CH629200A5 - 1,3-Benzodioxin derivatives - Google Patents

Abstract

The compounds correspond to the formula: <IMAGE> in which R'1 represents hydrogen or a C1-C5 alkyl, 2,3-dihydroxypropyl, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl or dialkylaminoalkyl (C1-C4 alkyl) radical, R2 represents hydrogen or a C1-C5 alkyl, R3 represents hydrogen, a C1-C5 alkyl or a phenyl and R4 and R5 represent hydrogen or a halogen. Their alkali metal, alkaline-earth metal, aluminium, ammonium and amine salts also form part of the invention, as do the salts formed by the dialkylaminoalkyl esters with acids. The compounds and their said salts have a hypolipaemiating activity and reduce plasma lipid levels; they can be used in the treatment of hyperlipaemia, of certain cardiac insufficiencies and of chronic anginal states.

Description

       

  
 

** ATTENTION ** start of the DESC field may contain end of CLMS **.

 



   8. Composition according to claim 7, characterized in that it contains one of the compounds of formula I or one of its pharmaceutically acceptable salts, as defined in claim 2.



   9. Composition according to claim 7, characterized in that it contains one of the compounds of formula I 'or one of its pharmaceutically acceptable salts, as defined in claim 3, 4 or 5.



   10. Composition according to claim 7, characterized in that it contains one of the compounds of claim 6.



   The subject of the present invention is new 1,3-benzodioxin derivatives of general formula:
EMI2.1
 in which R ′ represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a 2,3-dihydroxypropanyl radical, a (2,2-dimethyl 1,3-dioxolan 4-yl) methyl radical or a dialkylaminoalkyl radical in which the alkyl radicals contain from 1 to 4 carbon atoms, R2 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical, and R4 and R5, identical or different, represent a hydrogen atom or a halogen atom, in racemic or optically active forms or in the form of mixtures of these isomers, as well as alkaline, alkaline earth salts,

   of aluminum, ammonium and amines of the products of formula I 'in which R' represents a hydrogen atom and the addition salts with acids of the products of formula I 'in which R' represents a dialkoylaminoalkyl radical.



   The subject of the invention is in particular products of general formula:
EMI2.2
 in which R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms and R2, R3, R4 and Rs have the meanings indicated above, in racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline-earth, aluminum, ammonium and amine salts of the products of formula I in which R represents a hydrogen atom.



   The term alkyl containing from 1 to 5 carbon atoms can denote, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, terbutyl, pentyl radical. The term halogen atom can denote, for example, a chlorine atom, a bromine atom, a fluorine atom. By mixtures of these isomers is meant a mixture of racemic isomers or a mixture of optically active isomers, in whatever proportion. They may especially be mixtures in any proportion of racemates, mixtures in any proportion of two optical antipodes, mixtures in any proportion of two optically active diastereoisomeric products.



   The alkali or alkaline earth salts of the products of formula I in which R1 represents a hydrogen atom may be, for example, the salts of soldium, potassium, lithium or calcium.



   The amine salts of the products of formula I, in which R1 represents a hydrogen atom, are the usual amine salts.



  Among the usual amines, mention may be made of monoalkoylamines, such as, for example, methylamine, ethylamine, propylamine, dialkoylamines, such as, for example, dimethylamine, diethylamine, di-n-propylamine, trialcoylamines, such as triethylamine. Mention may also be made of piperidine, morpholine, piperazine and pyrrolidine.



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



   Among the products according to the invention, there may be mentioned in particular:
 the products as defined by general formula I above, characterized in that, in said formula I, R5 and R2, identical or different, represent a hydrogen atom or a methyl radical,
R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 represents a hydrogen atom or a chlorine atom in racemic or optically active forms or in the form of mixtures of these isomers , as well as the alkali, alkaline earth, aluminum, ammonium and amine salts of said products of formula I, in which
R, represents a hydrogen atom;

  ;
 the products as defined by general formula I above, characterized in that, in said formula I, R represents a hydrogen atom or a methyl radical, R2 represents a hydrogen atom, R3 represents a d atom hydrogen, a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 represents a chlorine atom, in racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkaline, alkaline-earth salts , aluminum, ammonium and amines of the said products of formula I, in which R represents a hydrogen atom,
 and in particular, in their racemic and optically active forms, the products named in the examples.

  Among these, there may be mentioned in particular in the form of A isomers, as obtained in the examples, the products whose names follow:
 methyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate;
 methyl 6-chloro 4- (3-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin2-carboxylate;
 ethyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate;
 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid;
 6-chloro 2,4-dimethyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid;
 sodium 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate;
 6-chloro 4- (3-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin-2-carboxylic acid;
 the d and 1 isomers of 6-chloro 4-methyl 4-phenyl [4H] 1, 3-benzodioxin-2-carboxylic acid.



   We can also cite:



   the piperidine salts of the two diastereoisomeric racemates A and
B 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid;
 the d and I isomers of the two diastereoisomeric racemates A and B of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid;
 as well as, in their racemic or optically active forms:
 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate of (2,2-dimethyl 1,3-dioxolan-4-yl) methyl;
 2,3-dihydroxypropanyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate, and
 2- (diethylamino) ethyl 6-chloro 4-methyl 4-phenyl [411] 1,3-benzodioxin-2-carboxylate, as well as its addition salts with acids.



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



   The compounds of formula I above as well as their salts mentioned above (when R represents hydrogen) can be prepared by a process according to which a product of formula is reacted:
EMI3.1
 in which R3, R4 and Rs are defined as above, with an alkali metal salt of a product of formula III:

  :
EMI3.2
 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 R, represents hydrogen, a salt which, if necessary, it is treated with an acid, to obtain the corresponding acid of formula I, an acid which, if necessary, is salified or esterified, to obtain the corresponding salt or ester and that, moreover , where appropriate, the products of formula I are isolated in racemic or optically active forms or in the form of mixtures of these isomers.



   It is preferable to carry out this process as follows:
 the alkali metal salt of the product of formula III can in particular be a sodium, potassium, lithium salt;
 The basic condensing agent can in particular be an alkaline alkylate, such as sodium methylate, sodium ethylate sodium terbutylate; an alkali hydride, such as sodium hydride, potassium hydride;

   an alkaline amide, such as sodium amide, potassium amide, lithium amide, sodium;
 the reaction of the product of formula II with the product of formula III is carried out in an organic solvent, such as, for example, benzene, toluene, xylene, ethyl ether, dioxane, dimethylformamide, tetrahydrofuran, hexamethyl phosphorotriamide or in a mixture of these solvents.



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



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



   The product of formula II is reacted with the basic condensing agent before being reacted with the product of formula III.



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



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



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



   The products of formula I, in which R, represents a methyl radical can also be prepared by the action of diazomethane on the product of formula I, in which R, represents a hydrogen atom within an organic solvent.



   The esters of general formula I can also be prepared in the usual manner from a functional derivative of the corresponding acid of formula I, such as, for example, acid chloride.



  The functional derivatives of the acids of formula I are prepared according to the usual methods.



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



   The base can be an inorganic or organic base, such as, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, aluminum hydroxide, sodium ethylate, potassium ethylate, ammonia or an amine, such as, for example, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, di-n-propylamine, triethylamine, piperidine, morpholine, piperazine or pyrrolidine.

 

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



   One can also prepare the compounds of formula I above as well as their salts mentioned above (when R1 represents hydrogen) by a process according to which a product of reacted
EMI3.3
 in which R3, R4 and Rs have the meaning indicated above, with an alkali metal salt of a product of formula III ':
EMI3.4
 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.



   This process is preferably carried out under conditions identical to those which have been described previously.



   A process has been described above for the preparation of products of formula I in which R represents a hydrogen atom or an alkyl radical containing from I to 5 carbon atoms, corresponding to a product of formula I ', in which R' l has the value of R1 above.



   According to an advantageous procedure for preparing products of formula 1 ′, as defined above, in which R ′ represents a 2,3-dihydroxypropanyl radical, 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, R3,
R4 and R5 being defined as above, in racemic or optically active forms or in the form of mixtures of these isomers, as well as addition salts with acids of the products of formula 1 'in which R' represents a dialkylaminoalkyl radical, we treats an acid of formula I in which R represents a hydrogen atom, or a functional derivative of this acid,

   with an alcohol of formula R ', OH in which R'l represents a (2,2-dimethyl 1,3-dioxolan-4-yl) methyl radical, or a dialkoylaminoalkyl radical, in which the alkyl radicals contain from 1 to 4 atoms carbon, treats, if necessary, the product obtained of formula I 'in which R'l represents a dialkylaminoalkyl radical, with an acid to form the salt, the product obtained of formula I' is treated, if necessary which R '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 ′ represents a 2,3-dihydroxypropanyl radical and, in addition, where appropriate, the products of formula I ′ or their salts are isolated in racemic or optically active forms,

   or as mixtures of these isomers.



   It is preferable to carry out this process as follows: the functional derivative of the acid of formula I can be, for example, an acid ester or halide (the functional derivative is prepared from acid of formula I in the usual way);
   the reaction is preferably carried out in an organic solvent such as, for example, benzene, toluene, xylene,
Ethyl ether;
   the salification reaction of the products of formula I 'in which R' represents a dialkylaminoalkyl 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.



   On the other hand, to obtain the products of formula I above, in which R4 and Rs represent a hydrogen atom, it is also possible to submit a product of formula I, in which R4 or R1 or
R4 and Rs represent a chlorine atom, to the action of hydrogen in the presence of a catalyst. One can then operate with advantage as follows: the catalyst can be in particular palladium;
   one operates in an alkaline medium; the base used can be, for example, triethylamine, trimethylamine, dimethylaniline, pyridine.



   One operates within an organic solvent, such as, for example,
Ethanol, methanol, isopropanol.



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



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



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



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



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



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



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



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



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



  Pharmacological study 1. Determination of lipid-lowering action:
 The study was carried out on batches of 8 male rats of strain
Sprague Dawley S.P.F., weighing approximately 200 g.



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



   The animals are kept for 16 hrs after the last administration of the product, then exsanguinated by abdominal puncture and, on the blood taken from sodium heparinate, assays of triglycerides, cholesterol and total lipids are carried out according to the following methods:
 - determination of triglycerides:
 (semi-automatic determination) technique by G. Kessler and H.



  Lederer, Automation in Analytical Chemistry, New York, 341 (1965), modified by J. R. Claude and F. Corre, Ann. Biol. Clin. , 26, 3-4, 451 (1968);
 - cholesterol dosage:
 technique by J. Levine, Symposium Technicon, 1967, vol. I, 25, adapted to the self-analyzer system I;
 - nephelometric measurement of total lipids:
 semi-automatic determination by H. C. Girard, J. Canal,
J. Delattre and J. Peynet, Technicon Symposium, 1970, Paris.

 

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



   The following results were obtained:
EMI4.1


 <tb> Product <SEP> from <SEP> Doses <SEP> Variation <SEP> (%) <SEP> from <SEP> rate <SEP> from
 <tb> Product <SEP> from <SEP> Doses
 <tb> <SEP> example <SEP> (mg / kg / d) <SEP> triglycerides <SEP> <SEP> cholesterol <SEP> lipids <SEP> totals
 <tb> <SEP> 41 <SEP> 5 <SEP> -43 <SEP> -4o <SEP> <SEP> -49
 <tb> 2. Determination of acute toxicity:
 The acute toxicity was determined on batches of 10 mice weighing 18 to 22 g. The product was administered in suspension in carboxymethylcellulose intraperitoneally.



