FR2494264A1 - NOVEL COMPOUNDS BELONGING TO THE FAMILY OF BIPHENYL, BENZYLPHENYL, BENZYLOXYPHENYL, BENZYLTHIOPHENYL ETHERS AND THIOETHERS OF A, O-GLYCOLS AND HYDROXYTHIOLS - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS AS NEW INDUSTRIAL PRODUCTS, COMPOUNDS RESPONDING TO THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH REPRESENTS A BOND OR A CH GROUP; Y IS A BOND OR AN ATOM OF OXYGEN OR SULFUR; X IS AN ATOM OF OXYGEN OR SULFUR; Z AND Z EACH REPRESENT HYDROGEN OR A HALOGEN OR A C-C ALKYL GROUP, C-C OR OH ALCOXY; AND N IS AN INTEGER FROM 4 TO 12; OR ONE OF THEIR ESTERS WITH A SOLUBILIZING ACID OR A SALT OF SAID ESTER; WITH THE ADDITIONAL CONDITIONS THAT: WHEN N IS EQUAL TO 4 AND A IS A LINK, Z IS OTHER THAN BR OR C1 AND Z IS OTHER THAN BR, CHO OR ISOPROPYL; WHEN N IS EQUAL TO 5 AND A AND Y FORM A BOND TOGETHER, Z IS OTHER THAN CHO; AND WHEN N IS 4-7 AND A AND Y FORM A BOND TOGETHER, Z IS OTHER THAN OH.

Description

New compounds belonging to the family of ethers and thioethers of

  biphenyl, benzylphenyl, benzyloxyphenyl, benzylthiophenyl

aw-glycols and hydroxythiols.

  The present invention relates as products

  industrial products, biphenyl ethers and thioethers, benzyl-

  phenyl, benzoxyphenyl and benzylthiophenyl, substituted or unsubstituted with C4-C12 straight or branched chain, glycosyl and hydroxythiols and esters thereof with pharmaceutically acceptable acids. These new products are useful in particular in therapeutics

as anti-rhinovirus agents.

  The novel compounds according to the invention correspond to the general formula Z 2 --A y - - (C) -OH (I) O 2 n Z 'in which A represents a single bond or a CH 2 group; Y is a bond or an oxygen or sulfur atom; X is a

  oxygen or sulfur atom; Z and Z 'each represent hydro-

  gene or a halogen or a C1-C4 alkyl, C1-C4 alkoxy or OH group; and n is an integer of 4 to 12; provided that when n is 4 and A is a bond, Z is other than Br or C1 and Z 'is other than Br, CH3O or isopropyl; when n is 5 and A and Y together form a bond, Z is other than CH30; and when n is 4-7 and A and Y together form a bond, Z is other than OH; their esters with solubilizing acids and the

salts of said esters.

  In the compounds of formula I, substituents A and Y are preferably each a bond, or A is CH2 and Y is oxygen. The substituent X is preferably an oxygen atom. The substituents X and Y may be arranged ortho, meta or para to each other on the benzene ring common to both, preferably in meta or para, and more

especially in para.

  The substituents Z and Z 'are each, independently of one another, a hydrogen or halogen atom or a straight or branched chain alkyl or alkoxy group or a hydroxy group. The alkyl groups are illustrated by methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The same oxygen-linked alkyl groups illustrate the alkoxy groups represented by Z or Z '. The halogen atom can be fluorine, chlorine, bromine or iodine. Z and Z 'can both be in any position of the benzene ring but,

  preferably, they are both hydrogen atoms.

  The linear saturated carbon chain connecting the X group to the hydroxyl group can have a length of 4 to 12 carbon atoms. Compounds having a chain length are preferred

of 6 methylene units.

  The therapeutically preferred compounds according to the invention are those wherein X = 0; A and Y together form a bond or a CH20 group; Z and Z 'are both hydrogen atoms; n = 6 and Y is para to X. The esters of the compounds of formula I with pharmaceutically acceptable acids also exhibit antirhinovirus activity. Alcohols are often not easily soluble

  in water. Esterification with a pharmaceutically acceptable acid

  table, preferably a polyacid; such as a polycarboxylic acid, a sulfonic acid or sulfurous acid or sulfuric acid increases the solubility in water and facilitates the absorption of the compound. Especially desirable esters include

  monoesters of polycarboxylic acids and / or the salts of these mono-

  esters, preferably the sodium salts. The polyhydric acid esters

  hydroxylated or halogenated acids are also advantageous.

