JPS6113473B2 - - Google Patents

Description

[Detailed description of the invention]

The subject of the invention is the following general formula ' [Here, R′ ₁ is a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, (2,2-dimethyl-1,3
-dioxolan-4-yl) methyl group or dialkylaminoalkyl group (where the alkyl group is 1-
_R2 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; _R3 represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms; or phenyl group, R ₄ and R ₅ may be the same or different and represent a hydrogen atom or a halogen atom] in the form of a racemic or optically active form or a mixture of these isomers, and alkali metal, alkaline earth metal, aluminum, ammonium and amine salts of compounds of formula ' in which R' ₁ represents a hydrogen atom, and addition salts with acids of compounds of formula ' in which R' ₁ represents a dialkylaminoalkyl group. be. More particularly, the subject matter of the invention is the following general formula:
(R ₁ and R ₂ may be the same or different and represent a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms, R ₃ is a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, represents a group or a phenyl group,
R ₄ and R ₅ may be the same or different and represent a hydrogen atom or a halogen atom) in the form of a racemic or optically active form or a mixture of these isomers, and R ₁ represents a hydrogen atom. Alkali metal, alkaline earth metal, aluminum, ammonium and amine salts of compounds of the formula. The term "alkyl group containing 1 to 5 carbon atoms" includes, for example, methyl, ethyl, n-propyl,
It can represent isopropyl, n-butyl, isobutyl, t-butyl or pentyl groups. The expression "halogen atom" can represent, for example, a chlorine atom, a bromine atom or a fluorine atom. The expression "mixture of these isomers" is to be understood as a mixture of racemic isomers or a mixture of optically active isomers in any proportion. In particular, mixtures of racemic compounds in any proportion,
A mixture of two optical enantiomers in any proportion or two
There are mixtures of optically active diastereomeric compounds in any proportion. Alkali metal or alkaline earth metal salts of compounds of the formula in which R ₁ represents a hydrogen atom may be, for example, sodium, potassium, lithium or calcium salts. The amine salt of the compound of the formula in which R ₁ represents a hydrogen atom is a common amine salt. Among the common amines, monoalkylamines such as methylamine, ethylamine and propylamine, such as dimethylamine, diethylamine and di-n-
Mention may be made of dialkylamines such as propylamine, for example trialkylamines such as triethylamine. Mention may also be made of piperidine, morpholine, piperazine and pyrrolidine. Addition salts with acids include, for example, hydrochloric acid, hydrobromic acid,
Alkanesulfonic acids such as hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid or propanesulfonic acid, e.g. α and β
- It may be a salt formed with an alkyl disulfonic acid such as ethanedisulfonic acid. More particularly, the subject matter of the present invention is that in the above formula R ₁ and R ₂ may be the same or different and represent a hydrogen atom or a methyl group;
A racemic or optical form defined by the above general formula, characterized in that R ₃ represents a hydrogen atom, a methyl group, or a phenyl group, R ₄ represents a hydrogen atom, and R ₅ represents a hydrogen atom or a chlorine atom. Compounds in the active form or in the form of mixtures of their isomers, and alkali metal, alkaline earth metal, aluminum, ammonium and amine salts of the compounds of the formula in which R ₁ represents a hydrogen atom, and in which R ₁ represents a hydrogen atom or a methyl group, R ₂ represents a hydrogen atom, R ₃ represents a hydrogen atom, a methyl group or a phenyl group, R ₄ represents a hydrogen atom, and R ₅ represents a chlorine atom; defined by the general formula,
Compounds in the form of racemic or optically active forms or mixtures of these isomers, as well as alkali metal, alkaline earth metal, aluminum, ammonium and amine salts of the compounds of the formula in which R ₁ represents a hydrogen atom. In particular, a subject of the invention is the compounds mentioned in the examples in racemic or optically active form. More particularly, the subject matter of the present invention is a compound in the form of isomer A, as obtained in the Examples, whose compound name is as follows. Methyl 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate, 6-chloro-4-(3-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2-
Methyl carboxylate, 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-ethyl carboxylate, 6-chloro-4-methyl-4-phenyl[4H]-1,3 -Benzodioxine-2-carboxylic acid, 6-chloro-2,4-dimethyl-4-phenyl [4H]-1,3-benzodioxin-2-carboxylic acid, 6-chloro-4-methyl-4-phenyl [ 4H]-1,3-benzodioxin-2-carboxylic acid sodium, 6-chloro-4-(3-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2-
Carboxylic acids and isomers d and l of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid. In addition, the following compounds may also be mentioned. Two diastereomeric racemates A and B of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid
Piperidine salt, two diastereomeric racemates A and B of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid
isomers d and l, and their racemic or optically active forms, 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (2,2-dimethyl- 1,3-dioxolan-4-yl)methyl, 2-(diethylamino)ethyl 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate and its addition with acid salt. The term "isomer A" means one or the other of two diastereomeric racemates of a compound of formula having two asymmetric carbon atoms. According to the invention, the alkali metal, alkaline earth metal, aluminum, ammonium and amine salts of the compounds defined by the above general formula and of the formula in which R ₁ represents a hydrogen atom can be prepared by the following formula: (where R ₃ , R ₄ and R ₅ are as defined above) in the presence of a basic condensing agent. (where R ₂ is as defined above) to obtain the alkali metal salt of the acid corresponding to the compound of the formula in which R ₁ represents a hydrogen atom, and if necessary the salt with an acid to obtain an acid of the corresponding formula, salt formation or esterification of the acid to obtain the corresponding salt or ester, if necessary, and further, if necessary, a compound of the formula in racemic or optically active form or The present invention relates to a method for producing a compound of the general formula and a salt thereof, which is characterized in that the compound is isolated in the form of a mixture of these isomers. Under preferred conditions for carrying out the invention, the above-described manufacturing process is carried out in the following manner. The alkali metal salt of the compound of formula may be especially the sodium, potassium or lithium salt. Basic condensing agents are in particular alkali metal alcoholates, such as sodium methylate, sodium ethylate or sodium t-butylate; alkali metal hydrides, such as sodium hydride or potassium hydride; sodium amide, potassium amide or lithium amide. or sodium. The reaction of compounds of the formula with compounds of the formula is carried out in organic solvents such as, for example, benzene, toluene, xylene, ethyl ether, dioxane, dimethylformamide, tetrahydrofuran and hexamethylphosphortriamide, or mixtures of these solvents. The reaction is also carried out preferably in the presence of a compound acting as an ether-crown type catalyst, such as dibenzo-18-crown-6, dicyclohexyl-18-crown-6 or 18-crown-6, for example dioxane. This can be carried out in the presence of an organic solvent such as. The reaction can be carried out at temperatures between -10°C and the reflux temperature of the reaction mixture. A compound of formula is reacted with a basic condensing agent before reacting it with a compound of formula. Compounds of the general formula in which R ₁ represents an alkyl group containing 1 to 5 carbon atoms, if they are prepared by esterification of the corresponding acids:
It is prepared by reacting the acid with an alcohol of the formula R ₁ OH, where R ₁ represents an alkyl group containing 1 to 5 carbon atoms, preferably in an acidic medium. For example, it is possible to carry out in the presence of an acid such as hydrochloric acid or p-toluenesulfonic acid or in the presence of an acid type resin. Esters of the general formula in which R ₁ represents an alkyl group containing 1 to 5 carbon atoms can also be prepared by transesterification. Furthermore, a compound of the formula in which R ₁ represents a methyl group can also be produced by reacting a compound of the formula in which R ₁ represents a hydrogen atom with diazomethane in an organic solvent. Esters of the general formula can also be prepared from functional derivatives of the corresponding acids of the formula, such as acid chlorides, in conventional manner. Functional derivatives of acids of formula are prepared by conventional methods. Alkali metals, alkaline earth metals, aluminum, compounds of the above formula in which R ₁ represents a hydrogen atom,
Ammonium and amine salts can be produced by reacting a compound of the formula with a corresponding base. Bases are inorganic or organic bases such as, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, aluminum hydroxide, sodium ethylate, potassium ethylate, ammonia or, for example, methylamine, ethylamine, propylamine, It may be an amine such as dimethylamine, diethylamine, di-n-propylamine, triethylamine, piperidine, morpholine, piperazine or pyrrolidine. Preferably, the reaction is carried out in a solvent or solvent mixture such as water, ethyl ether, ethanol, acetone or ethyl acetate. The subject of the invention is also a process for the preparation of compounds of the above formula and their alkali metal, alkaline earth metal, aluminum, ammonium and amine salts, comprising: (wherein R ₃ , R ₄ and R ₅ have the above-mentioned meanings) in the presence of a basic condensing agent. (wherein Y represents a bromine or iodine atom and R ₂ has the meaning given above) and, if necessary, the synthesis is continued as described above. . The preferred conditions for carrying out this method are the same as described above. The subject of the invention also provides that R′ ₁ is a (2,2-dimethyl-1,3-dioxolan-4-yl)methyl group or a dialkylaminoalkyl group, where the alkyl group contains 1 to 4 carbon atoms. ), and R ₂ , R ₃ , R ₄ and R ₅ are as defined above, in racemic or optically active form or in the form of a mixture of these isomers; A process for preparing an addition salt with an acid of a compound of the formula ' in which R' ₁ represents a dialkylaminoalkyl group, comprising an acid of the formula in which R ₁ represents a hydrogen atom or _a functional derivative of this acid; OH (here
R′ ₁ represents a (2,2-dimethyl-1,3-dioxolan-4-yl)methyl group or a dialkylaminoalkyl group (wherein the alkyl group contains 1 to 4 carbon atoms) alcohol; and the resulting compound of formula ' in which R' ₁ represents a dialkylaminoalkyl group is optionally treated with an acid to form a salt thereof, and if necessary the compound of formula ' or a salt thereof is treated with racemic The present invention relates to a process for producing a compound of general formula ' and a salt thereof, which is characterized in that the compound is isolated in the form of an optically active form or a mixture of these isomers. Under the preferred conditions under which the methods are carried out, they are carried out in the following manner. Functional derivatives of acids of the formula are, for example, acid esters or acid halides. This functional derivative is prepared from the acid of formula by conventional methods. The reaction is preferably carried out in an organic solvent such as benzene, toluene, xylene or ethyl ether. The salt-forming reaction of compounds of formula ' in which R' ₁ represents a dialkylaminoalkyl group is carried out by conventional methods. The hydrolysis reaction is carried out by acid hydrolysis. The acid used may be, for example, hydrochloric acid. According to the present invention, the compound of the above formula in which R ₄ or R ₅ represents a hydrogen atom is also characterized in that R ₄ or R ₅ or
By a method characterized in that a compound of the formula in which R ₄ and R ₅ represent a chlorine atom is reacted with hydrogen in the presence of a catalyst to obtain a compound of the corresponding formula in which R ₄ and R ₅ represent a hydrogen atom. can be manufactured. Under preferred conditions for carrying out the invention, the method described above is carried out in the following manner. The catalyst may in particular be palladium. The operation is carried out in an alkaline medium. The base used can be, for example, triethylamine, trimethylamine, dimethylaniline or pyridine. The reaction is carried out in an organic solvent such as ethanol, methanol or isopropanol. The compound of formula or ' as defined above may contain at least one
