CA1103685A - Process for the preparation of novel (l-3) benzodioxin derivatives - Google Patents

Abstract

1,3-Benzodioxin derivatives, corresponding to the general formula I ': (I') in which R'1 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a 2,3- radical dihy-droxypropanyl, a radical (2,2-dimethyl 1,3-dioxolan-4-yl) methyl or a dialkoylaminoalkyl radical in which the alkyl radicals contain from 1 to 4 carbon atoms, R2 represents a hydrogen atom or a radical alkyl 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, R2 and R3 cannot, however, simultaneously represent a hydrogen atom, and R4 and R5, identical or different, each 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 the alkali, alkaline earth, aluminum salts , ammonium and pharmaceutically acceptable amines of the products of formula I 'in the which R'1 represents a hydrogen atom and the addition salts with pharmaceutically acceptable acids of the products of formula I 'in which R'1 represents a dialkylaminoalkyl radical. These derivatives are endowed with lipid-lowering properties.

Description

The present invention relates to new derivatives of 1,3-benzodioxine, corresponding to general formula I ':

R ~ COOR ' R3 ~

, _ ... ..

in which R'l represents a hydrogen atom, a radical alkyl containing from 1 to 5 carbon atoms, a 2,3- radical dihydroxypropanyl, a radical (2,2-dimethyl 1,3-dioxolan-4-yl) methyl or a dialkoylaminoalkyl radical whose radicals alkyls contain 1 to 4 carbon atoms, R2 represents a hydrogen atom or an alkyl radical containing from 1 to 5 . carbonel atoms R3 represents a hydrogen atom, a radical alkyl containing from 1 to 5 carbon atoms or a phenyl radical, R2 and R3 cannot, however, simultaneously represent ~ a atom of hydro ~ ene, and R4 and R5, identical or different, represented by each feel a hydrogen atom or a halogen atom, under racemic or optically active forms or in the form of mixtures .. of these isomers, as well as the alkaline, alkaline-earth salts, aluminum, ammonium and pharmaceutically acceptable amines products of formula I 'in which R'l represents an atom of hydrogen and the addition salts with pharmaceutical acids only acceptable products of formula I 'in which R'1 represents a radic: al dial ~ oylaminoalcoyle. The invention relates also to a process: preparation of these new derivativesO

The invention relates in particular to the product of formula general I: ~
~. .

~ 33 ~ 35 VS

in which Rl and R2, identical or different, represent each a hydrogen atom or an alkyl radical containing 1 with 5 carbon atoms, R3 represents a hydrogen atom, a alkyl radical containing from 1 to 5 carbon atoms or a radical phenyl, R2 and R ~ cannot, however, represent simultaneously-ment a hydrogen atom, and R4 and R5, identical or different, each represents a hydrogen atom or a halogen atom, in racemic or optically active forms or in the form of mixtures of c ~ s isomers, as well as alkali, alkaline-earthy, aluminum, ammonium and amine products formula I in which R1 represents a hydrogen atom.
The term alkyl containing 1 to 5 carbon atoms may denote, for example, a methyl, ethyl, n-propyl radical, isopropyl, n-butyl, isobutyl, terbutyl, pentyl.
The term halogen atom may mean, for example, a chlorine atom, a bromine atom, a fluorine atom.
By the expression "mixtures of these isomers" is meant mixture of racemic isomers or mixture of isomers optically assets, in any proportion.
They may especially be mixtures in proportion any of racemates, mixtures in any proportion of two optic antipodes, mixtures in any proportion two optically active diastereoisomeric products.
The alkaline or alkaline earth salts of the products of formula I in which Rl represents a hydrogen atom, . ~ ~

:. ,. : .. .- ..: ~ - ~. ,,,. .,. .:

~ `~

can be, for example, sodium, potassium, lithium or calcium.
The amine salts of the products of Formula I, in the-which Rl represents a hydrogen atom, are the amine salts usual. Among the usual amines, there may be mentioned monoalkyl-amines, such as, for example, methylamine, ethylamine, propylamine, dialkylamines, l: they that, for example, dimethylamine, diethylamine, di-n-propylamine, trial.coyl-amines, such as triethylamine. We can also cite the piperidine, morpholine, piperazine and pyrrolidine.
The addition salts with acids can be, for example example, the salts formed with hydrochloric acids, bromhy-drique, iodhydrique, nitrique, sulfurique, phosphorique, acéti-that, maleic ~ fumaric, succinic, tartaric, acids alkylmonosulfonic, such as, for example, methane acid ~ - sulfonic, ethane sulfonic acid, propane sulfonic acid, alkydisulonic aids, such as, for example, acid , ~ -disulfonic ethane.
Among the products of the invention, mention may be made of particular:
- Products, as defined by the general formula I above, characterized in that, in said formula I, ~ 1 and R2, identical or different, represent a hydrogen atom or a methyl radical, R3 represents a methyl radical or a -radical phenyl, R4 represents a hydrogen atom and R5 represents a hydrogen atom or a chlorine atom in racemic forms or optically active or in ~ form of mixtures of these isomers, as well as alkali, alkaline earth, aluminum, of ammonium and amines of said products of formula I, in the-which R1 represents a hydrogen atom;
- Products, as defined by the formula gen-rale I above, characterized in that, in said formula I, 3Eii ~ 35 Rl represents a hydrogen atom or a methyl radical, R2 represents a hydrogen atom, R3 represents a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 - represents a chlorine atom, under: Racemic or optical forms -ment active or in the form of mixtures of these isomers, as well as alkali, alkaline earth, aluminum, ammonium and amines of said products of formula I, in which R1 represents -has a hydrogen atom, and in particular:
- In their ra ~ emic and optically active forms, the products referred to in the examples. Among these, we can cite notam ~
ment in the form of A isomers, as obtained in the examples, the products whose names follow:
- 6-chloro 4-methyl 4-phenyl r4 ~ 1,3-benæodioxin-2-carboxyl-methyl ate;
- 6-chloro 4- (3-chlorophenyl) 4-methyl ~ H ~ 1,3-benzodioxin-. Methyl 2-carboxylate;
- 6-chloro 4-methyl 4-phenyl ~ 4H ~ 1,3-benzodioxin-2-carboxyl-ethyl ate;
- acid.e 6-chloro 4-methyl 4-phenyl ~ H ~ 1,3-benzodioxin-2-carboxylic;
- 6-chloro 2,4-dimethyl 4-phenyl acid ~ 4H ~ lr3-benzodioxin-

-2-carboxylic, ' 6-chloro 4-methyl 4-phenyl ~ H, 7 1,3-benzodioxin-2-carboxyl-sodium ate;
- acid 6 ~ chloro 4-13-chlorophenyl) 4 methyl ~ H ~ 1,3-benzo-dioxin-2-carboxylic;
- the d and 1 isomers of 6-chloro 4-methyl 4-phenyl acid ~ H ~
1,3-benzodioxin-2-carboxylic.
We can also cite:

~ the piperidine salts of the two diastereoisomeric racemates A
and ~ 6-chloro 4-methyl 4-phenyl acid ~ H ~ -benzo dioxin-2-carboxylic; .
... r.! ~ 4-.., ~

~ 3 ~ 5 . : `` '' - the isomers cl and 1 of the two racemates diastereoisom ~ res A and B-6-chloro 4-methyl acid ~ -phenyl ~ 4H ~ 1,3-benzodioxin-2-carboxylic;
as well as, in their racemic or optically active forms:
- 6-chloro 4-methyl 4-phenyl / ~ H_ 7 1,3-benzodioxin-2-carboxyl-(2,2-dimethyl 1,3-dioxolan-4-yl) methyl ate;
- 6-chloro 4-methyl 4-phenyl / 4 ~ _ 7 1,3-benzodioxin-2-carboxyl-ate of 2,3-dihydroxy propanyl, and - 6-chloro 4-methyl 4-phenyl / 4H_ 7 1,3-benzodioxin-2-carboxyl-10 ate of 2- (diethylamino) ethyl, as well as its addition salts with acids.
One or the other denotes by the term "isomer A"
of the two diastereoisomeric racemic forms of the products of formula I which have two asymmetric carbon atoms.
-According to the invention, the products as defined by the general formula I above, as well as the alkaline salts, alkaline earth, aluminum, ammonium and pharmaceutical amines tically acceptable products of formula I, in which R
represents a hydrogen atom, are obtained by a process characterized in that one has to react a product of formula II:
OH

\ C / (II) R3 ~ R4 in which R3, R4 and R5 are defined as above, with an alkali metal salt of a product of formula III:

C-COOH (III) Cl in which R2 is defined as above, 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 68 ~ i Rl represents hydrog ~ ne, salt that, in the case expiring-t, one treated with an acid, to obtain the acid of formula I corresponding to laying, acid which, if necessary, is salified or esterified, to obtain the corresponding salt or ester and that, in addition, the where appropriate, the products of formula I are isolated in racial forms.
mics or optically active or in the form of mixtures of these isomers.
Under preferential conditions of implementation of 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 alkaline alkylate, such as sodium methylate, ethylate sodium, sodium terbutylate; an alkaline hydride, such as sodium hydride, potassium hydride; alkaline amide such as sodium amide, potassium amide, amide lithium, sodium.
- The reaction of the product of formula II with the product of formula III is carried out in an organic solvent, such that, for example, benzene, toluene, xylene, ether ~ thy-lique, dioxane, dimethylformamide, tetrahydrofuran, hexamethyl phosphorotriamide or within a mixture of these solvents.
We can also operate in the presence of a compound serving of catalyst, of ether-crown type, such as, for example, dibenæo-18 crown-6, dicyclohexyl-18 crown-6 or 18-crown-6, optionally mixed with an organic solvent, such as, for example, dioxane.
The reaction can be carried out at a temperature ranging from -10C to the reflux temperature of the reaction medium.

- We would react the product of formula II with the agent of basic condensation before reacting with the product of formula III.
The products of general formula I, in which Rl represents an alkyl radical containing from 1 to 5 carbon atoms, when prepared by esterification of the corresponding acid laying, are prepared by action on this acid of an alcohol of formula: ;

RlOH

in laguelle Rl represents an alkyl radical containing 1 a 5 carbon atoms, preferably in an acid medium.
We can operate, for example, in the presence of an acid, such as hydrochloric acid, paratoluene sulfonic acid, or in the presence of an acidic resin.
The esters of general formula I, in which Rl represents an alkyl radical containing from 1 to 5 carbon atoms, can also be prepared by transesterification.
The products of formula I, in which R1 represents a methyl radical can also be prepared by the action of dia ~ omethane on the product of formula I, in which R
represents a hydrogen atom in an organic solvent.
The esters of general formula I, can also be prepared in the usual way from a functional derivative corresponding acid of formula I, such as, for example, acid chloride Functional derivatives of acids formula I, are prepared according to the usual methods.
~ es alkali, alkaline earth, aluminum, of ammonium and amines of the products of formula I above, in which Rl represents a hydrogen atom, can be prepared by reaction, on said cheese products I, bases corresponding.

,. ... .. .. ....

36 ~ 5 The base can be a mineral or organic base, such that, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, aluminum hydroxide minium, sodium ethylate, potassium ethylate, ammonia or an amine, such as, for example, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, di-n-propyl-amine, triethylamine, piperidine, morpholine, pipe-razine 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.
According to a variant of the process for the preparation of products of formula I above, as well as their alkaline salts, alkaline earth, aluminum, ammonium and amines, we make - react a product of formula II:
~ Oh "JI, R3 / ~ I ~ R4 ~
in which R3, R4 and R5 have the meanings indicated above above, with an alkali metal salt of a product of formula III ':

l-COOH (III ') Y ~ ' in which Y represents a bromine atom or an iodine atom, and R2 has the meaning indicated above, in the presence of a; ~
basic condensing agent and, if necessary, continues the synthesis as above.
The preferential conclusions of implementation of this are identical to those which have been described above.
is lying.
. ~

-,. . . . ......... .. ... .

36 ~ 35 .
It has been described above a process for preparing products of formula I ~ in which Rl represents a hydro-gene or an alkyl radical containing from 1 to 5 carbon atoms, corresponding to a product of formula I, in which R'l has the value of Rl above.
As regards the products of formula I ', such as defined above, in which R'l represents a radical 2,3-dihydroxypropanyl, a radical (2,2-dimethyl 1,3-dioxolan-4-yl) methyl or a dialkoylaminoalkyl radical, the radicals of which alkyls contain from 1 to 4 carbon atoms, R2, R3, R ~ and R5 being defined as above, in racemic forms or optically active or in the form of mixtures of these isomers, as well as the addition salts with acids of the products of formula I 'in which R'l represents a dialkylamino-radical alkyl, these are obtained according to the invention by a process characterized in that an acid of formula I is treated in which Rl represents a hydrogen atom, or a functional derivative tional of this acid, with an alcohol of formula R'lOH in;
which R'l represents a radical (2,2-dimethyl 1,3-dioxolan-4-yl) methyl, or a dialkoylaminoalkyl radical, the radicals of which alkyls contain 1 to 4 carbon atoms, treats, if applicable if necessary, the product obtained of formula I ′ in which Rll represents a dialkoylaminoalkyl radical, by an acid to forming the salt, treating, if necessary, the product obtained from formula 1 'in which R'l represents a radical (2,2-dimé ~ hyl 1,3-dioxolan-4-yl) methyl by a hydrolysis agent to obtain the corresponding product of formula I ', in which R'l represents feels a 2,3-dihydroxypropanyl radical and that, moreover, the case where appropriate, the products of formula I ′ or their salts are isolated under racemic or optically active forms, or in the form of mixtures of these isomers.

~ .:. :. .
,, -. : ~

.g336 ~ 35 In preferential conditions, of realization of the above described process, the procedure is as follows:
- The functional derivative of the acid of formula I can be, for for example an ester or an acid halide.
The functional derivative is prepared from acid of formula I in the usual manner;
- The reaction is preferably carried out in a solvent organic such as, for example, ben ~ ene, toluene, xylene, ethyl ether;
- the salification reaction of the products of formula I 'in which R'l represents a dialkoylaminoalkyl radical is carried out in the usual manner;
- the hydrolysis reaction is carried out by acid hydrolysis, the acid used can be, for example, hydrochloric acid.
Also according to the invention, the products of formula general I above, in which R4 and R5 represent an at ~ me of hydrogen, can be prepared by a process, characterized in what we submit a product of formula I, in which R4 or R5 or R4 and R5 represent a chlorine atom with the action of hydro-. . r gene in the presence of a catalyst, and obtains the product of formula Corresponding I, in which R4 and R5 represent an atom of hydrogen.
Under preferential conditions of implementation of the invention, the process which has just been described is carried out as follows:
- The catalyst can in particular be palladium.
- We operate in an alkaline medium. The base used can be, for example, triethylamine, trimethylamine, dimethylaniline,] .a pyridine.
We operate in an organic solvent, such that, by example, ethanol, methanol, isopropanol.

36 ~ 5 The products of formula I or I 'above present at minus an asymmetric carbon (carbon in position 2) and can present a second (carbon in position 4) for some values of the substituents R3 and R4.
The product of ~ ormule II used at the start of the prepa-ration of products of formula I or I 'according to the invention, may not not present asymmetric carbon, for certain values of ~ R3 and R4 substituents.
; The reaction of such a product of formula II with a product of formula III or III 'above, according to the invention, leads to a product of formula I or I 'comprising a single asymmetric carbon atom in the form of a racemic, that we can then split into its optical antipodes by - ~
methods known in the art, such as, for example, training salts using optically active bases.
The product of formula II used may contain a asymmetric carbon atom. It can be used in its form racemic or in an optically active form.
The product of formula I or I 'obtained from a such product of formula II, contains two carbon atoms asyme-triques. There are, therefore, in different forms isomers which can be obtained separately by methods known in the art.
Racemates or dias optically active products tereoisomeres (which could be named by the prefixes cis and trans), can be obtained separately, for example, by selective crystallization, by counter-current distribution or by chromatograph: ie on column.
These racemates can, moreover, be resolved in their optic enantiomers by methods known in the art such as, for example, the formation of salts by means of optical bases only active.