  These suitable esters include esters of polycarboxylic acids or polyfunctional C 2 -C 12 monocarboxylic acids and having 1 to 5 hydroxyl groups, for example glycolic, citric, maleic, succinic, gallic, fumaric, lactic, glyceric, tartaric and malic acids. and salicylic; and the

  haloalkoxy and / or acyloxy acids, for example

  acetic, fluoroacetic, trichloroacetic, trifluoroacetic and

  2,4,5-trimethoxybenzoic. The esters of these acids and

  Formula I salts are prepared by well-known techniques.

  of the man of the art. Some, for example the maleates and

  are suitably prepared by reaction of the compound with

  maleic anhydride or succinic anhydride in pyridine, followed by

  deification and isolation of the monoester.

  The invention also relates to the esters of sulfuric acid

  Examples are methanesulphonic acid and the like, and esters, preferably diesters, sulfuric and sulfuric acids. The contemplated equivalents of the foregoing esters include any esters of a compound of Formula I which have improved water solubility relative to alcohol.

from which he derives.

  By way of illustration of the alcohols of the invention, mention may be made of the following compounds: 6- (4-phenylphenoxy) hexane-1-ol, 6- (4-phenylphenylthio) hexane-1-ol, 6- (4- phenoxyphienoxy) hexane-1-ol, 6- (4-phenoxyphenylthio) hexane-1-ol, 6- (4-phenylthiophenoxy) hexane-1-ol, 6- (4-phenylthiophenylthio) hexan-1-ol,

6- (4-benzylphénoxy) hexane-l-ol ,.

  6- (4-Benzylphenylthio) hexane-1-ol, 6- (4-benzyloxyphenoxy) hexane-1-ol, 6 (4-benzyloxyphenylthio) hexane-1-ol, 6- (4-benzylthiophenoxy) hexane-1-ol and

  6- (4-benzylthiophénylthio) hexane-l-ol.

  The invention also relates to compounds analogous to each of the above, having another straight alkylene chain

  in C4-C12 instead of hexamethylene chain, for example 4- (4-

  phenoxyphenoxy) butane-1-ol with 12- (4-phenoxyphenoxy) dodecan-1-ol,

  and the corresponding alcohols in each series above.

r

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  The invention also relates to the isomers of each of the above compounds having X and Y substituents in meta or ortho with respect to one another on the central benzene ring common to both, for example 8- (3-benzoxyphenoxy) octane. 1-ol, 11- (2-phenylthiophenoxy) undecan-1-ol, and the ortho isomers and

  corresponding meta of each of the other compounds above.

  Other compounds of the invention include the p-fluorosubstituted analogs of each of the above free alcohols and esters, for example: 6- [4- (4-fluorophenyl) phenoxy] hexane-1-ol, 4- [4 (4-fluorophenoxy) phenoxy] butane-1-ol, 8- [3- (4-fluorobenzoxy) phenoxy] octan-1-ol, and

  6- [4- (4-fluorophenyl) phenoxy] -1-hexyl succinate.

  Other examples are the ortho-fluoro isomers and

  meta-fluoro of each of the above compounds and the analog compounds

  with chlorine, bromine or iodine in place of

the fluorine atom.

  Other specific examples of the compounds of the invention

  are the monofluoro-substituted compounds having a fluorine atom at a position available on the central benzene ring corresponding to each of the aforementioned unsubstituted alcohols and esters, for example: 6- (4-phenyl-3-fluorophenoxy) hexane-1 -ol, 8- (3-benzyloxy-4-fluorophenoxy) octan-1-ol, 8- (3-benzyloxy-5-fluorophenoxy) octan-1-ol, 4- (4-phenoxy-2-fluorophenoxy) -l glycolate -butyl, and the monofluoro-substituted compounds at the corresponding central nucleus

  otherwise to each of the other non-substituted alcohols and esters

  above, but substituted at another available position on the central benzene ring. Compounds analogous to the preceding ones having a chlorine, bromine or iodine atom instead of the atom of

  fluorine are still specific examples of the compounds of the invention.