has asymmetric carbon atoms (carbon atoms in the 2-position),
And some of the substituents R ₃ and R ₄ can have a second asymmetric carbon atom (a carbon atom in the 4-position). Compounds of formula used according to the invention as a starting point for the preparation of compounds of formula or ' include the substituents R ₃ and
Certain types of R ₄ cannot have asymmetric carbon atoms. According to the invention, the reaction of a compound of such formula with a compound of formula or ' leads to a compound of formula or ' containing one asymmetric carbon atom in racemic form, which compound is then known in the art. It can be resolved into its optical antipodes by conventional methods, such as the formation of salts with optically active bases. The compounds of the formula used may contain one asymmetric carbon atom. It can be used in racemic or optically active form. Compounds of formula or ' obtained from compounds of such formula contain two asymmetric carbon atoms. As a result, it exists in different isomeric forms which can be obtained separately by methods known in the art. Racemic or optically active diastereomeric compounds (which may be referred to by the prefixes cis and trans) can be obtained separately, for example by selective crystallization, countercurrent separation or column chromatography. Additionally, these racemates can be resolved into their optical antipodes (enantiomers) by methods known in the art, such as salt formation with optically active bases. The different isomers so obtained can, if desired, be mixed to constitute the desired mixture. Compounds defined by the general formula ', especially in the form of racemic or optically active forms or mixtures of isomers thereof, and their alkali metal, alkaline earth metal, aluminum, ammonium and amine salts, and if necessary Their addition salts with acids have interesting pharmacological properties. They exhibit particularly marked blood lipid-reducing activity. They lower the amount of lipids in the plasma, namely triglycerides and cholesterol. These properties apply to the compounds defined by the above-mentioned formula ', in particular the formula and in the form of racemic or optically active form or mixtures of these isomers;
as well as pharmaceutically acceptable alkali metals thereof,
This justifies the use of alkaline earth metal, aluminum, ammonium and amine salts (when R ₁ or R' ₁ represents a hydrogen atom) as therapeutic agents. Among the compounds of the formula ', in particular of the formula, and their salts, in particular in the racemic or optically active form or in the form of mixtures thereof, and in which R ₁ and R ₂
may be the same or different and represent a hydrogen atom or a methyl group, R ₃ represents a hydrogen atom, a methyl group or a phenyl group, R ₄ represents a hydrogen atom, R ₅
A compound of the formula where represents a hydrogen atom or a chlorine atom,
and R ₁ represents a hydrogen atom or a methyl group, and R ₂
and a compound of the formula in which R ₄ represents a hydrogen atom, R ₂ represents a hydrogen atom, a methyl group or a phenyl group, and R ₅ represents a chlorine atom, and an alkali metal of the above compound of the formula in which R ₁ represents a hydrogen atom, Mention may be made of alkaline earth metal, aluminum, ammonium and amine salts. Among the compounds of formula ' and above, mention may be made in particular of those described in the Examples and in particular of their isomer A as defined above. All of the above-mentioned compounds represent very effective agents in human therapy, especially in the treatment of acute or chronic hyperlipidemia, heart failure of athermatous origin and chronic angina conditions. The effective dosage varies depending on the compound used, the patient being treated, and the disease, but for example, for adults when administered orally,
It should be 0.05-1g per serving. The subject of the invention is therefore a pharmaceutical composition characterized in that it contains as active ingredient at least one of the aforementioned compounds or salts. These compositions are made so that they can be administered by the gastrointestinal route or parenterally. These may be solid or liquid, for example
It can be provided in pharmaceutical forms commonly used in human medicine, such as tablets or dragees, gelatin capsules, granules, suppositories and injectable preparations. They are manufactured in the usual manner. The active ingredient may contain adjuvants commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch,
It can be incorporated into magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives. Finally, the subject matter of the invention is that as new technical compounds useful for the preparation of compounds of formula or
The following compounds are in racemic or optically active form. (a) 5-chloro-2-hydroxy-α-methyl-
α-phenylbenzene methanol, (b) following formula ′A (where R' ₄ represents a chlorine atom or a fluorine atom, R' ₅ represents a chlorine atom, R' ₃ represents an alkyl group containing 2 to 4 carbon atoms, and R ₃ represents R' When ₄ represents a fluorine atom, it can also represent a methyl group). Compounds of the formula are known for the most part. Compounds with the formula in which R ₃ represents a hydrogen atom that are not known are the following formula A The corresponding benzophenone derivatives can be prepared, for example, by reduction with mixed hydrides in organic solvents. Unknown compounds of the formula in which R ₃ represents an alkyl group containing 1 to 5 carbon atoms or a phenyl group may be prepared by adding the corresponding benzophenone derivative of formula A above in an organic solvent to the following formula R ₃ -Mg -Hal (Here, Hal represents a chlorine or bromine atom, and R ₃ has the above-mentioned meaning). Such a method is demonstrated in the experimental section below. The following examples illustrate the invention without limiting it. Example 1 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two diastereomeric racemates) with 8.1 g of sodium amide and 100 ml of toluene. Then, a solution obtained by dissolving 24.9 g of 5-chloro-2-hydroxy-α-methyl-α-phenylbenzene methanol in 250 ml of toluene was added dropwise with stirring, and the mixture was stirred for 4 hours. Reflux for 30 minutes, bring it to ambient temperature, add 18 g of potassium dichloroacetate in portions with stirring, add 20 ml of hexamethylphosphotriamide, reflux for 5 hours, cool the mixture to ambient and add 10 ml of acetic acid. Slowly add the ethyl and then dropwise add 250 ml of water. The aqueous phase is collected, the organic phase is extracted again with 3 x 100 ml of water, the aqueous extracts are combined and washed with 3 x 100 ml of ether. The aqueous extraction phase containing the potassium salt of the desired compound was acidified by bubbling with anhydrous sulfite and 4×
Extract with 100 ml of ether. Wash the ether extract phase with 3 x 50 ml of water. The organic phase is dried over magnesium sulphate, treated with activated carbon and the solvent is evaporated in vacuo. 24 g of crude product was obtained and crystallized from 100 ml of a 90:10 mixture of cyclohexane-benzene, the obtained crystals were dried and 15.2 g of 6-chloro-4-
Methyl-4-phenyl[4H]-1,3-benzodioxin-1-carboxylic acid is obtained. MP=142℃. Analysis: ( _C16H13CIO4 ) Calculation: C%63.06 H%4.30 Cl% _11.63 Actual measurement: 63.3 4.4 11.5 6 _- chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2- 5-chloro-2-hydroxy-α-methyl-α-phenylbenzene methanol used at the start of production of carboxylic acid can be produced by the following method. 14 g of magnesium cuttings were dispersed with stirring in 100 ml of anhydrous ether, and then a solution obtained by dissolving 76 g of methyl iodide in 200 ml of anhydrous ether was added dropwise with stirring.
Reflux for an hour, then bring the temperature to 15-20°C, then add a solution obtained by dissolving 59 g of 5-chloro-2-hydroxybenzophenone in 250 ml of anhydrous benzene at the above temperature, and partially distill off the ether. and then refluxed again for 2 hours. Then the mixture was
Cool to a temperature of ~10 °C and add 250 ml of 3N hydrochloric acid dropwise. The organic phase is recovered by decantation and the aqueous phase is then washed with 2×100 ml of benzene. The organic extract phase is washed with water, then with saturated sodium bicarbonate solution and finally with 2×50 ml of water.
The organic phase was dried over magnesium sulfate and the solvent was then evaporated under vacuum to obtain 58.9 g of crystals, which were dissolved in petroleum ether (BP 60-80 °C) to give 53 g of 5-chloro-2-hydroxy-α. -Methyl-α-
Obtain phenylbenzene methanol. MP=106
℃. Analysis: ( _{C14H13ClO2 )} Calculation: C%67.61 H%5.27 Cl%14.26 Actual measurement: 67.8 5.4 14.2 Example 2 6-chloro-4 _- methyl-4-phenyl[4H]-1,3-benzodioxin- Isomers A and B of methyl 2-carboxylate A solution of 2.25 g of diazomethane in 150 ml of methylene chloride was prepared, the solution was cooled to 5°C, and then 3.3 g of the two 6-chloro- as a mixture of diastereomeric racemates
A solution obtained by dissolving 4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid in 75 ml of methylene chloride was added dropwise at 5°C. Stir for 1 hour at ambient temperature, then let the solution stand for 24 hours. Then 10 ml of acetic acid are added and the solvent is then evaporated under vacuum. 4.2g of 6-chloro-4
-Methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate is recovered in the form of a mixture of two diastereomeric racemates.
The resulting residue was chromatographed on a silica column, eluting with a mixture (20:80) of ethyl ether and petroleum ether (BP = 60-80°C), and 1 g of 6-chloro-4-methyl Isomer A of methyl -4-phenyl[4H]-1,3-benzodioxin-2-carboxylate is obtained. MP=114～115
℃. Analysis: (C ₁₇ H ₁₅ ClO ₄ ) Calculation: C% 64.06 H% 4.74 Cl% 11.12 Actual measurement: 63.9 4.7 11.4 NMR spectrum (fundamental frequency of the equipment used 60
Hz) CH ₃ 117Hz COOCH ₃ 232Hz Hydrogen at 2-position 311Hz Aromatic 410-445Hz Also, 0.6g of 6-chloro-4-methyl-4-
Phenyl[4H]-1,3-benzodioxin-2
- Isomer B of methyl carboxylate is obtained. MP=102
℃. Analysis: (C ₁₇ H ₁₅ CIO ₄ ) Calculation: C% 64.06 H% 4.74 Cl% 11.12 Actual measurement: 64.0 4.8 11.13 NMR spectrum (fundamental frequency 60 of the equipment used
Hz) CH ₃ 125Hz COOCH ₃ 228Hz Hydrogen at 2-position 341Hz Aromatic 405-455Hz Example 3 Isomer A of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid 14 g of 6-chloro-4-methyl-4 obtained in Example 2
-Phenyl[4H]-1,3-benzodioxin-
Isomer A of methyl 2-carboxylate (after using the procedure described in Example 2 twice), 2.8 g of pelleted potassium hydroxide, 32 ml of water and 160 ml of methanol were mixed and heated at ambient temperature for 22 hours. Stir, add 320 ml of water, wash the aqueous phase twice with 160 ml of ether, then acidify the aqueous solution with 2N hydrochloric acid solution, extract the resulting precipitate with 320 ml of ether and extract the organic phase with 160 ml of water. Wash twice, dehydrate with magnesium sulfate, and dry. Obtain 15 g of crystals. 3.9 g of the crystals 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. MP=175-176℃. Analysis: (C ₁₆ H ₁₃ ClO ₄ ) Calculation: C% 63.06 H% 4.30 Cl% 11.63 Actual measurement: 63.3 4.6 11.3 NMR spectrum (fundamental frequency 60Hz) CH ₃ 117Hz Hydrogen at 2-position 313Hz COOH 468Hz Aromatic 412-443Hz Example 4 5.3 g of isomer B of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid 6-chloro-4-methyl- obtained in Example 2
Isomer B of methyl 4-phenyl[4H]-1,3-benzodioxin-2-carboxylate (after using the procedure described in Example 2 twice), 10 ml water, 1.2 g pelleted hydroxylated Mix potassium and 50 ml of methanol, stir at ambient temperature for 20 hours, add 200 ml of water, wash the aqueous phase twice with 80 ml of ether,
The aqueous solution was then acidified with 2N hydrochloric acid solution, extracted three times with 100 ml of ether, the extracts were combined and
Washed twice with 80 ml of water, dried the ethereal phase over magnesium sulfate, and evaporated the solvent under vacuum to 4.8
g crystals were obtained, which were recrystallized from a mixture of cyclohexane and ethyl acetate (80:20), dried,
4.4 g of isomer B of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid are obtained. MP=171℃. Analysis: (C ₁₆ H ₁₃ O ₄ Cl) Calculation: C% 63.06 H% 4.30 Cl% 11.63 Actual measurement: 63.1 4.4 11.7 NMR spectrum (fundamental frequency 60Hz) CH ₃ 124Hz COOH 329Hz Hydrogen at 2-position 341Hz Aromatic 408-445Hz Example 5 6-chloro-2,4-dimethyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two diastereomeric racemates) 8 g of sodium amide and 100 ml of toluene Mix while stirring and add 24.9 g of 5-chloro-2.
-Hydroxy-alpha-methyl-alpha-phenylbenzene A suspension obtained by dispersing methanol in 250 ml of toluene is added dropwise at ambient temperature, the mixture is refluxed for 6 hours, and the mixture is allowed to cool to ambient temperature. Cool, add 17 g of sodium 2,2-dichloropropionate in portions, reflux again for 6 hours, cool to ambient temperature and add 700 ml of water.