;

~ ~ Lr ~ 36 ~ 3S

The different isomeric forms thus obtained can also, if desired, be mixed to form the mixture wish.
Products, as defined by the 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 salts alkaline, alkaline earth, aluminum, ammonium, amines and, where appropriate, their addition salts with acids have interesting pharmacological properties; they handle in particular a marked lipid-lowering activity; they reduce plasma lipid levels: triglycerides and cholesterol.
These properties justify the use in therapist-ticks, as medicines, products as defined by the formula I ′ and in particular I above, in racemic forms.
or optically active or in the form of mixtures of these isomers,.
as well as their alkali, alkaline earth, aluminum, of pharmaceutically acceptable ammonium and amines, in the case where Rl or R'l represents a hydrogen atom, as well as addition salts with pharmaceutically acceptable acids of said products of formula I ', in which R'l represents a.: ~ -dialkoylaminoalkyl radical.
Among the said products of formula I 'and in particular I and ~.
said pharmaceutically acceptable salts that 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 Rl and R2, identical or different, represent each a hydrogen atom or a methyl radical, R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 represents a atom of hydrogen or a chlorine atom, as well as the products of formula I, in which R1 represents a hydrogen atom or a methyl radical, R ~ and R4 each represent a hydrogen atom, R3 represents a hydro ~ ene atom, a methyl radical or a phenyl radical and R5 represents a chlorine atom, thus as alkali, alkaline earth, aluminum, ammonium salts and amines of said products of formula I, in which R1 represents smells like a hydrogen atom.
Among the products of formulas I 'and I above, one can cite in particular those described in the examples and more particularly link their isomers ~ described and defined above.
All of the products defined above constitute drugs very useful in human therapy, in particular in the treatment of acute ~ or chronic hyperlipemia, insuff-;
fisances ~ cardiac of atheromatous origin, ~ anginal states chronicles.
The usual dosage, which varies depending on the product used, the subject treated and the affection in question, can be, for example 0.05 to 1 g per day 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 phar-maceuticals containing, as active principle, at least one of said products or salts.
These compositions are made so that be administered by the digestive or parenteral route. They can be solid or liquid and come in the forms pharmaceuticals commonly used in human medicine, such as for example, tablets, simple or agéified, capsules, granules, suppositories, injectable preparations;
they are prepared according to the usual methods.
The active ingredient (s) can be incorporated therein excipients usually used in these compositions pharmaceuticals, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, vehicles aqueous or non-aqueous cells, bodies ~ of animal or vegetable origin, paraffinic derivatives, glycols, various wet agents lants, dispersants cu emulsi ~ iants, preservatives.
The method of the invention makes it possible, of new industrial products useful for the preparation of products of formulas I and I ', the following products, under their racemic or optically active forms:
- 5-chloro 2-hydroxy a-methyl a-phenyl benzene methanol, - the products of formula II'A:

~ ~ / OH

~ I` ~ C - (II'A) R'3 ~ \
¦ ~ - R '~

in which R'4 represents a chlorine atom or an atom of fluorine, R'5 represents a chlorine atom, R'3 represents a alkyl radical containing from 2 to 4 carbon atoms, R'3 being able also represent a methyl radical when R'4 represents an atom of ~ luor.
The products of ~ ormule II are mostly known.
The products of ~ ormule II, which are not known, in which R3 represents a hydrogen atom, can be prepared by reducing the corresponding benzophenone derivatives of form mule A:

~ Oh R5 ~

~ / \ C ~
~ (A) ~ `/

~ 368S

using, for example, a mixed hydride, operating within of an organic solvent.
The products of formula II, which are not known, 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, in an organic solvent, an organic derivative magnesian of formula:

R3-Mg-Hal in which Hal represents a chlorine or bromine atom, and R3 has the value which has just been indicated above. Such process is illustrated below in the experimental part.
The examples given below illustrate the invention without however limiting it.
Example 1: Acid 6-chloro 4-methyl 4 ~ phenyl / 4H 7 1,3-benzodioxin-2-carboxylic (mixture of the two diastereoisomeric racemates) Mix with stirring 8.1 g of sodium amide and 100 ml of toluene, added drop by drop in ~ agitantj a solution obtained by dissolving 24.9 g of 5-chloro 2-hydroxy a-methyl a-phenyl benzene methanol in 250 ml of toluene, carries the mixture at reflux for 4 hours 30 minutes, bring the mixture to room temperature, add, in small fractions while stirring, 18 g potassium dichloracetate, add 20 ml hexamethylphos-phorotriamide, refluxed for 5 hours, cools the diaper until it is at room temperature, add slowly 10 ml of ethyl acetate, then, drop by drop, 250 ml of water. The aqueous phase is collected ~ extracted again the phase organic by 3 times 100 ml of water and combines the different extracts aqueous which is washed with 3 times 100 ml of ether. We acidify the aqueous extraction phase which contains the potassium salt of ~ 36 ~ 35 product stretched by bubbling sulfur dioxide and extracted with 4 times 100 ml of ether. The ethereal phase is washed extraction with 3 times 50 ml of water. The organic phase is dried on magnesium sulphate, treated with activated carbon, evaporates the solvent under vacuum. 24 g of crude product are obtained, which `crystallizes in 100 ml of a cyclohexane-benzene mixture 90 ~ 10, dries the crystals obtained and obtains 15.2 g of 6-chloro acid 4-methyl 4-phenyl / 4H_ 7 1,3-benzodioxin-2-carboxylic. F = 142C.
Analysis (C16Hl3cl ~) Calculates: C ~ 63.06 ~% 4.30 C1% 11.63 Found: 63.3 4.4 11.5 5-chloro 2-hydroxy a-methyl a-phenyl benzene methanol, used at the start of the preparation of 6-chloro acid 4-methyl 4-phenyl / 4H_ / 1,3-benzodioxin-2-carboxylic acid, may be prepares as follows:
Disperse by stirring 14 g ~ of magnesium spinning in 100 ml of anhydrous ether, add, drop by drop and with stirring, a solution obtained by dissolving 76 g of methyl iodide in 200 ml of anhydrous ether, bring to reflux for 1 hour, cools to a temperature of 15-20C, then adds to this temperature, a solution obtained by dissolving 59 g of 5-chloro 2-hydroxy benzophenone in 250 ml of anhydrous benzene, partially distills the ether, then brings to reflux again during 2 hours. The mixture is then cooled to a temperature of 5 - 10C and add, drop by drop, 250 ml of acid hydrochloric 3N.
Decant and collect the organic phase, wash the phase aqueous 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 per 2 times 50 ml of water. The organic phase is dried over d85 magnesium, then evaporates the solvent under vacuum, obtains 58.9 g of crystals which are taken up in petroleum ether (Eb. 60 - 80C) and obtains 53 g of 5-chloro 2-hydroxy a-methyl a-phenyl benzene methanol. F = 106 C.
Analysis (C14Hl3cl2) Calculates: C% 67.61 H% 5.27 Cl% 14.26 Found: 67.8 5.4 14.2 Example 2: Isomers A and B of 6-chloro 4-methyl 4-phenyl / 4H 7 Methyl 1,3-benzodioxin-2-carboxylate A solution of 2.25 g of diazomethane is prepared in 150 ml of methylene chloride, cools this solution to 5C, add thereto, drop by drop at 5C, a solution obtained by dissolving 3.3 g of 6-chloro 4-methyl 4-phenyl / 4H ~ 1.3- acid benzodioxin-2-carboxylic as a mixture of the two racemates diastereoisomers obtained in Example 1, in 75 ml of chloride methyl ~ ne. The mixture is stirred for one hour at room temperature, then gives the solution to stand for 24 hours. We then add 10 ml of acetic acid, then the solv ~ nt is evaporated under vacuum. We collects 4.2 g of 6-chloro 4-methyl 4-phenyl / 4H_ / 1,3-benzodioxin-Methyl 2-carboxylate, in the form of a mixture of the two racemates diastereoisomers.
The residue obtained is subjected to chromatography on silica column, eluting with an ethyl ether-ether mixture of petroleum (~ b. - 60 - 80C) (20 - 80), and obtains 1 g of isomer Has 6-chloro 4-methyl 4-phenyl / 4H_ / 1,3-benzodioxin-2-carboxy-methyl late. F = 114 - 115C.
Analysis: (C17H15C1 ~ 4) Calculates: C% 64.06 H% 4.74 Cl% 11.12 Found: 63.9 4.7 11.4 NMR spectrum (base frequency of the device used: 60 Hz).
- CH3 at 117 Hz;
- COOCH3 ~ 232 Hz;

- Hydrogen in position 2 at 311 Hz;
- Aromatics from 410 to 445 Hz;
0.6 g of isomer B of 6-chloro 4-methyl is also obtained.
Methyl 4-phenyl ~ 4H / 1,3-benzodioxin-2-carboxylate. F 102C.
Analysis: (Cl7Hl5clO4) Calculates: C% 64.06 El ~ 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-chlo ~ o 4-methyl 4-phenyl acid 1,3-benzodioxin-2-carboxylic 14 g of isomer A of 6-chloro 4-methyl are mixed Methyl 4-phenyl L4H] 1,3-benzodioxin-2-carboxylate obtained at l ~ example 2 and at the end of a second implementation of the mode procedure described in Example 2, 28 g of potassium hydroxide in tablets, 32 ml of water and 160 ml of methanol, stirred for 22 hours at room temperature, add 320 ml of water, wash it aqueous phase with twice 160 ml of ether, then acidifies the aqueous solution with a 2N hydrochloric acid solution, extract the precipitate obtained with 3 times 320 ml of ether, wash it organic extraction phase with twice 160 ml of water, dry on magnesium sulphate and brought to dryness. We obtain 13 g of crystals. We recrystallize 3.9 g in 100 ml of a mixture ethyl acetate ~ cyclohexane (20 - 80) and dry. We obtain

3.3 g of isomer A of 6-chloro 4-methyl 4-phenyl acid ~ 4H ~ 1,3-benzodioxin-2-carboxylic. F = 175 - 176C.
AnalySe: (Cl6Hl3clO4 Calculates: C ~ 63, ~ 6 H ~ 4.30 Cl ~ 11.63 Found: 63.3 4.6 11.3 ~ X ~ 3 ~; ~ 5 NMR spectrum (base frequency: 60 Hz) - CH3 at 117 Hz;
- Hydrogen in position 2 at 313 Hz;
- COOH ~ 468 Hz;
- Aromatics from 412 to 443 Hz.
Example 4: Isomer B of 6-chloro 4-methyl 4-phenyl L4H acid]
1,3-benzodioxin-2-carboxylic 5.3 g of isomer B of 6-chloro 4-methyl are mixed

4-phenyl [4H ~ 1,3-benzodioxin-2-carboxylate of meth ~ le obtained at example 2 and at the end of a second implementation of the mocle procedure described in Example 2, 10 ml of water, 1.2 g of hydroxide potassium tablets and 50 ml methanol, stir 20 hours at room temperature, add 200 ml of water, wash the phase aqueous with 2 times 30 ml of ether, then acidifies the aqueous solution with a 2N hydrochloric acid solution, extracted 3 times 100 ml diether, combine the extracts, wash the extract with twice 80 ml of water, dries the ethereal phase on magnesium sulfate, evaporates the solvent under vacuum and obtains 4.8 g of crystals which are recrystallizes from a cyclohexane-ethyl acetate mixture (80 - 20), dry and obtain 4.4 g of isomer B of 6-chloro acid 4-methyl 4-phenyl ~ 4H¦1,3-benzodioxin-2-carboxylic. F 171C.
Analysis (Cl6Hl3O4cl) Calculated: C% 63.06 H% 4.30 Cl% 11.63 Found: 63.1 4 ~ 4 11.7 NMR spectrum (base frequency: 6Q hz) - CH3 at 124 Hz;
- COOH at 329 Hz;
- Hydrogen in position 2 at 341 Hz;
- Aromatics: ics from 408 ~ 445 Hz.
3Q Example 5: 6-chloro 2,4-dimethyl 4-phenyl L4H ~ 1,3 ~ benzo- acid dioxin-2-carboxylic tmixture of ~ them racemates diastéreoi ~ omers) Mix with stirring 8 g of sodium amide and 100 ml ,:, ':

~ 3 ~ 5 `of toluene, add, drop by drop at room temperature, a suspension obtained by dispersing 24.9 g of 5-chloro 2-hydroxy ~ -methyl ~ -phenyl benzene methanol in 250 ml of toluene, bring the mixture to reflux for 6 hours, cool the mixture until it is at room temperature, add by small portions 17 g of dichloro 2,2-sodium propionate ~ m, door again at reflux for 6 hours, cools to tempera-room temperature and add 700 ml of water. Acidified by addition of a hydrochloric acid solution N, realkalized by addition saturated sodium bicarbonate solution. We collect the aqueous extraction phase which is washed with 3 times loo ml ether, acidifies the aqueous extract by adding a solution 2N hydrochloric acid and extracted with 3 times 100 ml of ether, combines the organic extracts which are washed with 3 times 80 ml water and dry over magnesium sulfate, then evaporate the solvent under vacuum and obtains 23 g of 6-chloro 2,4-dimethyl acid 4-phenyl / 4H / 1,3-benzodioxin-2-carboxylic. F = 181C.
Analysis: (Cl7Hl5clO4) Calculated: C ~ 64.06 H% 4.74 C1% 11.12 Found: 64.0 4.8 11.2 Example 6: Isom ~ res A and B of 6-chloro 2,4-dimethyl 4-phenyl [4H] methyl 1,3-benzodioxin-2-carboxylate 23 g of 6-chloro 2,4-dimethyl 4-phenyl acid are mixed L4H11, 3-benzodioxin-2-carboxylic as a mixture of two diastereoisomeric racemates A and B obtained in Example 5, 100 g of Redex "CF" resin ~ Cationic strong sulfonic resin acid), 250 ml of methanol, refluxed for 20 hours, cools down to room temperature, wring out the resin, rinse with solvent and concentrate the filtrate in vacuo. We 20 g of crude product are obtained which is chromatographed on a column of silica under pressure of 1.5 Kg, eluting with a mixture ethyl ether- ~ ther of petroleum (Eb. 60 - 80C) ~ 20 - ~ 0) and Trademark . .

3 6 ~ ~

obtains 1.7 g of isomer A of 6-chloro 2,4-dimethyl 4-phenyl ~ 4 ~ l3 Methyl 1,3-benzodioxin-2-carhoxylate. F- 134C.
Analysis: (C18H17C1O4) Calculated: C% 64.96 H ~ 5,] 5 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 are also obtained (in the form of a oil) 6-chloro 2,4-dimethyl 4-phenyl [4 ~ 1 ~ 1,3-benzodioxin-2-methyl carboxylate.
Analysis: ~ C18H17ClO ~) Calculated: C ~ 64.96 ~ ~ 5.15 Cl% 10.65 Found: 65.8 5.1 10.8 Spectrum R. Mo N. (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 acid r4H1 1,3-benxodioxin-2-carboxylic 1.6 gd is mixed ~ isomer A of 6-chloro 2,4-dimethyl Methyl 4-phenyl r4H] 1,3-benzodioxin-2-carboxylate obtained at Example 6, 20 ml of methanol, 2 ml of water and 0.56 g of hydroxide of potassium in pellets, shakes the mixture for 48 hours room temperature, add 100 ml of water, collect the phase aqueous which is washed with 3 times 50 ml of ether, acidifies the aqueous solution by addition of a hydrochloric acid solution 2N, and extracted with 4 times 50 ml of ether, combines the extracts ethereal which is washed with 3 times 50 ml of water, then dried over magnesium sulfate. The solvent is evaporated in vacuo and obtained 1.5 g of product which is recrystallized from ~ 0 ml of cyclohexane `` ~ $ J ~ 3 ~ d ~ 35 and obtains 1.2 g of the A-isomer of 6-chloro 2,4 dimethyl acid 4-phenyl EH] 1, 3-ben ~ odioxin-2-carboxylic. F = 184C.
Analysis: (cl7Hl5O4c) Calculated: C ~ 64.06 H ~ 4.74 Cl% 11.12 Found: 64.1 4, ~ 11.1 NMR spectrum (base frequency: 60 Hz) - CH3 at 101.5 Hz and 113 Hz;
- COOH at 342 Hz;
- Aromatics from 412 to 442 Hz.
Example 8 Isomer B of 6-chloro 2,4-dimethyl 4-phenyl acid ... ... ~
l4H11, 3-benzodioxin-2-carbox li ue L i - ~ q 8 g of isomer B of 6-chloro 2,4-dimethyl are mixed 4-phenyl ~ 4H] 1,3-benzodioxin ~ 2-carbo ~ methyl ylate obtained at example 6, 80 ml of methanol, 8 ml of water and 2.8 g of hyclroxide potassium pellets, stirred 24 hours at room temperature biante, 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 extract per 4 times 60 ml of ethyl ether. We gather the extracts ethereal and washed with twice 80 ml of water, then dried over - magnesium sulfate and evaporates the solvent under vacuum and obtains - 7.2 g of product which is recrystallized from 80 ml of cyclohexane.
It is dried and 4.5 g of isomer B of 6-chloro 2,4- acid are obtained.
dimethyl 4-phenyl r4H ~ 1,3-benzodioxin-2-carboxylic. F 125C.

Analysis: (CHO Cl) Calculated: C ~ 64.06 H ~ 4.7 ~ C1% 11.12 Found: 64t2 5.0 11.2 NMR spectrum (base frequency: 60 Hz) - CH at 104 and 119 Hz;
- Aromatics from 417 to $ 4 5 hz;
- COOH at ~ 540 Hz.

,:. :.:. ::. :.

~ 3 ~ 5 Example 9: Acid 6-chloro 4,4 ~ di h ~ n 1 r4Hl 1,3-benzodioxin-2-... P _ Y ~ ~. .. ~ ~ _ carboxylic 12.4 g of 5-chloro 2-hydroxy ~ q ~ -diphenyl are mixed benzene methanol, 150 ml of toluene, 3.2 g of sodium amide, brings the mixture to reflux for 6 hours, cools until at room temperature and add 6.8 g of dichloroacetate potassium, re-refluxed for 6 hours, cools to room temperature and add 300 ml of water. We acidifies l ~ slightly by adding w ~ e chlo- acid solution hydric N, then alkalinizes by adding a saturated solution sodium bicarbonate. Washed twice with 100 ml of chloride methylene, then acidifies by adding an acid solution hydrochloric 2N, extracted with 3 times 100 ml of ether, combines the ethereal extracts, washed twice with 80 ml of water, then dried over magnesium sulfate and treated with activated carbon. After evapora-tion of the solvan ~ under vacuum ~ 7 g of product are obtained which recrystallizes from 300 ml of benzene. 4.6 g of acid are obtained 6-chloro 4,4-diphenyl r4H ~ 1,3-benzodioxin-2-carboxylic.
F = 226C.
Analysis. (C21H15O4Cl) Calculated: C ~ 68.76 H% 4.12 Cl% 9.67 Found: C% 69.1 H ~ 4.3 Cl% 9.5 NMR spectrum (base frequency: 60 Hz ~
- Hydrogen in position 2 at 325 hz;
- COOH ~ r-313 hz;
- Aromatics from 405 to 443 Hz.
Example 10: Isomer A of 4-methyl 4-phenyl ~ 4H ~ 1,3-benzodloxin-M ~ 2-carboxylate 1.3 g of hydrogen chloride are introduced into a cell to be hydrogenated.
palladium on activated carbon at 10%, 11, ~ g of isomare A of 6-chloro 9-methyl 4-phenyl ~ 4H ~ 1,3-benzodioxin-2-carboxylate of methyl obtained in Example 2 and after a second placing I

~ 23-using the procedure described in Example 2, 500 ml ethanol, 10 ml of triethylamine, agitates the su ~ pension 50US
hydrogen flow, at room temperature. We wash the m ~ thylene chloride catalyst, then concentrates the ~ iltrate under vacuum, take up the residue in 100 ml of water, add 50 ml of a hydrochloric acid solution 2 ~, and extracted by 3 times 150 ml of methylene chloride, received: extracts, washed with 2 times 100 ml of water, dried over calcium chloride, then, after treatment with actl charcoal, evaporate the solvent under vacuum and obtains 9.7 g of the expected product.
A ~ sample of ~ e product was recrystallized ~ from methanol. F = 124C.
ANALYSIS: (Cl7Hl6o4) Calculated: C% 71.82. H ~ 5.67 Found: 72.1. 5.8 NMR spectrum (base frequency: 60 Hz ~
- Hydrogen in position 2 at 312 Hz;
- COOCH3 at 231 Hz;
- CH3 twin to phenyl: 1 ~ 7 Hz;
- Aromatics from 410 to 450 Hz.
.
Example 11: Isomer A of 4 methyl 4- 4- henyl ~ 1,3- acid benzodioxin-2 carDoxyli ~ eu 9.7 g of isomer A of 4-methyl are mixed with stirring Methyl 4-phenyl ~ 4H] 1,3-benzodioxin-2-carboxylate obtained Example 11, 4 g of potassium hydroxide in lozenges, 10 ml of water, 90 ml of methanol, keeps stirring for 16 hours at ambient temperature, add 400 ml of water, wash the aqueous phase with 2 times 100 ml of methyl chloride, acidifies the phase aqueous by addition of a 2N hydrochloric acid solution, extracted with 3 times 150 ml of methylene chloride, r ~ unites them extracts, washed twice with 80 ml of water, dried over chloride of calcium, evaporates the solvent under vacuum, collects 8 g of product I
~ ~ ~ ~ 2 ~ -. -.