   The animals were kept under observation for one week.



   The lethal dose 50 (LD 50) was determined and the following results were obtained:
EMI5.1


 <tb> Product <SEP> from <SEP> example <SEP> DL <SEP> 50 <SEP> (mg / kg)
 <tb> <SEP> 41 <SEP> ¯ <SEP> <SEP> 200
 <tb>
 These properties justify the therapeutic use, as medicaments, of products as defined by formula I 'and in particular I above, in racemic or optically active forms or in the form of mixtures of these isomers, as well as their salts. alkaline, alkaline earth, aluminum, ammonium and pharmaceutically acceptable 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 said products of formula I ′, and in particular I, and said salts, there may be mentioned in particular, in their racemic or optically active forms or in the form of mixtures of these isomers, the products of formula I, in which R1 and R2, identical or different, represent a hydrogen atom or a methyl radical,
R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 represents a hydrogen atom or a chlorine atom, as well as the products of formula I, in which Rl represents a hydrogen atom or a methyl radical, R2 and R4 represent a hydrogen atom, R3 represents a hydrogen atom, a methyl radical or a phenyl radical and R5 represents a chlorine atom, as well as the alkali salts,

   alkaline earth, aluminum, ammonium and amines of said products of formula I, in which R represents a hydrogen atom.



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



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



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



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



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



   The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or no, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.



   The following intermediate products are new, in their racemic or optically active forms: - 5-chloro 2-hydroxy x-methyl a-phenylbenzenemethanol, - products of formula II'A:
EMI5.2
 in which R'4 represents a chlorine atom or a fluorine atom, R'5 represents a chlorine atom, R'3 represents an alkyl radical containing from 2 to 4 carbon atoms, R'3 can also represent a methyl radical when R'4 represents a fluorine atom.



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



   The products of formula II which are not known, in which
R3 represents a hydrogen atom, can be prepared by reduction of the corresponding benzophenone derivatives of formula A:
EMI5.3
 by means, for example, of a mixed hydride, operating within an organic solvent.



   The products of formula II which are not known, in which
R3 represents an alkyl radical containing from I to 5 carbon atoms, or a phenyl radical, can be prepared by action on a corresponding benzophenone derivative of formula A above, within an organic solvent, of an organomagnesium derivative 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 a process is illustrated below in the experimental part.



   The examples given below illustrate the preparation of the 1,3-benzodioxins which are the subject of the invention.



  Example 1:
 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid (mixture of the two diastereoisomeric racemates).

 

   8.1 g of sodium amide and 100 ml of toluene are mixed with stirring, and a solution obtained by stirring is added dropwise while stirring. 24.9 g of 5-chloro 2-hydroxy x-methyl x-phenyl is dissolved. - benzenemethanol in 250 ml of toluene, brings the mixture to reflux for 41/2 h, brings the mixture to room temperature, adds, in small portions with stirring, 18 g of potassium dichloroacetate, adds 20 ml of hexamethylphosphorotriamide, brings to reflux for 5 h, cool the mixture until it is at room temperature, slowly add 10 ml of ethyl acetate then, drop by drop, 250 ml of water.

  The aqueous phase is collected, the organic phase is extracted again with 3 times 100 ml of water and the various aqueous extracts are combined and washed with 3 times 100 ml of ether. The aqueous extraction phase which contains the potassium salt of the expected product is acidified by bubbling sulfur dioxide and is extracted with 4 times 100 ml of ether. The ethereal extraction phase is washed with 3 times 50 ml of water. The organic phase is dried over magnesium sulphate, treated with active charcoal, the solvent is evaporated under vacuum.

  24 g of crude product are obtained which are crystallized from 100 ml of a 90/10 cyclohexane / benzene mixture, the crystals obtained are dried and 15.2 g of 6-chloro 4-methyl 4-phenyl acid [4H are obtained ] 1,3-benzodioxin-2-carboxylic. F = 142 C.



   Analysis for C16H13ClO4:
 Calculated: C 63.06 H 4.30 Cl 11.63%
 Found: C 63.3 H 4.4 Cl 11.5%
 5-chloro 2-hydroxy <-methyl x-phenylbenzenemethanol, used at the start of the preparation of 6-chloro 4-methyl 4-phenyl [4H] 1, 3-benzodioxin-2-carboxylic acid can be prepared as follows:

  :
 Disperse with stirring 14 g of magnesium in turnings in
 100 ml of anhydrous ether, add, drop by drop and with stirring, a
 solution obtained by dissolving 76 g of methyl iodide in
 200 ml of anhydrous ether, refluxed for 1 h, cools to
 the temperature of 15-20 C, then add, at this temperature, a
 solution obtained by dissolving 59 g of 5-chloro 2-hydroxy
 benzophenone in 250 ml of anhydrous benzene, partly distills
 ether, then brings to reflux again for 2 h. We then cool
 mix up to a temperature of 5-10 "C and add drop by drop
 drop, 250 ml of 3N hydrochloric acid.



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



   The organic extraction phase is washed with water, then with a
 saturated sodium bicarbonate solution, then finally twice
 50 ml of water. The organic phase is dried over magnesium sulfate,
 then evaporates the solvent under vacuum, obtains 58.9 g of crystals which are
 taken up in petroleum ether (Eb. 60-80 C) and obtained 53 g of
 5-chloro 2-hydroxy <-methyl x-phenylbenzenemethanol. F = 106 "C.



   Analysis for C14H13ClO2:
 Calculated: C 67.61 H 5.27 Cl 14.26%
 Found: C 67.8 H 5.4 Cl 14.2%
Example 2:
 Isomers A and B of 6-chloro 4-methyl 4-phenyl [4H] I, 3-benzodioxin-2-carhoxylate.



   A solution of 2.25 g of diazomethane in 150 ml of methylene chloride is prepared, this solution is cooled to 5 "C, added thereto, dropwise at 5" C, a solution obtained by dissolving 3.3 g of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid in the form of a mixture of the two diastereoisomeric racemates obtained in Example 1 in 75 ml of methylene chloride.



  The mixture is stirred for 1 h at room temperature, then the solution is left to stand for 24 h. 10 ml of acetic acid are then added, then the solvent is evaporated under vacuum. 4.2 g of methyl 6-chloro 4-methyl ephenyl [4H] 1, 3-benzodioxin-2-carboxylate are recovered in the form of a mixture of the two diastereoisomeric racemates.



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



     F = 114-115 C.



   Analysis for C17H15CIO4:
 Calculated: C 64.06 H 4.74 Cl 11.12%
 Found: C63.9 114.7 C111.4%
 NMR spectrum (base frequency of the device used: 60 Hz).



   - at 117 Hz.



     - COOCH3 at 232 Hz.



   - Hydrogen in position 2 at 311 Hz.



   - Aromatics from 410 to 445 Hz.



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



   Analysis for C17H15ClO4:
 Calculated: C 64.06 H 4.74 Cl 11.12%
 Found: C 64.0 H 4.8 Cl 11.3%
 NMR spectrum (base frequency of the device used: 60 Hz).



   - at 125 Hz.



   -COOCH3 at 228 Hz.



     Hydrogen in position 2 at 341 Hz.



     Aromatics from 405 to 455 Hz.



     Example 3:
 Isomer A of 6-chloro 4-methyl 4-phenyl acid [4H1
I, 3-benzodioxin-2-carboxylic.



   14 g of isomer A of 6-chloro 4-methyl 4-phenyl [4H] 1, 3-benzodioxin-2-carboxylate methyl obtained in Example 2 are mixed and, after a second setting, work of the procedure described in Example 2.2.8 g of potassium hydroxide in pellets, 32 ml of water and 160 ml of methanol, stirred for 22 h at room temperature, added 320 ml of water, washed the aqueous phase with 2 times 160 ml of ether, then acidify the aqueous solution with a 2N hydrochloric acid solution, extract the precipitate obtained with 3 times 320 ml of ether, wash the organic extraction phase with 2 times 160 ml of water, dries it over magnesium sulphate and brings to dryness. 13 g of crystals are obtained.

  3.9 g are recrystallized from 100 ml of an ethyl acetate / cyclohexane mixture (20/80) and dried. 3.3 g of isomer A of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid are obtained.



     F = 175-176 C.



   Analysis for ClIHl3CIO4: Calculated: C 63.06 H 4.30 Cl 11.63%
 Found: C 63.3 H 4.6 Cl 11.3%
 NMR spectrum (base frequency: 60 Hz).



      - CH3 at 17Hz.



     - Hydrogen in position 2 at 313 Hz.



   - COOH at 468Hz.



   - Aromatics from 412 to 443 Hz.



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



   5.3 g of isomer B of 6-chloro 4-ethyl 4-phenyl [4H] are mixed
   1, 3-benzodioxin-2-carboxylate obtained in Example 2 and, after a second implementation of the procedure described in Example 2, 10 ml of water, 1.2 g potassium hydroxide in pellets and 50 ml of methanol, stirred for 20 h at room temperature, add 200 ml of water, wash the aqueous phase with twice 80 ml of ether and then acidify the aqueous solution with an acid solution hydrochloric 2N, extracted with 3 times 100 ml of ether, combine the extracts, wash the extract with 2 times 80 ml of water, dry the ethereal phase over magnesium sulfate,

   the solvent is evaporated in vacuo and 4.8 g of crystals are obtained which are recrystallized from a cyclohexane / ethyl acetate mixture (80/20), dried and 4.4 g of B-isomer of acid 6 are obtained chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic. F = 171 C.



   Analysis for C1, H13ClO4:
 Calculated: C 63.06 H 4.30 Cl 11.63%
 Found: C63, l 114.4 C111.7%
 NMR spectrum (base frequency: 60 Hz).



   - at 124 Hz.



   - COOH at 329 Hz.



     - Hydrogen in position 2 at 341 Hz.



   - Aromatics from 408 to 445 Hz.



   Example 5:
 6-chloro 2,4-dimethyl 4-phenyl acid [4H1 1,3-benzodioxin
 2-carboxylic (mixture of the two diastereoisomeric racemates).



   8 g of sodium amide and 100 ml of
 toluene, add, drop by drop at room temperature, a
 suspension obtained by dispersing 24.9 g of 5-chloro 2-hydroxy
 -methyl a-phenylbenzenemethanol in 250 ml of toluene, bears the
 mixture at reflux for 6 h, cools the mixture until it
 either at room temperature, add in small portions 17 g of
 sodium dichloro 2,2-propionate, again refluxed for 6 h, cooled to room temperature and added 700 ml
 of water. Acidified by adding a hydrochloric acid solution
 than N, realkalinizes by adding a saturated sodium bicarbonate solution.

  The aqueous extraction phase is collected and washed with 3 times 100 ml of ether, the aqueous extract is acidified by adding a 2N hydrochloric acid solution and extracted with 3 times 100 ml of ether, combined the organic extracts which are washed with 3 times 80 ml of water and dried over magnesium sulphate, then the solvent is evaporated under vacuum and 23 g of 6-chloro 2,4-dimethyl 4-phenyl acid [4H are obtained ]
 1,3-benzodioxin-2-carboxylic. F = 181 C.