Acidify by adding 1N hydrochloric acid solution and make alkaline again by adding saturated sodium bicarbonate solution. The aqueous extract phase was collected and washed three times with 100 ml of ether, the aqueous extract was acidified by adding 2N hydrochloric acid solution and extracted three times with 100 ml of ether, the organic extracts were combined and washed with 80 ml of water. Washed three times, dried over magnesium sulfate, then evaporated the solvent under vacuum,
23 g of 6-chloro-2,4-dimethyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid are obtained. MP=181℃. Analysis: ( _C17H15ClO4 ) Calculation: C%64.06 H%4.74 Cl%11.12 Actual measurement: 64.0 4.8 11.2 _Example 6 6-chloro-2,4 _- dimethyl-4-phenyl[4H]-1,3-benzo Isomers A and B of methyl dioxine-2-carboxylate Two diastereomeric racemates A obtained in Example 5
23 g of 6-chloro- in the form of a mixture of and B
2,4-dimethyl-4-phenyl[4H]-1,3
-benzodioxin-2-carboxylic acid, 100 g
Redex CF (strong sulfonic acid type cation resin) and
Mix 250ml of methanol and reflux for 20 hours.
Cool to ambient temperature, filter the resin under vacuum, wash with solvent, and concentrate the solvent under vacuum. 20 g of crude product was obtained and chromatographed on a silica column under a pressure of 1.5 Kg, eluting with a mixture (20:80) of ethyl ether and petroleum ether (BP 60-80 °C),
1.7 g of 6-chloro-2,4-dimethyl-4-phenyl[4H]-1,3-benzodioxin-2-
Isomer A of methyl carboxylate is obtained. MP=134
℃. Analysis: ( _C18H17ClO4 ) Calculation: C% _64.96 H%5.15 Cl%10.65 Actual measurement: 65.2 5.2 10.9 NMR spectrum (fundamental frequency 60Hz) Both _{CH3 103} and 113Hz COOCH ₃ 172Hz Aromatic 419-447Hz Also 8.2 isomer B of methyl 6-chloro-2,4-dimethyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate (in the form of an oil) of g is obtained. Analysis: (C ₁₆ H ₁₇ ClO ₄ ) Calculation: C% 64.96 H% 5.15 Cl% 10.65 Actual measurement: 65.8 5.1 10.8 NMR spectrum (fundamental frequency 60Hz) Both CH ₃ 106 and 117Hz COOCH ₃ 224Hz Aromatic 415-455Hz Example 7 6 -Chloro-2,4-dimethyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid isomer A 1.6 g of 6-chloro-2,4-dimethyl-4 obtained in Example 6 -Methyl phenyl[4H]-1,3-benzodioxin-2-carboxylate isomer A, 2 ml
of water and 0.56 g of pelleted potassium hydroxide and stirred the mixture at ambient temperature for 48 hours;
Add 100 ml of water, collect the aqueous phase and wash three times with 50 ml of ether, acidify the aqueous solution by adding 2N hydrochloric acid solution, extract with 50 ml of ether, combine the ether extracts and wash three times with 50 ml of water. Wash and then dehydrate over magnesium sulfate. The solvent was evaporated under vacuum to give 1.5 g of product, which was recrystallized from 80 ml of cyclohexane to give 1.2 g of 6-chloro-2.
Isomer A of 4-dimethyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid is obtained. MP=184℃. Analysis: (C ₁₇ H ₁₅ O ₄ Cl) Calculation: C% 64.06 H% 4.74 Cl% 11.12 Actual measurement: 64.1 4.8 11.1 NMR spectrum (fundamental frequency 60Hz) Both CH ₃ 101.5Hz and 113Hz COOH 342Hz Aromatic 412-442Hz Example 8 Isomer B of 6-chloro-2,4-dimethyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid 8 g of 6-chloro-2,4-dimethyl-4 obtained in Example 6 - isomer B of methyl phenyl[4H]-1,3-benzodioxin-2-carboxylate, 80 ml of methanol, 8 ml of water and 2.8 g of pelleted potassium hydroxide are mixed and stirred at ambient temperature for 24 hours, Add 150 ml of water and collect the aqueous phase, which
Wash 3 times with 60 ml of ether. The aqueous solution is acidified by adding 2N hydrochloric acid solution and washed four times with 60 ml of ethyl ether. Combine the ether extracts and add 80
Washing twice with ml of water, then drying over magnesium sulfate and evaporating the solvent under vacuum gives 7.2 g of compound, which is recrystallized from 80 ml of cyclohexane. Drying yields 4.5 g of isomer B of 6-chloro-2,4-dimethyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid. MP
=125℃. Analysis: (C ₁₇ H ₁₅ O ₄ Cl) Calculation: C% 64.06 H% 4.74 Cl% 11.12 Actual measurement: 64.2 5.0 11.2 NMR spectrum (fundamental frequency 60Hz) Both CH ₃ 104 and 119Hz Aromatic 417-455Hz COOH 540Hz Example 9 6 -Chlor-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid 10.35 g of sodium amide and 100 ml of toluene were mixed, then 30.1 g of 5-chloro-2-hydroxy-α-phenyl Enylbenzene methanol 20
ml of anhydrous toluene was added dropwise with stirring at ambient temperature for 2 hours, the mixture was refluxed for 6 hours, the mixture was then cooled to ambient temperature and 22.3 g of dichloroacetic acid Add potassium in portions, then 20 ml of hexamethylphosphoramide, stir at ambient temperature for 20 hours, reflux the mixture for 4 hours, then return to ambient temperature, add 20 ml of ethyl acetate, then add 20 ml of water. Add slowly. The aqueous phase is collected, the organic phase is again extracted three times with 100 ml of water, the aqueous extracts are combined and this is washed three times with 100 ml of ether. The aqueous extraction phase containing the potassium salt of the desired compound is acidified by bubbling with anhydrous sulfite;
Extracted three times with 100 ml of ether, combined extracts, washed with 100 ml of water, dried over magnesium sulphate, treated with activated charcoal, evaporated the solvent under vacuum,
24 g of crude product was obtained, which was triturated in cyclohexane to obtain crystals and recrystallized from 520 ml of benzene-cyclohexane mixture (7:3) to give 5.3 g of 6-
Chlor-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid is obtained. MP=194℃. Analysis: (C ₁₅ H ₁₁ ClO ₄ ) Calculation: C% 61.97 H% 3.81 Cl% 12.20 Actual measurement: 62.2 3.9 12.1 NMR spectrum (fundamental frequency 60Hz) Hydrogen at 2 and 4 positions 343.5Hz and 364Hz COOH 514Hz Aromatic 398-442.5 Hz Example 10 6-chloro-4・4-diphenyl[4H]-1・
3-benzodioxin-2-carboxylic acid 12.4 g of 5-chloro-2-hydroxy-α・α
- Diphenylbenzene methanol, 150 ml toluene and 3.2 g sodium amide are mixed, the mixture is refluxed for 6 hours, cooled to ambient temperature,
Add 6.8 g of potassium dichloroacetate, reflux again for 6 hours, cool to ambient temperature and add 300 ml of water. Add 1N hydrochloric acid solution to make weakly acidic, then add saturated sodium bicarbonate solution to make alkaline. Wash twice with 100 ml of methylene chloride, then acidify by adding 2N hydrochloric acid solution, extract three times with 100 ml of ether, combine the ether extracts,
ml of water twice, then dried over magnesium sulfate and treated with activated carbon. After evaporating the solvent under vacuum, 7 g of product are obtained, which is recrystallized from 300 ml of benzene. 4.6g of 6-chloro-4.
4-diphenyl[4H]-1,3-benzodioxin-2-carboxylic acid is obtained. MP=226℃. Analysis: (C ₂₁ H ₁₅ O ₄ Cl) Calculation: C%68.76 H%4.12 Cl%9.67 Actual measurement: 69.1 4.3 9.5 NMR spectrum (fundamental frequency 60Hz) Hydrogen at 2-position 325Hz COOH 313Hz Aromatic 405-443Hz Example 11 4- Isomer A of methyl methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate In a hydrogenation vessel, 1.3 g of 10% palladium on activated carbon, 11.8 g of 6-chlor obtained in Example 2 -4-Methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate methyl isomer A (after using the procedure described in Example 2 twice), 500 ml of ethanol and 10 ml of Charge the triethylamine and stir the suspension into a stream of hydrogen at ambient temperature. The catalyst was washed with methylene chloride, then the liquid was concentrated under vacuum, the residue was dissolved in 100 ml of water and 50 ml of
A 2N hydrochloric acid solution was added, extracted three times with 150 ml of methylene chloride, the extracts were combined, washed twice with 100 ml of water, dried over calcium chloride and then treated with activated charcoal before the solvent was removed under vacuum. evaporate to
9.7 g of the expected compound are obtained. A portion of this compound is recrystallized from methanol. MP=124℃. Analysis: (C ₁₇ H ₁₆ O ₂ ) Calculation: C% 71.82 H% 5.67 Actual measurement: 72.1 5.8 NMR spectrum (fundamental frequency 60Hz) Hydrogen at 2-position 312Hz COOCH ₃ 231Hz Phenyl gem CH ₃ 117Hz Aromatic 410-450Hz Example 12 Isomer A of 4-methyl-4-phenyl-1,3-benzodioxin-2-carboxylic acid 9.7 g of 4-methyl-4-phenyl[4H]-1,3-benzodioxin-2 obtained in Example 11 - Isomer A of methyl carboxylate, 4 g of pelleted potassium hydroxide, 10 ml of water and 90 ml of methanol are mixed with stirring, stirring is continued for 16 hours at ambient temperature, 400 ml of water is added and the aqueous phase is dissolved in 100 ml of chloride. Washed twice with methylene, the aqueous phase was acidified by adding 2N hydrochloric acid solution, extracted three times with 150 ml of methylene chloride, the extracts were combined, washed twice with 80 ml of water, dried over calcium chloride, and the solvent was evaporated under vacuum to give 8 g of product which was recrystallized from a mixture of ethyl acetate and cyclohexane (20:80) to give 5.1 g of 4-methyl-4-phenyl-1,3-benzodioxin-2. - obtaining isomer A of the carboxylic acid. MP
=163℃. Analysis: (C ₁₆ H ₁₄ O ₄ ) Calculation: C% 71.10 H% 5.22 Actual measurement: 71.1 5.3 NMR spectrum (fundamental frequency 60Hz) CH ₃ 119Hz Hydrogen at 2-position 316Hz COOH 534Hz Aromatic 418-450Hz Example 13 4-Methyl- Isomer B of methyl 4-phenyl[4H]-1,3-benzodioxin-2-carboxylate In a hydrogenation vessel, 1.3 g of 10% palladium on activated carbon, 12.8 g of 6-chloro-4 obtained in Example 2 -isomer B of methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate (after using the procedure described in Example 2 twice), 10 ml of triethylamine and 200 ml of ethanol. A continuous stream of hydrogen was passed through the suspension and the suspension was stirred at ambient temperature for about 2 hours. filtrate, wash the catalyst with methylene chloride, evaporate the liquid under vacuum and collect 80 ml of the acid distillate.
of water, add 70ml of 2N hydrochloric acid solution, and add 100ml of
The extracts are combined, washed three times with 50 ml of water, dried over calcium chloride and the solvent is evaporated under vacuum. 10.2g
The desired compound is obtained. A portion of this product is recrystallized from methanol. MP=137℃. Analysis: (C ₁₇ H ₁₆ O ₄ ) Calculation: C% 71.82 H% 5.67 Actual measurement: 71.8 5.8 NMR spectrum (fundamental frequency 60Hz) CH ₃ 128Hz COOCH ₃ 234Hz Hydrogen at 2-position 347Hz Aromatic 410-465Hz Example 14 4-Methyl -4-Phenyl[4H]-1,3-benzodioxin-2-carboxylic acid isomer B 10.2 g of 4-methyl-4-phenyl[4H]-1,3-benzodioxin-2 obtained in Example 13 - Isomer B of methyl carboxylate, 4 g of pelleted potassium hydroxide, 10 ml of water and 90 ml of ethanol are mixed with stirring, stirring is continued for 16 hours at ambient temperature, 500 ml of water is added and the aqueous phase is chlorinated with 80 ml of chloride. Washed twice with methylene, acidified the aqueous phase by adding 2N hydrochloric acid solution and extracted three times with 100 ml of methylene chloride,
Washing twice with 80 ml of water, drying over calcium chloride and evaporating the solvent under vacuum gave 9 g of product, which was recrystallized from a mixture of ethyl acetate and cyclohexane (20:80), giving 6.7 g of The desired compound is obtained. MP=153℃. Analysis: (C ₁₆ H ₁₄ O ₄ ) Calculation: C% 71.10 H% 5.22 Actual measurement: 71.1 5.3 NMR spectrum (fundamental frequency 60Hz) CH ₃ 128Hz Hydrogen at 2-position 348Hz Aromatic 410-460Hz Example 15 6-Chlor-4. 4-diphenyl[4H]-1.