.
which is recrystallized from a mixture of ethyl acetate-cyclohexane ~ 20 - 80 ~ and obtains 5.1 g of isomer A of the acid 4-methyl 4-ph ~ nyl 1,3-benzodioxin-2-carboxylic. F = 163C.
Analysis: (Cl6Hl4o4) Calculation ~: C ~ H $ 71.10 5.22 Find . 71.1 5.3 NMR spectrum (base frequency: 60 Hz) - CH3 ~ 119 Hz;
- Hydrogen in position 2 ~ 316 Hz;
- COOH at 534 Hz;
- Aromatics from 418 to 450 Hz.
Example 12: Isomer B of 4-m ~ thyl 4-phenyl ~ H ~ _ 1,3-benzodioxin-Methyl 2-carboxylate 1.3 g of are introduced into a cell to be hydrogenated.
palladium on activated carbon ~ 10%, 12.8 g of isomer B of 6-ohloro 4-methyl 4-phenyl ~ 4H] 1,3-benzodioxin-2-carboxylate of methyl obtained in Example 2 and after a second placing using the procedure described in Example 2, 10 ml of triethylamine ~ 200 ml of ethanol, passes a direct current of hydrogen and stirred the suspension at room temperature for ~
about two hours. Filtered, rlnce the chloride catalyst of methylene, evaporates the filtrate ~ or vacuum, takes up the residue in 80 ml of water, add 70 ml of a hydrochloric acid solution that 2N, extracted with 3 times 100 ml of methylene chloride, combines the extracts and washed with 3 times 50 ml of water, dried over calcium chloride and evaporates the solvent in vacuo. We obtain 10.2 g of expected product.
A sample of this product is recrystallized from ~ methanol. F c137C.

Analysis: (CHO) 17 16 ~
Calculated: C% 71.82 ~% 5.67 Found: 71.8 5.8 I

~ 7 NMR spectrum (base frequency: 60 Hz) - CH3 at 12a hz;
- COOCH3 at 234 Hz;
- Hydrogen in position Z at 347 Hz;
- Aromatics from 410 to 4 ~ 55 Hz.
Example 13: Isomer B of 4-methyl 4-ph ~ nyl acid [4H ~ 1,3-benzodioxin-2-carboxylic 10.2 g of isomer B are mixed with stirring.
4-methyl 4-phenyl ¦4H] 1 3-benZOdiOXin-2-Car ~ Methyl OXY1ate obtained in Example 13, 4 g of potassium hydroxide in pellets, 10 ml of water and 90 ml of me ~ hanol, keep stirring for 16 hours ~ room temperature, add 500 ml of water, wash it aqueous phase with twice 80 ml of methylene chloride, acidifies the aqueous phase by adding an acid solution hydrochloric 2N, extracted with 3 times 100 ml of chloride methylene, washed with twice 80 ml of water, dried over chloride calcium, evaporates the solvent under vacuum, obtains 9 g of product which is recrystallized from an ethyl acetate mixture-cyclohexane (20 - 80 ~ and obtains 6.7 g of the expected product.
F -153C.
Analysis: ( Calculated: C% 71.10 ~% 5.22 Found: 71.1 S, 3 NMR spectrum (base frequency: 60 Hz) -- CH3 ~ 128 Hz;

- Hydrog ~ ene in position 2 ~ 348 Hz;

- Aromatics from 410 to 460 Hz.

Example 14: 6-chloro 4,4-diphenyl [4H] 1,3-benzodioxin-2-methyl carboxylate 11 g of 6-chloro 4,4- acid are mixed by stirring - diphenyl f4H ~ 1,3-benzodioxin-2-carboxylic obtained in the example ~ 26-, ~. .

~ 36 ~

10.50 g of Redex "C ~" resin (strong sulfonic cationic resin acid), 200 ml of methanol, brings to reflux for 16 hours, cools to room temperature, wring out the resin, wash with ether and concentrate the filtrate under vacuum.
The crude product obtained is taken up in 200 ml of ether, wash the organic phase with 100 ml of a bicarbonate solution sodium ~ 5%, then twice 100 ml of water. We dry the ethereal phase on magnesium sulfate, treated with activated carbon, evaporates the solvent and obtains 6.3 g of product which is recrystallizes from 140 ml of cyclohexane. We dry and get S, lg of expected product. F = 172C.
Analysis: C22H17O4C1 Calculated: C ~ 69.38 H ~ 4 50 C1% q, 31 Found: 69.7 4.6 9.3 NMR spectrum (base frequency 60 MHz) tdeuterochloroform) COOCH at 230 HZ
- Aromatics from 406 to 443 HZ
- Hydrogen in position 2 at 324 ~ Z.
Example 15: Isomer A of 6-chloro 4-methyl 4-phenyl E4H ~ 1 3 benzodioxin-2-car ~ e: thyl oxylate.
Stage A: Isomer A of 6-chloro acid chloride _______ ______________________________ __________ `4-methyl 4-phenyl ~ H ~ 1,3-benzodioxin-2-carboxylic.
__________________ _________________.____ __________ ,,.
4.9 g of the isomer A of 6-chloro 4-methyl 4-phenyl l4H ~ 1,3-benzodioxin ~ 2-because ~ oxylic obtained in Example 3, 50 ml of anhydrous benzene, cools the suspension to a temperature of 10C, then add 2.3 ml of triethylamine drop by drop, then add drop by drop at ~ same temperature, a solution of 1.5 ml of thionyl chloride in 25 ml of benzene anhy ~ re, carries the two hour solution ~ at reflux, refrnidit a te ~ nfiratllre room, wring the preci ~ it ~ and collect the expected Prodnit in solution.

.. ~, i '~ 3G85 .
Stage B: Isomer A of 6-chloro 4-methyl 4- ~ hényl _______ _____________ ______________ ____ ___ _ ~ 4 ~ lL3-ethyl benzodioxin-2-carboxylate.
__ ______________________ __________ __ 3 ml of absolute ethanol, 50 ml of benzene are mixed . anhydrous, 2.3 ml of triethylamine, added dropwise to room temperature the ac chloride solution obtained at stage A, keep stirring for twenty hours at room temperature, wring and ~ e the hydrochloride precipitate triethylamine with cold benzene, wash the filtrate in half times 40 ml of water, dries the organic phase on chloride calcium, treats with activated carbon, evaporates the solvent under vacuum, obtains 9 g of crude product which is recrystallized from 30 ml of hexane and after drying 4 g of the expected product is obtained.
F = 92C. ' Analysis: C18H1704Cl Calculated: C% 64.97 H% 5.15 C1% 10.65 Found: 65.1 5.3 10.8.
NMR spectrum (deuterochloroform ~
~ base frequency: 60 MHz) - CH3 from C2H5 to 72.5 - 79.5 - 87 Hz - CH3 in position 4 at 116 Hz - CH2 from C2H5 to 247.5 - 255 - 262 - 269 Hz - hydrogen in position 2 at 308 Hz - aromatics from 412 to 441 Hz.
Example i6. Isomer_A of 6-chloro 4-methyl 4-phenYl / 4 ~ / 1.3-sodium benzodioxin-2-carboxylate.
0.6 g of sodium hydroxide, 250 ml of ethanol are mixed absolute, add at room temperature, 4.6 g of the isomer A of 6-chloro 4-methyl 4-phenyl / 4 ~) 1,3-benzodioxin-2-carboxylic acid obtained in Example 3, the mixture is brought to the boil for 5 minutes.
tion, filters, cools to room temperature, adds 500 ml of ether in the filtrate and keep stirring for sixteen hours at room temperature. We filter and get ~ 28- ' ~ 31 ~ 85 .

after drying 3.8 g of the expected product. F. = 160C.
C16H124ClNa analysis Calculated: C% 58.82 H% 3.70 Cl% 10.85 Found: 58.5 3.8 10.7 Example 17 Isomers d and 1 of the A-isomer of 6-chloro acid 4-methyl 4-phenyl / 4 ~ / 1 3-benzodioxin-2-carboxylic, 1) Isomer 1 Stage A: Salt of 1 1- ~ -nitro ~ henyl_2-amino lL3- ~ ro ~ a-nediol of isomer 1 of isomer A of 6-chloro 4-methyl acid ________________________ ______ __, _____________________________ _ 4-phenyl ~ 4 ~ / 1,3-benzodioxin-2-carboxyli ~ eu.
__ ___ _ _________________________ __ __ 15.2 g of isomer A of 6-chloro 4- acid are mixed m ~ thyl 4-phenyl / 4 ~ J 1,3-benzodioxin-2-carboxylic obtained at Example 3, 16.2 g of 1 lp-nitrO ~ hényl 2-amino 1,3 propanediol and 800 ml of ethyl acetate.
We bring the mixture to reflux, we maintain the reflux after precipitation of the salt formed for five minutes, we bring at room temperature, wring out the precipitate obtained, rinse it with ethyl acetate, vacuum drying and recover 10 g of product gross. / The mother liquors are kept for the separation of the isomer d gross (see below ~ /.
The 10 g of crude product obtained are recrystallized in isopropanol and finally obtains 6.4 g of expected product î
F = 218C.
/ a / 20 = -84 + 2 (c = 1%, ethanol).
A sample of this product is recrystallized from a little isopropanol. F = 218C.
/ ~ / 20 = -84.5 + 2 (C = 1%, ethanol).
- Stade_B: isomer 1 of isomer A of 6-chloro acid 4-methyl 4- ~ henyl ~ 4HZ lL3-benzodioxin-2-carboxyli ~ eu The salt thus purified obtained is suspended in stage A above, in 150 ml of hydrochloric acid ~, then extract by trolis times 75 ml of ether, wash the organic phase ~ the ~ 3 ~ 5 extraction with three times 50 ml of water, dried over sulphate magnesium, The solvent is evaporated in vacuo, 3.5 g of crude product which is crystallized from cyclohexane, obtains 2.7 g of crystals which are purified by recrystallization from cyclohexane, obtains 2.3 g of crystals melting at 113-114C then recrystallizing and melting ~ 128C. We recrystallize ~ again in 80 ml of cyclohexane and obtains 1.8 g of the expected product melting at 113C.
We obtain, from the mother liquors of recrystalli ~ ations 0.5 g of expected product. We collect these 0.5 g of product and the 1.8 g of product obtained previously, recreated mix the 2.3 g of product in 50 ml of cyclohexane now reflux the solvent for twenty minutes and get then 2 g of expected product. F = 140C.
(Variations in different melting points identified for the expected product, are probably due to ~
variations in crystal structure).
Anal ~ Se: C16H13C14 Calculated: C% 63.06 H% 4.30 Cl% 11.63 20 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 - aromatic from 415 to 443 Hz - OH at around 540 Hz.
Rotating power / a / 20 = -157 + 2.5 (c = 1%, ethanol 95).
2) Isomer d Stage A: isomer dd ~ e isomer A of 6-chloro acid 30 4-methyl 4- ~ hényl / 4H7 1,3-benzodioxin-2-carboxyli ~ raw eue.
______ ____ ___ _______._ ______________________ __ _______ The mother liquors of ethyl acetate, salification of the A-isomer of 6-chloro 4-methyl acid ... ~

~ L ~ 36 ~ i 4-phenyl / 4 ~ / 1,3-benzodioxin-2-carboxylic by the 1 1-p-nitro-phenyl 2-amino 1,3-propanediol.
Concentrate the solution under vacuum, recover 17.8 g crude product which is treated with 200 ml of hydrochloric acid 2 ~, extracted with three times 100 ml of ether, washing the organic phase than twice 50 ml of water, dry over magnesium sulfate and concentrated in vacuo. We obtain ~, ~ g of residue which we taken up in 150 ml of a cyclohexane-ethyl acetate mixture (70/30) and brings to reflux, leaves to cool, wring out the acid residual starting racemic which crystallizes, concentrates the filtrate under vacuum, and obtains 7 g of expected raw product.
Stage B: Salt of d l- ~ -nltro ~ henyl 2-amlno 1L3-~ ropanediol of the d-isomer of 6-chloro 4-methyl 4- ~ hényl acid __ ________________________________ ___________ ____ ____ ___ _ / 4 ~ / 1,3-benzodioxin-2-carboxyli ~ eu.
The residue obtained above is taken up in 300 ml.
of ethyl acetate and added to the solution 7.4 g of d lp-nitrophenyl 2-amino, 1,3-propanediol.
The suspension is brought to reflux, allowed to cool, after precipitation of the salt formed up to room temperature, wring the precipitate, rinse with a little acé ~ ate of ethyl. We obtains after drying 11.4 g of expected product melting at 200 ~.
Recrystallized from 1.1 liters of isopropanol, obtained 6.2 g of expected product. F = 218C, which we recrystallize in 800 ml of isopropanol and obtains 5 g of the expected product.
F = 218C approximately.
Stage C: Isomer d of the A-isomer of 6-chloro acid _______ ____________________________________________ ~ 4-methyl 4- ~ h ~ nyl ~ 4HZ lL3-benzodioxin-2-carboxyli ~ eu.
______ ____ ___ __ ._ __ ______________________ __ __ We take the ~ el obtained previously in 150 ml of water, acidified with 2N hydrochloric acid, extracted with twice 100 ml of ether, wash the organic extraction phase twice with 50 ml of water, dry over magnesium sulfate and the solicitor is evaporated under vlde, 2.9 g of crude product are obtained . ~ ..

6 ~ 5 .

which is taken up in a mixture of ethyl ether - ether petroleum (Eb. 60 - 80C) (20 - 80).
After separation 2.4 g of expected product. F = 128C.
/ a / D ~ ~ 153 ~ 25 (c = 1%, ethanol).
This product is recrystallized from 100 ml of cyclohexane, obtains 2 g of the expected product. F = 128C.
/ ~ / D0 = + 153 ~ 2S (c = 1%, ethanol).
Recrystallized again from 60 ml of cyclohexane and finally obtains 1.7 g of the expected product, F = 140C.
(As for isomer 1, the d isomer has several melting points. This is probably due to variations in crystal structure).
ANALYSIS: ~ 16H13C14 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 ~ 440 Hz - aromatic 413 ~ 440 Hz - OH at 485 H ~
- hydrogen in 2 ~ 312.5 Hz.
Rotating power / a / D = + 1545 + 25 (c = 1%, ethanol).
Example 18: 6-chloro 4- (3-chlorophenyl) 4-methyl / 4H7 acid 1,3-benzodioxin-2-carboxylic (mixture of diastereois racemates -mothers).
10 g of sodium amide and 200 ml are mixed with stirring anhydrous toluene, then add ~ room temperature and by .- ^ ~
small portions, a suspension obtained by dissolving 28.3 g of 1- (5-chloro 2-hydroxy phenyl) 1- (3-chloro phenyl) ethanol in 250 ml of toluene, pui ~ the mixture is brought to r -32-~! ~ ", ~

3 ~ 155 reflux for six hours ~ (another 1 g of amide of sodium in the mixture). After cooling to temperature ambient, add in small portions with stirring 25 g of - potassium dichloroacetate, and again brings the mixture to reflux for six hours. After return to temperature ambient, 150 ml of water are slowly added, then 150 ml of HCl, 2N-. The organic phase is collected, and then extracted again the aqueous phase with twice 100 ml of ether. We wash the phase organic extraction two times 100 ml of water. We extract the organic phase with a saturated solution of bicarbonate sodium, then twice 100 ml of water. We wash the phase aqueous extraction with three times 100 ml of ether, then slowly acidifies the aqueous phase with u ~ e 2N HCl solution.
The aqueous phase is then extracted with three times 150 ml of ether.
The organic extraction phase is washed twice with 75 ml of water. It is treated with activated carbon and dried over sulphate magnesium. The solvent is evaporated under vacuum, and we obtain finally 29.3 g of expected product.
NMR spectrum (deuterochloroform) ~ base frequency: 60 MH7.) - CH3 at 117 and 125.5 Hz - Hydrogen in position 2 at 315.5 and 346 Hz - aromatic 412 to 455 Hz - COOH ~ 588 Hz.
1- (5-chloro-2-hydroxyphenyl) 1- (3-chlorophenyl ~
ethanol used at the start of the preparation of 6-chloro acid 4- (3-chlorophenylj4-methyl / 4 ~ / 1,3-benzodioxin-2-carboxylic can be prepared as follows:
Disperse by stirring 11 g of magnesium in turnings in 100 ml of anhydrous ether, add, drop ~ drop ~ temperature-ambient solution with stirring a solution obtained by dissolving tion of 64 g of methyl iodide in 100 ml of anhydrous ether, r A slight reflux of the solvent is maintained during the addition and ~ '' C}

.

continues reflux for one hour, brings back ~ temperature room, then add drop by drop in twenty-five minutes ~
a solution of 31.7 g of (5-chloro 2-hydroxyphenyl) (3-chloro-phenyl) 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 bring the solution to reflux for four hours.
The mixture is cooled to room temperature and maintaining at this temperature by means of an ice bath, hydrolyzed using a hydrochloric acid solution N.
The organic phase is collected, extracted again the aqueous phase with twice 80 ml of ether, wash the phase organic extraction with three times 80 ml of water, dries the phase organic over magnesium sulfate, then evaporates the solvent under vacuum.
31.5 g of expected product are then obtained, which recrystallizes from 750 ml of cyclohexane.
25.5 g of expected product are finally obtained.
F = 125C.
Analysis: C14H122C12 Calculated: C% 59.38 H% 4.27 Cl% 25.04 Found: 59.2 4.3 24.9.
(5-chloro 2-hydroxyphenyl) (3-chloroph ~ nyl) methanone used at the start of the preparation of l- (5-chloro 2-hydroxy-phenyl) 1- (3-chlorophenyl) ethanol above can be prepared as well ~
Stage A: 3-chloro benxoate of 4-chloro ~ hényle.
______. _____________________________ ___ __.
Mixed with stirring 5.37 g of 4-chlorophenol, 46.1 g of triethylamine and 250 ml of anhydrous benzane, cools ~ 10C
add a solution of 80 g of chloride drop by drop 3-chlorophenyl carboxylic acid in 100 ml of benz ~ ne anhydrous, keep stirring at room temperature for ~ 34-... ~; .

