as well as alkaline, alkaline-earth salts , aluminum, ammonium and amines of the products of formula I ', in which R' represents a hydrogen atom and addition salts with acids of the products of formula I ', in which R' , represents a dialkoylaminoalkyl radical.

The subject of the invention is in particular processes for preparing the products of general formula:

R

COOR

in which R and R2, which are identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical, and R4 and Rs, identical 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, as well as alkaline, alkaline-earth salts , aluminum, ammonium and amines of the products of formula I in which R! represents a hydrogen atom.

The term alkyl containing from 1 to 5 carbon atoms can denote, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, terbutyl, pentyl radical.

The term halogen atom can denote, for example, a chlorine atom, a bromine atom, a fluorine atom.

By the expression mixtures of these isomers is meant a mixture of racemic isomers or a mixture of optically active isomers, in any proportion whatsoever.

They may especially be mixtures in any proportion of racemates, mixtures in any proportion of two optical antipodes, mixtures in any proportion of two optically active diastereoisomeric products.

The alkali or alkaline earth salts of the products of formula I, in which R 1 represents a hydrogen atom, can be, for example, the sodium, potassium, lithium or calcium salts.

The amine salts of the products of formula I, in which R represents a hydrogen atom, are preferably the usual amine salts. Among the usual amines, there may be mentioned monoalkoylamines, such as, for example, methylamine, ethylamine, propylamine, dialkoylamines, such as, for example,

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for example, dimethylamine, diethylamine, di-n-propylamine, trialkylamines, such as triethylamine. Mention may also be made of piperidine, morpholine, piperazine and pyrrolidine.

The addition salts with the acids can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, maleic, fumaric, succinic, tartaric acids, alkyl-monosulfonic acids, such as , for example, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyl disulfonic acids, such as, for example, oc, ß-ethanedisulfonic acid.

Among the products obtained by the process of the invention, there may be mentioned in particular:

the products as defined by the general formula I above, in which R, and R2, identical or different, represent a hydrogen atom or a methyl radical, R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R, represents a hydrogen atom and R5 represents a hydrogen atom or a chlorine atom in racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkaline, alkaline-earth salts, d aluminum, ammonium and amines of said products of formula I, in which R represents a hydrogen atom;

- the products, as defined by the general formula I above, in which R represents a hydrogen atom or a methyl radical, R2 represents a hydrogen atom, R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R, represents a hydrogen atom and R5 represents a chlorine atom, in racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline-earth, aluminum, of ammonium and amines of said products of formula I, in which R! represents a hydrogen atom, and in particular, in their racemic and optically active forms, the products named in the examples. Among these, mention may in particular be made, in the form of A isomers, as obtained in the examples, of products whose names follow one another:

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

- methyl 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1,3-benzo-dioxin-2-carboxylate;

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

- 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-benzo-dioxin-2-carboxylic acid;

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

We can also cite:

- the piperidine salts of the two diastereoisomeric racemates A and B of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid;

- the isomers d and / of the two diastereoisomeric racemates A and B of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid;

as well as, in their racemic or optically active forms:

- 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate of (2,2-dimethyl 1,3-dioxolan-4-yl) methyl;

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

- 6-chloro 4-methyl 4-phenyl- [4H] -1.3-benzodioxin-2-

2- (diethylamino) ethyl carboxylate, as well as its addition salts with acids.

The term isomer A denotes one or the other of the two diastereoisomeric racemic forms of the products of formula I 5 which have two asymmetric carbon atoms.

According to the invention, the process for the preparation of the products as defined by the general formula I above, as well as the alkali, alkaline-earth, aluminum, ammonium and amine salts of the products of formula I in which R represents a hydrogen atom, is characterized in that a product of formula is reacted:

.5 "B.

(II)

X /

25

in which R3, R, and Rs are defined as above, with an alkali metal salt of a product of formula:

\ l £

\> CÛCH

V /

(III)

in which R2 is defined as above and Y represents a chlorine, bromine or iodine atom, in the presence of a basic condensing agent, and obtains an alkali metal salt of an acid corresponding to a product of formula I, in which R! represents hydrogen, salt which is treated with an acid, to obtain the acid of corresponding formula I, an acid which, if necessary, is salified.

According to a second process, the acid obtained or one of its functional derivatives is esterified with an alcohol R, OH, to obtain the corresponding ester. Where appropriate, the products of formula I are isolated in racemic or optically active forms or in the form of mixtures of these isomers.

Under preferred conditions for implementing the invention, the preparation process described above is carried out as follows:

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

- The basic condensing agent can be in particular an alkali so alkalate, such as sodium methylate, sodium ethylate, sodium terbutylate; an alkaline hydride, such as sodium hydride, potassium hydride; an alkaline amide, such as sodium amide, potassium amide, lithium amide, sodium.

The reaction of the product of formula II with the product of formula III is carried out in an organic solvent such as, for example, benzene, toluene, xylene, ethyl ether, dioxane, dimethylformamide, tetrahydrofuran, hexamethylphosphorotriamide or in a mixture of these 60 solvents.

It is also possible to operate in the presence of a compound serving as a catalyst, of ether-crown type, such as, for example, dibenzo-18 crown-6, dicyclohexyl-18 crown-6 or 18-crown-6, optionally mixed with an organic solvent 65, such as, for example, dioxane.

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

The product of formula II is reacted with the

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basic condensation before reacting it with the product of formula III.

The products of general formula I, in which R represents an alkyl radical containing from 1 to 5 carbon atoms, are prepared by esterification of the corresponding acid, by action on this acid of an alcohol of formula R, OH in which R represents an alkyl radical containing from 1 to 5 carbon atoms, preferably in an acid medium.

One can operate, for example, in the presence of an acid, such as hydrochloric acid, paratoluenesulfonic acid, or in the presence of an acidic resin.

The esters of general formula I, in which R represents an alkyl radical containing from 1 to 5 carbon atoms, are also prepared by transesterification.

The products of formula I, in which R 1 represents a methyl radical are also prepared by the action of diazome-thane on the product of formula I, in which R 1 represents a hydrogen atom within an organic solvent.

The esters of general formula I are also prepared in the usual manner from a functional derivative of the corresponding acid of formula I, such as, for example, acid chloride. The functional derivatives of the acids of formula I are prepared according to the usual methods.

The alkali, alkaline earth, aluminum, ammonium and amine salts of the products of formula I above, in which R 1 represents a hydrogen atom, can be prepared by reaction, on the said products of formula I , corresponding bases.

The base can be an inorganic or organic base, such as, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, aluminum hydroxide, ethylate sodium, potassium ethylate, ammonia, or an amine, such as, for example, 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.

There has been described above a process for the preparation of products of formula I in which Rt represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, corresponding to a product of formula I ', in which R 't has the value of Ri above.

The invention also relates to a process for the preparation of products of formula I ', as defined above, in which R'i represents a 2,3-dihydroxypropanyl radical, a radical (2,2-dimethyl l, 3 -dioxolan-4-yl) methyl or a dialkoylaminoalkyl radical, in which the alkyl radicals contain from 1 to 4 carbon atoms, R2, R3, R, and R5 being defined as above, in racemic or optically active forms or in the form of mixtures of these isomers, as well as addition salts with acids of the products of formula I 'in which R'i represents a dialkoylaminoalkyl radical, characterized in that an acid of formula I in which R] represents an atom is treated of hydrogen, or a functional derivative of this acid, by an alcohol of formula RjOH in which Rj represents a (2,2-dimethyl 1,3-dioxolan-4-yl) methyl radical, or a dialkoylaminoalkyl radical, the radicals of which alkyls contain from 1 to 4 carbon atoms, and processes, if necessary, the pro duit obtained of formula I ', in which R'i represents a dialkoylaminoalkyl radical, with an acid to form the salt.

If necessary, the product obtained of formula I ′, in which R 1 represents a (2,2-dimethyl 1,3-dioxo-lan-4-yl) methyl radical, can be treated with a hydrolysis agent to obtain the corresponding product of formula I ', in which R'j represents a 2,3-dihydroxypropanyl radical. Where appropriate, the products of formula I ′ or their salts are isolated in racemic or optically active forms or in the form of mixtures of these isomers.

In preferred conditions for carrying out said process, the procedure is as follows:

the functional derivative of the acid of formula I can be, for example an ester or an acid halide (the functional derivative is prepared from the acid of formula I in the usual way);

- The reaction is preferably carried out in an organic solvent such as, for example, benzene, toluene, xylene, ethyl ether;

- The salification reaction of the products of formula I ', in which R'i represents a dialkylaminoalkyl radical, is carried out in the usual manner.

The hydrolysis reaction can be carried out by acid hydrolysis, the acid used can be, for example, hydrochloric acid.

Also according to the invention, the acids of general formula I above, in which Rb R and R5 represent a hydrogen atom, can be prepared by a process, characterized in that a product of formula I is subjected , in which R, = H and R, or R5 or R, and R5 represent a chlorine atom, to the action of hydrogen in the presence of a catalyst, and obtains the corresponding product of formula I, in which R , and R5 represent a hydrogen atom.

Under preferred conditions for implementing the invention, the process which has just been described is carried out as follows;

- The catalyst can be in particular palladium;

- operating in an alkaline medium; the base used can be, for example, triethylamine, trimethylamine, dimethylaniline, pyridine.

The operation is carried out in an organic solvent, such as, for example, ethanol, methanol, isopropanol.

The products of formula I or I 'above have at least one asymmetric carbon (carbon in position 2) and may have a second carbon (carbon in position 4) for certain values of the substituents R3 and R4.

The product of formula II used at the start of the preparation of the products of formula I or I 'according to the invention may not have asymmetric carbon for certain values of the substituents R3 and R4.

The reaction of such a product of formula II with a product of formula III or III 'above, according to the invention, leads to the production of a product of formula I or I' comprising a single asymmetric carbon atom in racemic form, which can then be split into its optical antipodes by methods known in the art, such as for example the formation of salts by means of optically active bases.

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

The product of formula I or I 'obtained from such a product of formula II has two asymmetric carbon atoms. There are, therefore, in different isomeric forms which can be obtained separately by methods known in the art.

The racemates or the optically active diastereoisomeric products (which could be called by the prefixes eis and trans) can be obtained separately, for example by selective crystallization, by countercurrent distribution or by column chromatography.

These racemates can, moreover, be resolved into their optical enantiomers by methods known in the art, such as for example the formation of salts by means of optically active bases.

The different isomeric forms thus obtained can also, if desired, be mixed in order to constitute the desired mixture.

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The products, as defined by general formula I 'and in particular I, in racemic or optically active forms or in the form of mixtures of these isomers, as well as their alkali, alkaline-earth, aluminum, ammonium, d amines and, where appropriate, their addition salts with acids, have interesting pharmacological properties; in particular, they display marked lipid-lowering activity; they reduce plasma lipid levels: triglycerides and cholesterol.

Pharmacological study

1) Determination of the lipid-lowering action:

The study was carried out on batches of 8 male rats of Sprague Dawley SPF strain, weighing 200 g. about.

The animals are fed a diet which contains 50% sucrose and which is enriched with cholesterol (1%). They are treated for 10 days. with the product to be tested which is administered in suspension in water supplemented with carboxymethylcellulose, by esophageal probe.