Methyl 3-benzodioxin-2-carboxylate 11 g of 6-chloro-4,4-diphenyl[4H]-1,3-benzodioxin-2-carboxylic acid obtained in Example 10, 50 g of Redex CF (strong sulfonic acid) cationic resin) and 200 ml of methanol are mixed with stirring, refluxed for 16 hours, cooled to ambient temperature, filtered the resin under vacuum, washing it with ether and concentrating the liquid under vacuum. The crude product obtained is dissolved in 200 ml of ether and the organic phase is washed with 100 ml of 5% sodium bicarbonate solution and then twice with 100 ml of water. The ether phase was dried over magnesium sulfate, treated with activated carbon and the solvent was evaporated to give 6.3 g of product,
This is recrystallized from 140 ml of cyclohexane.
Drying yields 5.1 g of the expected compound. MP=172
℃. Analysis: _{(C22H17O4Cl ) Calculation} : C%69.38 H%4.50 Cl%9.31 Actual measurement: 69.7 4.6 9.3 NMR spectrum (fundamental frequency 60Hz, deuterochloroform) COOCH ₃ 230Hz Aromatic 406-443Hz Hydrogen at 2-position 324Hz Example 16 Isomer A of ethyl 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate Step A: 6-chloro-4-methyl-4-phenyl[4H] ]-1,3-benzodioxin-2-carboxylic acid chloride isomer A 4.9 g of 6-chloro-4-methyl- obtained in Example 3
Isomer A of 4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid and 50 ml of anhydrous benzene are mixed with stirring, the suspension is cooled to 10°C, and then 2.3 ml of triethylamine is added. dropwise and then add 1.5 ml of thionyl chloride at that temperature.
A solution in 25 ml of anhydrous benzene is added dropwise, the solution is refluxed for 2 hours, cooled to ambient temperature, the precipitate is filtered under vacuum and the expected compound is recovered in solution. Step B: Isomer A of ethyl 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate Mix 3 ml of anhydrous ethanol, 50 ml of anhydrous benzene, and 2.3 ml of triethylamine. and adding the solution of acid chloride obtained in step A dropwise at ambient temperature;
Continue stirring at ambient temperature for 20 hours, wash the triethylamine hydrochloride precipitate with cold benzene, and add 40 ml of the solution.
of water, the organic phase was dried over calcium chloride, treated with activated carbon, and the solvent was evaporated under vacuum.
9 g of crude product are obtained which is recrystallized from 30 ml of hexane and after drying 4 g of the expected compound are obtained. MP=92℃. Analysis: ( _C18H17O4Cl ) Calculation: C%64.97 H%5.15 _{Cl10.65 Actual} measurement: 65.1 _5.3 10.8 NMR spectrum (deuterochloroform, fundamental frequency 60Mhz) _CH3 of _C2H5 72.5−79.5−87Hz CH ₃ at 4-position 116Hz C ₂ H CH ₂ at ₅ 247.5-255-262-269Hz Hydrogen at 2-position 308Hz Aromatic 412-441Hz Example 17 6-chloro-4-methyl-4-phenyl[4H]-1.3 -isomer A of sodium benzodioxine-2-carboxylate 0.6 g of the sodium hydroxide obtained in Example 3 and 250 ml of absolute ethanol were mixed and 4.6 g of the 6 obtained in Example 3 were mixed.
-Chlor-4-methyl-4-phenyl[4H]-
Add isomer A of 1,3-benzodioxin-2-carboxylic acid at ambient temperature, boil for 5 minutes, filter, cool to ambient temperature, add 500 ml of ether to the liquid and continue stirring at ambient temperature for 16 hours. .
After filtration and drying, 3.8 g of the expected compound are obtained.
MP=160℃. Analysis: (C ₁₆ H ₁₂ O ₄ ClNa) Calculation: C% 58.82 H% 3.70 Cl% 10.85 Actual measurement: 58.5 3.8 10.7 Example 18 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin Isomers d and l of isomer A of -2-carboxylic acid (1) Isomer l Step A: 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-
l-1- of isomer l of isomer A of carboxylic acid
p-nitrophenyl-2-amino-1,3-
Propanediol salt. 15.2 g of isomer A of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid obtained in Example 3, 16.2 g of l
-1-p-nitrophenyl-2-amino-1.
Mix 3-propanediol and 800 ml of ethyl acetate. The mixture is brought to reflux and continued stirring for 5 minutes after which the salts formed are precipitated. ambient temperature,
The resulting precipitate was filtered under vacuum and washed with ethyl acetate.
Vacuum dry and collect 10 g of crude product. The mother liquor is saved for separation of crude isomer d as described below. 10 g of the crude product obtained are recrystallized from isopropanol, finally obtaining 6.4 g of the expected compound. MP=218℃. [α] ²⁰ _D = -84° ± 2° (c = 1%, ethanol). A portion of this compound is recrystallized from a small amount of isopropanol. MP=218℃. [α] ²⁰ _D = -84.5° ± 2° (c = 1%, ethanol). Step B: 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-
Isomer I of carboxylic acid isomer A Add 150 ml of the purified salt obtained in step A above.
It is suspended in 1N hydrochloric acid and then extracted three times with 75 ml of ether, the organic extract phase is washed three times with 50 ml of water and dried over magnesium sulphate. The solvent was evaporated under vacuum to obtain 3.5 g of crude product, which was crystallized from cyclohexane, 2.7 g of crystals were obtained, which was recrystallized from cyclohexane and 2.3 g was melted at 113-114 °C. , followed by recrystallization to obtain crystals which then melt at 128°C. again
Recrystallized from 80ml of cyclohexane, yielding 1.8g of
The desired compound with MP=113°C is obtained. 0.5 g of the expected compound is obtained from the mother liquor of the above recrystallization. 0.5 g of compound and 1.8 g of the above compound are collected, a total of 2.3 g of compound is recrystallized with 50 ml of cyclohexane while the solvent is refluxed for 20 minutes, and 2 g of the expected compound is obtained. MP
=140℃. (The different melting point changes recorded for the desired compound are probably due to changes in crystal structure.) Analysis: (C ₁₆ H ₁₃ ClO ₃ ) Calculated: C% 63.06 H% 4.30 Cl% 11.63 Observed: 63.2 4.4 11.6 NMR spectrum (deuterochloroform) (fundamental frequency 60Mhz) CH ₃ 116.5Hz Hydrogen at 2-position 313Hz Aromatic 415-443Hz OH Approximately 540Hz Optical rotation power [α] ²⁰ _D = -157゜±2.5゜ (c = 1 %, 95° ethanol) (2) Isomer d Step A: Crude 6-chloro-4-methyl-4-
Isomer d of isomer A of phenyl[4H]-1,3-benzodioxin-2-carboxylic acid 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid The ethyl acetate mother liquor obtained when isomer A is salted with l-1-p-nitrophenyl-2-amino-1,3-propanediol is collected. The solution was concentrated under vacuum and 17.8 g of crude product was recovered, which was treated with 200 ml of 2N hydrochloric acid and
Treat 3 times with 100 ml of ether and remove 50 ml of the organic phase.
Wash twice with water, dehydrate with magnesium sulfate,
Concentrate under vacuum. 8.4 g of a residue was obtained, which was dissolved in 150 ml of a cyclohexane-ethyl acetate mixture (70:30), cooled, the residual racemic acid starting material crystallizing out was filtered off in vacuo, and the liquid was concentrated in vacuo. , 7 g of crude expected compound are obtained. Step B: 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-
d-1-p-nitrophenyl-2-amino-1,3-propanediol salt of isomer d of carboxylic acid The residue obtained above was dissolved in 300 ml of ethyl acetate, and 7.4 g of d- Add 1-p-nitrophenyl-2-amino-1,3-propanediol. After the suspension has been brought to reflux and the resulting salt has precipitated, it is cooled to ambient temperature and the precipitate is filtered off and washed with a small amount of ethyl acetate. After drying, melt at 200℃
11.4 g of the expected compound are obtained. Recrystallized from isopropanol in 1.1 and 6.2
g of the desired compound, MP=218°C, was obtained, and this was
Recrystallized from 800ml of isopropanol, 5g
The desired compound is obtained. MP = approx. 218℃. Step C: 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-
Isomer d of isomer A of carboxylic acids The salt obtained above is dissolved in 150 ml of water, acidified with 2N hydrochloric acid, extracted twice with 100 ml of ether, the organic extract phase is washed with 50 ml of water, Dehydrate over magnesium sulfate, evaporate the solvent under vacuum,
2.9 g of crude product is obtained, which is dissolved in a mixture (20:80) of ethyl ether and petroleum ether (BP 60-80° C.). Finally, after separation 2.4 g of the expected compound are obtained. MP=128℃. [α] ²⁰ _D = +153° ± 2.5° (c = 1%, ethanol). This compound is recrystallized from 100 ml of cyclohexane to obtain 2 g of the expected compound. MP=128℃. [α] ²⁰ _D = +153° ± 2.5° (c = 1%, ethanol). Recrystallization is carried out again from 60 ml of cyclohexane, finally obtaining 1.7 g of the expected compound. MP=140℃. (Like isomer l, isomer d also has several melting points. This is probably due to changes in crystal structure.) Analysis: (C ₁₆ H ₁₃ ClO ₄ ) Calculation: C% 63.06 H% 4.30 Cl%11.63 Actual measurement: 63.2 4.3 11.6 NMR spectrum (deuterochloroform,
Fundamental frequency 60Mhz) CH ₃ 117Hz Monosubstituted phenyl 440Hz Aromatic 413-440Hz OH 485Hz Hydrogen at 2-position 312.5Hz Optical rotation power [α] ²⁰ _D = +154.5゜±2.5゜ (c = 1%, ethanol) Example 19 6 -Chlor-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 28.3 g of 1
-(5-chloro-2-hydroxyphenyl)-1-
A suspension of (3-chlorophenyl)ethanol in 250 ml of toluene is added in portions at ambient temperature, and the mixture (to which more than 1 g of sodium amide is added) is then refluxed for 6 hours. After cooling to ambient temperature, 25 g of potassium dichloroacetate are added in portions with stirring and the mixture is refluxed again for 6 hours. After returning to ambient temperature,
Slowly add 150 ml of water, then 150 ml of 2NHCl. The organic phase is collected and the aqueous phase is then washed twice with 100 ml of ether. The organic extract phase is washed twice with 100 ml of water, the organic phase is extracted with saturated sodium bicarbonate solution and then twice with 100 ml of water.