   Analysis for C ,, H ,, C104: Calculated: C 64.06 H 4.74 Cl 11.12%
 Found: C64.0 H4.8 C111.2%
Example 6:
 Isomers A and B of methyl 6-chloro 2,4-dimethyl4-phenyl [4H] 1,3-benzodioxin-2-carboxylate.



   23 g of 6-chloro 2,4-dimethyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid are mixed in the form of a mixture of the two diastereoisomeric racemates A and B obtained in Example 5, 100 g of Redex CF resin (strong acidic sulfonic cationic resin), 250 ml of methanol, refluxed for 20 h, cooled to room temperature, wrung out the resin, rinsed with solvent and concentrated the filtrate under vacuum. 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 of ethyl ether / petroleum ether (Eb. 60-80 C) (20/80) and obtains 1.7 g of isomer A of methyl 6-chloro 2,4-dimethyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate.



     F = 134 C.



   Analysis for Cl8Hl7CIO4:
 Calculated: C 64.96 H 5.15 Cl 10.65%
 Found: C 65.2 H 5.2 Cl 10.9%
 NMR spectrum (base frequency: 60 Hz).



   - CH3 Åa 103 and 113 Hz.



   - COOCH3ài72Hz.



   - Aromatics from 419 to 447 Hz.



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



   Analysis for C18H17ClO4:
 Calculated: C 64.96 H 5.15 Cl 10.65%
 Found: C 65.8 H 5.1 Cl 10.8%
 NMR spectrum (base 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 [4H]
I, 3-benzodioxin-2-carboxylic.



   1.6 g of isomer A of 6-chloro 2,4-dimethyl 4-phenyl [4H] 1, 3-benzodioxin-2-methyl carboxylate obtained in Example 6 are mixed, 20 ml of methanol, 2 ml water and 0.56 g of potassium hydroxide in pellets, stir the mixture for 48 h at room temperature, add 100 ml of water, collect the aqueous phase which is washed with 3 times 50 ml of ether , acidifies the aqueous solution by adding a 2N hydrochloric acid solution, and extracted with 4 times 50 ml of ether, combines the ethereal extracts which are washed with 3 times 50 ml of water, then dried over sulphate magnesium.

  The solvent is evaporated off under vacuum and 1.5 g of product are obtained which is recrystallized from 80 ml of cyclohexane and 1.2 g of isomer A of 6-chloro 2,4-dimethyl 4-phenyl [4H [4H] are obtained. ] 1,3-benzodioxin-2-carboxylic. F = 184 C.



   Analysis for C17H03ClO4: Calculated: C 64.06 H 4.74 C1 11.12%
 Found: C 64.1 H 4.8 Cl 11.1%
 NMR spectrum (base frequency: 60 Hz).



      - CH3 at 101.5 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 [4H] 1,3-benzodioxin-2-carboxylic acid.



   8 g of isomer B of 6-chloro 2,4-dimethyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate methyl obtained in Example 6 are mixed, 80 ml of methanol, 8 ml of water and 2.8 g of potassium hydroxide in pellets, stirred for 24 h at room temperature, add 150 ml of water, collect the aqueous phase which is washed with 3 times 60 ml of ether. The aqueous solution is acidified by adding a 2N hydrochloric acid solution and extracted with 4 times 60 ml of ethyl ether.

  The ethereal extracts are combined and washed with twice 80 ml of water, then dried over magnesium sulphate and the solvent is evaporated in vacuo and 7.2 g of product are obtained, which is recrystallized from 80 ml of cyclohexane. Dried and obtained 4.5 g of isomer B of 6-chloro 2,4-dimethyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid. F = 125 C.



   Analysis for C17H15ClO4:
 Calculated: C64.06 H4.74 Cl 11.12%
 Found: C 64.2 H 5.0 C111.2%
 NMR spectrum (base frequency: 60 Hz).



   - CH3 at 104 and 119 Hz.



   - Aromatics from 417 to 455 Hz.



   - COOH at N 540 Hz.



  Example 9:
 6-chloro 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid.



   10.35 g of sodium amide and 100 ml of toluene are mixed, introduced dropwise at room temperature and with stirring, a solution obtained by dissolving 30.1 g of 5-chloro 2-hydroxy x-phenylbenzenemethanol in 200 ml of anhydrous toluene, stir 2 h at room temperature, bring the mixture to reflux for 6 h, cool the mixture to room temperature and add in small portions 22.3 g of potassium dichioracetate, add 20 ml of hexamethylphosphoramide, stir 20 h at room temperature, bring the mixture to reflux of toluene for 4 h, leave to return to room temperature, add 20 ml of ethyl acetate, then slowly 250 ml of water.

  The aqueous phase is collected, the organic phase is extracted again with 3 times 100 ml of water and the various aqueous extracts are combined and washed with 3 times 100 ml of ether. The aqueous extraction phase which contains the potassium salt of the expected product is acidified by bubbling sulfur dioxide, extracted with 3 times 100 ml of ether, the extracts are combined, washed with 3 times 100 ml of water, dried over magnesium sulphate, treated with activated carbon, evaporates the solvent under vacuum and obtains 24 g of crude product which is disintegrated in cyclohexane,

   obtains crystals which are recrystallized from 520 ml of a benzene / cyclohexane mixture (7/3) and obtains 5.3 g of echloro 4-phenyl acid [4H] 1,3-benzodioxin-2-carboxylic. F = 194 C.



   Analysis for C15H1 1C1O4:
 Calculated: C 61.97 H 3.81 Cl 12.20%
 Found: C 62.2 H 3.9 Cl 12.1%
 NMR spectrum (base frequency: 60 Hz).



   - Hydrogen in position 2 and 4 at 343.5 and 364 Hz.



      - COOHà "" 514Hz.



   - Aromatics from 398 to 442.5 Hz.



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



   12.4 g of 5-chloro 2-hydroxy, -diphenylbenzene-methanol, 150 ml of toluene, 3.2 g of sodium amide are mixed, the mixture is refluxed for 6 h, cooled to room temperature and added 6.8 g of potassium dichloroacetate, brought to reflux again for 6 h, cooled to room temperature and added 300 ml of water. It is slightly acidified by addition of a solution of hydrochloric acid N, then basified by addition of a saturated solution of sodium bicarbonate.

  Washed with 2 times 100 ml of methylene chloride, then acidified by addition of a 2N hydrochloric acid solution, extracted with 3 times 100 ml of ether, combined the ethereal extracts, washed with 2 times 80 ml of water , then dried over magnesium sulphate and treated with activated carbon. After evaporation of the solvent under vacuum, 7 g of product are obtained which is recrystallized from 300 ml of benzene. 4.6 g of 6-chloro 4,4-diphenyl t4H] 1,3-benzodioxin-2-carboxylic acid are obtained. F = 226 C.



      Analysis for C21H15ClO4:
 Calculated: C 68.76 H 4.12 Cl 9.67%
 Found: C69.1 114.3 C19.5%
 NMR spectrum (base frequency: 60 Hz).



     - Hydrogen in position 2 at 325 Hz.



   - COOHà "" '- 313Hz.



   - Aromatics from 405 to 443 Hz.



  Example 11:
 Isomer A of methyl 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylate.



   1.3 g of palladium on activated carbon at 10%, 11.8 g of the isomer A of 6-chloro 4-methyl 4-phenyl [4H] 1, 3-benzodioxin-2- are introduced into a hydrogenating cell. methyl carboxylate obtained in example 2 and, at the end of a second implementation of the procedure described in example 2, 500 ml of ethanol, 10 ml of triethylamine, stir the suspension under current of hydrogen, at room temperature.

  The catalyst is washed with methylene chloride, then the filtrate is concentrated under vacuum, the residue is taken up in 100 ml of water, 50 ml of a 2N hydrochloric acid solution is added and extracted with 3 times 150 ml of methylene chloride, combines the extracts, washing them with 2 times 100 ml of water, drying over calcium chloride and then, after treatment with active carbon, evaporating the solvent under vacuum and obtaining 9.7 g of the expected product.



   A sample of this product was recrystallized from methanol.



     F = 1224C.



   Analysis for C11110O4:
 Calculated: C 71.82 H 5.67%
 Found: C 72.1 H 5.8%
 NMR spectrum (base frequency: 60 Hz).



     - Hydrogen in position 2 at 312 Hz.



     - COOCH3 at 231 Hz.



     - CH3 twin to phenyl: 117 Hz.



   - Aromatics from 410 to 450 Hz.



  Example 12:
 Isomer A of 4-methyl 4-phenyl 1,3-benzodioxin2-carboxylic acid.



   9.7 g of isomer A of 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate methyl obtained in Example 11.4 g of potassium hydroxide in pellets are mixed with stirring, 10 ml of water, 90 ml of methanol, keep stirring for 16 h at room temperature, add 400 ml of water, wash the aqueous phase with 2 times 100 ml of methylene chloride, acidify the aqueous phase by adding a 2N hydrochloric acid solution, extracted with 3 times 150 ml of methylene chloride, combines the extracts, washed with twice 80 ml of water, dried over calcium chloride, evaporates the solvent under vacuum,

   collects 8 g of product which is recrystallized from an ethyl acetate / cyclohexane mixture (20/80) and obtains 5.1 g of isomer A of 4-methyl 4-phenyl 1,3-benzodioxin- 2-carboxylic. F = 163 C.



      Analysis for C1, H14O4:
 Calculated: C 71.10 H 5.22%
 Found: C 71.1 H 5.3%
 NMR spectrum (base frequency: 60 Hz).



   - at 19 Hz.



     - Hydrogen in position 2 at 316 Hz.



   - COOH at 534 Hz.



   - Aromatics from 418 to 450 Hz.



   Example 13:
 Isomer B of methyl 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylate.



   1.3 g of 10% palladium on activated carbon, 12.8 g of the B-isomer of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2- are introduced into a hydrogenating cell. methyl carboxylate obtained in Example 2 and, at the end of a second implementation of the procedure described in Example 2, 10 ml of triethylamine, 200 ml of ethanol, causes a continuous stream of hydrogen and stir the suspension at room temperature for about 2 h.

  It is filtered, the catalyst is rinsed with methylene chloride, the filtrate is evaporated under vacuum, the residue is taken up in 80 ml of water, 70 ml of a 2N hydrochloric acid solution, extracted with 3 times 100 ml of methylene chloride are added. , combine the extracts and wash them with 3 times 50 ml of water, dry over calcium chloride and evaporate the solvent under vacuum. 10.2 g of expected product are obtained.

 

   A sample of this product is recrystallized from methanol.



     F = 137 C.



   Analysis for C17H16O4:
 Calculated: C 71.82 H 5.67%
 Found: C 71.8 H 5.8%
 NMR spectrum (base frequency: 60 Hz).



     - Ch3 at 128 Hz.



   - COOC113 at 234Hz.



   - Hydrogen in position 2 at 347 Hz.



   - Aromatics from 410 to 465 Hz.



  Example 14:
 Isomer B of 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid.



   10.2 g of the B isomer of methyl 4-methyl 4-phenyl [411] 1,3-benzodioxin-2-carboxylate obtained in Example 13 are mixed with stirring, 4 g of potassium hydroxide in pellets , 10 ml of water and 90 ml of methanol, stirred for 16 h at room temperature, add 500 ml of water, wash the aqueous phase with twice 80 ml of methylene chloride, acidify the aqueous phase by adding '' a 2N hydrochloric acid solution, extracted with 3 times 100 ml of methylene chloride, washed with 2 times 80 ml of water, dried over calcium chloride, the solvent is evaporated under vacuum,

   9 g of product are obtained, which is recrystallized from an ethyl acetate / cyclohexane mixture (20/80) and 6.7 g of expected product is obtained.