6 ~ 35 .
one night, filter, wring out the precipitate ~ of hydrochloride sort ~ hylamine, collect the filtrate and bring to seo. We obtain 122 g of crude product which is crystallized from 200 ml of a mixture of ethyl ether - petroleum ether ~ Eb7 60 - 80C) (20 - 80).
116 g of expected product are obtained. F -72C ~
Analysis: C13H8C1202 Calculated: C% 58.45 H ~ 3.02 Cl% 26.55 Find . 58.5 3.0 26.2 Stage B: (S-chloro 2-hydxoxyphenyl) (3-chlorophenyl) methanone _______ ___________ ~ _______________ ________________________ 64.5 g of 3-chlorobenzoate are mixed with stirring 4-chlorophenyl obtained in the previous stage and 32 g of chloride of aluminum, gradually heating, with stirring, the mixture at 160C, maintained at this temperature for thirty minutes, 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 ~ ue N, decanted the organic phase, then extract the aqueous phase by two times 70 ml of methylene chloride, wash the organic phase ~ 'extraction with three times 70 ml of water, dries the organic phase on calcium chloride and then the solvent is evaporated under vacuum. We finally obtains 60 g of crude product which is ristallized in a mixture ~ ther ethyl-petroleum ether tEb. 60 - 80C) ~ 20--80).
It is drained, dried and 41.3 g of expected product is obtained.
We recrystallize a sample of this product in the cyclohexane. F -72 ~ C.
Analysis: C13H8C120 ~
Ca} culé: C% 58t45 H ~ 3.02 Cl% 26.55 Found: 58.4 3.2 26.6 Example 9: A and B isomers of 6-chloro 4- (3-chloroph ~ nyl ~ _4-methyl r4H ~ methyl 1,3-benzodioxin-2-carboxylate.

5-. ~

36 ~ 3 ~
Mixed with stirring 29.3 g of 6-chloro acid 4- ~ 3-chloroph ~ nyl) 4-methyl r ~ H ~ 1,3-benzodioxin-2 carboxylic sub form of mixture of the two rac ~ diastereolsom mates res obtained at example 19, 300 ml of methanol and 30 gd ~ cationic resin 'strong acidic sulfur, refluxed for twenty hours, with stirring, cools down to room temperature, wring the resin, the rinsing with methanol and concentrating the filtrate under empty. 20 g of crude product are obtained which is chromatographed on a column of silica under pressure, eluting with a mixture ethyl ether - petroleum ether (Eb. 60 ~ 80C) (20 - 80) and obtained after fractionation and evaporation of the solvent:
9, S g of isomer A expected ~ which is purified 4 g by recrystallization from methanol: 3.2 g of isomer are obtained Waited purified. F = 112C.
Analysis C17H134C12 - Calculated: C% 57.97 H% 3.72 Cl% 20.13 - Found: 57.9 1 4.0 1 ~, 8l NMR spectrum (deuterochloroform) (basic frequency: 90 MHz) - CH3 at 172 Hz - COOCH3 ~ 345 Hz .
~ Hydrogen in position 2 at 461.5 Hz - - Aromatics from 623 to 660 Hz and 8.4 g of isomare B expected, SOU5 product form ~
~.
gross ~
Analysis: CHO Cl Calculated: C% 57.97 H% 3.72 1% 20.13 Found: 58.2 ~ 0 4.0 20.1 NMR spectrum (deut ~ rochloroform ~) (base frequency: 90 MHz) - CH3 at 184 Hz - COOCH3 at 343.5 Hz - hydrogen in position 2 at 509 Hz - Aromatics from 612 to 674 Hzo . , `, . . . , ~, 368 ~
Example 20: Isomer A of 6-chloro 4- (3-chloroph ~ n ~ l) acid 4-methyl EE3 1 3-benZOdi-OX1n-2-CarbOXY1iqUe.
One mixes with stirring 6.5 q of isomer A of 6-chloro 4-~ 3-chloroph ~ nyl ~ 4-methyl L4H31,3-berlzodioxin-2-carboxylate methyl, obtained ~ Example 20, 2.8 g of potassium hydroxide in tablets, 10 ml of water and L00 ml of methanol, agitates the mixture sixteen hours at room temperature, add 200 ml of water, wash the aqueous solution with two ~ 50 ml dlether, acidify the aqueous solution with a 2N hydrochloric acid solution, extract the aqueous phase with three times 80 ml of ether, wash the gold ~ anic phase of extraction with twice 50 ml of water, dry the ethereal phase on magnesium sulfate, evaporates the solvent under vacuum, 6.1 g of product is obtained which is recrystallized from 100 ml of cyclohexane. 3.6 g of expected product are obtained.
F = 131C.
Analysis: C16H12O4C12 Calculated: C% 56.66 H% 3.57 Cl% 20.90 Found: 56.7 3.7 20.6 NMR spectrum ~ deuterochloroform) (base frequency: 60 MHz) - CH3 at 174.5 Hz - Hydrogen in position 2 at 466.5 Hz - - Aromatics = peaks from 625 to 665 Hz.
Example 21: Isomer B of 6-chloro 4- ~ 3-chlorophenyl acid) 4-methyl [4H ~ 1,3-benzodiox n-2-carbox ~ eu.
One mixes by acting ~ ant 5.3 g of isomer B of 6-chloro 4- (3-chlorophenyl) 4-methyl [4H ~ 1,3-benzodioxin-2-carboxylate methyl, obtained in Example 20, 2.4 g of potassium hydroxide in tablets, 10 ml of water, 100 ml of methanol, stir the mixture overnight at room temperature, add 20 ml of water, wash in following the aqueous phase with twice 80 ml of ether, acidifies the aqueous solution with a hydrochloric acid solution ~ N, extract the aqueous phase with three times 80 ml of ethex, wash the ~ '~.

::, ,,. .:

36 ~ 35 organic phase with two ~ 50 ml water, dry the ethereal phase on magnesium sulphate, concentrated under vacuum ~ t obtains 5.3 g of expected product which is recrystallized from 110 ml of a cyclohexane-ethyl acetate mixture (80/30). We get 4 g of purified expected product. F- 177C.
lysis C16H124C12 Calculated: C% 56.66 ~% 3.87 Cl ~ 20.90 Found: 56.8 3.8 20.9 NMR spectrum tdeut ~ rochloroform) ~ base frequency ~ 90 MHz) - CH3 at 185.5 Hz - hydrogen in position 2 ~ 510 Hz - aromatic from 610 to 673 Hz Example 22 Acid 6-ch ~ oro 4-E (l-methyl) ethyl ~ 4-phenyl ~ 4H ~ 1,3-benzodioxin-2-carboxylic ~ melan ~ e of the two diastereo- racemates somères ~
8.1 g of 50% sodium hydride are mixed with stirring in oil, 60 ml of anhydrous dioxane and 3 ~ 0 mg of dibenzo-18 crown-6, of the type described in synthesis 1976 p. 168 adds in keeping the solution at room temperature, in 10 minutes 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, ~ g of 5-chloro ~ - [(l-methyl) ethy ~ 2-hydroxy - phenyl benzene methanol in 30 ml of anhydrous dioxane, heating la-suspension for 10 hours at 90-100C, brings to temperature ambient, added drop by drop while cooling with a water bath ice, 500 ml of water, wash the aqueous phase twice with 200 ml of ~ ther, extracts the ~ thested phase with three times 100 ml of hydroxide sodium ~ N. The aqueous phase is acidified with acid hydrochloric 2N and the acid released by three is extracted 150 ml of ether, wash the ~ thested phase with three times 100 ml of water, extract the acid formed in the form of sodium salt by extraction of the ethereal phase with saturated sodium bicarbonate solution, I

: --3 ~ -

6 ~ 5 .
then by three times 100 ml of water, wash the aqueous phase of extraction tion with twice 80 ml of ether, acidified by addition of acid hydrochloric 2N, extracts the acid thus released ~, by three ~ ois 150 ml of ether, wash the organic extraction phase by three times 80 ml of water, dries and treats with actift charcoal am ~ ne dry and obtains 8.8 g of the expected product, in the form of a oil.
NMR spectrum (deuterochloroform) (~ basal requirement of device 60 M ~ z).
Hydrogen in position 2 at 323 Hz (peak corresponding to isomer A), - Hydrog ~ ne in position 2 at 335 Hz ~ corresponding peak isomer B), the two radical CHs 3 ~ CH- from 49 to 69 Hz, CH
- the hydrogen of the radical ~ d ~ 100 ~ 190 Hz:

. 3 - - aromatic from 410 to 465 Hz - - OH at 490 Hz . . ~
5-chloro ~ - [(l-methyl ~ ethyl 2-hydroxy ~ -phenyl benzene methanol used from the above preparation, has been prepared as follows:
21.4 g of magnesium are mixed by stirring turnings, 200 ml of anhydrous ether and 2 ml of isopropyl bromide.
stir until 5th forms the expected magnis, then add drop by drop to maintain a slight reflux and at room temperature, a solution of 110.8 g of isopropyl bromide in 400 ml of anhydrous ether. When the addition is complete, the reflux is continued for two :.:: ..................... ::. :.,,.,, -:. ~. ~:: ... . . . .

36 ~

hours. In addition, 58.2 g of ~ S-chloro 2-hYdroxy are mixed) phenyl) phenyl methanone, 600 ml of anhydrous benzene, add then drop by drop at room temperature 520 ml of the magnesian solution prepared above.
The ether is distilled, gradually replacing it with benzene. The reflux is continued for 9X hours.
After cooling to room temperature, pour the reaction mixture onto ~ n Liter of an ice-cold solution of 10% ammonium chloride. The organic phase is decanted ~
extract the aqueous phase with twice 150 ml of ether. We gathers the organic phases, washes them in three ~ ais 100 ml of water, dries, treats with activated carbon, evaporates the solvent under empty. 74 g of crude product are obtained, which is chromatographed.
on a silica column, eluting with methylene chloride;
18 g of crude product are obtained after fractionation which is r taken up in 50 ml of cyclohexane. 8.7 g of product are obtained expected. F 114C.
A sample of this product is purified by recrystall-lization in cyclohexane, F 118C.
analysis - (Cl8Hl7O2cl3 Calculated: C% 69.43 H ~ 6.19 Cl% 12.81 Found: 69.7 6.2 12.8 NMR (deuterochloroform) (base frequency of the apparatus used 60 MHz) - the 2 CH3 dU radical ~ l-methyl) ethyl at 48-55 Hz and 63-70 Hz, - CH- a ^ ~ lÇ5 Hz (multiplet) - OH of m ~ thanol at 165 Hz - OH of 2-hydroxy ~ 537 Hz - aromatic from 395 ~ 455 Hz Example 23: Isomer A of 6-ch oro 4- r ~ lm ~ th ~ l ~ ethYl] 4-phen ~ l [4H ~ 1,3-benzodioxin-2-methyl carboxylate.

i -40-, ~

, ~ a ~ 3 ~
.
Stage A: Chloride of the A-isomer of 6-chloro-4 acid ~ (l-methyl) ethyl] 4-phenyl [4Hï 1,3-benzodioxin-2-carboxyllque.
_____ ~ ________________________________________________.________ Mix with stirring 8.8 g of 6-chloro 4- (1-methyl) ethyl 4-phenyl 4H 1,3-benzodioxin-2-carboxylic acid, obtained in Example 22 100 ml of anhydrous benzene, add in now at room temperature 3.7 ml of tri ~ thylamine, 3.8 ml thionyl chloride, 25 ml anhydrous benzene, door the mixture at reflux for three hours, cools to room temperature, spin and wash the precipitate a little anhydrous benzene and collects the filtrate which contains the expected product.
Stage B Isomer A of 6-chloro 4- [(l-methyl) ethy ~
Methyl 4-phenyl [4H1 1,3-benzodioxin-2-carboxylate.
_________________________________ ____ _______________ Mixed with stirring, 50 ml of anhydrous benzene, 4 ml anhydrous methanol and 3.7 ml of tri ~ thylamine, add drop to drop the filtrate obtained in stage A below at room temperature above, stir the mixture 50 hours at room temperature, spin and wash the precipitate with a little benzene, collect Ie filtrate, washed with 2N sodium hydroxide, then with water until neutral pH. The organic phase is dried, treated with activated charcoal, brings to dryness, obtains 7.3 g of crude product we crystallize in methanol, wring, dry the crystals obtained and collects 4.5 g of attenuated product which is purified by two recrystallizations from methanol. 1.8 g are obtained of product at ~ endu purified. F 114-115C.
Analysis: CH Cl O

Calculated: C% 65.80 H% 5.52 Cl% 10.22 - Found: 65.8 5.6 10.2 ~ NMR (deuterochloroform) ~ base frequency: 90 MHz ~
- the two CH3s of the (l-methyl) ethyl radical at 74 and 77 Hz - CH- of the (l-methyl) ethyl radical from 187 to 239 Hz - COOCH31, at 351 Hz ~ ,.

~ 3 ~ i8S

.
- Hydrogen in position 2 at 479 Hz - Aromatics: peaks of 616 ~ 681 Hz.

Example ~ 4: 6-chloro acid 4 [(1,1-dimethyl ~ ethyl] 4-phenyl ~. .
~ 4H ~ 1,3-benzodioxin-2-carbox ~ lique ~ mixture of the two racemates - diastereoisomers) Mixed with stirring 12.8 g of sodium hydride at 50 in oil, 100 ml of anhydrous dioxane, 600 mg of dibenzo 18-crown-6, then add drop by drop while maintaining the solution ~ room temperature, a solution of 5.82 ml of acid dichloroacetic in 100 ml of dioxane, maintains the suspension at room temperature, add a solution of 14.1 g of 5-chloro ~ (l, l-dim ~ thyl) ~ thyl 2-hydroxy ~ -phenyl benz ~ do methanol in 100 ml of dioxane, pUi5 heats the mixture at 80C for six hours, cools to temperature ambient and maintaining at this temperature by a water bath 400 ml of water are added, the aqueous phase is extracted with 600: ml of ether, extracted with three times 100 ml of hydroxide sodium O, lN, acidifies the aqueous extraction phase with 2N hydrochloric acid, extracted with three times 150 ml of ether, wash the organic extraction phase with three times 100 ml of water, .
extracts the acid as a sodium salt using a saturated salutation of sodium bicarbonate, then three times ~ 100 ml of water and collects the aqueous extracts.
. . The aqueous phase is washed with three times 100 ml of ther, acidifies the aqueous phase with 2N hydrochloric acid, extracted with four times 150 ml of ether, wash the ethereal phase with three times 100 ml of water, dry the ethereal phase on sulfate of magn ~ sium treated with actlf charcoal, am ~ na A ~ ec, ohtient 9,1 g of expected raw product.
NMR ~ deuterochloform ~ (base frequency of the device: 60 ~ Hz) - hydrogen in position 2 at 317 Hz (isom ~ re A), - hydrogen in position 2 ~ 340 Hz (isomer B), , ~ I

36 ~ S

- (1.1 dimethyl) ethyl at 63 and 65 EIz, - aromatics from 415 to 472 Hz - OH at 527 Hz.
5-chloro ~ dim ~ thyl) ethyl 2-hydroxy ~ -phenyl benzene methanol, used at the start of the preparation above, was prepared as follows:
40.2 g of (S-ch: Loro 2-hydroxy ph ~ nyl) ph ~ nyl are mixed methanone, 400 ml of anhydrous ether, add drop to ~ a room temperature, 192 ~ g of a so: Lution of ter-butyllithium in pentane, stirred for two hours at room temperature, distill the ether by gradually replacing it with 600 ml of - ~
anhydrous benzene, carries the reflux solution of benzene for sixteen hours, cools to room temperature, pours on a liter of an ice-cold solution of ammonium chloride a 10%, eliminates the organic phase by decantation, extracts the aqueous phase with twice 100 ml of ether, wash the organic phase:: ~
twice 70 ml of water, dried over magnesium sulfate, treated with activated carbon, dry amane, obtains 50 g of crude product ~
(in the form of an oil), which is chromatographed on a column ~:
silica eluting with chloride of m ~ thylene, obtained by ~ - ~
fractionation 14.1 g of product, of which one recrystallizes a sample in cyclohexane. F 146C.
Analysis s C17H19O2Cl Calculates: C% 70.22 H% 6.59 Cl% 12.19 Find: 70.5. 6/7 11.9 ~ IN (deuterochloform) ~ base frequency: 60 MHz) . -OH of the 2-hydroxy radical ~ 530 Hz - OH methanol ~ 175 Hz - - radicaL / (l, l-dimethyl) ethyl / at 75 Hz - aromatics of the phenyl radical into methanol from 420 a ~ 55 ~ z, - other aromatics from ~ 400 to 455 Hz.
I ';

~ -43-'3 ~ i ~ 3S
.
Example 25: Isomer A of 6 chloro 4- [(l, ld ~ methyl) ethyl] 4-phenyl C4H3 1,3-b ~ methyl nzodioxin-2-carboxyl?
Stage A: 6-chloro 4- ([l, l-dimethyl) acid chloride ________________ ~ _________._______________ ~ ______________ ethyl ~ 4-ph ~ nyl [4HJ 1,3-benzodioxin-2-carboxylic (mixture of ____________________________________.___________________________ racemates ~.
_________ 9.1 g of the mixture of racemates diasteraoiso- are mixed.
mothers of 6-chloro acid 4- [~ 1,1-dimethyl ~ ethyl] 4-phenyl L4H ~
1,3-benzodioxin-2-carboxylic prepared as indicated in the example 25 and 100 ml of anhydrous benzene.
We then add progressively by maintaining at room temperature 3.7 ml of tri ~ thylamine, then drop to drop a solution of 6.2 g of thionyl chloride in 25 ml anhydrous benzene, refluxed for three hours, cooled said up to room temperature, wring and wash the precipitate in anhydrous benzene, collects the filtrate and concentrates the solution under vacuum until a volume of solution of 30 ml is obtained.
Stage B Isomer A of 6 chloro 4- r ~ l, l-dim ~ thyl) ethyl ~ 4-phenyl ~ 4H ~ methyl 1,3-benzodioxin-2-carboxylate.