The aqueous extract phase is washed three times with 100 ml of ether and then the aqueous phase is slowly acidified with 2N HCl solution. The aqueous phase is then extracted three times with 150 ml of ether. Wash the organic extract phase twice with 75 ml of water. Treat with activated carbon and dehydrate with magnesium sulfate. The solvent is evaporated under vacuum, finally obtaining 29.3 g of the expected compound. NMR spectrum (deuterochloroform, fundamental frequency 60Mhz) CH ₃ 117 and 125.5Hz Hydrogen at 2-position 315.5 and 346Hz Aromatic 412-455Hz COOH 588Hz 6-chloro-4-(3-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2-
1-(5-chloro-2-hydroxyphenyl)-1-(3-chlorophenyl)ethanol used at the start of production of carboxylic acid can be produced by the following method. 11 g of magnesium cuttings are dispersed in 100 ml of anhydrous ether with stirring, and then a solution obtained by dissolving 64 g of methyl iodide in 100 ml of anhydrous ether is added dropwise with stirring at ambient temperature. The solvent was gently refluxed during this addition and reflux was continued for 1 hour to return to ambient temperature and then to 31.7
g (5-chloro-2-hydroxyphenyl)
A solution of (3-chlorophenyl)methanone dissolved in 100 ml of anhydrous ether and 150 ml of anhydrous benzene is added dropwise for 25 minutes. The ether is distilled off, 250 ml of anhydrous benzene are added and the solution is then refluxed for 4 hours. The mixture is cooled to ambient temperature, maintained at this temperature by an ice bath and hydrolyzed with 1N hydrochloric acid solution. The organic phase was collected, the aqueous phase was extracted again with 80 ml of ether, the organic extract phase was washed three times with 80 ml of water,
The organic phase is dried over magnesium sulphate and the solvent is then evaporated under vacuum. 31.5 g of the expected compound are obtained, which is recrystallized from 750 ml of cyclohexane. Finally, 25.5 g of the expected compound are obtained. MP=125
℃. Analysis: _{( C14H12O2Cl2 )} Calculation: C%59.38 H%4.27 Cl%25.04 Actual measurement: 59.2 4.3 24.9 The above 1-(5 _- chloro-2-hydroxyphenyl)-1-(3-chlorophenyl) ) (5-chloro-2-hydroxyphenyl)(3-chlorophenyl)methanone used at the beginning of ethanol production can be produced as follows. Step A: 4-Chlorphenyl 3-chlorobenzoate 5.87 g of 4-chlorophenol, 46.1 g of triethylamine and 250 ml of anhydrous benzene are mixed with stirring, cooled to 10°C, and 80 g of 3-chlorophenylcarboxylic acid chloride. in 100 ml of anhydrous benzene is added dropwise, stirring is continued overnight at ambient temperature, the triethylamine hydrochloride precipitate is filtered under vacuum, the liquid is collected and dried. 122
g of crude product was obtained, which was mixed with 200 ml of ethyl ether-petroleum ether (BP 60-80°C) mixture (20:
80). 116 g of the expected compound are obtained. MP=72℃. Analysis: ( _C13H8Cl2O2 ) Calculation: C%58.45 H%3.02 Cl%26.55 Actual measurement: 58.5 3.0 26.2 Step B: (5 _- chloro-2-hydroxyphenyl ₎ (3 _- chlorophenyl)methanone 64.5g 4-chlorophenyl 3-chlorobenzoate obtained in the above step of and 32 g of aluminum chloride are mixed with stirring, the mixture is heated to 160° C. with stirring, kept at this temperature for 30 minutes and then returned to ambient temperature, The crude product obtained was dissolved in methylene chloride, the organic solution was slowly hydrolyzed with 250 ml of 1N hydrochloric acid, the organic phase was decanted and the aqueous phase was diluted with 70 ml of methylene chloride.
Extract twice, wash the organic extract phase three times with 70 ml of water, dry the organic phase over calcium chloride and then evaporate the solvent under vacuum. Finally, 60 g of crude product was obtained,
This is mixed with ethyl ether and petroleum ether (BP60 ~
(80℃). Filter and dry under vacuum to obtain 41.3 g of the expected compound. A portion of this compound is recrystallized from cyclohexane. MP=72℃. Analysis: (C ₁₃ H ₈ Cl ₂ O ₂ ) Calculation: C% 58.45 H% 3.02 Cl% 26.55 Actual measurement: 58.4 3.2 26.6 Example 20 6-Chlor-4-(3-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2
- Isomers A and B of methyl carboxylate 29.3 g of 6-chloro-4- as a mixture of the two diastereomeric racemates obtained in Example 19
(3-chlorophenyl)-4-methyl[4H]-1.
3-benzodioxin-2-carboxylic acid, 300ml
of methanol and 30 g of strong sulfonic acid type cationic resin were mixed while stirring.
Reflux for an hour, then cool to ambient temperature, filter the resin in vacuo, wash it with methanol, and concentrate the liquid in vacuo. 20 g of crude product was obtained, which was chromatographed under pressure on a silica column, eluted with a mixture of ethyl ether and petroleum ether (BD 60-80 °C), fractionated, and after evaporation of the solvent. (1) Obtain 9.5 g of desired isomer A, and recrystallize 4 g from methanol to obtain 3.2 g of crude desired isomer A. MP=112℃. Analysis: (C ₁₇ H ₁₃ O ₄ Cl ₂ ) Calculation: C% 57.97 H% 3.72 Cl% 20.13 Actual measurement: 57.9 4.0 19.8 NMR spectrum (deuterochloroform,
Fundamental frequency 90 Mhz) CH ₃ 172 Hz COOCH ₃ 345 Hz Hydrogen in 2-position 461.5 Hz Aromatic 623-660 Hz (2) Furthermore, 8.4 g of the expected isomer B are obtained in the form of crude product. Analysis: (C ₁₇ H ₁₃ O ₄ Cl ₂ ) Calculation: C% 57.97 H% 3.72 Cl% 20.13 Actual measurement: 58.2 4.0 20.1 NMR spectrum (deuterochloroform,
Fundamental frequency 90Mhz) CH ₃ 184Hz COOCH ₃ 343.5Hz Hydrogen at 2-position 509Hz Aromatic 612-674Hz Example 21 6-Chlor-4-(3-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2
- 6.5 g of isomer A of carboxylic acid 6-chloro-4-(3-
Chlorphenyl)-4-methyl[4H]-1,3-
Isomer A of methyl benzodioxine-2-carboxylate, 2.8 g potassium hydroxide pellets, 10 ml
of water and 100 ml of methanol are mixed with stirring and the mixture is stirred at ambient temperature for 16 hours,
Add 200 ml of water, wash the aqueous solution twice with 50 ml of ether, acidify the aqueous solution with 2N hydrochloric acid solution, extract the aqueous phase three times with 80 ml of ether, and wash the organic extract phase twice with 50 ml of water. The ether phase is dried over magnesium sulfate and the solvent is evaporated under vacuum to give 6.1 g of product, which is recrystallized from 100 ml of cyclohexane. 3.6 g of the expected compound are obtained. MP=131℃. Analysis: (C ₁₆ H ₁₂ O ₄ Cl ₂ ) Calculation: C%56.66 H%3.57 Cl%20.90 Actual measurement: 56.7 3.7 20.6 NMR spectrum (deuterochloroform, fundamental frequency 60Mhz) CH ₃ 174.5Hz Hydrogen at 2-position 466.5Hz Aromatic Group 625-665Hz peak example 22 6-chloro-4-(3-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2
- 5.3 g of carboxylic acid isomer B 6-chloro-4-(3-
Chlorphenyl)-4-methyl[4H]-1,3-
Isomer B of methyl benzodioxine-2-carboxylate, 2.4 g of pelleted potassium hydroxide, 10 ml of water and 100 ml of methanol were mixed with stirring and the mixture was stirred at ambient temperature overnight, 250 g.
ml of water is added, then the aqueous phase is washed twice with 80 ml of ether, the aqueous solution is acidified with 2N hydrochloric acid solution, the aqueous phase is extracted three times with 800 ml of ether and the organic phase is
Washing twice with 50 ml of water, the ether phase is dried over magnesium sulfate and concentrated under vacuum to give 5.3 g of the expected product, which is recrystallized from 110 ml of a cyclohexane-ethyl acetate mixture (80:30). do. 4 g of purified expected compound are obtained. MP=177℃. Analysis: (C ₁₆ H ₁₂ O ₂ Cl ₂ ) Calculation: C%56.66 H%3.87 Cl%20.90 Actual measurement: 56.8 3.8 20.9 NMR spectrum (deuterochloroform, fundamental frequency 90Mhz) CH ₃ 185.5Hz Hydrogen at 2-position 510Hz Aromatic 610～673Hz Example 23 6-chloro-4-[(1-methyl)ethyl]-4
-Phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two diastene omer racemates) 8.1 g 50% sodium hydride in oil, 60 ml anhydrous dioxane and 360 mg dibenzo-18 - Crown-6 (of the type described in Synthesis 1976, p. 168) was mixed with stirring and a solution of 3.66 ml dichloroacetic acid dissolved in 60 ml anhydrous dioxane was added for 10 minutes, keeping the solution at ambient temperature. Add with stirring and then add 8.7 g of 5-chloro-
α-[(1-methyl)ethyl]-2-hydroxy-
A solution of α-phenylbenzene methanol in 30 ml of anhydrous dioxane is added at ambient temperature;
The suspension was heated at 90-100 °C for 10 h, then returned to ambient temperature, 500 ml of water was added while cooling in an ice bath, the aqueous phase was washed with 200 ml of ether, and the ether phase was oxidized with 100 ml of 2N hydroxide. Extract 3 times with sodium. The aqueous phase was acidified with 2N hydrochloric acid, the liberated acid was extracted three times with 150 ml of ether, and the ether phase was
Washing three times with 100 ml of water, extracting the ether phase with saturated sodium bicarbonate solution and extracting the resulting acid with the sodium salt, then extracting three times with 100 ml of water, and extracting the aqueous phase twice with 80 ml of ether. Wash and acidify by adding 2N hydrochloric acid to remove the liberated acid.
Extract 3 times with 150 ml of ether and reduce the organic extract to 80 ml of ether.
ml of water three times, dehydrated, treated with activated carbon,
Dryness gives 8.8 g of the expected compound as an oil. NMR spectrum (deuterochloroform, fundamental frequency 60Mhz) Hydrogen at 2-position 323Hz (peak corresponding to isomer A) Hydrogen at 2-position 335Hz (peak corresponding to isomer B) Group

Two CH ₃ 49-69Hz groups of [Formula]

[Formula] Hydrogen 100-190Hz Aromatic 410-465Hz OH 490Hz 5-Chlor-α- used at the start of the above production
[(1-methyl)ethyl]-2-hydroxy-α-
Phenylbenzene methanol was produced as follows. Mix 21.4 g of magnesium cuttings, 200 ml of anhydrous ether and 2 ml of isopropyl bromide with stirring. Stir until the desired magnesium derivative forms, then at ambient temperature with gentle reflux.
A solution of 110.8 g of isopropyl bromide dissolved in 400 ml of anhydrous ether is added dropwise. Once the addition is complete, reflux is continued for 2 hours. Separately, 58.2 g of [(5-chloro-2-hydroxy)phenyl]phenylmethanone and 600 ml of anhydrous benzene are mixed, and then 520 ml of the above magnesium derivative solution are added dropwise at ambient temperature. The ether is distilled off while gradually replacing it with benzene. Continue refluxing for 6 hours. After cooling to ambient temperature, the reaction mixture was
Pour onto an ice-cold solution of 10% ammonium chloride. The organic phase is decanted and the aqueous phase is extracted with 150 ml of ether. Collect the organic phase and dilute with 100 ml of water.
Wash twice, dehydrate, treat with activated charcoal and evaporate the solvent under vacuum. 74 g of crude product are obtained which is chromatographed on a silica column and eluted with methylene chloride. After fractionation, 18 g of crude product are obtained, which is dissolved in 50 ml of cyclohexane. The desired compound of 8.7 is obtained. MP=114℃. A portion of this compound is recrystallized from cyclohexane. MP=118℃. Analysis: (C ₁₈ H ₁₇ O ₂ Cl) Calculation: C% 69.43 H% 6.19 Cl% 12.81 Actual measurement: 69.7 6.2 12.8 NMR spectrum (deuterochloroform, fundamental frequency of the equipment used 60 Mhz) (1-methyl)ethyl group 2 CH ₃ 48-55Hz
and 63-70Hz 〓CH- 165Hz (multiplet) OH of methanol 165Hz OH of 2-hydroxy 537Hz Aromatic 395-455Hz Example 24 6-Chlor-4-[(1-methyl)ethyl]-4
-Phenyl[4H]-1,3-benzodioxin-2-methyl carboxylic acid isomer A Step A: 6-chloro-4-[(1-methyl)ethyl]-4-phenyl[4H]-1,3 8.8 g of isomer A of benzodioxine-2-carboxylic acid chloride 6-chloro-4-[(1
-methyl)ethyl]-4-phenyl[4H]-1.