  Other examples of specific compounds of the invention

  are those corresponding to each of the mono alcohols and esters

  above-mentioned fluoro-substituted radicals but having a methyl group instead of the fluorine atom as a substituent, those having a methoxy group instead of the fluorine atom and those having a

  hydroxy group instead of the fluorine atom.

  Other examples are the compounds in which the terminal benzene ring and the central benzene ring each carry a single fluorine atom, in positions similar to

  each of the monofluorocompounds above, for example 6- [4- (4-

  fluorophenyl) -2-fluorophenoxy] hexane-1-ol and the compounds 2,4'-

  difluoro-substituted corresponding otherwise to each of the others

  unsubstituted alcohols and esters mentioned above.

  Other examples of compounds of the invention include analogous compounds having a chlorine, bromine or

  iodine or a hydroxy, alkyl or alkoxy group, as illustrated below.

  above, instead of one or two fluorine atoms in each

  previous difluoro-substituted compounds.

  The invention also relates to the pharmaceutical esters

  of each of the above alcohols with various acids, more particularly the monoesters of citric, maleic, glycolic, glyceric, succinic, fumaric, lactic, malic, tartaric and methanesulphonic acids and the diesters of the acids.

sulfurous and sulfuric.

  The compounds of formula I and their suitable esters are of interest as anti-rhinovirus agents (With regard to their use as anti-rhinovirus agents, the term "compounds of formula I" embraces their suitable pharmaceutically acceptable esters.) rhinovirus group is part of the picornavirus group and contains more than 100 different types of antigens and is known to be responsible for many of the symptoms related to respiratory infections. The rhinovirus name indicates the prominent entry into the nasal passages that the in infections caused by these viruses, giving rise to

  characteristic syndromes of the current cooling. Rhinos

  viruses were classified into serotypes 1 to 89 and LA subtypes (88,89,90), with at least 20 other types to be added to the classification. Experimental studies indicate that nasal mucosal cells are more sensitive to rhinovirus than cells in the lower respiratory tract. Symptoms

2494264-

  of rhinovirus infection have also been experi-

  mentally by drip application of small amounts of the virus on the conjunctiva, indicating that the eye is another site susceptible to infection. The rhinovirus infection developed is characterized by hyperemia and edema of the mucous membrane with exudation of serous and mucinous fluid. 'The cavities

  nasal passages are narrowed by thickening of the membrane and engorged

turbinates.

  The compounds described herein have been shown to be effective as antiviral agents against many types of rhinoviruses, which makes them useful in treating the symptoms of rhinovirus.

  rhinovirus infection in hosts susceptible to said infections

  including humans, and some anthropoid apes such as chimpanzees. One skilled in the art knows that one can use several

  test systems for measuring antiviral activity against rhino-

  virus. For example, anti-rhinovirus activity can be measured using a plaque assay or a tube assay in which the activity of the compound against the test virus is measured in a cellular system. Using various assay systems, it has been found that the compounds of formula I are effective anti-rhinovirus agents when the test compound is administered before, after, or after

  concurrently with the test virus.

  The utility of the compounds described as anti-

  rhinovirus has been demonstrated in various test systems. For example, using G-Hela cell cultures supplemented with 30 to 100 CID50s of a rhinovirus test virus 39 concurrently with test compounds at a concentration of 4, 20 or 100 y / ml, after which the cell cultures are incubated for 48 hours, it is found on microscopic examination of cell cultures that the compounds of general formula I significantly inhibit the cytopathic effect of the virus, in comparison with cultures of cells containing the test virus alone. For example, when the compound of Example 1 is added at a concentration of 4 μg / ml to cell cultures in conjunction with 100 TCID 50 of virus

  rhinovirus-type 39 test, the cytopathic effect of the virus is entirely

  inhibited, compared to the control. We get the same result

  when the compound of Example 2 is tested in a similar manner.

  In none of the cases was cytotoxicity due to the compounds themselves at the concentration tested and at concentrations up to

y / ml.

  The broad spectrum activity of the compounds is determined

  examples 1 and 2 against 25 strains of rhinovirus at concentrations

  10-y / ml using human embryonic embryonic cells. The compound of the example, 6- (4-phenylphenoxy) hexane-1-ol, is active against 72% of the tested types of rhinovirus, while the compound of Example 2, 6- (4-benzoxyphenoxy) hexane-i-ol, is

  active against 36% of the 25 types tested for rhinovirus.