~, ____________________________________________________________ Mixed with stirring 3 ml of methanol, 50 ml of anhydrous benzene, 3.7 ml of triethylamine, cools juice ~ u'à
15-20C, add drop ~ drop ~ this temperature, the solution o ~ held at stage A above to which was added ~ 30 ml of anhydrous benzene, stirred for sixteen hours at temperature - ambient, drain and wash the precipitate with anhydrous benzene.
The filtrate is concentrated in vacuo and 6.5 g of crude product which is chromatographed on a silica column eluting with a mixture of ethyl ether and petroleum ether (Eb.

60 80C) (20 - 80) and obtains after Splitting then evaporation of the solvent the crude expected product which is crystallized read in 20 ml of methanol and obtain after s ~ chage the expected product.
F 85C.

.
; `-44-. :

3 ~ d ~ S

Analysis: C2oH21Cl O4 Calculates: C ~ ~ 6.57 H ~ S, 87 Cl ~ 9.82 Found: 66.5 6.0 10.0.
NMR (deuterochloform) (base frequency: 60 MHz).
~ dimethyl) ethyl ~ 62 Hz - COOCH3 at 117 Hz - hydrog ~ ne in position 2 d 338 Hz - aromatic: peaks from 412 to 468 Hz.
Example 26: Acid 6-fluoro 4 methyl ~ 1 L ~ 71,3-benzodioxin-2-carboxylic_ (mixture of diastereoisomeric racemates? ._ We mix, under an argon atmosphere, 26 g of hydride sodium, 350 cm3 of anhydrous dioxane, I, 55 g of diben20-18 crown-6, add in an hour, a solution of 16.5 cm3 of acid dichloroacetic in 150 cm3 of dioxane, pUi5 at the end of the reaction, add in an hour at 22C, a solution of 31 g of ~ -phenyl ~ -methyl ~ 5-fluoro 2-hydroxy) phenyl methanol in:
150 cm3 of anhydrous dioxane, heated to 80C, stirred for six hours: ~
at 80-85C, cools, pours over a galce-water mixture, extract at ether, acidifies the aqueous phase, extracts the aqueous phase to 20- ether, wash the ~ phase with water, extract with bicarbonate of sodium the ethereal phase, washing with methylene chloride, acidifies the alkaline phases, extracted with methylene chloride, wash with water, dry on sul ~ ate of magnesium and bring to dry under empty. 29.5 g of crude expected product are obtained (sou ~ form of an oil).
NMR
- hydrogen in position 2 at 310 Hz and CH3 at 117 Hz (peak corresponding to the A isomer of the acid obtained), - hydrog ~ ne in position 2 at 339 Hz and CH3 at 1 ~ 6 Hz ~ peak corresponding to the B isomer of the acid obtained), - aromatics from 400 to 450 Hz - OH at S05 Hz.
I

~; 45 ~!

3 ~ i85 The ~ -phenyl ~ -methyl t5-fluoro 2-h ~ droxy) ph ~ nyl methanol used from the above preparation, has been prepare ~ as follows:
Mixed, under argon atmosphere, with stirring, 13.3 g magnesium in turnings, 50 cm3 of anhy ~ re ether, then slowly a solution of 34.7 cm3 of methyl iodide in 250 cm3 of ether anhydrous, then heats for one hour at reflux. Then we add 220 cm3 of this ~ magn ~ olution obtained, to a solution 30 g of ~ -phenyl ~ 5-fluoro 2-hydroxy) phcnyl rnethanone in 150 cm3 of anhydrous benzene, distills the ether while replacing it rubbing with anhydrous benzene, then stir for four hours at about 70C, cools, pours over a chloride solution of ammonium, extracted with ether, washed with water, dried over sulphate magnesium and brings to dry vacuum. 32 g of product are obtained expected gross.
We recrystallize a sample of this product in the cyclohexane. F 122C.
ANALYSIS: C14 ~ 13F ~ 2 Calculation ~: C% 72.40 H ~ 5.64 F% 8.18 20 - Finds: 72.4 5.6 8.2 ~
Example 27 Isomer A of 6-fluoro 4-methyl 4- ~ h ~ nyl F4H] 1,3-benzodioxin-2-car ~ Methyl joxylate ~.
- We mix by stirring 29.5 g of the racemate mixture dice 6-fluoro 4-methyl 4-phanyl ~ 4H¦1,3-benzodioxin-2-carboxylic obtained in example 27, 300 cm3 of methanol, 130 g acid resin, door and hand ~ ient to reflux for 24 hours.
It is cooled, treated with activated carbon, filtered, rinsed with methanol, brings to dry, resumes with ether, washing the ether phase ~ e by three 200 cm3 of bicarbonate then with water, dried over sulphate magnesium, brings to dryness under vacuum and obtains 23 ~ 8 g of product crude which is taken up in 200 cm3 of methanol. We get 5 g of product which is recrystallized ~ 20 cm3 of methanol. We 6_ . ~ j 36s 4.4 g of expected product is obtained. F 95C.
Analog: C17H15 4 Calculated: C% 67.54 H% 5.00 F ~ 6.2B
Found: 67.7 5.0 6.2 NMR (deuterochloroform) (frequency of the device: 90 MHz) - CH at 171 Hz - COOCH3 at 345 Hz - hydrogen in position 2 ci 4 ~ 3 Hz - aromatic: peaks from ~ 15 to 6 ~ 0 Hz.
Example 28: Isom ~ re A of 6-chloro 4 methyl 4 ~ phen ~ 1 L4H; 1 3 ~ 2,2-dimethyl 1! 3-dioxolan ~ 4-yl benzodioxin-2-carboxylate?
methyl.
Stage A: chloride of the A-isomer of 6-chloro acid ___________ = _________________________________________ 4-methyl 4-phenyl [~ HJ 1,3-benzodioxin-2-car ~ oxyliq ~ e.
_________ _ ~ ____ ______________ _ 4.9 g of isomer A of the acid are mixed by stirring 6-chloro 4-methyl 4-phenyl 4H 1,3-benæodioxin-2-carboxylic obtained in Example 3, 50 ml of anhydrous benzene, cools down to 10C, add dropwise at this temperature I, 66 g of triethylamine. Then add at this temperature and drop - ~
drop a solution of 2.5 g of thionyl chloride in 25 ml of anhydrous benzene, then the mixture is brought to reflux for two hours. We cools the suspension to room temperature, wring out the precipitate t and collects the filtrate which contains the expected product.
Stage B: Isomer A of 6-chloro 4-methyl 4-phenyl ~ H] 1,3-____________________________________________________________ ~ 2,2-dimethyl ~ benzodioxin-2-carboxylate ~ 3 ~ dioxolan-4-yl) ___________________________ ~ _________________________________ methyl.
_______:

2.25 ~ of (2,2-dim ~ thyl 1,3-) is mixed by stirring dioxolan-4-yl) m ~ thanol, 50 ml of anhydrous benzene 2.3 ml of triethylamine, add drop ~ drop at room temperature on filtrate, collected in stage A above. We stir twenty hours at room temperature. Filter, wash the filtrate with a sodium carbonate solution ~ 10%, then wash with water until ~

~ a ~ -47 ~
. .

~ 33 ~ 5 .
neutral pH.
The benzene phase is dried over calcium chloride and treats with activated carbon, evaporates the solvent under vacuum, obtains 4.5 g of crude product which is chromatographed on a column of silica, ~ glowing with methylene chloride. We get, after fractionation, 2g of expected raw product, in the form of a colorless gum.
C22H23O6Cl analysis Calculated: C% 63.08 H% 5.53 Cl ~ 8.46 Found: 62.0 5.5 8.9 NMR (deuterochloroform) ~ base frequency of the device:
60 MHz - CH3-2,2-dimethyl dioxolan at ~ 81- ~ 2 ~ Iz - CH in position 4 at 115 Hz, - COO-CH2-fH- ~ H2 from 215 to 260 Hz 'OO ~' - aromatic from 411 to 441 Hz EXAMPLE 29 Hydrochloride of Isomer A of 6-chloro 4-methyl 4- h ~ nyl r4 ~ t 1,3-benzodioxin-2-car ~ 2- (diethylamino) oxylate P _ _ _ ~ thyle.
We bring to reflux under nitrogen ~ re ~ stirring a mixture of 6.2 g of isomer A of 6-chloro 4-methyl 4-phenyl 4H
Methyl 1,3-benzodioxin-2-carboxylate obtained as indicated - In Example 16, 100 ml of anhydrous toluene and 2.6 g of di ~ thyla mino ethanol e ~ a tiny amount of sodium hydride. We maintains at reflux for three hours, cools adds 5 ml of a solution of hydrochloric acid 4N in ether ~ adds 200 ml anhydrous ether, fi.ltre, wash ~ l! ether, dry and obtain 3.7 g of product which is taken up in 20 ml of isopropanol at 60C, treated with activated carbon, cooled to ~ 50 ml dlether, ~ ilter, dry and obtains 2.7 g of the expected product. F 110C.
Analysis: C22H27C12N4 .

36 ~ 5 .
: ~ Calculated: C ~ 60.00 H% 6.18 Cl% 16.10 N ~ 3.18 Found: 59.6 6.4 15, 3.4 g Example 30: 6-chloro 4-ethyl 4-phen acid ~ l ~ H ~ 1,3-benzodioxin-2-carboxylic ~ melan ~ e of the two racemates diaster ~ isomers) 250 cm3 of liquid ammonia are mixed with stirring that we condensed, with 100 mg in ~ ron of ferric nitrate, 4.8 g of sodium which is added in small fractions, add then in one hour thirty minutes below -28-30C a solution 26.2 g of 5-chloro ~ -ethyl 2-hydroxy ~ -ph ~ 7nyl benzene methanol in 200 cm3 of anhydrous toluene, increases the temperature and flushes ammonia releases ~ refluxing for three hours, : add 100 cm3 of toluene and at 50C, 18 g of dichloroacetate potassium, keep reflux overnight and add 9 g of potassium dichloroacetate, stirred for another two hours at reflux, cools, pours into water, removes organic phase, acidifies the aqueous phase and the ether extract, wash the ethereal phase with three times 500 cm3 of water, extract the ethereal phase three times 300 cm3 of sodium bicarbonate, washed twice 500 cm3 ether, acidifies the aqueous phase with hydrochloric acid 20 concentrate, extracted with three times 500 cm 3 of ether, washing with -.:
water, dry over magnesium sulfate, am ~ ne ~ dry under vacuum and obtains 27 g of crude expected product.
5- chloro ~ -ethyl 2-hydroxy ~ -phenyl benzene methanol, used at the start of the preparation of the product of Example 31 above can be prepared ~ as shown in Example 23, but by using ~ instead of isopropyl bromide of iodide of ethyl. F.-85Co Example 31 Isomers A and B of 6-chloro 4-eth ~ l 4-p ~ enyl .
1,3-benzodioxin-2-carbox ~ late from m _ yle.

We used for the preparation and isolation of the two . diastereoisomeric racemates A and B of 6-chloro 4-ethyl 4-ph ~ nyl L4H ~ 1,3-benzodioxi.n-2- methyl carboxylate, from the mixture ``
i! the '~ /'', ~ 7 s isomers A and B of the corresponding acids, mixture obtained 3 example 31, the same technique as that described in example 20..
There was thus obtained, from 26 g of the mixture of isomers A and B obtained in Example 31.
4.5 g of isomer A expected, which is recrystallized from m ~ thanol at reflux. 3.5 g of the expected isomer A are obtained.
purified. F 128C.
Analysis: C18H17C 4 .10 Calculated: C% 64.96 H ~ S, 15 Cl% 10.65 Found: 65.0 5.2 10.4 NMR spectrum ~ deuterochloroform) (base frequency: 60 MH ~) - ~ thyLe in 4 to 44 - 51 - 58 Hz 110 to 160 Hz, - COOCH at 232 Hz, - hydrogen in position 2 at 314 Hz, .-. - 1,3-benzodioxine ring aromatics from 415 to 450 Hz, - phenyl at 4 to 445 Hz, and 4 g of isomer B expected. F 10 ~ C.
. .
Example ~ 2 D 6-chloro acid 4- ~ 4-chlorophenyl) 4-methyl ~ 4H] 1,3-benzodioxin-2-carboxyli ~ eu (mixture of two racemates diaster ~ o-isomers) -. 250 cm3 of dioxane, 1.6 g are mixed with stirring of dibenzo-18 crown-6, 25 g of sodium hydride, then in 45 minutes, a solution of 16 cm3 of dichloroacean acid is added-tick dani 100 ~ n3 of dioxane, then in one hour, we add to 30C, a solution of 36.6 g of 5-chloro 2-hydroxy ~ - methyl d ~ - (4-chlorophenyl) benzene methanol in 150 cm3 of dioxane, heats to 80C for five hours, cools, pours on a mixture of ice and: water, extracted three times 500 cm3 ether, acidifies] .a aqueous phase with hydrochloric acid .
~ 5o_.

~ :. ; ,,. . : ~ .:.

~ 33 ~ 35 .
concentrated, extracted with three times 500 cm3 of ether, extracts the ethic phase ~ bicar ~ sodium onate ~ acidiEie phase aqueous and extr ~ it with four times 300 cm3 of ether, washed with water, dried over magnesium sulfate, brought to dry vacuum, and obtained 40 g of expected raw product.
NMR spectrum (deuterochloroform) (base frequency: 60 MHz) - hydrogen in position 2 at 309 Hz, - CH at 116 Hz, This corresponds to ~ one of the expected isomers ~ isomer A) - hydrogen in position 2 ~ 340 Hz, - CH3 at 124 Hz This corresponds to the other expected isomer 'isomer ~ e B) - aromatics from 405 to 445 H ~, - OH at 510 Hz.
5-chloro 2-hydroxy d ~ -methylo ~ - (4-chlorophenyl) benzene methanol used from the above preparation can be prepared as follows:
One mixes under magnetic stirring and under atmosphere argon:
. 13.5 g of 2-hydroxy 5-chloro acetophenone ~ 130 cm3 anhydrous ether, cooled externally by a water bath frozen, introduced drop by drop while maintaining the temperature between 10 and 20C: 330 cm3 of an ethereal solution, - freshly prepared and filtered from magn ~ sien l-chloro 4-bromobenzene titrating 0.46 Mole / liter, keeps stirring overnight at room temperature. We ice the yellow suspension and introduced drop ~ ea drop 125 cm3 of aqueous hydrochloric acid 2N ice-cold, d8cante, wash the organic phase with water ~ ur ~
soaium, treated with activated carbon, wring and brings to dryness, empty SVU5 ~
the residue is dissolved in 100 cm3 of cyclohexane and left crystallize with stirring, wring the pr ~ cipite, paste it by a little cyclohexane, dries it in an oven and obtains 19.3 g of I` ~ -51 ~

:.

aY ~ s expected product. F -130C.
Analysis: CHO Cl Calculated: C ~ 59.38 H% 4.27. Cl% 25.04 Found: 59.7 4.3 24.7 Example 33: Isomer A of 6-chloro 4- (4-chlorophenyl) 4-methyl .
L4H] 1 3-Benzodioxin-2-car ~ methyl oxylate.
40 g of the mixture of diastereois racemates are mixed 6-chloro 4- (4-chlorophenyl) 4-methyl ~ 4H ~ 1,3- acid mothers benzodioxin-2-carboxylic, mixture as obtained in Example 33, 400 cm3 of methanol, 180 g of strong sulfonic resin, stirred at reflux for eighteen hours, cools, spins, washes four times with 300 cm3 of ether, am ~ not dry under vacuum, resumes the residue with 500 cm3 of ether, washed with three times 300 cm3 of sodium bicarbonate, then four times 500 cm3 of water, dry on magnesium sulphate, am ~ does not dry under vacuum and obtains 35.5 g of product. The product obtained is treated with 100 cm3 of methanol, leave overnight at room temperature, spin dry, wash with iced methanol, obtains 10 g of product which is recrystallized in 60 cm3 of methanol, left overnight at room temperature, and obtains 9.1 g of the expected isomer A F = 108C.
Analysis: C17H14C12 4 Calculated: C ~ 57.81 H% 4.0 Cl ~ 20.0 Found: 58.0 4.0 19.9 NMR spectrum (deuterochloroform) (base frequency: 60 MHZ) - CH3 at 115 Hz - COOCH3 at 231 Hz - hvdroclane in position 2 at 308 Hz - aromatics from 412 to 442 Hz.
xample 34: 6-chloro 4-meth acid 1 4- hén 1 r4H ~ 1,3-benzodio-_ - YPYLI
xin-2-carboxyli ~ eu (mixture of the two diastereoisomeric racemates ~
4 g of sodium amide, 50 ml of tolu ~ are mixed anhydrous, add drop by drop at room temperature, one I

f -52-a ~
1. ~. ~. ... .