The animals are kept on an empty stomach at 4 p.m. after the last administration of the product, then exsanguinated by abdominal puncture and, on the blood taken on sodium heparinate, assays of triglycerides, cholesterol and total lipids are carried out according to 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);

- cholesterol dosage

Technique by J. Levine, "Symposium Technicon", 1967, vol.

I, 25, adapted to the self-analyzer system I;

- nephelometric measurement of total lipids Semi-automatic determination by H. C. Girard, J. Canal,

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

The variations (expressed as a percentage) of the triglyceride, cholesterol and total lipid levels were determined after administration of different doses of test product in the treated animals compared to the control animals.

The following results were obtained:

Example product

Doses (mg / kg / day)

Variation (%) of total lipid triglyceride cholesterol levels

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2) Determination of acute toxicity:

The acute toxicity was determined on batches of 10 mice weighing 18 to 22 g. The product was administered in suspension in carboxymethylcellulose intraperitoneally.

The animals were kept under observation for one week.

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

Example product

LD 50 (mg / kg)

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= 200

These properties justify the therapeutic use, as medicaments, of products, as defined by formula I ′ and in particular I above, in racemic or optically active forms or in the form of mixtures of these isomers, as well as their alkali, alkaline earth, aluminum, ammonium and pharmaceutically acceptable amine salts, in the case where R] or R, represent a hydrogen atom, as well as addition salts with pharmaceutically acceptable acids said products of formula I ', in which R' represents a dialkylaminoalkyl radical.

Among said products of formula I ′ and in particular I and said salts, there may be mentioned in particular, in their racemic or optically active forms or in the form of mixtures of these isomers, the products of formula I, in which R, and R2, identical or different, represent a hydrogen atom or a methyl radical, R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R, represents a hydrogen atom and R5 represents a hydrogen atom or a chlorine atom , as well as the products of formula I, in which R! represents a hydrogen atom or a methyl radical, R2 and R, represent a hydrogen atom, R3 represents a hydrogen atom, a methyl radical or a phenyl radical and R5 represents a chlorine atom, as well as the alkali salts , alkaline earth, aluminum, ammonium and amines of said products of formula I, in which R represents a hydrogen atom.

Among the products of formulas I 'and I above, there may be mentioned in particular those described in the examples and more particularly their A isomers described and defined above.

All of the products defined above constitute very useful drugs in human therapy, in particular in the treatment of acute or chronic hyperlipemia, cardiac insufficiencies of atheromatous origin, chronic anginal states.

The usual dosage, which varies according to the product used, the subject treated and the condition in question, can be, for example, from 0.05 to 1 g / d. in adults, orally.

The products of formulas I ′ and in particular I, as well as their pharmaceutically acceptable salts as defined above, can be used to prepare pharmaceutical compositions containing, as active principle, at least one of said products or salts.

These compositions are produced so that they can be administered by the digestive or parenteral route. They can be solid or liquid and come in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods.

The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

During the process, the following new intermediate products are obtained, in their racemic or optically active forms:

- 5-chloro 2-hydroxy a-methyl a-phenylbenzenemethanol,

- products with formulas II'A:

OH

OH

.VS

"

5

in which Ri represents a chlorine atom or a fluorine atom, R'5 represents a chlorine atom, R'3 represents an alkyl radical containing from 2 to 4 carbon atoms, R3

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can also represent a methyl radical when R'4 represents a fluorine atom.

The products of formula II are for the most part known.

The products of formula II which are not known, - formula in which R3 represents a hydrogen atom - can be prepared by reduction of the corresponding benzophenone derivatives of formula A:

by means, for example, of a mixed hydride, operating within an organic solvent. 20

The products of formula II which are not known - formula in which R3 represents an alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical - can be prepared by action on a corresponding benzophenone derivative of formula A above, within an organic solvent, an organomagnesium derivative of formula R3-Mg ~ Hal in which Hai represents a chlorine or bromine atom, and R3 has the value which has just been indicated above. Such a process is illustrated below in the experimental part.

The examples given below illustrate the invention. 30

Example 1: 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates)

8.1 g of sodium amide and 100 ml of toluene are mixed with stirring, a solution obtained dropwise with stirring is obtained by dissolving 24.9 g of 5-chloro 2-hydroxy a-methyl a- phenylbenzenemethanol in 250 ml of toluene, brings the mixture to reflux for 4 hours, brings the mixture to room temperature, adds, in small portions with stirring, 18 g of potassium dichloroacetate, adds 20 ml of hexamethyl-40

phosphorotriamide, refluxed for 5 h, cools the mixture until it is at room temperature, slowly adds 10 ml of ethyl acetate, then, drop by drop, 250 ml of water. The aqueous phase is collected, the organic phase is again extracted with 3 times 100 ml of water and the various aqueous extracts are combined and washed with 3 times 100 ml of ether. The aqueous extraction phase which contains the potassium salt of the expected product is acidified by bubbling sulfur dioxide and is extracted with 4 times 100 ml of ether. The ethereal extraction phase is washed with 3 times 50 ml of water. The organic phase is dried so on magnesium sulfate, treated with activated carbon, the solvent is evaporated in vacuo. 24 g of crude product are obtained which are crystallized from 100 ml of a 90/10 cyclohexane / benzene mixture,

dries the crystals obtained and obtains 15.2 g of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid. 55

F - 142 ° C.

Analysis: (C] 6HI3C104)

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

5-chloro 2-hydroxy a-methyl a-phenylbenzenemethanol, "> used at the start of the preparation of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid, can be prepared as follows:

Disperse with stirring 14 g of magnesium in turnings in 100 ml of anhydrous ether, add, drop by drop and with stirring, 65 a solution obtained by dissolving 76 g of methyl iodide in 200 ml of anhydrous ether, at reflux for 1 h, cools to the temperature of 15-20 ° C, then adds, to

at this temperature, a solution obtained by dissolving 59 g of 5-chloro 2-hydroxybenzophenone in 250 ml of anhydrous benzene, partly distills the ether, then brings again to reflux for 2 h. The mixture is then cooled to a temperature of 5-10 ° C. and 250 ml of 3N hydrochloric acid are added dropwise.

The organic phase is decanted and collected, the aqueous phase is washed with 2 times 100 ml of benzene.

The organic extraction phase is washed with water, then with a saturated solution of sodium bicarbonate, then finally with 2 times 50 ml of water. The organic phase is dried over magnesium sulphate, then the solvent is evaporated under vacuum, 58.9 g of crystals are obtained which are taken up in petroleum ether (bp 60-80 ° C.) and 53 g of 5-chloro 2-hydroxy a-methyl a-phenylbenzene-methanol. Mp 106 ° C.

Analysis: (CI4H13C102)

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

Example 2: Isomers A and B of methyl 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate

A solution of 2.25 g of diazomethane in 150 ml of methylene chloride is prepared, this solution is cooled to 5 ° C, added thereto, dropwise at 5 ° C, a solution obtained by dissolving 3.3 g of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid in the form of a mixture of the two diastereoisomeric racemates obtained in Example 1, in 75 ml of chloride. methylene. The mixture is stirred for 1 h at room temperature, then the solution is left standing for 24 h. 10 ml of acetic acid are then added, then the solvent is evaporated under vacuum. 4.2 g of methyl 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate are recovered in the form of a mixture of the two diastereoisomeric racemates.

The residue obtained is subjected to column chromatography on silica, eluting with an ethyl ether / petroleum ether mixture (20/80) (bp = 60-80 ° C), and 1 g of isomer A of 6 is obtained. -methyl chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate. Mp 114-115 ° C.

Analysis: (CnH15C104)

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

JRMN spectrum (base frequency of the device used: 60 Hz).

- CH3 at 117 Hz;

- COOCH3 at 232 Hz;

- Hydrogen in position 2 at 311 Hz;

- Aromatics from 410 to 445 Hz;

0.6 g of isomer B of methyl 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate is also obtained. Mp 102 ° C.

Analysis: (C17H15C104)

Calculated: C% 64.06 H% 4.74 Cl% 11.12

Found: 64.0 4.8 11.3

NMR spectrum (base frequency of the device used: 60 Hz).

- CH3 at 125 Hz;

- COOCH3 at 228 Hz;

- Hydrogen in position 2 at 341 Hz;

- Aromatics from 405 to 455 Hz.

Example 3: Isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid

14 g of isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate methyl obtained in Example 2 and after a second setting are mixed using the procedure described in Example 2, 2.8 g of potassium hydroxide in pellets, 32 ml of water and 160 ml of methanol, stirred for 22 h at room temperature, added 320 ml of water, wash the aqueous phase with twice 160 ml of ether, then acidify the aqueous solution with a 2N hydrochloric acid solution, extract the

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precipitate obtained with 3 times 320 ml of ether, wash the organic extraction phase with 2 times 160 ml of water, dry it over magnesium sulfate and bring to dryness. 13 g of crystals are obtained. 3.9 g are recrystallized from 100 ml of an ethyl acetate / cyclo-hexane mixture (20/80) and dried. 3.3 g of isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid are obtained. Mp 175-176 ° C.

Analysis: (C16H13C104)

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

NMR spectrum (basic frequency: 60 Hz)

- CH3 at 117 Hz;

- COOCHj at 468 Hz;

- Hydrogen in position 2 at 313 Hz;

- Aromatics from 412 to 443 Hz.

EXAMPLE 4 Isomer B of 6-chloro 4-methyl 4-phenyl- [4H] -I, 3-benzodioxin-2-carboxylic acid

5.3 g of isomer B of methyl 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate methyl obtained in Example 2 and after a second implementation of the procedure described in Example 2, 10 ml of water, 1.2 g of potassium hydroxide in pellets and 50 ml of methanol, stirred for 20 h at room temperature, added 200 ml of water , wash the aqueous phase with 2 times 80 ml of ether, then acidify the aqueous solution with a 2N hydrochloric acid solution, extracted with 3 times 100 ml of ether, combine the extracts, wash the extract with 2 times 80 ml of water, the ethereal phase is dried over magnesium sulphate, the solvent is evaporated under vacuum and 4.8 g of crystals are obtained which is recrystallized from a cyclohexane / ethyl acetate mixture (80/20), dried and obtained 4.4 g of isomer B of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid. M = 171 ° C.

Analysis: (C16H1304C1)

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

NMR spectrum (basic frequency: 60 Hz)

- CH3 at 124 Hz;

- COOCH3 at 329 Hz;

- Hydrogen in position 2 at 341 Hz;

- Aromatics from 408 to 445 Hz.

Example 5 6-chloro 2,4-dimethyl 4-phenyl- [4H] -1,3-benzo-dioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates)

8 g of sodium amide and 100 ml of toluene are mixed with stirring, a suspension obtained, dropwise, at room temperature, is added by dispersion of 24.9 g of 5-chloro 2-hydroxy a-methyl a-phenylbenzenemethanol in 250 ml of toluene, bring the mixture to reflux for 6 h, cool the mixture until it is at room temperature, add in small portions 17 g of dichloro 2,2-sodium propionate, bring again at reflux for 6 h, cools to room temperature and adds 700 ml of water. Acidified by adding a solution of hydrochloric acid N, realkalized by adding a saturated solution of sodium bicarbonate. The aqueous extraction phase is collected and washed with 3 times 100 ml of ether, the aqueous extract is acidified by addition of a 2N hydrochloric acid solution and extracted with 3 times 100 ml of ether, combined the organic extracts which are washed with 3 times 80 ml of water and dried over magnesium sulphate, then the solvent is evaporated under vacuum and 23 g of 6-chloro, 2,4-dimethyl 4-phenyl- [4H] -1.3-benzodioxin-2-carboxylic. Mp 181 ° C.