  It is known that rhinovirus is easily transmitted from one susceptible host to another, as happens, for example, among members of the same family, in classrooms

  and in military populations. The rhinovirus spreads

  shooting of the nose, the mouth and the eyes of infected individuals, it is worn on the skin, in particular the skin of the hands and face, and can be released into the environment by the manipulation of objects and by coughing, sneezing, breathing and speech. The

  susceptible individuals may be exposed to rhino

  virus through direct physical contact with infected individuals, by

  manipulation of objects contaminated by rhinovirus or by breathing

  air bearing rhinovirus. Person-to-person transmission of rhinovirus infection may be decreased by application of a compound of formula I to the skin of infected individuals, preventing the transfer of viable rhinoviruses to other individuals or objects; to the skin of uninfected individuals, preventing the transport of viable rhinoviruses to the mucosa or conjunctiva of these uninfected individuals; surrounding objects, preventing transfer of viable rhinoviruses to infected individuals in contact with the objects; or air in closed spaces, preventing inhalation by uninfected individuals of viable rhinovirus spread by infected individuals. For this purpose, the compound may be, for example, in the form of a skin cream, a gel, a lotion or a powder, a detergent composition or a disinfectant for rinsing, or an aerosol or

of a composition to be atomized.

  Examples of wording are detailed in the

  first divisional application of the French patent application No. 8102405.

  The compounds of formula I are generally prepared by the synthesis of Williamson's ethers (J. March, "Advanced Organic Chemistry Reactions, Mechanisms and Structure", McGraw-Hill Book Company, New York, 1968, page 316). The reaction is illustrated by the following equation: ## STR2 ##

(II) (III)

  In the above reaction equation, L represents a halogen atom such as chlorine, bromine or iodine or a sulphonic ester residue such as methanesulfonate or p-toluenesulfonate; E 'represents a metal cation such as lithium, sodium, potassium, silver or mercury; and A, X, Y, Z, Z 'and n are as defined for formula I.

  A phenolate or thiophenolate is reacted

  Formula II and suitably formed in situ by addi-

  base such as sodium ethoxide, potassium carbonate,

  sium, sodium hydride or phenol potassium hydroxide or

  corresponding thiophenol, with an alcohol bearing the eliminated group

  bound to the terminal carbon atom and having the formula III.

  Eliminable group moved, with formation of a link

  ether or thioether, carbon-oxygen or carbon-sulfur.

  The starting phenols which are the phenolate precursors are generally commercially available or can be obtained by quite conventional synthetic techniques well known to those skilled in the art. For example, benzoxyphenols can be prepared by reaction of benzyl halides with hydroquinones or resorcinols or with their monoesters,

with subsequent hydrolysis.

  Benzylphenols are easily prepared by reduction

  corresponding hydroxybenzophenones. These are pre-

  prepared, for example, by Friedel-Crafts benzoylation of phenyl acetate, by Fries rearrangement of phenyl benzoates,

  or by oxidation of benzhydryl alcohols.

  The phenoxyphenols can be prepared by the Ullmann reaction of a phenolate and a halophenyl ester in the presence of copper salts. See March, "Advanced Organic Chemistry", page 500

  (McGraw-Hill, New York, 1968). Thiophenoxyphenols are prepared

  res by reaction of thiophenolates with halophenyl esters,

  especially in amide solvents (ibid., pp. 500-501).

  The phenylphenols can be prepared by the reaction

  from Ullmann as indicated by March, op. cit., pp. 507-508.

  Halogenated phenols can also be prepared by reaction of a phenol with halogenating agents such as chloride.

  sulfuryl, according to conventional techniques.

  Thiophenols, which are the precursors of thio-

  phenolates 11, as well as the thiol analogs of the aforementioned phenol mononuclear intermediates, can be obtained from the corresponding phenols by conversion of phenol to

  its N, N = dimethylthiocarbamate with dimethylthiocarbamate chloride

  bamoyl, thermal rearrangement to N, N-dimethylthiolcarbamate, followed by alkaline hydrolysis, acidification, extraction and isolation of thiophenol. This reaction is carried out in substantially the same manner as the conversion of p-naphthol or e-thionaphthol indicated by Fieser and Fieser in "Reagents for Organic Synthesis",

  Volume 2, pp. 173-174 (Wiley Interscience, New York, 1969).