3-benzodioxin-2-carboxylic acid and 100ml
of anhydrous benzene, 3.7 ml of triethylamine, and 3.8 ml of triethylamine while stirring and keeping at ambient temperature.
of thionyl chloride and 25 ml of anhydrous benzene,
The mixture is refluxed for 3 hours, then cooled to ambient temperature, the precipitate is filtered under vacuum and washed with a small amount of anhydrous benzene, and the liquid containing the desired compound is recovered. Step B: Isomer A of methyl 6-chloro-4-[(1-methyl)ethyl]-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate 50 ml anhydrous benzene, 4 ml anhydrous methanol and 3.7 ml of triethylamine are mixed with stirring, the liquid obtained in step A above is added dropwise at ambient temperature, and the mixture is stirred at ambient temperature for 50 hours,
The precipitate is filtered under vacuum, washed with a small amount of benzene, and the liquid is collected and washed with 2N sodium hydroxide and then with water until a neutral pH. dehydrate the organic phase;
Treatment with activated carbon and drying yielded 7.3 g of crude product, which was crystallized from methanol, the resulting crystals were vacuum filtered and dried, and 4.5 g of the expected compound was recovered, which was Purification is achieved by recrystallizing twice from methanol. 1.8 g of purified expected compound are obtained. MP=114-115℃. Analysis: C ₁₉ H ₁₉ ClO ₄ Calculation: C % 65.80 H % 5.52 Cl % 10.22 Actual measurement: 65.8 5.6 10.2 NMR spectrum (deuterochloroform, fundamental frequency 90 Mhz) Two CH ₃ 74 and (1-methyl)ethyl groups 77
Hz (1-methyl)ethyl group〓CH- 187~239Hz COOCH ₃ 351Hz Hydrogen at 2-position 479Hz Aromatic Peak example from 616~681Hz 25 6-chloro-4-[(1-dimethyl)ethyl]-
4-Phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two diastereomeric racemates) 12.8 g 50% sodium hydride in oil, 100 ml anhydrous dioxane and 600 mg dibenzo- Mix 18-Crown-6 while stirring, then add 5.82ml
of dichloroacetic acid dissolved in 100 ml of dioxane was added dropwise to the above solution with stirring at ambient temperature, the suspension was kept at ambient temperature, and 14.1 g of 5-chloro-α-(1,1-dimethyl ) ethyl-
A solution of 2-hydroxy-α-phenylbenzene methanol in 100 ml of dioxane was added dropwise, and the mixture was then heated at 80° C. for 6 hours.
It is then cooled to ambient temperature, kept at this temperature with an ice-water bath, 400 ml of water is added, the aqueous phase is extracted with 600 ml of ether, three times with 100 ml of 0.1N sodium hydroxide, and the aqueous extracted phase is diluted with 2N acidified with hydrochloric acid,
Extract 3 times with 150 ml of ether and reduce the organic extract phase to 100 ml.
ml of water three times, and the acid was extracted as the sodium salt with saturated sodium bicarbonate solution, then 100 ml of water.
Extract 3 times with ml of water and collect the aqueous extract. The aqueous phase was washed three times with 100 ml of ether, the aqueous phase was acidified with 2N hydrochloric acid and extracted four times with 150 ml of ether, the ether phase was washed three times with 100 ml of water,
The ether phase is dried over magnesium sulfate, treated with activated carbon and brought to dryness to give 9.1 g of crude expected compound. NMR spectrum (deuterochloroform, instrument fundamental frequency 60Mhz) Hydrogen at position 2 317Hz (isomer A) Hydrogen at position 2 340Hz (isomer B) (1,1-dimethyl)ethyl 63 and 65Hz Aromatic 415-472Hz OH 527Hz 5-chlor-α- used at the start of the production above
(1,1-dimethyl)ethyl-2-hydroxy-
α-phenylbenzene methanol was obtained as follows. 40.2 g of (5-chloro-2-hydroxyphenyl)phenylmethanone and 400 ml of anhydrous ether are mixed, then a solution of 192 g of t-butyllithium in pentane is added dropwise at ambient temperature and stirred for 2 hours at ambient temperature. , the ether was distilled off with gradual displacement with 600 ml of anhydrous benzene, the benzene was refluxed from the solution for 6 hours, cooled to ambient temperature, poured onto an ice-cold 10% ammonium chloride solution of 1, and the organic phase was decanted. The aqueous phase was extracted twice with 100 ml of ether and the organic phase was extracted with 70 ml of ether.
ml of water twice, dehydrated with magnesium sulfate,
Treatment with activated carbon and drying gave 50 g of the expected product (as an oil), which was chromatographed on a silica column, eluted with methylene chloride and fractionated to give 14.1 g of product, A portion of it is recrystallized from cyclohexane. MP=146℃. Analysis: (C ₁₇ H ₁₉ O ₂ Cl) Calculation: C% 70.22 H% 6.59 Cl% 12.19 Actual measurement: 70.5 6.7 11.9 NMR spectrum (deuterochloroform, fundamental frequency 60Mhz) OH of 2-hydroxyl group 530Hz OH of methanol 175Hz [ (1,1-dimethyl)ethyl] group 75Hz Aromatic phenyl group at α position of methanol 420~
455Hz Other aromatics 400-455Hz Example 26 Isomer A of methyl 6-chloro-4-[(1,1-dimethyl)ethyl]-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate Step A: 6-chloro-4-[(1,1-dimethyl)
Ethyl]-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid chloride (racemic mixture) 9.1 g of 6-chloro-4-[(1. 1-dimethyl)ethyl]-4-phenyl[4H]-1,3-benzodioxin-2-
Mix the diastereomeric racemic mixture of carboxylic acids with 100 ml of anhydrous benzene. 3.7 ml of triethylamine were then slowly added, keeping at ambient temperature, followed by dropwise addition of a solution of 6.2 g of thionyl chloride in 25 ml of anhydrous benzene, refluxed for 3 hours, and then cooled to ambient temperature to remove the precipitate. Filtered under vacuum, washed with anhydrous benzene,
Collect the liquid and concentrate the solution under vacuum to obtain 30 ml of solution. Step B: 6-chloro-4-[(1,1-dimethyl)
Isomer A of methyl ethyl]-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate 3 ml methanol, 50 ml anhydrous benzene and
3.7 ml of triethylamine are mixed with stirring and cooled to 15-20°C, then the solution obtained in step A above and added with 30 ml of anhydrous benzene is added dropwise at this temperature and stirred for 16 hours at ambient temperature to remove the precipitate. Filter under vacuum and wash with anhydrous benzene. The liquid was concentrated under vacuum to obtain 6.5 g of crude product, which was chromatographed on a silica column and mixed with ethyl ether and petroleum ether (BP 60-80
After fractional distillation and evaporation of the solvent, the crude expected compound was obtained, which was crystallized from 20 ml of methanol and after drying,
The desired compound is obtained. MP=85℃. Analysis: _{( C20H21ClO4} ) Calculation: C%66.57 H%5.87 Cl%9.82 Actual measurement: _66.5 6.0 10.0 NMR spectrum (deuterochloroform, fundamental frequency 60Mhz) (1,1-dimethyl)ethyl 62Hz COOCH ₃ 117Hz 2 Hydrogen at position 338Hz Aromatic Peak example from 412 to 468Hz 27 6-Fluoro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of diastereomeric racemates) 25g Sodium hydride, 350 c.c. of anhydrous dioxane, and 1.55 g of dibenzo-18-crown-6 were mixed under an argon atmosphere, and then a solution of 16.5 cc of dichloroacetic acid dissolved in 150 c.c. of dioxane was prepared. 1 hour and then after the reaction was complete, 31 g of α-phenyl-α-methyl-(5-fluoro-2
- Hydroxy) phenylmethanol dissolved in 150 c.c. of anhydrous dioxane was added over 1 hour at 22°C, heated to about 80°C, stirred at 80-85°C for 6 hours, cooled, and mixed with an ice-water mixture. Pour on top, extract with ether, acidify the aqueous phase, extract the aqueous phase with ether, wash the ether phase with water, extract the ether phase with sodium bicarbonate, wash with methylene chloride, acidify the alkaline phase. , extracted with methylene chloride, washed with water, dried over magnesium sulfate and dried under vacuum. 29.5 g of crude expected compound (as oil) are obtained. NMR spectrum Hydrogen at position 2 310 Hz and CH ₃ 117 Hz (peak corresponding to isomer A of the obtained acid) Hydrogen at position 2 339 Hz and CH ₃ 126 Hz (peak corresponding to isomer B of the obtained acid) Aromatic 400-450Hz OH 505Hz α-phenyl-α- used at the start of the production above
Methyl-(5-fluoro-2-hydroxy)phenylmethanol was produced as follows. Mix 13.3 g of magnesium cuttings and 50 c.c. of anhydrous ether with stirring under an argon atmosphere, then slowly add a solution of 34.7 cc of methyl iodide in 250 c.c. of anhydrous ether. ,
Then, the mixture is heated under reflux for 1 hour. Next, 22.0 cc of the obtained magnesium derivative solution was added to a solution of 30 g of α-phenyl-(5-fluoro-2-hydroxy)phenylmethanone dissolved in 150 cc. of anhydrous benzene, and the ether was replaced with anhydrous benzene. then stirred at about 78° C. for 4 hours, cooled, poured onto ammonium chloride solution, extracted with ether, washed with water, dried over magnesium sulfate,
Dry under vacuum. 32 g of crude product are obtained. A portion of this compound is recrystallized from cyclohexane. MP=122℃. Analysis: ( _{C14H13FO2 )} Calculation: C%72.40 H%5.64 F%8.18 Actual measurement: 72.4 5.6 8.2 Example 28 6-fluoro-4-methyl-4 _- phenyl[4H]-1,3-benzodioxin- 29.5 g of isomer A of methyl 2-carboxylate, a racemic mixture of 6-fluoro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid obtained in Example 27;
300 c.c. of methanol and 130 g of acid type resin are mixed with stirring and then refluxed for 24 hours. Cool, treat with activated charcoal, filter, wash with methanol and dry, dissolve in ether and reduce the ether phase to 200
washed three times with cc bicarbonate solution, then water;
Dehydrate over magnesium sulfate, dry under vacuum,
23.8 g of crude product is obtained, which is dissolved in 200 c.c. of methanol. 5 g of the compound is obtained and recrystallized from 20 c.c. of methanol. 4.4 g of the expected compound are obtained.
MP=95℃. Analysis: (C ₁₇ H ₁₅ FO ₄ ) Calculation: C% 67.54 H% 5.00 F% 6.28 Actual measurement: 67.7 5.0 6.2 NMR spectrum (deuterochloroform, instrument frequency 90Mhz) CH ₃ 171Hz COOCH ₃ 345Hz Hydrogen at 2-position 463Hz Aromatic Group 615-680Hz peak example 29 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl ) Methyl isomer A Step A: 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid chloride isomer A 4.9 g of 6 obtained in Example 3 -Chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid isomer A and 50 ml of anhydrous benzene are mixed with stirring, cooled to about 10°C, and at this temperature Add 1.66 g of triethylamine dropwise. A solution of 2.5 g of thionyl chloride dissolved in 25 ml of anhydrous benzene is then added dropwise at the above temperature, followed by refluxing for 2 hours. The suspension is cooled to ambient temperature, the precipitate is filtered under vacuum, and the liquid containing the desired compound is recovered. Step B: Isomer of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid A 2.25 g of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol, 50 ml of anhydrous benzene and 2.3 ml of triethylamine are mixed with stirring, and the liquid collected in step A above is added dropwise at ambient temperature. do. Stir at ambient temperature for 20 hours.
filter, wash the liquid with 10% sodium carbonate solution,
Then wash with water to neutral pH. The benzene phase is dried over calcium chloride, treated with activated charcoal and the solvent is evaporated under vacuum to give 4.5 g of crude product, which is chromatographed on a silica column and eluted with methylene chloride. After separation, 2
g of the crude expected compound is obtained in the form of a colorless gum. Analysis: (C ₂₂ H ₂₃ O ₆ Cl) Calculation: C% 63.08 H% 5.53 Cl% 8.46 Actual measurement: 62.0 5.5 8.9 NMR spectrum (deuterochloroform, fundamental frequency of device 60 Mhz) CH ₃ 81 of 2,2-dimethyldioxolane −
82Hz 4 position CH ₃ 115Hz

[Formula] 215-260Hz Aromatic 411-441Hz Example 30 Isomer A of 2-(diethylamino)ethyl 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate Hydrochloride 6.2 g 6-chloro-4-methyl-4-phenyl[4H]-1.3 obtained as shown in Example 16
A mixture of isomer A of methyl benzodioxine-2-carboxylate, 100 ml of anhydrous toluene, 2.6 g of diethylaminoethanol and a very small amount of sodium hydride is brought to reflux with stirring under a nitrogen atmosphere. Continue to reflux for 3 hours, then cool and add 5 ml
of 4N hydrochloric acid in ether, then 200 ml of anhydrous ether, filtered, washed with ether,
After dehydration, 3.7 g of product was obtained, which was added to 20 ml of 60°C.