~ 3 ~ 3S

9.95 g solution of 5 ~ chloro 2-hydroxy ~ -methyl ~ -phenyl benzene methanol in l0 ml of anhydrous toluene. We wear the mix at reflux for six hours, cool to temp ~ ra-ambient, introduced 10.25 q of potassium dibromoacetate, again refluxed for six hours, cooled and taken up in 200 ml of water, decanted, extracted the organic phase by twice 80 ml of water, wash the aqueous phase twice with 80 ml ether, acidify the aqueous solution with 40 ml of chlorhy-drique 2N.
A precipitate is formed which is extracted three times 100 ml of ether. The organic phases are washed twice 80 ml of water, re-extracts the expected acid three times with 50 ml of a saturated aqueous 5% sodium bicarbonate solution.
The aqueous extraction phase is washed three times 80 ml of ether, the alkaline solution is acidified with 90 ml of a 2N hydrochloric acid solution. The expected acid is extracted per four times 100 ml of ~ ther. The organic phase is washed with water, dried over magnesium sulfate in the presence of charcoal active, eliminates the solvan ~ under vacuum, obtains 7.85 g of product crude which is taken up in hexane. We ~ ssore and dry -the crystals obtained, and obtains 6 g of the expected product.
F; _ 144C.
NMR ~ deuterochloroform) (base frequency: 60 MHz) CH3 at 117 Hz - hydrogen in position 2 at 312 Hz ~ corresponding to isomer A) - IEC3 at 125.5 Hz - hydrogen in posi ~ ion 2 at 342.5 Hz tcorresponding to isomer B) - aromatic from 405 to 450 Hz - OH at ~ 350 Hz.

Example ~ 5: 6-chloro 4-methyl 4-ph acid ~ nyl ~ 1,3-benzodio-xin-2-carboxylic (mixture of the two ereoisomeric diem racemates).

. -53-:. . :::. . .:
:. .,. ...
::,,. . ,.:.::.

~ 36 ~ 3 ~
We mix ~ 10 cm3 of dioxane, 1.35 g of sodium hydride 50 ~ in the oil; at 15C, add: 60 mg of dibenzo-18 crown- ~ then in five minutes, 0.61 cm3 of dichloroacid tick and 10 cm3 of dioxane.
1.25 g of 2- are introduced over ten minutes at 20C
hydroxy 5-chlvro ~ -methyl benzhydrol and 5 cm3 of dioxane.
We then heat for six hours around 80C, then cools to 20C, adds 2 cm3 of methanol, pours into water ice cream extracted three times with ethyl c ~ tate, washing five times with ice cold 0.1N sodium hydroxide. We reunite the aqueous phases, acidifies them to pH 1 with a solution 2N hydrochloric acid, extracted three times with chloride methylene, dries and brings to dryness and collects the expected product gross.
EXAMPLE 36 Piperidine salt of the A-isomer of 6-chloro acid 4-methyl 4-phenyl [4H ~ 1,3-benzodioxin-2 ~ carboxyl_que.
The mixture of the two diastereois racemates is dissolved.
6-chloro 4-methyl 4-phenyl acid ~ 4H ~ 1,3-benzodioxin- mothers 2-carboxylic obtained in Example 36 above in 4 cm3 unlaced-ethyl tate, add at 10C, 0.8 cm3 of piperidine. Salt expected piperidine crystallizes by scraping. We spin after 15 minutes, wash with ethyl acetate, with ether, dry at 20C
under vacuum and obtains 855 mg of the expected product.
The crystallization mother liquor is collected and the diluted with methylene chloride, washed with hydrochloric acid N
dry iced and brings to dry, takes up the residue with 12 cm3 of methylene chloride and add 0.6 cm3 of eth ~ trifluoride spleen of boron let stand for half an hour at 20C, pour on ice, washed twice with water, re-extracted with methylene chloride, dry and bring to dry, take up in 2 cm3 of ethyl acetate and 0.4 ~ cm3 of piper: idine, leaves to crystallize and isolates 545 g of expected product. A new operation carried out in the same way "~

11. ~ 4 ~ 3 ~
way, from the mother liquor of crystallization (isomerization with boron trifluoride, addition of piperidine) allows collection ~ ir another 130 mg of expected product. So we have obtained a total of 1.53 g of the expected product. F _ -165C.
EXAMPLE 37 Isomer A of 6-chloro 4-methyl 4- ~ henyl acid r4H11,3 -benzodioxin-2-carbox li ue.

.L ~ - Y, q.
The 1.53 g of the piperidine salt obtained is taken up in Example 37 above, with a mixture of methylene chloride and hydrochloric acid N, washes, dries, treats with activated carbon, concentrated by adding cyclohexane up to a volume of 3 cm3, spin dry, wash with cyclohexane, dry at 40C under vacuum and obtain 1.1 g of expected product. F = 175 C.
This product is identical to isomer A as obtained in Example 3.
Example 38:
_.
Tablets with the formula have been prepared next:
-Acid 6-chloro 4-methyl 4-phenyl ~ 4H ~ 1,3-benzodioxin-2-carboxylic (as isomer A) ~ O ~ 300 mg - - Excipient qs for one finished tablet-a .............. 500 mg.
(Details of excipient: lactose, starch, talc, stearate magnesium.) Example 39:
We have pr ~ by ~ capsules corresponding to the formula next:
- 6-chloro 4-m ~ thyl 4 ~ phenyl [4H] 1,3-benzodioxin-2-methyl carboxylate (as isomer A) ................ 25 mg - Excipient qs for one capsule ~ terminated at ..Oo ... 500 mg (Details of excipient: talc, magnesium stearate, aerosil).

Example 4 ~: Tablets corresponding to the formula were prepared:
- Isomer A as obtained in Example 20 ......., ............... 300 mg - Excipient qs ~ for one tablet, finished at ~ ..... ............. 500 mg I

.. ¢ ~
~, ",, j ~

-:. -:,. . - ...:.
,,,. ~. ~, ''; . ''. ;;, '....' s ~ Details of the excipient: talc, magnesium stearate, aerosil).
Example 41:
We prepared capsules r ~ laying the ormule general:
- Isomer d as obtained in Example 17 ............. 250 mg - Excipient qs for a gelule finished at ....... ~. 500 mg (Detail of the former container: talc, mangesium stearate, aerosil).
Pharmacological study 1. Determination of acute toxicity ~
Acute toxicity was determined on batches of 5 mice weighing from 18 to 22 g. The product was administered in suspension in carboxymethylcellulose by in ~ rap ~ ri ~ oneal.
The animals were kept under observation for one week;
The lethal dose 50 (LD 50) was determined and the following results:

Product of example LD 50 / mg ~ Kg _,. .. _ 1 to 130 3,159 15 Isomer A ~ 800 . . ._. - .. ..., 16 Isomer A r_ 200 . ~. _ 17 Isomer A
form 1 ~~ 250 . . ._ ~ -. . . .. ....... __ ~ 9 Isomere AC 1000 _. .,. ,. , _ 20 Isomer A _ ._ 2. Determination of the action hemipemiant:
______________._________________________ The study was carried out on batches of 8 male rats of che Sprague Dawley SPF, weighing approximately 200 g.

The animals receive a diet which. contains 50% of saccharos ~ st which is enriched in cholesterol ~ 1 ~). They are treated for ten days with the product to be tested ~ i is administered in suspension ~ ion in water with carboxymed-thylcellulose, by esophageal probe.
The animals are kept on an empty stomach for 16 hours after last administration of the product, then bleeding by puncture abdominal and on blood taken from sodium heparinate, realizes dosages of triglycerides, cholesterol and lipids totals using the following methods:
- Dosage of tri ~ lycérides:
(Semi-automatic determination) technique of - G. KESSLER and H. LEDERER, Automation in Analytical Chemistry, New-York, 341 (1965), modified by JR CL ~ UDE and F. CORRE, Ann.
~ iol. Clin. 26, 3-4, 451 11968);
- Determination of cholesterol:
.
Technique by J. LEVINE, Sy, Technicon 1967 symposium, Vol.

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

-i Nephelometric dose of total lipids:

Semi-automatic determination by HC GIRARD, ... ..
J. CANAL, J. DELATTRE and J. PEYNET, Technicon Symposium 1970, Paris.
Variations were determined (expressed as percentages) triqlyceride, cholesterol and total lipid levels after administration of different doses of a ~ ester product, in treated animals compared to control animals.
The following results were obtained:

.

I _ ~ 7 ~

.. ~
. .

:; . . ,.:
. ~

6 ~ 35 .
... _ `. ".. _.
Product of the example Doses Variation% of the rate of _ mg / kg / ~ _ _ _ Trigly- Choles- Lipids total terol cerides . ... __. .

. ~ .., _.A_.

. ... .. _ 15 Isomer A 2 ~ 32 -17 -25 . . . ... .
16 Isomer A 2 -57 -43 -47 _ _. _ . 17 Isomer A.
shape 1 2 -53 -47 -53 . . . . ._ ~ 9 Isomer A 1 -13 -36 -32 . . . . _.
20 Isomer A -62 -11 -25 _ ~ 8-1 'Y''.

36 ~ 5 ADDITIONAL DISCLOSURE

The purpose of this additional disclosure is to to illustrate with new examples the general formula I ' described in the main application and, in particular, certain values of the substituents R'l and R5.
More specifically, the invention of supplemental disclosure mental ~ ise of new drifts corresponding to the formula gen ~ -rale I ', which are:
- 7-chloro 4-methyl 4-phenyl ~ 4H ~ l, 3-benzodioxin-2-methyl carboxylate, in its racemic or optical forms-mentally active, - 6-chloro 4-methyl 4-phenyl ~ 4H ~ l, 3-benzodioxin-2-2-dimethylaminoethyl carboxylate, under its racemic forms - ques or optically active, as well as its addition salts with pharmaceutically acceptable acids.
The addition salts with acids can be, for example example, the salts formed with hydrochloric acids, bromine-hydric, hydroiodic, nitric, sulfuric, phosphoric, acetic, ~ random, fumaric, succinic, tartaric, aci-nonosulfonic alcohols, such as, for example, acid methane sulfonic, ethane sulfonic acid, propane acid sulfonic, alkyl disulfonic acids, such as, for example, a, ~ - ~ thane disulfonic acid.
The subject of the invention is very particularly the A-isomer hydrochloride of 6-chloro 4-methyl 4-phenyl . f ~ HJ 1,3-benzodioxin-2-carboxylate of 2-dimethylamino ~ thyle, such ~ u'obtenu below in the exp ~ rimentale part.
.We designate by the term "isomer A" one or the other of the two racemic diastereoisomeric forms of the products of formula I 'which have two asymmetric carbons.
7-ch: Loro 4-methyl 4-phenyl ~ 4H ~ l, 3-benzodioxin-2-methyl carboxylate, object of the invention, is prepared by G ~ - 59 days.
, ~.
t ~ 36 ~ 35 a process characterized in that one makes r ~ act 4-chloro 2-hydroxy a-methyl a-phen ~ l benzene methanol with a salt of alkali metal of dichloroacetic acid, in the presence of a basic condensing agent, to obtain the metal salt corresponding alkaline 7-chloro 4-methyl 4-phenyl acid ~ 4 ~ 1,3-Benzodioxin-2-carboxylic, which is treated with a acid then esterifies the acid obtained by action on this acid of methanol to obtain 7-chloro 4-methyl 4-phenyl ~ 1,3-methyl benzodioxin 2-carboxylate.

The preferential conditions for carrying out the process above dice are those already mentioned in the di: vulgation main.
Chloro 4-m ~ thyl 4-phenyl ~ 4HJ 1,3-benzodioxin-2-2-dim ~ thylamino ethyl carboxylate in its racemic forms ques and optically active as well as its addition salts with the acids are obtained in accordance with the invention by a process characterized in that 6-chloro acid is treated 4-methyl 4-phenyl ~ 4H ~ 1,3-benzodioxin-2-carboxylic or one functional derivative of this acid by dimethylaminoethanol and, if necessary, processes the product obtained with a phar-maceutically acceptable to form the salt then, if desired re, isolate the expected product or salt in racemic form or optically active desired.
The preferential conditions for carrying out the assigned above and, in particular, the isolation of the product under the st ~ reochemical ~ ouhaitée form, are those already mentioned in the ~ main disclosure.
The products obtained according to this disclosure additional have interesting pharmaco-logical: they manifest, notably, a hypoliped activity marked mint; they reduce the plasma levels of lipids, triglycerides and cholesterol.

-. . :. - ~ -. - ..,;,.

36 ~

These properties justify the use in therapy ~ title of m ~ drugs in its racy forms ~ ic and optical-ment-active, 7-chloro ~ -methyl 4-phenyl ~ 4H ~ 1,3-benzo-methyl dioxin-2-carboxylate, as well as 6-chloro 4-methyl 4-phenyl ~ 1,3-benzodioxin-2-2-dimethylamino- carboxylate ethyl and its addition salts with pharmaceutical acids only acceptable, especially hydrochloride of the A-isomer of 6-chloro 4-methyl 4-phenyl ~ 4H ~ 1,3-benzodi-2-dlmethylaminoeth ~ le oxin-2-carboxylate.

All of the products defined above constitute very useful drugs in human therapy, including ment, in the treatment of acute or chronic hyperlipemia, heart failure of atheromatous origin, chronic angina states:
The usual dosage, which varies depending on the product used, the subject treated and the affection in question, can be, for example from 0.05 g to 1 g per day in adults, orally.
The above products can thus be used for prepare pharmaceutical compositions containing, as active ingredient, at least one of the above drugs.

These compositions are made so that they can be administered by the digestive or parenteral route. They .. can be solid or liquid and can be found under pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, lules, granules, suppositories, preparations, in-disposable; they are prepared according to the usual methods, The active ingredient (s) can ~ be incorporated ~

usually excipients. used in these phar-maceuticals, such as talc, gum arabic, lactose, 30 starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal origin or ~ r ~ l 33 ~
vegetable, paraffinic rivets, glycols, various wetting, dispersing or emulsifying agents.
The invention makes it possible to prepare, as a product new industrial, in its racemic or optically active, 4-chloro 2-hydroxy a-methyl a-phenyl benzene methanol.
Finally, it should be noted that the products of formula II from which the products of general formula I 'can be obtained by action within of an organic solvent on a product of formula ~:

/ Oi ~ ' \ C ~ ((B) ,: .. ...
- of a magnesian of formula:
, .
2 0 ~ MtJ -Ha 1 R
- ~ ~ /
.
formulas in which R4 and R5 have the values ~ rs indicated in the main disclosure and Hal represents an atom halogen such as chlorine, bromine, The examples given below illustrate the invention additional disclosure, but not limit it.
EXAMPLE 42 7-chloro 4-methyl 4-phenyl acid ~ 4 ~ 1,3-benzo-dioxin-2-carboxylic (mixture of the two racemates_diastéreo-someres) 9.85 g of sodium hydride in 50% suspension in oil, 100 ml of dioxane, 0.73 g of ether are mixed.
. i, '' ~

J. ~

D3 ~ 85 .

18-crown-6, add ~ ambient tempera-ture, with stirring, a solution of 11.31 g of dichloroacetic acid in 120 ml of dioxane, then add, drop by drop, a colution of 14.550 g of 4-chloro 2-hydroxy ~ -methyl a-phenyl benzene me-thanol in 200 ml of dioxane and carries the mixture for 6 hours 95C, let the mixture cool, pour it over ice, add 10 ml of 2N sodium hydroxide, the ~ e the aqueous phase with 300 ml of ether, acidifies the aqueous phase with 20 ml concentrated hydrochloric acid, extract the acid with three 250 ml of ether, wash the ethereal phase with twice 100 ml of water, extract the acid from the organic phase twice - 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, extracted again the acid with four 250 ml of ether, decanted, washed the phase organic with water three times 100 ml, dried over sulphate magnesium in the presence of activated carbon, filters, removes the solvent under vacuum, obtains 19.5 g of the expected product.
SPECTRUM RM ~ CDCl 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 to 343. Hæ and hydrogen from CH3 in position 4 at 125 Hz (corresponding to the B isomer) 4-Chloro 2-hydroxy ~ -methyl a-phenyl benzene metha-.
nol, used at the start of the above preparation can be prepared as follows: -:
SOU9 is mixed with stirring 16.2 g of 2-hydroxy 4- (chlo-ro phenyl) ~ thanone in 170 ml of ~ ther then introduced, drop to drop, at 20C, 315 ml of a phenyl bromide solution magnesium in ether grading 0.8 mol / liter, leaves under shake overnight ~ room temperature, pour mixture on ice, acidified with 40 ml of acid . i '.