  The linear-substituted III alcohols used in the reaction are also generally commercially available or can be obtained by well known conventional synthesis methods. For example, a, W-diol can be transformed into

  w-haloalcohol using triphenylphosphine and a tetra-

  carbon halide (see C.A., 63, page 13137c (1965) for the

  preparation of 12-bromododecan-1-ol).

  The Williamson reaction can be carried out with or without a solvent. Suitable solvents for the reaction include lower alcohols such as ethanol and isopropanol, ketones

  such as acetone and butanone and amides such as dimethylformamide

  mide and dimethylacetamide. Other suitable solvents include

  dimethylsulfoxide, acetonitrile, dimethoxyethane, tetra-

hydrofuran and toluene.

  The reaction temperature may vary from about 0 ° C to the reflux temperature of the solvent and the reaction time from about 30 minutes to 80 hours.

  The reaction mixture is suitably treated by extrac-

  product in an organic solvent such as ether, dichloromethane

  methane, chloroform, toluene or the like, brine washing, drying over sodium or magnesium sulphate and evaporation of the solvent. Purification is generally carried out by distillation

  or recrystallization from a suitable solvent.

  The esters of the compounds of formula I are formed by conventional techniques, such as reaction of the alcohol of formula I with an acid, an acid halide, an anhydride or a

  other activated acyl derivative, often in the presence of an acid acceptor.

  The product is isolated in a conventional manner and purified by distillation.

  or recrystallization from a suitable solvent. The salts of monoesters of polyacids are prepared by addition of a base, by

  NaH, to an ether solution of the ester, followed by

the resulting precipitate.

  The following examples illustrate the invention without

however, limit its scope.

EXAMPLE 1

6- (4-phenylphenoxy) hexane-1-ol.

  A mixture of 34.0 g (0.2 mole) of p-phenylphenol (Eastman Company) and 10.8 g (0.2 mole) of sodium methoxide was heated and stirred in a steam bath for MCB) in 500 ml of anhydrous dimethylformamide, after which 27.3 g (0.2 mol) of 6-chlorohexan-1-ol (MCB) and about 2 g of sodium iodide are added. The mixture is refluxed with stirring and allowed to stand at room temperature. The reaction mixture is distributed between the ether-acetone mixture and the water and the organic phase is extracted with a base, washed with water and brine, dried over Na 2 SO 4 and the solvent evaporated. The resulting white solid product is recrystallized twice in the mixture

  methanol-acetone to give the desired product; F. 103-105 C.

EXAMPLE 2

  6- (4-benzoxyphénoxy) hexane-l-ol. A mixture of 106.0 g (0.53 moles) of p-benzoxyphenol (Eastman Company), 28.6 g (0.53 moles) of sodium methoxide (MCB) and about 2 g of potassium hydroxide was stirred for 5 minutes. sodium iodide in 600 ml of dimethylformamide, after which 73 g (0.53 moles) of 6-chlorohexan-1-ol (MCB) is added and the mixture is heated to reflux under reflux.

  stirring. The methanol formed in the reaction is allowed to distill.

  After 2 hours at reflux, the mixture is diluted with ice and water,

  500 ml of 10% potassium hydroxide is added and the

  resulting precipitate and dried. The solid is combined with 1 liter of butanone, heated to reflux and filtered. The residue consists of bis (benzoxyphenoxy) hexane as a by-product. The filtrate is cooled and the desired product crystallizes. The solid product is stirred with 1 liter of acetone at room temperature, the mixture is filtered to separate the additional insoluble by-product, the acetone is boiled off and replaced with methanol,

  and the methanolic solution is cooled to crystallize the

duit sought; F. 94-97 C.

EXAMPLE 3

  6- (4-benzylphénoxy) hexane-1-ol. A mixture of 40.0 g (0.217 mol) of p-benzylphenol (Eastman Company) and 29.7 g is stirred and heated to about 100 ° C.