     F = 153C.



   Analysis for Cl6Hl404:
 Calculated: C71.10 H 5.22%
 Found: C 71.1 H 5.3%
 NMR spectrum (base frequency: 60 Hz).



     - CH3 at 128 Hz.



     - Hydrogen in position 2 at 348 Hz.



   - Aromatics from 410 to 460 Hz.



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



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



   The crude product obtained is taken up in 200 ml of ether, the organic phase is washed with 100 ml of a 5% sodium bicarbonate solution, then with 2 times 100 ml of water. The ethereal phase is dried over magnesium sulfate, treated with active charcoal, the solvent is evaporated and 6.3 g of product are obtained which is recrystallized from 140 ml of cyclohexane. Dried and obtained 5.1 g of the expected product.



      F = 172 "C.



   Analysis for C22HI7CIO4:
 Calculated: C 69.38 H 4.50 Cl 9.31%
 Found: C 69.7 H 4.6 Cl 9.3%
 NMR spectrum (base frequency 60 MHz) (deuterochloroform).



     - COOCH3 at 230 Hz.



   - Aromatics from 406 to 443 Hz.



     Hydrogen in position 2 at 324 Hz.



  Example 16:
 Isomer A of ethyl 6-chioro 4-metfiyl 4phenyl [4H] 1,3-benzodioxin 2-carboxylate.



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



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



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



   3 ml of absolute ethanol, 50 ml of anhydrous benzene, 2.3 ml of triethylamine are mixed, the acid chloride solution obtained in Stage A is added dropwise at room temperature, kept stirring for 20 h at room temperature , drain and wash the precipitate of triethylamine hydrochloride with cold benzene, wash the filtrate with 2 times 40 ml of water, dry the organic phase on calcium chloride, treat with active charcoal, evaporate the solvent under vacuum, obtain 9 g of crude product which is recrystallized from 30 ml of hexane and after drying 4 g of the expected product is obtained.



   F = 92 "C.



   Analysis for C, 8H17CIO4:
 Calculated: C 64.97 H 5.15 Cl 10.65%
 Found: C 65.1 H 5.3 Cl 10.8%
 NMR spectrum (deuterochloroform) (base frequency: 60 MHz).



     - CHB of C2H5 at 72.5, 79.5, 87 Hz.



     - CH3 in position 4 at 116 Hz.



     - Ch2 from C2H5 at 247.5, 255, 262, 269 Hz.



     - Hydrogen in position 2 at 308 Hz.



   - Aromatics from 412 to 441 Hz.



  Example 17:
 Isomer A of sodium 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylate.



   0.6 g of sodium hydroxide, 250 ml of absolute ethanol are mixed, 4.6 g of the isomer A of 6-chloro 4-methyl 4-phenyl acid [4H] 1 are added at room temperature, 3-benzodioxin-2-carboxylic obtained in Example 3, the mixture is brought to the boil for 5 min, filtered, cooled to room temperature, added to the filtrate 500 ml of ether and stirred for 16 h at room temperature. Filtered and obtained after drying 3.8 g of the expected product. F = 160 "C.



   Analysis for C16H12O4ClNa:
 Calculated: C 58.82 H 3.70 Cl 10.85%
 Found: C 58.5 H 3.8 C 110.7%
Example 18:
 D and I isomers of the A-isomer of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid.



  1) Isomer
 Stage A: 1-p-nitrophenyl 2amine 1,3-propanediol salt of the isomer of isomer A of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid.



   15.2 g of isomer A of 6-chloro 4-methyl 4-phenyl acid [411] 1,3-benzodioxin.2-carboxylic obtained in Example 3 are mixed, 16.2 g of I lp- nitrophenyl 2-amino 1,3-propanediol and 800 ml of ethyl acetate.



   The mixture is brought to reflux, the reflux is maintained after precipitation of the salt formed for 5 min. The mixture is brought to ambient temperature, the precipitate obtained is drained, rinsed with ethyl acetate, dried under vacuum and recovering 10 g of crude product. [The mother liquors are kept for the separation of the crude d isomer (see below).]
The 10 g of crude product obtained are recrystallized from isopropanol and finally 6.4 g of expected product is obtained. F = 218 "C.



     [a] 2DO = -84 "+ 2" (c = 1%, ethanol).



   A sample of this product is recrystallized from a little isopropanol. F = 218 "C.



     [ <lb0 = -84.5 "+ 2" (c = 1%, ethanol).    



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



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

  It is recrystallized again from 80 ml of cyclohexane and 1.8 g of the expected product melting at 113 ° C. are obtained.     0.5 g of expected product is obtained from the mother liquors of previous recrystallizations.  This 0.5 g of product and the 1.8 g of product obtained above are combined, recrystallizes the 2.3 g of product from 50 ml of cyclohexane while maintaining the reflux of the solvent for 20 min and then obtains 2 g of the expected product. .  F = 140 C.  (The variations in the different melting points noted for the expected product are probably due to variations in crystal structure. )
 Analysis for C161113ClO4:
 Calculated: C 63.06 H 4.30 Cl 11.63%
 Found: C 63.2 H 4.4 Clin 6%
 NMR spectrum (deuterochloroform) (base frequency: 60
MHz). 



     - CH3 at 116.5 Hz.    



     - Hydrogen in position 2 at 313 Hz. 



   - Aromatics from 415 to 443 Hz. 



   OH at around 540 Hz. 



   Rotating power
   [& b0 = -157 i 2.5 (c = 1%, ethanol 95).    



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



   The mother liquors of ethyl acetate are taken up, salification of the A isomer of 6chloro 4-methyl 4-phenyl acid [4H]
 1,3-benzodioxin-2-carboxylic acid for 1 l-p-nitrophenyl 2-amino
 1,3-propanediol.  The solution is concentrated under vacuum, recovering 17.8 g of crude product which is treated with 200 ml of 2N hydrochloric acid, extracted with 3 times 100 ml of ether, washing the organic phase with 2 times 50 ml of water, dry over magnesium sulfate and concentrate in vacuo. 



  8.4 g of residue are obtained, which is taken up in 150 ml of a cyclohexane / ethyl acetate mixture (70/30) and brought to reflux, allowed to cool, wrung out the residual starting racemic acid which crystallizes, concentrates the filtrate under vacuum, and obtains 7 g of crude expected product. 



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



   The residue obtained above is taken up in 300 ml of ethyl acetate and added to the solution 7.4 g of d 1-p-nitrophenyl 2-amino 1,3-propanediol.  The suspension is brought to reflux, allowed to cool, after precipitation of the salt formed, to room temperature, the precipitate is drained, rinsed with a little ethyl acetate.  After drying, 11.4 g of expected product are obtained, melting at 200 C.  Recrystallized from 1.1 l of isopropanol, 6.2 g of expected product is obtained, F = 2180C, which is recrystallized from 800 ml of isopropanol and 5 g of expected product is obtained.  F = 218 C approximately. 



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



   The salt obtained above is taken up in 150 ml of water, acidified with 2N hydrochloric acid, extracted with 2 times 100 ml of ether, the organic extraction phase is washed with 2 times 50 ml of water, dried over magnesium sulfate and evaporates the solvent in vacuo; 2.9 g of crude product are obtained which is taken up in an ethyl ether / petroleum ether mixture (Eb.    60-80 C) (20/80).  Finally, after separation, 2.4 g of the expected product are obtained.  F = 128 C. 



     [&alpha;] D20 = + 1530 + 2.50 (c = 1%, ethanol).    



   This product is recrystallized from 100 ml of cyclohexane, 2 g of the expected product are obtained.  F = 128 C. 



     [cr] bo = + 153 2.5 (c = 1%, ethanol). 



   It is recrystallized again from 60 ml of cyclohexane and finally 1.7 g of expected product is obtained.  F = 140 C.  (As for isomer 1, the d isomer has several melting points.  This is probably due to variations in crystal structure. )
 Analysis for Cl6Hl3CIO4: Calculated: C 63.06 H 4.30 Cl 11.63%
 Found: C63.2 114.3 Cl 11.6%
 NMR spectrum (deuterochloroform) (base frequency: 60 MHz). 



   - at í 17 Hz.    



   - Monosubstituted phenyl at 440 Hz.    



   - Aromatics from 413 to Hz.    



   - at 485 Hz.    



     - Hydrogen in 2 at 312.5 Hz. 



   Rotating power
   [a] 2 = + 154.50 + 2.50 (c = 1%, ethanol). 



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



   10 g of sodium amide and 200 ml of anhydrous toluene are mixed with stirring, then a suspension obtained at room temperature and in small portions is obtained by dissolving 28.3 g of 1- [5-chloro 2-hydroxyphenyl] 1- [3-chlorophenyl] ethanol in 250 ml of toluene, then the mixture is brought to reflux for 6 h (a further 1 g of sodium amide is added to the mixture).  After cooling to room temperature, 25 g of potassium dichloroacetate are added in small portions, with stirring, and the mixture is again brought to reflux for 6 h. 

  After returning to ambient temperature, 150 ml of water are slowly added, then 150 ml of 2N HCl.     The organic phase is collected, then the aqueous phase is again extracted with 2 times 100 ml of ether.  The organic extraction phase is washed with 2 times 100 ml of water.  The organic phase is extracted with a saturated sodium bicarbonate solution, then with 2 times 100 ml of water.  The aqueous extraction phase is washed with 3 times 100 ml of ether, then the aqueous phase is slowly acidified with a 2N HCl solution.  The aqueous phase is then extracted with 3 times 150 ml of ether. 

  The organic extraction phase is washed with twice 75 ml of water.  It is treated with activated carbon and dried over magnesium sulfate.  The solvent is evaporated in vacuo, and finally 29.3 g of the expected product are obtained. 



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



   - at 117 and 125.5 Hz. 



   - Hydrogen in position 2 at 315.5 and 346 Hz.    



   - Aromatics 412 to 455 Hz.    



   - COOH at 588 Hz. 



   1- [5-chloro 2-hydroxyphenyl] 1- [3-chlorophenyl] ethanol used at the start of the preparation of 6-chloro 4- (3-chlorophenyl) 4-phenyl [4H] 1,3-benzodioxin2 acid -carboxylic can be prepared in the following way: One disperses by stirring 11 g of magnesium in turnings in 100 ml of anhydrous ether, adds, drop by drop at room temperature and with stirring, a solution obtained by dissolving 64 g of methyl iodide in 100 ml of anhydrous ether. 

  A slight reflux of the solvent is maintained during the addition and the reflux is continued for 1 h, brings back to room temperature, then drop by drop over 25 min a solution of 31.7 g of (5-chloro 2-hydroxyphenyl) (3 -chlorophenyl) methanone in 100 ml of anhydrous ether and 150 ml of anhydrous benzene.  The ether is distilled, 250 ml of anhydrous benzene are added, then the solution is brought to reflux for 4 h.  The mixture is cooled to ambient temperature and maintained at this temperature by means of an ice bath, hydrolysis is carried out using a solution of hydrochloric acid N.  

  The organic phase is collected, the aqueous phase is again extracted with 2 times 80 ml of ether, the organic extraction phase is washed with 3 times 80 ml of water, the organic phase is dried over magnesium sulfate, then the solvent is evaporated. under vacuum.  31.5 g of expected product are then obtained, which is recrystallized from 750 ml of cyclohexane.  25.5 g of expected product are finally obtained.    F = 1250C.    