Analysis: (C17H1SC104)

Calculated: C% 64.06 H% 4.74 Cl% 11.12

Found: 64.0 4.8 11.2

Example 6: Isomers A and B of methyl 6-chloro 2,4-dimethyl 4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylate

23 g of 6-chloro 2,4-dimethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid are mixed in the form of a mixture of the two diastereoisomeric racemates A and B obtained in Example 5, 100 g of Redex CF resin (strong acidic sulfonic cationic resin), 250 ml of methanol, refluxed for 20 h, cooled to room temperature, wrung out the resin, rinsed with solvent and concentrated the filtrate under empty. 20 g of crude product are obtained which is chromatographed on a 1.5 kg column of silica under pressure, eluting with a mixture of ethyl ether / petroleum ether (20/80) (bp 60-80 ° C) and 1.7 g of isomer A of methyl 6-chloro 2,4-dimethyl 4-phenyl- [4H] -1.3-benzo-dioxin-2-carboxylate are obtained. Mp 134 ° C.

Analysis: (CIgHI7C104)

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

NMR spectrum (base frequency: 60 Hz)

- CH3 at 103 and 113 Hz;

- COOCH3 at 172 Hz;

- Aromatics from 419 to 447 Hz.

8.2 g of isomer B (in the form of an oil) of 6-chloro 2,4-dimethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate are also obtained.

Analysis: (C18H17C104)

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

NMR spectrum (basic frequency: 60 Hz)

- CH3 at 106 and 117 Hz;

- COOCH3 at 224 Hz;

- Aromatics from 415 to 455 Hz.

Example 7: Isomer A of 6-chloro 2,4-dimethyl 4-phenyl- [4H] -I, 3-benzodioxin-2-carboxylic acid

1.6 g of isomer A of 6-chloro 2,4-dimethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate methyl obtained in Example 6 are mixed, 20 ml of methanol, 2 ml of water and 0.56 g of potassium hydroxide in pellets, stir the mixture for 48 h at room temperature, add 100 ml of water, collect the aqueous phase which is washed with 3 times 50 ml of ether, acidifies the aqueous solution by adding a 2N hydrochloric acid solution, and extracted with 4 times 50 ml of ether, combines the ethereal extracts which are washed with 3 times 50 ml of water, then dried on magnesium sulfate. The solvent is evaporated under vacuum and 1.5 g of product are obtained which is recrystallized from 80 ml of cyclohexane and 1.2 g of isomer A of 6-chloro 2,4-dimethyl 4-phenyl- are obtained. [4H] -1.3-benzodioxin-2-carboxylic. Mp 184 ° C. Analysis: (C17H15C104)

Calculated: C% 64.06 H% 4.74 Cl% 11.12 Found: 64.1 4.8 11.1

NMR spectrum (basic frequency: 60 Hz)

- CH3 at 101.5 Hz and 113 Hz;

- COOCH3 at 342 Hz;

- Aromatics from 412 to 442 Hz.

EXAMPLE 8 Isomer B of 6-chloro 2,4-dimethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid

8 g of isomer B of 6-chloro 2,4-dimethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate methyl obtained in Example 6 are mixed, 80 ml of methanol, 8 ml of water and 2.8 g of potassium hydroxide in pellets, stirred for 24 h at room temperature, add 150 ml of water, collect the aqueous phase which is washed with 3 times 60 ml of ether. The aqueous solution is acidified by adding a 2N hydrochloric acid solution and extracted with 4 times 60 ml of ethyl ether. The ethereal extracts are combined and washed with twice 80 ml of water, then dried over magnesium sulphate and the solvent is evaporated in vacuo and 7.2 g of product are obtained, which is recrystallized from 80 ml of cyclohexane. We dry and get 4.5 g

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B-isomer of 6-chloro acid

2,4-dimethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic. Mp 125 ° C.

Analysis: (Ci7H1504C1)

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

NMR spectrum (basic frequency: 60 Hz)

- CH3 at 104 and 119 Hz;

- COOCH3 at ^ 540 Hz;

- Aromatics from 417 to 455 Hz.

EXAMPLE 9 6-Chloro 4-phenyl- [4H] -1,3-Benzodioxin-2-carboxylic acid

10.35 g of sodium amide and 100 ml of toluene are mixed, introduced dropwise at room temperature and with stirring, a solution obtained by dissolving 30.1 g of 5-chloro 2-hydroxy a-phenylbenzenemethanol in 200 ml of anhydrous toluene, stir for 2 h at room temperature, bring the mixture to reflux for 6 h, cool the mixture to room temperature and add in small portions 22.3 g of potassium dichloro-tate, add 20 ml of hexamethylphosphoramide, stirred for 20 h at room temperature, brought the mixture to reflux of toluene for 4 h, allowed to return to room temperature, added 20 ml of ethyl acetate, then slowly 250 ml of water. The aqueous phase is collected, the organic phase is extracted again with 3 times 100 ml of water and the various aqueous extracts are combined and washed with 3 times 100 ml of ether. The aqueous extraction phase which contains the potassium salt of the expected product is acidified by bubbling sulfur dioxide, extracted with 3 times 100 ml of ether, the extracts are combined, washed with 3 times 100 ml of water, dried over magnesium sulphate, treated with activated carbon, evaporates the solvent under vacuum and obtains 24 g of crude product which is disintegrated in cyclohexane, obtains crystals which are recrystallized from 520 ml of a benzene / cyclohexane mixture (7 / 3) and obtains 5.3 g of 6-chloro 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid. F - 194 ° C.

Analysis: (C15HnC104)

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

NMR spectrum (basic frequency: 60 Hz)

- Hydrogens in positions 2 and 4 at 343.5 Hz and 364 Hz;

- COOH at = 514 Hz;

- Aromatics from 398 to 442.5 Hz.

Example 10 6-chloro 4,4-diphenyl- [4H] -1,3-benzodioxin-2-carboxylic acid

12.4 g of 5-chloro 2-hydroxy a, a-diphenylbenzene-methanol, 150 ml of toluene, 3.2 g of sodium amide are mixed,

brings the mixture to reflux for 6 h, cools to room temperature and adds 6.8 g of potassium dichloroacetate, brings to reflux for 6 h, cools to room temperature and adds 300 ml of water . It is slightly acidified by adding a solution of hydrochloric acid N, then basified by adding a saturated solution of sodium bicarbonate. Washed twice with 100 ml of methylene chloride,

then acidified by addition of a 2N hydrochloric acid solution, extracted with 3 times 100 ml of ether, combined the ethereal extracts, washed with 2 times 80 ml of water, then dried over magnesium sulfate and treated with activated carbon . After evaporation of the solvent under vacuum, 7 g of product are obtained which is recrystallized from 300 ml of benzene. 4.6 g of 6-chloro 4,4-diphenyl- [4H] -1,3-benzodioxin-2-carboxylic acid are obtained. M = 226 ° C.

Analysis: (C2] HI504C1)

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

NMR spectrum (basic frequency: 60 Hz)

- Hydrogen in position 2 at 325 Hz;

- COOH at = 313 Hz;

- Aromatics from 405 to 443 Hz.

Example 11 Isomer A of 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-methyl carboxylate

The title compound can be prepared analogously to the above.

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

Analysis: (C, 7H1604)

Calculated: C ° Xf "71.82 H% 5.67 Found: 72.1 5.8

NMR spectrum (basic frequency: 60 Hz)

- Hydrogen in position 2 at 312 Hz;

- COOCH3 at 231 Hz;

- CH3 twin to phenyl: 117 Hz;

- Aromatics from 410 to 450 Hz.

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

Was mixed with stirring 9.7 g of isomer A of 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate methyl obtained in Example 11, 4 g of potassium hydroxide pellets, 10 ml of water, 90 ml of methanol, keep stirring for 16 h at room temperature, add 400 ml of water, wash the aqueous phase with 2 times 100 ml of methylene chloride, acidify the aqueous phase by adding '' a 2N hydrochloric acid solution, extracted with 3 times 150 ml of methylene chloride, combines the extracts, washed with twice 80 ml of water, dried over calcium chloride, evaporates the solvent under vacuum, collects 8 g of product which is recrystallized from an ethyl acetate / cyclohexane mixture (20/80) and 5.1 g of isomer A of 4-methyl 4-phenyl- [4H] -1,3-benzodioxin acid are obtained -2-carboxylic. Mp = 163 ° C.

Analysis: (C16Hl404)

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

NMR spectrum (basic frequency: 60 Hz)

- CHj at 119 Hz;

- COOH3 at 534 Hz;

- Hydrogen in position 2 at 316 Hz;

- Aromatics from 418 to 450 Hz.

Example 13: Isomer B of 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-methyl carboxylate

The title compound can be prepared analogously to the above.

A sample of the product is recrystallized from methanol. Mp 137 ° C.

Analysis: (C] 7H, 604)

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

NMR spectrum (basic frequency: 60 Hz)

- CH3 at 128 Hz;

- COOCH3 at 234 Hz;

- Hydrogen in position 2 at 347 Hz;

- Aromatics from 410 to 465 Hz.

Example 14: Isomer B of 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid

10.2 g of the B-isomer of 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate methyl obtained in Example 13 are mixed with stirring, 4 g of potassium hydroxide in tablets, 10 ml of water and 90 ml of methanol, maintained under stirring for 16 h at room temperature, added 500 ml of water, washed the aqueous phase with twice 80 ml of methylene chloride, acidified the aqueous phase with addition of a 2N hydrochloric acid solution, extracted with 3 times 100 ml of methylene chloride, washed with 2 times 80 ml of water, dried over calcium chloride, evaporates the solvent under vacuum, obtains 9 g of product that recrystallized from an ethyl acetate / cyclohexane mixture (20/80) to obtain 6.7 g of the expected product. Mp 153 ° C.

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Analysis: (C, 6H1404)

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

NMR spectrum (basic frequency: 60 Hz)

- CH3 at 128 Hz;

- Hydrogen in position 2 at 348 Hz;

- Aromatics from 410 to 460 Hz.

Example 15: methyl 6-chloro 4,4-diphenyl- [4H] -1,3-benzodioxin-2-carboxylate.

11 g of 6-chloro 4,4-diphenyl- [4H] -1,3-benzodioxin-2-carboxylic acid obtained in Example 10 are mixed by stirring, 50 g of Redex CF resin (strong sulfonic acid cationic resin ), 200 ml of methanol, refluxed for 16 h, cooled to room temperature, wrung out the resin, washed with ether and concentrated the filtrate under vacuum.