~.
'. , f ; i 936 ~ i hydrochloric acid, extracted by qua-t ~ e times 250 ml of ~ ther, decant, wash the organic phases with four times 150 ml of water, dry the organic phase on magnesi sulfate ~ in the presence of activated carbon, dispersed in 50 ml of cyclohexane, passes to the oven under vacuum for 24 hours and obtains 14.45 g ~ e pro expected product which is recrystallized 0.200 g in cyclohexane.
F = 82C
A ~ ALYSE C14 H13 Cl 2 Calculated: C% 67.61 ~ / 0 5.27 Cl% 14.25 Found: 67.3 5.1 14.3 EXAMPLE 43 Isomer A of 7-chloro 4-methyl 4-phenyl ~ 4HJ
Methyl 1,3-benzodioxin-2-carboxylate.
19.5 g of the mixture of diastereois racemates are dissolved 7-chloro 4-methyl 4-phenyl acid isomers ~ 4 ~ 7 1,3-benzo-dioxin-2-carboxylic acid (obtained in Example 43) in 300 ml of methylene chloride, cools to 15C, adds, drop by drop ~
9.1 g of boron trifluoride etherate, leaves stirring at room temperature for 2 hours, then add 300 ml methanol, lalsse again with stirring overnight, pour over 500 ml of a saturated sodium chloride solution, extracted with three times 200 ml of methylene chloride, wash the organic phase with 50 ml of a saturated aqueous solution of bi-decanted sodium carbonate, wash the organic phase with 50 ml of an aqueous solution ~ saturated with sodium bicarbonate, decanted, wash the organic phase with twice 50 ml of water, (up to nine trality), dry the organic phase over magnesium sulfate in presence of activated carbon, - filter, removes solvent under vacuum and obtains 17.1 g of crude expected product which is recrystallized 16.6 g in methanol, dry and obtain 10.35 g of product expected F = 144C
ANALYSIS: C17 ~ 15 Cl 4 Calculated: C% 64.05 H% 4.74 Cl% 11.12 Found: 63.8 4.7 ~ 11.1 ? ~ -64-~ 36 ~ 5 S CTRE R ~ MN CDC13 60 MHz - Hydrogen in position 2 ~ 310 Hz - Hydrog ~ ne of CH3 in position 4 ~ 115 Hz - Hydrogen from COOCH3 ~ 230 Hz.
. EXAMPLE 44 ChlorhYdrate of the A-isomer of 6-chloro 4-methyl 4-phenyl ~ 4 ~ 2-tdimethyl- 1,3-benzodioxin-2-carboxylate amino ~ ethyl.
We mix ~ 7.1 g of isomer A of 6 chloro 4-methyl 4-phenyl ~ 4H ~ methyl 1,3-benzodioxin-2-carboxylate obtained as indicated below, 2.5 g of dimethylaminoethanol, 100 ml anhydrous toluene and traces of sodium hydride and carries at reflux for 5 hours, cools, treats with activated carbon, filter, collect the filtrate, add 7 ml of a solution to it hydrochloric acid 5 ~ in ether, filter, wring out the pre-Cipity obtained which is recrystallized from 40 ml of isopropanol.
4.8 g of the expected hydrochloride are obtained.
F = 185C.
A ~ ALYS ~: C20 H22 Cl N04 Calculated: C% 58.26 H% 5.62 Cl% 17.20 ~ / 0 3.40 ~ ~ - Found: 58.1 5.9 17.0 3.5 SPECTRUM NMR CDC13 -60 MHz - Hydrogen in position 2 at 312 Hz - COO-C ~ 2-CH2- ~ 285 and 235 Hz hydrogens CH
- Hydrogens of - ~ 172 Hz - ~ ydroglanes of CH3 in position 4 at 115 Hz - Aromatic hydrogens from 411 to 441 Hz The isomer A. of 6-chloro 4-methyl 4-phenyl ~ 4HJ 1,3-methyl benzodioxin-2-carboxylate used from the pr ~ paration above was prepared as shown ~ ~ 1'example 2 of the main disclosure.
, . ~.

7. -65-.
f .. .....

3 ~

a) we a) Tablets r prepared according to the formula:
- Isomer A as obtained ~ naked in Example 43 ..................... 300 mg - Excipient qs for a tablet finished at ~ ................. 500 mg - (detail of the excipient: talc, magnesium stearate, aerosol) b) Capsules corresponding to the formula have been prepared general:
- Isomer A hydrochloride, as obtained from Example 44 ........................... ~ ............. 250 mg - Excipient qs for a capsule terminated at 500 mg (detail of the excipient: talc, mangesium stearate ~
aerosol).
Pharmacological study 1) Determination of acute toxicity:

Acute toxicity was determined on lots of 10 mice weighing from 18 to 22 g. The product was administered in suspension in carboxymethylcellulose by intraperi tonal.
, The animals were kept under observation for one week.
The lethal dose 50 (LD 50) was determined and obtained following results:

_ _.
~ Product of the example: DL 50 ~ m ~ Kg _ 200 '' `~ ~`.
2) Determination of the lipid-lowering action:

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

.
~ 66-~ ':

The animals receive a diet which contains 50% of sucrose and which is enriched in cholest ~ rol (1% ~. They are treated for 10 days with the product ~ te ~ ter which is ~
ministré suspended in water with added carboxymethyl-cellulose, by esophageal probe.
The animals are kept on an empty stomach 16 hours after the last administration of the product, then bleeding by sanding abdominal tion and on the blood pr ~ raised on sodium heparinate, ~ triglycerides ~ wrinkles, cholesterol and total lipids according to the following methods:
- Triglyceride dose:
(Semi-automatic determination) technique of G.
KESSLER and H. LEDERER, Automation in Analytical Chemistry, New-York, 341 (1965), modified by JR CLAUDE and F. CORRE, AnnO Biol. Clin. 26, 3-4 451 (1968) . - Dosaq ~ _ u cholesterol:
Technique by J. LEVINE, Symposium Technicon 1967, Vol.
I, 25, adapted to the self-analyzer system I;
- Dosa ~ e néphél ~ metrigLue of total lipids:

Semi-automatic determination by HC GIRARD, J.
CANAL, J. DELATTRE and J. PEYNET, Technicon Symposium 1970, Paris.
. We determined ~ the variations (expressed in percent, - ~
-tages) triglyceride, cholesterol and lipid levels totals after administration of different ~ does of product to test, in the treated animals compared to the control animals.
The following ~ r ~ results were obtained:
... . ..

68 ~

-, I
(Product of ~ oses m ~ / Kg:% change in the rate of :
(example: / day,: Triglycerides: Cholesterol: Lipid ~ s totau ~
__________ .________.___________________________________________ ~
:
(44: 5: -43: -40: -49 , (::,:,:. _. 1 .
. . '~. '~

;,.

;:
,:.
,, ~ ' . I.

~ -6 ~.

Claims (76)

The embodiments of the invention, about which an exclusive right of property or privilege is claimed, are defined as follows: 1. Process for the preparation of 1,3-benzo- derivatives dioxin, corresponding to general formula I ':

(I ') in which R'1 represents a hydrogen atom, a radical alkyl containing from 1 to 5 carbon atoms, a 2,3- radical dihydroxypropanyl, a radical (2,2-dimethyl 1,3-dioxolan-4-yl) methyl or a dialkoylaminoalkyl radical whose radicals alkyls contain 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, a radical alkyl containing 1 to 5 carbon atoms or a radical phenyl, R2 and R3 cannot, however, represent simultaneously-ment a hydrogen atom, and R4 and R5, identical or different, each represents 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 alkali, alkaline-earthy, aluminum, ammonium and amines pharmaceutically acceptable products of formula I 'in which R'1 represents a hydrogen atom and addition salts with acids pharmaceutically acceptable products of formula I 'in which R'1 represents a dialkoylaminoalkyl radical, characterized in that:
a) reacting a product of formula II:

(II) in which R3, R4 and R5 are defined as above, with an alkali metal salt of a product of formula III:

(III) or with an alkali metal salt of a product of formula III ':

(III ') formulas in which R2 has the above meaning and Y
represents a bromine or iodine atom, in the presence of an agent of basic condensation and obtains an alkali metal salt of a acid corresponding to a product of formula I ', in which R'1 represents a hydrogen atom, salt which, if necessary, it is treated with an acid to obtain the acid of formula I ', corresponding; and b) if necessary, salifies the acid obtained of formula I ' in which R'1 represents a hydrogen atom, to obtain an alkali, alkaline earth, aluminum, ammonium or pharmaceutically acceptable amine; or c) if necessary, subject the acid obtained of formula I ' in which R'1 represents a hydrogen atom, to the action of diazomethane in an organic solvent to obtain a product of formula I 'in which R'1 represents a radical methyl; or d) if appropriate, esterifies the acid obtained of formula I 'in which R'1 represents a hydrogen atom, or a derivative functional of this acid, with an alcohol of formula R'1 OH in which R'1 represents an alkyl radical containing from 1 to 5 carbon atoms, a 2,3-dihydroxypropanyl radical, a radical (2,2-dimethyl 1,3-dioxolan-4-yl) methyl or a dialkyl radical-aminoalkyl of which the alkyl radicals contain from 1 to carbon atoms; and e) if necessary, processes the ester obtained with formula I 'in which R'1 represents a dialkoylaminoalkyl radical, with a pharmaceutically acceptable acid to form the salt corresponding addition; or f) if necessary, processes the ester obtained from formula I 'in which R'1 represents a radical (2,2-dimethyl 1,3-dioxolan-4-yl) methyl, by a hydrolysis agent to obtain the corresponding product of formula I ', in which R'1 represents feels a 2,3-dihydroxypropanyl radical, and g) if necessary, isolate the product obtained from formula I 'in racemic or optically active form, or in of a mixture of these isomers. 2. Method according to claim 1, for the preparation ration of derivatives corresponding to general formula I:

(I) in which R1 and R2, identical or different, represent each a hydrogen atom or an alkyl radical containing 1 to 5 carbon atoms, R3 represents a hydrogen atom, a alkyl radical containing from 1 to 5 carbon atoms or a radical phenyl, R2 and R3 cannot, however, represent simultaneously-ment a hydrogen atom, and R4 and R5, identical or different, each represents 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 alkali, alkaline-earthy, aluminum, ammonium and amines pharmaceutically acceptable products of formula 1 in which R1 represents a hydrogen atom, characterized in that:
a) reacting a product of formula II:

(II) in which R3, R4 and R5 have the abovementioned meaning, with an alkali metal salt of a product of formula III:

(III) or with an alkali metal salt of a product of formula III ':

(III ') formulas in which R2 and Y have the abovementioned meaning, in the presence of a basic condensing agent and obtains a alkali metal salt of an acid corresponding to a product of formula I, in which R1 represents a hydrogen atom, salt which, if necessary, is treated with an acid to obtain the acid of formula I, corresponding; and b) if necessary, salifies the acid obtained from formula I in which R1 represents a hydrogen atom, to obtain an alkali, alkaline earth, aluminum, ammonium or pharmaceutically acceptable amine; or c) if necessary, subject the acid obtained of formula I
in which R1 represents a hydrogen atom, to the action of diazomethane in an organic solvent to obtain a product of formula I in which R1 represents a radical methyl; or d) if appropriate, esterifies the acid obtained of formula I in which R1 represents a hydrogen atom, or a derivative functional of this acid, with an alcohol of formula R1OH in which R1 represents an alkyl radical containing from 1 to 5 carbon atoms; or e) if applicable, submit a product of formula I
in which R1 represents a hydrogen atom or a radical alkyl containing from 1 to 5 carbon atoms and R4 or R5 or R4 and R5 represents a chlorine atom, to the action of hydrogen in the presence of a catalyst to obtain the product of formula I
correspondent in which R4 and R5 represent a hydrogen atom uncomfortable; and f) if necessary, isolate the product obtained of formula I
in racemic or optically active form, or in the form of a mixture of these isomers. 3. Method according to claim 2, characterized in that a product of formula is reacted II in which R3 represents a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 represents a hydrogen or chlorine atom, with a salt of alkali metal of a product of formula III or III ', formulas in which R2 represents a hydrogen atom or a radical methyl and Y has the above meaning, in the presence of an agent of basic condensation and obtains an alkali metal salt of a acid corresponding to a product of formula I, in which R1 represents a hydrogen atom and R2, R3, R4 and R5 are defined as above, salt which, if necessary, is treated with an acid to obtain the acid of formula I, corresponding, acid that, if necessary, be salified for a salt alkaline, alkaline earth, aluminum, ammonium or amine pharmaceutically acceptable, either subject to the action of diazomethane in an organic solvent or treated, under form of acid or functional derivative, by methyl alcohol to obtain a product of formula I in which R1 represents a methyl radical and R2, R3, R4 and R5 are defined as above, and, if necessary, isolate the product obtained under racemic or optically active form, or as a mixture of these isomers. 4. Method according to claim 2, characterized in that a product of formula is reacted II in which R3 represents a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 represents a chlorine atom, with an alkali metal salt of a product of formula III or III ', formulas in which R2 represents a hydrogen atom and Y has the meaning above, in the presence of a basic condensing agent and obtains an alkali metal salt of an acid corresponding to a pro-duit of formula I, in which R1 represents a hydro-gene and R2, R3, R4 and R5 are defined as above, salt that, the if necessary, it is treated with an acid to obtain the acid of form mule I, corresponding, acid which, if necessary, is salified for an alkaline, alkaline earth, aluminum, ammonium or of pharmaceutically acceptable amine, either subject to the action of the dia-zomethane in an organic solvent or treated, in the form of acid or a functional derivative, with methyl alcohol to obtain a product of formula I in which R1 represents a methyl radical thyle and R2, R3, R4 and R5 are defined as above, and, if applicable if necessary, isolates the product obtained in racemic form or optically active, or in the form of a mixture of these isomers. 5. Method according to claim 2, characterized in that that we react the 5-chloro 2-hydroxy .alpha.-methyl .alpha.-phenyl benzè-does methanol with potassium dichloroacetate in the presence of a basic condensing agent, to obtain 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate of potassium which is treated te with an acid to obtain 6-chloro 4-methyl 4-phenyl acid [4H]
1,3-benzodioxin-2-carboxylic acid, in the form of a mixture of isomers racemic. 6. Method according to claim 5, characterized in that that we isolate the A-isomer of 6-chloro 4-methyl 4-phenyl acid [4H] 1,3-benzodioxin-2-carboxylic obtained. 7. Method according to claim 6, characterized in that that the A-isomer of 6-chloro 4-methyl 4-phenyl [4H] 1,3-ben-zodioxin-2-carboxylic is resolved into its optical enantiomers of and l. 8. Method according to claim 5, characterized in that that we isolate the B-isomer of 6-chloro 4-methyl 4-phenyl acid [4H] 1,3-benzodioxin-2-carboxylic obtained, which is then resolved in its optical enantiomers d and l. 9. Method according to claim 5, characterized in that that the A and B isomers of 6-chloro 4-methyl 4- acid are isolated phenyl [4H] 1,3-benzodioxin-2carboxylic obtained, which is subjected to-following the action of piperidine to obtain the piperidium salts do correspondents. 10. Method according to claim 5, characterized in that that we submit 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzo-dioxin-2-carboxylic obtained by the action of diazomethane within a organic solvent, to obtain 6-chloro 4-methyl 4-phenyl [4H]
Methyl 1,3-benzodioxin-2-carboxylate, as a mixture of racemic isomers. 11. Method according to claim 10, characterized in what is isolated isomer A of 6-chloro 4-methyl 4-phenyl [4H] 1,3-methyl benzodioxin-2-carboxylate obtained. 12. Method according to claim 5, characterized in that that we esterify 6-chloro 4-methyl 4-phenyl [4H] 1,3-ben-zodioxin-2-carboxylic obtained by action on this acid of ethanol, to obtain 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-ethyl carboxylate, as a mixture of racemic isomers. 13. Method according to claim 12, characterized in what is isolated isomer A of 6-chloro 4-methyl 4-phenyl [4H]

Ethyl 1,3-benzodioxin-2-carboxylate obtained. 14. Method according to claim 5, characterized in what we salify 6-chloro 4-methyl 4-phenyl acid [4H] 1,3-benzodioxin-2-carboxylic obtained by action on this acid of the hy-sodium hydroxide, to obtain 6-chloro 4-methyl 4-phenyl [4H]
Sodium 1,3-benzodioxin-2-carboxylate, as a mixture of racemic isomers. 15. Method according to claim 14, characterized in what is isolated isomer A of 6-chloro 4-methyl 4-phenyl [4H] 1,3-sodium benzodioxal-2-carboxylate obtained. 16. Method according to claim 2, characterized in that that reacts 5-chloro 2-hydroxy .alpha.-methyl .alpha.-phenyl benzene methanol with sodium dichloro 2,2-propionate in the presence of a basic condensing agent, to obtain 6-chloro 2,4-dimethyl Sodium 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate which is treated te with an acid to obtain 6-chloro 2,4-dimethyl 4-phenyl acid [4H] 1,3-benzodioxin-2-carboxylic, in the form of a mixture of iso-racemic mothers. 17. Method according to claim 16, characterized in what we isolate isomer A of 6-chloro 2,4-dimethyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic obtained. 18. Method according to claim 2, characterized in that that react the l- (5-chloro 2-hydroxyphenyl) 1- (3-chloro-phenyl) ethanol with potassium dichloroacetate in the presence of a basic condensing agent, to obtain 6-chloro 4 (3-chloro-phenyl) 4-methyl [4H] potassium 1,3-benzodioxin-2-carboxylate which are treated with an acid to obtain 6-chloro 4 (3-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin-2-carboxylic, under as a mixture of racemic isomers. 19. Method according to claim 18, characterized in what we isolate the A-isomer of 6-chloro 4 (3-chlorophenyl) acid 4-methyl [4H] 1,3-benzodioxin-2-carboxylic obtained. 20. Method according to claim 18, characterized in what we esterify 6-chloro 4 (3-chlorophenyl) 4-methyl acid [4H] 1,3-benzodioxin-2-carboxylic obtained by action on this acid methanol, to obtain 6-chloro 4 (3-chlorophenyl) 4-methyl [4H] methyl 1,3-benzodioxin-2-carboxylate, in the form of a mixture of racemic isomers. 21. Method according to claim 20, characterized in what we isolate the A-isomer of 6-chloro 4 (3-chlorophenyl) Methyl 4-methyl [4H] 1,3-benzodioxin-2-carboxylate obtained. 22. Method according to claim 2, characterized in what we react the 6-chloro 2-hydroxy .alpha.,. alpha.-diphenyl benzene methanol with potassium dichloroacetate pre-sence of a basic condensing agent, to obtain the 6-chloro 4,4-diphenyl [4H] 1,3-benzodioxin-2-carboxylate potassium which is treated with an acid to obtain the acid 6-chloro 4,4-diphenyl [4H] 1,3-benzodioxin-2-carboxylic. 23. Method according to claim 22, characterized in what is esterified 6-chloro 4,4-diphenyl [4H] 1,3-benzodioxin-2-carboxylic obtained by action on this acid of methanol, to obtain 6-chloro 4,4-diphenyl [4H] 1,3-benzo-methyl dioxin-2-carboxylate.