  (0.217 moles) 6-chlorohexan-1-ol (MCB) in 500 ml of dimethyl

  anhydrous formamide, after which 33.1 g (0.24 mol) of

  potassium bonate and the mixture was refluxed for 2 h 30 min. The mixture is cooled, poured into ice water and 50 ml of 10% NaOH are added. The mixture is extracted with ether, the ether extracts are washed with water and brine, dried over MgSO 4 and the ether evaporated. The resulting oil is redistilled to obtain the product as a clear oil fraction as

  distilling water at 140-175 ° C, at 0.05 mm Hg (0.67 mbar).

EXAMPLE 4

  12-chlorododecane-1-ol. A mixture of 70.0 g (0.347 mole) of dodecane-1,12-diol (Aldrich Chemical Company) and 540.0 g (3.5 mole) of carbon tetrachloride in 1 liter of anhydrous acetonitrile was heated to dissolve the diol, cool to room temperature, purge with argon and add 91.5 g (0.350 mol) of

  triphenylphosphine (Aldrich Company) in 15 min. We use a bath-

  It adjusts the heat produced during the addition of triphenylphosphine and keeps the reaction mixture near room temperature. When the addition is complete, the mixture is stirred at room temperature for 1 h 30 min and then heated overnight. The solvent is then distilled off under atmospheric pressure until

  that the volume is reduced to 200 ml, and then under high vacuum.

  The oily residue is extracted with hexane, the combined hexane extracts are evaporated to dryness and the yellow oil is distilled off in vacuo.

  resulting light. The desired product is obtained in the form of a fraction.

  distilling at 140-150 ° C at 0.02 mm Hg (0.27 mbar).

EXAMPLE 5

  12- (4-phenylphenoxy) dodecane-l-ol. By the procedure described in Example 2, but

  using p-phenylphenol instead of p-benzoxyphenol and using

  12-chlorododecan-1-ol prepared in Example 4 instead of

  6-chlorohaxane-1-ol, the solid precipitate obtained after dilution is isolated.

  of the reaction mixture with ice water and treatment with a base, dried and recrystallized twice in butanone to

  - obtain the desired product; F. 113-114 C.

EXAMPLE 6

4-phénylthiophénol. -

  Following the procedure for conversion of 9-naphthol to 5-thionaphthol of Fieser and Fieser "Reagents for Organic Synthesis, Volume 2", pp. 173174 (Wiley Interscience, New York,

  1969), p-phenylphenol is reacted with dimethyl chloride.

  thiocarbamoyl (Aldrich Chemical Company) to form biphenylyl dimethylthiocarbamate. A 10 g (0.04 mole) portion of this latter compound is heated at 300 ° C. for 45 min in an argon atmosphere, cooled and the reaction mixture is dissolved in 250 ml of ethanol. The ethanol solution was refluxed, treated with 50 ml of 20% KOH, refluxed for 1 hour, and the ethanol was distilled off and replaced with water. The mixture is cooled, diluted with water and extracted with ether. The aqueous layer is then acidified with concentrated HCl, cooled and extracted with ether, the ether layer is washed with water, dried and evaporated to dryness. Recrystallization of the crude product in ethanol gives the pure desired product; F. 108-111 C.

EXAMPLE 7

  6- (4-phenylenylthio) hexan-1-ol.

  Stirred for 15 minutes at room temperature,

  under an argon atmosphere a mixture of 8.2 g (0.044 mole) of p-phenyl-

  thiophenol prepared in Example 6 and 6.9 g (0.015 mol) of potassium carbonate in 200 ml of dimethylformamide. 6.8 g (0.05 mol) of 6-chlorohexan-1-ol are then added, the mixture is refluxed with stirring for 2 hours, cooled, diluted with water and extracted with ethereal mixture. acetone. The combined organic extracts are washed with water, dried and evaporated to dryness. We distill

  under vacuum the resulting crude solid product to obtain a fraction of

  increasing to 110-180 ° C at 0.1 mm Hg (1.3 mbar), mp 112-115 ° C.

  Recrystallization from acetone gives the pure desired product;

F. 114-115 ° C.

EXAMPLE 8

  2-chloro-4-benzoxyphénol. A mixture of 0 g (0.1 mol) of p-benzoxyphenol (Eastman Company) in 250 ml of glacial acetic acid is stirred at room temperature until a solution is obtained.

  clear. 14.8 g (0.11 mol) of sulphuryl chloride are then added.