The crude product obtained is taken up in 200 ml of ether, the organic phase is washed with 100 ml of a 5% sodium bicarbonate solution, then with (Games times 100 ml of water. The ethereal phase is dried over sulphate magnesium, treated with activated carbon,

the solvent is evaporated and 6.3 g of product is obtained which is recrystallized from 140 ml of cyclohexane. Dried and obtained 5.1 g of the expected product. M - 172 ° C.

Analysis: (C22H1704C1)

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

NMR spectrum (base frequency 60 MHz) (deuterochloroform)

- COOCHj at 230 Hz;

- Hydrogen in position 2 at 324 Hz;

- Aromatics from 406 to 443 Hz.

Example 16: Isomer A of ethyl 6-chloro 4-methyl 4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylate.

Stage A: Isomer of chloride of 6-chloro 4-methyl 4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylic acid.

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

Stage B: Isomer A of ethyl 6-chloro 4-methyl 4-phenyl- [4H] -1.3-benzodioxin-2-carboxyate.

3 ml of absolute ethanol, 50 ml of anhydrous benzene, 2.3 ml of triethylamine are mixed, the acid chloride solution obtained in stage A is added dropwise at room temperature, kept stirring for 20 h at room temperature , wring out and wash the precipitate of triethylamine hydrochloride with cold benzene, wash the filtrate with twice 40 ml of water, dry the organic phase on calcium chloride, treat with active carbon, evaporate the solvent under vacuum, obtain 9 g of crude product which is recrystallized from 30 ml of hexane and after drying 4 g of the expected product is obtained. Mp 92 ° C.

Analysis: (C18H, 704C1)

Calculated: C% 64.97 H% 5.15 Cl% 10.65

Found: 65.1 5.3 10.8

NMR spectrum (deuterochloroform) (base frequency: 60 MHz)

- CHj of C2H5 at 72.5-79.5-87 Hz;

- CH3 in position 4 at 116 Hz;

- CH2 from C2H5 at 247.5-255-262-269 Hz;

- Hydrogen in position 2 at 308 Hz;

- Aromatics from 412 to 441 Hz.

EXAMPLE 17 Isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1.3 sodium benzodioxin-2-carboxylate

0.6 g of sodium hydroxide, 250 ml of absolute ethanol are mixed, 4.6 g of the isomer A of 6-chloro 4-methyl 4-phenyl- [4H] acid are added at room temperature -1.3-benzodioxin-2-carboxylic obtained in Example 3, the mixture is brought to the boil for 5 min, filtered, cooled to room temperature, added to the filtrate 500 ml of ether and stirred for 16 h at ambient temperature. Filtered and obtained after drying 3.8 g of the expected product. F - 160 ° C.

Analysis: (C16HI204ClNa)

Calculated: C% 58.82 H% 3.70 Cl% 10.85

Found: 58.5 3.8 10.7

EXAMPLE 18 Isomers d and f of the A isomer of 6-chloro 4-methyl 4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylic acid

1) Isomer /

Stage A: Salt of / lp-nitrophenyl 2-amino 1,3-propanediol of the isomer / 'of the isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-acid benzodioxin-2-carboxylic.

15.2 g of isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid obtained in Example 3 are mixed, 16.2 g of f1 -p-nitrophenyl 2-amino 1,3-propanediol and 800 ml of ethyl acetate.

The mixture is brought to reflux, the reflux is maintained after precipitation of the salt formed for 5 min. The mixture is brought to ambient temperature, the precipitate obtained is drained, rinsed with ethyl acetate, dried under vacuum and recovering 10 g of crude product. (The mother liquors are kept for the separation of the crude d isomer (see below).)

The 10 g of crude product obtained are recrystallized from isopro-panol and finally 6.4 g of expected product is obtained. M = 218 ° C Md = —84 ° ± 2 ° (c = 1%, ethanol).

A sample of this product is recrystallized from a little isopropanol. F - 218 ° C.

[a] 2D ° = -84.5 ° ± 2 ° (c = 1%, ethanol).

Stage B: Isomer / 'of the A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -I, 3-benzodioxin-2-carboxylic acid.

The salt thus purified obtained is suspended in stage A above, in 150 ml of hydrochloric acid N, then extracted with 3 times 75 ml of ether, washing the organic extraction phase with 3 times 50 ml water, dry over magnesium sulfate. The solvent is evaporated under vacuum, 3.5 g of crude product are obtained which are crystallized from cyclohexane, 2.7 g of crystals are obtained which are purified by recrystallization from cyclohexane, 2.3 g of crystals are obtained at 113-114 ° C then recrystallizing and melting at 128 ° C. It is re-crystallized again in 80 ml of cyclohexane and 1.8 g of the expected product, melting at 113 ° C., are obtained.

0.5 g of expected product is obtained from the mother liquors of previous recrystallizations. These 0.5 g of product are combined and the 1.8 g of product obtained previously, recrystallizes the 2.3 g of product from 50 ml of cyclohexane while maintaining the reflux of the solvent for 20 min and then obtains 2 g of the expected product. . F - 140 ° C.

(The variations in the different melting points noted for the expected product are probably due to variations in crystal structure.)

Analysis: (C16H, 3C104)

Calculated: C% 63.06 H% 4.30 Cl% 11.63

Found: 63.2 4.4 11.6

NMR spectrum (deuterochloroform) (base frequency: 60 MHz)

- CH3 at 116.5 Hz;

- Hydrogen in position 2 at 313 Hz;

- Aromatics from 415 to 443 Hz;

- OH at around 540 Hz.

Rotating power

[a] o = -157 ° ± 2.5 ° (c = 1%, 95% ethanol).

2) Isomer d

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Stage A: Isomer d of the A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-ben2odioxin-2-carboxylic acid.

The mother liquors of ethyl acetate and salification of the A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid are taken up with 10 f1- p-nitrophenyl 2-amino 1,3-propanediol. ■

The solution is concentrated under vacuum, recovering 17.8 g of crude product which is treated with 200 ml of 2N hydrochloric acid, extracted with 3 times 100 ml of ether, washing the organic phase with 2 times 50 ml of water, dry over magnesium sulfate and concentrate in vacuo. 8.4 g of residue are obtained, which is taken up in 150 ml of a cyclohexane / ethyl acetate mixture (70/30) and brought to reflux, allowed to cool, wrung out the residual starting racemic acid which crystallizes, concentrates the filtrate under vacuum, and obtains 7 g of crude expected product.

Stage B: Salt of d 1-p-nitrophenyl 2-amino 1,3-propanediol of the d isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2- acid carboxylic.

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

The suspension is brought to reflux, allowed to cool, after precipitation of the salt formed up to room temperature, the precipitate is drained, rinsed with a little ethyl acetate. After drying, 11.4 g of expected product, melting at 200 ° C., is obtained.

Recrystallized from 1.1 l of isopropanol, 6.2 g of expected product is obtained, mp = 218 ° C., which is recrystallized from 800 ml of isopropanol and 5 g of expected product is obtained. Mp = 218 ° C approximately.

Stage C: Isomer d of the A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid.

The salt obtained above is taken up in 150 ml of water, acidified with 2N hydrochloric acid, extracted with 2 times 100 ml of ether, washing the organic extraction phase with 2 times 50 ml of water, drying over magnesium sulfate and evaporates the solvent in vacuo; 2.9 g of crude product are obtained which is taken up in a mixture of ethyl ether / petroleum ether (20/80) (bp 60-80 ° C).

Finally, after separation, 2.4 g of the expected product are obtained. Mp 128 ° C.

Md = + 153 ° ± 2.5 ° (c = 1%, ethanol).

This product is recrystallized from 100 ml of cyclohexane,

obtains 2 g of the expected product. Mp 128 ° C.

Md = + 153 ° ± 2.5 ° (c = 1%, ethanol).

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

(As with the isomer, the d isomer has several melting points. This is probably due to variations in crystal structure.)

Analysis: (C, 6H | 3C104)

Calculated: C% 63.06 H% 4.30 Cl% 11.63

Found: 63.2 4.3 11.6

NMR spectrum (deuterochloroform) (base frequency: 60 MHz)

- CH3 at 117 Hz;

- Monosubstituted phenyl at 440 Hz;

- Aromatics 413 to 440 Hz;

- OH at 485 Hz;

- Hydrogen in 2 at 312.5 Hz.

Rotating power

[a] 2D ° = + 154.5 ° ± 2.5 ° (c = 1%, ethanol).

Example 19: 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid (mixture of diastereoisomeric racemates)

10 g of sodium amide and 200 ml of anhydrous toluene are mixed with stirring, then a suspension obtained at room temperature and in small portions is obtained by dissolving 28.3 g of 1- [5-chloro 2-hydroxyphenyl] 1- [3-chloro phenylkethanol in 250 ml of toluene, then the mixture is brought to reflux for 6 h (a further 1 g of sodium amide is added to the mixture). After cooling to room temperature, 25 g of potassium dichloroacetate are added in small portions with stirring, and the mixture is again brought to reflux for 6 h. After returning to ambient temperature, 150 ml of water are slowly added, then 150 ml of 2N HCl. The organic phase is collected, then the aqueous phase is again extracted with 2 times 100 ml of ether. The organic extraction phase is washed with 2 times 100 ml of water. The organic phase is extracted with a saturated sodium bicarbonate solution, then with 2 times 100 ml of water. The aqueous extraction phase is washed with 3 times 100 ml of ether, then the aqueous phase is slowly acidified with a 2N HCl solution. The aqueous phase is then extracted with 3 times 150 ml of ether. The organic extraction phase is washed with twice 75 ml of water. It is treated with activated carbon and dried over magnesium sulfate. The solvent is evaporated in vacuo, and finally 29.3 g of the expected product are obtained.

NMR spectrum (deuterochloroform)

(base frequency: 60 MHz)

- CH3 at 117 and 125.5 Hz;

- COOH at 588 Hz;

- Hydrogen in position 2 at 315.5 and 346 Hz;

- Aromatics from 412 to 455 Hz.

L- [5-chloro 2-hydroxyphenyl] l- [3-chlorophenyl] ethanol used at the start of the preparation of 6-chloro 4- (3-chloro-phenyl) 4-methyl- [4H] -l acid , 3-benzodioxin-2-carboxylic can be prepared as follows:

11 g of magnesium are dispersed with stirring in turnings in 100 ml of anhydrous ether, a solution obtained dropwise at room temperature and with stirring is obtained by dissolving 64 g of methyl iodide in 100 ml of anhydrous ether . A slight reflux of the solvent is maintained during the addition and the reflux is continued for 1 h, brings back to room temperature, then drop by drop over 25 minutes a solution of 31.7 g of (5-chloro 2-hydroxyphenyl) (3 -chlorophenyl) methanone in 100 ml of anhydrous ether and 150 ml of anhydrous benzene.

The ether is distilled, 250 ml of anhydrous benzene are added, then the solution is brought to reflux for 4 h.

The mixture is cooled to room temperature and, maintained at this temperature by means of an ice bath, hydrolysis is carried out using a solution of hydrochloric acid N.

The organic phase is collected, the aqueous phase is again extracted with 2 times 80 ml of ether, the organic extraction phase is washed with 3 times 80 ml of water, the organic phase is dried over magnesium sulfate, then the solvent is evaporated. under vacuum.