   Analysis for C141112O2Cl2:
 Calculated: C 59.38 H 4.27 Cl 25.04%
 Found: C 59.2 H 4.3 Cl 24.9%
 The [5-chloro 2-hydroxyphenyl] [3-chlorophenyl] methanone used at the start of the preparation of the above 1- [5-chloro 2-hydroxy phenyl] 1- [3-chlorophenyl] ethanol can be prepared as follows:
 Stage A: 4-Chiorophenyl 3-chlorobenzoate.    



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



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



   Analysis for C13H8Cl2O2:
 Calculated: C 58.45 H 3.02 Cl 26.55%
 Found: C 58.5 H 3.0 C 126.2%
 Stage B: [5- Chloro 2-hydroxyphenyl] [3-chlorophenyl]
 methanone. 



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

  60 g of crude product are finally obtained which are crystallized from a ethyl ether / petroleum ether mixture (Eb.    60-80 "C) (20/80).  It is filtered, dried and 41.3 g of expected product is obtained.  A sample of this product is recrystallized from cyclohexane.  F = 72 "C.    



   Analysis for C13H8Cl2O2:
 Calculated: C 58.45 H 3.02 Cl 26.55%
 Found: C 58.4 H 3.2 Cl 26.6%
Example 20:
 A and B isomers of 6-chloro 4 (3-chlorophenyl) 4-methyl [4H]
   J, methyl 3-bcnzodiavin-2-carboxylate. 



   29.3 g of 6-chloro 4- (3-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin-2-carboxylic acid are mixed with stirring in the form of a mixture of the two diastereoisomeric racemates obtained with example 19,
 300 ml of methanol and 30 g of strong acidic sulfonic cationic resin, refluxed for 20 h, with stirring, cooled to room temperature, wrung out the resin, rinsed with methanol and concentrated the filtrate under vacuum. 

  20 g of crude product are obtained which is chromatographed on a column of silica under pressure, eluting with a ethyl ether / petroleum ether mixture (Eb.    60-80 C) (20/80) and obtains, after fractionation and evaporation of the solvent:
 - 9.5 g of expected A isomer, of which 4 g are purified by recrystallization from methanol: 3.2 g of purified expected A isomer is obtained.  F = 112 "C.    



   Analysis for C, 7Hs304C12:
 Calculated: C 57.97 H 3.72 Cl 20.13%
 Found: C 57.9 H 4.0 Cl 19.8%
 NMR spectrum (deuterochloroform) (base frequency: 90 MHz).    



   - CH, at 172 Hz.    



     - COOCH3 at 345 Hz.    



   - Hydrogen in position 2 at 461.5 Hz. 



   - Aromatics from 623 to 660 Hz; and
   - 8.4 g of isomer B expected, in the form of a crude product. 



   Analysis for C1H13O4Cl2:
 Calculated: C 57.97 H 3.72 Cl 20.13%
 Found: C 58.2 H 4.0 Cl 20.1%
 NMR spectrum (deuterochloroform) (base frequency: 90 MHz).    



   - at 184 Hz.    



     - COOCH3 at 343.3 Hz.    



     - Hydrogen in position 2 at 509 Hz. 



   - Aromatics from 612 to 674 Hz. 



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



   6.5 g of methyl isomer A of 6-chloro 4- (3-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin-2-carboxylate, obtained in Example 20, 2, are mixed with stirring. 8 g of potassium hydroxide in pellets, 10 ml of water and 100 ml of methanol, stir the mixture for 16 h at room temperature, add 200 ml of water, wash the aqueous solution with 2 times 50 ml of ether , acidify the aqueous solution with a 2N hydrochloric acid solution, extract the aqueous phase with 3 times 80 ml of ether, wash the organic extraction phase with 2 times 50 ml of water, dry the ethereal phase with magnesium, the solvent is evaporated 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 = 13l "C.    



   Analysis for Cl6H1204C12:
 Calculated: C 56.66 H 3.57 Cl 20.90%
 Found: C 56.7 H 3.7 C120.6%
 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 22:
 Isomer B of 6-chloro 4 (3-chlorophenyl) 4-methyl [4H] I, 3-benzodioxin-2-carboxylic acid.    



   5.3 g of methyl isomer B of 6-chloro 4- (3-chlorophenyl) 4-methyl [4H] 1, 3-benzodioxin-2-carboxylate, obtained in Example 20, 2, are mixed with stirring. 4 g of potassium hydroxide in pellets, 10 ml of water, 100 ml of methanol, stir the mixture overnight at room temperature, add 250 ml of water, then wash the aqueous phase with twice 80 ml of ether , acidify the aqueous solution with a 2N hydrochloric acid solution, extract the aqueous phase with 3 times 80 ml of ether, wash the organic phase with 2 times 50 ml of water, dry the ethereal phase with magnesium sulfate,

   concentrated in vacuo and obtained 5.3 g of the expected product which is recrystallized from 110 ml of a cyclohexane / ethyl acetate mixture (80/30).  4 g of expected purified product are obtained.  F = 177 "C.    



   Analysis for C161112O4Cl2:
 Calculated: C 56.66 H 3.87 Cl 20.90%
 Found: C 56.8 H 3.8 C120.9%
 NMR spectrum (deuterochloroform) (base frequency: 90 MHz). 



     - CH3 at 185.5 Hz. 



     - Hydrogen in position 2 at 510 Hz. 



   - Aromatics = from 610 to 673 Hz.   



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



   8.1 g of 50% sodium hydride in oil, 60 ml of anhydrous dioxane and 360 mg of dibenzo-18 crown-6, of the type described in Synthesis 1976, p.  168, adding, keeping the solution at room temperature, over 10 min with stirring, a solution of 3.66 ml of dichloroacetic acid in 60 ml of anhydrous dioxane;

   then add at room temperature a solution of 8.7 g of 5-chloro x - [(1-methyl) ethyl] 2-hydroxy & phenylbenzenemethanol in 30 ml of anhydrous dioxane, heat the suspension for 10 h at 90- 100 C, bring to room temperature, add drop by drop while cooling with an ice water bath 500 ml of water, wash the aqueous phase with 2 times 200 ml of ether, extract the ethereal phase with 3 times 100 ml d sodium hydroxide 2N. 

  The aqueous phase is acidified with 2N hydrochloric acid and the acid released is extracted with 3 times 150 ml of ether, the ether phase is washed with 3 times 100 ml of water, the acid formed is extracted in the form of a salt. of sodium by extraction of the ethereal phase with saturated sodium bicarbonate solution, then with 3 times 100 ml of water, washing the aqueous extraction phase with 2 times 80 ml of ether, acidified by addition of hydrochloric acid 2N, extract the acid thus released with 3 times 150 ml of ether, wash the organic extraction phase with 3 times 80 ml of water, dry and treat with activated carbon, bring to dryness and obtain 8.8 g of expected product, as an oil. 



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



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



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



   - The two radicals CH3:
EMI12. 1
   from 49 to 69 Hz.    



     The hydrogen of the radical
EMI12. 2

   Aromatics from 410 to 465 Hz.    



      OH OH at 490 Hz.    



   The 5-chloro x - [(1-methyl) ethyl] 2-hydroxy a-phenylbenzene-methanol used at the start of the above preparation was prepared as follows: 21.4 g of magnesium are mixed by stirring, 200 ml of anhydrous ether and 2 ml of isopropyl bromide. 



  The mixture is stirred until the expected magnesium is formed, then added dropwise so as to maintain a slight reflux and, at room temperature, a solution of 110.8 g of isopropyl bromide in 400 ml of ether anhydrous.  When the addition is complete, the reflux is continued for 2 h.  Furthermore, 58.2 g of [(5-chloro 2-hydroxy) phenyl] phenylmethanone, 600 ml of anhydrous benzene are mixed, then 520 ml of the magnesian solution prepared above is added dropwise at room temperature.  The ether is distilled, gradually replacing it with benzene.  The reflux is continued for 6 h.  After cooling to room temperature, the reaction mixture is poured over it with an ice-cold 10% ammonium chloride solution. 

  The organic phase is decanted, the aqueous phase is extracted with 2 times 150 ml of ether.  The organic phases are combined, washed with 3 times 100 ml of water, dried, treated with activated carbon, the solvent is evaporated in vacuo.  74 g of crude product are obtained, which product is chromatographed on a silica column, eluting with methylene chloride; 18 g of crude product are obtained, after fractionation, which is taken up in 50 ml of cyclohexane.  8.7 g of expected product are obtained. 



  F = 114 "C.     A sample of this product is purified by recrystallization from cyclohexane.  F = 118 "C.    



   Analysis for C13H17O2Cl:
 Calculated: C 69.43 H 6.19 Cl 12.81%
 Found: C 69.7 H 6.2 Cl 12.8%
 NMR spectrum (deuterochloroform) (base frequency of the device used: 60 MHz). 



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



   - CH- to "" 165 Hz (multiplet). 



   - OH methanol at 165 Hz. 



   - OH of 2-hydroxy) at 537 Hz.    



   - Aromatics from 395 to 455 Hz. 



  Example 24:
 Isomer A of methyl 6-chloro 4 - [(1-methyl) ethyll 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate. 



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



   Mixing with stirring 8.8 g of 6-chloro 4 - [(1-methyl) ethyl] 4-phenyl [4] 1,3-benzodioxin-2-carboxylic acid obtained in Example 23, 100 ml of benzene anhydrous, adding while maintaining at ambient temperature 3.7 ml of triethylamine, 3.8 ml of thionyl chloride, 25 ml of anhydrous benzene, bring the mixture to reflux for 3 h, cool to ambient temperature, drain and wash the precipitate with a little anhydrous benzene and collects the filtrate which contains the expected product. 



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



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



   Analysis for Cl ^ Hl ^ CIO4:
 Calculated: C 65.80 H 5.52 Cl 10.22%
 Found: C 65.8 H 5.6 C 110.2%
 NMR spectrum (deuterochloroform) (base frequency: 60 MHz). 



   - The two CH3s of the (I-methyl) ethyl radical at 74 and 77 Hz. 



     - The - CH - of the (I-methyl) ethyl radical from 187 to 239 Hz. 



     - COOCH3 at 351 Hz. 



   - Hydrogen in position 2 at 479 Hz.    

 

   - Aromatics: peaks from 616 to 681 Hz. 



  Example 25:
 6-chloro 4 - [(1,1-dimethyl) ethyll 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates).    



   12.8 g of 50% sodium hydride in oil, 100 ml of anhydrous dioxane, 600 mg of dibenzo 18-crown-6 are mixed with stirring, then added dropwise, keeping the solution at temperature. room, a solution of 5.82 ml of dichloroacetic acid in 100 ml of dioxane, maintains the suspension at room temperature, dropwise adds a solution of 14.1 g of 5-chloro x- (l, I 1.1 -dimethyl) ethyl 2-hydroxy x-phenylbenzene- methanol in 100 ml of dioxane, then heats the mixture to 80 "C
 for 6 h, cools to room temperature and
 now at this temperature by an ice water bath, we add
 400 ml of water, extract the aqueous phase with 600 ml of ether,

   extracted by
 3 times 100 ml of 0.1N sodium hydroxide, acidifies the aqueous phase
 extraction with 2N hydrochloric acid, extracted 3 times 150 ml
 ether, wash the organic extraction phase with 3 times 100 ml of water,
 extracts the acid as a sodium salt using a solution
 saturated with sodium bicarbonate, then with 3 times 100 ml of water and
 collects the aqueous extracts.  The aqueous phase is washed 3 times
   100ml of ether, acidifies the aqueous phase with hydrochloric acid
 que2N, extracted with 4 times 150 ml of ether, washing the ethereal phase with
 3 times 100 ml of water, dry the ethereal phase over magnesium sulfate,
 treated with activated carbon, brings to dryness, obtains 9.1 g of expected product
 gross. 