Dissolve in isopropanol, treat with activated charcoal, cool, add 50 ml of ether, filter and dry to obtain 2.7 g of the expected compound. MP=110℃. Analysis: ( _C22H27Cl2NO4 ) Calculation: C% _60.00 H%6.18 Cl% _16.10 Actual measurement: 59.6 6.4 15.9 N%3.18 3.4 Example ₃₁ 6-chloro-4-ethyl-4-phenyl[4H]-1・3-Benzodioxine-2-carboxylic acid (mixture of two diastereomeric racemates) 250 c.c. of condensed liquid ammonia is mixed with approximately 100 g of ferric nitrate and 4.8 g of sodium with stirring. Then, a solution of 26.2 g of 5-chloro-α-ethyl-2-hydroxy-α-phenylbenzene methanol dissolved in 200 c.c. of anhydrous toluene was added at 28 to 30°C for 1 hour and 30 minutes. Raise the temperature to drive off the liberated ammonia, heat under reflux for 3 hours, add 100 c.c. of toluene, then heat at 50°C.
Add 18 g potassium dichloroacetate, reflux overnight, add 9 g potassium dichloroacetate, stir at reflux for another 2 hours, cool, pour into water, remove organic phase, acidify aqueous phase and extract with ether. The ether phase was washed three times with 500 c.c. of water, the ether phase was extracted three times with 300 c.c. of sodium bicarbonate solution, the aqueous phase was concentrated and the aqueous phase was extracted with 500 c.c. of ether twice. Acidified with hydrochloric acid and diluted with 500 c.c. of ether.
Extracting twice, washing with water, drying over magnesium sulfate and drying under vacuum gives 27 g of crude expected compound. 5- used at the beginning of the preparation of the compound of Example 31 above.
Chlor-α-ethyl-2-hydroxy-α-phenylbenzene methanol can be prepared as described in Example 23, but using ethyl iodide instead of isopropyl bromide. MP
=85℃. Example 32 Isomers A and B of methyl 6-chloro-4-ethyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate 6-chloro-4-ethyl-4-phenyl[4H]- Two diastereomeric racemates of methyl 1,3-benzodioxin-2-carboxylate A
The mixture obtained in Example 31 and the same procedure as described in Example 20 were used to prepare and isolate B and B starting from a mixture of the isomers A and B of the corresponding acids. From the mixture of 26 g of isomer A and B obtained in Example 31, (a) 4.5 g of the expected isomer A are obtained, which is recrystallized from refluxing methanol. 3.5 g of purified desired isomer A are obtained. MP=128℃. Analysis: (C ₁₈ H ₁₇ ClO ₄ ) Calculation: C% 64.96 H% 5.15 Cl% 10.65 Actual measurement: 65.0 5.2 10.4 NMR spectrum (deuterochloroform,
Fundamental frequency 60Mhz) Ethyl at 4-position 44-51-58Hz, 110-160Hz COOCH ₃ 232Hz Hydrogen at 2-position 314Hz Aromatic of 1,3-benzodioxin nucleus 415~
450Hz Phenyl in position 4 445Hz (b) A further 4 g of the expected isomer B are obtained. MP＝
108℃. Example 33 6-chloro-4-(4-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2
-Carboxylic acid (mixture of two diastereomeric racemates) 250 c.c. dioxane, 1.6 g dibenzo-18-crown-6 and 25 g sodium hydride are mixed with stirring, then 16 c.c. dichloroacetic acid
A solution of 100 c.c. in dioxane was added over 45 minutes and an additional 36.6 g of 5-chloro-2-
A solution of hydroxy-α-methyl-α-(4-chlorophenyl)benzene methanol in 150 c.c. of dioxane was added at 30°C over 1 hour, heated at 80°C for 5 minutes, and then cooled. , poured onto a mixture of ice and water, extracted three times with 500 c.c. of ether, acidified the aqueous phase with concentrated hydrochloric acid, extracted three times with 500 c.c. of ether, and diluted the ethereal phase with sodium bicarbonate. Extract with solution, acidify the aqueous phase, extract 4 times with 300 c.c. of ether, wash with water, dry over magnesium sulfate and dry under vacuum to obtain 40 g of crude expected compound. NMR spectrum (deuterochloroform, fundamental frequency 60 Mhz) Hydrogen in position 2 309Hz CH ₃ 116Hz This corresponds to the desired isomer (isomer A). Hydrogen in position 2 340Hz CH ₃ 124Hz This corresponds to the other desired isomer (isomer A). Aromatic 405-445Hz OH 510Hz 5-chloro-2-hydroxy-α-methyl-α-(4-chlorophenyl)benzenemethanol used at the start of the production can be produced as follows. 13.5 g of 2-hydroxy-5-chloroacetophenone and 130 c.c. of anhydrous ether are mixed with magnetic stirring under an argon atmosphere, externally cooled in an ice-water bath, and then 1-chloro-4- Freshly prepared ethereal solution of bromobenzene magnesium derivative (concentration of 0.46 mol/330)
cc dropwise keeping the internal temperature between 10-20 °C and keep stirring overnight at ambient temperature. Cool the yellow suspension, add 125 c.c. of ice-cold 2N aqueous hydrochloric acid solution dropwise,
Decanted, washed the organic phase with water, dried over sodium sulfate, treated with activated charcoal, filtered under vacuum,
Dry under vacuum, dissolve the residue in 100 c.c. of cyclohexane, crystallize with stirring, filter the precipitate under vacuum, make it into a paste with a small amount of cyclohexane, dry in an oven, 19.3 g of the expected compound is obtained. MP=130℃. Analysis: (C ₁₄ H ₁₂ O ₂ Cl ₂ ) Calculation: C% 59.38 H% 4.27 Cl% 25.04 Actual measurement: 59.7 4.3 24.7 Example 34 6-Chlor-4-(4-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2
- Isomer A of methyl carboxylate 40 g of 6-chloro-4-(4-chlorophenyl)-4-methyl[4H]-1,3-benzodioxin-2-carboxylic acid, a mixture as obtained in Example 33. diastereomeric racemic mixture of 400
Mix cc of methanol and 180g of strong sulfonic acid resin, stir under reflux for 18 hours, cool,
Filtered in vacuo, washed 4 times with 300 c.c. of ether, dried under vacuum, the residue dissolved in 500 c.c. of ether and 3 times with 300 c.c. of sodium bicarbonate solution.
Wash twice, then four times with 500 c.c. of water, dry over magnesium sulfate and dry under vacuum to give 35.5 g of product. The resulting product was treated with 100 c.c. of methanol, left at ambient temperature overnight, filtered under vacuum,
Washing with ice-cold methanol gives 10 g of product, which is recrystallized from 60 c.c. of methanol and left overnight at ambient temperature to give 9.1 g of the desired isomer A. MP=
108℃. Analysis: (C ₁₇ H ₁₄ Cl ₂ O ₄ ) Calculation: C%57.81 H%4.0 Cl%20.0 Actual measurement: 58.0 4.0 19.9 NMR spectrum (deuterochloroform, fundamental frequency 60Mhz) CH ₃ 115Hz COOCH ₃ 231Hz Hydrogen at position 2 308Hz Aromatic 412-442Hz Example 35 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two diastereomeric racemates) with 4 g of sodium amide 50 ml of anhydrous toluene are mixed and a solution of 9.95 g of 5-chloro-2-hydroxy-α-methyl-α-phenylbenzene methanol dissolved in 150 ml of anhydrous toluene is added dropwise at ambient temperature. The mixture is refluxed for 6 hours, then cooled to ambient temperature, 10.25 g of potassium dibromoacetate are added and refluxed again for 6 hours.
Cool, dissolve in 200 ml of water, decant, extract the organic phase twice with 80 ml of water and reduce the aqueous phase to 80 ml.
Wash twice with ml of ether and acidify the aqueous solution with 40 ml of 2N hydrochloric acid. A precipitate forms and is extracted three times with 100 ml of ether. The organic phase is washed twice with 80 ml of water and the desired acid is re-extracted three times with 50 ml of 5% saturated aqueous sodium bicarbonate solution. The organic extract phase is washed three times with 80 ml of ether and the alkaline solution is acidified with 90 ml of 2N hydrochloric acid solution.
The desired acid is extracted four times with 100 ml of ether. The organic phase is washed with water, dried over magnesium sulfate in the presence of activated charcoal and the solvent is removed under vacuum, yielding 7.85 g of crude product, which is dissolved in hexane. The result obtained is filtered under vacuum and dried to obtain 6 g of the expected compound. MP=144℃. NMR spectrum (deuterochloroform, fundamental frequency 60Mhz) CH ₃ 117Hz Hydrogen at 2-position 312Hz (corresponds to isomer A) CH ₃ 125.5Hz Hydrogen at 2-position 342.5Hz (corresponds to isomer B) Aromatic 405-450Hz OH 350Hz Example 36 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two diastereomeric racemates) 10 c.c. of dioxane and 1.35 g of 60 mg dibenzo-18- mixed with 50% sodium hydride in oil at 15 °C.
Crown-6, then add 0.61 cc dichloroacetic acid and 10 cc dioxane over 5 minutes. 1.25 g of 2-hydroxy-5-chloro-α-methylbenzhydrol and 5 c.c. of dioxane are then added over a period of 10 minutes at about 20°C. Next, heat at about 80°C for 6 hours, then cool to about 20°C, add 2 c.c. of methanol, pour into ice water,
Extract three times with ethyl acetate and wash five times with ice-cold 0.1N sodium hydroxide. The aqueous phases are combined, acidified to PH1 with 2N hydrochloric acid solution, extracted three times with methylene chloride, dried and dried to give the crude expected compound. Example 37 Piperidine salt of isomer A of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid 6-chloro-4-methyl- obtained in Example 36 above 4
-Phenyl[4H]-1,3-benzodioxin-
A mixture of two diastereomeric racemates of 2-carboxylic acid was dissolved in 4 c.c. of ethyl acetate and heated at 10°C.