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

25.5 g of expected product are finally obtained. Mp 125 ° C.

Analysis: (Ci4H1202Cl2)

Calculated: C% 59.38 H% 4.27 Cl% 25.04

Found: 59.2 4.3 24.9

The above [5-chloro 2-hydroxyphenyl] [3-chlorophenyl] methanone used at the start of the preparation of l- [5-chloro 2-hydroxyphenyl] l- [3-chlorophenyl] ethanol can be prepared as follows:

Stage A: 4-chlorophenyl 3-chlorobenzoate.

Was mixed with stirring 5.87 g of 4-chlorophenol, 46.1 g of triethylamine and 250 ml of anhydrous benzene, cooled to 10 ° C, added dropwise a solution of 80 g of 3-chlorophenylcarboxylic acid chloride in 100 ml of anhydrous benzene, kept stirring at room temperature overnight, filter, drain the precipitate of triethylamine hydrochloride, collect the filtrate and bring to dryness. 122 g of crude product are obtained which are crystallized from 200 ml of a ethyl ether / petroleum ether mixture (20/80) (bp 60-80 ° C).

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116 g of expected product are obtained. M - 72 ° C.

Analysis: (C, 3H8C1202)

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

Stage B: [5-Chloro 2-hydroxyphenyl]

[3-chlorophenyl] methanone.

64.5 g of 4-chlorophenyl 3-chlorobenzoate obtained in the preceding stage and 32 g of aluminum chloride are mixed with stirring, the mixture is gradually heated, with stirring, to 160 ° C., maintained at this temperature for 30 min, brings back to room temperature, takes up the crude product obtained with methylene chloride, hydrolyzes the organic solution slowly at first, with 250 ml of hydrochloric acid N, decant the organic phase, then extracts the aqueous phase with 2 times 70 ml of methylene chloride, wash the organic extraction phase with 3 times 70 ml of water, dry the organic phase on calcium chloride, then evaporate the solvent under vacuum.

60 g of crude product are finally obtained which are crystallized from a ethyl ether / petroleum ether mixture (20/80) (bp 60-80 ° C).

It is filtered, dried and 41.3 g of expected product is obtained. A sample of this product is recrystallized from cyclohexane. M - 72 ° C.

Analysis: (C, 3H8C1202)

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

Example 20: Isomers A and B of methyl 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylate.

29.3 g of 6-chloro 4- (3-chloro-phenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid are mixed with stirring as the mixture of the two diastereoisomeric racemates obtained in Example 19, 300 ml of methanol and 30 g of strong acidic sulfonic cationic resin, refluxed for 20 h, with stirring, cooled to room temperature, wrung the resin, rinsed with methanol and concentrated the vacuum filtrate. 20 g of crude product are obtained which is chromatographed on a column of silica under pressure, eluting with a ethyl ether / petroleum ether mixture (20/80) (bp 60-80 ° C) and obtained after fractionation and evaporation of the solvent 9.5 g of expected A isomer, of which 4 g are purified by recrystallization from methanol: 3.2 g of purified expected A isomer are obtained. M - 112 ° C.

Analysis: (C17H, 304C12)

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

NMR spectrum (deuterochloroform) (base frequency: 90 MHz)

- CH3 at 172 Hz;

- COOCH3 at 345 Hz;

- Hydrogen in position 2 at 461.5 Hz;

- Aromatics from 623 to 660 Hz and 8.4 g of isomer B expected, in the form of a crude product. Analysis: (C] 7H, 304C12)

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

NMR spectrum (deuterochloroform)

(base frequency: 90 MHz)

- CHj at 184 Hz;

- COOCHj at 343.5 Hz;

- Hydrogen in position 2 at 509 Hz;

- Aromatics from 612 to 674 Hz.

Example 21: Isomer A of 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid.

6.5 g of methyl isomer A of 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylate, obtained in Example 20, are mixed with stirring. 2.8 g of potassium hydroxide in pellets, 10 ml of water and 100 ml of methanol, stir the mixture for 16 h at room temperature, add 200 ml of water, wash the aqueous solution with an acid solution 2N hydrochloric acid, extract the aqueous phase with 3 times 80 ml of ether, wash the organic extraction phase with 2 times 50 ml of water, dry the ethereal phase on magnesium sulphate, evaporate the solvent under vacuum, obtain 6, 1 g of product which is recrystallized from 100 ml of cyclohexane. 3.6 g of expected product are obtained.

M = 131 ° C.

Analysis: (C16H1204C12)

Calculated: C% 56.66 H% 3.57 Cl% 20.90

Found: 56.7 3.7 20.6

NMR spectrum (deuterochloroform)

(base frequency: 60 MHz)

- CHj at 174.5 Hz;

- Hydrogen in position 2 at 466.5 Hz;

- Aromatics - peaks from 625 to 665 Hz.

Example 22: Isomer B of 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid

5.3 g of methyl isomer B of 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylate, obtained in Example 20, are mixed with stirring 2.4 g of potassium hydroxide in pellets, 10 ml of water, 100 ml of methanol, stir the mixture overnight at room temperature, add 250 ml of water, then wash the aqueous phase twice with 80 ml of water. ether, acidify the aqueous solution with a 2N hydrochloric acid solution, extract the aqueous phase with 3 times 80 ml of ether, wash the organic phase with 2 times 50 ml of water, dry the ethereal phase over magnesium sulfate , concentrated under vacuum and obtained 5.3 g of the expected product which is recrystallized from 110 ml of a cyclohexane / ethyl acetate mixture (80/30). 4 g of expected purified product are obtained. M - 177 ° C.

Analysis: (Cl6Hi204Cl2)

Calculated: C% 56.66 H% 3.87 Cl% 20.90

Found: 56.8 3.8 20.9

NMR spectrum (deuterochloroform) (basic frequency 90 MHz)

- CH3 at 185.5 Hz;

- Hydrogen in position 2 at 510 Hz;

- Aromatics from 610 to 673 Hz.

Example 23: 6-chloro 4 [(1-methyl) ethyl] 4-phenyl- [4H] -I, 3-benzodioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates)

8.1 g of 50% sodium hydride in oil, 60 ml of anhydrous dioxane and 360 mg of dibenzo-18 crown-6, of the type described in "Synthesis", 1976, p. 168, adding while keeping the solution at room temperature, in 10 minutes with stirring, a solution of 3.66 ml of dichloroacetic acid in 60 ml of anhydrous dioxane, then add, at room temperature, a solution of 8.7 g of 5-chloro a - [(1-methyl) ethyl] 2-hydroxy a-phenylbenzenemethanol in 30 ml of anhydrous dioxane, heat the suspension for 10 h at 90-100 ° C, bring to room temperature, add drop by drop while cooling using an ice-water bath, 500 ml of water, washing the aqueous phase with 2 times 200 ml of ether, extracting the ethereal phase with 3 times 100 ml of 2N sodium hydroxide. The aqueous phase is acidified with 2N hydrochloric acid and the liberated acid is extracted with 3 times 150 ml of ether, the ethereal phase is washed with 3 times 100 ml of water, the acid formed is extracted as a salt of sodium by extraction of the ethereal phase with a saturated sodium bicarbonate solution, then with 3 times 100 ml of water, washing the aqueous extraction phase with 2 times 80 ml of ether, acidified by addition of hydrochloric acid 2N, extract the acid thus released, with 3 times 150 ml of ether, wash the organic extraction phase with 3 times 80 ml of water, dry and treat with activated carbon, bring to dryness and obtain 8.8 g of expected product, in the form of an oil.

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NMR spectrum (deuterochloroform) (base frequency of the device 60 MHz)

- Hydrogen in position 2 at 323 Hz (peak corresponding to isomer A),

- Hydrogen in position 2 at 335 Hz (peak corresponding to the B isomer),

CH3

the two CH3 of the radical ^ CH— from 49 to 69 Hz,

/

CH3

the hydrogen of the radical NCH— from 100 to 190 Hz ^ H3

- Aromatics from 410 to 465 Hz;

- OH at 490 Hz.

The 5-chloro a - [(1-methyl) ethyl] 2-hydroxy a-phenylbenzenemethanol, used from the above preparation, was prepared as follows:

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

The mixture is stirred until the expected magnesium is formed, then added dropwise, so as to maintain a slight reflux and at room temperature, a solution of 110.8 g of isopropyl bromide in 400 ml of ether anhydrous. When the addition is complete, the reflux is continued for 2 h. Furthermore, 58. '2 g of [(5-chloro 2-hydroxy) phenyl] phenylmetha-none, 600 ml of anhydrous benzene are mixed, then 520 ml of the prepared magnesium solution is added dropwise at room temperature. above.

The ether is distilled, gradually replacing it with benzene. The reflux is continued for 6 h.

After cooling to room temperature, the reaction mixture is poured onto 11 of an ice-cold 10% ammonium chloride solution. The organic phase is decanted, the aqueous phase is extracted with 2 times 150 ml of ether. The organic phases are combined, washed with 3 times 100 ml of water, dried, treated with activated carbon, the solvent is evaporated in vacuo. 74 g of crude product are obtained, which is chromatographed on a silica column, eluting with methylene chloride; after fractionation, 18 g of crude product are obtained which is taken up in 50 ml of cyclohexane. 8.7 g of expected product are obtained. M = 114 ° C.

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

Analysis: (C18H1702C1)

Calculated: C% 69.43 H% 6.19 Cl% 12.81

Found: 69.7 6.2 12.8

NMR spectrum (deuterochloroform) (base frequency of the device used = 60 MHz)

- the 2 CH3s of the (l-methyl) ethyl radical at 48-55 Hz and 63-70 Hz,

- CH— at = 165 Hz (multiplet);

- OH methanol at 165 Hz;

- OH of 2-hydroxy at 537 Hz;

- Aromatics from 395 to 455 Hz.

EXAMPLE 24 Isomer A of 6-chloro 4 - [(1-methyl) ethyl] 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate methyl

Stage A: Chloride of the A-isomer of 6-chloro 4 - [(1-methyl) ethyl] 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid.

8.8 g of 6-chloro 4 - [(1-methyl) ethyl] 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid obtained in Example 22 are mixed with stirring, 100 ml of anhydrous benzene, adding while maintaining at room temperature 3.7 ml of triethylamine, 3.8 ml of thionyl chloride, 25 ml of anhydrous benzene, bring the mixture to reflux for 3 h, cool to room temperature, spin and wash the precipitate with a little anhydrous benzene and collect the filtrate which contains the expected product.

Stage B: Isomer A of methyl 6-chloro 4 - [(1-methyl) ethyl] 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate.

50 ml of anhydrous benzene, 4 ml of anhydrous methanol and 3.7 ml of triethylamine are mixed with stirring, the filtrate obtained in stage A above is added dropwise at room temperature, the mixture is stirred for 50 h at room temperature , drain and wash the precipitate with a little benzene, collect the filtrate, wash with 2N sodium hydroxide, then with water until neutral pH. The organic phase is dried, treated with active charcoal, brought to dryness, 7.3 g of crude product is obtained which is crystallized from methanol, filtered, dried the crystals obtained and collected 4.5 g of the expected product as it is purified by two recrystallizations from methanol. 1.8 g of purified expected product are obtained. Mp 114-115 ° C.