   NMR spectrum (deuterochloroform) (base frequency of the appa
 reil: 60 MHz). 



   - Hydrogen in position 2 at 317 Hz (isomer A). 



   - Hydrogen in position 2 at 340 Hz (isomer B). 



     - (I, l-Dimethyl) ethyl at 63 and 65 Hz. 



   - Aromatics from 415 to 472 Hz.    



   - OH at 527 Hz. 



   5-chloro - (1,1-dimethyl) ethyl 2-hydroxy x-phenylbenzene-
 methanol used from the above preparation has been prepared
 as follows: 40.2 g (5-chloro 2-hydroxy phenyl) are mixed
 phenylmethanone, 400 ml of anhydrous ether, added dropwise to
 room temperature 192 g of a solution of terbutyllithium in the
 pentane, stirred for 2 h at room temperature, distills the ether in
 gradually replacing it with 600 ml of anhydrous benzene,
 the benzene reflux solution for 16 h, cools down to
 room temperature, pour over it an ice-cold chloride solution
 10% ammonium, eliminates the organic phase by decantation,
 extracts the aqueous phase with 2 times 100 ml of ether,

   wash the phase
 organic with 2 times 70 ml of water, dried over magnesium sulfate,
 treated with activated carbon, brings to dryness, obtains 50 g of crude product
 (in the form of an oil), which is chromatographed on a column of
 silica, eluting with methylene chloride, obtained by fractionation
 14.1 g of product, a sample of which is recrystallized in the
 cyclohexane.    F = 146 C.    



   Analysis for Cl, Hl902Cl:
 Calculated: C 70.22 H 6.59 Cl 12.19%
 Found: C 70.5 H 6.7 Cl 11.9%
 NMR spectrum (deuterochloroform) (base frequency:
 60 MHz). 



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



      OH OH methanol at 175 Hz.    



     Radical [(I, l-dimethyl) ethyl] at 75 Hz. 



     Aromatics of the phenyl radical into methanol from 420 to
 455 Hz. 



     - Other aromatics from 400 to 455 Hz. 



   Example 26:
 A-isomer of 6-chloro 4 - [(I, 1-dimethyl) ethyl] 4-phenyl [4H]
   Methyl 1,3-benzodioxin-2-carboxylate. 



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



   9.1 g of the mixture of diastereoisomeric racemates of 6-chloro 4 acid [(1,1-dimethyl) ethyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid prepared as indicated in 1 are mixed. 'example 25 and 100 mi of anhydrous benzene.  Then gradually added, maintaining at room temperature, 3.7 ml of triethylamine and then, drop by drop, a solution of 6.2 g of thionyl chloride in 25 ml of anhydrous benzene, brought to reflux for 3 h, cooled to at room temperature, drain and wash the precipitate with anhydrous benzene, collect the filtrate and concentrate the solution under vacuum until a volume of solution of 30 ml is obtained. 



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



   3 ml of methanol, 50 ml of anhydrous benzene, 3.7 ml of ethylamine are mixed with stirring, cooled to 15-20 ° C., the solution obtained in stage A above, to which 30 is added, is added dropwise to this temperature. ml anhydrous benzene, stirred for
 16 h at room temperature, drain and wash the precipitate with anhydrous benzene. 

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



   Analysis for C20H21CIO4:
 Calculated: C 66.57 H 5.87 C1 9.82%
 Found: C 66.5 H 6.0 C 110.0%
 NMR spectrum (deuterochloroform) (base frequency: 60 MHz. 



   - (1,1-Dimethyl) ethyl at 62 Hz. 



   - at 117 Hz.    



     - Hydrogen in position 2 at 338 Hz.    



   - Aromatics: peaks from 412 to 468 Hz. 



   Example 27:
 6-fluoro 4-methyl 4-phenyl [4H] 1,3-benzodioxin acid
 2-carboxylic (mixture of diastereoisomeric racemates). 



   25 g of sodium hydride are mixed under an argon atmosphere,
 350 cm3 of anhydrous dioxane, 1.55 g of dibenzo-18 crown-6,
 add in 1 hour a solution of 16.5 cm3 of dichloroacetic acid in
 150 cm3 of dioxane then, at the end of the reaction, add in 1 h at 22 "C
 a solution of 31 g of a-phenyl-methyl (5-fluoro 2-hydroxy) phenylmethanol in 150 cm3 of anhydrous dioxane, heated to
   80 "C, stir 6h at 80-85" C, cool, pour onto an ice / water mixture, extract with ether, acidify the aqueous phase, extract the aqueous phase with ether, wash the ethereal phase with water, extract with sodium bicarbonate the ethereal phase, wash with methylene chloride,

   acidifies the alkaline phases, extracted with methylene chloride, washed with water, dried over magnesium sulfate and brought to dryness under vacuum.  29.5 g of crude expected product are obtained (in the form of an oil). 



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



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



   - Aromatics from 400 to 450 Hz. 



   - at 505 Hz.    



     The cr-phenyl-methyl (5-fluoro 2-hydroxy) phenylmethanol used starting from the above preparation was prepared as follows: 13.3 g of magnesium are mixed, under an argon atmosphere, with stirring. turnings, 50 cm3 of anhydrous ether then, slowly, a solution of 34.7 cm3 of methyl iodide in 250 cm3 of anhydrous ether, then heating for 1 h at reflux.  220 cm3 of this magnesium solution obtained are then added to a solution of 30 g of: ephenyl (5-fluoro 2-hydroxy) phenylmethanone in 150 cm3 of anhydrous benzene, distilling the ether while replacing it with anhydrous benzene, then stir 4h at around 78 "C, cool, pour. on an ammonium chloride solution, extracted with ether, washed with water, dried over magnesium sulfate and brought to dryness under vacuum.  

  32 g of crude expected product are obtained.  A sample of this product is recrystallized from cyclohexane.    F = 122 C.    



   Analysis for C141113FO3:
 Calculated: C 72.40 H 5.64 F 8.18%
 Found: C 72.4 H 5.6 F 8.2%
Example 28:
 Isomer A of methyl 6-fluoro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylate. 



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



   Analysis for C ,, H ,, FO ,:
 Calculated: C 67.54 H 5.00 F 6.28%
 Found: C 67.7 H 5.0 F 6.2%
 NMR spectrum (deuterochloroform) (device frequency: 90 MHz).    



   - CH, at 171 Hz.    



     LOOCH3 at 345 Hz.    



     - Hydrogen in position 2 at 463 Hz. 



   - Aromatics: peaks from 615 to 680 Hz. 



  Example 29:
 Isomer A of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylate of (2,2-dimethyl 1,3-dioxolan-4-yl) methyl.    



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



   4.9 g of isomer A of 6-chloroemethyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid obtained in Example 3 are mixed by stirring, 30 ml of anhydrous benzene, cooled to 10 "C, add dropwise at this temperature 1.66 g of triethylamine.  Then a solution of 2.5 g of thionyl chloride in 25 ml of anhydrous benzene is added at this temperature and dropwise, then the mixture is brought to reflux for 2 h.  The suspension is cooled to room temperature, the precipitate is drained and the filtrate which contains the expected product is collected. 



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



   2.25 g of (2,2-dimethyl 1,3-dioxolan4-yl) methanol, 50 ml of anhydrous benzene, 2.3 ml of triethylamine are mixed by stirring, the filtrate is added dropwise at room temperature. stage A above.  The mixture is stirred for 20 h at room temperature.  It is filtered, the filtrate is washed with a 10% sodium carbonate solution, then washed with water until neutral pH.  The benzene phase is dried over calcium chloride and treated with active charcoal, the solvent is evaporated under vacuum, 4.5 g of crude product are obtained which is chromatographed on a silica column, eluting with methylene chloride.  After fractionation, 2 g of crude expected product are obtained, in the form of a colorless gum. 



  Analysis for C22H23OÏCI
 Calculated: C 63.08 H 5.53 Cl 8.46%
 Found: C 62.0 H 5.5 C18.9%
 NMR spectrum (deuterochloroform) (base frequency of the apparatus: 60 MHz). 



      The CH3s of 2,2-dimethyldioxolan at ¯ 81-82Hz.    



     CH3 in position 4 at 115 Hz. 
EMI14. 1




  - Aromatics from 411 to 441 Hz. 
Example 30:
 Isomer A hydrochloride of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate of 2- (diethylamine) ethyl. 



   A mixture of 6.2 g of A-isomer of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate obtained as indicated in Example 16, 100 ml of anhydrous toluene and 2.6 g of diethylamineethanol and a tiny amount of sodium hydride.  Maintained at reflux for 3 h, cooled, added 5 ml of a 4N hydrochloric acid solution in ether, added 200 ml of anhydrous ether, filtered, washed with ether, dried and obtained 3.7 g of product which is taken up in 20 ml of isopropanol at 60 ° C., treated with active carbon, cooled, added 50 ml of ether, filtered, dried and obtained 2.7 g of the expected product. 



     F = 110 C.    



   Analysis for C22H27CI2NO4:
 Calculated: C 60.00 H 6.18 Cl 16.10 N 3.18%
 Found: C 59.6 H 6.4 Cl 15.9 N 3.4%
Example 31:
 6-chloro 4-ethyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid (mixture of the two diastereoisomeric racemates). 



   250 cm3 of liquid ammonia, which has been condensed, are mixed with stirring, with approximately 10 mg of ferric nitrate, 4.8 g of sodium which is added in small portions, then added in 1 l / 2 h at 28-30 "C a solution of 26.2 g of 5-chloroethyl 2-hydroxy a-phenylbenzenemethanol in 200 cm3 of anhydrous toluene, increases the temperature and drives off the released ammonia, heats at reflux for 3 h, adds 100 cm3 of toluene and, at 50 ° C., 18 g of potassium dichloroacetate, maintains overnight at reflux and adds 9 g of potassium dichloroacetate, stirred for another 2 hours at reflux, cools, pours into water, eliminates the organic phase,

   acidifies the aqueous phase and extracts it with ether, wash the ethereal phase with 3 times 500 cm3 of water,
 extract the ethereal phase with 3 times 300 cm3 of sodium bicarbonate, wash with 2 times 500 cm3 of ether, acidify the aqueous phase with concentrated hydrochloric acid, extract with 3 times 500 cm3 of ether,
 wash with water, dry over magnesium sulfate, bring to dry vacuum and
 27 g of crude expected product are obtained. 



   5-chloroethyl 2-hydroxy a-phenylbenzenemethanol, used
 at the start of the preparation of the product of Example 31 above,
 can be prepared as shown in Example 23, but using, at
 instead of isopropyl bromide, ethyl iodide.  F = 85 "C.    



  Example 32:
 Isomers A and B of 6-chlorine 4-ethyl 4-phenyl [4H]
   Methyl 1,3-benzodioxin-2-carboxylate. 