  The mixture is filtered beforehand on sodium carbonate for 30 minutes, the mixture is stirred at room temperature for 3 hours, then heated on a water-bath for 1 hour and evaporated to dryness under reduced pressure. The resulting crude solid product is recrystallized from the etherhexane mixture to give the pure desired product;

F. 78-800C.

EXAMPLE 9

  6- (3-phenylphenoxy) hexane-1-ol. A mixture of 15.0 g (0.088 mol) of 3-hydroxybiphenyl, 13.3 g, is heated and refluxed for 3 hours.

  (0.097 mole) 6-chlorohexan-1-ol and 13.8 g (0.01 mole) of carbon.

  potassium nate in 250 ml of anhydrous dimethylformamide. The mixture is cooled to room temperature, diluted with water

  and extracted with ether, the ethereal extracts are dried and

  pore under reduced pressure to obtain a light yellow oil. The crude product is distilled under vacuum to obtain a boiling fraction.

  between 150 and 190C at 0.05 mm Hg (0.67 mbar) and solidifies

  relying on a soft solid corresponding to the desired pure product.

EXAMPLE 10

  Using the procedure of Example 2,

  can react the following phenolic compounds with the halogenated

  genoalcohols indicated to produce the compounds indicated below (Ph = phenyl): Phenol p-Pn-Ph-OH p-Ph-Ph-OH p-Ph-Ph-OH p-Ph-Ph-OH p- (Ph- CH2-O) Ph-OH p- (Ph-CH'2-O) -Ph-OH Halogenoalcohol 4-Cl- (CH2) 4-OH -Cl- (CH2) 5-OH 8Cl- (CH2) 8-OH -CH- (CH2) 10o-OH 4 -Cl- (CH2) 4-OH -Cl- (CH2) 5-OH Product p-PhIPh-O- (CH2) 4-OH p-Ph-Ph-O- ( CH 2) 5-OH p-Ph-Ph-O- (CH 2) 8 -OH p-Ph-Ph-O- (CH 2) 10 OH p- (Ph-CH 2 -O) -Ph-O- (CH 2) 4 OH p- (P [I-CH27O) -Ph-O- (CH2) 5-OH F. (o C) -113

108-109

103-106

107-108

97-99 -93 IO '

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EXAMPLE II

  By the procedure described in Example 9, the 2-chloro-4-benzoxyphenol prepared in Example 8 is reacted with

  6-chlorohexane-1-ol to produce 6- (2-chloro-4-benzoxyphenoxy) -

  hexane-1-ol, in the form of a light yellow oil distilling between

  and 200 C at 0.02 mm Hg (0.27 mbar).

  By the operating method described in Example 9,

  react 2-chloro-4-phenylphenol (Eastman Company) with 6-chloro

  hexane-1-ol to produce 6- (2-chloro-4-phenylphenoxy) hexane-1-ol,

F. 64-65 C.

EXAMPLE 12

  6- (2-hydroxy-5-phenylphenoxy) hexane-1-ol and 6- (2-hydroxy-4-phinylphenoxy) hexane-1-ol. A mixture of 55.9 g (0.3 mole) of 4-phenylpyrocatechol (Eastman Company) and 52.8 g is stirred at ambient temperature.

  (0.38 moles) of potassium carbonate in 500 ml of dimethylformate

  anhydrous mide. 45.1 g (0.33 mol of 6-chlorohexan-1-ol,

  the reaction flask is purged with nitrogen and stirred at room temperature.

  room temperature for 48 h, then heated at reflux for 5 h. The reaction mixture is cooled, diluted with water, acidified with 1 N HCl and extracted with ether. The ether layer is washed with water, dried and evaporated to dryness. The semi-solid residue is distilled under vacuum in a distillation column. The fractions passing at 150-170 ° C., 180-200 ° C. and 220 ° -240 ° C. are collected at 0.1 mmHg (1.3 mbar). The 180-200 ° C fraction is recrystallized from acetone-hexane to give the 2,4-substituted product. The fraction passing at 220 ° -240 ° C. is recrystallized from acetone-hexane to give the diether; F. 80-82 C. 2.4-Substituted product is obtained from the distillation residue of the fraction at 150 ° -170 ° C. The mother liquors of the preceding recrystallizations are combined and distilled under vacuum and fractions are obtained. to 160-165 ° C, 170-190 ° C and 210-220 ° C at 0.1-0.05 mm Hg (1.3-0.67 mbar). The fraction passing through 160-165 ° C is recrystallized from acetone-hexane, combined with the above-mentioned distillation residue and recrystallized to give the pure product 2.4; F. 122-123 C. The mother liquor of recrystallization is evaporated to dryness and redistilled and obtained