Analysis: (C19H1904)

Calculated: C% 65.80 H% 5.52 Cl% 10.22

Found: 65.8 5.6 10.2

NMR spectrum (deuterochloroform) (base frequency: 90 MHz)

- the two CH3s of the (1-methyl) ethyl radical at 74 and 77 Hz;

- the —CH— of the (l-methyl) ethyl radical from 187 to 239 Hz

I

- COOCHj at 351 Hz;

- Hydrogen in position 2 at 479 Hz;

- Aromatics: peaks from 616 to 681 Hz.

EXAMPLE 25 6-chloro 4 [(1,1-dimethyl) ethyl] 4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates)

12.8 g of 50% sodium hydride are mixed with stirring

in oil, 100 ml of anhydrous dioxane, 600 mg of dibenzo 18-crown-6, then add drop by drop while keeping the solution at room temperature, a solution of 5.82 ml of dichloroacetic acid in 100 ml of dioxane, keep the suspension at room temperature, drop by drop a solution of 14.1 g of 5-chloro a- (1,1-dimethyl) ethyl 2-hydroxy a-phenylbenzenemethanol in 100 ml of dioxane, then heat the mixture at 80 ° C for 6 h, cooled to room temperature and maintaining at this temperature in an ice-water bath, 400 ml of water are added, the aqueous phase is extracted with 600 ml of ether, extracted with 3 times 100 ml of 0.1N sodium hydroxide, acidifies the aqueous extraction phase with 2N hydrochloric acid, extracted with 3 times 150 ml of ether, washed the organic extraction phase with 3 times 100 ml of water, extract the acid in the form of sodium salt using a saturated solution of sodium bicarbonate, then with 3 times 100 ml of water and shave mix the aqueous extracts.

The aqueous phase is washed with 3 times 100 ml of ether, the aqueous phase is acidified with 2N hydrochloric acid, extracted with 4 times 150 ml of ether, the ethereal phase is washed with 3 times 100 ml of water, dried the ethereal phase on magnesium sulphate, treated with activated carbon, brings to dryness, obtains 9.1 g of crude expected product.

NMR spectrum (deuterochloroform) (base 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;

- Aromatics from 415 to 472 Hz;

- OH at 527 Hz.

The 5-chloro a- (1,1-dimethyl) ethyl 2-hydroxy a-phenylbenzenemethanol, used at the start of the above preparation, was prepared as follows:

40.2 g of (5-chloro 2-hydroxyphenyl) phenyl-methanone, 400 ml of anhydrous ether are mixed, 192 g of a solution of terbutyllithium in pentane are added dropwise at room temperature, stirred for 2 h at room temperature,

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distill the ether gradually replacing it with 600 ml of anhydrous benzene, bring the solution to reflux of the benzene for 16 h, cool to room temperature, pour onto 11 of an ice-cold solution of 10% ammonium chloride , eliminates the organic phase by decantation, extracts the aqueous phase with 2 times 100 ml of ether, washing the organic phase with 2 times 70 ml of water, dries over magnesium sulphate, treats with activated carbon, brings to dryness, obtains 50 g of crude product (in the form of an oil), which is chromatographed on a column of silica eluting with methylene chloride, obtains by fractionation 14.1 g of product, of which a sample is recrystallized from cyclohexane. F - 146 ° C.

Analysis: (C17H1902C1)

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

NMR spectrum (deuterochloroform)

(base frequency: 60 MHz)

- OH of the 2-hydroxy radical at 530 Hz;

- OH methanol at 175 Hz;

- Radical [(1,1-dimethyl) ethyl] at 75 Hz;

- Aromatics of the phenyl radical has methanol from 420 to 455 Hz;

- Other aromatics from 400 to 455 Hz.

Example 26: Isomer A of 6-chloro 4 - [(1,1-dimethyl) ethyl] 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate methyl

Stage A: Chloride of 6-chloro 4 - [(1,1-dimethyl) ethyl] 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid (mixture of racemates).

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

Then gradually added, maintaining at room temperature, 3.7 ml of triethylamine and then, dropwise, a solution of 6.2 g of thionyl chloride in 25 ml of anhydrous benzene, brought to reflux for 3 h, cooled to at room temperature, drain and wash the precipitate with anhydrous benzene, collect the filtrate and concentrate the solution under vacuum until a volume of solution of 30 ml is obtained.

Stage B: Isomer A of methyl 6-chloro 4 - [(1,1-dimethyl) ethyl] 4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylate.

3 ml of methanol, 50 ml of anhydrous benzene, 3.7 ml of triethylamine are mixed with stirring, cooled to 15-20 ° C.

add dropwise, at this temperature, the solution obtained in stage A above to which 30 ml of anhydrous benzene has been added, stirred for 16 h at room temperature, drain and wash the precipitate with anhydrous benzene.

The filtrate is concentrated in vacuo and 6.5 g of crude product is obtained, which is chromatographed on a silica column, eluting with ethyl ether / petroleum ether (20/80) (bp 60-80 ° C) and obtains, after fractionation and then evaporation of the solvent, the expected crude product which is crystallized from 20 ml of methanol and obtains, after drying, the expected product. F - 85 ° C.

Analysis: (C20H21C104)

Calculated: C% 66.57 H% 5.87 CL% 9.82 Found: 66.5 6.0 10.00

NMR spectrum (deuterochloroform) (base frequency: 60 MHz)

- (1,1-Dimethyl) ethyl at 62 Hz;

- COOCH3 at 117 Hz;

- Hydrogen in position 2 at 338 Hz;

- Aromatics: peaks from 412 to 468 Hz.

EXAMPLE 27 6-Fluoro 4-methyl 4-phenyl- [4H] -1,3-benzo-dioxin-2-carboxylic acid (mixture of diastereoisomeric racemates) 25 g of sodium hydride, 350 cm3 of anhydrous dioxane, 1.55 g of dibenzo-18 crown-6, add, in 1 h, a solution of 16.5 cm3 of dichloroacetic acid in 150 cm3 of dioxane then, at the end of the reaction, add, in 1 h at 22 ° C, a solution of 31 g of a-phenyl a-methyl (5-fluoro 2-hydroxy) phenylmethanol in 150 cm3 of anhydrous dioxane, heating to 80 ° C, stirred 6 h at 80-85 ° C, cools, pours over an ice / water mixture, extract with ether, acidify the aqueous phase, extract the aqueous phase with ether, wash the ethereal phase with water, bicarbonate extract of sodium the ethereal phase, wash with methylene chloride, acidify the alkaline phases, wash with methylene chloride, acidify the alkaline phases, extract with methylene chloride, wash with water, dry over magnesium sulfate and bring to dry under empty. 29.5 g of crude expected product are obtained (in the form of an oil).

NMR spectrum

- Hydrogen in position 2 at 310 Hz and CH3 at 117 Hz (peak corresponding to the A isomer of the acid obtained);

- Hydrogen in position 2 at 339 Hz and CH3 at 126 Hz (peak corresponding to the B isomer of the acid obtained);

- Aromatics from 400 to 450 Hz;

- OH at 505 Hz.

The α-phenyl α-methyl (5-fluoro 2-hydroxy) phenylmethanol used starting from the above preparation was prepared as follows:

13.3 g of magnesium in turnings, 50 cm3 of anhydrous ether are mixed under an argon atmosphere with stirring, then slowly a solution of 34.7 cm3 of methyl iodide in 250 cm3 of anhydrous ether , then heats for 1 hour at reflux. 220 cm3 of this magnesium solution obtained are then added to a solution of 30 g of a-phenyl (5-fluoro 2-hydroxy) phenyl metha-none in 150 cm3 of anhydrous benzene, distilling the ether while replacing it with anhydrous benzene, then stirred for 4 h at about 78 ° C., cooled, poured over an ammonium chloride solution, extracted with ether, washed with water, dried over magnesium sulphate and brought to dryness under vacuum. 32 g of crude expected product are obtained.

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

Analysis: (C14H13F02)

Calculated: C% 72.40 H% 5.64 F% 8.18

Found: 72.4 5.6 8.2.

EXAMPLE 28 Isomer A of 6-fluoro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate

29.5 g of the mixture of racemates of 6-fluoro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid obtained in Example 27 are mixed with stirring, 300 cm 3 of methanol , 130 g of acid residue, carries and maintains at reflux for 24 h. Cool, treat with activated carbon, filter, rinse with methanol, bring to dry, take up in ether, wash the ethereal passage with 3 times 200 cm3 of bicarbonate then with water, dry over magnesium sulphate, bring to dry under vacuum and obtains 23.8 g of crude product which is taken up in 200 cm3 of methanol. 5 g of product are obtained which is recrystallized from 20 cm 3 of methanol. 4.4 g of expected product are obtained. Mp 95 ° C.

Analysis: (CI7H | 5F04)

Calculated: C% 67.54 H% 5.00 F% 6.28

Found: 67.7 5.0 6.2.

NMR spectrum (deuterochloroform) device frequency: 90 MHz)

- CH, at 171 Hz;

- COOCH3 at 345 Hz;

- Hydrogen in position 2 at 463 Hz;

- Aromatics: peaks from 615 to 680 Hz.

EXAMPLE 29 Isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1.3-benzodioxin-2-carboxylate of (2,2-dimethyl 1,3-dioxolan-4-yl) methyl

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

4.9 g of isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid obtained in Example 3 are mixed by stirring, 50 ml of benzene anhydrous, cooled to around 10 ° C., added dropwise at this temperature 1.66 g of triethylamine. Then a solution of 2.5 g of thionyl chloride in 25 ml of anhydrous benzene is added at this temperature and dropwise, then the mixture is brought to reflux for 2 h. The suspension is cooled to room temperature, the precipitate is drained and the filtrate which contains the expected product is collected.

Stage B: Isomer A of 6-chloro 4-methyl 4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylate of (2,2-dimethyl 1,3-dioxolan-4-yl) methyl.

2.25 g of (2,2-dimethyl 1,3-dioxo-lan-4-yl) methanol, 50 ml of anhydrous benzene, 2.3 ml of triethylamine are mixed by stirring, added dropwise at room temperature. filtrate collected in stage A above. The mixture is stirred for 20 h at room temperature. It is filtered, the filtrate is washed with a 10% sodium carbonate solution, then washed with water until neutral pH.

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

Analysis: (C22H2306CI)

Calculated: C% 63.08 H% 5.53 Cl% 8.46

Found: 62.0 5.5 8.9.

NMR spectrum (deuterochloroform) (base frequency of the apparatus: 60 MHz)

- CH3 of 2,2-dimethyldioxolan at = 81-82 Hz;

- CH3 in position 4 at 115 Hz;

- COO-CH2-CH-CH2 from 215 to 260 Hz.

I I

O 0

- Aromatics from 411 to 441 Hz.

EXAMPLE 30 Hydrochloride of the A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1.3-benzodioxin-2-carboxylate of 2- (diethyl-amino) ethyl

A mixture of 6.2 g of isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate is brought to reflux under a nitrogen atmosphere, with stirring. obtained as indicated in Example 16,100 ml of anhydrous toluene and 2.6 g of diethylaminoethanol and a tiny amount of sodium hydride. Maintained at reflux for 3 h, cooled, added 5 ml of a 4N hydrochloric acid solution in ether, added 200 ml of anhydrous ether, filtered, washed with ether, dried and obtained 3.7 g of product which is taken up in 20 ml of isopropanol at 60 ° C., treated with activated carbon, cooled, added 50 ml of ether,

filter, dry and obtain 2.7 g of the expected product. Mp 110 ° C.