   Two diastereoisomeric racemates A and B of 6-chloro 4-ethyl 4-phenyl [4H] were used for the preparation and the isolation.
   Methyl 1,3-benzodioxin-2-carboxylate, from the mixture of the A and B isomers of the corresponding acids, mixture obtained in Example 31, the same technique as that described in Example 20.  There 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
 read in methanol at reflux.  3.5 g of the expected isomer A are obtained.
 purified.    F = 128 C.    

 

   Analysis for Cl8Hl7CIO4:
 Calculated: C 64.96 H 5.15 Cl 10.65%
 Found: C 65.0 H 5.2 Cl 10.4%
 NMR spectrum (deuterochloroform) (base frequency:
 60 MHz). 



   - in 4 to 44, 51, 58, 110 to 160 Hz.    



     - COOCH, at 232 Hz. 



     Hydrogen in position 2 at 314 Hz.      



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



   - Phenyl at 4 to 445 Hz, and 4 g of isomer B expected.  F = 108 "C.    



  Example 33:
 6-chloro 4- (4-chlorophenyl) 4-methyl [4H1 1,3-benzodioxin-2-carboxylic acid (mixture of the two diastereoisomeric racemates).    



   250 cm 3 of dioxane, 1.6 g of dibenzo-18 crown-6, 25 g of sodium hydride are mixed with stirring, then, in 45 min, a solution of 16 cm 3 of dichloroacetic acid in 100 cm 3 of dioxane is added, then , in 1 h, a solution of 36.6 g of 5-chloro 2-hydroxy r * -methyl - (4-chlorophenyl) benzene-methanol in 150 cm 3 of dioxane is added at 30 "C, the mixture is heated to 80" C for 5 h, cools, pours onto a mixture of ice and water, extracted with 3 times 500 cm3 of ether, acidifies the aqueous phase with concentrated hydrochloric acid, extracted with 3 times 500 cm3 of ether, extracts the ethereal phase with sodium bicarbonate, acidifies the aqueous phase and extracted with 4 times 300 cm3 of ether, washed with water, dried over magnesium sulfate, brings to dryness under vacuum and obtains 40 g of crude expected product. 



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



     Hydrogen in position 2 at 309 Hz.    



      - CH3 at 1l6Hz.    



   This corresponds to one of the expected isomers (isomer A). 



     Hydrogen in position 2 at 340 Hz. 



      CH3 at 124 Hz.    



   This corresponds to the other expected isomer (B isomer). 



     Aromatics from 405 to 445 Hz.    



      ¯¯ OH at 5.10Hz.    



   The 5-chloro 2-hydroxy x-methyl x- (4-chlorophenyl) benzene-methanol used starting from the above preparation can be prepared as follows: Mixing, with magnetic stirring and under an argon atmosphere, 13, 5 g of 2-hydroxy 5-chloroacetophenone, 130 cl 3 of anhydrous ether, cooled externally by an ice water bath, introduced dropwise, maintaining the internal temperature between 10 and 20OC, 330 cm3 of an ethereal solution , freshly prepared and filtered from the magnesium of 1-chloro 4-bromobenzene titrating 0.46 mol / l, keeps stirring overnight at room temperature. 

  The yellow suspension is ice-cold and 125 ml of ice-cold 2N aqueous hydrochloric acid are introduced dropwise, decanted, the organic phase is washed with water, dried over sodium sulfate, treated with active charcoal, drained and brought to dryness under vacuum , the residue is dissolved in 100 cm3 of cyclohexane and left to crystallize with stirring, the precipitate is drained, pasted with a little cyclohexane, dried in an oven and obtained 19.3 g of the expected product.  F = 130 "C.    



   Analysis for C141113O3Cl2:
 Calculated: C 59.38 H 4.27 Cl 25.04%
 Found: C 59.7 H 4.3 Cl 24.7%
Example 34:
 Isomer A of methyl 6-chloro 4- (4chlorophenyl) 4-methyl [4H] 1,3-ben odioxin-2-carboxylate. 



   40 g of the mixture of diastereoisomeric racemates of 6-chloro 4- (4-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin2-carboxylic acid are mixed, mixture as obtained in Example 33,400 cm3 of methanol, 180 g of strong sulphonic resin, stirred at reflux for 18 h, cooled, wrung, washed 4 times with 300 cm3 of ether, brought to dryness under vacuum, took up the residue in 500 cm3 of ether, washed with 3 300 cm3 of sodium bicarbonate, then 4 times 500 cm3 of water, dry over magnesium sulphate, bring to dryness under vacuum and obtain 35.5 g of product.  The product obtained is treated with 100 cm3 of methanol, left overnight at room temperature, filtered, washed with ice-cold methanol, 10 g of product are obtained which is recrystallized from 60 cm3 of methanol, left overnight at room temperature, and 9.1 g of isomer A expected. 

  F = 108 "C.    



      Analysis for C17H14Cl2O4:
 Calculated: C 57.81 H 4.0 Cl 20.0%
 Found: C 58.0 H 4.0 Cl 19.9%
 NMR spectrum (deuterochloroform) (base frequency: 60 MHz). 



      - CH3àil5Hz.    



     - COOCH3 at 231 Hz. 



   - Hydrogen in position 2 at 308 Hz. 



   - Aromatics from 412 to 442 Hz. 



  Example 35:
 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid (mixture of the two diastereoisomeric racemates).    



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

  A precipitate is formed which is extracted with 3 times 100 ml of ether. The organic phases are washed with 2 times 80 ml of water, the expected acid re-extracted 3 times with 50 ml of a saturated aqueous solution of 5% sodium bicarbonate. The aqueous extraction phase is washed with 3 times 80 ml of ether, the alkaline solution is acidified with 90 ml of a 2N hydrochloric acid solution.



  The expected acid is extracted with 4 times 100 ml of ether. The organic phase is washed with water, dried over magnesium sulfate in the presence of activated carbon, the solvent is removed in vacuo, 7.85 g of crude product is obtained which is taken up in hexane. The crystals are wrung and dried
 obtained, and obtains 6 g of the expected product. F = 144 "C.



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



   - at 117 Hz.



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



     - CH3 at 125.5 Hz.



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



   - Aromatics from 405 to 450 Hz.



   - OH has ¯ 350 Hz.



  Example 36:
 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid (mixture of the two diastereoisomeric racemates).



   10 cm 3 of dioxane, 1.35 g of 50% sodium hydride in oil are mixed; at 15 "C, 60 mg of dibenzo-18 crown-6 is added, then, in 5 min, 0.61 cm 3 of dichloroacetic acid and 10 nn 3 of dioxane. 1.25 g of 2-hydroxy 5-chloro a-methylbenzhydrol and 5 cmJ of dioxane. Then heated for 6 h to 80 "C, then cooled to 20" C, added 2 cm3 of methanol, poured into ice water, extracted 3 times with ethyl acetate, washed 5 times with 0.1N iced sodium hydroxide.

  The aqueous phases are combined, acidified to pH 1 with a 2N hydrochloric acid solution, extracted 3 times with methylene chloride, dried and brought to dryness and the crude expected product is collected.



  Example 37:
 Piperidine salt of the A-isomer of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid.



   The mixture of the two diastereoisomeric racemates of 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid obtained in Example 36 above is dissolved in 4 cm3 of ethyl acetate, add 0.8 cm3 of piperidine at 10 "C. The expected piperidine salt crystallizes by scraping. After 15 minutes, the product is drained, washed with ethyl acetate, with ether, dried at 20" C under vacuum and obtained 855 mg of expected product.

  The mother crystallization liquor is collected and diluted with methylene chloride, washed with ice-cold N hydrochloric acid, dried and brought to dryness, the residue is taken up in 12 cm3 of methylene chloride and 0.6 cm3 of etherate is added. boron trifluoride, leave to stand for 1/2 h at 20C, pour on ice, wash twice with water, reextract with methylene chloride, dry and bring to dryness, take up in 2 cm3 of ethyl acetate and 0.4 cm3 of piperidine, leaves to crystallize and isolates 545 mg of the expected product. A new operation carried out in the same way, starting from the mother liquor of crystallization (isomerization with boron trifluoride, addition of piperidine) makes it possible to collect a further 130 mg of expected product. A total of 1.53 g of expected product was therefore obtained.

  F = ¯ 165 "C.



  Example 38:
 Isomer A of 6-chloro 4-methyl 4-phenyl [4H] I, 3-benzodioxin-2-carboxylic acid.



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



  Example 39:
 7-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid (mixture of the two diastereoisomeric racemates).



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

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



   NMR spectrum CDCI3 60 MHz.



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



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



   The 4-chloro 2-hydroxy-methyl-phenylbenzenemethanol, used at the start of the above preparation can be prepared as follows: 16.2 g of 2-hydroxy 4- (chloro phenyl) ethanone are mixed with stirring in 170 ml of ether, then introduced, dropwise, at 20 "C, 315 ml of a solution of phenylmagnesium bromide in ether grading 0.8 mol / l, left stirring overnight at room temperature, pour the mixture on ice, acidified with 40 ml of hydrochloric acid, extracted with 4 times 250 ml of ether, decanted, washed the organic phases with 4 times 150 ml of water, dried the organic phase on magnesium sulfate in the presence of activated carbon, dispersed in 50 ml of cyclohexane,

   passes to the vacuum oven for 24 h and obtains 14.45 g of the expected product, which recrystallizes 0.200 g from cyclohexane. F = 82 "C.



   Analysis for C141113ClO3:
 Calculated: C 67.61 H 5.27 Cl 14.25%
 Found: C 67.3 H 5.1 Cl 14.3%
Example 40:
 Isomer A of methyl 7-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylate.



   19.5 g of the mixture of diastereoisomeric racemates of 7-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid (obtained in Example 39) are dissolved in 300 ml of chloride chloride. methylene, cools to 15 "C, adds, drop by drop, 9.1 gg of boron trifluoride etherate, leaves stirring at room temperature for 2 h, then adds 300 ml of methanol, leaves again under stirring for one overnight, pour over 500 ml of a saturated sodium chloride solution, extracted with 3 times 200 ml of methylene chloride, wash the organic phase with 50 ml of a saturated aqueous solution of sodium bicarbonate, decant, wash the phase organic by twice 50 ml of water (until neutral),

   the organic phase is dried over magnesium sulfate in the presence of activated carbon, filtered, the solvent is removed under vacuum and 17.1 g of crude expected product are obtained, of which 16.6 g are recrystallized from methanol, dried and obtained
 10.35 g of expected product. F = 144 "C.



      Analysis for C1H15ClO4:
 Calculated: C 64.05 H 4.74 Cl 11.12%
 Found: C 63.8 H 4.7 Cl 11.1%
 NMR spectrum CDCI3 60 MHz.



     - Hydrogen in position 2 at 310 Hz.



     - CH3 hydrogens in position 4 at 115 Hz.



     - COOCH3 hydrogens at 230 Hz.



  Example 41:
 Hydrochloride of the A-isomer of 6-chloro 4-methyl 4-phenyl [4H] I, 3-benzodioxin-2-carboxylate of 2- (dimethylamino) ethyl.



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

 

   Analysis for C20H22CINO4:
 Calculated: C 58.26 H 5.62 Cl 17.20 N 3.40%
 Found: C 58.1 H 5.9 Cl 17.0 N 3.5%
 RMNCDCLL3 spectrum 60 MHz.