. . . 24. Method according to claim 5, characterized in that we submit 6-chloro 4-methyl 4-phenyl acid [4H]
1,3-benzodioxin-2-carboxylic obtained by the action of hydrogen in the presence of a catalyst, to obtain 4-methyl acid 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic. 25. Method according to claim 10, characterized in that that we submit 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-Methyl 2-carboxylate obtained by the action of hydrogen in pre-sence of a catalyst, to obtain 4-methyl 4-phenyl Methyl 1,3-benzodioxin-2-carboxylate. 26. Process according to claim 2, characterized in that that reacts 5-chloro .alpha .- [(1-methyl) ethyl] 2-hydroxy a-phenyl benzene methanol with sodium dichloroacetate in presence of a basic condensing agent, to obtain 6-chloro 4 - [(1-methYl) ethyl] 4-phenyl [4H] 1,3-benzodioxin-2-car-sodium boxylate which is acidified to obtain 6-chloro acid 4 - [(1-methyl) ethyl] 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic, then esterifies the acid obtained by action on this acid of methanol to obtain 6-chloro 4 - [(1-methyl) ethyl] 4-phenyl [4H] 1,3-methyl benzodioxin-2-carboxylate, as a mixture of racemic isomers. 27. Method according to claim 2, characterized in that what we react the 5-chloro .alpha .- (1,1-dimethyl) ethyl 2 hydroxy a-phenyl benzene methanol with sodium dichloroacetate in the presence of a basic condensing agent to obtain 6-chloro 4 - [(1,1-dimethyl) ethyl] 4-phenyl [4H] 1,3-benzodioxin-2-sodium carboxylate which is acidified to obtain 6-chloro 4 - [(1,1-dimethyl) ethyl] 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic, then esterifies the acid obtained by action on this methanol acid to obtain 6-chloro 4 - [(1,1-dimethyl) ethyl]
Methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate, under as a mixture of racemic isomers. 28. Method according to claim 2, characterized in what we react the .alpha.-phenyl .alpha.-methyl (5-fluoro 2-hydroxy) phenyl methanol with sodium dichloroacetate in the presence of a basic condensing agent, to obtain 6-fluoro 4-methyl Sodium 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate which is acidified difie to obtain 6-fluoro 4-methyl 4-phenyl acid [4H] 1,3-benzodioxin-2-carboxylic, then esterifies the acid obtained by action on this methanol acid to obtain 6-fluoro 4-methyl 4-phenyl [4H] methyl 1,3-benzodioxin-2-carboxylate, in the form of a methyl mixture of racemic isomers. 29, Method according to claim 2, characterized in what we react the 5-chloro .alpha.-ethyl 2-hydroxy .alpha.-phenyl ben-methanol zene with potassium dichloroacetate in the presence of a basic condensing agent, to obtain 6-chloro 4-ethyl 4-phenyl [4H] 1,3-benzodioxin-2-potassium carboxylate which is acidified difie to obtain 6-chloro 4-ethyl acid 4-.beta.henyl [4H] 1,3-ben-zodioxin-2-carboxylic, then esterifies the acid obtained by action on this methanol acid to obtain 6-chloro 4-ethyl 4-phenyl [4H] methyl 1,3-benzodioxin-2-carboxylate, in the form of a mixture of racemic isomers. 30. Method according to claim 2, characterized in what we react the 5-chloro 2-hydroxy .alpha.-methyl .alpha .- (4-chloro-phenyl) benzene methanol with sodium dichloroacetate in the presence of a basic condensing agent, to obtain 6-chloro 4- (4-sodium chlorophenyl) 4-methyl [4H] 1,3-benzodioxin-2-carboxylate which is acidified to obtain 6-chloro 4- (4-chlorophenyl) acid 4-methyl [4H] 1,3-benzodioxin-2-carboxylic, then esterifies the acid obtained by action on this acid of methanol to obtain 6-chloro 4- (4-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin-2-carboxylate methyl, as a mixture of racemic isomers. 31. Method according to claim 1, characterized in what we react the 5-chloro 2-hydroxy .alpha.-methyl .alpha.-phenyl benzene methanol with potassium dichloroacetate in the presence of a basic condensing agent, to obtain 6-chloro 4-potassium methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate which is acidified to obtain 6-chloro 4-methyl 4-phenyl acid [4H] 1,3-benzodioxin-2-carboxylic, then esterifies the acid obtained by action on this acid of (2,2-dimethyl 1,3-dioxolan-4-yl) methanol to obtain 6-chloro 4-methyl 4-phenyl [4H]
(2,2-dimethyl 1,3-dioxolan-yl) 1,3-benzodioxin-2-carboxylate methyl, in the form of d! a mixture of racemic isomers. 32. Method according to claim 1, characterized in what we react the 5-chloro 2-hydroxy .alpha.-methyl .alpha.-phenyl benzene methanol with potassium dichloroacetate in the presence of a basic condensing agent, to obtain 6-chloro 4-potassium methyl 4-phenyl / 4H / 1,3-benzodioxin-2-carboxylate which is acidified to obtain 6-chloro 4-methyl 4-phenyl acid [4H] 1,3-benzodioxin-2-carboxylic, then esterifies the acid obtained by action on this acid of diethylamino ethanol for obtain 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-2- (diethylamino) ethyl carboxylate which is treated, if applicable where appropriate, with a pharmaceutically acceptable acid to form the corresponding addition salt. 33. The derivatives of 1,3-benzodioxine, responding to the general formula I ':

(I ') in which R'1 represents a hydrogen atom, a radical alkyl containing from 1 to 5 carbon atoms, a 2,3-dihy- radical droxypropanyl, a methyl (2,2-dimethyl 1,3-dioxolan-4-yl) radical or a dialkylaminoalkyl radical including alkyl radicals contain 1 to 4 carbon atoms, R2 represents a hy atom drogen or an alkyl radical of 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing 1 with 5 carbon atoms or a phenyl radical, R2 and R3 cannot however not simultaneously represent a hydrogen atom, and R4 and R5, identical or different, each represents an atom hydrogen or a halogen atom, in racemic forms or optically active or in the form of mixtures of these isomers, as well as alkali, alkaline earth, aluminum, am-monium and pharmaceutically acceptable amines of the formula I 'in which R'1 represents a hydrogen atom and the addition salts with pharmaceutically acceptable acids of products of formula I 'in which R'1 represents a radical dialkoylaminoalkyl, whenever they are obtained by a process according to claim 1 or its chemical equivalents manifestos. 34. The derivatives of 1,3-benzodioxine, responding to the general formula I:

(I) in which R1 and R2, identical or different, represent each a hydrogen atom or an alkyl radical containing 1 with 5 carbon atoms, R3 represents a hydrogen atom, a radical cal alkyl containing from 1 to 5 carbon atoms or a phe radical nyle, R2 and R3 cannot, however, represent simultaneously a hydrogen atom, and R4 and R5, identical or different, represent each feel a hydrogen atom or a halogen atom, in racemic forms or optically active or in the form of mixtures of these isomers, as well as alkali, alkaline earth, aluminum, am-monium and pharmaceutically acceptable amines of the formula 1 in which R1 represents a hydrogen atom each once they are obtained by a process according to claim 2 or its obvious chemical equivalents. 35. Derivatives according to claim 34 characterized in what R1 and R2, identical or different, each represents a hydrogen atom or a methyl radical, R3 represents a radical methyl or a phenyl radical, R4 represents a hydrogen atom and R5 represents a hydrogen atom or a chlorine atom, under racemic or optically active forms or as a mixture of these isomers, each time they are obtained by a process according to claim 3 or its obvious chemical equivalents. 36. Derivatives according to claim 34, characterized in that R1 represents a hydrogen atom or a methyl radical, R2 represents a hydrogen atom, R3 represents a radical methyl or a phenyl radical, R4 represents a hydrogen atom and R5 represents a chlorine atom, in racemic forms or optically active or in the form of mixtures of these isomers, each time they are obtained by a process according to the claim tion 4 or its obvious chemical equivalents. 37. 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzo- acid dioxin-2-carboxylic acid, whenever it is obtained by a process die according to claim 5 or its chemical equivalents manifestos. 38. The A-isomer of 6-chloro 4-methyl 4-phenyl acid [4H] 1,3-benzodioxin-2-carboxylic acid, each time it is obtained by a method according to claim 6 or its equivalents manifest chemicals. 39. The optical isomers d and 1 of racemate A of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2- acid carboxylic, each time they are obtained by a process according to claim 7 or its obvious chemical equivalents. 40. The optical isomers d and 1 of racemate B of 6-chloro 4-methyl 4-phenyl acid [4H] 1 3-benzodioxin-2-carbo-xylic, each time they are obtained by a process according to claim 8 or its obvious chemical equivalents. 41. The piperidine salts of racemates A and B of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxyli-that each time they are obtained by a process according to the res indication 9 or its obvious chemical equivalents. 42. 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-Methyl 2-carboxylate, each time it is obtained by a according to claim 10 or its chemical equivalents manifestos. 43. The A-isomer of 6-chloro 4-methyl 4-phenyl [4H]
Methyl 1,3-benzodioxin-2-carboxylate, whenever it is obtained by a process according to claim 11 or its equivalents manifest chemicals. 44. 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-Ethyl 2-carboxylate, each time it is obtained by a process according to claim 12 or its chemical equivalents manifestos. 45. The A-isomer of 6-chloro 4-methyl 4-phenyl [4H]
Ethyl 1,3-benzodioxin-2-carboxylate, whenever it is obtained by a process according to claim 13 or its equivalents manifest chemicals. 46, 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-Sodium 2-carboxylate, each time it is obtained by a process according to claim 14 or its chemical equivalents manifestos. 47. The A-isomer of 6-chloro 4-methyl 4-phenyl [4H]
Sodium 1,3-benzodioxin-2-carboxylate, whenever it is obtained by a process according to claim 15 or its equivalents manifest chemicals. 48, 6-Chloro 2,4-dimethyl 4-phenyl [4H] 1,3- acid benzodioxin-2-carboxylic acid, whenever it is obtained by a process according to claim 16 or its chemical equivalents manifestos. 49. The A-isomer of 6-chloro 2,4-dimethyl acid 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid, whenever it is obtained by a process according to claim 17 or its manifest chemical equivalents. 50. 6-chloro 4- (3-chlorophenyl) 4-methyl [4H] acid 1,3-benzodioxin-2-carboxylic acid, whenever it is obtained by a method according to claim 18 or its equivalents manifest chemicals. 51. The A-isomer of 6-chloro 4- (3-chlorophenyl) acid 4-methyl [4H] 1,3-benzodioxin-2-carboxylic acid, whenever it is obtained by a process according to claim 19 or its manifest chemical equivalents. 52. 6-chloro 4- (3, chlorophenyl) 4-methyl [4H]
Methyl 1,3-benzodioxin-2-carboxylate, whenever it is obtained by a process according to claim 20 or its equivalents manifest chemicals. 53. The A-isomer of 6-chloro 4 (3-chlorophenyl) 4-methyl [4H] methyl 1,3-benzodioxin-2-carboxylate, each once obtained by a process according to claim 21 or its obvious chemical equivalents. 54. 6-chloro 4,4-diphenyl [4H] 1,3-benzodio- acid xin-2-carboxylic acid, whenever it is obtained by a process according to claim 22 or its obvious chemical equivalents. 55. Chloro-6 4,4-diphenyl [4H] 1,3-benzodioxin-2-methyl carboxylate, whenever it is obtained by a process according to claim 23 or its chemical equivalents manifestos. 56. 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2- acid carboxylic, each time it is obtained by a process according to claim 24 or its obvious chemical equivalents. 57. 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-methyl carboxylate, whenever it is obtained by a process according to claim 25 or its chemical equivalents manifestos. 58 6-chloro 4 - [(1-methyl) ethyl] 4-phenyl [4H]
Methyl 1,3-benzodioxin-2-carboxylate, whenever it is obtained by a process according to claim 26 or its equivalents manifest chemicals. 59. 6-chloro 4 - [(1,1-dimethyl) ethyl] 4-phenyl [4H] methyl 1,3-benzodioxin-2-carboxylate, whenever is obtained by a process according to claim 27 or its manifest chemical equivalents. 60. 6-fluoro 4-methyl 4-phenyl [4H] 1,3-benzo-methyl dioxin-2-carboxylate, whenever it is obtained by a method according to claim 28 or its equivalents manifest chemicals. 61. 6-chloro 4-ethyl 4-phenyl [4H] 1,3-benzodio-methyl xin-2-carboxylate, each time it is obtained by a method according to claim 29 or its equivalents manifest chemicals. 62. 6-chloro 4- (4-chlorophenyl) 4-methyl [4H]
Methyl 1,3-benzodioxin-2-carboxylate, whenever it is obtained by a process according to claim 30 or its equivalents manifest slow chemicals. 63. 6-chloro 4-methyl 4-phenyl [4H] 1,3-(2,2-dimethyl 1,3-dioxolan-yl) benzodioxin-2-carboxylate thyle, each time it is obtained by a process according to the claim 31 or its obvious chemical equivalents. 64. 6-chloro 4-methyl 4-phenyl [4H] 1,3-2- (diethylamino) ethyl benzodioxin-2-carboxylate and its salts addition with pharmaceutically acceptable acids, each time they are obtained by a process according to the claim 33 or its obvious chemical equivalents.

SUPPORTED CLAIMS
BY ADDITIONAL DISCLOSURE 65. Method according to claim 2, characterized in what reacts 4-chloro 2-hydroxy .alpha.-methyl .alpha.-phenyl benzene methanol with an alkali metal salt of the acid di-chloroacetic, in the presence of a basic condensing agent, to obtain the corresponding alkali metal salt of the acid 7-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic that we treat with an acid and then esterify the 7-chloro acid 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic obtained by action on this methanol acid to obtain 7-chloro Methyl 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate, as a mixture of racemic isomers. 66. Method according to claim 65, characterized in what we isolate the A-isomer of 7-chloro 4-methyl 4-phenyl [4H] methyl 1,3-benzodioxin-2-carboxylate obtained. 67. Method according to claim 5, characterized in that that we treat 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic obtained, or a functional derivative of this acid, with dimethylaminoethanol to obtain 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate 2-dimethylaminoethyl which is treated, if necessary, with with a pharmaceutically acceptable acid to form the salt of corresponding addition then, if necessary, isolates the product or expected salt in racemic or optically active form desired. 68. Method according to claim 67, characterized in what we react the 6-chloro 4-methyl 4-phenyl [4H]
Methyl 1,3-benzodioxin-2-carboxylate with dimethylamino-ethanol. 69. Method according to claim 67, characterized in that the A-isomer of 6-chloro 4-methyl 4-phenyl is isolated [4H] 2-dimethylaminoethyl 1,3-benzodioxin-2-carboxylate got. 70. Method according to claim 67, characterized in what we submit 6-chloro 4-methyl 4-phenyl [4H] 1,3-2-dimethylaminoethyl benzodioxin-2-carboxylate obtained from the action of hydrochloric acid, then isolates the hydrochloride of the A-isomer of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzo-2-dimethylaminoethyl dioxin-2-carboxylate. 71. Method according to claim 68, characterized in that that we submit 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodio-2-dimethylaminoethyl xin-2-carboxylate obtained by the action of hydrochloric acid and then isolates the hydrochloride from the isomer A 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxy-2-dimethylaminoethyl late. 72 7-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-Methyl 2-carboxylate, each time it is obtained by a process according to claim 65 or its chemical equivalents manifestos. 73- The A-isomer of 7-chloro 4-methyl 4-phenyl [4H]
Methyl 1,3-benzodioxin-2-carboxylate, whenever it is obtained by a process according to claim 66 or its equivalents manifest chemical valents. 74. 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-dimethylaminoethyl 2-carboxylate and its salts addition with pharmaceutically acceptable acids, each time they are obtained by a process according to claims 67 or 68, or their manifest chemical equivalents your. 75, The A-isomer of 6-chloro 4-methyl 4-phenyl [4H]
2-dimethylaminoethyl 1,3-benzodioxin-2-carboxylate, each once it is obtained by a process according to claim 69 or its obvious chemical equivalents. 76. The hydrochloride of the A-isomer of 6-chloro 4-2-dimethyl- methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate aminoethyl, each time it is obtained by a process according to claims 70 or 71, or their chemical equivalents manifestos.