Analysis: Q2H27CI2NO4

Calculated: C% 60.00 H% 6.18 Cl% 16.10 N% 3.18

Found: 59.6 6.4 15.9 3.4.

Example 31 Acid 6-chloro 4-ethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates)

250 cm3 of liquid ammonia, which has been condensed, are mixed with stirring, with approximately 100 mg of ferric nitrate, 4.8 g of sodium which is added in small portions, then added in IV2 h at -28- 30 ° C a solution of 26.2 g of 5-chloro a-ethyl 2-hydroxy a-phenylbenzenemethanol in 200 cm3 of anhydrous toluene, increases the temperature and drives off the released ammonia, heats at reflux for 3 h, adds 100 cm3 toluene and, at 50 ° C., 18 g of potassium dichloroacetate, maintains reflux overnight and adds 9 g of potassium dichloroacetate, stirred for another 2 h at reflux, cools, pours into water, eliminates the organic phase, acidifies the aqueous phase and extract it with ether, wash the ethereal phase with 3 times 500 cm3 of water, extract the ethereal phase with 3 times 300 cm3 of sodium bicarbonate, wash with 2 times 500 cm3 of ether, acidifies the aqueous phase with concentrated hydrochloric acid, extracted with 3 times 500 cm3 of ether, washed with water, dried over magnesium sulfate, brings to dry under vacuum and obtains 27 g of raw expected product.

5-chloro a-ethyl 2-hydroxy a-phenylbenzenemethanol, used at the start of the preparation of the product of example 31 above, can be prepared as indicated in example 23, but using, instead of bromide isopropyl, ethyl iodide. Mp 85 ° C.

Example 32: Isomers A and B of methyl 6-chloro 4-ethyl- [4H] -1,3-benzo-dioxin-2-carboxylate

For the preparation and the isolation of the two diastereoisomeric racemates A and B of 6-chloro 4-ethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate, methyl was used. mixture of the A and B isomers of the corresponding acids,

mixture obtained in Example 31, the same technique as that described in Example 20.

There were thus obtained, from 26 g of the mixture of isomers A and B obtained in Example 31:

4.5 g of the expected isomer A, which is recrystallized from methanol at reflux. 3.5 g of purified expected isomer A are obtained. Mp 128 ° C.

Analysis: (CI8H17C104)

Calculated: C% 64.96 H% 5.15 Cl% 10.65

Found: 65.0 5.2 10.4.

NMR spectrum (deuterochloroform) base frequency: 60 MHz)

- Ethyl in 4 at 44-51-58 Hz

110-160 Hz;

- COOCH3 at 232 Hz;

- Hydrogen in position 2 at 314 Hz;

- Aromatics of the 1,3-benzodioxine nucleus from 415 to 450 Hz;

- Phenyl at 4 to 445 Hz,

and 4 g of isomer B expected. Mp 108 ° C.

Example 33: 6-chloro 5- (4-chlorophenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates)

250 cm3 of dioxane, 1.6 g of dibenzo-18 crown-6, 25 g of sodium hydride are mixed, with stirring, and then, in 45 minutes, a solution of 16 cm3 of dichloroacetic acid is added in 100 cm3 of dioxane then, in 1 hour, a solution of 36.6 g of 5-chloro 2-hydroxy a-methyl a- (4-chlorophenyl) benzenemethanol in 150 cm3 of dioxane is added at 30 ° C. at 80 ° C for 5 h, cooled, poured onto a mixture of ice and water, extracted with 3 times 500 cm3 of ether, acidifies the aqueous phase with concentrated hydrochloric acid, extracted with 3 times 500 cm3 d ether, extract the ethereal phase with sodium bicarbonate, acidify the aqueous phase and extract with 4 times 300 cm3 of ether, wash with water, dry over magnesium sulphate, bring to dryness under vacuum, and obtain 40 g of expected gross product.

NMR spectrum (deuterochloroform) (base frequency: 60 MHz)

- Hydrogen in position 2 at 309 Hz;

- CHj at 116 Hz,

this corresponds to one of the expected isomers (isomer A)

- Hydrogen in position 2 at 340 Hz;

- CH3 at 124 Hz,

this corresponds to the other expected isomer (isomer B)

- Aromatics from 405 to 445 Hz;

- OH at 510 Hz.

The 5-chloro 2-hydroxy a-methyl a- (4-chlorophenyl) benzene-methanol used from the above preparation can be prepared as follows:

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13.5 g of 2-hydroxy 5-chloroacetophenone, 130 cm 3 of anhydrous ether are mixed, under magnetic stirring and under an argon atmosphere, cooled externally by an ice-water bath, introduced dropwise while maintaining the internal temperature between 10 to 20 ° C, 330 cm3 of an ethereal solution, freshly prepared and filtered with magnesium of 1-chloro 4-bromobenzene grading 0.46 mol / 1, keeps stirring overnight at room temperature. The yellow suspension is ice-cold and 125 ml of ice-cold 2N aqueous hydrochloric acid are introduced dropwise, decanted, the organic phase is washed with water, dried over sodium sulphate, treated with activated carbon, drained and brought to dryness under vacuum , the residue is dissolved in 100 cm 3 of cyclohexane and left to crystallize with stirring, the precipitate is drained, the paste is mixed with a little cyclohexane, it is dried in an oven and 19.3 g of expected product is obtained. F - 130 ° C.

Analysis: (C14H1202C12)

Calculated: C% 59.38 H% 4.27 Cl% 25.04

Found: 59.7 4.3 24.7.

Example 34: Isomer A of methyl 6-chloro 4- (4-chlorophenyl) 4-methyl- [4H] -1.3-benzodioxin-2-carboxylate

40 g of the mixture of diastereoisomeric racemates of 6-chloro 4- (4-chlorophenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid are mixed, mixture as obtained at 1 'example 33, 400 cm3 of methanol, 180 g of strong sulphonic resin, stirred at reflux for 18 h, cooled, wrung, washed 4 times with 300 cm3 of ether, brought to dryness under vacuum, takes up the residue in 500 cm3 d ether, washed with 3 times 300 cm3 of sodium bicarbonate, then with 4 times 500 cm3 of water, dried over magnesium sulphate, brought to dryness under vacuum and obtained 35.5 g of product. The product obtained is treated with 100 cm3 of methanol, left overnight at room temperature, filtered, washed with ice-cold methanol, 10 g of product are obtained which is recrystallized from 60 cm3 of methanol, left overnight at room temperature, and 9.1 g of isomer A expected. Mp 108 ° C.

Analysis: (C ^ HhC ^ O.,)

Calculated: C% 57.81 H% 4.0 Cl% 20.0

Found: 58.0 4.0 19.9.

NMR spectrum (deuterochloroform) (base frequency: 60 MHz)

- CHj at 115 Hz;

- COOCH3 at 231 Hz;

- Hydrogen in position 2 at 308 Hz;

- Aromatics from 412 to 442 Hz.

Example 35: 6-Chloro 4-methyl 4-phenyl- [4H] -Il, 3-benzo-dioxin-2-carboxyIique acid (mixture of the two diastereoisomeric recemates).

4 g of sodium amide, 50 ml of anhydrous toluene are mixed, a solution of 9.95 g of 5-chloro 2-hydroxy a-methyl a-phenylbenzenemethanol in 150 ml of toluene is added dropwise at room temperature anhydrous. The mixture is brought to reflux for 6 h, cooled to room temperature, introduced 10.25 g of potassium dibromoacetate, again brought to reflux for 6 h. Cool and take up in 200 ml of water, decant, extract the organic phase with twice 80 ml of water, wash the aqueous phase with twice 80 ml of ether, acidify the aqueous solution with 40 ml of acid. hydrochloric 2N.

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

The aqueous extraction phase is washed with 3 times 80 ml of ether, the alkaline solution is acidified with 90 ml of a 2N hydrochloric acid solution. The expected acid is extracted with 4 times 100 ml of ether. The organic phase is washed with water, dried over magnesium sulfate in the presence of activated carbon, the solvent is removed in vacuo, 7.85 g of crude product is obtained which is taken up in hoxane. The crystals obtained are filtered off and dried, and 6 g of the expected product are obtained. F - 144 ° C.

NMR spectrum (deuterochloroform) (base frequency: 60 MHz)

- CH3 at 117 Hz;

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

- CH3 at 125.5 Hz;

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

- Aromatics from 405 to 450 Hz;

- OH at = 350 Hz.

Example 36 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzo-dioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates)

10 cm 3 of dioxane, 1.35 g of 50% sodium hydride in oil are mixed; at 15 ° C., 60 mg of dibenzo-18 crown-6 is added, then, in 5 mm, 0.61 cm3 of dichloroacetic acid and 10 cm3 of dioxane.

1.25 g of 2-hydroxy 5-chloro a-methylbenzhydrol and 5 cm 3 of dioxane are introduced in 10 mm, at around 20 ° C.

Then heated for 6 h at 80 ° C, then cooled to 20 ° C, added 2 cm3 of methanol, poured into ice water extracted 3 times with ethyl acetate, washed 5 times with hydroxide 0.1N sodium ice. The aqueous phases are combined, acidified to pH 1 with a 2N hydrochloric acid solution, extracted 3 times with methylene chloride, dried and brought to dryness and the crude expected product is collected.

EXAMPLE 37 Piperidine salt of the A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1.3-benzodioxin-2-carboxylic acid

The mixture of the two diastereoisomeric racemates of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid obtained in Example 36 above is dissolved in 4 cm3 of acetate ethyl, added at 10 ° C 0.8 cm3 of piperidine. The expected piperidine salt crystallizes by scraping. It is filtered after 15 mm, washed with ethyl acetate, with ether, dried at 20 ° C under vacuum and obtained 855 mg of the expected product.

The mother crystallization liquor is collected and diluted with methylene chloride, washed with ice-cold hydrochloric acid N, dried and brought to dryness, the residue is taken up in 12 cm3 of methylene chloride and 0.6 cm3 of etherate is added. boron trifluoride, let stand Vi h at 20 ° C, pour on ice, wash 2 times with water, reextract with methylene chloride, dry and bring to dryness, take up in 2 cm3 of ethyl acetate and 0.4 cm3 of piperidine, leaves to crystallize and isolates 545 mg of the expected product. A new operation carried out in the same way, starting from the mother liquor of crystallization (isomerization with boron trifluoride, addition of piperidine), allows another 130 mg of expected product to be collected. A total of 1.53 g of expected product was therefore obtained. F = ~ 165 ° C.

EXAMPLE 38 Isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid

The 1.53 g of the piperidine salt obtained in the preceding example 37 is taken up, with a mixture of methylene chloride and N hydrochloric acid, washed, dried, treated with activated carbon, concentrated by adding cyclohexane to a volume of 3 cm3, wrung, washed with cyclohoxane, dried at 40 ° C under vacuum and obtained 1.1 g of the expected product. Mp 175 ° C.