     - Hydrogen in position 2 at 312 Hz.



      - Hydrogens of COO-C112C112- at 285 and 235 Hz.



   CH3
   Hydrogens from -N to 172 Hz.



   CH3
 - CH3 hydrogens in position 4 at 115 Hz.



   - Aromatic hydrogens from 411 to 441 Hz.



   Example 42:
 Tablets corresponding to the following formula were prepared:
 - 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodi acid
 oxin-2-carboxylic (as isomer A) 300 mg
 - excipient q.s. for a tablet finished at 500 mg
 (detail of excipient: lactose, starch, talc, magnesium stearate).



     Example 43:
 We prepared capsules corresponding to the following formula:
   Methyl 6-chloro 4-methyl 4-phenyl [4H] I, 3-benzodioxin2-carboxylate (as isomer A) 25 mg
   excipient q.s. for a capsule finished at 500 mg (detail of the excipient: talc, magnesium stearate, aerosil).



  Example 44:
 Tablets corresponding to the formula have been prepared:
 - isomer A as obtained in Example 21 300 mg
 - excipient q.s. for one tablet, finished at 500 mg (detail of excipient: talc, magnesium stearate, aerosil).

 

  Example 45:
 We prepared capsules corresponding to the general formula:
 - d isomer as obtained in Example 18 250 mg
 - excipient q.s. for a capsule finished at 500 mg (detail of the excipient: talc, magnesium stearate, aerosil).



  Example 46:
 a) Tablets corresponding to the formula were prepared:
 - isomer A as obtained in Example 40 300 mg
 - excipient q.s. for a tablet finished at 500 mg (detail of excipient: talc, magnesium stearate, aerosil).



   b) Capsules corresponding to the general formula were prepared:
 - isomer A hydrochloride,
 as obtained in Example 41 250 mg
 - excipient q.s. for a capsule finished at 500 mg (detail of the excipient: talc, magnesium stearate, aerosil).


    

Claims (10)

 CLAIMS 1. Compounds of general formula I ': EMI1.1  in which R'l represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a 2,3-dihydroxypropanyl radical, a (2,2-dimethyl 1,3-dioxolan4-yl) methyl radical or a dialkylaminoalkyl radical in which the alkyl radicals contain from I to 4 carbon atoms, R2 represents a hydrogen atom or an alkyl radical containing from I to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 with 5 carbon atoms or a phenyl radical, and R4 and R5, identical or different, represent a hydrogen atom or a halogen atom, in racemic or optically active forms or in the form of mixtures of these isomers, as well as their alkaline salts,  alkaline earth, aluminum, ammonium and amines when R'l represents a hydrogen atom, and their addition salts with acids when R 'represents a dialkylaminoalkyl radical.  2. Compounds according to claim 1, of general formula: EMI1.2  in which R1 and R2, identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical, and R4 and R5, identical or different, represent a hydrogen atom or a halogen atom, in racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkaline, alkaline-earth salts, of aluminum, ammonium and amines of the products of formula I in which R1 represents a hydrogen atom.  3. Compounds according to claim 2, in which R and R2, which are identical or different, represent a hydrogen atom or a methyl radical, R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R4 represents an atom of hydrogen and R5 represents a hydrogen atom or a chlorine atom, in racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline-earth, aluminum, ammonium and amines of said products of formula I in which R1 represents a hydrogen atom.  4. Compounds according to claim 2, in which R1 represents a hydrogen atom or a methyl radical, R2 represents a hydrogen atom, R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R4 represents an atom of hydrogen and R5 represents a chlorine atom, in racemic or optically active forms, or in the form of mixtures of these isomers, as well as the alkali, alkaline-earth, aluminum, ammonium and amine salts of said products of formula I, in which R represents a hydrogen atom.  5. Compounds according to claim 2, in racemic or optically active form or in the form of mixtures of these isomers, the names of which follow:  6-chloro 4-methyl 4-phenyl [4H] 1, 3-benzodioxin 2-carboxylic acid;  6-chloro 2,4-dimethyl 4-phenyl [4H] 1, 3-benzodioxin2-carboxylic acid;  6-chloro 4-phenyl [4H] 1,3-benzodioxin -2-carboxylic acid;  6-chloro 4,4-diphenyl [4H] 1,3-benzodioxin2-carboxylic acid;  4-methyl 4-phenyl 1,3-benzodioxin-2-carboxylic acid;  methyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate;  methylene 6-chloro 4,4-diphenyl [4H] 1,3-benzodioxin-2-carboxylate; ;  ethyl 6-chloro 4-methyl 4-phenyl [4H] 1, 3-benzodioxin-2-carboxylate;  sodium 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate:  the piperidine salts of the two diastereoisomeric racemates A and B of 6-chloro 4-methyl 4-phenyl [4H] 1, 3-benzodioxin2-carboxylic acid;  the d and 1 isomers of the two diastereoisomeric racemates A and B of 6-chloro 4methyl 4-phenyl [4H] 1, 3-benzodioxin2-carboxylic acid;  methyl 6-chloro 4- (3-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin2-carboxylate;  6-chloro 4- (3-chlorophenyl) 4-methyl [4H] 1, 3-benzodioxin-2-carboxylic acid;  methyl 6-chloro 4 - [(1-methyl) ethyl] 4-phenyl [4H] 1,3-benzodioxin2-carboxylate; ;  methyl 6-chloro 4 [(1,1-dimethyl) ethyl] 4-phenyl [4H] 1,3-benzodioxin2-carboxylate;  methyl 6-fluoro 4-methyl 4-phenyl 1,3- [4H] -benzodioxin-2-carboxylate;  methyl 6-chloro 4ethyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate;  methyl 6-chloro 4- (4.chlorophenyl) 4-methyl [4H] 1,3-benzodioxin2-carboxylate;  (2,2-dimethyl 1,3-dioxolan-4-yl) methyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate;  2,3-dihydroxypropanyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate; ;  2- (diethylamino) ethyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate and its addition salts with acids;  The A-isomer of 6-chloro 4-methyl 4-phenyl acid [4H]  1, 3-benzodioxin-2-carboxylic;  the A-isomer of 6-chloro 2,4dinethyl 4-phenyl acid [4H]  1,3-benzodioxin-2-carboxylic;  The A-isomer of sodium 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylate;  The A-isomer of 6-ehloro 4- (3-chlorophenyl) 4-methyl [4H] 1, 3-benzodioxin-2-earboxylic acid; ;  the d and 1 isomers of the A isomer of 6-ehloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylic acid.  6. Compounds according to claim 1, the names of which follow:  the A-isomer of methyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylate;  The A-isomer of methyl 6-chloro 4- (3-ehlorophenyl) 4-methyl [411] 1,3-benzodioxin-2-carboxylate;  The A-isomer of ethyl 6-ehloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylate.  7. Pharmaceutical composition containing, as active principle, one of the compounds of formula I 'according to claim 1 or one of its pharmaceutically acceptable salts.  8. Composition according to claim 7, characterized in that it contains one of the compounds of formula I or one of its pharmaceutically acceptable salts, as defined in claim 2.  9. Composition according to claim 7, characterized in that it contains one of the compounds of formula I 'or one of its pharmaceutically acceptable salts, as defined in claim 3, 4 or 5.  10. Composition according to claim 7, characterized in that it contains one of the compounds of claim 6.  The subject of the present invention is new 1,3-benzodioxin derivatives of general formula: EMI2.1  in which R ′ represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a 2,3-dihydroxypropanyl radical, a (2,2-dimethyl 1,3-dioxolan 4-yl) methyl radical or a dialkylaminoalkyl radical in which the alkyl radicals contain from 1 to 4 carbon atoms, R2 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical, and R4 and R5, identical or different, represent a hydrogen atom or a halogen atom, in racemic or optically active forms or in the form of mixtures of these isomers, as well as alkaline, alkaline earth salts,  of aluminum, ammonium and amines of the products of formula I 'in which R' represents a hydrogen atom and the addition salts with acids of the products of formula I 'in which R' represents a dialkoylaminoalkyl radical.  The subject of the invention is in particular products of general formula: EMI2.2  in which R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms and R2, R3, R4 and Rs have the meanings indicated above, in racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkali, alkaline-earth, aluminum, ammonium and amine salts of the products of formula I in which R represents a hydrogen atom.  The term alkyl containing from 1 to 5 carbon atoms can denote, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, terbutyl, pentyl radical. The term halogen atom can denote, for example, a chlorine atom, a bromine atom, a fluorine atom. By mixtures of these isomers is meant a mixture of racemic isomers or a mixture of optically active isomers, in whatever proportion. They may especially be mixtures in any proportion of racemates, mixtures in any proportion of two optical antipodes, mixtures in any proportion of two optically active diastereoisomeric products.  The alkali or alkaline earth salts of the products of formula I in which R1 represents a hydrogen atom may be, for example, the salts of soldium, potassium, lithium or calcium.  The amine salts of the products of formula I, in which R1 represents a hydrogen atom, are the usual amine salts. Among the usual amines, mention may be made of monoalkoylamines, such as, for example, methylamine, ethylamine, propylamine, dialkoylamines, such as, for example, dimethylamine, diethylamine, di-n-propylamine, trialcoylamines, such as triethylamine. Mention may also be made of piperidine, morpholine, piperazine and pyrrolidine.  The addition salts with the acids can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, maleic, fumaric, succinic, tartaric acids, alkylmonosulfonic acids, such as, for example. example, methanesulfonic acid, ethanesulfonic acid, Propanesulfonic acid, alkyl disulfonic acids, such as, for example, x-i-ethanedisulfonic acid.  Among the products according to the invention, there may be mentioned in particular:  the products as defined by general formula I above, characterized in that, in said formula I, R5 and R2, identical or different, represent a hydrogen atom or a methyl radical, R3 represents a hydrogen atom, a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 represents a hydrogen atom or a chlorine atom in racemic or optically active forms or in the form of mixtures of these isomers , as well as the alkali, alkaline earth, aluminum, ammonium and amine salts of said products of formula I, in which R, represents a hydrogen atom; ;  the products as defined by general formula I above, characterized in that, in said formula I, R represents a hydrogen atom or a methyl radical, R2 represents a hydrogen atom, R3 represents a d atom hydrogen, a methyl radical or a phenyl radical, R4 represents a hydrogen atom and R5 represents a chlorine atom, in racemic or optically active forms or in the form of mixtures of these isomers, as well as the alkaline, alkaline-earth salts , aluminum, ammonium and amines of the said products of formula I, in which R represents a hydrogen atom,  and in particular, in their racemic and optically active forms, the products named in the examples. Among these, there may be mentioned in particular in the form of A isomers, as obtained in the examples, the products whose names follow:  methyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate;  methyl 6-chloro 4- (3-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin2-carboxylate;  ethyl 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate;  6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid;  6-chloro 2,4-dimethyl 4-phenyl [4H] 1,3-benzodioxin2-carboxylic acid;  sodium 6-chloro 4-methyl 4-phenyl [4H] 1,3-benzodioxin-2-carboxylate;  6-chloro 4- (3-chlorophenyl) 4-methyl [4H] 1,3-benzodioxin-2-carboxylic acid; ;  the d and 1 isomers of 6-chloro 4-methyl 4-phenyl [4H] 1, 3-benzodioxin-2-carboxylic acid. ** ATTENTION ** end of the CLMS field may contain start of DESC **.