Add 0.8cc piperidine. Upon stirring, the desired piperidine salt crystallizes out. After 15 minutes, it is filtered under vacuum, washed with ethyl acetate and then with ether, and dried under vacuum at 20° C. to obtain 855 mg of the expected compound. The mother liquor of crystallization was collected, diluted with methylene chloride, washed with ice-cold 1N hydrochloric acid, dried, dried, and the residue was dissolved in 12 c.c. of methylene chloride and dissolved in 0.6 c.c. of boron trifluoride. The etherate was added, left at 20°C for half an hour, poured onto ice, washed twice with water, re-extracted with methylene chloride, dried, dried, and dissolved in 2 c.c. of ethyl acetate and 0.4 cc of piperidine. , crystallizes and isolates 545 mg of the expected compound. Starting from the mother liquor of the crystallization, the same method was carried out anew (isomerization with boron trifluoride, addition of piperidine), 130
An additional mg of desired compound is recovered. A total of 1.53 g of the expected compound is thus obtained. NP165℃. Example 38 Isomer A of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid 1.53 g of the piperidine salt obtained in Example 37 above was mixed with methylene chloride 1N Dissolved in a mixture with hydrochloric acid, washed, dehydrated, treated with activated charcoal, added cyclohexane to 3 c.c., filtered under vacuum, washed with cyclohexane, dried under vacuum at 40°C, 1.1 g of the desired amount Obtain the compound. MP=175℃. This compound is identical to isomer A obtained in Example 3. Example 39 Compressed tablets corresponding to the following formulation were manufactured. 6-chloro-4-methyl-4-phenyl[4H]-
1,3-benzodioxin-2-carboxylic acid (as isomer A) …………300mg Supplementary agent …………Enough amount to make one tablet up to 500mg (Details of auxiliary agent: lactose, starch, talc, Example 40 Gelatin capsules corresponding to the following formulation were manufactured. 6-chloro-4-methyl-4-phenyl[4H]-
Methyl 1,3-benzodioxin-2-carboxylate (as isomer A) …………25 mg Auxiliary agent: Sufficient amount to make one capsule up to 500 mg (Details of auxiliary agent: talc, stearic acid) Example 41 Compressed tablets corresponding to the following formulation were manufactured. Isomer A as obtained in Example 21...300 mg Adjuvants... Sufficient amount to make one tablet up to 500 mg (adjuvant details: talc, magnesium stearate, Aerosil) Example 42 The following general Gelatin capsules were prepared corresponding to the recipe. Isomer d as obtained in Example 18...250 mg Adjuvants... Sufficient amount to give up to 500 mg per capsule (adjuvant details: talc, magnesium stearate, Aerosil) Pharmacological studies ( 1) Determination of acute toxicity Acute toxicity was determined on batches of 5 mice weighing 18-22 g. Compounds were administered by the intraperitoneal route as suspensions in carboxymethylcellulose. Animals were kept under observation for one week. The lethal dose 50 (LD50) was determined and the following results were obtained.

[Table] (2) Determination of blood lipid-reducing activity
A batch of eight male rats of the Dawley SPF strain were studied. Animals are fed a diet containing 50% sutucarose and rich in cholesterol (1%).
They are then treated for 10 days with the test compound, which is administered by probang as an aqueous suspension supplemented with carboxymethylcellulose. Animals were given 16 hours after the last dose of compound.
Once deprived of food, then bled by abdominal puncture, and blood samples taken on sodium heparate, quantification of triglycerides, cholesterol and total lipids is carried out by the method described below. Determination of triglycerides Semi-automatic determination method described by G. Kessler and H. Lederer in "Automation in Analytical Chemistry" New York, 341 (1965), J.
Revised by R. Claude and F. Corre, “Ann.Biol.
Clin. 26 , 3-4, 451 (1968). Determination of Cholesterol J. Levine's technique adapted to an automatic analyzer system, "Symposium Technicon 1967, vol.
twenty five. Nephelometric quantification of total lipids HCGirard, J. Canal, J. Delattre and J. Peynet.
Semi-automated quantitative method by each person. “Symposium
Technicon” 1970, Paris. After administration of various amounts of the test compound, the changes in the amount of triglycerides, cholesterol and total lipids (expressed in % by weight) in the treated animals are determined compared to the control animals. The following results were obtained.

【table】

Claims (1)

[Claims] First-order general formula' [Here, R′ ₁ is a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, (2,2-dimethyl-1,3
-dioxolan-4-yl) methyl group or dialkylaminoalkyl group (where the alkyl group is 1-
_R2 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; _R3 represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms; or phenyl group, R ₄ and R ₅ may be the same or different and represent a hydrogen atom or a halogen atom] in the form of a racemic or optically active form or a mixture of these isomers, and alkali metal, alkaline earth metal, aluminum, ammonium and amine salts of compounds of formula ' in which R' ₁ represents a hydrogen atom, and addition salts with acids of compounds of formula ' in which R' ₁ represents a dialkylaminoalkyl group. 2nd order general formula (R ₁ and R ₂ may be the same or different and represent a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms, R ₃ is a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, represents a group or a phenyl group,
R ₄ and R ₅ may be the same or different and represent a hydrogen atom or a halogen atom) in the form of a racemic or optically active form or a mixture of these isomers, and R ₁ represents a hydrogen atom. Compounds of general formula (') according to claim 1, which are alkali metal, alkaline earth metal, aluminum, ammonium and amine salts of compounds of formula ('). 3 In the above formula, R ₁ and R ₂ may be the same or different and represent a hydrogen atom or a methyl group,
The racemic form according to claim 2, wherein R ₃ represents a hydrogen atom, a methyl group, or a phenyl group, R ₄ represents a hydrogen atom, and R ₅ represents a hydrogen atom or a chlorine atom. Compounds in the form of optically active forms or mixtures of these isomeric forms and alkali metal, alkaline earth metal, aluminum, ammonium and amine salts of the compounds of the formula in which R ₁ represents a hydrogen atom. 4 In the above formula, R ₁ represents a hydrogen atom or a methyl group, R ₂ represents a hydrogen atom, R ₃ represents a hydrogen atom, methyl group, or phenyl group, R ₄ represents a hydrogen atom, and R ₅ represents a chlorine atom. and an alkali metal compound of the formula in which R ₁ represents a hydrogen atom, in the form of a racemic or optically active form or a mixture of these isomers, as claimed in claim 2, , alkaline earth metals, aluminum, ammonium and amine salts. 5. Compounds of the formula according to claim 2 in the form of racemic or optically active forms or mixtures of these isomers and having the following compound names: 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid, 6-chloro-2,4-dimethyl-4-phenyl[4H]-1,3-benzodioxin -2-carboxylic acid, 6-chloro-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid, 6-chloro-4,4-diphenyl[4H]-1.
3-benzodioxin-2-carboxylic acid, 4-methyl-4-phenyl-1,3-benzodioxin-2-carboxylic acid and 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzo Methyl dioxine-2-carboxylate. 6. Compounds of the formula according to claim 1 in the form of racemic or optically active forms or mixtures of these isomers and having the following compound names: 6-chloro-4・4-diphenyl[4H]-1・
Methyl 3-benzodioxin-2-carboxylate, ethyl 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate, 6-chloro-4-methyl-4-phenyl [4H]-1,3-benzodioxin-2-carboxylic acid sodium, two diastereomers of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid Semi-forms A and B
piperidine salt, two diastereomeric racemates A and B of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid
isomers d and l, 6-chloro-4-(3-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2-
Methyl carboxylate, 6-chloro-4-(3-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2-
Carboxylic acid, 6-chloro-4-[(1-methyl)ethyl]-4
-Phenyl[4H]-1,3-benzodioxin-
Methyl 2-carboxylate, 6-chloro-4-[(1,1-dimethyl)ethyl]-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate, 6-fluoro-4-methyl -4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid methyl, 6-chloro-4-ethyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid methyl, 6 -Chlor-4-(4-chlorophenyl)-4-
Methyl[4H]-1,3-benzodioxin-2-
Methyl carboxylate, 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl)methyl, 6 -2-(diethylamino)ethyl chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate and its addition salt with an acid. 7 Claim 5, which is isomer A of methyl 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate
Compounds described in Section. 8 6-chloro-4-(3-chlorophenyl)-4
-Methyl[4H]-1,3-benzodioxin-2
- The compound according to claim 6, which is isomer A of methyl carboxylate. 9 Claim 6, which is isomer A of ethyl 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylate
Compounds described in Section. 10 The compound name is isomer A of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid and 6-chloro-2,4-dimethyl-4-phenyl[4H] ]-1,3-Benzodioxine-2-carboxylic acid isomer A A compound of the formula according to claim 2. 11 The compound name is isomer A of 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-
Isomer A of carboxylic acid and isomer A of 6-chloro-4-methyl-4-phenyl[4H]-1,3-benzodioxin-2-carboxylic acid. Compound. 12 The following general formula (R ₁ represents a hydrogen atom, R ₂ is a hydrogen atom or 1 to
represents an alkyl group containing 5 carbon atoms,
R ₃ represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, or a phenyl group, R ₄ and R ₅
may be the same or different and represent a hydrogen atom or a halogen atom) in the racemic or optically active form or in the form of a mixture of these isomers, as well as alkali metal, alkaline earth metal, aluminum compounds of the formula , in producing ammonium and amine salts, the following formula (where R ₃ , R ₄ and R ₅ are as described above) in the presence of a basic condensing agent. (where R ₂ is as described above, X is chlorine,
(representing a bromine or iodine atom) to obtain the alkali metal salt of the corresponding acid, if necessary treating the salt with an acid to obtain the acid of the corresponding formula, if necessary. Compounds of the general formula, characterized in that the acid is salted to obtain the corresponding salt and, if necessary, the compound of the formula is further isolated in racemic or optically active form or in the form of a mixture of these isomers. and the method for producing the salt. 13 The following general formula' [Here, R' ₁ is an alkyl group containing 1 to 5 carbon atoms, a (2,2-dimethyl-1,3-dioxolan-4-yl)methyl group, or a dialkylaminoalkyl group (wherein the alkyl group is _R2 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms, and _R3 represents a hydrogen atom, containing 1 to 5 carbon atoms. R ₄ and R ₅ may be the same or different and represent a hydrogen atom or a halogen atom] Compounds in the form of racemic or optically active forms or mixtures of these isomers; In preparing an addition salt with an acid of a compound of formula ' in which R' ₁ represents a dialkylaminoalkyl group, the following formula (where R ₃ , R ₄ and R ₅ are as described above) in the presence of a basic condensing agent. (where R ₂ is as described above, X is chlorine,
(representing a bromine or iodine atom) with an alkali metal salt of a compound of the following formula: (Here, R ₁ represents a hydrogen atom, R ₂ , R ₃ , R ₄ and
R ₅ is as described above), converting this acid to a functional derivative if necessary, and then converting the acid of the formula or the functional derivative of this acid into the acid of the formula R′ ₁ OH (where R ' ₁ is an alkyl group containing 1 to 5 carbon atoms, (2,2-dimethyl-1,
3-dioxolan-4-yl) methyl group or dialkylaminoalkyl group (where the alkyl group is 1
containing up to 4 carbon atoms) and the resulting compound of formula ', in which R' ₁ represents a dialkylaminoalkyl group, is optionally treated with an acid to form its salt. and, if necessary, further isolation of the compound of formula ' or its salt in racemic or optically active form or in the form of a mixture of these isomers. 14 The following general formula (R ₁ represents a hydrogen atom, R ₂ is a hydrogen atom or 1 to
represents an alkyl group containing 5 carbon atoms,
R ₃ represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, or a phenyl group, R ₄ and R ₅
represents a hydrogen atom) in the racemic or optically active form or in the form of a mixture of these isomers, and the alkali metal, alkaline earth metal, aluminum, ammonium and amine salts of the compound of the formula: formula (wherein R ₃ is as described above and R ₄ or R ₅ or R ₄ and R ₅ represent a chlorine atom) in the presence of a basic condensing agent. (wherein X represents a chlorine, bromine or iodine atom and R ₂ has the meaning given above) to obtain the alkali metal salt of the corresponding acid; to obtain the corresponding compound of the formula in which R ₄ or R ₅ or R ₄ and R ₅ represent a chlorine atom, and this compound is treated with hydrogen in the presence of a catalyst so that R ₄ and R ₅ represent a hydrogen atom. to obtain a compound of the corresponding formula represented, if necessary, to form a salt to obtain the corresponding salt, and if necessary, to obtain a compound of the formula in racemic or optically active form or in the form of a mixture of these isomers. A method for producing a compound of the general formula and a salt thereof, which is characterized in that it is isolated. 15 The following general formula' [Here, R' ₁ represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms, R ₂ represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms, and R ₃ represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms. R ₄ represents an alkyl group or a phenyl group containing 1 to 5 carbon atoms;
and R ₅ may be the same or different and represent a hydrogen atom or a halogen atom] or a pharmaceutically acceptable salt thereof in the form of a racemic or optically active form or a mixture of these isomers. A composition for lowering blood lipids containing at least one of the following as an active ingredient.