a fraction passing at 160-165 ° C at 0.05 mm Hg (0.67 mbar) corresponding to

spawning to the product 2.5 pure.

EXAMPLE 13

  6- (4-Benzoxyphenoxy) -1-hexyl methanesulfonate.

  A mixture of 25 g (0.08 mole) of 6- (4-

  benzoxyphenoxy) hexane-1-ol prepared in Example 2, in 250 ml of pyridine with 28.6 g (0.25 moles) of methanesulfonyl chloride (Eastman Company) and stirred at room temperature for 3 h. The reaction mixture is distributed between the water and the ether; the ethereal extracts are washed, dried and evaporated to obtain the product

research; F. 80-82 C.

EXAMPLE 14

  Bis-4- (4-phenylphenoxy) -1-butyl sulfite.

  By the procedure of Example 13, we obtain

  the desired ester; F. 138-139 C using 4- (4-phenylphenoxy) -

  butan-1-ol and an excess of thionyl chloride.

EXAMPLE 15

  6- (4-phenylphenoxy) -1-hexyl hemisuccinate.

  A mixture of 10 g (0.037 mole) of 6- (4-phenylphenoxy) hexane-1-ol prepared at room temperature is refluxed with stirring for 3 hours.

  Example 1 and 10 g of succinic anhydride in 250 ml of pyridine.

  The pyridine is removed under vacuum in a water bath, where the residue is poured.

  in water and acidified with HC1. The resulting precipitate is collected

  so much, it is washed, dried and recrystallized in butanone

  to obtain the pure monoester; Mp 113-115 ° C.

  It is understood that the invention is not limited

  to the preferred embodiments described above as illus-

  and that those skilled in the art can make various modifications

  and various changes without departing from the framework and

took the invention.

Claims (11)

  1. New biphenyl ethers and thioethers, benzyl-   phenyl, benzoxyphenyl and benzylthiophenyl, substituted or unsubstituted with ato-wglycol and hydroxythiol, characterized in that they correspond to the general formula ZAY X- (CH n 2 OH z 'in which A represents a bond or a CH 2 group; Y is a bond or an oxygen or sulfur atom; X is an oxygen or sulfur atom; Z and Z 'each represent hydrogen or a halogen or a C1-C4 alkyl, C1-C4 alkoxy or OH group; and n is an integer of 4 to 12, with the following additional conditions when n is 4 and A is a bond, Z is other than Br or C 1 and -N is other than Br, CH 3 O or isopropyl; is equal to 5 and A and Y together form a bond, Z is other than CH30, and when n is 4-7 and A and Y together form a bond, Z is other than OH, and their esters with solubilizing acids and salts of said esters.   2. Compounds according to claim 1, characterized in what X is oxygen.   3. Compounds according to claim 1, characterized in   that A and Y form a bond or a CH20 group.   4. Compounds according to claim 1, characterized in   that Z and Z 'are each hydrogen.   5. Compounds according to claim 1, characterized in that X and Y are in the para position relative to each other on   the benzene ring to which both are linked.   6. Compounds according to claim 1, characterized in that A and Y together form a bond or a CH20 group,   X is oxygen and Z and Z 'are each hydrogen.   7. Compounds according to claim 1, characterized in that n is equal to 6.   8. A compound according to claim 1, characterized in that   it consists of 6- (4-phenylphenoxy) hexane-1-ol.   9. Compound according to claim 1, characterized in that   it consists of 6- (4-benzophenoxy) hexane-1-ol.   10. Compound according to claim 1, characterized in that   it consists of 6- (4-phenylphenoxy) -1-hexyl succinate.   11. Compound according to claim 1, characterized in that   it consists of 6- (4-benzyloxyphenoxy) methanesulphonate 1-hexyl.