This product is identical to the A isomer as obtained in Example 3.

Example 39 7-chloro 4-methyl 4-phenyl- [4H] -1,3-benzo-dioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates)

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9.85 g of sodium hydride in 50% suspension in oil, 100 ml of dioxane, 0.73 g of 18-crown-6 ether are mixed, and a mixture is added at room temperature with stirring. solution of 11.31 g of dichloroacetic acid in 120 ml of dioxane, then add, drop by drop, a solution of 14.550 g of 4-chloro 2-hydroxy a-methyl a-phenylbenzenemethanol in 200 ml of dioxane and brings the mixture 6 h at 95 ° C, let the mixture cool, pour it onto ice, add 10 ml of 2N sodium hydroxide, wash the aqueous phase with 300 ml of ether, acidify the aqueous phase with 20 ml of acid concentrated hydrochloric acid, extract the acid with 3 times 250 ml of ether,

wash the ethereal phase with 2 times 100 ml of water, extract the acid from the organic phase with 2 times 250 ml of sodium bicarbonate in 5% aqueous solution, wash the alkaline aqueous phase with 100 ml of ether, re-acidify with 50 ml of concentrated hydrochloric acid, extract the acid again with 4 times 250 ml of ether, decant, wash the organic phase with water by 3 times 100 ml, dry over magnesium sulfate in the presence of activated carbon , filter, remove the solvent under vacuum, obtains 19.5 g of the expected product.

NMR spectrum CDC13 60 MHz_

- Hydrogen in position 2 at 312 Hz and hydrogen from CH3 in position 4 at 116 Hz (corresponding to the A isomer);

- Hydrogen in position 2 at 343 Hz and hydrogen from CH3 in position 4 at 125 Hz (corresponding to the B isomer).

The 4-chloro 2-hydroxy a-methyl a-phenylbenzenemethanol, used at the start of the above preparation can be prepared as follows:

16.2 g of 2-hydroxy 4- (chloro-phenyl) ethanone are mixed with stirring in 170 ml of ether and then introduced, drop by drop, at 20 ° C, 315 ml of a solution of phenyl-magnesium bromide in ether grading 0.8 mol / 1, left stirring overnight at room temperature, pour the mixture onto ice, acidify with 40 ml of hydrochloric acid, extract with 4 times 250 ml of ether, decant , wash the organic phases with 4 times 150 ml of water, dry the organic phase over magnesium sulphate in the presence of activated carbon, disperse in 50 ml of cyclohexane, go to the oven under vacuum for 24 h and obtain 14.45 g of the expected product, of which 0.200 g is recrystallized from cyclohexane. M - 82 ° C.

Analysis: (C14H13C1 02)

Calculated: C% 67.61 H% 5.27 Cl% 14.25

Found: 67.3 5.1 14.3

Example 40: Isomer A of methyl 7-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate

19.5 g of the mixture of diastereois racemates are dissolved

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isomers of 7-chloro 4-methyl 4-phenyl- [4H] -1,3-benzo-dioxin-2-carboxylic acid (obtained in Example 39) in 300 ml of methylene chloride, cooled to 15 ° C, add, drop by drop, 9.1 g of boron trifluoride etherate, leave to stir at room temperature for 2 h, then add 300 ml of methanol, leave to stir again overnight, pour onto 500 ml of a saturated solution of sodium chloride, extracted with 3 times 200 ml of methylene chloride, washing the organic phase with 50 ml of a saturated aqueous solution of sodium bicarbonate, decanting, washing the organic phase with 2 times 50 ml of water (until neutral), dries the organic phase over magnesium sulfate in the presence of activated carbon, filter,

removes the solvent under vacuum and obtains 17.1 g of crude expected product, of which 16.6 g is recrystallized from methanol, dried and 10.35 g of expected product is obtained. F - 144 ° C.

Analysis: (C17HiSC1 04)

Calculated: C% 64.05 H% 4.74 Cl% 11.12 Found: 63.8 4.7 11.1

NMR spectrum CDC13 60 MHz

- Hydrogen in position 2 at 310 Hz;

- CH3 hydrogen in position 4 at 115 Hz;

- COOCH3 hydrogens at 230 Hz.

Example 41: Hydrochloride of the A-isomer of 6-chloro 4-methyl 4-phenyl- [4HJ-1,3-benzodioxin-2-carboxylate of 3- (dimethyl-amino) ethyl.

7.1 g of A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-methyl carboxylate obtained as indicated in Example 2 are mixed in, 2.5 g of dimethylaminoethanol, 100 ml of anhydrous toluene and traces of sodium hydride and refluxed for 5 h, cooled, treated with activated carbon, filtered, collected the filtrate, added 7 ml of a 5N hydrochloric acid solution to it ether, filter, drain the precipitate obtained which is recrystallized from 40 ml of isopropanol. 4.8 g of the expected hydrochloride are obtained. Mp 185 ° C.

Analysis: (C20H22C1N04)

Calculated: C% 58.26 H% 5.62 Cl% 17.20 N% 3.40 Found: 58.1 5.9 17.0 3.5 '

NMR spectrum CDC13 60 MHz

- Hydrogen in position 2 at 312 Hz;

- Hydrogens of COO — CH2 — CH2— at 285 and 235 Hz;

. CH3

- Hydrogens from —NC ^ to 172 Hz;

^ CH3

- CH3 hydrogens in position 4 at 115 Hz;

- Aromatic hydrogens from 411 to 441 Hz.

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R

Claims (14)

625517 1. Process for the preparation of the new 1,3-benzodioxin derivatives of general formula: R COOH in which R2 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical, and R4 and R5 , identical 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, as well as their alkali, alkaline-earth, aluminum, ammonium or amines, characterized in that a product of formula is reacted: in which R3, R4 and R5 are defined as above, with an alkali metal salt of a product of formula: \ Î2 y COOH (III) Y in which R2 is defined as above and Y represents a chlorine, bromine or iodine atom, in the presence of a basic condensing agent, and obtains an alkali metal salt of an acid, which is treated with an acid to obtain the acid of formula I above. 2. Method according to claim 1, characterized in that the products of formula I are prepared, in which R2 represents a hydrogen atom or a methyl radical, R3 represents a hydrogen atom, a methyl radical or a radical phenyl, R4 represents a hydrogen atom and R5 represents a hydrogen atom or a chlorine atom, in racemic or optically active forms or in the form of mixtures of these isomers, as well as their alkaline, alkaline-earth salts, aluminum, ammonium and amines. 3. Method according to claim 1, characterized in that the products of formula I are prepared, in which R2 represents a hydrogen atom, R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 represents a chlorine atom in racemic or optically active forms, or in the form of mixtures of these isomers, as well as their alkali, alkaline-earth, aluminum, ammonium and amine salts. 4. Method according to claim 1, characterized in that the derivatives of formula I are prepared, in racemic or optically active forms or in the form of mixtures of these isomers, the names of which follow: - 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid, its sodium salt; the piperidine salts of the two diastereoisomeric racemates A and B, and - the isomers d and / of the two diastereoisomeric racemates A and B of 6-chloro 4-methyl 4-phenyI- [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-benzodioxin-2-carboxylic acid; - 6-chloro 4,4-diphenyl- [4H] -1,3-benzodioxin-2-carboxylic acid; - 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxy-acid; - 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1,3-benzo-dioxin-2-carboxylic acid. 5. Method according to claim 1, characterized in that the A isomer is prepared of 6-chloro 4-methyl 4-phenyl- [4H] -l, 3-benzodioxin-2-carboxylic acid or the A-isomer of 6-chloro, 2,4-dimethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylic acid. 6. Method according to claim 1, characterized in that one prepares - the A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzo-dioxin-2-carboxylate sodium, - the A-isomer of 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1,3-benzodioxin-2-carboxylic acid, or - the isomers d and / of the isomer A of 6-chloro 4-methyl 4-phenyl- [4H] -1, 3-benzodioxin-2-carboxylic acid. 7. Method according to claim 1 for the preparation of products of formula I in which R2 and R3 are defined as in claim 1 and R4 and R5 represent a hydrogen atom, characterized in that the products obtained are subjected to formula I, in which R4 or R5 or Iti and R5 represent a chlorine atom, to the action of hydrogen in the presence of a catalyst. 8. Process for the preparation of the new 1,3-benzodioxin derivatives of general formula: COOR in which R2, R3, R4 and R5 are defined as in claim 1 and R represents an alkyl radical containing from 1 to 5 carbon atoms, a 2,3-dihydroxypropyl radical, a (2,2-dimethyl l, 3-dioxo! An-4-yl) methyl, a dialkylamino-noalkyl radical in which the alkyl radicals contain from 1 to 4 carbon atoms or this radical in the form of a salt with an acid, characterized in that the compounds of formula I are prepared by the process according to claim 1 and said compounds are esterified with an alcohol of formula R ^ H, in which R! has the above meaning. 9. Method according to claim 8, characterized in that the derivatives of formula I 'are prepared, in racemic forms or 2 5 10 15 20 25 30 35 40 45 50 55 60 65 3 625517 optically active or in the form of mixtures of these isomers, the names of which follow: - methyl 6-chloro 4,4-diphenyl- [4H] -1,3-benzodioxin-2-carboxylate; - 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-methyl and ethyl carboxylate; - methyl 6-chloro 4- (3-chlorophenyl) 4-methyl- (4H) -1,3-benzo-dioxin-2-carboxylate; - methyl 6-chloro 4 - [(1-methyl) ethyl] 4-phenyl- [4H] -1,3-benzo-dioxin-2-carboxylate; - methyl 6-chloro 4 [(1,1-dimethyl) ethyl] 4-phenyl- [4H] -1,3-benzo-dioxin-2-carboxylate; - methyl 6-fluoro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate; - 6-chloro 4-ethyl 4-phenyl- [4H] -1,3-benzodioxin-2-carbo-xylate; - methyl 6-chloro 4- (4-chlorophenyl) 4-methyl- [4H-1,3-benzo-dioxin-2-carboxylate. 10. The method of claim 8, characterized in that the A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate is prepared. 11. Method according to claim 8, characterized in that the A-isomer of 6-chloro 4- (3-chlorophenyl) 4-methyl- [4H] -1, 3-benzodioxin-2-carboxylate is prepared. . 12. Method according to claim 8, characterized in that the A-isomer of 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate is prepared. 13. Method according to claim 8, characterized in that the products of formula I 'are prepared, in racemic or optically active forms or in the form of mixtures of these isomers, the names of which follow: - 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate of (2,2-dimethyl 1,3-dioxolan-4-yl) methyl; - 2,3-dihydroxypropyl 6-chloro 4-methyl 4-phenyl- [4H] -1,3-benzodioxin-2-carboxylate; - 2- (diethylamino) ethyl 6-chloro 4-methyl 4-phenyl- [4H] -1.3-benzodioxin-2-carboxylate and its addition salts with acids. 14. Process for the preparation of the new 1,3-benzodioxin derivatives of general formula: 00 CH in which R2, R3, R, and R5 are defined as in claim 1, characterized in that compounds of formula I are prepared by the process according to claim 1 and that said compounds are methylated by action diazomethane in an organic solvent.